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Dunkler D.,McMaster University | Dunkler D.,Universitaetsklinikum Erlangen | Dunkler D.,Medical University of Vienna | Dehghan M.,McMaster University | And 12 more authors.
JAMA Internal Medicine | Year: 2013

Importance Type 2 diabetes mellitus and associated chronic kidney disease (CKD) have become major public health problems. Little is known about the influence of diet on the incidence or progression of CKD among individuals with type 2 diabetes. Objective To examine the association between (healthy) diet, alcohol, protein, and sodium intake, and incidence or progression of CKD among individuals with type 2 diabetes. Design, Setting, And Participants All 6213 individuals with type 2 diabetes without macroalbuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) were included in this observational study. Recruitment spanned from January 2002 to July 2003, with prospective follow-up through January 2008. Main Outcomes And Measures Chronic kidney diseasewas defined as new microalbuminuria or macroalbuminuria or glomerular filtration rate decline of more than 5% per year at 5.5 years of follow-up.We assessed diet using the modified Alternate Healthy Eating Index (mAHEI). The analyses were adjusted for known risk factors, and competing risk of death was considered. Results After 5.5 years of follow-up, 31.7%of participants had developed CKD and 8.3%had died. Compared with participants in the least healthy tertile of mAHEI score, participants in the healthiest tertile had a lower risk of CKD (adjusted odds ratio [OR], 0.74; 95%CI, 0.64-0.84) and lower risk of mortality (OR, 0.61; 95%CI, 0.48-0.78). Participants consuming more than 3 servings of fruits per week had a lower risk of CKD compared with participants consuming these food items less frequently. Participants in the lowest tertile of total and animal protein intake had an increased risk of CKD compared with participants in the highest tertile (total protein OR, 1.16; 95%CI, 1.05-1.30). Sodium intake was not associated with CKD. Moderate alcohol intake reduced the risk of CKD (OR, 0.75; 95%CI, 0.65-0.87) and mortality (OR, 0.69; 95%CI, 0.53-0.89). Conclusions And Relevance A healthy diet and moderate intake of alcohol may decrease the incidence or progression of CKD among individuals with type 2 diabetes. Sodium intake, within a wide range, and normal protein intake are not associated with CKD.


Hoehler T.,Prosper Hospital Recklinghausen | Von Wichert G.,Universitaetsklinikum Ulm | Schimanski C.,University of Mainz | Kanzler S.,Leopoldina Krankenhaus | And 8 more authors.
British Journal of Cancer | Year: 2013

Background:Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer.Methods:Two dose levels (I/II) were defined: capecitabine 850/1000 mg m -2 twice daily on days 1-14; oxaliplatin 100/130 mg m -2 on day 1; bevacizumab 7.5 mg kg -1 on day 1; imatinib 300 mg day -1 on days 1-21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS).Results:Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities.Conclusion:The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy. © 2013 Cancer Research UK.


Tochowicz A.,Max Planck Institute fuer Biochemie | Tochowicz A.,Genentech | Goettig P.,Max Planck Institute fuer Biochemie | Goettig P.,University of Salzburg | And 14 more authors.
Journal of Biological Chemistry | Year: 2011

Homodimerization is an essential step for membrane type 1 matrix metalloproteinase (MT1-MMP) to activate proMMP-2 and to degrade collagen on the cell surface. To uncover the molecular basis of the hemopexin (Hpx) domain-driven dimerization of MT1-MMP, a crystal structure of the Hpx domain was solved at 1.7 Å resolution. Two interactions were identified as potential biological dimer interfaces in the crystal structure, and mutagenesis studies revealed that the biological dimer possesses a symmetrical interaction where blades II and III of molecule A interact with blades III and II of molecule B. The mutations of amino acids involved in the interaction weakened the dimer interaction of Hpx domains in solution, and incorporation of these mutations into the full-length enzyme significantly inhibited dimer-dependent functions on the cell surface, including proMMP-2 activation, collagen degradation, and invasion into the three-dimensional collagen matrix, whereas dimer-independent functions, including gelatin film degradation and two-dimensional cell migration, were not affected. These results shed light on the structural basis of MT1-MMP dimerization that is crucial to promote cellular invasion. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | Monash University, University of Siena, Praxis fur Frauengesundheit, University of Sao Paulo and 15 more.
Type: Journal Article | Journal: Human reproduction (Oxford, England) | Year: 2016

Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)?A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE.Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE.International expert consensus based on a systematic review of literature.Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings.We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE.The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here.This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population.None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD.N/A.


Dunkler D.,Hamilton Health Sciences | Dunkler D.,Universitaetsklinikum Erlangen | Dunkler D.,Medical University of Vienna | Gao P.,Hamilton Health Sciences | And 11 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2015

Background and objectives Quantitative data for prediction of incidence and progression of early CKD are scarce in individuals with type 2 diabetes. Therefore, two risk prediction models were developed for incidence and progression of CKD after 5.5 years and the relative effect of predictors were ascertained. Design, setting, participants, & measurements Baseline and prospective follow-up data of two randomized clinical trials, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Outcome Reduction with Initial Glargine Intervention (ORIGIN), were used as development and independent validation cohorts, respectively. Individuals aged ≥55 years with type 2 diabetes and normo- or microalbuminuria at baseline were included. Incidence or progression of CKD after 5.5 years was defined as new micro- or macroalbuminuria, doubling of creatinine, or ESRD. The competing risk of death was considered as an additional outcome state in the multinomial logistic models. Results Of the 6766 ONTARGET participants with diabetes, 1079 (15.9%) experienced incidence or progression of CKD, and 1032 (15.3%) died. The well calibrated, parsimonious laboratory prediction model incorporating only baseline albuminuria, eGFR, sex, and age exhibited an externally validated c-statistic of 0.68 and an R2 value of 10.6%. Albuminuria, modeled to depict the difference between baseline urinary albumin/creatinine ratio and the threshold for micro- or macroalbuminuria, was mostly responsible for the predictive performance. Inclusion of clinical predictors, such as glucose control, diabetes duration, number of prescribed antihypertensive drugs, previous vascular events, or vascular comorbidities, increased the externally validated c-statistic and R2 value only to 0.69 and 12.1%, respectively. Explained variation was largely driven by renal and not clinical predictors. Conclusions Albuminuria and eGFR were the most important factors to predict onset and progression of early CKD in individuals with type 2 diabetes. However, their predictive ability is modest. Inclusion of demographic, clinical, and other laboratory predictors barely improved predictive performance. © 2015, by the American Society of Nephrology.


Patent
University of Duisburg - Essen, Universitaetsklinikum Erlangen, Zentralinstitut Fuer Seelische Gesundheit and Friedrich - Alexander - University, Erlangen - Nuremberg | Date: 2011-04-07

A method of using at least one quantitative ratio of two different amyloid beta-peptides in a sample of a body fluid from a patient for determining the patients probability of contracting Alzheimers disease (AD) or for determining the patients suffering from a precursor of Alzheimers disease includes obtaining the sample of the body fluid from the patient. The at least one quantitative ratio is calculated from the two different amyloid beta-peptides from the sample. The patients probability of contracting Alzheimers disease (AD) or the patients suffering from a precursor of Alzheimers disease is calculated using the at least one quantitative ratio. The two different amyloid beta-peptides are selected from (a) A(1-42), (b) A(2-40) and (c) A(2-42). The at least one quantitative ratio is selected from (a) A(1-42)/(b) A(2-40), (a) A(1-42)/(c) A(2-42), (b) A(2-40)/(a) A(1-42) and (c) A(2-42)/(a) A(1-42).


PubMed | McMaster University, Universitaetsklinikum Erlangen, Medical University of Vienna, Sunnybrook Health science Center and Hamilton Health Sciences
Type: Journal Article | Journal: Clinical journal of the American Society of Nephrology : CJASN | Year: 2015

Quantitative data for prediction of incidence and progression of early CKD are scarce in individuals with type 2 diabetes. Therefore, two risk prediction models were developed for incidence and progression of CKD after 5.5 years and the relative effect of predictors were ascertained.Baseline and prospective follow-up data of two randomized clinical trials, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Outcome Reduction with Initial Glargine Intervention (ORIGIN), were used as development and independent validation cohorts, respectively. Individuals aged 55 years with type 2 diabetes and normo- or microalbuminuria at baseline were included. Incidence or progression of CKD after 5.5 years was defined as new micro- or macroalbuminuria, doubling of creatinine, or ESRD. The competing risk of death was considered as an additional outcome state in the multinomial logistic models.Of the 6766 ONTARGET participants with diabetes, 1079 (15.9%) experienced incidence or progression of CKD, and 1032 (15.3%) died. The well calibrated, parsimonious laboratory prediction model incorporating only baseline albuminuria, eGFR, sex, and age exhibited an externally validated c-statistic of 0.68 and an R(2) value of 10.6%. Albuminuria, modeled to depict the difference between baseline urinary albumin/creatinine ratio and the threshold for micro- or macroalbuminuria, was mostly responsible for the predictive performance. Inclusion of clinical predictors, such as glucose control, diabetes duration, number of prescribed antihypertensive drugs, previous vascular events, or vascular comorbidities, increased the externally validated c-statistic and R(2) value only to 0.69 and 12.1%, respectively. Explained variation was largely driven by renal and not clinical predictors.Albuminuria and eGFR were the most important factors to predict onset and progression of early CKD in individuals with type 2 diabetes. However, their predictive ability is modest. Inclusion of demographic, clinical, and other laboratory predictors barely improved predictive performance.


Xiong G.,Saban Research Institute | Husseiny M.I.,Saban Research Institute | Husseiny M.I.,Zagazig University | Song L.,Baylor College of Medicine | And 6 more authors.
International Journal of Cancer | Year: 2010

Although tumors express potentially immunogenic tumor-associated antigens (TAAs), cancer vaccines often fail because of inadequate antigen delivery and/or insufficient activation of innate immunity. Engineering nonpathogenic bacterial vectors to deliver TAAs of choice may provide an efficient way of presenting TAAs in an immunogenic form. In this study, we used genes of Salmonella pathogenicity island 2 (SPI2) to construct a novel cancer vaccine in which a TAA, survivin, was fused to SseF effector protein and placed under control of SsrB, the central regulator of SPI2 gene expression. This construct uses the type III secretion system (T3SS) of Salmonella and allows preferential delivery of tumor antigen into the cytosol of antigen-presenting cells for optimal immunogenicity. In a screen of a panel of attenuated strains of Salmonella, we found that a double attenuated strain of Salmonella typhimurium, MvP728 (purD/htrA), was not toxic to mice and effectively expressed and translocated survivin protein inside the cytosol of murine macrophages. We also found that a ligand for CD1d-reactive natural killer T (NKT) cells, α- glucuronosylceramide (GSL1), enhanced MvP728-induced interleukin-12 production in human dendritic cells and that in vivo coadministration of a NKT ligand with MvP728-Llo or MvP728-survivin enhanced effector-memory cytotoxic T lymphocyte (CTL) responses. Furthermore, combined use of MvP728-survivin with GSL1 produced antitumor activity in mouse models of CT26 colon carcinoma and orthotopic DBT glioblastoma. Therefore, the use of TAA delivery via SPI-2-regulated T3SS of Salmonella and NKT ligands as adjuvants may provide a foundation for new cancer vaccines. © 2009 UICC.


De Vries I.J.M.,Radboud University Nijmegen | Castelli C.,Fondazione Instituto Of Ricovero E Cura A Carattere Scientifico | Huygens C.,Catholic University of Louvain | Jacobs J.F.M.,Radboud University Nijmegen | And 8 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Regulatory T cells (Tregs) are thought to inhibit antitumor immune responses, and their depletion could therefore have a synergistic effect with therapeutic cancer vaccines. We investigated the impact of three medications on blood Treg frequency in vaccinated cancer patients. Experimental Design: To date, the most specific marker for human Tregs is demethylation in the DNA that encodes the transcription factor FOXP3. Thus, we used a FOXP3 methylation-specific quantitative PCR assay (MS-qPCR) to measure Treg frequencies in the peripheral blood mononuclear cells (PBMCs) of melanoma patients. The patients participated in three clinical trials that combined tumor vaccines with potential Treg-depleting agents: low-dose cyclophosphamide, anti-CD25 monoclonal antibody daclizumab, and the IL-2/diphtheria toxin fusion protein denileukin diftitox. Results: In the nine control patients, blood Treg frequencies varied over time; there was a 46% reduction in one patient. In treated patients, a more than 2-fold decrease in Tregs was observed in one out of 11 patients receiving cyclophosphamide and in four out of 13 receiving daclizumab, but there was no such Treg decrease in any of the six patients who received denileukin diftitox. As a positive control, a more than 2-fold increase in blood Tregs was detected in four out of nine patients who were treated with interleukin-2. Conclusions: We used a MS-qPCR method that detects Tregs but not other activated T lymphocytes; however, none of the Treg-depleting strategies that we tested led, in the majority of patients, to a conservative 50% reduction in blood Tregs. ©2010 AACR.

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