tbuckley/cabot-search huggingface dataset:
Signaling and Transcriptional Changes Critical for Transformation of Human Cells by Simian Virus 40 Small Tumor Antigen or Protein Phosphatase 2A B56γ Knockdown
Authors: Carlos S. Moreno, Sumathi Ramachandran, Danita G. Ashby, Noelani Laycock, Courtney A. Plattner, Wen Chen, William C. Hahn, David C. Pallas
Journal: Cancer Research (2004)

Abstract One set of genes sufficient for transformation of primary human cells uses the combination of Ha-Ras-V12, the telomerase catalytic subunit hTERT, SV40 large tumor antigen (LT), and SV40 small tumor antigen (ST). Whereas SV40 LT inactivates the retinoblastoma protein and p53, the contribution of ST is poorly understood. The essential helper function of ST requires a functional interaction with protein phosphatase 2A (PP2A). Here we have identified changes in gene expression induced by ST and show that ST mediates these changes through both PP2A-dependent and PP2A-independent mechanisms. Knockdown of PP2A B56γ subunit can substitute for ST expression to fully transform cells expressing LT, hTERT, and Ras-V12. We also identify those genes affected similarly in two cell lines that have been fully transformed from a common parental line by two alternative mechanisms, namely ST expression or PP2A B56γ subunit knockdown. ST altered expression of genes involved in proliferation, apoptosis, integrin signaling, development, immune responses, and transcriptional regulation. ST reduced surface expression of MHC class I molecules, consistent with a need for SV40 to evade immune detection. ST expression enabled cell cycle progression in reduced serum and src phosphorylation in anchorage-independent media, whereas B56γ knockdown required normal serum levels for these phenotypes. Inhibitors of integrin and src signaling prevented anchorage-independent growth of transformed cells, suggesting that integrin and src activation are key ST-mediated events in transformation. Our data support a model in which ST promotes survival through constitutive integrin signaling, src phosphorylation, and nuclear factor κB activation, while inhibiting cell-cell adhesion pathways.
Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden
Authors: Lisbeth Ärlestig, Mohammed Mullazehi, Heidi Kokkonen, Joacim Rocklöv, Johan Rönnelid, Solbritt Rantapää Dahlqvist
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years. <h3>Objective</h3> To evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors. <h3>Methods</h3> 51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls. <h3>Results</h3> The concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the <i>PTPN22</i> T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives. <h3>Conclusions</h3> All anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.
Phylogenetic Mapping of Intron Positions: A Case Study of Translation Initiation Factor eIF2γ
Authors: Veiko Krauss, Marek Pecyna, Katrin Kurz, Heinz Sass
Journal: Molecular Biology and Evolution (2004)

Eukaryotic translation initiation factor 2 (eIF2) is a G protein that delivers the methionyl initiator tRNA to the small ribosomal subunit and releases it upon GTP hydrolysis after the recognition of the initiation codon. eIF2 is composed of three subunits, alpha, beta, and gamma. Subunit gamma shows the strongest conservation, and it confers both tRNA and GTP/GDP binding. Using intron positioning and protein sequence alignment, here we show that eIF2gamma is a suitable phylogenetic marker for eukaryotes. We determined or completed the sequences of 13 arthropod eIF2gamma genes. Analyzing the phylogenetic distribution of 52 different intron positions in 55 distantly related eIF2gamma genes, we identified ancient ones and shared derived introns in our data set. Obviously, intron positioning in eIF2gamma is evolutionarily conserved. However, there were episodes of complete and partial intron losses followed by intron gains. We identified 17 clusters of intron positions based on their distribution. The evolution of these clusters appears to be connected with preferred exon length and can be used to estimate the relative timing of intron gain because nearby precursor introns had to be erased from the gene before the new introns could be inserted. Moreover, we identified a putative case of intron sliding that constitutes a synapomorphic character state supporting monophyly of Coleoptera, Lepidoptera, and Diptera excluding Hymenoptera. We also performed tree reconstructions using the eIF2gamma protein sequences and intron positioning as phylogenetic information. Our results support the monophyly of Viridoplantae, Ascomycota, Homobasidiomyceta, and Apicomplexa.
The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients
Authors: Ragnar Gunnarsson, Øyvind Molberg, Inge-Margrethe Gilboe, Jan Tore Gran
Journal: Annals of the Rheumatic Diseases (2011)

Objectives Mixed connective tissue disease (MCTD) is an immune-mediated, systemic disorder of unknown aetiology. As the epidemiology of the disease is largely unknown, the authors performed a nationwide cross-sectional retrospective study to assess the prevalence and incidence of MCTD in Norway. Methods Every adult patient (≥18 years) with MCTD seen at one of the departments of rheumatology was reviewed for inclusion. Only patients who satisfied the following four criteria were included: clinical diagnosis of MCTD verified by a rheumatologist; positive serum anti-ribonucleoprotein antibody test; fulfilment of at least one of three of following criteria sets: the modified Sharp's criteria, the criteria of Alarcón-Segovia and Villareal and those of Kasukawa; and exclusion of other connective tissue diseases. Results The four inclusion criteria were fulfilled by 147 adult Caucasian patients. The female to male ratio was 3.3 and the mean age at diagnosis of adult-onset MCTD was 37.9 years (95% CI 35.3 to 40.4 years). At the end of 2008, the point prevalence of living adult MCTD patients in Norway was 3.8 (95% CI 3.2 to 4.4) per 100 000 adults. The incidence of adult-onset MCTD in Norway during the period from 1996 to 2005 was 2.1 (95% CI 1.7 to 2.5) per million per year. Conclusions MCTD has a female predominance and the incidence and prevalence of MCTD is low, and lower than reported figures for polymyositis, dermatomyositis, systemic sclerosis and systemic lupus erythematosus. The prevalence estimates were similar across the three criteria sets of MCTD.
Physiological concentrations of nitric oxide do not elicit an acute negative inotropic effect in unstimulated cardiac muscle.
Authors: A S Weyrich, X L Ma, M Buerke, T Murohara, V E Armstead, A M Lefer, J M Nicolas, A P Thomas, D J Lefer, J Vinten-Johansen
Journal: Circulation Research (1994)

We examined the effect of several nitric oxide (NO) donors, authentic NO gas, and L-arginine in isolated cat and rat papillary muscles. We did not observe significant inotropic effects in response to any NO donor (ie, SPM-5185, C87-3754, and S-nitroso-N-acetylpenicillamine [SNAP]) from 1 nmol/L to 100 mumol/L. Similarly, authentic NO, at concentrations far in excess of those that maximally dilate the coronary vasculature (ie, 500 nmol/L), also failed to exert a detectable inotropic effect in these preparations. However, in the presence of 5 mumol/L norepinephrine, 500 nmol/L NO exerted a 12 +/- 3% decrease in isolated rat papillary muscle contractility (P &lt; .05). Addition of L-arginine up to 25 mmol/L exerted no inotropic effects in isolated rat papillary muscles. However, at 50 mmol/L, L-arginine decreased contractile force by 21 +/- 4% (P &lt; .01). On further examination, the negative inotropic effect of 50 mmol/L L-arginine appeared to be nonspecific, since the inactive stereoisomer, D-arginine, at 50 mmol/L exerted the same effect. Further studies in isolated adult rat cardiac myocytes elicited similar results, in that 50 mmol/L of L- and D-arginine equally decreased contraction amplitude and the underlying cytosolic calcium transient. Moreover, 500 nmol/L of the NO donor SPM-5185 only modestly decreased contraction amplitude or intracellular calcium in isolated rat cardiac myocytes. These results indicate that administration of physiological concentrations of exogenous NO does not acutely depress the inotropic state of the rat or cat heart to a physiologically significant extent.(ABSTRACT TRUNCATED AT 250 WORDS)
Ring chromosome 18 abnormality in acute myelogenous leukemia: the clinical dilemma
Authors: Shanthi Sivendran, Stephen Gruenstein, Adriana K Malone, Vesna Najfeld
Journal: Journal of Hematology & Oncology (2010)

Abstract The ring chromosome is a circular, structural abnormality composed of either multiple chromosomes or a single chromosome with loss of genetic material at one or both ends. This chromosomal rearrangement is often unstable with frequent recombinations and may be accompanied by either loss or amplification of genetic material[1]. Considering that ring chromosomes are rare in acute myelogenous leukemia (AML), it is difficult to risk stratify patient prognosis, particularly when the ring chromosome occurs as the sole abnormality. Here we report a case of a ring chromosome 18 abnormality in a patient with newly diagnosed AML with monocytic differentiation. Cytogenetic analysis demonstrated 46, XY, r(18)(p11q21) karyotype in 19 of 34 evaluated metaphase cells. The patient received induction chemotherapy and subsequent allogeneic cord blood transplant from a sex-matched donor, and remained in hematologic and cytogenetic remission for 120 days post transplant. Soon after, he developed post transplant lymphoproliferative disorder and died of multi-organ failure. Although r(18) chromosomal abnormalities were not classified in the recent updated evidence-and expert opinion-based recommendations for the diagnosis and management of AML (likely due to the small number of reported cases), the patient was treated as high risk with stem cell transplantation. This was based on the unstable nature of the ring chromosome and the poor outcomes described in the literature of patients with sole ring 18 abnormalities.
Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013
Authors: Marie Ng, Tom Fleming, Margaret Robinson, Blake Thomson, Nicholas Graetz, Christopher Margono, Erin C Mullany, Stan Biryukov, Cristiana Abbafati, Semaw Ferede Abera, Jerry P Abraham, Niveen M E Abu-Rmeileh, Tom Achoki, Fadia S AlBuhairan, Zewdie A Alemu, Rafael Alfonso, Mohammed K Ali, Raghib Ali, Nelson Alvis Guzman, Walid Ammar, Palwasha Anwari, Amitava Banerjee, Simon Barquera, Sanjay Basu, Derrick A Bennett, Zulfiqar Bhutta, Jed Blore, Norberto Cabral, Ismael Campos Nonato, Jung-Chen Chang, Rajiv Chowdhury, Karen J Courville, Michael H Criqui, David K Cundiff, Kaustubh C Dabhadkar, Lalit Dandona, Adrian Davis, Anand Dayama, Samath D Dharmaratne, Eric L Ding, Adnan M Durrani, Alireza Esteghamati, Farshad Farzadfar, Derek F J Fay, Valery L Feigin, Abraham Flaxman, Mohammad H Forouzanfar, Atsushi Goto, Mark A Green, Rajeev Gupta, Nima Hafezi-Nejad, Graeme J Hankey, Heather C Harewood, Rasmus Havmoeller, Simon Hay, Lucia Hernandez, Abdullatif Husseini, Bulat T Idrisov, Nayu Ikeda, Farhad Islami, Eiman Jahangir, Simerjot K Jassal, Sun Ha Jee, Mona Jeffreys, Jost B Jonas, Edmond K Kabagambe, Shams Eldin Ali Hassan Khalifa, Andre Pascal Kengne, Yousef Saleh Khader, Young-Ho Khang, Daniel Kim, Ruth W Kimokoti, Jonas M Kinge, Yoshihiro Kokubo, Soewarta Kosen, Gene Kwan, Taavi Lai, Mall Leinsalu, Yichong Li, Xiaofeng Liang, Shiwei Liu, Giancarlo Logroscino, Paulo A Lotufo, Yuan Lu, Jixiang Ma, Nana Kwaku Mainoo, George A Mensah, Tony R Merriman, Ali H Mokdad, Joanna Moschandreas, Mohsen Naghavi, Aliya Naheed, Devina Nand, K M Venkat Narayan, Erica Leigh Nelson, Marian L Neuhouser, Muhammad Imran Nisar, Takayoshi Ohkubo, Samuel O Oti, Andrea Pedroza, Dorairaj Prabhakaran, Nobhojit Roy, Uchechukwu Sampson, Hyeyoung Seo, Sadaf G Sepanlou, Kenji Shibuya, Rahman Shiri, Ivy Shiue, Gitanjali M Singh, Jasvinder A Singh, Vegard Skirbekk, Nicolas J C Stapelberg, Lela Sturua, Bryan L Sykes, Martin Tobias, Bach X Tran, Leonardo Trasande, Hideaki Toyoshima, Steven van de Vijver, Tommi J Vasankari, J Lennert Veerman, Gustavo Velasquez-Melendez, Vasiliy Victorovich Vlassov, Stein Emil Vollset, Theo Vos, Claire Wang, XiaoRong Wang, Elisabete Weiderpass, Andrea Werdecker, Jonathan L Wright, Y Claire Yang, Hiroshi Yatsuya, Jihyun Yoon, Seok-Jun Yoon, Yong Zhao, Maigeng Zhou, Shankuan Zhu, Alan D Lopez, Christopher J L Murray, Emmanuela Gakidou
Journal: The Lancet (2014)
Phase II Study of Low-Dose Decitabine in Patients With Chronic Myelogenous Leukemia Resistant to Imatinib Mesylate
Authors: Jean-Pierre J. Issa, Vazganush Gharibyan, Jorge Cortes, Jaroslav Jelinek, Gail Morris, Srdan Verstovsek, Moshe Talpaz, Guillermo Garcia-Manero, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2005)

Purpose To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. Materials and Methods Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase). Decitabine was administered at 15 mg/m 2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay. Results Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% ± 1.4% (mean ± standard error of the mean) to 60.7% ± 1.4% after 1 week, 50.9% ± 2.4% after 2 weeks, and returned to 66.5% ± 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% ± 3.0% versus 26.8% ± 2.7% in responders versus nonresponders (P = .007). Conclusion Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.
Body Weight, Metabolic Dysfunction, and Risk of Type 2 Diabetes in Patients at High Risk for Cardiovascular Events or With Manifest Cardiovascular Disease: A Cohort Study
Authors: Bas T. Franssens, Yolanda van der Graaf, L. Jaap Kappelle, Jan Westerink, Gert J. de Borst, Maarten J. Cramer, Frank L.J. Visseren
Journal: Diabetes Care (2015)

OBJECTIVE To quantify the role of BMI and metabolic dysfunction in the risk of development of type 2 diabetes in patients at high risk or with manifest vascular disease. RESEARCH DESIGN AND METHODS A total of 6,997 patients participating in the prospective Secondary Manifestations of ARTerial disease (SMART) cohort study were classified according to BMI and metabolic dysfunction, defined as three or more of the modified National Cholesterol Education Program (NCEP) metabolic syndrome criteria (waist circumference replaced by hs-CRP ≥2 mg/L). Risk of type 2 diabetes (assessed with biannually questionnaires) was estimated with Cox proportional hazards analysis. RESULTS During a median follow-up of 6.0 years (interquartile range 3.1–9.1 years), 519 patients developed type 2 diabetes (incidence rate 12/1,000 person-years). In the absence of metabolic dysfunction (≤2 NCEP criteria), adiposity increased the risk of type 2 diabetes compared with normal-weight patients (HR 2.5 [95% CI 1.5–4.2] for overweight and HR 4.3 [95% CI 2.2–8.6] for obese patients). In the presence of metabolic dysfunction (≥3 NCEP criteria), an increased risk of type 2 diabetes was observed in patients with normal weight (HR 4.7 [95% CI 2.8–7.8]), overweight (HR 8.5 [95% CI 5.5–13.4]), and obesity (HR 16.3 [95% CI 10.4–25.6]) compared with normal-weight patients without metabolic dysfunction. CONCLUSIONS Adiposity, even in the absence of metabolic dysfunction, is a risk factor for type 2 diabetes. Moreover, presence of metabolic dysfunction increases the risk of type 2 diabetes in all BMI categories. This supports the assessment of adiposity and metabolic dysfunction in patients with vascular disease or at high risk for cardiovascular events.
A novel mutation in CD132 causes X-CID with defective T-cell activation and impaired humoral reactivity
Authors: Taco W. Kuijpers, Paul A. Baars, Daan J. aan de Kerk, Machiel H. Jansen, Ingrid A.M. Derks, Robbert G.M. Bredius, Elisabeth A.M. Sanders, Mirjam van der Burg, Marielle Alders, Rene A.W. van Lier
Journal: Journal of Allergy and Clinical Immunology (2011)
T lymphocytes specific for immunoglobulin allotype. I. Igh- 1(b)-specific T cells demonstrated by suppression in vivo and cytotoxicity in vitro
Authors: HR Snodgrass, DB Wilson, MJ Bosma
Journal: The Journal of Experimental Medicine (1981)

We show that determinants of IgG(2a) of C57BL/6 mice (Igh-1(b)) stimulate allotypespecific T cells in BALB/c mice. Such cells are detected in two different functional assays; chronic allotype suppression and T cell-mediated cytotoxicity. A population of suppressor T cells capable of inducing chronic Igh-1(b) suppression was demonstrated by rosetting procedures to possess Igh-1(b)-specific receptors, a result interpreted as indicating that suppressor T cells may act directly upon allotype-bearing B cells. From similar populations we were also able to demonstrate Igh-1(b)-specific cytotoxic T cells. Such cells were lytic for target myeloma cells expressing the Igh-1(b) allotype of IgG28, and were ineffective against a variant cell line failing to express Igh-1(b), and other target cell lines expressing different allotypes or isotypes. The similar specificity of suppressor T cells and cytotoxic T lymphocytes for Igh-1(b) allotype raises the possibility that the target in allotype suppression is a B cell, and that allotype-specific cytotoxic T cells may play some role in regulation of allotype expression in the suppressed state.
Developing countries could derail global anti-obesity plan
Authors: Fiona Fleck
Journal: BMJ (2004)

In a last minute submission to the World Health Organization 135 developing nations, including major sugar producers, expressed “concerns” about WHO's global plan to tackle obesity. Some countries threatened to vote against the final text, which WHO members are set to adopt at their annual meeting in May.

Earlier this year the United States, under pressure from its powerful food and drinks industry, opposed WHO's proposed global strategy on diet, physical activity, and health and rejected a link made in the draft text between junk food and obesity (31 January, p 245).

But as feedback poured in from governments to WHO to meet the deadline at the end …
Risk of Congenital Anomalies after the Opening of Landfill Sites
Authors: Stephen R. Palmer, Frank D.J. Dunstan, Hilary Fielder, David L. Fone, Gary Higgs, Martyn L. Senior
Journal: Environmental Health Perspectives (2005)

Concern that living near a particular landfill site in Wales caused increased risk of births with congenital malformations led us to examine whether residents living close to 24 landfill sites in Wales experienced increased rates of congenital anomalies after the landfills opened compared with before they opened. We carried out a small-area study in which expected rates of congenital anomalies in births to mothers living within 2 km of the sites, before and after opening of the sites, were estimated from a logistic regression model fitted to all births in residents living at least 4 km away from these sites and hence not likely to be subject to contamination from a landfill, adjusting for hospital catchment area, year of birth, sex, maternal age, and socioeconomic deprivation score. We investigated all births from 1983 through 1997 with at least one recorded congenital anomaly [International Classification of Diseases, Ninth Revision (ICD-9), codes 7400–7599; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), codes Q000–Q999]. The ratio of the observed to expected rates of congenital anomalies before landfills opened was 0.87 [95% confidence interval (CI), 0.75–1.00], and this increased to 1.21 (95% CI, 1.04–1.40) after opening, giving a standardized risk ratio of 1.39 (95% CI, 1.12–1.72). Enhanced congenital malformation surveillance data collected from 1998 through 2000 showed a standardized risk ratio of 1.04 (95% CI, 0.88–1.21). Causal inferences are difficult because of possible biases from incomplete case ascertainment, lack of data on individual-level exposures, and other socioeconomic and lifestyle factors that may confound a relationship with area of residence. However, the increase in risk after the sites opened requires continued enhanced surveillance of congenital anomalies, and site-specific chemical exposure studies.