Citations

Background: A concept for a tear glucose sensor based on amperometric measurement of enzymatic oxidation of glucose was previously presented, using glucose dehydrogenase flavin adenine dinucleotide (GDH-FAD) as the enzyme. Glucose dehydrogenase flavin adenine dinucleotide is further characterized in this article and evaluated for suitability in glucose-sensing applications in purified tear-like saline, with specific attention to the effect of interfering substances only. These interferents are specifically saccharides that could interact with the enzymatic activity seen in the sensor's performance. Methods: Bench top amperometric glucose assays were performed using an assay solution of GDH-FAD and ferricyanide redox mediator with samples of glucose, mannose, lactose, maltose, galactose, fructose, sucrose, and xylose at varying concentrations to evaluate specificity, linear dynamic range, signal size, and signal-to-noise ratio. A comparison study was done by substituting an equivalent activity unit concentration of glucose oxidase (GOx) for GDH-FAD. Results: Glucose dehydrogenase flavin adenine dinucleotide was found to be more sensitive than GOx, producing larger oxidation currents than GOx on an identical glucose concentration gradient, and GDH-FAD exhibited larger slope response (-5.65 × 10 −7 versus −3.11 × 10 −7 A/mM), signal-to-noise ratio (18.04 versus 2.62), and linear dynamic range (0–30 versus 0–10 mM), and lower background signal (−7.12 versus −261.63 nA) than GOx under the same assay conditions. GDH-FAD responds equally to glucose and xylose but is otherwise specific for glucose. Conclusion: Glucose dehydrogenase flavin adenine dinucleotide compares favorably with GOx in many sensor-relevant attributes and may enable measurement of glucose concentrations both higher and lower than those measurable by GOx. GDH-FAD is a viable enzyme to use in the proposed amperometric tear glucose sensor system and perhaps also in detecting extreme hypoglycemia or hyperglycemia in blood.

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.

Abstract Biomarkers are lacking for identifying the switch of transforming growth factor-beta (TGF-β) from tumor-suppressing to tumor-promoting. Mutated p53 (mp53) has been suggested to switch TGF-β to a tumor promoter. However, we found that mp53 does not always promote the oncogenic role of TGF-β. Here, we show that endogenous mp53 knockdown enhanced cell migration and phosphorylation of ERK in DU145 prostate cancer cells. Further, ectopic expression of mp53 in p53-null PC-3 prostate cancer cells enhanced Smad-dependent signaling, but inhibited TGF-β-induced cell migration by downregulating activated ERK. Reactivation of ERK by the expression of its activator, MEK-1, restored TGF-β-induced cell migration. Since TGF-β is known to activate MAPK/ERK pathway through direct phosphorylation of adaptor protein ShcA and MAPK/ERK signaling is pivotal to tumor progression, we investigated whether ShcA contributed to mp53-induced ERK inhibition and the conversion of TGF-β's role during carcinogenesis. We found that mp53 expression led to decrease of phosphorylated p52ShcA/ERK levels and increase of phosphorylated Smad levels in a panel of mp53-expressing cancer cell lines, and in mammary glands and tumors from mp53 knock-in mice. By manipulating ShcA levels to regulate ERK and Smad signaling in human untransformed and cancer cell lines, we show that TGF-β's role in regulating anchorage-dependent and -independent growth, and migration, can be shifted between growth suppression and migration promotion. Thus, our results, for the first time, suggest that mp53 disrupts ShcA's role in balancing Smad-dependent and -independent signaling activity of TGF-β and that ShcA/ERK signaling is a major pathway regulating the tumor-promoting activity of TGF-β. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1069. doi:1538-7445.AM2012-1069

Abstract To clarify the role of previous lung diseases (PLDs) (chronic bronchitis, emphysema, pneumonia, tuberculosis, asbestosis and silicosis) in the development of lung cancer we conducted a pooled analysis in the International Lung Cancer Consortium (ILCCO). Data from 16 studies (9 population based case-control, 4 hospital based case-control, 2 mixed case-control and 1 cohort - 10 from North America, 5 from Europe and 1 from Asia) were pooled, including 24044 cases and 81256 controls. Study-specific effect estimates were derived using logistic regression models for case-control studies and Cox proportional hazards models for cohort studies adjusted for age, sex, education and pack-years of smoking. Effect estimates were then pooled using random effects models where summary effects for each of the PLDs were evaluated separately. Stratified analyses were conducted based on smoking status, histology and study design or control source. Heterogeneity was evaluated using the Cochrane Q statistic and Galbraith plots, and publication bias was evaluated using funnel plots as well as the Begg test. A previous history of emphysema conferred a relative risk (RR) of 2.17, 95% confidence interval (CI): 1.67-2.82 (from 15 studies, p-het<.001). A previous history of chronic bronchitis conferred a RR of 1.49, 95% CI: 1.33-1.60 (from 12 studies, p-het.=0.434). Tuberculosis was associated with a RR of 1.54, 95% CI: 1.19-1.99 (from 15 studies, p-het.=0.001). Both asbestosis (RR 2.51, 95% CI: 1.53-4.12 (from 7 studies, p-het=0.379)) and silicosis (RR 1.70, 95% CI: 1.15-2.54, (from 3 studies, p-het. p=0.476)) were also associated with lung cancer risk. When the outlying studies were removed, effect estimates changed minimally and heterogeneity was reduced. Findings were consistent in subgroup analyses by smoking status and histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer). Effect estimates among never smokers were for emphysema a RR of 2.21, 95% CI: 0.99-4.90 (from 8 studies), for chronic bronchitis 1.12, 95% CI: 0.78-1.62 (from 9 studies), for pneumonia 1.37, 95% CI: 1.10-1.70 (from 10 studies) and for tuberculosis 1.54, 95% CI: 0.99-2.39 (from 9 studies). In this analysis of data from multiple continents, PLDs were associated with an increased risk of lung cancer. The evidence among never smokers supports a direct relationship between previous lung diseases and lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4826.

AbstractGenome‐wide association studies (GWAS) are being conducted at an unprecedented rate in population‐based cohorts and have increased our understanding of the pathophysiology of complex disease. Regardless of context, the practical utility of this information will ultimately depend upon the quality of the original data. Quality control (QC) procedures for GWAS are computationally intensive, operationally challenging, and constantly evolving. Here we enumerate some of the challenges in QC of GWAS data and describe the approaches that the electronic MEdical Records and Genomics (eMERGE) network is using for quality assurance in GWAS data, thereby minimizing potential bias and error in GWAS results. We discuss common issues associated with QC of GWAS data, including data file formats, software packages for data manipulation and analysis, sex chromosome anomalies, sample identity, sample relatedness, population substructure, batch effects, and marker quality. We propose best practices and discuss areas of ongoing and future research. Curr. Protoc. Hum. Genet. 68:1.19.1‐1.19.18 © 2011 by John Wiley & Sons, Inc.

Mammalian urine contains a range of macromolecule proteins that play critical roles in renal stone formation, among which Tamm-Horsfall protein (THP) is by far the most abundant. While THP is a potent inhibitor of crystal aggregation in vitro and its ablation in vivo predisposes one of the two existing mouse models to spontaneous intrarenal calcium crystallization, key controversies remain regarding the role of THP in nephrolithiasis. By carrying out a long-range follow-up of more than 250 THP-null mice and their wild-type controls, we demonstrate here that renal calcification is a highly consistent phenotype of the THP-null mice that is age and partially gene dosage dependent, but is gender and genetic background independent. Renal calcification in THP-null mice is progressive, and by 15 mo over 85% of all the THP-null mice develop spontaneous intrarenal crystals. The crystals consist primarily of calcium phosphate in the form of hydroxyapatite, are located more frequently in the interstitial space of the renal papillae than intratubularly, particularly in older animals, and lack accompanying inflammatory cell infiltration. The interstitial deposits of hydroxyapatite observed in THP-null mice bear strong resemblances to the renal crystals found in human kidneys bearing idiopathic calcium oxalate stones. Compared with 24-h urine from the wild-type mice, that of THP-null mice is supersaturated with brushite (calcium phosphate), a stone precursor, and has reduced urinary excretion of citrate, a stone inhibitor. While less frequent than renal calcinosis, renal pelvic and ureteral stones and hydronephrosis occur in the aged THP-null mice. These results provide direct in vivo evidence indicating that normal THP plays an important role in defending the urinary system against calcification and suggest that reduced expression and/or decreased function of THP could contribute to nephrolithiasis.

Abstract Caspases play a critical role in regulation of apoptosis, cell differentiation, inflammation, and innate immunity, and several are mutated or have altered expression in non-Hodgkin lymphoma (NHL). To study the impact of genetic variation in caspases on NHL risk, we analyzed tag single nucleotide polymorphisms (SNPs) in 12 caspase and related genes in 3 population-based case-control studies (1946 cases and 1808 controls). Gene-based analysis, adjusting for the number of tagSNPs genotyped in each gene, showed significant associations for CASP8, CASP9, and CASP1. SNP-based analysis showed that CASP8 rs6736233 (odds ratio (OR) CG = 1.21; ORCC = 2.13; P trend = .011); CASP9 rs4661636 (ORCT = 0.89; ORTT = 0.77; P trend = .011); and CASP1 rs1785882 (ORAT = 1.12; ORAA = 1.30; P trend = .0054) were significantly associated with NHL risk and consistent across studies. It is noteworthy that genetic variants in CASP8 were associated with risk of all major NHL subtypes. Our findings suggest that genetic variation in caspases may play an important role in lymphomagenesis.