tbuckley/cabot-search huggingface dataset:
The Association Between Depressive Symptoms and Systemic Inflammation in People With Type 2 Diabetes: Findings From the South London Diabetes Study
Authors: Jean-Pierre S. Laake, Daniel Stahl, Stephanie A. Amiel, Frank Petrak, Roy A. Sherwood, John C. Pickup, Khalida Ismail
Journal: Diabetes Care (2014)

The prevalence of depression and depressive symptoms is increased twofold in people with type 2 diabetes compared with the general population and is associated with worse biomedical outcomes and increased mortality. Type 2 diabetes, cardiovascular disease, and depression in nondiabetes subjects are independently associated with raised concentrations of circulating inflammatory markers, but it is not known if a similar association is observed in type 2 diabetes. We tested the hypothesis that higher depressive symptom scores in newly diagnosed type 2 diabetes patients were associated with higher concentrations of inflammatory markers.Depressive symptoms in adults with newly diagnosed type 2 diabetes recruited from primary care were assessed using the Patient Health Questionnaire-9. Twelve markers of inflammation (C-reactive protein [hs-CRP], interleukin-4 [IL-4], IL-6, IL-10, vascular endothelial growth factor [VEGF], tumor necrosis factor-α [TNF-α], IL-1β, IL-1 receptor antagonist [IL-1RA], monocyte chemotactic protein-1 [MCP-1], white blood cell count [WBC], adiponectin, and triglyceride [TG]) were measured. Covariates included sociodemographic factors, adiposity, macrovascular disease, HbA1c, and prescribed medication. The association between each inflammatory marker and depressive symptom score was estimated by multiple linear regression.The baseline cohort consisted of 1,790 participants. After adjusting for covariates, CRP (B = 0.13, P < 0.001), IL-1β (B = 0.06, P = 0.047), IL-1RA (B = 0.13, P < 0.001), MCP-1 (B = 0.11, P = 0.001), WBC (B = 0.13, P < 0.001), and TG (B = 0.10, P < 0.001) were associated with depressive symptoms.Increased inflammation may be involved in the pathogenesis of depressive symptoms in type 2 diabetes and contribute to the increased risk of complications and mortality in this group.
Comparison of statistically derived ASAS improvement criteria for ankylosing spondylitis with clinically relevant improvement according to an expert panel
Authors: A van Tubergen
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> To investigate whether the recently developed (statistically derived) “ASsessment in Ankylosing Spondylitis Working Group” improvement criteria (ASAS-IC) for ankylosing spondylitis (AS) reflect clinically relevant improvement according to the opinion of an expert panel. <b>Methods:</b> The ASAS-IC consist of four domains: physical function, spinal pain, patient global assessment, and inflammation. Scores on these four domains of 55 patients with AS, who had participated in a non-steroidal anti-inflammatory drug efficacy trial, were presented to an international expert panel (consisting of patients with AS and members of the ASAS Working Group) in a three round Delphi exercise. The number of (non-)responders according to the ASAS-IC was compared with the final consensus of the experts. The most important domains in the opinion of the experts were identified, and also selected with discriminant analysis. A number of provisional criteria sets that best represented the consensus of the experts were defined. Using other datasets, these clinically derived criteria sets as well as the statistically derived ASAS-IC were then tested for discriminative properties and for agreement with the end of trial efficacy by patient and doctor. <b>Results:</b> Forty experts completed the three Delphi rounds. The experts considered twice as many patients to be responders than the ASAS-IC (42 <i>v</i> 21). Overall agreement between experts and ASAS-IC was 62%. Spinal pain was considered the most important domain by most experts and was also selected as such by discriminant analysis. Provisional criteria sets with an agreement of ⩾80% compared with the consensus of the experts showed high placebo response rates (27–42%), in contrast with the ASAS-IC with a predefined placebo response rate of 25%. All criteria sets and the ASAS-IC discriminated well between active and placebo treatment (χ<sup>2</sup>=36–45; p&lt;0.001). Compared with the end of trial efficacy assessment, the provisional criteria sets showed an agreement of 71–82%, sensitivity of 67–83%, and specificity of 81–88%. The ASAS-IC showed an agreement of 70%, sensitivity of 62%, and specificity of 89%. <b>Conclusion:</b> The ASAS-IC are strict in defining response, are highly specific, and consequently show lower sensitivity than the clinically derived criteria sets. However, those patients who are considered as responders by applying the ASAS-IC are acknowledged as such by the expert panel as well as by patients’ and doctors’ judgments, and are therefore likely to be true responders.
Signal Transducer and Activator of Transcription 3 Is Required for the Oncogenic Effects of Non–Small-Cell Lung Cancer–Associated Mutations of the Epidermal Growth Factor Receptor
Authors: James V. Alvarez, Heidi Greulich, William R. Sellers, Matthew Meyerson, David A. Frank
Journal: Cancer Research (2006)

Abstract Somatic mutations in the epidermal growth factor receptor (EGFR) occur frequently in lung cancer and confer sensitivity to EGFR kinase inhibitors gefitinib and erlotinib. These mutations, which occur in the kinase domain of the protein, also render EGFR constitutively active and transforming. Signal transducers and activators of transcription 3 (STAT3) transduces signals from a number of oncogenic tyrosine kinases and contributes to a wide spectrum of human malignancies. Here, we show that STAT3 is activated by mutant EGFRs and is necessary for its downstream phenotypic effects. Inhibiting STAT3 function in fibroblasts abrogates transformation by mutant EGFR. In non–small-cell lung cancer cells, STAT3 activity is regulated by EGFR through modulation of STAT3 serine phosphorylation. Inhibiting STAT3 function increases apoptosis of these cells, suggesting that STAT3 is necessary for their survival. Finally, a group of genes constituting a STAT3 signature is enriched in lung tumors with EGFR mutations. Thus, STAT3 is a critical mediator of the oncogenic effects of somatic EGFR mutations and targeting STAT3 may be an effective strategy for treating tumors characterized by these mutations. (Cancer Res 2006; 66(6): 3162-8)
Cardiac Physiology in Transgenic Mice
Authors: Jeanne F. James, Timothy E. Hewett, Jeffrey Robbins
Journal: Circulation Research (1998)

By use of gene targeting and/or transgenesis, it is now possible to make defined changes in genes whose functions underlie mammalian cardiovascular function. Because of technical and economic considerations, these experiments are largely confined to the mouse. Genetic modification of the loci responsible for aspects of cardiac development, differentiation, and function via gene targeting, as well as modulation of the cardiac protein complement using transgenesis, has begun to provide mouse models of cardiac hypertrophy, dilated cardiomyopathy, and hypertrophic cardiomyopathies. In order to use these animal models fully and explore their phenotypes at the whole organ and whole animal levels, the extension of cardiovascular physiological methodologies to the mouse is imperative. Techniques for exploring aspects of cardiovascular function are well developed for larger animal models, but their modification for the small size of the mouse heart and for the animal's rapid cardiac cycle has proven to be a formidable challenge, requiring the combined efforts of the molecular biology, physiology, and cardiology communities. We review here the ability of present-day technology to obtain reproducible data on murine cardiac function at the whole organ and animal levels.
Plasticity of CD133+ cells: Role in pulmonary vascular remodeling
Authors: M DIEZ, J BARBERA, E FERRER, R FERNANDEZLLORIS, S PIZARRO, J ROCA, V PEINADO
Journal: Cardiovascular Research (2007)

Studies in pulmonary arteries (PA) of patients with chronic obstructive pulmonary disease (COPD) suggest that bone marrow-derived endothelial progenitor cells (CD133(+)) may infiltrate the intima and differentiate into smooth muscle cells (SMC). This study aimed to evaluate the plasticity of CD133(+) cells to differentiate into SMC and endothelial cells (EC) in both cell culture and human isolated PA.Plasticity of granulocyte-colony stimulator factor (G-CSF)-mobilized peripheral blood CD133(+) cells was assessed in co-cultures with primary lines of human PA endothelial cells (PAEC) or SMC (PASMC) and in isolated human PA. We also evaluated if the phenotype of differentiated progenitor cells was acquired by fusion or differentiation.The in vitro studies demonstrated CD133(+) cells may acquire the morphology and phenotype of the cells they were co-cultured with. CD133(+) cells co-incubated with human isolated PA were able to migrate into the intima and differentiate into SMC. Progenitor cell differentiation was produced without fusion with mature cells.We provide evidence of plasticity of CD133(+) cells to differentiate into both endothelial cells and SMC, reinforcing the idea of their potential role in the remodeling process of PA in COPD. This process was conducted by transdifferentiation and not by cell fusion.
Circulating smooth muscle progenitor cells: novel players in plaque stability
Authors: K. Satoh, B. C. Berk
Journal: Cardiovascular Research (2007)

Our understanding of the role of stem cells in the pathogenesis of vascular disease has been rapidly evolving. It is generally accepted that bone marrow (BM)-derived endothelial progenitor cells (EPCs) participate in arterial repair and angiogenesis after injury by homing to the injured vessel and differentiating into endothelial cells.1 BM-derived cells with smooth muscle cell (SMC)-like phenotype also participate in the pathogenesis of vascular disease.2 Recently, Simper et al .3 reported the existence of smooth muscle progenitor cells (SPCs) in human blood. Hashimoto et al .4 demonstrated the existence of BM-derived progenitors for collagen-producing fibroblasts. Inflammatory cells are clearly mobilized to sites of vascular injury.5 Intriguingly, a recent paper revealed an important role for T cells in hypertension and vascular dysfunction.6 The cytokines that recruit, activate, and promote differentiation of BM-derived vascular cells have been extensively studied and include GM-CSF,7 SDF-1,8 and erythropoietin.9,10 These accumulating data establish a close relationship between BM-derived cells and vascular pathogenesis. However, the role of BM-derived vascular progenitor cells in atherosclerosis remains poorly defined ( Figure 1 ).



 Figure 1  
Progenitor … 



*Corresponding author. Tel: +1 585 275 3407; fax: +1 585 273 1059. E-mail address : bradford_berk{at}urmc.rochester.edu
Home mechanical ventilation in Australia and New Zealand
Authors: Daniel J. Garner, David J. Berlowitz, James Douglas, Nick Harkness, Mark Howard, Nigel McArdle, Matthew T. Naughton, Alister Neill, Amanda Piper, Aeneas Yeo, Alan Young
Journal: European Respiratory Journal (2012)

This study aims to describe the pattern of home mechanical ventilation (HMV) usage in Australia and New Zealand. 34 centres providing HMV in the region were identified and asked to complete a questionnaire regarding centre demographics, patient diagnoses, HMV equipment and settings, staffing levels and methods employed to implement and follow-up therapy. 28 (82%) centres responded, providing data on 2,725 patients. The minimum prevalence of HMV usage was 9.9 patients per 100,000 population in Australia and 12.0 patients per 100,000 population in New Zealand. Variation existed across Australian states (range 4–13 patients per 100,000 population) correlating with population density (r=0.82; p&lt;0.05). The commonest indications for treatment were obesity hypoventilation syndrome (OHS) (31%) and neuromuscular disease (NMD) (30%). OHS was more likely to be treated in New Zealand, in smaller, newer centres, whilst NMD was more likely to be treated in Australia, in larger, older centres. Chronic obstructive pulmonary disease was an uncommon indication (8.0%). No consensus on indications for commencing treatment was found. In conclusion, the prevalence of HMV usage varies across Australia and New Zealand according to centre location, size and experience. These findings can assist HMV service planning locally and highlight trends in usage that may be relevant in other countries.
Introduction to a Discussion on Placenta Praevia
Authors: J. B. Hicks
Journal: BMJ (1889)

THE collective wisdom of the authorities of this Section having pronounced solemnly the fearful word " Blood," proceeded further to do me the honour of asking me to open a discussion that should, as the result of our combined talents and experience, draw out the plan best calculated to arrest its terrors and to staunich its stream; and then the same authoritative wisdom also thought that it would be helpful to the profession generally if that for- midable cause of blood loss-namely, placeiita prvevia-were the immediate subject ot your consideration.Thus it is that I find myself in this responsible position; and I would ask you kindly to take off some of its weight, the more so as the time allotted me is only fifteen minutes-a very short time to treat of only one case of placenta praevia-and you only ten minutes.As, therefore, all of us must necessarily be brief, I shall confine my remarlks to the treatment of this condition, passing over the theories whiclh have been advanced-and will be ad- vanced lalter on in this Section-to explain the cause and nature of the position, and only very briefly touching on the after- treatment.And, because I am anxious to present so important a subject free from personal considerations, lest these may be a hindrance to our conclusions, I shall avoid all reference to the authors of the various plans which have one way or other within the last thirty years reduced the death-rate from 30 per cent.to somewhere near 5 per cent.But I may say this much, that the early handling of these cases and the general antiseptic management of midwifery cases, both during and after delivery, can rightly claim to have had much to do with these excellent results.I think we shall all agree:1. Tlhat when the placenta is inserted somewlhere within the lower third of the uterus, there is very generally a liability to heuinorrhage.It wouldl be difficult to say that it is absolutely "unavoidable," because I have seen the placental edge a little
Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma.
Authors: O Feugeas, N Guriec, A Babin-Boilletot, L Marcellin, P Simon, S Babin, A Thyss, P Hofman, P Terrier, C Kalifa, M Brunat-Mentigny, L M Patricot, F Oberling
Journal: Journal of Clinical Oncology (1996)

PURPOSE The usual therapy of osteosarcoma is neoadjuvant chemotherapy, followed by surgery, then by postoperative chemotherapy. There is no prognostic factor to predict, at diagnosis, the histologic response and final outcome. Inactivation of the retinoblastoma-susceptibility gene RB is associated with the pathogenesis of several human cancers. In primary osteosarcomas, loss of heterozygosity (LOH) at the RB locus has been found in greater than 60% of cases. The aim of this study was to determine the potential early prognostic value of LOH of RB gene on the biopsy material at diagnosis. PATIENTS AND METHODS Forty-seven patients with primary osteosarcoma, treated in four French institutions, were studied. LOH was studied by polymerase chain reaction (PCR) of an informative RB DNA polymorphism. RESULTS Assessment of LOH at the RB gene could be completed on 34 heterozygous patients only. LOH was found in 24 cases (70%). The event-free survival (EFS) rate at 60 months is 100% for patients without LOH, 43% for all patients with RB LOH, and 65% for nonmetastatic patients with RB LOH. The difference in EFS is highly significant at P = .008 and P = .024, respectively. Histologic response after preoperative chemotherapy did not show significant correlation with LOH status. CONCLUSION RB gene LOH appears to be an early predictive feature for osteosarcomas that indicates a potential unfavorable outcome. RB LOH study might shortly help to identify high-risk patients earlier. If this is verified, therapy could then be adapted earlier to the individual's real risk of relapse.
Cabozantinib and Prostate Cancer: Inhibiting Seed and Disrupting Soil?
Authors: Richard J. Lee, Matthew R. Smith
Journal: Clinical Cancer Research (2013)

Abstract Treatment with cabozantinib, an inhibitor of MET and VEGFR2 signaling, has demonstrated clinical benefit in early trials in men with metastatic prostate cancer. Preclinical evidence suggests that cabozantinib can kill cancer cell seeds while disrupting angiogenesis and stromal cells in the metastatic soil. Clin Cancer Res; 20(3); 525–7. ©2013 AACR.
Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice
Authors: George S Vassiliou, Jonathan L Cooper, Roland Rad, Juan Li, Stephen Rice, Anthony Uren, Lena Rad, Peter Ellis, Rob Andrews, Ruby Banerjee, Carolyn Grove, Wei Wang, Pentao Liu, Penny Wright, Mark Arends, Allan Bradley
Journal: Nature Genetics (2011)
Genetics and pulmonary medicine bullet 8: Genetics and pulmonary medicine: asthma
Authors: I P Hall
Journal: Thorax (1999)

The field of asthma genetics has evolved in a markedly short time into a research field which potentially can provide a new level of understanding on the pathophysiology of the disease. There is consensus over a number of candidate genes that are likely to be important in the disease and also in chromosomal regions likely to contain other novel genes. It is, however, clear that there is no single major genetic risk factor for the development of asthma and the development of the disease in an individual will depend upon the interaction of a number of genes of moderate effect with environmental factors.
Vorinostat-Induced Apoptosis in Mantle Cell Lymphoma Is Mediated by Acetylation of Proapoptotic BH3-Only Gene Promoters
Authors: Sílvia Xargay-Torrent, Mónica López-Guerra, Ifigènia Saborit-Villarroya, Laia Rosich, Elias Campo, Gaël Roué, Dolors Colomer
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm with generally poor prognosis, for which current therapies have shown limited efficacy. Vorinostat is a histone deacetylase inhibitor (HDACi) that has been approved for the treatment of cutaneous T-cell lymphoma. Our purpose was to describe the molecular mechanism whereby vorinostat induces apoptosis in MCL with particular emphasis on the role of proapoptotic BH3-only proteins. Experimental Design: The sensitivity to vorinostat was analyzed in eight MCL cell lines and primary cells from 10 MCL patients. Determination of vorinostat mechanism of action was done by flow cytometry, immunoblotting, HDAC activity assay kit, quantitative reverse transcription PCR, chromatin immunoprecipitation, and siRNA-mediated transfection. Results: Vorinostat inhibited total histone deacetylase activity leading to selective toxicity toward tumor cells. Vorinostat-mediated cell death implied the activation of mitochondrial apoptosis, as attested by BAX and BAK conformational changes, mitochondrial depolarization, reactive oxygen species generation, and subsequent caspase-dependent cell death. This phenomenon was linked to H4 hyperacetylation on promoter regions and consequent transcriptional activation of the proapoptotic BH3-only genes BIM, BMF, and NOXA. Selective knockdown of the three corresponding proteins rescued cells from vorinostat-induced apoptosis. Moreover, vorinostat enhanced the activity of the BH3-mimetic ABT-263 in MCL cells, leading to synergistic apoptosis induction. Conclusion: These results indicated that transcriptional upregulation of BH3-only proteins plays an important role in the antitumoral activity of vorinostat in MCL, and that HDACi alone or in combination with BH3-mimetizing agents may represent a promising therapeutic approach for MCL patients. Clin Cancer Res; 17(12); 3956–68. ©2011 AACR.
Outpatient-based ifosfamide, carboplatin and etoposide (ICE) chemotherapy in transplant-eligible patients with non-Hodgkin’s lymphoma and Hodgkin’s disease
Authors: M.S. Hertzberg, C. Crombie, W. Benson, J. Taper, D. Gottlieb, K.F. Bradstock
Journal: Annals of Oncology (2003)
First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis
Authors: Matteo Cassina, Marta Donà, Elena Di Gianantonio, Pietro Litta, Maurizio Clementi
Journal: Human Reproduction Update (2014)

Metformin is generally considered a non-teratogenic drug; however, only a few studies specifically designed to assess the rate of congenital anomalies after metformin use have been published in the literature. The objects of the present study were to review all of the prospective and retrospective studies reporting on women treated with metformin at least during the first trimester of their pregnancy and to estimate the overall rate of major birth defects. Databases were searched for English language articles until December 2013. Inclusion criteria for the meta-analysis were: a case group of women with PCOS or pre-pregnancy type 2 diabetes and first-trimester exposure to metformin; a disease-matched control group which was not exposed to metformin or other oral anti-diabetic agents; and a list of the major anomalies in both the study and the control groups. A random effects model was used for the meta-analysis of data, using odds ratios. Studies not fulfilling the inclusion criteria for the meta-analysis but reporting relevant data on major malformations in women diagnosed with PCOS were then used to estimate the overall birth defects rate. Meta-analysis of nine controlled studies with women affected by PCOS detected that the rate of major birth defects in the metformin-exposed group was not statistically increased compared with the disease-matched control group and that there was no significant heterogeneity among the studies. The metformin-exposed sample was composed of 351 pregnancies and the OR of major birth defects was 0.86 (95% confidence interval: 0.18–4.08; Pheterogeneity = 0.71). By evaluating all of the non-overlapping PCOS studies reported in the literature, even those without an appropriate control group, the overall rate of major anomalies was 0.6% in the sample of 517 women who discontinued the therapy upon conception or confirmation of pregnancy and 0.5% in the sample of 634 women who were treated with metformin throughout the first trimester of their pregnancy. Regarding type 2 diabetic women, we did not identify a sufficient number of studies with metformin exposure during the first trimester to proceed with the meta-analysis. There is currently no evidence that metformin is associated with an increased risk of major birth defects in women affected by PCOS and treated during the first trimester. However larger ad hoc studies are warranted in order to definitely confirm the safety and efficacy of this drug in pregnancy.