tbuckley/cabot-search huggingface dataset:
Regression of Left Ventricular Hypertrophy After Surgical Therapy for Aortic Stenosis Is Associated With Changes in Extracellular Matrix Gene Expression
Authors: Thomas Walther, Andreas Schubert, Volkmar Falk, Christian Binner, Andreas Kanev, Sabine Bleiziffer, Claudia Walther, Nico Doll, Rüdiger Autschbach, Friedrich W. Mohr
Journal: Circulation (2001)

Regression of left ventricular hypertrophy (LVH) after surgical correction for aortic stenosis is not fully understood on the molecular level. The aim of this study was to examine whether there is an association between LVH regression and extracellular matrix (ECM) gene expression.A standard model of controlled LVH induction by supracoronary banding (A=baseline) was applied in 44 growing sheep (age, 6 to 8 months). Surgical correction to release the pressure gradient was performed 8.3+/-1 months later (B). The animals were killed after another 10.1+/-2 months (C). At all time points, hemodynamic evaluations and quantitative analysis of mRNA and protein expression for matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) was performed. Left ventricular mass index was 82+/-21 (A) versus 150+/-33 (B), P<0.01, and 78+/-18 g/m(2) (C), P<0.01. Left ventricular function and cardiac index remained stable. Myocardial fiber diameter index was 9.1+/-1.2 (A) versus 12.3+/-1.4 (B), P<0.01, and 8.4+/-1.3 micrometer/m(2) (C), P<0.01. In parallel to the development of LVH at B, gene expression was increased significantly for MMP-1, MMP-2, MMP-3, and MMP-9 and for TIMP-1 and TIMP-2 and decreased significantly for TIMP-3. After surgical correction (C), there was a complete regression of gene expression to baseline measures.Controlled induction of compensated LVH leads to significant increase in ECM gene expression. The regression of LVH after surgical therapy is associated with complete regression of ECM gene expression. However, no cause-and-effect relation could be demonstrated.
VEGF remains an interesting target in advanced pancreas cancer (APCA): results of a multi-institutional phase II study of bevacizumab, gemcitabine, and infusional 5-fluorouracil in patients with APCA
Authors: L K Martin, X Li, B Kleiber, E C Ellison, M Bloomston, M Zalupski, T S Bekaii-Saab
Journal: Annals of Oncology (2012)
SPOCK1 as a potential cancer prognostic marker promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/AKT pathway
Authors: Yi-Jun Shu, Hao Weng, Yuan-Yuan Ye, Yun-Ping Hu, Run-Fa Bao, Yang Cao, Xu-An Wang, Fei Zhang, Shan-Shan Xiang, Huai-Feng Li, Xiang-Song Wu, Mao-Lan Li, Lin Jiang, Wei Lu, Bao-San Han, Zhi-Gang Jie, Ying-Bin Liu
Journal: Molecular Cancer (2015)

Gallbladder cancer (GBC) is a leading cause of cancer-related death worldwide, and its prognosis remains poor, with 5-year survival of approximately 5%. In this study, we analyzed the involvement of a novel proteoglycan, Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), in the tumor progression and prognosis of human GBC.SPOCK1 expression levels were measured in fresh samples and stored specimens of GBC and adjacent nontumor tissues. The effect of SPOCK1 on cell growth, DNA replication, migration and invasion were explored by Cell Counting Kit-8, colony formation, EdU retention assay, wound healing, and transwell migration assays, flow cytometric analysis, western blotting, and in vivo tumorigenesis and metastasis in nude mice.SPOCK1 mRNA and protein levels were increased in human GBC tissues compared with those in nontumor tissues. Immunohistochemical analysis indicated that SPOCK1 levels were increased in tumors that became metastatic, compared with those that did not, which was significantly associated with histological differentiation and patients with shorter overall survival periods. Knockdown of SPOCK1 expression by lentivirus-mediated shRNA transduction resulted in significant inhibition of GBC cell growth, colony formation, DNA replication, and invasion in vitro. The knockdown cells also formed smaller xenografted tumors than control GBC cells in nude mice. Overexpression of SPOCK1 had the opposite effects. In addition, SPOCK1 promoted cancer cell migration and epithelial-mesenchymal transition by regulating the expression of relevant genes. We found that activation of the PI3K/Akt pathway was involved in the oncogenic functions of SPOCK1 in GBC.SPOCK1 activates PI3K/Akt signaling to block apoptosis and promote proliferation and metastasis by GBC cells in vitro and in vivo. Levels of SPOCK1 increase with the progression of human GBC. SPOCK1 acts as an oncogene and may be a prognostic factor or therapeutic target for patients with GBC.
G Protein-Coupled Receptor Allosterism and Complexing
Authors: A. Christopoulos
Journal: Pharmacological Reviews (2002)

G protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors. These receptors are natural allosteric proteins because agonist-mediated signaling by GPCRs requires a conformational change in the receptor protein transmitted between two topographically distinct binding sites, one for the agonist and another for the G protein. It is now becoming increasingly recognized, however, that the agonist-bound GPCR can also form ternary complexes with other ligands or "accessory" proteins and display altered binding and/or signaling properties in relation to the binary agonist-receptor complex. Allosteric sites on GPCRs represent novel drug targets because allosteric modulators possess a number of theoretical advantages over classic orthosteric ligands, such as a ceiling level to the allosteric effect and a potential for greater GPCR subtype-selectivity. Because of the noncompetitive nature of allosteric phenomena, the detection and quantification of such effects often relies on a combination of equilibrium binding, nonequilibrium kinetic, and functional signaling assays. This review discusses the development and properties of allosteric receptor models for GPCRs and the detection and quantification of allosteric effects. Moreover, we provide an overview of the current knowledge regarding the location of possible allosteric sites on GPCRs and candidate endogenous allosteric modulators. Finally, we discuss the potential for allosteric effects arising from the formation of GPCR oligomers or GPCRs complexed with accessory cellular proteins. It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.
The RB tumor suppressor: a gatekeeper to hormone independence in prostate cancer?
Authors: Kay F. Macleod
Journal: Journal of Clinical Investigation (2010)

The retinoblastoma tumor suppressor gene (RB1; encoding RB) is often cited as a gatekeeper, whose inactivation — direct or indirect — is a rate-limiting step for tumor initiation. However, in this issue of the JCI, Sharma et al. show that RB1 loss is a late event in human prostate cancer that is coincident with the emergence of castrate-resistant metastatic disease. This role for RB1 was linked to both E2F transcription factor 1–driven upregulation of the androgen receptor (AR) and increased recruitment of the AR to target gene promoters. This unexpected function for RB1 in late-stage cancer calls upon us to reassess the significance of RB1 inactivation in other cancers in terms of its timing, function in disease etiology, and relevance for cancer therapy.
Motor function of the proximal stomach and visceral perception in gastro-oesophageal reflux disease
Authors: R Penagini, G Hebbard, M Horowitz, J Dent, H Bermingham, K Jones, R H Holloway
Journal: Gut (1998)

The abnormally high postprandial rate of transient lower oesophageal sphincter relaxations seen in patients with reflux disease may be related to altered proximal gastric motor function. Heightened visceral sensitivity may also contribute to reporting of symptoms in these patients.To assess motor function of the proximal stomach and visceral perception in reflux disease with a barostat.Fasting and postprandial proximal gastric motility, sensation, and symptoms were measured in nine patients with reflux disease and nine healthy subjects. Gastric emptying of solids and liquids was assessed in six of the patients on a different day (and compared to historical controls).Minimal distending pressure and gastric compliance were similar in the two groups, whereas the patients experienced fullness at lower pressures (p < 0.05) and discomfort at lower balloon volumes (p < 0.005) during isobaric and isovolumetric distensions respectively. Maximal gastric relaxation induced by the meal was similar in the two groups. Late after the meal, however, proximal gastric tone was lower (p < 0.01) and the score for fullness higher (p < 0.01) in the reflux patients, in whom the retention of both solids and liquids in the proximal stomach was greater (p < 0.05).Reflux disease is associated with delayed recovery of proximal gastric tone after a meal and increased visceral sensitivity. The former may contribute to the increased prevalence of reflux during transient lower oesophageal sphincter relaxations and the delay in emptying from the proximal stomach, whereas both may contribute to symptom reporting.
Change in Suicide Rates in Switzerland Before and After Firearm Restriction Resulting From the 2003 “Army XXI” Reform
Authors: Thomas Reisch, Timur Steffen, Astrid Habenstein, Wolfgang Tschacher
Journal: American Journal of Psychiatry (2013)

Objective Firearms are the most common method of suicide among young men in Switzerland. From March 2003 through February 2004, the number of Swiss soldiers was halved as a result of an army reform (Army XXI), leading to a decrease in the availability of guns nationwide. The authors investigated the patterns of the overall suicide rate and the firearm suicide rate before and after the reform. Method Using a naturalistic study design, the authors compared suicide rates before (1995–2003) and after the intervention (2004–2008) in the affected population (men ages 18–43) and in two comparison groups (women ages 18–44 and men ages 44–53). Data were received from the Swiss Federal Statistical Office. Interrupted time series analysis was used to control for preexisting temporal trends. Alternative methods (Poisson regression, autocorrelation analysis, and surrogate data tests) were used to check validity. Results The authors found a reduction in both the overall suicide rate and the firearm suicide rate after the Army XXI reform. No significant increases were found for other suicide methods overall. An increase in railway suicides was observed. It was estimated that 22% of the reduction in firearm suicides was substituted by other suicide methods. The attenuation of the suicide rate was not compensated for during the follow-up years. Neither of the comparison groups showed statistically significant changes in firearm suicide rate and overall suicide rate. Conclusions The restriction of firearm availability in Switzerland resulting from the Army XXI reform was followed by an enduring decrease in the general suicide rate.
Pulmonary Vascular Complications of Liver Disease
Authors: Jason S. Fritz, Michael B. Fallon, Steven M. Kawut
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Hepatopulmonary syndrome and portopulmonary hypertension are two pulmonary vascular complications of liver disease. The pathophysiology underlying each disorder is distinct, but patients with either condition may be limited by dyspnea. A careful evaluation of concomitant symptoms, the physical examination, pulmonary function testing and arterial blood gas analysis, and echocardiographic, imaging, and hemodynamic studies is crucial to establishing (and distinguishing) these diagnoses. Our understanding of the pathobiology, natural history, and treatment of these disorders has advanced considerably over the past decade; however, the presence of either still increases the risk of morbidity and mortality in patients with underlying liver disease. There is no effective medical treatment for hepatopulmonary syndrome. Although liver transplantation can resolve hepatopulmonary syndrome, there appears to be worse survival even with transplantation. Liver transplantation poses a very high risk of death in those with significant portopulmonary hypertension, where targeted medical therapies may improve functional status and allow successful transplantation in a small number of select patients.
Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants
Authors: Marlies de Graaf, Johannes M.P.J. Breur, Martine F. Raphaël, Marike Vos, Corstiaan C. Breugem, Suzanne G.M.A. Pasmans
Journal: Journal of the American Academy of Dermatology (2011)
Predictors of survival in neonates with critical aortic stenosis.
Authors: L A Rhodes, S D Colan, S B Perry, R A Jonas, S P Sanders
Journal: Circulation (1991)

Failure of infants with critical aortic stenosis to survive after adequate valvotomy despite a left ventricular size that appears to be adequate indicates that additional preoperative anatomic features may contribute to mortality.Discriminant analysis was used to determine which of several echocardiographically measured left heart structures were independent predictors of survival after valvotomy for neonatal critical aortic stenosis. It was possible to predict outcome after classic valvotomy (two-ventricle-type repair) with 95% accuracy based on mitral valve area, long-axis dimension of the left ventricle relative to the long-axis dimension of the heart, diameter of the aortic root, and body surface area. Left ventricular volume was not a major determinant in this study, in part because patients who had initial valvotomy had been preselected in favor of an adequately sized left ventricle. Patients with multiple small left ventricular structures were found to have significantly improved survival after initial Norwood operation. In contrast, balloon valvotomy with subsequent Norwood procedure was usually unsuccessful.The adverse effects of small inflow, outflow, and/or cavity size of the left ventricle are cumulative. The accuracy of prediction of outcome based only on preoperative anatomy indicates that adequacy of valvotomy is not generally a limiting factor for survival in this group of patients. It is possible to identify subjects whose chance of survival is better after a Norwood procedure rather than valvotomy, even if left ventricular volume is not critically small.
Increased risk of mycobacterial infections associated with anti-rheumatic medications
Authors: S. K. Brode, F. B. Jamieson, R. Ng, M. A. Campitelli, J. C. Kwong, J. M. Paterson, P. Li, A. Marchand-Austin, C. Bombardier, T. K. Marras
Journal: Thorax (2015)

<h3>Rationale</h3> Anti-tumour necrosis factor (TNF) agents and other anti-rheumatic medications increase the risk of TB in rheumatoid arthritis (RA). Whether they increase the risk of infections with nontuberculous mycobacteria (NTM) is uncertain. <h3>Objectives</h3> To determine the effect of anti-TNF therapy and other anti-rheumatic drugs on the risk of NTM disease and TB in older patients with RA. <h3>Methods</h3> Population-based nested case–control study among Ontario seniors aged ≥67 years with RA who were prescribed at least one anti-rheumatic medication between 2001 and 2011. We identified cases of TB and NTM disease microbiologically and identified drug exposures using linked prescription drug claims. We estimated ORs using conditional logistic regression, controlling for several potential confounders. <h3>Measurements and main results</h3> Among 56 269 older adults with RA, we identified 37 cases of TB and 211 cases of NTM disease; each case was matched to up to 10 controls. Individuals with TB or NTM disease were both more likely to be using anti-TNF therapy (compared with non-use); adjusted ORs (95% CIs) were 5.04 (1.27 to 20.0) and 2.19 (1.10 to 4.37), respectively. Exposure to leflunomide and other anti-rheumatic drugs with high immunosuppressing potential also were associated with both TB and NTM disease, while oral corticosteroids and hydroxychloroquine were associated with NTM disease. <h3>Conclusions</h3> Anti-TNF use is associated with increased risk of both TB and NTM disease, but appears to be a relatively greater risk for TB. Several other anti-rheumatic drugs were also associated with mycobacterial infections.
Increased incidence of acute nonlymphocytic leukemia following therapy in patients with small cell carcinoma of the lung.
Authors: L Y Chak, B I Sikic, M A Tucker, R C Horns, R S Cox
Journal: Journal of Clinical Oncology (1984)

A group of 158 patients with small cell carcinoma of the lung were followed for 174.5 person-years of observation to determine the risk of acute leukemia. Three cases of acute nonlymphocytic leukemia were observed at 2.3, 2.7, and 3.0 years. The relative risk of developing leukemia was 316 (95% confidence limit, 76-818) and the actuarial risk was 25% +/- 13% at 3.1 years. The relative risk for leukemia was significantly increased in these patients (p less than 0.0001).
Widespread remodeling of mid-coding sequence nucleosomes by Isw1
Authors: Itay Tirosh, Nadejda Sigal, Naama Barkai
Journal: Genome biology (2010)

The positions of nucleosomes along eukaryotic DNA are defined by the local DNA sequence and are further tuned by the activity of chromatin remodelers. While the genome-wide effect of most remodelers has not been described, recent studies in Saccharomyces cerevisiae have shown that Isw2 prevents ectopic expression of anti-sense and suppressed transcripts at gene ends. We examined the genome-wide function of the Isw2 homologue, Isw1, by mapping nucleosome positioning in S. cerevisiae and Saccharomyces paradoxus strains deleted of ISW1. We found that Isw1 functions primarily within coding regions of genes, consistent with its putative role in transcription elongation. Upon deletion of ISW1, mid-coding nucleosomes were shifted upstream (towards the 5' ends) in about half of the genes. Isw1-dependent shifts were correlated with trimethylation of H3K79 and were enriched at genes with internal cryptic initiation sites. Our results suggest a division of labor between Isw1 and Isw2, whereby Isw2 maintains repressive chromatin structure at gene ends while Isw1 has a similar function at mid-coding regions. The differential specificity of the two remodelers may be specified through interactions with particular histone marks.
Live patient and partner survey on pulmonary fibrosis
Authors: J.W. Kraan, B. Van den Blink, L.M. Van den Toorn, M. Gerrits, M. Kap, H.C. Hoogsteden, M.S. Wijsenbeek
Journal: European Respiratory Journal (2014)

Introduction / Rationale   Pulmonary Fibrosis (PF) not only has impact on physical but also on social and emotional well-being of patient and partner. In general, their needs in these domains are ill documented. The objective of this project was to interactively acquire knowledge about patient9s and partner9s perspectives on and preferences in care for social and emotional well-being.   Methods   During a pulmonary fibrosis patient meeting in our hospital we interviewed patients and partners using voting boxes. Participants could answer anonymously to the 28 questions posed. The system recorded the number of voters. The results were directly presented. Permission to use the data was obtained at forehand.   Results   65 patients with PF and 63 partners were present. In brackets number of voters is shown. Self-reported diagnoses were Idiopathic PF (46), collagen vascular disease (9), exposure related (6) and unknown (3). 68% of patients (63) would prefer talking about end of life in an early stage of disease. Patients (50) and partners (50) reported the same levels of anxiety on a general anxiety and distress score. Patients (50) and partners (52) feel equally poor understood (94% vs 90%) because people do not know what PF is. 78% of the voters (67) would be interested in patient and partner support groups in their own hospital. After this meeting 47% of the participants (89) felt more secure and in control, 11% felt less secure and in control. The majority considered the meeting very useful (93% of N=100).   Conclusion   The interactive interviewing of patients with PF along with their partners can provide the opportunity not only to improve care but also to offer better support regarding the problems that patients and partners encounter.
Current and future therapeutic approaches in idiopathic pulmonary fibrosis
Authors: D. Bouros, K. M. Antoniou
Journal: European Respiratory Journal (2005)

Idiopathic pulmonary fibrosis (IPF) is a lethal form of idiopathic diffuse lung disorders for which no current treatment is effective. The aim of the present study was to systematically review the current status and novel therapies of IPF, with emphasis on controlled trials. The studies selected included randomised controlled trials using drugs alone and/or in combination for the treatment of adults with IPF and meta-analyses, published in English. Abstracts of identified articles were retrieved and articles possibly fulfilling inclusion criteria were retrieved in full. Two reviewers independently assessed trial quality if there were any included studies. Data quality was based on place of publication and relevance to clinical care. There is a lack of good-quality studies regarding the effectiveness of the most used drugs, including corticosteroids and noncorticosteroid immunosuppressive agents. Oral corticosteroids are the usual treatment. Other therapies either alone or in combination with corticosteroids are widely used, including azathioprine, cyclophosphamide and colchicine. Interestingly, clinical trials with novel drugs, mainly antifibrotic, anticytokine and immunoregulatory, are currently being investigated in various trial phases. In conclusion, at present, there are no evidence-based therapies for idiopathic pulmonary fibrosis. Further controlled studies are warranted to improve the evidence base for clinical practice.
Intracoronary Brachytherapy After Stenting De Novo Lesions in Diabetic Patients
Authors: Manel Sabaté, Gela Pimentel, Carlos Prieto, José María Corral, Camino Bañuelos, Dominick J. Angiolillo, Fernando Alfonso, Rosana Hernández-Antolín, Javier Escaned, Panayotis Fantidis, Cristina Fernández, Antonio Fernández-Ortiz, Raúl Moreno, Carlos Macaya
Journal: Journal of the American College of Cardiology (2004)