tbuckley/cabot-search huggingface dataset:
Adenylyl Cyclase Isoform–Selective Regulation of Vascular Smooth Muscle Proliferation and Cytoskeletal Reorganization
Authors: Robert Gros, Qingming Ding, Jozef Chorazyczewski, J. Geoffrey Pickering, Lee E. Limbird, Ross D. Feldman
Journal: Circulation Research (2006)

Compartmentation of cAMP signaling been demonstrated to be attributable to the structural association of protein kinase A (PKA) (via association with A-kinase anchoring proteins [AKAPs]) with phosphodiesterase and AKAP-dependent effector molecules. However, other mechanisms contributing to compartmentalization have not been rigorously explored, including the possibility that different isoforms of adenylyl cyclase (AC) may be functionally "compartmentalized" because of differential association with tethering or signaling molecules. To this end, we examined the effect of adenoviral transduction of representative AC isoforms (AC1, AC2, AC5, and AC6) on cellular cAMP production, PKA activation, extracellular signal-regulated kinase (ERK) activation, cell doubling and proliferation, as well as arborization responses (an index of cAMP-mediated cytoskeletal re-organization) in vascular smooth muscle cells. When isoforms were expressed at levels to achieve comparable forskolin-stimulated AC activity, only gene transfer of AC6 significantly enhanced PKA-dependent vasodilator-stimulated phosphoprotein (VASP) phosphorylation and arborization responses. Treatment of control cells, which express AC6 endogenously, as well as vascular smooth overexpressing the AC6 isoform with small interfering RNA directed against AC6, significantly suppressed both isoproterenol-stimulated cAMP accumulation and arborization. Notably, the selective effects of AC6 expression were abrogated in the presence of phosphodiesterase suppression. In contrast, only the expression of AC1 enhanced forskolin-stimulated association of ERK with AC, demonstrated by coimmuno-isolation of ERK with Flag-tagged AC1, but not with Flag-tagged AC6. To determine whether these isoform-selective effects of AC were unique to differentiated and morphologically compartmentalized vascular smooth muscle cells or were a general property of these isoforms, we examined the consequence of expression of these various isoforms in human embryonic kidney (HEK) cells. Indeed, we observed similar isoform-dependent association of AC1 with ERK, activation of ERK by stimulation of AC1 with forskolin, and AC1-dependent lengthening of doubling time, indicating that these properties of AC1 are cell autologous and likely result from AC1-dependent protein-protein interactions. In aggregate, these findings suggest that isoform-selective signaling complexes likely contribute to various functional consequences of cAMP elevation in vascular smooth muscle cells.
Kinetics of the Inhibitory Effect of Pepstatin on the Reaction of Hog Renin with Rat Plasma Substrate
Authors: HELMUT ORTH, EBERHARD HACKENTHAL, JEFFREY LAZAR, ULRIKE MIKSCHE, FRANZ GROSS
Journal: Circulation Research (1974)

The reaction between hog renin and rat angiotensinogen followed Michaelis-Menten kinetics. A K m value of 1,109 ng angiotensin/ml was determined for the rate of angiotensin formation at pH 7.4 and 37°C. The pH optimum for the reaction of hog renin with rat angiotensinogen was between 6.8 and 7.0. Pepstatin inhibited the reaction in a noncompetitive way. The maximum inhibitory effect occurred at approximately pH 6; at values above pH 8.0, pepstatin had no inhibitory effect. The effect of pepstatin was reversible, since renin activity could be restored by 24 hours of dialysis against distilled water. A 50% inhibition of the enzymatic activity of 0.01 dog units of hog renin was obtained with 0.45 µg pepstatin/ml.
Long-term outcome for gastric marginal zone lymphoma treated with radiotherapy: a retrospective, multi-centre, International Extranodal Lymphoma Study Group study
Authors: A. Wirth, M. Gospodarowicz, B.M.P. Aleman, M. Bressel, A. Ng, M. Chao, R.T. Hoppe, C. Thieblemont, R. Tsang, L. Moser, L. Specht, T. Szpytma, A. Lennard, J.F. Seymour, E. Zucca
Journal: Annals of Oncology (2013)
Allogeneic Transplant with Reduced Intensity Conditioning Regimens may Overcome the Poor Prognosis of B-Cell Chronic Lymphocytic Leukemia with Unmutated Immunoglobulin Variable Heavy-Chain Gene and Chromosomal Abnormalities (11q− and 17p−)
Authors: Dolores Caballero, Jose A. García-Marco, Rodrigo Martino, Victoria Mateos, José M. Ribera, José Sarrá, Angel León, Guillermo Sanz, Javier de la Serna, Rafael Cabrera, Marcos González, Jorge Sierra, Jesús San Miguel
Journal: Clinical Cancer Research (2005)

To evaluate the efficacy of reduced intensity conditioning (RIC) allogeneic transplant in 30 patients with poor-prognosis chronic lymphocytic leukemia (CLL) and/or high-risk molecular/cytogenetic characteristics.Eighty-three percent of patients had active disease at the moment of transplant. That is, 14 of the 23 patients analyzed (60%) had unmutated immunoglobulin variable heavy-chain gene (IgV(H)) status; 8 of 25 patients (32%) had 11q-, with four of them also displaying unmutated IgV(H); and six (24%) had 17p- (five were also unmutated).After a median follow-up of 47.3 months, all 22 patients alive are disease free; overall survival and event-free survival (EFS) at 6 years were 70% and 72%, respectively. According to molecular/cytogenetic characteristics, overall survival and EFS for unmutated CLL and/or with 11q- aberration (n = 13) were 90% and 92%, respectively, not significantly different to those with normal in situ hybridization, 13q- and +12, or mutated CLL (n = 7). All six patients with 17p deletion were transplanted with active disease, including three with refractory disease; all except one reached complete remission after the transplant and two are alive and disease free. Nonrelapse mortality (NRM) was 20%; more than two lines before transplant is an independent prognostic factor for NRM (P = 0,02), EFS (P = 0.02), and overall survival (P = 0.01). Patients older than 55 years have a higher risk of NRM (hazard ratio, 12.8; 95% confidence interval, 1.5-111). Minimal residual disease was monitored by multiparametric flow cytometry in 21 patients. Clearance of CD79/CD5/CD19/CD23 cells in bone marrow was achieved in 68% and 94% of the patients at days 100 and 360, respectively.According to these results, RIC allogeneic transplant could overcome the adverse prognosis of patients with unmutated CLL as well as those with 11q- or 17p-.
Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions
Authors: L. Schmidt, T. Kling, N. Monsefi, M. Olsson, C. Hansson, S. Baskaran, B. Lundgren, U. Martens, M. Haggblad, B. Westermark, K. Forsberg Nilsson, L. Uhrbom, L. Karlsson-Lindahl, P. Gerlee, S. Nelander
Journal: Neuro-Oncology (2013)

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, and despite state-of-the-art treatment, survival remains poor and novel therapeutics are sorely needed. The aim of the present study was to identify new synergistic drug pairs for GBM. In addition, we aimed to explore differences in drug-drug interactions across multiple GBM-derived cell cultures and predict such differences by use of transcriptional biomarkers. We performed a screen in which we quantified drug-drug interactions for 465 drug pairs in each of the 5 GBM cell lines U87MG, U343MG, U373MG, A172, and T98G. Selected interactions were further tested using isobole-based analysis and validated in 5 glioma-initiating cell cultures. Furthermore, drug interactions were predicted using microarray-based transcriptional profiling in combination with statistical modeling. Of the 5 × 465 drug pairs, we could define a subset of drug pairs with strong interaction in both standard cell lines and glioma-initiating cell cultures. In particular, a subset of pairs involving the pharmaceutical compounds rimcazole, sertraline, pterostilbene, and gefitinib showed a strong interaction in a majority of the cell cultures tested. Statistical modeling of microarray and interaction data using sparse canonical correlation analysis revealed several predictive biomarkers, which we propose could be of importance in regulating drug pair responses. We identify novel candidate drug pairs for GBM and suggest possibilities to prospectively use transcriptional biomarkers to predict drug interactions in individual cases.
Ground-based walking training improves quality of life and exercise capacity in COPD
Authors: Sally L. Wootton, L.W. Cindy Ng, Zoe J. McKeough, Sue Jenkins, Kylie Hill, Peter R. Eastwood, David R. Hillman, Nola Cecins, Lissa M. Spencer, Christine Jenkins, Jennifer A. Alison
Journal: European Respiratory Journal (2014)

This study was designed to determine the effect of ground-based walking training on health-related quality of life and exercise capacity in people with chronic obstructive pulmonary disease (COPD). People with COPD were randomised to either a walking group that received supervised, ground-based walking training two to three times a week for 8-10 weeks, or a control group that received usual medical care and did not participate in exercise training. 130 out of 143 participants (mean±sd age 69±8 years, forced expiratory volume in 1 s 43±15% predicted) completed the study. Compared to the control group, the walking group demonstrated greater improvements in the St George's Respiratory Questionnaire total score (mean difference -6 points (95% CI -10- -2), p<0.003), Chronic Respiratory Disease Questionnaire total score (mean difference 7 points (95% CI 2-11), p<0.01) and endurance shuttle walk test time (mean difference 208 s (95% CI 104-313), p<0.001). This study shows that ground-based walking training is an effective training modality that improves quality of life and endurance exercise capacity in people with COPD.
Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients
Authors: Anne Joutel, Katayoun Vahedi, Christophe Corpechot, Alain Troesch, Hugues Chabriat, Céline Vayssière, Corinne Cruaud, Jacqueline Maciazek, Jean Weissenbach, Marie-Germaine Bousser, Jean-François Bach, Elisabeth Tournier-Lasserve
Journal: The Lancet (1997)
Oxysterol-induced apoptosis of smooth muscle cells is under the control of a soluble adenylyl cyclase
Authors: Avinash Appukuttan, Sascha Andreas Kasseckert, Sanjeev Kumar, H. Peter Reusch, Yury Ladilov
Journal: Cardiovascular Research (2013)

Apoptosis of vascular smooth muscle cells (VSMC) in advanced atherosclerotic plaques is an important cause of plaque instability. Oxysterols have been suggested as important inducers of apoptosis in VSMC, but the precise mechanism is still poorly understood. Here we aimed to analyse the role of the soluble adenylyl cyclase (sAC). VSMC derived from rat aorta were treated with either 25-hydroxycholesterol or 7-ketocholesterol for 24 h. Apoptosis was detected by TUNEL staining and caspases cleavage. Oxysterols treatment led to the activation of the mitochondrial pathway of apoptosis (cytochrome c release and caspase-9 cleavage) and mitochondrial ROS formation, which were suppressed by the pharmacological inhibition or knockdown of sAC. Scavenging ROS with N-acetyl-l-cysteine prevented oxysterol-induced apoptosis. Analyses of the downstream pathway suggest that protein kinase A (PKA)-dependent phosphorylation and the mitochondrial translocation of the pro-apoptotic protein Bax is a key link between sAC and oxysterol-induced ROS formation and apoptosis. To distinguish between intra-mitochondrial and extra-mitochondrial/cytosolic sAC pools, sAC was overexpressed in mitochondria or in the cytosol. sAC expression in the cytosol, but not in mitochondria, significantly promoted apoptosis and ROS formation during oxysterol treatment. These results suggest that the sAC/PKA axis plays a key role in the oxysterol-induced apoptosis of VSMC by controlling mitochondrial Bax translocation and ROS formation and that cytosolic sAC, rather than the mitochondrial pool, is involved in the apoptotic mechanism.
Attributes of Interventions That Stop Smoking
Authors: Michael P. O'Donnell
Journal: JAMA (1988)

To the Editor.—  I read with great interest the article by Kottke et al 1 entitled Attributes of Successful Smoking Cessation Interventions in Medical Practice: A Meta-analysis of 39 Controlled Trials in the May 20 issue of JAMA . If we are to enhance our ability to help smokers quit, we need to know the characteristics of successful smoking cessation programs. This article, which is generally well written and based on solid analysis, makes an ambitious effort in that direction and provides conclusions that deserve further attention. However, the conclusions must be viewed with skepticism for at least two reasons.  First, while the requirement to limit the analysis to studies with a control group is understandable given that controlled studies generally produce higher-quality scientific evidence than noncontrolled studies, this severely limits the sample size and makeup and makes one wonder if it is representative of all high-quality smoking cessation efforts. The
Skin Autofluorescence Is a Strong Predictor of Cardiac Mortality in Diabetes
Authors: Robbert Meerwaldt, Helen L. Lutgers, Thera P. Links, Reindert Graaff, John W. Baynes, Rijk O.B. Gans, Andries J. Smit
Journal: Diabetes Care (2006)

OBJECTIVE—Advanced glycation end products (AGEs) are biomarkers of metabolic stress and are thought to contribute to the increase of coronary heart disease (CHD) in diabetes. Tissue autofluorescence is related to the accumulation of AGEs. The aim of the present study was to evaluate the relationship between skin autofluorescence and metabolic burden (hyperglycemia and hyperlipidemia) and its relationship with CHD and mortality. RESEARCH DESIGN AND METHODS—Skin autofluorescence was measured noninvasively with an autofluorescence reader in 48 type 1 and 69 type 2 diabetic patients and 43 control subjects. The presence of CHD was observed at baseline and mortality during a follow-up period of 5 years. RESULTS—Autofluorescence correlated with mean A1C, triglycerides, and LDL. Autofluorescence values further increased with age, microalbuminuria, dialysis treatment, and diabetes duration. Autofluorescence was strongly related to the presence of CHD (odds ratio 7.9) and predicted mortality (3.0). Multivariate analysis showed that autofluorescence was more strongly associated with CHD and mortality compared with A1C, triglycerides, and LDL. CONCLUSIONS—Skin autofluorescence is strongly related to cumulative metabolic burden. Skin autofluorescence seems strongly associated with cardiac mortality and may provide important clinical information for risk assessment.
Level of β-Adrenergic Receptor Kinase 1 Inhibition Determines Degree of Cardiac Dysfunction After Chronic Pressure Overload–Induced Heart Failure
Authors: Hideo Tachibana, Sathyamangla V. Naga Prasad, Robert J. Lefkowitz, Walter J. Koch, Howard A. Rockman
Journal: Circulation (2005)

Heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased level of myocardial betaAR kinase 1 (betaARK1). Our previous studies have shown that inhibition of betaARK1 with the use of the Gbetagamma sequestering peptide of betaARK1 (betaARKct) can prevent cardiac dysfunction in models of heart failure. Because inhibition of betaARK activity is pivotal for amelioration of cardiac dysfunction, we investigated whether the level of betaARK1 inhibition correlates with the degree of heart failure.Transgenic (TG) mice with varying degrees of cardiac-specific expression of betaARKct peptide underwent transverse aortic constriction (TAC) for 12 weeks. Cardiac function was assessed by serial echocardiography in conscious mice, and the level of myocardial betaARKct protein was quantified at termination of the study. TG mice showed a positive linear relationship between the level of betaARKct protein expression and fractional shortening at 12 weeks after TAC. TG mice with low betaARKct expression developed severe heart failure, whereas mice with high betaARKct expression showed significantly less cardiac deterioration than wild-type (WT) mice. Importantly, mice with a high level of betaARKct expression had preserved isoproterenol-stimulated adenylyl cyclase activity and normal betaAR densities in the cardiac membranes. In contrast, mice with low expression of the transgene had marked abnormalities in betaAR function, similar to the WT mice.These data show that the level of betaARK1 inhibition determines the degree to which cardiac function can be preserved in response to pressure overload and has important therapeutic implications when betaARK1 inhibition is considered as a molecular target.
Year in review 2014. Paediatric and adult clinical studies
Authors: A. Bush, I. Pavord
Journal: Thorax (2015)

Our prizes for best papers in the last year have become as eagerly awaited as the Oscars and are much more glamorous. As before, we have awarded GOLD, SILVER and BRONZE prizes in the following categories: paediatrics, adult clinical, basic science and epidemiology. This is the first of two reviews of manuscripts published in Thorax in 2014 dealing with manuscripts on the clinical aspects of paediatrics and adult respiratory medicine. Decisions are purely those of the editors and deputy editors. Our only restriction has been to not consider manuscripts exclusively from Imperial and Oxford because we have conflicts of interest. Next month we deal with basic science and epidemiology manuscripts and reveal the overall winner.

The year 2014 has featured a large number of strong paediatric manuscripts covering the whole range of respiratory medicine, including really important data on the early origins of adult lung disease. Patients with traditional ‘paediatric’ diseases, such as cystic fibrosis (CF) and Duchenne muscular dystrophy are now surviving into adult life, further blurring the barriers between adult and paediatric chest physicians. But nonetheless, this year has re-emphasised that aspects of what appears to be the same disease are different and show developmental changes. We cannot unlock the secrets of disease in children by studying adults.

The early bird gets an unwanted worm: Early life events are of huge importance long term. The Melbourne cohort has run for >40 years; and this year they showed that severe asthma at the age of 10 years is a bigger risk factor for COPD than smoking, at least in their cohort, and furthermore, at age 10 years the COPD adults had the lowest spirometry.1 Interestingly, the rate of decline of lung function did not seem different between the groups. Our editorialists highlight the key importance of optimising lung health early—a …
Controlling passive smoking through legislation in Ireland: an attack on civil liberty or good public health policy?
Authors: W.T. McNicholas
Journal: European Respiratory Journal (2004)

On March 29, 2004, comprehensive legislation was enacted in Ireland banning all forms of smoking in the workplace. This legislation was designed to prevent any worker being subjected to passive smoking and represented the first legislation of its kind in Europe. While broadly similar legislation is in place in parts of the USA, particularly in New York and California, the Irish legislation represented the first national legislation banning smoking in the workplace. Similar legislation has followed in Norway, and is likely to be introduced shortly in several other European countries.

The Irish legislation represents the culmination of efforts on the part of the national government and health authorities, dating back several decades, to reduce tobacco consumption. Successive legislation and regulations from the 1970s onwards prohibited tobacco advertising on radio and TV, and limited advertising in the print media. Taxes on tobacco products were maintained among the highest in Europe and discount selling was prohibited. Furthermore, spending on advertising and promotion by tobacco companies was strictly regulated.

Education programmes were also developed by the Health Promotion Unit of the Irish Department of Health to promote voluntary smoking cessation, and a voluntary ban on smoking in the workplace was developed in conjunction with major trade union and employer organisations. Organisations such as the Irish Heart Foundation, Irish Cancer Society, Irish Thoracic Society, and Action on Smoking and Health (ASH) were actively involved in lobbying efforts and education programmes aimed at reducing the level of tobacco consumption.

The measures described above had considerable success in that the prevalence of smoking in Ireland fell from 45% in the mid 1970s to below 30% in the mid 1990s. However, smoking-related diseases remained highly prevalent and international statistics demonstrate that Ireland has one of the highest mortality rates in Europe from ischaemic heart disease. Furthermore, the …
Angiogenesis in metastatic colorectal cancer and the benefits of targeted therapy
Authors: Weijing Sun
Journal: Journal of Hematology & Oncology (2012)

The diverse pathways and molecules involved in angiogenesis, the formation of new blood vessels, have been targeted for the treatment of colorectal and other cancers. Vascular endothelial growth factor (VEGF)-A binding to VEGF receptor (VEGFR)-2 is believed to be the key signaling pathway mediating angiogenesis. Other VEGF pathways involved in angiogenesis include VEGF-A, VEGF-B, and placental growth factor binding to VEGFR-1, and VEGF-C and VEGF-D binding to VEGFR-2 and VEGFR-3. VEGF signaling also intersects with other pathways, including angiopoietin/Tie, Notch, hypoxia-inducible factor, and integrin pathways. The roles of these pathways in tumor angiogenesis and in various human cancers will be explored in this article. In addition, preclinical and clinical data on bevacizumab, aflibercept (known as ziv-aflibercept in the US), and investigational antiangiogenic agents in development for the treatment of colorectal and other cancers will be reviewed.
Morphological and Molecular Characterization of Adult Cardiomyocyte Apoptosis During Hypoxia and Reoxygenation
Authors: Peter M. Kang, Armin Haunstetter, Hiroki Aoki, Anny Usheva, Seigo Izumo
Journal: Circulation Research (2000)

Abstract —Apoptosis has been implicated in ischemic heart disease, but its mechanism in cardiomyocytes has not been elucidated. In this study, we investigate the effects of hypoxia and reoxygenation in adult cardiomyocytes and the molecular mechanism involved in cardiomyocyte apoptosis. Morphologically, reoxygenation induced rounding up of the cells, appearance of membrane blebs that were filled with marginated mitochondria, and ultrastructural findings characteristic of apoptosis. Reoxygenation (18 hours of reoxygenation after 6 hours of hypoxia) and prolonged hypoxia (24 hours of hypoxia) resulted in a 59% and 51% decrease in cellular viability, respectively. During reoxygenation, cell death occurred predominantly via apoptosis associated with appearance of cytosolic cytochrome c and activation of caspase-3 and -9. However, nonapoptotic cell death predominated during prolonged hypoxia. Both caspase inhibition and Bcl-2 overexpression during reoxygenation significantly improved cellular viability through inhibition of apoptosis but had minimal effect on hypoxia-induced cell death. Bcl-2 overexpression blocked reoxygenation-induced cytochrome c release and activation of caspase -3 and -9, but caspase inhibition alone did not block cytochrome c release. These results suggest that apoptosis predominates in cardiomyocytes after reoxygenation through a mitochondrion-dependent apoptotic pathway, and Bcl-2 prevents reoxygenation-induced apoptosis by inhibiting cytochrome c release from the mitochondria and prevents activation of caspase-3 and -9. (Circ Res. 2000;87:118-125.)