tbuckley/cabot-search huggingface dataset:
Effect of Increasing Baseline Immunosuppression on the Prevalence of Clinical and Subclinical Rejection
Authors: PETER NICKERSON, JOHN JEFFERY, JAMES GOUGH, PAUL GRIMM, RACHEL MCKENNA, PATRICIA BIRK, DAVID RUSH
Journal: Journal of the American Society of Nephrology (1999)

Abstract. This group has reported that treatment of subclinical rejection in the first 3 mo posttransplant with corticosteroids decreases late clinical rejections and improves graft function at 2 yr in renal transplant recipients. The current study was performed to determine whether an increase in baseline immunosuppression would decrease the prevalence of early subclinical rejections, as well as the incidence of early and late clinical rejections. Patients received mycophenolate mofetil (MMF) and Neoral cyclosporin A (CsA) posttransplant ( n = 29), of which 17 underwent protocol biopsies at months 1, 2, 3, and 6 (Neoral + MMF Protocol Biopsy [Bx]), while 12 declined protocol biopsies (Neoral + MMF Control). These individuals were compared with 72 historical control patients treated with Sandimmune CsA and Imuran, of which 36 had undergone protocol biopsies at months 1, 2, 3, and 6 (Sandimmune + Azathioprine [AZA] Protocol Bx), and 36 had a protocol biopsy at month 6 (Sandimmune + AZA Control). Baseline immunosuppression with Neoral + MMF decreased the incidence of early clinical rejections (0 to 3 mo) and cumulative corticosteroid exposure, but had no impact on the prevalence of early subclinical rejection. Moreover, to maximally decrease the risk of developing late clinical rejections (months 7 to 12) in Neoral + MMF patients required that protocol biopsies be done and that subclinical rejection be treated. The paradoxical finding of recent clinical trials that a reduction in acute clinical rejection has not improved long-term graft outcome may be explained in part by the failure to control subclinical rejection.
The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor
Authors: Alexandre Regamey, Daniel Hohl, Jia Wei Liu, Thierry Roger, Priit Kogerman, Rune Toftgård, Marcel Huber
Journal: The Journal of Experimental Medicine (2003)

Cylindromas are benign adnexal skin tumors caused by germline mutations in the CYLD gene. In most cases the second wild-type allele is lost in tumor tissue, suggesting that CYLD functions as tumor suppressor. CYLD is a protein of 956 amino acids harboring a functional deubiquitinating domain at the COOH-terminal end. To shed more light on the function of CYLD, we have performed a yeast two hybrid screen using an HaCaT cDNA library that identified the RING finger protein TRIP (TRAF-interacting protein) as interactor with full-length CYLD. Mapping of the interacting domains revealed that the central domain of CYLD binds to the COOH-terminal end of TRIP. Far Western analysis and coimmunoprecipitations in mammalian cells confirmed that full-length CYLD binds to the COOH-terminal domain of TRIP. Because TRIP is an inhibitor of nuclear factor (NF)-κB activation by tumor necrosis factor (TNF), the effect of CYLD on NF-κB activation was investigated in HeLa cells. The results established that CYLD down-regulates NF-κB activation by TNF-α. The inhibition by CYLD depends on the presence of the central domain interacting with TRIP and its deubiquitinating activity. These findings indicate that cylindromas arise through constitutive NF-κB activation leading to hyperproliferation and tumor growth.
Genome-wide association study reveals genetic risk underlying Parkinson's disease
Authors: Javier Simón-Sánchez, Claudia Schulte, Jose M Bras, Manu Sharma, J Raphael Gibbs, Daniela Berg, Coro Paisan-Ruiz, Peter Lichtner, Sonja W Scholz, Dena G Hernandez, Rejko Krüger, Monica Federoff, Christine Klein, Alison Goate, Joel Perlmutter, Michael Bonin, Michael A Nalls, Thomas Illig, Christian Gieger, Henry Houlden, Michael Steffens, Michael S Okun, Brad A Racette, Mark R Cookson, Kelly D Foote, Hubert H Fernandez, Bryan J Traynor, Stefan Schreiber, Sampath Arepalli, Ryan Zonozi, Katrina Gwinn, Marcel van der Brug, Grisel Lopez, Stephen J Chanock, Arthur Schatzkin, Yikyung Park, Albert Hollenbeck, Jianjun Gao, Xuemei Huang, Nick W Wood, Delia Lorenz, Günther Deuschl, Honglei Chen, Olaf Riess, John A Hardy, Andrew B Singleton, Thomas Gasser
Journal: Nature Genetics (2009)
Peroral esophageal segmentectomy and anastomosis with single transthoracic trocar: a step forward in thoracic NOTES
Authors: C. Rolanda, D. Silva, C. Branco, I. Moreira, G. Macedo, J. Correia-Pinto
Journal: Endoscopy (2011)

A transesophageal natural orifice transluminal endoscopic surgery (NOTES) approach has been proposed for thoracic and mediastinal access. Similarly to transgastric surgery, serious limitations remain related to creating an esophagotomy and its safe closure. A hybrid approach in thoracic NOTES could work as an intermediate step before pure transesophageal NOTES. We assessed the benefit of hybrid thoracic NOTES for peroral segmental esophagectomy and subsequent complete esophageal anastomosis with a single transthoracic port.Two protocols were used to attempt esophago-esophageal anastomosis: ex vivo using a phantom model (n = 5), and in vivo after esophageal mobilization, and segmental esophagectomy achieved using either a gastroscope (flexible) (n = 5) or thoracoscope (rigid) instruments (n = 5). A forward-viewing double-channel endoscope and a transthoracic operative thoracoscope with a working channel were coordinated in order to create a complete single-layer, end-to-end esophageal anastomosis ex vivo as well as in vivo. Feasibility and anastomosis quality were evaluated by inside and outside assessment of: patency, the incorporation of mucosa in all stitches, and a leak test.Anastomosis was achieved in all ex vivo experiments and thoracoscopically-led in vivo procedures. All anastomoses were patent, allowing distal passage of the endoscope, with mucosa incorporation. In in vivo experiments, a leak was detected in three animals and corrected with additional stitching.Peroral esophageal anastomosis with a single transthoracic trocar is feasible, which may represent a step forward in thoracic NOTES.
Gene Therapy Expressing Amino-Terminal Truncated Monocyte Chemoattractant Protein-1 Prevents Renal Ischemia-Reperfusion Injury
Authors: Kengo Furuichi, Takashi Wada, Yasunori Iwata, Kiyoki Kitagawa, Ken-ichi Kobayashi, Hiroyuki Hashimoto, Yoshiro Ishiwata, Naohisa Tomosugi, Naofumi Mukaida, Kouji Matsushima, Kensuke Egashira, Hitoshi Yokoyama
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Ischemia-reperfusion is closely associated with tissue damage in various organs, including kidney. Despite clinical investigations, useful therapy for renal ischemia-reperfusion injury is not available so far. This study evaluated therapeutic effects of gene therapy expressing an amino-terminal deletion mutant of MCP-1 called 7ND to inhibit monocyte chemoattractant protein (MCP)-1/CCR2 signaling in vivo on renal ischemia-reperfusion injury. 7ND gene was transferred into the femoral muscle of Balb/c mice. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells were observed, as was marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury in control mice, while these lesions were significantly decreased in 7ND gene-transfected mice. Macrophages in the interstitial region, most of which were CCR2-positive, were markedly decreased in 7ND gene-transfected mice after reperfusion. Although macrophages infiltrated around MCP-1-positive cells in control mice, the smaller number of F4/80-positive cells could infiltrate into the neighbor of MCP-1-positive cells in 7ND-treated mice. These results provide evidence that gene therapy by 7ND is potentially a powerful therapeutic approach to inhibit MCP-1/CCR2 signaling, resulting in rescue from renal ischemia-reperfusion injury. E-mail: [email protected]
Epidermal Growth Factor Receptor Targeting in Head and Neck Cancer: Have We Been Just Skimming the Surface?
Authors: Aaron R. Hansen, Lillian L. Siu
Journal: Journal of Clinical Oncology (2013)

Despite extensive research in squamous cell carcinoma of thehead and neck (SCCHN), the epidermal growth factor receptor(EGFR)remainstheonlynonchemotherapeuticmoleculartargetthathas been successfully translated into a biologic therapy with clinicalbeneﬁt. Targeting this transmembrane tyrosine kinase growth factorreceptor in SCCHN is an attractive and rational strategy given thatmore than 90% of these tumors overexpress EGFR. The potentialvalue of EGFR as a therapeutic target is also supported by the obser-vation that poor prognostic outcomes have been correlated with in-creased EGFR protein expression or
Adherence to positive airway pressure in non-sleepy patients with obstructive sleep apnoea: Table 1–
Authors: Frédéric Gagnadoux, Marc Le Vaillant, Audrey Paris, Thierry Pigeanne, Sylvaine Chollet, Philippe Masson, Acya Bizieux-Thaminy, Marie-Pierre Humeau, Nicole Meslier
Journal: European Respiratory Journal (2013)

CPAP therapy is highly acceptable and associated with self-reported benefits in non-sleepy OSA patients http://ow.ly/my739
Adaptive Evolution Drives the Diversification of Zinc-Finger Binding Domains
Authors: D. Schmidt
Journal: Molecular Biology and Evolution (2004)

The human genome is estimated to contain 700 zinc-finger genes, which perform many key functions, including regulating transcription. The dramatic increase in the number of these genes as we move from yeast to C. elegans to Drosophila and to humans, as well as the clustered organization of these genes in humans, suggests that gene duplication has played an important role in expanding this family of genes. Using likelihood methods developed by Yang and parsimony methods introduced by Suzuki and Gojobori, we have investigated four clusters of zinc-finger genes on human chromosome 19 and found evidence that positive selection was involved in diversifying the family of zinc-finger binding motifs.
Direct Action of Endothelin-1 on Podocytes Promotes Diabetic Glomerulosclerosis
Authors: Olivia Lenoir, Marine Milon, Anne Virsolvy, Carole Hénique, Alain Schmitt, Jean-Marc Massé, Yuri Kotelevtsev, Masashi Yanagisawa, David J. Webb, Sylvain Richard, Pierre-Louis Tharaux
Journal: Journal of the American Society of Nephrology (2014)

The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre×Ednra(lox/lox)×Ednrb(lox/lox) [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total β-catenin and phospho-NF-κB expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total β-catenin and phospho-NF-κB compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-κB and β-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis.
Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy
Authors: Howard I. Scher, Karim Fizazi, Fred Saad, Mary-Ellen Taplin, Cora N. Sternberg, Kurt Miller, Ronald de Wit, Peter Mulders, Kim N. Chi, Neal D. Shore, Andrew J. Armstrong, Thomas W. Flaig, Aude Fléchon, Paul Mainwaring, Mark Fleming, John D. Hainsworth, Mohammad Hirmand, Bryan Selby, Lynn Seely, Johann S. de Bono
Journal: New England Journal of Medicine (2012)

Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy.In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival.The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide.Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.).
The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice
Authors: Santiago Zelenay, Anna M. Keller, Paul G. Whitney, Barbara U. Schraml, Safia Deddouche, Neil C. Rogers, Oliver Schulz, David Sancho, Caetano Reis e Sousa
Journal: Journal of Clinical Investigation (2012)

DNGR-1 (CLEC9A) is a receptor for necrotic cells required by DCs to cross-prime CTLs against dead cell antigens in mice. It is currently unknown how DNGR-1 couples dead cell recognition to cross-priming. Here we found that DNGR-1 did not mediate DC activation by dead cells but rather diverted necrotic cell cargo into a recycling endosomal compartment, favoring cross-presentation to CD8+ T cells. DNGR-1 regulated cross-priming in non-infectious settings such as immunization with antigen-bearing dead cells, as well as in highly immunogenic situations such as infection with herpes simplex virus type 1. Together, these results suggest that DNGR-1 is a dedicated receptor for cross-presentation of cell-associated antigens. Our work thus underscores the importance of cross-priming in immunity and indicates that antigenicity and adjuvanticity can be decoded by distinct innate immune receptors. The identification of specialized receptors that regulate antigenicity of virus-infected cells reveals determinants of antiviral immunity that might underlie the human response to infection and vaccination.
Health and climate change
Authors: M Jay, M G Marmot
Journal: BMJ (2009)

Will a global commitment be made at the UN climate change conference in December?

Expectations are running high for the United Nations climate change conference in Copenhagen this December. But will we get the global commitment for radical cuts in carbon dioxide emissions that the world so urgently needs? The scientific evidence that global temperatures are rising and that man is responsible has been widely accepted since the Intergovernmental Panel on Climate Change’s report in 2007.1 There is now equally wide consensus that we need to reduce carbon dioxide emissions to at most 50% of 1990 levels by 2050 if we are to have even a 50% chance of preventing temperatures from exceeding preindustrial levels by more than 2 degrees, considered by many to be the tipping point for catastrophic and irreversible climate change.2 The economic argument that taking action now rather than later will be cheaper has also been widely accepted since the Stern report in 2006.3 The election of President Obama has shifted policy in the United States from seeking to block an agreement to seeking to find one.

So the chances of success should be good but …
Exposure-sensitization relationship for alpha-amylase allergens in the baking industry.
Authors: R Houba, D J Heederik, G Doekes, P E van Run
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Fungal alpha-amylase is an important occupational allergen in the bakery industry. Epidemiologic studies focusing on the relationship between alpha-amylase allergen exposure and work-related respiratory allergy, however, have not been reported yet. In this cross-sectional study, sensitization to occupational allergens and work-related symptoms were studied in 178 bakery workers and related to allergen exposure. Alpha-amylase allergen concentrations were measured in personal dust samples, using a sandwich enzyme immunoassay. All workers were categorized into groups on the basis of their job histories and the alpha-amylase exposure levels of their job titles. Of all workers 25% had one or more work-related symptoms. As much as 9% of the bakery workers showed a positive skin prick test reaction to fungal amylase, and in 8% amylase-specific IgE was demonstrated. Alpha-amylase exposure and atopy appeared to be the most important determinants of skin sensitization, with prevalence ratios for atopy of 20.8 (95% CI, 2.74 to 158) and for medium and high alpha-amylase exposure groups of 8.6 (95% CI, 1.01 to 74) and 15.9 (95% CI, 1.95 to 129), respectively. Furthermore, a positive association was found between positive skin prick tests to alpha-amylase and work-related respiratory symptoms. In conclusion, this study has shown that there is a strong and positive relationship between alpha-amylase allergen exposure levels in bakeries and specific sensitization in bakery workers.
Cervicovaginal Human Papillomavirus Infection in Human Immunodeficiency Virus-1 (HIV)-Positive and High-Risk HIV-Negative Women
Authors: J M Palefsky, H Minkoff, L A Kalish, A Levine, H S Sacks, P Garcia, M Young, S Melnick, P Miotti, R Burk
Journal: JNCI Journal of the National Cancer Institute (1999)

Human papillomavirus (HPV) infection is associated with precancerous cervical squamous intraepithelial lesions commonly seen among women infected with human immunodeficiency virus-1 (HIV). We characterized HPV infection in a large cohort of HIV-positive and HIV-negative women participating in the Women's Interagency HIV Study to determine the prevalence of and risk factors for cervicovaginal HPV infection in HIV-positive women.HIV-positive (n = 1778) and HIV-negative (n = 500) women were tested at enrollment for the presence of HPV DNA in a cervicovaginal lavage specimen. Blood samples were tested for HIV antibody status, level of CD4-positive T cells, and HIV RNA load (copies/mL). An interview detailing risk factors was conducted. Univariate and multivariate analyses were performed.Compared with HIV-negative women, HIV-positive women with a CD4+ cell count of less than 200/mm3 were at the highest risk of HPV infection, regardless of HIV RNA load (odds ratio [OR] = 10.13; 95% confidence interval [CI] = 7.32-14.04), followed by women with a CD4+ count greater than 200/mm3 and an HIV RNA load greater than 20,000 copies/mL (OR = 5.78; 95% CI = 4.17-8.08) and women with a CD4+ count greater than 200/mm3 and an HIV RNA load less than 20,000 copies/mL (OR = 3.12; 95% CI = 2.36-4.12), after adjustment for other factors. Other risk factors among HIV-positive women included racial/ethnic background (African-American versus Caucasian, OR = 1.64; 95% CI = 1.19-2.28), current smoking (yes versus no; OR = 1.55; 95% CI = 1.20-1.99), and younger age (age < 30 years versus > or = 40 years; OR = 1.75; 95% CI = 1.23-2.49).Although the strongest risk factors of HPV infection among HIV-positive women were indicators of more advanced HIV-related disease, other factors commonly found in studies of HIV-negative women, including racial/ethnic background, current smoking, and age, were important in HIV-positive women as well.
Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies
Authors: Y. K. Loke, R. Cavallazzi, S. Singh
Journal: Thorax (2011)

The effect of inhaled corticosteroids (ICS) on fracture risk in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to evaluate the association between ICS and fractures in COPD.MEDLINE, EMBASE, regulatory documents and company registries were searched up to August 2010. Randomised controlled trials (RCTs) of budesonide or fluticasone versus control treatment for COPD (≥24 weeks duration) and controlled observational studies reporting on fracture risk with ICS exposure vs no exposure in COPD were included. Peto OR meta-analysis was used for fracture risk from RCTs while ORs from observational studies were pooled using the fixed effect inverse variance method. Dose-response analysis was conducted using variance-weighted least squares regression in the observational studies. Heterogeneity was assessed using the I(2) statistic.Sixteen RCTs (14 fluticasone, 2 budesonide) with 17,513 participants, and seven observational studies (n=69,000 participants) were included in the meta-analysis. ICSs were associated with a significantly increased risk of fractures (Peto OR 1.27; 95% CI 1.01 to 1.58; p=0.04; I(2)=0%) in the RCTs. In the observational studies, ICS exposure was associated with a significantly increased risk of fractures (OR 1.21; 95% CI 1.12 to 1.32; p<0.001; I(2)=37%), with each 500 μg increase in beclomethasone dose equivalents associated with a 9% increased risk of fractures, OR 1.09 (95% CI 1.06 to 1.12; p<0.001).Among patients with COPD, long-term exposure to fluticasone and budesonide is consistently associated with a modest but statistically significant increased likelihood of fractures.