tbuckley/cabot-search huggingface dataset:
The Use of Quantitative Real-Time Reverse Transcriptase PCR for 5′ and 3′ Portions of <i>ALK</i> Transcripts to Detect <i>ALK</i> Rearrangements in Lung Cancers
Authors: Rui Wang, Yunjian Pan, Chenguang Li, Haichuan Hu, Yang Zhang, Hang Li, Xiaoyang Luo, Jie Zhang, Zhaoyuan Fang, Yuan Li, Lei Shen, Hongbin Ji, David Garfield, Yihua Sun, Haiquan Chen
Journal: Clinical Cancer Research (2012)

Approximately 3% to 7% of non-small cell lung cancers (NSCLC) harbor an ALK fusion gene, thus defining a tumor group that may be responsive to targeted therapy. The breakpoint in ALK consistently occurs at exon 20 and EML4 or other fusion partners, thus driving a strong expression of ALK kinase domain and resulting in an unbalanced expression in 5' and 3' portions of ALK transcripts. We have developed a rapid and accurate method by simultaneously detecting the expression in 5' and 3' portions of ALK mRNA.Quantitative real-time reverse transcriptase PCR (qRT-PCR) was used to examine expression levels of the 5' and 3' portions of ALK transcripts in177 NSCLCs, in which EGFR, KRAS, HER2, and BRAF mutations were absent. If unbalanced ALK mRNA expression was seen, ALK rearrangement was assumed to exist. ALK FISH was used to confirm the accuracy of qRT-PCR. RT-PCR and 5' RACE coupling sequencing identified the fusion variants.Real-time RT-PCR showed excellent sensitivity and specificity (100% and 100%, respectively) for detection of ALK rearrangements in resected specimens. In addition, six novel ALK fusion variants were identified, including one KIF5B-ALK (E17;A20) and five EML4-ALK variants (E6a;A19, E6a/b ins 18;A20, E17b ins 39;A20, E10a/b, E13;A20, and E17 ins 65;A20).Real-time RT-PCR is a rapid and accurate method for diagnosing ALK-rearranged lung cancers. Coupling of 5' RACE to this method should further facilitate rapid identification of novel ALK fusion genes.
Safe Interruption of Maintenance Therapy against Previous Infection with Four Common HIV-Associated Opportunistic Pathogens during Potent Antiretroviral Therapy
Authors: Ole Kirk, Peter Reiss, Caterina Uberti-Foppa, Markus Bickel, Jan Gerstoft, Christian Pradier, Ferdinand W. Wit, Bruno Ledergerber, Jens D. Lundgren, Hansjakob Furrer
Journal: Annals of Internal Medicine (2002)

Background: The safety of interrupting maintenance therapy for previous opportunistic infections other than Pneumocystis carinii pneumonia among patients with HIV infection who respond to potent antiretroviral therapy has not been well documented. Objective: To assess the safety of interrupting maintenance therapy for cytomegalovirus (CMV) end-organ disease, disseminated Mycobacterium avium complex (MAC) infection, cerebral toxoplasmosis, and extrapulmonary cryptococcosis in patients receiving antiretroviral therapy. Design: Observational study. Setting: Seven European HIV cohorts. Patients: 358 patients taking potent antiretroviral therapy (≥ 3 drugs) who interrupted maintenance therapy at a CD4 lymphocyte count greater than 50 × 106 cells/L. Measurements: Recurrence of opportunistic infection after interruption of maintenance therapy. Results: 379 interruptions of maintenance therapy were identified: 162 for CMV disease, 103 for MAC infection, 75 for toxoplasmosis, and 39 for cryptococcosis. During 781 person-years of follow-up, five patients had relapse. Two relapses (one of CMV disease and one of MAC infection) were diagnosed after maintenance therapy was interrupted when the CD4 lymphocyte count was less than 100 × 106 cells/L or when only one recent measurement exceeded this value. Two relapses (one of CMV disease and one of MAC infection) were diagnosed after maintenance therapy was interrupted once CD4 counts were greater than 100 × 106 cells/L for 10 and 8 months, respectively. One relapse (toxoplasmosis) was diagnosed after maintenance therapy interruption at a CD4 lymphocyte count greater than 200 × 106 cells/L for 15 months. The overall incidences of recurrent CMV disease, MAC infection, toxoplasmosis, and cryptococcosis were 0.54 per 100 person-years (95% CI, 0.07 to 1.95 per 100 person-years), 0.90 per 100 person-years (CI, 0.11 to 3.25 per 100 person-years), 0.84 per 100 person-years (CI, 0.02 to 4.68 per 100 person-years), and 0.00 per 100 person-years (CI, 0.00 to 5.27 per 100 person-years), respectively. Conclusion: Maintenance therapy against previous infection with CMV, MAC, Toxoplasma gondii, or Cryptococcus neoformans in patients with HIV infection can be interrupted after sustained CD4 count increases to greater than 200 (or possibly 100 to 200) × 106 cells/L for at least 6 months after the start of potent antiretroviral therapy. *For members of the participating European HIV cohorts, see the Appendix.
Interferon-β induces a long-lasting antiviral state in human respiratory epithelial cells
Authors: Giel R. Gaajetaan, Tanja H. Geelen, Juanita H. Vernooy, Mieke A. Dentener, Niki L. Reynaert, Gernot G. Rohde, Erik V. Beuken, Gert E. Grauls, Cathrien A. Bruggeman, Frank R. Stassen
Journal: Journal of Infection (2012)
Phosphorylation by Casein Kinase I Promotes the Turnover of the Mdm2 Oncoprotein via the SCFβ-TRCP Ubiquitin Ligase
Authors: Hiroyuki Inuzuka, Alan Tseng, Daming Gao, Bo Zhai, Qing Zhang, Shavali Shaik, Lixin Wan, Xiaolu L. Ang, Caroline Mock, Haoqiang Yin, Jayne M. Stommel, Steven Gygi, Galit Lahav, John Asara, Zhi-Xiong Jim Xiao, William G. Kaelin, J. Wade Harper, Wenyi Wei
Journal: Cancer Cell (2010)
Acetylation: A Novel Link between Double-Strand Break Repair and Autophagy
Authors: Ghadeer Shubassi, Thomas Robert, Fabio Vanoli, Saverio Minucci, Marco Foiani
Journal: Cancer Research (2012)

Abstract Histone deacetylase (HDAC) inhibitors are clinically relevant because they are used as anticancer drugs. Recent evidence sheds light on an intriguing connection among the DNA damage response (DDR), protein acetylation, and autophagy. HDAC inhibitors have been shown to counteract key steps in the cellular response to double-strand break formation by affecting checkpoint activation, homologous recombination–mediated repair of DNA lesions, and stability of crucial enzymes involved in resection of DNA ends. The degradation of the resection factors depends on autophagy, which plays a detrimental role when cells are in a hyperacetylated state and experience treatment with radiomimetic anticancer drugs. Future work will be required to further investigate the mechanisms underlying the link between acetylation, autophagy, and the DDR, as well as the significance of mTORC1 inhibitors, which are potent inducers of autophagy that are now used in cancer treatment. Cancer Res; 72(6); 1332–5. ©2012 AACR.
Cholesterol depletion associated with Leishmania major infection alters macrophage CD40 signalosome composition and effector function
Authors: Abdur Rub, Ranadhir Dey, Meenakshi Jadhav, Rohan Kamat, Santhosh Chakkaramakkil, Subrata Majumdar, Robin Mukhopadhyaya, Bhaskar Saha
Journal: Nature Immunology (2009)
mTOR Inhibitors Suppress Homologous Recombination Repair and Synergize with PARP Inhibitors via Regulating SUV39H1 in BRCA-Proficient Triple-Negative Breast Cancer
Authors: Wei Mo, Qingxin Liu, Curtis Chun-Jen Lin, Hui Dai, Yang Peng, Yulong Liang, Guang Peng, Funda Meric-Bernstam, Gordon B. Mills, Kaiyi Li, Shiaw-Yih Lin
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and has the worst outcome among all subtypes of breast cancers. Although PARP inhibitors represent a promising treatment in TNBC with BRCA1/BRCA2 mutations, there is great interest in identifying drug combinations that can extend the use of PARP inhibitors to a majority of TNBC patients with wild-type BRCA1/BRCA2. Here we explored whether mTOR inhibitors, through modulating homologous recombination (HR) repair, would provide therapeutic benefit in combination with PARP inhibitors in preclinical models of BRCA-proficient TNBC. Experimental Design: We have studied the effects of mTOR inhibitors on HR repair following DNA double-strand breaks (DSB). We further demonstrated the in vitro and in vivo activities of combined treatment of mTOR inhibitors with PARP inhibitors in BRCA-proficient TNBC. Moreover, microarray analysis and rescue experiments were used to investigate the molecular mechanisms of action. Results: We found that mTOR inhibitors significantly suppressed HR repair in two BRCA-proficient TNBC cell lines. mTOR inhibitors and PARP inhibitors in combination exhibited strong synergism against these TNBC cell lines. In TNBC xenografts, we observed enhanced efficacy of everolimus in combination with talazoparib (BMN673) compared with either drug alone. We further identified through microarray analysis and by rescue assays that mTOR inhibitors suppressed HR repair and synergized with PARP inhibitors through regulating the expression of SUV39H1 in BRCA-proficient TNBCs. Conclusions: Collectively, these findings strongly suggest that combining mTOR inhibitors and PARP inhibitors would be an effective therapeutic approach to treat BRCA-proficient TNBC patients. Clin Cancer Res; 22(7); 1699–712. ©2015 AACR.
A Prospective Study of Fruit and Vegetable Intake and the Risk of Type 2 Diabetes in Women
Authors: Simin Liu, Mary Serdula, Sok-Ja Janket, Nancy R. Cook, Howard D. Sesso, Walter C. Willett, JoAnn E. Manson, Julie E. Buring
Journal: Diabetes Care (2004)

Fruits and vegetables contain many beneficial nutrients and phytochemicals that are thought to protect against cardiovascular disease (1,2) and diabetes (3–5). Further, different types of vegetables and fruits may differ in their contents of carbohydrates, antioxidants, vitamins, minerals, and other unidentified phytochemicals. However, epidemiologic data on fruit and vegetable intake and type 2 diabetes are very limited. To evaluate the hypothesis that a high intake of fruits and vegetables protects against the incidence of type 2 diabetes and to explore whether specific subgroups of fruits and vegetables differentially affect diabetes risk, we analyzed prospective data from the Women’s Health Study (WHS) from 1993 to 2003.

The WHS comprised 39,876 female health professionals aged ≥45 years who were free of heart disease, stroke, or cancer at baseline. Detailed diet information was provided by 38,018 (95%) of the participants without previously diagnosed diabetes at baseline and who completed a 131-item semiquantitative food frequency questionnaire (6).

This semiquantitative food frequency questionnaire, including 28 vegetable and 16 fruit items, has demonstrated reasonably good validity as a measure of long-term dietary intakes in women (6). The average daily intakes of individual fruits and vegetables were calculated by multiplying the intake frequency by the portion size of the specific items. Intake of total fruits and vegetables was then computed by summing over the intake of individual items. We divided the vegetables into groups, including cruciferous (broccoli, …
Multivariate modelling of testosterone-dominance associations
Authors: Helmuth Nyborg
Journal: Behavioral and Brain Sciences (2004)

Mazur &amp; Booth (1998) (M&amp;B) suggested that high testosterone (T) relates to status, dominance, and (anti-) social behaviour. However, low T also relates to status and to formal dominance. The General Trait Covariance (GTC) model predicts both relations under the assumption that high and low T modulates the genotype in ways that enforce the development of almost polar covariant patterns of body, brain, intellectual, and personality traits, irrespective of race. The precise modelling of these dose-dependent molecular body-intelligence-personality-behaviour relations requires that causes, mechanisms, and effects enjoy equal operational standing.
Ten-year trends in hospital admissions for adverse drug reactions in England 1999–2009
Authors: Tai-Yin Wu, Min-Hua Jen, Alex Bottle, Mariam Molokhia, Paul Aylin, Derek Bell, Azeem Majeed
Journal: Journal of the Royal Society of Medicine (2010)

Summary Objectives Adverse drug reactions (ADR) are an important cause of morbidity and mortality. We analysed trends in hospital admissions associated with ADRs in English hospitals between 1999 and 2008. Design Data from the Hospital Episode Statistics database were examined for all English hospital admissions (1999–2008) with a primary or secondary diagnosis of an ADR recorded. Setting All NHS (public) hospitals in England. Main outcome measures The number of admissions and in-hospital mortality rate with a primary (codes including ‘adverse drug reaction’, ‘drug-induced’, ‘due to drug’, ‘due to medicament’ or ‘drug allergy’) or secondary diagnosis of ADR (ICD-10 Y40-59) were obtained and analysed. Further analysis for the year 2008–2009 was performed with regard to age, gender, proportion aged &gt;65 yrs and total bed-days. Results Between 1999 and 2008, there were 557,978 ADR-associated admissions, representing 0.9% of total hospital admissions. Over this period the annual number of ADRs increased by 76.8% (from 42,453 to 75,076), and in-hospital mortality rate increased by 10% (from 4.3% to 4.7%). In 2008, there were 6,830,067 emergency admissions of which 75,076 (1.1%) were drug-related. Systemic agents were most commonly implicated (19.2%), followed by analgesics (13.3%) and cardiovascular drugs (12.9%).There has been a near two-fold increase in nephropathy and cardiovascular consequences secondary to drugs and a 6.8% fall in mental and behavioural disorders due to drugs. Conclusions ADRs have a major impact on public health. Our data suggest the number of ADR admissions has increased at a greater rate than the increase in total hospital admissions; some of this may be due to improved diagnostic coding. However, in-hospital mortality due to ADR admissions also increased during the period. Our findings should prompt policymakers to implement further measures to reduce ADR incidence and their associated in-hospital mortality, and methods to improve the recording of ADRs.
Hyperdynamic circulation in a chronic murine schistosomiasis model of portal hypertension
Authors: Shiv K. Sarin, Piergiorgio Mosca, Carlo Sabbà, Roberto J. Groszmann
Journal: Hepatology (1991)

Chronic murine schistosomiasis is a natural disease model of portal hypertension closely mimicking the clinical and histological features of human hepatic schistosomiasis. We studied the splanchnic and systemic hemodynamics in the murine model of schistosomiasis by radioactive microsphere technique. Mice infected with 60 cercariae of Schistosoma mansoni (n = 8) were studied hemodynamically 11 wk after the infection and were compared with age-matched healthy controls (n = 11). Mean portal venous inflow in the infected mice (3.82 +/- 0.32 ml/min) was 61% higher than in the healthy animals (2.37 +/- 0.25 ml/min; p less than 0.01). A twofold increase in hepatic arterial flow was also seen in mice with schistosomiasis (0.47 +/- 0.14 ml/min) as compared with controls (0.16 +/- 0.03 ml/min; p less than 0.05), whereas splanchnic arteriolar resistance (60.91 +/- 7.64 vs. 101.21 +/- 11.06 mm Hg.min.ml-1.gm; p less than 0.05) and peripheral vascular resistance (112.05 +/- 14.05 vs 254.53 +/- 29.86 mm Hg.min.ml-1.gm; p less than 0.01) were reduced. There was a significant increase in cardiac index (752 +/- 99 vs. 453 +/- 55 ml.min-1.kg body weight-1; p less than 0.05) and reduction in mean arterial pressure (81.37 +/- 3.09 vs. 101.45 +/- 5.85 mm Hg; p less than 0.05) in the infected animals compared with controls. These observations clearly demonstrate the existence of a hyperdynamic circulatory state in this model of portal hypertension.
Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage
Authors: C. Knauf
Journal: Journal of Clinical Investigation (2005)

Intestinal glucagon-like peptide–1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9–39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.
First-Phase Insulin Secretion Restoration and Differential Response to Glucose Load Depending on the Route of Administration in Type 2 Diabetic Subjects After Bariatric Surgery
Authors: Serenella Salinari, Alessandro Bertuzzi, Simone Asnaghi, Caterina Guidone, Melania Manco, Geltrude Mingrone
Journal: Diabetes Care (2008)

The purpose of this study was to elucidate the mechanisms of diabetes reversibility after malabsorptive bariatric surgery.Peripheral insulin sensitivity and beta-cell function after either intravenous (IVGTT) or oral glucose tolerance (OGTT) tests and minimal model analysis were assessed in nine obese, type 2 diabetic subjects before and 1 month after biliopancreatic diversion and compared with those in six normal-weight control subjects. Insulin-dependent whole-body glucose disposal was measured by the euglycemic clamp, and glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were also measured.The first phase of insulin secretion after the IVGTT was fully normalized after the operation. The disposition index from OGTT data was increased about 10-fold and became similar to the values found in control subjects, and the disposition index from IVGTT data increased about 3.5-fold, similarly to what happened after the euglycemic clamp. The area under the curve (AUC) for GIP decreased about four times (from 3,000 +/- 816 to 577 +/- 155 pmol x l(-1) x min, P < 0.05). On the contrary, the AUC for GLP1 almost tripled (from 150.4 +/- 24.4 to 424.4 +/- 64.3 pmol x l(-1) . min, P < 0.001). No significant correlation was found between GIP or GLP1 percent changes and modification of the sensitivity indexes independently of the route of glucose administration.Restoration of the first-phase insulin secretion and normalization of insulin sensitivity in type 2 diabetic subjects after malabsorptive bariatric surgery seem to be related to the reduction of the effect of some intestinal factor(s) resulting from intestinal bypass.
Why Do Americans Have Shorter Life Expectancy and Worse Health Than Do People in Other High-Income Countries?
Authors: Mauricio Avendano, Ichiro Kawachi
Journal: Annual Review of Public Health (2014)

Americans lead shorter and less healthy lives than do people in other high-income countries. We review the evidence and explanations for these variations in longevity and health. Our overview suggests that the US health disadvantage applies to multiple mortality and morbidity outcomes. The American health disadvantage begins at birth and extends across the life course, and it is particularly marked for American women and for regions in the US South and Midwest. Proposed explanations include differences in health care, individual behaviors, socioeconomic inequalities, and the built physical environment. Although these factors may contribute to poorer health in America, a focus on proximal causes fails to adequately account for the ubiquity of the US health disadvantage across the life course. We discuss the role of specific public policies and conclude that while multiple causes are implicated, crucial differences in social policy might underlie an important part of the US health disadvantage.
Uneven Distribution of Maternal and Fetal Placental Blood Flow, as Demonstrated Using Macroaggregates, and Its Response to Hypoxia*
Authors: Gordon G. Power, Lawrence D. Longo, Henry N. Wagner, David E. Kuhl, Robert E. Forster
Journal: Journal of Clinical Investigation (1967)

A technique is described for studying the distribution of blood flow to the maternal and fetal placental vessels in sheep and dogs with radioactive labeled macroaggregates of albumin. When the maternal animal breathed room air the distribution of maternal placental blood flow was uneven among the cotyledons as well as within a given cotyledon. Fetal blood flow was also distributed nonuniformly among and within the cotyledons. The relation of maternal to fetal placental blood flow was also markedly uneven (coefficient of correlation, tau = 0.066). After the animal was made hypoxic by breathing 10-12% O(2) the distribution of maternal, fetal, and maternal/fetal placental flows became more uniform. The coefficient of correlation of maternal to fetal flow was high (tau = 0.53, P < 0.01). While the maternal animal breathed room air, after ligation of a major branch of the umbilical artery the distribution of maternal, fetal, and maternal/fetal flows in the remaining two-thirds to three-fourths of the placenta became more uniform. The correlation coefficient for maternal to fetal flow was high (tau = 0.35, P < 0.01).It appears that under normal circumstances with uneven distribution of blood flows there is a considerable portion of the placenta that does not receive blood flow in optimum quantities to promote efficient O(2) exchange. Failure to consider the influence of nonuniform maternal flow/fetal flow will result in overestimation of mean maternal-fetal oxygen tension gradients, and thus underestimation of the placental diffusing capacity for oxygen. In response to maternal hypoxia or compromise of the fetal placental circulation the distribution of maternal, fetal, and maternal/fetal flows becomes more uniform, thereby increasing the efficiency of placental O(2) exchange.
Factors Correlated With Progression-Free Survival After High-Dose Chemotherapy and Hematopoietic Stem Cell Transplantation for Metastatic Breast Cancer
Authors: Philip A. Rowlings, Stephanie F. Williams, Karen H. Antman, Karen K. Fields, Joseph W. Fay, Elizabeth Cecile Reed, Corey J. Pelz, John P. Klein, Kathleen A. Sobocinski, M. John Kennedy, Cesar O. Freytes, Philip L. McCarthy, Roger H. Herzig, Edward A. Stadtmauer, Hillard M. Lazarus, Andrew L. Pecora, Jacob D. Bitran, Steven N. Wolff, Robert Peter Gale, James Olen Armitage, William P. Vaughan, Gary Spitzer, Mary M. Horowitz
Journal: JAMA (1999)

tasized beyond regional lymph nodes or has recurred after primary treatment (designated as advanced breast cancer in this article) is an incurable disease. 1 High-dose che-
Incidence and Clinical Impact of Dual Nonresponsiveness to Aspirin and Clopidogrel in Patients With Drug-Eluting Stents
Authors: Anna Maria Gori, Rossella Marcucci, Angela Migliorini, Renato Valenti, Guia Moschi, Rita Paniccia, Piergiovanni Buonamici, Gian Franco Gensini, Ruben Vergara, Rosanna Abbate, David Antoniucci
Journal: Journal of the American College of Cardiology (2008)