tbuckley/cabot-search huggingface dataset:
Role of B Cell–Activating Factor in Chronic Obstructive Pulmonary Disease
Authors: Leen J. M. Seys, Fien M. Verhamme, Anja Schinwald, Hamida Hammad, Danen Mootoosamy Cunoosamy, Claudie Bantsimba-Malanda, Alan Sabirsh, Eileen McCall, Liz Flavell, Ronald Herbst, Sharen Provoost, Bart N. Lambrecht, Guy F. Joos, Guy G. Brusselle, Ken R. Bracke
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

B cell-activating factor (BAFF) plays a major role in activation of B cells and in adaptive humoral immune responses. In chronic obstructive pulmonary disease (COPD), lymphoid follicles have been associated with disease severity, and overexpression of BAFF has been demonstrated within lymphoid follicles of patients with severe COPD.To investigate expression and localization of BAFF in the lungs of patients with COPD and to study the role of BAFF in COPD by antagonizing BAFF in a mouse model of chronic cigarette smoke (CS) exposure.We quantified and localized BAFF expression in lungs of never-smokers, smokers without COPD, and patients with COPD and in lungs of air- or CS-exposed mice by reverse-transcriptase polymerase chain reaction, ELISA, immunohistochemistry, and confocal imaging. Next, to investigate the role of BAFF in COPD, we antagonized BAFF by prophylactic or therapeutic administration of a soluble fusion protein of the BAFF-receptor, BAFFR-Fc, in mice exposed to air or CS for 24 weeks and evaluated several hallmarks of COPD and polarization of lung macrophages.BAFF expression was significantly increased in lungs of patients with COPD and CS-exposed mice. BAFF staining in lymphoid follicles was observed around B cells, CD4(+) cells, dendritic cells, follicular dendritic cells, and fibroblastic reticular cells. Prophylactic and therapeutic administration of BAFFR-Fc in mice reduced pulmonary B-cell numbers and prevented CS-induced formation of lymphoid follicles and increases in immunoglobulin levels. Interestingly, prophylactic BAFFR-Fc administration significantly attenuated pulmonary inflammation and destruction of alveolar walls. Moreover, antagonizing BAFF altered the phenotype of alveolar and interstitial macrophages.BAFF is significantly increased in lungs of patients with COPD and is present around both immune and stromal cells within lymphoid follicles. Antagonizing BAFF in CS-exposed mice attenuates pulmonary inflammation and alveolar destruction.
Microvascular Complications in Diabetic Erectile Dysfunction
Authors: Yoram Vardi
Journal: Diabetes Care (2009)

Advances in the management of erectile dysfunction (ED) and its adverse effects on the quality of life of men and their partners have encouraged researchers to look for new solutions for treating and curing ED. The introduction of phosphodiesterase type 5 inhibitors to treat ED in 1998 was revolutionary in that it heralded the onset of a new era of effective and safe treatment for restoring male sexual function.

Today, PDE5 inhibitors are used as first-line therapy for the management of ED irrespective of its etiology. Despite the fact that millions of men with ED worldwide have been treated successfully with these drugs, several questions regarding their efficacy and safety and the high dropout rate in men to whom these medications are prescribed remain unanswered. This is especially evident in diabetes because the frequency of ED in men with diabetes is higher than that of the general population. In fact, the frequency of ED in diabetic men has been reported to be as high as 75% in men with longstanding disease (1–3). In contrast to the high efficacy rate of PDE5 inhibitors in the general population (70–89%), just over 50% of diabetic men with ED respond favorably to these drugs (4). Impaired neural and penile vascular functions are believed to be the main reasons for the high incidence of ED in men with diabetes, and the underlying causes of this drug resistance are not fully understood.

Recent data indicate that PDE5 inhibitors have beneficial effects in other chronic diseases. Sildenafil has been approved recently for the treatment of idiopathic pulmonary hypertension (5). Lately, several reports have suggested that PDE5 inhibitors may improve arterial function (6–9). Moreover, improvement of lower urinary tract symptoms in patients with benign prostatic hyperplasia has also been reported (10). Finally, the results …
Moderate Alcohol Consumption Lowers the Risk of Type 2 Diabetes
Authors: Lando L.J. Koppes, Jacqueline M. Dekker, Henk F.J. Hendriks, Lex M. Bouter, Robert J. Heine
Journal: Diabetes Care (2005)

OBJECTIVE—This meta-analysis was undertaken to obtain insight regarding the shape and strength of the relationship between alcohol consumption and the risk of type 2 diabetes, the effects of adjustment for confounders, and the effect of modification by type 2 diabetes definition, sex, and BMI. RESEARCH DESIGN AND METHODS—The 15 original prospective cohort studies that were included comprise 11,959 incident cases of type 2 diabetes in 369,862 individuals who, on average, were followed for 12 years. RESULTS—After pooling the data, a U-shaped relationship was found. Compared with nonconsumers, the relative risk (RR) for type 2 diabetes in those who consumed ≤6 g/day alcohol was 0.87 (95% CI 0.79–0.95). For the moderate consumption ranges of 6–12, 12–24, and 24–48 g/day, RRs of 0.70 (0.61–0.79), 0.69 (0.58–0.81), and 0.72 (0.62–0.84) were found, respectively. The risk of type 2 diabetes in heavy drinkers (≥48 g/day) was equal to that in nonconsumers (1.04 [0.84–1.29]). In general, nonsignificant trends for larger RR reduction associated with moderate alcohol consumption were observed for women compared with men, for crude compared with multivariate-adjusted analyses, and for studies that used self-reports instead of testing for type 2 diabetes definition. No differences in RR reductions were found between individuals with low or high BMI. CONCLUSIONS—The present evidence from observational studies suggests an ∼30% reduced risk of type 2 diabetes in moderate alcohol consumers, whereas no risk reduction is observed in consumers of ≥48 g/day.
The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development
Authors: Céline Colacios, Audrey Casemayou, Anne S. Dejean, Frédérique Gaits-Iacovoni, Christophe Pedros, Isabelle Bernard, Dominique Lagrange, Marcel Deckert, Lucille Lamouroux, Maja Jagodic, Tomas Olsson, Roland S. Liblau, Gilbert J. Fournié, Abdelhadi Saoudi
Journal: The Journal of Experimental Medicine (2011)

CD4+ regulatory T cells (Treg cells) expressing the transcription factor Foxp3 play a pivotal role in maintaining peripheral tolerance by inhibiting the expansion and function of pathogenic conventional T cells (Tconv cells). In this study, we show that a locus on rat chromosome 9 controls the size of the natural Treg cell compartment. Fine mapping of this locus with interval-specific congenic lines and association experiments using single nucleotide polymorphisms (SNPs) identified a nonsynonymous SNP in the Vav1 gene that leads to the substitution of an arginine by a tryptophan (p.Arg63Trp). This p.Arg63Trp polymorphism is associated with increased proportion and absolute numbers of Treg cells in the thymus and peripheral lymphoid organs, without impacting the size of the Tconv cell compartment. This polymorphism is also responsible for Vav1 constitutive activation, revealed by its tyrosine 174 hyperphosphorylation and increased guanine nucleotide exchange factor activity. Moreover, it induces a marked reduction in Vav1 cellular contents and a reduction of Ca2+ flux after TCR engagement. Together, our data reveal a key role for Vav1-dependent T cell antigen receptor signaling in natural Treg cell development.
Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells
Authors: Xiaojie Zhang, Xiangmei Chen, Di Wu, Weiping Liu, Jianzhong Wang, Zhe Feng, Guangyan Cai, Bo Fu, Quan Hong, Jing Du
Journal: Journal of the American Society of Nephrology (2006)

Connexin 43 (Cx43) plays an important role in cell differentiation and growth control, but whether it can be regulated by high glucose and whether it can mediate in glomerular mesangial cells (GMC) the phenotype alterations that are induced by high glucose still remain to be explored. In this study, RNA interference and gene transfer techniques were used to knock down and overexpress Cx43 gene in rat GMC to determine the contribution of Cx43 to GMC senescence that was induced by high glucose. The results show that high glucose (30 mM) not only downregulated Cx43 mRNA and protein expression (P<0.05) but also increased the percentage of senescence-associated beta-galactosidase (SA-beta-gal) stained cells and expression of p21cip1 and p27kip1 (P<0.05), indicating that high glucose promoted rat GMC senescence. Knocking down Cx43 gene expression significantly increased the percentage of SA-beta-gal stained cells and p27kip1 and p21cip1 expression in GMC (P<0.05), whereas overexpression of Cx43 significantly decreased the percentage of SA-beta-gal stained cells (P<0.05). These results demonstrate for the first time that downregulation of Cx43 expression by high glucose promotes the senescence of GMC, which may be involved in the pathogenesis of diabetic nephropathy.
Locked Nucleic Acid <i>In situ</i> Hybridization Analysis of miR-21 Expression during Colorectal Cancer Development
Authors: Nobutake Yamamichi, Ryoichi Shimomura, Ken-ichi Inada, Kouhei Sakurai, Takeshi Haraguchi, Yuka Ozaki, Shuji Fujita, Taketoshi Mizutani, Chihiro Furukawa, Mitsuhiro Fujishiro, Masao Ichinose, Kazuya Shiogama, Yutaka Tsutsumi, Masao Omata, Hideo Iba
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To better understand microRNA miR-21 function in carcinogenesis, we analyzed miR-21 expression patterns in different stages of colorectal cancer development using in situ hybridization (ISH). Experimental Design: Locked nucleic acid (LNA)/DNA probes and a biotin-free tyramide signal amplification system were used in ISH analyses of miRNA expression. Conditions for specific detection of miR-21 were determined using human cell lines and miR-21–expressing lentiviral vectors. Expression was determined in 39 surgically excised colorectal tumors and 34 endoscopically resected colorectal polyps. Results: In the surgical samples, miR-21 expression was much higher in colorectal cancers than in normal mucosa. Strong miR-21 expression was also observed in cancer-associated stromal fibroblasts, suggesting miR-21 induction by cancer-secreted cytokines. Protein expression of PDCD4, a miR-21 target, was inversely correlated with miR-21 expression, confirming that miR-21 is indeed a negative regulator of PDCD4 in vivo. In the endoscopic samples, miR-21 expression was very high in malignant adenocarcinomas but was not elevated in nontumorigenic polyps. Precancerous adenomas also frequently showed miR-21 up-regulation. Conclusion: Using the LNA-ISH system for miRNA detection, miR-21 was detectable in precancerous adenomas. The frequency and extent of miR-21 expression increased during the transition from precancerous colorectal adenoma to advanced carcinoma. Expression patterns of miR-21 RNA and its target, tumor suppressor protein PDCD4, were mutually exclusive. This pattern may have clinical application as a biomarker for colorectal cancer development and might be emphasized by self-reinforcing regulatory systems integrated with the miR-21 gene, which has been previously shown in cell culture.
The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories
Authors: A Kohlmann, H-U Klein, S Weissmann, S Bresolin, T Chaplin, H Cuppens, E Haschke-Becher, B Garicochea, V Grossmann, B Hanczaruk, K Hebestreit, C Gabriel, I Iacobucci, J H Jansen, G te Kronnie, L van de Locht, G Martinelli, K McGowan, M R Schweiger, B Timmermann, P Vandenberghe, B D Young, M Dugas, T Haferlach
Journal: Leukemia (2011)
Risk factors for postoperative stricture after endoscopic submucosal dissection for superficial esophageal carcinoma
Authors: Qiang Shi, Hui Ju, Li-Qing Yao, Ping-Hong Zhou, Mei-Dong Xu, Tao Chen, Jia-Min Zhou, Tian-yin Chen, Yun-Shi Zhong
Journal: Endoscopy (2014)

<b>Background and study aims:</b> Endoscopic submucosal dissection (ESD) is accepted as an established treatment modality for superficial esophageal carcinoma (SEC). The aim of this study was to identify risk factors for postoperative stricture after ESD for SEC. <b>Patients and methods:</b> This was a retrospective study at a single institution. A total of 362 patients with SEC treated by ESD at Zhongshan Hospital, Shanghai, were enrolled between January 2007 and February 2012. Demographic and clinical parameters, including patient-, lesion-, and procedure-related factors, were analyzed for postoperative stricture risk factors. <b>Results:</b> The postoperative stricture rate was 11.6 % (42/362). The mean and median time from ESD to stricture was 58.5 ± 12.3 days (range 21 – 90 days) and 28 days, respectively. Mild, median, and severe stricture were observed in 16.7 % (7/42), 38.1 % (16 /42), and 45.2 % (19/42) of patients, respectively. Multivariate analysis revealed that circumferential extension of > 3/4 (odds ratio [OR] 44.2, 95 % confidence interval [CI] 4.4 – 443.6) and the depth of invasion above m2 (OR 14.2, 95 %CI 2.7 – 74.2) were independent risk factors for stricture. The degree of stricture was also related to lesion circumferential extension (relational coefficient φ = 0.47; <i>P</i> < 0.05) and histological depth (relational coefficient φ = 0.647; <i>P</i> < 0.05). <b>Conclusions:</b> Circumferential extension and histological depth were reliable risk factors for postoperative stricture.
Prospective Cost-Effectiveness Analysis of Cetuximab in Metastatic Colorectal Cancer: Evaluation of National Cancer Institute of Canada Clinical Trials Group CO.17 Trial
Authors: N. Mittmann, H.-J. Au, D. Tu, C. J. O'Callaghan, P. K. Isogai, C. S. Karapetis, J. R. Zalcberg, W. K. Evans, M. J. Moore, J. Siddiqui, B. Findlay, B. Colwell, J. Simes, P. Gibbs, M. Links, N. C. Tebbutt, D. J. Jonker
Journal: JNCI Journal of the National Cancer Institute (2009)

The National Cancer Institute of Canada Clinical Trials Group CO.17 study showed that patients with advanced colorectal cancer had improved overall survival when cetuximab, an epidermal growth factor receptor-targeting antibody, was given in addition to best supportive care. We conducted a cost-effectiveness analysis using prospectively collected resource utilization and health utility data for patients in the CO.17 study who received cetuximab plus best supportive care (N = 283) or best supportive care alone (N = 274).Direct medical resource utilization data were collected, including medications, physician visits, toxicity management, blood products, emergency department visits, and hospitalizations. Mean survival times for the study arms were calculated for the entire population and for the subset of patients with wild-type KRAS tumors over an 18- to 19-month period. All costs were presented in 2007 Canadian dollars. One-way and probabilistic sensitivity analysis was used to determine the robustness of the results. Cost-effectiveness acceptability curves were determined. The 95% confidence intervals (CIs) for the incremental cost-effectiveness ratios and the incremental cost-utility ratios were estimated by use of a nonparametric bootstrapping method (with 1000 iterations).For the entire study population, the mean improvement in overall and quality-adjusted survival with cetuximab was 0.12 years and 0.08 quality-adjusted life-years (QALYs), respectively. The incremental cost with cetuximab compared with best supportive care was $23,969. The incremental cost-effectiveness ratio was $199,742 per life-year gained (95% CI = $125,973 to $652,492 per life-year gained) and the incremental cost-utility ratio was $299,613 per QALY gained (95% CI = $187,440 to $898,201 per QALY gained). For patients with wild-type KRAS tumors, the incremental cost with cetuximab was $33,617 and mean gains in overall and quality-adjusted survival were 0.28 years and 0.18 QALYs, respectively. The incremental cost-effectiveness ratio was $120,061 per life-year gained (95% CI = $88,679 to $207,075 per life-year gained) and the incremental cost-utility ratio was $186,761 per QALY gained (95% CI = $130,326 to $334,940 per QALY gained). In a sensitivity analysis, cetuximab cost and patient survival were the only variables that influenced cost-effectiveness.The incremental cost-effectiveness ratio of cetuximab over best supportive care alone in unselected advanced colorectal cancer patients is high and sensitive to drug cost. Incremental cost-effectiveness ratios were lower when the analysis was limited to patients with wild-type KRAS tumors.
Effect of Exogenous Intravenous Administrations of GLP-1 and/or GIP on Circulating Pro-Atrial Natriuretic Peptide in Subjects With Different Stages of Glucose Tolerance
Authors: Natalia Rudovich, Olga Pivovarova, Özlem Gögebakan, Andrea Sparwasser, Wolfram Doehner, Stefan D. Anker, Ayman M. Arafat, Andreas Bergmann, Michael A. Nauck, Andreas F.H. Pfeiffer
Journal: Diabetes Care (2014)

GLP-1 receptor agonists have antihypertensive properties, explained via release of atrial natriuretic peptide (ANP) as shown in mice (1). Whether GLP-1 directly interacts with the natriuretic peptide system in humans was studied in a single report (2).

Here, we studied interaction of two major incretins, glucose-dependent insulinotropic peptide (GIP) and GLP-1, both administered exogenously, with ANP in patients with type 2 diabetes (nine men and three women, 61 ± 10 years, BMI 30.0 ± 3.7 kg/m2, HbA1c 7.3 ± 1.5%). Placebo (vehicle: 0.9% NaCl with 1% human serum albumin), GIP (4 pmol · kg−1 · min−1), GLP-1(7–36)-amide (1.2 pmol · kg−1 · min−1), or a combination of both hormones were infused over 360 min on different days in randomized order (3). Additionally, eight male overweight subjects with normal glucose tolerance (49.9 ± 3.2 years, BMI 32.9 ± 0.7 kg/m2) were given GIP infusion (2 pmol · kg−1 · min−1) and placebo (isotonic saline) infusion for 240 min (4).

In cohort I, intact, biologically active GIP and GLP-1 were measured as described previously (3). In cohort II, total GIP was determined by commercial ELISA kit (Linco Research, St. Charles, MO). Midregional pro-ANP (MR-proANP) was measured with an immunoassay (MR-proANP LIA; B.R.A.H.M.S GmbH, Hennigsdorf, Germany).

In subjects with type 2 diabetes, exogenous GIP elevated the total concentrations of GIP …
Fixing DNA breaks during class switch recombination
Authors: Christopher J. Jolly, Adam J.L. Cook, John P. Manis
Journal: The Journal of Experimental Medicine (2008)

Immunoglobulin (Ig) class switch recombination (CSR) involves the breakage and subsequent repair of two DNA sequences, known as switch (S) regions, which flank IgH constant region exons. The resolution of CSR-associated breaks is thought to require the nonhomologous end-joining (NHEJ) DNA repair pathway, but the role of the NHEJ factor DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in this process has been unclear. A new study, in which broken IgH-containing chromosomes in switching B cells were visualized directly, clearly demonstrated that DNA-PKcs and, unexpectedly, the nuclease Artemis are involved in the resolution of switch breaks.
Natural History and Treatment of Wilms's Tumour: An Analysis of 335 Cases Occurring in England and Wales 1962-6
Authors: E. M. Ledlie, L. S. Mynors, G. J. Draper, P. D. Gorbach
Journal: BMJ (1970)

Hospital records and other data relating to Wilms9s tumour were analysed to elucidate both thenatural history of the disease and the effects of treatment, with special reference to actinomycin D. The age of maximum incidence was about 18 months; left-sided tumours were significantly more common than right-sided ones. Prognosis was related to stage of the disease at the initial operation and to the occurrence of metastasis. The three-year survival rate for cases having a nephrectomy was 35%; no child who did not have a nephrectomy survived. Recurrence of the tumour was observed in two-thirds of the cases, almost always within two years of the initial treatment, irrespective of the child9s age. The three-year survival rate for this group was 11%. The effects of radiotherapy and chemotherapy are considered in detail. Very little improvement in survival rate could be ascribed to actinomycin D. The reasons for this and for the variations found in earlier reports on selected cases are possibly the addition of other components of treatment and differences in drug regimens. The findings suggest the need for controlled clinical trials.
A Randomized, Controlled Trial of Sequential Bilateral Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression
Authors: Paul B. Fitzgerald, Jessica Benitez, Anthony de Castella, Z. Jeff Daskalakis, Timothy L. Brown, Jayashri Kulkarni
Journal: American Journal of Psychiatry (2006)

High-frequency left-side repetitive transcranial magnetic stimulation (rTMS) and low-frequency stimulation to the right prefrontal cortex have both been shown to have antidepressant effects, but doubts remain about the magnitude of previously demonstrated treatment effects. The authors evaluated sequentially combined high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex for treatment-resistant depression.The authors conducted a 6-week double-blind, randomized, sham-controlled trial in 50 patients with treatment-resistant depression. Three trains of low-frequency rTMS to the right prefrontal cortex of 140 seconds' duration at 1 Hz were applied daily, followed immediately by 15 trains of 5 seconds' duration of high-frequency left-side rTMS at 10 Hz. Sham stimulation was applied with the coil angled at 45 degrees from the scalp, resting on the side of one wing of the coil. The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale.There was a significantly greater response to active than sham stimulation at 2 weeks and across the full duration of the study. A significant proportion of the study group receiving active treatment met response (11 of 25 [44%]) or remission (nine of 25 [36%]) criteria by study end compared to the sham stimulation group (two of 25 [8%] and none of 25 respectively).Sequentially applying both high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex, has substantial treatment efficacy in patients with treatment-resistant major depression. The treatment response accumulates to a clinically meaningful level over 4 to 6 weeks of active treatment.