Diabetes mellitus and human immunodeficiency virus (HIV) infection in people with tuberculosis in Odisha, India.

BACKGROUND: Modelling studies have indicated that approximately 20% of all tuberculosis (TB) cases may suffer from diabetes mellitus (DM). DM increases the risk of developing active TB disease by 2-3 times. People living with HIV (PLHIV) are more likely to develop TB disease, and TB is a leading cause of hospitalization and death among PLHIV. Despite the substantial burden of DM and HIV in India, few studies have evaluated the prevalence of DM and HIV among active cases of TB, and its impact on the treatment outcome for TB. This study evaluated the burden of HIV and DM in TB cases from Odisha during 2019, and its impact on the TB treatment outcome. METHODS: The study utilized data on TB patients of Odisha during 2019, from the NIKSHAY portal, the health management information system (HMIS) of TB in India. This is a retrospective observational registry-based cohort study, which evaluated a linkage between socio-demographic predictors, clinical diagnostic and treatment predictors, time of treatment predictors, and co-morbidity with TB. Data were retrieved electronically in Microsoft-Excel and analysis was done using STATA 16 (StataCorp. 2019, College Station, TX: StataCorp LLC). RESULTS: Data for 47,831 TB cases of Odisha as study population was extracted from the Nikshay application for the year 2019. The highest prevalence (31.1%, 14,863/47,831) of TB was observed among young participants aged 15-30 years, whereas the prevalence was least among children <14 years (4.4%, 2124/47,831). Males had a higher prevalence of TB (66.7%, 31,878/47,831). Of the 47,831 TB cases included in the study, 7.6% (3659/47,831) had diabetes mellitus (DM), along with TB. 1.2% (571/47,831) had HIV along with TB, while only 0.08% (37/47,831) had both DM and HIV along with TB. 88.2% (3148/3569) of cases with DM and TB had a favorable outcome, compared to 82.3% (449/541) of cases with HIV and TB. People with TB who did not have DM had a significantly higher favorable outcome (OR 1.6, 95% CI 1.5-1.8) compared to those with TB and DM. Similarly, TB cases who did not have HIV infection had a significantly higher favorable outcome (OR 2.4, 95% CI 1.9-3.0) compared to those with TB and HIV. CONCLUSION: Our study showed that presence of DM and/or HIV in TB patients had an impact on the TB treatment outcome. There is a crucial need to prevent comorbidities such as DM and HIV from occurring and to prioritize early diagnosis and management of these conditions.

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

Unexpected structural preference with metallophilic Ag-Au contacts in silver(I)-N-heterocyclic carbene cluster; experimental and theoretical approach.

A novel synthetic donor-atom-selective approach has been adopted for the synthesis of a heterobimetallic cluster of a new NCN-pincer, 1,3-bis-(1-methyl-1H-benzo[d]imidazol-2-yl-methyl)-1H-imidazol-3-ium hexafluorophosphate (1·HPF6). The complex [Ag3(1)3][PF6]3 (2) has been prepared via the Ag2O route; which undergoes transmetallation to yield a cluster that seems to be the first example of the heterobimetallic trinuclear system [Au-Ag2(1)2Cl][PF6]2, 3. Finally, the trinuclear cluster geometries of 2 and 3 were confirmed via SCXRD studies. Interestingly, Au(I) binds preferentially with soft donor Ccarbene, which transmetallated from the cluster of 2. In both the cyclic trinuclear clusters, the M-M interactions were further inspected using gauge independent atomic orbital (GIAO) computations. Both 2 and 3 are luminescent and possess σ-aromaticity; the NICS values indicate that 3 is more aromatic than 2.

Pre-clinical lung squamous cell carcinoma mouse models to identify novel biomarkers and therapeutic interventions.

Primary lung carcinoma or lung cancer (LC) is classified into small-cell or non-small-cell (NSCLC) lung carcinoma. Lung squamous cell carcinoma (LSCC) is the second most common subtype of NSCLC responsible for 30% of all LCs, and its survival remains low with only 24% of patients living for five years or longer post-diagnosis primarily due to the advanced stage of tumors at the time of diagnosis. The pathogenesis of LSCC is still poorly understood and has hampered the development of effective diagnostics and therapies. This review highlights the known risk factors, genetic and epigenetic alterations, miRNA biomarkers linked to the development and diagnosis of LSCC and the lack of therapeutic strategies to target specifically LSCC. We will also discuss existing animal models of LSCC including carcinogen induced, transgenic and xenograft mouse models, and their advantages and limitations along with the chemopreventive studies and molecular studies conducted using them. The importance of developing new and improved mouse models will also be discussed that will provide further insights into the initiation and progression of LSCC, and enable the identification of new biomarkers and therapeutic targets.

Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy.

Non-small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic. SIGNIFICANCE: Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies. See related commentary by Johnson and Haigis, p. 4005.

Nutritional status of reproductive age group women: A community-based study.

Introduction: Anemia continues to be a major public health problem worldwide, particularly among females of reproductive age in developing country settings. The prevalence of anemia in South Asia is among the highest in the world, mirroring overall high rates of malnutrition. Objective: 1) To estimate the prevalence of anemia and undernutrition among reproductive age group females. 2) To study factors associated with anemia and undernutrition among reproductive age group females. Material and Method: This was cross-sectional study, which was carried out from June 2011 to December 2012 at Nanded City in Maharashtra state among nonpregnant ever-married women of 15-49 years age with a sample size of 750 selected using probability proportional to size sampling technique. Percentage, Chi-square test, analysis of variance (ANOVA) test, and Student's t test were used for analyzing the data. Results: The prevalence of anemia among reproductive age group women was 554 (73.9%). 20.8% of women were undernourished and 4.1% were obese. There was a significant difference in the hemoglobin percentage of study subjects in relation to their age at marriage, weight, and body mass index (BMI). Mean BMI increases significantly as the age of women and duration of marriage increases. Conclusion: Nutritional status has a significant effect on the grade of anemia. Women of reproductive age groups are affected by anemia irrespective of age and parity.

Aim2 suppresses cigarette smoke-induced neutrophil recruitment, neutrophil caspase-1 activation and anti-Ly6G-mediated neutrophil depletion.

Increased inflammasome responses are strongly implicated in inflammatory diseases; however, their specific roles are incompletely understood. Therefore, we sought to examine the roles of nucleotide-binding oligomerization domain-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) and absent in melanoma-2 (AIM2) inflammasomes in cigarette smoke-induced inflammation in a model of experimental chronic obstructive pulmonary disease (COPD). We targeted NLRP3 with the inhibitor MCC950 given prophylactically or therapeutically and examined Aim2-/- mice in cigarette smoke-induced experimental COPD. MCC950 treatment had minimal effects on disease development and/or progression. Aim2-/- mice had increased airway neutrophils with decreased caspase-1 levels, independent of changes in lung neutrophil chemokines. Suppressing neutrophils with anti-Ly6G in experimental COPD in wild-type mice reduced neutrophils in bone marrow, blood and lung. By contrast, anti-Ly6G treatment in Aim2-/- mice with experimental COPD had no effect on neutrophils in bone marrow, partially reduced neutrophils in the blood and had no effect on neutrophils or neutrophil caspase-1 levels in the lungs. These findings identify that following cigarette smoke exposure, Aim2 is important for anti-Ly6G-mediated depletion of neutrophils, suppression of neutrophil recruitment and mediates activation of caspase-1 in neutrophils.

Aspirin Inhibition of Group VI Phospholipase A2 Induces Synthetic Lethality in AAM Pathway Down-Regulated Gingivobuccal Squamous Carcinoma.

BACKGROUND: To elucidate the role of iPLA2/PLA2G6 in gingivobuccal squamous cell carcinoma (GB-SCC) and to ascertain the synthetic lethality-based chemoprevention role of aspirin in arachidonic acid metabolism (AAM) pathway down-regulated GB-SCC. METHODS: The in vitro efficacy of aspirin on GB-SCC cells (ITOC-03 and ITOC-04) was assessed by cell proliferation, colony formation, apoptosis, cell migration, cell cycle assay and RNA-seq, while inhibition of PLA2G6 and AAM pathway components was affirmed by qPCR, Western blot and immunofluorescence staining. The in vivo effect of aspirin was evaluated using NOD-SCID mice xenografts and immunohistochemical analysis. RESULTS: We found that aspirin, which has been reported to act through the COX pathway, is inhibiting PLA2G6, and thereby the COX and LOX components of the AAM pathway. The findings were validated using PLA2G6 siRNA and immunohistochemical marker panel. Moreover, a pronounced effect in ITOC-04 cells and xenografts implied aspirin-induced synthetic lethality in the AAM pathway down-regulated GB-SCC. CONCLUSIONS: This study reveals that aspirin induces the anti-tumor effect by a previously unrecognized mechanism of PLA2G6 inhibition. In addition, the effect of aspirin is influenced by the baseline AAM pathway status and could guide precision prevention clinical trials of AAM pathway inhibitors.

Microbial remediation of fluoride-contaminated water via a novel bacterium Providencia vermicola (KX926492).

The present study emphasizes on the isolation, identification and characterization of a fluoride-resistant bacteria from contaminated groundwater of a severely affected rural area. The isolate was investigated for its possible role towards bioremediation of fluoride. Bacterial growth was determined by various carbon and nitrogen sources. Influence of parameters like initial fluoride concentration (5-25 mg L-1), pH (3-9) and temperature (15-42 °C) on fluoride removal by Providencia sp. KX926492 were also examined. SEM, EDX and FTIR were performed to analyse the surface texture, elemental composition and functional groups of the bacterium involved in the uptake of fluoride ions. 16S rRNA sequencing was performed to identify the isolate. Plackett-Burman design was employed to optimize the various parametric conditions of fluoride removal. Maximum removal of 82% was achieved when the initial fluoride concentration was 20 mgL-1 at pH 7 and 37 °C temperature with dextrose and nitrogen concentrations of 5 and 4 g per 50 mL respectively. Results suggested that Providencia vermicola (KX926492) could be a potential bacterium in removal of fluoride from contaminated water.