tbuckley/cabot-search huggingface dataset:
Structure-Specific Endonucleases Xpf and Mus81 Play Overlapping but Essential Roles in DNA Repair by Homologous Recombination
Authors: Koji Kikuchi, Takeo Narita, Van T. Pham, Junko Iijima, Kouji Hirota, Islam Shamima Keka, None Mohiuddin, Katsuya Okawa, Tetsuya Hori, Tatsuo Fukagawa, Jeroen Essers, Roland Kanaar, Matthew C. Whitby, Kaoru Sugasawa, Yoshihito Taniguchi, Katsumi Kitagawa, Shunichi Takeda
Journal: Cancer Research (2013)

DNA double-strand breaks (DSB) occur frequently during replication in sister chromatids and are dramatically increased when cells are exposed to chemotherapeutic agents including camptothecin. Such DSBs are efficiently repaired specifically by homologous recombination (HR) with the intact sister chromatid. HR, therefore, plays pivotal roles in cellular proliferation and cellular tolerance to camptothecin. Mammalian cells carry several structure-specific endonucleases, such as Xpf-Ercc1 and Mus81-Eme1, in which Xpf and Mus81 are the essential subunits for enzymatic activity. Here, we show the functional overlap between Xpf and Mus81 by conditionally inactivating Xpf in the chicken DT40 cell line, which has no Mus81 ortholog. Although mammalian cells deficient in either Xpf or Mus81 are viable, Xpf inactivation in DT40 cells was lethal, resulting in a marked increase in the number of spontaneous chromosome breaks. Similarly, inactivation of both Xpf and Mus81 in human HeLa cells and murine embryonic stem cells caused numerous spontaneous chromosome breaks. Furthermore, the phenotype of Xpf-deficient DT40 cells was reversed by ectopic expression of human Mus81-Eme1 or human Xpf-Ercc1 heterodimers. These observations indicate the functional overlap of Xpf-Ercc1 and Mus81-Eme1 in the maintenance of genomic DNA. Both Mus81-Eme1 and Xpf-Ercc1 contribute to the completion of HR, as evidenced by the data that the expression of Mus81-Eme1 or Xpf-Ercc1 diminished the number of camptothecin-induced chromosome breaks in Xpf-deficient DT40 cells, and to preventing early steps in HR by deleting XRCC3 suppressed the nonviability of Xpf-deficient DT40 cells. In summary, Xpf and Mus81 have a substantially overlapping function in completion of HR.
Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress
Authors: Kenshi Suzuki, Ariungerel Gerelchuluun, Zhengshan Hong, Lue Sun, Junko Zenkoh, Takashi Moritake, Koji Tsuboi
Journal: Neuro-Oncology (2013)

Refractoriness of glioblastoma multiforme (GBM) largely depends on its radioresistance. We investigated the radiosensitizing effects of celecoxib on GBM cell lines under both normoxic and hypoxic conditions. Two human GBM cell lines, U87MG and U251MG, and a mouse GBM cell line, GL261, were treated with celecoxib or γ-irradiation either alone or in combination under normoxic and hypoxic conditions. Radiosensitizing effects were analyzed by clonogenic survival assays and cell growth assays and by assessing apoptosis and autophagy. Expression of apoptosis-, autophagy-, and endoplasmic reticulum (ER) stress–related genes was analyzed by immunoblotting. Celecoxib significantly enhanced the radiosensitivity of GBM cells under both normoxic and hypoxic conditions. In addition, combined treatment with celecoxib and γ-irradiation induced marked autophagy, particularly in hypoxic cells. The mechanism underlying the radiosensitizing effect of celecoxib was determined to be ER stress loading on GBM cells. Celecoxib enhances the radiosensitivity of GBM cells by a mechanism that is different from cyclooxygenase-2 inhibition. Our results indicate that celecoxib may be a promising radiosensitizing drug for clinical use in patients with GBM.
A METHOD FOR DETERMINING CARDIAC OUTPUT BY THE DIRECT FICK PRINCIPLE WITHOUT GAS ANALYSIS 12
Authors: Jacob Grossman, Raymond E. Weston, Louis Leiter, R. S. Aaron, E. R. Borun, A. S. Buchberg, L. N. Hallinger, I. B. Hanenson, H. Mark, M. Wolfman
Journal: Journal of Clinical Investigation (1953)

t Based upon the total plasma clearance as calculated from the infusion rate and arterial plasma concentration
Traumatic Brain Injury in High School Athletes
Authors: John W. Powell
Journal: JAMA (1999)

The potential seriousness of mild traumatic brain injury (MTBI) is increasingly recognized; however, information on the frequency of MTBI among high school athletes is limited.To identify the type, frequency, and severity of MTBI in selected high school sports activities.Observational cohort study.Two hundred forty-six certified athletic trainers recorded injury and exposure data for high school varsity athletes participating in boys' football, wrestling, baseball and field hockey, girls' volleyball and softball, boys' and girls' basketball, and boys' and girls' soccer at 235 US high schools during 1 or more of the 1995-1997 academic years.Rates of reported MTBI, defined as a head-injured player who was removed from participation and evaluated by an athletic trainer or physician prior to returning to participation. National incidence figures for MTBI also were estimated.Of 23566 reported injuries in the 10 sports during the 3-year study period, 1219 (5.5%) were MTBIs. Of the MTBIs, football accounted for 773 (63.4%) of cases; wrestling, 128 (10.5%); girls' soccer, 76 (6.2%); boys' soccer, 69 (5.7%); girls' basketball, 63 (5.2%); boys' basketball, 51 (4.2%); softball, 25 (2.1%); baseball, 15 (1.2%); field hockey, 13 (1.1%); and volleyball, 6 (0.5%). The injury rates per 100 player-seasons were 3.66 for football, 1.58 for wrestling, 1.14 for girls' soccer, 1.04 for girls' basketball, 0.92 for boys' soccer, 0.75 for boys' basketball, 0.46 for softball, 0.46 for field hockey, 0.23 for baseball, and 0.14 for volleyball. The median time lost from participation for all MTBIs was 3 days. There were 6 cases of subdural hematoma and intracranial injury reported in football. Based on these data, an estimated 62816 cases of MTBI occur annually among high school varsity athletes participating in these sports, with football accounting for about 63% of cases.Rates of MTBI vary among sports and none of the 10 popular high school sports we studied is without the occurrence of an MTBI. Continued involvement of high school sports sponsors, researchers, medical professionals, coaches, and sports participants is essential to help minimize the risk of MTBI.
Identification of a Novel Peptide That Interferes With the Chemical Regulation of Connexin43
Authors: Junko Shibayama, Rebecca Lewandowski, Fabien Kieken, Wanda Coombs, Sejal Shah, Paul L. Sorgen, Steven M. Taffet, Mario Delmar
Journal: Circulation Research (2006)

The carboxyl-terminal domain of connexin43 (Cx43CT) is involved in various intra- and intermolecular interactions that regulate gap junctions. Here, we used phage display to identify novel peptidic sequences that bind Cx43CT and modify Cx43 regulation. We found that Cx43CT binds preferentially to peptides containing a sequence RXP, where X represents any amino acid and R and P correspond to the amino acids arginine and proline, respectively. A biased “RXP library” led to the identification of a peptide (dubbed “RXP-E”) that bound Cx43CT with high affinity. Nuclear magnetic resonance data showed RXP-E–induced shifts in the resonance peaks of residues 343 to 346 and 376 to 379 of Cx43CT. Patch-clamp studies revealed that RXP-E partially prevented octanol-induced and acidification-induced uncoupling in Cx43-expressing cells. Moreover, RXP-E increased mean open time of Cx43 channels. The full effect of RXP-E was dependent on the integrity of the CT domain. These data suggest that RXP-based peptides could serve as tools to help determine the role of Cx43 as a regulator of function in conditions such as ischemia-induced arrhythmias.
Circulating Levels of Plasminogen Activator Inhibitor Type-1, Tissue Plasminogen Activator, and Thrombomodulin in Hemodialysis Patients
Authors: ALFONS SEGARRA, PILAR CHACO[Combining Acute Accent]N, CRISTINA MARTINEZ-EYARRE, XAVIER ARGELAGUER, JOSEFA VILA, PILAR RUIZ, JOAN FORT, JORGE BARTOLOME[Combining Acute Accent], JOAQUIN CAMPS, ERNESTO MOLINER, ANTONI PELEGRI[Combining Acute Accent], FERNANDO MARCO, ANTONIO OLMOS, LLUIS PIERA
Journal: Journal of the American Society of Nephrology (2001)

Abstract. This study investigated the relationship between the circulating levels of the endothelial cell glycoproteins plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (TPA), and thrombomodulin (TM) and the major vascular risk factors described in dialysis patients. In addition, the role of these endothelial cell products as independent predictors of coronary artery disease (CAD) was analyzed. Levels of TM, TPA antigen (Ag), TPA activity, PAI-1 Ag, PAI-1 activity, TPA/PAI complexes, thrombin-antithrombin complexes, fibrinopeptide A, C-reactive protein (CRP), interleukin-1β and tumor necrosis factor-α, lipids, apoproteins A1 and B, and albumin were measured in a group of 200 nondiabetic dialysis patients and 100 healthy matched volunteers. When compared with healthy controls, dialysis patients showed increased levels of CRP, TM, TPA, and PAI-1 and evidence of increased thrombin-dependent fibrin formation. Increased levels of active PAI-1 were associated to a great extent with major classic vascular risk factors and to a lesser extent with CRP and serum triglycerides. Forty-six patients (23%) had evidence of CAD. Variables associated with CAD in the univariate analysis included age, time on dialysis, male gender, number of packs of cigarettes per year, high BP, fibrinogen, apolipoprotein B, albumin, PAI-1 activity, CRP, thrombin-antithrombin complexes, and fibrinopeptide A. Logistic regression analysis found age, high-density lipoprotein cholesterol, gender, high BP, CRP, time on dialysis, and PAI-1 activity to be independent predictors of CAD. This model classified correctly 85% of patients as having CAD and showed adequate goodness of fit for all risk categories. Our data support a pathogenic link among activated inflammatory response, endothelial injury, and CAD in hemodialysis patients and suggest that assessment of circulating PAI-1 levels could be an additional tool to identify dialysis patients who are at risk for developing atheromatous cardiovascular disease.
Phase I and Pharmacokinetic Study of Trabectedin as a 1- or 3-hour Infusion Weekly in Patients with Advanced Solid Malignancies
Authors: Bahram Forouzesh, Manuel Hidalgo, Quincy Chu, Alain Mita, Monica Mita, Garry Schwartz, José Jimeno, Javier Gómez, Vicente Alfaro, Claudia Lebedinsky, Patrik Zintl, Eric K. Rowinsky
Journal: Clinical Cancer Research (2009)

Abstract Purpose: This study was designed to determine the safety, tolerability, and pharmacokinetics, and to seek preliminary evidence of anticancer activity of trabectedin, a novel marine-derived DNA minor grove binder, when administered as a 1-hour or 3-hour i.v. infusion for 3 consecutive weeks every 4 weeks in patients with advanced solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) levels of trabectedin on these schedules, as well as to recommend doses for disease-directed studies. Experimental Design: A total of 32 and 31 patients were treated in sequential cohorts with trabectedin on the 1-hour schedule (doses ranging from 0.46 to 0.80 mg/m2) and on the 3-hour schedule (doses ranging from 0.30 to 0.65 mg/m2). Results: Neutropenia, transient elevations in hepatic transaminases and creatine phosphokinase, and fatigue precluded dose escalation above 0.70 mg/m2 (1-hour schedule) and 0.65 mg/m2 (3-hour schedule), which were determined to be the MTD levels, respectively. The pharmacokinetics of trabectedin on both schedules were characterized by a high clearance rate, a long terminal half-life, and a large volume of distribution. A patient with soft tissue sarcoma had partial response, and several soft tissue sarcoma patients had prolonged (≥6 months) stable disease. Conclusions: The MTD levels of trabectedin given weekly for 3 weeks every 4 weeks is 0.61 mg/m2 as a 1-hour infusion and 0.58 mg/m2 as a 3-hour infusion. The manageable toxicities at the MTDs, preliminary evidence of antitumor activity, pharmacokinetic profile, and the unique mechanistic aspects of trabectedin warrant further disease-directed evaluations on weekly schedules.
Pretreatment prognostic factors and treatment outcome in elderly patients with de novo acute myeloid leukemia
Authors: C.-C. Chen, C.-F. Yang, M.-H. Yang, K.-D. Lee, W.-K. Kwang, J.-Y. You, Y.-B. Yu, C.-H. Ho, C.-H. Tzeng, W.-K. Chau, H.-C. Hsu, J.-P. Gau
Journal: Annals of Oncology (2005)
Central Role of Peroxisome Proliferator–Activated Receptors in the Actions of Peroxisome Proliferators
Authors: J. Christopher Corton, Steven P. Anderson, Anja Stauber
Journal: The Annual Review of Pharmacology and Toxicology (2000)

Peroxisome proliferators (PPs) are a large class of structurally dissimilar chemicals that have diverse effects in rodents and humans. Most, if not all, of the diverse effects of PPs are mediated by three members of the nuclear receptor superfamily called peroxisome proliferator-activated receptors (PPARs). In this review, we define the molecular mechanisms of PPs, including PPAR binding specificity, alteration of gene expression through binding to DNA response elements, and cross talk with other signaling pathways. We discuss the roles of PPARs in growth promotion in rodent hepatocarcinogenesis and potential therapeutic effects, including suppression of cancer growth and inflammation.
Genetic Variations in Radiation and Chemotherapy Drug Action Pathways Predict Clinical Outcomes in Esophageal Cancer
Authors: Xifeng Wu, Jian Gu, Tsung-Teh Wu, Stephen G. Swisher, Zhongxin Liao, Arlene M. Correa, Jun Liu, Carol J. Etzel, Christopher I. Amos, Maosheng Huang, Silvia S. Chiang, Luke Milas, Walter N. Hittelman, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2006)

Purpose Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. Methods We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. Results In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72). Conclusion Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.
Enhanced Expression of Melanoma-Associated Antigens and β&lt;sub&gt;2&lt;/sub&gt;-Microglobulin on Cultured Human Melanoma Cells by Interferon&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: S K Liao, P C Kwong, M Khosravi, P B Dent
Journal: JNCI Journal of the National Cancer Institute (1982)

The effect of human leukocyte Interferon (IFN) on the in vitro growth and expression of melanoma-associated antigens (MAA), β2-microglobulin (β2m) and HLA-DR antigen on cultured human melanoma cells was studied. Exposure of melanoma cells to IFN for 64 hours resulted in a dose-dependent inhibition of growth with 46% reduction in cell number at 103 U IFN/ml and 74% reduction at 105 U/ml. Quantitative absorption experiments in the mixed hemadsorption assay determined that the expression of MAA and β2m on treated cells was enhanced at 102–105 U IFN/ml, twofold to fivefold for MAA and fivefold to twelvefold for β2m. No change was seen in HLA-DR antigen expression. The IFN-induced enhancement of MAA and β2m could be detected as early as after 16 hours and a maximum expression was reached at 96 hours after IFN exposure. The IFN-induced enhancement of MAA and β2m on melanoma cells was reversible. Studies with melanoma cells grown in stationary phase and serum-deprived conditions indicated that IFN-induced augmentation of MAA and β2m did not require cell proliferation. The data suggest that the effect of IFN on antigen expression is independent of its effect on cell growth. Further studies are needed to fully elucidate the mechanism.
pRb2/p130, Vascular Endothelial Growth Factor, p27(KIP1), and Proliferating Cell Nuclear Antigen Expression in Hepatocellular Carcinoma
Authors: Pier Paolo Claudio, Giuseppe Russo, Christine A. C. Y. Kumar, Corrado Minimo, Antonio Farina, Steve Tutton, Gennaro Nuzzo, Felice Giuliante, Giulia Angeloni, Vellone Maria, Fabio Maria Vecchio, Cristiana Di Campli, Antonio Giordano
Journal: Clinical Cancer Research (2004)

Abstract Hepatocarcinoma (HCC) is the fifth most common cancer, with more than one million fatalities occurring annually worldwide. Multiple risk factors are associated with HCC disease etiology, the highest incidence being in patients with chronic hepatitis B virus and hepatitis C virus, although other factors such as genetic makeup and environmental exposure are involved. Multiple genetic alterations including the activation of oncogenes and inactivation of tumor suppressor genes are required for malignancy in human cancers and are correlated with increased stages of carcinogenesis and further tumor progression. In this study of 21 HCC patients, we analyzed pRb2/p130, vascular endothelial growth factor (VEGF), p27(KIP1), and proliferating cell nuclear antigen as potential HCC molecular biomarkers. In our sample set, we found that p27(KIP1) was absent. Univariate survival analysis showed that proliferating cell nuclear antigen expression (diffuse staining &amp;gt;50% of positive cells in tumor) was confirmed as a significant HCC prognostic biomarker for determining patient survival agreeing with previous studies (P = 0.0126, log-rank test). Lower pRb2/p130 expression was associated to a borderline P value of inverse correlation with tumor malignancy and to a positive correlation with respect to the time from HCC diagnosis (Spearman coefficient = 0.568; P &amp;lt; 0.05). Conversely, higher VEGF expression was associated with a poor survival (P = 0.0257, log-rank test). We demonstrate for the first time that pRb2/p130 is inversely correlated with VEGF expression and tumor aggressiveness (P &amp;lt; 0.05) in p27(KIP1)-negative HCC patients. pRb2/p130 and VEGF expression are independent from tumor staging, suggesting their possible role as independent prognostic molecular biomarkers in HCC. Furthermore, we have evidence that VEGF together with pRb2/p130 may act as new HCC biomarkers in a p27(KIP1)-independent manner. Additional studies with larger numbers of patient data would allow the use of multivariable techniques and would be able to further identify patients with poorer survival.
Cd1-Restricted Nk T Cells Protect Nonobese Diabetic Mice from Developing Diabetes
Authors: Bin Wang, Yan-Biao Geng, Chyung-Ru Wang
Journal: The Journal of Experimental Medicine (2001)

NK T cells are a unique subset of T cells that recognize lipid antigens presented by CD1d. After activation, NK T cells promptly produce large amounts of cytokines, which may modulate the upcoming immune responses. Previous studies have documented an association between decreased numbers of NK T cells and the progression of some autoimmune diseases, suggesting that NK T cells may control the development of autoimmune diseases. To investigate the role of NK T cells in autoimmune diabetes, we crossed CD1 knockout (CD1KO) mutation onto the nonobese diabetic (NOD) genetic background. We found that male CD1KO NOD mice exhibited significantly higher incidence and earlier onset of diabetes compared with the heterozygous controls. The diabetic frequencies in female mice showed a similar pattern; however, the differences were less profound between female CD1KO and control mice. Early treatment of NOD mice with alpha-galactosylceramide, a potent NK T cell activator, reduced the severity of autoimmune diabetes in a CD1-dependent manner. Our results not only suggest a protective role of CD1-restricted NK T cells in autoimmune diabetes but also reveal a causative link between the deficiency of NK T cells and the induction of insulin-dependent diabetes mellitus.
Urinary Levels of Cigarette Smoke Constituent Metabolites Are Prospectively Associated with Lung Cancer Development in Smokers
Authors: Jian-Min Yuan, Yu-Tang Gao, Sharon E. Murphy, Steven G. Carmella, Renwei Wang, Yan Zhong, Kristin A. Moy, Andrew B. Davis, Li Tao, Menglan Chen, Shaomei Han, Heather H. Nelson, Mimi C. Yu, Stephen S. Hecht
Journal: Cancer Research (2011)

Polycyclic aromatic hydrocarbons (PAH) are believed to be among the principal causative agents for lung cancer in smokers, but no epidemiologic studies have evaluated the relationship of PAH uptake and metabolism to lung cancer. In this study, we quantified prediagnostic urinary levels of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a validated biomarker of PAH uptake and metabolism, as well as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and cotinine and its glucuronides (total cotinine), validated biomarkers of uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and nicotine, respectively, in relation to lung cancer risk among current smokers in a nested case-control study within a cohort of 18,244 Chinese men in Shanghai, China. Urinary levels of PheT, total NNAL, and total cotinine were significantly higher in cases than controls (N = 476 matched pairs). ORs (95% confidence intervals) for lung cancer in the second, third, fourth, and fifth quintiles of PheT were 1.70 (1.00-2.88), 1.07 (0.62-1.84), 1.48 (0.86-2.53), and 2.34 (1.33-4.11), respectively, relative to the lowest quartile (P(trend) = 0.023) after adjustment for self-reported smoking intensity and duration and urinary total NNAL and total cotinine. This study also confirmed that urinary total NNAL and total cotinine are independently related to lung cancer risk.