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201 | 22313602_1 | In this model , cancer cells secrete hydrogen peroxide ( H2O2 ) , initiating oxidative stress and aerobic glycolysis in the tumor stroma . | [
"none"
] |
202 | 22313602_2 | This , in turn , drives L-lactate secretion from cancer-associated fibroblasts . | [
"none"
] |
203 | 22313602_3 | Secreted L-lactate then fuels oxidative mitochondrial metabolism ( OXPHOS ) in epithelial cancer cells , by acting as a paracrine onco-metabolite . | [
"none"
] |
204 | 22313602_4 | We have previously termed this type of two-compartment tumor metabolism the " Reverse Warburg Effect, " as aerobic glycolysis takes place in stromal fibroblasts , rather than epithelial cancer cells . | [
"none"
] |
205 | 22313602_5 | Here , we used MCT4 immuno-staining of human breast cancer tissue microarrays ( TMAs ; > 180 triple-negative patients ) to directly assess the prognostic value of the " Reverse Warburg Effect. " | [
"none"
] |
206 | 22313602_6 | MCT4 expression is a functional marker of hypoxia , oxidative stress , aerobic glycolysis , and L-lactate efflux . | [
"none"
] |
207 | 22313602_7 | Remarkably , high stromal MCT4 levels ( score = 2 ) were specifically associated with decreased overall survival ( < 18% survival at 10 y post-diagnosis ) . | [
"none"
] |
208 | 22313602_8 | In contrast , patients with absent stromal MCT4 expression ( score = 0 ) , had 10-y survival rates of ( p-value < 10 ( -32 ) ) . | [
"none"
] |
209 | 22313602_9 | High stromal levels of MCT4 were strictly correlated with a loss of stromal Cav-1 ( p-value < 10 ( -14 ) ) , a known marker of early tumor recurrence and metastasis . | [
"none"
] |
210 | 22313602_10 | In fact , the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely identify high-risk triple-negative breast cancer patients , consistent with the goal of individualized risk-assessment and personalized cancer treatment . | [
"none"
] |
211 | 22313602_11 | However , epithelial MCT4 staining had no prognostic value , indicating that the " conventional " Warburg effect does not predict clinical outcome . | [
"none"
] |
212 | 22313602_12 | Thus , the " Reverse Warburg Effect " or " parasitic " energy-transfer is a key determinant of poor overall patient survival . | [
"none"
] |
213 | 22313602_13 | As MCT4 is a druggable-target , MCT4 inhibitors should be developed for the treatment of aggressive breast cancers , and possibly other types of human cancers . | [
"none"
] |
214 | 22313602_14 | Similarly , we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT-inhibitors ( such as , AR-C155858 , AR-C117977 , and AZD-3965 ) . | [
"none"
] |
215 | 23143302_0 | Mps one binder 1a ( MOB1A ) and MOB1B are key components of the Hippo signaling pathway and are mutated or inactivated in many human cancers . | [
"none"
] |
216 | 23143302_1 | Here we show that intact Mob1a or Mob1b is essential for murine embryogenesis and that loss of the remaining WT Mob1 allele in Mob1a(\u0394/\u0394)1b(tr/+) or Mob1a(\u0394/+)1b(tr/tr) mice results in tumor development . | [
"none"
] |
217 | 23143302_2 | Because most of these cancers resembled trichilemmal carcinomas , we generated double-mutant mice bearing tamoxifen-inducible , keratinocyte-specific homozygous-null mutations of Mob1a and Mob1b ( kDKO mice). kDKO mice showed hyperplastic keratinocyte progenitors and defective keratinocyte terminal differentiation and soon died of malnutrition. kDKO keratinocytes exhibited hyperproliferation , apoptotic resistance , impaired contact inhibition , enhanced progenitor self renewal , and increased centrosomes . | [
"resisting cell death",
"sustaining proliferative signaling",
"evading growth suppressors"
] |
218 | 23143302_3 | Examination of Hippo pathway signaling in kDKO keratinocytes revealed that loss of Mob1a/b altered the activities of the downstream Hippo mediators LATS and YAP1 . | [
"none"
] |
219 | 23143302_4 | Similarly , YAP1 was activated in some human trichilemmal carcinomas , and some of these also exhibited MOB1A/1B inactivation . | [
"none"
] |
220 | 23143302_5 | Our results clearly demonstrate that MOB1A and MOB1B have overlapping functions in skin homeostasis , and exert their roles as tumor suppressors by regulating downstream elements of the Hippo pathway . | [
"none"
] |
221 | 22460537_0 | OBJECTIVES/HYPOTHESIS Head and neck squamous cell carcinoma ( HNSCC ) is a complex disease process involving interactions with carcinoma-associated fibroblasts and endothelial cells . | [
"none"
] |
222 | 22460537_1 | We further investigated these relationships by suppressing stromal cell growth through the inhibition of fibroblast growth factor receptor ( FGFR ) . | [
"none"
] |
223 | 22460537_2 | STUDY DESIGN Preclinical investigation . | [
"none"
] |
224 | 22460537_3 | METHODS HNSCC cell lines ( FADU , OSC19 , Cal27 , SCC1 , SCC5 , SCC22A ) , fibroblast ( HS27 ) , and endothelial cells ( human umbilical vascular endothelial cell ) were cultured individually or in coculture . | [
"none"
] |
225 | 22460537_4 | Proliferation was assessed following treatment with a range of physiologic concentrations of FGFR inhibitor PD173074 . | [
"none"
] |
226 | 22460537_5 | Mice bearing established HNSCC xenografts were treated with PD173074 ( 12 mg/kg ) , and tumor histology was analyzed for stromal composition , proliferation ( Ki67 staining ) , and apoptosis ( TUNEL [ terminal deoxynucleotidyl transferase dUTP nick end labeling ] staining ) . | [
"none"
] |
227 | 22460537_6 | RESULTS In vitro , inhibition of FGFR with PD173074 dramatically reduced proliferation of fibroblasts and endothelial cells compared to untreated controls . | [
"none"
] |
228 | 22460537_7 | However , HNSCC cell proliferation was not affected by inhibition of FGFR . | [
"sustaining proliferative signaling"
] |
229 | 22460537_8 | When cocultured with fibroblasts , HNSCC cells proliferation increased by 15% to 80% ( P < .01 ) . | [
"sustaining proliferative signaling"
] |
230 | 22460537_9 | Furthermore , this fibroblast-enhanced tumor cell growth was suppressed by FGFR inhibition . | [
"sustaining proliferative signaling"
] |
231 | 22460537_10 | Additionally , treatment of mice bearing HNSCC xenografts with PD173074 resulted in significant growth inhibition ( P < .001 ) . | [
"none"
] |
232 | 22460537_11 | Additionally , those tumors from mice treated with PD173074 had a smaller stromal component , decreased proliferation , and increased apoptosis . | [
"resisting cell death",
"sustaining proliferative signaling"
] |
233 | 22460537_12 | CONCLUSIONS Targeting the FGFR pathway in head and neck cancer acts through the stromal components to decrease HNSCC growth in vivo and in vitro . | [
"none"
] |
234 | 23185620_0 | There are contradictory observations about the different radiosensitivities of cancer stem cells and cancer non-stem cells . | [
"none"
] |
235 | 23185620_1 | To resolve these contradictory observations , we studied radiosensitivities by employing breast cancer stem cell ( CSC)-like MDA-MB231 and MDA-MB453 cells as well as their corresponding non-stem cells . | [
"none"
] |
236 | 23185620_2 | CSC-like cells proliferate without differentiating and have characteristics of tumor-initiating cells [ 1 ] . | [
"none"
] |
237 | 23185620_3 | These cells were exposed to \u03b3-rays ( 1.25-8.75 Gy ) and survival curves were determined by colony formation . | [
"none"
] |
238 | 23185620_4 | A final slope , D(0) , of the survival curve for each cell line was determined to measure radiosensitivity . | [
"none"
] |
239 | 23185620_5 | The D(0) of CSC-like and non-stem MDA-MB-453 cells were 1.16 Gy and 1.55 Gy , respectively . | [
"none"
] |
240 | 23185620_6 | Similar results were observed in MDA-MB-231 cells ( 0.94 Gy vs. 1.56 Gy ) . | [
"none"
] |
241 | 23185620_7 | After determination of radiosensitivity , we investigated intrinsic cellular determinants which influence radiosensitivity including cell cycle distribution , free-radical scavengers and DNA repair . | [
"none"
] |
242 | 23185620_8 | We observed that even though cell cycle status and antioxidant content may contribute to differential radiosensitivity , differential DNA repair capacity may be a greater determinant of radiosensitivity . | [
"genomic instability and mutation"
] |
243 | 23185620_9 | Unlike non-stem cells , CSC-like cells have little/no sublethal damage repair , a low intracellular level of ataxia telangiectasia mutated ( ATM ) and delay of \u03b3-H2AX foci removal ( DNA strand break repair ) . | [
"genomic instability and mutation"
] |
244 | 23185620_10 | These results suggest that low DNA repair capacity is responsible for the high radiosensitivity of these CSC-like cells . | [
"genomic instability and mutation"
] |
245 | 12408370_0 | Hormone replacement therapy , which is a common menopausal treatment , is contraindicated in women with breast cancers due to concerns regarding the potential for breast cell proliferation . | [
"none"
] |
246 | 12408370_1 | As such , there is a need for alternative methods for treating menopausal symptoms . | [
"none"
] |
247 | 12408370_2 | To determine the influence of one such alternative , black cohosh ( Cimicifuga racemosa [ CR] ) , on estrogen-dependent mammary cancers , we conducted an in vitro investigation of the effect of an isopropanolic CR-extract on the proliferation of estrogen receptor-positive breast cancer cells . | [
"none"
] |
248 | 12408370_3 | The experiments were performed using the human breast adenocarcinoma ( MCF-7 ) cell test system , an established in vitro model for estrogen-dependent tumors . | [
"none"
] |
249 | 12408370_4 | The influence of CR-extract on the proliferation of the MCF-7 cells was determined by measuring the incorporation of radioactively labeled thymidine . | [
"none"
] |
250 | 12408370_5 | Under estrogen-deprived conditions , the CR-extract ( 10(-3)-10(-5) dilutions ) significantly inhibited MCF-7 cell proliferation . | [
"sustaining proliferative signaling"
] |
251 | 12408370_6 | Additionally , application of the CR-extract inhibited estrogen-induced proliferation of MCF-7 cells . | [
"sustaining proliferative signaling"
] |
252 | 12408370_7 | Moreover , the proliferation-inhibiting effect of tamoxifen was enhanced by the CR-extract . | [
"sustaining proliferative signaling"
] |
253 | 12408370_8 | Such data that suggest a non-estrogenic , or estrogen-antagonistic effect of CR on human breast cancer cells lead to the conclusion that CR treatment may be a safe , natural remedy for menopausal symptoms in breast cancer . | [
"none"
] |
254 | 12136428_0 | We have recently developed surface-shielded transferrin-polyethylenimine ( Tf-PEI)/DNA delivery systems that target reporter gene expression to distant tumors after systemic application . | [
"none"
] |
255 | 12136428_1 | In the present study , we used surface-shielded Tf-PEI/DNA complexes for delivering the gene for a highly potent cytokine , tumor necrosis factor-alpha ( TNFalpha ) . | [
"none"
] |
256 | 12136428_2 | TNFalpha is known for its ability to induce hemorrhagic tumor necrosis and tumor regression . | [
"none"
] |
257 | 12136428_3 | However , the therapeutic application of TNFalpha is hampered by its high systemic toxicity dictating the need to target TNFalpha activity to the tumor . | [
"none"
] |
258 | 12136428_4 | Systemic application of surface-shielded Tf-PEI complexes with the TNFalpha gene resulted in preferential expression of TNFalpha in the tumor without detectable TNFalpha serum levels , in contrast to the application of nontargeted complexes . | [
"none"
] |
259 | 12136428_5 | Tumor-targeted TNFalpha gene delivery induced pronounced hemorrhagic tumor necrosis and inhibition of tumor growth in three murine tumor models of different tissue origins , Neuro2a neuroblastoma , MethA fibrosarcoma , and M-3 melanoma , with complete tumor regressions observed in the MethA model . | [
"resisting cell death"
] |
260 | 12136428_6 | No systemic TNF-related toxicity was observed due to the localization of the TNFalpha activity to the tumor . | [
"none"
] |
261 | 12136428_7 | Targeted gene therapy may be an attractive strategy applicable to highly active , yet toxic , molecules such as TNFalpha . | [
"none"
] |
262 | 1281554_0 | Angiogenic factors produced by monocytes-macrophages are involved in the pathogenesis of chronic inflammatory disorders characterized by persistent angiogenesis . | [
"none"
] |
263 | 1281554_1 | The possibility was tested that interleukin-8 ( IL-8 ) , which is a cytokine that is chemotactic for lymphocytes and neutrophils , is also angiogenic . | [
"none"
] |
264 | 1281554_2 | Human recombinant IL-8 was potently angiogenic when implanted in the rat cornea and induced proliferation and chemotaxis of human umbilical vein endothelial cells . | [
"inducing angiogenesis"
] |
265 | 1281554_3 | Angiogenic activity present in the conditioned media of inflamed human rheumatoid synovial tissue macrophages or lipopolysaccharide-stimulated blood monocytes was equally blocked by antibodies to either IL-8 or tumor necrosis factor-alpha . | [
"inducing angiogenesis"
] |
266 | 1281554_4 | An IL-8 antisense oligonucleotide specifically blocked the production of monocyte-induced angiogenic activity . | [
"inducing angiogenesis"
] |
267 | 1281554_5 | These data suggest a function for macrophage-derived IL-8 in angiogenesis-dependent disorders such as rheumatoid arthritis , tumor growth , and wound repair . | [
"inducing angiogenesis"
] |
268 | 1282003_0 | We have observed previously that treatment of plateau-phase L5178Y murine lymphoblasts in vitro with 2'-deoxycoformycin plus deoxyadenosine ( dCF/dAdo ) can inhibit the repair of X-irradiation-induced DNA single-strand breaks ( SSB ) in these cells and that this effect is associated with synergistic cell kill . | [
"none"
] |
269 | 1282003_1 | In this study we examined the effect of a combination treatment of plateau-phase L5178Y cells with bleomycin ( BLM ) plus dCF/dAdo . | [
"none"
] |
270 | 1282003_2 | Incubation of BLM-treated cells with dCF/dAdo resulted in significant inhibition of the repair of BLM-induced DNA SSB . | [
"genomic instability and mutation"
] |
271 | 1282003_3 | However , an additive , but not a synergistic , increase in cell kill was observed when cells were treated with a combination of BLM plus dCF/dAdo . | [
"resisting cell death"
] |
272 | 22784709_0 | Src kinase is elevated in breast tumors that are ER/PR negative and do not overexpress HER2 , but clinical trials with Src inhibitors have shown little activity . | [
"none"
] |
273 | 22784709_1 | The present study evaluated preclinical efficacy of a novel peptidomimetic compound , KX-01 ( KX2-391 ) , that exhibits dual action as an Src and pretubulin inhibitor . | [
"none"
] |
274 | 22784709_2 | KX-01 was evaluated as a single-agent and in combination with paclitaxel in MDA-MB-231 , MDA-MB-157 , and MDA-MB-468 human ER/PR/HER2-negative breast cancer cells . | [
"none"
] |
275 | 22784709_3 | Treatments were evaluated by growth/apoptosis , isobologram analysis , migration/invasion assays , tumor xenograft volume , metastasis , and measurement of Src , focal adhesion kinase ( FAK ) , microtubules , Ki67 , and microvessel density . | [
"none"
] |
276 | 22784709_4 | KX-01 inhibited cell growth in vitro and in combination with paclitaxel resulted in synergistic growth inhibition . | [
"none"
] |
277 | 22784709_5 | KX-01 resulted in a dose-dependent inhibition of MDA-MB-231 and MDA-MB-157 tumor xenografts ( 1 and 5 mg/kg , twice daily ) . | [
"none"
] |
278 | 22784709_6 | KX-01 inhibited activity of Src and downstream mediator FAK in tumors that was coincident with reduced proliferation and angiogenesis and increased apoptosis . | [
"resisting cell death",
"sustaining proliferative signaling",
"inducing angiogenesis"
] |
279 | 22784709_7 | KX01 also resulted in microtubule disruption in tumors . | [
"none"
] |
280 | 22784709_8 | Combination of KX-01 with paclitaxel resulted in significant regression of MDA-MB-231 tumors and reduced metastasis to mouse lung and liver . | [
"activating invasion and metastasis"
] |
281 | 22784709_9 | KX-01 is a potently active Src/pretubulin inhibitor that inhibits breast tumor growth and metastasis . | [
"activating invasion and metastasis"
] |
282 | 22784709_10 | As ER/PR/HER2-negative patients are candidates for paclitaxel therapy , combination with KX-01 may potentiate antitumor efficacy in management of this aggressive breast cancer subtype . | [
"none"
] |
283 | 20658731_0 | PURPOSE Overproduction of reactive oxygen species ( ROS ) intermediates above the functional capability of cellular antioxidants may result in instability of important macromolecules and represents the molecular basis of many diseases including inflammation processes , cardiovascular alterations , cancer etc . | [
"none"
] |
284 | 20658731_1 | The purpose of this study was to determine plasma level of superoxide anion , hydrogen-peroxide and malondialdehyde ( MDA ) as markers of oxidative stress and activities of superoxide dismutase ( SOD ) , catalase ( CAT ) and glutathione peroxidase ( GPx ) as antioxidant enzymes in B-chronic lymphocytic leukemia ( B-CLL ) patients . | [
"none"
] |
285 | 20658731_2 | METHODS The study included 29 untreated B-CLL patients in stage A , and 21 in stages B and C , classified according to the Binet system ; 31 healthy volunteers formed the control group . | [
"none"
] |
286 | 20658731_3 | After centrifugation of heparinized peripheral blood , plasma levels of all investigated parameters were determined using spectrophotometric methods . | [
"none"
] |
287 | 20658731_4 | RESULTS Plasma CAT activity was increased in B-CLL patients compared with control subjects ; also , progression of disease was related with significantly higher plasma activity of CAT . | [
"tumor promoting inflammation"
] |
288 | 20658731_5 | Also , B-CLL patients showed significantly higher plasma concentration of MDA compared with controls . | [
"none"
] |
289 | 20658731_6 | No statistically significant differences of superoxide anion and hydrogen peroxide as well as plasma activity of SOD and GPx between the tested groups were noted . | [
"tumor promoting inflammation"
] |
290 | 20658731_7 | CONCLUSION Increase of CAT activity in B-CLL patients indicates that there is stimulation of the antioxidant enzyme system , while the increase of MDA concentration shows increased lipid peroxidation level . | [
"tumor promoting inflammation"
] |
291 | 20658731_8 | According to these results it could be concluded that an imbalance exists between oxidants and antioxidants in the plasma of B-CLL patients . | [
"tumor promoting inflammation"
] |
292 | 22431001_0 | Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with exposure to silica . | [
"none"
] |
293 | 22431001_1 | Rats were exposed to crystalline silica by inhalation ( 15 mg m(-3) , 6 h per day , 5 days ) and global gene expression profile was determined in the lungs by microarray analysis at 1 , 2 , 4 , 8 and 16 weeks following termination of silica exposure . | [
"none"
] |
294 | 22431001_2 | The number of significantly differentially expressed genes ( >1.5-fold change and <0.01 false discovery rate P-value ) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats . | [
"none"
] |
295 | 22431001_3 | Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings . | [
"none"
] |
296 | 22431001_4 | The number of biological functions , canonical pathways and molecular networks significantly affected by silica exposure , as identified by the bioinformatics analysis of the significantly differentially expressed genes detected during the post-exposure time intervals , also exhibited a steady increase similar to the silica-induced pulmonary toxicity . | [
"none"
] |
297 | 22431001_5 | Genes involved in oxidative stress , inflammation , respiratory diseases , cancer , and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs ; however , unresolved inflammation was the single most significant biological response to pulmonary exposure to silica . | [
"tumor promoting inflammation"
] |
298 | 22431001_6 | Excessive mucus production , as implicated by significant overexpression of the pendrin coding gene , SLC26A4 , was identified as a potential novel mechanism for silica-induced pulmonary toxicity . | [
"none"
] |
299 | 22431001_7 | Collectively , the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat . | [
"none"
] |
300 | 22431001_8 | Published 2012 . | [
"none"
] |