Assessing the impact of MSH3 and MSH6 polymorphisms on lung cancer risk in North Indian patients undergoing platinum chemotherapy through molecular dynamics simulation.

The present study investigated the relationship between MSH3 and MSH6 genes in lung cancer patients. Genotyping of lung cancer patients and healthy controls was performed. Odds ratio values were calculated and survival analysis performed. Patients with mutant genotype (TT) for MSH6 polymorphism have 1.5-fold risk for the development of lung cancer (p = 0.03). For non-smokers, the mutant-type genotype had a threefold increased risk of lung cancer (p = 0.01). Patients administered with docetaxel and carbo/cisplatin and carrying GT genotype for MSH6 polymorphism, patients reported a decrease in median survival time (4.9 vs 9.13 months). MSH3 and MSH6 polymorphisms are involved in modulating the risk towards lung cancer. MSH6 polymorphism is associated with high mortality rate for patients undergoing cisplatin and docetaxel chemotherapy.

Electrochemically-driven difunctionalization of the isocyanide and Mumm rearrangement cascade: expeditious synthesis of N-acyl-N-alkyl S-thiocarbamates.

We describe the novel electrochemical multicomponent reaction (e-MCR) of readily available isocyanides, thiols and carboxylic acids to form N-substituted S-thiocarbamate derivatives that are found in several biologically active compounds. The effectiveness of the µ-electro flow reactor (µ-EFR) was showcased through significant reduction in electrolyte volume during the reaction, achieving gram-scale production of 4a within a short 12 min residence time using a Pt/Pt flow cell.

Screening and analysis of single nucleotide polymorphism in the 3'-UTR microRNA target regions and its implications for lung tumorigenesis.

Aim: The study aims to identify high-impact single nucleotide polymorphisms (SNPs) in miRNA target sites of genes associated with lung cancer. Materials & methods: Lung cancer genes were obtained from Uniprot KB. miRNA target site SNPs were mined from MirSNP, miRdSNP and TargetScan. SNPs were shortlisted based on binding impact, minor allele frequency and conservation. Gene expression was analyzed in genes with high-impact SNPs in healthy versus lung cancer tissue. Additionally, enrichment, pathway and network analyzes were performed. Results: 19 high-impact SNPs were identified in miRNA target sites of lung cancer-associated genes. These SNPs affect miRNA binding and gene expression. The genes are involved in key cancer related pathways. Conclusion: The identified high-impact miRNA target site SNPs and associated genes provide a starting point for case-control studies in lung cancer patients in different populations.

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GST polymorphism as a predictive biomarker for modulating the susceptibility to chronic obstructive pulmonary disease: A North Indian study.

Chronic obstructive pulmonary disease (COPD) is commonly characterized by shortness of breath, coughing or expectoration. Smoking is the leading cause of COPD development, but only a small percentage of smokers develop symptoms, implying a genetic component. Glutathione S-transferase enzymes are responsible for detoxifying cigarette smoke components. The role of glutathione S-transferase T1 (GSTT1) and glutathione S-transferase M1 (GSTM1) gene polymorphism was assessed with COPD susceptibility and associated clinical parameters in the North Indian population. This was a cross-sectional study involving 200 COPD patients and 200 healthy individuals, with peripheral blood sampling and adequate questionnaires. Multiplex PCR was used for genotyping GSTT1 and GSTM1 gene polymorphism. Logistic regression was used to calculate the odds ratio and 95% confidence intervals to assess the COPD risk and GST polymorphisms. The GSTT1 gene deletion rate was higher in COPD cases (34.5%) than in healthy individuals (20.5%). A statistical relationship between the GSTT1(-) null genotype and COPD risk was observed (odds ratio = 2.04, 95% CI = 1.30-3.20, P = 0.0019). After adjusting for covariates like age, sex and smoking status, a significant association was found for GSTT1(-) null genotype and COPD risk (adjusted odds ratio = 2.90, 95% CI = 1.43-5.87, P = 0.003). The GSTT1(-) genotype was also significantly correlated with clinical parameters for COPD risk. Another primary observation was that females with the GSTT1(-) null genotype were more vulnerable to COPD than males with the same gene deletion. The GSTT1(-) null genotype strongly correlates with COPD development, while no association was observed in the GSTM1(-) null genotype in the North Indian population.

Li Salt Assisted Highly Flexible Carbonaceous Ni3N@polyimide Electrode for an Efficient Asymmetric Supercapacitor.

This work used a highly flexible, sustainable polyimide tape as a substrate to deposit ductile-natured carbonaceous Ni3N (C/Ni3N@polyimide) material for supercapacitor application. C/Ni3N was prepared using a co-sputtering technique, and this method also provided better adhesion of the electrode material over the substrate, which is helpful in improving bending performance. The ductile behavior of the sputter-grown electrode and the high flexibility of the polyimide tape provide ultimate flexibility to the C/Ni3N@polyimide-based supercapacitor. To achieve optimum electrochemical performance, a series of electrochemical tests were done in the presence of various electrolytes. Further, a flexible asymmetric supercapacitor (NC-FSC) (C/Ni3N//carbon@polyimide) was assembled by using C/Ni3N as a cathode and a carbon thin film as an anode, separated by a GF/C-glass microfiber soaked in optimized 1 M Li2SO4 aqueous electrolyte. The NC-FSC offers a capacitance of 324 mF cm-2 with a high areal energy density of 115.26 µWh cm-2 and a power density of 811 µW cm-2, with ideal bending performance.

Role of thioredoxin in chronic obstructive pulmonary disease (COPD): a promising future target.

INTRODUCTION: Thioredoxin (Trx) is a secretory protein that acts as an antioxidant, redox regulator, anti-allergic, and anti-inflammatory molecule. It has been used to treat dermatitis and inflammation of the digestive tract. In the lungs, Trx has a significant anti-inflammatory impact. On the other hand, Chronic Obstructive Pulmonary Disease (COPD) is one of the significant causes of death in the developed world, with a tremendous individual and socioeconomic impact. Despite new initiatives and endless treatment trials, COPD incidence and death will likely escalate in the coming decades. AREAS COVERED: COPD is a chronic inflammatory disease impacting the airways, lung parenchyma, and pulmonary vasculature. Oxidative stress and protease-antiprotease imbalances are thought to be involved in the process. The most popular respiratory inflammatory and allergic disorders therapies are corticosteroids and ß-receptor agonists. These medications are helpful but have some drawbacks, such as infection and immunosuppression; thus, addressing Trx signalling treatments may be a viable COPD treatment approach. This review shall cover the pathophysiology of COPD, the pharmacognosy of anti-COPD drugs, including the assets and liabilities of each, and the role and mechanism of Trx in COPD treatment. EXPERT OPINION: Limited research has targeted the thioredoxin system as an anti-COPD drug. Spectating the increase in the mortality rates of COPD, this review article would be an interesting one to research.

Understanding immune checkpoints and PD-1/PD-L1-mediated immune resistance towards tumour immunotherapy.

Immunotherapy has emerged as a transformative approach in the treatment of various cancers, offering new hope for patients previously faced with limited treatment options. A cornerstone of cancer immunotherapy lies in targeting immune checkpoints, particularly the programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway. Immune checkpoints serve as crucial regulators of the immune response, preventing excessive immune activity and maintaining self-tolerance. PD-1, expressed on the surface of T cells, and its ligand PD-L1, expressed on various cell types, including cancer cells and immune cells, play a central role in this regulatory process. Although the success rate associated with these immunotherapies is very promising, most patients still show intrinsic or acquired resistance. Since the mechanisms related to PD-1/PD-L1 resistance are not well understood, an in-depth analysis is necessary to improve the success rate of anti-PD-1/PD-L1 therapy. Hence, here we provide an overview of PD-1, its ligand PD-L1, and the resistance mechanism towards PD-1/PD-L1. Furthermore, we have discussed the plausible solution to increase efficacy and clinical response. For the following research, joint endeavours of clinicians and basic scientists are essential to address the limitation of resistance towards immunotherapy.

Genotyping, in silico screening and molecular dynamics simulation of SNPs of MGMT and ERCC1 gene in lung cancer patients treated with platinum-based doublet chemotherapy.

Lung cancer, the leading cause of death worldwide, arises from an intricate combination of genetic and environmental factors. Genetic variations can influence the chemotherapeutic response of lung cancer patients in DNA repair genes. This study examines the response to platinum-based drugs among lung cancer patients of North Indian descent who possess genetic variations in the MGMT and ERCC1 genes. P CR-RFLP method was used for genotypic analysis. MedCalc statistical software was used to calculate odds ratios and Median Survival Time (MST). GROMACS software was used to perform Molecular dynamic simulation. ADCC Patients revealed a significant association with MGMT in the heterozygous genotype (HR= 1.56, p=0.02) and also with ERCC1 in both mutant and combined variants (HR= 1.25, p=0.01; HR=0.78, p=0.03). SQCC subjects harbouring ERCC1 polymorphism also reported a 2-fold increase in hazard ratio and a corresponding decrease in survival time for heterozygous and combined variants (HR= 2.55, p=0.02; HR 2.33, p=0.01, respectively). MD simulation results demonstrate a lower RMSD, stable radius of gyration, and lower RMSF, indicating the mutated MGMT protein is more stable than the wild. Further, the docking score for DNA-Wild and DNA-L84F mutants are -201.6 and -131.8, respectively. MD Simulation of the complexes further validated the results. Our study concludes that MGMT and ERCC1 polymorphisms are associated with decreased overall survival. Further, computational analysis of MGMT (rs12917) polymorphism revealed that mutated MGMT cannot bind properly to the DNA and hence cannot properly repair DNA, resulting in lower overall survival.Communicated by Ramaswamy H. Sarma.

Electrochemical Post-Ugi Cyclization for the Synthesis of Highly Functionalized Spirolactams.

The combination of the Ugi reaction and electro-organic synthesis can aid in the creation of novel heterocycles that have not been previously explored. In this study, a new strategy utilizing bis-amides from the Ugi reaction has been developed, which can produce C-S, C-Se, and C-C═O functionalized five-membered spirolactams mediated by electricity under catalyst- and metal-free conditions. Notably, this approach can be applied using a microelectro-flow reactor (µ-EFR) for gram-scale synthesis. The described strategy can synthesize complex azaspiro-fused tricyclic scaffolds with high diastereo- and regioselectivity, highlighting its versatility and potential.

Morphological changes in white blood cells in systemic inflammatory response syndrome (SIRS) with and without sepsis: An observational study.

Background: This is an observational study which aims to research morphological changes of white blood cells in patients with Systemic Inflammatory Response Syndrome (SIRS) with and without sepsis and evaluate morphological changes in white blood cells as predictors of sepsis. Methods: Patients aged 18 years or more with SIRS with sepsis and SIRS without sepsis were included and those with haematological disorders or pregnant patients were excluded. A total of 52 patients with SIRS with sepsis and 32 patients of SIRS without sepsis were included. Peripheral blood smear was prepared from the venous blood sample drawn. The presence of toxic granules, cytoplasmic vacuoles, and Dohle bodies in both cases of SIRS with sepsis without sepsis were assessed and it was compared with culture-positive sepsis and shock. Results: The difference in the presence of toxic granules (55.8% vs. 12.5%; p <0.001), cytoplasmic vacuoles (30.8% vs. 6.3%; p -0.012), and Dohle bodies (17.3% vs. 0%; p = 0.012) was significantly higher in the SIRS with sepsis group, compared to the SIRS without sepsis group. In the subgroup analysis of patients in the sepsis group, it was observed that patients with positive blood culture (9%) had a significantly higher proportion of toxic granules (100% vs. 51.1%; p=0.059), cytoplasmic vacuoles (40% vs. 29.8%; p=0.637) and Dohle bodies (40% vs. 14.9%; p=0.202). However, these differences were not statistically significant. Conclusion: Toxic granules and cytoplasmic vacuoles in the neutrophils of patients with SIRS with sepsis were found more frequently, compared to patients of SIRS without sepsis. Dohle bodies were found only in patients with sepsis and not in those with SIRS without sepsis.

Machine learning-based ensemble approach in prediction of lung cancer predisposition using XRCC1 gene polymorphism.

The employment of machine learning approaches has shown promising results in predicting cancer. In the current study, polymorphisms data of five single nucleotide polymorphisms (SNPs) of DNA repair gene XRCC1 (XRCC1 399, XRCC1 194, XRCC1 206, XRCC1 632, XRCC1 280) of the north Indian population along with four smoking status data is considered as an input to the proposed ensemble model to predict the risk of individual susceptibility to the lung cancer. The prediction accuracy of the proposed ensemble model for cancer predisposition was found to be 85%. The model performance is also evaluated using sensitivity, specificity, precision and the Gini index, which is found in the range of 0.83-0.87. The proposed model also outperformed in all evaluation parameters when compared with the individual Model (LM, SVM, RF, KNN and baseline neural net). Collectively, current results suggest the potential of the proposed ensemble model in predicting the risk of cancer based on XRCC1 SNPs data.Communicated by Ramaswamy H. Sarma.

Association of IL4RA and IL-8 polymorphism in predicting susceptibility towards tuberculosis.

Mycobacterium tuberculosis is an infectious bacterial disease frequently affecting the lungs. With two fatalities from tuberculosis (TB) occurring every three minutes, India has the highest disease burden. The aetiology of tuberculosis has been linked to IL-8 and IL-4RA. Thus, the impact of the IL4RAQ576R and IL8 gene polymorphism on TB susceptibility was assessed. 301 healthy and 301 TB patients participated in a cross-sectional study. PCR RFLP was performed to identify the genotype of the IL4RAQ576R and IL-8 +781C/T gene polymorphism. The odds ratio and 95% confidence intervals were calculated using logistic regression to evaluate the risk of TB with IL4RAQ576R and IL-8 +781C/T polymorphism. A significant association was found between IL-4RA (p=0.04) and IL-8 +781 C/T (p= 0.03) in tuberculosis. Further, when clinical symptoms were compared with both polymorphisms, two of them, i.e., cough in IL-4RA576R (p=0.04) and breathlessness (p=0.01) in IL-8 +781C/T, showed a significant association. Moreover, different combinations of the SNPS were made, and the 3 risk allele shows a significant protective role (p=0.02). There is considerable evidence which shows that M. tuberculosis causes TB, an infectious disease that is genetically predisposed. The results of our study also showed that IL-4 RA Q576R and IL-8 +781 C/T played a significant protective function against tuberculosis, confirming the claim mentioned earlier. However, only the cough in IL-4RA576R and the dyspnea in IL-8 +781C/T exhibited a significant co-relation in TB patients when symptoms were examined. Additionally, the combined effects of the two SNPs were investigated, and it was discovered that the 3-risk allele has a strong association with tuberculosis. Therefore, the polymorphisms mentioned earlier, which may also be influenced by ethnicity, may significantly impact the chance of developing tuberculosis.

Association of IL4RA polymorphism in predicting susceptibility toward chronic obstructive pulmonary disease.

Background: The cytokine IL-4 plays vital role in the intercellular signalling network during immune responses to allergen exposure. Methods: This cross-sectional study involved 202 chronic obstructive pulmonary disease (COPD) patients and 203 healthy individuals. The genotyping of IL4RAQ576R gene polymorphism was determined using PCR restriction fragment length polymorphism analysis. Results: Significant association between mutant genotype (GG) and combined (AA+AG) genotype for the risk of COPD was found (odds ratio [OR]: 4.32; p = 0.04). A significant protective effect was observed between the IL4RAQ576R polymorphism and Global Strategy for Obstructive Lung Disease (GOLD) stage four patients in a recessive model (AA+AG vs GG; p = 0.002). In GOLD A, a substantial relationship was found between the AG and wild-type genotypes (AA) for COPD risk (OR: 2.38; p = 0.03). A strong association was found for COPD duration of 5-10 years (OR: 8.80; p = 0.01). Conclusion: IL4RAQ576R polymorphism is associated with COPD susceptibility.

Cell Voltage-Dependent Structural Dichotomy: Electrochemical C-H Acyloxylation and N-Acylation of 2H-Indazoles.

A simple and efficient electrochemical method that utilizes modulation of the cell voltage to cause structural alterations in 2H-indazole is introduced. This method enables the C-3 acyloxylation of 2H-indazole and promotes the transfer of the acyl group from C-3 to N-1, allowing the N-acylation of 2H-indazoles. Additionally, the application of the µ-electro flow reactor was demonstrated, showcasing its effectiveness in achieving gram-scale production of 3x within a short residence time.

Merging Electrochemical Synthesis and Post-Ugi Cyclization for the Synthesis of Diverse 4-Imidazolidinones.

Despite the appreciation for electro-organic synthesis, postmulticomponent reaction transformation chemistry rarely exploits this powerful technology. Herein, we explore post-Ugi cyclization reactions using N-centered radical-mediated intramolecular ipso cyclization to synthesize diverse spirocyclic variants of 4-imidazolidinones through the use of electrochemically generated amidyl radicals from the bis-amides of the Ugi adducts. This protocol features an undivided cell setup under constant-current conditions with carbon-platinum electrodes. These metal- and reagent-free reactions are scalable and have broad substrate scope.

18 F-FDG PET/CT in Extensive Follicular Dendritic Cell Sarcoma With Response Assessment to Chemotherapy.

ABSTRACT: Follicular dendritic cell sarcoma (FDCS) is a low-grade sarcoma of mesenchymal dendritic cell origin, and it constitutes <0.4% of soft tissue sarcomas. We report a rare case of FDCS in a 32-year-old man. 18 F-FDG PET/CT demonstrated the involvement of cervical, axillary, mediastinal, abdominal, and pelvic groups of lymph nodes and spleen. A cervical lymph node biopsy suggested FDCS. 18 F-FDG PET/CT scan done after 3 cycles of chemotherapy (CHOP regime) revealed a complete metabolic response. This case presents the rarity of extensive presentation and complete response to the CHOP regime.

Association of MLH1-93G>A polymorphisms toward lung cancer susceptibility and its association with clinical outcome in North Indian patients treated with platinum-based chemotherapy.

Background: Lung cancer is one of the most prevalent and main causes of malignancy-related deaths worldwide, especially in developed countries. Epidemiological studies have demonstrated that individuals having alterations in a particular gene may have a high risk of developing certain types of cancer. Materials and Methods: In the present study, 500 Indian lung cancer patients and 500 healthy controls were enrolled. Polymerase chain reaction-restriction fragment length polymorphism method was used to identify the genotype of enrolled individuals and MedCalc statistical package was used for carrying out statistical analysis. Results: In this study, we found a reduced risk of developing adenocarcinoma in patients harboring variant (P = 0.0007) and combined type genotype (P = 0.008), whereas an increased risk for small-cell lung carcinoma (SCLC) development for those subject harboring GA genotypes (P = 0.03) was also observed. Further, heterozygous type and combined type genotype of heavy smokers for MLH1 polymorphism reported a 2-fold (P = 0.001) and 1.8-fold increased risk toward lung cancer development, respectively (P = 0.007). In case of females, the subjects harboring a variant allele have a significantly reduced risk for lung cancer development (P = 0.0001). For MLH1 polymorphism, reduced risk of developing tumor to T3 or T4 stage was observed (P = 0.04). Moreover, this is the first study reporting overall survival (OS) association for north Indian lung cancer patients with platinum-based doublet chemotherapy; for docetaxel, a three-fold increase in hazard ratio and corresponding low median standard survival time (8.4 months) for mutant and combined type genotype (P = 0.04) was observed. Conclusions: These results suggest that MLH1-93G>A polymorphism is involved in modulating the risk toward lung cancer. Our study also concluded a negative association of OS in patients undergoing carboplatin/cisplatin and docetaxel chemotherapy.