tbuckley/cabot-search huggingface dataset:
SDHA Loss-of-Function Mutations in KIT-PDGFRA Wild-Type Gastrointestinal Stromal Tumors Identified by Massively Parallel Sequencing
Authors: M. A. Pantaleo, A. Astolfi, V. Indio, R. Moore, N. Thiessen, M. C. Heinrich, C. Gnocchi, D. Santini, F. Catena, S. Formica, P. L. Martelli, R. Casadio, A. Pession, G. Biasco
Journal: JNCI Journal of the National Cancer Institute (2011)

Approximately 10%–15% of gastrointestinal stromal tumors (GISTs) in adults do not harbor any mutation in the KIT or PDGFRA genes (ie, KIT/PDGFRA wild-type GISTs). Recently, mutations in SDHB and SDHC (which encode succinate dehydrogenase subunits B and C, respectively) but not in SDHA and SDHD (which encode subunits A and D, respectively) were identified in KIT/PDGFRA wild-type GISTs. To search for novel pathogenic mutations, we sequenced the tumor transcriptome of two young adult patients who developed sporadic KIT/PDGFRA wild-type GISTs by using a massively parallel sequencing approach. The only variants identified as disease related by computational analysis were in SDHA . One patient carried the homozygous nonsense mutation p.Ser384X, the other patient was a compound heterozygote harboring a p.Arg31X nonsense mutation and a p.Arg589Trp missense mutation. The heterozygous nonsense mutations in both patients were present in germline DNA isolated from peripheral blood. Protein structure analysis indicates that all three mutations lead to functional inactivation of the protein. This is the first report, to our knowle dge, that identifies SDHA inactivation as a common oncogenic event in GISTs that lack a mutation in KIT and PDGFRA .
B lymphocyte maturation in Wegener's granulomatosis: a comparative analysis of VH genes from endonasal lesions
Authors: Jan Voswinkel, Antje Mueller, Jan A Kraemer, Peter Lamprecht, Karen Herlyn, Konstanze Holl-Ulrich, Alfred C Feller, Silke Pitann, Angela Gause, Wolfgang L Gross
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) are highly specific for Wegener's granulomatosis (WG). Evidence for a pivotal role of PR3-ANCA in the induction of vasculitis has been demonstrated. B cell clusters have been observed within endonasal biopsy specimens. <b>Objectives:</b> To determine whether B cell selection and maturation take place in granulomatous lesions of WG. <b>Methods:</b> Granulomatous lesions and the immunoglobulin (VH) gene repertoire from nasal tissue of six WG patients—two active and two smouldering localised WG (ANCA negative, restricted to respiratory tract), plus one active and one smouldering PR3-ANCA positive generalised WG—were characterised by immunohistochemistry, polymerase chain reaction, cloning, DNA sequencing and database comparison. <b>Results:</b> B lymphocyte-rich, follicle-like areas were observed proximal to PR3 positive cells and plasma cells in granulomatous lesions; 184 VH genes from these granulomatous lesions were compared with 84 VH genes from peripheral blood of a healthy donor. The mutational pattern of VH genes from active WG resembled memory B cells. Structural homologies of VH genes from granulomatous lesions to PR3-ANCA encoding genes were detected. Significantly more genes (55%, 45%, and 53%, respectively) from active WG compared with the healthy repertoire carried mutations to negatively charged amino acids within the binding site coding regions, favouring affinity to the positively charged PR3. <b>Conclusions:</b> Selection and affinity maturation of potentially PR3-ANCA producing autoreactive B cells may start in granulomatous lesions, thereby contributing to disease progression from ANCA negative localised to PR3-ANCA positive generalised WG.
Depot Injections in Treatment of Hay-fever and Pollen Asthma
Authors: R. S. B. Pearson
Journal: BMJ (1965)

A Fifth Freedom ?-Baird logically disturbed environment ?In a world where there are too many children should women be forced to endure this tyranny of unwanted pregnancies ?If the answer is no, we must plan accordingly.In Britain this means making contraceptive advice freely avail- able under the National Health Service and offering tubal ligation to women who have had the desired number of children.This would help to free women from the tyranny of unwanted preg- nancies and also make them more independent and able to choose freely how they will use their training and skills, especially after their desired number of children have been born.The world outside the home needs the skill and pro- ductivity of trained workers, and women, as well as men, need the satisfaction of education to, their maximum potential ability and the opportunity to exercise their skills in a wider sphere than the immediate family.To quote Huxley again: " The progress of medical science, besides accomplishing control of disease, must also improve the quality of life by providing greater fulfilment for more human beings.Fulfilment in this sense involves physical, mental and spiritual well-being."To achieve this the world needs a Fifth Freedom-freedom from the tyranny of civilized man's excessive fertility.
Multiple Transcriptional Domains, With Distinct Left and Right Components, in the Atrial Chambers of the Developing Heart
Authors: Diego Franco, Marina Campione, Robert Kelly, Peter S. Zammit, Margaret Buckingham, Wouter H. Lamers, Antoon F. M. Moorman
Journal: Circulation Research (2000)

During heart development, 2 fast-conducting regions of working myocardium balloon out from the slow-conducting primary myocardium of the tubular heart. Three regions of primary myocardium persist: the outflow tract, atrioventricular canal, and inflow tract, which are contiguous throughout the inner curvature of the heart. The contribution of the inflow tract to the definitive atrial chambers has remained enigmatic largely because of the lack of molecular markers that permit unambiguous identification of this myocardial domain. We now report that the genes encoding atrial natriuretic factor, myosin light chain (MLC) 3F, MLC2V, and Pitx-2, and transgenic mouse lines expressing nlacZ under the control of regulatory sequences of the mouse MLC1F/3F gene, display regionalized patterns of expression in the atrial component of the developing mouse heart. These data distinguish 4 broad transcriptional domains in the atrial myocardium: (1) the atrioventricular canal that will form the smooth-walled lower atrial rim proximal to the ventricles; (2) the atrial appendages; (3) the caval vein myocardium (systemic inlet); and (4) the mediastinal myocardium (pulmonary inlet), including the atrial septa. The pattern of expression of Pitx-2 reveals that each of these transcriptional domains has a distinct left and right component. This study reveals for the first time differential gene expression in the systemic and pulmonary inlets, which is not shared by the contiguous atrial appendages and provides evidence for multiple molecular compartments within the atrial chambers. Furthermore, this work will allow the contribution of each of these myocardial components to be studied in congenitally malformed hearts, such as those with abnormal venous return.
Normal ultrasonic myocardial reflectivity in athletes with increased left ventricular mass. A tissue characterization study.
Authors: F Lattanzi, V Di Bello, E Picano, M T Caputo, L Talarico, C Di Muro, L Landini, G Santoro, C Giusti, A Distante
Journal: Circulation (1992)

BACKGROUND Ultrasonic integrated backscatter of myocardial walls is directly related to the morphometrically evaluated collagen content. The integrated backscatter is also increased in hypertrophic cardiomyopathy, probably because of fiber disarray. The purpose of this study was to investigate myocardial tissue reflectivity in subjects with physiological hypertrophy caused by intense physical training and to assess the relation between the acoustic properties of myocardial tissue and left ventricular wall thickness assessed by conventional two-dimensional echocardiography. METHODS AND RESULTS Twenty-four young male athletes (14 professional cyclists and 10 weight lifters, all in full agonistic activity) were studied together with 10 normal age-matched controls with sedentary life. By means of a commercially available two-dimensional echocardiograph, standard measurements were obtained according to the recommendations of the American Society of Echocardiography. With a prototype implemented in our Institute, an on-line radiofrequency analysis of ultrasound signals was also performed to obtain quantitative operator-independent measurements of the integrated backscatter of the myocardial walls. The integrated values of the radiofrequency signal were normalized for the pericardial interface and expressed in percent integrated backscatter (%IB). Compared with control subjects, athletes showed greater thickness values of septum (controls, 9 +/- 1; cyclists, 14 +/- 2; weight lifters, 15 +/- 1 mm, mean +/- SD; p less than 0.01) and posterior wall (9 +/- 1, 12 +/- 2, and 12 +/- 1 mm, respectively; p less than 0.01) but similar values of %IB for both septum (23 +/- 4%, 21 +/- 7%, and 23 +/- 8%, p = NS) and posterior wall (10 +/- 2%, 9 +/- 2%, and 11 +/- 2%, p = NS). In athletes, no correlation was found between septal and posterior wall thickness and the corresponding regional myocardial reflectivity (r = 0.23, p = NS and r = 0.01, p = NS, respectively). Furthermore, we compared the quantitative ultrasonic data between two subsets of 10 athletes and 10 patients with hypertrophic cardiomyopathy and similar degrees of septal thickness (16 +/- 1 versus 17 +/- 1 mm, respectively, p = NS). Septal and posterior wall %IB results were significantly higher in patients with hypertrophic cardiomyopathy (53 +/- 13% and 36 +/- 9%, respectively) than in athletes (21 +/- 7% and 10 +/- 3%, respectively; p less than 0.01 for both). CONCLUSIONS We conclude that 1) endurance athletes show a normal pattern of quantitatively assessed ultrasonic backscatter despite of a marked left ventricular hypertrophy and 2) athletes and patients with hypertrophic cardiomyopathy and similar degrees of myocardial wall thickness can be differentiated on the basis of quantitative analysis of backscattered signal.
Black oesophagus--cause?
Authors: A Sako
Journal: Gut (2005)

Background: Oesophageal squamous cell carcinoma (OSCC) has a very poor prognosis, which is largely due to late diagnosis.Successful early detection strategies will require identification of clinically relevant precursor lesions that can be targets for screening and treatment.Aims: To identify the clinically relevant histological precursors of OSCC.Subjects: A cohort of 682 endoscoped patients from a high risk rural population in Linxian, China.Methods: Subjects were endoscoped and biopsied at baseline and followed for 13.5 years.We estimated the relative risk of developing OSCC for each of the initial histological diagnoses using Cox proportional hazards regression models.Results: A total of 114 (16.7%) patients developed OSCC during the follow up period.After adjusting for potential confounding factors, relative risks (95% confidence intervals) for incidence of this tumour, by initial histological diagnosis, were: normal 1.0 (reference), oesophagitis 0.8 (0.2-3.2), basal cell hyperplasia 1.9 (0.8-4.5), mild dysplasia 2.9 (1.6-5.2),moderate dysplasia 9.8 (5.3-18.3),severe dysplasia 28.3 (15.3-52.3),and carcinoma in situ 34.4 (16.6-71.4).Conclusions: In this study, squamous dysplasia and carcinoma in situ were the only histological lesions associated with a significantly increased risk of developing OSCC within 13.5 years after endoscopy.There was no evidence that oesophagitis predisposed to this tumour.Increasing grades of dysplasia were strongly associated with increasing risk, indicating that the histological grading was clinically meaningful.The follow up experience of severe dysplasia and carcinoma in situ was equivalent, suggesting that this distinction is not clinically relevant.Documenting these precursor lesions of OSCC should assist in the development of effective prevention, early detection, and treatment strategies for this disease.www.gutjnl.com
Loss of histone acetyltransferase cofactor transformation/transcription domain-associated protein impairs liver regeneration after toxic injury
Authors: Vivek Shukla, Cyrille Cuenin, Nileshkumar Dubey, Zdenko Herceg
Journal: Hepatology (2010)

Abstract Organ regeneration after toxin challenge or physical injury requires a prompt and balanced cell-proliferative response; a well-orchestrated cascade of gene expression is needed to regulate transcription factors and proteins involved in cell cycle progression and cell proliferation. After liver injury, cell cycle entry and progression of hepatocytes are believed to require concerted efforts of transcription factors and histone-modifying activities; however, the actual underlying mechanisms remain largely unknown. The purpose of our study was to investigate the role of the histone acetyltransferase (HAT) cofactor transformation/transcription domain-associated protein (TRRAP) and histone acetylation in the regulation of cell cycle and liver regeneration. To accomplish our purpose, we used a TRRAP conditional knockout mouse model combined with toxin-induced hepatic injury. After we treated the mice with a carbon tetrachloride toxin, conditional ablation of the TRRAP gene in those mice severely impaired liver regeneration and compromised cell cycle entry and progression of hepatocytes. Furthermore, loss of TRRAP impaired the induction of early and late cyclins in regenerating livers by compromising histone acetylation and transcription factor binding at the promoters of the cyclin genes. Our results demonstrate that TRRAP and TRRAP/HAT-mediated acetylation play an important role in liver regeneration after toxic injury and provide insight into the mechanism by which TRRAP/HATs orchestrate the expression of the cyclin genes during cell cycle entry and progression. (Hepatology 2011)
Contribution of inherited factors to rheumatoid arthritis.
Authors: C M Deighton, J Wentzel, G Cavanagh, D F Roberts, D J Walker
Journal: Annals of the Rheumatic Diseases (1992)

A total of 231 sibships of the same sex (186 female, 45 male), in which the proband had classical or definite rheumatoid arthritis (RA) have been selected from rheumatology clinics. Each sibship member was questioned about symptomatic joints, which were then examined. Hospital records, radiographs, and rheumatoid factor measurements allowed each sibling to be classified as having classical, definite, probable, or no RA. Each sibling was typed for HLA-A and B and was classified as sharing two, one, or zero HLA haplotypes with the proband. Concordance rates for classical and definite RA were three times greater in sibships of women than of men (9.3 v 3.0%). Concordance rates in HLA identical sibships were twice those in hemi- and non-identical sibships (15.5, 7.1, and 5.2%, respectively). Probable RA was more common in male and HLA hemi- and non-identical sibships. These results suggest that female sex and the two inherited HLA haplotypes are important for the presence and expression of RA. Although environmental factors may be shared more in twins than siblings, a concordance rate of 20.5% in seropositive HLA identical sibships of the same sex compared with 30% in monozygotic twins suggests that sex and HLA type account for about two thirds of the inherited risk of RA.
Cod liver oil intake and incidence of asthma in Norwegian adults—the HUNT study
Authors: Xiao-Mei Mai, Arnulf Langhammer, Yue Chen, Carlos A Camargo
Journal: Thorax (2012)

<h3>Background</h3> Cod liver oil is an important source of vitamin D, but also contains other fat-soluble components such as vitamin A. Before 1999, the cod liver oil formula in Norway contained a high concentration of vitamin A (1000 µg per 5 ml). High vitamin A status is associated with increased risks of several chronic diseases. <h3>Objective</h3> To investigate the association between cod liver oil intake and asthma development. <h3>Methods</h3> In the Nord-Trøndelag Health Study, a total of 25 616 Norwegian adults aged 19–55 years were followed up from 1995–1997 to 2006–2008. Current analysis based on 17 528 subjects who were free of asthma and had complete information on cod liver oil intake at baseline. Cod liver oil intake was defined as daily intake ≥1 month during the year prior to baseline. Incident asthma was reported as new-onset asthma during the 11-year follow-up. <h3>Results</h3> Of the 17 528 subjects, 18% (n=3076) consumed cod liver oil daily for ≥1 month over the past year. Cod liver oil intake was significantly associated with incident asthma with an OR of 1.62 (95% CI 1.32 to 1.98) after adjustment for age, sex, daily smoking, physical activity, education, socio-economic status, family history of asthma, and body mass index (BMI). The positive association was consistent across age (&lt;40/≥40 years), sex (men/women), family history of asthma (yes/no) and BMI subgroups (&lt;25/≥25 kg/m<sup>2</sup>). <h3>Conclusions</h3> Intake of cod liver oil with high vitamin A content was significantly associated with increased incidence of adult-onset asthma.
Anti-HLA antibodies in pemphigoid gestationis (herpes gestationis)
Authors: J.K. SHORNICK, R.E. JENKINS, D.C. BRIGGS, K.I. WELSH, S.E. KELLY, M.P. GARVEY, M.M. BLACK
Journal: British Journal of Dermatology (1993)

Pemphigoid gestationis (PG; herpes gestationis) is a rare autoimmune disease associated with pregnancy, currently defined by the presence of complement deposition along the cutaneous basement membrane zone. It is known to be associated with HLA‐DR 3 and DR4, and an increase in anti‐HLA antibodies in those with a history of PG has been reported. We have studied 39 patients with an immunofluorescence‐confirmed diagnosis of PG for the presence and specificity of anti‐HLA antibodies. Anti‐HLA antibodies were found in all 39 patients. Specificity was against class 1 antigens in 98% (controls 10%: P>0.001) and class II antigens in 25% (controls 8.5%: P>0.001), Almost all anti‐ HLA antibodies were cytotoxic. The universal presence of anti‐HLA antibodies in PG suggests that they may develop coincidently with anti basement membrane antibodies, and may reflect a common immunological event.
Leprosy and Cancer: A Retrospective Cohort Study in Hawaii 2
Authors: Laurence N. Kolonel, Tomio Hirohata
Journal: JNCI Journal of the National Cancer Institute (1977)

We used data collected on a retrospective cohort of 1,1231eprosy patients living in Hawaii between 1940 and 1970, to test the hypotheses that patients with lepromatous leprosy, who have an impairment in their cellular immune response, would have an increased risk for cancer and that patients with tuberculoid leprosy, who are immunologically competent, would have a normal or even a reduced cancer risk from beneficial stimulation of their cellular Immune system by exposure to the Mycobacterium leprae organisms. Based on a survival analysis method, the results of the study supported the predicted increase in cancer cases among the lepromatous leprosy patients (19 observed, 12.7 expected; risk ratlo=1.5) and the predicted decrease among the tuberculoid leprosy patients (14 observed, 17.8 expected; risk ratio=0.8); In both groups, the findings were consistent across the five racial categories of the study. However, none of these differences between observed and expected cases was statistically significant at the 5% level. The study provided no support for the alternate hypothesis that chronic antigenic stimulation by the M. leprae organisms might lead to an increase in tumors of the lymphoreticular system.
Massive pulmonary arteriovenous malformation presenting with tamponading haemothorax
Authors: A A Khan, I Hunt, K Hamdane, J Tambiah, R P Deshpande, J F Reidy
Journal: Thorax (2007)

We welcome the study by Slader et al 1 recently published in Thorax as the current state of our knowledge on breathing techniques for asthma is deplorable,2 although such techniques are frequently used by physiotherapists when treating patients with asthma.3

Several aspects in this study …
Zonal changes of hepatobiliary taurocholate transport in intrahepatic cholestasis induced by 17α-ethinyl estradiol: A histoautoradiographic study in rats
Authors: Hans-Peter Buscher, Inge Meder, Sabine Macnelly, Wolfgang Gerok
Journal: Hepatology (1993)

The liver has a great reserve capacity for hepatobiliary bile salt transport. This study was performed to elucidate the significance of this capacity in ethinyl estradiol-induced cholestasis by direct visualization of the zonal involvement in taurocholate transport. The acinar distribution of [3H]taurocholate was determined by histoautoradiographical study of cryopreserved liver slices in normal rats and rats treated with ethinyl estradiol for 5 days. Silver grain densities over the different acinar zones were estimated on digitized image analysis. In control animals, histoautoradiographical study performed 4 min after the start of perfusion showed restriction of taurocholate to acinar zone 1. In contrast, in ethinyl estradiol-treated animals, taurocholate was also found in zone 2 and, in smaller concentrations, in zone 3. In control animals, the relative blackenings by silver grains of acinar zones 1, 2 and 3 were 66% +/- 1.2%, 25% +/- 1.6% and 5% +/- 0.6%, respectively. After 5 days of ethinyl estradiol treatment, blackenings were 58% +/- 1.5%, 36% +/- 2.1% and 12% +/- 0.8%, respectively. As early as 15 sec after injection of [3H]taurocholate, the bile canalicular areas of the cell plates and the bile ductules of ethinyl estradiol-treated animals were labeled as intensely as those of control animals. Our results demonstrate ethinyl estradiol-induced recruitment of the acinar zones 2 and 3 for hepatobiliary taurocholate transport. This recruitment may largely compensate for reduction of transport capacity of periportal hepatocytes in early cholestasis.