tbuckley/cabot-search huggingface dataset:
Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma
Authors: Prakash Chinnaiyan, Sajeel Chowdhary, Lisa Potthast, Antony Prabhu, Ya-Yu Tsai, Bhaswati Sarcar, Soumen Kahali, Steven Brem, H. Michael Yu, Amyn Rojiani, Ryan Murtagh, Edward Pan
Journal: Neuro-Oncology (2011)

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.
Rheumatoid Arthritis—A Molecular Understanding
Authors: J. Bruce Smith, Mark K. Haynes
Journal: Annals of Internal Medicine (2002)

The application of molecular immunology techniques in the study of rheumatoid arthritis has resulted in an explosion of knowledge on the risk factors for the disease, predictors of disease severity, the molecular mechanisms of inflammatory responses, and mechanisms of tissue destruction. We know, for example, that inheriting certain genes in the major histocompatibility complex partly dictates susceptibility and severity of rheumatoid arthritis. These genes and others in the major histocompatibility complex are critical for the occurrence of immune responses both constructive (prevention of infection, surveillance for malignant cells) and destructive (development of autoimmune diseases). We also now understand mechanisms of cell communication, regulation of immune responses, how the cells that mediate immune responses and tissue injury accumulate in tissues, and how the injury occurs. The knowledge itself is satisfying, but more important, based on this knowledge, effective and reasonably safe treatments that address basic mechanisms of the disease process have been developed and are now widely used. In fact, the newer treatments represent the "tip of the iceberg," and as our basic knowledge increases, so too will the armamentarium with which we can fight rheumatoid arthritis and other similar autoimmune diseases.
Two Sites of Bile Formation as Determined by Mannitol and Erythritol Clearance in the Guinea Pig*
Authors: E. L. Forker
Journal: Journal of Clinical Investigation (1967)

If water and inert solutes are assumed to pass from blood to bile through a fixed population of membrane pores, the changes in clearance produced by dehydrocholate suggest that osmotic filtration rather than diffusion is the predominant mode of transfer for mannitol and erythritol. Bile produced in the canaliculi is modified in the interlobular ducts by the action of secretin. If distal fluid transfer is an important determinant of the choleresis evoked by dehydrocholate, the mechanism appears to effect a net secretion or reabsorption of fluid at a rate roughly proportional to the rate of flow in the canaliculi.
Angiotensin-Converting Enzyme Inhibitors or β-Blockers in Heart Failure
Authors: James C. Fang
Journal: Circulation (2005)

ngiotensin-converting enzyme (ACE) inhibitors and ␤-blockers are potent therapies in heart failure.They lower total mortality and heart failure hospitalizations by 25% to 40% across all ages, functional capacities, degrees of left ventricular dysfunction, and causes. 1,2But does it matter which intervention is given first?There are 2 primary reasons why clinicians initiate heart failure therapy with ACE inhibitors for patients with systolic dysfunction: (1) ACE inhibitors were the first agents to demonstrate a mortality benefit in heart failure and therefore have since served as background therapy for all heart failure trials, and (2) heart failure is a hemodynamic as well as a neurohormonal condition that acutely improves with vasodilation. 3In acutely decompensated patients, initial hemodynamic stabilization through vasodilation improves the neurohormonal profile, including a reduction in norepinephrine levels. 4his stabilization may allow the subsequent introduction of ␤-blockers, which are acutely associated with a decline in ventricular function. 5,
HOMOZYGOUS AUTOSOMAL DOMINANT HYPERCHOLESTEROLEMIA IN THE NETHERLANDS: PREVALENCE, GENOTYPE-PHENOTYPE RELATIONSHIP AND CLINICAL OUTCOME
Authors: Barbara Sjouke, Dorothe Kusters, Iris Kindt, Joost Besseling, Joep Defesche, Eric Sijbrands, Jeanine Roeters van Lennep, Anton Stalenhoef, Albert Wiegman, Jacqueline de Graaf, Sigrid Fouchier, John Kastelein, G Kees Hovingh
Journal: Journal of the American College of Cardiology (2014)
Health Care in the 2004 Presidential Election
Authors: Robert J. Blendon, Drew E. Altman, John M. Benson, Mollyann Brodie
Journal: New England Journal of Medicine (2004)

We examined the importance for voters of health care as an issue in the presidential election of 2004, how this ranking compares with the importance of health care in past elections, and which issues voters regard as the most important health care issues in the months before the election.We studied data from 22 national opinion surveys, 9 of them conducted as telephone surveys during the 2004 presidential campaign, 10 conducted as telephone surveys during the previous three presidential elections, and 3 conducted as national exit polls of voters.Voters ranked health care as the fourth most important issue in deciding their vote for president in 2004. The top health care issues for voters were the costs of health care and prescription drugs, prescription-drug benefits for the elderly, the uninsured, and Medicare. Bioterrorism and abortion were also important issues for voters. The voters most concerned about health care were older persons and those who identified themselves as Democrats. Four issues less salient to voters were racial disparities in health care, aid to developing countries to prevent and treat human immunodeficiency virus infection and the acquired immunodeficiency syndrome, medical malpractice, and the quality of care.Although health care ranks higher in importance among voters than most other domestic issues, it is only fourth in importance in deciding their vote for president. The health care issues of greatest concern are the affordability of health care and health care insurance. Health care issues do not appear likely to play a decisive role in the presidential election in 2004, but they might make a difference in some swing states if the race is close.
ATTEMPTS TO REPRODUCE RHEUMATIC FEVER IN ANIMALS
Authors: Louis Gross, Leo Loewe, Benjamin Eliasoph
Journal: The Journal of Experimental Medicine (1929)

Experiments have been described in which we attempted to reproduce in animals the lesions characteristic of rheumatic fever in the human. A large number of animals representing 7 species was employed. Among other materials, streptococci isolated in pure culture from the blood of rheumatic patients (proved to be so by biopsy or by autopsy) as well as whole blood, plasma, serum, pericardial, pleural and hydrocele fluid, filtrates from tonsils, subcutaneous nodules, lymph nodes, and nasopharyngeal washings obtained from such patients were used in a variety of combinations and with a number of procedures calculated to predispose the animal to the disease. A discussion is given of the criteria whose fulfillment is essential for the establishment of the experimental production of rheumatic disease in animals. Judged by these criteria, we have failed to reproduce the disease. This conclusion, we believe, holds true for all the work thus far reported in the literature.
Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence
Authors: Rebecca Dent, Maureen Trudeau, Kathleen I. Pritchard, Wedad M. Hanna, Harriet K. Kahn, Carol A. Sawka, Lavina A. Lickley, Ellen Rawlinson, Ping Sun, Steven A. Narod
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To compare the clinical features, natural history, and outcomes for women with “triple-negative” breast cancer with women with other types of breast cancer. Experimental Design: We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women's College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative. The prognostic significance of triple-negative breast cancer was explored. Results: The median follow-up time of the 1,601 women was 8.1 years. One hundred and eighty of 1,601 patients (11.2%) had triple-negative breast cancer. Compared with other women with breast cancer, those with triple-negative breast cancer had an increased likelihood of distant recurrence (hazard ratio, 2.6; 95% confidence interval, 2.0-3.5; P &amp;lt; 0.0001) and death (hazard ratio, 3.2; 95% confidence interval, 2.3-4.5; P &amp;lt; 0.001) within 5 years of diagnosis but not thereafter. The pattern of recurrence was also qualitatively different; among the triple-negative group, the risk of distant recurrence peaked at ∼3 years and declined rapidly thereafter. Among the “other” group, the recurrence risk seemed to be constant over the period of follow-up. Conclusions: Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.
Antiarrhythmic Drug Therapy for Atrial Fibrillation
Authors: Peter Zimetbaum
Journal: Circulation (2012)

A ntiarrhythmic medications have been available for nearly 100 years and remain a mainstay in the management of atrial fibrillation (AF).Goals of therapy with the use of these drugs include a reduction in the frequency and duration of episodes of arrhythmia as well an emerging goal of reducing mortality and hospitalizations associated with AF.The use of these drugs has been limited by both proarrhythmic and noncardiovascular toxicities as well as often modest antiarrhythmic efficacy.Despite these limitations, antiarrhythmic drugs remain widely prescribed for the management of symptomatic AF, and a host of new antiarrhythmic drugs are in various stages of clinical development.This review will focus primarily on antiarrhythmic drug use in patients with AF in the absence of significant structural heart disease or congestive heart failure.
No Difference in Small or Large Nerve Fiber Function Between Individuals With Normal Glucose Tolerance and Impaired Glucose Tolerance
Authors: Kaveh Pourhamidi, Lars B. Dahlin, Elisabet Englund, Olov Rolandsson
Journal: Diabetes Care (2012)

To assess small and large nerve fiber function in people with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D).
Reply to A. Molfino et al
Authors: Ørnulf Paulsen, Nina Aass, Pål Klepstad, Stein Kaasa
Journal: Journal of Clinical Oncology (2015)

We thank Molfino et al for their thoughtful comments regarding our article. Anorexia is a burdensome symptom for patients with cancer, and is significantly associated with survival. Anorexia is associated with systemic inflammatory response in cancer. Therefore, loss of appetite was chosen as a secondary outcome in our trial assessing the effects of methylprednisolone for cancer pain. Our trial showed a significant improvement of appetite loss, which coincides with the findings of Yennurajalingam et al. They also found a significant improvement in anorexia using the Functional Assessment of Anorexia/Cachexia Therapy subscale of 4.89 points on day 15 (P .013) in favor of the dexamethasone group as compared with the placebo group. As Molfino et al correctly point out, appetite is only one part of the symptom complex causing anorexia and reduced food intake. In addition to appetite, changes in taste and GI motility are important, together with secondary factors caused by the disease itself or the treatment, such as stomatitis, diarrhea, and constipation. Furthermore, food intake is an important item to measure separately, as it shows only a weak association with loss of appetite. Consequently, it is recommended to assess all these symptoms as well as food intake in cancer cachexia trials. Different assessment tools have been proposed to assess the anorexia symptom, including the Functional Assessment of Anorexia/ Cachexia Therapy, which rates the intensity of anorexia and cachexia and the related symptoms on a verbal rating scale 0 to 4. The abridged Patient-Generated Subjective Global Assessment assesses the symptoms on a yes or no basis together with nutritional and functional levels. Finally, loss of appetite can be quantitatively evaluated by a numeric rating scale like the Edmonton Symptom Assessment System, and the European Association for Palliative Care minimum data set, or health-related quality-of-life tools like the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). Loss of appetite can be measured by the EORTC QLQ-C30 in a reliable way. Indeed, the EORTC group is currently developing a lack of appetite item bank for computer-adaptive testing as a further development of this single item. Due to the risk of adverse effects in prolonged use, it is generally agreed that corticosteroids should be used to treat anorexia in the end-of-life setting. In patients with short life expectancy, the primary foci are symptom control and quality of life. Therefore, patientreported outcomes are recommended at this stage of disease, and only a minor improvement in appetite may be important to the patients. The risk of adverse effects from the use of high-dose corticosteroids is substantial. This needs to be assessed and may counterbalance the positive effects on appetite. Ornulf Paulsen Telemark Hospital Trust, Skien; Norwegian University of Science and Technology, Trondheim, Norway
Questionnaire-based diagnosis of hidradenitis suppurativa: specificity, sensitivity and positive predictive value of specific diagnostic questions
Authors: S. Esmann, D.N. Dufour, G.B.E. Jemec
Journal: British Journal of Dermatology (2010)

Background Estimates of the prevalence of hidradenitis suppurativa (HS) range from 0·33% to 4%. Further epidemiological data are therefore needed. Because of the hidden nature of the disease, physical screening may be cumbersome and questionnaire-based screening may be more appropriate. Objectives To establish the sensitivity (SE), specificity (SP) and positive predictive value (PPV) of simple diagnostic questions used in HS. Methods Potential diagnostic questions regarding HS were identified and sent to 85 patients with HS and to an age- and sex-matched control group randomly selected among outpatients not being treated for HS. All respondents were recruited in the Department of Dermatology in Roskilde Hospital. Results In total, 74 of 85 patients with HS (87%) returned the questionnaire (61 women and 13 men). Of these, 72 reported repeated outbreaks of painful nodules or boils in locations typical for HS compared with 13 patients in the control group. The SE ranged from 0·92 to 0·97, the SP from 0·82 to 0·86 and the PPV from 0·85 to 0·89. Boils appeared significantly more often in patients with HS, who also reported significantly greater suffering from their lesions. Conclusions The high diagnostic power suggests that all the questions are potentially useful. The clear symptomatology of HS may be a key factor. It is suggested that further improvement may be achieved by adding definitions of pimples, nodules or boils to future questionnaires. Similarly, adding the possibility to indicate uncommon locations, duration and quality-of-life impairment may benefit the diagnostic power.
Jaks and Stats as therapeutic targets
Authors: J. J O'Shea
Journal: Annals of the Rheumatic Diseases (2000)

Cytokines have critical functions in regulating immune responses. A large number of these factors bind related receptors termed the Type I and Type II families of cytokine receptors. These receptors activate Janus kinases (Jaks) and Stat family of transcription factors. The essential and specific function of Jaks and Stats is particularly well illustrated by human and mouse mutations. The possibility that these molecules could be targeted to produce novel immunosuppressive compounds is considered in this review.
Detection of Borrelia afzelii, Borrelia burgdorferi sensu stricto, Borrelia garinii and group VS116 by PCR in skin biopsies of patients with erythema migrans and acrodermatitis chronica atrophicans
Authors: Sjoerd G.T. Rijpkema, Dig J. Tazelaar, Marc J.C.H. Molkenboer, Gerda T. Noordhoek, Grietsje Plantinga, Leo M. Schouls, Joop F.P. Schellekens
Journal: Clinical Microbiology and Infection (1997)
Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)
Authors: John B Buse, Julio Rosenstock, Giorgio Sesti, Wolfgang E Schmidt, Eduard Montanya, Jason H Brett, Marcin Zychma, Lawrence Blonde
Journal: The Lancet (2009)
The Epothilones: Translating from the Laboratory to the Clinic
Authors: James J. Lee, Sandra M. Swain
Journal: Clinical Cancer Research (2008)

Abstract The epothilones are macrolide compounds that have been shown to stabilize microtubules. The epothilones are strong promoters of tubulin polymerization in vitro and have significant antitumor activity against human cancer cells that are taxane resistant, express the multidrug resistance gene MDR-1 (ABCB1), and have acquired tubulin mutations. Several epothilones have been evaluated in clinical trials in a variety of tumor types. Ixabepilone (aza-epothilone B) has significant antitumor activity in breast cancer resistant to an anthracycline and a taxane, and has been approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic or locally advanced breast cancer. There have been sustained efforts to develop pharmacodynamic markers to monitor the pharmacologic effect of the epothilones on tumors and normal tissues. The development of predictive markers for epothilone chemotherapy is highly desired to provide more tailored therapy for patients with cancer.
Triglycerides and HDL Cholesterol
Authors: Rafael Bitzur, Hofit Cohen, Yehuda Kamari, Aviv Shaish, Dror Harats
Journal: Diabetes Care (2009)

Diabetes carries a high risk of atherosclerosis, and cardiovascular disease, especially coronary heart disease (CHD) and stroke, is by far the leading cause of death among patients with type 2 diabetes. Although statins reduce the risk of major vascular events by about one-fifth per millimole per liter reduction in LDL cholesterol, with similar proportional reductions in major coronary events, stroke, and the need for coronary revascularization, the residual risk remains high. In the Scandinavian Simvastatin Survival Study (4S) (1), although the relative risk reduction in diabetic patients was larger than in nondiabetic patients, simvastatin-treated diabetic patients were still at higher risk of death than the placebo-treated nondiabetic patients. Multifactorial intervention reduces the risk even further, but significant danger remains. Current guidelines call for an aggressive treatment strategy to reduce LDL cholesterol, blood pressure, and glucose levels in diabetic patients, but data concerning the management of high triglyceride (TG) levels and low HDL cholesterol levels remains inconclusive. This article reviews the data concerning diabetic dyslipidemia and its management.

The cluster of lipid abnormalities associated with type 2 diabetes is defined by a high concentration of TG and small dense LDL and a low concentration of HDL cholesterol. Plasma LDL cholesterol levels are generally normal. Insulin resistance is believed to contribute to this atherogenic dyslipidemia by increasing the hepatic secretion of VLDL and other apolipoprotein (apo)B-containing lipoprotein particles, as a result of increased free fatty acid flux to the liver (2,3). This may also be the result of a diminished suppressive effect of insulin on apoB secretion, either at the level of the regulation of apoB degradation, or inhibition of microsomal TG transfer protein activity (4). Through the action of cholesterol ester transfer protein, TGs are transferred from VLDL to HDL, creating TG-rich HDL particles, which are hydrolyzed by hepatic …
Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes
Authors: Barbara Testoni, David Durantel, Fanny Lebossé, Judith Fresquet, François Helle, Francesco Negro, Maria Francesca Donato, Massimo Levrero, Fabien Zoulim
Journal: Gut (2015)

<h3>Objectives</h3> Caveats in the understanding of ribavirin (RBV) mechanisms of action has somehow prevented the development of better analogues able to further improve its therapeutic contribution in interferon (IFN)-based and direct antiviral agent-based regimens for chronic HCV or other indications. Here, we describe a new mechanism by which RBV modulates IFN-stimulated genes (ISGs) and contributes to restore hepatic immune responsiveness. <h3>Design</h3> RBV effect on ISG expression was monitored in vitro and in vivo, that is, in non-transformed hepatocytes and in the liver of RBV mono-treated patients, respectively. Modulation of histone modifications and recruitment of histone-modifying enzymes at target promoters was analysed by chromatin immunoprecipitation in RBV-treated primary human hepatocytes and in patients' liver biopsies. <h3>Results</h3> RBV decreases the mRNA levels of several abnormally preactivated ISGs in patients with HCV, who are non-responders to IFN therapy. RBV increases G9a histone methyltransferase recruitment and histone-H3 lysine-9 dimethylation/trimethylation at selected ISG promoters in vitro and in vivo. G9a pharmacological blockade abolishes RBV-induced ISG downregulation and severely impairs RBV ability to potentiate IFN antiviral action and induction of ISGs following HCV infection of primary human hepatocytes. <h3>Conclusions</h3> RBV-induced epigenetic changes, leading to decreased ISG expression, restore an IFN-responsive hepatic environment in patients with HCV, which may also prove useful in IFN-free regimens.