Citations

Abstract Lung cancer is the deadliest cancer in the United States, contributing approximately 25% of all cancer deaths. Lung cancer risk is well-documented to increase in response to environmental factors, particularly tobacco smoking. As one might expect for a complex trait, there is also a significant genetic risk component in lung cancer, though it is not very well studied. We obtained whole exome sequencing (WES) genotype data from Washington University on 204 subjects from 25 extended families. These individuals were recruited from families with a history of lung cancer and previous analyses showed these 25 families be informative. The purpose of this study is to identify potential risk variants for lung cancer by performing genetic linkage analysis. Quality control was performed on the sequence data, filtering on parameters such as depth (less than 10), genotype quality (less than 10), missingness, and Mendelian inconsistencies. Identity-by-descent (IBD) values were also calculated to verify correct familial relationships. Quality control procedures left approximately 500,000 SNVs and indels for analysis. We performed two-point parametric linkage analysis assuming an autosomal dominant mode of inheritance with a disease allele frequency of 1%, a 10% penetrance for carriers and a 1% penetrance for non-carriers. Two discrete sets of linkage analyses were performed. One was a variant-based analysis, which evaluated linkage between the phenotype and individual SNVs or indels. The second was gene-based analysis, which created a multi-allelic pseudomarker corresponding to a gene from haplotypes of rare variants (minor allele frequency <= 0.01) located within that particular gene. Two-point linkage analysis was then performed on the pseudomarkers. While the variant-based analysis did not identify any genome-wide significant results, several were identified by the gene-based analysis. The highest HLOD scores were both greater than the genome-wide significance level of HLOD = 3.3 and were located on two regions of chromosome 1q: 1q42.13-43 and 1q21.2-21.1. In both regions, the significant HLOD scores clustered around known cancer genes. At the 1q42.13-43 region, signals centered on the cancer-implicated genes OBSCN and RYR2 (also a known mesothelioma gene), while at 1q21.2-21.1 the signals centered on five genes in the neuroblastoma breakpoint family (NBPF) genes, a cluster of recently duplicated genes. NBPF genes have previously been implicated in a variety of different cancers including lung cancer. We are currently performing additional analyses to corroborate the significant results, as well as examining the individual families to determine which families are driving the significant signals. Citation Format: Anthony M. Musolf, Haiming Sun, Bilal A. Moiz, Diptasri Mandal, Mariza de Andrade, Colette Gaba, Ping Yang, Yafang Li, Ming You, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson. Whole exome sequencing identifies significantly linked regions on multiple chromosomes in families with a history of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3276.

Abstract Objective Genome-wide association studies (GWAS) identify associations of individual SNPs with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants has been shown for many disorders to be a powerful tool in discovering novel networks of susceptibility genes. Design We have conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product (sARTP) method to identify novel gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDA) in 9,040 cases and 12,495 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes identified in PDA-associated gene sets and pathways. Results We identified 14 gene sets and pathways associated with PDA at FDR < 0.05. Five of the strongest signals (P-value ≤ 1.3x10-5 Bonferroni corrected) were in genes from KEGG maturity onset diabetes of the young, Reactome regulation of beta cell development, Biocarta role of epidermal growth factor (EGF) receptor transactivation by G-protein-coupled receptors in cardiac hypertrophy pathway, Nikolsky breast cancer chr17q11-q21 amplicon gene set, and Pujana ATM Pearson correlation coefficient (PCC) network gene set. We identified and validated rs876493 and three correlated SNPs (PGAP3) and rs3124737 (CASP7) as eQTLs in two normal derived pancreas tissue datasets. Conclusion Our agnostic gene set and pathway analysis integrated with functional annotation and eQTL analysis provides novel insight into genes and pathways that may be biologically relevant for risk of PDA. Citation Format: Naomi Walsh, Han Zhang, Paula L. Hyland, Qi Yang, Evelina Mocci, Mingfeng Zhang, Erica J. Childs, Zhaoming Wang, Stephen Chanock, Patricia Hartge, Robert Hoover, Peter Kraft, Donghui Li, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Kai Yu, Alison P. Klein, Rachael Z. Stolzenberg-Solomon. Large pathway and gene set analysis of GWAS data identifies novel associations for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 242.

ABSTRACT Kidney stone disease involves the aggregation of stone-forming salts consequent to solute supersaturation in urine. The development of novel therapeutic agents for this predominantly metabolic and biochemical disorder have been hampered by the lack of a practical pre-clinical model amenable to drug screening. Here, Drosophila melanogaster, an emerging model for kidney stone disease research, was adapted as a high-throughput functional drug screening platform independent of the multifactorial nature of mammalian nephrolithiasis. Through functional screening, the therapeutic potential of a novel compound commonly known as arbutin that specifically binds to oxalate, a key component of kidney calculi, was identified. Through isothermal titration calorimetry, high-performance liquid chromatography and atomic force microscopy, arbutin was determined to interact with calcium and oxalate in both free and bound states, disrupting crystal lattice structure, growth and crystallization. When used to treat patient urine samples, arbutin significantly abrogated calculus formation in vivo and outperformed potassium citrate in low pH urine conditions, owing to its oxalate-centric mode of action. The discovery of this novel antilithogenic compound via D. melanogaster, independent of a mammalian model, brings greater recognition to this platform, for which metabolic features are primary outcomes, underscoring the power of D. melanogaster as a high-throughput drug screening platform in similar disorders. This is the first description of the use of D. melanogaster as the model system for a high-throughput chemical library screen. This article has an associated First Person interview with the first authors of the paper.

AbstractIntroductionThe outcomes of repeated cardiovascular implantable electronic device (CIED) lead extraction have not been well studied. We sought to determine the indications, outcomes, and safety of repeated lead extraction procedures.MethodsThis retrospective study was conducted using data from two medical centers, including 38 patients who had undergone two or more lead extraction procedures compared to 439 patients who had a single procedure. The electronic medical records and procedural databases were reviewed to determine the indications, procedural characteristics, and outcomes. The outcomes of the first procedure were compared to the outcomes of subsequent procedures.ResultsThe 5‐year cumulative probability of a repeated extraction procedure was 11% (95% confidence interval, 7%–15%). In 439 patients who underwent single lead extractions, 72% had device and lead related infections as the procedure indication compared to 39% for 38 patients who underwent repeated extraction (P < 0.001). The mean duration from device reimplant to repeated extraction procedures was 63 ± 48 months. Ninety‐eight percent of the leads were removed completely in repeated procedures, similar to the 95% success rate of the first procedure (P = 0.51). There was no significant difference in major complication rate in the first or repeated extractions (2.6% vs 5.2%, P = 0.79).ConclusionsRepeated transvenous lead extraction is not uncommon. It had a high success rate comparable to that of the initial procedure and was not associated with an increased incidence of adverse events.

Acute liver failure (ALF) is a catastrophic condition that can occur after major liver resection. The aim of this study was to determine the effects of the spheroid reservoir bio‐artificial liver (SRBAL) on survival, serum chemistry, and liver regeneration in posthepatectomy ALF pigs. Wild‐type large white swine (20 kg‐30 kg) underwent intracranial pressure (ICP) probe placement followed by 85% hepatectomy. Computed tomography (CT) volumetrics were performed to measure the extent of resection, and at 48 hours following hepatectomy to assess regeneration of the remnant liver. Animals were randomized into three groups based on treatment delivered 24‐48 hours after hepatectomy: Group1—standard medical therapy (SMT, n = 6); Group2—SMT plus bio‐artificial liver treatment using no hepatocytes (0 g, n = 6); and Group3—SMT plus SRBAL treatment using 200 g of primary porcine hepatocyte spheroids (200 g, n = 6). The primary endpoint was survival to 90 hours following hepatectomy. Death equivalent was defined as unresponsive grade 4 hepatic encephalopathy or ICP greater than 20 mmHg with clinical evidence of brain herniation. All animals in both (SMT and 0 g) control groups met the death equivalent before 51 hours following hepatectomy. Five of 6 animals in the 200‐g group survived to 90 hours ( P < 0.01). The mean ammonia, ICP, and international normalized ratio values were significantly lower in the 200‐g group. CT volumetrics demonstrated increased volume regeneration at 48 hours following hepatectomy in the 200‐g group compared with the SMT ( P < 0.01) and 0‐g (P < 0.01) groups. Ki‐67 staining showed increased positive staining at 48 hours following hepatectomy ( P < 0.01). Conclusion: The SRBAL improved survival, reduced ammonia, and accelerated liver regeneration in posthepatectomy ALF. Improved survival was associated with a neuroprotective benefit of SRBAL therapy. These favorable results warrant further clinical testing of the SRBAL.