tbuckley/cabot-search huggingface dataset:
The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs
Authors: Michela Boi, Eugenio Gaudio, Paola Bonetti, Ivo Kwee, Elena Bernasconi, Chiara Tarantelli, Andrea Rinaldi, Monica Testoni, Luciano Cascione, Maurilio Ponzoni, Afua Adjeiwaa Mensah, Anastasios Stathis, Georg Stussi, María Eugenia Riveiro, Patrice Herait, Giorgio Inghirami, Esteban Cvitkovic, Emanuele Zucca, Francesco Bertoni
Journal: Clinical Cancer Research (2015)

In cancer cells, the epigenome is often deregulated, and inhibition of the bromodomain and extra-terminal (BET) family of bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET bromodomain inhibitor OTX015.We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound.OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240 nmol/L, without significant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC- and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell-like diffuse large B-cell lymphoma, bearing wtTP53, mutations in MYD88, and CD79B or CARD11.Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies.
Responses of normal children and young adults to controlled bicycle exercise.
Authors: F W James, S Kaplan, C J Glueck, J Y Tsay, M J Knight, C J Sarwar
Journal: Circulation (1980)

Exercise responses were obtained from 149 children and young adults (average age 14.5 years) and divided by sex and body surface area (BSA): children with BSA less than 1 m2; children with BSA 1--1.19 m2; males with BSA greater than or equal to 1.2 m2; and females with BSA greater than or equal to 1.2 m2. Total work, mean and maximal power outputs were more affected by body size (height) than age in children with BSA less than 1 m2 and in males and females with BSA greater than or equal to 1.2 m2. Mean systolic pressure increased up to 64% above the preexercise supine value at peak effort, with the level of mean maximal systolic pressure having a positive relationship with body size (height), power output and preexercise sitting systolic pressure in all subgroups except children with BSA 1--1.19 m2. Mean diastolic pressure increased up to 24% above the preexercise supine value at peak effort. ST-segment depression of 1--2 mm was recorded in 12.1% (18 of 149) of the population at peak exercise. These changes occurred in 8.9% of all males and in 16.9% of all females (p greater than 0.1). The data from this study reveal the importance of sex and body size in the clinical interpretation of exercise responses in growing subjects, provide a reference for objective evaluation of subjects with or without cardiac abnormalities and provide a guide for careful monitoring of subjects during an exercise study.
Community health profile of Windsor, Ontario, Canada: anatomy of a Great Lakes area of concern.
Authors: M Gilbertson, J Brophy
Journal: Environmental Health Perspectives (2001)

The rates of mortality, morbidity as hospitalizations, and congenital anomalies in the Windsor Area of Concern ranked among the highest of the 17 Areas of Concern on the Canadian side of the Great Lakes for selected end points that might be related to pollution in this relatively highly industrialized city. Mortality and morbidity rates from all causes were higher than in the rest of the province. Anomalously high rates of diseases included various cancers; endocrine, nutritional, metabolic, and immunity disorders; diseases of the blood and blood-forming organs, nervous system and sense organs, circulatory and respiratory systems, digestive system, genitourinary system, skin and subcutaneous tissue, musculoskeletal system and connective tissues; congenital anomalies, and infant mortality. Of particular concern was the early onset of the elevated rates of many of these diseases and conditions. Comparison of these incident rates with those in Hamilton, another industrial municipality in southern Ontario, suggested that in addition to a variety of local sources of industrial pollution from automobile manufacturing and use, transboundary air and water pollution from Detroit, Michigan, should be investigated as potentially important causes of these health outcomes in the Windsor Area of Concern. Some of the institutional and political trends of the past decade may need to be reversed before effective remedial programs are implemented for cleaning up contaminated sediments and for containment of leaking hazardous waste sites. This pilot project would seem to be a useful preliminary method of integrating human health concerns and of priority setting for the administration of the Great Lakes Water Quality Agreement and the Canada-United States Air Quality Agreement.
Allelic imbalance of insulin-like growth factor II gene expression in cancerous and precancerous lesions of the liver
Authors: Tomohiko Aihara, Shinzaburo Noguchi, Yasuo Miyoshi, Hiroshi Nakano, Yo Sasaki, Yusuke Nakamura, Morito Monden, Shingi Imaoka
Journal: Hepatology (1998)

Allelic imbalance of the insulin-like growth factor II (IGF II) gene expression is often seen in hepatocellular carcinoma (HCC). To investigate the role of allelic imbalance in hepatocarcinogenesis, we have studied allelic expression status of the IGF II gene in dysplastic nodules, which are precancerous lesions of HCC, as well as in HCCs of different histological grade, and the influence of the allelic imbalance on IGF II gene expression has also been examined. Allelic imbalance was observed in 3 of 7 dysplastic nodules, in 7 of 9 well-differentiated HCCs, and in 8 of 9 moderately differentiated HCCs. IGF II gene expression level, which was studied by a semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR), was significantly higher (3.6-fold) in the dysplastic nodules than the control livers, but a significant increase in the IGF II gene expression was not observed in well- and moderately differentiated HCCs as compared with the control livers. These results demonstrate that the allelic imbalance of the IGF II gene expression is seen in the early stage (precancerous lesions) of hepatocarcinogenesis. Association of the allelic imbalance with an increased expression of the IGF II gene in the precancerous lesions might suggest a possible involvement of an IGF II autocrine loop in the pathogenesis of these lesions.
Sphingosine Kinase 1 Is Associated with Gastric Cancer Progression and Poor Survival of Patients
Authors: Wen Li, Chun-Ping Yu, Jin-tang Xia, Ling Zhang, Gui-Xiang Weng, Hai-qing Zheng, Qing-li Kong, Li-juan Hu, Mu-Sheng Zeng, Yi-xin Zeng, Mengfeng Li, Jun Li, Li-Bing Song
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The present study was to investigate the clinical significance of sphingosine kinase 1 (SPHK1), an oncoenzyme, in the development and progression of gastric cancer. Experimental Design: mRNA and protein levels of SPHK1 expression in normal gastric epithelial cells, gastric cancer cell lines, and paired gastric cancer lesions and the adjacent noncancerous tissues were examined using reverse transcription-PCR and Western blotting. Immunohistochemistry was employed to analyze SPHK1 expression in 175 clinicopathologically characterized gastric cancer cases. Statistical analyses were applied to derive prognostic and diagnostic associations. Results: Levels of SPHK1 mRNA and protein were higher in gastric cancer cell lines than in normal gastric epithelial cells. SPHK1 protein level was up-regulated in gastric cancer lesions compared with that in the paired adjacent noncancerous tissues. Gastric cancer tissues from 115 of 175 (65.7%) patients revealed high level of SPHK1 protein expression in contrast to the undetectable or marginally detectable expression of SPHK1 in the adjacent noncancerous gastric tissues. Significantly different expression levels of SPHK1 were found in patients at different clinical stages (P = 0.003), T classification (P = 0.035), and M classification (P = 0.020). Patients with higher SPHK1 expression had shorter overall survival time, whereas those with lower SPHK1 expression survived longer. Further multivariate analysis suggested that SPHK1 up-regulation was an independent prognostic indicator for the disease. Conclusions: SPHK1 protein could be a useful marker for the prognosis of gastric cancer. Further study on the potential use of SPHK1 as a therapeutic target is also warranted.
Long-term self-administered subcutaneous heparin in pregnancy
Authors: S. L B Duncan
Journal: BMJ (1978)

treatment is restarted and continued for a further 12 weeks.We agree with the authors that selfadministered subcutaneous heparin is safe and effective and has revolutionised the manage- ment of thromboembolism of pregnancy; we would encourage patients on long-term anticoagulants to discontinue oral warfarin and change to self-administered subcutaneous heparin well before conception takes place.
A Case of Resection of the Knee for Bony Ankylosis, with the Limb in Faulty Position
Authors: J. E. Adams
Journal: BMJ (1872)

succumbs to poisoning caused by the absorption of the putrid products engendered by this gangrenous phlegmon".The experiment is of great interest, and, as Chauveau says, well worthy of the attention of the sur- geon, but it is too widely different from ours to admit of comparison with it.To make this difference evident, all that is necessary is to refer to the professed purpose for which it was made.M. Chauveau's object was, to use his own expression, to investigate the action of " pus putride"-i.e., of stinking pus.Our object, on the contrary, was not to inquire into the properties of putrid liquids, but of the products of inflammation; and for this reason, the most fastidious care was used to avoid the introduction of the element of putridity at any stage of our experimental procedure, by preserving our liquids from the pos- sibility of septic contamination.In the first inoculation, the " pyremic Jiquid" (as M. Chauveau calls it) used was simply the product of an
THE AKR THYMIC ANTIGEN AND ITS DISTRIBUTION IN LEUKEMIAS AND NERVOUS TISSUES
Authors: Arnold E. Reif, Joan M. V. Allen
Journal: The Journal of Experimental Medicine (1964)

A clear-cut serological differentiation between AKR lymphocytes of thymic and non-thymic origin is reported: these two cell types are antigenically distinct. In newborn mice, the AKR thymic antigen was found at a high concentration only in thymus. In adult mice, the antigen was present at a high level in thymus, all nervous tissues tested, and some leukemias. It was present at much lower levels in lymph node lymphocytes, splenic lymphocytes, appendix, lung, and certain other leukemias, which appeared to be of non-thymic origin. The AKR thymic antigen was present at a high level in thymus and nervous tissues of RF mice, but was absent from thymocytes of sixteen other mouse strains. These sixteen strains possessed the C3HeB/Fe thymic antigen. The distribution of this antigen in neonatal and adult tissues of the strains tested was similar to that of the AKR thymic antigen in AKR mice. No exceptions were found. These results were obtained by use of immune cytolysis, and of a new method for the quantitative treatment of data from absorption experiments.
Pulmonary Veno-occlusive Disease
Authors: Peter J. McDonnell, Warren R. Summer, Grover M. Hutchins
Journal: JAMA (1981)

A 47-year-old man with a history of industrial exposure and interstitial lung disease was admitted for acute pulmonary decompensation. Clinical course was characterized by severe dyspnea at rest, fever, hypoxemia, and elevated pulmonary arterial pressures. At autopsy, pulmonary problems were explained by a selective veno-occlusive process. Associated with pulmonary phlebitis was cerebral vasculitis and lymph node enlargement with erythrophagocytosis suggesting underlying viral infection. Pulmonary veno-occlusive disease should be considered in cases of pulmonary fibrosis, pulmonary hypertension with cor pulmonale, and pulmonary edema and congestion with normal left atrial pressures. (<i>JAMA</i>1981;246:667-671)
Gene expression shift towards normal B cells, decreased proliferative capacity and distinct surface receptors characterize leukemic blasts persisting during induction therapy in childhood acute lymphoblastic leukemia
Authors: P Rhein, S Scheid, R Ratei, C Hagemeier, K Seeger, R Kirschner-Schwabe, A Moericke, M Schrappe, R Spang, W-D Ludwig, L Karawajew
Journal: Leukemia (2007)
PWE-151 Comparison Of Type 1 Autoimmune Hepatitis Patients’ Characteristic In Caucasian, Asian And Black Ethnic Groups: A Single Centre Experience
Authors: NN Than, J Mann, R Gupta, J Hodson, P Nightingale, D Adams, YH Oo
Journal: Gut (2014)

<h3>Introduction</h3> Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies.<sup>1,2</sup> It is associated with Human leucocyte antigen (HLA) DR3/DR4 allotypes which are common in European Caucasian population.<sup>2</sup> Previous published studies reported late clinical presentations and poor outcome in non-Caucasian ethnic groups. <h3>Methods</h3> This is a retrospective analysis of patients with type 1 AIH at a single centre tertiary liver transplant unit between year 1995 and 2012. Patients with simplified AIH score of more than or equal to 6 were included in the study. Data were collected thoroughly from electronic case notes, clinical letters and treatment charts. Basic demographics, clinical presentations, blood parameters such as biochemistry and immunology, liver histology and presence of other associated autoimmune conditions were documented. Those factors were compared among three ethnic groups: Caucasian, Asian and Black-African. <h3>Results</h3> A total of 190 patients are included in the study. The majority (78%) of AIH patients are females. Majority (84%) were Caucasian and Asian ethnicity constitutes 12% of the study population with the remainder (4%) being Black ethnicity. Age of diagnosis is slightly higher among Caucasian groups although non-significantly (Median age 50.5 vs 34.9 in Asian and 45.3 in Black). No significant differences were detected for associated autoimmune conditions, DR3/DR4 association or liver biochemistry blood results among three ethnic groups. Immunoglobulin G and Immunoglobulin A are significantly lower in Caucasian compared to non-Caucasian populations (p = 0.029, 0.005 respectively). There are no differences in clinical outcomes such as cirrhosis, development of hepatocellular carcinoma (HCC) or liver decompensation among three different ethnic groups. <h3>Conclusion</h3> Clinical presentations and blood parameters were similar among three groups except Ig G and Ig A which were lower in Caucasian ethnic populations. Overall transplant free survival was similar among the three groups <h3>References</h3> Zachou K, <i>et al</i>. Review article: autoimmune hepatitis – current management and challenges. <i>Alimentary Pharmacology and Therapeutics</i> 2013. 38(8):887–913 Albert J, Czaja PTD. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. <i>Immunological Reviews</i> 2000;174:250–259 <h3>Disclosure of Interest</h3> None Declared.
Bacteriuria and Hemoglobin Levels in Pregnancy
Authors: Joseph H. Abramson
Journal: JAMA (1971)

An association between significant bacteriuria and low hemoglobin values was found among women attending three antenatal clinics in Jerusalem. In the first two trimesters the mean hemoglobin value of women who were found (at any stage of pregnancy) to have definite or probable significant bacteriuria was 12.10 gm/100 ml, while that of nonbacteriuric women was 12.48 gm/100 ml. In the third trimester the corresponding mean values were 11.70 and 12.22 gm/100 ml. This association did not appear to be produced solely by effects connected with age, parity, education, social class, region of birth, date of immigration, or diet.
Care of older people: Maintaining the dignity and autonomy of older people in the healthcare setting
Authors: K. Lothian
Journal: BMJ (2001)

This is the first in a series of four articles 

This series will explore key issues in the quality of health care for older people. The basis of these articles is the extensive literature reviews undertaken to inform the development of a national service framework for NHS care of older people in England. As a result of an investigation by the Observer newspaper in 1997, the UK Health Advisory Service published a report with 17 recommendations,1 including the establishment of the national service framework, made up of key indicators of quality care and service provision. Background work for the framework covered evidence about quality in the organisation and delivery of health care for older people. It included health promotion; disease prevention; primary health care; general hospital care; specialist care by geriatric, psychogeriatric, and palliative care services; intermediate care and long term care in the community; and residential and nursing homes. Detailed attention was also given to the care of older people with stroke, falls and their consequences, depression, and dementia. Advice was based not only on evidence based practice but also on the value of fair access to care, a person centred approach, and whole systems working. This series will focus on four areas relating to health care for older people. This first article examines issues relating to the dignity and autonomy of older people.

#### Summary points

Anecdotal evidence suggests that older people's dignity and autonomy is being undermined in the health care setting

Many healthcare professionals hold stereotypical, negative attitudes towards older people

Tackling negative attitudes through exposure and education can help to preserve older patients' dignity and autonomy

Giving older people and their carers adequate information for them to make informed choices about care further increases autonomy

Health services should aim to preserve dignity and autonomy and minimise distress …
Clozapine for Treatment of Schizophrenia-Reply
Authors: David Pickar
Journal: JAMA (1996)

<h3>In Reply.</h3> —Dr Orr questions the use of a placebo period described in the selected patient who was reported in our article. This patient participated in a carefully controlled, prospective, double-blind treatment trial with the then-experimental and atypical antipsychotic clozapine.<sup>1</sup>This study resulted in the first non—industry-supported data indicating the superiority of clozapine in comparison with a representative traditional antipsychotic. Informed written consent was required prior to entry into the study; the patient's continuing assent and understanding of experimental procedures were monitored regularly throughout the study. Withdrawal of consent at any time and for any reason is justification for termination of participation. The inclusion of a placebo period in the crossover design enabled biological and clinical investigation into the effects of clozapine with minimal contamination by prior drug treatment. This approach led to a number of observations pertaining to the mechanism of action and clinical effectiveness of clozapine.<sup>2,3</sup>
Historical increases in expert performance suggest large possibilities for improvement of performance without implicating innate capacities
Authors: Andreas C. Lehmann
Journal: Behavioral and Brain Sciences (1998)

Innate talents supposedly limit an individual's highest attainable level of performance and the rate of skill acquisition. However, Howe et al. have not reviewed evidence that the level of expert performance has increased dramatically over the last few centuries. Those increases demonstrate that the highest levels of performance may be less constrained by innate capacities than is commonly believed.
For Fun and Profit
Authors: Theodore B. Schwartz
Journal: New England Journal of Medicine (1982)

Most of us cherish the vision of a serene old age spent in the bosom of an adoring family. Nobody wants to "end up in a nursing home" — a facility that is seen by the fearful elderly as a fate worse than death and arouses echoes of a "final solution" in guilty relatives. Fortunately, these perceptions may be unreal and unrealistic. Like that of most of our institutions, the quality of nursing homes ranges from excellent to atrocious. They serve an indispensable function for the many aged persons who are alone, abandoned, or afflicted with problems well beyond the . . .
A -Val360: a marker of neutrophil elastase and COPD disease activity
Authors: Richard I. Carter, Michael J. Ungurs, Richard A. Mumford, Robert A. Stockley
Journal: European Respiratory Journal (2012)

Forced expiratory volume in 1 s is currently the most widely used marker of chronic obstructive pulmonary disease (COPD) severity; however, it is a poor surrogate of the emphysematous component and the underlying pathophysiological mechanism, and therefore new markers are urgently needed. Neutrophil elastase (NE) is likely to play a key pathophysiological role in COPD and the current study explores a marker of NE activity as a potential indicator of COPD disease activity. Aα-Val 360 was measured in 81 subjects with a clinical diagnosis of COPD, both in the stable state and at presentation with an acute exacerbation, and comparisons were made using lung function tests and computed tomography imaging. The relationship of Aα-Val 360 with disease progression was also assessed in 40 of the subjects over a 4-yr period. Baseline Aα-Val 360 related to physiological and radiological markers of disease severity, was higher at presentation with an acute exacerbation than in the stable state and (at least partly) related to disease progression over the subsequent 4 yrs. We demonstrate that Aα-Val 360 is a marker of cross-sectional COPD disease severity and possibly disease progression, and represents a new concept of specific biomarkers. This study therefore reports the first in vivo data to support the pathophysiological role of NE in COPD.
Importance of CMR Within the Task Force Criteria for the Diagnosis of ARVC in Children and Adolescents
Authors: Yousef Etoom, Sindu Govindapillai, Robert Hamilton, Cedric Manlhiot, Shi-Joon Yoo, Maryam Farhan, Samir Sarikouch, Brigitte Peters, Brian W. McCrindle, Lars Grosse-Wortmann
Journal: Journal of the American College of Cardiology (2015)