tbuckley/cabot-search huggingface dataset:
Protective Alterations in Phase 1 and 2 Metabolism of Aflatoxin B1 by Oltipraz in Residents of Qidong, People's Republic of China
Authors: J.-S. Wang, X. Shen, X. He, Y.-R. Zhu, B.-C. Zhang, J.-B. Wang, G.-S. Qian, S.-Y. Kuang, A. Zarba, P. A. Egner, L. P. Jacobson, A. Munoz, K. J. Helzlsouer, J. D. Groopman, T. W. Kensler
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Residents of Qidong, People's Republic of China, are at high risk for development of hepatocellular carcinoma, in part due to consumption of foods contaminated with aflatoxins, which require metabolic activation to become carcinogenic. In a randomized, placebo-controlled, double-blind phase IIa chemoprevention trial, we tested oltipraz, an antischistosomal drug that has been shown to be a potent and effective inhibitor of aflatoxin-induced hepatocarcinogenesis in animal models. METHODS: In 1995, 234 adults from Qidong were enrolled. Healthy eligible individuals were randomly assigned to receive by mouth 125 mg oltipraz daily, 500 mg oltipraz weekly, or a placebo. Sequential immunoaffinity chromatography and liquid chromatography coupled to mass spectrometry or to fluorescence detection were used to identify and quantify phase 1 and phase 2 metabolites of aflatoxin B 1 in the urine of study participants. Reported P values are two-sided. RESULTS: One month of weekly administration of 500 mg oltipraz led to a 51% decrease in median levels of the phase 1 metabolite aflatoxin M 1 excreted in urine compared with administration of a placebo ( P = .030), but it had no effect on levels of a phase 2 metabolite, aflatoxin-mercapturic acid ( P = .871). By contrast, daily intervention with 125 mg oltipraz led to a 2.6-fold increase in median aflatoxin-mercapturic acid excretion ( P = .017) but had no effect on excreted aflatoxin M 1 levels ( P = .682). CONCLUSIONS: Intermittent, high-dose oltipraz inhibited phase 1 activation of aflatoxins, and sustained low-dose oltipraz increased phase 2 conjugation of aflatoxin, yielding higher levels of aflatoxin-mercapturic acid. While both mechanisms can contribute to protection, this study highlights the feasibility of inducing phase 2 enzymes as a chemopreventive strategy in humans.
<i>HLA-B</i>*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer
Authors: Chun-Fang Xu, Toby Johnson, Xiaojing Wang, Chris Carpenter, Alan P. Graves, Liling Warren, Zhengyu Xue, Karen S. King, Dana J. Fraser, Sandy Stinnett, Linda P. Briley, Ionel Mitrica, Colin F. Spraggs, Matthew R. Nelson, Hiroomi Tada, Andreas du Bois, Thomas Powles, Neil Kaplowitz, Lini N. Pandite
Journal: Clinical Cancer Research (2015)

Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury.The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted.The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation [P = 5.0 × 10(-5) for maximum on-treatment ALT (MaxALT); P = 4.8 × 10(-4) for time to ALT > 3× upper limit of normal (ULN) event; P = 4.1 × 10(-5) for time to ALT > 5× ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 × 10(-4) for ALT > 3× ULN, P = 9.8 × 10(-3) for ALT > 5× ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 × 10(-5) for MaxALT, P = 5.1 × 10(-6) for time to ALT > 3×ULN event, P = 5.8 × 10(-6) for time to ALT > 5× ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3× ULN was 31% and 19%, respectively, and frequency of ALT > 5× ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation.These data indicate that HLA-B*57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients.
Suppression of PTEN Expression Is Essential for Antiapoptosis and Cellular Transformation by Oncogenic Ras
Authors: Krishna Murthi Vasudevan, Ravshan Burikhanov, Anindya Goswami, Vivek M. Rangnekar
Journal: Cancer Research (2007)

Abstract Ras is one of the most commonly mutated oncogenes in the array of human cancers. The mechanism by which Ras induces cellular transformation is, however, not fully elucidated. We present here evidence that oncogenic Ras suppresses the expression of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 (PTEN), and this action of oncogenic Ras is mediated by the Raf-mitogen-activated protein kinase/extracellular signal–regulated kinase (ERK) kinase (MEK)-ERK pathway via up-regulation of c-Jun. Jun+/+ cells undergo cellular transformation by oncogenic Ras, and restoration of wild-type PTEN, but not a phosphate-defective mutant of PTEN, induces apoptosis in these cells. Conversely, in Jun−/− cells, oncogenic Ras neither suppresses PTEN nor causes transformation, but rather it induces PTEN-dependent apoptosis. An apoptotic response to oncogenic Ras in Jun−/− cells can be prevented by suppressing PTEN expression. These findings imply that oncogenic Ras suppresses the apoptotic gene PTEN via the Raf-MEK-ERK-c-Jun pathway to induce antiapoptosis and cellular transformation. Together, our findings identify a novel molecular interface between the oncogenic and tumor suppressor pathways that regulates cellular transformation and survival. [Cancer Res 2007;67(21):10343–50]
Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner
Authors: Silvia S. Barbieri, Patrizia Amadio, Sara Gianellini, Eva Tarantino, Elena Zacchi, Fabrizio Veglia, Louise R. Howe, Babette B. Weksler, Luciana Mussoni, Elena Tremoli
Journal: Circulation (2012)

Selective inhibitors of cyclooxygenase (COX)-2 increase the risk of myocardial infarction and thrombotic events, but the responsible mechanisms are not fully understood.We found that ferric chloride-induced arterial thrombus formation was significantly greater in COX-2 knockout compared with wild-type mice. Cross-transfusion experiments excluded the likelihood that COX-2 knockout platelets, despite enhanced aggregation responses to collagen and thrombin, are responsible for increased arterial thrombus formation in COX-2 knockout mice. Importantly, we observed that COX-2 deletion decreased prostacyclin synthase and production and peroxisome proliferator-activated receptor- and sirtuin-1 (SIRT1) expression, with consequent increased upregulation of tissue factor (TF), the primary initiator of blood coagulation. Treatment of wild-type mice with a prostacyclin receptor antagonist or a peroxisome proliferator-activated receptor-δ antagonist, which predisposes to arterial thrombosis, decreased SIRT1 expression and increased TF activity. Conversely, exogenous prostacyclin or peroxisome proliferator-activated receptor-δ agonist completely reversed the thrombotic phenotype in COX-2 knockout mice, restoring normal SIRT1 levels and reducing TF activity. Furthermore, inhibition of SIRT1 increased TF expression and activity and promoted generation of occlusive thrombi in wild-type mice, whereas SIRT1 activation was sufficient to decrease abnormal TF activity and prothrombotic status in COX-2 knockout mice.Modulation of SIRT1 and hence TF by prostacyclin/peroxisome proliferator-activated receptor-δ pathways not only represents a new mechanism in controlling arterial thrombus formation but also might be a useful target for therapeutic intervention in the atherothrombotic complications associated with COX-2 inhibitors.
Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk
Authors: Douglas Moeckel, Soon Soeg Jeong, Xiaofeng Sun, M. Johan Broekman, Annie Nguyen, Joan H. F. Drosopoulos, Aaron J. Marcus, Simon C. Robson, Ridong Chen, Dana Abendschein
Journal: Science Translational Medicine (2014)

APT102, an optimized human apyrase designed for treatment of myocardial infarction, improves recanalization of occluded arteries and decreases heart muscle damage, without an increased bleeding risk.
Synergistic Effects of Metformin Treatment in Combination with Gefitinib, a Selective EGFR Tyrosine Kinase Inhibitor, in LKB1 Wild-type NSCLC Cell Lines
Authors: Floriana Morgillo, Ferdinando Carlo Sasso, Carminia Maria Della Corte, Donata Vitagliano, Elena D'Aiuto, Teresa Troiani, Erika Martinelli, Ferdinando De Vita, Michele Orditura, Raffaele De Palma, Fortunato Ciardiello
Journal: Clinical Cancer Research (2013)

EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) have been found to be effective against lung cancer, but clinical resistance to these agents has developed as their usage has increased. Metformin is a widely used antidiabetic drug and also displays significant growth-inhibitory and proapoptotic effects in several cancer models, alone or in combination with chemotherapeutic drugs.The effects of gefitinib, a selective EGFR-TKI, and metformin on a panel of non-small cell lung cancer (NSCLC) cell lines were assessed by using MTT, bromide assay, flow cytometry, anchorage-independent growth, coimmunoprecipitation, and Western blot analysis.The combination of metformin with gefitinib induced a strong antiproliferative and proapoptotic effect in NSCLC cell lines that harbored wild-type LKB1 gene. Treatment with metformin as single agent, however, induced an activation and phosphorylation of mitogen-activated protein kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization. The inhibition of EGFR phosphorylation and of downstream signaling by adding gefitinib to metformin treatment abrogated this phenomenon and induced a strong apoptotic effect in vitro and in vivo.Metformin and gefitinib are synergistic in LKB1 wild-type NSCLC cells. However, further studies are required to investigate better the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use metformin in combination with molecular targeted agents.
Noninvasive clinical assessment of port‐wine stain birthmarks using current and future optical imaging technology: a review
Authors: S.A. Sharif, E. Taydas, A. Mazhar, R. Rahimian, K.M. Kelly, B. Choi, A.J. Durkin
Journal: British Journal of Dermatology (2012)

Port-wine stain (PWS) birthmarks are one class of benign congenital vascular malformation. Laser therapy is the most successful treatment modality of PWS. Unfortunately, this approach has limited efficacy, with only 10% of patients experiencing complete blanching of the PWS. To address this problem, several research groups have developed technologies and methods designed to study treatment outcome and improve treatment efficacy. This article reviews seven optical imaging techniques currently in use or under development to assess treatment efficacy, focusing on: reflectance spectrophotometers/tristimulus colorimeters; laser Doppler flowmetry and laser Doppler imaging; cross-polarized diffuse reflectance colour imaging system; reflectance confocal microscopy; optical coherence tomography; spatial frequency domain imaging; and laser speckle imaging.
Nomogram Predicting Long-Term Survival After D2 Gastrectomy for Gastric Cancer
Authors: Dong-Seok Han, Yun-Suhk Suh, Seong-Ho Kong, Hyuk-Joon Lee, Yunhee Choi, Susumu Aikou, Takeshi Sano, Byung-Joo Park, Woo-Ho Kim, Han-Kwang Yang
Journal: Journal of Clinical Oncology (2012)

The aim of this study was to combine clinicopathologic variables associated with overall survival after gastric resection with D2 lymphadenectomy (D2 gastrectomy) for gastric cancer into a prediction nomogram.We retrospectively analyzed 7,954 patients who underwent D2 gastrectomy for gastric cancer at Seoul National University Hospital (SNUH) in Seoul, Korea. Two thirds of the patients were randomly assigned to the training set (n = 5,300), and one third were assigned to the validation set (n = 2,654). Multivariate analysis by Cox proportional hazards regression was performed using the training set, and the nomogram was constructed. Discrimination and calibration were performed using the SNUH validation set. Additional external validation was performed using the data set (n = 2,500) from Cancer Institute Ariake Hospital (CIAH) in Tokyo, Japan.The multivariate Cox model identified age at diagnosis, sex, location, depth of invasion, number of metastatic lymph nodes, and number of examined lymph nodes as covariates associated with survival. In the SNUH validation set, the nomogram exhibited superior discrimination power compared with the seventh American Joint Committee on Cancer TNM classification (Harrell's C-index, 0.78 v 0.69, respectively; P < .001). Calibration of the nomogram predicted survival corresponding closely with the actual survival. In the CIAH validation set, discrimination was good (C-index, 0.79), and the predicted survival was within a 10% margin of ideal nomogram.We developed a nomogram predicting 5- and 10-year overall survival after D2 gastrectomy for gastric cancer. Validation using the SNUH and CIAH data sets revealed good discrimination and calibration, suggesting good clinical utility. The nomogram improved individualized predictions of survival.
Oncolytic Virotherapy Needs Trials, Not Access Programs
Authors: Kevin J. Harrington
Journal: Clinical Cancer Research (2013)

Oncolytic virotherapy is a novel treatment for cancer that exerts direct lytic and indirect immune-mediated antitumor effects. A Finnish research team has reported on an advanced therapy access program for oncolytic adenovirus. The strengths and weaknesses of this approach are highlighted with a view to informing future study conduct.
Haemodynamic studies during short-term preservation of the autoperfusing heart-lung preparation
Authors: D. K. C. COOPER
Journal: Cardiovascular Research (1975)

Preservation of the donor heart in a viable state for even a few hours would greatly facilitate clinical cardiac transplantation. The autoperfusing heart-lung preparation has been investigated for periods of 2 to 6 has a means of short-term preservation of the heart. Its functional capability has been assessed by observations of a number of haemodynamic parameters, including those parameters believed to give an indication of the state of myocardial contractility. Although conversion of the normal circulation to that of the preparation was accompanied by considerable falls in max dP/dt and its derivative max dP/dt/P, there was a subsequent stabilization or improvement in these parameters during the period of autoperfusion. Haematoxylin-basic fuchsin-picric acid staining of the myocardium showed no evidence of myocardial ischaemia during the perfusion period. These observations, together with other haemodynamic and histological observations, suggested that myocardial perfusion by this technique was satisfactory. The effects of a coronary dilator such as dipyridamole have been observed, and its value in approximating the coronary and pulmonary blood flows in such a preparation is discussed. These studies would suggest that the autoperfusing heart-lung preparation can provide a simple and satisfactory form of short-term storage of the heart and, with further experience, may prove of value in clinical cardiac transplantation.
Predictive Properties of Impaired Glucose Tolerance for Cardiovascular Risk Are Not Explained by the Development of Overt Diabetes During Follow-Up
Authors: Qing Qiao, Pekka Jousilahti, Johan Eriksson, Jaakko Tuomilehto
Journal: Diabetes Care (2003)

OBJECTIVE—To evaluate the relationship of impaired glucose tolerance (IGT) at baseline to coronary heart disease (CHD) incidence, and cardiovascular disease (CVD) and total mortality at follow-up, and to analyze whether the relationship is independent of the subsequent development of diabetes during follow-up. RESEARCH DESIGN AND METHODS—A baseline screening survey for diabetes was performed in 1987 using a 2-h 75-g oral glucose tolerance test. A total of 1,234 men and 1,386 women aged 45–64 years, who were free of diabetes at baseline, were followed up for 10 years. During the follow-up, 153 subjects had an incident CHD event, 224 died, and 100 deaths were due to cardiovascular causes. Multivariate adjusted (adjusted for age, sex, waist-to-hip ratio, systolic blood pressure, cholesterol, HDL cholesterol, and smoking) hazard ratio (HR) was estimated using Cox regression analysis. RESULTS—In subjects who had IGT at baseline and who did not progress to diabetes during the follow-up, the multivariate adjusted HR (95% CI) was 1.49 (0.95–2.34) for CHD incidence, 2.34 (1.42–3.85) for CVD mortality, and 1.65 (1.13–2.40) for all-cause mortality. CONCLUSIONS—Baseline IGT was an independent risk predictor for cardiovascular morbidity and mortality and for total mortality, which was not confounded by the subsequent development of overt diabetes.
Cost comparison of axillary sentinel lymph node detection and axillary lymphadenectomy in early breast cancer. A national study based on a prospective multi-institutional series of 985 patients ‘on behalf of the Group of Surgeons from the French Unicancer Federation’
Authors: J.M. Classe, S. Baffert, B. Sigal-Zafrani, M. Fall, C. Rousseau, S. Alran, P. Rouanet, C. Belichard, H. Mignotte, G. Ferron, F. Marchal, S. Giard, C. Tunon de Lara, G. Le Bouedec, J. Cuisenier, R. Werner, I. Raoust, J.-F. Rodier, F. Laki, P.-E. Colombo, S. Lasry, C. Faure, H. Charitansky, J.-B. Olivier, M.-P. Chauvet, E. Bussières, P. Gimbergues, B. Flipo, G. Houvenaeghel, F. Dravet, A. Livartowski
Journal: Annals of Oncology (2011)
Development of adiposity in adolescence: five year longitudinal study of an ethnically and socioeconomically diverse sample of young people in Britain
Authors: Jane Wardle, Naomi Henning Brodersen, Tim J Cole, Martin J Jarvis, David R Boniface
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To examine the developmental trajectory of obesity in adolescence in relation to sex, ethnicity, and socioeconomic status. <b>Design</b> Five year longitudinal cohort study of a socioeconomically and ethnically diverse sample of school students aged 11-12 years at baseline. <b>Setting</b> 36 London schools recruited to the study in 1999 by a stratified random sampling procedure. <b>Participants</b> 5863 students participated in one or more years. <b>Main outcome measures</b> Weight, height, and waist circumference measured annually by trained researchers; overweight and obesity defined according to International Obesity Task Force criteria; adiposity and central adiposity indexed by body mass index (BMI) and waist standard deviation scores relative to 1990 British reference values. <b>Results</b> In school year 7 (age 11-12), the prevalence of overweight and obesity combined was almost 25%, with higher rates in girls (29%) and students from lower socioeconomic backgrounds (31%) and the highest rates in black girls (38%). Prevalence of obesity increased over the five years of the study at the expense of overweight, but no reduction occurred in the proportion of students with BMIs in the healthy range. Waist circumferences were high compared with 1990 norms at age 11 (by 0.79 SD in boys and by 1.15 SD in girls) and increased further over time. Both BMI and waist circumference tracked strongly over the five years. <b>Conclusions</b> Prevalence of overweight and obesity was high in London school students, with significant socioeconomic and ethnic inequalities. Little evidence was found of new cases of overweight or obesity emerging over adolescence, but few obese or overweight adolescents reduced to a healthy weight. The results indicate that persistent obesity is established before age 11 and highlight the need to target efforts to prevent obesity in the early years.
Process of Progression of Coronary Artery Lesions From Mild or Moderate Stenosis to Moderate or Severe Stenosis
Authors: Koichi Yokoya, Hisato Takatsu, Takahiko Suzuki, Hiroaki Hosokawa, Shinsuke Ojio, Tetsuo Matsubara, Tsutomu Tanaka, Sachiro Watanabe, Norihiko Morita, Kazuhiko Nishigaki, Genzou Takemura, Toshiyuki Noda, Shinya Minatoguchi, Hisayoshi Fujiwara
Journal: Circulation (1999)

Background —The process of progression in coronary artery disease is unknown. Methods and Results —The subjects were 36 patients with 36 objective vessels with clinically significant progression of coronary artery disease (≥15% per year) in whom 4 serial coronary arteriograms (CAGs) were performed at intervals of ≈4 months in a 1-year period. The degree of progression of percent stenosis between each of 2 serial CAGs was classified as marked (M: ≥15%), slight (S: 5% to 14%), and no progression (N: &lt;5%). From the pattern of progression, the 36 vessels were classified as 14 type 1 vessels with marked progression (N→N→M in 13 vessels and S→S→M in 1 vessel) and 22 type 2 vessels without marked progression (S→S→S in 18 vessels, N→S→S in 4). Percent stenosis at the first, second, third, and final CAGs was 44±14%, 46±13%, 46±13%, and 88±10% ( P &lt;0.05 versus first CAG) in type 1 vessels and 44±11%, 50±9%, 59±9%, and 67±9% in type 2 vessels ( P &lt;0.05 for second, third, and final CAGs versus first CAG). Type 1 vessels featured the sudden appearance of severe stenosis due to marked progression, angina pectoris, or myocardial infarction (71%) and Ambrose type II eccentric lesions indicating plaque rupture or thrombi (57%). Type 2 vessels featured continuous slight progression of stenosis with smooth vessel walls; angina pectoris (14%) occurred when the percent stenosis reached a severe level. An increase in serum C-reactive protein was observed only in the type 2 vessel group, which suggests a relation between continuous slight progression and inflammatory change. Conclusions —Two types of stenosis progression provide a new insight into the mechanism of coronary artery disease.
Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel
Authors: M. Aapro, P.A. Abrahamsson, J.J. Body, R.E. Coleman, R. Colomer, L. Costa, L. Crinò, L. Dirix, M. Gnant, J. Gralow, P. Hadji, G.N. Hortobagyi, W. Jonat, A. Lipton, A. Monnier, A.H.G. Paterson, R. Rizzoli, F. Saad, B. Thürlimann
Journal: Annals of Oncology (2007)