tbuckley/cabot-search huggingface dataset:
Dual Blockade of the Renin-Angiotensin System in Diabetic Nephropathy
Authors: Kasper Rossing, Per K. Christensen, Berit R. Jensen, Hans-Henrik Parving
Journal: Diabetes Care (2002)

OBJECTIVE—Many patients with diabetic nephropathy (DN) have levels of albuminuria &amp;gt;1 g/day and blood pressure &amp;gt;135/85 mmHg, despite antihypertensive combination therapy, including recommended doses of ACE inhibitors, e.g., lisinopril/enalapril at 20 mg daily. We tested the concept that such patients might benefit from dual blockade of the renin-angiotensin system (RAS). RESEARCH DESIGN AND METHODS—We performed a randomized double-blind crossover study of 2 months treatment with candesartan cilexetil 8 mg once daily and placebo in addition to previous antihypertensive treatment. We included 18 type 2 diabetic patients with DN fulfilling the above-mentioned criteria. All received recommended doses of ACE inhibitor and, in addition, 15 patients received diuretics, 11 received a calcium channel antagonist, and 3 received a β-blocker. At the end of each treatment period, we measured the glomerular filtration rate (GFR), 24-h blood pressure, albuminuria, and IgGuria . RESULTS—The addition of candesartan to usual antihypertensive therapy induced a mean (95% CI) reduction in albuminuria of 25% (2–58), P = 0.036 (geometric mean [95% CI] from 1,764 mg/24 h [1,225–2,540] to 1,334 mg/24 h [890–1,998]). It also produced a mean reduction of 35% (9–53) in the fractional clearance of albumin (P = 0.016), a reduction of 32% (1–54) in fractional clearance of IgG (P = 0.046), a reduction in 24-h systolic blood pressure of 10 mmHg (2–18) (P = 0.019) (mean ± ± SE) from 148 ± 3 to 138 ± 5 mmHg, and a mean reduction in GFR of 5 ml · min−1 · 1.73 m−2 (0.1–9) (P = 0.045). CONCLUSIONS—Dual blockade of the RAS reduces albuminuria and blood pressure in type 2 diabetic patients with DN responding insufficiently to previous antihypertensive therapy, including ACE inhibitors in recommended doses.
ISOLATION AND PARTIAL CHARACTERIZATION OF THE TWO PRINCIPAL INHERITED GROUP-SPECIFIC COMPONENTS OF HUMAN SERUM
Authors: Hartwig Cleve, John H. Prunier, Alexander G. Bearn
Journal: The Journal of Experimental Medicine (1963)

The group-specific component (Gc), an α2-globulin of human plasma with inherited variations in relative electrophoretic mobility, has been isolated from plasma and partially characterized. The isolation procedure combines ammonium sulfate fractionation, anion exchange chromatography, preparative zone electrophoresis, and gel filtration. The method is suitable for the isolation and purification of the group-specific components. The Gc proteins representing the gene products of the two common homozygous Gc-types) Gc 1-1 and Gc 2-2, have been prepared. Gc belongs to the group of α2-globulins of relatively low molecular weight (4.1S, molecular weight 50,800) and relatively low carbohydrate content (3.3 per cent). The total amino acid composition of the two homozygous group-specific components is very similar; treatment with reducing agents and alkylation provides no evidence for the presence of more than a single polypeptide chain in the Gc molecule.
Serotonin promotes the proliferation of serum-deprived hepatocellular carcinoma cells via upregulation of FOXO3a
Authors: Chao Liang, Wei Chen, Xiao Zhi, Tao Ma, Xuefeng Xia, Hao Liu, Qi Zhang, Qida Hu, Yun Zhang, Xueli Bai, Tingbo Liang
Journal: Molecular Cancer (2013)

Peripheral serotonin is involved in tumorigenesis and induces a pro-proliferative effect in hepatocellular carcinoma (HCC) cells; however, the intracellular mechanisms by which serotonin exerts a mitogenic effect remain unclear. In this research, we examined whether FOXO3a, a transcription factor at the interface of crucial cellular processes, plays a role downstream of serotonin in HCC cells.The cell viability and expression of FOXO3a was assessed in three HCC cell lines (Huh7, HepG2 and Hep3B) during serum deprivation in the presence or absence of serotonin. Serum free media significantly inhibited HCC proliferation and led to reduced expression and nuclear accumulation of FOXO3a. Knockdown of FOXO3a enhanced the ability of serum deprivation to inhibit HCC cells proliferation. And overexpression of non-phosphorylated FOXO3a in HCC cells reversed serum-deprivation-induced growth inhibition. Serotonin reversed the serum-deprivation-induced inhibition of cell proliferation and upregulated FOXO3a in Huh7 cells; however, serotonin had no effect on the proliferation of serum-deprived HepG2 or Hep3B cells. In addition to proliferation, serotonin also induced phosphorylation of AKT and FOXO3a in serum-deprived Huh7 cells but not in HepG2 and Hep3B cells. However, the phosphorylation of FOXO3a induced by serotonin did not export FOXO3a from nucleus to cytoplasm in serum-deprived Huh7 cells. Consequently, we demonstrated that serotonin promoted the proliferation of Huh7 cells by increasing the expression of FOXO3a. We also provide preliminary evidence that different expression levels of the 5-HT2B receptor (5-HT2BR) may contribute to the distinct effects of serotonin in different serum-deprived HCC cells.This study demonstrates that FOXO3a functions as a growth factor in serum-deprived HCC cells and serotonin promotes the proliferation of serum-deprived HCC cells via upregulation of FOXO3a, in the presence of sufficient levels of the serotonin receptor 5-HT2BR. Drugs targeting the serotonin-5-HT2BR-FOXO3a pathway may provide a novel target for anticancer therapy.
Emergency Department Use of Aspirin in Patients with Possible Acute Myocardial Infarction
Authors: B. Benjamin Saketkhou
Journal: Annals of Internal Medicine (1997)

Efforts have been made to improve the suboptimal use of aspirin after hospitalization.To assess the frequency and timing of aspirin administration in emergency department patients with possible myocardial infarction.Retrospective record review.Emergency departments of four hospitals affiliated with the same university.All patients who were admitted to the four hospitals in 1994 for evaluation and treatment of suspected acute myocardial infarction.The frequency and timing of aspirin administration and the definitive diagnosis established before discharge from the hospital.Aspirin was not given to 253 of 463 emergency department patients (55%) who had a definitive diagnosis of acute myocardial infarction. Seventy-eight percent of patients who did receive aspirin received it more than 30 minutes after arrival in the emergency department.Aspirin therapy is underutilized as the first intervention in patients who are admitted with suspected myocardial infarction.
Facilitation of β Selection and Modification of Positive Selection in the Thymus of Pd-1–Deficient Mice
Authors: Hiroyuki Nishimura, Tasuku Honjo, Nagahiro Minato
Journal: The Journal of Experimental Medicine (2000)

PD-1 is an immunoglobulin superfamily member bearing an immunoreceptor tyrosine-based inhibitory motif, and disruption of the PD-1 gene results in the development of lupus-like autoimmune diseases. In this study, we examined effects of the PD-1 deficiency on the thymocyte differentiation at the clonal level using T cell receptor (TCR)-β (Vβ8) and TCR-α/β (H-Y and 2C) transgenic mice. In these TCR transgenic lines, PD-1 expression in the thymus was variably augmented, but as in the normal mice, confined largely to the CD4−CD8− thymocytes. The transgenic mice crossed with PD-1−/− mice in the neutral genetic backgrounds exhibited selective increase in the CD4+CD8+ (DP) population with little effect on other thymocytes subsets. Similarly, the absence of PD-1 facilitated expansion of DP thymocytes in recombination activating gene (RAG)-2−/− mice by anti-CD3ε antibody injection. On the other hand, H-Y or 2C transgenic PD-1−/− mice with the positively selecting background showed significantly reduced efficiency for the generation of CD8+ single positive cells bearing the transgenic TCR-α/β in spite of the increased DP population. These results collectively indicate that PD-1 negatively regulates the β selection and modulates the positive selection, and suggest that PD-1 deficiency may lead to the significant alteration of mature T cell repertoire.
Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial
Authors: J. de Jager, A. Kooy, P. Lehert, M. G. Wulffele, J. van der Kolk, D. Bets, J. Verburg, A. J. M. Donker, C. D. A. Stehouwer
Journal: BMJ (2010)

<b>Objectives</b> To study the effects of metformin on the incidence of vitamin B-12 deficiency (&lt;150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin. <b>Design</b> Multicentre randomised placebo controlled trial. <b>Setting</b> Outpatient clinics of three non-academic hospitals in the Netherlands. <b>Participants</b> 390 patients with type 2 diabetes receiving treatment with insulin. <b>Intervention</b> 850 mg metformin or placebo three times a day for 4.3 years. <b>Main outcome measures</b> Percentage change in vitamin B-12, folate, and homocysteine concentrations from baseline at4, 17, 30, 43, and 52 months. <b>Results</b> Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of −19% (95% confidence interval −24% to −14%; P&lt;0.001) and in folate concentration of −5% (95% CI −10% to −0.4%; P=0.033), and an increase in homocysteine concentration of 5% (95% CI −1% to 11%; P=0.091). After adjustment for body mass index and smoking, no significant effect of metformin on folate concentrations was found. The absolute risk of vitamin B-12 deficiency (&lt;150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group (95% CI 2.3 to 12.1; P=0.004), with a number needed to harm of 13.8 per 4.3 years (95% CI 43.5 to 8.3). The absolute risk of low vitamin B-12 concentration (150-220 pmol/l) at study end was 11.2 percentage points higher in the metformin group (95% CI 4.6 to 17.9; P=0.001), with a number needed to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 µmol/l (95% CI 18.8 to 30.0 µmol/l), compared with a mean homocysteine level of 18.1 µmol/l (95% CI 16.7 to 19.6 µmol/l; P=0.003) for patients with a low vitamin B-12 concentration and 14.9 µmol/l (95% CI 14.3 to 15.5 µmol/l; P&lt;0.001 compared with vitamin B-12 deficiency; P=0.005 compared with low vitamin B-12) for patients with a normal vitamin B-12 concentration (&gt;220 pmol/l). <b>Conclusions</b> Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered. <b>Trial registration</b> Clinicaltrials.gov NCT00375388.
Release of TNF-α during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers
Authors: S Gilles
Journal: Cardiovascular Research (2003)

Objectives: Our study sought to elucidate the role of oxidative stress for shedding of tumor necrosis factor-α (TNF-α) and for activating TNF-α-converting enzyme (TACE). Background: TNF-α, a central inflammatory cytokine, is discussed as one of the mediators of reperfusion injury. Shedding of membrane-bound pro-TNF-α is thought to be largely due to TNF-α-converting enzyme (TACE). Methods: Release of TNF-α and TACE dependency were studied in isolated rat hearts and in the human mast cell line HMC-1. Results: In reperfused hearts, interstitial release of TNF-α occurred in two phases (2–10 and >45 min). It depended on the presence of oxygen during reperfusion and was attenuated by reduced glutathione. Infusion of the oxidants H2O2 or HOCl elicited release in non-ischemic hearts. TNF-α release was inhibited in hearts treated with degranulation inhibitors ketotifen or cromoglycate, suggesting mast cells as major source for myocardial TNF-α. This was confirmed by tissue staining. Post-ischemic release of histamine, however, did not parallel that of TNF-α. Heart tissue contained mainly mature TACE. HMC-1 expressed abundant pro-TACE and cleaved the pro-TNF-α-peptide Ac-SPLAQAVRSSSR-NH2. However, cleavage was nonspecific and only partly inhibited by TACE inhibitor TAPI-2 (10–100 μmol/l), while it was stimulated by H2O2 and HOCl and fully blocked by the nonspecific metalloprotease inhibitor o-phenanthroline. Conclusions: The mechanism underlying TNF-α release from post-ischemic myocardium is oxidation-dependent but largely independent of activation of TACE. Mast cell stabilizers may be useful in preventing TNF-α release during reperfusion.
Laminar-Turbulent Transition Process in Pulsatile Flow
Authors: EDWARD L. YELLIN
Journal: Circulation Research (1966)

A controlled ex-vivo study of a simple, sinusoidally oscillating flow in a rigid, constant-area, smooth tube, has produced significant insight into the laminar-turbulent transition phenomenon. The development of turbulence was studied by analyzing the dynamic characteristics of the transition process; i.e., the velocity, growth rate, and intermittency which describe the generation and propagation of turbulent slugs. A new concept, the relaxation time, has been introduced to interpret the effect of a periodic flow component superposed on a mean flow. Classical stability concepts, such as the point of inflection criterion and the Reynolds number, which have been derived from steady-flow analysis, are shown to require modification when applied to an oscillatory flow. Neither the mean nor the instantaneous Reynolds number is a sufficient criterion for determining the transition of laminar to turbulent flow in a pulsatile system. Other necessary criteria are: (1) a source of disturbances, (2) the relaxation time, and (3) the distance from the fluid under observation to the source of disturbance. The concept of relaxation time indicates that slowly oscillating flows of large amplitude tend to suppress or destroy turbulence downstream from sources of disturbance. Qualitative observations are presented which indicate that systolic acceleration may be laminar regardless of the large value of the instantaneous Reynolds number, while diastolic deceleration probably produces disturbed, but not turbulent or highly dissipative, flow.
Pexelizumab and Infarct Size in Patients With Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Manesh R. Patel, Stephen G. Worthley, Amanda Stebbins, Thorsten Dill, Frank E. Rademakers, Uma S. Velleti, Gregory W. Barsness, Frans Van de Werf, Christian W. Hamm, Paul W. Armstrong, Christopher B. Granger, Raymond J. Kim
Journal: JACC. Cardiovascular imaging (2010)
Can the liver be induced to say no?
Authors: John W. Wiley
Journal: Hepatology (1993)

The incubation of primary cultures of rat hepatocytes with lipopolysaccharide (LPS) or biologically active phorbol esters promotes the release of nitric oxide to the incubation medium. This process is the result of the induction of the Ca 2+ - and calmodulinindependent form of nitric oxide synthase. Both the release of nitric oxide to the incubation medium and the expression of nitric oxide synthase activity exhibited a lag period of about 45-60 min after cell stimulation. Exposure of hepatocytes to both stimuli produced an antagonistic effect on nitric oxide release, with a half-maximal inhibition obtained with 14 nM phorbol 12,13-dibutyrate at saturating concentration of LPS. Incubation of cells with α-phorbol 12,13- didecanoate failed to counteract the effect of LPS or to induce nitric oxide synthase, suggesting that activation of protein kinase C was involved in this process.
Constitutive Activation of Signal Transducer and Activator of Transcription 5 Contributes to Tumor Growth, Epithelial-Mesenchymal Transition, and Resistance to Epidermal Growth Factor Receptor Targeting
Authors: Priya Koppikar, Vivian Wai Yan Lui, David Man, Sichuan Xi, Raymond Liu Chai, Elizabeth Nelson, Allison B.J. Tobey, Jennifer Rubin Grandis
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Signal transducer and activator of transcription 5 (STAT5) is activated in squamous cell carcinoma of the head and neck (SCCHN), where targeting of STAT5 inhibits tumor growth in vitro and in vivo. The role of STAT5 activation in carcinogenesis, tumor progression, and response to therapy remains incompletely understood. In this study, we investigated the effects of STAT5 activation on squamous epithelial carcinogenesis and response to therapy. Experimental Design: The functional consequences of STAT5 activation in squamous epithelial carcinogenesis were examined using cells derived from normal (Het-1A) and transformed mucosal epithelial cells engineered to express constitutive-active mutants of STAT5. Results: The growth rate of stable clones derived from both normal and transformed squamous epithelial cells expressing the constitutive-active STAT5 was increased. In SCCHN xenografts, tumor volumes were increased in constitutive-active STAT5 mutant cells compared with vector-transfected controls. Constitutive activation of STAT5 significantly increased cell migration and invasion through Matrigel, as well as the transforming efficiency of SCCHN cells in vitro, as assessed by soft agar assays. The constitutive-active STAT5 clones derived from SCCHN cells showed changes consistent with an epithelial-mesenchymal transition including decreased expression of E-cadherin and increased vimentin in comparison with control transfectants. In these cells, STAT5 activation was associated with resistance to cisplatin-mediated apoptosis and growth inhibition induced by the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Conclusions: These results suggest that constitutive STAT5 signaling enhances tumor growth, invasion, and epithelial-to-mesenchymal transition in squamous epithelial carcinogenesis and may contribute to resistance to epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy.
Engineering Synthetic Vectors for Improved DNA Delivery: Insights from Intracellular Pathways
Authors: Charles M. Roth, Sumati Sundaram
Journal: Annual Review of Biomedical Engineering (2004)

▪ Abstract Significant progress has been made in the area of nonviral gene delivery to date. Yet, synthetic vectors remain less efficient by orders of magnitude than their viral counterparts. Research continues toward unraveling and overcoming various barriers to the efficient delivery of DNA, whether in plasmid form encoding a gene or as an oligonucleotide for the selective inhibition of target gene expression. Novel components for overcoming these hurdles are continually being incorporated into the design of synthetic vectors, leading to increasingly more virus-like particles. Despite these advances, general principles defining the design of synthetic vectors are yet to be developed fully. A more quantitative analysis of the cellular uptake and intracellular processing of these vectors is required for the rational manipulation of vector design. Mathematical frameworks with a more conceptual basis will help obtain an integrated perspective on these complex systems. In this review, we critically examine the progress made toward the improved design of synthetic vectors by the strategic exploitation of intracellular mechanisms and explore newer possibilities to overcome obstacles in the practical realization of this field.
Gene Expression–Based Classification As an Independent Predictor of Clinical Outcome in Juvenile Myelomonocytic Leukemia
Authors: Silvia Bresolin, Marco Zecca, Christian Flotho, Luca Trentin, Andrea Zangrando, Laura Sainati, Jan Stary, Barbara de Moerloose, Henrik Hasle, Charlotte M. Niemeyer, Geertruy te Kronnie, Franco Locatelli, Giuseppe Basso
Journal: Journal of Clinical Oncology (2010)

PURPOSE Juvenile myelomonocytic leukemia (JMML) is a rare early childhood myelodysplastic/myeloproliferative disorder characterized by an aggressive clinical course. Age and hemoglobin F percentage at diagnosis have been reported to predict both survival and outcome after hematopoietic stem cell transplantation (HSCT). However, no genetic markers with prognostic relevance have been identified so far. We applied gene expression-based classification to JMML samples in order to identify prognostic categories related to clinical outcome. PATIENTS AND METHODS Samples of 44 patients with JMML were available for microarray gene expression analysis. A diagnostic classification (DC) model developed for leukemia and myelodysplastic syndrome classification was used to classify the specimens and identify prognostically relevant categories. Statistical analysis was performed to determine the prognostic value of the classification and the genes identifying prognostic categories were further analyzed through R software. RESULTS The samples could be divided into two major groups: 20 specimens were classified as acute myeloid leukemia (AML) -like and 20 samples as nonAML-like. Four patients could not be assigned to a unique class. The 10-year probability of survival after diagnosis of AML-like and nonAML-like patients was significantly different (7% v 74%; P = .0005). Similarly, the 10-year event-free survival after HSCT was 6% for AML-like and 63% for nonAML-like patients (P = .0010). CONCLUSION Gene expression-based classification identifies two groups of patients with JMML with distinct prognosis outperforming all known clinical parameters in terms of prognostic relevance. Gene expression-based classification could thus be prospectively used to guide clinical/therapeutic decisions.
Versatile Prostate Cancer Treatment with Inducible Caspase and Interleukin-12
Authors: Ekaterina Yu. Nikitina, Smruti A. Desai, Xiuqin Zhao, Weitao Song, Annie Z. Luo, Rama D. Gangula, Kevin M. Slawin, David M. Spencer
Journal: Cancer Research (2005)

Abstract To establish optimized conditions for immunity against prostate cancer, we compared the efficacy of multiple approaches in autochthonous and s.c. transgenic adenocarcinoma of the mouse prostate (TRAMP)-based models. Mice immunized with interleukin (IL)-12–containing apoptotic, but not necrotic TRAMP-C2 cell–based, vaccines were resistant to TRAMP-C2 tumor challenge and re-challenge, independently of the route of vaccination (s.c. or i.p.). Administration of γ-irradiated TRAMP-C2 cells preinfected with adenovirus containing both B7-1 and IL-12 genes, unlike adenovirus containing B7-1 alone, considerably protected C57BL/6 mice from TRAMP-C2 tumor growth and extended the life span of TRAMP mice. Vaccines that included dendritic cells, instead of IL-12, were equally efficient. Whereas injections of ligand-inducible caspase-1– and IL-12–containing adenoviruses cured small s.c. TRAMP-C2 tumors, nanopump-regulated delivery of viruses led to elimination of much larger tumors. The antitumor immune responses involved CD4+-, CD8+-, and natural killer cells and were strengthened by increasing the number of vaccinations. Intraprostatic administration of inducible caspase-1– and IL-12–containing adenoviruses resulted in local cell death and improved survival of adenocarcinoma-bearing TRAMP mice. Thus, tumor cell apoptosis induced by caspase in situ and accompanied by IL-12 is efficient against prostate cancer in a preclinical model.