University of Cologne

About: University of Cologne is a education organization based out in Cologne, Germany. It is known for research contribution in the topics: Population & Transplantation. The organization has 32050 authors who have published 66350 publications receiving 2210092 citations. The organization is also known as: Universität zu Köln & Universitatis Coloniensis.

Isavuconazole Treatment for Mucormycosis: A Single-Arm Open-Label Trial and Case-Control Analysis

Abstract: Summary Background Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. Methods In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response—ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)—according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. Findings Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19–179, range 2–882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). Interpretation Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. Funding Astellas Pharma Global Development, Basilea Pharmaceutica International.

Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial.

Abstract: PurposeGenetic alterations causing overexpression of programmed death-1 ligands are near universal in classic Hodgkin lymphoma (cHL). Nivolumab, a programmed death-1 checkpoint inhibitor, demonstrated efficacy in relapsed/refractory cHL after autologous hematopoietic cell transplantation (auto-HCT) in initial analyses of one of three cohorts from the CheckMate 205 study of nivolumab for cHL. Here, we assess safety and efficacy after extended follow-up of all three cohorts.MethodsThis multicenter, single-arm, phase II study enrolled patients with relapsed/refractory cHL after auto-HCT treatment failure into cohorts by treatment history: brentuximab vedotin (BV)–naive (cohort A), BV received after auto-HCT (cohort B), and BV received before and/or after auto-HCT (cohort C). All patients received nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary end point was objective response rate per independent radiology review committee.ResultsOverall, 243 patients were treated...

The Nuclear Bulge of the Galaxy. III. Large-Scale Physical Characteristics of Stars and Interstellar Matter

Abstract: We analyse IRAS and COBE DIRBE data at wavelengths between 2.2 and 240 of the central 500 pc of the Galaxy and derive the large-scale distribution of stars and interstellar matter in the Nuclear Bulge. Models of the Galactic Disk and Bulge are developed in order to correctly decompose the total surface brightness maps of the inner Galaxy and to apply proper extinction corrections. The Nuclear Bulge appears as a distinct, massive disk-like complex of stars and molecular clouds which is, on a large scale, symmetric with respect to the Galactic Centre. It is distinguished from the Galactic Bulge by its flat disk-like morphology, very high density of stars and molecular gas, and ongoing star formation. The Nuclear Bulge consists of an R^(-2) Nuclear Stellar Cluster at the centre, a large Nuclear Stellar Disk with radius 230 ± 20 pc and scale height 45 ± 5 pc, and the Nuclear Molecular Disk of same size. The total stellar mass and luminosity of the Nuclear Bulge are 1.4 ± 0.6 x 10^9 and 2.5 ± 1 x 10^9, respectively. About 70% of the luminosity is due to optical and UV radiation from young massive Main-Sequence stars which are most abundant in the Nuclear Stellar Cluster. For the first time, we derive a photometric mass distribution for the central 500 pc of the Galaxy which is fully consistent with the kinematic mass distribution. We find that the often cited R^(-2) distribution holds only for the central ~30 pc and that at larger radii the mass distribution is dominated by the Nuclear Stellar Disk which has a flatter density profile. The total interstellar hydrogen mass in the Nuclear Bulge is M_H = 2 ± 0.3 x 10^7, distributed in a warm inner disk with R = 110 ± 20 pc and a massive, cold outer torus which contains more than 80% of this mass. Interstellar matter in the Nuclear Bulge is very clumpy with ~90% of the mass contained in dense and massive molecular clouds with a volume filling factor of only a few per cent. This extreme clumpiness, probably caused by the tidal stability limit in the gravitational potential of the Nuclear Bulge, enables the strong interstellar radiation field to penetrate the entire Nuclear Bulge and explains the relatively low average extinction towards the Galactic Centre. In addition, we find 3 x 10^7 of cold and dense material outside the Nuclear Bulge at positive longitudes and 1 x 10^7 at negative longitudes. This material is not heated by the stars in the Nuclear Bulge and gives rise to the observed asymmetry in the distribution of interstellar matter in the Central Molecular Zone.

Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism

Abstract: The contribution of altered post-transcriptional gene silencing to the development of insulin resistance and type 2 diabetes mellitus so far remains elusive. Here, we demonstrate that expression of microRNA (miR)-143 and 145 is upregulated in the liver of genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, impairs insulin-stimulated AKT activation and glucose homeostasis. Conversely, mice deficient for the miR-143-145 cluster are protected from the development of obesity-associated insulin resistance. Quantitative-mass-spectrometry-based analysis of hepatic protein expression in miR-143-overexpressing mice revealed miR-143-dependent downregulation of oxysterol-binding-protein-related protein (ORP) 8. Reduced ORP8 expression in cultured liver cells impairs the ability of insulin to induce AKT activation, revealing an ORP8-dependent mechanism of AKT regulation. Our experiments provide direct evidence that dysregulated post-transcriptional gene silencing contributes to the development of obesity-induced insulin resistance, and characterize the miR-143-ORP8 pathway as a potential target for the treatment of obesity-associated diabetes.