tbuckley/cabot-search huggingface dataset:
Xist localization and function: new insights from multiple levels
Authors: Andrea Cerase, Greta Pintacuda, Anna Tattermusch, Philip Avner
Journal: Genome biology (2015)

In female mammals, one of the two X chromosomes in each cell is transcriptionally silenced in order to achieve dosage compensation between the genders in a process called X chromosome inactivation. The master regulator of this process is the long non-coding RNA Xist. During X-inactivation, Xist accumulates in cis on the future inactive X chromosome, triggering a cascade of events that provoke the stable silencing of the entire chromosome, with relatively few genes remaining active. How Xist spreads, what are its binding sites, how it recruits silencing factors and how it induces a specific topological and nuclear organization of the chromatin all remain largely unanswered questions. Recent studies have improved our understanding of Xist localization and the proteins with which it interacts, allowing a reappraisal of ideas about Xist function. We discuss recent advances in our knowledge of Xist-mediated silencing, focusing on Xist spreading, the nuclear organization of the inactive X chromosome, recruitment of the polycomb complex and the role of the nuclear matrix in the process of X chromosome inactivation.
Islet Autoantibody Seroconversion in the DPT-1 Study
Authors: Kendra Vehik, Michael J. Haller, Craig A. Beam, Desmond A. Schatz, Diane K. Wherrett, Jay M. Sosenko, Jeffrey P. Krischer
Journal: Diabetes Care (2011)

OBJECTIVE Although type 1 diabetes autoimmunity frequently begins in childhood, little is known about the relationship between age and autoimmunity development. Our aim was to determine the timing of seroconversion to diabetes-associated autoantibody (DAA) positivity and risk in first- and second-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Study subjects were identified through the Diabetes Prevention Trial-Type 1 (DPT-1). Children 3–18 years of age (n = 42,447) were screened for DAAs; 1,454 were ICA positive (≥10 JDF units), 1,758 were GAD65 positive, and 899 were ICA512 positive at the time of initial screening. Subjects who were initially antibody negative (n = 39,212) were recalled for rescreening, and 11,813 returned for rescreening. RESULTS DAA seroconversion occurred in 469 (4%) children; 258 seroconverted to ICA, 234 to GAD65, and 99 to ICA512. The median time to seroconversion was 2 years. The 2-year risk for DAAs was highest in early childhood. For each 1-year increase in age in this cohort, the risk of any autoantibody seroconversion (HR 0.95, 95% CI 0.92–0.97) decreased by 5%, and for any two autoantibodies risk decreased by 13% (0.87, 0.82–0.93). CONCLUSIONS Risk of autoantibody seroconversion among children followed in DPT-1 is age dependent. Younger children have the highest risk for DAAs, with the majority of children seroconverting by 13 years of age (75%). This suggests that annual screenings should be started in early childhood and continued through early adolescence to identify the majority of subjects at risk for type 1 diabetes and eligible for prevention trials.
Potentiation of Baroreceptor Reflex Response by Heat Shock Protein 70 in Nucleus Tractus Solitarii Confers Cardiovascular Protection During Heatstroke
Authors: Pei-Lun Li, Yung-Mei Chao, Samuel H. H. Chan, Julie Y. H. Chan
Journal: Circulation (2001)

Background —Whereas hypotension and bradycardia seen during the onset of heatstroke may be protected by prior induction of heat shock protein 70 (HSP70) in the brain, the underlying mechanism is not fully understood. We evaluated the hypothesis that HSP70 may confer cardiovascular protection during heatstroke by potentiating the baroreceptor reflex (BRR) control of peripheral hemodynamic performance. Methods and Results —Adult male Sprague-Dawley rats subjected to a brief hyperthermic heat shock (HS; 42°C for 15 minutes) induced discernible expression of HSP70 in the bilateral nucleus tractus solitarii (NTS), the terminal site in the brain stem for primary baroreceptor afferents. This HSP70 expression was detected at 8 hours, peaked at 24 hours, and returned to baseline by 48 hours after HS. Brief hyperthermia also significantly potentiated the BRR response in a temporal profile that correlated positively with changes in HSP70 expression at the NTS. Prior HS also appreciably alleviated hyperthermia, severe hypotension, and bradycardia manifested during the onset of heatstroke (45°C for 60 minutes) elicited 24 hours later. Microinjection bilaterally of anti-HSP70 antiserum (1:20) into the NTS or denervation of the sinoaortic baroreceptor afferents significantly reversed the enhancement of BRR response and cardiovascular protection during heatstroke induced by prior HS. Conclusions —These results suggest that HS-induced expression of HSP70 in the NTS may alleviate severe hypotension and bradycardia exhibited during the onset of heatstroke by potentiating both the sensitivity and capacity of BRR response.
Hemolytic Plaque Formation by Leukocytes in Vitro CONTROL BY VASOACTIVE HORMONES
Authors: Kenneth L. Melmon, Henry R. Bourne, Yacob Weinstein, G. M. Shearer, Jerrold Kram, Sara Bauminger
Journal: Journal of Clinical Investigation (1974)

Histamine, beta-adrenergic amines, and prostaglandins inhibited hemolytic plaque formation by splenic leukocytes from immunized mice. The same agents had previously been shown to prevent both the IgE-mediated release of histamine from human basophils and the immunologically specific cytolytic activity of murine lymphocytes, through stimulation of the production of cyclic AMP in leukocytes. We therefore tested the hypothesis that cyclic AMP might mediate an inhibitory effect of these drugs by comparing the ability of these agents to inhibit plaque formation with their effects on cyclic AMP accumulation in leukocytes. In splenic cells from three mouse strains, the dose-dependent effects of these agents of cyclic AMP correlated with their inhibition of plaque formation. Beta- but not alpha-adrenergic agonists were effective in both systems, and the effects of isoproterenol were inhibited by propranolol. Histamine was approximately equipotent with isoproterenol in both systems. Two prostaglandins (E1 and E2) were effective in both systems, but prostaglandin F2α was not. Dibutyryl cyclic AMP, a lipid-soluble analog of the endogenous nucleotide, inhibited plaque formation by cells of all three strains. Theophylline, an inhibitor of cyclic AMP degradation, inhibited plaque formation slightly, but potentiated the effects of histamine, isoproterenol, and the prostaglandins on both cyclic AMP accumulation and plaque formation. Finally, cholera enterotoxin, a potent activator of adenyl cyclase, produced a delayed inhibition of plaque formation and a parallel increase in leukocyte cyclic AMP content; both effects of the toxin were blocked by canine antitoxin. These results suggest that leukocyte cyclic AMP may act as a “second messenger” to suppress plaque formation in vitro. The inhibitory effects of hormones and cyclic AMP on plaque formation are strikingly similar to their effects on in vitro models of immediate and cell-mediated hypersensitivity. The physiologic significance of these findings is not yet known.
Perinatal outcomes after bariatric surgery: nationwide population based matched cohort study
Authors: N. Roos, M. Neovius, S. Cnattingius, Y. Trolle Lagerros, M. Saaf, F. Granath, O. Stephansson
Journal: BMJ (2013)

<b>Objective</b> To compare perinatal outcomes in births of women with versus without a history of bariatric surgery. <b>Design</b> Population based matched cohort study. <b>Setting</b> Swedish national health service. <b>Participants</b> 1 742 702 singleton births identified in the Swedish medical birth register between 1992 and 2009. For each birth to a mother with a history of bariatric surgery (n=2562), up to five control births were matched by maternal age, parity, early pregnancy body mass index, early pregnancy smoking status, educational level, and year of delivery. Secondary control cohorts, including women eligible for bariatric surgery (body mass index ≥35 or ≥40), were matched for the same factors except body mass index. History of maternal bariatric surgery was ascertained through the Swedish national patient register from 1980 to 2009. <b>Main outcome measures</b> Preterm birth (&lt;37 weeks), small for gestational age birth, large for gestational age birth, stillbirth (≥28 weeks), and neonatal death (0-27 days). <b>Results</b> Post-surgery births were more often preterm than in matched controls (9.7% (243/2511) <i>v</i> 6.1% (750/12 379); odds ratio 1.7, 95% confidence interval 1.4 to 2.0; P&lt;0.001). Body mass index seemed to be an effect modifier (P=0.01), and the increased risk of preterm birth was only observed in women with a body mass index &lt;35. A history of bariatric surgery was associated with increased risks of both spontaneous (5.2% (130/2511) <i>v</i> 3.6% (441/12 379); odds ratio 1.5, 1.2 to 1.9; P&lt;0.001) and medically indicated preterm birth (4.5% (113/2511) <i>v</i> 2.5% (309/12 379); odds ratio 1.8, 1.4 to 2.3; P&lt;0.001). A history of bariatric surgery was also associated with an increased risk of a small for gestational age birth (5.2% (131/2507) <i>v</i> 3.0% (369/12 338); odds ratio 2.0, 1.5 to 2.5; P&lt;0.001) and lower risk of a large for gestational age birth (4.2% (105/2507) <i>v</i> 7.3% (895/12 338); odds ratio 0.6, 0.4 to 0.7; P&lt;0.001). No differences were detected for stillbirth or neonatal death. The increased risks for preterm and small for gestational age birth, as well as the decreased risk for large for gestational age birth, remained when post-surgery births were compared with births of women eligible for bariatric surgery. <b>Conclusion</b> Women with a history of bariatric surgery were at increased risk of preterm and small for gestational age births and should be regarded as a risk group during pregnancy.
Management of Neonatal Asphyxia
Authors: Herman A. Hein
Journal: JAMA (1980)

<h3>To the Editor.—</h3> In a recent letter inThe Journal, Albert D. Warshauer, MD (242:1969, 1979), advocated mouth-to-mouth ventilation as a third alternative to intubation or bagand-mask ventilation for oxygendepressed neonates. Few would dispute the advocacy of this method in an environment other than a modern hospital. However, a serious question must be raised over the advisability of mouth-to-mouth ventilation when resuscitating a neonate in a hospital. In 1980 hospitals that provide obstetric services should possess the necessary laryngoscopes, endotracheal tubes, or appropriately sized bags and masks for neonatal resuscitation. Furthermore, providers who deliver and care for neonates should be skilled in proper resuscitation techniques. I strongly support Dr Warshauer's contention that severe hypoxemia is an emergency and that swift remedial action is essential. However, therapy based only on expediency may produce a less than salutary result; to wit: 1. Meconium aspiration.—Dr Warshauer notes: "Preliminary suctioning ordinarily is omitted. There
A Phase II Trial of Erlotinib in Combination with Bevacizumab in Patients with Metastatic Breast Cancer
Authors: Maura N. Dickler, Hope S. Rugo, Carey A. Eberle, Edi Brogi, James F. Caravelli, Katherine S. Panageas, Jeff Boyd, Benjamin Yeh, Diana E. Lake, Chau T. Dang, Teresa A. Gilewski, Jacqueline F. Bromberg, Andrew D. Seidman, Gabriella M. D'Andrea, Mark M. Moasser, Michele Melisko, John W. Park, Janet Dancey, Larry Norton, Clifford A. Hudis
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To evaluate the efficacy and toxicity of erlotinib plus bevacizumab in patients with metastatic breast cancer (MBC), targeting the epidermal growth factor receptor (EGFR/HER1) and the vascular endothelial growth factor (VEGF) pathway. Experimental Design: Thirty-eight patients with MBC were enrolled and treated at two institutions with erlotinib, a small molecule EGFR tyrosine kinase inhibitor (150 mg p.o. daily) plus bevacizumab, an anti-VEGF antibody (15 mg/kg i.v. every 3 weeks). Patients had one to two prior chemotherapy regimens for metastatic disease. The primary end point was response rate by Response Evaluation Criteria in Solid Tumors criteria using a Simon 2-stage design. Secondary end points included toxicity, time to progression, response duration, and stabilization of disease of ≥26 weeks. Correlative studies were done on tumor tissue, including EGFR expression and mutation analysis. Results: One patient achieved a partial response for 52+ months. Fifteen patients had stable disease at first evaluation at 9 weeks; 4 of these patients had stable disease beyond 26 weeks. Median time to progression was 11 weeks (95% confidence interval, 8-18 weeks). Diarrhea of any grade was observed in 84% of patients (grade 3 in 3%); 76% experienced grade 1 or 2 skin rash, and 18% developed hypertension (grade 3 in 11%). The level of EGFR expression was not predictive of response to therapy. Conclusions: The combination of erlotinib and bevacizumab was well-tolerated but had limited activity in unselected patients with previously treated MBC. Biomarkers are needed to identify those MBC patients likely to respond to anti-EGFR/HER1 plus anti-VEGF therapy.
Sonographic incidence of tendon microtears in athletes with chronic Achilles tendinosis.
Authors: W W Gibbon, J R Cooper, G S Radcliffe
Journal: British Journal of Sports Medicine (1999)

To assess the number and distribution of tendon microtears in asymptomatic controls and athletes with chronic Achilles tendinitis or partial thickness tears using high resolution ultrasound.The mean number of microtears in three random tendon cross sections were recorded per tendon third in 19 asymptomatic volunteers, 16 athletes with symptomatic chronic Achilles tendinitis, and eight athletes with partial Achilles tendon rupture.Microtears were most numerous in the middle third section of the Achilles tendon. Some 67% of tendons in the control group had no microtears, and 28% showed a single microtear. Only 18% of the athletes with chronic Achilles tendinitis and none of the athletes with partial tendon rupture were without microtears in the middle third of their Achilles tendon. Of the tendons with chronic tendinitis, 13% had more than three microtears per section which increased to 87% in tendons exhibiting partial rupture.There appears to be an association between microtear formation and Achilles tendon rupture.
Part 8: Adult Advanced Cardiovascular Life Support
Authors: Robert W. Neumar, Charles W. Otto, Mark S. Link, Steven L. Kronick, Michael Shuster, Clifton W. Callaway, Peter J. Kudenchuk, Joseph P. Ornato, Bryan McNally, Scott M. Silvers, Rod S. Passman, Roger D. White, Erik P. Hess, Wanchun Tang, Daniel Davis, Elizabeth Sinz, Laurie J. Morrison
Journal: Circulation (2010)

A dvanced cardiovascular life support (ACLS) impacts mul- tiple key links in the chain of survival that include interventions to prevent cardiac arrest, treat cardiac arrest, and improve outcomes of patients who achieve return of spontaneous circulation (ROSC) after cardiac arrest.ACLS interventions aimed at preventing cardiac arrest include airway management, ventilation support, and treatment of bradyarrhythmias and tachyarrhythmias.For the treatment of cardiac arrest, ACLS interventions build on the basic life support (BLS) foundation of immediate recognition and activation of the emergency response system, early CPR, and rapid defibrillation to further increase the likelihood of ROSC with drug therapy, advanced airway management, and physiologic monitoring.Following ROSC, survival and neurologic outcome can be improved with integrated post-cardiac arrest care.Part 8 presents the 2010 Adult ACLS Guidelines: 8.1: "Adjuncts for Airway Control and Ventilation"; 8.2: "Management of Cardiac Arrest"; and 8.3: "Management of Symptomatic Bradycardia and Tachycardia."Post-cardiac arrest interventions are addressed in Part 9: "Post-Cardiac Arrest Care."
SKIN CHANGES CAUSED BY CANCER CHEMOTHKRAPY.
Authors: G. FALKSON, E. J. SCHULZ
Journal: British Journal of Dermatology (1964)

Journal Article SKIN CHANGES CAUSED BY CANCER CHEMOTHKRAPY. Get access G. FALKSON, G. FALKSON Department of Radiotherapy, Section of Dermatology, University of Pretoria, South Africa Search for other works by this author on: Oxford Academic Google Scholar E. J. SCHULZ E. J. SCHULZ Department of Radiotherapy, Section of Dermatology, University of Pretoria, South Africa Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 76, Issue 7, 1 July 1964, Pages 309–314, https://doi.org/10.1111/j.1365-2133.1964.tb14534.x Published: 01 July 1964
Meta-Analysis of Phase II Cooperative Group Trials in Metastatic Stage IV Melanoma to Determine Progression-Free and Overall Survival Benchmarks for Future Phase II Trials
Authors: Edward L. Korn, Ping-Yu Liu, Sandra J. Lee, Judith-Anne W. Chapman, Donna Niedzwiecki, Vera J. Suman, James Moon, Vernon K. Sondak, Michael B. Atkins, Elizabeth A. Eisenhauer, Wendy Parulekar, Svetomir N. Markovic, Scott Saxman, John M. Kirkwood
Journal: Journal of Clinical Oncology (2008)

Objective tumor response rates observed in phase II trials for metastatic melanoma have historically not provided a reliable indicator of meaningful survival benefits. To facilitate using overall survival (OS) or progression-free survival (PFS) as an endpoint for future phase II trials, we evaluated historical data from cooperative group phase II trials to attempt to develop benchmarks for OS and PFS as reference points for future phase II trials.Individual-level and trial-level data were obtained for patients enrolled onto 42 phase II trials (70 trial arms) that completed accrual in the years 1975 through 2005 and conducted by Southwest Oncology Group, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, North Central Cancer Treatment Group, and the Clinical Trials Group of the National Cancer Institute of Canada. Univariate and multivariate analyses were performed to identify prognostic variables, and between-trial(-arm) variability in 1-year OS rates and 6-month PFS rates were examined.Statistically significant individual-level and trial-level prognostic factors found in a multivariate survival analysis for OS were performance status, presence of visceral disease, sex, and whether the trial excluded patients with brain metastases. Performance status, sex, and age were statistically significant prognostic factors for PFS. Controlling for these prognostic variables essentially eliminated between-trial variability in 1-year OS rates but not in 6-month PFS rates.Benchmarks are provided for 1-year OS or OS curves that make use of the distribution of prognostic factors of the patients in the phase II trial. A similar benchmark for 6-month PFS is provided, but its use is more problematic because of residual between-trial variation in this endpoint.
Blocking Very Late Antigen-4 Integrin Decreases Leukocyte Entry and Fatty Streak Formation in Mice Fed an Atherogenic Diet
Authors: Peggy T. Shih, Marie-Luise Brennan, Devendra K. Vora, Mary C. Territo, Dana Strahl, Mariano J. Elices, Aldons J. Lusis, Judith A. Berliner
Journal: Circulation Research (1999)

Abstract —Atherosclerotic lesion development is characterized by the recruitment of leukocytes, principally monocytes, to the vessel wall. Considerable interest has been focused on the adhesion molecule(s) involved in leukocyte/endothelial interactions. The goal of the present study was to determine the role of the very late antigen-4 (VLA-4) integrin/ligand interaction in fatty streak development using murine models. Because α4 null mice are not viable, a peptidomimetic was used to block VLA-4–mediated leukocyte binding. The ability of a synthetic peptidomimetic of connecting segment-1 (CS-1 peptide) to block the recruitment of leukocytes and the accumulation of lipid in the aortic sinus of either wild-type mice (strain C57BL/6J) or mice with a low-density lipoprotein null mutation (LDLR−/−) maintained on an atherogenic diet was assessed. The active (Ac) CS-1 peptide or scrambled (Sc) CS-1 peptide was delivered subcutaneously into mice using a mini osmotic pump. Mice were exposed to the peptide for 24 to 36 hours before the onset of the atherogenic diet. In C57BL/6J mice, leukocyte entry into the aortic sinus, as assessed by en face preparations, was inhibited by the active peptide (Ac=28±4, Sc=54±6 monocytes/valve; P =0.004). Additionally, frozen sections stained with Oil Red O were analyzed to assess lipid accumulation in the aortic sinus. C57BL/6J mice that received the (Ac) compound demonstrated significantly reduced lesion areas as compared with mice that received the (Sc) peptide (Ac=4887±4438 μm 2 , Sc=15 009 ±5619 μm 2 ; P &lt;0.0001). In a separate study, LDLR−/− mice were implanted with pumps containing either the (Ac) or (Sc) peptide before initiation of the atherogenic diet. Because LDLR−/− mice fed a chow diet displayed small lesions at 14 weeks, the effects of the peptide seen in these animals represented a change in early lipid accumulation rather than initiation. By using whole-mount preparations, the (Ac) but not the (Sc) peptide significantly reduced the area of lipid accumulation in the aortic sinus, resulting in an approximate 66% decrease. Plasma analysis from all studies revealed concentrations of peptide to be present at levels previously determined by in vitro analysis to block adhesion. (Ac) CS-1 peptide, which blocks VLA-4 on the leukocyte surface, is effective in reducing leukocyte recruitment and lipid accumulation in the aortic sinus. The present study provides in vivo evidence that the VLA-4 integrin plays an important role in the initiation of the atherosclerotic lesion and lipid accumulation, and it suggests a potential therapeutic strategy for this disease.
Lung Myeloid Dendritic Cells Coordinately Induce T <sub>H</sub> 1 and T <sub>H</sub> 17 Responses in Human Emphysema
Authors: Ming Shan, Han-Fang Cheng, Li-zhen Song, Luz Roberts, Linda Green, Joan Hacken-Bitar, Joseph Huh, Faisal Bakaeen, Harvey O. Coxson, Claudine Storness-Bliss, Mahesh Ramchandani, Seung-Hyo Lee, David B. Corry, Farrah Kheradmand
Journal: Science Translational Medicine (2009)

Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.