tbuckley/cabot-search huggingface dataset:
Selective Class I Histone Deacetylase Inhibition Suppresses Hypoxia-Induced Cardiopulmonary Remodeling Through an Antiproliferative Mechanism
Authors: Maria A. Cavasin, Kim Demos-Davies, Todd R. Horn, Lori A. Walker, Douglas D. Lemon, Nicholas Birdsey, Mary C.M. Weiser-Evans, Julie Harral, David C. Irwin, Adil Anwar, Michael E. Yeager, Min Li, Peter A. Watson, Raphael A. Nemenoff, Peter M. Buttrick, Kurt R. Stenmark, Timothy A. McKinsey
Journal: Circulation Research (2012)

Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with associated right ventricular cardiac remodeling are poorly understood.This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension.Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression.By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for pulmonary hypertension that will complement vasodilator standards of care.
Colonoscopy in Colorectal-Cancer Screening for Detection of Advanced Neoplasia
Authors: Jaroslaw Regula, Maciej Rupinski, Ewa Kraszewska, Marcin Polkowski, Jacek Pachlewski, Janina Orlowska, Marek P. Nowacki, Eugeniusz Butruk
Journal: New England Journal of Medicine (2006)

Recommendations for colorectal-cancer screening are based solely on age and family history of cancer, not sex.
The potential for emerging therapeutic options forClostridium difficileinfection
Authors: Harsh Mathur, Mary C Rea, Paul D Cotter, R Paul Ross, Colin Hill
Journal: Gut Microbes (2014)

Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review.
Protracted Intermittent Schedule of Topotecan in Children With Refractory Acute Leukemia: A Pediatric Oncology Group Study
Authors: W. L. Furman
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of a protracted, intermittent schedule of daily 30-minute infusions of topotecan (TPT) for up to 12 consecutive days, every 3 weeks, in children with refractory leukemia. PATIENTS AND METHODS: Forty-nine children were enrolled onto this phase I trial (24 with acute nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m2/d for 5 days and 2.4 mg/m2/d from 7 days to the same dose for 9 and 12 days in cohorts of three to six patients when no DLT was identified. TPT pharmacokinetics were studied in 33 children once or twice (first and last doses in patients who received TPT for > 7 days). RESULTS: Seventy assessable courses of TPT were administered to 49 children who had refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and the MTD was 2.4 mg/m2/d for 9 days in this group of heavily pretreated children. In 33 patients, the median TPT lactone clearance after the first dose was 19.2 L/h/m2 (range, 9.4 to 45.9 L/h/m2) and did not change during the course. There were significant responses (one complete response [CR] and four partial responses [PR] in patients with ANLL and one CR and two PRs in patients with ALL), and all but one were at dosages of TPT given for at least 9 days. CONCLUSION: The MTD was 2.4 mg/m2/d for 9 days. Further testing is warranted of TPT's schedule dependence in children with leukemia.
Responses of Treatment Primary Eosinophilic Gastrointestinal Disorders with Corticosteroid, Montelukast and Ketotifen, 3 Cases Report
Authors: S. Nanthapisal, N. Vithayasai, T. Dangsuwan, S. Jennuwat, J. Sirikul, G. Pongsamat, M. Vangveeravong
Journal: Journal of Allergy and Clinical Immunology (2007)
Exercise and Cardiac Work Response at High Altitude
Authors: ERNEST O. THEILEN, DONALD E. GREGG, ANDRÉS ROTTA
Journal: Circulation (1955)

The response to treadmill exercise of the left ventricle of natives of the region of Morococha, Peru (elevation 14,900 feet), and of natives of the region of Lima, Peru (elevation 500 feet), was studied at the elevation where they had always lived. In both groups the external work of the left ventricle was effected by a combination of a large increase in cardiac output and a mild increase in systemic blood pressure. Stroke volume and stroke work were only mildly elevated since the heart rate was concurrently greatly increased. As a result, the increase in work of the left ventricle was largely accomplished by an increase in heart rate and to a lesser extent by an increase in stroke work. For comparable amounts of external work, the left ventricle of the native to high altitude and performing at high altitude responded with considerably greater effort than did the left ventricle of the native of low altitude performing at sea level. Some of the data may have approximated the maximum effort of which the normal left ventricle was capable.
Attenuation of Colon Inflammation through Activators of the Retinoid X Receptor (Rxr)/Peroxisome Proliferator–Activated Receptor γ (Pparγ) Heterodimer
Authors: Pierre Desreumaux, Laurent Dubuquoy, Sophie Nutten, Michel Peuchmaur, Walter Englaro, Kristina Schoonjans, Benoit Derijard, Beatrice Desvergne, Walter Wahli, Pierre Chambon, Mark D. Leibowitz, Jean-Frédéric Colombel, Johan Auwerx
Journal: The Journal of Experimental Medicine (2001)

The peroxisome proliferator–activated receptor γ (PPARγ) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARγ and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARγ1/− and RXRα1/− mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARγ heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARγ agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARγ and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor α and interleukin 1β mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor κB DNA binding activity, c-Jun NH2-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARγ and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARγ heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARγ ligands might hold promise in the clinic due to their synergistic effects.
Policy-makers in the Pharmaceutical Industry
Authors: S. Bradshaw
Journal: BMJ (1965)

MEDIBCLJOURNAtrue, since the more disturbed patients have a greater range within which to show improvement.Secondly, the three measures used to assess drug effect are obviously not independent of each other.This means that not only is nothing added by three such measures but also bias in one will contaminate the others.Thirdly, in an effort to deal with the problem of to what extent measurements were affected by known characteristic drug effects and side-effects, they adopt the rather naive procedure of asking the doctors on what they based their opinion as to the treatment used.Despite the fact that 5 3°, of the chlor- methiazole group as opposed to 25 (, of the placebo group were sedated, we are told that in only 20", of the cases was sedation the reason for their opinion.Furthermore, the authors point out that in the chlormethiazole group, sedation and the doctor's improvement rating were significantly related.Presumably, therefore, sedative effects were obvious to the doctor doing the assessment, and it is difficult to accept that such an important variable affected the clinician's judgment in only a minority of cases.Following the example of Sereny and Kalant' we are attempting to objectify our measures of withdrawal symptoms.This has several advantages.The strict comparability of groups is not necessary, since statistical techniques, such as analysis of covariance, can be used which take into account group variation in initial scores, the insurmountable problems entailed in the use of clinical assess- ment of improvement are avoided, and the differential effect of the drug can be observed.Furthermore, if data are expressed in scores, making the use of more powerful statistical tests possible, the researcher can dispense with large groups, which rarely compensate for errors in experimental design.-Weare, etc.,
A developmental perspective on the integration of language production and comprehension
Authors: Saloni Krishnan
Journal: Behavioral and Brain Sciences (2013)

Abstract The integration of language production and comprehension processes may be more specific in terms of developmental timing than Pickering &amp; Garrod (P&amp;G) discuss in their target article. Developmental studies do reveal links between production and comprehension, but also demonstrate that the integration of these skills changes over time. Production-comprehension links occur within specific language skills and specific time windows.
Two Clinical Phenotypes in Polycythemia Vera
Authors: Jerry L. Spivak, Michael Considine, Donna M. Williams, Conover C. Talbot, Ophelia Rogers, Alison R. Moliterno, Chunfa Jie, Michael F. Ochs
Journal: New England Journal of Medicine (2014)

Polycythemia vera is the ultimate phenotypic consequence of the V617F mutation in Janus kinase 2 (encoded by JAK2), but the extent to which this mutation influences the behavior of the involved CD34+ hematopoietic stem cells is unknown.
What infants know about intentional action and how they might come to know it
Authors: Camille Wilson-Brune, Amanda L. Woodward
Journal: Behavioral and Brain Sciences (2004)

Carpendale &amp; Lewis (C&amp;L) propose that social knowledge is constructed from triadic interactions. This account generates testable predictions concerning social knowledge in infancy. Current evidence is not entirely consistent with these predictions. Infants possess action knowledge before they engage in triadic interactions, and triadic use of an action does not always precede knowledge about the action.
CD36-specific antibodies block release of HIV-1 from infected primary macrophages and its transmission to T cells
Authors: Stefano Berre, Raphaël Gaudin, Bruna Cunha de Alencar, Marion Desdouits, Mélanie Chabaud, Nadia Naffakh, Marc Rabaza-Gairi, François-Xavier Gobert, Mabel Jouve, Philippe Benaroch
Journal: The Journal of Experimental Medicine (2013)

HIV-1–infected macrophages likely represent viral reservoirs, as they accumulate newly formed virions in internal virus-containing compartments (VCCs). However, the nature and biogenesis of VCCs remain poorly defined. We show that upon HIV-1 infection of primary human macrophages, Gag is recruited to preexisting compartments containing the scavenger receptor CD36, which then become VCCs. Silencing of CD36 in HIV-1–infected macrophages decreases the amount of virions released. Strikingly, soluble anti-CD36 antibodies, but not the natural ligands of CD36, inhibit release of virions from HIV-1–infected macrophages and the transmission of virus to CD4+ T cells. The effect of the antibodies is potent, rapid, and induces the retention of virions within VCCs. Ectopic expression of CD36 in HeLa cells renders them susceptible to the inhibitory effect of the anti-CD36 mAb upon HIV-1 infection. We show that the anti-CD36 mAb inhibits HIV-1 release by clustering newly formed virions at their site of budding, and that signaling via CD36 is not required. Thus, HIV-1 reservoirs in macrophages may be tackled therapeutically using anti-CD36 antibodies to prevent viral dissemination.
Partition of Blood Flow to the Cutaneous and Muscular Beds of the Forearm at Rest and during Leg Exercise in Normal Subjects and in Patients with Heart Failure
Authors: ROBERT ZELIS, DEAN T. MASON, EUGENE BRAUNWALD
Journal: Circulation Research (1969)

The purpose of this study was to determine the relative effects of various levels of exercise on blood flow to skin and muscle of the resting extremity of normal subjects and the manner in which this distribution is modified by congestive heart failure. Blood flow to the skin and muscle of the forearm was determined plethysmographically with the aid of epinephrine iontophoresis at rest and during supine leg exercise in 12 normal subjects and in 9 patients with failure. In normal resting subjects, forearm blood flow averaged 6.30 ml/min/100 ml, 52% partitioned to muscle and 48% to skin. In the patients, forearm blood flow averaged 2.94 ml/min/100 ml, with 48% to muscle and 52% to skin. In normal subjects performing mild exercise, forearm muscle flow was not significantly changed, but during moderate and strenuous activity it was significantly reduced. Cutaneous blood flow, however, declined early at all levels of exertion. In the normal subjects, cutaneous hyperemia occurred late during moderate exercise but with strenuous exercise, was delayed until after exercise had been discontinued. In contrast, in the patients, forearm muscle blood flow decreased strikingly during leg exercise, cutaneous flow fell and remained depressed during the entire period of exercise, and no postexercise hyperemia occurred. Thus, in congestive heart failure, both the cutaneous and muscle beds of the forearm are abnormally constricted at rest, there is excessive vasoconstriction in both beds during leg exercise, and postexercise cutaneous vasodilation is abolished.
A Roadmap of Tandemly Arrayed Genes in the Genomes of Human, Mouse, and Rat
Authors: Valia Shoja, Liqing Zhang
Journal: Molecular Biology and Evolution (2006)

Tandemly arrayed genes (TAGs) play an important functional and physiological role in the genome. Most previous studies have focused on individual TAG families in a few species, yet a broad characterization of TAGs is not available. Here we identified all TAGs in the genomes of humans, mouse, and rat and performed a comprehensive analysis of TAG distribution, TAG sizes, TAG orientations and intergenic distances, and TAG functions. TAGs account for about 14–17% of all genes in the genome and nearly one-third of all duplicated genes, highlighting the predominant role that tandem duplication plays in gene duplication. For all species, TAG distribution is highly heterogeneous along chromosomes and some chromosomes are enriched with TAG forests, whereas others are enriched with TAG deserts. The majority of TAGs are of size 2 for all genomes, similar to the previous findings in Caenorhabditis elegans, Arabidopsis thaliana, and Oryza sativa, suggesting that it is a rather general phenomenon in eukaryotes. The comparison with the genome patterns shows that TAG members have a significantly higher proportion of parallel gene orientation in all species, corroborating Graham's claim that parallel orientation is the preferred form of orientation in TAGs. Moreover, TAG members with parallel orientation tend to be closer to each other than all neighboring genes in the genome with parallel orientation. The analyses of Gene Ontology function indicate that genes with receptor or binding activities are significantly overrepresented by TAGs. Computer simulation reveals that random gene rearrangements have little effect on the statistics of TAGs for all genomes. Finally, the average proportion of TAGs shows a trend of increase with the increase of family sizes, although the correlation between TAG proportions in individual families and family sizes is not significant.
Endothelin-1 release from cultured endothelial cells induced by sera from patients with systemic lupus erythematosus.
Authors: T Yoshio, J Masuyama, A Mimori, A Takeda, S Minota, S Kano
Journal: Annals of the Rheumatic Diseases (1995)

To clarify the pathophysiological role of endothelin-1 (ET-1) in the vascular injury associated with systemic lupus erythematosus (SLE) by investigating the effect of sera from patients with SLE on ET-1 release from cultured human umbilical vein endothelial cells.Confluent monolayers of cultured human umbilical vein endothelial cells were incubated with serum samples (diluted 1:10) from 25 patients with SLE and 16 normal controls for two hours at 37 degrees C and ET-1 concentration in the culture supernatant was measured by enzyme immunoassay.The mean release of ET-1 from endothelial cells in the presence of serum from SLE patients was greater than in the presence of serum from normal controls (p < 0.005). ET-1 release from endothelial cells significantly correlated with the titre of IgM anti-endothelial cell antibodies (IgM-AECA) and immune complex concentration in sera from SLE patients (p < 0.05 and p < 0.01, respectively). After gel chromatography of the serum from an SLE patient, those fractions containing IgM-AECA or immune complex were shown to stimulate ET-1 release from endothelial cells. Heat aggregated IgG also stimulated ET-1 release from endothelial cells in a concentration dependent manner.IgM-AECA and immune complexes may stimulate ET-1 release from endothelial cells and ET-1 may play an important role in the initiation and development of vascular injury, such as pulmonary hypertension and lupus nephritis, in SLE.
Complexity of Terminal Airspace Geometry Assessed by Computed Tomography in Asthma
Authors: Fumihiro Mitsunobu, Kozo Ashida, Yasuhiro Hosaki, Hirofumi Tsugeno, Makoto Okamoto, Kazunori Nishida, Shingo Takata, Tadashi Yokoi, Michiaki Mishima, Yoshiro Tanizaki
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Low attenuation areas in computed tomography images from patients with chronic obstructive pulmonary disease have been reported to represent macroscopic and/or microscopic emphysema. The cumulative size distribution of the clusters has been shown to follow a power law characterized by the exponent D, a measure of the complexity of the terminal airspace geometry. We have previously found increased low attenuation areas in nonsmoking subjects with asthma. We examined the size distribution of the clusters in nonsmoking subjects with asthma compared with both nonsmoking control subjects and subjects with asthma with a smoking history. The percentage of lung field occupied by low attenuation areas (LAA%) and D in subjects with asthma with a smoking history differed significantly from nonsmoking subjects with asthma and control subjects. In nonsmoking subjects with asthma, both parameters differed significantly between severe asthma and mild or moderate asthma. The LAA% differed significantly between moderate and mild asthma, but D did not. In mild and moderate asthma, a highly significant correlation between LAA% and D was observed in patients with a smoking history, but not in nonsmoking subjects with asthma. Our results suggest that decreased D is mostly related to emphysematous change, and both measurements of LAA% and D may provide useful information to characterize low attenuation areas in subjects with asthma.
Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study.
Authors: H Safran, T P King, H Choy, P J Hesketh, B Wolf, E Altenhein, W Sikov, A Rosmarin, W Akerley, K Radie-Keane, G Cicchetti, F Lopez, K Bland, H J Wanebo
Journal: Journal of Clinical Oncology (1997)

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and potential antitumor activity of weekly paclitaxel with concurrent radiation (RT) for locally advanced pancreatic and gastric cancer. PATIENTS AND METHODS Thirty-four patients with locally advanced adenocarcinoma of the pancreas or stomach were studied. The initial dose of paclitaxel was 30 mg/m2 by 3-hour intravenous (I.V.) infusion repeated every week for 6 weeks with 50 Gy RT. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients until dose-limiting toxicity was observed. RESULTS The dose-limiting toxicities at 60 mg/m2/wk were abdominal pain within the RT field, nausea, and anorexia. Of 23 patients with assessable disease, 11 (seven with gastric, four with pancreatic cancer) had objective responses for an overall response rate of 48%. CONCLUSION Concurrent paclitaxel with upper abdominal RT is well tolerated at dosages that have substantial activity. A phase II trial of neoadjuvant paclitaxel and RT at the MTD of 50 mg/m2/wk is underway.