tbuckley/cabot-search huggingface dataset:
Phosphatase-Mediated Enhancement of Cardiac cAMP-Activated Cl <sup>−</sup> Conductance by a Cl <sup>−</sup> Channel Blocker, Anthracene-9-Carboxylate
Authors: Shi-Sheng Zhou, Akira Takai, Makoto Tominaga, Yasunobu Okada
Journal: Circulation Research (1997)

Abstract An aromatic carboxylate, anthracene-9-carboxylic acid (9-AC), is known as a Cl − channel blocker. However, variable 9-AC effects have hitherto been reported on the cardiac cAMP-activated Cl − conductance, when applied extracellularly. We have reexamined the 9-AC effect on the Cl − conductance activated by isoproterenol or forskolin in guinea pig ventricular myocytes under whole-cell patch-clamp conditions. The inward current was blocked by 9-AC at ≥0.5 mmol/L, but in contrast, the outward current was enhanced at much lower concentrations (ED 50 , ≈13 μmol/L). 9-AC applied by the intracellular perfusion technique increased both the inward and outward currents. In the presence of intracellular 9-AC, deactivation of the conductance after washout of isoproterenol or forskolin was largely prevented. 9-AC produced an enhancing effect, even after inhibiting the deactivation process by okadaic acid (OA), whereas it failed to produce additional effects in the presence of orthovanadate. Intracellular application of 9-AC together with OA virtually abolished the current deactivation. The 9-AC effects on the Cl − conductance were not dependent on intracellular Ca 2+ or pH. Putative inhibitors of alkaline (bromotetramisole) and acid phosphatases (tartrate) were without effect. 9-AC failed to inhibit the activities of purified protein phosphatase (PP)-1, -2A, and -2C. In the extract of guinea pig ventricle, 9-AC (≥10 μmol/L for full action) significantly inhibited a fraction of endogenous phosphatase activity that was sensitive to orthovanadate but not to OA, bromotetramisole, and tartrate. It is concluded that 9-AC blocks cardiac cAMP-activated (cystic fibrosis transmembrane conductance regulator) Cl − conductance from the extracellular side but enhances the conductance from the intracellular side by inhibiting an orthovanadate-sensitive phosphatase distinct from PP-1, -2A, -2B, or -2C and alkaline or acid phosphatase.
Risks of Different Testosterone Preparations
Authors: Margaret E. Wierman
Journal: JAMA Internal Medicine (2015)

tio [HR], 1.26; 95% CI, 1.18-1.35), hospitalization (HR, 1.16; 95% CI, 1.13-1.19), and death (HR, 1.34; 95% CI, 1.15-1.56) compared with testosterone gel or patch formulations. The outcomes of the analysis support the hypothesis that intermittent pharmacologic levels of testosterone, which are inevitable with an injectable depo-testosterone administration every 2 to 3 weeks, result in an association with an increase in the combined outcome of cardiovascular and cerebrovascular morbidity and death. The absolute risk between testosterone therapy groups was small in this epidemiologic analysis, but the risk does raise concern considering the marked increase in testosterone prescriptions both in the United States and internationally 5 and prior associations in large data sets of increased risks in men receiving vs those not receiving treatment. 3,4 In addition, Layton and colleagues 1 did not include a comparison group of men not receiving testosterone, so overall risks and benefits of the therapy cannot be compared between the groups. Layton et al 1 acknowledge the limitations of the study, including lack of information concerning the indication for treatment and only partial data concerning testosterone levels before initiating or during therapy. However, their findings are consistent with those of other large epidemiologic studies 3,4 and the recent alarming US Food and Drug Administration report that more than 25% of testosterone prescriptions in the United States are written without determination of a level and that more than 30% of patients receiving testosterone therapy do not have follow-up laboratory testing. 5 Taken together, these
Carcinoma-Associated Fibroblast–Like Differentiation of Human Mesenchymal Stem Cells
Authors: Pravin J. Mishra, Prasun J. Mishra, Rita Humeniuk, Daniel J. Medina, Gabriela Alexe, Jill P. Mesirov, Sridhar Ganesan, John W. Glod, Debabrata Banerjee
Journal: Cancer Research (2008)

Carcinoma-associated fibroblasts (CAF) have recently been implicated in important aspects of epithelial solid tumor biology, such as neoplastic progression, tumor growth, angiogenesis, and metastasis. However, neither the source of CAFs nor the differences between CAFs and fibroblasts from nonneoplastic tissue have been well defined. In this study, we show that human bone marrow-derived mesenchymal stem cells (hMSCs) exposed to tumor-conditioned medium (TCM) over a prolonged period of time assume a CAF-like myofibroblastic phenotype. More importantly, these cells exhibit functional properties of CAFs, including sustained expression of stromal-derived factor-1 (SDF-1) and the ability to promote tumor cell growth both in vitro and in an in vivo coimplantation model, and expression of myofibroblast markers, including alpha-smooth muscle actin and fibroblast surface protein. hMSCs induced to differentiate to a myofibroblast-like phenotype using 5-azacytidine do not promote tumor cell growth as efficiently as hMSCs cultured in TCM nor do they show increased SDF-1 expression. Furthermore, gene expression profiling revealed similarities between TCM-exposed hMSCs and CAFs. Taken together, these data suggest that hMSCs are a source of CAFs and can be used in the modeling of tumor-stroma interactions. To our knowledge, this is the first report showing that hMSCs become activated and resemble carcinoma-associated myofibroblasts on prolonged exposure to conditioned medium from MDAMB231 human breast cancer cells.
Sirolimus-Eluting Stent Implantation in ST-Elevation Acute Myocardial Infarction
Authors: Francesco Saia, Pedro A. Lemos, Chi-Hang Lee, Chourmouzios A. Arampatzis, Angela Hoye, Muzaffer Degertekin, Kengo Tanabe, Georgios Sianos, Pieter C. Smits, Eugene McFadden, Sjoerd H. Hofma, Willem J. van der Giessen, Pim J. de Feyter, Ron T. van Domburg, Patrick W. Serruys
Journal: Circulation (2003)

Sirolimus-eluting stents (SES) have recently been proven to reduce restenosis and reintervention compared with bare stents. Safety and effectiveness of SES in acute myocardial infarction remain unknown.Since April 16, 2002, a policy of routine SES implantation has been instituted in our hospital, with no clinical or anatomic restrictions, as part of the RESEARCH (Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital) registry. During 6 months of enrollment, 96 patients with ST-elevation acute myocardial infarction underwent percutaneous recanalization and SES implantation; these patients comprise the study population. The incidence of major adverse cardiac events (death, nonfatal myocardial infarction, reintervention) was evaluated. Six-month angiographic follow-up was scheduled per protocol. At baseline, diabetes mellitus was present in 12.5% and multivessel disease in 46.9%. Primary angioplasty was performed in 89 patients (92.7%). Infarct location was anterior in 41 (42.7%) of the cases, and 12 patients (12.5%) had cardiogenic shock. Postprocedural TIMI-3 flow was achieved in 93.3% of the cases. In-hospital mortality was 6.2%. One patient (1.1%) had reinfarction and target lesion reintervention the first day as a result of distal dissection and acute vessel occlusion. During follow-up (mean follow-up of 218+/-75 days), 1 patient died (1.1%), no patient had recurrent myocardial infarction, and there were no additional reinterventions. No early or late stent thromboses were documented. At angiographic follow-up (70%), late loss was -0.04+/-0.25, and no patient presented angiographic restenosis.In this study, sirolimus-eluting stent implantation for patients with ST-elevation acute myocardial infarction was safe without documented angiographic restenosis at 6 months.
Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart
Authors: M. Maczewski, U. Mackiewicz
Journal: Cardiovascular Research (2008)

β-Blockers reduce mortality and morbidity in heart failure. Many of their benefits can be explained solely by heart rate reduction (HRR). We aimed to verify whether the β-blocker, metoprolol, and the pure heart-rate-reducing agent, ivabradine, have the same effects on haemodynamic function, ventricular remodeling, and Ca2+ handling in post-myocardial infarction (MI) heart failure in rat. Metoprolol (250 mg/kg/day) or ivabradine (10 mg/kg/day), offering similar HRR, or no treatment, was started 24 h after an induction of MI or sham surgery in rat. Eight weeks post-MI metoprolol and ivabradine similarly partially prevented deterioration of left ventricular (LV) ejection fraction and reduced post-MI LV wall stress. However, metoprolol partially prevented LV dilation, whereas ivabradine potentiated LV hypertrophy. Metoprolol, but not ivabradine, partially prevented post-MI chronotropic incompetence. Metoprolol markedly, whereas ivabradine mildly, increased the amplitude of the Ca2+ transient in post-MI cardiomyocytes. Ivabradine, but not metoprolol, partially prevented the MI-induced depression of sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity, while metoprolol, but not ivabradine, suppressed Na+/Ca2+ exchanger (NCX) overactivity and normalized Ca2+ sensitivity of ryanodine receptors. Although both metoprolol and ivabradine comparably prevented post-MI deterioration of haemodynamic function in the rat, metoprolol had additional potentially beneficial effects; it prevented LV dilation and hypertrophy, chronotropic incompetence, strongly increased contractility of isolated cardiomyocytes, and prevented the potentially proarrhythmic increase in NCX activity. This indicates that pure HRR does not account for effects of β-blockade in the post-MI setting. Metoprolol and ivabradine similarly improve LV function, although differently affect LV morphology and cellular Ca2+ handling in the post-infarction rat heart.
Severe bullous drug eruption due to sibutramine (ReductilR)
Authors: B.K. Goh, P.P.L. Ng, Y.C. Giam
Journal: British Journal of Dermatology (2003)

Journal Article Severe bullous drug eruption due to sibutramine (Reductil®) Get access B.K. Goh, B.K. Goh National Skin Centre, 1 Mandalay Road, Singapore 308205 E‐mail: bkgoh@nsc.gov.sg Search for other works by this author on: Oxford Academic Google Scholar P.P.L. Ng, P.P.L. Ng National Skin Centre, 1 Mandalay Road, Singapore 308205 E‐mail: bkgoh@nsc.gov.sg Search for other works by this author on: Oxford Academic Google Scholar Y.C. Giam Y.C. Giam National Skin Centre, 1 Mandalay Road, Singapore 308205 E‐mail: bkgoh@nsc.gov.sg Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 149, Issue 1, 1 July 2003, Pages 215–216, https://doi.org/10.1046/j.1365-2133.2003.05413.x Published: 01 July 2003
Lung function tests and a `vertical' P wave axis in the electrocardiogram
Authors: T. T. Chapman
Journal: Thorax (1974)

<b>Chapman, T. T. (1974).</b><i>Thorax</i>, <b>29</b>, 106-109. <b>Lung function tests and a `vertical9 P wave axis in the electrocardiogram.</b> The relationship between a vertical P wave axis and impaired lung function was studied in 1,144 patients with chronic non-specific lung disease. There was a significant relationship between a vertical P wave axis and reduction in forced expiratory volume (FEV<sub>1</sub>), FEV<sub>1</sub> as a percentage of vital capacity (FEV<sub>1</sub>%VC), residual volume (RV), and transfer factor (TF); this relationship was closest in the case of the FEV<sub>1</sub>%VC. There was no significant correlation between P wave axis and the forced inspiratory volume (FIV<sub>1</sub>).
New-onset psoriasis in a patient treated with interferon beta-1a
Authors: I. López-Lerma, P. Iranzo, C. Herrero
Journal: British Journal of Dermatology (2009)

Journal Article New‐onset psoriasis in a patient treated with interferon beta‐1a Get access I. López‐Lerma, I. López‐Lerma Dermatology Department, Hospital Clínic, C/Villarroel 170, 08036 Barcelona, Spain E‐mail: ilopez@clinic.ub.es Search for other works by this author on: Oxford Academic Google Scholar P. Iranzo, P. Iranzo Dermatology Department, Hospital Clínic, C/Villarroel 170, 08036 Barcelona, Spain E‐mail: ilopez@clinic.ub.es Search for other works by this author on: Oxford Academic Google Scholar C. Herrero C. Herrero Dermatology Department, Hospital Clínic, C/Villarroel 170, 08036 Barcelona, Spain E‐mail: ilopez@clinic.ub.es Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 160, Issue 3, 1 March 2009, Pages 716–717, https://doi.org/10.1111/j.1365-2133.2008.09005.x Published: 01 March 2009
Insulin Sensitivity Measured With Euglycemic Clamp Is Independently Associated With Glomerular Filtration Rate in a Community-Based Cohort
Authors: Elisabet Nerpin, Ulf Risérus, Erik Ingelsson, Johan Sundström, Magnus Jobs, Anders Larsson, Samar Basu, Johan Ärnlöv
Journal: Diabetes Care (2008)

OBJECTIVE—To investigate the association between insulin sensitivity and glomerular filtration rate (GFR) in the community, with prespecified subgroup analyses in normoglycemic individuals with normal GFR. RESEARCH DESIGN AND METHODS—We investigated the cross-sectional association between insulin sensitivity (M/I, assessed using euglycemic clamp) and cystatin C–based GFR in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1,070). We also investigated whether insulin sensitivity predicted the incidence of renal dysfunction at a follow-up examination after 7 years. RESULTS—Insulin sensitivity was directly related to GFR (multivariable-adjusted regression coefficient for 1-unit higher M/I 1.19 [95% CI 0.69–1.68]; P &amp;lt; 0.001) after adjusting for age, glucometabolic variables (fasting plasma glucose, fasting plasma insulin, and 2-h glucose after an oral glucose tolerance test), cardiovascular risk factors (hypertension, dyslipidemia, and smoking), and lifestyle factors (BMI, physical activity, and consumption of tea, coffee, and alcohol). The positive multivariable-adjusted association between insulin sensitivity and GFR also remained statistically significant in participants with normal fasting plasma glucose, normal glucose tolerance, and normal GFR (n = 443; P &amp;lt; 0.02). In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function (GFR &amp;lt;50 ml/min per 1.73 m2) during follow-up independently of glucometabolic variables (multivariable-adjusted odds ratio for 1-unit higher of M/I 0.58 [95% CI 0.40–0.84]; P &amp;lt; 0.004). CONCLUSIONS—Our data suggest that impaired insulin sensitivity may be involved in the development of renal dysfunction at an early stage, before the onset of diabetes or prediabetic glucose elevations. Further studies are needed in order to establish causality.
The Novel Nuclear Factor-κB Inhibitor LC-1 Is Equipotent in Poor Prognostic Subsets of Chronic Lymphocytic Leukemia and Shows Strong Synergy with Fludarabine
Authors: Saman Hewamana, Thet Thet Lin, Chris Jenkins, Alan K. Burnett, Craig T. Jordan, Chris Fegan, Paul Brennan, Clare Rowntree, Chris Pepper
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We have recently shown that the novel nuclear factor-κB (NF-κB) inhibitor LC-1 is effective in primary chronic lymphocytic leukemia (CLL) cells. Here we elucidated the mechanism of action of LC-1, evaluated its relative cytotoxicity in prognostic subsets, and investigated its potential synergistic interaction with fludarabine. Experimental Design: Ninety-six fully characterized CLL cases were assessed for in vitro sensitivity to LC-1 and fludarabine. In selected cases, caspase activation, inhibition of Rel A DNA binding, and the transcription of CFLAR, BIRC5, and BCL2 were measured before and after exposure to LC-1. In addition, the efficacy of LC-1 was assessed in the presence of the survival factors CD154 and interleukin-4, and the potential synergistic interaction between LC-1 and fludarabine was evaluated. Results: Cell death was associated with caspase-3 activation mediated via activation of both caspase-8 and caspase-9. Apoptosis was preceded by a reduction of nuclear Rel A DNA binding and inhibition of CFLAR, BIRC5, and BCL2 transcription. Importantly, LC-1 overcame the cytoprotective effects by interleukin-4 and CD40 ligand and was equipotent in CLL cells derived from good and bad prognostic subsets. LC-1 exhibited strong synergy with fludarabine, and the combination produced a highly significant mean dose reduction index for fludarabine of &amp;gt;1,000. Conclusions: In view of imminent first-in-man study of LC-1 in Cardiff, these data show an important mechanistic rationale for the use of LC-1 in this disease. Furthermore, it validates the concept of targeting nuclear factor-κB in CLL and identifies the therapeutic potential of LC-1 in combination with fludarabine even in patients with fludarabine resistance.
Molecular Characterization of Inflammatory Genes in Sentinel and Nonsentinel Nodes in Melanoma
Authors: Hitoe Torisu-Itakura, Jonathan H. Lee, Randall P. Scheri, Young Huynh, Xing Ye, Richard Essner, Donald L. Morton
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Identification of regional node metastasis is important for accurate staging and optimal treatment of early melanoma. We hypothesize that the nodal profile of immunoregulatory cytokines can confirm the identity of the first tumor-draining regional node, i.e., the sentinel node (SN) and indicate its tumor status. Experimental Design: RNA was extracted from freshly dissected and preserved nodal tissue of 13 tumor-negative SNs, 10 tumor-positive SNs (micrometastases &amp;lt;2 mm), and 11 tumor-negative non-SNs (NSN). RNA was converted into cDNA and then amplified by PCR. Expression of 96 cytokines and chemokines was assessed using cDNA microarray and compared by using hierarchical clustering. Results: Fifty-seven genes were expressed at significantly (P &amp;lt; 0.05) different levels in SNs and NSNs (4 genes had higher expression, and 53 genes had lower expression in SNs). Expression levels of interleukin-13 (IL-13), leptin, lymphotoxin β receptor (LTbR), and macrophage inflammatory protein 1b (MIP1b) were significantly higher (P &amp;lt; 0.04, P &amp;lt; 0.01, P &amp;lt; 0.05, and P &amp;lt; 0.01, respectively), and expression level of IL-11Ra was lower (P &amp;lt; 0.03) for tumor-positive as compared with tumor-negative SN. Receiver-operator characteristics curve analyses showed that the area under the curve (AUC) for IL-13, leptin, LTbR, MIP1b, and IL-11Ra was 0.79, 0.83, 0.75, 0.81, and 0.77, respectively. The AUC for the five genes in combination was 0.973, suggesting high concordance of gene-expression profiles with SN staging. Conclusions: SNs have a different immunoregulatory cytokine profile than NSNs. The cytokine profile of tumor-positive SNs; increased expression of IL-13, leptin, LTbR, and MIP1b and decreased expression of IL-11Ra, may provide clues to the local tumor lymph node interaction seen in the earliest steps of melanoma metastasis.
Survival of Patients with Newly Diagnosed Glioblastoma Treated with Radiation and Temozolomide in Research Studies in the United States
Authors: Stuart A. Grossman, Xiaobu Ye, Steven Piantadosi, Serena Desideri, Louis B. Nabors, Myrna Rosenfeld, Joy Fisher
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Novel agents are currently combined with radiation and temozolomide (RT + TMZ) in newly diagnosed glioblastoma using overall survival as the primary end point. Results of these phase II studies are typically compared with the phase III European Organization for Research and Treatment of Cancer (EORTC) survival data that resulted in RT + TMZ becoming standard therapy. Experimental Design: The New Approaches to Brain Tumor Therapy (NABTT) Consortium assigned 365 patients with glioblastoma to four single-cohort studies with similar eligibility criteria. Patients received RT + TMZ with talampanel (n = 72), poly-ICLC (n = 97), or cilengitide (n = 112) or RT + TMZ alone with monitoring of CD4 counts (n = 84). Overall survival of those ages 18 to 70 years with glioblastoma was compared with published EORTC data. Results: NABTT and EORTC patients had comparable performance status and debulking surgery. Median, 12-month, and 24-month survival rates for the EORTC patients (n = 287) and the comparable NABTT patients receiving RT + TMZ and novel agents (n = 244) are 14.6 versus 19.6 months, 61% versus 81%, and 27% versus 37%, respectively. This represents a 37% reduction in odds of death (P &amp;lt; 0.0001) through 2 years of follow-up. NABTT and EORTC patients receiving only RT + TMZ had similar survival. Conclusions: Newly diagnosed glioblastoma treated recently with RT + TMZ and talampanel, poly-ICLC, or cilengitide had significantly longer survival than similar patients treated with only RT + TMZ accrued internationally from 2000 to 2002. These differences could result from the novel agents or changing patterns of care. Until the reasons for these different survival rates are clarified, comparisons of outcomes from phase II studies with published RT + TMZ survival data should be interpreted with caution. Clin Cancer Res; 16(8); 2443–9. ©2010 AACR.
Regulation of Arachidonic Acid Production by Intracellular Calcium in Parathyroid Cells
Authors: Yolanda Almadén, Antonio Canalejo, Evaristo Ballesteros, Gracia Añón, Sagrario Cañadillas, Mariano Rodríguez
Journal: Journal of the American Society of Nephrology (2002)

The action of extracellular calcium on the calcium receptor in parathyroid cells results in activation of phospholipase C (PLC), PLD, and PLA(2). The PLA(2)-arachidonic acid (AA) intracellular signaling pathway mediates inhibition of parathyroid hormone (PTH) secretion. In addition, stimulation of the calcium receptor produces increases in intracellular calcium levels. It was demonstrated that high extracellular phosphate levels reduce the production of AA, a mechanism by which phosphate may stimulate PTH secretion. The objective was to determine, in parathyroid tissue, whether AA production is stimulated by increases in intracellular calcium levels and to investigate whether the decreased AA production induced by high extracellular phosphate levels could be modified by increases in intracellular calcium levels. Experiments were performed in vitro using parathyroid tissue. The intracellular calcium level was increased by incubation with an ionophore (A23187), which increases calcium influx across the cell membrane, or thapsigargin, which releases calcium from intracellular stores. The phosphate concentration in the medium was normal (1 mM) or high (4 mM). The response to calcium was evaluated by incubation with 0.6 or 1.35 mM calcium concentrations. AA production by parathyroid tissue was measured by gas chromatography. In parathyroid tissue incubated with either a calcium ionophore or thapsigargin, there was an increase in AA production, together with inhibition of PTH secretion, suggesting that PLA(2) is activated by the elevation in intracellular calcium levels. Therefore, the effect of intracellular calcium level elevation on AA production in the presence of high extracellular phosphate levels was evaluated. The results demonstrate that, despite high phosphate levels in the medium, both the ionophore and thapsigargin were capable of inducing a marked increase in AA production, which was associated with a decrease in PTH secretion. In conclusion, in parathyroid tissue, AA levels can be regulated by an ionophore and thapsigargin, both of which increase cytosolic calcium concentrations. The stimulation of PTH secretion by high phosphate levels can be prevented by increases in intracellular calcium levels.
Obesity and coronary risk factors among South Asians
Authors: M.S. Djurhuus, J.E. Henriksen, N.A. Klitgaard, H. Beck-Nielsen, BihariS. Raheja, Paul Mckeigue, Michael Marmot, HamidB. Mukhtar, J.M. Beattie, W.A. Littler, Y.K. Seedat, F.G.H. Mayet
Journal: The Lancet (1991)