tbuckley/cabot-search huggingface dataset:
Carbonyl Reductase 1 Offers a Novel Therapeutic Target to Enhance Leukemia Treatment by Arsenic Trioxide
Authors: Miran Jang, Yeonghwan Kim, Hyeran Won, Sangbin Lim, Jyothi K.R, Amarjargal Dashdorj, Yoo Hong Min, Si-Young Kim, Kevan M. Shokat, Joohun Ha, Sung Soo Kim
Journal: Cancer Research (2012)

Abstract Arsenic trioxide (As2O3) is used, in current practice, as an effective chemotherapeutic agent for acute promyelocytic leukemia (APL). However, the side effects and relatively low efficacy of As2O3 in treating other leukemias have limited its wider use in therapeutic applications. In the present study, we found that the expression of carbonyl reductase 1 (CBR1) affects the resistance to As2O3 in leukemias, including APL; As2O3 upregulated CBR1 expression at the transcriptional level by stimulating the activity of the transcription factor activator protein-1. Moreover, CBR1 overexpression was sufficient to protect cells against As2O3 through modulation of the generation of reactive oxygen species, whereas the attenuation of CBR1 was sufficient to sensitize cells to As2O3. A combination treatment with the specific CBR1 inhibitor hydroxy-PP-Me remarkably increased As2O3-induced apoptotic cell death compared with As2O3 alone, both in vitro and in vivo. These results were confirmed in primary cultured human acute and chronic myeloid leukemia cells, with no significant cell death observed in normal leukocytes. Taken together, our findings indicate that CBR1 contributes to the low efficacy of As2O3 and, therefore, is a rational target for the development of combination chemotherapy with As2O3 in diverse leukemias including APL. Cancer Res; 72(16); 4214–24. ©2012 AACR.
Training Police in Community Relations and Urban Problems
Authors: JOHN A. TALBOTT, SUSAN W. TALBOTT
Journal: American Journal of Psychiatry (1971)

A training program in community relations and urban problems for police trainees in New York City enabled them, in their newly created role of precinct service officers, to function effectively as bridges between the police and community youth. The expansion of such programs reflects the realization that the policeman is the primary service agent for most urban residents, that community service is a vital part of police work, and that efforts to improve community mental health must involve all purveyors of service in the community.
Tuberculosis and Race/Ethnicity in the United States
Authors: MICHAEL F. CANTWELL, MATTHEW T. McKENNA, EUGENE McCRAY, IDA M. ONORATO
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Despite the long-standing observation that tuberculosis (TB) case rates are higher among racial and ethnic minorities than whites in the United States (U.S.), the proportion of this increased risk attributable to socioeconomic status (SES) has not been determined. Values for six SES indicators (crowding, income, poverty, public assistance, unemployment, and education) were assigned to U.S. TB cases reported from 1987–1993 by ZIP code- and demographic-specific matching to 1990 U.S. Census data. TB risk between racial/ethnic groups was then evaluated by quartile for each SES indicator utilizing univariate and Poisson multivariate analyses. Relative risk (RR) of TB increased with lower SES quartile for all six SES indicators on univariate analysis (RRs 2.6–5.6 in the lowest versus highest quartiles). The same trend was observed in multivariate models containing individual SES indicators (RRs 1.8–2.5) and for three SES indicators (crowding, poverty, and education) in the model containing all six indicators. Tuberculosis risk increased uniformly between SES quartile for each indicator except crowding, where risk was concentrated in the lowest quartile. Adjusting for SES accounted for approximately half of the increased risk of TB associated with race/ethnicity among U.S.-born blacks, Hispanics, and Native Americans. Even more of this increased risk was accounted for in the final model, which also adjusted for interaction between crowding and race/ethnicity. SES impacts TB incidence via both a strong direct effect of crowding, manifested predominantly in overcrowded settings, and a TB-SES health gradient, manifested at all SES levels. SES accounts for much of the increased risk of TB previously associated with race/ethnicity.
New Strategies for Triple-Negative Breast Cancer—Deciphering the Heterogeneity
Authors: Ingrid A. Mayer, Vandana G. Abramson, Brian D. Lehmann, Jennifer A. Pietenpol
Journal: Clinical Cancer Research (2014)

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease; gene expression analyses recently identified six distinct TNBC subtypes, each displaying a unique biology. Exploring novel approaches to treatment of these subtypes is critical because less than 30% of women with metastatic breast cancer survive five years and virtually all women with metastatic TNBC will ultimately die of their disease despite systemic therapy. To date, not a single targeted therapy has been approved for the treatment of TNBC and cytotoxic chemotherapy remains the standard treatment. We discuss the current and upcoming therapeutic strategies being explored in an attempt to “target” TNBC. Clin Cancer Res; 20(4); 782–90. ©2014 AACR.
The Effect of Haplotype-Block Definitions on Inference of Haplotype-Block Structure and htSNPs Selection
Authors: K. Ding
Journal: Molecular Biology and Evolution (2004)

It has been recently suggested that the human genome is organized as a series of haplotype blocks, and efforts to create a genome-wide haplotype map are already underway. Several computational algorithms have been proposed to partition the genome. However, little is known about their behaviors in relation to the haplotype-block partitioning and haplotype-tagging SNPs selection. Here, we present a systematic comparison of three classes of haplotype-block partition definitions, a diversity-based method, a linkage-disequilibrium (LD)-based method, and a recombination-based method. The data used were derived from a coalescent simulation under both a uniform recombination model and one that assumes recombination hotspots. There were considerable differences in haplotype information loss in the measure of entropy when the partition methods were compared under different population-genetics scenarios. Under both recombination models, the results from the LD-based definition and the recombination-based definition were more similar to each other than were the results from the diversity-based definition. This work demonstrates that when undertaking haplotype-based association mapping, the choice of haplotype-block definition and SNP selection requires careful consideration.
Issues of Agricultural Safety and Health
Authors: Arthur L. Frank, Robert McKnight, Steven R. Kirkhorn, Paul Gunderson
Journal: Annual Review of Public Health (2004)

Agricultural work is the most prevalent type of employment in the world. In the United States only a few are engaged in creating food and fiber for many. Agriculture includes farming, ranching, fishing, and forestry, and together they carry significant risk for the development of injury or illness. There are numerous special-population issues related to agriculture. Farmers are old and growing older, many workers are children, and migrant and seasonal help, often foreign born, make up a large percentage of the workforce. It has been only relatively recently that concerns of agricultural safety and health have become a major research focus in the United States.
Taurolithocholate-induced MRP2 retrieval involves MARCKS phosphorylation by protein kinase Cϵ in HUH-NTCP Cells
Authors: Christopher M. Schonhoff, Cynthia R. L. Webster, Sawkat M. Anwer
Journal: Hepatology (2013)

Abstract Taurolithocholate (TLC) acutely inhibits the biliary excretion of multidrug-resistant associated protein 2 (Mrp2) substrates by inducing Mrp2 retrieval from the canalicular membrane, whereas cyclic adenosine monophosphate (cAMP) increases plasma membrane (PM)–MRP2. The effect of TLC may be mediated via protein kinase Cε (PKCε). Myristoylated alanine-rich C kinase substrate (MARCKS) is a membrane-bound F-actin crosslinking protein and is phosphorylated by PKCs. MARCKS phosphorylation has been implicated in endocytosis, and the underlying mechanism appears to be the detachment of phosphorylated myristoylated alanine-rich C kinase substrate (pMARCKS) from the membrane. The aim of the present study was to test the hypothesis that TLC-induced MRP2 retrieval involves PKCε-mediated MARCKS phosphorylation. Studies were conducted in HuH7 cells stably transfected with sodium taurocholate cotransporting polypeptide (HuH-NTCP cells) and in rat hepatocytes. TLC increased PM–PKCε and decreased PM-MRP2 in both HuH-NTCP cells and hepatocytes. cAMP did not affect PM-PKCε and increased PM-MRP2 in these cells. In HuH-NTCP cells, dominant-negative (DN) PKCε reversed TLC-induced decreases in PM-MRP2 without affecting cAMP-induced increases in PM-MRP2. TLC, but not cAMP, increased MARCKS phosphorylation in HuH-NTCP cells and hepatocytes. TLC and phorbol myristate acetate increased cytosolic pMARCKS and decreased PM-MARCKS in HuH-NTCP cells. TLC failed to increase MARCKS phosphorylation in HuH-NTCP cells transfected with DN-PKCε, and this suggested PKCε-mediated phosphorylation of MARCKS by TLC. In HuH-NTCP cells transfected with phosphorylation-deficient MARCKS, TLC failed to increase MARCKS phosphorylation or decrease PM-MRP2. Conclusion : Taken together, these results support the hypothesis that TLC-induced MRP2 retrieval involves TLC-mediated activation of PKCε followed by MARCKS phosphorylation and consequent detachment of MARCKS from the membrane. (HEPATOLOGY 2013;)
Urine Analysis and Protein Networking Identify Met as a Marker of Metastatic Prostate Cancer
Authors: Andrea L. Russo, Kimberly Jedlicka, Meredith Wernick, Debbie McNally, Melissa Kirk, Mary Sproull, Sharon Smith, Uma Shankavaram, Aradhana Kaushal, William D. Figg, William Dahut, Deborah Citrin, Donald P. Bottaro, Paul S. Albert, Philip J. Tofilon, Kevin Camphausen
Journal: Clinical Cancer Research (2009)

Metastatic prostate cancer is a major cause of death of men in the United States. Expression of met, a receptor tyrosine kinase, has been associated with progression of prostate cancer.To investigate met as a biomarker of disease progression, urinary met was evaluated via ELISA in men with localized (n = 75) and metastatic (n = 81) prostate cancer. Boxplot analysis was used to compare the distribution of met values between each group. We estimated a receiver operating characteristic curve and the associated area under the curve to summarize the diagnostic accuracy of met for distinguishing between localized and metastatic disease. Protein-protein interaction networking via yeast two-hybrid technology supplemented by Ingenuity Pathway Analysis and Human Interactome was used to elucidate proteins and pathways related to met that may contribute to progression of disease.Met distribution was significantly different between the metastatic group and the group with localized prostate cancer and people with no evidence of cancer (P < 0.0001). The area under the curve for localized and metastatic disease was 0.90, with a 95% confidence interval of 0.84 to 0.95. Yeast two-hybrid technology, Ingenuity Pathway Analysis, and Human Interactome identified 89 proteins that interact with met, of which 40 have previously been associated with metastatic prostate cancer.Urinary met may provide a noninvasive biomarker indicative of metastatic prostate cancer and may be a central regulator of multiple pathways involved in prostate cancer progression.
Surgeons' advice will be essential for GP consortiums to succeed, warns royal college
Authors: A. O'Dowd
Journal: BMJ (2010)

Advice from specialists such as surgeons will be crucial for the new commissioning consortiums to succeed once the reforms of the NHS in England are fully adopted, it has been claimed.

On 4 October the Royal College of Surgeons of England published its consultation response to the government’s white paper Equity and Excellence: Liberating the NHS , which sets out reforms creating powerful commissioning groups of GPs, overseen by an NHS commissioning board.

The college said that the reforms would work only if partnerships between primary care and hospital clinicians were strong.

In its response to the white paper the college broadly welcomed much of the government’s proposals, saying, “It is essential that the proposed GP consortia and the independent NHS commissioning board have access to timely and relevant clinical information and expertise to ensure that decisions are based on the best available evidence.”

It was worried, however, that skills in …
Sequential changes of KL-6 in sera of patients with interstitial pneumonia associated with polymyositis/dermatomyositis
Authors: S. Bandoh
Journal: Annals of the Rheumatic Diseases (2000)

KL-6 is a mucin-like high molecular weight glycoprotein, which is strongly expressed on type II alveolar pneumocytes and bronchiolar epithelial cells. It has been demonstrated that the KL-6 antigen is a useful marker for estimating the activity of interstitial pneumonia. In this study, it is hypothesised that serum KL-6 is a useful marker to evaluate the activity of interstitial pneumonia associated with polymyositis/dermatomyositis (PM/DM).KL-6 was measured in sera in 16 patients diagnosed with PM/DM. Five had non-specific interstitial pneumonia (NSIP), three had diffuse alveolar damage (DAD), and eight had no pulmonary involvement, and 10 were normal non-smokers as a control group. The correlation was also evaluated between the KL-6 level and each clinical course in patients with pulmonary involvement associated with PM/DM. Immunohistochemical analysis using monoclonal anti-KL-6 antibody was also performed.KL-6 concentrations in sera of patients with interstitial pneumonia associated with PM/DM were significantly high compared with those of PM/DM without interstitial pneumonia, and normal non-smokers. KL-6 concentrations in sera in patients with DAD significantly increased compared with those of other groups. KL-6 values in sera changed according to the progression or improvement of interstitial pneumonia. Immunohistochemical study using pulmonary tissues obtained from patients with DAD demonstrated that the hyaline membrane, proliferating type II pneumocytes, bronchial epithelial cells and some endothelial cells in pulmonary veins were stained by antihuman KL-6 antibody.These data demonstrate that measurement of serum KL-6 was a useful marker to evaluate the activity of acute interstitial pneumonia associated with PM/DM.
Abstract 5143: Pharmacological Inhibition of Phosphoinositide 3-kinase Gamma Suppresses Reparative Neovascularization and Impairs Recovery From Myocardial Infarction
Authors: Mauro Siragusa, Rajesh G Katare, Costanza Emanueli, Paolo Madeddu
Journal: Circulation (2009)

Phosphoinositide 3-kinase gamma (PI3K γ ) is primarily involved in G i -coupled receptor-mediated signaling controlling innate and adaptive immune response. Recently, PI3K γ inhibitors have been proposed as anti-inflammatory agents in a wide spectrum of pathologies, including cardiovascular disease. We have shown previously that PI3K γ plays a pivotal role in vasculogenesis and reparative angiogenesis. Here we aimed to determine whether inhibition of PI3K γ could be detrimental for recovery from myocardial infarction (MI). MI was induced in CD1 mice by permanent LAD ligation. The PI3K γ -selective inhibitor AS605240 (AS) or DMSO (control) was injected i.p. daily from 3 days before MI until either 3 or 14 days post-MI. In AS-treated infarcted hearts, echocardiographic measurements carried out at 14 days post-MI showed extensive wall thinning, reduced stroke volume (24.9±2.5 vs. 36.1±3.6 μ l, P&lt;0.05), ejection fraction (19.2±1.9 vs. 26.4±3.0%, P&lt;0.05), fractional shortening (9.1±0.9 vs. 12.5±1.5%, P&lt;0.05) and cardiac output (12.1±1.3 vs. 18.0±1.8 ml/min, P&lt;0.05). Histological assessment of fibrosis revealed that infarct size was increased by 1.4 fold (P&lt;0.01 vs. control). In control hearts at 14 days post-MI, the density of capillaries and arterioles in the peri-infarct area increased by 1.3 and 2.6 folds, respectively (P&lt;0.01 vs. remote area for both comparisons). In contrast, neovascularization response in the peri-infarct area of AS-treated hearts was completely suppressed at both capillary and arteriole level. Interestingly, at 3 days post-MI the number of apoptotic microvascular endothelial cells and cardiomyocytes in the peri-infarct area was increased by 2.6 and 2 folds, respectively (P&lt;0.01 vs. control for both comparisons). Furthermore, PI3K γ inhibition strongly reduced the number of CD45 + MNCs infiltrating the interstitial space (15.8±6.9 vs. 106.9±28.2 cells/mm 2 , P&lt;0.05) and surrounding arterioles (0.1±0.1 vs. 1.2±0.3 cells/arteriole, P&lt;0.001) of the peri-infarct area at 3 days post-MI. Our results indicate that PI3K γ is a key modulator of post-infarct remodeling and reparative neovascularization. Caution is recommended when using PI3K γ inhibitors as anti-inflammatory drugs in patients with coronary heart disease.
Genetic Inflammatory Factors Predict Restenosis After Percutaneous Coronary Interventions
Authors: Pascalle S. Monraats, Nuno M.M. Pires, Willem R.P. Agema, Aeilko H. Zwinderman, Abbey Schepers, Moniek P.M. de Maat, Pieter A. Doevendans, Robbert J. de Winter, René A. Tio, Johannes Waltenberger, Rune R. Frants, Paul H.A. Quax, Bart J.M. van Vlijmen, Douwe E. Atsma, Arnoud van der Laarse, Ernst E. van der Wall, J. Wouter Jukema
Journal: Circulation (2005)

Restenosis is a negative effect of percutaneous coronary intervention (PCI). No clinical factors are available that allow good risk stratification. However, evidence exists that genetic factors are important in the restenotic process as well as in the process of inflammation, a pivotal factor in restenosis. Association studies have identified genes that may predispose to restenosis, but confirmation by large prospective studies is lacking. Our aim was to identify polymorphisms and haplotypes in genes involved in inflammatory pathways that predispose to restenosis.The GENetic DEterminants of Restenosis (GENDER) project is a multicenter prospective study, including 3104 consecutive patients after successful PCI. Forty-eight polymorphisms in 34 genes in pathways possibly involved in the inflammatory process were analyzed. The 16Gly variant of the beta2-adrenergic receptor gave an increased risk of target vessel revascularization (TVR). The rare alleles of the CD14 gene (-260T/T), colony-stimulating factor 2 gene (117Thr/Thr), and eotaxin gene (-1328A/A) were associated with decreased risk of TVR. However, through the use of multiple testing corrections with permutation analysis, the probability of finding 4 significant markers by chance was 12%.Polymorphisms in 4 genes considered involved in the inflammatory reaction showed an association with TVR after PCI. Our results may contribute to the unraveling of the restenotic process. Given the explorative nature of this analysis, our results need to be replicated in other studies.
Association of antibodies against phospholipids with heart valve disease in systemic lupus erythematosus
Authors: M.A. Khamashta, R. Cervera, R.A. Asherson, G.R.V. Hughes, D.J. Coltart, J. Font, M. Ingelmo, C. Paré, A. Gil, J.J. Vázquez, J. Oliver
Journal: The Lancet (1990)
Renal Hyperfiltration and Arterial Stiffness in Humans With Uncomplicated Type 1 Diabetes
Authors: David Z.I. Cherney, Etienne B. Sochett, Vesta Lai, Maria G. Dekker, Cameron Slorach, James W. Scholey, Timothy J. Bradley
Journal: Diabetes Care (2010)

OBJECTIVE We have reported that renal hyperfiltration is associated with endothelial dysfunction in early type 1 diabetes. However, the relationship between renal hyperfiltration and arterial stiffness is unknown. Accordingly, we measured arterial stiffness in type 1 diabetic subjects with hyperfiltering (n = 20) or normofiltering (n = 18). RESEARCH DESIGN AND METHODS Augmentation index (AIx), aortic pulse wave velocity (PWV), renal hemodynamic function (inulin and paraaminohippurate clearances), and urinary and circulating plasma cGMP were measured in normoalbuminuric subjects with type 1 diabetes during clamped euglycemia (glucose 4–6 mmol/l) and hyperglycemia (glucose 9–11 mmol/l). RESULTS During clamped euglycemia, hyperfiltering subjects (glomerular filtration rate ≥135 ml/min/1.73 m2) exhibited lower AIx values (−6.1 ± 2.9 vs. 13.9 ± 2.7%, P = 0.001) and higher cGMP levels in urine and plasma compared with normofiltering subjects. These differences were maintained during clamped hyperglycemia. As expected, renal hemodynamic responses to clamped hyperglycemia were exaggerated in normofilterers, but values for AIx remained unchanged. CONCLUSIONS Renal hyperfiltration is associated with reduced arterial stiffness in subjects with uncomplicated type 1 diabetes.
Effect of parathyroid hormone on rat heart cells.
Authors: E Bogin, S G Massry, I Harary
Journal: Journal of Clinical Investigation (1981)

Myocardiopathy is common in uremia, but its cause in unknown. Excessive entry of calcium in heart cells by catecholamines has been shown to cause necrosis of myocardium. The high blood levels of parathyroid hormone (PTH) in uremia may also enhance entry of calcium into heart cells and exert deleterious effects on the heart. We examined the effect of PTH on rat heart cells grown in culture. Both amino-terminal (1-34) PTH and intact (1-84) PTH, but not the carboxy-terminal (53-84) PTH produced immediate and sustained significant rise in beats per minute and the cells died earlier than control. The effect was reversed if PTH was removed from medium, and was abolished by inactivation of the hormone. There was a dose-response relationship between both moieties of PTH and the rise in heart beats, but the effect of 1-84 PTH was significantly greater than that of 1-34 moiety. PTH stimulated cyclic AMP production within 1 min, and cyclic AMP remained significantly elevated thereafter. The effect of PTH required calcium, was mimicked by calcium ionophore, was prevented by verapamil and was not abolished by alpha- or beta-adrenergic blockers. PTH action was additive to phenylephrine and synergistic with isoproterenol. Sera from uremic parathyroidectomized rats did not effect heart beats, but sera from uremic rats with intact parathyroid glands or from uremic-parathyroidectomized rats treated with PTH had effects similar to PTH. Data indicate that (a) heart cell is a target organ for PTH and may have receptors for the hormone; (b) PTH increases beating rate of heart cells and causes early death of cells; (c) PTH effect appears to be due to calcium entry into heart cells; (d) the locus of action through which PTH induces calcium entry is different from that for catecholamines; and (e) uremic serum has no effect unless it contains PTH. Data suggest that myocardial damage may occur in uremia due to prolonged exposure to very high blood levels of PTH, and assign new dimensions to PTH toxicity in uremia.