tbuckley/cabot-search huggingface dataset:
FGFR3, PIK3CA and RAS mutations in benign lichenoid keratosis
Authors: L. Groesser, E. Herschberger, M. Landthaler, C. Hafner
Journal: British Journal of Dermatology (2011)

Benign lichenoid keratoses (BLKs) are solitary skin lesions which have been proposed to represent a regressive form of pre-existent epidermal tumours such as solar lentigo or seborrhoeic keratosis. However, the genetic basis of BLK is unknown.FGFR3, PIK3CA and RAS mutations have been shown to be involved in the pathogenesis of seborrhoeic keratosis and solar lentigo. We thus investigated whether these mutations are also present in BLK.After manual microdissection and DNA isolation, 52 BLKs were screened for FGFR3, PIK3CA and RAS hotspot mutations using SNaPshot(®) multiplex assays.We identified 6/52 (12%) FGFR3 mutations, 10/52 (19%) PIK3CA mutations, 6/52 (12%) HRAS mutations and 2/52 (4%) KRAS mutations. FGFR3 and RAS mutations were mutually exclusive. One BLK showed a simultaneous PIK3CA and HRAS mutation. In nine BLKs with a mutation, nonlesional control tissue from the epidermal margin and the dermal lymphocytic infiltrate were wild-type, indicating that these mutations are somatic. To demonstrate that these findings are specific, 10 samples of lichen planus were analysed without evidence for FGFR3, PIK3CA or RAS mutations.Our results indicate that FGFR3, PIK3CA and RAS mutations are present in approximately 50% of BLKs. These findings support the concept on the molecular genetic level that at least a proportion of BLKs represents regressive variants resulting from former benign epidermal tumours such as seborrhoeic keratosis and solar lentigo.
Downregulation of natriuretic peptide C-receptor protein in the hypertrophied ventricle of the aortovenocaval fistula rat
Authors: L Brown
Journal: Cardiovascular Research (1997)

Objectives: This study examined the expression of the C-type receptor for the natriuretic peptide family (NPR-C) in the ventricles of normal and aortovenocaval (AV)-fistula rats, the latter a model of cardiac volume overload producing hypertrophy of both ventricles. Methods: Western blotting with a rabbit anti-NPR-C antibody was used to quantify NPR-C levels in ventricular membranes. NPR-C expression was localised anatomically and measured in frozen sections of cardiac tissue by histochemistry and in vitro autoradiography. Results: Western blot analysis revealed a single band (∼120 kDa) in ventricular membranes which was reduced to ∼60 kDa after treatment with β-mercaptoethanol. NPR-C immunoreactivity and [125I]rat ANP1–28 binding (displaceable by the NPR-C-specific ligand C-ANP 4–23) were localised to the endocardium. NPR-C protein levels, as measured by all three techniques, were reduced significantly in the hypertrophied ventricles of AV-fistula rats compared to sham-operated animals. Conclusions: Volume-induced cardiac hypertrophy in the AV-fistula rat is associated with downregulation of endocardial NPR-C. This may be one mechanism by which the endocardium regulates the myocardial response to changes in haemodynamic load.
Etiology of Pancreatic Cancer, With a Hypothesis Concerning the Role of N-Nitroso Compounds and Excess Gastric Acidity
Authors: H. A. Risch
Journal: JNCI Journal of the National Cancer Institute (2003)

In the United States, pancreatic cancer is the fourth most frequent cause of cancer death in males as well as females, after lung, prostate or breast, and colorectal cancer. Each year, approximately 30 000 Americans are diagnosed with pancreatic cancer and about the same number die of it. Germline mutations in a few genes including p16 and BRCA2 have been implicated in a small fraction of cases, as has chronic pancreatitis. The one established risk factor for pancreatic cancer is cigarette smoking: current smokers have two to three times the risk of nonsmokers. Studies of dietary factors have not been entirely consistent but do suggest associations of higher risk with consumption of smoked or processed meats or with animal foods in general and lower risk with consumption of fruits and vegetables. Colonization by Helicobacter pylori appears to increase risk, and a history of diabetes mellitus may also increase risk. The purpose of this epidemiologic review is to consider the possibility that risk of pancreatic cancer is increased by factors associated with pancreatic N-nitrosamine or N-nitrosamide exposures and with chronic excess gastric or duodenal acidity. Host genetic variation in inflammatory cytokine mechanisms may also be involved in this process. Many features of the evidence bearing on the pathophysiology of pancreatic cancer appear to support connections with N-nitroso compounds and with gastric acidity.
Informing participants of allocation to placebo at trial closure: postal survey
Authors: Z. Di Blasi
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objectives:</b> To assess whether and how investigators of placebo controlled randomised trials inform participants of their treatment allocation at trial closure and to assess barriers to feedback. <b>Design</b>: Postal survey with a semistructured questionnaire. <b>Participants</b>: All investigators who published a placebo controlled randomised trial in 2000 in five leading medical journals, and a random sample of 120 trials listed in the national research register database. <b>Main outcome measures</b>: Number of investigators who informed participants of their treatment allocation at trial closure, methods for delivering the information, and barriers to unmasking treatment. <b>Results</b>: 45% of investigators informed either all or most participants of their treatment allocation, and 55% did not inform any participant or only informed those who asked. The main reasons for not informing participants were that the investigators never considered this option (40%) or to avoid biasing results at study follow up (24%). <b>Conclusion</b>: Further research is required to examine sensitive ways to communicate treatment information to trial participants.
Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination
Authors: Liam Smeeth, Sara L. Thomas, Andrew J. Hall, Richard Hubbard, Paddy Farrington, Patrick Vallance
Journal: New England Journal of Medicine (2004)

There is evidence that chronic inflammation may promote atherosclerotic disease. We tested the hypothesis that acute infection and vaccination increase the short-term risk of vascular events.
More Informative Abstracts Revisited
Authors: R B Haynes, C D Mulrow, E J Huth, D G Altman, M J Gardner
Journal: Annals of Internal Medicine (1990)

Following proposals in 1987 and 1988, several medical journals have provided more informative abstracts ("structured abstracts") for articles of clinical interest. Structured abstracts for original studies require authors to systematically disclose the objective, basic research design, clinical setting, participants, interventions (if any), main outcome measurements, results, and conclusions; and for literature reviews the objective, data sources, methods of study selection, data extraction and synthesis, and conclusions. More informative abstracts of this kind can facilitate peer review before publication, assist clinical readers to find articles that are both scientifically sound and applicable to their practices, and allow more precise computerized literature searches. We review the feasibility, acceptability, and dissemination of structured abstracts, reassess the underlying strategy, and describe modifications of the approach. This innovation can aid communication from scientists to clinicians, and other clinical journals are invited to join this effort.
DNA methylation is not likely to be responsible for aggrecan down regulation in aged or osteoarthritic cartilage
Authors: E Poschl
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> Expression of aggrecan is reduced during aging and osteoarthritic cartilage degeneration. CpG methylation may have a role in the down regulation of aggrecan transcriptions. <b>Objective:</b> To investigate whether a correlation between gene methylation and expression of aggrecan in chondrocytes exists. <b>Methods:</b> The human aggrecan promoter region was analysed computationally for CpG-rich regions. These were investigated for the methylation of C residues in normal (aged) and osteoarthritic chondrocytes by the bisulphite method for modifying DNA as well as sequence analysis using DNA directly extracted from normal and osteoarthritic cartilage tissue. Additionally, chondrocytic cell lines were investigated for methylation within the aggrecan promoter region. <b>Results:</b> The CpG-rich promoter region of the human aggrecan gene contains a 0.6 kb region that meets the criteria of a CpG island as defined by prediction programmes. A significant correlation of aggrecan mRNA expression levels and methylation status in normal (aged) and osteoarthritic chondrocytes as well as in different chondrocytic cell lines was not found. <b>Conclusions:</b> Expression of aggrecan in normal cartilage and diseased states is not modulated by gross changes of CpG methylation of its promoter region. CpG methylation does not have a central role in the switch off of aggrecan promoter activity in human adult articular chondrocytes.
Living Near Major Traffic Roads and Risk of Deep Vein Thrombosis
Authors: Andrea Baccarelli, Ida Martinelli, Valeria Pegoraro, Steven Melly, Paolo Grillo, Antonella Zanobetti, Lifang Hou, Pier Alberto Bertazzi, Pier Mannuccio Mannucci, Joel Schwartz
Journal: Circulation (2009)

Background— Particulate air pollution has been consistently linked to increased risk of arterial cardiovascular disease. Few data on air pollution exposure and risk of venous thrombosis are available. We investigated whether living near major traffic roads increases the risk of deep vein thrombosis (DVT), using distance from roads as a proxy for traffic exposure. Methods and Results— From 1995 through 2005, we examined 663 patients with DVT of the lower limbs and 859 age-matched controls from cities with population &gt;15 000 inhabitants in Lombardia Region, Italy. We assessed distance from residential addresses to the nearest major traffic road using geographic information system methodology. The risk of DVT was estimated from logistic regression models adjusting for multiple clinical and environmental covariates. The risk of DVT was increased (odds ratio=1.33; 95% confidence interval, 1.03 to 1.71; P =0.03 in age-adjusted models; odds ratio=1.47; 95% confidence interval, 1.10 to 1.96; P =0.008 in models adjusted for multiple covariates) for subjects living near a major traffic road (index distance of 3 meters, 10th centile of the distance distribution) compared with those living farther away (reference distance of 245 meters, 90th centile). The increase in DVT risk was approximately linear over the observed distance range (from 718 to 0 meters) and was not modified after adjusting for background levels of particulate matter (odds ratio=1.47; 95% confidence interval, 1.11 to 1.96; P =0.008 for 10th versus 90th distance centile in models adjusting for area levels of particulate matter &lt;10 μm in aerodynamic diameter in the year before diagnosis). Conclusions— Living near major traffic roads is associated with increased risk of DVT.
Role of Intrinsic Muscle Atrophy in the Etiology of Claw Toe Deformity in Diabetic Neuropathy May Not Be as Straightforward as Widely Believed
Authors: Sicco A. Bus, Mario Maas, Robert P.J. Michels, Marcel Levi
Journal: Diabetes Care (2009)

Clawing of the toes in the diabetic neuropathic foot is believed to be caused by muscle imbalance resulting from intrinsic muscle atrophy. However, experimental data that support this mechanism are lacking. The aim of this study was to evaluate this hypothesis using magnetic resonance imaging (MRI).In 20 neuropathic diabetic patients, 10 with claw toe deformity and 10 with normally aligned toes, multiple plane images of the foot and lower leg were acquired using T1-weighted spin-echo MRI. Atrophy of the intrinsic and extrinsic muscles controlling the toes was assessed using a semiquantitative 5-point atrophy scale. An intrinsic-to-extrinsic foot muscle imbalance score was derived from these atrophy scores, and correlation coefficients were established.The mean +/- SD intrinsic muscle atrophy score was 3.1 +/- 1.1 for the toe deformity group and 2.6 +/- 1.2 for the non-deformity group (not significantly different). The intrinsic muscle atrophy score was not significantly correlated with degree of toe deformity (r = -0.18). The muscle imbalance score was not significantly different between study groups and was not significantly correlated with degree of toe deformity (r = -0.14).Neither intrinsic muscle atrophy nor muscle imbalance discriminated between neuropathic patients with or without claw toe deformity, suggesting that the role of these muscle factors in claw toe development may not be primary or as straightforward as previously believed. These findings shed new light on the etiology of foot deformity in diabetes and suggest a more complex nature of development, potentially involving anatomical and physiological predisposing factors.
Human Glomerulonephritis Accompanied by Active Cellular Infiltrates Shows Effector T Cells in Urine
Authors: Minoru Sakatsume, Yuansheng Xie, Mitsuhiro Ueno, Hiroaki Obayashi, Shin Goto, Ichiei Narita, Noriyuki Homma, Kazuyuki Tasaki, Yasushi Suzuki, Fumitake Gejyo
Journal: Journal of the American Society of Nephrology (2001)

Leukocyturia is associated with postinfectious glomerulonephritis (GN), interstitial nephritis, and renal allograft rejection. In addition, prominent infiltration of T cells and macrophages is commonly observed in the renal tissues of patients with GN, accompanied by cellular crescent formation and/or interstitial cell infiltration. Because these infiltrating T cells were thought to participate in the development of the diseases and to appear in the urinary space while functioning as effector cells in the renal inflammatory lesion, the study focused on the characterization of T cells that appeared in urine. Freshly voided urine cells were analyzed by flow cytometry to determine their phenotype and by reverse transcriptase-PCR to detect cytokine mRNA. In urine from patients with different forms of GN, including IgA nephropathy, Henoch-Schönlein purpura nephritis, and anti-neutrophil cytoplasmic antibody-associated GN, T cells appeared together with macrophages. The urine T cells were mainly CD45RA(-), CD45RO(+), and CD62L (L-selectin)(-), which are the phenotypic features of effector T cells. In agreement with this finding, T cells infiltrating glomeruli, crescents, and tubulointerstitial lesions were also effector type. Moreover, these urine cells expressed mRNA of the T helper lymphocyte 1 cytokines, interleukin-2, and/or interferon-gamma. These findings suggest that the appearance of effector T cells in urine may reflect the cellular immune reaction that occurs in the kidneys of patients with GN accompanied by active cell infiltration.
A Parkinsonian Syndrome in Methcathinone Users and the Role of Manganese
Authors: Ainārs Stepens, Ināra Logina, Viesturs Liguts, Pauls Aldiņš, Ilze Ekšteina, Ardis Platkājis, Inese Mārtiņsone, Elmārs Tērauds, Baiba Rozentāle, Michael Donaghy
Journal: New England Journal of Medicine (2008)

A distinctive extrapyramidal syndrome has been observed in intravenous methcathinone (ephedrone) users in Eastern Europe and Russia.We studied 23 adults in Latvia who had extrapyramidal symptoms and who had injected methcathinone for a mean (+/-SD) of 6.7+/-5.1 years. The methcathinone was manufactured under home conditions by potassium permanganate oxidation of ephedrine or pseudoephedrine. All patients were positive for hepatitis C virus, and 20 were also positive for the human immunodeficiency virus (HIV).The patients reported that the onset of their first neurologic symptoms (gait disturbance in 20 and hypophonia in 3) occurred after a mean of 5.8+/-4.5 years of methcathinone use. At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward; 11 patients were falling daily, and 1 of these patients used a wheelchair. Twenty-one patients had hypophonic speech in addition to gait disturbance, and one of these patients was mute. No patient reported decline in cognitive function. T(1)-weighted magnetic resonance imaging (MRI) showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all 10 active methcathinone users. Among the 13 former users (2 to 6 years had passed since the last use), lesser degrees of change in the MRI signal were noted. Whole-blood manganese levels (normal level, <209 nmol per liter) averaged 831 nmol per liter (range, 201 to 2102) in the active methcathinone users and 346 nmol per liter (range, 114 to 727) in former users. The neurologic deficits did not resolve after patients discontinued methcathinone use.Our observation of a distinctive extrapyramidal syndrome, changes in the MRI signal in the basal ganglia, and elevated blood manganese levels in methcathinone users suggests that manganese in the methcathinone solution causes a persistent neurologic disorder.
Predicting the Coupling Specificity of G-protein Coupled Receptors to G-proteins by Support Vector Machines
Authors: Cui-Ping Guan, Zhen-Ran Jiang, Yan-Hong Zhou
Journal: Genomics Proteomics & Bioinformatics (2005)

Abstract G-protein coupled receptors (GPCRs) represent one of the most important classes of drug targets for pharmaceutical industry and play important roles in cellular signal transduction. Predicting the coupling specificity of GPCRs to G-proteins is vital for further understanding the mechanism of signal transduction and the function of the receptors within a cell, which can provide new clues for pharmaceutical research and development. In this study, the features of amino acid compositions and physiochemical properties of the full-length GPCR sequences have been analyzed and extracted. Based on these features, classifiers have been developed to predict the coupling specificity of GPCRs to G-proteins using support vector machines. The testing results show that this method could obtain better prediction accuracy.
Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy.
Authors: Y Magnusson, S Marullo, S Hoyer, F Waagstein, B Andersson, A Vahlne, J G Guillet, A D Strosberg, A Hjalmarson, J Hoebeke
Journal: Journal of Clinical Investigation (1990)

The presence and properties of serum autoantibodies against beta-adrenergic receptors in patients with idiopathic dilated cardiomyopathy were studied using synthetic peptides derived from the predicted sequences of the human beta-adrenergic receptors. Peptides corresponding to the sequences of the second extracellular loop of the human beta 1- and beta 2-adrenergic receptors were used as antigens in an enzyme immunoassay to screen sera from patients with dilated cardiomyopathy (n = 42), ischemic heart disease (n = 17), or healthy blood donors (n = 34). The sera of thirteen dilated cardiomyopathy patients, none of the ischemic heart disease patients, and four of the healthy controls monospecifically recognized the beta 1-peptide. Only affinity-purified antibodies of these patients had a inhibitory effect on radioligand binding to the beta 1 receptor of C6 rat glioma cells. They recognized the receptor protein by immunoblot and bound in situ to human myocardial tissue. We conclude that a subgroup of patients with idiopathic dilated cardiomyopathy have in their sera autoantibodies specifically directed against the second extracellular loop of the beta 1-adrenergic receptor. These antibodies could serve as a marker of an autoimmune response with physiological and/or pathological implications.
Co-existing conjunctival non-Hodgkin's lymphoma and pulmonary sarcoidosis.
Authors: P J Ryan, P Stableforth, D T McLeod
Journal: Thorax (1996)

A 55 year old woman with a conjunctival non-Hodgkin9s lymphoma was found to have pulmonary nodules on a thoracic computed tomographic scan which were initially thought to be lymphomatous deposits. A subsequent biopsy specimen demonstrated granulomas consistent with sarcoidosis. The relationship between sarcoidosis and malignancy, in particular lymphoma, is discussed.
Prognostic Significance of <i>ASXL1</i> Mutations in Patients With Myelodysplastic Syndromes
Authors: Felicitas Thol, Inna Friesen, Frederik Damm, Haiyang Yun, Eva M. Weissinger, Jürgen Krauter, Katharina Wagner, Anuhar Chaturvedi, Amit Sharma, Martin Wichmann, Gudrun Göhring, Christiane Schumann, Gesine Bug, Oliver Ottmann, Wolf-Karsten Hofmann, Brigitte Schlegelberger, Michael Heuser, Arnold Ganser
Journal: Journal of Clinical Oncology (2011)

Purpose To study the incidence and prognostic impact of mutations in Additional sex comb-like 1 (ASXL1) in a large cohort of patients with myelodysplastic syndrome (MDS). Patients, Materials, and Methods Overall, 193 patients with MDS and 65 healthy volunteers were examined for ASXL1 mutations by direct sequencing and for expression levels of ASXL1. The prognostic impact of ASXL1 mutation and expression levels was evaluated in the context of other clinical and molecular prognostic markers. Results Mutations in ASXL1 occurred with a frequency of 20.7% in MDS (n = 40 of 193) with 70% (n = 28) of mutations being frameshift mutations and 30% (n = 12) being heterozygous point mutations leading to translational changes. ASXL1 mutations were correlated with an intermediate-risk karyotype (P = .002) but not with other clinical parameters. The presence of ASXL1 mutations was associated with a shorter overall survival for frameshift and point mutations combined (hazard ratio [HR], 1.744; 95% CI, 1.08 to 2.82; P = .024) and for frameshift mutations only (HR, 2.06; 95% CI, 1.21 to 3.50; P = .008). ASXL1 frameshift mutations were associated with a reduced time to progression of acute myeloid leukemia (AML; HR 2.35; 95% CI, 1.17 to 4.74; P = .017). In multivariate analysis, when considering karyotype, transfusion dependence, and IDH1 mutation status, ASXL1 frameshift mutations remained an independent prognostic marker in MDS (overall survival: HR, 1.85; 95% CI, 1.03 to 3.34; P = .040; time to AML progression: HR, 2.39; 95% CI, 1.12 to 5.09; P = .024). Conclusion These results suggest that ASXL1 mutations are frequent molecular aberrations in MDS that predict an adverse prognostic outcome. Screening of patients for ASXL1 mutations might be useful for clinical risk stratification and treatment decisions in the future.