tbuckley/cabot-search huggingface dataset:
Suppressor T cell growth and differentiation. Identification of a cofactor required for suppressor T cell function and distinct from interleukin 2.
Authors: S Rich, M R Carpino, C Arhelger
Journal: The Journal of Experimental Medicine (1984)

This report describes a Ts costimulator assay and its use to analyze cofactors required for the expression of suppressor T cell function. Activation of primed MLR-Ts (alloantigen-activated suppressor T cells suppressive of mixed leukocyte reaction) to suppressor T cell factor (TsF) production typically fails in the presence of glutaraldehyde-fixed rather than irradiated allogeneic stimulator cells. However, MLR-TsF production was restored by the addition of 48-h primary MLR supernates; MLR-derived Ts costimulator neither activated primed MLR-Ts in the absence of fixed allogeneic stimulators nor directly suppressed assay MLR. Lack of antigen specificity or genetic restriction and failure to activate unprimed MLR-Ts precursors suggested that Ts costimulator activity differed from previously described Ts inducer functions and was more closely aligned with the lymphocyte- or monocyte-derived interleukins (IL). Three findings distinguished Ts costimulator from IL-2. Depletion of IL-2 activity from MLR supernates by HT2 adsorption failed to affect Ts costimulator function. In addition, MLR supernates prepared in the presence of cyclosporin A contained no IL-2 but expressed Ts costimulator activity. Finally, gel chromatography demonstrated Ts costimulator in peaks of 21,000 and 43,000 mol wt that were largely distinct from the IL-2-containing fractions. Ts costimulator activity was also identified in phorbol myristate acetate (PMA)-induced EL4 supernates and was retained in those supernates after IL-2 depletion by HT2 adsorption. In preliminary functional characterization, MLR supernate-derived Ts costimulator triggered MLR-TsF production from irradiated MLR-Ts in the absence of proliferation. Thus a differentiative rather than proliferative stimulus required for primed MLR-Ts function appears to be provided by this Ts costimulator and has been provisionally termed Ts differentiative factor ( TsDF ). This initial characterization may thus identify one of a possibly distinctive family of interleukins required in the alloantigen-driven activation of suppressor T cells to effector function.
Sildenafil Inhibits Hypoxia-Induced Pulmonary Hypertension
Authors: L. Zhao, N.A. Mason, N.W. Morrell, B. Kojonazarov, A. Sadykov, A. Maripov, M.M. Mirrakhimov, A. Aldashev, M.R. Wilkins
Journal: Circulation (2001)

This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice.In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O(2) for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean+/-SD mm Hg]: normoxia 16.0+/-2.1 versus hypoxia 25.0+/-4.8) was almost abolished by sildenafil (normoxia 16.0+/-2.1 versus hypoxia 18.0+/-3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg. kg(-1). d(-1)) throughout 3 weeks of exposure to hypoxia (10% O(2)) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3+/-9.9 versus 29.9+/-9.7 mm Hg, P<0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling.Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.
Activity of Androgen Receptor Antagonist Bicalutamide in Prostate Cancer Cells Is Independent of NCoR and SMRT Corepressors
Authors: Myles C. Hodgson, Inna Astapova, Anthony N. Hollenberg, Steven P. Balk
Journal: Cancer Research (2007)

Abstract The mechanisms by which androgen receptor (AR) antagonists inhibit AR activity, and how their antagonist activity may be abrogated in prostate cancer that progresses after androgen deprivation therapy, are not clear. Recent studies show that AR antagonists (including the clinically used drug bicalutamide) can enhance AR recruitment of corepressor proteins [nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid receptors (SMRT)] and that loss of corepressors may enhance agonist activity and be a mechanism of antagonist failure. We first show that the agonist activities of weak androgens and an AR antagonist (cyproterone acetate) are still dependent on the AR NH2/COOH-terminal interaction and are enhanced by steroid receptor coactivator (SRC)-1, whereas the bicalutamide-liganded AR did not undergo a detectable NH2/COOH-terminal interaction and was not coactivated by SRC-1. However, both the isolated AR NH2 terminus and the bicalutamide-liganded AR could interact with the SRC-1 glutamine-rich domain that mediates AR NH2-terminal binding. To determine whether bicalutamide agonist activity was being suppressed by NCoR recruitment, we used small interfering RNA to deplete NCoR in CV1 cells and both NCoR and SMRT in LNCaP prostate cancer cells. Depletion of these corepressors enhanced dihydrotestosterone-stimulated AR activity on a reporter gene and on the endogenous AR-regulated PSA gene in LNCaP cells but did not reveal any detectable bicalutamide agonist activity. Taken together, these results indicate that bicalutamide lacks agonist activity and functions as an AR antagonist due to ineffective recruitment of coactivator proteins and that enhanced coactivator recruitment, rather than loss of corepressors, may be a mechanism contributing to bicalutamide resistance. [Cancer Res 2007;67(17):8388–95]
Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies.
Authors: R A Larson, R Mick, R T Spielberger, S M O'Brien, M J Ratain
Journal: Journal of Clinical Oncology (1996)

The optimal dose and schedule for cladribine (2CdA) therapy of malignant hematologic diseases have not been determined. This dose-escalation study was designed to assess toxicity when 2CdA is given using five daily 1-hour intravenous infusions.Forty-two adults with advanced hematologic malignancies were treated in one of nine cohorts, starting at 2.5 mg/m2/d for 5 days. Plasma drug concentrations were measured by high-performance liquid chromatography. Responses were assessed by bone marrow biopsy on day 15 of the first course and by clinical measurements after each course. Patients received one to four courses each.Nonhematologic toxicity was mild, and dose-limiting nonhematologic toxicity was not observed, even at the highest dose level of 21.5 mg/m2/d. In particular, neurotoxicity was not observed. The maximum-tolerated dose (MTD) was not identified. However, prolonged cytopenias and severe infections were more common in the higher 2CdA dose cohorts. Logistic regression analysis suggested that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were identified as having a PS of 0 and platelet count > or = 80,000/microL, PS of 1 and platelet count > or = 120,000/microL, or PS of 2 and platelet count > or = 160,000/microL. Sustained complete responses (CRs) and partial responses (PRs) were observed in eight patients.2CdA can be administered using five daily 1-hour infusions at 21.5 mg/m2/d without dose-limiting nonhematologic toxicity. Unlike continuous intravenous infusions, neurotoxicity was not observed using this schedule. Further dose escalation may be possible in good PS patients with adequate platelet counts.
Gastrin Enhances the Angiogenic Potential of Endothelial Cells via Modulation of Heparin-Binding Epidermal-Like Growth Factor
Authors: Philip A. Clarke, Jacqueline H. Dickson, Joseph C. Harris, Anna Grabowska, Susan A. Watson
Journal: Cancer Research (2006)

This study examined whether gastrin modulates endothelial cell activity via heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression. Human umbilical vascular endothelial cells (HUVEC) were assessed for tubule formation in the presence of amidated gastrin-17 (G17) and glycine-extended gastrin-17 (GlyG17) peptides. HB-EGF gene and protein expressions were measured by quantitative reverse transcription-PCR, immunocytochemistry, and Western blotting, and HB-EGF shedding by ELISA. Matrix metalloproteinases MMP-2, MMP-3, and MMP-9 were assessed by Western blotting. Chick chorioallantoic membrane studies measured the in vivo angiogenic potential of gastrin and microvessel density (MVD) was assessed in large intestinal premalignant lesions of hypergastrinaemic APC(Min) mice. MVD was also examined in human colorectal tumor and resection margin normals and correlated with serum-amidated gastrin levels (via RIA) and HB-EGF protein expression (via immunohistochemistry). HUVEC cells showed increased tubule and node formation in response to G17 (186%, P < 0.0005) and GlyG17 (194%, P < 0.0005). This was blockaded by the cholecystokinin-2 receptor (CCK-2R) antagonists JB95008 and JMV1155 and by antiserum to gastrin and HB-EGF. Gastrin peptides increased HB-EGF gene expression/protein secretion in HUVEC and microvessel-derived endothelial cells and the levels of MMP-2, MMP-3, and MMP-9. G17 promoted angiogenesis in a chorioallantoic membrane assay, and MVD was significantly elevated in premalignant large intestinal tissue from hypergastrinaemic APC(Min) mice. In terms of the clinical situation, MVD in the normal mucosa surrounding colorectal adenocarcinomas correlated with patient serum gastrin levels and HB-EGF expression. Gastrin peptides, acting through the CCK-2R, enhance endothelial cell activity in models of angiogenesis. This may be mediated through enhanced expression and shedding of HB-EGF, possibly resulting from increased activity of matrix metalloproteinases. This proangiogenic effect translates to the in vivo and human situations and may add to the tumorigenic properties attributable to gastrin peptides in malignancy.
Effect of Upper Extremity Exercise on Secondary Lymphedema in Breast Cancer Patients: A Pilot Study
Authors: Donald C. McKenzie, Andrea L. Kalda
Journal: Journal of Clinical Oncology (2003)

To examine the effect of a progressive upper-body exercise program on lymphedema secondary to breast cancer treatment.Fourteen breast cancer survivors with unilateral upper extremity lymphedema were randomly assigned to an exercise (n = 7) or control group (n = 7). The exercise group followed a progressive, 8-week upper-body exercise program consisting of resistance training plus aerobic exercise using a Monark Rehab Trainer arm ergometer. Lymphedema was assessed by arm circumference and measurement of arm volume by water displacement. Patients were evaluated on five occasions over the experimental period. The Medical Outcomes Trust Short-Form 36 Survey was used to measure quality of life before and after the intervention. Significance was set at alpha < or = 0.01.No changes were found in arm circumference or arm volume as a result of the exercise program. Three of the quality-of-life domains showed trends toward increases in the exercise group: physical functioning (P =.050), general health (P =.048), and vitality (P =.023). Mental health increased, although not significantly, for all subjects (P =.019). Arm volume measured by water displacement was correlated with calculated arm volume (r =.973, P <.001), although the exercise and control group means were significantly different (P <.001).Participation in an upper-body exercise program caused no changes in arm circumference or arm volume in women with lymphedema after breast cancer, and they may have experienced an increase in quality of life. Additional studies should be done in this area to determine the optimum training program.
Superoxide Anions Induce the Maturation of Human Dendritic Cells
Authors: Salomé Kantengwa, Lan Jornot, Christiane Devenoges, Laurent P. Nicod
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Dendritic cells play a key role in immune responses. There is growing evidence that reactive oxygen species participate in signaling pathways involving nuclear factor (NF)-kappaB, leading to expression of important immune system genes. We found that, unlike H2O2, reactive oxygen species generated by the reaction of oxidase on xanthine induced early phenotypic maturation of dendritic cells by upregulating specific markers CD80, CD83, and CD86 and downregulating mannose receptor-mediated endocytosis. Maturation induced by xanthine oxidase was prevented by allopurinol, an inhibitor of xanthine oxidase activity, and by N-acetylcysteine. The proteasome inhibitor MG-132, which blocks NF-kappaB activation, also inhibited CD86 upregulation, but not endocytosis downregulation by reactive oxygen species. Finally, xanthine-xanthine oxidase enhanced or blocked antigen presentation by dendritic cells depending on whether they had been prepulsed or not with the antigen. Taken together, these results demonstrate that oxidative stress induces phenotypic and functional maturation of dendritic cells, partly through an NF-kappaB-dependent mechanism.
Expression of endogenous xenotropic retrovirus by methylcholanthrene-induced squamous cell carcinoma of the mouse respiratory tract.
Authors: P Ebenstein, B Kinder, D O Bankole, F F Richards, M Y Armstrong
Journal: The Journal of Experimental Medicine (1979)

As a model for human lung cancer, squamous cell carcinomas were induced by 3-methylcholanthrene in mouse tracheas which had been explanted to a subcutaneous site. The tumors that developed were examined for both ecotropic and xenotropic infectious murine leukemia virus (MuLV). From all squamous carcinomas--six out of six--a xenotropic MuLV was isolated. From some of the fibrosarcomas that occurred incidentally in our induction system, ecotropic MuLV was isolated. However, in the fibrosarcomas, no xenotropic MuLV at all was found.
Angiotensin-(1–7) modulates vascular resistance and sympathetic neurotransmission in kidneys of spontaneously hypertensive rats
Authors: J Stegbauer
Journal: Cardiovascular Research (2003)

Objective: Angiotensin (Ang)-(1–7) generated from Ang I and II is reported to act as an endogenous angiotensin-converting enzyme (ACE) inhibitor and angiotensin type 1 (AT1)-receptor antagonist in vitro and in vivo. Ang-(1–7) has been suggested to play an important role in hypertension. Methods and results: Therefore, we tested whether Ang-(1–7) differentially modulates vascular resistance and neurotransmission in isolated kidneys of spontaneously hypertensive rats stroke prone (SHR-SP) and Wistar–Kyoto rats (WKY). Ang-(1–7) was administered in three concentrations (0.1, 1 and 10 μmol/l) to prevent Ang I- and Ang II-induced pressor responses and facilitation of noradrenaline release. There were indeed concentration-dependent strain differences. Ang-(1–7) prevented Ang I- and Ang II-mediated changes in vascular resistance more potently in SHR-SP than in WKY by inhibiting ACE and by blocking AT1-receptors. Ang-(1–7) by itself had no influence on renal vascular tone in both strains. Ang-(1–7) inhibited Ang I-mediated facilitation of noradrenaline release more potently than Ang II-mediated facilitation of noradrenaline release. Ang-(1–7) by itself enhanced noradrenaline release from SHR-SP, but not from WKY kidneys. Conclusion: Ang-(1–7) had a greater impact on Ang I and Ang II modulation of renal vascular resistance in SHR-SP than in normotensive rats. Furthermore, Ang-(1–7) by itself has facilitatory presynaptic effects on noradrenaline release but no postsynaptic effects on renal vascular resistance in SHR-SP. Since plasma levels of Ang-(1–7) accumulate during ACE-inhibitor or AT1-receptor antagonist therapy, Ang-(1–7) could contribute to antihypertensive effects of these agents.
Effect of smoking on exhaled nitric oxide and flow-independent nitric oxide exchange parameters
Authors: A. Malinovschi, C. Janson, T. Holmkvist, D. Norbäck, P. Meriläinen, M. Högman
Journal: European Respiratory Journal (2006)

It is a well-known fact that smoking is associated with a reduction in exhaled nitric oxide (NO) levels. There is, however, limited knowledge relating to the smoking-induced changes in production or exchange of NO in different compartments of the airways. This study comprised 221 adult subjects from the European Community Respiratory Health Survey II, who were investigated in terms of their exhaled NO, lung function, immunoglobulin E sensitisation and smoking habits. The following parameters were determined using extended NO analysis: airway tissue nitric oxide concentration ( C aw,NO ), airway transfer factor (or diffusing capacity) for nitric oxide ( D aw,NO ), alveolar nitric oxide concentration ( C A,NO ) and fractional exhaled nitric oxide concentration at a flow rate of 50 mL·s -1 ( F eNO,0.05 ). Maximum total airway nitric oxide flux ( J ' aw,NO ) was calculated from D aw,NO ( C aw,NO – C A,NO ). Current smokers (n = 35) exhibited lower (geometric mean) F eNO,0.05 (14.0 versus 22.8 ppb), C aw,NO (79.0 ;versus 126 ppb) and J ' aw,NO (688 versus 1,153 pL·s -1 ) than never-smokers (n = 111). Ex-smokers (n = 75) were characterised by lower F eNO,0.05 (17.7 versus 22.8 ppb) and J aw,NO (858 versus 1,153 pL·s -1 ) than never-smokers. These relationships were maintained after adjusting for potential confounders (sex, age, height, immunoglobulin E sensitisation and forced expiratory volume in one second), and, in this analysis, a negative association was found between current smoking and C A,NO . Snus (oral moist snuff) consumption (n = 21) in ex-smokers was associated with an increase in D aw,NO and a reduction in C aw,NO , after adjusting for potential confounders. Passive smoking was associated with a higher C A,NO . Using extended nitric oxide analysis, it was possible to attribute the reduction in exhaled nitric oxide levels seen in ex- and current smokers to a lower total airway nitric oxide flux in ex-smokers and reduced airway and alveolar nitric oxide concentrations in current smokers. The association between snus (oral tobacco) use and reduced nitric oxide concentrations in the airways and increased nitric oxide transfer from the airways warrants further studies.
Randomized Study of Three Different Doses of Suramin Administered With a Fixed Dosing Schedule in Patients With Advanced Prostate Cancer: Results of Intergroup 0159, Cancer and Leukemia Group B 9480
Authors: Eric J. Small, Susan Halabi, Mark J. Ratain, Gary Rosner, Walter Stadler, David Palchak, Ernest Marshall, Randall Rago, Vera Hars, George Wilding, Daniel Petrylak, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent. PATIENTS AND METHODS: Patients were randomized with equal probability to receive low-, intermediate-, or high-dose suramin (total doses 3.192, 5.320, and 7.661 g/m 2 , respectively). Overall survival, time to progression, and response rate (prostate-specific antigen [PSA] and objective) for each treatment arm were compared. Relationships between plasma suramin concentrations and response, toxicity, and survival were also evaluated. RESULTS: Three hundred ninety patients were randomized. For the low-, intermediate-, and high-dose arms, the median survival time was 16, 14, and 13 months, respectively (P = .49). The objective response rate was 9%, 7%, and 15%, respectively (P = .10). PSA response rates were 24%, 28%, and 34%, respectively (P = .082). Landmark analyses of a 50% decline in PSA at 20 weeks showed a significant correlation with survival. There was a dose-response relationship between dose and toxicity. After adjusting for treatment arm, the measured suramin concentration was not associated with clinical response, PSA response, survival, or toxicity. CONCLUSION: Although high-dose suramin was associated with higher objective and PSA response rates, these were not statistically significant. Overall, no dose-response relationship was observed for survival or progression-free survival, but toxicity was increased with the higher dose. Patients treated with the low-dose level experienced modest toxicity, making it the preferred arm on this study. The lack of a dose-response relationship and the toxicity profile observed raise questions regarding the utility of suramin, particularly high-dose suramin, as administered on this schedule.
Vascular Endothelial Growth Factor165 Resolves Glomerular Inflammation and Accelerates Glomerular Capillary Repair in Rat Anti–Glomerular Basement Membrane Glomerulonephritis
Authors: Akira Shimizu, Yukinari Masuda, Takahiro Mori, Hiroshi Kitamura, Masamichi Ishizaki, Yuichi Sugisaki, Yuh Fukuda
Journal: Journal of the American Society of Nephrology (2004)

Vascular endothelial growth factor (VEGF) is essential for maintenance of the glomerular capillary network. The present study investigated the effects of VEGF in rats with progressive crescentic glomerulonephritis (GN). Necrotizing and crescentic GN was induced in rats by injection of anti-rat glomerular basement membrane (GBM) antibody. The alterations of glomerular capillaries and glomerular VEGF expression were assessed. In addition, the effects of continuous VEGF<sub>165</sub> administration (10 μg/100 g per d) on glomerular capillaries, glomerular inflammation, and the course of crescentic GN were examined. The appropriate timing of VEGF administration in progressive GN also was evaluated. In anti-GBM GN, necrotizing and crescentic glomerular lesions occurred by day 7, and newly formed necrotizing lesions reoccurred by week 3. Expression of VEGF was markedly reduced in necrotizing and crescentic lesions. Capillary repair was impaired after capillary destruction in necrotizing and crescentic glomeruli, which rapidly progressed to sclerotic glomeruli with chronic renal failure. In contrast, in the rats that received VEGF<sub>165</sub> administration from day 7, the necrotizing and crescentic lesions recovered and renal function significantly improved in week 4. This was evident by proliferating endothelial cells and glomerular capillary repair. In addition, VEGF administration decreased intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 expression in glomeruli (particularly on endothelial cells), reduced glomerular infiltrating CD8-postive and ED-1–positive cells, and inhibited the newly formed necrotizing lesions. VEGF administration was apparently effective against both the inflammatory and necrotizing glomerular lesions. These results suggest that VEGF administration resolves glomerular inflammation and accelerates glomerular recovery in the progressive necrotizing and crescentic GN. The therapeutic application of VEGF may be clinically useful for severe GN accompanied by extensive glomerular inflammation and endothelial injury.
Inhibition of Respiratory Syncytial Virus (RSV) Replication in Cell Culture by Small Interfering RNA (siRNA)
Authors: M.R. Khaitov, V.S. Akimov, E.B. Faizuloev, A.A. Nikonova, L.P. Alexeev, V.V. Zverev, L.M. DuBuske
Journal: Journal of Allergy and Clinical Immunology (2007)