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)

Emotional engagements predict and enhance social cognition in young chimpanzees

Social cognition in infancy is evident in coordinated triadic engagements, that is, infants attending jointly with social partners and objects. Current evolutionary theories of primate social cognition tend to highlight species differences in cognition based on human-unique cooperative motives. We consider a developmental model in which engagement experiences produce differential outcomes. We conducted a 10-year-long study in which two groups of laboratory-raised chimpanzee infants were given quantifiably different engagement experiences. Joint attention, cooperativeness, affect, and different levels of cognition were measured in 5- to 12-month-old chimpanzees, and compared to outcomes derived from a normative human database. We found that joint attention skills significantly improved across development for all infants, but by 12 months, the humans significantly surpassed the chimpanzees. We found that cooperativeness was stable in the humans, but by 12 months, the chimpanzee group given enriched engagement experiences significantly surpassed the humans. Past engagement experiences and concurrent affect were significant unique predictors of both joint attention and cooperativeness in 5- to 12-month-old chimpanzees. When engagement experiences and concurrent affect were statistically controlled, joint attention and cooperation were not associated. We explain differential social cognition outcomes in terms of the significant influences of previous engagement experiences and affect, in addition to cognition. Our study highlights developmental processes that underpin the emergence of social cognition in support of evolutionary continuity

An assessment of the carbon balance of Arctic tundra:Comparisons among observations, process models, and atmospheric inversions

Although Arctic tundra has been estimated to cover only 8% of the global land surface, the large and potentially labile carbon pools currently stored in tundra soils have the potential for large emissions of carbon (C) under a warming climate. These emissions as radiatively active greenhouse gases in the form of both CO<sub>2</sub> and CH<sub>4</sub> could amplify global warming. Given the potential sensitivity of these ecosystems to climate change and the expectation that the Arctic will experience appreciable warming over the next century, it is important to assess whether responses of C exchange in tundra regions are likely to enhance or mitigate warming. In this study we compared analyses of C exchange of Arctic tundra between 1990 and 2006 among observations, regional and global applications of process-based terrestrial biosphere models, and atmospheric inversion models. Syntheses of flux observations and inversion models indicate that the annual exchange of CO<sub>2</sub> between Arctic tundra and the atmosphere has large uncertainties that cannot be distinguished from neutral balance. The mean estimate from an ensemble of process-based model simulations suggests that Arctic tundra has acted as a sink for atmospheric CO<sub>2</sub> in recent decades, but based on the uncertainty estimates it cannot be determined with confidence whether these ecosystems represent a weak or a strong sink. Tundra was 0.6 °C warmer in the 2000s compared to the 1990s. The central estimates of the observations, process-based models, and inversion models each identify stronger sinks in the 2000s compared with the 1990s. Some of the process models indicate that this occurred because net primary production increased more in response to warming than heterotrophic respiration. Similarly, the observations and the applications of regional process-based models suggest that CH<sub>4</sub> emissions from Arctic tundra have increased from the 1990s to 2000s because of the sensitivity of CH<sub>4</sub> emissions to warmer temperatures. Based on our analyses of the estimates from observations, process-based models, and inversion models, we estimate that Arctic tundra was a sink for atmospheric CO<sub>2</sub> of 110 Tg C yr<sup>−1</sup> (uncertainty between a sink of 291 Tg C yr<sup>−1</sup> and a source of 80 Tg C yr<sup>−1</sup>) and a source of CH<sub>4</sub> to the atmosphere of 19 Tg C yr<sup>−1</sup> (uncertainty between sources of 8 and 29 Tg C yr<sup>−1</sup>). The suite of analyses conducted in this study indicate that it is important to reduce uncertainties in the observations, process-based models, and inversions in order to better understand the degree to which Arctic tundra is influencing atmospheric CO<sub>2</sub> and CH<sub>4</sub> concentrations. The reduction of uncertainties can be accomplished through (1) the strategic placement of more CO<sub>2</sub> and CH<sub>4</sub> monitoring stations to reduce uncertainties in inversions, (2) improved observation networks of ground-based measurements of CO<sub>2</sub> and CH<sub>4</sub> exchange to understand exchange in response to disturbance and across gradients of climatic and hydrological variability, and (3) the effective transfer of information from enhanced observation networks into process-based models to improve the simulation of CO<sub>2</sub> and CH<sub>4</sub> exchange from Arctic tundra to the atmosphere

Subjective memory complaints are associated with brain activation supporting successful memory encoding

Neuro Imaging Researc

Hamiltonian Light-Front Field Theory: Recent Progress and Tantalizing Prospects

Fundamental theories, such as Quantum Electrodynamics (QED) and Quantum Chromodynamics (QCD) promise great predictive power addressing phenomena over vast scales from the microscopic to cosmic scales. However, new non-perturbative tools are required for physics to span from one scale to the next. I outline recent theoretical and computational progress to build these bridges and provide illustrative results for Hamiltonian Light Front Field Theory. One key area is our development of basis function approaches that cast the theory as a Hamiltonian matrix problem while preserving a maximal set of symmetries. Regulating the theory with an external field that can be removed to obtain the continuum limit offers additional possibilities as seen in an application to the anomalous magnetic moment of the electron. Recent progress capitalizes on algorithm and computer developments for setting up and solving very large sparse matrix eigenvalue problems. Matrices with dimensions of 20 billion basis states are now solved on leadership-class computers for their low-lying eigenstates and eigenfunctions.Comment: 8 pages with 2 figure

An updated systematic review of the cost-effectiveness of therapies for metastatic breast cancer

Purpose: The goal of this systematic review is to provide an update to the review by Pouwels et al. by conducting a systematic review and an assessment of the reporting quality of the economic analyses conducted since 2014. Methods: This systematic review identified published articles focused on metastatic breast cancer treatment using the Medline/PubMed and Scopus databases and the following search criteria: (((cost effectiveness[MeSH Terms]) OR (cost effectiveness) OR (cost-effectiveness) OR (cost utility) OR (cost–utility) OR (economic evaluation)) AND ((“metastatic breast cancer”) OR (“advanced breast cancer”))). The reporting quality of the included articles was evaluated using the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results: Of the 256 identified articles, 67 of the articles were published after October 2014 when the prior systematic review stopped its assessment (Pouwels et al. in Breast Cancer Res Treat 165:485–498, 2017). From the 67 articles, we narrowed down to include 17 original health economic analyses specific to metastatic or advanced breast cancer. These articles were diverse with respect to methods employed and interventions included. Conclusion: Although each of the articles contributed their own analytic strengths and limitations, the overall quality of the studies was moderate. The review demonstrated that the vast majority of the reported incremental cost-effectiveness ratios exceeded the typically employed willingness to pay thresholds used in each country of analysis. Only three of the reviewed articles studied chemotherapies rather than treatments targeting either HER2 or hormone receptors, demonstrating a gap in the literature

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

Exceptional chemotherapy response in metastatic colorectal cancer associated with hyper-indel-hypermutated cancer genome and comutation of POLD1 and MLH1

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years.Wesequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients withPOLE- and/orPOLD1- mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G > A[p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel-hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy