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.

Genetic polymorphisms in the mismatch repair pathway (MMR) genes contribute to hematological and gastrointestinal toxicity in North Indian lung cancer patients treated with platinum-based chemotherapy.

The present study investigated the relationship between MLH1, MSH2, MSH3, and MSH6 polymorphisms and toxicity due to platinum-based doublet chemotherapy for North Indian lung cancer patients. Polymerase chain reaction-restriction fragment length polymorphism technique was used to assess the polymorphism. For MSH2 IVS1 + 9G > C polymorphism variant type genotype reported a 1.4-fold increased risk of anemia (AOR = 1.4; 95% CI = 0.98-1.99; p = 0.04) and decreased risk of developing gastrointestinal toxicity (diarrhea) (AOR = 0.53; 95% CI = 0.28-1.01; p = 0.04). Further, we also reported a 10-fold increased risk of developing severe grade anorexia in combined genotype (GC + CC) (AOR = 9.18; 95% CI = 0.98-86.1; p = 0.05). For MSH2 T > C/-6 polymorphism, variant type reported a 3-fold and 2-fold increased risk of developing severe grade leukopenia (AOR = 3.37; 95% CI = 1.44-7.88; p = 0.005) and neutropenia respectively (AOR = 2.23; 95% CI = 1.07-4.66; p = 0.03). For MSH3 G > A polymorphism, heterozygous (GA) and combined genotype (GA + AA) reported a 7-fold and 6-fold increased risk of developing anemia (AOR = 7.23; 95% CI = 1.51-34.6; p = 0.01, AOR = 6.39; 95% CI = 1.53-26.6; p = 0.01). Our results suggest that polymorphisms in DNA mismatch repair genes are associated with hematological, and gastrointestinal toxicities and might be considered a predictor for pretreatment evaluation in lung cancer patients.

Identification of SNPs in hMSH3/MSH6 interaction domain affecting the structure and function of MSH2 protein.

MutS homolog 2 (MSH2) is a mismatch repair gene that plays a critical role in DNA repair pathways, and its mutations are associated with different cancers. The present study aimed to find out the single nucleotide polymorphisms (SNPs) of MSH2 protein associated with causing structural and functional changes leading to the development of cancer with the help of computational tools. Four different tools for predicting deleterious SNPs (SIFT, PROVEAN, PANTHER, and PolyPhen), two tools each for identifying disease association (PhD-SNP and SNP&GO) and estimating stability (I-mutant and MUPro) were employed. Homology modeling, energy minimization, and root mean square deviation calculation were used to estimate structural variations. Twenty-seven SNPs and five SNPs (double amino acid change) were identified based on a consensus approach that might be associated with the structural and functional change in MSH2 protein. Molecular docking reveals that six SNPs affect the interaction of MSH2 and MSH6. Twelve identified SNPs were reported to be linked with hereditary nonpolyposis, colorectal cancer, and Lynch syndrome. Further, selected SNPs need to be validated in an in vitro system for their precise association with cancer predisposition.

Enhancing cancer immunotherapy: Exploring strategies to target the PD-1/PD-L1 axis and analyzing the associated patent, regulatory, and clinical trial landscape.

Cancer treatment modalities and their progression is guided by the specifics of cancer, including its type and site of localization. Surgery, radiation, and chemotherapy are the most often used conventional treatments. Conversely, emerging treatment techniques include immunotherapy, hormone therapy, anti-angiogenic therapy, dendritic cell-based immunotherapy, and stem cell therapy. Immune checkpoint inhibitors' anticancer properties have drawn considerable attention in recent studies in the cancer research domain. Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) checkpoint pathway are key regulators of the interactions between activated T-cells and cancer cells, protecting the latter from immune destruction. When the ligand PD-L1 attaches to the receptor PD-1, T-cells are prevented from destroying cells that contain PD-L1, including cancer cells. The PD-1/PD-L1 checkpoint inhibitors block them, boosting the immune response and strengthening the body's defenses against tumors. Recent years have seen incredible progress and tremendous advancement in developing anticancer therapies using PD-1/PD-L1 targeting antibodies. While immune-related adverse effects and low response rates significantly limit these therapies, there is a need for research on methods that raise their efficacy and lower their toxicity. This review discusses various recent innovative nanomedicine strategies such as PLGA nanoparticles, carbon nanotubes and drug loaded liposomes to treat cancer targeting PD-1/PD-L1 axis. The biological implications of PD-1/PD-L1 in cancer treatment and the fundamentals of nanotechnology, focusing on the novel strategies used in nanomedicine, are widely discussed along with the corresponding guidelines, clinical trial status, and the patent landscape of such formulations.

Single-nucleotide polymorphisms of nucleotide excision repair genes and their association with overall survival in North Indian lung cancer patients treated with platinum-based doublet chemotherapy.

Background: The aim of the study is to understand the association of Nucleotide excision repair (NER) inter-genetic polymorphic combinations with overall survival (OS) in lung cancer as well as its histological subtypes in the North Indian population. Materials and Methods: Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. For survival analysis, the univariate Kaplan-Meier and multivariate Cox regression model were applied. Recursive partitioning method, survival analysis tree was applied to study unfavorable genotypic combinations in NER single-nucleotide polymorphisms. Results: Combinatorial studies suggested no association between polymorphic combinations of NER genes and OS in lung cancer patients. When stratified as per lung cancer histological subtypes, adenocarcinomas patients with XPG 670 and XPC 499 polymorphism a significant increase in OS in combined heterozygous and mutant genotype with a lower hazardous ratio (Hazard Ratio1 (HR) = 0.20; P = 0.004). Small-cell lung carcinoma (SCLC) patients with XPF 11985A>G and XPD Arg156Arg polymorphism showed a 4-fold hazard ratio among heterozygous genotype (HR1 = 4.84; P = 0.007) where no significant results are obtained in patients suffering from squamous cell carcinoma histological subtypes. STREE showed XPG Asp1104His (W), XPD Lys751Gln (H + M), XPF Arg415Gln (H + M) genotype was associated with a lower hazard ratio (P = 0.0007) showing survival of 11.6 months when compared with the reference (median survival time = 3.52). Conclusion: It can be concluded that SCLC patients with polymorphic combinations of the NER pathway were associated with a higher risk of mortality. STREE depicted the association of NER polymorphic combinations with a lower hazard ratio predicting them to be a good prognostic factor for lung cancer.

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.

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.

Structural, functional analysis and association of MSH6 rs1800932, rs1042821 polymorphisms with clinical outcome in North Indian lung cancer patients treated with platinum-based doublet chemotherapy.

BACKGROUND: In this study, we have done structural and functional analysis of rs1800932 rs1042821 polymorphisms and tried to estimate any association of these polymorphisms with clinical outcomes in north Indian lung cancer patients. METHODS: Genotyping of 500 lung cancer patients was completed utilizing PCR-RFLP (Polymerase chain reaction- Restriction fragment length polymorphism). MedCalc statistical software was used to calculate adjusted and unadjusted odds ratios. Various computational tools like SIFT PROVEAN are used for functional analysis. Structural analysis was completed via MODELLER and CHIMERA. RESULTS: In our study, patients suffering from small cell lung cancer (SCLC) and harboring heterozygous genotype (AG) for MSH6 (rs1800932) polymorphism have reported a significant increase in median survival time (MST) (20.6 vs. 7.6 months, p = 0.03). Furthermore, for MSH6 rs1042821 polymorphism, patients undergoing docetaxel and carbo/cisplatin combination chemotherapeutic regimen and carrying heterogeneous genotype (CT) reported a significant increase in MST (16.6 vs.8.36 months, p = 0.03) and a corresponding decrease in hazard ratio 0.42 (95% CI= 0.18-1.03). Structural and Functional analysis of rs1042821 polymorphism revealed that it is present in the non-coding region of MSH6 protein and is significantly associated with increased overall survival. CONCLUSIONS: These results suggest that MSH6 rs1800932 rs1042821 polymorphisms are involved in increasing the overall survival of lung cancer patients, further confirmed by computational analysis.

Polymorphisms in the MSH2 gene predict poor survival of North Indian lung cancer patients undergoing chemotherapy.

Aim: To estimate if MSH2 polymorphisms, viz. rs63749993, rs2303425, rs2303426, rs4987188, rs2303428 and rs17217772, have any association with clinical outcomes in North Indian lung cancer patients. Materials & methods: PCR-RFLP was used for genotyping 500 cases. Logistic regression and survival analysis was performed by utilizing MedCalc software. Results & conclusion: Our study concluded, adenocarcinoma subjects having heterozygous genotype for rs2303425 have increased survival time (MST = 12.43, p = 0.03). In lung cancer patients undergoing paclitaxel therapy, heterozygous carriers for the rs17217772 polymorphism have reduced survival time (MST = 7.96 vs 2.63 months; HR = 2.09; p = 0.02). For rs63749993 polymorphism undergoing irinotecan therapy, subjects having mutant genotype showed poor survival (13.26 vs 6.06 months; HR = 5.37; p = 0.0004). The results suggest that MSH2 polymorphisms are involved in decreasing overall survival for patients undergoing platinum-based chemotherapy.

Ability of the LACE index to predict 30-day hospital readmissions in patients with community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: Hospital readmissions within 30 days are used as an indicator of quality of hospital care. We aimed to evaluate the ability of the LACE (Length of stay, Acuity of admission, Comorbidities based on Charlson comorbidity score and number of Emergency visits in the last 6 months) index to predict the risk of 30-day readmissions in patients hospitalised for community-acquired pneumonia (CAP). METHODS: In this retrospective cohort study a LACE index score was calculated for patients with a principal diagnosis of CAP admitted to a tertiary hospital in Sydney, Australia. The predictive ability of the LACE score for 30-day readmissions was assessed using receiver operator characteristic curves with C-statistic. RESULTS: Of 3996 patients admitted to hospital for CAP at least once, 8.0% (n=327) died in hospital and 14.6% (n=584) were readmitted within 30 days. 17.8% (113 of 636) of all 30-day readmissions were again due to CAP, followed by readmissions for chronic obstructive pulmonary disease, heart failure and chest pain. The LACE index had moderate discriminative ability to predict 30-day readmission (C-statistic=0.6395) but performed poorly for the prediction of 30-day readmissions due to CAP (C-statistic=0.5760). CONCLUSIONS: The ability of the LACE index to predict all-cause 30-day hospital readmissions is comparable to more complex pneumonia-specific indices with moderate discrimination. For the prediction of 30-day readmissions due to CAP, the performance of the LACE index and modified risk prediction models using readily available variables (sex, age, specific comorbidities, after-hours, weekend, winter or summer admission) is insufficient.