Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers

The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Biomarkers in autism.

Autism spectrum disorders (ASDs) are complex, heterogeneous disorders caused by an interaction between genetic vulnerability and environmental factors. In an effort to better target the underlying roots of ASD for diagnosis and treatment, efforts to identify reliable biomarkers in genetics, neuroimaging, gene expression, and measures of the body's metabolism are growing. For this article, we review the published studies of potential biomarkers in autism and conclude that while there is increasing promise of finding biomarkers that can help us target treatment, there are none with enough evidence to support routine clinical use unless medical illness is suspected. Promising biomarkers include those for mitochondrial function, oxidative stress, and immune function. Genetic clusters are also suggesting the potential for useful biomarkers

Biomarkers in autism.

Autism spectrum disorders (ASDs) are complex, heterogeneous disorders caused by an interaction between genetic vulnerability and environmental factors. In an effort to better target the underlying roots of ASD for diagnosis and treatment, efforts to identify reliable biomarkers in genetics, neuroimaging, gene expression, and measures of the body's metabolism are growing. For this article, we review the published studies of potential biomarkers in autism and conclude that while there is increasing promise of finding biomarkers that can help us target treatment, there are none with enough evidence to support routine clinical use unless medical illness is suspected. Promising biomarkers include those for mitochondrial function, oxidative stress, and immune function. Genetic clusters are also suggesting the potential for useful biomarkers

Testing Time-Geographic Density Estimation for Home Range Analysis Using an Agent-Based Model of Animal Movement

Time-geographic density estimation (TGDE) is a method of movement pattern analysis that generates a continuous intensity surface from a set of tracking data. TGDE has recently been proposed as a method of animal home range estimation, where the goal is to delineate the spatial extents that an animal occupies. This paper tests TGDE’s effectiveness as a home range estimator using simulated movement data. First, an agent-based model is used to simulate tracking data under 16 movement scenarios representing a variety of animal life history traits (habitat preferences, homing behaviour, mobility) and habitat configurations (levels of habitat fragmentation). Second, the accuracy of TGDE is evaluated for four temporal sampling frequencies using three adaptive velocity parameters for 30 sample data sets from each scenario. Third, TGDE accuracy is compared to two other common home range estimation methods, kernel density estimation (KDE) and characteristic hull polygons (CHP). The results demonstrate that TGDE is the most effective at estimating core areas, home ranges and total areas at high sampling frequencies, while CHP performs better at low sampling frequencies. KDE was ineffective across all scenarios explored

Transportation, childcare, lodging, and meals: Key for participant engagement and inclusion of historically underrepresented populations in the healthy brain and child development birth cohort

Abstract Introduction: Participant recruitment and retention (R&R) are well-documented challenges in longitudinal studies, especially those involving populations historically underrepresented in research and vulnerable groups (e.g., pregnant people or young children and their families), as is the focus of the HEALthy Brain and Child Development (HBCD) birth cohort study. Subpar access to transportation, overnight lodging, childcare, or meals can compromise R&R; yet, guidance on how to overcome these “logistical barriers” is sparse. This study’s goal was to learn about the HBCD sites’ plans and develop best practice recommendations for the HBCD consortium for addressing these logistical barriers. Methods: The HBCD’s workgroups developed a survey asking the HBCD sites about their plans for supporting research-related transportation, lodging, childcare, and meals, and about the presence of institutional policies to guide their approach. Descriptive statistics described the quantitative survey data. Qualitative survey responses were brief, not warranting formal qualitative analysis; their content was summarized. Results: Twenty-eight respondents, representing unique recruitment locations across the U.S., completed the survey. The results indicated substantial heterogeneity across the respondents in their approach toward supporting research-related transportation, lodging, childcare, and meals. Three respondents were aware of institutional policies guiding research-related transportation (10.7%) or childcare (10.7%). Conclusions: This study highlighted heterogeneity in approaches and scarcity of institutional policies regarding research-related transportation, lodging, childcare, and meals, underscoring the need for guidance in this area to ensure equitable support of participant R&R across different settings and populations, so that participants are representative of the larger community, and increase research result validity and generalizability