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Background/Purpose:Genome‐wide association studies have identified susceptibility loci for many autoimmune diseases, including rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). About 5% of children with JIA have rheumatoid factor positive arthritis that is phenotypically similar to adult seropositive RA, thus representing childhood onset RA (CORA). To understand the genetic architecture of CORA risk relative to other autoimmune diseases, we genotyped CORA cases and controls on the Immunochip, a custom array designed by the Immunochip Consortium to fine map autoimmune disease‐associated loci shared across 11 autoimmune phenotypes.Methods:Genotyping was completed on 340 CORA cases (mean onset age: 10.2 ± 4.2 yrs) and 11624 controls. Standard SNP and sample QC was performed (e.g., removing samples with call rate <98%, admixture outliers). To test for SNP association with CORA a logistic regression model was computed with Caucasian admixture proportions (ADMIXTURE) as covariates (SNPLash). False discovery rate (FDR) adjusted p‐values (PFDR) are reported to account for the actual number of tests computed.Results:SNP rs3129769, near HLA DRB1 was the most significantly associated (PFDR <3×10‐25), and is in linkage disequilibrium with the HLA DRB1 SNP reported in RA (rs660895, PFDR <1×10‐24). Outside the HLA region, 28 regions had ≥1 SNP meeting genome‐wide significance (PFDR<0.05). The best signal of association was on 22q13 (rs9610687, OR = 0.57, PFDR < 0.0002) near IL2RB, followed by the PTPN22 locus (rs6679677, OR = 1.83, PFDR < 0.0005), an intergenic SNP on chromosome 4 (rs970036, OR = 1.78, PFDR < 0.002) and an intronic SNP (19p13, rs3787016 PFDR < 0.002) in the POLR2E gene, which encodes a subunit of RNA polymerase II. Some loci which have previously been implicated in RA had evidence of association including MMEL (rs751358 PFDR < 0.003), IRF5 (rs4731531 PFDR < 0.006) and CCR6 (rs11575078 PFDR < 0.03). In addition using the FDR‐based threshold we identified several potential SNPs (rs10918214, 1q23; rs28491312, 14q31) not previously implicated in RA.Conclusion:Immunochip analysis of the largest cohort of CORA investigated to date has confirmed the HLA DRB1 association and identified several other loci associated with CORA. Comparisons among loci associated with CORA and those identified in RA and other forms of JIA are underway and will help delineate the unique genetic factors for CORA susceptibility.

Basement membrane abnormalities have often been observed in kidney cysts of polycystic kidney disease (PKD) patients and animal models. There is an abnormal deposition of extracellular matrix molecules, including laminin-α3,β3,γ2 (laminin-332), in human autosomal dominant PKD (ADPKD). Knockdown of PKD1 paralogs in zebrafish leads to dysregulated synthesis of the extracellular matrix, suggesting that altered basement membrane assembly may be a primary defect in ADPKD. In this study, we demonstrate that laminin-332 is aberrantly expressed in cysts and precystic tubules of human autosomal recessive PKD (ARPKD) kidneys as well as in the kidneys of PCK rats, an orthologous ARPKD model. There was aberrant expression of laminin-γ2 as early as postnatal day 2 and elevated laminin-332 protein in postnatal day 30, coinciding with the formation and early growth of renal cysts in PCK rat kidneys. We also show that a kidney cell line derived from Oak Ridge polycystic kidney mice, another model of ARPKD, exhibited abnormal lumen-deficient and multilumen structures in Matrigel culture. These cells had increased proliferation rates and altered expression levels of laminin-332 compared with their rescued counterparts. A function-blocking polyclonal antibody to laminin-332 significantly inhibited their abnormal proliferation rates and rescued their aberrant phenotype in Matrigel culture. Furthermore, abnormal laminin-332 expression in cysts originating from collecting ducts and proximal tubules as well as in precystic tubules was observed in a human end-stage ADPKD kidney. Our results suggest that abnormal expression of laminin-332 contributes to the aberrant proliferation of cyst epithelial cells and cyst growth in genetic forms of PKD.

AbstractBackgroundSurvival rates for children with medulloblastoma have risen over the past decade, in part due to the addition of cisplatin‐containing adjuvant chemotherapy. Total dose of cisplatin required for optimal treatment is unknown. The purpose of this study was to evaluate the survival outcomes based on cumulative cisplatin doses (CCD) in children with newly diagnosed average‐risk medulloblastoma.ProcedureCCD data were reviewed for 363 patients in a prospective study evaluating patients between 3 and 21 years with a newly diagnosed average‐risk medulloblastoma and treated with craniospinal radiation and post‐radiation cisplatin based adjuvant chemotherapy.ResultsEight‐year event‐free survival (EFS) and overall survival (OS) estimates were 78.2 ± 2.6% and 83.9 ± 2.4%, respectively. Only 73 patients received the protocol specified CCD of 600 mg/m2, primarily due to mandated cisplatin toxicity‐related dose reductions. The median CCD given to those without relapse or death on treatment was 487.5 mg/m2. CCD, as a time‐dependent covariate, was not associated with EFS (P = 0.54) or OS (P = 0.11). The 343 patients who completed chemotherapy failure‐free were categorized into four groups according to CCD (n = 10; 75–150 mg/m2), (n = 26; 151–300 mg/m2), (n = 113; 301–450 mg/m2), and (n = 194; 451–600 mg/m2). There were no statistically significant differences in distributions of EFS (P = 0.53) or OS (P = 0.49) among these four groups.ConclusionCCD is not associated with EFS or OS suggesting that lower doses of cisplatin may be incorporated into future medulloblastoma trials, thereby limiting its toxicity profile without affecting survival. If ototoxicity is encountered, more stringent cisplatin dose modification/cessation rules seem warranted. Pediatr Blood Cancer 2014;61:102–106. © 2013 Wiley Periodicals, Inc.

According to recent statistics from the American Heart Association, Heart Failure (HF) affects 5.7 million Americans [1]. HF is characterized by the global dilation of the heart, which leads to an increase in ventricular volume and a reduction in pumping efficiency. Several treatment strategies have been investigated to combat the adverse remodeling that leads to the progression of HF [2,3]. These therapies include reshaping the heart by means of surgical intervention and implantation of medical devices.