tbuckley/cabot-search huggingface dataset:
Late-breaking abstract: β-blockers are associated with a reduction in COPD exacerbations in COPDGene
Authors: Surya Bhatt, James Wells, Gregory Kinney, George Washko, Young-il Kim, William Bailey, John Hokanson, Edwin Silverman, James Crapo, Mark Dransfield
Journal: European Respiratory Journal (2014)

Background  While some retrospective studies have suggested that β-blocker use in patients with chronic obstructive pulmonary disease (COPD) is associated with a reduction in the frequency of acute exacerbations and lower mortality, there is concern that their use in patients with severe COPD on home oxygen is harmful. We analyzed prospectively collected data from the COPDGene cohort and hypothesized that β-blockers would be associated with a reduction in exacerbations across the spectrum of COPD severity.  Methods  Subjects with GOLD stage 2 to 4 were included. Total and severe exacerbation rates were compared between groups categorized by β-blocker use using negative binomial regression analyses, after adjustment for demographics, airflow obstruction, %emphysema on computed tomography, respiratory medications, presence of coronary artery disease (CAD) and congestive heart failure (CHF), and also for the propensity to prescribe β-blockers based on the presence of CAD, CHF and the severity of airflow obstruction.  Results  3464 subjects were included. CAD was present in 16.3% of patients of whom 37.5% were on β-blockers. On follow-up (median 2.1 years), β-blocker use was associated with a significantly lower rate of total (Incidence risk ratio, IRR 0.78,95%CI 0.65 to 0.95;p=0.012) and severe exacerbations (IRR 0.63,95%CI 0.47 to 0.86;p=0.004). In those with GOLD stage 3 and 4 and on home oxygen, use of β-blockers was again associated with a reduction in the rate of total (IRR 0.40,95%CI 0.24 to 0.67;p=0.001) and severe exacerbations (IRR 0.49,95%CI 0.25 to 0.98;p=0.045).  Conclusions  β-blockers are associated with a significant reduction in COPD exacerbations regardless of severity of airflow obstruction.
BRCA1 protein expression as a predictor of outcome following chemotherapy in sporadic epithelial ovarian cancer (EOC)
Authors: J. E. Carser, J. E. Quinn, C. O. Michie, W. G. McCluggage, A. R. Williams, P. B. Mullan, C. M. Gourley, D. P. Harkin
Journal: Journal of Clinical Oncology (2009)

5527 Background: Reduced expression of BRCA1 is observed in a substantial proportion of sporadic EOC. First line management of EOC involves platinum and taxane based chemotherapy. In vitro studies demonstrate that reduction in BRCA1 protein expression leads to enhanced sensitivity to platinum but relative resistance to taxane chemotherapy. We investigated the relationship between BRCA1 protein expression by immunohistochemistry (IHC) and survival in EOC patients, correlating outcome with type of chemotherapy received. Methods: 97 archival formalin-fixed, paraffin embedded tumour samples were identified from the Edinburgh Cancer Centre ovarian database. All patients received platinum based chemotherapy (platinum only n = 50, platinum/taxane n = 47). Tumour sections were stained for BRCA1 protein and scored by two independent reviewers. Tumours were graded from 0 (no BRCA1 protein) to 4 (&gt;90% cells positive). BRCA1 protein expression was correlated with progression-free (PFS) and overall survival (OS) by Kaplan-Meier analysis. Results: Overall, patients with no detectable BRCA1 protein had a significantly improved PFS compared to those with positive staining (17.4 months vs 12.2 months, p = 0.04). Specifically, patients receiving platinum only regimens had a significantly improved PFS if they had no detectable BRCA1 protein compared to those with positive staining (14.5 months vs 10.8 months, p = 0.035).In contrast, patients positive for BRCA1 protein (grades 1–4) had a significant increase in both OS (43.7 months vs 20.4 months, p = 0.03) and PFS (12.7 months vs 10.9 months p = 0.02) if they received platinum/taxane combination over platinum alone. Patients with no detectable BRCA1 protein (grade 0) had no significant difference in OS or PFS whether they were treated with combination or platinum only chemotherapy. Conclusions: This study provides initial evidence that BRCA1 protein expression may be a predictive marker of chemotherapy response in sporadic EOC. Specifically, patients with positive BRCA1 staining demonstrate a better clinical outcome with platinum/taxane based chemotherapy over platinum alone whereas no such difference was seen in those with no BRCA1. Further prospective clinical studies are required to validate these findings. No significant financial relationships to disclose.
Contribution of the Interleukin‐6/STAT‐3 Signaling Pathway to Chondrogenic Differentiation of Human Mesenchymal Stem Cells
Authors: Masahiro Kondo, Kunihiro Yamaoka, Kei Sakata, Koshiro Sonomoto, Lin Lin, Kazuhisa Nakano, Yoshiya Tanaka
Journal: Arthritis & Rheumatology (2015)

Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into chondrocytes. Articular cartilage contains MSC-like chondroprogenitor cells, which suggests their involvement in the maintenance of cartilage homeostasis by a self-repair mechanism. Interleukin-6 (IL-6) is a cytokine with a wide range of physiologic functions, which are produced by MSCs in a steady manner and in large quantities. The purpose of this study was to investigate the involvement of IL-6 signaling in MSC differentiation into chondrocytes.Human bone marrow-derived MSCs were cultured using a pellet culture system in medium containing transforming growth factor β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression.IL-6 was detected at a high concentration in culture supernatants during chondrogenic differentiation. The expression of the IL-6 receptor (IL-6R) was significantly increased, accompanied by markedly increased phosphorylation and expression of STAT-3. Addition of IL-6 and soluble IL-6R (sIL-6R) to the chondrogenic culture resulted in concentration-dependent increases in cartilage matrix accumulation and cartilage marker gene expression (type II collagen/aggrecan/type X collagen). Phosphorylation of the master transcription factor SOX9 was enhanced upon addition of IL-6 and sIL-6R. STAT-3 knockdown suppressed chondrogenic differentiation. IL-6 and the MSC markers CD166 and nestin were colocalized in macroscopically normal human cartilage taken from the lateral femoral compartment of knees with medial tibiofemoral osteoarthritis.During differentiation of human MSCs into chondrocytes, the activation of IL-6/STAT-3 signaling positively regulated chondrogenic differentiation. The presence of IL-6 around MSC-like cells in the cartilage tissue was identified, suggesting that IL-6 contributes to homeostasis and cartilage self-repair by promoting chondrogenic differentiation.
Michael Francis Oliver
Authors: Anna Sayburn
Journal: BMJ (2015)

Cardiologist whose research contributed to changing the way we think about heart disease



The link between serum cholesterol and heart disease is now well known. Yet when cardiologist Michael Oliver started his career in the mid-1940s, the controversy over lipid lowering treatment for cardiovascular disease was yet to come. Oliver was part of a cohort of doctors who qualified immediately after the second world war and worked in the newly formed NHS. In the early 1950s, after two years of working as a general practitioner in Leith, he began his cardiology research as a fellow at Edinburgh University. In a series of publications, he outlined the properties of cholesterol and other lipoproteins, reporting on their links to endocrine and heart disease. Working with colleagues at Edinburgh’s departments of biochemistry and medicine, he observed that patients with coronary heart disease had higher concentrations of cholesterol than an age matched control group.1

Oliver was initially an enthusiastic promoter of …
Primary Management of Early Stage Cervical Cancer (IA1-IB) and Appropriate Selection of Adjuvant Therapy
Authors: Heidi J. Gray
Journal: Journal of the National Comprehensive Cancer Network (2008)

Cervical cancer is the third most common gynecologic malignancy in the United States but the leading gynecologic cancer worldwide. Most patients will present with clinical early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage IA1-IB). These patients are a clinically heterogeneous group, and primary treatment can be either surgery or radiotherapy. Standard surgery is either radical hysterectomy with lymphadenectomy (stage IA2-IB2) or simple hysterectomy for microinvasive disease (stage IA1). Interest has been increasing in using conservative fertility-sparing surgery through radical trachelectomy as an option for select patients with early-stage disease who want future fertility. Primary radiotherapy is delivered as a combination of external-beam teletherapy and brachytherapy. It is given with concurrent cisplatin-based chemotherapy, based on 5 large randomized controlled trials that showed significant improvement in overall survival with the addition of chemotherapy. Using either radical surgery or radiation therapy in stage IB disease yields 5-year survival rates of 87% to 92%. The addition of postoperative adjuvant radiation with concurrent chemotherapy is recommended in patients with high- or intermediate-risk disease after radical hysterectomy to reduce risk for recurrence and improve progression-free survival. In select patients with stage IB2 disease with bulky tumors undergoing primary chemoradiation, adjuvant hysterectomy may provide benefit after treatment.
Statins induce insulin-degrading enzyme secretion from astrocytes via an autophagy-based unconventional secretory pathway
Authors: Sung Min Son, Seokjo Kang, Heesun Choi, Inhee Mook-Jung
Journal: Molecular Neurodegeneration (2015)

Insulin degrading enzyme (IDE) is a major protease of amyloid beta peptide (Aβ), a prominent toxic protein in Alzheimer's disease (AD) pathogenesis. Previous studies suggested that statins promote IDE secretion; however, the underlying mechanism is unknown, as IDE has no signal sequence. In this study, we found that simvastatin (0.2 μM for 12 h) induced the degradation of extracellular Aβ40, which depended on IDE secretion from primary astrocytes. In addition, simvastatin increased IDE secretion from astrocytes in a time- and dose-dependent manner. Moreover, simvastatin-mediated IDE secretion was mediated by an autophagy-based unconventional secretory pathway, and autophagic flux regulated simvastatin-mediated IDE secretion. Finally, simvastatin activated autophagy via the LKB1-AMPK-mTOR signaling pathway in astrocytes. These results demonstrate a novel pathway for statin-mediated IDE secretion from astrocytes. Modulation of this pathway could provide a potential therapeutic target for treatment of Aβ pathology by enhancing extracellular clearance of Aβ.
Factors Predicting for Efficacy and Safety of Docetaxel in a Compassionate-Use Cohort of 825 Heavily Pretreated Advanced Breast Cancer Patients
Authors: J. Alexandre, P. Bleuzen, J. Bonneterre, W. Sutherland, J.L. Misset, J.-P. Guastalla, P. Viens, S. Faivre, A. Chahine, M. Spielman, A. Bensmaïne, M. Marty, M. Mahjoubi, E. Cvitkovic
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To identify predictive factors for efficacy and safety in advanced breast cancer (ABC) patients treated in the French compassionate-use docetaxel program. PATIENTS AND METHODS: A total of 825 ABC patients treated with docetaxel (100 mg/m 2 every 3 weeks) were source-reviewed and analyzed for prognostic factors associated with overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), febrile neutropenia, mucositis, and severe fluid retention syndrome by univariate and multivariate analysis. RESULTS: The ORR was 22.9% (95% confidence interval, 20.2% to 26.2%). The median TTF and OS were 4.0 and 9.8 months, respectively. By multivariate analysis, secondary anthracycline-resistant disease was significantly associated (P &lt; .05) with lower ORR and shorter TTF and OS, whereas anthracycline-refractory disease was associated with shorter OS. Poor performance status was associated with lower ORR, shorter TTF, and shorter OS. Liver dysfunction (transaminase levels &gt; 1.5 times the upper limit of normal [ULN] and alkaline phosphatase [AP] level &gt; three times ULN) and time since first relapse less than 24 months were associated with shorter TTF and OS. Other significant correlations included the following: elevated CA 15-3 serum level with lower ORR; more than two involved sites, and minor transaminase and AP level abnormalities with shorter OS; and no previous chemotherapy for ABC with shorter TTF. According to multivariate analysis, ORR, TTF, and OS were not decreased in patients with liver metastases but without liver dysfunction. CONCLUSION: Docetaxel activity was maintained in heavily pretreated ABC patients and in those with liver metastasis; docetaxel must be used cautiously, however, in patients with liver dysfunction in whom high morbidity risk necessitates strict adherence to dose-adaptation guidelines.
Occurrence of Certain Multiple Primary Cancers in Females2
Authors: Bruce S. Schoenberg, Richard A. Greenberg, Henry Eisenberg
Journal: JNCI Journal of the National Cancer Institute (1969)

Occurrence of Certain Multiple Primary Cancers in Females Bruce S. Schoenberg, M.D., Bruce S. Schoenberg, M.D. National Cancer Institute,4Bethesda, Maryland 20014; Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06510; and Connecticut State Department of Health, Hartford, Connecticut 06103 Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard A. Greenberg, Ph.D., Richard A. Greenberg, Ph.D. National Cancer Institute,4Bethesda, Maryland 20014; Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06510; and Connecticut State Department of Health, Hartford, Connecticut 06103 Search for other works by this author on: Oxford Academic PubMed Google Scholar Henry Eisenberg, M.D., M.P.H. Henry Eisenberg, M.D., M.P.H. National Cancer Institute,4Bethesda, Maryland 20014; Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06510; and Connecticut State Department of Health, Hartford, Connecticut 06103 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 43, Issue 1, July 1969, Pages 15–32, https://doi.org/10.1093/jnci/43.1.15 Published: 01 July 1969 Article history Received: 14 February 1968 Accepted: 09 April 1969 Published: 01 July 1969
Tumor-specific correlation of tumor-type M2 pyruvate kinase (Tu M2-PK) in patients with cervical carcinoma
Authors: S. Kuemmel, S. Jeschke, S. Landt, S. Korlach, P. Schmid, J. Sehouli, J. Blohmer, K. Ulm, W. Lichtenegger, A. Thomas
Journal: Journal of Clinical Oncology (2006)

5044 Background: Pyruvate kinase is a key enzyme in glycosis. Proliferating cells express the tetrameric isoenzyme pyruvate kinase type M2 (M2-PK), which decomposes to the dimeric form during tumor development (Tu M2-PK). This suggests that Tu M2-PK can be used as a tumor marker. The goal of the present study was to investigate the diagnostic value of Tu M2-PK in patients with cervix carcinoma and in patients with preinvasive lesions (CIN I-III). Methods: Plasma samples were investigated from a total of 116 patients using the quantitative sandwich enzyme immunoassay for Tu M2-PK (ScheBo, Tech GmbH). The patients were divided up into 3 groups depending on the severity of their condition: Group 1 (n = 43): CIN I-III; Group2 (n = 49): cervix carcinoma FIGO stage I-IV; Group3 (n = 24): relapse of cervical cancer. Results: The differentiation into three groups depending on the severity of the condition gave significant results, with the group of patients with relapsed cervix carcinoma having the highest concentration of Tu M2-PK (p &lt; 0.001) (mean rank: Group 1 - 33.67, Group 2 - 62.48, Group 3 - 94.85 U/ml). In addition, there was a significant differentiation with respect to the FIGO stage, with increasing concentration for increasing stages (p &lt; 0.001). In contrast with this there was no significant differentiation in patients with preinvasive lesions (p &lt; 0.99). In the evaluation of the correlation with prognosis factors of cervix carcinoma (lymph-node status: N(+), N(−); lymphangioinvasion: L1;L0; angioinvasion: V1, V0 and grading G1–3) there were significantly higher values with positive lymph nodes (N+) (p &lt; 0.0001). No significant differences were determined in the analysis of different tumor sub-types (squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma) (p = 0.076). Conclusions: These are first results which indicate that Tu M2-PK can be used as a marker to differentiate between malignant and premalignant lesions for patients with cervical cancer. In addition, the concentration correlates with the stage of the disease. No significant financial relationships to disclose.
Alteration of the immune response to streptococcus pneumoniae during COPD exacerbation in mice
Authors: Muriel Pichavant, Gaëlle Rémy, Gwenola Kervoaze, Riti Sharan, Eva Vilain, Philippe Gosset
Journal: European Respiratory Journal (2013)

Background: Acute episodes of bacterial exacerbations mark the progression of chronic obstructive pulmonary disorder (COPD). These exacerbations often result in an increased inflammation of the respiratory tract causing death in many cases. Streptococcus pneumoniae is one of the most commonly isolated bacteria during these episodes. Mechanisms responsible for the increased susceptibility to this pathogen are unknown.  Objectives: Our aim is to define the alteration of the immune response to Streptococcus pneumoniae infection by using a mouse model of COPD.  Methods: C57BL/6 wild type mice were chronically exposed to cigarette smoke for 12 weeks. The mice were subsequently intranasally challenged with a sub-lethal dose of Streptococcus pneumoniae (4x104cfu; serotype 1) and sacrificed at 1 and 3 days post-infection. Systemic and local inflammation and immune responses, bacterial burden and histopathological changes were evaluated.  Results: Our results revealed that naive mice are able to clear the bacteria within 24 hour post-infection, whereas COPD mice develop a strong lung infection. COPD mice show an increased bacterial load in their lung compartment as well as an increased inflammatory reaction (higher recruitment of neutrophils in the BAL). COPD mice show also a defect in NKT cell activation, in dendritic cell maturation, and in IL17 and IL22 production in response to Streptococcus pneumoniae.  Conclusions: An increased susceptibility to Streptococcus pneumoniae infection was observed in COPD mice. The observed decrease in IL17 and IL22 production might be involved in the increased susceptibility of COPD mice to Streptococcus pneumoniae infection.
<i>IL36RN</i>gene mutations are not associated with sporadic generalized pustular psoriasis in Chinese patients
Authors: M. Li, Z. Lu, R. Cheng, H. Li, Y. Guo, Z. Yao
Journal: British Journal of Dermatology (2012)

Journal Article IL36RN gene mutations are not associated with sporadic generalized pustular psoriasis in Chinese patients Get access M. Li, M. Li Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China Search for other works by this author on: Oxford Academic Google Scholar Z. Lu, Z. Lu Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China Search for other works by this author on: Oxford Academic Google Scholar R. Cheng, R. Cheng Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China Search for other works by this author on: Oxford Academic Google Scholar H. Li, H. Li Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China Search for other works by this author on: Oxford Academic Google Scholar Y. Guo, Y. Guo Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China Search for other works by this author on: Oxford Academic Google Scholar Z. Yao Z. Yao Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China Zhirong Yao. E‐mail: zryaosmu@sohu.com Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 168, Issue 2, 1 February 2013, Pages 452–455, https://doi.org/10.1111/j.1365-2133.2012.11195.x Published: 01 February 2013
Induction of cathelicidin (LL-37) in rhinovirus-induced COPD exacerbations
Authors: Rosa Sotero, Patrick Mallia, Joseph Footitt, Maria-Belen Trujillo-Torralbo, Tatiana Kebadze, Contoli Marco, Alberto Papi, Girolamo Pelaia, Rosario Maselli, Sebastian Johnston
Journal: European Respiratory Journal (2011)

Cathelicidin (LL-37) is a cationic antimicrobial peptide and has both antimicrobial and immunomodulatory effects. The majority of LL-37 is stored in neutrophil granules for release at sites of infection. LL-37 has demonstrated anti-viral effects but the role of LL-37 in virus-induced COPD exacerbations is unknown.   Methods:  We infected 3 groups of subjects–COPD GOLD stage II (N=20), smokers with normal lung function (SMK, N=21) and non-smokers (NS, N=11)–with rhinovirus 16 (RV). Induced sputum was collected post-inoculation. In a subset of COPD (N=10) and SMK (N=12) BAL was collected on day 7. Sputum and BAL cytospins were prepared and cell counts determined. LL-37 and cytokines were measured in sputum supernatants by ELISA and virus load by quantitative PCR.   Results:  In all subjects combined post-infection peak sputum LL-37 levels correlated with peak sputum virus load (P=0.0018,r=0.43) and peak sputum total inflammatory cells (P   Conclusions:  LL-37 in sputum and BAL following rhinovirus infection correlates with inflammatory cells, pro-inflammatory cytokines and virus load. Further studies are required to determine whether LL-37 contributes to neutrophilic inflammation in virus-induced exacerbations or is a component of the anti-viral innate immune response.
Abstract 10579: Endothelial Specific Redox Signalling Regulates Susceptibility to Aortic Dissection Through Endothelial Cyclophilin A secretion
Authors: Lampson Fan, Gillian Douglas, Jenny Bendall, Eileen McNeill, Keith Channon
Journal: Circulation (2011)

Aortic dissection is a severe and often fatal condition, and has been shown to be associated with vascular oxidative stress. One of the main sources of oxidative stress in the vasculature is NADPH ...