Competing risk multistate censored data modeling by propensity score matching method.

The potential contribution of the paper is the use of the propensity score matching method for updating censored observations within the context of multi-state model featuring two competing risks.The competing risks are modelled using cause-specific Cox proportional hazard model.The simulation findings demonstrate that updating censored observations tends to lead to reduced bias and mean squared error for all estimated parameters in the risk of cause-specific Cox model.The results for a chemoradiotherapy real dataset are consistent with the simulation results.

Alcohol Consumption, High-Density Lipoprotein Particles and Subspecies, and Risk of Cardiovascular Disease: Findings from the PREVEND Prospective Study.

The associations of HDL particle (HDL-P) and subspecies concentrations with alcohol consumption are unclear. We aimed to evaluate the interplay between alcohol consumption, HDL parameters and cardiovascular disease (CVD) risk. In the PREVEND study of 5151 participants (mean age, 53 years; 47.5% males), self-reported alcohol consumption and HDL-P and subspecies (small, medium, and large) by nuclear magnetic resonance spectroscopy were assessed. Hazard ratios (HRs) with 95% CIs for first CVD events were estimated. In multivariable linear regression analyses, increasing alcohol consumption increased HDL-C, HDL-P, large and medium HDL, HDL size, and HDL subspecies (H3P, H4P, H6 and H7) in a dose-dependent manner. During a median follow-up of 8.3 years, 323 first CVD events were recorded. Compared with abstainers, the multivariable adjusted HRs (95% CIs) of CVD for occasional to light, moderate, and heavy alcohol consumers were 0.72 (0.55-0.94), 0.74 (0.54-1.02), and 0.65 (0.38-1.09), respectively. These associations remained consistent on additional adjustment for each HDL parameter. For CVD, only HDL-C was associated with a statistically significant decreased risk of CVD in a fully adjusted analysis (HR 0.84, 95% CI 0.72-0.97 per 1 SD increment). For coronary heart disease, HDL-C, HDL-P, medium HDL, HDL size, and H4P showed inverse associations, whereas HDL-C and HDL size modestly increased stroke risk. Except for H6P, alcohol consumption did not modify the associations between HDL parameters and CVD risk. The addition of HDL-C, HDL size, or H4P to a CVD risk prediction model containing established risk factors improved risk discrimination. Increasing alcohol consumption is associated with increased HDL-C, HDL-P, large and medium HDL, HDL size, and some HDL subspecies. Associations of alcohol consumption with CVD are largely independent of HDL parameters. The associations of HDL parameters with incident CVD are generally not attenuated or modified by alcohol consumption.

Phase 3 RCT comparing docetaxel-platinum with docetaxel-platinum-5FU as neoadjuvant chemotherapy in borderline resectable oral cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) with TPF (docetaxel, cisplatin, and 5FU) is one of the treatment options in very locally advanced oral cancer with a survival advantage over PF (cisplatin and 5FU). TP (docetaxel and cisplatin) has shown promising results with a lower rate of adverse events but has never been compared to TPF. METHODS: In this phase 3 randomized superiority study, adult patients with borderline resectable locally advanced oral cancers were randomized in a 1:1 fashion to either TP or TPF. After the administration of 2 cycles, patients were evaluated in a multidisciplinary clinic and further treatment was planned. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and adverse events. RESULTS: 495 patients were randomized in this study, 248 patients in TP arm and 247 in TPF arm. The 5-year OS was 18.5% (95% CI 13.8-23.7) and 23.9% (95% CI 18.1-30.1) in TP and TPF arms, respectively (Hazard ratio 0.778; 95% CI 0.637-0.952; P = 0.015). Following NACT, 43.8% were deemed resectable, but 34.5% underwent surgery. The 5-year OS was 50.7% (95% CI 41.5-59.1) and 5% (95%CI 2.9-8.1), respectively, in the surgically resected versus unresected cohort post NACT (P < 0.0001). Grade 3 or above adverse events were seen in 97 (39.1%) and 179 (72.5%) patients in the TP and TPF arms, respectively (P < 0.0001). CONCLUSION: NACT with TPF has a survival benefit over TP in borderline resectable oral cancers, with an increase in toxicity which is manageable. Patients who undergo surgery achieve a relatively good, sustained survival.

Assessing the potential of Psidium guajava derived phytoconstituents as anticholinesterase inhibitor to combat Alzheimer's disease: an in-silico and in-vitro approach.

Acetylcholinesterase (AChE) inhibitors play a crucial role in the treatment of Alzheimer's disease. These drugs increase acetylcholine levels by inhibiting the enzyme responsible for its degradation, which is a vital neurotransmitter involved in memory and cognition. This intervention intermittently improves cognitive symptoms and augments neurotransmission. This study investigates the potential of Psidium guajava fruit extract as an acetylcholinesterase (AChE) inhibitor for Alzheimer's disease treatment. Molecular characteristics and drug-likeness were analyzed after HR-LCMS revealed phytocompounds in an ethanolic extract of Psidium guajava fruit. Selected phytocompounds were subjected to molecular docking against AChE, with the best-docked compound then undergoing MD simulation, MMGBSA, DCCM, FEL, and PCA investigations to evaluate the complex stability. The hit compound's potential toxicity and further pharmacokinetic features were also predicted. Anticholinesterase activity was also studied using in vitro assay. The HR-LCMS uncovered 68 compounds. Based on computational analysis, Fluspirilene was determined to have the highest potential to inhibit AChE. It was discovered that the Fluspirilene-AChE complex is stable and that Fluspirilene has a high binding affinity for AChE. Extract of Psidium guajava fruit significantly inhibits AChE (88.37% at 200 µg/ml). It is comparable to the standard AChE inhibitor Galantamine. Fluspirilene exhibited remarkable binding to AChE. Psidium guajava fruit extract demonstrated substantial AChE inhibitory activity, indicating its potential for Alzheimer's treatment. The study underscores natural sources' significance in drug discovery.Communicated by Ramaswamy H. Sarma.

Walking pace and the time between the onset of noncommunicable diseases and mortality: a UK Biobank prospective cohort study.

PURPOSE: To estimate time spent in various cardiovascular disease (CVD) and cancer states, according to self-reported walking pace. METHODS: In total, 391,744 UK Biobank participants were included (median age = 57 years; 54.7% women). Data were collected 2006-2010, with follow-up collected in 2021. Usual walking pace was self-defined as slow, steady, average, or brisk. Multistate modeling determined the transition rate and mean sojourn time in and across three different states (healthy, CVD or cancer, and death) upon a time horizon of 10 years. RESULTS: The mean sojourn time in the healthy state was longer, while that in the CVD or cancer state was shorter in individuals reporting an average or brisk walking pace (vs. slow). A 75-year-old woman reporting a brisk walking pace spent, on average, 8.4 years of the next 10 years in a healthy state; an additional 8.0 (95% CI: 7.3, 8.7) months longer than a 75-year-old woman reporting a slow walking pace. This corresponded to 4.3 (3.7, 4.9) fewer months living with CVD or cancer. Similar results were seen in men. CONCLUSIONS: Adults reporting an average or brisk walking pace at baseline displayed a lower transition to disease development and a greater proportion of life lived without CVD or cancer. AVAILABILITY OF DATA AND MATERIALS: Research was conducted using the UK Biobank resource under Application #33266. The UK Biobank resource can be accessed by researchers on application. Variables derived for this study have been returned to the UK Biobank for future applicants to request. No additional data are available.

Subgroup identification of targeted therapy effects on biomarker for time to event data.

BACKGROUND: The initiation biomarker-driven trials have revolutionized oncology drug development by challenging the traditional phased approach and introducing basket studies. Notable successes in non-small cell lung cancer (NSCLC) with ALK, ALK/ROS1, and EGFR inhibitors have prompted the need to expand this approach to other cancer sites. OBJECTIVES: This study explores the use of dose response modeling and time-to-event algorithms on the biomarker molecular targeted agent (MTA). By simulating subgroup identification in MTA-related time-to-event data, the study aims to develop statistical methodology supporting biomarker-driven trials in oncology. METHODS: A total of n patients are selected assigned for different doses. A dataset is prepared to mimic the situation on Subgroup Identification of MTA for time to event data analysis. The response is measured through MTA. The MTA value is also measured through ROC. The Markov Chain Monte Carlo (MCMC) techniques are prepared to perform the proposed algorithm. The analysis is carried out with a simulation study. The subset selection is performed through the Threshold Limit Value (TLV) by the Bayesian approach. RESULTS: The MTA is observed with range 12-16. It is expected that there is a marginal level shift of the MTA from pre to post-treatment. The Cox time-varying model can be adopted further as causal-effect relation to establishing the MTA on prolonging the survival duration. The proposed work in the statistical methodology to support the biomarker-driven trial for oncology research. CONCLUSION: This study extends the application of biomarker-driven trials beyond NSCLC, opening possibilities for implementation in other cancer sites. By demonstrating the feasibility and efficacy of utilizing MTA as a biomarker, the research lays the foundation for refining and validating biomarker use in clinical trials. These advancements aim to enhance the precision and effectiveness of cancer treatments, ultimately benefiting patients.

Self-reported walking pace and 10-year cause-specific mortality: A UK biobank investigation.

OBJECTIVE: To investigate associations of self-reported walking pace (SRWP) with relative and absolute risks of cause-specific mortality. PATIENTS AND METHODS: In 391,652 UK Biobank participants recruited in 2006-2010, we estimated sex- and cause-specific (cardiovascular disease [CVD], cancer, other causes) mortality hazard ratios (HRs) and 10-year mortality risks across categories of SRWP (slow, average, brisk), accounting for confounders and competing risk. Censoring occurred in September 30, 2021 (England, Wales) and October 31, 2021 (Scotland). RESULTS: Over a median follow-up of 12.6 years, 22,413 deaths occurred. In women, the HRs comparing brisk to slow SRWP were 0.74 (95% CI: 0.67, 0.82), 0.40 (0.33, 0.49), and 0.29 (0.26, 0.32) for cancer, CVD, and other causes of death, respectively, and 0.71 (0.64, 0.78), 0.38 (0.33, 0.44), and 0.29 (0.26, 0.32) in men. Compared to CVD, HRs were greater for other causes (women: 39.6% [6.2, 72.9]; men: 31.6% [9.8, 53.5]) and smaller for cancer (-45.8% [-58.3, -33.2] and - 45.9% [-54.8, -36.9], respectively). For all causes in both sexes, the 10-year mortality risk was higher in slow walkers, but varied across sex, age, and cause, resulting in different risk reductions comparing brisk to slow: the largest were for other causes of death at age 75 years [women: -6.8% (-7.7, -5.8); men: -9.5% (-10.6, -8.4)]. CONCLUSION: Compared to slow walkers, brisk SRWP was associated with reduced cancer (smallest reduction), CVD, and other (largest) causes of death and may therefore be a useful clinical predictive marker. As absolute risk reductions varied across age, cause, and SRWP, certain groups may particularly benefit from interventions to increase SRWP.

Targeting Melanoma with a phytochemical pool: Tailing Makisterone C.

BACKGROUND AND OBJECTIVE: According to World Health Organization, melanoma claims the lives of about 48000 people worldwide each year. The purpose of this study was to identify potential phytochemical pool from Diplazium esculentum against proteins that contribute to melanoma development. METHODS: The research was carried to locate potentially bioactive molecules and conduct a theoretical analysis of active ingredients from DE to impact melanoma. Network pharmacology, pharmacokinetics, protein network interaction, gene enrichment, survival, and infiltration analysis were conducted. Furthermore, molecular docking and molecular dynamics simulation was carried out for makisterone C-MAPK1, MAPK3, and AKT1 complexes. RESULTS: The potential phytochemical pool were identified (stigmast-5-en-3-ol, esculentic acid, rutin, and makisterone C) and based on network pharmacology and molecular docking studies, makisterone-C was proposed to be the most promising ingredient. Furthermore, the investigation revealed 14 genes as critical "hubs" involved in combating melanoma that are manipulated by the above-mentioned 4 active ingredients and modulate multiple signaling in melanoma development. CONCLUSION: This study insights into the potential anti-melanoma effects of phytochemical pool from Diplazium esculentum using network pharmacology analysis, molecular docking, and simulation tailing makisterone C as a lead moiety and suggests the need for makisterone C further evaluation in intervening melanoma progression.

Gene co-expression network construction and analysis for identification of genetic biomarkers associated with glioblastoma multiforme using topological findings.

BACKGROUND: Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system tumors. GBM patients usually have a poor prognosis. Identification of genes associated with the progression of the disease is essential to explain the mechanisms or improve the prognosis of GBM by catering to targeted therapy. It is crucial to develop a methodology for constructing a biological network and analyze it to identify potential biomarkers associated with disease progression. METHODS: Gene expression datasets are obtained from TCGA data repository to carry out this study. A survival analysis is performed to identify survival associated genes of GBM patient. A gene co-expression network is constructed based on Pearson correlation between the gene's expressions. Various topological measures along with set operations from graph theory are applied to identify most influential genes linked with the progression of the GBM. RESULTS: Ten key genes are identified as a potential biomarkers associated with GBM based on centrality measures applied to the disease network. These genes are SEMA3B, APS, SLC44A2, MARK2, PITPNM2, SFRP1, PRLH, DIP2C, CTSZ, and KRTAP4.2. Higher expression values of two genes, SLC44A2 and KRTAP4.2 are found to be associated with progression and lower expression values of seven gens SEMA3B, APS, MARK2, PITPNM2, SFRP1, PRLH, DIP2C, and CTSZ are linked with the progression of the GBM. CONCLUSIONS: The proposed methodology employing a network topological approach to identify genetic biomarkers associated with cancer.

Metronomic adjuvant chemotherapy evaluation in locally advanced head and neck cancers post radical chemoradiation - a randomised trial.

Background: Locally advanced head and neck cancers treated with radical chemoradiation have unsatisfactory outcomes. Oral metronomic chemotherapy improves outcomes in comparison to maximum tolerated dose chemotherapy in the palliative setting. Limited evidence suggests that it may do so in an adjuvant setting. Hence this randomized study was conducted. Methods: Patients of head and neck (HN) cancer with primary in oropharynx, larynx or hypopharynx, with PS 0-2 post radical chemoradiation with documented complete response were randomized 1:1 to either observation or oral metronomic adjuvant chemotherapy (MAC) for 18 months. MAC consisted of weekly oral methotrexate (15 mg/m2) and celecoxib (200 mg PO BD). The primary endpoint was OS and the overall sample size was 1038. The study had 3 planned interim analyses for efficacy and futility. Trial registration- Clinical Trials Registry- India (CTRI): CTRI/2016/09/007315 [Registered on: 28/09/2016] Trial Registered Prospectively. Findings: 137 patients were recruited and an interim analysis was done. The 3 year PFS was 68.7% (95% CI 55.1-79.0) versus 60.8% (95% CI 47.9-71.4) in the observation and metronomic arm respectively (P value = 0.230). The hazard ratio was 1.42 (95% CI 0.80-2.51; P value = 0.231). The 3 year OS was 79.4% (95% CI 66.3-87.9) versus 62.4% (95% CI 49.5-72.8) in the observation and metronomic arm respectively (P value = 0.047). The hazard ratio was 1.83 (95% CI 1.0-3.36; P value = 0.051). Interpretation: In this phase 3 randomized study, oral metronomic combinations of weekly methotrexate and daily celecoxib failed to improve the PFS or OS. Hence observation post-complete response post radical chemoradiation remains the standard of care. Funding: ICON funded this study.

Safety, immunogenecity and effectiveness of ChAdOx1 nCoV-19 vaccine during the second wave of pandemic in India: a real-world study.

OBJECTIVES: This real-world study was conducted to assess the adverse effects following immunization (AEFI) and immunogenicity of ChAdO×1 nCoV-19 vaccine in terms of neutralising antibody titers and to study the effects of covariates such as age, sex, comorbidities and prior COVID status on these outcomes. Also, the effectiveness of the vaccine based on interval between the two doses was also investigated. METHODS: A total of 512 participants (M/F=274/238) aged 35(18-87) years comprising a mixed population of healthcare workers, other frontline workers and general public were enrolled between March and May 2021. Records for adverse events if any were collected telephonically by following up with participants up to 6 months post first dose and graded as per Common Terminology Criteria for Adverse Events (CTCAE) version 5. Blood samples for measuring antibody titers against the receptor binding domain (RBD) were collected serially using a convenient sampling strategy up to 6 months after the first dose. Data on breakthrough COVID infection was collected telephonically till December 2021. RESULTS: Incidence of local reactions was higher after first dose at 33.4 % (171/512) compared to those after second dose at 12.9 % (66/512). Commonest side effect observed was injection site pain after the first (87.1 %; 149/171) and second (87.9 %; 56/66) dose respectively. Among systemic reactions, fever was the most common manifestation followed by myalgia and headache. Female sex (p<0⸱001) and age less than 60 years (p<0⸱001) had significantly higher predilection for systemic toxicities. Age ≤60 years (p=0.024) and prior-COVID (p<0.001) were found to be significantly associated with higher antibody titers, however, no association was found between these variables and breakthrough COVID infection. Longer spacing between the doses (≥6 weeks) was found to offer better protection against breakthrough infection compared to a spacing of 4 weeks. All breakthroughs were mild-moderate in severity, not requiring hospitalization. CONCLUSIONS: The ChAdOx1 nCov-19 vaccine is apparently safe and effective against SARS-CoV-2 virus infection. Prior COVID infection and younger age group achieve higher antibody titers, but no additional protection. Delaying the second dose up to at least 6 weeks is more effective compared to shorter spacing between doses.

Results of Phase III Randomized Trial for Use of Docetaxel as a Radiosensitizer in Patients With Head and Neck Cancer, Unsuitable for Cisplatin-Based Chemoradiation.

PURPOSE: There is a lack of published literature on systemic therapeutic options in cisplatin-ineligible patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) undergoing chemoradiation. Docetaxel was assessed as a radiosensitizer in this situation. METHODS: This was a randomized phase II/III study. Adult patients (age ≥ 18 years) with LAHNSCC planned for chemoradiation and an Eastern Cooperative Oncology Group performance status of 0-2 and who were cisplatin-ineligible were randomly assigned in 1:1 to either radiation alone or radiation with concurrent docetaxel 15 mg/m2 once weekly for a maximum of seven cycles. The primary end point was 2-year disease-free survival (DFS). RESULTS: The study recruited 356 patients between July 2017 and May 2021. The 2-year DFS was 30.3% (95% CI, 23.6 to 37.4) versus 42% (95% CI, 34.6 to 49.2) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.673; 95% CI, 0.521 to 0.868; P value = .002). The corresponding median overall survival (OS) was 15.3 months (95% CI, 13.1 to 22.0) and 25.5 months (95% CI, 17.6 to 32.5), respectively (log-rank P value = .035). The 2-year OS was 41.7% (95% CI, 34.1 to 49.1) versus 50.8% (95% CI, 43.1 to 58.1) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.747; 95% CI, 0.569 to 0.980; P value = .035). There was a higher incidence of grade 3 or above mucositis (22.2% v 49.7%; P < .001), odynophagia (33.5% v 52.5%; P < .001), and dysphagia (33% v 49.7%; P = .002) with the addition of docetaxel. CONCLUSION: The addition of docetaxel to radiation improved DFS and OS in cisplatin-ineligible patients with LAHNSCC.[Media: see text].

Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study.

PURPOSE: The regimens approved for the treatment of advanced head and neck squamous cell carcinoma are accessible to only 1%-3% of patients in low- and middle-income countries because of their cost. In our previous study, metronomic chemotherapy improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low-dose nivolumab to triple metronomic chemotherapy (TMC) improved overall survival (OS). METHODS: This was a randomized phase III superiority study. Adult patients with recurrent or newly diagnosed advanced head and neck squamous cell carcinoma being treated with palliative intent with an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Patients were randomly assigned 1:1 to TMC consisting of oral methotrexate 9 mg/m2 once a week, celecoxib 200 mg twice daily, and erlotinib 150 mg once daily, or TMC with intravenous nivolumab (TMC-I) 20 mg flat dose once every 3 weeks. The primary end point was 1-year OS. RESULTS: One hundred fifty-one patients were randomly assigned, 75 in TMC and 76 in the TMC-I arm. The addition of low-dose nivolumab led to an improvement in the 1-year OS from 16.3% (95% CI, 8.0 to 27.4) to 43.4% (95% CI, 30.8 to 55.3; hazard ratio, 0.545; 95% CI, 0.362 to 0.820; P = .0036). The median OS in TMC and TMC-I arms was 6.7 months (95% CI, 5.8 to 8.1) and 10.1 months (95% CI, 7.4 to 12.6), respectively (P = .0052). The rate of grade 3 and above adverse events was 50% and 46.1% in TMC and TMC-I arms, respectively (P = .744). CONCLUSION: To our knowledge, this is the first-ever randomized study to demonstrate that the addition of low-dose nivolumab to metronomic chemotherapy improved OS and is an alternative standard of care for those who cannot access full-dose checkpoint inhibitors.

Discovery of a novel inhibitor against urokinase-type plasminogen activator, a potential enzyme with a role in atherosclerotic plaque instability.

The buildup of lipids, cholesterol, and other substances in and on the walls of the arteries is known as atherosclerosis and deposition is known as atherosclerotic plaque. Urokinase-type plasminogen activator (uPA) has multiple roles in the atherosclerotic plaque formation and even work simultaneously in making the atherosclerotic plaque unstable. Extracellular matrix plays a major role in the plaque remodeling and rapture. In this study, we have accessed that a higher interaction was observed in the molecular interaction score for uPA with ZINC380065722 having a GOLD fitness score of about 67.60, which is much higher as compared to the known standard inhibitor UK 122 which has reported an interaction score of 59.14. Ser217 and Asp192 are found to be the key amino acid residues in almost all the interactions. Protein frustration analysis has shown that these amino acid residues play a crucial role in the retention of the active pocket conformation and any mutation of these two residues can causes serious decrease in the overall function of the protein. It was observed that the molecule ZINC380065722 remained bound to the protein till 100 ns of simulation time. The average SASA for the apo-uPA and uPA-ligand complex was found to be stable. The network of hydrogen bonds for the intramolecular protein secondary structure and with the solvent system for the apo-protein and the uPA-ligand complex was found to be consistent.Communicated by Ramaswamy H. Sarma.

Potentilla fulgens upregulate GLUT4, AMPK, AKT and insulin in alloxan-induced diabetic mice: an in vivo and in silico study.

OBJECTIVE: This study was designed to investigate whether the glucose lowering effects of Potentilla fulgens acts by modulating GLUT4, AKT2 and AMPK expression in the skeletal muscle and liver tissues. METHODOLOGY: Alloxan-induced diabetic mice treated with Potentilla fulgens was assessed for their blood glucose and insulin level, mRNA and protein expression using distinguished methods. Additionally, GLUT4, AKT2 and AMPK were docked with catechin, epicatechin, kaempferol, metformin, quercetin and ursolic acid reportedly present in Potentilla fulgens. RESULTS: Potentilla fulgens ameliorates hyperglycaemia and insulin sensitivity via activation of AKT2 and AMPK, increases the expression of GLUT4, AKT2, AMPKα1 and AMPKα2 whose levels are reduced under diabetic condition. Molecular docking revealed interacting residues and their binding affinities (-4.56 to -8.95 Kcal/mol). CONCLUSIONS: These findings provide more clarity vis-avis the mechanism of action of the phytoceuticals present in Potentilla fulgens extract which function through their action on GLUT4, PKB and AMPK.

Behavioural interventions for tobacco cessation in India: A systematic review and meta-analysis.

Tobacco consumption is an area of public health concern in India. One of the unmet needs of many low-resource countries is to provide cost-effective tobacco cessation interventions for reducing tobacco-related mortality. This article reviews studies on non-pharmacological interventions for tobacco cessation in India. A systematic review by PICO (population, intervention, comparison, outcome) of behavioural intervention-based tobacco cessation studies that met the inclusion criteria, with a minimum 1-month follow-up, reporting outcomes in terms of frequencies or percentages published between 2010 and 2020 was performed. Following the review stages, 16 studies comprising 9,613 participants were included in the review. A pooled estimate was derived using both fixed-effects and random-effects models. The intervention showed good overall efficacy for any tobacco user (relative risk [RR] = 1.73 [95% confidence interval [CI]: 1.58-1.90) (fixed-effect model)] and (RR = 2.02 [95% CI: 1.64-2.48] [random-effects model]). Behavioural intervention studies targeted towards only smokers (RR of 1.81 [95% CI: 1.55-2.11] and 1.96 [95% CI: 1.52-2.53]) and combined smoking and smokeless tobacco users (RR of 1.69 [95% CI: 1.50-1.90] and 2.12 [95% CI: 1.49-3.01]) were equally efficacious. The review provides the effectiveness of behavioural interventions in quitting tobacco among users of both smoking and smokeless forms of tobacco. The review findings are of particular significance to inform health policy decisions on the integration of cost-effective brief behavioural intervention into existing health care services in resource-constrained countries.

Multi-Epitope Vaccine Design against Monkeypox Virus via Reverse Vaccinology Method Exploiting Immunoinformatic and Bioinformatic Approaches.

(1) Background: The monkeypox virus is a zoonotic orthopox DNA virus that is closely linked to the virus. In light of the growing concern about this virus, the current research set out to use bioinformatics and immunoinformatics to develop a potential vaccine against the virus. (2) Methods: A multiepitope vaccine was constructed from the B-cell and T-cell epitopes of the MPXVgp181 strain using adjuvant and different linkers. The constructed vaccine was predicted for antigenicity, allergenicity, toxicity, and population coverage. In silico immune simulation studies were also carried out. Expression analysis and cloning of the constructed vaccine was carried out in the pET-28a(+) vector using snapgene. (3) Results: The constructed vaccine was predicted to be antigenic, non-allergenic, and non-toxic. It was predicted to have excellent global population coverage and produced satisfactory immune response. The in silico expression and cloning studies were successful in E. coli, which makes the vaccine construct suitable for mass production in the pharmaceutical industry. (4) Conclusion: The constructed vaccine is based on the B-cell and T-cell epitopes obtained from the MPXVgp181 strain. This research can be useful in developing a vaccine to combat the monkeypox virus globally after performing in-depth in vitro and in vivo studies.

A pro-oxidant combination of resveratrol and copper down-regulates hallmarks of cancer and immune checkpoints in patients with advanced oral cancer: Results of an exploratory study (RESCU 004).

Background: Our earlier studies have shown that cell-free chromatin particles (cfChPs) that are released from dying cancer cells are readily internalised by bystander cells leading to activation of two hallmarks of cancer viz. genome instability and inflammation. These hallmarks could be down-regulated by deactivating cfChPs via medium of oxygen radicals generated upon admixing small quantities of the nutraceuticals resveratrol (R) and copper (Cu). In this exploratory study, we investigated whether oral administration of R and Cu (R-Cu) would down-regulate the hallmarks of cancer and immune checkpoints in advanced squamous cell carcinoma of oral cavity (OSCC). Patients and methods: The study comprised of 25 patients divided into 5 equal groups. Five patients acted as controls; the remaining 20 were given R-Cu in four escalating doses. The lowest dose of R-Cu was 5.6mg and 560ng respectively, and the highest dose was 500mg and 5mg respectively. An initial biopsy was taken from patients at first presentation, and a second biopsy was taken 2 weeks later on the operating table. R-Cu was administered orally twice daily in the intervening period. Confocal microscopy was performed on tumour sections after fluorescent immuno-staining with anti-DNA and anti-histone antibodies to detect presence of cfChPs in the tumour micro-environment (TME). Immunofluorescence analysis was performed for 23 biomarkers representing the 10 Hallmarks of cancer, including 5 immune checkpoints, defined by Hanahan and Weinberg. Results: Confocal microscopy detected copious presence of cfChPs in TME of OSCC, which were eradicated/deactivated following two-week treatment with R-Cu. Eradication of cfChPs from TME was associated with marked down-regulation of 21/23 biomarkers, including the five immune checkpoints. The lower two doses of R-Cu were more effective than the higher doses. No adverse effects attributable to R-Cu were observed. Conclusion: These results suggest that cfChPs released into TME from dying cancer cells are global instigators for cancer hallmarks and immune checkpoints in surviving cancer cells. The ability of R-Cu to deactivate cfChPs raises the prospect of a novel and non-toxic form of cancer treatment which sans killing of cancer cells, and instead induces healing by down-regulating cancer hallmarks and immune check-points. Clinical Trial Registration: http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19801&EncHid=&userName=CTRI/2018/03/012459.