tbuckley/cabot-search huggingface dataset:
Epidemiological study of the workforce after an outbreak of occupational asthma due to chromium and cobalt in an aerospace factory
Authors: Gareth Walters, Alastair Robertson, Vicky Moore, Cedd Burge, Arun Vellore, Sherwood Burge
Journal: European Respiratory Journal (2011)

An outbreak of asthma due to chromium and cobalt in 4 employees at an aerospace factory occurred after coolant oils were changed in 2004 (6-24 month latency). The factory machined high chrome and nickel alloys with hard metal tipped tools containing cobalt. Oils and mist exposure met exposure standards. This prompted an investigation of the workforce, in order to measure extent and cause of outbreak. 62 (of 65) employees (m=54;f=8; mean age 34.5; 58% currently working with coolant oils; 58% never smoked) undertook a self-completed symptom questionnaire, lung function, urinalysis and received expert consultation. 74.1% had urinary chromium excretion indicating occupational exposure. 66.1% had at least one respiratory symptom, most symptoms from after 2003. Clinical opinion identified cases of definite or probable lung disease: OA (5; 8%, 3 with positive challenges to chrome and one with cobalt, one not challenged), symptomatic pre-existing asthma (17; 27%) and occupational rhinitis (OR) (18; 29%). All 5 OA cases and 15/18 OR cases worked with coolant oils. Employees with OA, asthma or OR were compared with asymptomatic workers (n=37). Those with OA or OR were of similar age and no more likely to be smokers, have abnormal spiromtery or FeNO than controls. Those with OA and OR had significantly higher urine chromium (p=0.05) and cobalt (p
Clinical Activity of the Oral Selective Inhibitor of Nuclear Export (Sine) Selinexor (Kpt-330) in Patients with Head &amp; Neck Squamos Cell Carcinoma (Hn-Scc)
Authors: A. Mahipal, N.Y. Gabrail, A. Sukari, H. Mahaseth, M. Mau-Sorensen, S. Shacham, J. Saint-Martin, S. Friedlander, Y. Landesman, J. Ellis, E. Shacham, J. McCartney, T. Marshall, D. Vincent, T. Rashal, M. Kauffman, M.R. Mirza, A.R.A. Razak
Journal: Annals of Oncology (2014)
Effect of inhalation of tobramycin on reduction of hospitalisation rate in severe COPD
Authors: Peter Haidl
Journal: European Respiratory Journal (2012)

Introduction: Exacerbation in severe COPD often requires hospital treatment and has a negative impact on patients prognosis. An important cause of frequent exacerbations is lower airway bacterial colonization in stable disease. In addition moderate bronchiectasis are present in up to 50% in severe COPD. The study investigated the effect of daily inhalation of tobramycin on hospitalisation rate in severe COPD.  Methods: At six centers we randomly assigned 44 patients (30 males) with severe COPD (FEV 1 of predicted value 42.8 ±7.1 Tobra and 33.5±10.3 placebo) and a minimum of two hospitalisations in the year before inclusion. Patients inhaled twice daily for 12 months 80 mg tobramycin (GERNEBCIN®) or isotonic saline (placebo) with a jet nebulizer (Pari Boy SX). Primary endpoint was hospitalisation rate in the period of study, secondary endpoints time to first hospitalisation and 6 MWD.  Results:  ITT1 = number of patients which took study medication for at least 28 days  Conclusion:  Inhalation with 160 mg tobramycin by means of a nebulizer over a 12 month period didn9t reduce the hospitalisation rate for patients with severe COPD and a minimum of two hospitalisations compared to placebo. The statistical relevance is reduced by a high drop-out rate specifically in the tobramycin-group unrelated to side effects during inhalation of tobramycin. However, the underlying reason remains unexplained.
Novel Risk Loci for Rheumatoid Arthritis in Han Chinese and Congruence With Risk Variants in Europeans
Authors: Lei Jiang, Jian Yin, Lingying Ye, Jian Yang, Gibran Hemani, Ai‐jun Liu, Hejian Zou, Dongyi He, Lingyun Sun, Xiaofeng Zeng, Zhanguo Li, Yi Zheng, Yiping Lin, Yi Liu, Yongfei Fang, Jianhua Xu, Yinong Li, Shengming Dai, Jianlong Guan, Lindi Jiang, Qianghua Wei, Yi Wang, Yang Li, Cibo Huang, Xiaoxia Zuo, Yu Liu, Xin Wu, Libin Zhang, Ling Zhou, Qing Zhang, Ting Li, Ling Chen, Zhen Xu, Xiaoping Yang, Feng Qian, Weilin Xie, Wei Liu, Qian Guo, Shaolan Huang, Jing Zhao, Mengmeng Li, Yanhua Jin, Jie Gao, Ying Lv, Yiwen Wang, Li Lin, Aihua Guo, Patrick Danoy, Dana Willner, Catherine Cremin, Johanna Hadler, Fengchun Zhang, Yan Zhao, Mengtao Li, Tao Yue, Xiaolei Fan, Jianping Guo, Rong Mu, Jingyi Li, Chao Wu, Ming Zeng, Jiucun Wang, Shilin Li, Li Jin, Binbin Wang, Jing Wang, Xu Ma, Liangdan Sun, Xuejun Zhang, Matthew A. Brown, Peter M. Visscher, Ding‐feng Su, Huji Xu
Journal: Arthritis & Rheumatology (2014)

To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans.A genome-wide association study was conducted in China with 952 patients and 943 controls, and 32 variants were followed up in 2,132 patients and 2,553 controls. A transpopulation meta-analysis with results from a large European RA study was also performed to compare the genetic architecture across the 2 ethnic remote populations.Three non-major histocompatibility complex (non-MHC) loci were identified at the genome-wide significance level, the effect sizes of which were larger in anti-citrullinated protein antibody (ACPA)-positive patients than in ACPA-negative patients. These included 2 novel variants, rs12617656, located in an intron of DPP4 (odds ratio [OR] 1.56, P = 1.6 × 10(-21) ), and rs12379034, located in the coding region of CDK5RAP2 (OR 1.49, P = 1.1 × 10(-16) ), as well as a variant at the known CCR6 locus, rs1854853 (OR 0.71, P = 6.5 × 10(-15) ). The analysis of ACPA-positive patients versus ACPA-negative patients revealed that rs12617656 at the DPP4 locus showed a strong interaction effect with ACPAs (P = 5.3 × 10(-18) ), and such an interaction was also observed for rs7748270 at the MHC locus (P = 5.9 × 10(-8) ). The transpopulation meta-analysis showed genome-wide overlap and enrichment in association signals across the 2 populations, as confirmed by prediction analysis.This study has expanded the list of alleles that confer risk of RA, provided new insight into the pathogenesis of RA, and added empirical evidence to the emerging polygenic nature of complex trait variation driven by common genetic variants.
How Does Cardiovascular Disease First Present in Women and Men?
Authors: Julie George, Eleni Rapsomaniki, Mar Pujades-Rodriguez, Anoop Dinesh Shah, Spiros Denaxas, Emily Herrett, Liam Smeeth, Adam Timmis, Harry Hemingway
Journal: Circulation (2015)

Given the recent declines in heart attack and stroke incidence, it is unclear how women and men differ in first lifetime presentations of cardiovascular diseases (CVDs). We compared the incidence of 12 cardiac, cerebrovascular, and peripheral vascular diseases in women and men at different ages.We studied 1 937 360 people, aged ≥ 30 years and free from diagnosed CVD at baseline (51% women), using linked electronic health records covering primary care, hospital admissions, acute coronary syndrome registry, and mortality (Cardiovascular Research Using LInked Bespoke Studies and Electronic Records [CALIBER] research platform). During 6 years median follow-up between 1997 and 2010, 114 859 people experienced an incident cardiovascular diagnosis, the majority (66%) of which were neither myocardial infarction nor ischemic stroke. Associations of male sex with initial diagnoses of CVD, however, varied from strong (age-adjusted hazard ratios, 3.6-5.0) for abdominal aortic aneurysm, myocardial infarction, and unheralded coronary death (particularly >60 years), through modest (hazard ratio, 1.5-2.0) for stable angina, ischemic stroke, peripheral arterial disease, heart failure, and cardiac arrest, to weak (hazard ratio <1.5) for transient ischemic attack, intracerebral hemorrhage, and unstable angina, and inverse (0.69) for subarachnoid hemorrhage (all P<0.001).The majority of initial presentations of CVD are neither myocardial infarction nor ischemic stroke, yet most primary prevention studies focus on these presentations. Sex has differing associations with different CVDs, with implications for risk prediction and management strategies.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01164371.
Influence of X Irradiation and the Milk Agent on Growth of Transplanted Mouse Mammary Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Richmond T. Prehn
Journal: JNCI Journal of the National Cancer Institute (1969)

Prior sublethal X irradiation of recipient syngeneic mice regularly increased the growth of grafts of virus-induced mammary tumors when, and only when, the recipient animals lacked the mammary-tumor milk agent. Conversely, prior X irradiation actually inhibited the growth of subsequent tumor grafts when the animals harbored this virus. These results imply that the mammary tumors were antigenic in syngeneic mice free of the milk agent. Direct attempts to demonstrate antigenicity by immunization suggested that the antigenicity was relatively weak. Thus comparative growth of tumor implants in X-rayed and normal recipients may provide a simple and relatively sensitive method of testing for transplantation antigenicity.
Detection of primary ciliary dyskinesia by hand-held tidal breathing nasal nitric oxide measurements in a tertiary referral population
Authors: Tamara Paff, Kirsten de Fluiter, Jerica Sinkeldam, Johannes Daniels, Pieter Postmus, Gerard Pals, Eric Haarman
Journal: European Respiratory Journal (2014)

Background:Hand-held tidal breathing nasal nitric oxide (nNO) measurements reliably discriminate between patients with primary ciliary dyskinesia (PCD), cystic fibrosis (CF) and healthy subjects [Marthin et al. 2013 PLoS One].  Objective:To assess the accuracy of detecting PCD by hand-held nNO measurements in a tertiary referral population.  Methods:Patients of 4 years and older referred to the Dutch National PCD diagnostic center from November 2011 to October 2013, received two nNO measurements prior to a nasal curette biopsy. In addition, nNO measurements were performed in PCD patients during a regular visit to the outpatient clinic. PCD diagnosis was based on a combination of clinical symptoms, evaluation of ciliary movement by high-speed videomicroscopy and/or ciliary ultrastructure by electron microscopy.  Results:142 referred patients underwent PCD diagnostics (median age 10.0 years, IQR 6.7-15.3). nNO levels were measured successfully in 132 of 142 referred patients (93,0%) of which 129 (97,8%) could be measured in duplicate. In all known PCD patients (n=22) a duplicate nNO measurement could be performed. Median nNO level (ppb) in PCD referrals (24.0 IQR 11.0-33.8) and known PCD patients (26.8 IQR 18.3-84.1) was significantly lower compared to non-PCD referrals (221.8 IQR 81.9-426.0). Sensitivity and specificity for detecting PCD was 89.7% and 80.6%, respectively, using a cut-off of 71 ppb. The area under the ROC curve reached 0.88 (95% CI 0.79-0.97).  Conclusion:Hand-held tidal breathing nasal nitric oxide measurements show a high success rate and reasonable accuracy in detecting primary ciliary dyskinesia in a tertiary referral population.
The RAB39B p.G192R mutation causes X-linked dominant Parkinson’s disease
Authors: Ignacio F. Mata, Yongwoo Jang, Chun-Hyung Kim, David S. Hanna, Michael O. Dorschner, Ali Samii, Pinky Agarwal, John W. Roberts, Olga Klepitskaya, David R. Shprecher, Kathryn A. Chung, Stewart A. Factor, Alberto J. Espay, Fredy J. Revilla, Donald S. Higgins, Irene Litvan, James B. Leverenz, Dora Yearout, Miguel Inca-Martinez, Erica Martinez, Tiffany R. Thompson, Brenna A. Cholerton, Shu-Ching Hu, Karen L. Edwards, Kwang-Soo Kim, Cyrus P. Zabetian
Journal: Molecular Neurodegeneration (2015)

To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD). We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders.
Semi-national surveillance of fungaemia in Denmark 2004–2006: increasing incidence of fungaemia and numbers of isolates with reduced azole susceptibility
Authors: M.C. Arendrup, K. Fuursted, B. Gahrn-Hansen, H.C. Schønheyder, J.D. Knudsen, I.M. Jensen, B. Bruun, J.J. Christensen, H.K. Johansen
Journal: Clinical Microbiology and Infection (2008)
Fulminant Ulcerative Colitis in Late Pregnancy and the Puerperium
Authors: J B Anderson, G M Turner, R C N Williamson
Journal: Journal of the Royal Society of Medicine (1987)

Four patients underwent emergency colectomy during pregnancy or the puerperium for complications of ulcerative proctocolitis. Three had inactive colitis at conception, while in the fourth the disease started during pregnancy. Three patients required subtotal colectomy and ileostomy for toxic dilatation during the third trimester or within 5 days of delivery, and the fourth underwent proctocolectomy postpartum for intractable colitis. There were no maternal deaths but 2 of 4 infants died. One child weighing 1.4 kg survived vaginal delivery during the 33rd week of pregnancy, 2 weeks after his mother had undergone emergency colectomy.
Collagen V overexpression correlates with IL-17+ cells in C57BL/6 mice pulmonary remodeling
Authors: Priscila Cristina Andrade, Ana Paula Pereira Velosa, Antonio dos Santos Filho, Sandra de Morais, Esmeralda Miristeni Eher, Sérgio Catanozi, Vera Luisa Capelozzi, Walcy Rosolia Teodoro
Journal: European Respiratory Journal (2014)

Background: Studies have suggested a possible contribution for IL-17 in the development and progression of pulmonary fibrosis. Besides, IL-17 induced type V collagen (COLV) overexpression in obliterative bronchiolitis. COLV is a quantitatively minor collagen that regulates the fibrillogenesis. Recently COLV overexpression was described in the early fibrosis processes. Objectives: To correlate COLV expression with IL-17+ cells in the pulmonary tissues of C57BL/6 mice immunized with COLV. Methods: C57BL/6 female mice (n=6) were subcutaneously immunized with 150µg/200µl of COLV in complete Freund´s adjuvant (FA). Control mice (n=6) were immunized with FA. Total collagen and COLV deposit in pulmonary interstitium were evaluated by picrossirius and immunostaining and quantified by image analysis. IL-17+ cells were evaluated by immunohistochemistry and point counting method. Results: Immunized mice presented prominent thickness of the septal and bronchovascular interstitium with thick collagen fibers, characteristic of the fibrotic process. Also, these mice showed high expression of COLV thick fibers along the bronchovascular and septal interstitium, differing from its normal fibrilar pattern of thin fibers found in control mice (18.11±0.65 vs. 4.61±0.66, p=0.002). The amount of IL-17+ cells in the pulmonary interstitium was higher in immunized mice when compared to controls (47.05±5.17 vs. 12.21±5.17, p=0.001). Conclusions: COLV high expression was correlated with more IL-17+ cells expression, suggesting that this cytokine can play a role in inducing COLV overexpression in pulmonary remodeling. Strategies to block IL-17+ cells may represent a promissory therapeutic target to fibrosis process.
Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development
Authors: Eric K. Rowinsky, Jolene J. Windle, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (1999)

ABSTRACT: Ras proteins are guanine nucleotide–binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approximately 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first—and most critical—modification is the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biologically active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clinical evaluations of FTase inhibitors to determine the feasibility of administering them on dose schedules like those that portend optimal therapeutic indices in preclinical studies. Because of the unique biologic aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.
Effectiveness of exercise in patients with osteoarthritis of hip or knee: nine months' follow up
Authors: M E van Baar, J Dekker, R A B Oostendorp, D Bijl, Th B Voorn, J W J Bijlsma
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> To determine whether the effects of an exercise programme in patients with osteoarthritis of hip or knee are sustained at six and nine months9 follow up. <h3>METHODS</h3> A randomised, single blind, clinical trial was conducted in a primary care setting. Patients with osteoarthritis of hip or knee (ACR criteria) were selected. Two intervention groups were compared. Both groups received treatment from their general practitioner, including patient education and drug treatment if necessary. The experimental group also received exercise treatment from a physiotherapist in primary care. The treatment period was 12 weeks, with an ensuing 24 week follow up. The main outcome measures were pain, drug use (non-steroidal anti-inflammatory drugs), and observed disability. <h3>RESULTS</h3> 201 patients were randomly allocated to the exercise or control group, and 183 patients completed the trial. At 24 weeks exercise treatment was associated with a small to moderate effect on pain during the past week (difference in change between the two groups −11.5 (95% CI −19.7 to −3.3). At 36 weeks no differences were found between the groups. <h3>CONCLUSIONS</h3> Beneficial effects of exercise decline over time and finally disappear.
Role of Local Radiation Therapy in Cancer Immunotherapy
Authors: Sandra Demaria, Encouse B. Golden, Silvia C. Formenti
Journal: JAMA Oncology (2015)

The recent success of cancer immunotherapy has demonstrated the power of the immune system to clear tumors, generating renewed enthusiasm for identifying ways to induce antitumor immune responses in patients. Natural antitumor immune responses are detectable in a fraction of patients across multiple malignant neoplasms and can be reactivated by targeting rate-limiting immunosuppressive mechanisms. In most patients, however, interventions to induce a de novo antitumor immune response are necessary. We review growing evidence that radiation therapy targeted to the tumor can convert it into an in situ tumor vaccine by inducing release of antigens during cancer cell death in association with proinflammatory signals that trigger the innate immune system to activate tumor-specific T cells. In addition, radiation's effects on the tumor microenvironment enhance infiltration of activated T cells and can overcome some of the barriers to tumor rejection. Thus, the complementary effects of radiation on priming and effector phases of antitumor immunity make it an appealing strategy to generate immunity against a patient's own individual tumor, that through immunological memory, can result in long-lasting systemic responses. Several anecdotal cases have demonstrated the efficacy of combining radiation with available immunotherapies, and results of prospective trials are forthcoming.
Impact of a New Fusion Receptor on PD-1–Mediated Immunosuppression in Adoptive T Cell Therapy
Authors: Sebastian Kobold, Simon Grassmann, Michael Chaloupka, Christopher Lampert, Susanne Wenk, Fabian Kraus, Moritz Rapp, Peter Düwell, Yi Zeng, Jan C. Schmollinger, Max Schnurr, Stefan Endres, Simon Rothenfußer
Journal: JNCI Journal of the National Cancer Institute (2015)

Adoptive T cell transfer (ACT) is currently under investigation for the treatment of metastatic cancer. Recent evidence suggests that the coinhibitory PD-1-PD-L1 axis plays a major role in ACT failure. We hypothesized that a new fusion receptor reverting PD-1-mediated inhibition into CD28 costimulation may break peripheral tolerance.Different PD-1-CD28 fusion receptor constructs were created and retrovirally transduced into primary T cell receptor transgenic murine CD8(+) T cells specific for ovalbumin (OT-1). Cytokine release, proliferation, cytotoxicity, and tumor recognition were analyzed in vitro. Antitumor efficacy and mode of action were investigated in mice bearing subcutaneous tumors induced with the pancreatic carcinoma cell line Panc02 expressing the model antigen ovalbumin (Panc-OVA). For antitumoral efficacy, six to eight mice per group were used. All statistical tests are two-sided.Transduction of the PD-1-CD28 receptor constructs mediated enhanced cytokine release, T cell proliferation, and T cell-induced lysis of target tumor cells. The PD-1-CD28 receptor function was dependent on two of the CD28-signaling motifs and IFN-γ release. Treatment of mice with established Panc-OVA tumors with fusion receptor-transduced OT-1 T cells mediated complete tumor regression. Mice rejecting the tumor were protected upon subsequent rechallenge with either ovalbumin-positive or -negative tumors, indicative of a memory response and epitope spreading in nine of 11 mice vs none of the six naïve mice (P < .001). Treatment efficacy was associated with accumulation of IFN-γ-producing T cells and an increased ratio of CD8(+) T cells to immunosuppressive myeloid-derived suppressor cells in the tumors.Transduction of T cells with this new PD-1-CD28 receptor has the potential of breaking the PD-1-PD-L1-immunosuppressive axis in ACT.