Divyansh Agarwal

Evaluating the gray and white matter energy budgets of human brain function

The insatiable appetite for energy to support human brain function is mainly supplied by glucose oxidation (CMRglc(ox)). But how much energy is consumed for signaling and nonsignaling processes in gray/white matter is highly debated. We examined this issue by combining metabolic measurements of gray/white matter and a theoretical calculation of bottom-up energy budget using biophysical properties of neuronal/glial cells in conjunction with species-exclusive electrophysiological and morphological data. We calculated a CMRglc(ox)-derived budget and confirmed it with experimental results measured by PET, autoradiography, 13C-MRS, and electrophysiology. Several conserved principles were observed regarding the energy costs for brain’s signaling and nonsignaling components in both human and rat. The awake resting cortical signaling processes and mass-dependent nonsignaling processes, respectively, demand ∼70% and ∼30% of CMRglc(ox). Inhibitory neurons and glia need 15–20% of CMRglc(ox), with the rest demanded by excitatory neurons. Nonsignaling demands dominate in white matter, in near opposite contrast to gray matter demands. Comparison between 13C-MRS data and calculations suggests ∼1.2 Hz glutamatergic signaling rate in the awake human cortex, which is ∼4 times lower than signaling in the rat cortex. Top-down validated bottom-up budgets could allow computation of anatomy-based CMRglc(ox) maps and accurate cellular level interpretation of brain metabolic imaging.

Analysis of National Institutes of Health Funding to Departments of Urology

OBJECTIVE To elucidate the current portfolio of National Institutes of Health (NIH) funding to departments of urology at U.S. medical schools. MATERIALS AND METHODS The NIH Research Portfolio Online Reporting Tools Expenditures and Results was used to generate a comprehensive analysis of NIH research grants awarded to urology departments during 2014. Costs, mechanisms, and institutes were summarized with descriptive statistics. Demographic data were obtained for principal investigators and project abstracts were categorized by research type and area. Fiscal totals were calculated for 2005-2014 and compared with other surgical departments during 2014. RESULTS One hundred one investigators at 36 urology departments received

Craniofacial Surgery Fellowship Websites.

55,564,952 in NIH funding during 2014. NIH-funded investigators were predominately male (79%) and PhD scientists (52%). Funding totals did not vary by terminal degree or sex, but increased with higher academic rank (P < .001). The National Cancer Institute (54.7%) and National Institute of Diabetes and Digestive and Kidney Diseases (32.2%) supported the majority of NIH-funded urologic research. The R01 grant accounted for 41.0% of all costs. The top 3 NIH-funded clinical areas were urologic oncology (62.1%), urinary tract infection (8.8%), and neurourology (7.6%). A minority of costs supported clinical research (12.9%). In 2014, urology had the least number of NIH grants relative to general surgery, ophthalmology, obstetrics & gynecology, otolaryngology, and orthopedic surgery. CONCLUSION NIH funding to urology departments lags behind awards to departments of other surgical disciplines. Future interventions may be warranted to increase NIH grant procurement in urology.

Characterization of DNA variants in the human kinome in breast cancer

AbstractApplicants for craniofacial surgery fellowships utilize Internet-based resources like the San Francisco (SF) Match to manage applications. The purpose of this study was to evaluate the accessibility and content of craniofacial surgery fellowship websites (CSFWs). A list of available craniofacial surgery fellowships was compiled from directories of the American Society of Craniofacial Surgery (ACSFS) and SF Match. Accessibility of CSFWs was assessed via links from these directories and a Google search. Craniofacial surgery fellowship websites were evaluated on education and recruitment content and compared via program characteristics. Twenty-four of the 28 US-based craniofacial surgery fellowship programs had a CSFW (86%). The ACSFS and SF Match databases had limited CSFW accessibility, but a Google search revealed most CSFWs had the top search result (76%). In total, CSFWs provided an average of 39% of education and recruitment variables. While most programs provided fellowship program descriptions (96%), application links (96%), and faculty listings (83%), relatively few provided rotation schedules (13%), fellow selection process information (13%), or interview dates (8%). CSFW content did not vary by program location, faculty size, accreditation status, or institutional affiliations (P > 0.05). Craniofacial surgery fellowships often lack readily accessible websites from national program lists and have limited information for interested applicants. The consistent lack of online information across programs suggests future opportunities exist to improve these educational resources.

Signal sequences in the genome of Mononegavirales regulate the generation of copy-back defective viral genomes

Kinases play a key role in cancer biology, and serve as potential clinically useful targets for designing cancer therapies. We examined nucleic acid variations in the human kinome and several known cancer-related genes in breast cancer. DNA was extracted from fine needle biopsies of 73 primary breast cancers and 19 metastatic lesions. Targeted sequencing of 518 kinases and 68 additional cancer related genes was performed using the SOLiD sequencing platform. We detected 1561 unique, non-synonymous variants in kinase genes in the 92 cases, and 74 unique variants in 43 kinases that were predicted to have major functional impact on the protein. Three kinase groups—CMGC, STE and TKL—showed greater mutational load in metastatic compared to primary cancer samples, however, after correction for multiple testing the difference was significant only for the TKL group (P = 0.04). We also observed that a higher proportion of histologic grade 1 and 2 cases had high functional impact variants in the SCYL2 gene compared with grade 3 cases. Our findings indicate that individual breast cancers harbor a substantial number of potentially functionally important nucleotide variations in kinase genes, most of which are present in unique combinations and include both somatic and germline functional variants.

Immune response to influenza vaccination in the elderly is altered by chronic medication use

Copy-back defective viral genomes (cbDVGs) are the primary initiators of antiviral immunity during infection with respiratory syncytial virus (RSV), parainfluenza virus, and other common pathogens. However, the mechanism governing cbDVG generation remains unknown limiting our ability to manipulate their content during infection. Here we developed VODKA (Viral Opensource DVG Key Algorithm) to identify cbDVGs from RNA-Seq data from infected samples and used these DVG sequences to identify signals that regulate cbDVG generation. After validation using data from an in vitro Sendai virus infection and Ebola virus-infected non-human primates, we applied VODKA to datasets from RSV-positive patients. VODKA identified common cbDVGs across multiple samples, and predicted specific genomic regions that mediate RSV cbDVG formation. Using an RSV minigenome system, we demonstrate that these viral sequences drive cbDVG wroduction. Importantly, the region involved in polymerase rejoin and reinitiation was highly conserved and its nucleotide composition determined the quality of cbDVGs generated. Our results indicate that generation of cbDVGs during natural infection is regulated by specific viral sequences and open the possibility to manipulate DVG formation during infection.

Functional germline variants as potential co-oncogenes

BackgroundThe elderly patient population is the most susceptible to influenza virus infection and its associated complications. Polypharmacy is common in the aged, who often have multiple co-morbidities. Previous studies have demonstrated that commonly used prescription drugs can have extensive impact on immune defenses and responses to vaccination. In this study, we examined how the dynamics of immune responses to the two influenza A virus strains of the trivalent inactivated influenza vaccine (TIV) can be affected by patient’s history of using the prescription drugs Metformin, NSAIDs or Statins.ResultsWe provide evidence for differential antibody (Ab) production, B-cell phenotypic changes, alteration in immune cell proportions and transcriptome-wide perturbation in individuals with a history of long-term medication use, compared with non-users. We noted a diminished response to TIV in the elderly on Metformin, whereas those on NSAIDs or Statins had higher baseline responses but reduced relative increases in virus-neutralizing Abs (VNAs) or Abs detected by an enzyme-linked immunosorbent assay (ELISA) following vaccination.ConclusionCollectively, our findings suggest novel pathways that might underlie how long-term medication use impacts immune response to influenza vaccination in the elderly. They provide a strong rationale for targeting the medication-immunity interaction in the aged population to improve vaccination responses.

Assessing cost-utility of predictive biomarkers in oncology: a streamlined approach

Germline variants that affect the expression or function of proteins contribute to phenotypic variation in humans and likely determine individual characteristics and susceptibility to diseases including cancer. A number of high penetrance germline variants that increase cancer risk have been identified and studied, but germline functional polymorphisms are not typically considered in the context of cancer biology, where the focus is primarily on somatic mutations. Yet, there is evidence from familial cancers indicating that specific cancer subtypes tend to arise in carriers of high-risk germline variants (e.g., triple negative breast cancers in mutated BRCA carriers), which suggests that pre-existing germline variants may determine which complementary somatic driver mutations are needed to drive tumorigenesis. Recent genome sequencing studies of large breast cancer cohorts reported only a handful of highly recurrent driver mutations, suggesting that different oncogenic events drive individual cancers. Here, we propose that germline polymorphisms can function as oncogenic modifiers, or co-oncogenes, and these determine what complementary subsequent somatic events are required for full malignant transformation. Therefore, we propose that germline aberrations should be considered together with somatic mutations to determine what genes drive cancer and how they may be targeted.

Functional polymorphisms in cancer.

Abstract Evaluation of cost-utility is critical in assessing the medical utility of predictive or prognostic biomarkers. Current methods involve complex state-transition models, requiring comprehensive data inputs. We propose a simplified decision-analytic tool to explore the relative effect of factors contributing to the cost-utility of a biomarker. We derived a cost-utility metric, the “test incremental cost-effectiveness ratio” (TICER) for biomarker-guided treatment compared to no biomarker use. This method uses data inputs readily accessible through clinical literature. We compared our results with traditional cost-effectiveness analysis of predictive biomarkers for established (HER2-guided trastuzumab, ALK-guided crizotinib, OncotypeDX-guided adjuvant chemotherapy) and emerging (ROS1-guided crizotinib) targeted treatments. We conducted sensitivity analysis to determine which factors had the greatest impact on TICER estimates. Base case TICER for HER2 was

Semblance: A Rank-Based Kernel on Probability Spaces for Niche Detection.

149,600/quality-adjusted life year (QALY), for ALK was