Recurrence of nephrotic syndrome following kidney transplantation is associated with initial native kidney biopsy findings

Background and objectives: Steroid-resistant nephrotic syndrome (SRNS) due to focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is a leading cause of end-stage kidney disease in children. Recurrence of primary disease following transplantation is a major cause of allograft loss. The clinical determinants of disease recurrence are not completely known. Our objectives were to determine risk factors for recurrence of FSGS/MCD following kidney transplantation and factors that predict response to immunosuppression following recurrence. Methods: Multicenter study of pediatric patients with kidney transplants performed for ESKD due to SRNS between 1/2006 and 12/2015. Demographics, clinical course, and biopsy data were collected. Patients with primary-SRNS (PSRNS) were defined as those initially resistant to corticosteroid therapy at diagnosis, and patients with late-SRNS (LSRNS) as those initially responsive to steroids who subsequently developed steroid resistance. We performed logistic regression to determine risk factors associated with nephrotic syndrome (NS) recurrence. Results: We analyzed 158 patients; 64 (41%) had recurrence of NS in their renal allograft. Disease recurrence occurred in 78% of patients with LSRNS compared to 39% of those with PSRNS. Patients with MCD on initial native kidney biopsy had a 76% recurrence rate compared with a 40% recurrence rate in those with FSGS. Multivariable analysis showed that MCD histology (OR; 95% CI 5.6; 1.3–23.7) compared to FSGS predicted disease recurrence. Conclusions: Pediatric patients with MCD and LSRNS are at higher risk of disease recurrence following kidney transplantation. These findings may be useful for designing studies to test strategies for preventing recurrence

Innovative Multi-Touch Interaction

Given the rise of touch-screen technology in recent years, it makes sense to explore new possibilities to employ them. So too thought the municipality of Delft. For their planned new office, they are currently experimenting with different ways and technologies to boost productivity. These experiments take place in the innovation lab, or iLab. One such experi-ment aims to find innovative uses for touch- screens. The muncipality of Delft has outsourced part of this experiment to teams of students from the Delft University of Technology as their Bachelor project. A collaborative multi touch game, called Jest, was chosen as the product to meet these needs. By focusing on the interaction and the user experience, familiarity with innovative techniques can be nourished. This report documents the development process of Jest. In order to ensure a modicum of technical quality, proven techniques such as unit testing and pair programming were used. An external party also evaluated the code artifacts of the product, and commended the clear structure and simple separation of concerns, but found some amount of code duplication in the tests. In Jest, players have to create a network of paths and instructions to guide vehicles carrying cargo to their destinations. Players face several challenges along the way, such as timing issues and interesting level properties. Jest is developed for the JVM in the Clojure language, loosely following a system design focusing on clear module separation and scalability. Jest is deployable on both Windows and GNU/Linux. Several hurdles had to be overcome while developing Jest, such as the fact that the JVM originally did not support the multi touch API on Windows, requiring jumping through several hoops to make this work. The project was delayed, mostly due to developer inexperience, which led to the project lasting 18 instead of 10 weeks. Aside from some rough spots in the planning and development process, the project resulted in a working prototype which can easily be improved upon for many different situations.Computer Graphics and VisualizationElectrical Engineering, Mathematics and Computer Scienc

Twist-1 is upregulated by NSD2 and contributes to tumour dissemination and an epithelial-mesenchymal transition-like gene expression signature in t(4;14)-positive multiple myeloma

Approximately 15% of patients with multiple myeloma (MM) harbour the t(4;14) chromosomal translocation, leading to the overexpression of the histone methyltransferase NSD2. Patients with this translocation display increased tumour dissemination, accelerated disease progression and rapid relapse. Using publicly available gene expression profile data from NSD2(high) (n=135) and NSD2(low) (n=878) MM patients, we identified 39 epithelial-mesenchymal transition (EMT)-associated genes which are overexpressed in NSD2(high) MM plasma cells. In addition, our analyses identified Twist-1 as a key transcription factor upregulated in NSD2(high) MM patients and t(4;14)-positive cell lines. Overexpression and knockdown studies confirmed that Twist-1 is involved in driving the expression of EMT-associated genes in the human MM cell line KMS11 and promoted the migration of myeloma cell lines in vitro. Notably, Twist-1 overexpression in the mouse MM cell line 5TGM1 significantly increased tumour dissemination in an intratibial tumour model. These findings demonstrate that Twist-1, downstream of NSD2, contributes to the induction of an EMT-like signature in t(4;14)-positive MM and enhances the dissemination of MM plasma cells in vivo, which may, in part, explain the aggressive disease features associated with t(4;14)-positive MM.Chee Man Cheong, Krzysztof M. Mrozik, Duncan R. Hewett, Elyse Bell, Vasilios Panagopoulos, Jacqueline E. Noll, Jonathan D. Licht, Stan Gronthos, Andrew C.W. Zannettino, Kate Vandyk

The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial–mesenchymal transition and invasive properties of prostate cancer

Epigenetic deregulation of gene expression has a role in the initiation and progression of prostate cancer (PCa). The histone methyltransferase MMSET/WHSC1 (Multiple Myeloma SET domain) is overexpressed in a number of metastatic tumors, but its mechanism of action has not been defined. In this work, we found that PCa cell lines expressed significantly higher levels of MMSET compared with immortalized, non-transformed prostate cells. Knockdown experiments showed that, in metastatic PCa cell lines, dimethylation of lysine 36 and trimethylation of lysine 27 on histone H3 (H3K36me2 and H3K27me3, respectively) depended on MMSET expression, whereas depletion of MMSET in benign prostatic cells did not affect chromatin modifications. Knockdown of MMSET in DU145 and PC-3 tumor cells decreased cell proliferation, colony formation in soft agar and strikingly diminished cell migration and invasion. Conversely, overexpression of MMSET in immortalized, non-transformed RWPE-1 cells promoted cell migration and invasion, accompanied by an epithelial-mesenchymal transition (EMT). Among a panel of EMT-promoting genes analyzed, TWIST1 expression was strongly activated in response to MMSET. Chromatin immunoprecipitation analysis demonstrated that MMSET binds to the TWIST1 locus and leads to an increase in H3K36me2, suggesting a direct role of MMSET in the regulation of this gene. Depletion of TWIST1 in MMSET-overexpressing RWPE-1 cells blocked cell invasion and EMT, indicating that TWIST1 was a critical target of MMSET, responsible for the acquisition of an invasive phenotype. Collectively, these data suggest that MMSET has a role in PCa pathogenesis and progression through epigenetic regulation of metastasis-related genes

Genomic structure of the human PLZF gene

The human PLZF (promyelocytic leukaemia zinc finger) gene encodes a Krüppel-like zinc finger protein, which was identified via the reciprocal translocation t(11;17)(q23;q21) fusing it to the retinoic acid receptor alpha ( RARα) gene in promyelocytic leukaemia. To determine its complete genomic organisation, we constructed a cosmid-map fully containing the hPLZF gene. The gene has seven exons, including a novel 5′ untranslated exon, varying in size from 87 to 1358 bp and spans at least 120 kb. Flanking intronic sequences were identified and all splice acceptor and donor sites conformed to the gt/ag rule. Five polymorphic markers could be fine located in its vicinity. These data will facilitate mutation analysis of hPLZF in t(11;17) leukaemia cases, as well as assist mapping and loss-of-heterozygosity analysis. Here we have tested hPLZF as a possible candidate for the PGL1 locus involved in hereditary head and neck paragangliomas. However, mutation analysis revealed no aberration in 12 paraganglioma patients from different families