Protein Kinase C Epsilon Overexpression in Prostate Adenocarcinoma is Associated with Oncogenesis

Background: PKCε, an isozyme of serine-threonine kinase, has been implicated in epithelial cancer metastasis and progression. This study investigates the impact of the oncogenic PKCε, overexpressed abnormally in human Prostate tumor samples and cell lines, to understand its efficacy. Methods: The microarray dataset, GSE86257, was processed for normalization. The identification of upregulated and downregulated genes was based on FDR >1 and p <0.05 values. Cytoscape analysis and functional enrichment of significant genes were done. The identified genes were validated on the TCGA dataset and survival analysis was performed by Kaplan-Meier analysis. Results: A total of 1524 DEGs were identified with 728 upregulated genes and 818 downregulated genes. The two significant modules with MCODE score:9.0 and Venn analysis provided cyclin-dependent kinase inhibitor protein (CDK1), Cyclin B1 (CCNB1), Phospholipase C Gamma 1 (PLCG1), Cyclin Dependent Kinase 9 (CDK9), Phosphoinositide-3-Kinase Regulatory Subunit 3 (PIK3R3), H4 Clustered Histone 6 (H4C6), Phospholipase C Gamma 2 (PLCG2) as most interacting genes. TCGA data analysis and Prognostic analysis revealed CCNBI, CDK9, and PLCG1 associated with poor prognosis. Conclusion: PKCε regulates genes that are responsible for cancer progression. Therefore, targeting PKCε in Prostate cancer may serve as an important regulatory effect and may improve the prognosis of the disease.&nbsp

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Methodology for Selecting an Ideal Thermal Gasification Technique for Municipal Solid Waste Using Multi-Criteria Decision Analysis

Awareness of the consequences of waste mismanagement has resulted in urban planners looking for effective disposal techniques with the added benefit of energy generation. The decision regarding an energy conversion technique to adopt on a community level is based on different technology assessment factors with maximum weightage on environmental effects. Gasification techniques in general and thermal gasification strategies in particular are appropriate methods when environmental impacts are to be minimized. Thermal gasification techniques have evolved with different configurations, syngas generation rates, and other advantages and disadvantages; hence, the selection of the right technique is essential, and establishing guidelines for decision-makers is necessary. The six different gasifiers considered in the present study were updraft gasifiers, downdraft gasifiers, cross-draft gasifiers, bubbling fluidized bed gasifiers, circulating fluidized bed gasifiers, and dual-bed fluidized bed gasifiers. The assessments performed in the present study are based on the attributes of the different techniques using the multi-criteria decision method. Multi-criteria decision analysis is an appropriate method proven to be an ideal procedure in these situations. Attribute values for gasifier performance, environmental effects, economic performance indices, and fuel requirements were determined from collected waste assessment data and published information. Analysis was performed for both recycling and non-recycling scenarios of waste utilization by applying different weight scenarios for the attributes. Results of the study indicate that downdraft gasifiers showed the best performance in terms of environmental effects under the recycling scenario, with 0.1% and 0.0125% by volume of carbon dioxide and methane emissions, and under the non-recycling scenario, with 0.125% and 0.02% by volume of carbon dioxide and methane emissions. Downdraft gasifiers had high overall rankings in performance when evaluated against different entropy weights for both scenarios. The results of the study can be applied to urban communities in different climatic regions as well as for different scales of operation

Identification of a novel Sorcin isoform with a different C-terminal but intact dimerization property

Abstract Sorcin (Sri), a member of penta EF-hand protein family plays a diverse role in maintaining calcium homeostasis, cell cycle and vesicular trafficking. Sri is highly conserved amongst mammals and consists of N-terminal glycine rich domain and C-terminal calcium binding domain that mediates its dimerization and interacts with different compounds. In the present study, with the help of combination of computational and molecular biology techniques, we have identified a novel isoform (Sri-N) in mouse which differs only in the C-terminal domain with that of Sri reported earlier. The novel isoform contains a new last exon that is different from the one present in the reported transcript (Sri). The presence of the novel isoform was further validated in different tissues by RT-PCR and DNA sequencing. The transcript was conceptually translated and subjected to in-silico analysis using different bioinformatics tools. The novel transcript variant encodes for a longer protein isoform without any change in the sub-cellular localization as predicted by PSORT-II online tool. Molecular modelling was performed to compare the structural changes in Sri-N and Sri isoforms. The structural characterization of the novel isoform using MD simulation depicted its overall stability under the physiological conditions. The molecular docking of proteins with various chemotherapeutic drugs revealed that their binding affinity is more for Sri-N as compared to that for the previously reported transcript Sri

Interaction of 6 mercaptopurine with calf thymus DNA--deciphering the binding mode and photoinduced DNA damage.

DNA is one of the major intracellular targets for a wide range of anticancer and antibiotic drugs. Elucidating the binding between small molecules and DNA provides great help in understanding drug-DNA interactions and in designing of new and promising drugs for clinical use. The ability of small molecules to bind and interfere with DNA replication and transcription provides further insight into how the drugs control the expression of genes. Interaction of an antimetabolite anticancer drug 6 mercaptopurine (6MP) with calf thymus DNA was studied using various approaches like UV-visible spectroscopy, fluorescence spectroscopy, CD, viscosity and molecular docking. UV-visible spectroscopy confirmed 6MP-DNA interaction. Steady state fluorescence experiments revealed a moderate binding constant of 7.48 × 10(3) M(-1) which was consistent with an external binding mode. Competitive displacement assays further confirmed a non-intercalative binding mode of 6MP which was further confirmed by CD and viscosity experiments. Molecular docking further revealed the minimum energy conformation (-119.67 kJ/mole) of the complex formed between DNA and 6MP. Hence, the biophysical techniques and in-silico molecular docking approaches confirmed the groove binding/electrostatic mode of interaction between 6MP and DNA. Further, photo induced generation of ROS by 6MP was studied spectrophotometrically and DNA damage was assessed by plasmid nicking and comet assay. There was a significant increase in ROS generation and consequent DNA damage in the presence of light

Experimental investigation of volume fraction in an annulus using electrical resistance tomography

Horizontal drilling technology has shown to improve the production and cost-effectiveness of the well by generating multiple extraction points from a single vertical well. The efficiency of hole cleaning is reduced because of the solid-cuttings accumulation in the annulus in cases of extended-reach drilling. It is difficult to study the complex flow behavior in a drilling annulus using the existing visualization techniques. In this study, experiments were carried out in the multiphase flow-loop system consisting of a simulated drilling annulus using electrical resistance tomography (ERT) and a high-speed camera. Real-time tomographic images (quantitative visualization) of multiphase flow from ERT were compared to the actual photographs of the flow conditions in a drilling annulus. The quantitative analy- sis demonstrates that ERT has a wide potential application in studying the hole-cleaning issues in the drilling industry. - 2019 Society of Petroleum Engineers.The authors are grateful to the Qatar Foundation, Texas A&M University at Qatar, and Qatar University. The authors would also like to acknowledge the startup fund provided by Texas A&M University at Qatar. This publication was made possible by the grant NPRP10-0101-170091 from the Qatar National Research Fund (a member of the Qatar Foundation). Statements made herein are solely the responsibility of the authors. The authors declare no competing financial interests.Scopu

Improving access to the treatment of hepatitis C in low- and middle-income countries:evaluation of a patient assistance programme

Background Modern antiviral treatments have high cure rates against the hepatitis C virus however, the high cost associated with branded medicines and diagnostic tests, have resulted in poor access for many low-income patients residing in low-and-middle-income countries. Objective This study aimed to evaluate the role of a patient assistance programme and generic medicines in improving access to treatment of low-income hepatitis C patients in a low-and-middle-income country. Setting A major teaching public hospital in Islamabad, Pakistan. Methods Hepatitis C patients who presented and enrolled for the patient assistance programme during 12 months (1st July 2015 and 30th June 2016) were included. Demography, prescription characteristics, the total costs of Hepatitis C treatment, medicine cost supported by the programme, out-of-pocket cost borne by the patient and average cost effectiveness ratio per sustained virologic response were calculated and compared for different generic and branded regimens. Main outcome measure cost contribution of patient assistance programme. Results A total of 349 patients initiated the treatment through the programme and of those 334 (95.7%) completed the prescribed treatment. There were 294 (88.02%) patients who achieved sustained virologic response. Patient assistance programme contributed medicines cost averaging 60.28–86.26% of the total cost of treatment ($1634.6) per patient. The mean (SE) cost per patient for generic option (Sofosbuvir/Ribavirin) was the lowest [$658.36 (22.3) per patient, average cost effectiveness ratio = $720.1/SVR] than branded option (Sovaldi/Ribavirin) [$2218.66 (37.6) per patient, average cost effectiveness ratio = $2361.8/SVR] of the three available treatment regimens. From patients’ perspectives, the mean (SE) out-of-pocket cost was$296.9 (6.7) which primarily included diagnostic cost (69.9%) of the total cost. Conclusions Patient assistance programme, combined with generic brands of newer hepatitis C treatment offered a significant reduction in cost and widens access to hepatitis C treatment in low-and middle-income countries. However, substantial out-of-pocket costs of the treatment presents an important barrier for service access. There is a scope to widen such financial assistance programme to offer other costs attributed to patients, specifically for diagnosis, to widen service use in low-and-middle-income countries

Molecular docked structure of 6MP complex with DNA.

<p>Dodecamer duplex sequence (CGCGAATTCGCG)₂ (PDB ID: 1BNA) was used in the docking studies. The binding energy of the complex system was found to be −116.97 kJ/mole.</p