Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles

Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.Merit Review Award, Medical Research Service, Department of Veterans AffairsUS Department of Veterans Affairs [I01 BX000545]; Veterans AffairsUS Department of Veterans Affairs [I01BX000545] Funding Source: NIH RePORTERPart of A. H.'s time was supported by a Merit Review Award (I01 BX000545), Medical Research Service, Department of Veterans Affairs

Chemical Characterization and Source Apportionment of Household Fine Particulate Matter in Rural, Peri-urban, and Urban West Africa

Household air pollution in sub-Saharan Africa and other developing regions is an important cause of disease burden. Little is known about the chemical composition and sources of household air pollution in sub-Saharan Africa, and how they differ between rural and urban homes. We analyzed the chemical composition and sources of fine particles (PM2.5) in household cooking areas of multiple neighborhoods in Accra, Ghana, and in peri-urban (Banjul) and rural (Basse) areas in The Gambia. In Accra, biomass burning accounted for 39–62% of total PM2.5 mass in the cooking area in different neighborhoods; the absolute contributions were 10–45 μg/m3. Road dust and vehicle emissions comprised 12–33% of PM2.5 mass. Solid waste burning was also a significant contributor to household PM2.5 in a low-income neighborhood but not for those living in better-off areas. In Banjul and Basse, biomass burning was the single dominant source of cooking-area PM2.5, accounting for 74–87% of its total mass; the relative and absolute contributions of biomass smoke to PM2.5 mass were larger in households that used firewood than in those using charcoal, reaching as high as 463 μg/m3 in Basse homes that used firewood for cooking. Our findings demonstrate the need for policies that enhance access to cleaner fuels in both rural and urban areas, and for controlling traffic emissions in cities in sub-Saharan Africa

Metformin Treatment Has No Beneficial Effect in a Dose-Response Survival Study in the SOD1G93A Mouse Model of ALS and Is Harmful in Female Mice

Background: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurological disorder characterized by selective degeneration of upper and lower motor neurons. The primary triggers for motor neuron degeneration are unknown but inflammation, oxidative stress and mitochondrial defects have been identified as potential contributing factors. Metformin is an anti-type II diabetes drug that has anti-inflammatory and anti-oxidant properties, can bring about mitochondrial biogenesis and has been shown to attenuate pathology in mouse models of Huntington’s disease and multiple sclerosis. We therefore hypothesized that it might increase survival in the SOD1G93A murine model of ALS. Methodology/Principal Findings: Treatment of male and female SOD1G93A mice (n = $6 per sex) with 2 mg/ml metformin in the drinking water from 35 days, resulted in a significant increase in motor unit survival, as measured by in vivo electrophysiology at 100 days, in male EDL muscles (24+/22 vs. 14+/22 motor units, p,0.005) and female TA muscles (21+/ 21 vs. 15+/22 motor units, P = 0.0134). We therefore continued to test the effect of 0.5, 2 and 5 mg/ml metformin in the drinking water from 35 days on disease onset and progression (identified by twice weekly determination of weight and neurological score) as well as survival in male and female SOD1G93A mice (n =$14 per sex). Results for all groups were compared using Kaplan-Meier time to event analyses. In this survival study, metformin was unable to reduce pathology at any dose and had an unexpected dose-dependent negative effect on the onset of neurological symptoms (P = 0.0236) and on disease progression (P = 0.0362) in female mice. Conclusions/Significance: This study suggests that metformin is a poor candidate for clinical trial in ALS patients and that the possibility of harmful effects of metformin in female ALS patients with type II diabetes should be investigated

Comparison of molecular testing strategies for COVID-19 control: a mathematical modelling study

BACKGROUND: WHO has called for increased testing in response to the COVID-19 pandemic, but countries have taken different approaches and the effectiveness of alternative strategies is unknown. We aimed to investigate the potential impact of different testing and isolation strategies on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We developed a mathematical model of SARS-CoV-2 transmission based on infectiousness and PCR test sensitivity over time since infection. We estimated the reduction in the effective reproduction number (R) achieved by testing and isolating symptomatic individuals, regular screening of high-risk groups irrespective of symptoms, and quarantine of contacts of laboratory-confirmed cases identified through test-and-trace protocols. The expected effectiveness of different testing strategies was defined as the percentage reduction in R. We reviewed data on the performance of antibody tests reported by the Foundation for Innovative New Diagnostics and examined their implications for the use of so-called immunity passports. FINDINGS: If all individuals with symptoms compatible with COVID-19 self-isolated and self-isolation was 100% effective in reducing onwards transmission, self-isolation of symptomatic individuals would result in a reduction in R of 47% (95% uncertainty interval [UI] 32-55). PCR testing to identify SARS-CoV-2 infection soon after symptom onset could reduce the number of individuals needing to self-isolate, but would also reduce the effectiveness of self-isolation (around 10% would be false negatives). Weekly screening of health-care workers and other high-risk groups irrespective of symptoms by use of PCR testing is estimated to reduce their contribution to SARS-CoV-2 transmission by 23% (95% UI 16-40), on top of reductions achieved by self-isolation following symptoms, assuming results are available at 24 h. The effectiveness of test and trace depends strongly on coverage and the timeliness of contact tracing, potentially reducing R by 26% (95% UI 14-35) on top of reductions achieved by self-isolation following symptoms, if 80% of cases and contacts are identified and there is immediate testing following symptom onset and quarantine of contacts within 24 h. Among currently available antibody tests, performance has been highly variable, with specificity around 90% or lower for rapid diagnostic tests and 95-99% for laboratory-based ELISA and chemiluminescent assays. INTERPRETATION: Molecular testing can play an important role in prevention of SARS-CoV-2 transmission, especially among health-care workers and other high-risk groups, but no single strategy will reduce R below 1 at current levels of population immunity. Immunity passports based on antibody tests or tests for infection face substantial technical, legal, and ethical challenges. FUNDING: UK Medical Research Council

Online Game Addiction and the Level of Depression Among Adolescents in Manila, Philippines

Introduction: World Health Organization recognizes online game addiction as a mental health condition. The rise of excessive online gaming is emerging in the Philippines, with 29.9 million gamers recorded in the country. The incidence of depression is also increasing in the country. The current correlational analysis evaluated the association between online game addiction and depression in Filipino adolescents. Methods: A paper-and-pencil self-administered questionnaire assessing depression and online game addiction was distributed from August to November, 2018. The questionnaire included socio-demographic profiles of the respondents, and the 14-item Video Game Addiction Test (VAT) (Cronbach's ?=0.91) and the Patient Health Questionnaire-9 (Cronbach's ?=0.88) to determine levels of online game addiction and depression, respectively. Multiple regression analyses were used to test the association between depression and online game addiction. Results: Three hundred adolescents (59% males, 41% females) participated in the study. Fifty-three out of 300 respondents (12.0% males, 5.7% females) had high level of online game addiction as reflected in their high VAT scores. In this study, 37 respondents (6.7% males, 5.7% females) had moderately severe depression and 6 (2.0%) females had severe depression. Online game addiction was positively correlated with depression in this study (r=0.31; p<0.001). When multiple regression analysis was computed, depression was found to be a predictor of online game addiction (Coefficient=0.0121; 95% CI-8.1924 - 0.0242; p=0.05). Conclusion: Depression, as associated with online game addiction, is a serious threat that needs to be addressed. High level of online game addiction, as positively correlated to the rate of depression among adolescents in Manila, could potentially be attributed to the booming internet industry and lack of suffiicent mental health interventions in the country. Recommended interventions include strengthening depression management among adolescents and improving mental health services for this vulnerable population groups in schools and within the communities

Characterization of the First Conotoxin from Conus ateralbus, a Vermivorous Cone Snail from the Cabo Verde Archipelago

Conus ateralbus is a cone snail endemic to the west side of the island of Sal, in the Cabo Verde Archipelago off West Africa. We describe the isolation and characterization of the first bioactive peptide from the venom of this species. This 30AA venom peptide is named conotoxin AtVIA (δ-conotoxin-like). An excitatory activity was manifested by the peptide on a majority of mouse lumbar dorsal root ganglion neurons. An analog of AtVIA with conservative changes on three amino acid residues at the C-terminal region was synthesized and this analog produced an identical effect on the mouse neurons. AtVIA has homology with δ-conotoxins from other worm-hunters, which include conserved sequence elements that are shared with δ-conotoxins from fish-hunting Conus. In contrast, there is no comparable sequence similarity with δ-conotoxins from the venoms of molluscivorous Conus species. A rationale for the potential presence of δ-conotoxins, that are potent in vertebrate systems in two different lineages of worm-hunting cone snails, is discussed.This work was supported by grants to BMO from the National Institute of General Medical Science, GM 48677 and GM103362. Partial funding was obtained through a PhD grant to JLBN (SFRH/BD/51477/2011) from the European Regional Development Fund (ERDF) through the COMPETE—Operational Competitiveness Program and from national funds through FCT—Foundation for Science and Technology—under the project FCT Project UID/Multi/04423/ and by the project H2020 RISE project EMERTOX—Emergent Marine Toxins in the North Atlantic and Mediterranean: New Approaches to Assess their Occurrence and Future Scenarios in the Framework of Global Environmental Changes—Grant Agreement No. 778069. The sample collection in Cabo Verde was supported by Fundação Calouste Gulbenkian