tbuckley/cabot-search huggingface dataset:
Novel genes for QTc interval. How much heritability is explained, and how much is left to find?
Authors: Yalda Jamshidi, Ilja M Nolte, Timothy D Spector, Harold Snieder
Journal: Genome Medicine (2010)

The corrected QT (QTc) interval is a complex quantitative trait, believed to be influenced by several genetic and environmental factors. It is a strong prognostic indicator of cardiovascular mortality in patients with and without cardiac disease. More than 700 mutations have been described in 12 genes (LQT1-LQT12) involved in congenital long QT syndrome. However, the heritability (genetic contribution) of QTc interval in the general population cannot be adequately explained by these long QT syndrome genes. In order to further investigate the genetic architecture underlying QTc interval in the general population, genome-wide association studies, in which up to one million single nucleotide polymorphisms are assayed in thousands of individuals, are now being employed and have already led to the discovery of variants in seven novel loci and five loci that are known to cause congenital long or short QT syndrome. Here we show that a combined risk score using 11 of these loci explains about 10% of the heritability of QTc. Additional discovery of both common and rare variants will yield further etiological insight and accelerate clinical applications.
Rearrangement of<i>MYC</i>Is Associated With Poor Prognosis in Patients With Diffuse Large B-Cell Lymphoma Treated in the Era of Rituximab
Authors: Sharon Barrans, Simon Crouch, Alex Smith, Kathryn Turner, Roger Owen, Russell Patmore, Eve Roman, Andrew Jack
Journal: Journal of Clinical Oncology (2010)

Rearrangement of MYC occurs in a proportion of diffuse large B-cell lymphomas (DLBCL), where they may be associated with an adverse clinical outcome. The aim of this study was to determine the frequency of MYC translocations in DLBCL and their prognostic impact in the era of cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (CHOP-R) therapy.Three hundred three patients with previously untreated DLBCL, with no evidence of underlying follicular lymphoma, were investigated using immunohistochemistry and interphase fluorescent in situ hybridization for MYC, BCL6, and t(14;18)/BCL2 rearrangements. All patients (median age, 71.1 years; range, 23 to 96 years) were treated when CHOP-R was standard therapy for DLBCL and observed for a maximum of 4 years. Overall survival (OS) at 3 years was 49% (95% CI, 42% to 56%).MYC rearrangements were demonstrated in 35 (14%) of 245 biopsies with data available. Of these, 26 (74%) also had a t(14;18), 10 (26%) were BCL6 and MYC rearranged, and seven had all three abnormalities. Only age, International Prognostic Index, and MYC rearrangement retained prognostic significance in the final model. OS was significantly worse for patients with rearrangement of MYC (survival probability at 2 years = 0.35 in v 0.61 in the nonrearranged group).The presence of a MYC rearrangement is a strongly adverse prognostic factor in CHOP-R-treated patients and can be used in combination with patients' age and IPI to accurately predict clinical outcome. In DLBCL, rearrangement of MYC is rarely found as the sole genetic abnormality and the poor prognosis of these patients is likely to reflect a synergistic effect alongside deregulation of BCL6 or BCL2.
Enhancement of basophil histamine release by a human basophil-like cell promoting activity
Authors: Y. Morita, K. Hirai, Y. Misaki, T. Takaishi, S. Suzuki, K. Ito, B. M. Stadler, T. Miyamoto
Journal: Allergy (1990)

A basophil-like cell promoting activity (BaPA) is a lymphokine which has the ability to proliferate metachromatically staining cells in human bone marrow. We studied the effect of BaPA on histamine release from human peripheral basophils. BaPA did not directly induce histamine release from basophils. However BaPA ranging from 0.001 to 0.5 U/ml enhanced histamine release from basophils stimulated with anti-IgE, calcium ionophore A23187 or FMLP in a dose-dependent manner. On the basis of recent observations that in addition to their capacity for proliferating progenitor cells, colony-stimulating factors are capable of regulating functions of end-stage cells of the same lineage, this finding that BaPA is able to modulate a basophil function raises the possibility that BaPA also regulates progenitors of basophils.
T Cells Modulate Neutrophil-Dependent Acute Renal Failure during Endotoxemia
Authors: Kai Singbartl, Susanne Große Bockhorn, Alexander Zarbock, Mirco Schmolke, Hugo Van Aken
Journal: Journal of the American Society of Nephrology (2005)

Sepsis still represents a leading cause of acute renal failure (ARF). Both lymphocytes and neutrophils (PMN) have been proposed as crucial mediators during sepsis. For further elucidation of the mechanisms of interactions between them, a murine model of LPS-induced ARF was used. In wild-type mice (WT), LPS administration led to a strong influx of PMN into the kidney (2.8-fold greater renal myeloperoxidase activity after 24 h) and to severe ARF (3.3-fold higher plasma creatinine concentrations after 24 h). By contrast, mice that were gene deficient for CD28 (CD28(-/-)), a co-stimulatory molecule for T cell activation, exhibited only minor renal dysfunction (50% protection compared with WT) and almost no PMN recruitment. When PMN(-) depleted, both WT and CD28(-/-) developed only mild ARF, similar to untreated CD28(-/-). Flow cytometry demonstrated that CD28 was vastly expressed on CD3(+) cells but not on PMN. Injecting wild-type CD3(+) cells into CD28(-/-) before LPS injection abolished the protection seen before. At baseline, both WT and CD28(-/-) displayed similar plasma concentrations of keratinocyte-derived chemokine (KC), a growth-related oncogene 1 gene product and PMN-specific chemokine. As opposed to WT, CD28(-/-) showed a greatly attenuated increase in plasma KC 4 h after LPS (2.5- versus 138.5-fold over controls, respectively). Moreover, CD28(-/-) showed less intense upregulation of renal growth-related oncogene 1 mRNA expression. Immunohistochemistry revealed considerable PMN but no T cell infiltrates in the kidney after LPS injection. In a PMN-dependent model of endotoxemic ARF, T cells, via the CD28 pathway, modulate kidney function and renal PMN recruitment. The effect on PMN is a remote one and presumably due to altered expression of PMN-specific chemokines.
Effect of cortisone treatment on the active transport of calcium by the small intestine
Authors: Daniel V. Kimberg, Richard D. Baerg, Elaine Gershon, Ruta T. Graudusius
Journal: Journal of Clinical Investigation (1971)

It is generally recognized that glucocorticoid administration may diminish calcium absorption in vivo as well as the active transport of calcium by the intestine in vitro. Recent studies by others have emphasized the possibility of an alteration in the metabolism of vitamin D to 25-hydroxycholecalciferol in accounting for the steroid effects on calcium absorption. The results obtained in the present studies fail to support this hypothesis.
Chest MRI in patients with cystic fibrosis: a radiation-free method
Authors: Bruno Hochhegger, Klaus L Irion, Edson Marchiori
Journal: Thorax (2012)

We read with great interest the well written manuscript by Mott et al ,1 which reported their experience with CT for the detection of structural lung disease in infants and young children with cystic fibrosis (CF). They emphasised the importance of an early diagnosis because disease progression occurs over the course of 1 year in most cases. However, we would like to discuss some aspects of imaging studies in these …
Biological and Prognostic Significance of Chromosome 5q Deletions in Myeloid Malignancies
Authors: Aristoteles A.N. Giagounidis, Ulrich Germing, Carlo Aul
Journal: Clinical Cancer Research (2006)

Abstract The presence of del(5q), either as the sole karyotypic abnormality or as part of a more complex karyotype, has distinct clinical implications for myelodysplastic syndromes (MDS) and acute myeloid leukemia. The 5q− syndrome, a subtype of low-risk MDS, is characterized by an isolated 5q deletion and &amp;lt;5% blasts in the bone marrow and can serve as a useful model for studying the role of 5q deletions in the pathogenesis and prognosis of myeloid malignancies. Recent clinical results with lenalidomide, an oral immunomodulatory drug, have shown durable erythroid responses, including transfusion independence and complete cytogenetic remissions in patients with del(5q) MDS with or without additional chromosomal abnormalities. These results indicate that lenalidomide can overcome the pathogenic effect of 5q deletion in MDS and restore bone marrow balance. The data provide important new insights into the pathobiology of 5q chromosomal deletions in myeloid malignancies.
Disclosure of Clinical Trial Results When Product Development Is Abandoned
Authors: Michael A. Rogawski, Howard J. Federoff
Journal: Science Translational Medicine (2011)

Currently, sponsors are not required to report the outcomes of clinical research on drugs or devices that do not lead to an approved product. Consequently, the public cannot benefit from scientific information derived from all failed or abandoned drugs and devices. Provisions in the U.S. Food and Drug Administration Amendments Act of 2007 provide an opportunity for the Department of Health and Human Services to rectify this situation. By reporting the results of clinical trials of abandoned products in a publicly accessible database and in the peer-reviewed journal literature, sponsors would satisfy a core ethical obligation of clinical research and enhance translational science.
Obesity and Hormone Therapy in Breast Cancer: An Unfinished Puzzle
Authors: Pamela J. Goodwin, Kathleen I. Pritchard
Journal: Journal of Clinical Oncology (2010)

The relationship between obesity and breast cancer is a complex one. 1 Obesity is associated with breast cancer risk in qualitatively different ways before and after menopause (with decreased risk in premenopausal women and increased risk in postmenopausal women), whereas similar associations of obesity with prognosis are seen in pre- and postmenopausal women (obese women in both groups experience poorer outcomes). This complexity likely reflects, atleastinpart,thevariablerelationshipsbetweenobesityandestrogen (a major contributor to the growth of hormone receptor‐positive breast cancer) before and after menopause. Before menopause, obesity may interfere with normal menstrual cycling, potentially leading to reductions in estrogen levels; after menopause, increased production of estrogen in excess adipose tissue in obese women is associated with higher estrogen levels. It is likely that the complexity of the relationshipbetweenobesityandbreastcanceralsoreflectsimportant contributions of obesity-related factors other than estrogen to both breast cancer risk and prognosis. 2 These factors include insulin, adipocytokines such as leptin, and adiponectin, as well as inflammatory markers such as C-reactive protein and interleukins. In this issue of Journal of Clinical Oncology, Sestak et al 3 report intriguingresultsofananalysisoftheimpactofobesityontheefficacy of tamoxifen and anastrozole in 5,172 postmenopausal women with hormone receptor‐positive breast cancer who participated in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial. The population studied was predominantly overweight (body mass index [BMI] 25 to 30 kg/m 2 ; 36.7% of the study population) or obese (BMI 30 kg/m 2 ; 27.3% of the study population). This pattern of obesity is similar to that reported in many recent trials in early breast cancer. The authors reported a significant increase in risk of breast cancerrecurrenceanddeathafterbreastcancerrecurrenceforwomen with higher BMIs but not an increase in the risk of death without recurrence. The authors also demonstrated a significant interaction between treatment and obesity on risk of recurrence—there was a significantlygreaterriskofrecurrenceinoverweightwomenreceiving anastrozole but not in those receiving tamoxifen (Table 4 in Sestak et al 3 ). Furthermore, the relative reduction in risk of recurrence with anastrozole (v tamoxifen) was insignificantly smaller for heavier womenthanforlighterwomen(Fig2inSestaketal 3 ).Theseobserva
Clinical Efficacy of Two Hypocaloric Diets That Vary in Overweight Patients With Type 2 Diabetes
Authors: Tracey McLaughlin, Susan Carter, Cindy Lamendola, Fahim Abbasi, Patricia Schaaf, Marina Basina, Gerald Reaven
Journal: Diabetes Care (2007)

Approximately 80% of patients with type 2 diabetes are overweight/obese (1), and weight loss is the mainstay of treatment for these individuals. However, there is growing controversy as to whether reduced-fat or reduced-carbohydrate diets are best suited for this purpose, and results (2–8) in nondiabetic subjects suggest that lower carbohydrate diets are similarly or more efficacious in improving weight, triglycerides, and HDL cholesterol. There are no published randomized studies evaluating the role of dietary macronutrients with respect to weight loss and cardiovascular risk improvement in patients with type 2 diabetes. Thus, we randomized diet-treated patients with type 2 diabetes to hypocaloric diets, moderately restricted in either carbohydrate or fat, to determine whether weight loss or metabolic improvement differed as a function of macronutrient composition.

A total of 29 patients with diet-treated type 2 diabetes were recruited from the San Francisco Bay area. All subjects gave written informed consent. Inclusion criteria included BMI 27–36 kg/m2, fasting plasma glucose concentration 7.2–8.3 mmol/l, no use of antihyperglycemic medications, and stable weight for 3 months. Subjects on anti-hypertensive or cholesterol-lowering drugs or aspirin were allowed to continue their medications.

Insulin-mediated glucose uptake was quantified by a modification (9) of the insulin suppression test as originally described (10) and validated (11). In this test, a 180-min infusion of somatostatin (0.27 μg/m2 per min), insulin (25 mU/m2 per min), …
Therapeutic Targeting of SPINK1-Positive Prostate Cancer
Authors: Bushra Ateeq, Scott A. Tomlins, Bharathi Laxman, Irfan A. Asangani, Qi Cao, Xuhong Cao, Yong Li, Xiaoju Wang, Felix Y. Feng, Kenneth J. Pienta, Sooryanarayana Varambally, Arul M. Chinnaiyan
Journal: Science Translational Medicine (2011)

SPINK1 is a therapeutic target in a subset of patients with SPINK1 + /ETS − prostate cancer.
The effects of eccentric versus concentric resistance training on muscle strength and mass in healthy adults: a systematic review with meta-analysis
Authors: M Roig, K O’Brien, G Kirk, R Murray, P McKinnon, B Shadgan, W D Reid
Journal: British Journal of Sports Medicine (2008)

The aim of this systematic review was to determine if eccentric exercise is superior to concentric exercise in stimulating gains in muscle strength and mass. Meta-analyses were performed for comparisons between eccentric and concentric training as means to improve muscle strength and mass. In order to determine the importance of different parameters of training, subgroup analyses of intensity of exercise, velocity of movement and mode of contraction were also performed. Twenty randomised controlled trials studies met the inclusion criteria. Meta-analyses showed that when eccentric exercise was performed at higher intensities compared with concentric training, total strength and eccentric strength increased more significantly. However, compared with concentric training, strength gains after eccentric training appeared more specific in terms of velocity and mode of contraction. Eccentric training performed at high intensities was shown to be more effective in promoting increases in muscle mass measured as muscle girth. In addition, eccentric training also showed a trend towards increased muscle cross-sectional area measured with magnetic resonance imaging or computerised tomography. Subgroup analyses suggest that the superiority of eccentric training to increase muscle strength and mass appears to be related to the higher loads developed during eccentric contractions. The specialised neural pattern of eccentric actions possibly explains the high specificity of strength gains after eccentric training. Further research is required to investigate the underlying mechanisms of this specificity and its functional significance in terms of transferability of strength gains to more complex human movements.
Cyclooxygenase and 5‐lipoxygenase pathways in the vessel wall: Role in atherosclerosis
Authors: Luís Vila
Journal: Medicinal Research Reviews (2004)

Abstract Prostaglandins (PGs), thromboxanes (Txs), and leukotrienes (LTs) play a relevant role in cardiovascular physiology and pathophysiology. Recent reports concerning cardiovascular risk associated with cyclooxygenase‐2 selective inhibitors have prompted questions about the “protective” or “deleterious” role of each COX isoform in cardiovascular disease, and the cloning and expression of inducible PGE‐synthase (PGES) open the possibility that PGES could be a new therapeutical target in this context. Predominance of constricting or relaxing prostanoids depends not only on COX activity but also to downstream enzymes such as PGI‐synthase (PGIS) and PGES. In the vessel wall, PGIS and PGES seem to be major downstream enzymes in the endothelium and smooth muscle, respectively. Like COX, activity of these enzymes can also be regulated by several factors, which include nitrogen oxides, cytokines, and lipid peroxides. LTs are important inflammatory mediators also involved in the pathophysiology of cardiovascular disease, which are targets for pharmacological intervention. Unlike COX pathway, the biosynthesis of chemotactic and vaso‐constrictor LTs in the vasculature strongly depends on leukocyte recruitment and activation, and on cell‐cell interaction between leukocytes and vascular cells in the inflamed areas. The present review emphasizes the role of vascular‐derived prostanoids and LTs on atherosclerosis. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 4, 399–324, 2004
Chronic lymphocytic leukemia in china
Authors: Dane R. Boggs, Shu Chang Chen, Zhi‐Nan Zhang, An Zhang
Journal: American Journal of Hematology (1987)

Abstract Chronic lymphocytic leukemia (CLL) is a very common form of leukemia among middle‐aged and elderly persons in Western countries. In the Japanese, or in those with Japanese ancestry born and living in the USA, CLL is rather rare. It is also rare in China, but convincing data to support this statement are found primarily in the Chinese literature. We have reviewed previously unpublished data from Peking Union Medical College (PUMC) concerning the frequency of CLL among adult patients with the four common types of leukemia. Of 4,174 such patients (1952–1986), 4.6% had CLL; 22.9% chronic myeloid leukemia (CML); 50.3% acute myeloid leukemia (AML); and 22.3% acute lymphoblastic leukemia (ALL). This low frequency of CLL is none the less higher than that found in a multiinstitutional collection of Chinese patients with leukemia. Various clinical and laboratory aspects of a carefully studied, previously published group of patients with CLL from PUMC were compared to similar published findings in patients from the University of Utah. No differences in the overall nature of the disease were detected between these groups. However, not unexpectedly, the duration of symptoms before the diagnosis was made longer in Chinese than in USA patients and the proportion diagnosed at a time when no CLL related symptoms had been noted was less in Chinese. Neither differences in life span in the two populations nor an excess of CML, AML, and ALL at the expense of CLL were viable hypotheses to explain the rarity of CLL in China. We suggest that the dearth of CLL in Chinese is on a genetic basis, as it is thought to be in the Japanese.
Tumor Antigen–Specific T-Cell Expansion Is Greatly Facilitated by<i>In vivo</i>Priming
Authors: Yushe Dang, Keith L. Knutson, Vivian Goodell, Corazon dela Rosa, Lupe G. Salazar, Doreen Higgins, Jennifer Childs, Mary L. Disis
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Adoptive T-cell therapy is a promising strategy for the treatment of patients with established tumors but is often limited to specific cancers where tumor-infiltrating lymphocytes, the source of T cells for ex vivo culture, can be obtained. In this study, we evaluated the feasibility of expanding HER-2/neu–specific T cells derived from peripheral blood ex vivo following in vivo priming with a HER-2/neu peptide vaccine. Experimental Design: Peripheral blood mononuclear cells from cytomegalovirus (CMV)–seronegative and CMV-seropositive donors as well as HER-2/neu–positive cancer patients who had or had not been vaccinated with a HER-2/neu peptide–based vaccine was used as a source of T lymphocytes. Antigen-specific T-cell lines were generated by in vitro stimulation with antigen followed by nonspecific expansion on CD3/CD28 beads. The ability to expand antigen-specific T cells was assessed using IFN-γ and granzyme B enzyme-linked immunosorbent spot. The phenotype of the resultant T-cell lines was evaluated by flow cytometry, including the presence of FOXP3-expressing CD4+ T cells. Results: The frequencies of CMV-specific T cells generated from CMV+ donors were &amp;gt;11-fold higher than the frequencies from CMV− donors (P = 0.001), with 22-fold increase of total number of CD3+ T cells. The frequencies of HER-2/neu–specific T cells generated from the primed patients were &amp;gt;25-fold higher than the frequencies from unvaccinated patients (P = 0.006), with an average of a 19-fold increase of total number of CD3+ T cells. Using peripheral blood as the source of T cells did not result in concurrent expansion of FOXP3+CD4+ regulatory T cells despite the use of interleukin-2 in in vitro culture. Both CD4+ and CD8+ HER-2/neu–specific T cells could be expanded. The extent of ex vivo expansion correlated with the magnitude of immunity achieved during immunization (P = 0.008). Conclusion: Tumor-specific T cells can be efficiently expanded from the peripheral blood ex vivo following in vivo priming with a vaccine. This approach provides an effective method to generate tumor-specific polyclonal T cells for therapeutic use that could be applied to cancer patients with any tumor type.
Elevated Plasma Plasminogen Activator Inhibitor-1 in CD36 Deficiency
Authors: Hidekatsu Yanai, Hitoshi Chiba, Kazuhiko Matsuno
Journal: Diabetes Care (2008)

CD36 is a fatty acid transporter expressed in various tissues including adipose, heart, and skeletal muscle tissues. The elevated fasting triglyceride levels,intermediate-density lipoprotein cholesterol levels, and postprandial hyperlipidemia observed in human CD36 deficiency have been suggested as being due to abnormal fatty acid metabolism and insulin resistance (1,2). Lipid abnormalities and insulin resistance in CD36 deficiency are atherogenic; however, the association between CD36 deficiency and atherosclerosis …