tbuckley/cabot-search huggingface dataset:
Inhibitory Effects of Castration in an Orthotopic Model of Androgen-Independent Prostate Cancer Can Be Mimicked and Enhanced by Angiogenesis Inhibition
Authors: Peter Hammarsten, Sofia Halin, Pernilla Wikstöm, Roger Henriksson, Stina Häggström Rudolfsson, Anders Bergh
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Today, the most important treatment of advanced prostate cancer is castration; unfortunately, however, the long-term effect of this therapy is insufficient. Recent studies suggest that castration-induced prostate involution could be caused by primary effects in the prostate vasculature; therefore, we examined if antivascular treatments could mimic the effects of castration. Experimental Design: Androgen-independent AT-1 prostate cancer cells were grown inside the ventral prostate in adult rats. Tumor-bearing animals were treated with an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor signaling, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine (ZD6474, AstraZeneca, Södertälje, Sweden), and short-term effects (after 3 days) were compared with those induced by castration. Results: Castration caused decreased vascular density in the normal tissue surrounding the tumor and consequently increased tumor hypoxia and apoptosis, and moderately decreased tumor growth. ZD6474 treatment resulted in decreased tumor vascular density accompanied by increased tumor hypoxia, apoptosis, and decreased tumor growth, suggesting that castration and antiangiogenic therapy work through similar mechanisms. Interestingly, castration or ZD6474 alone worked by reducing vascular density in the surrounding normal tissue and ZD6474 also in the tumor. Combined treatment with castration + ZD6474 was more effective than castration and ZD6474 alone in inducing tumor hypoxia, apoptosis, necrosis, and decreasing tumor vascular density. Conclusion: These findings show that a drug that targets the vasculature in the tumor and in the surrounding ventral prostate lobe could mimic and even enhance the effects of castration. Our present findings thus suggest that castration + ZD6474 could be a particularly effective way to treat prostate tumors.
Effect on Glycemic Control of Exenatide (Synthetic Exendin-4) Additive to Existing Metformin and/or Sulfonylurea Treatment in Patients With Type 2 Diabetes
Authors: Mark S. Fineman, Thomas A. Bicsak, Larry Z. Shen, Kristin Taylor, Eling Gaines, Amanda Varns, Dennis Kim, Alain D. Baron
Journal: Diabetes Care (2003)

OBJECTIVE—AC2993 (synthetic exendin-4; exenatide) is a peptide that enhances glucose-dependent insulin secretion, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. AC2993 also promotes β-cell proliferation and neogenesis in vitro and in animal models. This study examines the activity and safety of subcutaneously injected AC2993 in patients with type 2 diabetes currently treated with diet and/or oral antidiabetic agents (OAAs). RESEARCH DESIGN AND METHODS—A total of 109 patients treated with diet and a sulfonylurea and/or metformin were enrolled in a blinded study. Patients were randomly assigned to one of three subcutaneously (SC) injected regimens of AC2993 (0.08 μg/kg) or placebo for 28 days. RESULTS—All three AC2993 regimens led to significant reductions in serum fructosamine relative to placebo (P ≤ 0.004). Mean reductions ranged from 39 to 46 μmol/l. All AC2993 groups had reductions in HbA1c ranging from 0.7 to 1.1% (P ≤ 0.006). An end-of-study HbA1c &amp;lt;7% was achieved by 15% of AC2993 patients versus 4% of placebo patients, confirming AC2993 effects on fasting and postprandial glycemia. On days 14 and 28, the β-cell index (homeostasis model assessment) for patients treated with AC2993 was 50–100% higher than baseline, contrasting with unchanged levels for placebo. The most common adverse event was transient mild-to-moderate nausea. CONCLUSIONS—AC2993 is a promising therapeutic for patients with type 2 diabetes. In this study, it had significant effects on HbA1c levels in patients not currently achieving optimal glucose control with diet and/or OAAs.
Autoantibodies to small ubiquitin-like modifier activating enzymes in Japanese patients with dermatomyositis: comparison with a UK Caucasian cohort
Authors: Manabu Fujimoto, Takashi Matsushita, Yasuhito Hamaguchi, Kenzo Kaji, Yoshihide Asano, Fumihide Ogawa, Toshifumi Yamaoka, Keita Fujikawa, Toshiaki Tsukada, Keita Sato, Takeshi Echigo, Minoru Hasegawa, Kazuhiko Takehara
Journal: Annals of the Rheumatic Diseases (2012)

Dermatomyositis (DM) is a heterogeneous disease with varying degrees and time courses of skin eruptions, myositis and internal organ involvement.1 Increasing evidence has demonstrated that myositis-specific autoantibodies (MSAs) are closely associated with distinct clinical subsets.2 Recently, Betteridge et al 3 ,4 reported a novel MSA against small ubiquitin-like modifier activating enzyme (SAE) in DM patients. In this study, we detected this autoantibody in a Japanese DM cohort and assessed its clinical correlations.

We screened 456 consecutive Japanese patients with DM (11 children, 445 adults); 373 fulfilled the criteria of Bohan and Peter5 ,6 and the remaining 83 fulfilled Sontheimer's criteria for clinically amyopathic DM (CADM).7 Controls included 62 patients with polymyositis, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with interstitial lung disease (ILD) alone. The institutional review board approved the study protocol.

Immunoprecipitation assays were performed as described.8 Protein A-agarose beads preincubated with sera were incubated with 35S-methionine-labelled or unlabelled K562 cell extracts. Immunoprecipitants were fractionated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis, followed by autoradiography or …
International Union of Basic and Clinical Pharmacology. LXXXV: Calcium-Activated Chloride Channels
Authors: Fen Huang, Xiuming Wong, Lily Y. Jan
Journal: Pharmacological Reviews (2011)

Calcium-activated chloride channels (CaCCs) are widely expressed in various tissues and implicated in physiological processes such as sensory transduction, epithelial secretion, and smooth muscle contraction. Transmembrane proteins with unknown function 16 (TMEM16A) has recently been identified as a major component of CaCCs. Detailed molecular analysis of TMEM16A will be needed to understand its structure-function relationships. The role this channel plays in physiological systems remains to be established and is currently a subject of intense investigation.
Transforming Growth Factor β Blocks Tec Kinase Phosphorylation, Ca2+ Influx, and NFATc Translocation Causing Inhibition of T Cell Differentiation
Authors: Chang-Hung Chen, Carole Seguin-Devaux, Nancy A. Burke, Timothy B. Oriss, Simon C. Watkins, Neil Clipstone, Anuradha Ray
Journal: The Journal of Experimental Medicine (2003)

Transforming growth factor (TGF)-β inhibits T cell proliferation and differentiation. TGF-β has been shown to inhibit the expression of transcription factors such as GATA-3 and T-bet that play important roles in T cell differentiation. Here we show that TGF-β inhibits T cell differentiation at a more proximal step. An early event during T cell activation is increased intracellular calcium levels. Calcium influx in activated T cells and the subsequent activation of transcription factors such as NFATc, events essential for T cell differentiation, are modulated by the Tec kinases that are downstream of the T cell receptor and CD28. We show that in stimulated CD4+ T cells, TGF-β inhibits phosphorylation and activation of the Tec kinase Itk, increase in intracellular Ca2+ levels, NFATc translocation, and activation of the mitogen-activated protein kinase ERK that together regulate T cell differentiation. Our studies suggest that by inhibiting Itk, and consequently Ca2+ influx, TGF-β limits T cell differentiation along both the Th1 and Th2 lineages.
Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death
Authors: P Chen
Journal: Cardiovascular Research (2001)

The purpose of this article is to review the nerve sprouting hypothesis of sudden cardiac death. It is known that sympathetic stimulation is important in the generation of sudden cardiac death. For example, there is a diurnal variation of sudden death rate in patients with myocardial infarction. Beta blockers, or drugs with beta blocking effects, are known to prevent sudden cardiac death. It was unclear if the cardiac nerves in the heart play only a passive role in the mechanisms of sudden death. To determine if nerve sprouting and neural remodeling occur after myocardial infarction, we performed immunocytochemical studies of cardiac nerves in explanted native hearts of transplant recipients. We found that there was a positive correlation between nerve density and a clinical history of ventricular arrhythmia. Encouraged by these results, we performed a study in dogs to determine whether or not nerve growth factor (NGF) infusion to the left stellate ganglion can facilitate the development of ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). The results showed that augmented myocardial sympathetic nerve sprouting through NGF infusion plus atrioventricular (AV) block and MI result in a 44% incidence (four of nine dogs) of SCD and a high incidence of VT in the chronic phase of MI. In contrast, none of the six dogs (with AV block and MI) without NGF infusion died suddenly or had frequent VT episodes. Based on these findings, we propose the nerve sprouting hypothesis of ventricular arrhythmia and SCD. The hypothesis states that MI results in nerve injury, followed by sympathetic nerve sprouting and regional (heterogeneous) myocardial hyperinnervation. The coupling between augmented sympathetic nerve sprouting with electrically remodeled myocardium results in VT, VF and SCD. Modification of nerve sprouting after MI may provide a novel opportunity for arrhythmia control.
Comparative Effects of Enalapril and Verapamil on Myocardial Blood Flow in Systemic Hypertension
Authors: Oberdan Parodi, Danilo Neglia, Carlo Palombo, Gianmario Sambuceti, Assuero Giorgetti, Claudio Marabotti, Michela Gallopin, Ignazio Simonetti, Antonio L’Abbate
Journal: Circulation (1997)

Background The comparative effects of calcium channel blockers and ACE inhibitors on myocardial blood flow (MBF) in hypertensive patients after long-term treatment are still unknown. Methods and Results Twenty hypertensive subjects with normal coronary arteries were randomly assigned to verapamil 240 to 480 mg/d or enalapril 10 to 40 mg/d. MBF was quantified at rest, during pacing tachycardia, and after dipyridamole by positron emission tomography and 13 N-ammonia before and 6 months after treatment after 1 week of pharmacological washout. In both groups, blood pressure and heart rate during flow measurements were not different before and after therapy. Before treatment, mean MBF at rest, during pacing tachycardia, and after dipyridamole infusion was similar in the two groups; however, pacing and dipyridamole flows were significantly lower than those obtained in a control group of normotensive subjects. After treatment, in the enalapril-treated patients, MBF did not change in the three study conditions. In the verapamil-treated patients, MBF did not change at rest and significantly increased during pacing and after dipyridamole. The inhomogeneity of regional MBF distribution, evaluated from the coefficient of variation, decreased at rest after both treatments and, in the enalapril group, also during pacing. No relation was found between changes in MBF and changes in left ventricular mass. Conclusions In arterial hypertension, MBF during pacing tachycardia and after dipyridamole is impaired. Successful therapy with verapamil increases MBF response to these stimuli, independent of changes in perfusion pressure and left ventricular mass. These results suggest that verapamil directly improves coronary microcirculatory function in hypertension. Enalapril does not significantly change MBF but reduces the inhomogeneity of regional flow distribution.
Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats.
Authors: S W Chang, C O Feddersen, P M Henson, N F Voelkel
Journal: Journal of Clinical Investigation (1987)

Within 20 min after intraperitoneal injection of Salmonella enteritidis endotoxin in rats, blood platelet-activating factor (PAF) increased from 4.3 +/- 1.3 to 13.7 +/- 2.0 ng/ml (P less than 0.01) and lung PAF from 32.3 +/- 4.9 to 312.3 +/- 19.6 ng (P less than 0.01), but not lung lavage PAF. We tested the effect of PAF receptor antagonists, CV 3988 and SRI 63-441, on endotoxin-induced hemodynamic changes and lung vascular injury. Pretreatment with CV 3988 attenuated systemic hypotension, preserved hypoxic pulmonary vasoconstriction, and prolonged survival of awake catheter-implanted endotoxin-treated (20 mg/kg) rats. Pretreatment with SRI 63-441 prevented the depressed hypoxic pulmonary vasoconstriction after low dose (2 mg/kg) endotoxin. Both CV 3988 and SRI 63-441 blocked the increased extravascular accumulation of 125I-albumin and water in perfused lungs isolated from endotoxin-treated rats. We conclude that PAF is produced in the lung during endotoxemia and may be an important mediator of the systemic and pulmonary hemodynamic changes as well as the acute lung vascular injury after endotoxemia.
Alterations of humoral, cell mediated and antibody dependent cell mediated cytotoxic responses during the course of amoebic infection in guinea pigs.
Authors: V K Vinayak, A Saxena, A K Malik
Journal: Gut (1987)

The cellular and antibody dependent cellular cytotoxic (ADCC) responses of splenic lymphocytes and peritoneal macrophages obtained from animals at variable intervals after inoculation were studied against trophozoites of axenic E histolytica (NIH:200). Cytotoxic responses of effector cells from infected animals were compared with those of effector cells from vaccine stimulated and unstimulated uninfected control animals. Cellular and antibody-dependent cellular cytotoxic responses of the effector cells from animals during the establishment and acute phase of infection were significantly suppressed, compared with unstimulated uninfected and vaccinated (FI amoebic proteins stimulated) effector cells. The effector cells from animals recovered from infection showed enhanced cytotoxic responses against trophozoites of E histolytica. The suppressed cytotoxic response was accompanied by impairment of cytotoxic cell activities and lack, or very low level of anti-FI antibodies in the sera of animals during the establishment phase of infection. With the rise in anti-FI antibodies in the sera of animals ADCC could be induced effectively against trophozoites of E histolytica, which seem to result in clearance of amoebic infection.
Developmental changes in contractile protein adenosine 5'-triphosphatase in the rabbit heart.
Authors: T Nakanishi, M Nagae, A Takao
Journal: Circulation Research (1986)

This study was designed to investigate developmental changes in contractile protein adenosine 5'-triphosphatase in the rabbit heart. Myofibrils and myosin were isolated from ventricular muscles from the fetal, newborn, and adult rabbits. Actin and troponin-tropomyosin complex were isolated from the adult skeletal muscle. Myofibrillar (actomyosin) adenosine 5'-triphosphatase measured at low ionic strength increased with development. In contrast, myofibrillar calcium adenosine 5'-triphosphatase at high ionic strength was the greatest in the newborn and the lowest in the adult. Myosin calcium adenosine 5'-triphosphatase and actin-activated myosin adenosine 5'-triphosphatase were also the greatest in the newborn and the lowest in the adult. The relative proportion of myosin isozyme V1 was the greatest in the newborn and the lowest in the adult. The addition of troponin-tropomyosin complex stimulated myosin adenosine 5'-triphosphatase in the presence of calcium in the adult, but not in the newborn and fetus. As a result, actin-activated myosin adenosine 5'-triphosphatase in the presence of troponin-tropomyosin complex was the greatest in the adult, followed by the newborn and fetus. These data suggest that the low myofibrillar adenosine 5'-triphosphatase activity at low ionic strength in the premature heart may be due to the age-related difference in the interaction of myosin with troponin-tropomyosin. Developmental change in myosin calcium adenosine 5'-triphosphatase (which is determined by the relative proportion of isomyosin V1 and V3) may not be directionally identical to that of the physiologically important myofibrillar adenosine 5'-triphosphatase.
Short-term beneficial effects of methylene blue on kidney damage in septic shock patients
Authors: Suzanne Heemskerk, Frank M. P. van Haren, Norbert A. Foudraine, Wilbert H. M. Peters, Johannes G. van der Hoeven, Frans G. M. Russel, Rosalinde Masereeuw, Peter Pickkers
Journal: Intensive Care Medicine (2007)

We previously demonstrated that upregulation of renal inducible nitric oxide synthase (iNOS) is associated with proximal tubule injury during systemic inflammation in humans. In this study we investigated the short-term effect of methylene blue (MB), an inhibitor of the NO pathway, on kidney damage and function in septic shock patients.A prospective clinical study conducted in an intensive care unit.Nine patients (four men, five women, mean age 71 +/- 3 years) with confirmed or suspected bacterial infection and with refractory septic shock defined as a mean arterial pressure < or = 70 mmHg despite norepinephrine infusion > or = 0.2 microg/kg per minute.A 4 h continuous intravenous infusion of 1 mg/kg MB per hour.The urinary excretion of NO metabolites decreased with median 90% (range 75-95%) from baseline to 6 h after MB administration. The first 24 h creatinine clearance improved by 51% (18-173%) after MB treatment but was still strongly impaired. During the first 6 h after the start of MB treatment both the urinary excretion of cytosolic glutathione S-transferase A1-1 and P1-1, markers for proximal and distal tubule damage, respectively, decreased by 45% (10-70%) and 70% (40-85) vs. baseline. After termination of the MB infusion the NO metabolites and markers of tubular injury returned to pretreatment levels.In septic patients with refractory shock short-term infusion of MB is associated with a decrease in NO production and an attenuation of the urinary excretion of renal tubular injury markers.
Evaluation of disease extent with the Crohn's disease endoscopic index of severity
Authors: Philippe Marteau
Journal: Gut (2013)

Sir,

I read with interest the review by Markus Neurath and Simon Travis on mucosal healing in IBD.1 There is an error in their figure 1 illustrating an example of calculation of the Crohn's disease endoscopic index of severity (CDEIS), and we think that even if this may just be a typing error it deserves correction and some comment. We agree with the authors that calculating the CDEIS is complex and requires careful reading on how to use the score and training of the investigator. The CDEIS was built after establishing which endoscopic lesions have an acceptable interobserver variation.2–4 After …
Joint Effects of Obesity and Vitamin D Insufficiency on Insulin Resistance and Type 2 Diabetes
Authors: Shaum M. Kabadi, Brian K. Lee, Longjian Liu
Journal: Diabetes Care (2012)

The possible interaction of serum 25-hydroxyvitamin D [25(OH)D] and obesity in regard to type 2 diabetes and insulin resistance has not been well studied. To explore the effect modification of obesity on the association between 25(OH)D and insulin resistance/type 2 diabetes, data were examined from a nationally representative sample.
Popliteus tendon tenosynovitis
Authors: S M Blake, N J Treble
Journal: British Journal of Sports Medicine (2005)

This case report highlights an unusual cause of anterolateral knee pain. The popliteus muscle arises from three origins--that is, the lateral femoral condyle, the fibula head, and the lateral meniscus--and inserts into the proximal tibia above the soleal line. It may be subjected to a number of pathologies including tenosynovitis, acute calcific tendonitis, rupture, and even avulsion. In this case, the diagnosis of popliteus tendon tenosynovitis was not made from magnetic resonance imaging findings, but was confirmed and successfully treated during arthroscopic examination.
Teamwork Matters
Authors: Bita Moghaddam, Jesse Wood
Journal: JAMA Psychiatry (2013)

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Molecular Indices of Apoptosis After Intermittent Blood and Crystalloid Cardioplegia
Authors: Jun Feng, Cesario Bianchi, Jennifer L. Sandmeyer, Jianyi Li, Frank W. Sellke
Journal: Circulation (2005)

We investigated whether intermittent blood and crystalloid cardioplegia differentially affect myocardial apoptosis and apoptosis gene-related proteins.Rabbit hearts were perfused with Krebs-Henseleit buffer on a Langendorff apparatus. Control hearts (n=6) were perfused for 120 minutes without cardioplegic ischemia. Hearts were arrested for 60 minutes with warm (37 degrees C) crystalloid cardioplegia (iW-CCP) (n=8) or with warm blood cardioplegia (iW-BCP) (n=8) administered intermittently. In cold (0 to 4 degrees C) groups, hearts were arrested for 60 minutes with cold crystalloid cardioplegia (iC-CCP; n=8) or with cold blood cardioplegia (iC-BCP; n=6) administered intermittently. The hearts were reperfused for 30 minutes with Krebs-Henseleit buffer. iC-BCP significantly preserved the recovery of left ventricular and microvascular function compared with the other 3 experimental groups. There were no significant differences in total protein levels of caspase 3, Bcl-2, Bad, and Bax among the groups. iC-BCP significantly induced greater phosphorylation of Bad (5.6+/-0.8-fold) as compared with the other 3 groups (3.4+/-0.6-fold in iC-CCP, P<0.05; 2.5+/-0.3 in iW-BCP, P<0.05; and 1.4+/-0.2 in iW-CCP, P<0.01). iC-BCP induced less caspase 3 activation and apoptosis than the other 3 groups.iC-BCP is superior to the other cardioplegic solutions in increasing the phosphorylation of Bad, inhibiting the activation of caspase 3, and preventing apoptosis. These effects of iC-BCP were associated with preserved left ventricular function and endothelium-dependent relaxation of coronary microvessels.
A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference
Authors: Douglas A Rubinson, Christopher P Dillon, Adam V Kwiatkowski, Claudia Sievers, Lili Yang, Johnny Kopinja, Dina L Rooney, Mingdi Zhang, Melanie M Ihrig, Michael T McManus, Frank B Gertler, Martin L Scott, Luk Van Parijs
Journal: Nature Genetics (2003)