tbuckley/cabot-search huggingface dataset:
Adverse outcomes after major surgery in patients with systemic lupus erythematosus: a nationwide population-based study
Authors: Jui-An Lin, Chien-Chang Liao, Yi-Jui Lee, Chih-Hsiung Wu, Wen-Qi Huang, Ta-Liang Chen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To investigate the postoperative adverse outcomes among surgical patients with preoperative systemic lupus erythematosus (SLE) in a nationwide population-based study. <h3>Methods</h3> We used Taiwan9s National Health Insurance Research Database to identify 4321 surgical inpatients with SLE and 17 284 sex- and age-matched controls receiving major surgery. Sociodemographic characteristics, preoperative comorbidities, postoperative 30-day in-hospital major complications and mortality were analysed among surgical patients with and without SLE. <h3>Results</h3> Surgical patients with SLE had a higher prevalence of preoperative coexisting medical conditions and postoperative major complications. The OR of 30-day postoperative mortality for surgical patients with SLE was 1.71 (95% CI 1.09 to 2.67) after adjustment. Surgical patients who had received more recent (within 6 months) preoperative SLE-related inpatient care had higher risks of 30-day postoperative acute renal failure (OR=7.23, 95% CI 4.52 to 11.6), pneumonia (OR=2.60, 95% CI 1.82 to 3.72), pulmonary embolism (OR=4.86, 95% CI 1.20 to 19.7), septicaemia (OR=3.43, 95% CI 2.48 to 4.74), stroke (OR=2.01, 95% CI 1.38 to 2.92), overall complications (OR=2.30, 95% CI 1.89 to 2.80) and 30-day postoperative mortality (OR=2.39, 95% CI 1.28 to 4.45) than surgical patients without SLE. SLE-related preoperative steroid injections showed a dose-dependent relationship with postoperative complications and mortality. <h3>Conclusions</h3> SLE significantly increased the risks of surgical patients for overall major complications and mortality after major surgery. Our findings demonstrated the need for integrated care and revised protocols for perioperative management to improve outcomes for surgical patients with SLE.
Keir Hall Fisher
Authors: M. S. P. v. Kaehne
Journal: BMJ (2015)

Keir Hall Fisher came from a medical family; his father was a senior anaesthetist at Glasgow Royal Infirmary. He was a Glaswegian through and through. His identical twin brother, Ian, started medicine before Keir, but transferred to the Church rapidly. This caused great confusion when they visited each other’s “parishes.” After house jobs in Glasgow, Keir went to Kilmacolm as a trainee general practitioner. One day he was talking to a lawyer, who, as it happened, also acted for two Scottish GPs in rural England and was told they had a vacancy for a third partner. …
Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling
Authors: Ming Quan, Jiujie Cui, Tian Xia, Zhiliang Jia, Dacheng Xie, Daoyan Wei, Suyun Huang, Qian Huang, Shaojiang Zheng, Keping Xie
Journal: Cancer Research (2015)

Abstract Merlin, the protein encoded by the NF2 gene, is a member of the band 4.1 family of cytoskeleton-associated proteins and functions as a tumor suppressor for many types of cancer. However, the roles and mechanism of Merlin expression in pancreatic cancer have remained unclear. In this study, we sought to determine the impact of Merlin expression on pancreatic cancer development and progression using human tissue specimens, cell lines, and animal models. Decreased expression of Merlin was pronounced in human pancreatic tumors and cancer cell lines. Functional analysis revealed that restored expression of Merlin inhibited pancreatic tumor growth and metastasis in vitro and in vivo. Furthermore, Merlin suppressed the expression of Wnt/β-catenin signaling downstream genes and the nuclear expression of β-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/β-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of β-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/β-catenin signaling, suggesting that targeting novel Merlin/FOXM1/β-catenin signaling is an effective therapeutic strategy for pancreatic cancer. Cancer Res; 75(22); 4778–89. ©2015 AACR.
Using Germline Genomics to Individualize Pediatric Cancer Treatments
Authors: Navin Pinto, Susan L. Cohn, M. Eileen Dolan
Journal: Clinical Cancer Research (2012)

Abstract The amazing successes in cure rates for children with cancer over the last century have come in large part from identifying clinical, genetic, and molecular variables associated with response to therapy in large cooperative clinical trials and stratifying therapies according to the predicted risk of relapse. There is an expanding interest in identifying germline genomic variants, as opposed to genetic variants within the tumor, that are associated with susceptibility to toxicity and for risk of relapse. This review highlights the most important germline pharmacogenetic and pharmacogenomic studies in pediatric oncology. Incorporating germline genomics into risk-adapted therapies will likely lead to safer and more effective treatments for children with cancer. Clin Cancer Res; 18(10); 2791–800. ©2012 AACR.
DNA Methylation Signatures for Prediction of Biochemical Recurrence After Radical Prostatectomy of Clinically Localized Prostate Cancer
Authors: Christa Haldrup, Kamilla Mundbjerg, Else Marie Vestergaard, Philippe Lamy, Peter Wild, Wolfgang A. Schulz, Christian Arsov, Tapio Visakorpi, Michael Borre, Søren Høyer, Torben F. Ørntoft, Karina D. Sørensen
Journal: Journal of Clinical Oncology (2013)

Purpose Diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, causing overtreatment of indolent PC and risk of delayed treatment of aggressive PC. Here, we identify six novel candidate DNA methylation markers for PC with promising diagnostic and prognostic potential. Methods Microarray-based screening and bisulfite sequencing of 20 nonmalignant and 29 PC tissue specimens were used to identify new candidate DNA hypermethylation markers for PC. Diagnostic and prognostic potential was evaluated in 35 nonmalignant prostate tissue samples, 293 radical prostatectomy (RP) samples (cohort 1, training), and 114 malignant RP samples (cohort 2, validation) collected in Denmark, Switzerland, Germany, and Finland. Sensitivity and specificity for PC were evaluated by receiver operating characteristic analyses. Correlations between DNA methylation levels and biochemical recurrence were assessed using log-rank tests and univariate and multivariate Cox regression analyses. Results Hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B was highly cancer specific (area under the curve, 0.89 to 0.98). Furthermore, high C1orf114 methylation was significantly (P &lt; .05) associated with biochemical recurrence in multivariate analysis in cohort 1 (hazard ratio [HR], 3.10; 95% CI, 1.89 to 5.09) and was successfully validated in cohort 2 (HR, 3.27; 95% CI, 1.17 to 9.12). Moreover, a significant (P &lt; .05) three-gene prognostic methylation signature (AOX1/C1orf114/HAPLN3), classifying patients into low- and high-methylation subgroups, was trained in cohort 1 (HR, 1.91; 95% CI, 1.26 to 2.90) and validated in cohort 2 (HR, 2.33; 95% CI, 1.31 to 4.13). Conclusion We identified six novel candidate DNA methylation markers for PC. C1orf114 hypermethylation and a three-gene methylation signature were independent predictors of time to biochemical recurrence after RP in two PC patient cohorts.
Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype
Authors: Jenny K. Gustafsson, Anna Ermund, Daniel Ambort, Malin E.V. Johansson, Harriet E. Nilsson, Kaisa Thorell, Hans Hebert, Henrik Sjövall, Gunnar C. Hansson
Journal: The Journal of Experimental Medicine (2012)

Cystic fibrosis (CF) is caused by a nonfunctional chloride and bicarbonate ion channel (CF transmembrane regulator [CFTR]), but the link to the phenomenon of stagnant mucus is not well understood. Mice lacking functional CFTR (CftrΔ508) have no lung phenotype but show similar ileal problems to humans. We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice. The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM). In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties. This knowledge may provide novel therapeutic options for CF.
IL-32, a Novel Proinflammatory Cytokine in Chronic Obstructive Pulmonary Disease
Authors: Fiorella Calabrese, Simonetta Baraldo, Erica Bazzan, Francesca Lunardi, Federico Rea, Piero Maestrelli, Graziella Turato, Kim Lokar-Oliani, Alberto Papi, Renzo Zuin, Paolo Sfriso, Elisabetta Balestro, Charles A. Dinarello, Marina Saetta
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder of the lung, yet the mechanisms that regulate this immune-inflammatory response are not fully understood.We investigated whether IL-32, a newly discovered cytokine, was related to markers of inflammation and clinical progression in COPD.Using immunohistochemistry, expression of IL-32 was examined in surgically resected specimens from 40 smokers with COPD (FEV(1) = 39 +/- 4% predicted), 11 smokers with normal lung function, and 9 nonsmoking control subjects. IL-32 was quantified in alveolar macrophages, alveolar walls, bronchioles, and arterioles, and confirmed by molecular analysis. The levels of IL-32 were correlated with the cellular infiltrates, markers of inflammation, and clinical data.Macrophage staining for IL-32 was increased in smokers with COPD compared with control smokers and nonsmokers (P = 0.0014 and P < 0.0001, respectively), and similar differences were observed in alveolar walls (P = 0.0004 and P = 0.0005) and bronchiolar epithelium (P = 0.004 and P = 0.0009). This increase was also detected at the mRNA level (P = 0.007 vs. control smokers and P = 0.029 vs. nonsmokers) and was mainly due to non-alpha isoforms. Moreover, IL-32 expression was positively correlated with tumor necrosis factor-alpha (P = 0.004, r(s)=0.70), CD8(+)cells (P = 0.02, r(s)=0.46), phospho p38MAPK (P < 0.01, r(s)=0.60) and negatively with FEV(1) values (P = 0.004, r(s)= -0.53).This is the first study to demonstrate increased expression of IL-32 in lung tissue of patients with COPD, where it was colocalized with tumor necrosis factor-alpha and correlated with the degree of airflow obstruction. These results suggest that IL-32 is implicated in the characteristic immune response of COPD, with a possible impact on disease progression.
Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis
Authors: Maria Juarez, Holger Bang, Friederike Hammar, Ulf Reimer, Bernard Dyke, Ilfita Sahbudin, Christopher D Buckley, Benjamin Fisher, Andrew Filer, Karim Raza
Journal: Annals of the Rheumatic Diseases (2015)

Objective To investigate serum antibody reactivity against a panel of post-translationally modified vimentin peptides (PTMPs) in patients with early inflammatory arthritis. Methods A panel of PTMPs was developed. Microtitre plates were coated with peptides derived from vimentin that were identical in length and composition except at one amino acid that was changed to introduce one of three post-translational modifications (PTMs)—either a citrullinated, carbamylated or acetylated residue. Sera of 268 treatment-naive patients with early inflammatory arthritis and symptoms ≤3 months' duration were tested. Patients were assigned to one of three outcome categories at 18-month follow-up (rheumatoid arthritis (RA), persistent non-RA arthritis and resolving arthritis). Results Antibodies against citrullinated, carbamylated and acetylated vimentin peptides were detected in the sera of patients with early inflammatory arthritis. The proportion of patients seropositive for all antibody types was significantly higher in the RA group than in the other groups. Anti cyclic citrullinated peptide (CCP)-positive patients with RA had higher numbers of peptides recognised and higher levels of antibodies against those peptides, representing a distinct profile compared with the other groups. Conclusions We show for the first time that antibodies against acetylated vimentin are present in the sera of patients with early RA and confirm and extend previous observations regarding anticitrullinated and anticarbamylated antibodies.
Impact of Dyslipidemia in End-Stage Renal Disease
Authors: Sarah S. Prichard
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Heart disease is a major cause of morbidity and mortality among patients with renal failure. Premature atherosclerotic coronary heart disease is driven by multiple risk factors, including dyslipidemia and oxidative stress. In the nondialysis population, there is overwhelming evidence that treatment of dyslipidemia can significantly improve cardiovascular outcomes. Accumulating data indicate that dialysis patients have atherogenic lipid abnormalities. Although LDL cholesterol (LDL-C) levels in patients who undergo hemodialysis are normal or near normal, increased oxidized LDL-C, triglycerides, and lipoprotein (a) [Lp(a)]; decreased HDL cholesterol (HDL-C); and triglyceride-rich VLDL have been noted. Patients who receive peritoneal dialysis have a more atherogenic lipid profile with increased LDL-C, apolipoprotein B, oxidized LDL-C, triglycerides, and Lp(a) and decreased HDL-C. Furthermore, the LDL particles of peritoneal dialysis patients are small and dense. However, there is a dearth of information regarding the goals, efficacy, and safety of dyslipidemia treatment among dialysis patients. Given the strong evidence of risk reduction and the benefits of lipid-lowering treatment in the nondialysis population, the emerging consensus is that dialysis patients should be treated aggressively for dyslipidemia to an LDL-C goal below 100 mg/dl. Although physicians and patients may be reluctant to add medications because of concerns about polypharmacy, potential decreased compliance, and increased cost, the use of agents such as sevelamer that can serve multiple functions, including phosphate control, lipid lowering (decreased LDL-C and total cholesterol), and anti-inflammatory effects (decreased high-sensitivity C-reactive protein), should be explored and considered for patients who would benefit from such treatment. E-mail: [email protected]
Sarcoidosis and tuberculosis: A rare combination?
Authors: Diana Calaras, Oxana Munteanu, Victor Botnaru
Journal: European Respiratory Journal (2012)

Tuberculosis and sarcoidosis are chronic granulomatous diseases that are similar in many aspects, although different. They occur concomitantly very rarely. TB is an infectious disease caused by M. tuberculosis morphologically defined by granulomas with caseous necrosis. Sarcoidosis is a systemic disease of unknown etiology, and is characterized by noncaseous granulomas.

Aim of the study: to evaluate weather the high incidence of TB in our country affects the diagnosis and management of sarcoidosis.

Material and methods: We performed an analysis of 97 patient's clinical records with biopsy proven or highly suggestive of sarcoidosis, cases registered in a third level medical institution, during year 2011.

Results: we found 3 (3,1%) patients with concomitant diagnosis of TB and sarcoidosis, in whom sputum culture revealed M. tuberculosis (1-MDR tuberculosis, 1- poly-resistant). After 2 months of standard anti-TB treatment we have obtained culture conversion, but no improvement in chest X-ray and HRCT. Supplementation with corticosteroids (CS) leaded to full resorption of pulmonary lesions. Other 8 (8,2%) patients from 97, microbiologically negative, where initially diagnosed with pulmonary TB based on histological examination (caseating granulomas). Anti-TB treatment inefficiency imposed reconsideration of the diagnosis and initiation of steroid treatment, with clinical and radiological improvement after 4 months of CS.

Conclusion: Infection with M. tuberculosis , seems to be not so infrequent in patients with sarcoidosis. The finding of necrotizing granulomas alone is not sufficient for the final clinical diagnosis of tuberculosis. Due to high incidence of tuberculosis in our country there is a tendency to overdiagnose tuberculosis.
Recalcitrant lithium-induced psoriasis in a suicidal patient alleviated by tumour necrosis factor-? inhibition
Authors: T. Wachter, W.M. Murach, E.-B. Bröcker, M.P. Schön
Journal: British Journal of Dermatology (2007)

Journal Article Recalcitrant lithium‐induced psoriasis in a suicidal patient alleviated by tumour necrosis factor‐α inhibition Get access T. Wachter, T. Wachter Department of Dermatology, Venereology and Allergology Search for other works by this author on: Oxford Academic Google Scholar W.M. Murach, W.M. Murach Department of Psychiatry and Psychotherapy Search for other works by this author on: Oxford Academic Google Scholar E.‐B. Bröcker, E.‐B. Bröcker Department of Dermatology, Venereology and Allergology Search for other works by this author on: Oxford Academic Google Scholar M.P. Schön M.P. Schön Department of Dermatology, Venereology and AllergologyRudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Bayerische Julius Maximilians University, 97978 Würzburg, Germany Correspondence: Michael P. Schön. E‐mail: michael.schoen@virchow.uni‐wuerzburg.de Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 157, Issue 3, 1 September 2007, Pages 627–629, https://doi.org/10.1111/j.1365-2133.2007.08052.x Published: 01 September 2007
Allergen exposed primary human bronchial epithelial cells have inhibited transport of salbutamol sulphate only when functional organic cation tranporters are present
Authors: Qingxiang Zeng, Qi Ge, Mehra Haghi, Janet Rimmer, Richard Harvey, Paul Young, Daniela Traini, Jianbo Shi, Judy Black, Janette Burgess, Brian Oliver
Journal: European Respiratory Journal (2014)

Background: Salbutamol sulphate (SS) is a short acting β2-agonist used to treat bronchospasm. House dust mite (HDM) is the most prevalent allergen associated with bronchospasm. Whether SS transports actively or passively across the airway epithelium is controversial and little is known about the effects of allergens on this transport.

Aims: To assess the effects of HDM on salbutamol sulphate transport across human primary bronchial epithelial cells (HBECs).

Methods: HBECs were cultured at an air-liquid interface (ALI) and apically treated (1H) with 50µg/ml HDM, 5mM triethylamine (TEA, an antagonist of organic cation transporters) or 6mM EGTA followed by 0.1mM SS. SS transport over 4 hours was assessed by HPLC. Barrier integrity was evaluated by fluorescein sodium(Flu-Na).

Results: Transport of SS in primary HBECs occurred through two different mechanisms. In around 50% of cells, TEA inhibited transport of SS from an apparent permeability (Papp) of 1.12×10-6 cm/s (SS alone) to 6.02×10-7 cm/s (SS+TEA), P<0.05, n=6) whilst in the other 50% of cells TEA was without effect (1.31×10-6 cm/s SS±TEA). Interestingly, only in the TEA sensitive cells, HDM stimulation inhibited the transport of SS (Papp 5.99×10-7 cm/s (n=6, p <0.05)). Flu-Na paracellular permeability was shown to be unaffected by HDM treatment. Destruction of tight junctions by EGTA increased SS transport.

Conclusions: SS flux occurs via either active absorption or passive diffusion. Furthermore, HDM affected active transport of SS suggesting that in the clinical scenario some patients may have impaired response to rescue medication when they are exposed to allergens.
Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction
Authors: Mihai Gheorghiade, Stephen J. Greene, Javed Butler, Gerasimos Filippatos, Carolyn S. P. Lam, Aldo P. Maggioni, Piotr Ponikowski, Sanjiv J. Shah, Scott D. Solomon, Elisabeth Kraigher-Krainer, Eliana T. Samano, Katharina Müller, Lothar Roessig, Burkert Pieske
Journal: JAMA (2015)

Worsening chronic heart failure (HF) is a major public health problem.To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF).Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic.Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks.The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point.Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively.Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF.clinicaltrials.gov Identifier: NCT01951625.