Description: Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality. Methods: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes— BRIP1 , BARD1 , PALB2 and NBN —in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided. Results: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) ( P = 1 x 10 –4 and 8 x 10 –4 , respectively), but no differences for BARD1 ( P = .39), NBN1 ( P = .61), or PALB2 ( P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients ( P = 5.5 x 10 –4 ). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10 –4 ) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10 –5 ). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7 x 10 –7 ). Conclusions: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.

Description: Purpose: The role of infiltrating B cells in hepatocellular carcinoma has been overlooked for many years. This study is aimed to delineate the distribution, prognostic value, and functional status of B cells in human hepatocellular carcinoma. Experimental design: Immunohistochemistry was used to investigate the distribution and clinical significance of infiltrating CD20 + B cells in a series of 120 patients with hepatocellular carcinoma. The results were further tested in an independent series of 200 patients with hepatocellular carcinoma. The functional status of CD20 + B cells was determined by flow cytometry, immunofluorescence, and in vitro coculture assay. Results: Infiltrating CD20 + B cells were predominantly concentrated in the tumor invasive margin, compared with the peri- and intratumor areas. High density of margin-infiltrating B lymphocytes (MIL-B) positively correlated with small tumor size, absence of vascular invasion, and increased density of CD8 + T cells ( P 〈 0.05). Survival analyses revealed that increased number of MIL-Bs and their penetration through the tumor capsule were significantly associated with improved overall and recurrence-free survival, and were identified as independent prognosticators for patients with hepatocellular carcinoma ( P 〈 0.05). Importantly, the results were further validated in another independent hepatocellular carcinoma cohort. Moreover, we found that MIL-Bs featured an atypical memory phenotype (IgD – IgG + CD27 – CD38 – ), expressed surface markers characteristic of antigen-presenting cells, possessed tumor-killing potential by producing IFN-, interleukin 12p40 (IL-12p40), granzyme B, and TRAIL, and acted in cooperation with CD8 + T cells. Conclusions: The profile of CD20 + B cells in situ is a new predictor of prognosis for patients with hepatocellular carcinoma and provides a novel target for an optimal immunotherapy against this fatal malignancy. Clin Cancer Res; 19(21); 5994–6005. ©2013 AACR .

Description: Purpose: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET). Experimental Design: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors. Results: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, whereas microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, P 〈 0.001). ALT also strongly correlated with lymphovascular ( P 〈 0.001) and perineural invasion ( P = 0.001) and the presence of lymph node ( P 〈 0.001) and distant metastases ( P = 0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival [HR = 3.38; 95% confidence interval (CI), 1.83–6.27; P 〈 0.001]. Interestingly, when limiting to patients with distant metastases, those with ALT-positive primary tumors had significantly better overall survival (HR = 0.23; 95% CI, 0.08–0.68; P = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT ( P 〈 0.001), aggressive clinical behavior, and reduced recurrence-free survival ( P 〈 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival ( P = 0.003). Conclusions: Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of the disease. Clin Cancer Res; 23(6); 1598–606. ©2016 AACR .

Description: Due to increasing concerns about human infection by various H7 influenza viruses, including recent H7N9 viruses, we evaluated the genetic relationships and cross-protective efficacies of three different Eurasian H7 avian influenza viruses. Phylogenic and molecular analyses revealed that recent Eurasian H7 viruses can be separated into two different lineages, with relatively high amino acid identities within groups (94.8 to 98.8%) and low amino acid identities between groups (90.3 to 92.6%). In vivo immunization with representatives of each group revealed that while group-specific cross-reactivity was induced, cross-reactive hemagglutination inhibition (HI) titers were approximately 4-fold lower against heterologous group viruses than against homologous group viruses. Moreover, the group I (RgW109/06) vaccine protected 100% of immunized mice from various group I viruses, while only 20 to 40% of immunized mice survived lethal challenge with heterologous group II viruses and exhibited high viral titers in the lung. Moreover, while the group II (RgW478/14) vaccine also protected mice from lethal challenge with group II viruses, it failed to elicit cross-protection against group I viruses. However, it is noteworthy that vaccination with RgAnhui1/13, a virus of a sublineage of group I, cross-protected immunized mice against lethal challenge with both group I and II viruses and significantly attenuated lung viral titers. Interestingly, immune sera from RgAnhui1/13-vaccinated mice showed a broad neutralizing spectrum rather than the group-specific pattern observed with the other viruses. These results suggest that the recent human-infective H7N9 strain may be a candidate broad cross-protective vaccine for Eurasian H7 viruses. IMPORTANCE Genetic and phylogenic analyses have demonstrated that the Eurasian H7 viruses can be separated into at least two different lineages, both of which contain human-infective fatal H7 viruses, including the recent novel H7N9 viruses isolated in China since 2013. Due to the increasing concerns regarding the global public health risk posed by H7 viruses, we evaluated the genetic relationships between Eurasian H7 avian influenza viruses and the cross-protective efficacies of three different H7 viruses: W109/06 (group I), W478/14 (group II), and Anhui1/13 (a sublineage of group I). While each vaccine induced group-specific antibody responses and cross-protective efficacy, only Anhui1/13 was able to cross-protect immunized hosts against lethal challenge across groups. In fact, the Anhui1/13 virus induced not only cross-protection but also broad serum neutralizing antibody responses against both groups of viruses. This suggests that Anhui1/13-like H7N9 viruses may be viable vaccine candidates for broad protection against Eurasian H7 viruses.

Description: Vertebrate corpse decomposition provides an important stage in nutrient cycling in most terrestrial habitats, yet microbially mediated processes are poorly understood. Here we combine deep microbial community characterization, community-level metabolic reconstruction, and soil biogeochemical assessment to understand the principles governing microbial community assembly during decomposition of mouse and human corpses on different soil substrates. We find a suite of bacterial and fungal groups that contribute to nitrogen cycling and a reproducible network of decomposers that emerge on predictable time scales. Our results show that this decomposer community is derived primarily from bulk soil, but key decomposers are ubiquitous in low abundance. Soil type was not a dominant factor driving community development, and the process of decomposition is sufficiently reproducible to offer new opportunities for forensic investigations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metcalf, Jessica L -- Xu, Zhenjiang Zech -- Weiss, Sophie -- Lax, Simon -- Van Treuren, Will -- Hyde, Embriette R -- Song, Se Jin -- Amir, Amnon -- Larsen, Peter -- Sangwan, Naseer -- Haarmann, Daniel -- Humphrey, Greg C -- Ackermann, Gail -- Thompson, Luke R -- Lauber, Christian -- Bibat, Alexander -- Nicholas, Catherine -- Gebert, Matthew J -- Petrosino, Joseph F -- Reed, Sasha C -- Gilbert, Jack A -- Lynne, Aaron M -- Bucheli, Sibyl R -- Carter, David O -- Knight, Rob -- 3 R01 HG004872-03S2/HG/NHGRI NIH HHS/ -- 5 U01 HG004866-04/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2016 Jan 8;351(6269):158-62. doi: 10.1126/science.aad2646. Epub 2015 Dec 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO 80309, USA. Department of Pediatrics, University of California, San Diego, San Diego, CA 92037, USA. robknight@ucsd.edu jessica.metcalf@colorado.edu. ; Department of Pediatrics, University of California, San Diego, San Diego, CA 92037, USA. ; Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO 80303, USA. ; Department of Ecology and Evolution, University of Chicago, 1101 East 57th Street, Chicago, IL 60637, USA. Institute for Genomic and Systems Biology, University of Chicago, 900 East 57th Street, Chicago, IL 606037, USA. ; Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. ; Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO 80309, USA. Department of Pediatrics, University of California, San Diego, San Diego, CA 92037, USA. ; Department of Ecology and Evolution, University of Chicago, 1101 East 57th Street, Chicago, IL 60637, USA. Biosciences Division, Argonne National Laboratory, South Cass Avenue, Argonne, IL 60439, USA. ; Department of Ecology and Evolution, University of Chicago, 1101 East 57th Street, Chicago, IL 60637, USA. Biosciences Division, Argonne National Laboratory, South Cass Avenue, Argonne, IL 60439, USA. Department of Surgery, University of Chicago, A27 South Maryland Avenue, Chicago, IL 60637, USA. ; Department of Biological Sciences, Sam Houston State University, Huntsville, TX 77340, USA. ; Nestle Institute of Health Sciences, Ecole Polytechnique Federale Lausanne, Batiment H, 1015 Lausanne, Switzerland. ; BioFrontiers Institute, University of Colorado, Boulder, CO 80303, USA. ; Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. ; U.S. Geological Survey, Southwest Biological Science Center, Moab, UT 84532, USA. ; Department of Ecology and Evolution, University of Chicago, 1101 East 57th Street, Chicago, IL 60637, USA. Institute for Genomic and Systems Biology, University of Chicago, 900 East 57th Street, Chicago, IL 606037, USA. Biosciences Division, Argonne National Laboratory, South Cass Avenue, Argonne, IL 60439, USA. Department of Surgery, University of Chicago, A27 South Maryland Avenue, Chicago, IL 60637, USA. Marine Biological Laboratory, 7 MBL St, Woods Hole, MA 02543, USA. ; Laboratory of Forensic Taphonomy, Forensic Sciences Unit, Division of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI 96816, USA. ; Department of Pediatrics, University of California, San Diego, San Diego, CA 92037, USA. Department of Computer Science and Engineering, University of California, San Diego, San Diego, CA 92037, USA. robknight@ucsd.edu jessica.metcalf@colorado.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26657285" target="_blank"〉PubMed〈/a〉