Identification of Germline Variants in Tumor Genomic Sequencing Analysis

This Correspondence relates to the article by Li et al (Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and the College of American Pathologists. J Mol Diagn 2017, 19:4–23)

Identifying transcriptional profiles and evaluating prognostic biomarkers of HIV-associated diffuse large B-cell lymphoma from Malawi

Lymphoma incidence in sub-Saharan Africa (SSA) is increasing due to HIV and population aging. Diffuse Large B-cell lymphoma (DLBCL), the most common lymphoma in SSA and worldwide, is highly associated with HIV, but molecular studies of HIV-associated DLBCL are scarce globally. We describe profiling of DLBCL from Malawi, aiming to elucidate tumor biology and identify clinically meaningful biomarkers specifically for SSA. Between June 1, 2013 and June 1, 2016, 59 cases of DLBCL (32 HIV+/27 HIV−) enrolled in the Kamuzu Central Hospital Lymphoma Study were characterized, of which 54 (92%) were negative for Epstein–Barr virus. Gene expression profiling (GEP) by whole transcriptome sequencing was performed on the first 36 cases (22 HIV+/14 HIV−). Immunohistochemistry (IHC) and GEP results were compared with published data and correlated to clinical outcome and pathologic features. Unsupervised clustering strongly segregated DLBCL by HIV status (p = 0.0003, Chi-squared test), indicating a marked contribution of HIV to expression phenotype. Pathway analysis identified that HIV-associated tumors were enriched in hypoxia, oxidative stress, and metabolism related gene expression patterns. Cell-of-origin subtype, determined by sequencing and IHC, did not associate with differences in overall survival (OS), while Ki-67 proliferation index ≥80% was associated with inferior OS in HIV+ DLBCL only (p = 0.03) and cMYC/BCL2 co-expression by IHC was negatively prognostic across the entire cohort (p = 0.01). This study provides among the first molecular characterizations of DLBCL from SSA, demonstrates marked gene expression differences by HIV status, and identifies genomic and immunophenotypic characteristics that can inform future basic and clinical investigations

The High Magnetic Field Phase Diagram of a Quasi-One Dimensional Metal

We present a unique high magnetic field phase of the quasi-one dimensional organic conductor (TMTSF)$_2$ClO$_4$. This phase, termed "Q-ClO$_4$", is obtained by rapid thermal quenching to avoid ordering of the ClO$_4$ anion. The magnetic field dependent phase of Q-ClO$_4$ is distinctly different from that in the extensively studied annealed material. Q-ClO$_4$ exhibits a spin density wave (SDW) transition at $\approx$ 5 K which is strongly magnetic field dependent. This dependence is well described by the theoretical treatment of Bjelis and Maki. We show that Q-ClO$_4$ provides a new B-T phase diagram in the hierarchy of low-dimensional organic metals (one-dimensional towards two-dimensional), and describe the temperature dependence of the of the quantum oscillations observed in the SDW phase.Comment: 10 pages, 4 figures, preprin

An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma

The incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing and implicated in more than 60% of all oropharyngeal carcinomas (OPSCCs). Although whole-genome, transcriptome, and proteome analyses have identified altered signaling pathways in HPV-induced HNSCCs, additional tools are needed to investigate the unique pathobiology of OPSCC. Herein, bioinformatics analyses of human HPV(+) HNSCCs revealed that all tumors express full-length E6 and identified molecular subtypes based on relative E6 and E7 expression levels. To recapitulate the levels, stoichiometric ratios, and anatomic location of E6/E7 expression, we generated a genetically engineered mouse model whereby balanced expression of E6/E7 is directed to the oropharyngeal epithelium. The addition of a mutant PIK3CAE545K allele leads to the rapid development of pre-malignant lesions marked by immune cell accumulation, and a subset of these lesions progress to OPSCC. This mouse provides a faithful immunocompetent model for testing treatments and investigating mechanisms of immunosuppression

Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays

Purpose: In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing (NGS) assays should adequately reflect the burden of somatic mutations in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired Foundation Medicine NGS assays. Experimental Design: This was a retrospective cohort study of individuals undergoing NGS of solid tumors from two large cancer centers. We identified and quantified mutations in genes known to be frequently altered in clonal hematopoiesis (DNMT3A, TET2, ASXL1, TP53, ATM, CHEK2, SF3B1, CBL, JAK2) that were returned to physicians on clinical Foundation Medicine reports. For a subset of patients, we explored the frequency of true clonal hematopoiesis by comparing mutations on Foundation Medicine reports with matched blood sequencing. Results: Mutations in genes that are frequently altered in clonal hematopoiesis were identified in 65% (1,139/1,757) of patients undergoing NGS. When excluding TP53, which is often mutated in solid tumors, these events were still seen in 35% (619/1,757) of patients. Utilizing paired blood specimens, we were able to confirm that 8% (18/226) of mutations reported in these genes were true clonal hematopoiesis events. The majority of DNMT3A mutations (64%, 7/11) and minority of TP53 mutations (4%, 2/50) were clonal hematopoiesis. Conclusions: Clonal hematopoiesis mutations are commonly reported on unpaired NGS testing. It is important to recognize clonal hematopoiesis as a possible cause of misattribution of mutation origin when applying NGS findings to a patient's care

Evidence of Color Coherence Effects in W+jets Events from ppbar Collisions at sqrt(s) = 1.8 TeV

We report the results of a study of color coherence effects in ppbar collisions based on data collected by the D0 detector during the 1994-1995 run of the Fermilab Tevatron Collider, at a center of mass energy sqrt(s) = 1.8 TeV. Initial-to-final state color interference effects are studied by examining particle distribution patterns in events with a W boson and at least one jet. The data are compared to Monte Carlo simulations with different color coherence implementations and to an analytic modified-leading-logarithm perturbative calculation based on the local parton-hadron duality hypothesis.Comment: 13 pages, 6 figures. Submitted to Physics Letters

Chronic Stress, Sense of Belonging, and Depression Among Survivors of Traumatic Brain Injury

To test whether chronic stress, interpersonal relatedness, and cognitive burden could explain depression after traumatic brain injury (TBI). Design : A nonprobability sample of 75 mild-to-moderately injured TBI survivors and their significant others, were recruited from five TBI day-rehabilitation programs. All participants were within 2 years of the date of injury and were living in the community. Methods : During face-to-face interviews, demographic information, and estimates of brain injury severity were obtained and participants completed a cognitive battery of tests of directed attention and short-term memory, responses to the Perceived Stress Scale, Interpersonal Relatedness Inventory, Sense of Belonging Instrument, Neurobehavioral Functioning Inventory, and Center for Epidemiological Studies Depression Scale;. Findings : Chronic stress was significantly and positively related to post-TBI depression. Depression and postinjury sense of belonging were negatively related. Social support and results from the cognitive battery did not explain depression. Conclusions : Postinjury chronic stress and sense of belonging were strong predictors of post-injury depression and are variables amenable to interventions by nurses in community health, neurological centers, or rehabilitation clinics. Future studies are needed to examine how these variables change over time during the recovery process.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72593/1/j.1547-5069.2002.00221.x.pd

Transitory Microbial Habitat in the Hyperarid Atacama Desert

Traces of life are nearly ubiquitous on Earth. However, a central unresolved question is whether these traces always indicate an active microbial community or whether, in extreme environments, such as hyperarid deserts, they instead reflect just dormant or dead cells. Although microbial biomass and diversity decrease with increasing aridity in the Atacama Desert, we provide multiple lines of evidence for the presence of an at times metabolically active, microbial community in one of the driest places on Earth. We base this observation on four major lines of evidence: a physico-chemical characterization of the soil habitability after an exceptional rain event, identified biomolecules indicative of potentially active cells [e.g., presence of ATP, phospholipid fatty acids (PLFAs), metabolites, and enzymatic activity], measurements of in situ replication rates of genomes of uncultivated bacteria reconstructed from selected samples, and microbial community patterns specific to soil parameters and depths. We infer that the microbial populations have undergone selection and adaptation in response to their specific soil microenvironment and in particular to the degree of aridity. Collectively, our results highlight that even the hyperarid Atacama Desert can provide a habitable environment for microorganisms that allows them to become metabolically active following an episodic increase in moisture and that once it decreases, so does the activity of the microbiota. These results have implications for the prospect of life on other planets such as Mars, which has transitioned from an earlier wetter environment to today's extreme hyperaridity. [Abstract copyright: Copyright © 2018 the Author(s). Published by PNAS.