Citations

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

AbstractMany common genetic variants have been associated with non-Hodgkin lymphoma (NHL), but individual study results are often conflicting. To confirm the role of putative risk alleles in B-cell NHL etiology, we performed a validation genotyping study of 67 candidate single nucleotide polymorphisms within InterLymph, a large international consortium of NHL case-control studies. A meta-analysis was performed on data from 5633 B-cell NHL cases and 7034 controls from 8 InterLymph studies. rs3789068 in the proapoptotic BCL2L11 gene was associated with an increased risk for B-cell NHL (odds ratio = 1.21, P random = 2.21 × 10−11), with similar risk estimates for common B-cell subtypes. PRRC2A rs3132453 in the HLA complex class III region conferred a reduced risk of B-cell NHL (odds ratio = 0.68, P random = 1.07 × 10−9) and was likewise evident for common B-cell subtypes. These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes.

Vascular access dysfunction causes morbidity in hemodialysis patients. This study examined the generation and pathobiological significance of superoxide anion in a rat femoral arteriovenous fistula (AVF). One week after AVF creation, there was increased production of superoxide anion accompanied by decreased total superoxide dismutase (SOD) and Cu/Zn SOD activities and induction of the redox-sensitive gene heme oxygenase-1. Immunohistochemical studies of nitrotyrosine formation demonstrated that peroxynitrite, a product of superoxide anion and nitric oxide, was present in increased amounts in endothelial and smooth muscle cells in the AVF. Because uncoupled NOS isoforms generate superoxide anion, and NOS coupling requires tetrahydrobiopterin (BH4) as a cofactor, we assessed NOS uncoupling by determining the ratio of BH4to dihydrobiopterin (BH2); the BH4-to-BH2ratio was markedly attenuated in the AVF. Because Src is a vasculopathic signaling species upstream and downstream of superoxide anion, such expression was evaluated; expression of Src and phosphorylated Src was both markedly increased in the AVF. Expression of NADPH oxidase (NOX) 1, NOX2, NOX4, cyclooxygenase (COX) 1, COX2, p47phox, and p67phoxwas all unchanged, as assessed by Western analyses, thereby suggesting that these proteins may not be involved in increased production of superoxide anion. Finally, administration of tempol, a superoxide anion scavenger, decreased neointima formation in the juxta-anastomotic venous segment and improved AVF blood flow. We conclude that the AVF exhibits increased superoxide anion generation that may reflect the combined effects of decreased scavenging by SOD and increased generation by uncoupled NOS, and that enhanced superoxide anion production promotes juxta-anastomotic stenosis and impairs AVF function.

Protein aggregation within the central nervous system has been recognized as a defining feature of neurodegenerative diseases since the early 20th century. Since that time, there has been a growing list of neurodegenerative disorders, including Parkinson disease, which are characterized by inclusions of specific pathogenic proteins. This has led to the long‐held dogma that these characteristic protein inclusions, which are composed of large insoluble fibrillar protein aggregates and visible by light microscopy, are responsible for cell death in these diseases. However, the correlation between protein inclusion formation and cytotoxicity is inconsistent, suggesting that another form of the pathogenic proteins may be contributing to neurodegeneration. There is emerging evidence implicating soluble oligomers, smaller protein aggregates not detectable by conventional microscopy, as potential culprits in the pathogenesis of neurodegenerative diseases. The protein α‐synuclein is well recognized to contribute to the pathogenesis of Parkinson disease and is the major component of Lewy bodies and Lewy neurites. However, α‐synuclein also forms oligomeric species, with certain conformations being toxic to cells. The mechanisms by which these α‐synuclein oligomers cause cell death are being actively investigated, as they may provide new strategies for diagnosis and treatment of Parkinson disease and related disorders. Here we review the possible role of α‐synuclein oligomers in cell death in Parkinson disease and discuss the potential clinical implications. ANN NEUROL 2013;73:155–169

Abstract A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development. Cancer Res; 72(16); 3901–5. ©2012 AACR.

Background About one in four patients suffers from postoperative nausea and vomiting. Fortunately, risk scores have been developed to better manage this outcome in hospitalized patients, but there is currently no risk score for postdischarge nausea and vomiting (PDNV) in ambulatory surgical patients. Methods We conducted a prospective multicenter study of 2,170 adults undergoing general anesthesia at ambulatory surgery centers in the United States from 2007 to 2008. PDNV was assessed from discharge until the end of the second postoperative day. Logistic regression analysis was applied to a development dataset and the area under the receiver operating characteristic curve was calculated in a validation dataset. Results The overall incidence of PDNV was 37%. Logistic regression analysis of the development dataset (n=1,913) identified five independent predictors (odds ratio; 95% CI): female gender (1.54; 1.22 to 1.94), age less than 50 yr (2.17; 1.75 to 2.69), history of nausea and/or vomiting after previous anesthesia (1.50; 1.19 to 1.88), opioid administration in the postanesthesia care unit (1.93; 1.53 to 2.43), and nausea in the postanesthesia care unit (3.14; 2.44-4.04). In the validation dataset (n=257), zero, one, two, three, four, and five of these factors were associated with a PDNV incidence of 7%, 20%, 28%, 53%, 60%, and 89%, respectively, and an area under the receiver operating characteristic curve of 0.72 (0.69 to 0.73). Conclusions PDNV affects a substantial number of patients after ambulatory surgery. We developed and validated a simplified risk score to identify patients who would benefit from long-acting prophylactic antiemetics at discharge from the ambulatory care center.

Abstract Introduction The presence of blood in the urine (hematuria) is one of the hallmark symptoms of bladder cancer. Thus, the current best practice policy suggests that patients with hematuria undergo cystoscopic examination. However, hematuria can be present in healthy individuals as well as in individuals with various non-life threatening conditions such that a majority of patients with blood in the urine (∼95%) who are screened by cystoscopy do not have bladder cancer. In addition, recent studies have found that a majority of patients with hematuria are not referred on to a specialist for further invasive tests, despite the guidelines. This suggests that the prevalence of cancer in this population may be lower than 5%, making screening by cystoscopy inefficient and, in a large number of cases, unnecessary. We are developing a non-invasive diagnostic assay utilizing urinary protein and DNA biomarkers to triage those patients who do not have cancer from those who should go on to be existing invasive screening modalities. Methods Urine samples were obtained from 48 cancer patients and 256 patients who were evaluated for hematuria but who did not have cancer upon cystoscopic evaluation (Hem+/Cysto−). Twist1 and Nid2 methylation status was assessed using methylation-specific PCR primers and FGFR3 mutational status was determined by quantitative PCR. Matrix Metalloproteinases (MMPs) levels were determined by ELISA. Results Using a novel combination of these DNA and protein markers we identified with high confidence (99% negative predictive value) those patients who do not have cancer and who could be excluded from further testing. Cutoffs could be adjusted such that at 94% sensitivity, 65% of patients who do not have cancer could be excluded. Conclusions The Multi-Analyte Diagnostic Readout (MADR) assay described here combines the best performance characteristics of protein and DNA biomarkers into one assay for optimal clinical performance. Using this approach, the detection of FGFR3 mutations and Twist1 and Nid2 methylation in the urine of hematuria patients undergoing screening for bladder cancer effectively increases the sensitivity and negative predictive value at an established MMP protein cutoff. This non-invasive urinary diagnostic assay could lead to the more efficient triage of hematuria patients by identifying those patients who do not have cancer and could be excluded from receiving invasive procedures. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-313. doi:10.1158/1538-7445.AM2011-LB-313