tbuckley/cabot-search huggingface dataset:
Effects of Structured Versus Usual Care on Renal Endpoint in Type 2 Diabetes: The SURE Study
Authors: Juliana C. Chan, Wing-Yee So, Chun-Yip Yeung, Gary T. Ko, Ip-Tim Lau, Man-Wo Tsang, Kam-Piu Lau, Sing-Chung Siu, June K. Li, Vincent T. Yeung, Wilson Y. Leung, Peter C. Tong
Journal: Diabetes Care (2009)

Multifaceted care has been shown to reduce mortality and complications in type 2 diabetes. We hypothesized that structured care would reduce renal complications in type 2 diabetes.A total of 205 Chinese type 2 diabetic patients from nine public hospitals who had plasma creatinine levels of 150-350 micromol/l were randomly assigned to receive structured care (n = 104) or usual care (n = 101) for 2 years. The structured care group was managed according to a prespecified protocol with the following treatment goals: blood pressure <130/80 mmHg, A1C <7%, LDL cholesterol <2.6 mmol/l, triglyceride <2 mmol/l, and persistent treatment with renin-angiotensin blockers. The primary end point was death and/or renal end point (creatinine >500 micromol/l or dialysis).Of these 205 patients (mean +/- SD age 65 +/- 7.2 years; disease duration 14 +/- 7.9 years), the structured care group achieved better control than the usual care group (diastolic blood pressure 68 +/- 12 vs. 71 +/- 12 mmHg, respectively, P = 0.02; A1C 7.3 +/- 1.3 vs. 8.0 +/- 1.6%, P < 0.01). After adjustment for age, sex, and study sites, the structured care (23.1%, n = 24) and usual care (23.8%, n = 24; NS) groups had similar end points, but more patients in the structured care group attained >or=3 treatment goals (61%, n = 63, vs. 28%, n = 28; P < 0.001). Patients who attained >or=3 treatment targets (n = 91) had reduced risk of the primary end point (14 vs. 34; relative risk 0.43 [95% CI 0.21-0.86] compared with that of those who attained <or=2 targets (n = 114).Attainment of multiple treatment targets reduced the renal end point and death in type 2 diabetes. In addition to protocol, audits and feedback are needed to improve outcomes.
Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial
Authors: Theodore M. Brasky, Amy K. Darke, Xiaoling Song, Catherine M. Tangen, Phyllis J. Goodman, Ian M. Thompson, Frank L. Meyskens, Gary E. Goodman, Lori M. Minasian, Howard L. Parnes, Eric A. Klein, Alan R. Kristal
Journal: JNCI Journal of the National Cancer Institute (2013)

Studies of dietary ω-3 fatty acid intake and prostate cancer risk are inconsistent; however, recent large prospective studies have found increased risk of prostate cancer among men with high blood concentrations of long-chain ω-3 polyunsaturated fatty acids ([LCω-3PUFA] 20:5ω3; 22:5ω3; 22:6ω3]. This case–cohort study examines associations between plasma phospholipid fatty acids and prostate cancer risk among participants in the Selenium and Vitamin E Cancer Prevention Trial. Case subjects were 834 men diagnosed with prostate cancer, of which 156 had high-grade cancer. The subcohort consisted of 1393 men selected randomly at baseline and from within strata frequency matched to case subjects on age and race. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between fatty acids and prostate cancer risk overall and by grade. All statistical tests were two-sided. Compared with men in the lowest quartiles of LCω-3PUFA, men in the highest quartile had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). Associations were similar for individual long-chain ω-3 fatty acids. Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01); however, there was no dose response. This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA. The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis. Recommendations to increase LCω-3PUFA intake should consider its potential risks.
Combined Use of Erythropoietin and Granulocyte Colony-Stimulating Factor Does Not Decrease Blood Transfusion Requirements During Induction Therapy for High-Risk Neuroblastoma: A Randomized Controlled Trial
Authors: Lars M. Wagner, Catherine A. Billups, Wayne L. Furman, Bhaskar N. Rao, Victor M. Santana
Journal: Journal of Clinical Oncology (2004)

Purpose To evaluate the efficacy of recombinant erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) in reducing blood transfusion requirements and stimulating hematopoiesis in children with high-risk neuroblastoma. Patients and Methods Thirty-eight patients given six cycles of intensive induction chemotherapy for high-risk neuroblastoma were randomized to receive G-CSF (n = 20) or G-CSF + EPO (n = 18). Cytokines were given subcutaneously each day, starting 24 hours after each chemotherapy cycle and continuing until 48 hours before the start of the next cycle. The primary end point was the effect of EPO on total red cell transfusion requirements during induction therapy. Results Patients who received G-CSF + EPO had a higher red cell transfusion requirement (median, 161.0 mL/kg) than did those who received G-CSF alone (median, 106.6 mL/kg; P = .005). In addition, among patients given transfusions for hemoglobin ≤ 8 g/dL, those in the G-CSF + EPO group received more red cell transfusions than did those given G-CSF alone (median per patient, 10 v 8, respectively; P = .044). The two treatment groups had similar cumulative durations of neutropenia, incidences of febrile neutropenia, platelet transfusion requirements, and numbers of platelet transfusions; they also received induction chemotherapy for similar durations and had similar probabilities of progression-free survival and overall survival. Conclusion The addition of EPO to the G-CSF regimen provides no benefit for patients receiving intensive induction chemotherapy for high-risk neuroblastoma.
Transmural gradients in ventricular tissue metabolites produced by stopping coronary blood flow in the dog.
Authors: R B Dunn, D M Griggs
Journal: Circulation Research (1975)

To determine whether transmural metabolite gradients develop in the contracting, ischemic left ventricle due to factors other than a nonuniform distribution of myocardial blood flow, right and left coronary artery inflow was completely stopped with vessel occluders in open-chest dogs for 15 or 30 seconds before a transmural myocardial tissue sample was obtained for regional analysis of creatine phosphate, adenosine triphosphate (ATP), and lactate. Heart rate was controlled, and the decline in left ventricular systolic pressure during the period in which coronary blood flow was stopped was attenuated by aortic constriction. Studies were also performed in dogs that were (1) pretreated with propranolol, (2) subjected to ventricular fibrillation, and (3) volume loaded. Control studies revealed no transmural metabolite gradients in the normally perfused ventricle, but creatine phosphate was slightly lower in the inner region than it was in the outer and middle ventricular wall regions. With coronary blood flow stopped for 30 seconds, a significant lactate gradient, increasing from the outer to the inner region, was present. Propranolol-treated dogs with their coronary blood flow stopped for 30 seconds also exhibited a lactate gradient, but dogs with ventricular fibrillation and their coronary blood flow stopped for 30 seconds did not. Volume-loaded dogs with their coronary blood flow stopped for only 15 seconds had a significant lactate gradient. Reciprocal gradients occurred in creatine phosphate but not in ATP. The findings suggest that the contracting ventricle uses energy unevenly and that in myocardial ischemia one of the factors causing greater subendocardial vulnerability is a greater energy need in this region.
Differential expression and role of p21cip/waf1 and p27kip1 in TNF-α-induced inhibition of proliferation in human glioma cells
Authors: Pabbisetty Sudheer Kumar, Anjali Shiras, Gowry Das, Jayashree C Jagtap, Vandna Prasad, Padma Shastry
Journal: Molecular Cancer (2007)

Abstract Background The role of TNF-α in affecting the fate of tumors is controversial, while some studies have reported apoptotic or necrotic effects of TNF-α, others provide evidence that endogenous TNF-α promotes growth and development of tumors. Understanding the mechanism(s) of TNF-α mediated growth arrest will be important in unraveling the contribution of tissue associated macrophages in tumor resistance. The aim of this study was to investigate the role of Cyclin Dependent Kinase Inhibitors (CDKI) – p21 cip/waf1 and p27 kip1 in TNF-α mediated responses in context with p53 and activation of NF-κB and Akt pathways. The study was done with human glioma cell lines -LN-18 and LN-229 cells, using monolayer cultures and Multicellular Spheroids (MCS) as in vitro models. Results TNF-α induced inhibition of proliferation and enhanced the expression of p21 cip/waf1 and p27 kip1 in LN-18 cells. p21 was induced on exposure to TNF-α, localized exclusively in the nucleus and functioned as an inhibitor of cell cycle but not as an antiapoptotic protein. In contrast, p27 was constitutively expressed, localized predominantly in the cytoplasm and was not involved in arrest of proliferation. Our data using IκBα mutant LN-18 cells and PI3K/Akt inhibitor-LY294002 revealed that the expression of p21 is regulated by NF-κB. Loss of IκBα function in LN-229 cells (p53 positive) did not influence TNF-α induced accumulation of pp53 (Ser-20 p53) suggesting that p53 was not down stream of NF-κB. Spheroidogenesis enhanced p27 expression and p21 induced by TNF-α was significantly increased in the MCS compared to monolayers. Conclusion This study demarcates the functional roles for CDKIs-p21 cip/waf1 and p27 kip1 during TNF-α stimulated responses in LN-18 glioma cells. Our findings provide evidence that TNF-α-induced p21 might be regulated by NF-κB or p53 independently. p21 functions as an inhibitor of cell proliferation and does not have a direct role in rendering the cells resistant to TNF-α mediated cytotoxicity.
Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis
Authors: P. Tugwell, C. Bombardier, P. Tugwell, M. Gent, K.J. Bennett, R.S. Roberts, D. Ludwin, W.G. Bensen, S. Carette, A. Chalmers, A.V. Klinkhoff, J.M. Esdaile, G.R. Kraag
Journal: The Lancet (1990)
Epigenetic Modification of the <i>FMR1</i> Gene in Fragile X Syndrome Is Associated with Differential Response to the mGluR5 Antagonist AFQ056
Authors: Sébastien Jacquemont, Aurore Curie, Vincent des Portes, Maria Giulia Torrioli, Elizabeth Berry-Kravis, Randi J. Hagerman, Feliciano J. Ramos, Kim Cornish, Yunsheng He, Charles Paulding, Giovanni Neri, Fei Chen, Nouchine Hadjikhani, Danielle Martinet, Joanne Meyer, Jacques S. Beckmann, Karine Delange, Amandine Brun, Gerald Bussy, Fabrizio Gasparini, Talita Hilse, Annette Floesser, Janice Branson, Graeme Bilbe, Donald Johns, Baltazar Gomez-Mancilla
Journal: Science Translational Medicine (2011)

An antagonist for the metabotropic glutamate receptor may improve symptoms in patients with fragile X syndrome whose FMR1 promoters are fully methylated.
Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training
Authors: Tohru Fukai, Martin R. Siegfried, Masuko Ushio-Fukai, Yian Cheng, Georg Kojda, David G. Harrison
Journal: Journal of Clinical Investigation (2000)

The bioactivity of endothelium-derived nitric oxide (NO) reflects its rates of production and of inactivation by superoxide (O2•–), a reactive species dismutated by extracellular superoxide dismutase (ecSOD). We have now examined the complementary hypothesis, namely that NO modulates ecSOD expression. The NO donor DETA-NO increased ecSOD expression in a time- and dose-dependent manner in human aortic smooth muscle cells. This effect was prevented by the guanylate cyclase inhibitor ODQ and by the protein kinase G (PKG) inhibitor Rp-8-CPT-cGMP. Expression of ecSOD was also increased by 8-bromo-cGMP, but not by 8-bromo-cAMP. Interestingly, the effect of NO on ecSOD expression was prevented by inhibition of the MAP kinase p38 but not of the MAP kinase kinase p42/44, suggesting that NO modulates ecSOD expression via cGMP/PKG and p38MAP kinase–dependent pathways, but not through p42/44MAP kinase. In aortas from mice lacking the endothelial nitric oxide synthase (eNOS), ecSOD was reduced more than twofold compared to controls. Treadmill exercise training increased eNOS and ecSOD expression in wild-type mice but had no effect on ecSOD expression in mice lacking eNOS, suggesting that this effect of exercise is meditated by endothelium-derived NO. Upregulation of ecSOD expression by NO may represent an important feed-forward mechanism whereby endothelial NO stimulates ecSOD expression in adjacent smooth muscle cells, thus preventing O2•–-mediated degradation of NO as it traverses between the two cell types.
Deficiency of the Cyclin Kinase Inhibitor p21(WAF-1/CIP-1) Promotes Apoptosis of Activated/Memory T Cells and Inhibits Spontaneous Systemic Autoimmunity
Authors: Brian R. Lawson, Roberto Baccala, Jianxun Song, Michael Croft, Dwight H. Kono, Argyrios N. Theofilopoulos
Journal: The Journal of Experimental Medicine (2004)

A characteristic feature of systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G1-arrested cells express high levels of cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation and apoptosis, and produce large amounts of proinflammatory cytokines. Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction. Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential. Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax. Proliferation and apoptosis of B cells were also increased in p21−/− lupus mice. Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.
CCL2 Mediates Cross-talk between Cancer Cells and Stromal Fibroblasts That Regulates Breast Cancer Stem Cells
Authors: Akihiro Tsuyada, Amy Chow, Jun Wu, George Somlo, Peiguo Chu, Sofia Loera, Thehang Luu, Arthur Xuejun Li, Xiwei Wu, Wei Ye, Shiuan Chen, Weiying Zhou, Yang Yu, Yuan-Zhong Wang, Xiubao Ren, Hui Li, Peggy Scherle, Yukio Kuroki, Shizhen Emily Wang
Journal: Cancer Research (2012)

Cancer stem cells (CSC) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer stem cells. We found that compared with normal fibroblasts, primary cancer-associated fibroblasts (CAF) and fibroblasts activated by cocultured breast cancer cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in breast cancer cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse breast cancer-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in breast cancer cells, constituting a cancer-stroma-cancer signaling circuit. In a xenograft model of paired fibroblasts and breast cancer tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary breast cancers, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression.
InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma
Authors: Yufang Ma, Nan Tang, Reid C. Thompson, Bret C. Mobley, Steven W. Clark, Jann N. Sarkaria, Jialiang Wang
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Aberrant activation of EGFR is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast with the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma. Experimental Design: We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild-type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy cotargeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R). Results: Insulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not express InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors. Conclusions: Our results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma. Clin Cancer Res; 22(7); 1767–76. ©2015 AACR.
Tissue plasminogen activator prevents white matter damage following stroke
Authors: Fernando Correa, Maxime Gauberti, Jérôme Parcq, Richard Macrez, Yannick Hommet, Pauline Obiang, Miriam Hernangómez, Axel Montagne, Géraldine Liot, Carmen Guaza, Eric Maubert, Carine Ali, Denis Vivien, Fabian Docagne
Journal: The Journal of Experimental Medicine (2011)

Tissue plasminogen activator (tPA) is the only available treatment for acute stroke. In addition to its vascular fibrinolytic action, tPA exerts various effects within the brain, ranging from synaptic plasticity to control of cell fate. To date, the influence of tPA in the ischemic brain has only been investigated on neuronal, microglial, and endothelial fate. We addressed the mechanism of action of tPA on oligodendrocyte (OL) survival and on the extent of white matter lesions in stroke. We also investigated the impact of aging on these processes. We observed that, in parallel to reduced levels of tPA in OLs, white matter gets more susceptible to ischemia in old mice. Interestingly, tPA protects murine and human OLs from apoptosis through an unexpected cytokine-like effect by the virtue of its epidermal growth factor-like domain. When injected into aged animals, tPA, although toxic to the gray matter, rescues white matter from ischemia independently of its proteolytic activity. These studies reveal a novel mechanism of action of tPA and unveil OL as a target cell for cytokine effects of tPA in brain diseases. They show overall that tPA protects white matter from stroke-induced lesions, an effect which may contribute to the global benefit of tPA-based stroke treatment.
Mammary Tumorigenesis following Transgenic Expression of a Dominant Negative CHK2 Mutant
Authors: Eunice L. Kwak, Sang Kim, Jianmin Zhang, Robert D. Cardiff, Emmett V. Schmidt, Daniel A. Haber
Journal: Cancer Research (2006)

A truncating allele of the cell cycle checkpoint kinase CHK2 is present in 1% of the population, conferring a moderate increase in breast cancer risk, and inactivation of chk2 enhances mammary tumorigenesis in mice with targeted inactivation of brca1. We used the mouse mammary tumor virus (MMTV) promoter to target expression of a kinase-dead CHK2 allele (D347A). Mammary tumors, of predominantly micropapillary histology, developed in 40% of MMTV-CHK2-D347A transgenic mice with an average latency of 20 months. Tumors metastasized to lung and spleen; tumor-derived cell lines were frequently aneuploid and showed suppression of irradiation-induced p53 function. Primary hematopoietic malignancies were also observed in the spleen, another site of MMTV expression. The increased rate of tumor formation in MMTV-CHK2-D347A mice, compared with the relatively low incidence in chk2-null mice, provides a model to study modifiers of CHK2-dependent transformation.
Evolutionary Pressures on Apicoplast Transit Peptides
Authors: Stuart A. Ralph, Bernardo J. Foth, Neil Hall, Geoffrey I. McFadden
Journal: Molecular Biology and Evolution (2004)

Malaria parasites (species of the genus Plasmodium) harbor a relict chloroplast (the apicoplast) that is the target of novel antimalarials. Numerous nuclear-encoded proteins are translocated into the apicoplast courtesy of a bipartite N-terminal extension. The first component of the bipartite leader resembles a standard signal peptide present at the N-terminus of secreted proteins that enter the endomembrane system. Analysis of the second portion of the bipartite leaders of P. falciparum, the so-called transit peptide, indicates similarities to plant transit peptides, although the amino acid composition of P. falciparum transit peptides shows a strong bias, which we rationalize by the extraordinarily high AT content of P. falciparum DNA. 786 plastid transit peptides were also examined from several other apicomplexan parasites, as well as from angiosperm plants. In each case, amino acid biases were correlated with nucleotide AT content. A comparison of a spectrum of organisms containing primary and secondary plastids also revealed features unique to secondary plastid transit peptides. These unusual features are explained in the context of secondary plastid trafficking via the endomembrane system.
Susceptibility to Influenza A in HIV-Positive Patients
Authors: James P. Cohen
Journal: JAMA (1989)

To the Editor.—  The Centers for Disease Control (CDC) recently recommended the use of influenza vaccine for persons infected with human immunodeficiency virus (HIV), 1 although the incidence of serious illness caused by influenza A in this population is unknown. We investigated the impact of HIV status on susceptibility to symptomatic illness from influenza A during a recent outbreak.  Study. —  Affected individuals were residents of Spectrum House, a long-term, drug-free residential treatment center situated 48 km (30 miles) west of Boston. The 58 inhabitants—primarily former intravenous abusers of cocaine and heroin—were preponderantly white men and women aged 20 through 45 years. Testing for HIV was encouraged but not mandatory and clients were not segregated for work duties or sleep quarters based on HIV status.  Seventeen clients sought medical attention during the week of March 11, 1988, for a symptom complex that included fever, chills, myalgia, sore throat, headache, and