Citations

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.

ObjectiveChildren with childhood‐onset rheumatoid arthritis (RA) include those with rheumatoid factor or anti–citrullinated protein antibody–positive juvenile idiopathic arthritis. To test the hypothesis that adult‐onset RA–associated variants are also associated with childhood‐onset RA, we investigated RA‐associated variants at 5 loci in a cohort of patients with childhood‐onset RA. We also assessed the cumulative association of these variants in susceptibility to childhood‐onset RA using a weighted genetic risk score (wGRS).MethodsA total of 155 children with childhood‐onset RA and 684 healthy controls were genotyped for 5 variants in the PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High‐resolution HLA–DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with childhood‐onset RA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios (ORs) for the alleles investigated, and used logistic regression to test the wGRS for association with childhood‐onset RA.ResultsChildhood‐onset RA was associated with TNFAIP3 rs10499194 (OR 0.60 [95% confidence interval 0.44–0.83]), PTPN22 rs2476601 (OR 1.61 [95% confidence interval 1.11–2.31]), and STAT4 rs7574865 (OR 1.41 [95% confidence interval 1.06–1.87]) variants. The wGRS was significantly different between cases and controls (P < 2 × 10−16). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to baseline (individuals in the first quintile). Higher wGRS was associated with increased risk of childhood‐onset RA, especially among males.ConclusionThe magnitude and direction of the association between TNFAIP3, STAT4, and PTPN22 variants and childhood‐onset RA are similar to those observed in RA, suggesting that adult‐onset RA and childhood‐onset RA share common genetic risk factors. Using a wGRS, we have demonstrated the cumulative association of RA‐associated variants with susceptibility to childhood‐onset RA.