tbuckley/cabot-search huggingface dataset:
Molecular Pathways: How Can BRCA-Mutated Tumors Become Resistant to PARP Inhibitors?
Authors: Peter Bouwman, Jos Jonkers
Journal: Clinical Cancer Research (2013)

Abstract PARP inhibition is synthetic lethal with defective DNA repair via homologous recombination. Phase I and II clinical trials show that PARP inhibitors are effective at well-tolerated doses and have antitumor activity for BRCA1- and BRCA2-associated cancers. However, not all patients respond equally well and tumors may eventually become resistant. Thus far, the only resistance mechanism that has been found in human tumors is genetic reversion that corrects or bypasses the original BRCA1- or BRCA2-inactivating mutation. However, data from fundamental and preclinical research suggest that resistance to PARP inhibitors may be induced by additional mechanisms involving hypomorphic activity of mutant BRCA1 alleles, upregulation of drug efflux pumps, and rewiring of the DNA damage response. Preclinical models will be instrumental to develop methods for adequate patient stratification, as well as treatment strategies that prevent or counteract resistance to PARP inhibitors. Clin Cancer Res; 20(3); 540–7. ©2013 AACR.
Risk of Venous Thromboembolism in Patients With Cancer Treated With Cisplatin: A Systematic Review and Meta-Analysis
Authors: Sonia Seng, Ziyue Liu, Sophia K. Chiu, Tracy Proverbs-Singh, Guru Sonpavde, Toni K. Choueiri, Che-Kai Tsao, Menggang Yu, Noah M. Hahn, William K. Oh, Matthew D. Galsky
Journal: Journal of Clinical Oncology (2012)

Purpose Several reports suggest that cisplatin is associated with an increased risk of thromboembolism. However, because the excess risk of venous thromboembolic events (VTEs) with cisplatin-based chemotherapy has not been well described, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of VTEs associated with cisplatin-based chemotherapy. Methods PubMed was searched for articles published from January 1, 1990, to December 31, 2010. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based versus non–cisplatin-based chemotherapy in patients with solid tumors. Data on all-grade VTEs were extracted. Study quality was calculated using Jadad scores. Incidence rates, relative risks (RRs), and 95% CIs were calculated using a random effects model. Results A total of 8,216 patients with various advanced solid tumors from 38 randomized controlled trials were included. The incidence of VTEs was 1.92% (95% CI, 1.07 to 2.76) in patients treated with cisplatin-based chemotherapy and 0.79% (95% CI, 0.45 to 1.13) in patients treated with non–cisplatin-based regimens. Patients receiving cisplatin-based chemotherapy had a significantly increased risk of VTEs (RR, 1.67; 95% CI, 1.25 to 2.23; P = .01). Exploratory subgroup analysis revealed the highest RR of VTEs in patients receiving a weekly equivalent cisplatin dose &gt; 30 mg/m 2 (2.71; 95% CI, 1.17 to 6.30; P = .02) and in trials reported during 2000 to 2010 (1.72; 95% CI, 1.27 to 2.34; P = .01). Conclusion Cisplatin is associated with a significant increase in the risk of VTEs in patients with advanced solid tumors when compared with non–cisplatin-based chemotherapy.
Prevalence, Predictors, and Outcomes of Premature Discontinuation of Thienopyridine Therapy After Drug-Eluting Stent Placement
Authors: John A. Spertus, Richard Kettelkamp, Clifton Vance, Carole Decker, Philip G. Jones, John S. Rumsfeld, John C. Messenger, Sanjaya Khanal, Eric D. Peterson, Richard G. Bach, Harlan M. Krumholz, David J. Cohen
Journal: Circulation (2006)

Although drug-eluting stents (DES) significantly reduce restenosis, they require 3 to 6 months of thienopyridine therapy to prevent stent thrombosis. The rate and consequences of prematurely discontinuing thienopyridine therapy after DES placement for acute myocardial infarction (MI) are unknown.We used prospectively collected data from a 19-center study of MI patients to examine the prevalence and predictors of thienopyridine discontinuation 30 days after DES treatment. We then compared the mortality and cardiac hospitalization rates for the next 11 months between those who stopped and those who continued thienopyridine therapy. Among 500 DES-treated MI patients who were discharged on thienopyridine therapy, 68 (13.6%) stopped therapy within 30 days. Those who stopped were older, less likely to have completed high school or be married, more likely to avoid health care because of cost, and more likely to have had preexisting cardiovascular disease or anemia at presentation. They were also less likely to have received discharge instructions about their medications or a cardiac rehabilitation referral. Patients who stopped thienopyridine therapy by 30 days were more likely to die during the next 11 months (7.5% versus 0.7%, P<0.0001; adjusted hazard ratio=9.0; 95% confidence interval=1.3 to 60.6) and to be rehospitalized (23% versus 14%, P=0.08; adjusted hazard ratio=1.5; 95% confidence interval=0.78 to 3.0).Almost 1 in 7 MI patients who received a DES were no longer taking thienopyridines by 30 days. Prematurely stopping thienopyridine therapy was strongly associated with subsequent mortality. Strategies to improve the use of thienopyridines are needed to optimize the outcomes of MI patients treated with DES.
Improving Diabetes Care: The Model for Health Care Reform
Authors: Richard Kahn, John E. Anderson
Journal: Diabetes Care (2009)

As policy makers now debate the elements of health care reform, the medical management of diabetes is an excellent “case study” and in nearly all ways epitomizes the problems the country faces. The most obvious way in which diabetes epitomizes the need for health care reform is that chronic diseases, not acute infectious disorders, are the current and growing health-related financial drain on the country. Of the six leading causes of death in the U.S., four are chronic diseases (1). In 2005, 44% of adult Americans had at least one chronic condition, and diabetes (without complications), hypertension, and hyperlipidemia were the three most prevalent, accounting for 31% of all reported chronic disease (2).

Coupling the current impact of chronic disease with the increases that are expected to occur (3), future health care spending for diabetes is likely to worsen. Lest one believe that the financial burden of health care does not reach the public directly, Emanuel and Fuchs (4) point out that government exacts its share through taxation or by reducing other services that benefit citizens. Employers pass on health care costs in the form of lower wages or higher prices. As for direct spending by the public, Paez et al. (2) reported that out-of-pocket health care spending from 1996 to 2005 rose 45% (adjusted for inflation and changing disease prevalence), with the greatest growth occurring in those with multiple chronic diseases, as seen in those with diabetes.

### Are we getting our money's worth?

One might take relief if we were paying a lot of money for health care and getting stellar results, but by virtually every measure this is far from true. Comparing the U.S. with other countries puts us near the bottom on most measures of health status among all developed countries (5). In the U.S., slightly more than half of all adults …
Mechanisms of Bone Metastasis
Authors: G David Roodman
Journal: New England Journal of Medicine (2004)

Extract: Cancer frequently spreads to bone, a process termed bone metastasis. Up to 70% of patients with breast cancer or prostate cancer, and 15 to 30% of patients with lung, colon, bladder or kidney cancer develop bone metastasis. Once tumors go to bone, such as in patients with breast cancer or prostate cancer, they are incurable, and only 20% of patients with breast cancer are still alive five years after they are found to have bone metastasis. It is estimated that about 350,000 people die with bone metastasis each year in the United States. Bone metastasis causes severe bone pain and can result in fractures without any injury, as well as other life-threatening conditions. There are two major types of bone metastasis, one in which bone destruction is the predominant feature and the other one in which new bone formation is predominant. Bone metastasis where bone destruction is the predominant feature is known as osteolytic, and that in which new bone formation is the primary feature is called osteoblastic. This classification for metastasis is really two extremes of a continuum because many patients can have both osteolytic and osteoblastic or mixtures of both in their bone metastasis. In fact, patients with prostate cancer who usually have bone metastasis that shows increased new bone formation also have increased bone destruction in the same lesions.
Pulmonary and systemic distribution of inhaled ultrafine silver particles in rats.
Authors: S Takenaka, E Karg, C Roth, H Schulz, A Ziesenis, U Heinzmann, P Schramel, J Heyder
Journal: Environmental Health Perspectives (2001)

The cardiovascular system is currently considered a target for particulate matter, especially for ultrafine particles. In addition to autonomic or cytokine mediated effects, the direct interaction of inhaled materials with the target tissue must be examined to understand the underlying mechanisms. In the first approach, pulmonary and systemic distribution of inhaled ultrafine elemental silver (EAg) particles was investigated on the basis of morphology and inductively coupled plasma mass spectrometry (ICP-MS) analysis. Rats were exposed for 6 hr at a concentration of 133 microg EAg m(3) (3 x 10(6) cm(3), 15 nm modal diameter) and were sacrificed on days 0, 1, 4, and 7. ICP-MS analysis showed that 1.7 microg Ag was found in the lungs immediately after the end of exposure. Amounts of Ag in the lungs decreased rapidly with time, and by day 7 only 4% of the initial burden remained. In the blood, significant amounts of Ag were detected on day 0 and thereafter decreased rapidly. In the liver, kidney, spleen, brain, and heart, low concentrations of Ag were observed. Nasal cavities, especially the posterior portion, and lung-associated lymph nodes showed relatively high concentrations of Ag. For comparison, rats received by intratracheal instillation either 150 microL aqueous solution of 7 microg silver nitrate (AgNO(3) (4.4 microg Ag) or 150 microL aqueous suspension of 50 microg agglomerated ultrafine EAg particles. A portion of the agglomerates remained undissolved in the alveolar macrophages and in the septum for at least 7 days. In contrast, rapid clearance of instilled water-soluble AgNO(3) from the lung was observed. These findings show that although instilled agglomerates of ultrafine EAg particles were retained in the lung, Ag was rapidly cleared from the lung after inhalation of ultrafine EAg particles, as well as after instillation of AgNO(3), and entered systemic pathways.
Treatment of Idiopathic Pulmonary Fibrosis with Etanercept
Authors: Ganesh Raghu, Kevin K. Brown, Ulrich Costabel, Vincent Cottin, Roland M. du Bois, Joseph A. Lasky, Michiel Thomeer, James P. Utz, Rezaul K. Khandker, Lawrence McDermott, Saeed Fatenejad
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

An efficacious medical therapy for idiopathic pulmonary fibrosis (IPF) remains elusive.To explore the efficacy and safety of etanercept in the treatment of IPF.This was a randomized, prospective, double-blind, placebo-controlled, multicenter exploratory trial in subjects with clinically progressive IPF. Primary endpoints included changes in the percentage of predicted FVC and lung diffusing capacity for carbon monoxide corrected for hemoglobin (Dl(CO(Hb))) and change in the alveolar to arterial oxygen pressure difference P(a-a)(O(2)) at rest from baseline over 48 weeks.Eighty-eight subjects received subcutaneous etanercept (25 mg) or placebo twice weekly as their sole treatment for IPF. No differences in baseline demographics and disease status were detected between treatment groups; the mean time from first diagnosis was 13.6 months and mean FVC was 63.9% of predicted. At 48 weeks, no significant differences in efficacy endpoints were observed between the groups. A nonsignificant reduction in disease progression was seen in several physiologic, functional, and quality-of-life endpoints among subjects receiving etanercept. There was no difference in adverse events between treatment groups.In this exploratory study in patients with clinically progressive IPF, etanercept was well tolerated. Although there were no differences in the predefined endpoints, a decreased rate of disease progression was observed on several measures. Further evaluation of TNF antagonists in the treatment of IPF may be warranted. Clinical trial registered with www.clinicaltrials.gov (NCT 00063869).
Adalimumab and methotrexate is more effective than adalimumab alone in patients with established rheumatoid arthritis: results from a 6-month longitudinal, observational, multicentre study
Authors: M S Heiberg
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objectives:</b> To compare the effectiveness of adalimumab monotherapy and adalimumab and methotrexate (MTX) combination therapy in patients with established rheumatoid arthritis. <b>Methods:</b> Data from an ongoing longitudinal observational study in Norway were used to compare response to treatment with two different adalimumab regimens (monotherapy, n = 84; combination with MTX, n = 99). Patients were assessed with measures of disease activity, health status and utility scores. Within-group changes were analysed from baseline to follow-up at 3 and 6 months and the changes were compared between groups after adjustment for the propensity score. The groups were also compared for the proportions of patients achieving European League Against Rheumatism (EULAR) good response, Disease Activity Score (DAS)28 remission and treatment terminations. <b>Results:</b> The improvement from baseline was significant for all measures in the adalimumab and MTX group, but only for DAS28, joint counts, two Short-form Health Survey with 36 questions (SF-36) dimensions and patient's and investigator's global assessment in the monotherapy group. All between-group differences were numerically in favour of combination therapy and significant for C reactive protein, joint counts, DAS28, Modified Health Assessment Questionnaire, investigator's global assessment, four SF-36 dimensions and Short Form 6D at 6 months. More patients in the combination therapy group reached EULAR good response (p&lt;0.001) and remission (p = 0.07). At 6 months, 80.8% of the patients in the combination therapy group and 59.5% in the monotherapy group remained on treatment (p = 0.002). More withdrawals in the monotherapy group were due to adverse events. <b>Conclusions:</b> Our results were consistent across several categories of end points and suggest that adalimumab combined with MTX is effective in patients with rheumatoid arthritis treated in daily clinical practice and is superior to adalimumab monotherapy.
Traumatic lung pseudocyst.
Authors: T Shirakusa, Y Araki, M Tsutsui, R Motonaga, M Iwanaga, H Ogami, K Matsuba
Journal: Thorax (1987)

Traumatic lung pseudocyst is an uncommon lung injury due to closed chest trauma. Four cases are reported; all were male and one was a child. Three cases showed spontaneous resolution of the pseudocyst and in one case, where resolution was slow, lobectomy was carried out at the patient9s insistence. Diagnosis poses no serious problems as there is inevitably a history of substantial chest trauma. The chest radiograph shows a characteristic cavitatory lesion. The pseudocysts may be multiple. Tomography may be helpful in diagnosis and computed tomography can be particularly useful in the demonstration of paramediastinal traumatic pseudocysts.
Calcifying panniculitis following subcutaneous injections of nadroparin-calcium in a patient with osteomalacia
Authors: A. Campanelli, G. Kaya, I. Masouyé, L. Borradori
Journal: British Journal of Dermatology (2005)

Calcifying panniculitis is a rare form of calcinosis cutis belonging to the spectrum of calciphylaxis that has almost invariably been described in patients with severe renal disturbances. We report a patient with osteomalacia without chronic renal failure, who developed calcifying panniculitis following subcutaneous administration of nadroparin-calcium. Light microscopy studies of biopsy specimens revealed multiple foci of microcalcification within the adipose lobules, in the interadipocyte spaces, in connective tissue septa and in the media of small arteries in the subcutis. The patient had an elevated level of intact parathyroid hormone, whereas the calcium-phosphorus product was normal. The lesions slowly resolved upon discontinuation of nadroparin. We conclude that calcifying panniculitis is a rare complication associated with the subcutaneous administration of nadroparin-calcium that may rarely also occur in the absence of renal disturbances. Low molecular weight calcium-containing heparins should probably be used with caution in the presence of hyperparathyroidism.
The Course of Life: Psychoanalytic Contributions Toward Understanding Personality Development, Vol. I. Infancy and Early Childhood; The Course of Life: Psychoanalytic Contributions Toward Understanding Personality Development, Vol. II. Latency, Adolescence and Youth; The Course of Life: Psychoanalytic Contributions Toward Understanding Personality Development, Vol. III. Adulthood and the Aging Process
Authors: MICHAEL H. SACKS
Journal: American Journal of Psychiatry (1982)
Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11
Authors: Sean F. Landrette, Ya-Huei Kuo, Karen Hensen, Sahar Barjesteh van Waalwijk van Doorn-Khosrovani, Paola N. Perrat, Wim J. M. Van de Ven, Ruud Delwel, Lucio H. Castilla
Journal: Blood (2004)
Active Stiffness of the Intact Canine Left Ventricle
Authors: STANLEY A. FORWAND, KEVIN M. McINTYRE, JOSE G. LIPANA, HERBERT J. LEVINE
Journal: Circulation Research (1966)

Three methods were employed to measure the overall active stiffness of the intact left ventricle in anesthetized dogs. In two of these, isovolumic contractions of the ventricle were examined, and in the third the response to a minor increase in afterload was analyzed. The average modulus of active stiffness of the normal left ventricle by all three methods was found to be lower than that reported for the cat papillary muscle (57-76%). Myocardial infarction studied 1 hour and 2 to 3 weeks following ligation of the anterior descending coronary artery did not alter active stiffness of the left ventricle. When sufficient time had elapsed, however, for complete scarring and thinning of the infarction to occur, active stiffness was significantly reduced. It is suggested that a functional defect of the overall active stiffness (series elasticity) of the ventricle may be operative in the pathogenesis of congestive failure due to ventricular aneurysm.
Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment
Authors: Mika Gustafsson, Måns Edström, Danuta Gawel, Colm E Nestor, Hui Wang, Huan Zhang, Fredrik Barrenäs, James Tojo, Ingrid Kockum, Tomas Olsson, Jordi Serra-Musach, Núria Bonifaci, Miguel Pujana, Jan Ernerudh, Mikael Benson
Journal: Genome Medicine (2014)

Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases.We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases.The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4(+) T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification.In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles.
Arc/Arg3.1 Interacts with the Endocytic Machinery to Regulate AMPA Receptor Trafficking
Authors: Shoaib Chowdhury, Jason D. Shepherd, Hiroyuki Okuno, Gregory Lyford, Ronald S. Petralia, Niels Plath, Dietmar Kuhl, Richard L. Huganir, Paul F. Worley
Journal: Neuron (2006)
PHASE I STUDIES OF 2',3'-DIDEOXYCYTIDINE IN SEVERE HUMAN IMMUNODEFICIENCY VIRUS INFECTION AS A SINGLE AGENT AND ALTERNATING WITH ZIDOVUDINE (AZT)
Authors: Robert Yarchoan, Rose V. Thomas, Jean Pierre Allain, Nanette Mcatee, Richard Dubinsky, Hiroaki Mitsuya, Thomas J. Lawley, Bijan Safai, Charles E. Myers, Carlo Federico Perno, Raymond W. Klecker, Robert J. Wills, Margaret A. Fischl, M. Carol Mcneely, James M. Pluda, Michael Leuther, Jerry M. Collins, Samuel Broder
Journal: The Lancet (1988)
Prospective Risk-Adjusted [<sup>18</sup>F]Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography Assessment of Radiation Response in Head and Neck Cancer
Authors: Benjamin J. Moeller, Vishal Rana, Blake A. Cannon, Michelle D. Williams, Erich M. Sturgis, Lawrence E. Ginsberg, Homer A. Macapinlac, J. Jack Lee, K. Kian Ang, K.S. Clifford Chao, Gregory M. Chronowski, Steven J. Frank, William H. Morrison, David I. Rosenthal, Randal S. Weber, Adam S. Garden, Scott M. Lippman, David L. Schwartz
Journal: Journal of Clinical Oncology (2009)

[(18)F]Fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) imaging may improve assessment of radiation response in patients with head and neck cancer, but it is not yet known for which patients this is most useful. We conducted a prospective trial to identify patient populations likely to benefit from the addition of functional imaging to the assessment of radiotherapy response.
A Salt-Induced Reno-Cerebral Reflex Activates Renin-Angiotensin Systems and Promotes CKD Progression
Authors: Wei Cao, Aiqing Li, Liangliang Wang, Zhanmei Zhou, Zhengxiu Su, Wei Bin, Christopher S Wilcox, Fan Fan Hou
Journal: Journal of the American Society of Nephrology (2015)

Salt intake promotes progression of CKD by uncertain mechanisms. We hypothesized that a salt-induced reno-cerebral reflex activates a renin-angiotensin axis to promote CKD. Sham-operated and 5/6-nephrectomized rats received a normal-salt (0.4%), low-salt (0.02%), or high-salt (4%) diet for 2 weeks. High salt in 5/6-nephrectomized rats increased renal NADPH oxidase, inflammation, BP, and albuminuria. Furthermore, high salt activated the intrarenal and cerebral, but not the systemic, renin-angiotensin axes and increased the activity of renal sympathetic nerves and neurons in the forebrain of these rats. Renal fibrosis was increased 2.2-fold by high versus low salt, but intracerebroventricular tempol, losartan, or clonidine reduced this fibrosis by 65%, 69%, or 59%, respectively, and renal denervation or deafferentation reduced this fibrosis by 43% or 38%, respectively (all P<0.05). Salt-induced fibrosis persisted after normalization of BP with hydralazine. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral reflex that is activated by salt and promotes oxidative stress, fibrosis, and progression of CKD independent of BP.