tbuckley/cabot-search huggingface dataset:
Is microsomal triglyceride transfer protein the missing link in abetalipoproteinemia?
Authors: Robert L. Hamilton, Richard J. Havel
Journal: Hepatology (1993)

In the study reported by Wetterau et al., a recently characterized heterodimeric protein called microsomal triglyceride transfer protein was undetectable on immunoblotting of samples from intestinal biopsies of human subjects with the genetic disorder abetalipoproteinemia. With only one fourth to one fifth the soluble proteins of homogenized intestinal biopsy specimens of normal human subjects and patients with different fat-absorption defects, the 88-kD subunit of microsomal triglyceride transfer protein was clearly detectable. Protein disulfide isomerase, the 55-kD subunit of microsomal triglyceride transfer protein, was present in tissue of all subjects tested, including those with abetalipoproteinemia. Consistent results were obtained with an in vitro assay that measures triglyceride transfer between phospholipid membranes: triglyceride transfer continued at constant rates for more than 1 hr in samples from biopsies in normal human subjects, whereas no measurable triglyceride transfer was detected in the same material from abetalipoproteinemia patients. The apparent absence of the 88-kD subunit of microsomal triglyceride transfer protein most likely explains this debilitating disorder. This new observation coincides with the recent articulation of a novel hypothesis about the subcellular mechanisms by which enterocytes and hepatocytes assemble triglyceride-rich particles containing the large hydrophobic protein apolipoprotein B in two steps. In the first step, a small (≈ 200 Å), apolipoprotein B–rich microemulsion particle containing small amounts of triglycerides and cholesteryl esters in its core is formed and released into the lumen of the rough endoplasmic reticulum. The second step requires the synthesis of larger triglyceride-rich particles lacking apolipoprotein B in the smooth endoplasmic reticulum. Fusion of these two particles is postulated to yield nascent very low density lipoproteins or chylomicrons that can be secreted by hepatocytes and enterocytes, respectively. In classic abetalipoproteinemia patients, no apolipoprotein B is found in blood plasma, and chylomicrons, very low density lipoproteins and low-density lipoproteins are absent. The two-step model of triglyceride-rich particle formation predicts that, in the absence of microsomal triglyceride transfer protein, newly synthesized apolipoprotein B bound to the rough endoplasmic reticulum membrane cannot be core-lipidated and thus cannot be efficiently dissociated from the rough endoplasmic reticulum membrane. In other words, the first step cannot occur in the absence of microsomal triglyceride transfer protein. Consequently, apolipoprotein B-containing lipoproteins cannot be produced and sequestered in the lumen of the endoplasmic reticulum in abetalipoproteinemia, and no such lipoproteins are secreted.
Fibrinogen Bellingham: A ?-chain R275C substitution and a ?-promoter polymorphism in a thrombotic member of an asymptomatic family
Authors: M.L. Linenberger, J. Kindelan, R.L. Bennett, A.P. Reiner, H.C.F. C�t�
Journal: American Journal of Hematology (2000)

Congenital dysfibrinogenemia is a rare cause of unexplained thrombosis. However, most individuals with dysfibrinogenemia are asymptomatic, suggesting that co-morbid factors contribute to thrombo-embolic events. The potential roles of additional genetic or acquired prothrombotic risk factors are poorly understood because detailed family studies are lacking. Herein, we describe a family whose propositus was a young Caucasian man with recurrent venous thrombo-emboli and dysfibrinogenemia due to heterozygosity for an Arg→Cys substitution at residue 275 in the γ-chain. The only additional thrombophilic abnormality found in the proband was heterozygosity for a G/A transition at position −455 in the fibrinogen β-chain promoter; a genotype associated with high acute phase levels of fibrinogen. The proband's father, who died of a cerebral artery thrombosis, carried the γR275C substitution but not the β-promoter −455 variant. Among 14 living relatives, eight were heterozygous for one or the other mutation and only one, a 21-year-old niece, was dually affected. None had suffered bleeding or thrombosis. In vitro studies of the proband's purified fibrinogen revealed markedly abnormal thrombin-catalyzed polymerization and delayed fibrin clot lysis by tPA-activated plasmin. We hypothesize that the γR275C substitution predisposes to thrombosis by generating clots that are relatively resistant to fibrinolysis. The clinical risk is low, however, in the absence of an additional thrombophilic mutation. The β-promoter variant could, theoretically, contribute to this risk by augmenting expression of the dysfibrinogen under conditions of stress. Like the common hereditary thrombophilias, heterozygous familial dysfibrinogenemia induces thrombosis in the setting of multiple prothrombotic influences. Am. J. Hematol. 64:242–250, 2000. © 2000 Wiley-Liss, Inc.
Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial
Authors: Siân E Clarke, Matthew CH Jukes, J Kiambo Njagi, Lincoln Khasakhala, Bonnie Cundill, Julius Otido, Christopher Crudder, Benson BA Estambale, Simon Brooker
Journal: The Lancet (2008)
Pathogenesis of Plexiform Neurofibroma: Tumor-Stromal/Hematopoietic Interactions in Tumor Progression
Authors: Karl Staser, Feng-Chun Yang, D. Wade Clapp
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, which include myeloid leukemia, optic glioma, and plexiform neurofibroma. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, nontumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation, accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate neurofibroma tissue, mediate key mitogenic signals that contribute to vascular ingrowth, collagen deposition, and tumor growth. Thus, the plexiform neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system that depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and are clearly relevant to medical management of these neurofibromas.
Ethics and Evidence-Based Medicine: Fallibility and Responsibility in Clinical Science
Authors: N. W Goodman
Journal: Journal of the Royal Society of Medicine (2003)

There can be few better illustrations of why the term ‘evidence-based medicine’ is misleading than the title of Kenneth W Goodman's (no relation) thought-provoking book. The question has been asked many times, but what other sort of medicine is there? Medicine that is intentionally divorced from evidence is unworthy even of ethical consideration. It is the subtitle of the book that is the author's real subject—fallibility and responsibility in clinical science—though even that is wrongly phrased. Had the title been ‘The Ethics of Uncertainty in Clinical Medicine’, I would have started reading with less prejudice.
Increased insulin clearance in peroxisome proliferator-activated receptor γ2 Pro12Ala
Authors: Otto Tschritter, Andreas Fritsche, Norbert Stefan, Michael Haap, Claus Thamer, Oliver Bachmann, Dominik Dahl, Elke Maerker, Anna Teigeler, Fausto Machicao, Hans Häring, Michael Stumvoll
Journal: Metabolism (2003)
Cyclin D1 Overexpression and Response to Bortezomib Treatment in a Breast Cancer Model
Authors: Yuki Ishii, Andreja Pirkmaier, James V. Alvarez, David A. Frank, Inna Keselman, Diomedes Logothetis, John Mandeli, Matthew J. O'Connell, Samuel Waxman, Doris Germain
Journal: JNCI Journal of the National Cancer Institute (2006)

Cyclin D1 is frequently overexpressed in breast cancer, and its overexpression is, surprisingly, associated with improved survival. One potential mechanism for this association involves signal transducer and activator of transcription 3 (STAT3).Cyclin D1 and STAT3 expression were assessed in human tumors using microarray analysis and in breast cancer cell lines HBL100, T47D, MCF7, MDA-MB-453, and BT20 and in HBL100 and T47D cells stably overexpressing cyclin D1 using immunoblot analysis. Cyclin D1 protein was stabilized by treatment with the proteasome inhibitor bortezomib, and the effects on STAT3 expression in vitro was determined by using immunoblotting and on xenograft tumor growth and apoptosis in vivo was determined by using terminal deoxyuridine nick-end labeling assays. All statistical tests were two-sided.Tumors with high cyclin D1 expression (n = 17) had low STAT3 expression (mean = 274 arbitrary units), and those with low cyclin D1 expression (n = 31) had high STAT3 expression (mean = 882 arbitrary units) (P<.001). In HBL100 and T47D parental and cyclin D1-overexpressing cells, cyclin D1 overexpression was also inversely associated with STAT3 expression, and cyclin D1 directly reduced the expression of STAT3. Stabilization of cyclin D1 protein by bortezomib treatment further amplified the cyclin D1-dependent repression of STAT3 in vitro and slowed tumor growth in vivo (week 7: untreated mean = 185.7 mm3 versus treated mean = 136.2 mm3, difference = 49.5 mm3, 95% confidence interval [CI] = 18 to 81 mm3, P = .007; week 8: untreated mean = 240.2 mm3 versus treated mean = 157.3 mm3, difference = 82.9 mm3, 95% CI = 9.1 to 156.7 mm3, P = .0014; and week 9: untreated mean = 256.4 mm3 versus treated mean = 170.2 mm3, difference = 86.2 mm3, 95% CI = 22.8 to 149.6 mm3, P = .006) and increased apoptosis (untreated mean = 19% versus treated mean = 54%, difference = 35%, 95% CI = 24.7% to 45.4%; P = .013) of xenograft tumors.Cyclin D1 repression of STAT3 expression may explain the association between cyclin D1 overexpression and improved outcome in breast cancer. In addition, bortezomib can amplify the proapoptotic function of cyclin D1, raising the possibility that cyclin D1 levels may be a marker for predicting the response to this novel drug.
Bevacizumab is equally effective and no more toxic in elderly patients with advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised controlled trial of Capecitabine, Bevacizumab and Mitomycin C
Authors: T.J. Price, D. Zannino, K. Wilson, R.J. Simes, J. Cassidy, G.A. Van Hazel, B.A. Robinson, A. Broad, V. Ganju, S.P. Ackland, N.C. Tebbutt
Journal: Annals of Oncology (2011)
Comparative Genome Analysis Identifies the Vitamin D Receptor Gene as a Direct Target of p53-Mediated Transcriptional Activation
Authors: Reo Maruyama, Fumio Aoki, Minoru Toyota, Yasushi Sasaki, Hirofumi Akashi, Hiroaki Mita, Hiromu Suzuki, Kimishige Akino, Mutsumi Ohe-Toyota, Yumiko Maruyama, Haruyuki Tatsumi, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino
Journal: Cancer Research (2006)

p53 is the most frequently mutated tumor suppressor gene in human neoplasia and encodes a transcriptional coactivator. Identification of p53 target genes is therefore key to understanding the role of p53 in tumorigenesis. To identify novel p53 target genes, we first used a comparative genomics approach to identify p53 binding sequences conserved in the human and mouse genome. We hypothesized that potential p53 binding sequences that are conserved are more likely to be functional. Using stringent filtering procedures, 32 genes were newly identified as putative p53 targets, and their responsiveness to p53 in human cancer cells was confirmed by reverse transcription-PCR and real-time PCR. Among them, we focused on the vitamin D receptor (VDR) gene because vitamin D3 has recently been used for chemoprevention of human tumors. VDR is induced by p53 as well as several other p53 family members, and analysis of chromatin immunoprecipitation showed that p53 protein binds to conserved intronic sequences of the VDR gene in vivo. Introduction of VDR into cells resulted in induction of several genes known to be p53 targets and suppression of colorectal cancer cell growth. In addition, p53 induced VDR target genes in a vitamin D3-dependent manner. Our in silico approach is a powerful method for identification of functional p53 binding sites and p53 target genes that are conserved among humans and other organisms and for further understanding the function of p53 in tumorigenesis.
Immunoglobulin switch μ sequence causes RNA polymerase II accumulation and reduces dA hypermutation
Authors: Deepa Rajagopal, Robert W. Maul, Amalendu Ghosh, Tirtha Chakraborty, Ahmed Amine Khamlichi, Ranjan Sen, Patricia J. Gearhart
Journal: The Journal of Experimental Medicine (2009)

Repetitive DNA sequences in the immunoglobulin switch μ region form RNA-containing secondary structures and undergo hypermutation by activation-induced deaminase (AID). To examine how DNA structure affects transcription and hypermutation, we mapped the position of RNA polymerase II molecules and mutations across a 5-kb region spanning the intronic enhancer to the constant μ gene. For RNA polymerase II, the distribution was determined by nuclear run-on and chromatin immunoprecipitation assays in B cells from uracil-DNA glycosylase (UNG)–deficient mice stimulated ex vivo. RNA polymerases were found at a high density in DNA flanking both sides of a 1-kb repetitive sequence that forms the core of the switch region. The pileup of polymerases was similar in unstimulated and stimulated cells from Ung−/− and Aid−/−Ung−/− mice but was absent in cells from mice with a deletion of the switch region. For mutations, DNA was sequenced from Ung−/− B cells stimulated in vivo. Surprisingly, mutations of A nucleotides, which are incorporated by DNA polymerase η, decreased 10-fold before the repetitive sequence, suggesting that the polymerase was less active in this region. We propose that altered DNA structure in the switch region pauses RNA polymerase II and limits access of DNA polymerase η during hypermutation.
Effects of Lowering LDL Cholesterol on Progression of Kidney Disease
Authors: Richard Haynes, David Lewis, Jonathan Emberson, Christina Reith, Lawrence Agodoa, Alan Cass, Jonathan C. Craig, Dick de Zeeuw, Bo Feldt-Rasmussen, Bengt Fellström, Adeera Levin, David C. Wheeler, Rob Walker, William G. Herrington, Colin Baigent, Martin J. Landray, Colin Baigent, Martin J. Landray, Christina Reith, Jonathan Emberson, David C. Wheeler, Charles Tomson, Christoph Wanner, Vera Krane, Alan Cass, Jonathan Craig, Bruce Neal, Lixin Jiang, Lai Seong Hooi, Adeera Levin, Lawrence Agodoa, Mike Gaziano, Bertram Kasiske, Rob Walker, Ziad A. Massy, Bo Feldt-Rasmussen, Udom Krairittichai, Vuddidhej Ophascharoensuk, Bengt Fellström, Hallvard Holdaas, Vladimir Tesar, Andrzej Wiecek, Diederick Grobbee, Dick de Zeeuw, Carola Grönhagen-Riska, Tanaji Dasgupta, David Lewis, Will Herrington, Marion Mafham, William Majoni, Karl Wallendszus, Richard Grimm, Terje Pedersen, Jonathan Tobert, Jane Armitage, Alex Baxter, Christopher Bray, Yiping Chen, Zhengming Chen, Michael Hill, Carol Knott, Sarah Parish, David Simpson, Peter Sleight, Alan Young, Rory Collins
Journal: Journal of the American Society of Nephrology (2014)

Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.
Preparedness, phobias, and the Panglossian paradigm
Authors: Richard J. McNally
Journal: Behavioral and Brain Sciences (1995)

Abstract In his critique of preparedness theory, Davey does not address the limitations of adaptationism. The purpose of this commentary is to outline problems that arise when one assumes that mental illness (e.g., phobic disorder) must have had adaptive significance for it to have survived the vicissitudes of natural selection.
A TATA binding protein regulatory network that governs transcription complex assembly
Authors: Kathryn L Huisinga, B Franklin Pugh
Journal: Genome biology (2007)

Abstract Background Eukaryotic genes are controlled by proteins that assemble stepwise into a transcription complex. How the individual biochemically defined assembly steps are coordinated and applied throughout a genome is largely unknown. Here, we model and experimentally test a portion of the assembly process involving the regulation of the TATA binding protein (TBP) throughout the yeast genome. Results Biochemical knowledge was used to formulate a series of coupled TBP regulatory reactions involving TFIID, SAGA, NC2, Mot1, and promoter DNA. The reactions were then linked to basic segments of the transcription cycle and modeled computationally. A single framework was employed, allowing the contribution of specific steps to vary from gene to gene. Promoter binding and transcriptional output were measured genome-wide using ChIP-chip and expression microarray assays. Mutagenesis was used to test the framework by shutting down specific parts of the network. Conclusion The model accounts for the regulation of TBP at most transcriptionally active promoters and provides a conceptual tool for interpreting genome-wide data sets. The findings further demonstrate the interconnections of TBP regulation on a genome-wide scale.
Influence of <b> <i>Helicobacter pylori</i> </b> Infection During Atherogenesis In Vivo in Mice
Authors: François Mach, Galina K. Sukhova, Murielle Michetti, Peter Libby, Pierre Michetti
Journal: Circulation Research (2002)

Inflammatory diseases may have a role in the pathogenesis of atherosclerosis. Several epidemiological and clinical studies have explored the possible association between Helicobacter pylori seropositivity, cardiovascular risk factors, and ischemic heart disease. The contradictory results of these studies have fueled a debate regarding the link between H pylori infection and atherogenesis. This study tested the hypothesis that H pylori infection might influence atherosclerosis in vivo in mice. Male wild-type C57/Bl6 mice and LDL-receptor deficient congenic mice were randomly assigned for infection with H pylori . All animals were fed a high-cholesterol diet (1.25%) for 6 or 12 weeks. At autopsy, we compared aortic atherosclerotic lesion formation and lipid deposition. H pylori infection influenced neither the progression of atherosclerotic lesions nor lipid deposition. Moreover, the cellularity of atherosclerotic lesions (macrophages and T cells) did not differ between mice infected or not infected with H pylori . This in vivo study performed in a mouse model of atherosclerosis revealed no indication that H pylori infection might contribute to the development of atherosclerotic lesion formation. The full text of this article is available at http://www.circresaha.org.
Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells
Authors: Christoph Sauvant, Hildegard Holzinger, Michael Gekle
Journal: Journal of the American Society of Nephrology (2002)

<h3>Abstract</h3> <h3>Objectives</h3> Mental illness stigma is a barrier to engagement in mental health services. This study assesses our hypothesis that specific racial identity dimensions influences mental health behavior including stigma. <h3>Methods</h3> We performed an online cross sectional observational study among Black adults (n = 248, ages 18-65). We examined the relationship between an individual’s approach to their racial identity in the community and stigma behavior towards mental health; generalized linear models were performed. We assessed demographic characteristics as moderators of the primary association. <h3>Results</h3> Black adults with higher centrality reported lower past stigma behavior (RR=1.57, CI: 1.11–2.21, p=0.01), but higher future intended stigma behavior (RR=0.93, CI: 0.88–0.99, p=0.02). Majority of respondents reported high centrality and high assimilation; however, assimilation did not appear to correlate with mental health stigma behavior. Age, education and ethnicity appeared to have a limited moderating effect on the association between centrality and stigma behavior. <h3>Conclusions</h3> Centrality was associated with mental health stigma behavior. By understanding the intersecting characteristics that may increase the likelihood for mental illness stigma, we will be better able to reduce mental illness stigma and optimize engagement in mental health services.
Sodium in soluble paracetamol may be linked to raised blood pressure
Authors: Lucy Douglas, Mohammed Akil
Journal: BMJ (2006)

<h3>Abstract</h3> Plant genomes encode a complex and evolutionary diverse regulatory grammar that forms the basis for most life on earth. A wealth of regulome and epigenome data have been generated in various plant species, but no common, standardized resource is available so far for biologists. Here we present ChIP-Hub, an integrative web-based platform in the ENCODE standards that bundles publicly available datasets reanalyzed from &gt;40 plant species, allowing visualization and meta-analysis.