Citations

Abstract Recently, Wilson et al. (doi:10.1038/onc.2013.396) found that EYA4 was frequently inactivated biallelically in sporadic lung cancer, displays tumor suppressor gene-like properties and affects DNA repair, and that 5 of 17 common SNPs in this 0.3Mb region showed nominal association to familial lung cancer (FLC, p<0.05) although these associations are not genome-wide significant after correction for multiple testing.. However, this is an interesting candidate gene for FLC risk because it is located on chromosome 6q in a region where we previously showed evidence of linkage to FLC (PMID: 15272417, 20215501). Here, we sequenced 75 individuals from our 9 most strongly 6q-linked families, using Illumina technology and a custom Agilent kit to capture 37Mb of chromosome 6 from 130Mb to 167Mb. We closely examined a region around EYA4, between 133Mb and 135Mb. This region contains a number of other genes in addition to EYA4, including the Vanin cluster; ribosomal protein S12; the tumor suppressor gene TCF21 and its antisense RNA TARID which directs methylation and activation of TCF21; solute carriers SLC18B1 and SLC2A12 and the serum/glucocorticoid regulated kinase SGK1. To detect sharing of variants among affecteds in each family while allowing for phenocopies, singlepoint affected-only linkage analysis was performed on lung cancer affection status for all sequence variants using the Elston-Stewart algorithm implemented in the R package paramlink assuming penetrance of 0.01, 0.1 and 0.1 for dd/Dd/DD and a disease allele (D) frequency of 0.01, at a recombination fraction (theta) of 0. The highest total LOD score (summed over all 9 families) in the entire 37Mb targeted region was not near EYA4. In only one family was there any variant in EYA4 that appeared on the linked haplotype with close to the highest family-specific LOD score: Family 30 had a LOD of 0.6514 at several EYA4 variants (max LOD across region 0.6519). However, many variants across the region had similar LODs. In the remaining families, all EYA4 variants had LODs much lower than the maximum family-specific LOD score in the region. Thus, EYA4 variants are unlikely to explain our 6q linkage peak in these 6q-linked families. The second highest total LOD score for the entire 37Mb targeted region was found near EYA4 at 133.9Mb (LOD = 3.82), in the middle of the TARID antisense RNA gene. This variant appears to be entirely novel, as it is not present in any of the online variant databases, such as NHLBI's ESP or 1000 Genomes. In two families, the family LOD score at this locus was at or close to the highest in the region: in Family 44 the LOD score was 1.206 (max LOD across entire region 1.207) and in Family 35 the LOD score was 0.3958 (max LOD across region 0.3959). Therefore this variant in the TARID antisense RNA is a candidate in some of our families most strongly linked to chromosome 6q. Citation Format: Joan E. Bailey-Wilson, Claire L. Simpson, Susan M. Pinney, Mariza de Andrade, Colette Gaba, Ping Yang, Ming You, Elena Y. Kupert, Ann G. Schwartz, Diptasri Mandal, Christopher I. Amos, Marshall W. Anderson. Evaluation of EYA4 as a candidate risk locus in familial lung cancer families linked to 6q. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2757. doi:10.1158/1538-7445.AM2015-2757

Abstract Emerging evidence demonstrates that the DNA repair kinase DNA-PK exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PK functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PK inhibits tumor metastases. Clinical assessment revealed that DNA-PK is significantly elevated in advanced disease, and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PK in advanced tumors is highly activated, independently of DNA damage indicators. Combined, these findings put forth new paradigms for DNA-PK function, identify DNA-PK as a potent driver of tumor progression and metastases, and nominate DNA-PK as a therapeutic target for advanced malignancies. Citation Format: Jonathan F. Goodwin, Vishal Kothari, Justin M. Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher McNair, Michael S. Magee, Robert B. Den, Ziqi Zhu, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen. DNA-PK-mediated transcriptional regulation drives tumor progression and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1860. doi:10.1158/1538-7445.AM2015-1860

Objectives: Patients with patellar instability and tibial tubercle to trochlear groove (TT-TG) distances ≥ 20 mm are often considered to have pathologic lateralization of the tibial tubercle (TT) relative to the femoral trochlea and may be candidates for TT realignment surgery. Although this variable has proven valuable in predicting risk of recurrent dislocations, the measure is limited in that it is not individualized to the patient and does not consider patient size, bony morphology, or patellofemoral mechanics. The purpose of this study was to develop a Patellar Instability Ratio (PIR) that predicts the risk of recurrent instability based on the TT-TG distance relative to patient specific anatomy. Methods: Fifty-nine patients with a clinical diagnosis of patellar instability were included in the study. A number of measures were calculated on MRI by two observers (one staff orthopedic surgeon and one senior resident) in a blinded and randomized fashion. Variables analyzed included: TT-TG, tibial tubercle to posterior cruciate ligament distance (TT-PCL), sagittal patellar length (PL), sagittal trochlear length (TL), axial patellar width (PW), axial trochlear width (TW), sagittal patellofemoral engagement (SPE; SPE=TL/PL) and axial patellofemoral engagement (APE; APE=PW/TW). Patients were divided into two groups: those with ≤ 1 dislocation and those with ≥ 2 dislocations. Using these groups, the ability of TT-TG, TT-PCL, and 12 different ratios with cut-off values to predict recurrent instability was assessed by calculating odds ratios (OR), C-statistics, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each of the ratios. P values < 0.05 were considered significant. Results: Mean follow up was 6.6 years. Twelve patients (20%) did not experience recurrent instability while 47 (80%) sustained two or more dislocations during the study period. Pathologic TT-TG (≥ 20 mm) was predictive of recurrent instability with an OR of 5.38 (p=0.29). The highest OR's for recurrent instability were noted for TT-TG/PW ≥ 0.40 (OR > 7.37, p=0.02) and TT-TG/TW ≥ 0.5 (OR 8.88, p=0.04)(Table 1). PW was defined as the largest medial to lateral width of the articular surface of the patella. TW is defined as the largest articular width of the trochlea that is articulating with the patella and can be conceptualized as the “jump distance” that must be overcome for the patella to dislocate. The sensitivity and specificity of TT-TG/PW ratio ≥ 0.40 was 61% and 83% and that of TT-TG/TW ≥ 0.50 was 59% and 92%, respectively. PPV for TT-TG/PW ≥ 0.40 was 94% while that of TT-TG/TW ≥ 0.49 was 97%. Conclusion: Two distinct PIR (TT-TG/PW and TT-TG/TW) have been identified that predict recurrent patellar instability more accurately than TT-TG ≥ 20 mm with PPV's ≥ 94% and OR's > 7 for both measures. These ratios take into consideration the TT-TG relative to patient specific size and anatomy. Further research is needed to determine if patients with increased PIR benefit from TT osteotomy.

Background: The morphologic characteristics of the labrum in patients with symptomatic acetabular dysplasia have been described to some extent in smaller retrospective series, but the need remains to further define these disease characteristics and their importance as a diagnostic feature of hip instability. Purpose: To (1) characterize the morphologic characteristics of the labrum in patients with symptomatic acetabular dysplasia and (2) test the relationships between specific labral variants, severity of dysplasia, and duration of symptoms. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Thirteen surgeons from 10 centers enrolled patients undergoing periacetabular osteotomy (PAO) for symptomatic acetabular dysplasia from 2008 to 2014. Patient demographics, presenting characteristics, preoperative radiographic data, operative data, and intraoperative findings were prospectively collected and retrospectively reviewed. Results: A total of 942 patients (972 hips) met the initial inclusion criteria, with a mean age of 25.2 years (range, 9-51 years; 84% female, 16% male). In addition to having PAO, 52.6% of hips had an anterior arthrotomy and 19.8% had a hip arthroscopy either to perform an osteochondroplasty of the femoral head-neck junction or to address labral pathologic changes. Of these 553 hips in which the labrum was visualized, labral morphologic status was graded as hypertrophic in 50%, normal in 45%, hypoplastic in 4%, and ossified in less than 1%. Decreased lateral center-edge angle and anterior center-edge angle and increased acetabular inclination were associated with labral hypertrophy, but chronicity of symptoms was not. Of the 553 hips, 64% had tears of the labrum, with the majority being degenerative-type tears. Conclusion: Labral pathologic changes are common in patients with symptomatic acetabular dysplasia. Labral hypertrophy, however, is not a universal finding, particularly in hips with mild dysplasia, and therefore should not be considered a reliable diagnostic criterion for instability.

BackgroundWhile central obesity increases gastroesophageal reflux (GER) by mechanically disrupting the anti‐reflux barrier, limited data exist on pathways by which central obesity may potentiate esophageal injury by non‐mechanical means. Obesity has been associated with an impaired epithelial intestinal barrier.ObjectiveWe aimed to assess the influence of central obesity and reflux on the squamous esophageal epithelial intercellular space diameter (ICSD).MethodsThe ICSD was measured using electron microscopy in esophageal biopsies from individuals who underwent ambulatory pH monitoring and endoscopy. Anthropometric measurements were obtained on all participants. Participants were classified into four groups: with and without central obesity and reflux.ResultsSixteen individuals were studied with four in each study group. The mean ICSD was almost three‐fold greater (p < 0.001) in the group with central obesity without reflux, compared to controls without central obesity and reflux. It was also comparable to the ICSD in groups with acid reflux only and those with both reflux and central obesity.ConclusionsThere is evidence of esophageal squamous ICSD increase in individuals with central obesity who do not have evidence of acid and nonacid reflux on ambulatory pH monitoring. This may reflect a mechanism by which central obesity potentiates reflux‐induced esophageal injury and inflammation.

AbstractIntroductionAlzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders.MethodsWe review the contributions of the MRI core from present and past cycles of ADNI (ADNI‐1, ‐Grand Opportunity and ‐2). We also review plans for the future‐ADNI‐3.ResultsContributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials.DiscussionOver the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future.

Background/Objectives. Vagal block therapy (vBloc) is effective for moderate to severe obesity at one year.Subjects/Methods. The ReCharge trial is a double-blind, randomized controlled clinical trial of 239 participants with body mass index (BMI) of 40 to 45 kg/m or 35 to 40 kg/m with one or more obesity-related conditions. Interventions were implantation of either vBloc or Sham devices and weight management counseling. Mixed models assessed percent excess weight loss (%EWL) and total weight loss (%TWL) in intent-to-treat analyses. At 18 months, 142 (88%) vBloc and 64 (83%) Sham patients remained enrolled in the study.Results. 18-month weight loss was 23% EWL (8.8% TWL) for vBloc and 10% EWL (3.8% TWL) for Sham (P<0.0001). vBloc patients largely maintained 12-month weight loss of 26% EWL (9.7% TWL). Sham regained over 40% of the 17% EWL (6.4% TWL) by 18 months. Most weight regain preceded unblinding. Common adverse events of vBloc through 18 months were heartburn/dyspepsia and abdominal pain; 98% of events were reported as mild or moderate and 79% had resolved.Conclusions. Weight loss with vBloc was sustained through 18 months, while Sham regained weight between 12 and 18 months. vBloc is effective with a low rate of serious complications.