Citations

Abstract Introduction Pancreatic cancer is a highly lethal malignancy due to late diagnosis and aggressiveness of the tumor. Characterization of high-risk populations for monitoring, intervention and early detection remains challenging. Obesity and diabetes are potentially modifiable contributors to pancreatic cancer. Genetic factors modifying the risk of obesity- and diabetes-induced pancreatic cancer have previously not been fully investigated at the genome-wide level. Hypothesis There are potential genetic factors modifying the associations between obesity/diabetes and pancreatic cancer. Methods Integrating genotype with risk factor data from a GWAS for the Pancreatic Cancer Case Control Consortium, we performed a genome-wide gene-environment interaction (G x E) scan for 457,688 SNPs in a discovery study of 2,028 cases and 2,109 controls using state-of-the-art methods including case-only (CO), case-control (CC), Empirical Hierarchical Bayes (EHB), Empirical-Bayes test (EB) and three 2-step approaches (DG2, EG2, DGEG2). Results We detected a genome-wide significant (P < 1.09 x 10-7 ) interaction of diabetes with rs13061928 (in CNTN4) in CO (P = 8.8 x 10-8 ), which was independent of diabetes in control group (P = 0.08). The minor allele was in a synergism with diabetes on the cancer risk: diabetics carrying GA/AA genotype had a 3.39-fold (95% CI: 2.47-4.65) increased disease risk compared with non-diabetics carrying GG genotype. Consistently, the SNP-diabetes interaction had a high ranking statistic in EHB (No.1) and high p-value ranks for EG2 and DGEG2 methods (No.1, P= 5.44 x 10-5). Conclusions These observations, once validated/confirmed, may help define at-risk subpopulation and initiate targeted intervention and prevention of pancreatic cancer. Genome-wide G x E analysis requires larger sample size than genetic main effects scan; combining the CO method with alternative methods may be the optimal scheme for genome-wide G x E analysis. Citation Format: Hongwei Tang, Eric J. Duell, Harvey A. Risch Risch, Sara H. Olson, H. Bas Bueno-de-Mesquita, Steven Gallinger, Elizabeth A. Holly, Gloria M. Petersen, Paige M. Bracci, Robert R. McWilliams, Mazda Jenab, Elio Riboli, Anne Tjønneland, Marie Christine Boutron-Ruault, Rudolf Kaaks, Dimitrios Trichopoulos, Salvatore Panico, Malin Sund, Petra H. M Peeters, Kay-Tee Khaw, Christopher I Amos, Donghui Li, Peng Wei. Genome-wide gene-diabetes and gene-obesity interaction scan in the pancreatic cancer case control consortium. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2214. doi:10.1158/1538-7445.AM2014-2214

BACKGROUND Although hypogammaglobulinemia is a well recognized complication in patients with chronic lymphocytic leukemia (CLL), its prevalence at the time of CLL diagnosis, and association with novel prognostic markers and clinical outcome is not well understood. METHODS All patients at the Mayo Clinic between January 1999 and July 2013 who had newly diagnosed CLL and had a baseline assessment of serum immunoglobulin G (IgG) were included. The relation between hypogammaglobulinemia at diagnosis and the novel prognostic parameters time to first treatment (TFT) and overall survival (OS) were evaluated. RESULTS Of 1485 patients who met the eligibility criteria, 382 (26%) had hypogammaglobulinemia (median IgG, 624 mg/dL), whereas the remaining 1103 patients (74%) had normal serum IgG levels (median IgG, 1040 mg/dL). Patients who had hypogammaglobulinemia at diagnosis were more likely to have advanced Rai stage (III‐IV; P = .001) and higher expression of CD49d ( P < .001) compared with patients who had normal IgG levels. Although the median TFT for patients who had hypogammaglobulinemia was shorter compared with that for patients who had normal IgG levels (3.8 years vs 7.4 years; P < .001), on multivariable analysis, there was no difference in OS between these 2 groups (12.8 years vs 11.3 years, respectively; P = .73). Of 1103 patients who had CLL with normal IgG levels at diagnosis and who did not receive CLL therapy, the risk of acquired hypogammaglobulinemia was 11% at 5 years and 23% at 10 years. CONCLUSIONS Hypogammaglobulinemia is present in 25% of patients with newly diagnosed CLL. Approximately 25% of patients who have CLL with normal IgG levels at diagnosis will subsequently develop hypogammaglobulinemia on long‐term follow‐up. The presence of hypogammaglobulinemia does not appear to impact overall survival. Cancer 2015;121:2883–2891. © 2015 American Cancer Society .

SummaryAimsNeurodegenerative disorders are caused by progressive neuronal loss in the brain, and hence, compounds that could promote neuritogenesis may have therapeutic values. In this study, the effects of bis(heptyl)‐cognitin (B7C), a multifunctional dimer, on neurite outgrowth were investigated in both PC12 cells and primary cortical neurons.MethodsImmunocytochemical staining was used to evaluate the proneuritogenesis effects, and Western blot and short hairpin RNA assays were applied to explore the underlying mechanisms.ResultsB7C (0.1–0.5 μM) induced robust neurite outgrowth in PC12 cells, as evidenced by the neurite‐bearing morphology and upregulation of growth‐associated protein‐43 expression. In addition, B7C markedly promoted neurite outgrowth in primary cortical neurons as shown by the increase in the length of β‐III‐tubulin‐positive neurites. Furthermore, B7C rapidly increased ERK phosphorylation. Specific inhibitors of alpha7‐nicotinic acetylcholine receptor (α7‐nAChR) and MEK, but not those of p38 or JNK, blocked the neurite outgrowth as well as ERK phosphorylation induced by B7C. Most importantly, genetic depletion of α7‐nAChR significantly abolished B7C‐induced neurite outgrowth in PC12 cells.ConclusionB7C promoted neurite outgrowth through the activation of α7‐nAChR/ERK pathway, which offers novel insight into the potential application of B7C in the treatment of neurodegenerative disorders.

ABSTRACTAchilles tendon is one of the most commonly injured tendons. Mechanical force is regarded as a major causative factor. However, the biomechanics of Achilles tendon and mechanical mechanism of the injuries are unclear. Lubricin expresses at regions exposed to sliding motion and shear force in a number of tissues. This study investigated the distribution and concentration of lubricin in human Achilles tendons for better understanding the biomechanics of Achilles tendon. Achilles tendons were harvested from nine cadavers. Lubricin was extracted from various locations proximal to the calcaneal insertion and quantified with ELISA. The distribution of lubricin was investigated with immunohistochemistry. Lubricin was mainly identified at the interfaces of tendon fascicles, especially in the mid‐portion of the tendon. The concentration of lubricin in Achilles tendons varied by individual and the distance from its calcaneal insertion. The distal portion of the tendon had a higher concentration of lubricin than the proximal regions of the tendon. This study suggests the presence of intratendinous sliding motion of fascicles and shear force at interfaces of fascicles in human Achilles tendon. Shear force could be an important mechanical factor for the development of Achilles tendinopathy and rupture. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:932–937, 2015.

AimsEpithelioid haemangioendothelioma (EHE) is a malignant vascular neoplasm. Subsets have been characterized previously by translocations resulting in either WWTR1–CAMTA1 or YAP1–TFE3 fusion. We sought to develop molecular and immunohistochemical (IHC) assays to aid in the diagnosis and characterization of EHE.Methods and resultsFifty‐two formalin‐fixed, paraffin‐embedded (FFPE) cases diagnosed between 2002 and 2014 were retrieved from the pathology files of our institutions. Reverse transcription–polymerase chain reaction (RT–PCR) assays were optimized to detect WWTR1–CAMTA1 and YAP1–TFE3 fusion transcripts in FFPE tissue and transcription factor E3 (TFE3) protein accumulation was examined by immunohistochemistry (IHC). RNA was extracted from 33 adequate samples, with more recent cases providing a greater yield of high quality RNA. Fourteen of 18 informative cases were positive for WWTR1–CAMTA1 fusion transcripts, four of which showed higher‐grade cytological features termed by some as ‘malignant EHE’. Novel in‐frame fusion transcripts were identified in four cases by direct sequencing. IHC revealed variable nuclear TFE3 staining in six of 17 cases; three with patchy staining showed WWTR1–CAMTA1 fusion. One of 18 informative cases was positive for YAP1–TFE3 fusion and showed strong nuclear TFE3 staining by IHC.ConclusionsThis study confirms the high incidence of WWTR1–CAMTA1 and YAP1–TFE3 rearrangements in EHE and indicates that the staining pattern for TFE3 IHC is critical for specificity.

AbstractObjectivesDiffuse large B‐cell lymphoma (DLBCL) is an aggressive subtype of non‐Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. The first large‐scale genome‐wide association study (GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome‐wide significance, and two SNPs that showed a suggestive association with DLBCL risk.MethodsTo evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand.ResultsThree of the five genome‐wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome‐wide significance in our data (per allele OR = 2.04, 95% CI = 1.63–2.56; ptrend = 3.9 × 10−10). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR = 1.34, 95% CI = 1.19–1.52; ptrend = 2.1 × 10−6), which was the second strongest finding in the GWAS, and with HLA‐B rs2523607 (per allele OR = 3.05, 95% CI = 1.32–7.05; ptrend = 0.009).ConclusionsOur study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations.