tbuckley/cabot-search huggingface dataset:
Frequent concerted genetic mechanisms disrupt multiple components of the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in thyroid cancer
Authors: Victor D Martinez, Emily A Vucic, Larissa A Pikor, Kelsie L Thu, Roland Hubaux, Wan L Lam
Journal: Molecular Cancer (2013)

Reactive oxygen species contribute to normal thyroid function. The NRF2 oxidative response pathway is frequently and constitutively activated in multiple tumor types, including papillary thyroid carcinoma (PTC). Genetic mechanisms underlying NRF2 pathway activation in PTC are not fully understood. Thus, we aimed to determine whether inactivating patterns of DNA-level alterations affect genes encoding for individual NRF2 inhibitor complex components (CUL3/KEAP1/RBX1) occur in PTC. Combined patterns of epi/genetic alterations for KEAP1/CUL3/RBX1 E3 ubiquitin-ligase complex components were simultaneously interrogated for a panel of 310 PTC cases and 40 adjacent non-malignant tissues. Data were obtained from The Cancer Genome Atlas project. Enrichment of NRF2 pathway activation was assessed by gene-set enrichment analysis using transcriptome data. Our analyses revealed that PTC sustain a strikingly high frequency (80.6%) of disruption to multiple component genes of the NRF2 inhibitor complex. Hypermethylation is the predominant inactivating mechanism primarily affecting KEAP1 (70.6%) and CUL3 (20%), while copy number loss mostly affects RBX1 (16.8%). Concordantly, NRF2-associated gene expression signatures are positively and significantly enriched in PTC. The KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is almost ubiquitously affected by multiple DNA-level mechanisms and downstream NRF2 pathway targets are activated in PTC. Given the importance of this pathway to normal thyroid function as well as to cancer; targeted inhibition of NRF2 regulators may impact strategies for therapeutic intervention involving this pathway.
Effects of Gene Expression on Molecular Evolution in Arabidopsis thaliana and Arabidopsis lyrata
Authors: Stephen I. Wright, C. B. Kenneth Yau, Mark Looseley, Blake C. Meyers
Journal: Molecular Biology and Evolution (2004)

We analyzed the complete genome sequence of Arabidopsis thaliana and sequence data from 83 genes in the outcrossing A. lyrata, to better understand the role of gene expression on the strength of natural selection on synonymous and replacement sites in Arabidopsis. From data on tRNA gene abundance, we find a good concordance between codon preferences and the relative abundance of isoaccepting tRNAs in the complete A. thaliana genome, consistent with models of translational selection. Both EST-based and new quantitative measures of gene expression (MPSS) suggest that codon preferences derived from information on tRNA abundance are more strongly associated with gene expression than those obtained from multivariate analysis, which provides further support for the hypothesis that codon bias in Arabidopsis is under selection mediated by tRNA abundance. Consistent with previous results, analysis of protein evolution reveals a significant correlation between gene expression level and amino acid substitution rate. Analysis by MPSS estimates of gene expression suggests that this effect is primarily the result of a correlation between the number of tissues in which a gene is expressed and the rate of amino acid substitution, which indicates that the degree of tissue specialization may be an important determinant of the rate of protein evolution in Arabidopsis.
Estimating the prevalence of polymyositis and dermatomyositis from administrative data: age, sex and regional differences
Authors: S Bernatsky, L Joseph, C A Pineau, P Belisle, J F Boivin, D Banerjee, A E Clarke
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To estimate the prevalence of polymyositis and dermatomyositis using population-based administrative data, the sensitivity of case ascertainment approaches and patient demographics and these parameters. <h3>Methods:</h3> Cases were ascertained from Quebec physician billing and hospitalisation databases (approximately 7.5 million beneficiaries). Three different case definition algorithms were compared, and statistical methods were also used that account for imperfect case ascertainment, to generate estimates of disease prevalence and case ascertainment sensitivity. A hierarchical Bayesian latent class regression model was developed to assess patient characteristics with respect to these parameter estimates. <h3>Results:</h3> Using methods that account for the imperfect nature of both billing and hospitalisation databases, the 2003 prevalence of polymyositis and dermatomyositis was estimated to be 21.5/100 000 (95% credible interval (CrI) 19.4 to 23.9). Prevalence was higher for women and for older individuals, with a tendency for higher prevalence in urban areas. Prevalence estimates were lowest in young rural men (2.7/100 000, 95% CrI 1.6 to 4.1) and highest in older urban women (70/100 000, 95% CrI 61.3 to 79.3). Sensitivity of case ascertainment tended to be lower for older versus younger individuals, particularly for rheumatology billing data. Billing data appeared more sensitive in ascertaining cases in urban (vs rural) regions, whereas hospitalisation data seemed most useful in rural areas. <h3>Conclusions:</h3> Marked variations were found in the prevalence of polymyositis and dermatomyositis according to age, sex and region. These methods allow adjustment for the imperfect nature of multiple data sources and estimation of the sensitivity of different case ascertainment approaches.
Glomerular Filtration
Authors: Tracy E. Hunley, Valentina Kon
Journal: Journal of the American Society of Nephrology (2009)

Methodologic and analytic advances in molecular genetics identify many disease-predisposing variants in the human genome. One of the challenges presented by these studies is to define the mechanisms by which a given genetic variant affects a pathophysiologic disorder. This inevitable quandary confronts the study of Chen et al. 1 in this issue of JASN . The authors previously reported that a genetic polymorphism of chromatogranin A (CHGA), a soluble protein released from secretory granules of chromaffin cells and sympathetic nerves, predicts hypertensive ESRD in black patients. Using population genetic techniques, they further showed that the CHGA locus is a trans -QTL for endothelin-1 secretion and that CHGA stimulates endothelin release from endothelial cells. In view of the major role for endothelin postulated in the pathogenesis of a variety of cardiovascular and renal diseases, the authors questioned whether endothelin secretion is the mechanistic link between CHGA and renal dysfunction.

Using cultured human umbilical vein endothelial cells, Chen et al. 1 now show that CHGA increases release of endothelin along with other peptides typically stored in Weibel-Palade bodies, including von Willebrand factor and angiopoietin 2. CHGA also increases endothelin secretion from mouse glomerular endothelial cells, and co-culture of CHGA-exposed glomerular endothelial cells with mesangial cells potentiates secretion of TGF-β1. In humans, plasma CHGA correlates positively with plasma endothelin and negatively with GFR. A promoter haplotype for CHGA predicts the level of GFR in individuals with GFRs in the normal range, whereas CHGA haplotypes in the 3′ untranslated region associate with GFR in individuals with progressive renal disease. The conclusion that CHGA triggers exocytotic release of endothelin from the glomerular endothelium and that this, in turn, regulates the level of GFR in normal and declining renal function offers some novel implications. These include …
Adverse Effect of Older Age on the Recurrence of Soft Tissue Sarcoma of the Extremities and Trunk
Authors: David J. Biau, Peter C. Ferguson, Robert E. Turcotte, Peter Chung, Marc H. Isler, Soha Riad, Anthony M. Griffin, Charles N. Catton, Brian O'Sullivan, Jay S. Wunder
Journal: Journal of Clinical Oncology (2011)

Purpose To examine the effect of age on the recurrence of soft tissue sarcoma in the extremities and trunk. Patients and Methods This was a multicenter study that included 2,385 patients with median age at surgery of 57 years. The end points considered were local recurrence and metastasis. Cox proportional hazards models were used to estimate hazard ratios across the age ranges with and without adjustment for known confounding factors. Results Older patients presented with tumors that were larger (P &lt; .001) and of higher grade (P &lt; .001). The proportion of positive margins increased significantly as patients age (P &lt; .001), but radiation therapy was relatively underused in patients older than age 60 years. The 5-year cumulative incidences of local recurrence were 7.2% (95% CI, 4% to 11.7%) for patients age 30 years or younger and 12.9% (95% CI, 9.1% to 17.5%) for patients age 75 years or older. The corresponding 5-year cumulative incidences of metastasis were 17.5% (95% CI, 12.1% to 23.7%) and 33.9% (95% CI, 28.1% to 39.8%) for the same groups. Regression models showed that age was significantly associated with local recurrence (P &lt; .001) and metastasis (P &lt; .001) in nonadjusted models. After adjusting for imbalance in presentation and treatment variables, age remained significantly associated with local recurrence (P = .031) and metastasis (P = .019). Conclusion Older patients have worse outcomes because they tend to present with worse tumors and are treated less aggressively. However, there remained a significant increase in the risk of both local and systemic recurrence associated with increasing age that could not be explained by tumor or treatment characteristics.
Molecular Evolution and Structure of α-Actinin
Authors: Ana Virel, Lars Backman
Journal: Molecular Biology and Evolution (2004)

The N-terminal actin-binding domain of alpha-actinin is connected to the C-terminal EF-hands by a rod domain. Because of its ability to form dimers, alpha-actinin can cross-link actin filaments in muscle cells as well as in nonmuscle cells. In the prototypic alpha-actinins, the rod domain contains four triple helical bundles, or so-called spectrin repeats. We have found some atypical alpha-actinins in early diverging organisms, such as protozoa and yeast, where the rod domain contains one and two spectrin repeats, respectively. This implies that the four repeats present in modern alpha-actinins arose after two consecutive intragenic duplications from an alpha-actinin with a single repeat. Further, the evolutionary gene tree of alpha-actinins shows that the appearance of four distinct alpha-actinin isoforms may have occurred after the vertebrate-invertebrate split. The topology of the tree lends support to the hypothesis that two rounds (2R) of genome duplication occurred early in the vertebrate radiation. The phylogeny also considers these atypical isoforms as the most basal to alpha-actinins of vertebrates and other eukaryotes. The analysis also positioned alpha-actinin of the fungi Encephalitozoo cuniculi close to the protozoa, supporting the suggestion that microsporidia are early eukaryotes. Because alpha-actinin is considered the basal member of the spectrin family, our studies will improve the understanding of the origin and evolution of this superfamily.
Autoimmune hepatitis triggered by hepatitis A
Authors: G Singh, S Palaniappan, O Rotimi, P J Hamlin
Journal: Gut (2007)

We describe a case of autoimmune hepatitis triggered by an acute hepatitis A infection. A young woman presented with a 10 day history of nausea and dark urine having returned from Tunisia a month previously. She had marked transaminitis. Viral serology demonstrated positive hepatitis A immunoglobulin M. Other viral serology was negative. Autoantibody screening revealed positive antismooth muscle antibodies (titre 1 in 80) but negative antinuclear (ANA), antimitochondrial, and antiliver, kidney and pancreas (LKM) antibodies. Immunoglobulin levels revealed normal IgA and IgG levels …
CD20 deficiency in humans results in impaired T cell–independent antibody responses
Authors: Taco W. Kuijpers, Richard J. Bende, Paul A. Baars, Annette Grummels, Ingrid A.M. Derks, Koert M. Dolman, Tim Beaumont, Thomas F. Tedder, Carel J.M. van Noesel, Eric Eldering, René A.W. van Lier
Journal: Journal of Clinical Investigation (2009)

CD20 was the first B cell differentiation antigen identified, and CD20-specific mAbs are commonly used for the treatment of B cell malignancies and autoantibody-mediated autoimmune diseases. Despite this the role of CD20 in human B cell physiology has remained elusive. We describe here a juvenile patient with CD20 deficiency due to a homozygous mutation in a splice junction of the CD20 gene (also known as MS4A1) that results in “cryptic” splicing and nonfunctional mRNA species. Analysis of this patient has led us to conclude that CD20 has a central role in the generation of T cell–independent (TI) antibody responses. Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient. Consistent with this, TI antipolysaccharide B cell responses were severely impeded in CD20-deficient mice. Our study therefore identifies what we believe to be a novel type of humoral immunodeficiency caused by CD20 deficiency and characterized by normal development of antigen-independent B cells, along with a reduced capacity to mount proper antibody responses.
Not So Different After All: A Comparison of Methods for Detecting Amino Acid Sites Under Selection
Authors: Sergei L. Kosakovsky Pond, Simon D. W. Frost
Journal: Molecular Biology and Evolution (2005)

We consider three approaches for estimating the rates of nonsynonymous and synonymous changes at each site in a sequence alignment in order to identify sites under positive or negative selection: (1) a suite of fast likelihood-based "counting methods" that employ either a single most likely ancestral reconstruction, weighting across all possible ancestral reconstructions, or sampling from ancestral reconstructions; (2) a random effects likelihood (REL) approach, which models variation in nonsynonymous and synonymous rates across sites according to a predefined distribution, with the selection pressure at an individual site inferred using an empirical Bayes approach; and (3) a fixed effects likelihood (FEL) method that directly estimates nonsynonymous and synonymous substitution rates at each site. All three methods incorporate flexible models of nucleotide substitution bias and variation in both nonsynonymous and synonymous substitution rates across sites, facilitating the comparison between the methods. We demonstrate that the results obtained using these approaches show broad agreement in levels of Type I and Type II error and in estimates of substitution rates. Counting methods are well suited for large alignments, for which there is high power to detect positive and negative selection, but appear to underestimate the substitution rate. A REL approach, which is more computationally intensive than counting methods, has higher power than counting methods to detect selection in data sets of intermediate size but may suffer from higher rates of false positives for small data sets. A FEL approach appears to capture the pattern of rate variation better than counting methods or random effects models, does not suffer from as many false positives as random effects models for data sets comprising few sequences, and can be efficiently parallelized. Our results suggest that previously reported differences between results obtained by counting methods and random effects models arise due to a combination of the conservative nature of counting-based methods, the failure of current random effects models to allow for variation in synonymous substitution rates, and the naive application of random effects models to extremely sparse data sets. We demonstrate our methods on sequence data from the human immunodeficiency virus type 1 env and pol genes and simulated alignments.
Immunological studies in inflammatory bowel disease.
Authors: D Zauli, M Fusconi, C Crespi, G Cometti, F B Bianchi, E Pisi
Journal: Gut (1984)

Immunological studies in inflammatory bowel disease SIR,-The leading article by Ferguson (Gut 1983; 24: 687-91) on immunological studies in inflammatory bowel disease, and the paper by Fiocchi et al (pp.692-701) prompted us to refer our data on T function in Crohn's disease.While studying T rosette serum inhibitory factors in chronic active liver disease,' we also tested, as a disease control group, 14 sera from coeliac disease untreated patients.Rosette inhibitory factors were detected in 36% coeliac disease sera and they were associated with immunoglobulin factors reacting in immunofluorescence with purified T lymphocyte.Furthermore, inhibitory activity was abolished by treatment of sera with (NH4I2S02, which precipi- tates gammaglobulin fraction.We conclude that in some coeliac disease cases serum immunoglobulin factors, which can interfere with T lymphocyte functions, are present.We agree that direct studies on intestinal lymphoid system are likely to be the best way to detect immunological abnormalities underlying these diseases, but we would like to point out that also at this level results are rather conflicting.In fact, other authors2 have reported reduced suppressor cell activity in intestinal lymphocytes from patients with coeliac disease.Furthermore, our data would suggest that systemic factors also may be relevant in modulating immune reactions in these conditions.
The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years
Authors: A E Feldstein, P Charatcharoenwitthaya, S Treeprasertsuk, J T Benson, F B Enders, P Angulo
Journal: Gut (2009)

<h3>Objectives:</h3> The long-term prognosis of non-alcoholic fatty liver disease (NAFLD) in children remains uncertain. We aimed at determining the long-term outcomes and survival of children with NAFLD. <h3>Design:</h3> Retrospective longitudinal hospital-based cohort study. <h3>Patients:</h3> Sixty-six children with NAFLD (mean age 13.9 (SD 3.9) years) were followed up for up to 20 years with a total of 409.6 person-years of follow-up. <h3>Results:</h3> The metabolic syndrome was present in 19 (29%) children at the time of NAFLD diagnosis with 55 (83%) presenting with at least one feature of the metabolic syndrome including obesity, hypertension, dyslipidaemia and/or hyperglycaemia. Four children with baseline normal fasting glucose developed type 2 diabetes 4–11 years after NAFLD diagnosis. A total of 13 liver biopsies were obtained from five patients over a mean of 41.4 (SD 28.8) months showing progression of fibrosis stage in four children. During follow-up, two children died and two underwent liver transplantation for decompensated cirrhosis. The observed survival free of liver transplantation was significantly shorter in the NAFLD cohort as compared to the expected survival in the general United States population of the same age and sex (log-rank test, p&lt;0.00001), with a standardised mortality ratio of 13.6 (95% confidence interval, 3.8 to 34.8). NAFLD recurred in the allograft in the two cases transplanted, with one patient progressing to cirrhosis and requiring re-transplantation. <h3>Conclusions:</h3> Children with NAFLD may develop end-stage liver disease with the consequent need for liver transplantation. NAFLD in children seen in a tertiary care centre may be associated with a significantly shorter survival as compared to the general population.
Cardiovascular Magnetic Resonance Assessment of Human Myocarditis
Authors: Heiko Mahrholdt, Christine Goedecke, Anja Wagner, Gabriel Meinhardt, Anasthasios Athanasiadis, Holger Vogelsberg, Peter Fritz, Karin Klingel, Reinhard Kandolf, Udo Sechtem
Journal: Circulation (2004)

Background— Myocarditis can occasionally lead to sudden death and may progress to dilated cardiomyopathy in up to 10% of patients. Because the initial onset is difficult to recognize clinically and the diagnostic tools available are unsatisfactory, new strategies to diagnose myocarditis are needed. Methods and Results— Cardiovascular MR imaging (CMR) was performed in 32 patients who were diagnosed with myocarditis by clinical criteria. To determine whether CMR visualizes areas of active myocarditis, endomyocardial biopsy was taken from the region of contrast enhancement and submitted to histopathologic analysis. Follow-up was performed 3 month later. Contrast enhancement was present in 28 patients (88%) and was usually seen with one or several foci in the myocardium. Foci were most frequently located in the lateral free wall. In the 21 patients in whom biopsy was obtained from the region of contrast enhancement, histopathologic analysis revealed active myocarditis in 19 patients (parvovirus B19, n=12; human herpes virus type 6 [HHV 6], n=5). Conversely, in the remaining 11 patients, in whom biopsy could not be taken from the region of contrast enhancement, active myocarditis was found in one case only (HHV6). At follow-up, the area of contrast enhancement decreased from 9±11% to 3±4% of left ventricular mass as the left ventricular ejection fraction improved from 47±19% to 60±10%. Conclusions— Contrast enhancement is a frequent finding in the clinical setting of suspected myocarditis and is associated with active inflammation defined by histopathology. Myocarditis occurs predominantly in the lateral free wall. Contrast CMR is a valuable tool for the evaluation and monitoring of inflammatory heart disease.
The relative potency of the Crick-Harper-Raper unit and the GIH clinical unit of secretin.
Authors: J M Braganza, H T Howat, G Kay
Journal: Gut (1975)

A reinvestigation of the relationship between the Crick-Harper-Raper (CHR) and the GIH clinical units (CU) of secretin has been undertaken in anaesthetized cats with the knowledge that for some time before 1970 the CHR standard used by The Boots Company to assay secretin had lost some specific activity. One clinical unit of GIH secretin (batch no. 17421) is 3-8 times more potent than 1 Crick-Harper-Raper unit of restandardized Boots secretin (batch no. 142) in increasing the flow rate of pancreatic juice, and four times more potent in increasing the amount of bicarbonate.
Performance of Technical Skills of Diabetes Management: Increased Independence After a Camp Experience
Authors: Francine L Lebovitz, George J Ellis, Jay S Skyler
Journal: Diabetes Care (1978)

This study examines some educational effects of a camp experience on independent performance of tasks in the management of diabetes mellitus. One hundred and eleven children were studied with regard to insulin administration, urine glucose testing, recognition of hypoglycemic reactions, adherence to diet, and over-all independence. There was a significant increase in independent measurement of insulin dose, administration of insulin injections, and urine glucose testing. No significant differences were seen in dietary adherence or ability to recognize hypoglycemic reactions. Precamp data indicated that returning campers demonstrated greater independence in insulin administration prior to camp than did new campers. After camp, both new and returning campers showed significant increases in independent performance of dose measurement and injection. It is concluded that a camp educational experience contributes to both the knowledge and performance of self-care techniques required in the management of diabetes mellitus.