Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease.

Abstract The renin-angiotensin system (RAS), bone morphogenetic protein (BMP), and WNT pathways are involved in pathogenesis of diabetic kidney disease (DKD). This study characterized assays for urinary angiotensinogen (AGT), gremlin-1, and matrix metalloproteinase 7 (MMP-7), components of the RAS, BMP, and WNT pathways and examined their excretion in DKD. We measured urine AGT, gremlin-1, and MMP-7 in individuals with type 1 diabetes and prevalent DKD (n = 20) or longstanding (n = 61) or new-onset (n = 10) type 1 diabetes without DKD. These urine proteins were also quantified in type 2 DKD (n = 11) before and after treatment with candesartan. The utilized immunoassays had comparable inter- and intra-assay and intraindividual variation to assays used for urine albumin. Median (IQR) urine AGT concentrations were 226.0 (82.1, 550.3) and 13.0 (7.8, 20.0) μg/g creatinine in type 1 diabetes with and without DKD, respectively (P < 0.001). Median (IQR) urine gremlin-1 concentrations were 48.6 (14.2, 254.1) and 3.6 (1.7, 5.5) μg/g, respectively (P < 0.001). Median (IQR) urine MMP-7 concentrations were 6.0 (3.8, 10.5) and 1.0 (0.4, 2.9) μg/g creatinine, respectively (P < 0.001). Treatment with candesartan was associated with a reduction in median (IQR) urine AGT/creatinine from 23.5 (1.6, 105.1) to 2.0 (1.4, 13.7) μg/g, which did not reach statistical significance. Urine gremlin-1 and MMP-7 excretion did not decrease with candesartan. In conclusion, DKD is characterized by markedly elevated urine AGT, MMP-7, and gremlin-1. AGT decreased in response to RAS inhibition, suggesting that this marker reflects therapeutic response. Urinary components of the RAS, BMP, and WNT pathways may identify risk of DKD and aid development of novel therapeutics

REESTRUTURAÇÃO DO MODELO DE ENSINO DE UM CURSO DE ENGENHARIA DE PRODUÇÃO BUSCANDO FOMENTAR A INOVAÇÃO E O EMPREENDEDORISMO

Em um cenário de acirrada concorrência e desenvolvimento tecnológico, a capacidade de continuamente inovar e empreender apresentam-se como principais determinantes do sucesso de uma empresa, e consequentemente, a qualidade dos recursos humanos envolvidos no processo de inovação. Porém, como ensinar e desenvolver empreendedorismo? Com o objetivo que responder a essa questão, o presente artigo descreve o modelo de reestruturação que está se realizando no curso de Engenharia de Produção, ofertado pela Universidade Federal do Rio Grande do Sul, Brasil. Apresenta-se também algumas das iniciativas já realizadas, que são resultados dos esforços para reformular o modelo de ensino

High resolution combined molecular and structural optical imaging of colorectal cancer in a xenograft mouse model

With the emergence of immunotherapies for cancer treatment, there is a rising clinical need to visualize the tumor microenvironment (TME) non-invasively in detail, which could be crucial to predict the efficacy of therapy. Nuclear imaging techniques enable whole-body imaging but lack the required spatial resolution. Conversely, near-infrared immunofluorescence (immuno-NIRF) is able to reveal tumor cells and/or other cell subsets in the TME by targeting the expression of a specific membrane receptor with fluorescently labeled monoclonal antibodies (mAb). Optical coherence tomography (OCT) provides three-dimensional morphological imaging of tissues without exogenous contrast agents. The combination of the two allows molecular and structural contrast at a resolution of ~15 µm, allowing for the specific location of a cell-type target with immuno-NIRF as well as revealing the three-dimensional architectural context with OCT. For the first time, combined immuno-NIRF and OCT of a tumor is demonstrated in situ in a xenograft mouse model of human colorectal cancer, targeted by a clinically-safe fluorescent mAb, revealing unprecedented details of the TME. A handheld scanner for ex vivo examination and an endoscope designed for imaging bronchioles in vivo are presented. This technique promises to complement nuclear imaging for diagnosing cancer invasiveness, precisely determining tumor margins, and studying the biodistribution of newly developed antibodies in high detail

Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation

Background: The role of DNA methylation in the regulation of the anti-donor-directed immune response after organ transplantation is unknown. Here, we studied the methylation of two mediators of the immune response: the pro-inflammatory cytokine interferon γ (IFNγ) and the inhibitory receptor programmed death 1 (PD1) in naïve and memory CD8+ T cell subsets in kidney transplant recipients receiving immunosuppressive medication. Both recipients experiencing an episode of acute allograft rejection (rejectors) as well as recipients without rejection (non-rejectors) were included. Results: CpGs in the promoter regions of both IFNγ and PD1 were significantly (p < 0.001) higher methylated in the naïve CD8+ T cells compared to the memory T cell subsets. The methylation status of both IFNγ and PD1 inversely c

Treatments and costs for recurrent and/or metastatic squamous cell carcinoma of the head and neck in the Netherlands

__Abstract__ For patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), chemotherapy can prolong life and alleviate symptoms. However, expected gains may be small, not necessarily outweighing considerable toxicity and high costs. Treatment choice is to a large extent dependent on preferences of doctors and patients and data on these choices are scarce. The purpose of this study is to obtain real-world information on palliative systemic treatment and costs of R/M SCCHN in the Netherlands. In six Dutch head and neck treatment centers, data were collected on patient and tumor characteristics, treatment patterns, disease progression, survival, adverse events, and resource use for R/M SCCHN, between 2006 and 2013. 125 (14 %) out of 893 R/M SCCHN patients received palliative, non-trial first-line systemic treatment, mainly platinum + 5FU + cetuximab (32 %), other platinum-based combination therapy (13 %), methotrexate monotherapy (27 %) and capecitabine monotherapy (14 %). Median progression-free survival and overall survival were 3.4 and 6.0 months, respectively. 34 (27 %) patients experienced severe adverse events. Mean total hospital costs ranged from €10,075 (±€9,891) (methotrexate monotherapy) to €39,459 (±€21,149) (platinum + 5FU + cetuximab). Primary cost drivers were hospital stays and anticancer drug treatments. Major health care utilization and costs are involved in systemically treating R/M SCCHN patients with a limited survival

Donor-Derived Cell-Free DNA for the Detection of Heart Allograft Injury:The Impact of the Timing of the Liquid Biopsy

Background: In heart transplant recipients, donor-derived cell-free DNA (ddcfDNA) is a potential biomarker for acute rejection (AR), in that increased values may indicate rejection. For the assessment of ddcfDNA as new biomarker for rejection, blood plasma sampling around the endomyocardial biopsy (EMB) seems a practical approach. To evaluate the effect of the EMB procedure on ddcfDNA values, ddcfDNA values before the EMB were pairwise compared to ddcfDNA values after the EMB. We aimed at evaluating whether it matters whether the ddcfDNA sampling is done before or after the EMB-procedure. Methods: Plasma samples from heart transplant recipients were obtained pre-EMB and post-EMB. A droplet digital PCR method was used for measuring ddcfDNA, making use of single-nucleotide polymorphisms that allowed both relative quantification, as well as absolute quantification of ddcfDNA. Results: Pairwise comparison of ddcfDNA values pre-EMB with post-EMB samples (n = 113) showed significantly increased ddcfDNA concentrations and ddcfDNA% in post-EMB samples: an average 1.28-fold increase in ddcfDNA concentrations and a 1.31-fold increase in ddcfDNA% was observed (p = 0.007 and p = 0.03, respectively). Conclusion: The EMB procedure causes iatrogenic injury to the allograft that results in an increase in ddcfDNA% and ddcfDNA concentrations. For the assessment of ddcfDNA as marker for AR, collection of plasma samples before the EMB procedure is therefore essential

Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in dutch Caucasians

Context: Activating transcription factor 6 (ATF6) is critical for initiation and full activation of the unfolded protein response. An association between genetic variation in ATF6 and type 2 diabetes (DM2) was recently reported in Pima Indians. Objectives: To investigate the broader significance of this association for DM2, replication studies in distinct ethic populations are required. We investigated ATF6 for its association with DM2 in Dutch Caucasians. Design/Setting: A genetic association study was conducted at an academic research laboratory. Study Participants: Two independent Dutch cohorts were studied. Cohort 1 (n = 154) was used to evaluate genetic variation in the ATF6 gene in relation to glucose homeostasis in the general population. Cohort 2 (n = 798) consisted of patients with DM2, impaired glucose tolerance, impaired fasting glucose, and normoglycemic control subjects, and was used to investigate ATF6 polymorphisms for their contribution to disturbed glucose homeostasis and DM2. Main Outcome Measures: There were 16 tag single nucleotide polymorphisms genotyped in all subjects of both cohorts. Those single nucleotide polymorphisms included three nonsynonymous coding variants and captured all common allelic variation of ATF6. Results: Our data show that common ATF6 variants are associated with elevated glucose levels in the general population (cohort 1, P = 0.005-0.05). Furthermore, the majority of these variants, and haplotypes thereof, were significantly associated with impaired fasting glucose, impaired glucose tolerance, and DM2 ( cohort 2, P = 0.006-0.05). Associated variants differ from those identified in Pima Indians. Conclusions: Our results strengthen the evidence that one or more variants in ATF6 are associated with disturbed glucose homeostasis and DM2

Proposal for a definition for response to treatment, inactive disease and damage for JIA associated uveitis based on the validation of a uveitis related JIA outcome measures from the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC)

Correction: PEDIATRIC RHEUMATOLOGY Volume: 18 Issue: 1 Article Number: 14 DOI: 10.1186/s12969-019-0396-4Background JIA-associated uveitis (JIAU) is a serious, sight-threatening disease with significant long-term complications and risk of blindness, even with improved contemporary treatments. The MIWGUC was set up in order to propose specific JIAU activity and response items and to validate their applicability for clinical outcome studies. Methods The group consists of 8 paediatric rheumatologists and 7 ophthalmologists. A consensus meeting took place on November 2015 in Barcelona (Spain) with the objective of validating the previously proposed measures. The validation process was based on the results of a prospective open, international, multi-centre, cohort study designed to validate the outcome measures proposed by the initial MIWGUC group meeting in 2012. The meeting used the same Delphi and nominal group technique as previously described in the first paper from the MIWGUC group (Arthritis Care Res 64:1365-72, 2012). Patients were included with a diagnosis of JIA, aged less than 18 years, and with active uveitis or an uveitis flare which required treatment with a disease-modifying anti-rheumatic drug. The proposed outcome measures for uveitis were collected by an ophthalmologist and for arthritis by a paediatric rheumatologist. Patient reported outcome measures were also measured. Results A total of 82 patients were enrolled into the validation cohort. Fifty four percent (n = 44) had persistent oligoarthritis followed by rheumatoid factor negative polyarthritis (n = 15, 18%). The mean uveitis disease duration was 3.3 years (SD 3.0). Bilateral eye involvement was reported in 65 (79.3%) patients. The main findings are that the most significant changes, from baseline to 6 months, are found in the AC activity measures of cells and flare. These measures correlate with the presence of pre-existing structural complications and this has implications for the reporting of trials using a single measure as a primary outcome. We also found that visual analogue scales of disease activity showed significant change when reported by the ophthalmologist, rheumatologist and families. The measures formed three relatively distinct groups. The first group of measures comprised uveitis activity, ocular damage and the ophthalmologists' VAS. The second comprised patient reported outcomes including disruption to school attendance. The third group consisted of the rheumatologists' VAS and the joint score. Conclusions We propose distinctive and clinically significant measures of disease activity, severity and damage for JIAU. This effort is the initial step for developing a comprehensive outcome measures for JIAU, which incorporates the perspectives of rheumatologists, ophthalmologists, patients and families.Peer reviewe