Oral cancer in India.

OBJECTIVES: To describe the epidemiological status of oral cancer (OC) in India along with updates on risk factors, advances and gaps in preventive measures, treatment, costs of care and monitoring. METHODS: Two national estimates of incidence and mortality were cited, one for 2016 by the Global Burden of Disease India Study and one based on projections for 2020 by GLOBOCAN. The National Cancer Registry Project provided local and regional incidence and trends using data from 2012-2016. Scientific literature, reports of the NCRP, the IARC and government press releases were also consulted. RESULTS: Tobacco and areca nut habits are the major risk factors for OC in India. In the 1980s, intervention studies on oral screening, awareness generation and habit cessation in rural areas reduced tobacco use and oral leukoplakia. Lately, adoption of the tobacco control law and mass media communications have resulted in decreased tobacco use. However, the increasing popularity of highly carcinogenic tobacco products containing areca nut, with evasion of their bans, is increasing OC incidence. CONCLUSION: Despite advances in care, there is growing incidence of OC, persisting poor awareness about the need to quit tobacco/areca nut/alcohol use and go for screening. Major efforts are needed to implement preventive activities.

"The ban is there, but it is not there": perceptions of cigarette users and tobacco vendors regarding ban on the sale of loose cigarettes in India.

Introduction: Banning the sales of loose cigarettes is recommended by Article 16 of the World Health Organization - Framework Convention on Tobacco Control. This study aims to understand the perceptions of cigarette users and tobacco vendors regarding such a ban. Methods: Using a systematic recruitment and interview protocol, we interviewed cigarette users (n = 28) and tobacco vendors (n = 28) from two Indian cities where sales of loose cigarettes were banned (Mumbai) or not banned (Delhi). Separate semi-structured interview guides were used for users and vendors. Interview questions focused on reasons for purchasing loose cigarettes, preference for buying and selling loose vs. packs, thoughts on the necessity of banning loose cigarettes, and the perceived impact of the policy ban for vendors and cigarette users. We performed thematic analysis and used NVivo for organizing transcript coding. Results: The main reasons users cited for purchasing loose cigarettes were financial constraints, social restrictions (fear of getting caught), and limiting cigarette consumption. In Mumbai, awareness of the existing ban was poor among both users and vendors. Those who were aware did not think the policy had been implemented. Users thought that loose cigarettes promoted smoking initiation and prevented them from quitting. Both users and vendors reported that a ban on loose cigarettes would reduce cigarette consumption and promote quit attempts as it would not be possible for everyone to purchase packs because of financial and social reasons. Conclusion: Users in both cities reported easy access to and widespread availability of loose cigarettes. Low awareness of the ban in Mumbai suggested inadequate enforcement. A country-wide ban on the sale of loose cigarettes could be highly effective in preventing smoking initiation and promoting quitting.

Propeller vs. free fasciocutaneous flap in reconstruction of complex lower limb defects-A prospective study.

BACKGROUND: Of all body regions, lower extremity wounds have been and remain the greatest challenge. Free flaps have been accepted as a reasonable option to solve this dilemma, but they require the complexity of microsurgery. This study aimed to compare the postoperative and clinical outcomes of propeller flap and fasciocutaneous free flap in the reconstruction of complex lower limb defects. MATERIALS AND METHODS: This randomized controlled trial was conducted from July 2021 to June 2023. Selected patients were randomized into two groups: the propeller flap group and fasciocutaneous free flap group. Demographic data, preoperative parameters, and postoperative parameter, including esthetic analysis, scar assessment, neurosensory analysis, psychosocial analysis, and lower extremity function, were estimated and statistically significant compared between the two study groups. RESULTS: Road traffic accident (73.3%) was the most common etiology for lower limb defects in both groups. The foot and lower third of the leg were the most common site of defect, constituting 79.99%. The duration of surgery was significantly shorter in propeller flap as compared to fasciocutaneous free flaps. Flap size was smaller, with better neurosensory improvements in propeller flap group. Esthetic analysis, scar assessment, psychosocial analysis, and lower extremity functional analysis yielded similar results in both study groups. CONCLUSION: Propeller flap has better outcomes compared to free flap in terms of smaller size of flap, shorter duration of surgery, and reduced length of hospital stay. Comparable results were obtained with respect to esthetic score, scar assessment score, psychosocial analysis, and neurosensory recovery and lower extremity functional score.

Diabetes and gastric cancer incidence and mortality in the Asia Cohort Consortium: A pooled analysis of more than a half million participants.

BACKGROUND: Evidence suggests a possible link between diabetes and gastric cancer risk, but the findings remain inconclusive, with limited studies in the Asian population. We aimed to assess the impact of diabetes and diabetes duration on the development of gastric cancer overall, by anatomical and histological subtypes. METHODS: A pooled analysis was conducted using 12 prospective studies included in the Asia Cohort Consortium. Among 558 981 participants (median age 52), after a median follow-up of 14.9 years and 10.5 years, 8556 incident primary gastric cancers and 8058 gastric cancer deaths occurred, respectively. Cox proportional hazard regression models were used to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) and pooled using random-effects meta-analyses. RESULTS: Diabetes was associated with an increased incidence of overall gastric cancer (HR 1.15, 95% CI 1.06-1.25). The risk association did not differ significantly by sex (women vs men: HR 1.31, 95% CI 1.07-1.60 vs 1.12, 1.01-1.23), anatomical subsites (noncardia vs cardia: 1.14, 1.02-1.28 vs 1.17, 0.77-1.78) and histological subtypes (intestinal vs diffuse: 1.22, 1.02-1.46 vs 1.00, 0.62-1.61). Gastric cancer risk increased significantly during the first decade following diabetes diagnosis (HR 4.70, 95% CI 3.77-5.86), and decreased with time (nonlinear p < .01). Positive associations between diabetes and gastric cancer mortality were observed (HR 1.15, 95% CI 1.03-1.28) but attenuated after a 2-year time lag. CONCLUSION: Diabetes was associated with an increased gastric cancer incidence regardless of sex, anatomical subsite, or subtypes of gastric cancer. The risk of gastric cancer was particularly high during the first decade following diabetes diagnosis.

Constructing the scale to measure entrepreneurial traits by using the modified delphi method.

Higher entrepreneurial traits significantly increase the likelihood of graduate students venturing into entrepreneurship. This study intended to develop a scale for assessing the entrepreneurial traits of graduate students, recognizing a gap in existing literature and measurement tools predominantly developed for countries with conducive entrepreneurial climates. Aligned with Ajzen's theory of planned behavior, the study employed a modified Delphi method, including prototype development, two Delphi surveys, and subsequent statistical analyses. The robustness of the final items and scale in effectively capturing the entrepreneurial traits of graduate students is supported by descriptive statistical analyses (SD ≤ 1.5, Interquartile Range ≤1, and Level of Agreement ≥70%), content validity analysis (I-CVI≥ 0.8, S-CVI/Ave = 0.92; S-CVI/UA = 0.4), and Kendall's Coefficient of Concordance analysis (X2 (37, N = 30) = 700.504, W = 0.631, p < 0.01). Ultimately, the scale comprises 38 items organized into three overarching thematic areas: life philosophy, creating and utilizing mindset, and supportive and motivating environment. Consistent with existing literature, entrepreneurial traits are intricately linked to individuals' life perspectives, often characterized by a desire for self-autonomy. Additionally, the ability to create or leverage available resources and the presence of a conducive external environment emerge as pivotal dimensions in entrepreneurial traits. Notably, the study highlights the critical influence of a country's environment and policies, mainly through university courses and short-term programs, in shaping the development of entrepreneurial traits.

Diabetes is associated with increased liver cancer incidence and mortality in adults: A report from Asia Cohort Consortium.

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust.

Prevalence, Reach of Anti-smokeless Tobacco Messages and Quit Attempts by Product Type: A Secondary Data Analysis from the Global Adult Tobacco Survey (GATS - 2016-17).

OBJECTIVE: India has the highest number of smokeless tobacco (SLT) products available in different forms, consumed in various ways. The current study aimed to understand the pattern of daily SLT use according to different product categories and whether Quit intention and Quit attempts vary by SLT type and exposure to media messages. METHODS: Data from Global Adult Tobacco Surveys (GATS), 2016-17, was used to find access to media messages and warning labels by SLT type. Quit attempt and Quit intention were calculated for each of the SLT types. Logistic regression analyses were employed to identify whether access to media messages, warning labels influenced, quit intention and attempts vary by SLT type. RESULTS: Khaini or tobacco lime mixture was the most common SLT type consumed by 37% of SLT users, whereas SLT users consuming more than one product accounted for 23% of SLT users. Exposure to media messages and warning labels was high among Gutkha/ paan masala tobacco users (74.7% and 81.2%) and low among oral tobacco (Mishri, Gul, Gudakhu) users (56.1% and 60.0%). Quit attempts and quit intention were high among Gutkha/ paan masala tobacco users (38.3% and 22.3%) and low among oral tobacco (Mishri, Gul, Gudakhu) users (25.3% and 13.6%). Users of Oral tobacco and khaini or tobacco-lime mixture were significantly less likely to attempt quitting (AOR 0.806(95%CI: 0.676-0.962), 0.839(95%CI: 0.736-0.956), and have quit intention (AOR 0.681(95%CI: 0.702-0.976), 0.733(95%CI: 0.627-0.857) compared to Gutkha/ paan masala with tobacco users. CONCLUSION: The reach of media messages and warning labels varies by SLT type. Quit intention and attempts vary by SLT type and access to media messages and warning labels. There is a need to re-strategise the tobacco control Information, Education and Communication (IEC) to reach out with effective messaging to the most unreached.

Myositis in H1N1 Infection Compounds to Myasthenic Crisis.

ABSTRACT: Infection is an important trigger of myasthenic crisis (MC), and those infections manifest with pneumonia and muscle involvement may result in more frequent MC. We report two myasthenia gravis (MG) patients with H1N1 infection, and highlight the reasons for deterioration. Two patients with MG had H1N1 infection. The diagnosis of MG was confirmed by neostigmine, repetitive nerve stimulation, and anti-acetylcholine receptor antibody tests. H1N1 was confirmed by nucleic acid detection study, and myositis by creatinine kinase. The patient with pneumonia and myositis had MC needing mechanical ventilation for 10 days, and the other patient without myositis did not have MC. They were treated with oseltamivir 75 mg twice daily for 5 days, and the patients with MC received ceftriaxone intravenously. Both the patients were on prednisolone and azathioprine, and none received prior H1N1 vaccination. The lady with MC with myositis was discharged on day 27 in wheelchair bound state, and the other one patient without myositis or MC was discharged on 6th day with full recovery. These patients highlight the need for evaluation for myositis along with pneumonia in the MG patients with H1N1 infection. Vaccination in MG patients on immunosuppression may be useful.

MANEC TUMOR OF RECTUM. A RARE CASE SERIES OF 3 PATIENTS AND A LITERATURE REVIEW.

The term Mixed Adeno-Neuro-Endocrine Carcinoma (MANEC) was introduced in 2010 by the WHO Classification of Tumors of the Digestive System. It refers to a neoplasm with dual epithelial and neuroendocrine differentiation, each component representing at least 30% of the tumor. It is an uncommon tumor accounting for < 3% of all colon and rectum malignancies. We report three cases of this extremely rare MANEC of the rectum. All three cases presented with hematochezia, variable constipation, and abdominal pain. They were diagnosed and staged appropriately with colonoscopy, biopsy with immunohistochemistry, and imaging. They underwent an anterior resection with circular stapled anastomoses. Because of the low incidence of this histotype, we reviewed the clinical presentation, diagnostic characteristics, and treatment of MANEC of the colon and rectum.

Evaluation of the effectiveness of the Indian government's policies to strengthen health warning labels on smokeless tobacco products: findings from the 2010-2019 Tobacco Control Project India Surveys.

BACKGROUND: Smokeless tobacco (SLT) packaging in India had a single symbolic (a scorpion) health warning label (HWL) in 2009 covering 40% of the front surface. In 2011, it was replaced with four pictorial images. In 2016, HWLs were enlarged to 85% on the front and back. This study aimed to assess the effectiveness of the old (symbolic and smaller images) and larger HWLs. METHODS: Data were from the Tobacco Control Project India Survey and included respondents who used SLT in Wave 1 (2010-2011, n=5911), Wave 2 (2012-2013, n=5613) and Wave 3 (2018-2019, n=5636). Using a repeated-measures design, weighted logistic regression models assessed whether there were changes in seven HWL effectiveness measures within the domains of awareness, salience, cognitive and behavioural responses. A cohort design was employed to test whether HWL effectiveness in Waves 1 and 2 was associated with quitting SLT in Waves 2 and 3, respectively. RESULTS: The 2011 HWL revision did not result in any significant changes in HWL effectiveness. There was no significant change in HWL awareness and salience after larger HWLs were introduced in 2016, but respondents were more likely to consider SLT health risks (Wave 2=17.9%, Wave 3=33.6%, p<0.001) and quitting SLT (Wave 2=18.9%, Wave 3=36.5, p<0.001). There was no change in HWLs stopping SLT use (Wave 2=36.6%, Wave 3=35.2%, p=0.829); however, respondents were more likely to avoid looking at HWLs (Wave 2=10.1%, Wave 3=40.2%, p<0.001). Effectiveness of older, symbolic and smaller pictorial HWLs was not associated with quitting SLT. DISCUSSION: There was no significant change in HWL effectiveness following the revision from a symbolic to a pictorial image, but enlarging pictorial images resulted in some improved cognitive and behavioural effects. Results suggested wear-out of HWL salience and that the effectiveness of warnings depends on both their design and time since implementation.

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium.

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Lung Cancer Risk Prediction Models for Asian Ever-Smokers.

INTRODUCTION: Although lung cancer prediction models are widely used to support risk-based screening, their performance outside Western populations remains uncertain. This study aims to evaluate the performance of 11 existing risk prediction models in multiple Asian populations and to refit prediction models for Asians. METHODS: In a pooled analysis of 186,458 Asian ever-smokers from 19 prospective cohorts, we assessed calibration (expected-to-observed ratio) and discrimination (area under the receiver operating characteristic curve [AUC]) for each model. In addition, we developed the "Shanghai models" to better refine risk models for Asians on the basis of two well-characterized population-based prospective cohorts and externally validated them in other Asian cohorts. RESULTS: Among the 11 models, the Lung Cancer Death Risk Assessment Tool yielded the highest AUC (AUC [95% confidence interval (CI)] = 0.71 [0.67-0.74] for lung cancer death and 0.69 [0.67-0.72] for lung cancer incidence) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model had good calibration overall (expected-to-observed ratio [95% CI] = 1.06 [0.90-1.25]). Nevertheless, these models substantially underestimated lung cancer risk among Asians who reported less than 10 smoking pack-years or stopped smoking more than or equal to 20 years ago. The Shanghai models were found to have marginal improvement overall in discrimination (AUC [95% CI] = 0.72 [0.69-0.74] for lung cancer death and 0.70 [0.67-0.72] for lung cancer incidence) but consistently outperformed the selected Western models among low-intensity smokers and long-term quitters. CONCLUSIONS: The Shanghai models had comparable performance overall to the best existing models, but they improved much in predicting the lung cancer risk of low-intensity smokers and long-term quitters in Asia.

Antimony precipitation and removal by antimony hyper resistant strain Achromobacter sp. 25-M.

Microbes have been confirmed to play key role in biogeochemistry of antimony. However, the impact of indigenous bacteria (from active mines) on the behavior of dissolved antimony remained poorly understood. In current study, the hyper antimony-resistant strain, Achromobacter sp. 25-M, isolated from the world largest antimony deposit, Xikuangshan antimony deposit, was evaluated for its role in dissolved Sb(V) and Sb(III) precipitation and removal. Despite of the high resistance to Sb(III) (up to 50 mM), the facultative alkaliphile, 25-M was not capable of Sb(III) oxidation. Meanwhile 25-M can produce high amount of exopolymeric substance (EPS) with the presence of Sb, which prompted us to investigate the potential role of EPS in the precipitation and removal of Sb. To this end, 2 mM of Sb(III) and Sb(V) were added into the experimental systems with and without 25-M to discern the interaction mechanism between microbe and antimony. After 96 hrs' incubation, 88% [1.73 mM (210 mg/L)] of dissolved Sb(V) and 80% [1.57 mM (190 mg/L)] of dissolved Sb(III) were removed. X-ray diffraction and energy dispersive spectroscopy analysis confirmed the formation of valentinite (Sb2O3) in Sb(III) amended system and a solitary Sb(V) mineral mopungite [NaSb(OH)6] in Sb(V) amended group with microbes. Conversely, no precipitate was detected in abiotic systems. Morphologically valentinite was bowtie and mopungite was pseudo-cubic as indicated by scanning electronic microscopy. EPS was subjected to fourier transform infrared (FT-IR) analysis. FT-IR analysis suggested that -OH and -COO groups were responsible for the complexation and ligand exchange with Sb(III) and Sb(V), respectively. Additionally, the C-H group and N-H group could be involved in π-π interaction and chelation with Sb species. All these interactions between Sb and functional groups in EPS may subsequently favore the formation of valentinite and mopungite. Collectively, current results suggested that EPS play fundamental role in bioprecipitation of Sb, which offered a new strategy in Sb bioremediation.

mRNA profiling of cytokines to understand paradoxical response in HIV-uninfected tuberculous meningitis.

Paradoxical reaction (PR) in tuberculous meningitis (TBM) is a major management issue. We report mRNA profiling of cytokines to understand PR in HIV-uninfected TBM patients. 72 patients with TBM were included, and their clinical, MRI, and mRNA profiling of tumor necrosis factor (TNF) α, interleukin (IL) 6, IL10 and interferon (IFN) γ genes in the peripheral blood mononuclear cells were done at admission and 6 weeks of antitubercular treatment. Cytokine profiling was done using reverse transcriptase polymerase chain reaction. PR was defined if repeat MRI at 6 weeks revealed new or increase in exudates, tuberculoma, hydrocephalus or infarctions. Outcome was defined at 6 months using modified Rankin Scale (mRS), and categorized as death, poor and good. 44 (61.1 %) patients had PR, and 28 (38.9 %) had paradoxical tuberculoma (PT). The expression of IL6 and TNFα genes were higher in PR and PT groups. Stage of meningitis and hydrocephalus at admission predicted PR. Patients with PR and PT had more frequently poor outcome. About three-fifth HIV-uninfected TBM patients have PR and two-fifth have PT. Paradoxical reaction is associated with higher expression of IL6 and TNFα. Patients with severe meningitis with hydrocephalus develop PR more frequently.

Upscaling a behavioural intervention program for tobacco use cessation - A randomised controlled study.

A randomised control trial was conducted among school teachers in Bihar, India for upscaling a tested, evidence-based tobacco intervention using train-the-trainer model. Six blocks in three districts were selected and randomised into intervention and control blocks. Cluster coordinators in intervention blocks were given training in the details of intervention. Cluster coordinators routinely train headmasters and they were asked to include intervention training in their routine. Except for the training material, no additional resources were provided to cluster coordinators and headmasters. Headmasters implemented the intervention along with the teachers in the school. Post-intervention random sample of 70 schools out of 219 schools from intervention blocks and 70 schools out of 224 schools in control blocks were surveyed. The survey was self-administered among 429 school teachers in intervention schools and 331 among control schools. For all 140 headmasters, the survey was interviewer administered. Almost all headmasters in intervention schools had attended the training and had involved teachers in the intervention program. Odds ratios for carrying out the recommended activities in intervention schools compared to control schools were very high and significant. In addition, intervention schools also conducted activities such as including intervention messages in classroom teaching and conveying them to parents, activities that were not directly recommended in intervention program. Thus, this train-the-trainer model demonstrated that it is possible to upscale the intervention programs successfully with the resources within the system.

Measuring multi-dimensional disparity index: A case of Nepal.

This study introduces Multi-dimensional Disparity Index (MDI) to measure multi-form of disparity in different level of governments referencing Nepal. The measurement scale of MDI was developed by adopting Santos and Alkire's (2011) approaches. A wide range of thematic experts was consulted, employing the Semi-Delphi approach to determine its dimensions and indicators. The MDI in this study includes six dimensions and 34 indicators composited with dimension-wise indices like Economy Disparity Index [ECODI], Educational Disparity Index [EDUDI], Health Disparity Index [HDI], Geography and Climatic Vulnerability Index [GCVI], Living Standard Disparity Index [LSDI], and Demography Disparity Index [DDI]. Overall, the study revealed the extent of multi-dimensional disparity across three tiers of government in Nepal. More specifically, Nepal scored 0.388 MDI value. Karnali and Bagmati provinces are accounted as the highest and least deprived. This study contributes essential knowledge, particularly in exploring the dimensions and their indicators and develops an approach to measure multi-dimensional disparities. Most existing approaches for assessing disparities are mono-dimensional and measure the disparities in a single aspect. In this context, MDI provides a broader approach to consider multiple dimensions and measures multiple aspects in a country like Nepal, where disparity manifests at multiple levels.

Computational studies to explore inhibitors against the cyclin-dependent kinase 12/13 enzyme: an insilco pharmacophore modeling, molecular docking and dynamics approach.

Cancer is enlisted among the deadliest disease all over the world. The cyclin-dependent kinases 12 and 13 have been identified as cell cycle regulators. They conduct transcription and co-transcriptional processes by phosphorylating the C-terminal of RNA polymerase-II. Inhibition of CDK12 and 13 selectively presents a novel strategy to treat triple-negative breast cancer, but dual inhibitors are still lacking. Here, we report the screening of the natural product compound class against the dual CDK12/13 enzyme by employing various in silico methods. Complexes of CDK12 enzymes are used to form common feature pharmacophore models, whereas we perform receptor-based pharmacophore modelling on CDK13 enzyme owing to the availability of a single PDB. On conducting screening over the representative pharmacophores, the common drug-like screened natural products were shortlisted for conducting molecular docking studies. After molecular docking calculations, the candidates that showed crucial interaction with CDK12 and CDK13 enzymes were shortlisted for simulation studies. Five common docked candidates were selected for molecular dynamics simulations and free energy calculations. Based on the cut-off criteria of free energy calculations, one common hit was selected as the dual CDK12/13 inhibitor. The outcome concluded that the hit with ID CNP0386383 possesses drug-like properties, displays crucial interaction in the binding pocket, and shows stable dynamic behaviour and higher binding energy than the experimentally reported inhibitor of both CDK12 and CDK13 enzymes.Communicated by Ramaswamy H. Sarma.

Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach.

Cancer has been viewed as one of the deadliest diseases worldwide. Among various types of cancer, breast cancer is the most common type of cancer in women. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a promising druggable target and is overexpressed in cancerous cells, like, breast cancer. We conducted structure-based modeling on the allosteric site of the enzyme. Targeting the allosteric site avoids the problem of drug resistance. Pharmacophore modeling, molecular docking, HYDE assessment, drug-likeness, ADMET predictions, simulations, and free-energy calculations were performed. The RMSD, RMSF, RoG, SASA, and Hydrogen-bonding studies showed that seven candidates displayed stable behaviour. As per the literature, average superimposed simulated structures revealed a similar protein conformational change in the αE'-ßf' loop, causing its displacement away from the allosteric site. The MM-PBSA showed tight binding of six compounds with the allosteric pocket. The effect of inhibitors interacting in the allosteric site causes a decrease in the binding energy of J49 (active-site inhibitor), suggesting the effect of allosteric binding. The PCA and FEL analysis revealed the significance of the docked compounds in the stable behaviour of the complexes. The outcome can contribute to the development of potential natural products with drug-like properties that can inhibit the MTHFD2 enzyme.

The quest for leadership qualities in cooperative societies: An exploratory analysis.

Successful leadership is imperative for a cooperative to flourish. However, there is limited literature concerning leadership qualities in the context of cooperatives, most particularly in cooperatives in the global south. This study applied the participatory Delphi research technique to identify effective leadership qualities in the context of community-based cooperative societies in rural Nepal. A survey of 1255 leaders and team members from 210 cooperatives was undertaken and the qualities of leadership were obtained by using explorative factor analysis. The results identified four dimensions of effective leadership: Role Model, Empowering the Team, Performance-based Rewards, and Skills of the Sector. These four dimensions, unified in the 'REPS' Model of leadership, are presented as a contextualized model of cooperative leadership that can serve to inform both further research and cooperative development practice.