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http://www.ncbi.nlm.nih.gov/pubmed/28203581 | 1. J Investig Med High Impact Case Rep. 2017 Feb 1;5(1):2324709617691307. doi:
10.1177/2324709617691307. eCollection 2017 Jan-Mar.
Long-Term Response and Possible Cure of Patients With B-Cell Malignancies With
Dose-Escalated Rituximab.
Jacobs LM(1), Wiernik PH(2), Dutcher JP(2), Muxi P(3).
Author information:
(1)George Washington University, Washington, DC, USA.
(2)Cancer Research Foundation of New York, Chappaqua, NY, USA.
(3)British Hospital, Montevideo, Uruguay.
Rituximab (R), a chimeric monoclonal antibody targeting CD20 antigen on B-cells,
has become a standard of care in the treatment of B-cell malignancies, most
often in conjunction with cytotoxic chemotherapy. Activity has been demonstrated
in many subtypes of B-cell lymphoma, including diffuse large cell lymphoma,
follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic
leukemia (CLL), lymphocyte-predominant Hodgkin lymphoma, and Waldenström
macroglobulinemia (WM). Additionally, dose escalation of R as a single agent has
demonstrated improved activity in previously treated/poor prognosis CLL. We
present 4 cases of B-cell malignancy (2 CLL variants/MCL, 1 FL, 1 WM) who
received dose-escalated R as a single agent and achieved complete response (3
patients) and stable disease/partial response (1 patient) of 6.5+ to 15+ years
duration. They have been off treatment for 6.5+ to 15+ years. Toxicity was
minimal, with initial infusion reactions similar to those observed with standard
dose infusions. There were no serious treatment-related adverse events or
infections. Dose escalated R as a single agent may possibly be curative for some
patients with B-cell malignancies, unlike the standard empiric dose of 375
mg/m2, and deserves further study.
DOI: 10.1177/2324709617691307
PMCID: PMC5298442
PMID: 28203581
Conflict of interest statement: Declaration of Conflicting Interests: The
author(s) declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/29174092 | 1. Eur J Med Genet. 2018 Mar;61(3):145-151. doi: 10.1016/j.ejmg.2017.11.008. Epub
2017 Nov 23.
Rare copy number variants identified in prune belly syndrome.
Boghossian NS(1), Sicko RJ(2), Giannakou A(3), Dimopoulos A(3), Caggana M(2),
Tsai MY(4), Yeung EH(3), Pankratz N(4), Cole BR(4), Romitti PA(5), Browne ML(6),
Fan R(7), Liu A(3), Kay DM(2), Mills JL(3).
Author information:
(1)Department of Epidemiology and Biostatistics, Arnold School of Public Health,
University of South Carolina, Columbia, SC, United States; Division of
Intramural Population Health Research, Eunice Kennedy Shriver National Institute
of Child Health and Human Development, National Institutes of Health, Bethesda,
MD, United States. Electronic address: nboghoss@mailbox.sc.edu.
(2)Division of Genetics, Wadsworth Center, Department of Health, Albany, NY,
United States.
(3)Division of Intramural Population Health Research, Eunice Kennedy Shriver
National Institute of Child Health and Human Development, National Institutes of
Health, Bethesda, MD, United States.
(4)Department of Laboratory Medicine and Pathology, University of Minnesota
Medical School, Minneapolis, MN, United States.
(5)Department of Epidemiology, College of Public Health, The University of Iowa,
Iowa City, IA, United States.
(6)New York State Department of Health, Congenital Malformations Registry,
Albany, NY, United States; University at Albany School of Public Health,
Rensselaer, NY, United States.
(7)Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown
University Medical Center (GUMC), Washington, DC, United States.
Prune belly syndrome (PBS), also known as Eagle-Barrett syndrome, is a rare
congenital disorder characterized by absence or hypoplasia of the abdominal wall
musculature, urinary tract anomalies, and cryptorchidism in males. The etiology
of PBS is largely unresolved, but genetic factors are implicated given its
recurrence in families. We examined cases of PBS to identify novel pathogenic
copy number variants (CNVs). A total of 34 cases (30 males and 4 females) with
PBS identified from all live births in New York State (1998-2005) were genotyped
using Illumina HumanOmni2.5 microarrays. CNVs were prioritized if they were
absent from in-house controls, encompassed ≥10 consecutive probes, were ≥20 Kb
in size, had ≤20% overlap with common variants in population reference controls,
and had ≤20% overlap with any variant previously detected in other birth defect
phenotypes screened in our laboratory. We identified 17 candidate autosomal
CNVs; 10 cases each had one CNV and four cases each had two CNVs. The CNVs
included a 158 Kb duplication at 4q22 that overlaps the BMPR1B gene;
duplications of different sizes carried by two cases in the intron of STIM1
gene; a 67 Kb duplication 202 Kb downstream of the NOG gene, and a 1.34 Mb
deletion including the MYOCD gene. The identified rare CNVs spanned genes
involved in mesodermal, muscle, and urinary tract development and
differentiation, which might help in elucidating the genetic contribution to
PBS. We did not have parental DNA and cannot identify whether these CNVs were de
novo or inherited. Further research on these CNVs, particularly BMP signaling is
warranted to elucidate the pathogenesis of PBS.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.ejmg.2017.11.008
PMCID: PMC5803418
PMID: 29174092 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: None. |
http://www.ncbi.nlm.nih.gov/pubmed/26604506 | 1. J Oral Maxillofac Pathol. 2015 May-Aug;19(2):255-9. doi:
10.4103/0973-029X.164545.
Ill-fitting dentures as primary presentation of mantle cell lymphoma: A case
report and literature review of the primary mantle cell lymphomas of the hard
palate.
Dereci Ö(1), Ay S(1), Açıkalın MF(2), Karagülle M(3).
Author information:
(1)Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Eskişehir
Osmangazi University, Eskişehir, Turkey.
(2)Department of Pathology, Eskişehir Osmangazi University, Eskişehir, Turkey.
(3)Department of Hematology, Faculty of Medicine, Eskişehir Osmangazi
University, Eskişehir, Turkey.
Mantle cell lymphoma (MCL) is a subtype of B-cell non-Hodgkin's lymphoma seen
predominantly in males. Common extra-nodal sites of involvement of MCL are
Waldeyer's ring, gastrointestinal tract, bone marrow and peripheral blood. The
extra-nodal palatal localization of MCL is quite uncommon. MCL is seen in
predominantly older patients, therefore undiagnosed MCL patients are likely to
have total prosthesis. In this study, a case of MCL, initially presenting as
palatal swelling was reported with relevant literature review and the possible
role of dental professionals in the diagnosis of this rare entity was discussed.
DOI: 10.4103/0973-029X.164545
PMCID: PMC4611938
PMID: 26604506 |
http://www.ncbi.nlm.nih.gov/pubmed/10942246 | 1. Leukemia. 2000 Aug;14(8):1483-9. doi: 10.1038/sj.leu.2401829.
Mantle cell lymphoma proliferates upon IL-10 in the CD40 system.
Visser HP(1), Tewis M, Willemze R, Kluin-Nelemans JC.
Author information:
(1)Dept of Hematology, Leiden, The Netherlands.
Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma, characterized by
a poor response to therapy and short survival. To assess the proliferative
capacity, we cultured MCL cells, using irradiated 3T6 mouse fibroblasts
transfected with human CD40L ('CD40 system') in the presence of different
cytokines. Proliferation was measured by 3H-thymidine incorporation and by CFSE
fluorescence. Thirteen out of 16 MCL cases proliferated well in the CD40 system.
In 10 cases a strong response upon further addition of IL-10 was seen, whereas
IL-4 had an additional effect in only four cases. CFSE staining of cells before
and after culture showed an increased number of cell divisions in the
IL-10/CD40L stimulated cells. The MCL cells remained CD5+CD19+. Neither plasma
cell differentiation nor isotype switching was seen. The light chain expression
was strictly monoclonal. IL-1beta, IL-2, IL-6, G-CSF and GM-CSF did not
stimulate MCL proliferation. IL-10 receptor expression correlated with the
response to IL-10 in the culture system and the effect of added IL-10 could be
blocked by antibodies directed against IL-10 and the IL-10 receptor. Autocrine
IL-10 production by the MCL cells was detected in eight of 10 cases tested.
IL-10 receptor blocking decreased proliferation when no exogenous IL-10 was used
in four of seven cases tested. EBV assessed by EBER in situ hybridization was
not detected in six cases tested. In conclusion, MCL can successfully be
cultured upon CD40 stimulation if 3T6 CD40L+ cells are used. In this context
IL-10 is a costimulatory factor. IL-10 receptor expression seems to correlate
with response to CD40 crosslinking and IL-10. Autocrine IL-10 production might
play a role in the proliferation of this lymphoma. This culture system may be
useful to test new treatment strategies for this, thus far, therapy-resistant
lymphoma.
DOI: 10.1038/sj.leu.2401829
PMID: 10942246 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8649059 | 1. Leukemia. 1996 Jun;10 Suppl 2:s78-83.
Mantle cell lymphoma: a lymphoproliferative disorder associated with aberrant
function of the cell cycle.
Garcia-Conde J(1), Cabanillas F.
Author information:
(1)Lymphoma Section, MD Anderson Cancer Center, Houston, TX 77030, USA.
Mantle cell lymphoma is a B cell lymphoproliferative disorder cytogenetically
characterized by the t(11;14)(q13;q32) which at molecular level involves the
Bcl-1/PRAD-1 gene. Immunophenotypically it is characterized by co-expression of
CD5+/CD20+ and CD23- antigens. Histologic patterns are recognized as: diffuse,
mantle zone and nodular. Diffuse mantle lymphoma is the most frequent and is
associated with a poor prognosis. The rearrangement of the Bcl-1/PRAD-1
increases the synthesis of cyclin D1. Cyclin D1 binds to Cdk4 and forms a
complex, then binds to and phosphorylates Rb protein thus triggering cells to
progress from G0/G1 to S and thus drives cellular proliferation. The 5-year
survival in the MD Anderson series was less than 30% and anthracycline regimens
do not appear to have any major impact on the outcomes of cases with nodular or
diffuse histopathological patterns. Intensive therapeutic programs and first
line autologous or allogeneic bone marrow transplantation remains experimental.
PMID: 8649059 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22555177 | 1. Mod Pathol. 2012 Sep;25(9):1227-35. doi: 10.1038/modpathol.2012.84. Epub 2012
May 4.
Increased tumor cell proliferation in mantle cell lymphoma is associated with
elevated insulin-like growth factor 2 mRNA-binding protein 3 expression.
Hartmann EM(1), Beà S, Navarro A, Trapp V, Campo E, Ott G, Rosenwald A.
Author information:
(1)Institute of Pathology, University of Würzburg, Germany.
Mantle cell lymphoma is an aggressive, non-curable B-cell lymphoma,
characterized by the translocation t(11;14)(q13;q32) involving CCND1 and a high
number of additional genetic alterations. Chromosomal gains of 7p are frequent
in mantle cell lymphoma, with insulin-like growth factor II mRNA-binding protein
3 (IGF2BP3 aka IMP3) being the most upregulated gene in this region. IGF2BP3 is
a member of the IGF II mRNA-BP family, and increased IGF2BP3 expression is
associated with an aggressive behavior in many malignant tumors. We here analyze
selected genes related to IGF signaling in gene expression and genomic array
data of 8 mantle cell lymphoma cell lines and 12 primary mantle cell lymphomas
and study IGF2BP3 protein expression in 172 well-characterized primary mantle
cell lymphomas by immunohistochemistry. The majority of mantle cell lymphoma
cell lines and primary cases showed elevated IGF2BP3 mRNA expression and a
subset also expressed the IGF1 and IGF2 receptors. On the protein level, 66 of
172 primary mantle cell lymphomas showed IGF2BP3 expression in >50% of tumor
cells, and strong IGF2BP3 protein expression was highly associated with
increased proliferation as measured by the Ki-67 index, but not with overall
survival of mantle cell lymphoma patients. Only a subset of mantle cell
lymphomas with marked IGF2BP3 expression had an underlying chromosomal gain in
7p, suggesting that additional mechanisms are involved in the upregulation of
IGF2BP3 in mantle cell lymphoma. In seven paired mantle cell lymphoma samples,
IGF2BP3 protein expression remained constant between primary diagnosis and
relapse. Increased IGF2BP3 expression and, potentially, enhanced IGF signaling
may contribute proproliferative stimuli in the evolution of mantle cell lymphoma
tumor cells.
DOI: 10.1038/modpathol.2012.84
PMID: 22555177 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8277026 | 1. J Am Acad Dermatol. 1994 Jan;30(1):23-30. doi: 10.1016/s0190-9622(94)70002-8.
Mantle zone lymphoma: an immunohistologic study of skin lesions.
Bertero M(1), Novelli M, Fierro MT, Bernengo MG.
Author information:
(1)Clinica Dermatologica I, Università degli Studi di Torino, Italy.
BACKGROUND: Mantle zone lymphoma (MZL) is a B-cell proliferation regarded as the
follicular variant of intermediate lymphocytic lymphoma (ILL). Neoplastic small
lymphoid cells proliferate as wide mantles around atrophic centers of benign
appearance.
OBJECTIVE: The clinical, histologic, and immunohistochemical features of four
cases of MZL, heralded by cutaneous lesions, are described and correlated with
the lymph node pattern.
RESULTS: All specimens showed extensive nodules in the reticular dermis invading
the subcutaneous tissue. They were mainly composed of a proliferation of small
lymphocytes with slightly irregular nuclear contours and clumped chromatin,
forming wide mantles around small atrophic germinal centers. Serial biopsy
specimens in case 1 revealed evolution of the skin lesions from pseudolymphoma
into MZL. Their immunohistochemistry was similar to that of lymph nodes and
showed that the neoplastic cells were CD5+, CD20+, CD22+, CD25+, CD74+, Leu-8+,
HLA-DR+, IgM+, IgD+ with restriction for the lambda light chain, CD10-, and
CD71-, whereas the germinal center cells were polyclonal. In three cases many
CD38+, PCA-1+ plasma cells were present both in the grenz zone and in bordering
neoplastic nodules. The clinical course was chronic. The only death occurred
from unrelated causes; one patient is still alive 17 years after onset.
CONCLUSION: Skin lesions may be the only manifestation of MZL for an extended
period. The differentiation between pseudolymphoma and other lymphoma subtypes
is based not only on the histologic and cytologic features but also on the
architecture, followed by immunohistochemical confirmation.
DOI: 10.1016/s0190-9622(94)70002-8
PMID: 8277026 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33197439 | 1. Exp Cell Res. 2020 Dec 15;397(2):112365. doi: 10.1016/j.yexcr.2020.112365.
Epub 2020 Nov 14.
Expression and role of MIG/CXCR3 axis in mantle cell lymphoma.
Zhu MX(1), Wan WL(1), Hong Y(1), Wang YF(1), Dong F(1), Jing HM(2).
Author information:
(1)Department of Hematology and Lymphoma Research Center, Peking University
Third Hospital, Beijing, 100191, PR China.
(2)Department of Hematology and Lymphoma Research Center, Peking University
Third Hospital, Beijing, 100191, PR China. Electronic address:
hongmeijing2020@163.com.
Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphoma
with a generally aggressive and heterogeneous clinical course. Chemokines are
one of the complex components in the tumor microenvironment (TME), and they play
a vital role in tumor progression and metastasis. There is no information about
the monokine induced by gamma interferon (MIG)/CXC chemokine receptor 3 (CXCR3)
axis in patients with MCL. In the present study, we discovered that CXCR3 was
highly expressed in MCL tissues and some cell lines including Maver, Z138, and
Jeko-1, and significantly associated with clinical factors reflecting high tumor
burden in MCL patients. Moreover, elevated serum MIG at diagnosis showed a close
relationship with advanced disease and poor prognosis in MCL patients.
Additionally, the role of CXCR3 in promoting the proliferation and inhibiting
the apoptosis of primary MCL cells and Jeko-1 cells was validated by in vitro
experiments. Further research indicated that the MIG/CXCR3 axis mediated MCL
cell migration to the TME through the PI3K/AKT signaling pathway. Therefore, the
MIG/CXCR3 axis might be a potential target with fewer off-target side effects
than other targets in MCL.
Copyright © 2020. Published by Elsevier Inc.
DOI: 10.1016/j.yexcr.2020.112365
PMID: 33197439 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10463985 | 1. Cancer. 1999 Sep 1;86(5):850-7. doi:
10.1002/(sici)1097-0142(19990901)86:5<850::aid-cncr22>3.0.co;2-z.
Mantle cell lymphoma in leukemic phase: characterization of its broad cytologic
spectrum with emphasis on the importance of distinction from other chronic
lymphoproliferative disorders.
Wong KF(1), Chan JK, So JC, Yu PH.
Author information:
(1)Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
BACKGROUND: Mantle cell lymphoma is a mature, virgin B-cell neoplasm
characterized immunologically by a panB+, CD5+, CD23-, cyclin D1+ phenotype and
genetically by t(11;14)(q13;q32) with overexpression of the cyclin D1 (bcl-1)
gene. It usually presents as advanced stage disease, involving lymph nodes,
spleen, bone marrow, and extranodal sites, particularly the gastrointestinal
tract. However, frank leukemic presentation with high white cell counts is
uncommon and can be difficult to distinguish from other chronic
lymphoproliferative disorders. The aim of this study was to characterize the
morphologic spectrum of leukemic mantle cell lymphoma.
METHODS: During the period July 1994 through October 1998, 14 patients with
mantle cell lymphoma in leukemic phase were diagnosed at the Department of
Pathology, Queen Elizabeth Hospital, Hong Kong. The diagnosis of mantle cell
lymphoma was based on histologic and immunocytochemical findings and was
confirmed by cyclin D1 immunoreactivity in all cases. The clinical records and
laboratory results were reviewed. Peripheral blood smears, bone marrow, and
other tissue biopsies were examined, with particular attention to the cytologic
features of the leukemic mantle cells.
RESULTS: Mantle cell lymphoma in leukemic phase showed a very aggressive
clinical course. Eight patients died at a mean of 13 months, and only 1 patient
was disease free. Morphologically, the leukemic mantle cells exhibited a broad
morphologic spectrum, with several cytologic patterns identified: 1) mixed small
and medium-sized cells, 2) predominantly medium-sized cells, 3) predominantly
large cells, and 4) giant cells. Despite variations in the size and nuclear
shape, the leukemic mantle cells could usually be recognized by the nuclear
irregularity and clefting, moderately dense but evenly distributed chromatin,
small nucleoli, and scant cytoplasm.
CONCLUSIONS: Recognition of the characteristic cytologic features of leukemic
mantle cells can help to distinguish them from other chronic lymphoproliferative
disorders. In contrast to the latter, the clinical course is aggressive and
response to conventional chemotherapy is poor.
Copyright 1999 American Cancer Society.
DOI: 10.1002/(sici)1097-0142(19990901)86:5<850::aid-cncr22>3.0.co;2-z
PMID: 10463985 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36299369 | 1. ERJ Open Res. 2022 Oct 24;8(4):00240-2022. doi: 10.1183/23120541.00240-2022.
eCollection 2022 Oct.
Phase I studies of BI 1015550, a preferential phosphodiesterase 4B inhibitor, in
healthy males and patients with idiopathic pulmonary fibrosis.
Maher TM(1)(2), Schlecker C(3), Luedtke D(4), Bossert S(4), Zoz DF(5), Schultz
A(6).
Author information:
(1)Inflammation, Repair, and Development Section, National Heart and Lung
Institute, Imperial College London, London, UK.
(2)Keck Medicine of USC, Los Angeles, CA, USA.
(3)Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany.
(4)Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
(5)Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA.
(6)CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany.
INTRODUCTION: BI 1015550 is a phosphodiesterase 4 (PDE4) inhibitor that has
antifibrotic properties. Phase I and Ic studies were conducted to investigate
the safety, tolerability and pharmacokinetics of BI 1015550 in healthy male
subjects and patients with idiopathic pulmonary fibrosis (IPF).
METHODS: In the phase I study, 42 subjects were partially randomised to receive
placebo or BI 1015550 in single rising doses of 36 mg and 48 mg, or multiple
rising doses of 6 mg and 12 mg twice daily over 14 days. In the phase Ic study,
15 patients with IPF were randomised to receive 18 mg BI 1015550 or placebo
twice daily for up to 12 weeks. For both studies, the primary endpoint was the
number of subjects with drug-related adverse events (AEs).
RESULTS: In the Phase I study, drug-related AEs were reported for 50.0% of
healthy male subjects treated with a single dose of BI 1015550, compared with
16.7% receiving placebo. For those receiving multiple doses, drug-related AEs
were reported for 37.5% of those treated with BI 1015550 and 12.5% receiving
placebo. The most frequently reported AEs by organ class were nervous system
disorders, which were largely driven by headache. In the Phase Ic study,
drug-related AEs were reported in 90.0% of patients treated with BI 1015550,
compared with 60.0% of those receiving placebo. The most frequent AEs by organ
class were gastrointestinal AEs.
CONCLUSIONS: BI 1015550 had an acceptable safety profile in healthy male
subjects and male and female patients with IPF, supporting further development
in larger trials.
Copyright ©The authors 2022.
DOI: 10.1183/23120541.00240-2022
PMCID: PMC9589333
PMID: 36299369
Conflict of interest statement: Conflict of interest: T.M. Maher has received
consultancy fees from Boehringer Ingelheim, Roche/Genentech, AstraZeneca, Bayer,
Blade Therapeutics, Bristol-Myers Squibb, Galapagos, Galecto, GlaxoSmithKline,
IQVIA, Pliant, Respivant, Theravance and Veracyte; and honoraria from Boehringer
Ingelheim and Roche/Genentech. C. Schlecker, D. Leudtke, S. Bossert and D.F. Zoz
are employees of Boehringer Ingelheim. A. Schultz is an employee of CRS Clinical
Research Services Mannheim GmbH. |
http://www.ncbi.nlm.nih.gov/pubmed/35569036 | 1. N Engl J Med. 2022 Jun 9;386(23):2178-2187. doi: 10.1056/NEJMoa2201737. Epub
2022 May 15.
Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary
Fibrosis.
Richeldi L(1), Azuma A(1), Cottin V(1), Hesslinger C(1), Stowasser S(1),
Valenzuela C(1), Wijsenbeek MS(1), Zoz DF(1), Voss F(1), Maher TM(1); 1305-0013
Trial Investigators.
Collaborators: Otaola M, Elias P, Arce G, Glaspole I, Corte T, Olschewski H,
Idzko M, Lamprecht B, Anees S, Moran Mendoza O, Mallet M, Ryerson C, Manganas H,
Silva Orellana A, Salinas Fénero M, Zhang J, Xu J, Xu Z, Hong Q, Wen F,
Sterclova M, Pauk N, Bendstrup E, Shaker S, Titlestad I, Myllärniemi M,
Kilpeläinen M, Strander I, Purokivi M, Kaarteenaho R, Koschel D, Wiewrodt R,
Behr J, Kreuter M, Hammerl P, Bonella F, Blaas S, Antoniou A, Bouros D,
Tzouvelekis A, Muller V, Richeldi L, Albera C, Balestro E, Bargagli E, Lacedonia
D, Ravaglia C, Rogliani P, Kondo Y, Izumi S, Nakamura Y, Kitamura H, Inoue Y,
Okamoto M, Mostard RLM, Wijsenbeek-Lourens M, Veltkamp M, Nossent EJ, Piotrowski
W, Sieminska A, Kim YH, Song JW, Choi SM, Bazdyrev E, Moiseev S, Yakusevich V,
Shmelev E, Rumyantseva O, Molina-Molina M, Roldán Sánchez J, Valenzuela C,
Sellares J, Sauleda J, Arias M, Dziublyk O, Bielosludtseva K, Molyneaux P,
Adamali H, Patel D, Sigal B, Weigt S, Andrews C, Averill F, Scholand M, Hamblin
M, Bhatt N, Ettinger N, Criner G, Morrow L, Moua T, Azuma A, Cottin V,
Wijsenbeek MS, Maher TM, Costabel U, Cornelis Grutters J, Horton MR, Rossman MD,
Anstrom K.
Author information:
(1)From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico
Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome
(L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre
National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon,
Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and
Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare
Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational
Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach
(C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.),
Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit,
Department of Pulmonology, Hospital Universitario de la Princesa, University
Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine,
Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer
Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine,
University of Southern California, Los Angeles (T.M.M.); and the National Heart
and Lung Institute, Imperial College London, London (T.M.M.).
Comment in
N Engl J Med. 2022 Jun 9;386(23):2235-2236. doi: 10.1056/NEJMe2205411.
N Engl J Med. 2022 Aug 25;387(8):761. doi: 10.1056/NEJMc2209529.
N Engl J Med. 2022 Aug 25;387(8):761-762. doi: 10.1056/NEJMc2209529.
BACKGROUND: Phosphodiesterase 4 (PDE4) inhibition is associated with
antiinflammatory and antifibrotic effects that may be beneficial in patients
with idiopathic pulmonary fibrosis.
METHODS: In this phase 2, double-blind, placebo-controlled trial, we
investigated the efficacy and safety of BI 1015550, an oral preferential
inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis.
Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose
of 18 mg twice daily or placebo. The primary end point was the change from
baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with
a Bayesian approach separately according to background nonuse or use of an
antifibrotic agent.
RESULTS: A total of 147 patients were randomly assigned to receive BI 1015550 or
placebo. Among patients without background antifibrotic use, the median change
in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550
group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group
(median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability
that BI 1015550 was superior to placebo, 0.998). Among patients with background
antifibrotic use, the median change in the FVC was 2.7 ml (95% credible
interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible
interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95%
credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to
placebo, 0.986). A mixed model with repeated measures analysis provided results
that were consistent with those of the Bayesian analysis. The most frequent
adverse event was diarrhea. A total of 13 patients discontinued BI 1015550
treatment owing to adverse events. The percentages of patients with serious
adverse events or severe adverse events were similar in the two trial groups.
CONCLUSIONS: In this placebo-controlled trial, treatment with BI 1015550, either
alone or with background use of an antifibrotic agent, prevented a decrease in
lung function in patients with idiopathic pulmonary fibrosis. (Funded by
Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2201737
PMID: 35569036 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35517783 | 1. Front Pharmacol. 2022 Apr 20;13:838449. doi: 10.3389/fphar.2022.838449.
eCollection 2022.
BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral
Treatment of Idiopathic Pulmonary Fibrosis.
Herrmann FE(1), Hesslinger C(1), Wollin L(1), Nickolaus P(1).
Author information:
(1)Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Erratum in
Front Pharmacol. 2023 May 30;14:1219760. doi: 10.3389/fphar.2023.1219760.
The anti-inflammatory and immunomodulatory abilities of oral selective
phosphodiesterase 4 (PDE4) inhibitors enabled the approval of roflumilast and
apremilast for use in chronic obstructive pulmonary disease and
psoriasis/psoriatic arthritis, respectively. However, the antifibrotic potential
of PDE4 inhibitors has not yet been explored clinically. BI 1015550 is a novel
PDE4 inhibitor showing a preferential enzymatic inhibition of PDE4B. In vitro,
BI 1015550 inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-α
(TNF-α) and phytohemagglutinin-induced interleukin-2 synthesis in human
peripheral blood mononuclear cells, as well as LPS-induced TNF-α synthesis in
human and rat whole blood. In vivo, oral BI 1015550 shows potent
anti-inflammatory activity in mice by inhibiting LPS-induced TNF-α synthesis ex
vivo and in Suncus murinus by inhibiting neutrophil influx into bronchoalveolar
lavage fluid stimulated by nebulized LPS. In Suncus murinus, PDE4 inhibitors
induce emesis, a well-known gastrointestinal side effect limiting the use of
PDE4 inhibitors in humans, and the therapeutic ratio of BI 1015550 appeared to
be substantially improved compared with roflumilast. Oral BI 1015550 was also
tested in two well-known mouse models of lung fibrosis (induced by either
bleomycin or silica) under therapeutic conditions, and appeared to be effective
by modulating various model-specific parameters. To better understand the
antifibrotic potential of BI 1015550 in vivo, its direct effect on human
fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) was
investigated in vitro. BI 1015550 inhibited transforming growth
factor-β-stimulated myofibroblast transformation and the mRNA expression of
various extracellular matrix proteins, as well as basic fibroblast growth factor
plus interleukin-1β-induced cell proliferation. Nintedanib overall was
unremarkable in these assays, but interestingly, the inhibition of proliferation
was synergistic when it was combined with BI 1015550, leading to a roughly
10-fold shift of the concentration-response curve to the left. In summary, the
unique preferential inhibition of PDE4B by BI 1015550 and its anticipated
improved tolerability in humans, plus its anti-inflammatory and antifibrotic
potential, suggest BI 1015550 to be a promising oral clinical candidate for the
treatment of IPF and other fibro-proliferative diseases.
Copyright © 2022 Herrmann, Hesslinger, Wollin and Nickolaus.
DOI: 10.3389/fphar.2022.838449
PMCID: PMC9065678
PMID: 35517783
Conflict of interest statement: FEH, CH, LW, and PN are employees of Boehringer
Ingelheim Pharma GmbH & Co. KG. |
http://www.ncbi.nlm.nih.gov/pubmed/26785833 | 1. Eur J Hum Genet. 2016 Aug;24(9):1255-61. doi: 10.1038/ejhg.2015.283. Epub 2016
Jan 20.
Online genetic counseling from the providers' perspective: counselors'
evaluations and a time and cost analysis.
Otten E(1), Birnie E(1), Ranchor AV(2), van Langen IM(1).
Author information:
(1)Department of Genetics, University of Groningen, University Medical Center
Groningen, Groningen, The Netherlands.
(2)Department of Health Psychology, University of Groningen, University Medical
Center Groningen, Groningen, The Netherlands.
Telemedicine applications are increasingly being introduced in patient care in
various disciplines, including clinical genetics, mainly to increase access to
care and to reduce time and costs for patients and professionals. Most
telegenetics reports describe applications in large geographical areas, showing
positive patients' and professionals' satisfaction. One economic analysis
published thus far reported lower costs than in-person care. We hypothesized
that telegenetics can also be beneficial from the professional's view in
relatively small geographical areas. We performed a pilot study in the Northern
Netherlands of 51 home-based online counseling sessions for cardiogenetic and
oncogenetic cascade screening, and urgent prenatal counseling. Previously, we
showed patient satisfaction, anxiety, and perceived control of online counseling
to be comparable to in-person counseling. This study focuses on expectations,
satisfaction, and practical evaluations of the involved counselors, and the
impact in terms of time and costs. Most counselors expected disadvantages of
online counseling for themselves and their patients, mainly concerning
insufficient non-verbal communication; few expected advantages for themselves.
Afterwards, counselors additionally raised the disadvantage of insufficient
verbal communication, and reported frequent technical problems. Their overall
mean telemedicine satisfaction itemscore was 3.38 before, and 2.95 afterwards,
being afterwards slightly below the minimum level we set for a satisfactory
result. We estimated reduced time and costs by online counseling with about 8%
and 10-12%, respectively. We showed online genetic counseling to be effective,
feasible and cost-efficient, but technical improvements are needed to increase
counselors' satisfaction.
DOI: 10.1038/ejhg.2015.283
PMCID: PMC4989197
PMID: 26785833 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34155820 | 1. Wiley Interdiscip Rev RNA. 2022 Mar;13(2):e1678. doi: 10.1002/wrna.1678. Epub
2021 Jun 21.
Microexon alternative splicing of small GTPase regulators: Implication in
central nervous system diseases.
Lee JS(1)(2), Lamarche-Vane N(3)(4), Richard S(1)(5)(2).
Author information:
(1)Segal Cancer Center, Lady Davis Institute for Medical Research, Montreal,
Quebec, Canada.
(2)Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
(3)Research Institute of the McGill University Health Centre, Cancer Research
Program, Montreal, Quebec, Canada.
(4)Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec,
Canada.
(5)Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec,
Canada.
Microexons are small sized (≤51 bp) exons which undergo extensive alternative
splicing in neurons, microglia, embryonic stem cells, and cancer cells, giving
rise to cell type specific protein isoforms. Due to their small sizes,
microexons provide a unique challenge for the splicing machinery. They
frequently lack exon splicer enhancers/repressors and require specialized
neighboring trans-regulatory and cis-regulatory elements bound by RNA binding
proteins (RBPs) for their inclusion. The functional consequences of including
microexons within mRNAs have been extensively documented in the central nervous
system (CNS) and aberrations in their inclusion have been observed to lead to
abnormal processes. Despite the increasing evidence for microexons impacting
cellular physiology within CNS, mechanistic details illustrating their
functional importance in diseases of the CNS is still limited. In this review,
we discuss the unique characteristics of microexons, and how RBPs participate in
regulating their inclusion and exclusion during splicing. We consider recent
findings of microexon alternative splicing and their implication for regulating
the function of small GTPases in the context of the microglia, and we
extrapolate these findings to what is known in neurons. We further discuss the
emerging evidence for dysregulation of the Rho GTPase pathway in CNS diseases
and the consequences contributed by the mis-splicing of microexons. This article
is categorized under: RNA Processing > Splicing Mechanisms RNA Processing >
Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in
Disease.
© 2021 Wiley Periodicals LLC.
DOI: 10.1002/wrna.1678
PMID: 34155820 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35347281 | 1. Nat Med. 2022 Apr;28(4):780-788. doi: 10.1038/s41591-022-01737-y. Epub 2022
Mar 28.
In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a
phase 1 and 2 trial.
Gurevich I(1), Agarwal P(2), Zhang P(2), Dolorito JA(1), Oliver S(2), Liu H(2),
Reitze N(2), Sarma N(2), Bagci IS(1), Sridhar K(1), Kakarla V(1), Yenamandra
VK(1), O'Malley M(2), Prisco M(3), Tufa SF(4), Keene DR(4), South AP(3),
Krishnan SM(2), Marinkovich MP(5)(6).
Author information:
(1)Program in Epithelial Biology and Department of Dermatology, Stanford
University School of Medicine, Stanford, CA, USA.
(2)Krystal Biotech, Pittsburgh, PA, USA.
(3)Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA,
USA.
(4)Microscopy Unit, Shriners Hospital for Children, Portland, OR, USA.
(5)Program in Epithelial Biology and Department of Dermatology, Stanford
University School of Medicine, Stanford, CA, USA. mpm@stanford.edu.
(6)Veterans Affairs Medical Center, Palo Alto, Stanford, CA, USA.
mpm@stanford.edu.
Comment in
Med. 2022 May 13;3(5):273-275. doi: 10.1016/j.medj.2022.04.008.
Trends Mol Med. 2022 Jul;28(7):533-535. doi: 10.1016/j.molmed.2022.05.001.
Recessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis
associated with blistering, wounding, and scarring caused by mutations in
COL7A1, the gene encoding the anchoring fibril component, collagen VII (C7).
Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating
COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB
skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice
and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase
1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB
patients receiving topical B-VEC or placebo repeatedly over 12 weeks. No grade 2
or above B-VEC-related adverse events or vector shedding or tissue-bound skin
immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at
baseline or increased after B-VEC treatment without an apparent impact on safety
or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril
assembly, wound surface area reduction, duration of wound closure, and time to
wound closure following B-VEC treatment were met. A patient-reported
pain-severity secondary outcome was not assessed given the small proportion of
wounds treated. A global assessment secondary endpoint was not pursued due to
redundancy with regard to other endpoints. These studies show that B-VEC is an
easily administered, safely tolerated, topical molecular corrective therapy
promoting wound healing in patients with RDEB.
© 2022. This is a U.S. government work and not under copyright protection in the
U.S.; foreign copyright protection may apply.
DOI: 10.1038/s41591-022-01737-y
PMCID: PMC9018416
PMID: 35347281 [Indexed for MEDLINE]
Conflict of interest statement: M.P.M. received funding from Krystal Biotech to
conduct this study through a sponsored research award administered through the
Stanford University Office of Research Management. M.P.M. is also an
investigator for the following companies that are studying molecular corrective
therapies for recessive dystrophic epidermolysis bullosa: Castle Creek
Pharmaceuticals, Abeona Therapeutics, WINGS therapeutics and Phoenix Tissue
Repair. A.P.S. owns stock in Krystal Biotech. P.A., P.P.Z. and S.O., as well as
H.L., N.R., N.S., M.O. and S.M.K. are employees of Krystal Biotech. All other
authors have no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/1836514 | 1. Lab Invest. 1991 Nov;65(5):588-600.
Hairpatches, a single gene mutation characterized by progressive renal disease
and alopecia in the mouse. A potential model for a newly described heritable
human disorder.
Shultz LD(1), Lane PW, Coman DR, Taylor S, Hall E, Lyons B, Wood BG, Schlager G.
Author information:
(1)Jackson Laboratory, Bar Harbor, Maine.
A new murine mutation, hairpatches (Hpt), is on chromosome 4, 18.1 recombination
units distal to brown near the interferon alpha and beta chain structural gene
complex. On the inbred HPT/Le strain background, Hpt is semi-dominant, and
Hpt/Hpt mice die in utero by 6 to 8 days of gestation. Such death in utero is
associated with abnormalities of embryonic ectodermal derivatives. However on
the (C57BL/6J x C3HeB/FeJ-a/a) segregating hybrid background, Hpt is a fully
dominant mutation. HPT/Le Hpt/+ mice can be recognized by 3 to 4 days of age by
patches of lightly pigmented skin. These mice show reduced numbers of hair
follicles, abnormalities in hair follicle structure, and patchy absence of hair
throughout life. By 2 weeks of age, abnormal hair follicle development is
accompanied by thickening of the epidermis, reduction in levels of subcutaneous
fat, and dermal inflammation. Progressive glomerulosclerosis, resulting in
chronic kidney failure, is accompanied by increases in glomerular mesangial
matrix, deposition of immune complexes, and glomerular enlargement. Scanning
electron microscopic studies revealed abnormalities of podocytes including
disorganization, swelling, and fusion of the foot processes. Increase in serum
blood urea nitrogen levels accompanies conspicuous renal histopathologic
changes. Cardiovascular changes in Hpt/+ mice are evidenced by hypertrophy of
the left heart ventricle. Increased systolic blood pressure in these animals was
found by 3 months of age. Anemia occurs in Hpt/+ mice by 40 weeks. The Hpt/+
mutation provides a valuable new animal model for chronic kidney disease
accompanied by skin abnormalities and ventricular hypertrophy. The pathologic
changes caused by this mutation are similar to those reported in affected family
members with a newly described autosomal dominant human disease.
PMID: 1836514 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23301070 | 1. PLoS One. 2013;8(1):e53426. doi: 10.1371/journal.pone.0053426. Epub 2013 Jan
2.
Retrotransposon insertion in the T-cell acute lymphocytic leukemia 1 (Tal1) gene
is associated with severe renal disease and patchy alopecia in Hairpatches (Hpt)
mice.
Hosur V(1), Cox ML, Burzenski LM, Riding RL, Alley L, Lyons BL, Kavirayani A,
Martin KA, Cox GA, Johnson KR, Shultz LD.
Author information:
(1)The Jackson Laboratory, Bar Harbor, Maine, United States of America.
"Hairpatches" (Hpt) is a naturally occurring, autosomal semi-dominant mouse
mutation. Hpt/Hpt homozygotes die in utero, while Hpt/+ heterozygotes exhibit
progressive renal failure accompanied by patchy alopecia. This mutation is a
model for the rare human disorder "glomerulonephritis with sparse hair and
telangiectases" (OMIM 137940). Fine mapping localized the Hpt locus to a 6.7 Mb
region of Chromosome 4 containing 62 known genes. Quantitative real time PCR
revealed differential expression for only one gene in the interval, T-cell acute
lymphocytic leukemia 1 (Tal1), which was highly upregulated in the kidney and
skin of Hpt/+ mice. Southern blot analysis of Hpt mutant DNA indicated a new
EcoRI site in the Tal1 gene. High throughput sequencing identified an endogenous
retroviral class II intracisternal A particle insertion in Tal1 intron 4. Our
data suggests that the IAP insertion in Tal1 underlies the histopathological
changes in the kidney by three weeks of age, and that glomerulosclerosis is a
consequence of an initial developmental defect, progressing in severity over
time. The Hairpatches mouse model allows an investigation into the effects of
Tal1, a transcription factor characterized by complex regulation patterns, and
its effects on renal disease.
DOI: 10.1371/journal.pone.0053426
PMCID: PMC3534690
PMID: 23301070 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/23244814 | 1. Value Health. 2012 Dec;15(8):1108-18. doi: 10.1016/j.jval.2012.06.019. Epub
2012 Nov 3.
Comparisons of Food and Drug Administration and European Medicines Agency risk
management implementation for recent pharmaceutical approvals: report of the
International Society for Pharmacoeconomics and outcomes research risk benefit
management working group.
Lis Y(1), Roberts MH, Kamble S, J Guo J, Raisch DW.
Author information:
(1)PAREXEL International, Uxbridge, UK.
OBJECTIVE: 1) To compare the Food and Drug Administration's (FDA's) Risk
Evaluation and Mitigation Strategies (REMS) and European Medicines Agency's
(EMA's) Risk Management Plan (RMP) guidances and 2) to compare REMS and RMPs for
specific chemical entities and biological products.
METHODS: FDA, EMA, and pharmaceutical company Web sites were consulted for
details pertaining to REMS and RMPs. REMS requirements include medication
guides, communication plans, elements to ensure safe use, implementation
systems, and specified assessment intervals. RMP requirements are increased
pharmacovigilance and risk minimization activities. We compared these
requirements for drugs requiring both REMS and RMPs.
RESULTS: We identified 95 drugs on FDA's REMS list as of March 2010. Of these,
there were 29 drugs (11 biologics and 18 new chemical entities) with EMA RMPs.
REMS and RMPs are similar in objectives, with comparable toolkits. Both allow
flexibility in product-specific actions, recognizing adverse effects of
potential concern. Of the 29 drugs reviewed, REMS requirements not included in
RMPs were patient medication guides (100% of the drugs), provider communication
plans (38%), and routine monitoring of REMS (66%). RMP requirements not included
in REMS were specific adverse event reporting (45% of the drugs), prospective
registry studies (34%), prospective epidemiology studies (24%), additional trial
data (28%), and Summary of Product Characteristics contraindications (76%).
CONCLUSIONS: Both REMS and RMPs provide positive guidance for identification,
monitoring, and minimization of risk to patient safety. Currently, neither
agency provides specific guidance on how risk should be related to benefit
either qualitatively or quantitatively.
Copyright © 2012 International Society for Pharmacoeconomics and Outcomes
Research (ISPOR). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jval.2012.06.019
PMID: 23244814 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34346508 | 1. Int J Cancer. 2021 Nov 15;149(10):1787-1800. doi: 10.1002/ijc.33758. Epub 2021
Aug 16.
Alternative microexon splicing by RBFOX2 and PTBP1 is associated with metastasis
in colorectal cancer.
Mochizuki Y(1)(2), Funayama R(1), Shirota M(3), Kikukawa Y(1), Ohira M(1),
Karasawa H(2), Kobayashi M(1)(2), Ohnuma S(2), Unno M(2), Nakayama K(1).
Author information:
(1)Department of Cell Proliferation, ART, Graduate School of Medicine, Tohoku
University, Sendai, Japan.
(2)Department of Surgery, Graduate School of Medicine, Tohoku University,
Sendai, Japan.
(3)Division of Interdisciplinary Medical Science, ART, Graduate School of
Medicine, Tohoku University, Sendai, Japan.
The splicing of microexons (very small exons) is frequently dysregulated in the
brain of individuals with autism spectrum disorder. However, little is known of
the patterns, regulatory mechanisms and roles of microexon splicing in cancer.
We here examined the transcriptome-wide profile of microexon splicing in matched
colorectal cancer (CRC) and normal tissue specimens. Out of 1492 microexons
comprising 3 to 15 nucleotides, 21 (1%) manifested differential splicing between
CRC and normal tissue. The 21 genes harboring the differentially spliced
microexons were enriched in gene ontology terms related to cell adhesion and
migration. RNA interference-mediated knockdown experiments identified two
splicing factors, RBFOX2 and PTBP1, as regulators of microexon splicing in CRC
cells. RBFOX2 and PTBP1 were found to directly bind to microexon-containing
pre-mRNAs and to control their splicing in such cells. Differential microexon
splicing was shown to be due, at least in part, to altered expression of RBFOX2
and PTBP1 in CRC tissue compared to matched normal tissue. Finally, we found
that changes in the pattern of microexon splicing were associated with CRC
metastasis. Our data thus suggest that altered expression of RBFOX2 and PTBP1
might influence CRC metastasis through the regulation of microexon splicing.
© 2021 UICC.
DOI: 10.1002/ijc.33758
PMID: 34346508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36267868 | 1. J Pediatr Genet. 2021 Mar 10;11(4):267-271. doi: 10.1055/s-0041-1725118.
eCollection 2022 Dec.
Cribriform Appearance of White Matter in Canavan Disease Associated with Novel
Mutations of ASPA Gene.
Bhat MD(1), Manjunath N(2), Kumari R(3), Faruq M(4), Pal PK(2), Prasad C(1),
Mundlamuri RC(2), Nalini A(2), Udupi GA(5), Baishya PP(1), Kulanthaivelu K(1).
Author information:
(1)Department of Neuroimaging and Interventional Radiology, National Institute
of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
(2)Department of Neurology, National Institute of Mental Health and
Neurosciences, Bengaluru, Karnataka, India.
(3)Genomics and Molecular Medicine, CSIR Institute of Genomics and Integrative
Biology, New Delhi.
(4)Department of Genomics and Molecular Medicine, CSIR-Institute of Genomics and
Integrative Biology, New Delhi, India.
(5)Department of Human Genetics, National Institute of Mental Health and
Neurosciences, Bengaluru, Karnataka, India.
Cribriform appearance of the brain in Canavan disease is a rare finding. The two
presented cases broaden the magnetic resonance imaging (MRI) phenotype wherein
numerous oval, cystic structures, a few resembling dilated Virchow-Robin (VR)
spaces, were noted in the centrum semiovale, periventricular, and lobar white
matter producing a cribriform pattern. Besides, discrete round to oval cysts
were present at the gray-white matter junctions in the second case, which were
larger and appeared morphologically distinct from the VR spaces. These cysts did
not elongate in any plane on imaging and were more representative of giant
intramyelinic vacuoles. Genetic analysis revealed novel mutations in the
aspartoacylase or ASPA gene that possibly accounts for the severe form of
Canavan disease, which probably explains the imaging findings. The multicystic
appearance of the white matter in Canavan disease is unusual and possibly
represents two different histopathological substrates.
Thieme. All rights reserved.
DOI: 10.1055/s-0041-1725118
PMCID: PMC9578778
PMID: 36267868
Conflict of interest statement: Conflict of Interest None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/35636725 | 1. Drug Discov Today. 2022 Sep;27(9):2467-2483. doi:
10.1016/j.drudis.2022.05.019. Epub 2022 May 27.
The pathogenesis of, and pharmacological treatment for, Canavan disease.
Wei H(1), Moffett JR(2), Amanat M(3), Fatemi A(4), Tsukamoto T(5), Namboodiri
AM(6), Slusher BS(7).
Author information:
(1)Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine,
855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns
Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205,
USA; Department of Pharmacology and Molecular Science, Johns Hopkins University
School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA.
(2)Department of Anatomy, Physiology and Genetics and Neuroscience Program,
Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd.,
Bethesda, MD 20814, USA. Electronic address: john.moffett@usuhs.edu.
(3)Kennedy Krieger Institute, Baltimore, MD 21205, USA.
(4)Department of Neurology, Johns Hopkins University School of Medicine, 855 N.
Wolfe Street, Baltimore, MD 21205, USA; Department of Behavioral Science, Johns
Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205,
USA; Department of Pediatrics, Johns Hopkins University School of Medicine, 855
N. Wolfe Street, Baltimore, MD 21205, USA; Kennedy Krieger Institute, Baltimore,
MD 21205, USA.
(5)Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine,
855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns
Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205,
USA.
(6)Department of Anatomy, Physiology and Genetics and Neuroscience Program,
Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd.,
Bethesda, MD 20814, USA.
(7)Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine,
855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns
Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205,
USA; Department of Pharmacology and Molecular Science, Johns Hopkins University
School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of
Oncology, Johns Hopkins University School of Medicine, 855 N. Wolfe Street,
Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University
School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of
Psychiatry, Johns Hopkins University School of Medicine, 855 N. Wolfe Street,
Baltimore, MD 21205, USA. Electronic address: bslusher@jhmi.edu.
Canavan disease (CD) is an inherited leukodystrophy resulting from mutations in
the gene encoding aspartoacylase (ASPA). ASPA is highly expressed in
oligodendrocytes and catalyzes the cleavage of N-acetylaspartate (NAA) to
produce aspartate and acetate. In this review, we examine the pathologies and
clinical presentation in CD, the metabolism and transportation of NAA in the
brain, and the hypothetical mechanisms whereby ASPA deficiency results in
dysmyelination and a failure of normal brain development. We also discuss
therapeutic options that could be used for the treatment of CD.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.drudis.2022.05.019
PMID: 35636725 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35637731 | 1. iScience. 2022 May 11;25(6):104391. doi: 10.1016/j.isci.2022.104391.
eCollection 2022 Jun 17.
Therapeutic development for Canavan disease using patient iPSCs introduced with
the wild-type ASPA gene.
Chao J(1), Feng L(1), Ye P(1), Chen X(1), Cui Q(1), Sun G(1)(2), Zhou T(1), Tian
E(1), Li W(1), Hu W(3), Riggs AD(2), Matalon R(4), Shi Y(1).
Author information:
(1)Division of Stem Cell Biology Research, Department of Stem Cell Biology and
Regenerative Medicine, Beckman Research Institute of City of Hope, 1500 E.
Duarte Road, Duarte, CA 91010, USA.
(2)Diabetes and Metabolism Research Institute, City of Hope, 1500 E. Duarte
Road, Duarte, CA 91010, USA.
(3)Department of Molecular Imaging and Therapy, Beckman Research Institute of
City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA.
(4)Department of Pediatrics, The University of Texas Medical Branch at
Galveston, 301 University Boulevard, Galveston, TX 77555-0359, USA.
Canavan disease (CD) is a devastating neurological disease that lacks effective
therapy. Because CD is caused by mutations of the aspartoacylase (ASPA) gene, we
introduced the wild-type (WT) ASPA gene into patient iPSCs through lentiviral
transduction or CRISPR/Cas9-mediated gene editing. We then differentiated the WT
ASPA-expressing patient iPSCs (ASPA-CD iPSCs) into NPCs and showed that the
resultant ASPA-CD NPCs exhibited potent ASPA enzymatic activity. The ASPA-CD
NPCs were able to survive in brains of transplanted CD mice. The engrafted
ASPA-CD NPCs reconstituted ASPA activity in CD mouse brains, reduced the
abnormally elevated level of NAA in both brain tissues and cerebrospinal fluid
(CSF), and rescued hallmark pathological phenotypes of the disease, including
spongy degeneration, myelination defects, and motor function impairment in
transplanted CD mice. These genetically modified patient iPSC-derived NPCs
represent a promising cell therapy candidate for CD, a disease that has neither
a cure nor a standard treatment.
© 2022.
DOI: 10.1016/j.isci.2022.104391
PMCID: PMC9142666
PMID: 35637731
Conflict of interest statement: A patent application related to this work has
been filed. The authors declare no other competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35929936 | 1. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Aug 10;39(8):859-863. doi:
10.3760/cma.j.cn511374-20210612-00499.
[Genetic analysis and prenatal diagnosis for a Chinese pedigree affected with
Canavan disease].
[Article in Chinese]
Sun G(1), Zhu X, Hu S, Liu L, Wang L, Kong X.
Author information:
(1)Center of Genetics and Prenatal Diagnosis, Department of Obstetrics and
Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou,
Henan 450052, China. kongxd@263.net.
OBJECTIVE: To explore the genetic basis for a Chinese patient suspected for
Canavan disease.
METHODS: Whole exome sequencing (WES) was carried out for the proband, and
candidate variants were verified by Sanger sequencing of the proband, her
parents and brother. Prenatal diagnosis was provided to her mother by chorionic
villi sampling (CVS) upon her subsequent pregnancy.
RESULTS: The proband, a 4-month-old female infant, had manifested drowsiness,
hypotonia and apathy. Urine metabolism screening showed elevated
N-acetylaspartic acid. Cranial magnetic resonance imaging revealed abnormal
myelination and multiple abnormal signals in large brain areas. WES revealed
that the proband has harbored compound heterozygous variants of the ASPA gene,
namely c.187A>G (p.Arg63Gly) in exon 1 and c.634+1G>A (P.?) in exon 4. Sanger
sequencing confirmed that the c.187A>G (p.Arg63Gly) and c.634+1G>A (p.?)
variants were respectively inherited from her mother and father. Her
phenotypically normal brother has carried a heterozygous c.634+1G>A (p.?)
variant. Prenatal diagnosis by CVS indicated that the fetus was a heterozygous
carrier of the c.187A>G variant.
CONCLUSION: WES can facilitate the diagnosis of Canavan disease, particularly
for those lacking specific phenotypes of the disease. The compound heterozygous
variants of the ASPA gene probably underlay the Canavan disease in this patient,
and the result has enabled prenatal diagnosis for this family.
DOI: 10.3760/cma.j.cn511374-20210612-00499
PMID: 35929936 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29213721 | 1. Dement Neuropsychol. 2011 Jan-Mar;5(1):54-57. doi:
10.1590/S1980-57642011DN05010010.
Congenital prosopagnosia: A case report.
Schultz RR(1), Bertolucci PHF(2).
Author information:
(1)Head, Behavior Neurology Section, University of Santo Amaro, São Paulo SP,
Brazil; Behavior Neurology Section, Department of Neurology and Neurosurgery,
Escola Paulista de Medicina, Federal University of São Paulo, São Paulo SP,
Brazil.
(2)Head, Behavior Neurology Section, Department of Neurology and Neurosurgery,
Escola Paulista de Medicina, Federal University of São Paulo, São Paulo SP,
Brazil.
Prosopagnosia is a visual agnosia characterized by an inability to recognize
previously known human faces and to learn new faces. The aim of this study was
to present a forty-six year-old woman with congenital prosopagnosia, and to
discuss the neural bases of perception and recognition of faces. The patients
had a lifetime impairment in recognizing faces of family members, close friends,
and even her own face in photos. She also had impairment in recognizing animals
such as discriminating between cats and dogs. The patient's basic visual skills
showed impairment in identifying and recognizing the animal form perception on
the coding subtest of the WAIS-R, recognizing overlapping pictures (Luria), and
in identifying silhouettes depicting animals and objects (VOSP). Unconventional
tests using pictures evidenced impairment in her capacity to identify famous
faces, facial emotions and animals. Her face perception abilities were
preserved, but recognition could not take place. Therefore, it appears that the
agnosia in this case best fits the group of categories termed "associative".
Publisher: Prosopagnosia é uma agnosia visual caracterizada por uma incapacidade
de reconhecer faces humanas vistas anteriormente e aprender outras. O objetivo é
apresentar uma mulher de 46 anos com prosopagnosia congênita e discutir as bases
neurais da percepção e do reconhecimento de faces. Ela nos procurou referindo
apresentar desde a infância problemas no reconhecimento de faces de membros da
família, amigos próximos e mesmo para sua própria imagem numa fotografia. Também
diz apresentar prejuízo no reconhecimento de animais, como discriminar cães de
gatos. Apresentou dificuldades em identificar e reconhecer animais desenhados;
reconhecer figuras sobrepostas (Luria), incorrendo em paragnosias visuais e
identificar silhuetas de animais (VOSP). Em testes não convencionais, usando
figuras, evidenciou diminuição da capacidade em identificar faces famosas,
expressões faciais e animais, mas não em estimar o sexo e a idade das pessoas.
Concluindo, suas habilidades perceptuais para face estão preservadas, mas há um
déficit de reconhecimento. Tudo indica que sua agnosia pertence ao grupo das
associativas.
DOI: 10.1590/S1980-57642011DN05010010
PMCID: PMC5619140
PMID: 29213721
Conflict of interest statement: Disclosure: The authors reports no conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/29213598 | 1. Dement Neuropsychol. 2008 Oct-Dec;2(4):353-355. doi:
10.1590/S1980-57642009DN20400021.
Developmental prosopagnosia and adaptative compensatory strategies: Case study.
Rodrigues A(1), Bolognani SAP(1), Brucki SMD(2), Bueno OFA(3).
Author information:
(1)Neuropsychologist. Head of Centro Paulista de Neuropsicologia, Departamento
de Psicobiologia, UNIFESP-EPM.
(2)Neurologist. Head of Centro Paulista de Neuropsicologia, Departamento de
Psicobiologia, UNIFESP-EPM.
(3)Psychologist, Head of Centro Paulista de Neuropsicologia, Departamento de
Psicobiologia, UNIFESP-EPM.
Prosopagnosia is a type of visual agnosia with inability to identify faces,
usually secondary to brain lesion in associative cortex areas, but there is also
a congenital form known as developmental prosopagnosia.
OBJECTIVES: To describe a case of developmental prosopagnosia that illustrates
the specificity of the pathways for perception of faces in the visual system.
Also, we will describe possible mechanisms of recognition used by this patient.
METHODS: R.S., a 50 year-old woman, was referred for neuropsychological
assessment due to difficulties in perception of familiar faces since childhood,
unexplained by any loss of visual acuity.
RESULTS: The exam showed good performance for comprehension, reasoning, concept
formation, constructional abilities, criticism, judgment, mental control, memory
and visual perception for other kinds of stimuli. No difficulties were seen
regarding identification of ethnicity, age and types of animals. The patient was
able to match celebrities' faces in different positions, but could not identify
the matching pictures for unknown people.
CONCLUSIONS: These findings indicate the patient had developed strategies,
throughout life, to recognize familiar faces (relatives, celebrities) from
memorized fragments, but still had difficulties in identifying non-familiar
faces holistically.
Publisher: A prosopagnosia é um tipo de agnosia visual que pode surgir em
decorrência de lesão cerebral em áreas do córtex associativo, mas também pode
constituir uma condição congênita, também chamada de prosopagnosia de
desenvolvimento.
OBJETIVOS: Descrição de um caso de prosopagnosia de desenvolvimento, que ilustra
mecanismos específicos de percepção visual, bem como vias alternativas
utilizadas no reconhecimento de pessoas.
MÉTODOS: A paciente, 50 anos, foi encaminhada para avaliação neuropsicológica
com queixas de dificuldades de percepção visual não justificáveis por perda de
acuidade. Desde criança teve dificuldades em reconhecer rostos de pessoas
conhecidas.
RESULTADOS: Na avaliação a paciente mostrou bons resultados quanto a capacidade
de compreensão e expressão de idéias, raciocínio e conceituação,
visuo-construção, crítica, julgamento, controle mental, memória e percepção
visual para outras modalidades de estímulos. Também não obteve prejuízos no
reconhecimento de etnias, expressões faciais, identificação de faixas etárias e
tipos de animais. A paciente foi capaz de parear fotos de rostos familiares
famosos em diferentes posições, mas não conseguiu parear rostos não familiares.
CONCLUSÕES: O conjunto dos achados indica que a paciente desenvolveu estratégias
ao longo da vida para reconhecer rostos conhecidos (familiares, celebridades) a
partir de fragmentos memorizados, mas continua tendo dificuldades para
identificar holisticamente faces não familiares.
DOI: 10.1590/S1980-57642009DN20400021
PMCID: PMC5619093
PMID: 29213598 |
http://www.ncbi.nlm.nih.gov/pubmed/30625291 | 1. Neuropsychologia. 2019 Feb 18;124:87-97. doi:
10.1016/j.neuropsychologia.2018.12.022. Epub 2019 Jan 6.
Perception of musical pitch in developmental prosopagnosia.
Corrow SL(1), Stubbs JL(2), Schlaug G(3), Buss S(3), Paquette S(3), Duchaine
B(4), Barton JJS(2).
Author information:
(1)Human Vision and Eye Movement Laboratory, Departments of Medicine
(Neurology), Ophthalmology and Visual Science, University of British Columbia,
Vancouver, Canada; Department of Psychology, Bethel University, St. Paul, MN,
USA. Electronic address: s-corrow@bethel.edu.
(2)Human Vision and Eye Movement Laboratory, Departments of Medicine
(Neurology), Ophthalmology and Visual Science, University of British Columbia,
Vancouver, Canada.
(3)Music and Neuroimaging Laboratory, Department of Neurology, Beth Israel
Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
(4)Department of Psychological and Brain Sciences, Dartmouth College, Hanover,
NH, USA.
Studies of developmental prosopagnosia have often shown that developmental
prosopagnosia differentially affects human face processing over non-face object
processing. However, little consideration has been given to whether this
condition is associated with perceptual or sensorimotor impairments in other
modalities. Comorbidities have played a role in theories of other developmental
disorders such as dyslexia, but studies of developmental prosopagnosia have
often focused on the nature of the visual recognition impairment despite
evidence for widespread neural anomalies that might affect other sensorimotor
systems. We studied 12 subjects with developmental prosopagnosia with a battery
of auditory tests evaluating pitch and rhythm processing as well as voice
perception and recognition. Overall, three subjects were impaired in fine pitch
discrimination, a prevalence of 25% that is higher than the estimated 4%
prevalence of congenital amusia in the general population. This was a selective
deficit, as rhythm perception was unaffected in all 12 subjects. Furthermore,
two of the three prosopagnosic subjects who were impaired in pitch
discrimination had intact voice perception and recognition, while two of the
remaining nine subjects had impaired voice recognition but intact pitch
perception. These results indicate that, in some subjects with developmental
prosopagnosia, the face recognition deficit is not an isolated impairment but is
associated with deficits in other domains, such as auditory perception. These
deficits may form part of a broader syndrome which could be due to distributed
microstructural anomalies in various brain networks, possibly with a common
theme of right hemispheric predominance.
Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.neuropsychologia.2018.12.022
PMCID: PMC10262916
PMID: 30625291 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20850465 | 1. Neuropsychologia. 2010 Nov;48(13):3725-32. doi:
10.1016/j.neuropsychologia.2010.09.008. Epub 2010 Sep 17.
Superior voice recognition in a patient with acquired prosopagnosia and object
agnosia.
Hoover AE(1), Démonet JF, Steeves JK.
Author information:
(1)Centre for Vision Research, York University, Toronto, Canada.
Anecdotally, it has been reported that individuals with acquired prosopagnosia
compensate for their inability to recognize faces by using other person identity
cues such as hair, gait or the voice. Are they therefore superior at the use of
non-face cues, specifically voices, to person identity? Here, we empirically
measure person and object identity recognition in a patient with acquired
prosopagnosia and object agnosia. We quantify person identity (face and voice)
and object identity (car and horn) recognition for visual, auditory, and bimodal
(visual and auditory) stimuli. The patient is unable to recognize faces or cars,
consistent with his prosopagnosia and object agnosia, respectively. He is
perfectly able to recognize people's voices and car horns and bimodal stimuli.
These data show a reverse shift in the typical weighting of visual over auditory
information for audiovisual stimuli in a compromised visual recognition system.
Moreover, the patient shows selectively superior voice recognition compared to
the controls revealing that two different stimulus domains, persons and objects,
may not be equally affected by sensory adaptation effects. This also implies
that person and object identity recognition are processed in separate pathways.
These data demonstrate that an individual with acquired prosopagnosia and object
agnosia can compensate for the visual impairment and become quite skilled at
using spared aspects of sensory processing. In the case of acquired
prosopagnosia it is advantageous to develop a superior use of voices for person
identity recognition in everyday life.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.neuropsychologia.2010.09.008
PMID: 20850465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26321070 | 1. Cortex. 2015 Oct;71:390-7. doi: 10.1016/j.cortex.2015.07.030. Epub 2015 Aug 4.
The processing of voice identity in developmental prosopagnosia.
Liu RR(1), Corrow SL(2), Pancaroglu R(3), Duchaine B(4), Barton JJ(5).
Author information:
(1)Human Vision and Eye Movement Laboratory, Departments of Medicine
(Neurology), Ophthalmology and Visual Sciences, University of British Columbia,
Eye Care Centre, Vancouver, BC, Canada. Electronic address: r.liu@alumni.ubc.ca.
(2)Human Vision and Eye Movement Laboratory, Departments of Medicine
(Neurology), Ophthalmology and Visual Sciences, University of British Columbia,
Eye Care Centre, Vancouver, BC, Canada. Electronic address:
sherryse.corrow@eyecarecentre.org.
(3)Human Vision and Eye Movement Laboratory, Departments of Medicine
(Neurology), Ophthalmology and Visual Sciences, University of British Columbia,
Eye Care Centre, Vancouver, BC, Canada. Electronic address: raikap@gmail.com.
(4)Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA.
Electronic address: bradley.c.duchaine@dartmouth.edu.
(5)Human Vision and Eye Movement Laboratory, Departments of Medicine
(Neurology), Ophthalmology and Visual Sciences, University of British Columbia,
Eye Care Centre, Vancouver, BC, Canada. Electronic address: jasonbarton@shaw.ca.
BACKGROUND: Developmental prosopagnosia is a disorder of face recognition that
is believed to reflect impairments of visual mechanisms. However, voice
recognition has rarely been evaluated in developmental prosopagnosia to clarify
if it is modality-specific or part of a multi-modal person recognition syndrome.
OBJECTIVE: Our goal was to examine whether voice discrimination and/or
recognition are impaired in subjects with developmental prosopagnosia.
DESIGN/METHODS: 73 healthy controls and 12 subjects with developmental
prosopagnosia performed a match-to-sample test of voice discrimination and a
test of short-term voice familiarity, as well as a questionnaire about face and
voice identification in daily life.
RESULTS: Eleven subjects with developmental prosopagnosia scored within the
normal range for voice discrimination and voice recognition. One was impaired on
discrimination and borderline for recognition, with equivalent scores for face
and voice recognition, despite being unaware of voice processing problems.
CONCLUSIONS: Most subjects with developmental prosopagnosia are not impaired in
short-term voice familiarity, providing evidence that developmental
prosopagnosia is usually a modality-specific disorder of face recognition.
However, there may be heterogeneity, with a minority having additional voice
processing deficits. Objective tests of voice recognition should be integrated
into the diagnostic evaluation of this disorder to distinguish it from a
multi-modal person recognition syndrome.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.cortex.2015.07.030
PMCID: PMC4575891
PMID: 26321070 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1796436 | 1. Tidsskr Nor Laegeforen. 1991 Nov 30;111(29):3505-6.
[Prosopagnosia. A rare disorder of visual perception].
[Article in Norwegian]
Wolland AM(1), Hagelsteen JH.
Author information:
(1)Haukåsen barnenevrologiske poliklinikk, Oslo.
Prosopagnosia is a rare neurological sign, characterized by disturbance of
recognition of faces. It is important to remember that prosopagnosia can appear
as a result of a brain injury, and as such may be a major disability to the
patient. We report a case of a nine year old boy with prosopagnosia due to brain
injury at the age of 18 months. The main injury was localized to the boy's left
hemisphere, but his right hemisphere was probably also affected. Most post
mortem examinations of patients suffering from prosopagnosia show bilateral or
right-sided parietal, temporal and occipetal pathological changes.
PMID: 1796436 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28539812 | 1. Eye Brain. 2016 Sep 26;8:165-175. doi: 10.2147/EB.S92838. eCollection 2016.
Prosopagnosia: current perspectives.
Corrow SL(1)(2), Dalrymple KA(3), Barton JJ(1)(2).
Author information:
(1)Human Vision and Eye Movement Laboratory, Neurology Division, Department of
Medicine.
(2)Department of Ophthalmology and Visual Science, University of British
Columbia, Vancouver, Canada.
(3)Institute of Child Development, University of Minnesota, Minneapolis, MN,
USA.
Prosopagnosia is a selective visual agnosia characterized by the inability to
recognize the identity of faces. There are both acquired forms secondary to
brain damage and developmental forms without obvious structural lesions. In this
review, we first discuss the diagnosis of acquired and developmental
prosopagnosia, and the challenges present in the latter case. Second, we discuss
the evidence regarding the selectivity of the prosopagnosic defect, particularly
in relation to the recognition of other objects, written words (another visual
object category requiring high expertise), and voices. Third, we summarize
recent findings about the structural and functional basis of prosopagnosia from
studies using magnetic resonance imaging, functional magnetic resonance imaging,
and event-related potentials. Finally, we discuss recent attempts at
rehabilitation of face recognition in prosopagnosia.
DOI: 10.2147/EB.S92838
PMCID: PMC5398751
PMID: 28539812
Conflict of interest statement: Disclosure This work was supported by CIHR
operating grant (MOP-102567) to JB. JB was supported by a Canada Research Chair
and the Marianne Koerner Chair in Brain Diseases. SC was supported by National
Eye Institute of the National Institutes of Health under award number F32
EY023479-02 and Loan Repayment Program. The authors report no other conflicts of
interest in this work. |
http://www.ncbi.nlm.nih.gov/pubmed/15098192 | 1. Rev Neurol. 2004 Apr 1-15;38(7):682-6.
[Prosopagnosia: is it a single or a multiple entity?].
[Article in Spanish]
García García R(1), Cacho Gutiérrez LJ.
Author information:
(1)Departamento de Psicología Básica, Facultad de Psicologia, Universidad de
Salamanca. Salamanca, España. rigar@usal.es
INTRODUCTION: The prosopagnosia has generally been defined as an incapacity to
recognize familiar faces, or faces previously known, due to certain lesions to
certain areas of the cerebral cortex. Yet it seems that there is no universal
consensus neither on its definition nor in relation to the specific lesions that
might cause it. There seems to be no consensus either around the criteria that
might enable us to identify different types of prosopagnosia.
OBJECTIVE: We make an attempt to revise the definition of prosopagnosia and to
see if it is appropriate to consider it as a single entity or, on the contrary,
we are able to differentiate specific types of prosopagnosia according to its
origin, brain lesion associated with it or the patients characteristics. On the
other hand, we questioned ourselves whether different exams usually utilized for
the identification of prosopagnosia in fact measure the same concept.
CONCLUSIONS: We propose that we could distinguish different types of
prosopagnosia with different clinical characteristics. Then we went on to
differentiate between developed prosopagnosias and acquired prosopagnosias by
bilateral brain lesion as opposed with those associated with a fundamentally
aperceptive deficit, as opposed to those linked with a fundamentally associative
deficit. Lastly, we propose that different types of exams of recognition and
identification can measure distinct aspects linked to prosopagnosia.
PMID: 15098192 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17402670 | 1. Perception. 2007;36(2):299-301. doi: 10.1068/p5716.
Prosopagnosia in biographies and autobiographies.
Grüter T(1), Grüter M.
Author information:
(1)Department of Psychological Basic Research, Faculty of Psychology, University
of Vienna, Vienna, Austria. thomas.grueter@univie.ac.at
Prosopagnosia is a selective impairment of the visual learning and recognition
of faces. The congenital type, which is not accompanied by detectable brain
damage or malformation, was recently found to be far more common than previously
known. Therefore, one should expect that at least a few biographies or
autobiographies would reveal a prosopagnosia. In this paper we present an
autobiography and a biography describing five cases of congenital prosopagnosia.
These biographic descriptions of prosopagnosia add further evidence to the
assumption that the congenital type of prosopagnosia is not a rare condition,
and not as socially crippling as one might expect.
DOI: 10.1068/p5716
PMID: 17402670 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17981784 | 1. Front Biosci. 2008 Jan 1;13:3150-8. doi: 10.2741/2916.
Congenital prosopagnosia--a common hereditary cognitive dysfunction in humans.
Kennerknecht I(1), Pluempe N, Welling B.
Author information:
(1)Institut fuer Humangenetik, Westfaelische Wilhelms Universitaet, Muenster,
Germany. kennerk@uni-muenster.de
The apparent selectivity of agnosia for faces is termed prosopagnosia or face
blindness. This cognitive dysfunction can be seen after traumatic
events--involving at least the right occipital temporal region--or very
frequently congenital in the absence of any detectable lesions. The familiarity
of congenital prosopagnosia was studied in two independently ascertained
collections of subjects with prosopagnosia. One was an unselected group of
pupils and students who underwent a questionnaire based screening. The others
were self reported subjects after having heard for the first time about the
phenomenon of prosopagnosia from mass media citing our studies and/or from our
homepage (www.prosopagnosia.de). Those who agreed with consecutive studies of
their family members had mostly one or more prosopagnosic first degree
relatives. The segregation patterns derived from 39 families are compatible with
autosomal dominant inheritance. Hence, mutation(s) in one gene are sufficient
for manifestation of the phenotype. Still fitting the concept of autosomal
dominant inheritance, we have evidence for a slightly reduced penetrance (4
normal transmitters from distinct families) and one or two de novo mutations.
DOI: 10.2741/2916
PMID: 17981784 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20182942 | 1. J Clin Exp Neuropsychol. 2010 Aug;32(7):763-6. doi: 10.1080/13803390903512686.
Epub 2010 Feb 24.
Not all patients labeled as "prosopagnosia" have a real prosopagnosia.
Gainotti G(1).
Author information:
(1)Center for Neuropsychological Research, Department of Neurosciences,
Policlinico Gemelli, Catholic University of Rome, Rome, Italy. gainotti@
rm.unicatt.it
Since face recognition is the most powerful source of information for
identifying familiar people, patients showing a multimodal defect in people
recognition have been sometimes considered as affected by
"prosopagnosia"-namely, by a form of visual agnosia, specifically affecting face
recognition. In this note we report two anatomoclinical observations and a
neuroanatomical study in which an inappropriate use of the term "prosopagnosia"
was made, because the person recognition defect was not confined to the visual
(face) modality, but also concerned voice and/or name of the target person. The
dangers of this inappropriate use of the term prosopagnosia are briefly
discussed.
DOI: 10.1080/13803390903512686
PMID: 20182942 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17186317 | 1. J Hum Genet. 2007;52(3):230-236. doi: 10.1007/s10038-006-0101-6. Epub 2006 Dec
22.
Hereditary prosopagnosia (HPA): the first report outside the Caucasian
population.
Kennerknecht I(1), Plümpe N(2), Edwards S(3), Raman R(4).
Author information:
(1)Institut für Humangenetik, Westfälische Wilhelms Universität, Münster,
Germany. kennerk@uni-muenster.de.
(2)Institut für Humangenetik, Westfälische Wilhelms Universität, Münster,
Germany.
(3)Department of Psychology, Zululand University, P. Bag X1001, KwaDlangezwa,
3886, South Africa.
(4)Department of Zoology and Molecular and Human Genetics, Banaras Hindu
University, Varanasi, 221005, India.
Prosopagnosia (PA) or face blindness is characterized by a deficiency in
identifying familiar faces. Almost all reports are single cases or collections
of unrelated patients who acquired prosopagnosia after brain injuries, strokes
or atrophy of at least the right occipito-temporal cortex. Until 2001, the
inborn form - in the absence of any brain lesions - was described in fewer than
20 probands exclusively of Caucasian origin. We recently found that in the
German Caucasian population, congenital prosopagnosia has a very high prevalence
of at least 2.5% and that it is genetically determined. It is best described by
autosomal-dominant inheritance in the more than 50 families investigated. We
therefore introduced the term non-syndromic hereditary PA for the congenital
form of a monosymptomatic or isolated PA. This surprisingly high frequency in
the Caucasian population prompted us to extend our search to other ethnic
groups. We performed a questionnaire-based screening among 198 native Indian
students at Banaras Hindu University in Varanasi. In a then selected subset, we
found after further detailed diagnostic interviews one Bengali female student
with visual agnosia for face recognition only. Several other members of her
large family reported the same impairment of face recognition. The segregation
pattern of PA in this family is also compatible with autosomal-dominant
inheritance.
DOI: 10.1007/s10038-006-0101-6
PMID: 17186317 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2697897 | 1. Recenti Prog Med. 1989 Dec;80(12):633-7.
[Agnosia].
[Article in Italian]
De Renzi E.
The term agnosia defines an impairment of stimulus recognition, limited to one
modality and not explainable in terms of sensory deficits or general mental
deterioration. Visual object agnosia refers to the inability to recognize
objects and prosopagnosia to the failure to recognize faces that are well
familiar to the patient, when stimuli are visually perceived. Both deficits may
appear in an apperceptive form, where it is the internal and external structure
of the stimulus to be unrecognized and an associative form where the patient
achieves a good percept, but cannot assign it a meaning. Apperceptive forms are
preferentially associated with bilateral occipital damage, object associative
agnosia with left occipital damage and associative prosopagnosia with right
occipital damage.
PMID: 2697897 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33184411 | 1. Sci Rep. 2020 Nov 12;10(1):19757. doi: 10.1038/s41598-020-76819-3.
Normal recognition of famous voices in developmental prosopagnosia.
Tsantani M(1), Cook R(2).
Author information:
(1)Department of Psychological Sciences, Birkbeck, University of London, Malet
Street, London, WC1E 7HX, UK.
(2)Department of Psychological Sciences, Birkbeck, University of London, Malet
Street, London, WC1E 7HX, UK. richard.cook@bbk.ac.uk.
Developmental prosopagnosia (DP) is a condition characterised by lifelong face
recognition difficulties. Recent neuroimaging findings suggest that DP may be
associated with aberrant structure and function in multimodal regions of cortex
implicated in the processing of both facial and vocal identity. These findings
suggest that both facial and vocal recognition may be impaired in DP. To test
this possibility, we compared the performance of 22 DPs and a group of typical
controls, on closely matched tasks that assessed famous face and famous voice
recognition ability. As expected, the DPs showed severe impairment on the face
recognition task, relative to typical controls. In contrast, however, the DPs
and controls identified a similar number of voices. Despite evidence of
interactions between facial and vocal processing, these findings suggest some
degree of dissociation between the two processing pathways, whereby one can be
impaired while the other develops typically. A possible explanation for this
dissociation in DP could be that the deficit originates in the early perceptual
encoding of face structure, rather than at later, post-perceptual stages of face
identity processing, which may be more likely to involve interactions with other
modalities.
DOI: 10.1038/s41598-020-76819-3
PMCID: PMC7661722
PMID: 33184411 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/2684250 | 1. No To Shinkei. 1989 Jul;41(7):703-10.
[Non-verbal facial and topographic visual object agnosia--a problem of
familiarity in prosopagnosia and topographic disorientation].
[Article in Japanese]
Takahashi N(1), Kawamura M, Hirayama K, Tagawa K.
Author information:
(1)Department of Neurology, School of Medicine, Chiba University, Japan.
In recent years, prosopagnosia is defined as the "loss of ability to recognize
the well-acquainted persons like the family members by their physiognomy." There
are many reports based on this definition. However, from the viewpoint of
symptomatology, there are many problems not entirely solved yet. And the
mechanism of its manifestation is not clearly explained. Topographic
disorientation, which often accompanies prosopagnosia, is studied even less.
From the results of the postmortem examination in the literature, bilateral
occipito-temporal lesions have been known to cause prosopagnosia. However, the
recent radiographical examination by the computed tomography revealed that the
prosopagnosia is also caused by the right occipito-temporal lesions only. We
experienced a case with prosopagnosia and topographic disorientation which were
considered to be caused by infarction in the territory of the right posterior
cerebral artery. Detailed symptomatological, morphological and functional
examinations were carried out by means of various psychological testing, X-ray
computed tomography (CT), magnetic resonance imaging (MRI) and positron emission
tomography (PET). The patient was a 70-year-old right-handed man who suffered
from sudden visual loss on both eyes, and was admitted to our hospital after
four weeks. On examination, a decrease of visual acuity and right homonymous
hemianopsia were recognized. When visual acuity was recovered, he was unable to
recognize the faces of his relatives and friends, with whom he has been well
acquainted for many years. He also found his own house, the buildings and
streets around it as entirely unfamiliar. Seven months after the onset of the
disease, examination showed he had definite prosopagnosia and topographic
disorientation.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 2684250 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16767465 | 1. Psychol Res. 2007 Sep;71(5):583-90. doi: 10.1007/s00426-006-0068-0. Epub 2006
Jun 10.
Gaze behaviour in hereditary prosopagnosia.
Schwarzer G(1), Huber S, Grüter M, Grüter T, Gross C, Hipfel M, Kennerknecht I.
Author information:
(1)University of Giessen, Otto-Behaghel-Strasse 10F, 35394 Giessen, Germany.
gudrun.schwarzer@psychol.uni-giessen.de
Prosopagnosia is the inability to recognize someone by the face alone in the
absence of sensory or intellectual impairment. In contrast to the acquired form
of prosopagnosia we studied the congenital form. Since we could recently show
that this form is inherited as a simple monogenic trait we called it hereditary
form. To determine whether not only face recognition and neuronal processing but
also the perceptual acquisition of facial information is specific to
prosopagnosia, we studied the gaze behaviour of four hereditary prosopagnosics
in comparison to matched control subjects. This rarely studied form of
prosopagnosia ensures that deficits are limited to face recognition. Whereas the
control participants focused their gaze on the central facial features, the
hereditary prosopagnosics showed a significantly different gaze behaviour. They
had a more dispersed gaze and also fixated external facial features. Thus, the
face recognition impairment of the hereditary prosopagnosics is reflected in
their gaze behaviour.
DOI: 10.1007/s00426-006-0068-0
PMID: 16767465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33817891 | 1. J Genet Couns. 2021 Aug;30(4):924-937. doi: 10.1002/jgc4.1418. Epub 2021 Apr
4.
Benefits and limitations of telegenetics: A literature review.
Gorrie A(1), Gold J(2), Cameron C(1), Krause M(1)(3), Kincaid H(1).
Author information:
(1)Department of General Genetics, Monash Medical Centre, Melbourne, Victoria,
Australia.
(2)Independent Consultant, Melbourne, Victoria, Australia.
(3)Department of Medicine, Dentistry and Health Sciences, University of
Melbourne, Melbourne, Victoria, Australia.
Telegenetics involves the use of technology (generally video conferencing) to
remotely provide genetic services. A telegenetics platform is critical for those
with limitations or vulnerabilities compromising their ability to attend clinic
in-person, including individuals in rural areas. As the demand for remote
genetics services increases, and amidst the COVID-19 pandemic with social
distancing practices in place, we conducted a literature review to examine the
benefits and limitations of telegenetics and explore the views of patients and
health professionals utilizing telegenetics. Searches of the PubMed database
identified 21 relevant primary studies for inclusion. The majority of studies
found acceptability of telegenetics to be high among patients and health
professionals and that telegenetics provided access to genetics services for
underserved communities. The main benefits cited include cost-effectiveness and
reduction in travel time for genetics services providing outreach clinics and
patients who would otherwise travel long distances to access genetics. Patients
appreciated the convenience of telegenetics including the reduced wait times,
although a minority of patients reported their psychosocial needs were not
adequately met. Eight studies compared outcomes between telegenetics and
in-person services; findings suggested when comparing telegenetics patients to
their in-person counterparts, telegenetics patients had a similar level of
knowledge and understanding of genetics and similar psychological outcomes. Some
studies reported challenges related to establishing rapport and reading and
responding to verbal cues via telegenetics, while technical issues were not
generally found to be a major limitation. Some service adaptations, for example,
counseling strategies, may be required to successfully deliver telegenetics.
Further research may be necessary to gather and examine data on how telegenetics
outcomes compare to that of in-person genetic counseling and adapt services
accordingly.
© 2021 National Society of Genetic Counselors.
DOI: 10.1002/jgc4.1418
PMID: 33817891 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35576529 | 1. Blood. 2022 Nov 10;140(19):2053-2062. doi: 10.1182/blood.2022015403.
A phase 1 dose escalation study of the pyruvate kinase activator mitapivat
(AG-348) in sickle cell disease.
Xu JZ(1), Conrey A(1), Frey I(1), Gwaabe E(1), Menapace LA(1), Tumburu L(1),
Lundt M(1), Lequang T(1), Li Q(2), Glass K(2), Dunkelberger EB(2), Iyer V(3),
Mangus H(3), Kung C(3), Dang L(3), Kosinski PA(3), Hawkins P(3), Jeffries N(4),
Eaton WA(2), Lay Thein S(1).
Author information:
(1)Sickle Cell Branch, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, MD.
(2)Laboratory of Chemical Physics, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health, Bethesda, MD.
(3)Agios Pharmaceuticals, Inc., Cambridge, MA.
(4)Office of Biostatistics Research, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, MD.
Comment in
Blood. 2022 Nov 10;140(19):2005-2006. doi: 10.1182/blood.2022016930.
Polymerization of deoxygenated hemoglobin S underlies the pathophysiology of
sickle cell disease (SCD). In activating red blood cell pyruvate kinase and
glycolysis, mitapivat (AG-348) increases adenosine triphosphate (ATP) levels and
decreases the 2,3-diphosphoglycerate (2,3-DPG) concentration, an upstream
precursor in glycolysis. Both changes have therapeutic potential for patients
with SCD. Here, we evaluated the safety and tolerability of multiple ascending
doses of mitapivat in adults with SCD with no recent blood transfusions or
changes in hydroxyurea or l-glutamine therapy. Seventeen subjects were enrolled;
1 subject was withdrawn shortly after starting the study. Sixteen subjects
completed 3 ascending dose levels of mitapivat (5, 20, and 50 mg, twice daily
[BID]) for 2 weeks each; following a protocol amendment, the dose was escalated
to 100 mg BID in 9 subjects. Mitapivat was well tolerated at all dose levels,
with the most common treatment-emergent adverse events (AEs) being insomnia,
headache, and hypertension. Six serious AEs (SAEs) included 4 vaso-occlusive
crises (VOCs), non-VOC-related shoulder pain, and a preexisting pulmonary
embolism. Two VOCs occurred during drug taper and were possibly drug related; no
other SAEs were drug related. Mean hemoglobin increase at the 50 mg BID dose
level was 1.2 g/dL, with 9 of 16 (56.3%) patients achieving a hemoglobin
response of a ≥1 g/dL increase compared with baseline. Mean reductions in
hemolytic markers and dose-dependent decreases in 2,3-DPG and increases in ATP
were also observed. This study provides proof of concept that mitapivat has
disease-modifying potential in patients with SCD. This trial was registered at
www.clinicaltrials.gov as #NCT04000165.
DOI: 10.1182/blood.2022015403
PMCID: PMC9837441
PMID: 35576529 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest disclosure: V.I., H.M.,
C.K., L.D., P.A.K., and P.H. are employed by and are stockholders in Agios. H.M.
and P.H. are stockholders in Bristol-Myers Squibb. V.I. is a stockholder in
Novartis. The remaining authors declare no competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35988546 | 1. Lancet Haematol. 2022 Oct;9(10):e724-e732. doi: 10.1016/S2352-3026(22)00214-9.
Epub 2022 Aug 18.
Mitapivat in adult patients with pyruvate kinase deficiency receiving regular
transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial.
Glenthøj A(1), van Beers EJ(2), Al-Samkari H(3), Viprakasit V(4), Kuo KHM(5),
Galactéros F(6), Chonat S(7), Porter J(8), Zagadailov E(9), Xu R(9), Oluyadi
A(9), Hawkins P(9), Gheuens S(9), Beynon V(9), Barcellini W(10); ACTIVATE-T
investigators.
Author information:
(1)Department of Haematology, Copenhagen University Hospital - Rigshospitalet,
Copenhagen, Denmark. Electronic address: andreas.glenthoej@regionh.dk.
(2)Benign Hematology Center, Van Creveldkliniek, University Medical Center
Utrecht, University Utrecht, Utrecht, the Netherlands.
(3)Division of Hematology, Massachusetts General Hospital, Harvard Medical
School, Boston, MA, USA.
(4)Siriraj Hospital, Mahidol University, Bangkok, Thailand.
(5)Division of Hematology, University of Toronto, Toronto, ON, Canada.
(6)Unité des Maladies Génétiques du Globule Rouge, CHU Henri Mondor, Créteil,
France.
(7)Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and
Department of Pediatrics, Emory University, Atlanta, GA, USA.
(8)Department of Haematology, University College London Cancer Institute,
London, UK.
(9)Agios Pharmaceuticals, Cambridge, MA, USA.
(10)Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Comment in
Lancet Haematol. 2022 Oct;9(10):e708-e709. doi:
10.1016/S2352-3026(22)00249-6.
BACKGROUND: Mitapivat, an oral activator of pyruvate kinase (PK) in red blood
cells (RBCs), has shown significant improvements in haemoglobin and haemolysis
among patients with pyruvate kinase deficiency who were not receiving regular
transfusions. We aimed to evaluate the efficacy and safety of mitapivat in
adults with pyruvate kinase deficiency receiving regular transfusions.
METHODS: ACTIVATE-T was an open-label, single-arm, phase 3 trial conducted in 20
centres across Europe, North America, and Asia. Eligible participants were
adults (aged ≥18 years) with a clinical laboratory confirmation of pyruvate
kinase deficiency receiving regular transfusions (at least six episodes in the
previous year). Participants received oral mitapivat during a 16-week
dose-optimisation period (5 mg, 20 mg, 50 mg twice daily) and 24-week fixed-dose
period. The primary endpoint was a reduction in transfusion burden (≥33%
reduction in number of RBC units transfused during the fixed-dose period,
compared with the participant's individual historical transfusion burden,
standardised to 24 weeks). Efficacy and safety were assessed in all participants
who received at least one dose of mitapivat. This trial is registered with
ClinicalTrials.gov, NCT03559699, and is complete.
FINDINGS: Between June 26, 2018, and Feb 4, 2020, 27 participants (20 [74%]
female and seven [26%] male; 20 [74%] White, three [11%] Asian, and four [15%]
not reported) were enrolled and received at least one dose of mitapivat. Median
duration of exposure to mitapivat was 40·3 weeks (IQR 40·0-41·3). A reduction in
transfusion burden by at least 33% was found in ten (37%) participants (95% CI
19-58; p=0·0002). The most common treatment-emergent adverse events were
increase in alanine aminotransferase (ten [37%] participants), headache (ten
[37%]), increase in aspartate aminotransferase (five [19%]), fatigue (five
[19%]), and nausea (five [19%]). Two grade 3 treatment-emergent adverse events
were related to study treatment: joint swelling (one participant [4%]) and an
increase in aspartate aminotransferase (one participant [4%]). Three
participants had serious treatment-emergent adverse events, none related to the
study treatment: increased blood triglycerides, ovarian cyst, and renal colic
(each in one participant [4%]). No treatment-related deaths were observed.
INTERPRETATION: Mitapivat represents a novel therapy that can reduce transfusion
burden in some adults with pyruvate kinase deficiency receiving regular
transfusions, and is the first disease-modifying agent approved in this disease.
FUNDING: Agios Pharmaceuticals.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S2352-3026(22)00214-9
PMID: 35988546 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests EZ, RX, AO, PH, SG, and
VB are employees and shareholders of Agios Pharmaceuticals. AG has received fees
for consultancy work and as a member of advisory boards from Agios
Pharmaceuticals, bluebird bio, Celgene, Novartis, and Novo Nordisk; and research
grants from Alexion, Saniona, and Sanofi. EJvB has received fees as a member of
advisory board from Agios Pharmaceuticals; and research funding from Agios
Pharmaceuticals, Novartis, Pfizer, and RR Mechatronics. HA-S has received fees
for consultancy work from Agios Pharmaceuticals, argenx, Dova–Sobi, Novartis,
Rigel, Forma Therapeutics, and Moderna; and research funding from Agios
Pharmaceuticals, Dova, and Amgen. VV has received fees for consultancy work,
honoraria, research funding, and speakers bureau from Bristol-Myers Squibb; and
fees for consultancy work and research funding from Agios Pharmaceuticals,
Ionis, La Jolla Pharmaceuticals, Protagonist Therapeutics, and Vifor Pharma.
KHMK has received fees for consultancy work from Agios Pharmaceuticals, Alexion,
Apellis, bluebird bio, Celgene, Pfizer, and Novartis; honoraria from Alexion and
Novartis; research funding from Pfizer; and membership on an entity's Board of
Directors or advisory committees from Bioverativ. FG has been on board
membership or advisory committee for Addmedica. SC has received fees for
consultancy work from Agios Pharmaceuticals, Alexion, Daiichi Sankyo, Novartis,
and Takeda; and research funding from Agios Pharmaceuticals, Alexion, Apellis,
Global Blood Therapeutics, Novartis, and Takeda. WB has received honoraria from
Agios Pharmaceuticals, Alexion, and Novartis; and been on board membership or
advisory committee for Bioverativ and Incyte. JP declares no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/35964609 | 1. Lancet. 2022 Aug 13;400(10351):493-501. doi: 10.1016/S0140-6736(22)01337-X.
Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults
with non-transfusion dependent α-thalassaemia or β-thalassaemia: an open-label,
multicentre, phase 2 study.
Kuo KHM(1), Layton DM(2), Lal A(3), Al-Samkari H(4), Bhatia J(5), Kosinski
PA(5), Tong B(5), Lynch M(5), Uhlig K(5), Vichinsky EP(3).
Author information:
(1)Division of Haematology, University of Toronto, Toronto, ON, Canada.
Electronic address: kevin.kuo@uhn.ca.
(2)Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
(3)Division of Hematology, University of California San Francisco Benioff
Children's Hospital, Oakland, CA, USA.
(4)Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
(5)Agios Pharmaceuticals, Cambridge, MA, USA.
Comment in
Lancet. 2022 Aug 13;400(10351):470-471. doi: 10.1016/S0140-6736(22)01431-3.
Cell Rep Med. 2022 Oct 18;3(10):100790. doi: 10.1016/j.xcrm.2022.100790.
BACKGROUND: Patients with non-transfusion-dependent thalassaemia (NTDT),
although they do not require regular blood transfusions for survival, can still
accrue a heavy burden of comorbidities. No approved disease-modifying therapies
exist for these patients. We aimed to investigate the safety and efficacy of
mitapivat (Agios Pharmaceuticals, Cambridge, MA, USA), a pyruvate kinase
activator, in adults with non-transfusion-dependent (NTD) α-thalassaemia or NTD
β-thalassaemia.
METHODS: In this open-label, multicentre, phase 2 study, patients were recruited
from four academic clinical study sites in Oakland, CA, and Boston, MA, USA;
Toronto, ON, Canada; and London, UK. Patients were eligible if they were aged 18
years or older, with NTDT (including β-thalassaemia with or without α-globin
gene mutations, haemoglobin E β-thalassaemia, or α-thalassaemia), and a baseline
haemoglobin concentration of 10·0 g/dL or lower. During a 24-week core period,
mitapivat was administered orally at 50 mg twice daily for the first 6 weeks
followed by an escalation to 100 mg twice daily for 18 weeks thereafter. The
primary endpoint was haemoglobin response (a ≥1·0 g/dL increase in haemoglobin
concentration from baseline at one or more assessments between weeks 4 and 12).
Efficacy and safety were assessed in the full analysis set (ie, all patients who
received at least one dose of study drug). This study is registered with
ClinicalTrials.gov, NCT03692052, and is closed to accrual.
FINDINGS: Between Dec 28, 2018, and Feb 6, 2020, 27 patients were screened, of
whom 20 were enrolled (15 [75%] with β-thalassaemia and five [25%] with
α-thalassaemia) and received mitapivat. The median age of patients was 44 years
(IQR 35-56), 15 (75%) of 20 patients were female, five (25%) were male, and ten
(50%) identified as Asian. 16 (80% [90% CI 60-93]) of 20 patients had a
haemoglobin response (p<0·0001), five (100%) of five with α-thalassaemia and 11
(73%) of 15 with β-thalassaemia. 17 (85%) patients had a treatment-emergent
adverse event, and 13 had a treatment-emergent event that was considered to be
treatment related. One serious treatment-emergent adverse event occurred (grade
3 renal impairment), which was considered unrelated to study drug, resulting in
discontinuation of treatment. The most commonly reported treatment-emergent
adverse events were initial insomnia (ten [50%] patients), dizziness (six
[30%]), and headache (five [25%]). No patients died during the 24-week core
period.
INTERPRETATION: These efficacy and safety results support the continued
investigation of mitapivat for the treatment of both α-thalassaemia and
β-thalassaemia.
FUNDING: Agios Pharmaceuticals.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(22)01337-X
PMID: 35964609 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests KHMK reports
consultancy fees from Agios Pharmaceuticals, Alexion, Apellis, bluebird bio,
Celgene, Forma, Pfizer, and Novartis; honoraria from Alexion and Novartis;
membership on an advisory committee for Agios Pharmaceuticals and
Bioverativ/Sanofi/Sangamo; and research funding from Pfizer. DML reports
consultancy fees from Agios Pharmaceuticals and membership on the Board of
Directors or advisory committee for Agios Pharmaceuticals and Cerus. AL reports
research funding from bluebird bio, Celgene, Insight Magnetics, La Jolla
Pharmaceutical Company, Novartis, Protagonist Therapeutics, Terumo Corporations,
and Forma; consultancy fees from Agios Pharmaceuticals and Chiesi USA; and
membership on the Board of Directors or advisory committee for Celgene and
Protagonist Therapeutics. HA-S reports consultancy fees from Agios
Pharmaceuticals, argenx, Dova/Sobi, Moderna, Novartis, Rigel, and Forma and
research funding from Agios Pharmaceuticals, Amgen, and Dova. JB, PAK, BT, ML,
and KU are employees and shareholders of Agios Pharmaceuticals. EPV reports
consultancy fees and research funding from Agios Pharmaceuticals, bluebird bio,
Global Blood Therapeutics, Novartis, and Pfizer. |
http://www.ncbi.nlm.nih.gov/pubmed/28388403 | 1. Cell. 2017 Apr 6;169(2):186-187. doi: 10.1016/j.cell.2017.03.030.
ESCRTing Necroptosis.
Guo H(1), Kaiser WJ(2).
Author information:
(1)Department of Microbiology, Immunology, and Molecular Genetics, University of
Texas Heath San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
(2)Department of Microbiology, Immunology, and Molecular Genetics, University of
Texas Heath San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Electronic address: kaiserw@uthscsa.edu.
Comment on
Cell. 2017 Apr 6;169(2):286-300.e16. doi: 10.1016/j.cell.2017.03.020.
Necroptosis is a highly inflammatory form of programmed cell death that results
from MLKL-mediated disruption of the cell membrane. In this issue of Cell, Gong
et al. challenge the notion that MLKL activation is a point of no return by
identifying mechanisms to counterbalance necroptosis, sustain plasma membrane
integrity, and prolong cell viability.
Copyright © 2017 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2017.03.030
PMID: 28388403 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28388412 | 1. Cell. 2017 Apr 6;169(2):286-300.e16. doi: 10.1016/j.cell.2017.03.020.
ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its
Consequences.
Gong YN(1), Guy C(1), Olauson H(2), Becker JU(3), Yang M(1), Fitzgerald P(1),
Linkermann A(4), Green DR(5).
Author information:
(1)Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
38105, USA.
(2)Division of Renal Medicine, Clinical Sciences, Intervention and Technology,
Karolinska Institutet, 171 76 Stockholm, Sweden.
(3)Institute of Pathology, University Hospital of Cologne, 50674 Cologne,
Germany.
(4)Division of Nephrology, Department of Internal Medicine III, University
Hospital Carl Gustav Carus at the Technische Universität Dresden, 01307 Dresden,
Germany. Electronic address: andreas.linkermann@ukdd.de.
(5)Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
38105, USA. Electronic address: douglas.green@stjude.org.
Comment in
Cell. 2017 Apr 6;169(2):186-187. doi: 10.1016/j.cell.2017.03.030.
Nat Rev Mol Cell Biol. 2017 Jun;18(6):342-343. doi: 10.1038/nrm.2017.46.
Immunity. 2017 Jul 18;47(1):1-3. doi: 10.1016/j.immuni.2017.07.002.
The activation of mixed lineage kinase-like (MLKL) by receptor-interacting
protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form
of regulated necrosis, called necroptosis. Here, we show that, during
necroptosis, MLKL-dependent calcium (Ca2+) influx and phosphatidylserine (PS)
exposure on the outer leaflet of the plasma membrane preceded loss of PM
integrity. Activation of MLKL results in the generation of broken, PM "bubbles"
with exposed PS that are released from the surface of the otherwise intact cell.
The ESCRT-III machinery is required for formation of these bubbles and acts to
sustain survival of the cell when MLKL activation is limited or reversed. Under
conditions of necroptotic cell death, ESCRT-III controls the duration of plasma
membrane integrity. As a consequence of the action of ESCRT-III, cells
undergoing necroptosis can express chemokines and other regulatory molecules and
promote antigenic cross-priming of CD8+ T cells.
Copyright © 2017 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2017.03.020
PMCID: PMC5443414
PMID: 28388412 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31138766 | 1. Sci Signal. 2019 May 28;12(583):eaaw3423. doi: 10.1126/scisignal.aaw3423.
Flotillin-mediated endocytosis and ALIX-syntenin-1-mediated exocytosis protect
the cell membrane from damage caused by necroptosis.
Fan W(1)(2), Guo J(1)(2), Gao B(1)(2), Zhang W(1)(2), Ling L(1)(2), Xu T(1)(2),
Pan C(1)(2), Li L(1)(2), Chen S(1)(2), Wang H(3)(4), Zhang J(3)(5), Wang
X(6)(2).
Author information:
(1)National Institute of Biological Sciences, Beijing, No. 7 Science Park Road,
Zhongguancun Life Science Park, Beijing 102206, China.
(2)Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua
University, Beijing 102206, China.
(3)Department of Pathology, School of Basic Medical Sciences, Peking University
Health Science Center, Beijing 100191, China.
(4)Department of Pathology, Peking University Third Hospital, Beijing 100191,
China.
(5)Department of Pathology, University of Washington School of Medicine,
Seattle, WA, USA.
(6)National Institute of Biological Sciences, Beijing, No. 7 Science Park Road,
Zhongguancun Life Science Park, Beijing 102206, China. wangxiaodong@nibs.ac.cn.
Necroptosis is a form of regulated necrosis that is implicated in various human
diseases including Alzheimer's disease. Necroptosis requires the translocation
of the pseudokinase MLKL from the cytosol to the plasma membrane after its
phosphorylation by the kinase RIPK3. Using protein cross-linking followed by
affinity purification, we detected the lipid raft-associated proteins
flotillin-1 and flotillin-2 and the ESCRT-associated proteins ALIX and
syntenin-1 in membrane-localized MLKL immunoprecipitates. Phosphorylated MLKL
was removed from membranes through either flotillin-mediated endocytosis
followed by lysosomal degradation or ALIX-syntenin-1-mediated exocytosis. Thus,
cells undergoing necroptosis need to overcome these independent suppressive
mechanisms before plasma membrane disruption can occur.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American
Association for the Advancement of Science. No claim to original U.S. Government
Works.
DOI: 10.1126/scisignal.aaw3423
PMID: 31138766 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31490656 | 1. ACS Chem Biol. 2019 Oct 18;14(10):2286-2294. doi: 10.1021/acschembio.9b00616.
Epub 2019 Sep 20.
Membrane Disruption by Very Long Chain Fatty Acids during Necroptosis.
Parisi LR(1), Sowlati-Hashjin S(2)(3), Berhane IA(1), Galster SL(1), Carter
KA(4), Lovell JF(4), Chemler SR(1), Karttunen M(2)(5)(3), Atilla-Gokcumen GE(1).
Author information:
(1)Department of Chemistry , University at Buffalo, The State University of New
York , Buffalo , New York 14260 , United States.
(2)Department of Chemistry , The University of Western Ontario , 1151 Richmond
Street , London , Ontario N6A 5B7 , Canada.
(3)The Centre of Advanced Materials and Biomaterials Research , The University
of Western Ontario , 1151 Richmond Street , London , Ontario N6A 5B7 , Canada.
(4)Department of Biomedical Engineering , University at Buffalo, The State
University of New York , Buffalo , New York 14260 , United States.
(5)Department of Applied Mathematics , The University of Western Ontario , 1151
Richmond Street , London , Ontario N6A 5B7 , Canada.
Necroptosis is a form of regulated cell death which results in loss of plasma
membrane integrity, release of intracellular contents, and an associated
inflammatory response. We previously found that saturated very long chain fatty
acids (VLCFAs), which contain ≥20 carbons, accumulate during necroptosis. Here,
we show that genetic knockdown of Fatty Acid (FA) Elongase 7 (ELOVL7) reduces
accumulation of specific very long chain FAs during necroptosis, resulting in
reduced necroptotic cell death and membrane permeabilization. Conversely,
increasing the expression of ELOVL7 increases very long chain fatty acids and
membrane permeabilization. In vitro, introduction of the VLCFA C24 FA disrupts
bilayer integrity in liposomes to a greater extent than a conventional C16 FA.
To investigate the microscopic origin of these observations, atomistic Molecular
Dynamics (MD) simulations were performed. MD simulations suggest that fatty
acids cause clear differences in bilayers based on length and that it is the
interdigitation of C24 FA between the individual leaflets that results in
disorder in the region and, consequently, membrane disruption. We synthesized
clickable VLCFA analogs and observed that many proteins were acylated by VLCFAs
during necroptosis. Taken together, these results confirm the active role of
VLCFAs during necroptosis and point to multiple potential mechanisms of membrane
disruption including direct permeabilization via bilayer disruption and
permeabilization by targeting of proteins to cellular membranes by fatty
acylation.
DOI: 10.1021/acschembio.9b00616
PMCID: PMC6800604
PMID: 31490656 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing financial
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35365636 | 1. Cell Death Dis. 2022 Apr 1;13(4):291. doi: 10.1038/s41419-022-04740-w.
The Lck inhibitor, AMG-47a, blocks necroptosis and implicates RIPK1 in
signalling downstream of MLKL.
Jacobsen AV(1)(2), Pierotti CL(1)(2), Lowes KN(1)(2), Au AE(1)(2), Zhang
Y(1)(2), Etemadi N(1), Fitzgibbon C(1)(2), Kersten WJA(1), Samson AL(1)(2), van
Delft MF(1)(2), Huang DCS(1)(2), Sabroux HJ(1)(2), Lessene G(1)(2)(3), Silke
J(4)(5), Murphy JM(6)(7).
Author information:
(1)The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC,
Australia.
(2)Department of Medical Biology, The University of Melbourne, Parkville, VIC,
Australia.
(3)Department of Pharmacology and Therapeutics, The University of Melbourne,
Parkville, VIC, Australia.
(4)The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC,
Australia. silke@wehi.edu.au.
(5)Department of Medical Biology, The University of Melbourne, Parkville, VIC,
Australia. silke@wehi.edu.au.
(6)The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC,
Australia. jamesm@wehi.edu.au.
(7)Department of Medical Biology, The University of Melbourne, Parkville, VIC,
Australia. jamesm@wehi.edu.au.
Necroptosis is a form of caspase-independent programmed cell death that arises
from disruption of cell membranes by the mixed lineage kinase domain-like (MLKL)
pseudokinase after its activation by the upstream kinases, receptor interacting
protein kinase (RIPK)-1 and RIPK3, within a complex known as the necrosome.
Dysregulated necroptosis has been implicated in numerous inflammatory
pathologies. As such, new small molecule necroptosis inhibitors are of great
interest, particularly ones that operate downstream of MLKL activation, where
the pathway is less well defined. To better understand the mechanisms involved
in necroptosis downstream of MLKL activation, and potentially uncover new
targets for inhibition, we screened known kinase inhibitors against an activated
mouse MLKL mutant, leading us to identify the lymphocyte-specific protein
tyrosine kinase (Lck) inhibitor AMG-47a as an inhibitor of necroptosis. We show
that AMG-47a interacts with both RIPK1 and RIPK3, that its ability to protect
from cell death is dependent on the strength of the necroptotic stimulus, and
that it blocks necroptosis most effectively in human cells. Moreover, in human
cell lines, we demonstrate that AMG-47a can protect against cell death caused by
forced dimerisation of MLKL truncation mutants in the absence of any upstream
signalling, validating that it targets a process downstream of MLKL activation.
Surprisingly, however, we also found that the cell death driven by activated
MLKL in this model was completely dependent on the presence of RIPK1, and to a
lesser extent RIPK3, although it was not affected by known inhibitors of these
kinases. Together, these results suggest an additional role for RIPK1, or the
necrosome, in mediating human necroptosis after MLKL is phosphorylated by RIPK3
and provide further insight into reported differences in the progression of
necroptosis between mouse and human cells.
© 2022. The Author(s).
DOI: 10.1038/s41419-022-04740-w
PMCID: PMC8976052
PMID: 35365636 [Indexed for MEDLINE]
Conflict of interest statement: CLP, KNL, AEA, YZ, NE, CF, WJAK, ALS, HJS, GL,
JS and JMM contribute, or have contributed, to a project developing necroptosis
inhibitors in collaboration with Anaxis Pty Ltd. AVJ, MFvD, and DCSH declare no
conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/27158445 | 1. F1000Res. 2015 Nov 19;4:F1000 Faculty Rev-1297. doi:
10.12688/f1000research.7046.1. eCollection 2015.
Post-translational control of RIPK3 and MLKL mediated necroptotic cell death.
Murphy JM(#)(1)(2), Vince JE(#)(1)(2).
Author information:
(1)The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria,
Australia.
(2)Department of Medical Biology, University of Melbourne, Parkville, Victoria,
Australia.
(#)Contributed equally
Several programmed lytic and necrotic-like cell death mechanisms have now been
uncovered, including the recently described receptor interacting protein
kinase-3 (RIPK3)-mixed lineage kinase domain-like (MLKL)-dependent necroptosis
pathway. Genetic experiments have shown that programmed necrosis, including
necroptosis, can play a pivotal role in regulating host-resistance against
microbial infections. Alternatively, excess or unwarranted necroptosis may be
pathological in autoimmune and autoinflammatory diseases. This review highlights
the recent advances in our understanding of the post-translational control of
RIPK3-MLKL necroptotic signaling. We discuss the critical function of
phosphorylation in the execution of necroptosis, and highlight the emerging
regulatory roles for several ubiquitin ligases and deubiquitinating enzymes.
Finally, based on current evidence, we discuss the potential mechanisms by which
the essential, and possibly terminal, necroptotic effector, MLKL, triggers the
disruption of cellular membranes to cause cell lysis.
DOI: 10.12688/f1000research.7046.1
PMCID: PMC4851234
PMID: 27158445
Conflict of interest statement: Competing interests: James M. Murphy co-leads a
program funded by Catalyst Therapeutics Pty Ltd and the Walter and Eliza Hall
Institute to develop necroptosis inhibitors. James E. Vince declares that he has
no competing interests. No competing interests were disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/31766571 | 1. Cells. 2019 Nov 21;8(12):1486. doi: 10.3390/cells8121486.
Molecular Insights into the Mechanism of Necroptosis: The Necrosome As a
Potential Therapeutic Target.
Chen J(1), Kos R(1), Garssen J(1)(2), Redegeld F(1).
Author information:
(1)Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences,
Faculty of Science, Utrecht University, 3508 TB Utrecht, The Netherlands.
(2)Danone Nutricia Research, Uppsalaan 12, 3584 CT, Utrecht, The Netherlands.
Necroptosis, or regulated necrosis, is an important type of programmed cell
death in addition to apoptosis. Necroptosis induction leads to cell membrane
disruption, inflammation and vascularization. It plays important roles in
various pathological processes, including neurodegeneration, inflammatory
diseases, multiple cancers, and kidney injury. The molecular regulation of
necroptotic pathway has been intensively studied in recent years. Necroptosis
can be triggered by multiple stimuli and this pathway is regulated through
activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and
pseudokinase mixed lineage kinase domain-like (MLKL). A better understanding of
the mechanism of regulation of necroptosis will further aid to the development
of novel drugs for necroptosis-associated human diseases. In this review, we
focus on new insights in the regulatory machinery of necroptosis. We further
discuss the role of necroptosis in different pathologies, its potential as a
therapeutic target and the current status of clinical development of drugs
interfering in the necroptotic pathway.
DOI: 10.3390/cells8121486
PMCID: PMC6952807
PMID: 31766571 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that no conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/29076500 | 1. Cell Res. 2018 Jan;28(1):9-21. doi: 10.1038/cr.2017.133. Epub 2017 Oct 27.
Plasma membrane changes during programmed cell deaths.
Zhang Y(1), Chen X(1), Gueydan C(2), Han J(1).
Author information:
(1)State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell
Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian
361005, China.
(2)Laboratoire de Biologie Moléculaire du Gène, Faculté des Sciences, Université
Libre de Bruxelles, 1050 Brussels, Belgium.
Ruptured and intact plasma membranes are classically considered as hallmarks of
necrotic and apoptotic cell death, respectively. As such, apoptosis is usually
considered a non-inflammatory process while necrosis triggers inflammation.
Recent studies on necroptosis and pyroptosis, two types of programmed necrosis,
revealed that plasma membrane rupture is mediated by MLKL channels during
necroptosis but depends on non-selective gasdermin D (GSDMD) pores during
pyroptosis. Importantly, the morphology of dying cells executed by MLKL channels
can be distinguished from that executed by GSDMD pores. Interestingly, it was
found recently that secondary necrosis of apoptotic cells, a previously believed
non-regulated form of cell lysis that occurs after apoptosis, can be programmed
and executed by plasma membrane pore formation like that of pyroptosis. In
addition, pyroptosis is associated with pyroptotic bodies, which have some
similarities to apoptotic bodies. Therefore, different cell death programs
induce distinctive reshuffling processes of the plasma membrane. Given the fact
that the nature of released intracellular contents plays a crucial role in
dying/dead cell-induced immunogenicity, not only membrane rupture or integrity
but also the nature of plasma membrane breakdown would determine the fate of a
cell as well as its ability to elicit an immune response. In this review, we
will discuss recent advances in the field of apoptosis, necroptosis and
pyroptosis, with an emphasis on the mechanisms underlying plasma membrane
changes observed on dying cells and their implication in cell death-elicited
immunogenicity.
DOI: 10.1038/cr.2017.133
PMCID: PMC5752838
PMID: 29076500 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33848465 | 1. Cell Chem Biol. 2021 Sep 16;28(9):1298-1309.e7. doi:
10.1016/j.chembiol.2021.03.012. Epub 2021 Apr 12.
Protein acylation by saturated very long chain fatty acids and endocytosis are
involved in necroptosis.
Pradhan AJ(1), Lu D(1), Parisi LR(1), Shen S(2), Berhane IA(1), Galster SL(1),
Bynum K(3), Monje-Galvan V(4), Gokcumen O(5), Chemler SR(1), Qu J(2), Kay JG(3),
Atilla-Gokcumen GE(6).
Author information:
(1)Department of Chemistry, University at Buffalo, The State University of New
York, Buffalo, NY 14260, USA.
(2)Department of Pharmaceutical Sciences, University at Buffalo, The State
University of New York, Buffalo, NY 14214, USA.
(3)Department of Oral Biology, University at Buffalo, The State University of
New York, Buffalo, NY 14214, USA.
(4)Department of Chemical and Biological Engineering, University at Buffalo, The
State University of New York, Buffalo, NY 14260, USA.
(5)Department of Biological Sciences, University at Buffalo, The State
University of New York, Buffalo, NY 14260, USA.
(6)Department of Chemistry, University at Buffalo, The State University of New
York, Buffalo, NY 14260, USA. Electronic address: ekinatil@buffalo.edu.
Necroptosis is a form of cell death characterized by receptor-interacting
protein kinase activity and plasma membrane permeabilization via mixed-lineage
kinase-like protein (MLKL). This permeabilization is responsible for the
inflammatory properties of necroptosis. We previously showed that very long
chain fatty acids (VLCFAs) are functionally involved in necroptosis, potentially
through protein fatty acylation. Here, we define the scope of protein acylation
by saturated VLCFAs during necroptosis. We show that MLKL and phosphoMLKL, key
for membrane permeabilization, are exclusively acylated during necroptosis.
Reducing the levels of VLCFAs decreases their membrane recruitment, suggesting
that acylation by VLCFAs contributes to their membrane localization. Acylation
of phosphoMLKL occurs downstream of phosphorylation and oligomerization and
appears to be, in part, mediated by ZDHHC5 (a palmitoyl transferase). We also
show that disruption of endosomal trafficking increases cell viability during
necroptosis, possibly by preventing recruitment, or removal, of phosphoMLKL from
the plasma membrane.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.chembiol.2021.03.012
PMCID: PMC8529612
PMID: 33848465 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors declare no
competing interest. |
http://www.ncbi.nlm.nih.gov/pubmed/30709919 | 1. J Cell Sci. 2019 Feb 28;132(5):jcs220996. doi: 10.1242/jcs.220996.
Activated MLKL attenuates autophagy following its translocation to intracellular
membranes.
Frank D(1)(2), Vaux DL(1)(2), Murphy JM(1)(2), Vince JE(3)(4), Lindqvist
LM(5)(2).
Author information:
(1)Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute
of Medical Research, 1G Royal Parade, Melbourne, Victoria 3052, Australia.
(2)Department of Medical Biology, The University of Melbourne, Parkville,
Victoria 3050, Australia.
(3)Department of Medical Biology, The University of Melbourne, Parkville,
Victoria 3050, Australia Lisa.Lindqvist@csl.com.au vince@wehi.edu.au.
(4)Inflammation Division, The Walter and Eliza Hall Institute of Medical
Research, 1G Royal Parade, Melbourne, Victoria 3052, Australia.
(5)Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute
of Medical Research, 1G Royal Parade, Melbourne, Victoria 3052, Australia
Lisa.Lindqvist@csl.com.au vince@wehi.edu.au.
Necroptosis is an inflammatory form of programmed cell death mediated by the
pseudokinase mixed-lineage kinase domain-like protein (MLKL). Upon
phosphorylation by receptor-interacting protein kinase-3 (RIPK3), MLKL
oligomerizes, and translocates to and disrupts the plasma membrane, thereby
causing necroptotic cell lysis. Herein, we show that activation of necroptosis
in mouse dermal fibroblasts (MDFs) and HT-29 human colorectal cancer cells
results in accumulation of the autophagic marker, lipidated LC3B (also known as
MAP1LC3B), in an MLKL-dependent manner. Unexpectedly, the necroptosis-induced
increase in lipidated LC3B was due to inhibition of autophagic flux, not the
activation of autophagy. Inhibition of autophagy by MLKL correlated with a
decrease in autophagosome and/or autolysosome function, and required the
association of activated MLKL with intracellular membranes. Collectively, our
findings uncover an additional role for the MLKL pseudokinase, namely to inhibit
autophagy during necroptosis.
© 2019. Published by The Company of Biologists Ltd.
DOI: 10.1242/jcs.220996
PMID: 30709919 [Indexed for MEDLINE]
Conflict of interest statement: Competing interestsD.L.V. used to be on the
scientific advisory board for TetraLogic Pharmaceuticals. J.M.M. is a scientific
advisory board member of Anaxis Pharma. |
http://www.ncbi.nlm.nih.gov/pubmed/30344099 | 1. Mol Cell. 2018 Nov 1;72(3):457-468.e5. doi: 10.1016/j.molcel.2018.09.011. Epub
2018 Oct 18.
Mixed Lineage Kinase Domain-like Protein MLKL Breaks Down Myelin following Nerve
Injury.
Ying Z(1), Pan C(2), Shao T(1), Liu L(1), Li L(1), Guo D(1), Zhang S(1), Yuan
T(1), Cao R(1), Jiang Z(1), Chen S(1), Wang F(1), Wang X(3).
Author information:
(1)National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun
Life Science Park, Beijing 102206, China; Tsinghua Institute of
Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
(2)School of Life Sciences, Tsinghua University, Beijing 100084, China.
(3)National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun
Life Science Park, Beijing 102206, China; Tsinghua Institute of
Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
Electronic address: wangxiaodong@nibs.ac.cn.
Comment in
Mol Cell. 2018 Nov 1;72(3):397-399. doi: 10.1016/j.molcel.2018.10.025.
Successful regeneration of severed peripheral nerves requires the breakdown and
subsequent clearance of myelin, tightly packed membrane sheaths of Schwann cells
that protect nerve fibers and harbor nerve growth-inhibitory proteins. How
Schwann cells initiate myelin breakdown in response to injury is still largely
unknown. Here we report that, following sciatic nerve injury, MLKL, a
pseudokinase known to rupture cell membranes during necroptotic cell death, is
induced and targets the myelin sheath membrane of Schwann cells to promote
myelin breakdown. The function of MLKL in disrupting myelin sheaths requires
injury-induced phosphorylation of serine 441, an activation signal distinct from
the necroptosis-inducing phosphorylation by RIP3 kinase. Mice with Mlkl
specifically knocked out in Schwann cells showed delayed myelin sheath
breakdown. Lack of MLKL reduced nerve regeneration following injury, whereas
overexpression of MLKL accelerated myelin breakdown and promoted the
regeneration of axons.
Copyright © 2018 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2018.09.011
PMID: 30344099 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30148498 | 1. J Vis Exp. 2018 Aug 7;(138):58088. doi: 10.3791/58088.
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis.
McNamara DE(1), Quarato G(2), Guy CS(2), Green DR(2), Moldoveanu T(3).
Author information:
(1)Department of Structural Biology, St. Jude Children's Research Hospital;
Department of Chemical Biology and Therapeutics, St. Jude Children's Research
Hospital.
(2)Department of Immunology, St. Jude Children's Research Hospital.
(3)Department of Structural Biology, St. Jude Children's Research Hospital;
Department of Chemical Biology and Therapeutics, St. Jude Children's Research
Hospital; Tudor.Moldoveanu@stjude.org.
Necroptosis is a programmed cell death pathway triggered by activation of
receptor interacting protein kinase 3 (RIPK3), which phosphorylates and
activates the mixed lineage kinase-like domain pseudokinase, MLKL, to rupture or
permeabilize the plasma membrane. Necroptosis is an inflammatory pathway
associated with multiple pathologies including autoimmunity, infectious and
cardiovascular diseases, stroke, neurodegeneration, and cancer. Here, we
describe protocols that can be used to characterize MLKL as the executioner of
plasma membrane rupture in necroptosis. We visualize the process of necroptosis
in cells using live-cell imaging with conventional and confocal
fluorescence microscopy, and in fixed cells using electron microscopy, which
together revealed the redistribution of MLKL from the cytosol to the plasma
membrane prior to induction of large holes in the plasma membrane. We present in
vitro nuclear magnetic resonance (NMR) analysis using lipids to identify
putative modulators of MLKL-mediated necroptosis. Based on this method, we
identified quantitative lipid-binding preferences and phosphatidyl-inositol
phosphates (PIPs) as critical binders of MLKL that are required for plasma
membrane targeting and permeabilization in necroptosis.
DOI: 10.3791/58088
PMCID: PMC6126679
PMID: 30148498 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33654612 | 1. Cureus. 2021 Jan 27;13(1):e12932. doi: 10.7759/cureus.12932.
Dermatillomania: A Case Report and Literature Review.
Malayala SV(1), Rehman H(2), Vasireddy D(3).
Author information:
(1)Internal Medicine, Temple University Hospital, Philadelphia, USA.
(2)Internal Medicine, Physicians for American Healthcare Access, Philadelphia,
USA.
(3)Pediatrics, Pediatric Group of Acadiana, Lafayette, USA.
Skin picking disorder, also termed dermatillomania is a condition that leads to
repetitive picking of their skin ending up in skin and soft tissue damage. It is
classified in Diagnostic and Statistical Manual of Mental Disorder Fifth edition
under the "obsessive compulsive and related disorders" section. Often associated
with other psychiatric conditions like autism, alcohol abuse, obsessive
compulsive, body dysmorphic, mood, anxiety and borderline personality disorders,
it is a disorder that is quite often underreported. The patient in this case
report is a 58-year-old male with a diagnosis of obsessive compulsive disorder
(OCD) who reported severe anxiety and skin picking episodes over several years.
He presented to the emergency room with an extensive wound on distal left foot
with exposure of the underlying muscle tissue, that resulted from the excessive
picking of skin from the left foot. This compulsive behavior started off with
picking the skin around his nail beds and slowly got worse. The skin picking
would get worse whenever he gets nervous or anxious. The wound was treated with
topical wound care and antibiotics. At the time of discharge, he was prescribed
oral antibiotics to complete his course of treatment and was referred to the
hospital's cognitive behavioral therapy (CBT) program that specializes in
treatment of OCD and anxiety disorders. Treatment of dermatillomania is a
multipronged approach and should include treatment of the underlying psychiatric
illness, the treatment for pruritus and topical treatment of the
lesions. Selective serotonin reuptake inhibitors (SSRIs) have proved to be the
most effective in treating the psychiatric component of dermatillomania.
Non-pharmacological treatments such as behavioral therapy, habit reversal
exercises and support groups have also proved to be helpful and are well
tolerated amongst patients suffering from dermatillomania.
Copyright © 2021, Malayala et al.
DOI: 10.7759/cureus.12932
PMCID: PMC7910222
PMID: 33654612
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21323095 | 1. Cutis. 2011 Jan;87(1):14-8.
Pathologic grooming behavior: facial dermatillomania.
Harris SS(1), Kushon D, Benedetto E.
Author information:
(1)Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Scott.Harris@hotmail.com
Dermatillomania is a pathologic grooming disorder characterized by repetitive,
ritualistic, impulsive skin picking without an underlying dermatologic
condition. It can lead to skin damage and distress and can affect patient
function. This disorder has not received much attention in the literature, with
few studies reporting treatment efficacy. Patients with dermatillomania
typically present to primary care physicians and frequently are referred to
dermatologists; only rarely do patients receive additional psychiatric
consultation that may improve treatment efficacy and decrease morbidity. We
provide a case report of long-standing facial dermatillomania and our multimodal
treatment approach.
PMID: 21323095 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32839552 | 1. Cell Res. 2020 Dec;30(12):1063-1077. doi: 10.1038/s41422-020-00393-6. Epub
2020 Aug 24.
Myofiber necroptosis promotes muscle stem cell proliferation via releasing
Tenascin-C during regeneration.
Zhou S(1)(2), Zhang W(1)(2), Cai G(3), Ding Y(4)(5), Wei C(1), Li S(1), Yang
Y(1)(2), Qin J(1), Liu D(1), Zhang H(6), Shao X(7), Wang J(7), Wang H(1), Yang
W(1), Wang H(4)(8), Chen S(3)(9), Hu P(10)(11)(12)(13)(14)(15), Sun
L(16)(17)(18).
Author information:
(1)State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular
Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese
Academy of Sciences, University of Chinese Academy of Sciences, Shanghai,
200031, China.
(2)University of Chinese Academy of Sciences, Beijing, 100049, China.
(3)National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun
Life Science Park, Beijing, 102206, China.
(4)Li Ka Shing Institute of Health Sciences, The Chinese University of Hong
Kong, Prince of Wales Hospital, New Territories, 999077, Hong Kong SAR, China.
(5)Department of Chemical Pathology, The Chinese University of Hong Kong, Prince
of Wales Hospital, New Territories, 999077, Hong Kong SAR, China.
(6)Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese
Medicine, Shanghai, 201203, China.
(7)Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai
Jiao Tong University School of Medicine, Shanghai, 200092, China.
(8)Department of Orthopaedics and Traumatology, The Chinese University of Hong
Kong, Prince of Wales Hospital, New Territories, 999077, Hong Kong SAR, China.
(9)Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua
University, Beijing 102206, China.
(10)State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular
Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese
Academy of Sciences, University of Chinese Academy of Sciences, Shanghai,
200031, China. hup@sibcb.ac.cn.
(11)University of Chinese Academy of Sciences, Beijing, 100049, China.
hup@sibcb.ac.cn.
(12)Institute for Stem Cell and Regeneration, Chinese Academy of Sciences,
Beijing, 100101, China. hup@sibcb.ac.cn.
(13)Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong
Laboratory), Guangzhou, Guangdong, 510005, China. hup@sibcb.ac.cn.
(14)Bio-Research Innovation Center, Shanghai Institute of Biochemistry and Cell
Biology, Suzhou, Jiangsu, 215121, China. hup@sibcb.ac.cn.
(15)Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai,
200120, China. hup@sibcb.ac.cn.
(16)State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular
Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese
Academy of Sciences, University of Chinese Academy of Sciences, Shanghai,
200031, China. liming.sun@sibcb.ac.cn.
(17)University of Chinese Academy of Sciences, Beijing, 100049, China.
liming.sun@sibcb.ac.cn.
(18)Institute for Stem Cell and Regeneration, Chinese Academy of Sciences,
Beijing, 100101, China. liming.sun@sibcb.ac.cn.
Necroptosis, a form of programmed cell death, is characterized by the loss of
membrane integrity and release of intracellular contents, the execution of which
depends on the membrane-disrupting activity of the Mixed Lineage Kinase
Domain-Like protein (MLKL) upon its phosphorylation. Here we found myofibers
committed MLKL-dependent necroptosis after muscle injury. Either pharmacological
inhibition of the necroptosis upstream kinase Receptor Interacting Protein
Kinases 1 (RIPK1) or genetic ablation of MLKL expression in myofibers led to
significant muscle regeneration defects. By releasing factors into the muscle
stem cell (MuSC) microenvironment, necroptotic myofibers facilitated muscle
regeneration. Tenascin-C (TNC), released by necroptotic myofibers, was found to
be critical for MuSC proliferation. The temporary expression of TNC in myofibers
is tightly controlled by necroptosis; the extracellular release of TNC depends
on necroptotic membrane rupture. TNC directly activated EGF receptor (EGFR)
signaling pathway in MuSCs through its N-terminus assembly domain together with
the EGF-like domain. These findings indicate that necroptosis plays a key role
in promoting MuSC proliferation to facilitate muscle regeneration.
DOI: 10.1038/s41422-020-00393-6
PMCID: PMC7784988
PMID: 32839552 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/36198538 | 1. Rinsho Ketsueki. 2022;63(9):1126-1134. doi: 10.11406/rinketsu.63.1126.
[Current status and future prospects of diffuse large B-cell lymphoma
treatment].
[Article in Japanese]
Yamaguchi M(1).
Author information:
(1)Department of Hematological Malignancies, Mie University Graduate School of
Medicine.
R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and
prednisone) has been used as the standard treatment regimen for patients with
newly diagnosed diffuse large B-cell lymphoma (DLBCL), since the introduction of
rituximab in the early 2000s. Recently, polatuzumab vedotin and anti-CD19
chimeric antigen receptor T-cell (CAR-T) therapy have been introduced as
potential treatment options for relapsed or refractory DLBCL. The effectiveness
of polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone
for newly diagnosed CD20-positive DLBCL, except for the low-risk group of the
international prognostic index, was reported in 2022. Bispecific antibodies such
as epcoritamab, mosunetuzumab, and glofitamab, anti-CD19 antibody drug
tafasitamab combined with lenalidomide, CD19 antibody drug conjugate
loncastuximab tesirine, oral selective inhibitor of nuclear export selinexor,
and several new agents have been investigated for DLBCL. For non-germinal center
B-cell type DLBCL, R-CHOP combined with acalabrutinib is being evaluated. This
review summarizes the current standard of care for DLBCL and outlines the
recently introduced therapeutic agents or those that are under development in
Japan.
DOI: 10.11406/rinketsu.63.1126
PMID: 36198538 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35626120 | 1. Cancers (Basel). 2022 May 20;14(10):2516. doi: 10.3390/cancers14102516.
Glofitamab Treatment in Relapsed or Refractory DLBCL after CAR T-Cell Therapy.
Rentsch V(1), Seipel K(2), Banz Y(3), Wiedemann G(4), Porret N(4), Bacher U(5),
Pabst T(1).
Author information:
(1)Department of Medical Oncology, Inselspital, Bern University Hospital, 3010
Bern, Switzerland.
(2)Department of Biomedical Research, University of Bern, 3008 Bern,
Switzerland.
(3)Institute of Pathology, Inselspital, University of Bern, 3008 Bern,
Switzerland.
(4)Center of Laboratory Medicine (ZLM), Inselspital, Bern University Hospital,
3010 Bern, Switzerland.
(5)Department of Hematology, Inselspital, Bern University Hospital, 3010 Bern,
Switzerland.
Chimeric antigen receptor T-cells (CAR T) treatment has become a standard option
for patients with diffuse large B-cell lymphomas (DLBCL), which are refractory
or relapse after two prior lines of therapy. However, little evidence exists for
treatment recommendations in patients who relapse after CAR T-cell treatment and
the outcome for such patients is poor. In this study, we evaluated the safety
and efficacy of a monotherapy with the bispecific CD20xCD3 antibody glofitamab
in patients who progressed after CAR T treatment. We report nine consecutive
patients with progressive DLBCL after preceding CAR T-cell therapy. The patients
received a maximum of 12 cycles of glofitamab after a single obinutuzumab
pre-treatment at an academic institution. CRS was observed in two patients
(grade 2 in both patients). We observed an overall response rate of 67%, with
four patients achieving a complete response and a partial remission in two
patients. Interestingly, we identified increased persistence of circulating CAR
T-cells in peripheral blood in three of the five patients with measurable CAR
T-cells. Our data suggest that glofitamab treatment is well tolerated and
effective in patients with DLBCL relapsing after CAR T-cell therapy and can
enhance residual CAR T-cell activity.
DOI: 10.3390/cancers14102516
PMCID: PMC9139991
PMID: 35626120
Conflict of interest statement: The authors declare no conflict of interest. No
financial support was received from Roche Pharma; data were analyzed and the
manuscript was written completely independently from the company. |
http://www.ncbi.nlm.nih.gov/pubmed/34941996 | 1. Blood Adv. 2022 Feb 8;6(3):1025-1037. doi: 10.1182/bloodadvances.2021005954.
Pharmacodynamics and molecular correlates of response to glofitamab in
relapsed/refractory non-Hodgkin lymphoma.
Bröske AE(1), Korfi K(2), Belousov A(3), Wilson S(3), Ooi CH(3), Bolen CR(4),
Canamero M(1), Alcaide EG(3), James I(5), Piccione EC(4), Carlile DJ(6), Dimier
N(6), Umaña P(2), Bacac M(2), Weisser M(1), Dickinson M(7).
Author information:
(1)Roche Innovation Center Munich, Roche Pharma Research and Early Development,
Penzberg, Germany.
(2)Roche Innovation Center Zürich, Roche Pharma Research and Early Development,
Zürich, Switzerland.
(3)Roche Innovation Center Basel, Roche Pharma Research and Early Development,
Basel, Switzerland.
(4)Genentech, Inc., South San Francisco, CA.
(5)A4P Consulting Ltd., Sandwich, United Kingdom.
(6)Roche Innovation Center Welwyn, Roche Pharma Research and Early Development,
Welwyn Garden City, United Kingdom; and.
(7)Peter MacCallum Cancer Centre, Royal Melbourne Hospital and The University of
Melbourne, Melbourne, VIC, Australia.
Glofitamab, a novel CD20xCD3, T-cell-engaging bispecific antibody, exhibited
single-agent activity in Study NP30179, a first-in-human, phase 1 trial in
relapsed/refractory B-cell non-Hodgkin lymphoma. Preclinical studies showed that
glofitamab leads to T-cell activation, proliferation, and tumor cell killing
upon binding to CD20 on malignant cells. Here, we provide evidence of
glofitamab's clinical activity, including pharmacodynamic profile, mode of
action, and factors associated with clinical response, by evaluating biomarkers
in patient samples from the dose-escalation part of this trial. Patients
enrolled in Study NP30179 received single-dose obinutuzumab pretreatment (1000
mg) 7 days before IV glofitamab (5 µg-25 mg). Glofitamab treatment lasted ≤12
cycles once every 2 or 3 weeks. Blood samples were collected at predefined time
points per the clinical protocol; T-cell populations were evaluated centrally by
flow cytometry, and cytokine profiles were analyzed. Immunohistochemical and
genomic biomarker analyses were performed on tumor biopsy samples.
Pharmacodynamic modulation was observed with glofitamab treatment, including
dose-dependent induction of cytokines, and T-cell margination, proliferation,
and activation in peripheral blood. Gene expression analysis of pretreatment
tumor biopsy samples indicated that tumor cell intrinsic factors such as TP53
signaling are associated with resistance to glofitamab, but they may also be
interlinked with a diminished effector T-cell profile in resistant tumors and
thus represent a poor prognostic factor per se. This integrative biomarker data
analysis provides clinical evidence regarding glofitamab's mode of action,
supports optimal biological dose selection, and will further guide clinical
development. This trial was registered at www.clinicaltrials.gov as
#NCT03075696.
© 2022 by The American Society of Hematology. Licensed under Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0),
permitting only noncommercial, nonderivative use with attribution. All other
rights reserved.
DOI: 10.1182/bloodadvances.2021005954
PMCID: PMC8945294
PMID: 34941996 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35665782 | 1. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022
Jun 5.
Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.
Modi S(1), Jacot W(1), Yamashita T(1), Sohn J(1), Vidal M(1), Tokunaga E(1),
Tsurutani J(1), Ueno NT(1), Prat A(1), Chae YS(1), Lee KS(1), Niikura N(1), Park
YH(1), Xu B(1), Wang X(1), Gil-Gil M(1), Li W(1), Pierga JY(1), Im SA(1), Moore
HCF(1), Rugo HS(1), Yerushalmi R(1), Zagouri F(1), Gombos A(1), Kim SB(1), Liu
Q(1), Luo T(1), Saura C(1), Schmid P(1), Sun T(1), Gambhire D(1), Yung L(1),
Wang Y(1), Singh J(1), Vitazka P(1), Meinhardt G(1), Harbeck N(1), Cameron
DA(1); DESTINY-Breast04 Trial Investigators.
Collaborators: Kühr T, Schmitt C, Greil R, Egle D, Wildiers H, Gombos A, Canon
JL, Duhoux F, Henning JW, Asselah J, Xu B, Hu X, Zhang Q, Sun T, Liu Q, Li W,
Wang X, Pan Y, Wang X, Wu X, Chen X, Luo T, Hu W, Wang J, Lin X, Jacot W,
Bourgeois H, Lefeuvre-Plesse C, Hardy Bessard AC, Frenel JS, Gligorov J, Pierga
JY, Levy C, Grenier J, Helissey-Danis C, André F, Augereau P, Sahir J, Viret F,
Simon H, Villanueva C, Tsiatas M, Papazisis K, Mavroudis D, Zagouri F,
Papandreou C, Boukovinas I, Baka S, Kotsakis A, Rubovszky G, Mezei K,
Sonnenblick A, Bernstein Molho R, Yerushalmi R, Perets R, Evron E, Uziely B,
Gianni L, Zamagni C, Tassone PF, Soto Parra H, Cazzaniga ME, Portarena I,
Colleoni M, Masci G, Tamburini E, De Laurentiis M, Pedersini R, Bria E, Gori S,
Naito Y, Yonemori K, Kobayashi T, Iwata H, Iwasa T, Sagara Y, Tanabe Y,
Yamashita T, Aogi K, Tokunaga E, Hayashi T, Tomioka N, Yasojima H, Inoue K,
Miyoshi Y, Ito M, Tsurutani J, Niikura N, Im SA, Park YH, Kim JH, Kim SB, Sohn
JH, Lee KS, Chae YS, Lee MH, Sousa AR, Salgado M, Faria AL, Moreira Pinto A,
Teira A, Rodrigues A, Portela C, Ganshina I, Stroyakovskiy D, Kislov N, Cortes
Castan J, Gil-Gil M, Vidal M, Antolin Novoa S, Fernandez Abad M, Garcia Saenz
JA, Saura Manich C, Servitja Tormo S, Nogales Fernandez E, Bermejo Perez MJ,
Cruz Jurado J, Ruiz Borrego M, Lindman H, Wennstig AK, Weibring K, Müller A,
Vetter M, Huober J, Dedes K, Zaman K, Schwitter M, Chung WP, Lu YS, Hou MF,
Schmid P, Wheatley D, Madhusudan S, Modi S, McAndrew N, Shtivelband M, Ueno N,
Mitri Z, Dyar S, Litvak A, Raymond J, McKnight J, Ahn E, Lynch C, Rugo H, Krop
I, Chan D, Moore H, Mahtani R, Niravath P, Bahadur S, Dakhil S, Milillo-Naraine
A, Riaz F, Schumaker D, Lammers P, Pluard T, Adams S, Han H, Kayali F, Hamilton
E.
Author information:
(1)From the Memorial Sloan Kettering Cancer Center, New York (S.M.); Institut du
Cancer de Montpellier, Université Montpellier, INSERM Unité 1194, Montpellier
(W.J.), and Institut Curie, Université Paris Cité, Paris (J.-Y.P.) - both in
France; Kanagawa Cancer Center, Yokohama (T.Y.), Kyushu Cancer Center, National
Hospital Organization, Fukuoka (E.T.), Showa University Hospital, Tokyo (J.T.),
and Tokai University School of Medicine, Isehara-shi (N.N.) - all in Japan;
Yonsei Cancer Center, Yonsei University Health System (J. Sohn), Samsung Medical
Center (Y.H.P.), Seoul National University Hospital, Cancer Research Institute,
Seoul National University College of Medicine, Seoul National University
(S.-A.I.), and Asan Medical Center, University of Ulsan College of Medicine
(S.-B.K.), Seoul, Kyungpook National University Chilgok Hospital, Daegu
(Y.S.C.), and the National Cancer Center, Goyang-si (K.S.L.) - all in South
Korea; the Department of Medical Oncology, Hospital Clínic de Barcelona (M.V.,
A.P.), Translational Genomics and Targeted Therapies in Solid Tumors, Institut
d'Investigacions Biomèdiques August Pi i Sunyer (A.P.), the Department of
Medicine, University of Barcelona (A.P.), the Breast Cancer Unit, Institute of
Oncology (IOB)-Quirón Salud (A.P.), Institut Catala d'Oncologia
l'Hospitalet-Hospital Duran i Reynals (M.G.-G.), and Vall d'Hebron University
Hospital, Vall d'Hebron Institute of Oncology (C.S.) - all in Barcelona; the
University of Texas M.D. Anderson Cancer Center, Houston (N.T.U.); Cancer
Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing (B.X.), Zhejiang Cancer Hospital, Hangzhou (X.W.), the First Hospital of
Jilin University, Changchun (W.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen
University, Guangzhou (Q.L.), West China Hospital, Sichuan University, Chengdu
(T.L.), and Liaoning Cancer Hospital and Institute, Shenyang (T.S.) - all in
China; the Cleveland Clinic Foundation, Cleveland (H.C.F.M.); the University of
California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San
Francisco (H.S.R.); Rabin Medical Center, Petah Tikva, Tel Aviv University, Tel
Aviv, Israel (R.Y.); Alexandra Regional General Hospital, Athens (F.Z.);
Institut Jules Bordet, Brussels (A.G.); Queen Mary University of London, London
(P.S.), and Edinburgh Cancer Centre, Institute of Genetics and Cancer,
University of Edinburgh, Edinburgh (D.A.C.) - both in the United Kingdom;
Daiichi Sankyo, Basking Ridge, NJ (D.G., L.Y., Y.W., J. Singh, P.V., G.M.); and
the Breast Center, Department of Obstetrics and Gynecology, and Comprehensive
Cancer Center Munich, Ludwig Maximilian University Hospital, Munich, Germany
(N.H.).
Comment in
Nat Rev Clin Oncol. 2022 Aug;19(8):493. doi: 10.1038/s41571-022-00663-9.
N Engl J Med. 2022 Jul 7;387(1):75-76. doi: 10.1056/NEJMe2206661.
N Engl J Med. 2022 Sep 22;387(12):1143-1144. doi: 10.1056/NEJMc2210368.
N Engl J Med. 2022 Sep 22;387(12):1144. doi: 10.1056/NEJMc2210368.
J Nucl Med. 2023 Jul;64(7):1164-1165. doi: 10.2967/jnumed.123.265434.
BACKGROUND: Among breast cancers without human epidermal growth factor receptor
2 (HER2) amplification, overexpression, or both, a large proportion express low
levels of HER2 that may be targetable. Currently available HER2-directed
therapies have been ineffective in patients with these "HER2-low" cancers.
METHODS: We conducted a phase 3 trial involving patients with HER2-low
metastatic breast cancer who had received one or two previous lines of
chemotherapy. (Low expression of HER2 was defined as a score of 1+ on
immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results
on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to
receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The
primary end point was progression-free survival in the hormone receptor-positive
cohort. The key secondary end points were progression-free survival among all
patients and overall survival in the hormone receptor-positive cohort and among
all patients.
RESULTS: Of 557 patients who underwent randomization, 494 (88.7%) had hormone
receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease.
In the hormone receptor-positive cohort, the median progression-free survival
was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the
physician's choice group (hazard ratio for disease progression or death, 0.51;
P<0.001), and overall survival was 23.9 months and 17.5 months, respectively
(hazard ratio for death, 0.64; P = 0.003). Among all patients, the median
progression-free survival was 9.9 months in the trastuzumab deruxtecan group and
5.1 months in the physician's choice group (hazard ratio for disease progression
or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months,
respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade
3 or higher occurred in 52.6% of the patients who received trastuzumab
deruxtecan and 67.4% of those who received the physician's choice of
chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis
occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had
grade 5 events.
CONCLUSIONS: In this trial involving patients with HER2-low metastatic breast
cancer, trastuzumab deruxtecan resulted in significantly longer progression-free
and overall survival than the physician's choice of chemotherapy. (Funded by
Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number,
NCT03734029.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2203690
PMCID: PMC10561652
PMID: 35665782 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36239213 | 1. Rapid Commun Mass Spectrom. 2023 Jan 15;37(1):e9414. doi: 10.1002/rcm.9414.
Analysis of N-nitrosodimethylamine in metformin hydrochloride products by
high-resolution accurate mass gas chromatography mass spectrometry.
Kee CL(1), Zeng Y(1), Ge X(1), Lim JQ(1), Teo Jessie HG(1), Low MY(1).
Author information:
(1)Health Sciences Authority, Pharmaceutical Laboratory, Applied Sciences Group,
Singapore.
RATIONALE: The high resolving power of the Orbitrap mass spectrometer in a
high-resolution accurate mass gas chromatography (HRAM-GC-MS) system provides
greater selectivity and sensitivity for the identification and quantification of
volatile analytes at low parts per billion (ppb) levels. Hence, it can be
applied for the analysis of pharmaceutical impurities like
N-nitrosodimethylamine (NDMA) in metformin hydrochloride products (METs).
METHODS: Different METs extracted by a dichloromethane/aqueous system were
analyzed by HRAM-GC-MS under softer electron ionization (EI) at 30 eV. The
accurate masses of NDMA and its internal standard NDMA-d6 were analyzed by full
scan and targeted selected ion monitoring modes under 60 000 and 30 000 full
width at half maximum at m/z 200, respectively. Data acquisition and processing
were managed by Xcalibur and Trace Finder software, respectively.
RESULTS: Limits of detection (LOD) and quantification (LOQ) at 10 and 20 ng/g
were achieved, which is below the allowed daily intake of 32 ng/g. The mass
errors measured from experimental data were within ±2 ppm of the theoretical
values over a period of a week. Sample analysis showed that 180 out of 212
samples (85%) were below LOD and 15 out of 212 samples (7 %) were within LOD and
LOQ. Only 17 samples (8%) were found to be above LOQ, comprising one active
pharmaceutical ingredient (API), five immediate-release METs and 11
extended-released METs. Amongst these, seven extended-release METs and one API
exceeded the daily allowed intake, 32 ng/g.
CONCLUSIONS: The validated method has been successfully applied for NDMA
analysis in various forms of METs. The method is rather straightforward without
an additional clean-up step. The scope can also be extended to other volatile
impurities in finished pharmaceutical products.
© 2022 John Wiley & Sons Ltd.
DOI: 10.1002/rcm.9414
PMID: 36239213 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35666611 | 1. Cancer Discov. 2022 Aug 5;12(8):1828. doi: 10.1158/2159-8290.CD-NB2022-0043.
T-DXd: New Standard for HER2-Low Breast Cancer.
[No authors listed]
Findings from the phase III DESTINY-Breast04 trial indicate that the
antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is effective for patients
with inoperable/metastatic HER2-low breast cancer. T-DXd should be considered a
new standard of care for these patients, who otherwise have limited options.
©2022 American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-NB2022-0043
PMID: 35666611 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36150260 | 1. Spectrochim Acta A Mol Biomol Spectrosc. 2023 Jan 15;285:121889. doi:
10.1016/j.saa.2022.121889. Epub 2022 Sep 16.
The spectroscopic and computational study of anthracene based chemosensor -
Ag(+) interactions.
Kumar A(1), Virender(2), Mohan B(3), Parikh J(4), Modi K(5).
Author information:
(1)Department of Chemistry, Kurukshetra University Kurukshetra, Kurukshetra
136119, India. Electronic address: akumarchem@kuk.ac.in.
(2)Department of Chemistry, Kurukshetra University Kurukshetra, Kurukshetra
136119, India.
(3)College of Ocean Food and Biological Engineering, Jimei University, 185
Yinjiang Road, Jimei District, Xiamen 361021, China.
(4)Faculty of Science, Department of Chemistry, Ganpat University, Gujarat,
India.
(5)Department of Humanity and Science, School of Engineering, Indrashil
University, Mehsana 382740, Gujarat, India. Electronic address:
kmodi5033@gmail.com.
Here in, we demonstrate a selective detection of Ag+ ion by the anthracene-based
schiff base sensor AMC. The recognition event among sensor AMC and Ag+ ion was
investigated by enhanced absorption band, red-shifted quenched emission spectra,
electrochemical studies and DFT computational studies. The presence of Ag+ ion
to solution of AMC quenched almost 50 % emission intensity of the ligand band.
Data from high-resolution electrospray ionization mass spectrometry (ESI-HRMS),
Ag+ titrations, and Job's plot studies all show that Ag+ binds to AMC in a 1:1
stoichiometric ratio.The quantitative parameters of sensor for silver ion are
determined as the limit of detection (LOD) 5.95 × 10-7 M, and limit of
quantitation (LOQ) 1.98 × 10-8 M in the linear range 3.48-20.31 × 10-6 M with
good association affinity of 5.030 × 103 M-1. LMCT phenomenon from insilico
studies, is in good agreement with the results obtained from other performed
spectroscopic techniques. In addition, this sensor AMC was also successfully
applied to real water samples for the identification and measurement of Ag+
ions.
Copyright © 2022. Published by Elsevier B.V.
DOI: 10.1016/j.saa.2022.121889
PMID: 36150260 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. |
http://www.ncbi.nlm.nih.gov/pubmed/21603916 | 1. Anal Bioanal Chem. 2011 Aug;401(2):717-26. doi: 10.1007/s00216-011-5089-x.
Epub 2011 May 21.
Determination of the LOQ in real-time PCR by receiver operating characteristic
curve analysis: application to qPCR assays for Fusarium verticillioides and F.
proliferatum.
Nutz S(1), Döll K, Karlovsky P.
Author information:
(1)Molecular Phytopathology and Mycotoxin Research, Georg August University
Göttingen, Göttingen, Germany.
Real-time PCR (qPCR) is the principal technique for the quantification of
pathogen biomass in host tissue, yet no generic methods exist for the
determination of the limit of quantification (LOQ) and the limit of detection
(LOD) in qPCR. We suggest using the Youden index in the context of the receiver
operating characteristic (ROC) curve analysis for this purpose. The LOQ was
defined as the amount of target DNA that maximizes the sum of sensitivity and
specificity. The LOD was defined as the lowest amount of target DNA that was
amplified with a false-negative rate below a given threshold. We applied this
concept to qPCR assays for Fusarium verticillioides and Fusarium proliferatum
DNA in maize kernels. Spiked matrix and field samples characterized by melting
curve analysis of PCR products were used as the source of true positives and
true negatives. On the basis of the analysis of sensitivity and specificity of
the assays, we estimated the LOQ values as 0.11 pg of DNA for spiked matrix and
0.62 pg of DNA for field samples for F. verticillioides. The LOQ values for F.
proliferatum were 0.03 pg for spiked matrix and 0.24 pg for field samples. The
mean LOQ values correspond to approximately eight genomes for F. verticillioides
and three genomes for F. proliferatum. We demonstrated that the ROC analysis
concept, developed for qualitative diagnostics, can be used for the
determination of performance parameters of quantitative PCR.
DOI: 10.1007/s00216-011-5089-x
PMCID: PMC3132422
PMID: 21603916 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28911409 | 1. J Food Drug Anal. 2016 Jan;24(1):56-62. doi: 10.1016/j.jfda.2015.04.009. Epub
2015 May 29.
Comparing determination methods of detection and quantification limits for
aflatoxin analysis in hazelnut.
Şengül Ü(1).
Author information:
(1)Giresun University, Central Research Laboratory, Giresun, Turkey.
Hazelnut is a type of plant that grows in wet and humid climatic conditions.
Adverse climatic conditions result in the formation of aflatoxin in hazelnuts
during the harvesting, drying, and storing processes. Aflatoxin is considered an
important food contaminant, which makes aflatoxin analysis important in the
international produce trade. For this reason, validation is important for the
analysis of aflatoxin in hazelnuts. The limit of detection (LOD) and limit of
quantification (LOQ) are two important parameters in validation. In this study,
the LOD and LOQ values have been determined using the Association of Official
Agricultural Chemists (AOAC) Method 991.31, which is one of the most viable
high-performance liquid chromatography analysis methods in the analysis of
aflatoxin in hazelnuts. Several approaches can be used to calculate LOD and LOQ
values. In this study, to calculate the LOD and LOQ values, the visual
evaluation (empirical) method, the signal-to-noise method, and calibration curve
approaches were applied. The most appropriate approaches were compared. Our
conclusion is that the visual evaluation method provided much more realistic LOD
and LOQ values.
Copyright © 2015. Published by Elsevier B.V.
DOI: 10.1016/j.jfda.2015.04.009
PMCID: PMC9345422
PMID: 28911409
Conflict of interest statement: Conflicts of interest The author has no conflict
of interest relevant to this article. |
http://www.ncbi.nlm.nih.gov/pubmed/36206626 | 1. Talanta. 2023 Feb 1;253:123970. doi: 10.1016/j.talanta.2022.123970. Epub 2022
Sep 29.
Development of a digital anti-Müllerian hormone immunoassay: ultrasensitive,
accurate and practical strategy for reduced ovarian reserve monitoring and
assessment.
Kuang X(1), Wei L(2), Huang Y(2), Ji M(2), Tang Y(2), Wei B(2), Yang S(3), Lai
D(4), Xu H(5).
Author information:
(1)School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao
Tong University, Shanghai, China; The International Peace Maternity and Child
Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai,
China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.
(2)The International Peace Maternity and Child Health Hospital, School of
Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key
Laboratory of Embryo Original Diseases, Shanghai, China.
(3)Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai,
China.
(4)The International Peace Maternity and Child Health Hospital, School of
Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key
Laboratory of Embryo Original Diseases, Shanghai, China. Electronic address:
laidongmei@hotmail.com.
(5)School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao
Tong University, Shanghai, China. Electronic address: xuhong@sjtu.edu.cn.
Anti-Müllerian hormone (AMH) is an ideal biomarker for the assessment of ovarian
reserve. However, its application in determining ovarian reserve reduction is
restricted due to the low sensitivity of existing AMH assays. Herein, a homebrew
ultrasensitive digital AMH assay (UD-AMH) was established based on a
single-molecule array (SiMoA, HD-X platform), and the analytical performance of
UD-AMH was evaluated systematically. The limit of detection (LoD) and limit of
quantitation (LoQ) of UD-AMH were 0.13 and 0.14 pg/mL, respectively, which is
approximately 100-fold higher than that of the current reported general clinical
AMH assay. A comparison study showed a high correlation, with r = 0.988 for the
Beckman Access AMH assay and r = 0.945 for the Kangrun AMH assay. In addition,
we found that the AMH concentrations of premature ovarian insufficiency (POI)
patients were very low (2.59 (0.86, 31.79) pg/mL) and similar to those of
perimenopausal women (2.37 (0.65, 35.88) pg/mL) but significantly higher than
those of menopausal women (0.43 (0.28, 1.17) pg/mL). Furthermore, we observed
that the AMH concentration of most hormone therapy (HT) treated POI patients
decreased sharply, suggesting that the ovarian reserve of POI patients declines
over time even under HT-treatment.
Copyright © 2022 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.talanta.2022.123970
PMID: 36206626 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. |
http://www.ncbi.nlm.nih.gov/pubmed/36308687 | 1. Methods Mol Biol. 2023;2426:119-129. doi: 10.1007/978-1-0716-1967-4_6.
Left-Censored Missing Value Imputation Approach for MS-Based Proteomics Data
with GSimp.
Wei R(1), Wang J(2).
Author information:
(1)The University of Texas MD Anderson Cancer Center, Department of Genetics,
Houston, TX, USA. rwei2@mdanderson.org.
(2), Houston, TX, USA.
Missing values caused by the limit of detection or quantification (LOD/LOQ) were
widely observed in mass spectrometry (MS)-based omics studies and could be
recognized as missing not at random (MNAR). MNAR leads to biased statistical
estimations and jeopardizes downstream analyses. Although a wide range of
missing value imputation methods was developed for omics studies, a limited
number of methods were designed appropriately for the situation of MNAR. To
facilitate MS-based omics studies, we introduce GSimp, a Gibbs sampler-based
missing value imputation approach, to deal with left-censor missing values in
MS-proteomics datasets. In this book, we explain the MNAR and elucidate the
usage of GSimp for MNAR in detail.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-1967-4_6
PMID: 36308687 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8013092 | 1. Clin Chem. 1994 Jul;40(7 Pt 1):1233-8.
Limit of detection (LQD)/limit of quantitation (LOQ): comparison of the
empirical and the statistical methods exemplified with GC-MS assays of abused
drugs.
Armbruster DA(1), Tillman MD, Hubbs LM.
Author information:
(1)Armstrong Laboratory Drug Testing Division, Human Systems Center (AFMC),
Brooks AFB, TX 78235-5240.
Comment in
Clin Chem. 1994 Jul;40(7 Pt 1):1218-9.
The limit of detection (LOD) for any analytical procedure, the point at which
analysis is just feasible, may be determined by a statistical approach based on
measuring replicate blank (negative) samples or by an empirical approach,
consisting of measuring progressively more dilute concentrations of analyte. The
limit of quantitation (LOQ), or concentration at which quantitative results can
be reported with a high degree of confidence, may likewise be determined by
either approach. We used both methods to determine LOD and LOQ for forensic gas
chromatographic-mass spectrometric (GC-MS) analyses of abused drugs. The
statistically determined LOD and LOQ values for these assays underestimated the
LOD because of the large imprecision associated with blank measurements and the
inability of blank samples to meet typical GC-MS acceptance criteria. The
empirical method provided much more realistic LOD values, supported by
reasonable experimental data, and are 0.5-0.03 the magnitude of the
corresponding statistical LODs. The empirical LODs and LOQs are identical for
these GC-MS assays. The observations made here about the LOD/LOQ for specific
forensic GC-MS procedures are generally applicable to any type of analysis.
PMID: 8013092 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18852857 | 1. Clin Biochem Rev. 2008 Aug;29 Suppl 1(Suppl 1):S49-52.
Limit of blank, limit of detection and limit of quantitation.
Armbruster DA(1), Pry T.
Author information:
(1)Global Scientific Affairs, Abbott Diagnostics, Abbott Park, IL 60064, USA.
David.Armbruster@abbott.com
* Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation
(LoQ) are terms used to describe the smallest concentration of a measurand that
can be reliably measured by an analytical procedure. * LoB is the highest
apparent analyte concentration expected to be found when replicates of a blank
sample containing no analyte are tested. LoB = mean(blank) + 1.645(SD(blank)). *
LoD is the lowest analyte concentration likely to be reliably distinguished from
the LoB and at which detection is feasible. LoD is determined by utilising both
the measured LoB and test replicates of a sample known to contain a low
concentration of analyte. * LoD = LoB + 1.645(SD (low concentration sample)). *
LoQ is the lowest concentration at which the analyte can not only be reliably
detected but at which some predefined goals for bias and imprecision are met.
The LoQ may be equivalent to the LoD or it could be at a much higher
concentration.
PMCID: PMC2556583
PMID: 18852857 |
http://www.ncbi.nlm.nih.gov/pubmed/33799266 | 1. Food Chem. 2021 Sep 1;355:129525. doi: 10.1016/j.foodchem.2021.129525. Epub
2021 Mar 11.
An effective analytical droplet digital PCR approach for identification and
quantification of fur-bearing animal meat in raw and processed food.
Yu N(1), Ren J(2), Huang W(1), Xing R(1), Deng T(1), Chen Y(3).
Author information:
(1)Chinese Academy of Inspection and Quarantine, Beijing, 100176.
(2)Chinese Academy of Inspection and Quarantine, Beijing, 100176; Beijing Food &
Wine Inspection and Testing 1st Station, Beijing, 101111.
(3)Chinese Academy of Inspection and Quarantine, Beijing, 100176. Electronic
address: chenyingcaiq@163.com.
Available nuclear gene sequences for meat detection are still rare and little
applicability in the investigation of new types of meat adulteration such as
fox, mink and raccoon dog was performed. In the present work, we developed a
reliable qualitative and quantitative detection method for fur-bearing animal
meat based on droplet digital PCR (ddPCR). Three sets of primers and probes
targeted nuclear genes for fox, mink and raccoon dog were designed for ddPCR
system; In addition, turkey was selected as internal reference to transform the
copy numbers to the fraction of target species. Results indicated that the
dynamic ranges of three fur-bearing animals were all from 1% to 90%; the limit
of detection (LOD) and limit of quantification (LOQ) for three fur-bearing
animals were same, with LOD 0.1% (w/w) and LOQ 1% (w/w). Moreover, we confirmed
that different additives had no effect on quantification accuracy in the ddPCR
assay.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.foodchem.2021.129525
PMID: 33799266 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32308686 | 1. Int J Anal Chem. 2020 Mar 19;2020:5417549. doi: 10.1155/2020/5417549.
eCollection 2020.
A Simple Spectrophotometric Method for Determination of Glyoxylic Acid in Its
Synthesis Mixture.
Abdulwahed M(1), Mamoly L(1), Bosnali W(1).
Author information:
(1)Damascus University, Faculty of Sciences, Damascus, Syria.
A new simple and reliable spectrophotometric method is described to determine
glyoxylic acid in its synthesis reaction mixture containing oxalic acid,
glycolic acid, acetic acid, glyoxal, and ethylene glycol by means of a modified
Hopkins-Cole reaction between glyoxylic acid and tryptophan in presence of
ferric chloride and concentrated sulphuric acid. The linear range of glyoxylic
acid concentration is 0-0.028 M. The limits of detection (LOD) and quantitation
(LOQ) are 0.0019 M and 0.00577 M, respectively. The LOD, LOQ, standard
deviation, relative standard deviation, and recovery ratio of the proposed
method are comparable with a selected HPLC reference method. Both methods
displayed same precision and credibility. Reaction stoichiometry between
tryptophan and glyoxylic acid is assumed to be 2 : 3. Reaction mechanism has
been postulated based on identified molar ratios of reactants. Glyoxal gave a
negative test with tryptophan although it is a dialdehyde.
Copyright © 2020 Mazhar Abdulwahed et al.
DOI: 10.1155/2020/5417549
PMCID: PMC7155763
PMID: 32308686
Conflict of interest statement: The authors declare that they have no conflicts
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33972799 | 1. Nat Genet. 2021 May;53(5):650-662. doi: 10.1038/s41588-021-00842-x. Epub 2021
May 10.
Histone acetylation dynamics modulates chromatin conformation and
allele-specific interactions at oncogenic loci.
Sungalee S(#)(1)(2), Liu Y(#)(2)(3)(4), Lambuta RA(1)(2), Katanayeva N(1)(2),
Donaldson Collier M(1)(5), Tavernari D(2)(3)(4), Roulland S(6), Ciriello
G(2)(3)(4), Oricchio E(7)(8).
Author information:
(1)Swiss Institute for Experimental Cancer Research, School of Life Sciences,
EPFL, Lausanne, Switzerland.
(2)Swiss Cancer Center Leman, Lausanne, Switzerland.
(3)Department of Computational Biology, University of Lausanne, Lausanne,
Switzerland.
(4)Swiss Institute of Bioinformatics, Lausanne, Switzerland.
(5)Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam,
the Netherlands.
(6)Aix-Marseille University, CNRS, INSERM, Centre d'Immunologie de
Marseille-Luminy, Marseille, France.
(7)Swiss Institute for Experimental Cancer Research, School of Life Sciences,
EPFL, Lausanne, Switzerland. elisa.oricchio@epfl.ch.
(8)Swiss Cancer Center Leman, Lausanne, Switzerland. elisa.oricchio@epfl.ch.
(#)Contributed equally
In cancer cells, enhancer hijacking mediated by chromosomal alterations and/or
increased deposition of acetylated histone H3 lysine 27 (H3K27ac) can support
oncogene expression. However, how the chromatin conformation of
enhancer-promoter interactions is affected by these events is unclear. In the
present study, by comparing chromatin structure and H3K27ac levels in normal and
lymphoma B cells, we show that enhancer-promoter-interacting regions assume
different conformations according to the local abundance of H3K27ac. Genetic or
pharmacological depletion of H3K27ac decreases the frequency and the spreading
of these interactions, altering oncogene expression. Moreover, enhancer
hijacking mediated by chromosomal translocations influences the epigenetic
status of the regions flanking the breakpoint, prompting the formation of
distinct intrachromosomal interactions in the two homologous chromosomes. These
interactions are accompanied by allele-specific gene expression changes.
Overall, our work indicates that H3K27ac dynamics modulates interaction
frequency between regulatory regions and can lead to allele-specific chromatin
configurations to sustain oncogene expression.
DOI: 10.1038/s41588-021-00842-x
PMID: 33972799 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21662779 | 1. Anal Chem. 1999 Jul 1;71(13):2288-93. doi: 10.1021/ac981087y.
Trace determination of glycols by HPLC with UV and electrospray ionization mass
spectrometric detections.
Holčapek M(1), Virelizier H, Chamot-Rooke J, Jandera P, Moulin C.
Author information:
(1)Faculty of Chemical Technology, Department of Analytical Chemistry,
University of Pardubice, nám. Čs.legií 565, 53210 Pardubice, Czech Republic, and
CEA Saclay, DPE/SPCP/LASO, 91191 Gif sur Yvette Cedex, France.
A high-performance liquid chromatography/mass spectrometry (HPLC/MS) method is
developed for trace determination of glycols (ethylene glycol, 1,2- and
1,3-propylene glycols, and 2,3-butylene glycol) in water after derivatization
with benzoyl chloride. Benzoyl esters of glycols are separated by microcolumn
reversed-phase HPLC. Sensitivity and linearity of UV detection at 237 nm is
compared with electrospray ionization mass spectrometric (ESI-MS) detection
using selected ion monitoring. Limits of detection (LOD) and quantitation (LOQ)
for UV detection are 1 and 2 mg/L, respectively. For ESI-MS detection, LOD and
LOQ are in the ranges 10-25 and 20-50 μg/L, respectively. LOD obtained by ESI-MS
for the determination of glycols is improved by 2-3 orders of magnitude in
comparison to previously published methods. The effect of the structure of
isomeric glycols on their electrospray mass spectra is discussed. The method has
been applied for the determination of glycols in aqueous matrixes containing
high concentrations of salts occurring in nuclear waste disposal treatment.
DOI: 10.1021/ac981087y
PMID: 21662779 |
http://www.ncbi.nlm.nih.gov/pubmed/32764680 | 1. Leukemia. 2021 Apr;35(4):1012-1022. doi: 10.1038/s41375-020-1001-z. Epub 2020
Aug 6.
KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL
rearrangements.
Au YZ(#)(1)(2)(3), Gu M(#)(2), De Braekeleer E(2), Gozdecka M(2)(4), Aspris
D(2), Tarumoto Y(5), Cooper J(2), Yu J(1)(6), Ong SH(1), Chen X(7), Tzelepis
K(2)(8), Huntly BJP(4)(9)(10), Vassiliou G(11)(12)(13), Yusa K(14)(15).
Author information:
(1)Stem Cell Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
(2)Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton,
Cambridge, UK.
(3)Dana-Farber Cancer Institute, Boston, MA, USA.
(4)Wellcome Trust-MRC Stem Cell Institute, Cambridge Biomedical Campus,
University of Cambridge, Cambridge, UK.
(5)Stem Cell Genetics, Institute for Frontier Life and Medical Sciences, Kyoto
University, Kyoto, Japan.
(6)Department of Cell Biology, The Francis Crick Institute, London, UK.
(7)Gene Expression Genomics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
(8)Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, UK.
(9)Department of Haematology, Cambridge University Hospitals NHS Trust,
Cambridge, UK.
(10)Cambridge Institute for Medical Research, University of Cambridge,
Cambridge, UK.
(11)Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton,
Cambridge, UK. gsv20@sanger.ac.uk.
(12)Wellcome Trust-MRC Stem Cell Institute, Cambridge Biomedical Campus,
University of Cambridge, Cambridge, UK. gsv20@sanger.ac.uk.
(13)Department of Haematology, Cambridge University Hospitals NHS Trust,
Cambridge, UK. gsv20@sanger.ac.uk.
(14)Stem Cell Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
k.yusa@infront.kyoto-u.ac.jp.
(15)Stem Cell Genetics, Institute for Frontier Life and Medical Sciences, Kyoto
University, Kyoto, Japan. k.yusa@infront.kyoto-u.ac.jp.
(#)Contributed equally
Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from
acetyl-CoA to lysine residues of histones and play a central role in
transcriptional regulation in diverse biological processes. Dysregulation of HAT
activity can lead to human diseases including developmental disorders and
cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of
the MYST family as fitness genes for acute myeloid leukemia (AML). Here we
investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by
the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete
loss of both H3K14ac and H4K12ac marks, in association with reduced
proliferation, increased apoptosis, and differentiation of AML cells.
Acetyltransferase activity of KAT7 is essential for the proliferation of these
cells. Mechanistically, our data propose that acetylated histones provide a
platform for the recruitment of MLL-fusion-associated adaptor proteins such as
BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA
polymerase II rapidly dissociate from several MLL-fusion target genes that are
essential for AML cell proliferation, including MEIS1, PBX3, and SENP6. Our
findings reveal that KAT7 is a plausible therapeutic target for this poor
prognosis AML subtype.
DOI: 10.1038/s41375-020-1001-z
PMCID: PMC7610570
PMID: 32764680 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests G.S.V. is a consultant for
Kymab and Oxstem. |
http://www.ncbi.nlm.nih.gov/pubmed/33373635 | 1. Int J Biol Macromol. 2021 Feb 15;170:326-335. doi:
10.1016/j.ijbiomac.2020.12.173. Epub 2020 Dec 26.
Histone acetyl transferases and their epigenetic impact on bone remodeling.
Gomathi K(1), Akshaya N(1), Srinaath N(1), Rohini M(1), Selvamurugan N(2).
Author information:
(1)Department of Biotechnology, School of Bioengineering, SRM Institute of
Science and Technology, Kattankulathur 603 203, Tamil Nadu, India.
(2)Department of Biotechnology, School of Bioengineering, SRM Institute of
Science and Technology, Kattankulathur 603 203, Tamil Nadu, India. Electronic
address: selvamun@srmist.edu.in.
Bone remodeling is a complex event that maintains bone homeostasis. The
epigenetic mechanism of the regulation of bone remodeling has been a major
research focus over the past decades. Histone acetylation is an influential
post-translational modification in chromatin architecture. Acetylation affects
chromatin structure by offering binding signals for reader proteins that harbor
acetyl-lysine recognition domains. This review summarizes recent data of histone
acetylation in bone remodeling. The crux of this review is the functional role
of histone acetyltransferases, the key promoters of histone acetylation. The
functional regulation of acetylation via noncoding RNAs in bone remodeling is
also discussed. Understanding the principles governing histone acetylation in
bone remodeling would lead to the development of better epigenetic therapies for
bone diseases.
Copyright © 2020 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ijbiomac.2020.12.173
PMID: 33373635 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11878590 | 1. J AOAC Int. 2002 Jan-Feb;85(1):122-7.
Optimization and validation of arsenic determination in foods by hydride
generation flame atomic absorption spectrometry.
Kabengera C(1), Bodart P, Hubert P, Thunus L, Noirfalise A.
Author information:
(1)Université Nationale du Rwanda, Butare. Charles.Kabengera@student.ulg.ac.be
A hydride generation flame atomic absorption spectrometric method was developed
and optimized to quantitate arsenic (As) in foods. A wet digestion of the
samples with HNO3 + H2O2 was performed and excess oxidants were eliminated by
addition of hydrochloric acid and urea. As5+ in As3+ was then reduced by
potassium iodide. The As3+ solution was analyzed by generation of arsine with
sodium tetrahydroborate. As determination ranged from 2.5 to 20 microg/L, with a
determination coefficient of 0.997. The limits of detection (LOD) and
quantitation (LOQ) were 0.6 and 2.1 microg/L, respectively. The method was
validated and good results were obtained for recovery, precision, accuracy, LOD,
and LOQ. This method is now used to analyze foods from Rwanda.
PMID: 11878590 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10790315 | 1. Anal Biochem. 2000 May 1;280(2):308-14. doi: 10.1006/abio.2000.4546.
A continuous, nonradioactive assay for histone acetyltransferases.
Kim Y(1), Tanner KG, Denu JM.
Author information:
(1)Department of Biochemistry and Molecular Biology, Oregon Health Sciences
University, Portland, Oregon, 97201-3098, USA.
Histone acetyltransferases (HATs) catalyze the acetyl-group transfer from
acetyl-CoA to the epsilon-amino group of specific lysine residues within core
histone proteins. HATs and other chromatin-remodeling enzymes have been recently
shown to regulate gene activation within specific loci. To facilitate
mechanistic studies, we have developed two continuous, nonradioactive assays for
the prototypical GCN5 HAT. The CoASH generated in the HAT reactions was
continuously measured by using a coupled enzyme system with either
alpha-ketoglutarate dehydrogenase or pyruvate dehydrogenase. The CoASH-dependent
oxidation of alpha-ketoglutarate or pyruvate is accompanied by the reduction of
NAD to NADH, which was measured spectrophotometrically at 340 nm. The
steady-state rate constants with substrates acetyl-CoA and a synthetic peptide
(corresponding to the first 20 amino acids of H3 histone) were determined. The
resulting rate constants were not significantly different between the two
coupled assays, providing strong validation of these methods. Rate constants
were also determined using the commonly employed radioactive filter-binding
assay and compared. The 1.5- to 5-fold lower values obtained in the radioactive
end-point assay are discussed in terms of the technical problems and limitations
of this assay. The coupled assays should be widely applicable since the
production of CoASH is common to all HAT enzymes, regardless of protein
substrate.
Copyright 2000 Academic Press.
DOI: 10.1006/abio.2000.4546
PMID: 10790315 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32791974 | 1. Reprod Biol Endocrinol. 2020 Aug 13;18(1):84. doi: 10.1186/s12958-020-00637-5.
Histone acetylation and the role of histone deacetylases in normal cyclic
endometrium.
Gujral P(1), Mahajan V(1)(2), Lissaman AC(1)(2), Ponnampalam AP(3)(4)(5).
Author information:
(1)The Liggins Institute, The University of Auckland, Auckland, New Zealand.
(2)Department of Obstetrics and Gynaecology, Faculty of Medical and Health
Sciences, The University of Auckland, Auckland, New Zealand.
(3)The Liggins Institute, The University of Auckland, Auckland, New Zealand.
a.ponnampalam@auckland.ac.nz.
(4)Department of Obstetrics and Gynaecology, Faculty of Medical and Health
Sciences, The University of Auckland, Auckland, New Zealand.
a.ponnampalam@auckland.ac.nz.
(5)Department of Physiology, Faculty of Medical and Health Sciences, The
University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
a.ponnampalam@auckland.ac.nz.
Histone acetylation is a critical epigenetic modification that changes chromatin
architecture and regulates gene expression by opening or closing the chromatin
structure. It plays an essential role in cell cycle progression and
differentiation. The human endometrium goes through cycles of
regeneration, proliferation, differentiation, and degradation each month; each
phase requiring strict epigenetic regulation for the proper functioning of the
endometrium. Aberrant histone acetylation and alterations in levels of two
acetylation modulators - histone acetylases (HATs) and histone deacetylases
(HDACs) - have been associated with endometrial pathologies such as endometrial
cancer, implantation failures, and endometriosis. Thus, histone acetylation is
likely to have an essential role in the regulation of endometrial remodelling
throughout the menstrual cycle.
DOI: 10.1186/s12958-020-00637-5
PMCID: PMC7425564
PMID: 32791974 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/26440431 | 1. Trends Plant Sci. 2015 Oct;20(10):614-621. doi: 10.1016/j.tplants.2015.07.005.
Histone Acetylation Enzymes Coordinate Metabolism and Gene Expression.
Shen Y(1), Wei W(2), Zhou DX(3).
Author information:
(1)Institute of Plant Sciences Paris-Saclay (IPS2), University Paris-sud 11,
91405 Orsay, France.
(2)Institute of interdisciplinary Scientific Research, Jianghan University,
430056, Wuhan, China.
(3)Institute of Plant Sciences Paris-Saclay (IPS2), University Paris-sud 11,
91405 Orsay, France. Electronic address: dao-xiu.zhou@u-psud.fr.
Histone lysine acetylation is well known for being important in the epigenetic
regulation of gene expression in eukaryotic cells. Recent studies have uncovered
a plethora of acetylated proteins involved in important metabolic pathways, such
as photosynthesis and respiration in plants. Enzymes involved in histone
acetylation and deacetylation are being identified as regulators of acetylation
of metabolic enzymes. Importantly, key metabolites, such as acetyl-CoA and
NAD(+), are involved in protein acetylation and deacetylation processes, and
their cellular levels may regulate the activity of histone acetyltransferases
(HAT) and deacetylases (HDAC). Further research is required to determine whether
and how HATs and HDACs sense cellular metabolite signals to control gene
expression and metabolic enzyme activity through lysine acetylation and
deacetylation.
Copyright © 2015 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tplants.2015.07.005
PMID: 26440431 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10373413 | 1. J Biol Chem. 1999 Jun 25;274(26):18157-60. doi: 10.1074/jbc.274.26.18157.
Catalytic mechanism and function of invariant glutamic acid 173 from the histone
acetyltransferase GCN5 transcriptional coactivator.
Tanner KG(1), Trievel RC, Kuo MH, Howard RM, Berger SL, Allis CD, Marmorstein R,
Denu JM.
Author information:
(1)Department of Biochemistry and Molecular Biology, Oregon Health Sciences
University, Portland, Oregon 97201-3098, USA.
Within chromatin, reversible acetylation of core histones is critical for
transcriptional activation of eukaryotic target genes. The recent identification
of intrinsic histone acetyltransferase (HAT) catalytic activity from a number of
transcriptional co-activators (including yeast GCN5, p300/CBP, P/CAF, and
TAFII250), has underscored the importance of protein acetylation in
transcriptional control. The GCN5 family is the prototype for a diverse group of
at least four distinct human HATs families. Although there is now a clear link
between in vivo HAT catalytic activity and gene activation, little is known
about the molecular mechanisms of histone acetylation. Herein, we report the
first detailed biochemical study that probes the catalytic mechanism and the
function of invariant glutamic acid 173 within the GCN5 family of HATs. Our
results suggest that the HAT reaction involves the formation of a ternary
complex (histones, acetyl-CoA, and enzyme) where the epsilon-amino group of
histone lysine residues directly attacks the bound acetyl-CoA. The acetylation
reaction requires deprotonation of the epsilon-amino group prior to nucleophilic
attack. Employing site-directed mutagenesis, chemical modification,
steady-state, and pH-dependent rate analysis, it is demonstrated that glutamic
acid 173 is an essential catalytic residue, acting as a general base catalyst by
deprotonating the histone substrate.
DOI: 10.1074/jbc.274.26.18157
PMID: 10373413 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12368900 | 1. Nat Struct Biol. 2002 Nov;9(11):862-9. doi: 10.1038/nsb849.
The catalytic mechanism of the ESA1 histone acetyltransferase involves a
self-acetylated intermediate.
Yan Y(1), Harper S, Speicher DW, Marmorstein R.
Author information:
(1)The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania
19104, USA.
Comment in
Nat Struct Biol. 2002 Dec;9(12):888-91. doi: 10.1038/nsb1202-888.
Yeast ESA1 is a member of the MYST subfamily of histone acetyltransferases
(HATs), which use acetyl-coenzyme A (CoA) to acetylate specific Lys residues
within histones to regulate gene expression. The structure of an ESA1-CoA
complex reveals structural similarity to the catalytic core of the GCN5/PCAF
subfamily of HAT proteins. Here we report additional structural and functional
studies on ESA1 that demonstrate that histone acetylation proceeds through an
acetyl-cysteine enzyme intermediate. This Cys residue is strictly conserved
within the MYST members, suggesting a common mode of catalysis by this HAT
subfamily. However, this mode of catalysis differs dramatically from the
GCN5/PCAF subfamily, which mediate direct nucleophilic attack of the acetyl-CoA
cofactor by the enzyme-deprotonated substrate lysine of the histone. These
results demonstrate that different HAT subfamilies can use distinct catalytic
mechanisms, which have implications for their distinct biological roles and for
the development of HAT-specific inhibitors.
DOI: 10.1038/nsb849
PMID: 12368900 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26065557 | 1. Assay Drug Dev Technol. 2015 May;13(4):210-20. doi: 10.1089/adt.2015.636. Epub
2015 May 28.
Effective Quenchers Are Required to Eliminate the Interference of Substrate:
Cofactor Binding in the HAT Scintillation Proximity Assay.
Ngo L(1), Wu J(1), Yang C(1), Zheng YG(1).
Author information:
(1)Department of Pharmaceutical and Biomedical Sciences, The University of
Georgia , Athens, Georgia .
Histone acetyltransferases (HATs) mediate the transfer of an acetyl group from
the cofactor, acetyl-CoA, to the side chain amino group of specific lysines in
diverse protein substrates, most notably nuclear histones. The deregulation of
HATs is connected to a number of disease states. Reliable and rapid biochemical
assays for HATs are critical for understanding biological functions of protein
acetylation, as well as for screening small-molecule inhibitors of HAT enzymes.
In this report, we present a scintillation proximity assay (SPA) for the
measurement of HAT enzymatic activities. The acetyl donor was [(3)H]Ac-CoA, and
a biotin-modified histone peptide served as the HAT substrate. After the HAT
reaction, streptavidin-coated beads were added to induce proximity of acetylated
substrate to the scintillant molecules. However, we observed strong nonspecific
binding between the cofactor and the histone peptide substrates, which adversely
complicated the SPA performance. To prevent this problem, a set of chemical
agents were evaluated to eliminate the cofactor-substrate interaction, thus
providing reliable SPA readings. With optimization, the SPA showed consistent
and robust performance for HAT activity measurement and HAT inhibitor
evaluation. Overall, this mix-and-measure assay does not require any washing
procedure, can be utilized in the microplate format, and is well suited for
high-throughput screening of HAT chemical modulators.
DOI: 10.1089/adt.2015.636
PMCID: PMC4490742
PMID: 26065557 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17694092 | 1. Oncogene. 2007 Aug 13;26(37):5528-40. doi: 10.1038/sj.onc.1210619.
Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism
and implications for effector design.
Hodawadekar SC(1), Marmorstein R.
Author information:
(1)The Wistar Institute and The Department of Chemistry, University of
Pennsylvania, Philadelphia, PA 19104, USA.
The post-translational modification of histones plays an important role in
chromatin regulation, a process that insures the fidelity of gene expression and
other DNA transactions. Of the enzymes that mediate post-translation
modification, the histone acetyltransferase (HAT) and histone deacetylase (HDAC)
proteins that add and remove acetyl groups to and from target lysine residues
within histones, respectively, have been the most extensively studied at both
the functional and structural levels. Not surprisingly, the aberrant activity of
several of these enzymes have been implicated in human diseases such as cancer
and metabolic disorders, thus making them important drug targets. Significant
mechanistic insights into the function of HATs and HDACs have come from the
X-ray crystal structures of these enzymes both alone and in liganded complexes,
along with associated enzymatic and biochemical studies. In this review, we will
discuss what we have learned from the structures and related biochemistry of
HATs and HDACs and the implications of these findings for the design of protein
effectors to regulate gene expression and treat disease.
DOI: 10.1038/sj.onc.1210619
PMID: 17694092 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28240169 | 1. Curr Med Chem. 2017;24(37):4121-4150. doi: 10.2174/0929867324666170223153115.
Epigenetic Modulation Using Small Molecules - Targeting Histone
Acetyltransferases in Disease.
Richters A(1), Koehler AN(1)(2).
Author information:
(1)David H. Koch Institute for Integrative Cancer Research, Department of
Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA,
United States.
(2)Broad Institute of MIT and Harvard, Cambridge, MA, United States.
Histone acetyltransferases (HATs) are epigenetic drivers that catalyze the
acetyl transfer from acetyl-CoA to lysines of both histone and non-histone
substrates and thereby induce transcription either by chromatin remodeling or
direct transcription factor activation. Histone deacetylases (HDACs) conduct the
reverse reaction to counter HAT activity. Physiological processes such as cell
cycle progression or apoptosis require a thoroughly balanced equilibrium of the
interplay between acetylation and deacetylation processes to maintain or, if
required, alter the global acetylome status. Aberrant HAT activity has recently
been demonstrated to play a crucial role in the progression of various diseases
such as prostate, lung, and colon cancers as well as glioblastomas and
neurodegenerative diseases. Recent investigations have aimed for the
identification of HAT modulators to further decipher the complexity of acetyl
transferase related signaling cascades and discover potential leads for drug
design approaches. HDACs have been extensively characterized and targeted by
small molecules, including four FDA-approved HDAC inhibitors; in contrast, HATs
have not been active targets for therapeutic development. This review will
summarize the status of HAT associated diseases and the arsenal of currently
known and available HAT inhibitors with respect to their discovery, further
improvements, and current applications.
Copyright© Bentham Science Publishers; For any queries, please email at
epub@benthamscience.org.
DOI: 10.2174/0929867324666170223153115
PMID: 28240169 |
http://www.ncbi.nlm.nih.gov/pubmed/21908798 | 1. J Biomol Screen. 2011 Dec;16(10):1186-95. doi: 10.1177/1087057111418653. Epub
2011 Sep 9.
Advances in label-free screening approaches for studying histone
acetyltransferases.
Rye PT(1), Frick LE, Ozbal CC, Lamarr WA.
Author information:
(1)Agilent Technologies, Inc., Life Sciences Group, Wakefield, Massachusetts
01880, USA. peter.rye@agilent.com
Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from
an acetyl-coenzyme A donor molecule to specific lysine residues within proteins.
The acetylation state of proteins, particularly histones, is known to modulate
their intermolecular binding properties and control various cellular processes,
most notably transcriptional activation. In addition, deregulation of HAT
activity has been linked to the development of a number of cancers; therefore,
compounds that affect these enzymes have strong potential as therapeutic agents.
The research presented here demonstrates three label-free HAT screening
approaches, all based on the fast and direct measurement of one or more
substrate-product pairs by high-throughput mass spectrometry techniques. The
first approach involves monitoring all possible acetylation states of a peptide
concurrently to measure HAT activity. The second approach measures acetylation
reactions, on both peptides and whole protein substrates, via direct detection
of the acetyl-coenzyme A cosubstrate and coenzyme A coproduct. Lastly, the
authors demonstrate the ability to monitor directly the acetylation state of
whole histone proteins in the same high-throughput manner using time-of-flight
mass spectrometry. The generation of compound-mediated inhibition data using
each of these techniques establishes mass spectrometry as a versatile,
label-free, and biologically relevant screening approach to this challenging
target class.
DOI: 10.1177/1087057111418653
PMID: 21908798 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31606071 | 1. Methods Enzymol. 2019;626:1-21. doi: 10.1016/bs.mie.2019.07.013. Epub 2019 Aug
12.
Crosstalk between cellular metabolism and histone acetylation.
Trefely S(1), Doan MT(2), Snyder NW(3).
Author information:
(1)A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA, United
States; Abramson Family Cancer Research Institute, University of Pennsylvania
Perelman School of Medicine, Philadelphia, PA, United States.
(2)A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA, United
States.
(3)A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA, United
States. Electronic address: nws28@drexel.edu.
Dynamic interplay between cellular metabolism and histone acetylation is a key
mechanism underlying metabolic control of epigenetics. In particular, the
central metabolite acetyl-coenzyme A (acetyl-CoA) acts as the acetyl-donor for
histone acetylation in both an enzymatic and non-enzymatic manner. Since members
of the family of histone acetyl transferases (HATs) that catalyze the
acetylation of histone tails possess a Michaelis constant (Km) within the range
of physiological cellular acetyl-CoA concentrations, changing concentrations of
acetyl-CoA can restrict or promote enzymatic histone acetylation. Likewise,
non-enzymatic histone acetylation occurs at physiological concentrations. These
concepts implicate acetyl-CoA as a rheostat for nutrient availability acting, in
part, by controlling histone acetylation. Histone acetylation is an important
epigenetic modification that controls gene expression and acetyl-CoA dependent
changes in both histone acetylation and gene expression have been shown in yeast
and mammalian systems. However, quantifying the metabolic conditions required to
achieve specific changes in histone acetylation is a major challenge. The
relationship between acetyl-CoA and histone acetylation may be influenced by a
variety of factors including sub-cellular location of metabolites and enzymes,
relative quantities of metabolites, and substrate availability/preference. A
diversity of substrates can contribute the two-carbon acyl-chain to acetyl-CoA,
a number of pathways can create or degrade acetyl-CoA, and only a handful of
potential mechanisms for the crosstalk between metabolism and histone
acetylation have been explored. The centrality of acetyl-CoA in intermediary
metabolism means that acetyl-CoA levels may change, or be resistant to change,
in unexpected ways. Thus, quantification of relevant metabolites is critical
evidence in understanding how the nutrient rheostat is set in normal and
pathological contexts. Coupling metabolite quantitation with isotope tracing to
examine fate of specific metabolites is critical to the crosstalk between
metabolism and histone acetylation, including but not limited to acetyl-CoA
provides necessary context. This chapter provides guidance on experimental
design of quantification with isotope dilution and/or tracing of acetyl-CoA
within a targeted or highly multiplexed multi-analyte workflow.
© 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/bs.mie.2019.07.013
PMID: 31606071 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35042977 | 1. Nat Rev Mol Cell Biol. 2022 May;23(5):329-349. doi:
10.1038/s41580-021-00441-y. Epub 2022 Jan 18.
Modulation of cellular processes by histone and non-histone protein acetylation.
Shvedunova M(1), Akhtar A(2).
Author information:
(1)Department of Chromatin Regulation, Max Planck Institute of Immunobiology and
Epigenetics, Freiburg im Breisgau, Germany.
(2)Department of Chromatin Regulation, Max Planck Institute of Immunobiology and
Epigenetics, Freiburg im Breisgau, Germany. akhtar@ie-freiburg.mpg.de.
Lysine acetylation is a widespread and versatile protein post-translational
modification. Lysine acetyltransferases and lysine deacetylases catalyse the
addition or removal, respectively, of acetyl groups at both histone and
non-histone targets. In this Review, we discuss several features of acetylation
and deacetylation, including their diversity of targets, rapid turnover,
exquisite sensitivity to the concentrations of the cofactors acetyl-CoA,
acyl-CoA and NAD+, and tight interplay with metabolism. Histone acetylation and
non-histone protein acetylation influence a myriad of cellular and physiological
processes, including transcription, phase separation, autophagy, mitosis,
differentiation and neural function. The activity of lysine acetyltransferases
and lysine deacetylases can, in turn, be regulated by metabolic states, diet and
specific small molecules. Histone acetylation has also recently been shown to
mediate cellular memory. These features enable acetylation to integrate the
cellular state with transcriptional output and cell-fate decisions.
© 2022. Springer Nature Limited.
DOI: 10.1038/s41580-021-00441-y
PMID: 35042977 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12624111 | 1. J Biol Chem. 2003 May 23;278(21):19134-40. doi: 10.1074/jbc.M301580200. Epub
2003 Mar 6.
Small molecule modulators of histone acetyltransferase p300.
Balasubramanyam K(1), Swaminathan V, Ranganathan A, Kundu TK.
Author information:
(1)Transcription and Disease Laboratory, Molecular Biology and Genetics Unit,
Jawaharlal Nehru Center for Advanced Scientific Research, Jakkur, Bangalore
560064, India.
Histone acetyltransferases (HATs) are a group of enzymes that play a significant
role in the regulation of gene expression. These enzymes covalently modify the
N-terminal lysine residues of histones by the addition of acetyl groups from
acetyl-CoA. Dysfunction of these enzymes is often associated with the
manifestation of several diseases, predominantly cancer. Here we report that
anacardic acid from cashew nut shell liquid is a potent inhibitor of p300 and
p300/CBP-associated factor histone acetyltranferase activities. Although it does
not affect DNA transcription, HAT-dependent transcription from a chromatin
template was strongly inhibited by anacardic acid. Furthermore, we describe the
design and synthesis of an amide derivative
N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide (CTPB)
using anacardic acid as a synthon, which remarkably activates p300 HAT activity
but not that of p300/CBP-associated factor. Although CTPB does not affect DNA
transcription, it enhances the p300 HAT-dependent transcriptional activation
from in vitro assembled chromatin template. However, it has no effect on histone
deacetylase activity. These compounds would be useful as biological switching
molecules for probing into the role of p300 in transcriptional studies and may
also be useful as new chemical entities for the development of anticancer drugs.
DOI: 10.1074/jbc.M301580200
PMID: 12624111 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15313419 | 1. Biochem Pharmacol. 2004 Sep 15;68(6):1215-20. doi: 10.1016/j.bcp.2004.05.038.
Implications of small molecule activators and inhibitors of histone
acetyltransferases in chromatin therapy.
Varier RA(1), Swaminathan V, Balasubramanyam K, Kundu TK.
Author information:
(1)Transcription and Disease Laboratory, Molecular Biology and Genetics Unit,
Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore
560064, India.
Histone acetylation is a diagnostic feature of transcriptionally active
chromatin. The group of enzymes, histone acetyltransferases (HATs), involved in
this crucial step of gene regulation, covalently modifies the N-terminal lysine
residues of histones by the addition of an acetyl group from acetyl coenzyme A.
Dysfunction of these enzymes is often associated with several diseases, ranging
from neurodegenerative disorders to cancer. These enzymes thus are potential new
targets for therapeutics. We have discovered few small molecule compounds, which
target HATs and either activate or inhibit the enzyme potently. These compounds
would be useful as biological switching molecules for probing into the role of
HATs in gene regulation and cell cycle and may be useful as new chemical
entities for the development of new drugs.
DOI: 10.1016/j.bcp.2004.05.038
PMID: 15313419 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32157780 | 1. Aging Cell. 2020 Apr;19(4):e13129. doi: 10.1111/acel.13129. Epub 2020 Mar 11.
Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and
human cell lines.
Huang B(1), Zhong D(1), Zhu J(1), An Y(1), Gao M(1), Zhu S(1), Dang W(2), Wang
X(1), Yang B(1)(3), Xie Z(1)(4).
Author information:
(1)State Key Laboratory of Natural and Biomimetic Drugs, Department of
Pharmacology, School of Basic Medical Sciences, Peking University, Beijing,
China.
(2)Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
(3)Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education,
Beijing, China.
(4)Peking University International Cancer Institute, Peking University, Beijing,
China.
Histone acetyltransferases (HATs) are important enzymes that transfer acetyl
groups onto histones and thereby regulate both gene expression and chromosomal
structures. Previous work has shown that the activation of sirtuins, which are
histone deacetylases, can extend lifespan. This suggests that inhibiting HATs
may have a similar beneficial effect. In the present study, we utilized a range
of HAT inhibitors or heterozygous Gcn5 and Ngg1 mutants to demonstrate marked
yeast life extension. In human cell lines, HAT inhibitors and selective
RNAi-mediated Gcn5 or Ngg1 knockdown reduced the levels of aging markers and
promoted proliferation in senescent cells. Furthermore, this observed lifespan
extension was associated with the acetylation of histone H3 rather than that of
H4. Specifically, it was dependent upon H3K9Ac and H3K18Ac modifications. We
also found that the ability of caloric restriction to prolong lifespan is Gcn5-,
Ngg1-, H3K9-, and H3K18-dependent. Transcriptome analysis revealed that these
changes were similar to those associated with heat shock and were inversely
correlated with the gene expression profiles of aged yeast and aged worms.
Through a bioinformatic analysis, we also found that HAT inhibition activated
subtelomeric genes in human cell lines. Together, our results suggest that
inhibiting the HAT Gcn5 may be an effective means of increasing longevity.
© 2020 The Authors. Aging Cell published by the Anatomical Society and John
Wiley & Sons Ltd.
DOI: 10.1111/acel.13129
PMCID: PMC7189995
PMID: 32157780 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/10579936 | 1. Methods. 1999 Nov;19(3):410-6. doi: 10.1006/meth.1999.0877.
Transcriptional analysis of purified histone acetyltransferase complexes.
Steger DJ(1), Workman JL.
Author information:
(1)Department of Biochemistry and Biophysics, University of California at San
Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0448, USA.
Acetylation of lysine residues within the amino-terminal tails of the core
histone proteins is strongly correlated to the regulation of gene transcription
in vivo. To directly study the effects of histone acetylation on transcription,
we have developed a biochemical system examining the regulation of RNA
polymerase II-directed transcription by native histone acetyltransferases
(HATs). For the promoter sequences investigated, it has been demonstrated that
HATs facilitate transcription from nucleosomal DNA templates in an
acetyl-CoA-dependent fashion but do not affect transcription from histone-free
templates. Here, protocols are presented describing the in vitro assembly of
evenly spaced nucleosomal arrays on DNA fragments harboring gene regulatory
sequences and the use of these templates with purified HAT complexes in
transcription assays.
Copyright 1999 Academic Press.
DOI: 10.1006/meth.1999.0877
PMID: 10579936 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10485713 | 1. Nature. 1999 Sep 2;401(6748):93-8. doi: 10.1038/43487.
Structure of Tetrahymena GCN5 bound to coenzyme A and a histone H3 peptide.
Rojas JR(1), Trievel RC, Zhou J, Mo Y, Li X, Berger SL, Allis CD, Marmorstein R.
Author information:
(1)The Wistar Institute, Department of Chemistry, University of Pennsylvania,
Philadelphia 19104, USA.
Gene activation is a highly regulated process that requires the coordinated
action of proteins to relieve chromatin repression and to promote
transcriptional activation. Nuclear histone acetyltransferase (HAT) enzymes
provide a mechanistic link between chromatin destabilization and gene activation
by acetylating the epsilon-amino group of specific lysine residues within the
aminoterminal tails of core histones to facilitate access to DNA by
transcriptional activators. Here we report the high-resolution crystal structure
of the HAT domain of Tetrahymena GCN5 (tGCN5) bound with both its
physiologically relevant ligands, coenzyme A (CoA) and a histone H3 peptide, and
the structures of nascent tGCN5 and a tGCN5/acetyl-CoA complex. Our structural
data reveal histone-binding specificity for a random-coil structure containing a
G-K-X-P recognition sequence, and show that CoA is essential for reorienting the
enzyme for histone binding. Catalysis appears to involve water-mediated proton
extraction from the substrate lysine by a glutamic acid general base and a
backbone amide that stabilizes the transition-state reaction intermediate.
Comparison with related N-acetyltransferases indicates a conserved structural
framework for CoA binding and catalysis, and structural variability in regions
associated with substrate-specific binding.
DOI: 10.1038/43487
PMID: 10485713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15955204 | 1. J Gastroenterol Hepatol. 2005 Jul;20(7):988-94. doi:
10.1111/j.1440-1746.2005.03807.x.
Histone deacetylase inhibitors, anticancerous mechanism and therapy for
gastrointestinal cancers.
Fang JY(1).
Author information:
(1)Shanghai Second Medical University Renji Hospital, Shanghai Institute of
Digestive Disease, China. jingyuanfang@yahoo.com
Histone acetylation regulates gene transcription. Histone acetylation is a
reversible process: histone acetyltransferases (HAT) transfer the acetyl moiety
from acetyl coenzyme A to the lysine, and histone deacetylases (HDAC) remove the
acetyl groups re-establishing the positive charge in the histones. HDAC
inhibitors have antiproliferative activity against human cancer cells via cell
cycle arrest, pro-differentiation, and pro-apoptosis. In recent years, many
studies have shown that specific HDAC inhibitors are helpful for
gastrointestinal cancer therapy.
DOI: 10.1111/j.1440-1746.2005.03807.x
PMID: 15955204 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25707943 | 1. Biochem Cell Biol. 2015 Apr;93(2):149-57. doi: 10.1139/bcb-2014-0119. Epub
2014 Dec 16.
Acetyl-lysine erasers and readers in the control of pulmonary hypertension and
right ventricular hypertrophy.
Stratton MS(1), McKinsey TA.
Author information:
(1)Department of Medicine, Division of Cardiology, University of Colorado
Denver, 12700 E. 19th Ave, Aurora, CO 80045-0508, USA.
Acetylation of lysine residues within nucleosomal histone tails provides a
crucial mechanism for epigenetic control of gene expression. Acetyl groups are
coupled to lysine residues by histone acetyltransferases (HATs) and removed by
histone deacetylases (HDACs), which are also commonly referred to as "writers"
and "erasers", respectively. In addition to altering the electrostatic
properties of histones, lysine acetylation often creates docking sites for
bromodomain-containing "reader" proteins. This review focuses on epigenetic
control of pulmonary hypertension (PH) and associated right ventricular (RV)
cardiac hypertrophy and failure. Effects of small molecule HDAC inhibitors in
pre-clinical models of PH are highlighted. Furthermore, we describe the recently
discovered role of bromodomain and extraterminal (BET) reader proteins in the
control of cardiac hypertrophy, and provide evidence suggesting that one member
of this family, BRD4, contributes to the pathogenesis of RV failure. Together,
the data suggest intriguing potential for pharmacological epigenetic therapies
for the treatment of PH and right-sided heart failure.
L'acétylation des lysines situées á l'intérieur des queues des histones
nucléosomales constitue un mécanisme crucial de contrôle épigénétique de
l'expression génique. Les groupes acétyles sont couplés aux lysines par les
histone acétytransférases (HAT) et sont enlevés par les histone déacétylases
(HDAC), dont on dit qu'elles sont respectivement des « rédacteurs » et des «
effaceurs ». En plus de modifier les propriétés électrostatiques des histones,
l'acétylation des lysines crée souvent un site d'amarrage des protéines
comportant un bromodomaine qu'on dit « lectrices ». Cet article de revue se
concentre sur le contrôle épigénétique de l‘hypertension pulmonaire (HP), et de
l'hypertrophie et de l'insuffisance cardiaques ventriculaires droites qui lui
sont associées. Les effets de petites molécules qui inhibent les HDAC dans des
modèles précliniques d'HP sont soulignés. De plus, les auteurs décrivent le rôle
récemment découvert des protéines lectrices BET (bromodomaine et domaine
terminal) dans le contrôle de l'hypertrophie cardiaque, et présentent des
indices qui suggèrent qu'un membre de cette famille, BRD4, contribue á la
pathogenèse de l'insuffisance ventriculaire droite. Dans l'ensemble, les données
suggèrent que les thérapies pharmacologiques épigénétiques possèdent un
potentiel de traitement intéressant de l'HP et de l'insuffisance cardiaque
localisée du côté droit. [Traduit par la Rédaction]
DOI: 10.1139/bcb-2014-0119
PMCID: PMC4975937
PMID: 25707943 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11479283 | 1. J Biol Chem. 2001 Oct 12;276(41):38307-19. doi: 10.1074/jbc.M100290200. Epub
2001 Jul 30.
Regulation of global acetylation in mitosis through loss of histone
acetyltransferases and deacetylases from chromatin.
Kruhlak MJ(1), Hendzel MJ, Fischle W, Bertos NR, Hameed S, Yang XJ, Verdin E,
Bazett-Jones DP.
Author information:
(1)Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 1X8,
Canada.
Histone acetylation, a reversible modification of the core histones, is widely
accepted to be involved in remodeling chromatin organization for genetic
reprogramming. Histone acetylation is a dynamic process that is regulated by two
classes of enzymes, the histone acetyltransferases (HATs) and histone
deacetylases (HDACs). Although promoter-specific acetylation and deacetylation
has received most of the recent attention, it is superimposed upon a broader
acting and dynamic acetylation that profoundly affects many nuclear processes.
In this study, we monitored this broader histone acetylation as cells enter and
exit mitosis. In contrast to the hypothesis that HATs and HDACs remain bound to
mitotic chromosomes to provide an epigenetic imprint for postmitotic
reactivation of the genome, we observed that HATs and HDACs are spatially
reorganized and displaced from condensing chromosomes as cells progress through
mitosis. During mitosis, HATs and HDACs are unable to acetylate or deacetylate
chromatin in situ despite remaining fully catalytically active when isolated
from mitotic cells and assayed in vitro. Our results demonstrate that HATs and
HDACs do not stably bind to the genome to function as an epigenetic mechanism of
selective postmitotic gene activation. Our results, however, do support a role
for spatial organization of these enzymes within the cell nucleus and their
relationship to euchromatin and heterochromatin postmitotically in the
reactivation of the genome.
DOI: 10.1074/jbc.M100290200
PMID: 11479283 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9708888 | 1. FEBS Lett. 1998 Jul 17;431(2):131-3. doi: 10.1016/s0014-5793(98)00752-2.
How do histone acetyltransferases select lysine residues in core histones?
Kimura A(1), Horikoshi M.
Author information:
(1)Department of Cellular Biology, Institute of Molecular and Cellular
Biosciences, The University of Tokyo, Japan.
Acetylation of specific lysines of core histone N-terminal tails correlates with
chromatin assembly and specific regulation of gene expression. Core histones
acetylated at particular lysines mediate effects on chromatin function; however,
the manner in which different histone acetyltransferases (HATs) discriminate
lysines is unknown. Here we propose a putative rule for lysine selection by HATs
based on the primary sequence in the vicinity of lysines in the core histone
N-terminal tails and in flanking sequence. This provides insight into the
molecular basis of site selection of core histones by HATs.
DOI: 10.1016/s0014-5793(98)00752-2
PMID: 9708888 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9780836 | 1. Bioessays. 1998 Aug;20(8):615-26. doi:
10.1002/(SICI)1521-1878(199808)20:8<615::AID-BIES4>3.0.CO;2-H.
Roles of histone acetyltransferases and deacetylases in gene regulation.
Kuo MH(1), Allis CD.
Author information:
(1)Department of Biology, University of Rochester, NY, USA.
Acetylation of internal lysine residues of core histone N-terminal domains has
been found correlatively associated with transcriptional activation in
eukaryotes for more than three decades. Recent discoveries showing that several
transcriptional regulators possess intrinsic histone acetyltransferase (HAT) and
deacetylase (HDAC) activities strongly suggest that histone acetylation and
deacetylation each plays a causative role in regulating transcription.
Intriguingly, several HATs have been shown an ability to acetylate nonhistone
protein substrates (e.g., transcription factors) in vitro as well, suggesting
the possibility that internal lysine acetylation of multiple proteins exists as
a rapid and reversible regulatory mechanism much like protein phosphorylation.
This article reviews recent developments in histone acetylation and
transcriptional regulation. We also discuss several important, yet unanswered,
questions.
DOI: 10.1002/(SICI)1521-1878(199808)20:8<615::AID-BIES4>3.0.CO;2-H
PMID: 9780836 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17325692 | 1. Cell Res. 2007 Mar;17(3):195-211. doi: 10.1038/sj.cr.7310149.
HDACs, histone deacetylation and gene transcription: from molecular biology to
cancer therapeutics.
Gallinari P(1), Di Marco S, Jones P, Pallaoro M, Steinkühler C.
Author information:
(1)Istituto di Ricerche di Biologia Molecolare P. Angeletti-IRBM-Merck Research
Laboratories Rome, Pomezia, Italy.
Histone deacetylases (HDACs) and histone acetyl transferases (HATs) are two
counteracting enzyme families whose enzymatic activity controls the acetylation
state of protein lysine residues, notably those contained in the N-terminal
extensions of the core histones. Acetylation of histones affects gene expression
through its influence on chromatin conformation. In addition, several
non-histone proteins are regulated in their stability or biological function by
the acetylation state of specific lysine residues. HDACs intervene in a
multitude of biological processes and are part of a multiprotein family in which
each member has its specialized functions. In addition, HDAC activity is tightly
controlled through targeted recruitment, protein-protein interactions and
post-translational modifications. Control of cell cycle progression, cell
survival and differentiation are among the most important roles of these
enzymes. Since these processes are affected by malignant transformation, HDAC
inhibitors were developed as antineoplastic drugs and are showing encouraging
efficacy in cancer patients.
DOI: 10.1038/sj.cr.7310149
PMID: 17325692 [Indexed for MEDLINE] |