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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" ]