Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer

Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-κB, and Wnt/β-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an

Nations within a nation: variations in epidemiological transition across the states of India, 1990–2016 in the Global Burden of Disease Study

18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016

Sequential phosphorylation of CST subunits by different cyclin-Cdk1 complexes orchestrate telomere replication

<p>Telomeres are nucleoprotein structures that cap the ends of linear chromosomes. Telomere homeostasis is central to maintaining genomic integrity. In budding yeast, Cdk1 phosphorylates the telomere-specific binding protein, Cdc13, promoting the recruitment of telomerase to telomere and thereby telomere elongation. Cdc13 is also an integral part of the CST (<u>C</u>dc13-<u>S</u>tn1-<u>T</u>en1) complex that is essential for telomere capping and counteracting telomerase-dependent telomere elongation. Therefore, telomere length homeostasis is a balance between telomerase-extendable and CST-unextendable states. In our earlier work, we showed that Cdk1 also phosphorylates Stn1 which occurs sequentially following Cdc13 phosphorylation during cell cycle progression. This stabilizes the CST complex at the telomere and results in telomerase inhibition. Hence Cdk1-dependent phosphorylations of Stn1 acts like a molecular switch that drives Cdc13 to complex with Stn1-Ten1 rather than with telomerase. However, the underlying mechanism of how a single cyclin-dependent kinase phosphorylates Cdc13 and Stn1 in temporally distinct windows is largely unclear. Here, we show that S phase cyclins are necessary for telomere maintenance. The S phase and mitotic cyclins facilitate Cdc13 and Stn1 phosphorylation respectively, to exert opposing outcomes at the telomere. Thus, our results highlight a previously unappreciated role for cyclins in telomere replication.</p

Energy Analysis and Diagnostics Data Analysis From Industrial Energy Assessments for Manufacturing Industries

The Industrial Assessment Center (IAC) at West Virginia University has been functioning since 1992. During this time, the center has performed over 100 industrial assessments for small and medium sized manufacturing plants. Significant data has been collected as a result of these assessments. Although waste minimization and productivity improvements have been recommended on some of these assessments in addition to energy savings, this paper focuses on energy analysis and diagnostics information. The data shows the types of industries in our geographical area which have benefited from the industrial assessments and outlines the relationships between these industry types and variables such as energy consumption, types of recommendations, sales, plant size, and implementation status. The paper discusses some key findings with respect to the data analysis performed

Open government data for regulation of energy resources in India : final report

This paper is part of the larger project “From Data to Development: Exploring the Emerging Impact of Open Government Data in Developing Countries.” The study proposes better public access and greater openness in government data in India. In an extractive economy, while companies and governments benefit, the poor are often left worse off. Similarly in India, a major reason for better governance in the extractive sector is that it has led to huge profits for companies, but left local communities largely impoverished. Results indicate that data cataloguing and disaggregated publication are performed inadequately by government agencies

Supporting data for Open government data for regulation of energy resources in India

<p>This dataset contains supporting tables from the paper "Open government data for regulation of energy resources in India" published as part of the Exploring the Emerging Impacts of Open Data in Developing Countries project.</p> <p>Contextual information on each table is provided in the associated report.</p

MECHANISMS OF IMMUNE RESISTANCE IN PEDIATRIC POSTERIOR FOSSA TUMORS

Posterior fossa tumors (PFT) such as medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT) are aggressive and malignant pediatric brain tumors. Tumor recurrence is common with no available cure. The current standard-of-care can cause significant morbidities including a sharply elevated risk for secondary malignancies, ototoxicity and neurophysiological sequelae. Here, we offer a new therapeutic approach for children with recurrent/refractory PFT, which harnesses the killing capacity of natural killer (NK) cells. This is predicated on our ability to deliver ex vivo expanded and activated clinical grade NK cells to the tumor microenvironment through an ommaya reservoir. In pre-clinical studies we observed that many MBs and ATRT were susceptible to NK cells in vitro and in vivo. These observations provided support for a first in humans Phase I trial (NCT02271711) to examine the safety and feasibility of infusing NK cells into the fourth ventricle of patients with recurrent/refractory PFTs. Our in vitro studies also identified resistance to NK-mediated lysis in a subset of MBs and ATRTs. This resistance was caused by the epigenetic upregulation of the growth and differentiation factor-1 (GDF-1), a member of the TGF-beta family, in ATRTs and the elevated expression of the programmed death-ligand 1 (PD-L1) in MBs. Their genetic and pharmacological manipulation countered tumor cell resistance to cytolysis by NK cells. Mis-regulation of these molecules was also observed in patient samples, setting the stage for their development as biomarkers to predict tumor response, and providing justification for subsequent clinical trials combining NK cells with epigenetic modifiers