tbuckley/cabot-search huggingface dataset:
Common Defects of ABCG2, a High-Capacity Urate Exporter, Cause Gout: A Function-Based Genetic Analysis in a Japanese Population
Authors: Hirotaka Matsuo, Tappei Takada, Kimiyoshi Ichida, Takahiro Nakamura, Akiyoshi Nakayama, Yuki Ikebuchi, Kousei Ito, Yasuyoshi Kusanagi, Toshinori Chiba, Shin Tadokoro, Yuzo Takada, Yuji Oikawa, Hiroki Inoue, Koji Suzuki, Rieko Okada, Junichiro Nishiyama, Hideharu Domoto, Satoru Watanabe, Masanori Fujita, Yuji Morimoto, Mariko Naito, Kazuko Nishio, Asahi Hishida, Kenji Wakai, Yatami Asai, Kazuki Niwa, Keiko Kamakura, Shigeaki Nonoyama, Yutaka Sakurai, Tatsuo Hosoya, Yoshikatsu Kanai, Hiroshi Suzuki, Nobuyuki Hamajima, Nariyoshi Shinomiya
Journal: Science Translational Medicine (2009)

Gout based on hyperuricemia is a common disease with a genetic predisposition, which causes acute arthritis. The ABCG2/BCRP gene, located in a gout-susceptibility locus on chromosome 4q, has been identified by recent genome-wide association studies of serum uric acid concentrations and gout. Urate transport assays demonstrated that ABCG2 is a high-capacity urate secretion transporter. Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Quantitative trait locus analysis of 739 individuals showed that a common dysfunctional variant of ABCG2, Q141K, increases serum uric acid. Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Furthermore, 10% of gout patients (16 out of 159 cases) had genotype combinations resulting in more than 75% reduction of ABCG2 function (odds ratio, 25.8). Our findings indicate that nonfunctional variants of ABCG2 essentially block gut and renal urate excretion and cause gout.
Designing Therapeutic Clinical Trials for Older and Frail Adults With Cancer: U13 Conference Recommendations
Authors: Arti Hurria, William Dale, Margaret Mooney, Julia H. Rowland, Karla V. Ballman, Harvey J. Cohen, Hyman B. Muss, Richard L. Schilsky, Betty Ferrell, Martine Extermann, Kenneth E. Schmader, Supriya G. Mohile
Journal: Journal of Clinical Oncology (2014)

A majority of cancer diagnoses and deaths occur in patients age ≥ 65 years. With the aging of the US population, the number of older adults with cancer will grow. Although the coming wave of older patients with cancer was anticipated in the early 1980s, when the need for more research on the cancer-aging interface was recognized, many knowledge gaps remain when it comes to treating older and/or frailer patients with cancer. Relatively little is known about the best way to balance the risks and benefits of existing cancer therapies in older patients; however, these patients continue to be underrepresented in clinical trials. Furthermore, the available clinical trials often do not include end points pertinent to the older adult population, such as preservation of function, cognition, and independence. As part of its ongoing effort to advance research in the field of geriatric oncology, the Cancer and Aging Research Group held a conference in November 2012 in collaboration with the National Cancer Institute, the National Institute on Aging, and the Alliance for Clinical Trials in Oncology. The goal was to develop recommendations and establish research guidelines for the design and implementation of therapeutic clinical trials for older and/or frail adults. The conference sought to identify knowledge gaps in cancer clinical trials for older adults and propose clinical trial designs to fill these gaps. The ultimate goal of this conference series is to develop research that will lead to evidence-based care for older and/or frail adults with cancer.
Immunosuppression, IBD, and risk of lymphoma
Authors: J R Bebb, G P Aithal, R P H Logan
Journal: Gut (2002)

We read with interest the two recent reports of lymphoma in patients with inflammatory bowel disease (IBD) (Farrell et al , Gut 2000; 47 :514–19 and Palli et al , Gastroenterology 2000; 119 :647–53). We believe the report from Farrell of four cases of lymphoma in a cohort of 782 patients (of whom 238 had received immunosuppression) considerably overestimates the relative risk of lymphoma in IBD patients. They calculate a relative risk of lymphoma as 31 for the whole cohort and 59 …
Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats
Authors: Carla Frau, Roberto Loi, Annalisa Petrelli, Andrea Perra, Silvia Menegon, Marta Anna Kowalik, Silvia Pinna, Vera Piera Leoni, Francesca Fornari, Laura Gramantieri, Giovanna Maria Ledda‐Columbano, Silvia Giordano, Amedeo Columbano
Journal: Hepatology (2014)

Thyroid hormone receptors (TRs) are ligand‐dependent transcription factors that mediate most of the effects elicited by the thyroid hormone, 3,5,3′‐L‐triiodothyronine (T3). TRs have been implicated in tumorigenesis, although it is unclear whether they act as oncogenes or tumor suppressors, and at which stage of tumorigenesis their dysregulation occurs. Using the resistant‐hepatocyte rat model (R‐H model), we found down‐regulation of TRβ1 and TRα1 and their target genes in early preneoplastic lesions and hepatocellular carcinoma (HCCs), suggesting that a hypothyroid status favors the onset and progression of preneoplastic lesions to HCC. Notably, TRβ1 and, to a lesser extent, TRα1 down‐regulation was observed only in preneoplastic lesions positive for the progenitor cell marker, cytokeratin‐19 (Krt‐19) and characterized by a higher proliferative activity, compared to the Krt‐19 negative ones. TRβ1 down‐regulation was observed also in the vast majority of the analyzed human HCCs, compared to the matched peritumorous liver or to normal liver. Hyperthyroidism induced by T3 treatment caused up‐regulation of TRβ1 and of its target genes in Krt‐19 + preneoplastic rat lesions and was associated with nodule regression. In HCC, TRβ1 down‐regulation was not the result of hypermethylation of its promoter, but was associated with an increased expression of TRβ1‐targeting microRNAs ([miR]‐27a, ‐181a, and ‐204). An inverse correlation between TRβ1 and miR‐181a was also found in human cirrhotic peritumoral tissue, compared to normal liver. Conclusion : Down‐regulation of TRs, especially TRβ1, is an early and relevant event in liver cancer development and is species and etiology independent. The results also suggest that a hypothyroid status of preneoplastic lesions may contribute to their progression to HCC and that the reversion of this condition may represent a possible therapeutic goal to interfere with the development of this tumor. (H epatology 2015;61:249–259)
Effect of a specific neutrophil elastase inhibitor, ONO-5046, on endotoxin-induced acute lung injury.
Authors: F Sakamaki, A Ishizaka, T Urano, K Sayama, H Nakamura, T Terashima, Y Waki, S Tasaka, N Hasegawa, K Sato, N Nakagawa, T Obata, M Kanazawa
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Because excessive neutrophil elastase (NE) activity is involved in the pathogenesis of acute lung injury, we speculated that administering anti-NE might prevent lung injury. In a guinea pig model of acute lung injury induced by Escherichia coli endotoxin (lipopolysaccharide [LPS]), we investigated the effect of ONO-5046, a low-molecular-weight and specific inhibitor of NE. ONO-5046 produced concentration-dependent inhibition of guinea pig NE, whereas there were no inhibitory effects on neutrophil chemotaxis or the expression of adhesion molecules in endothelial cells. Detectable NE activity in bronchoalveolar lavage (BAL) fluid was present in the LPS-alone group. No NE activity in BAL fluid was detected in the LPS+ONO-5046 groups. Neutrophil counts in BAL fluid, the lung tissue wet to dry weight ratio, and the lung tissue or BAL fluid to plasma ratio of 125I-albumin were increased in the LPS-alone group as compared with the saline group (p < 0.05). In the LPS+ONO-5046 group, neutrophil counts in BAL fluid, the lung tissue wet to dry weight ratio and BAL fluid to plasma ratio of 125I-albumin were decreased as compared with the LPS-alone group (p < 0.05). These data suggest that ONO-5046 can attenuate LPS-induced acute lung injury.
Dual Inhibition of PI3Kα and mTOR as an Alternative Treatment for Kaposi's Sarcoma
Authors: Risa Chaisuparat, Jiadi Hu, Bruno C. Jham, Zachary A. Knight, Kevan M. Shokat, Silvia Montaner
Journal: Cancer Research (2008)

Abstract Rapamycin (or sirolimus), the prototypical inhibitor of the mammalian target of rapamycin (mTOR) and an immunosuppressant used for the prevention of renal transplant rejection, has recently emerged as an effective treatment for Kaposi's sarcoma (KS), an enigmatic vascular tumor and a model for pathologic angiogenesis. Indeed, recent work supports a role for mTOR as a central player in the transformation of endothelial cells by the KS-associated herpesvirus–encoded G protein–coupled receptor (vGPCR), the viral oncogene believed to be responsible for causing KS. However, emerging evidence that rapamycin may transiently promote the activation of Akt may limit its use as an anti-KS therapy. Here, we show that activation of Akt in endothelial cells expressing vGPCR is augmented by treatment with rapamycin, resulting in the up-regulation of several Akt proliferative and survival pathways. However, use of a novel dual phosphatidylinositol 3-kinase α (PI3Kα)/mTOR inhibitor, PI-103, effectively and independently blocked activation of both PI3K and mTOR in vGPCR-expressing endothelial cells. This resulted in more effective inhibition of endothelial cell proliferation and survival in vitro and tumor growth in vivo. Our results suggest that PI-103 may be an effective therapeutic option for the treatment of patients with KS. Moreover, as KS may serve as a model for pathologic angiogenesis, our results further provide the basis for the early assessment of PI-103 as an antiangiogenic chemotherapeutic. [Cancer Res 2008;68(20):8361–8]
Prolongation of minimal action potential duration in sustained fibrillation decreases complexity by transient destabilization
Authors: Brian O. Bingen, Saïd F.A. Askar, Martin J. Schalij, Ivan V. Kazbanov, Dirk L. Ypey, Alexander V. Panfilov, Daniël A. Pijnappels
Journal: Cardiovascular Research (2012)

Sustained ventricular fibrillation (VF) is maintained by multiple stable rotors.Destabilization of sustained VF could be beneficial by affecting VF complexity (defined by the number of rotors).However, underlying mechanisms affecting VF stability are poorly understood.Therefore, the aim of this study was to correlate changes in arrhythmia complexity with changes in specific electrophysiological parameters, allowing a search for novel factors and underlying mechanisms affecting stability of sustained VF. Methods and resultsNeonatal rat ventricular cardiomyocyte monolayers and Langendorff-perfused adult rat hearts were exposed to increasing dosages of the gap junctional uncoupler 2-aminoethoxydiphenyl borate (2-APB) to induce arrhythmias.Ion channel blockers/openers were added to study effects on VF stability.Electrophysiological parameters were assessed by optical mapping and patch-clamp techniques.Arrhythmia complexity in cardiomyocyte cultures increased with increasing dosages of 2-APB (n .38), leading to sustained VF: 0.0 + 0.1 phase singularities/cm 2 in controls vs. 0.0 + 0.1, 1.0 + 0.9, 3.3 + 3.2, 11.0 + 10.1, and 54.3 + 21.7 in 5, 10, 15, 20, and 25 mmol/L 2-APB, respectively.Arrhythmia complexity inversely correlated with wavelength.Lengthening of wavelength during fibrillation could only be induced by agents (BaCl 2 /BayK8644) increasing the action potential duration (APD) at maximal activation frequencies (minimal APD); 123 + 32%/117 + 24% of control.Minimal APD prolongation led to transient VF destabilization, shown by critical wavefront collision leading to rotor termination, followed by significant decreases in VF complexity and activation frequency (52%/37%).These key findings were reproduced ex vivo in rat hearts (n ¼ 6 per group). ConclusionThese results show that stability of sustained fibrillation is regulated by minimal APD.Minimal APD prolongation leads to transient destabilization of fibrillation, ultimately decreasing VF complexity, thereby providing novel insights into anti-fibrillatory mechanisms.
Detection of antinuclear antibodies: added value of solid phase assay?
Authors: Xavier Bossuyt, Steffen Fieuws
Journal: Annals of the Rheumatic Diseases (2013)

Agmon-Levin et al 1 formulated recommendations for the assessment of antinuclear antibodies (ANA). Indirect immunofluorescence (IIF) is considered the reference method for ANA screening, which is in agreement with the American College of Rheumatology (ACR) position statement.2 The recommendations are based on current knowledge and expert experience. However, as recognised by Meroni and Schur,2 no well-planned studies comparing the diagnostic accuracy of the old IIF and the new methods have been undertaken.

In a recent study, IIF was compared to a new automated method for connective disease screening (fluoroenzymeimmunoassay (FEIA) (EliA CTD screen, Thermo Fisher)) using samples obtained at the time of diagnosis from well-characterised patients and controls.3 Diagnostic accuracy data (for systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Sjogren's syndrome (SS)) from this study is recapitulated in table 1. …
An Overview of a Psychiatric Clinic Population
Authors: PETER E. SIFNEOS
Journal: American Journal of Psychiatry (1973)

The author describes a set of criteria designed as guidelines in the evaluation of persons who apply for treatment at a psychiatric clinic. The main focus in this paper is on determining which patients are good candidates for short-term anxiety-provoking psychotherapy, but it is hoped that this will lead to the establishment of selection criteria for a variety of therapeutic techniques.
Association of HLA-DQ Genotype in Autoantibody-Negative and Rapid-Onset Type 1 Diabetes
Authors: Shoichiro Tanaka, Tetsuro Kobayashi, Koji Nakanishi, Rikako Koyama, Minoru Okubo, Toshio Murase, Masato Odawara, Hidetoshi Inoko
Journal: Diabetes Care (2002)

OBJECTIVE—Some type 1 diabetic patients have a distinct phenotype characterized by the absence of pancreatic autoantibodies and fulminant clinical symptoms at onset, including marked hyperglycemia, severe diabetic ketoacidosis, and normal to near-normal HbA1c levels with complete destruction of β-cells. However, little is known about genetic factors of this distinct subtype of diabetes (fulminant autoantibody-negative type 1 diabetes). RESEARCH DESIGN AND METHODS—We analyzed HLA-DQ genotypes in fulminant autoantibody-negative type 1 diabetes (n = 22) and autoantibody-positive type 1 diabetes (immune-mediated type 1 diabetes, n = 78) recruited from a cohort between 1980 and 2000. RESULTS—Fulminant autoantibody-negative type 1 diabetes had a significantly high prevalence of the HLA-DQA1*0303-DQB1*0401 haplotype in a homozygous manner (RR 39) or in a heterozygous manner with the HLA-DQA1*0302-DQB1*0303 haplotype (RR 13). In contrast, autoantibody-positive type 1 diabetic patients had a high prevalence of the HLA-DQA1*0302-DQB1*0303 haplotype in a homozygous manner (RR 10) or in a heterozygous manner with the HLA-DQA1*0303-DQB1*0401 haplotype (RR 12). CONCLUSIONS—Pathogenic roles of genotypic combinations of specific HLA-DQ haplotypes in a homozygous manner are suggested as causative mechanisms of aggressive β-cell damage in a subtype of autoantibody-negative type 1 diabetes with fulminant clinical features.
Flow-dependent dilation in a resistance artery still occurs after endothelium removal.
Authors: J A Bevan, E H Joyce, G C Wellman
Journal: Circulation Research (1988)

Infusion of physiological saline solution into the lumen of a tonically contracted resistance artery in vitro caused active relaxation. After endothelium removal by rubbing, confirmed by scanning electron microscopy and loss of the relaxation response to acetylcholine (1 microM), flow relaxation was reduced from a mean of 70% to 37%. The latter change was significant (p less than 0.01). It is concluded that flow-relaxation in the resistance artery of the rabbit originates from both the tunica intima and the media.
Social Contacts and Mixing Patterns Relevant to the Spread of Infectious Diseases
Authors: Joël Mossong, Niel Hens, Mark Jit, Philippe Beutels, Kari Auranen, Rafael Mikolajczyk, Marco Massari, Stefania Salmaso, Gianpaolo Scalia Tomba, Jacco Wallinga, Janneke Heijne, Malgorzata Sadkowska-Todys, Magdalena Rosinska, W. John Edmunds
Journal: PLoS Medicine (2008)

Mathematical modelling of infectious diseases transmitted by the respiratory or close-contact route (e.g., pandemic influenza) is increasingly being used to determine the impact of possible interventions. Although mixing patterns are known to be crucial determinants for model outcome, researchers often rely on a priori contact assumptions with little or no empirical basis. We conducted a population-based prospective survey of mixing patterns in eight European countries using a common paper-diary methodology.7,290 participants recorded characteristics of 97,904 contacts with different individuals during one day, including age, sex, location, duration, frequency, and occurrence of physical contact. We found that mixing patterns and contact characteristics were remarkably similar across different European countries. Contact patterns were highly assortative with age: schoolchildren and young adults in particular tended to mix with people of the same age. Contacts lasting at least one hour or occurring on a daily basis mostly involved physical contact, while short duration and infrequent contacts tended to be nonphysical. Contacts at home, school, or leisure were more likely to be physical than contacts at the workplace or while travelling. Preliminary modelling indicates that 5- to 19-year-olds are expected to suffer the highest incidence during the initial epidemic phase of an emerging infection transmitted through social contacts measured here when the population is completely susceptible.To our knowledge, our study provides the first large-scale quantitative approach to contact patterns relevant for infections transmitted by the respiratory or close-contact route, and the results should lead to improved parameterisation of mathematical models used to design control strategies.
Children in Adult Intensive Therapy Units
Authors: J. R. Harper, G. Varakis
Journal: BMJ (1970)

From experience in the Northampton/Kettering area 9 to 10% of all patients in a general hospital requiring care in an intensive therapy unit were aged 12 years or under. Fifty-nine children were admitted to the intensive therapy unit of Northampton General Hospital between May 1967 and August 1969. Of these, 22 had been injured in road traffic accidents, five were surgical emergencies, five had meningitis, four status epilepticus, and four respiratory infections.All of the 30 families interviewed were in favour of their child being admitted to the unit, and none considered that the experience had had any lasting adverse psychological effect on the child. It is suggested that certain carefully selected child patients do benefit from the facilities of an intensive therapy unit, and for this reason such units must be designed, equipped, and staffed with this in mind.
An Epstein-Barr virus-associated superantigen.
Authors: N Sutkowski, T Palkama, C Ciurli, R P Sekaly, D A Thorley-Lawson, B T Huber
Journal: The Journal of Experimental Medicine (1996)

More than 90% of adults are latently infected with Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, a self-limiting lymphoproliferative disease characterized by extensive T cell activation. Reactivation of this herpesvirus during immunosuppression is often associated with oncogenesis. These considerations led us to analyze the early events that occur after exposure of the immune system to EBV. Strong major histocompatibility complex (MHC) class II-dependent but not MHC-restricted, T cell proliferation was observed in vitro in response to autologous, lytically infected EBV-transformed B cells. By measuring the appearance of the early activation marker CD69 on individual T cell V beta subsets, we could demonstrate selective activation of human V beta 13- T cells. This was confirmed with murine T cell hybridomas expressing various human BV genes. While EBV- Burkitt's lymphoma cells were nonstimulatory, they induced V beta-restricted T cell activation after EBV infection. EBV specific activation was also demonstrated in cord blood cells, excluding a recall-antigen response. Thus, all of the characteristics of a superantigen-stimulated response are seen, indicating that induction of the EBV lytic cycle is associated with the expression of a superantigen in B cells. A model is presented proposing a role for the superantigen in infection, latency, and oncogenesis.
Who Will Deliver Our Grandchildren?
Authors: Alastair MacLennan, Karin B Nelson, Gary Hankins, Michael Speer
Journal: JAMA (2005)

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