tbuckley/cabot-search huggingface dataset:
Comparative genomics reveals multistep pathogenesis of E2A-PBX1 acute lymphoblastic leukemia
Authors: Jesús Duque-Afonso, Jue Feng, Florian Scherer, Chiou-Hong Lin, Stephen H.K. Wong, Zhong Wang, Masayuki Iwasaki, Michael L. Cleary
Journal: Journal of Clinical Investigation (2015)

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer; however, its genetic diversity limits investigation into the molecular pathogenesis of disease and development of therapeutic strategies. Here, we engineered mice that conditionally express the E2A-PBX1 fusion oncogene, which results from chromosomal translocation t(1;19) and is present in 5% to 7% of pediatric ALL cases. The incidence of leukemia in these mice varied from 5% to 50%, dependent on the Cre-driving promoter (Cd19, Mb1, or Mx1) used to induce E2A-PBX1 expression. Two distinct but highly similar subtypes of B cell precursor ALLs that differed by their pre-B cell receptor (pre-BCR) status were induced and displayed maturation arrest at the pro-B/large pre-B II stages of differentiation, similar to human E2A-PBX1 ALL. Somatic activation of E2A-PBX1 in B cell progenitors enhanced self-renewal and led to acquisition of multiple secondary genomic aberrations, including prominent spontaneous loss of Pax5. In preleukemic mice, conditional Pax5 deletion cooperated with E2A-PBX1 to expand progenitor B cell subpopulations, increasing penetrance and shortening leukemia latency. Recurrent secondary activating mutations were detected in key signaling pathways, most notably JAK/STAT, that leukemia cells require for proliferation. These data support conditional E2A-PBX1 mice as a model of human ALL and suggest targeting pre-BCR signaling and JAK kinases as potential therapeutic strategies.
Data quality in predictive toxicology: identification of chemical structures and calculation of chemical properties.
Authors: C Helma, S Kramer, B Pfahringer, E Gottmann
Journal: Environmental Health Perspectives (2000)

Every technique for toxicity prediction and for the detection of structure-activity relationships relies on the accurate estimation and representation of chemical and toxicologic properties. In this paper we discuss the potential sources of errors associated with the identification of compounds, the representation of their structures, and the calculation of chemical descriptors. It is based on a case study where machine learning techniques were applied to data from noncongeneric compounds and a complex toxicologic end point (carcinogenicity). We propose methods applicable to the routine quality control of large chemical datasets, but our main intention is to raise awareness about this topic and to open a discussion about quality assurance in predictive toxicology. The accuracy and reproducibility of toxicity data will be reported in another paper.
HLA-B60 and the HLA-B27/HLA-B60 genotype are not risk factors for acute anterior uveitis
Authors: Floris A van Gaalen, Willem Verduijn, Dave L Roelen, Tom W J Huizinga, Désiree van der Heijde, René E M Toes
Journal: Annals of the Rheumatic Diseases (2013)

Ankylosing spondylitis (AS) is the prototypical example of an human leukocyte antigen (HLA) -B27-associated rheumatic disease. Recently, we confirmed that HLA-B60 is also genetic risk factor for AS (OR in meta-analysis 2.2; 95% CI 1.8 to 2.8).1 

Moreover, while 18% of AS patients had both HLA-B27 and HLA-B60, this combination of two HLA-alleles in one person (HLA-B27/HLA-B60) was very rare in blood donors (0.4%). As a result, individuals with the HLA-B27/HLA-B60 genotype are at a very high risk of developing AS.1 Acute anterior uveitis (AAU) may complicate AS but is also an HLA-B27-associated disease in itself.2 Given that AAU share clinical and genetic features with AS, we investigated if HLA-B60 is a risk factor for AAU.

Patients were found by retrospective review of …
Regulation of tumor necrosis factor receptor-1 and the IKK-NF-κB pathway by LDL receptor–related protein explains the antiinflammatory activity of this receptor
Authors: Alban Gaultier, Sanja Arandjelovic, Sherry Niessen, Cheryl D. Overton, MacRae F. Linton, Sergio Fazio, W. Marie Campana, Benjamin F. Cravatt, Steven L. Gonias
Journal: Blood (2008)
Body Build and Risk of Cardiovascular Events in Hypertension and Left Ventricular Hypertrophy
Authors: Giovanni de Simone, Kristian Wachtell, Vittorio Palmieri, Darcy A. Hille, Gareth Beevers, Björn Dahlöf, Ulf de Faire, Frej Fyhrquist, Hans Ibsen, Stevo Julius, Sverre E. Kjeldsen, Ole Lederballe-Pedersen, Lars H. Lindholm, Markku S. Nieminen, Per Omvik, Suzanne Oparil, Richard B. Devereux
Journal: Circulation (2005)

Background— Obesity may independently increase the risk of adverse events in hypertension with target-organ damage. We investigated whether body build was independently associated with higher cardiovascular risk and whether treatment with losartan relative to atenolol influenced the impact of body build on the primary composite end point of cardiovascular death, stroke, and myocardial infarction and on cardiovascular death in patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Methods and Results— The population of 9079 patients was divided as follows: thin (body mass index [BMI] &lt;20 kg/m 2 , 2%), normal weight (BMI 20 to 24.9, 24%), overweight (BMI 25 to 29.9, 45%), and obese (class I: BMI 30 to 34.9, 21%; class II: BMI 35 to 39.9, 6%; class III: BMI ≥40, 2%). Incident diabetes increased progressively with BMI and was somewhat higher in the atenolol arm. Differences in gender and race were detected among the body build groups. Rates (Cox proportional hazard analysis) of the primary composite end point did not differ among body build groups after adjustment for age, gender, race, smoking habit, prevalent cardiovascular disease, and left ventricular hypertrophy. Cardiovascular death was more frequent among thin ( P &lt;0.05) and pooled class II-III obesity (both P &lt;0.04) than normal-weight groups. Risk was not attenuated significantly by losartan treatment, nor did it interfere with the greater benefit of losartan- as opposed to atenolol-based treatment. Conclusions— In the LIFE study, stratification for classes of body build identified increased risk of cardiovascular mortality in both thin and moderately-to-severely obese individuals. This risk was not attenuated significantly by losartan treatment, nor did it interfere with the greater benefit of losartan-based treatment as opposed to atenolol-based treatment.
INHERITED DELETION AT DUCHENNE DYSTROPHY LOCUS IN NORMAL MALE
Authors: R.J Bartlett, A.P Walker, N.G Laing, J Koh, S.L Secore, M.A Pericak-Vance, L.H Yamaoka, R Kandt, M.C Speer, W.-Y Hung, T Siddique, A.D Roses
Journal: The Lancet (1989)
The Cost-Effectiveness of Continuous Glucose Monitoring in Type 1 Diabetes
Authors: Elbert S. Huang, Michael O'Grady, Anirban Basu, Aaron Winn, Priya John, Joyce Lee, David Meltzer, Craig Kollman, Lori Laffel, William Tamborlane, Stuart Weinzimer, Tim Wysocki
Journal: Diabetes Care (2010)

OBJECTIVE Continuous glucose monitoring (CGM) has been found to improve glucose control in type 1 diabetic patients. We estimated the cost-effectiveness of CGM versus standard glucose monitoring in type 1 diabetes. RESEARCH DESIGN AND METHODS This societal cost-effectiveness analysis (CEA) was conducted in trial populations in which CGM has produced a significant glycemic benefit (A1C ≥7.0% in a cohort of adults aged ≥25 years and A1C &amp;lt;7.0% in a cohort of all ages). Trial data were integrated into a simulation model of type 1 diabetes complications. The main outcome was the cost per quality-adjusted life-year (QALY) gained. RESULTS During the trials, CGM patients experienced an immediate quality-of-life benefit (A1C ≥7.0% cohort: 0.70 quality-adjusted life-weeks [QALWs], P = 0.49; A1C &amp;lt;7.0% cohort: 1.39 QALWs, P = 0.04) and improved glucose control. In the long-term, CEA for the A1C ≥7.0% cohort, CGM was projected to reduce the lifetime probability of microvascular complications; the average gain in QALYs was 0.60. The incremental cost-effectiveness ratio (ICER) was $98,679/QALY (95% CI −60,000 [fourth quadrant] to −87,000 [second quadrant]). For the A1C &amp;lt;7.0% cohort, the average gain in QALYs was 1.11. The ICER was $78,943/QALY (15,000 [first quadrant] to −291,000 [second quadrant]). If the benefit of CGM had been limited to the long-term effects of improved glucose control, the ICER would exceed $700,000/QALY. If test strip use had been two per day with CGM long term the ICER for CGM would improve significantly. CONCLUSIONS Long-term projections indicate that CGM is cost-effective among type 1 diabetic patients at the $100,000/QALY threshold, although considerable uncertainty surrounds these estimates.
Mechanism of intestinal secretion. Effect of serotonin on rabbit ileal crypt and villus cells.
Authors: U Sundaram, R G Knickelbein, J W Dobbins
Journal: Journal of Clinical Investigation (1991)

To determine the mechanism of action of an intestinal secretagogue, serotonin, we have isolated crypt and villus cells and demonstrated Na:H and Cl:HCO3 exchange activity using the intracellular pH-sensitive fluorescent dye, 2,7-bis (carboxy-ethyl)-5,6-carboxy-fluorescein. Serotonin alkalinized both crypt and villus cells. Alkalinization in villus cells was HCO3 dependent and Na independent. In contrast, alkalinization in crypt cells was HCO3 independent and Na dependent. In villus cells, recovery from an alkaline load induced by Cl removal, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid or propionate pulse, known to occur via the Cl:HCO3 exchange, is inhibited by serotonin. In contrast, in crypt cells, recovery from an acid load induced by Na removal, amiloride and NH4Cl pulse, known to occur via Na:H exchange, is stimulated by serotonin. These data suggest that serotonin is inhibiting Cl:HCO3 exchange in villus cells and stimulating Na:H exchange in crypt cells. These effects of serotonin would be expected to inhibit coupled Na and Cl absorption by villus cells and stimulate HCO3 secretion by crypt cells in the intact ileum.
Intracellular cytokine repertoire in different T cell subsets from patients with sarcoidosis
Authors: M Mollers
Journal: Thorax (2001)

Pulmonary sarcoidosis is characterised by a mononuclear alveolitis with a predominance of CD4+ T cells and macrophages. We determined the intracellular expression of interferon (IFN)gamma, interleukin (IL)-2, tumour necrosis factor (TNF)alpha, IL-4, IL-5 and IL-10 in CD4+ and CD8+, naive and memory lymphocytes from blood and bronchoalveolar lavage (BAL) fluid using three colour flow cytometry.Eighteen untreated patients with pulmonary sarcoidosis were evaluated and stratified according to whether they had acute or chronic disease.Significantly more T cells expressed Th1 than Th2 type cytokines in both BAL fluid and peripheral blood samples, regardless of clinical presentation. Significantly greater proportions of T cells secreted Th1 type cytokines in BAL fluid than in peripheral blood. Th1 type cytokines were more frequently expressed by peripheral and alveolar T cells in acute disease than in chronic disease. There were no significant differences between CD4+ and CD8+ T cells. Concerning naive and memory lymphocytes, significantly higher CD45RO:CD45RA ratios were found in BAL fluid than in blood, and increased expression of Th2 type cytokines was found in peripheral compared with alveolar memory T cells.Our data support the immunopathogenetic concept of Th1/Th2 imbalance and compartmentalisation in pulmonary sarcoidosis and suggest that the cytokine patterns change during the course of disease. Expression of Th2 type cytokines in memory lymphocytes is decreased in the alveolar compartment compared with peripheral blood.
Fatty Acid Supply to the Human Fetus
Authors: Paul Haggarty
Journal: Annual Review of Nutrition (2010)

Deposition of fat in the fetus increases exponentially with gestational age, reaching its maximal rate—around 7 g/day or 90% of energy deposition—at term. In late pregnancy, many women consuming contemporary Western diets may not be able to meet the fetal demand for n-3 long chain polyunsaturated fatty acids (LCPUFAs) from the diet alone. Numerous mechanisms have evolved to protect human offspring from extreme variation or deficiency in the maternal diet during pregnancy. Maternal adipose tissue is an important source of LCPUFA. Temporal changes in placental function are synchronized with maternal metabolic and physiological changes to ensure a continuous supply of n-3 and n-6 LCPUFA-enriched fat to the fetus. LCPUFA storage in fetal adipose tissue provides an important source of LCPUFA during the critical first months of postnatal life. An appreciation of these adaptations is important in any nutritional strategy designed to improve the availability of fatty acids to the fetus.
Cold urticaria with persistent weals
Authors: LENNART JUHLIN
Journal: British Journal of Dermatology (1981)

A patient with cold urticaria is described in whom weals appeared immediately after an ice cube test for 3 min and persisted for a week as a red, tender swelling. The duration of the oedema was dependent on the intensity of the immediate reaction. If the immediate wealing was blocked by treatment with an oral antihistamine 3 h before the ice cube test, no delayed reaction was seen. Antihistamines given after the immediate wealing had occurred did not influence the delayed reaction. Reactions to intradermally injected histamine, prostaglandin E, kallikrein, serotonin and serum appeared normal.
CagA mediates epigenetic regulation to attenuate let-7 expression in<i>Helicobacter pylori</i>-related carcinogenesis
Authors: Yoshito Hayashi, Masahiko Tsujii, Jun Wang, Jumpei Kondo, Tomofumi Akasaka, Ying Jin, Wei Li, Toru Nakamura, Tsutomu Nishida, Hideki Iijima, Shingo Tsuji, Sunao Kawano, Norio Hayashi, Tetsuo Takehara
Journal: Gut (2012)

<h3>Objective</h3> MicroRNAs (miRNAs) act as tumour suppressor genes or oncogenes in the regulation of multiple carcinogenic processes. Aberrant miRNA expression is reported in <i>Helicobacter pylori</i> (<i>H pylori</i>)-related gastritis and gastric cancer. The cytotoxin-associated gene A (CagA) of <i>H pylori</i> has a pathophysiologically important role in gastric carcinogenesis. A study was undertaken to evaluate the effect of CagA on miRNA expression and its regulatory mechanism. <h3>Methods</h3> The effect of CagA on miRNA expression was assessed by comprehensive miRNA microarray. The mechanisms of the in vitro and in vivo effects of CagA on histone modification and DNA methylation and the involvement of CagA-dysregulated signal transduction on let-7, an important representative miRNA in gastric carcinogenesis, were investigated. <h3>Results</h3> In in vitro experiments, CagA significantly attenuated let-7 expression leading to Ras pathway activation. CagA enhanced c-myc, DNA methyltransferase 3B (DNMT3B) and Enhancer of Zeste homologue 2 (EZH2) expression and attenuated miR-26a and miR-101 expression, which resulted in the attenuation of let-7 expression by histone and DNA methylation. Experiments performed in CagA transgenic mice revealed that c-myc, EZH2 and DNMT3B expression were enhanced and let-7 expression was attenuated to induce Ras oncoprotein expression in the stomach, with no associated inflammation. <h3>Conclusions</h3> <i>H pylori</i> CagA induces aberrant epigenetic silencing of let-7 expression, leading to Ras upregulation.
Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL)
Authors: Asher Chanan-Khan, Kena C. Miller, Kenichi Takeshita, Alexandra Koryzna, Kathleen Donohue, Zale P. Bernstein, Alice Mohr, Donald Klippenstein, Paul Wallace, Jerome B. Zeldis, Christine Berger, Myron S. Czuczman
Journal: Blood (2005)
Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease
Authors: Noriyoshi Kurihara, Yuko Hiruma, Hua Zhou, Mark A. Subler, David W. Dempster, Frederick R. Singer, Sakamuri V. Reddy, Helen E. Gruber, Jolene J. Windle, G. David Roodman
Journal: Journal of Clinical Investigation (2006)

Paget disease is the most exaggerated example of abnormal bone remodeling, with the primary cellular abnormality in the osteoclast. Mutations in the p62 (sequestosome 1) gene occur in one-third of patients with familial Paget disease and in a minority of patients with sporadic Paget disease, with the P392L amino acid substitution being the most commonly observed mutation. However, it is unknown how p62(P392L) mutation contributes to the development of this disease. To determine the effects of p62(P392L) expression on osteoclasts in vitro and in vivo, we introduced either the p62(P392L) or WT p62 gene into normal osteoclast precursors and targeted p62(P392L) expression to the osteoclast lineage in transgenic mice. p62(P392L)-transduced osteoclast precursors were hyperresponsive to receptor activator of NF-kappaB ligand (RANKL) and TNF-alpha and showed increased NF-kappaB signaling but did not demonstrate increased 1,25-(OH)(2)D(3) responsivity, TAF(II)-17 expression, or nuclear number per osteoclast. Mice expressing p62(P392L) developed increased osteoclast numbers and progressive bone loss, but osteoblast numbers were not coordinately increased, as is seen in Paget disease. These results indicate that p62(P392L) expression on osteoclasts is not sufficient to induce the full pagetic phenotype but suggest that p62 mutations cause a predisposition to the development of Paget disease by increasing the sensitivity of osteoclast precursors to osteoclastogenic cytokines.
Many US parents have poor understanding of proper antibiotic use, study finds
Authors: Michael McCarthy
Journal: BMJ (2015)

Despite recent efforts to educate the public about the proper use of antibiotics many parents of young children continue to have a poor understanding of when they are indicated and when they are not, a new US study has shown—particularly parents whose children are covered by Medicaid, the US health insurance plan for people with low incomes.

In the study Louise Elaine Vaz, lead author, from Oregon Health and Science University in Portland, Oregon, and colleagues surveyed 707 parents with a child under the …
Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice
Authors: Wei Zhong, Wenliang Zhang, Qiong Li, Guoxiang Xie, Qian Sun, Xiuhua Sun, Xiaobing Tan, Xinguo Sun, Wei Jia, Zhanxiang Zhou
Journal: Journal of Hepatology (2014)
Regulation of parasite-induced eosinophilia: selectively increased interleukin 5 production in helminth-infected patients.
Authors: A P Limaye, J S Abrams, J E Silver, E A Ottesen, T B Nutman
Journal: The Journal of Experimental Medicine (1990)

Production of the eosinophilogenic cytokines interleukin 3 (IL-3), granulocyte/macrophage colony-stimulating factor (GM-CSF), and IL-5 by mitogen-stimulated peripheral blood mononuclear cells was compared between 11 noneosinophilic individuals and seven patients with helminth-induced eosinophilia. Both the kinetics and quantities of IL-3 and GM-CSF were similar in the two groups. In contrast, IL-5 production at both the protein and the mRNA level was markedly greater in the eosinophilic patients, an observation suggesting that IL-5 may be particularly important in mediating the selective eosinophilia seen in filarial and other helminth infections.
Targeted Killing of Virally Infected Cells by Radiolabeled Antibodies to Viral Proteins
Authors: Ekaterina Dadachova, Mahesh C Patel, Sima Toussi, Christos Apostolidis, Alfred Morgenstern, Martin W Brechbiel, Miroslaw K Gorny, Susan Zolla-Pazner, Arturo Casadevall, Harris Goldstein
Journal: PLoS Medicine (2006)

Background The HIV epidemic is a major threat to health in the developing and western worlds. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells. The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo. Methods and Findings Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 (213Bi) and rhenium 188 (188Re) selectively killed chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMCs) in vitro. Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected hPBMCs in their spleens with a 213Bi- or 188Re-labeled monoclonal antibody (mAb) to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner. The number of HIV-1-infected thymocytes decreased 2.5-fold in the human thymic implant grafts of SCID mice treated with the 188Re-labeled antibody to gp41 compared with those treated with the 188Re-control mAb. The treatment did not cause acute hematologic toxicity in the treated mice. Conclusions The current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV.
Patients With Malignancy Requiring Urgent Therapy
Authors: Taiji Yokote, Toshikazu Akioka, Satoshi Hara, Satoko Oka, Hiroyuki Miyamoto, Takeshi Yamano, Masakazu Sugino, Motomu Tsuji, Toshiaki Hanafusa
Journal: Journal of Clinical Oncology (2005)
Corticosteroids for severe alcoholic hepatitis: what constitutes response?
Authors: R. Hamid, H. Lafferty, E. Watson, J. Winter, A. J. Morris, A. J. Stanley, E. H. Forrest
Journal: Gut (2011)

<h3>Introduction</h3> Severe alcoholic hepatitis (AH) is associated with high short term mortality. Although still attracting some controversy, many hospitals will treat severe AH with corticosteroids (CS). Early identification of patients not responding to CS treatment is crucial as continuing treatment may be associated with side-effects and be considered futile. More importantly, identification of CS non-responders (NR) is essential as alternative therapies may be considered to improve their poor survival prognosis. The aim of the present study was to compare three previously published markers of CS response: Early Change in Bilirubin (ECBL); 25% fall in bilirubin from baseline (25%↓B); and the Lille Score. <h3>Methods</h3> 83 patients with severe AH (Glasgow Alcoholic Hepatitis Score ≥9) treated with CS between 2004 and 2009 were analysed. Unit protocol was for discontinuation of CS treatment if there was not a 25%↓B, however some patients continued CS treatment at the discretion of the responsible consultant. ECBL, 25%↓B, and Lille Scores were calculated and outcome evaluated at day 28 and 84. Prognostic utility of the various scores was determined by generating a receiver operating characteristic curve (ROC) and assessed by comparison of area under ROC curves (AUROC). <h3>Results</h3> Overall 28 and 84 day mortalities were 24% and 37% respectively. The AUROCs (95% CI) for each indicator of CS response are shown in table 1. For those patients who continued CS treatment irrespective of response, a 25%↓B to identify poor outcome at 28 days had a sensitivity of 78% and a specificity of 76%. The equivalent Lille Score cut off point of 0.45 had a sensitivity of 88% and a specificity of 69%. An ECBL had a sensitivity of 33% and a specificity of 96% (figure 1). The 28 and 84 day mortalities for NR were as follows: ECBL NR (n=20) 55%, 80%; 25%↓B NR (n=44) 41%, 54%; Lille NR (n=47) 40%, 55%. <h3>Conclusion</h3> Response to CS treatment is an important marker of prognosis in severe AH. Although the Lille Score has a slightly greater AUROC for outcome after CS treatment, this was not statistically significant. A 25%↓B retains reasonable sensitivity and specificity and is certainly easier to calculate than the Lille Score, making it a simple and practical marker in determining CS response in AH.