Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine.

Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to improved understanding of the intricate network encompassing various signalling pathways and molecular cross-talk in solid tumors. In the present review, we underscore the current trends in omics technologies and highlight their role in understanding genotypic-phenotypic co-relation in cancer with respect to 3-D in vitro tumor models. We further discuss the challenges associated with omics technologies and provide our outlook on the future applications of these technologies in drug discovery and precision medicine for improved management of cancer.

Comparative Effectiveness of Oral Hypoglycemic Agents for Glycemic Control and Glycemic Variability in Patients with Type 2 Diabetes Mellitus: Using Flash Glucose Monitoring.

AIM: The study aimed to compare the effectiveness of oral hypoglycemic agents (OHAs) as monotherapy, dual and quadruple therapy for glycemic control (GC) and glycemic variability (GV) in patients with type-2 diabetes (T2DM) using flash glucose monitoring system (FGM). BACKGROUND: Diabetes management largely relies on HbA1c monitoring. Glycemic variability (GV) has been an evolving glycemic target for preventing complications related to type 2 diabetes mellitus (T2DM). OBJECTIVE: The purpose of the study was to compare glycemic control (GC) measures and glycemic variability (GV) measures among study groups and to study the relationships between GC and GV indices. METHODS: Retrospectively, FGM data were collected from 50 T2DM patients. The patients were classified based on prescribed number of OHAs as monotherapy [group 1: dipeptidyl peptidase- 4 (DPP-4) inhibitors (n=10), group 2: sodium-glucose co-transporter-2 (SGLT2) inhibitors (n=10), group 3: sulphonylureas (n=10), group 4: dual therapy (n=10), and group 5: quadruple therapy (n=10)]. Measures of GC and GV were evaluated. RESULTS: Significant differences between study groups were observed in GC and GV measurements. The SGLT2 inhibitors monotherapy group demonstrated optimal GC [eA1c (%): 6.5 ± 2.2; MBG: 140.80 ± 63.94; TIR: 60.60 ± 19.96] and GV (SD: 42.38 ± 34.57; CV: 27.85 ± 6.68; MAGE: 96.76 ± 52.47; MODD: 33.96 ± 22.91) in comparison to other study groups. On using Pearson correlation analysis, mean blood glucose (MBG) and mean amplitude of glycemic excursion (MAGE) showed moderate correlation (r = 0.742)(r2 = 0.551), depicting distinct glucose variabilities at the same mean blood glucose levels. CONCLUSION: The monotherapy group of SGLT2 inhibitors demonstrated glucose-lowering effects with reduced glycemic variability. Hence, optimum glycemic control is associated with decreased glycemic variability.

Cholecalciferol Exhibits no Antibacterial Effect on Staphylococcus aureus and Escherichia coli: an in-vitro Study.

BACKGROUND: The pleiotropic effect of cholecalciferol (vitamin D3) has gained significant momentum and has been explored widely. OBJECTIVES: The study aimed to investigate the antimicrobial effect of cholecalciferol against S. aureus and E. coli. METHODS: An in-vitro study was performed for the antimicrobial effect of cholecalciferol against S. aureus and E. coli. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined following the broth microdilution method. RESULTS: The MIC value of cholecalciferol against both S. aureus and E. coli was 0.312 mg/ml, and the MBC for both organisms was 1.25 mg/ml. However, we also observed a significant antimicrobial effect in the dimethyl sulfoxide (DMSO) control at 12.5% (v/v). Therefore, the observed antimicrobial effect may be attributed to DMSO, indicating cholecalciferol does not directly inhibit S. aureus and E. coli. CONCLUSION: This study indicates that cholecalciferol does not directly inhibit S. aureus and E. coli. Hence, we suggest exploring the antibacterial properties of other vitamin D analogs, such as calcitriol or its synergetic effect with other antimicrobial agents.

The association between micronutrient levels and diabetic foot ulcer: A systematic review with meta-analysis.

Background: Diabetic foot ulcers (DFU) are a major complication of diabetes mellitus (DM). Nutrient deficiencies are among the major risk factors in DFU development and healing. In this context, we aimed to investigate the possible association between micronutrient status and risk of DFU. Methods: A systematic review (Prospero registration: CRD42021259817) of articles, published in PubMed, Web of Science, Scopus, CINAHL Complete, and Embase, that measured the status of micronutrients in DFU patients was performed. Results: Thirty-seven studies were considered, of which thirty were included for meta-analysis. These studies reported levels of 11 micronutrients: vitamins B9, B12, C, D, E, calcium, magnesium, iron, selenium, copper, and zinc. DFU, compared to healthy controls (HC) had significantly lower vitamin D (MD: -10.82 14 ng/ml, 95% CI: -20.47, -1.16), magnesium (MD: -0.45 mg/dL, 95% CI: -0.78, -0.12) and selenium (MD: -0.33 µmol/L, 95% CI: -0.34, -0.32) levels. DFU, compared to DM patients without DFU, had significantly lower vitamin D (MD: -5.41 ng/ml, 95% CI: -8.06, -2.76), and magnesium (MD: -0.20 mg/dL, 95% CI: -0.25, -0.15) levels. The overall analysis showed lower levels of vitamin D [15.55ng/ml (95% CI:13.44, 17.65)], vitamin C [4.99µmol/L (95% CI:3.16, 6.83)], magnesium [1.53mg/dL (95% CI:1.28, 1.78)] and selenium [0.54µmol/L (95% CI:0.45, 0.64)]. Conclusion: This review provides evidence that micronutrient levels significantly differ in DFU patients, suggesting an association between micronutrient status and risk of DFU. Therefore, routine monitoring and supplementations are warranted in DFU patients. We suggest that personalized nutrition therapy may be considered in the DFU management guidelines. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=259817, identifier CRD42021259817.

Impact of tuberculosis disease on human gut microbiota: a systematic review.

INTRODUCTION: This systematic review evaluates the gut microbiota (GM) status in tuberculosis (TB) patients compared to healthy volunteers due to the disease or its treatment. AREAS COVERED: We conducted a systematic review of all articles published in PubMed, Web of Science, and Embase that assessed the impact of TB disease and anti-tubercular therapy (ATT) on GM from inception till January 2022 (Protocol registration number in PROSPERO: CRD42021261884). Regarding the microbial diversity indices and taxonomy, we found a significant difference in GM status between the TB and healthy control (HC) groups. We found an overabundance of Phylum Proteobacteria and depletion of some short-chain fatty acid-producing bacteria genera like Bifidobacteria, Roseburia, and Ruminococcus in the TB group. We found that ATT exacerbates the degree of dysbiosis caused by Mycobacteria tuberculosis disease. EXPERT OPINION: The modulation of GM in TB patients in clinical practice may serve as a promising target to reverse the dysbiosis caused. Moreover, this can optimistically change the TB treatment outcome. We expect that appropriate probiotic supplementation with antimycobacterial treatment during tuberculosis disease will help stabilize the GM throughout the treatment phase and protect the GM from dysbiosis.

Vitamin D attenuates biofilm-associated infections via immunomodulation and cathelicidin expression: a narrative review.

INTRODUCTION: Infections are becoming more difficult to treat, at least partly on account of microbes that produce biofilms. Reports suggest that decreased levels of antimicrobial peptides like cathelicidin, elevated levels of inflammatory cytokines, and biofilm formation are all associated with vitamin D deficiency, making vitamin D - deficient individuals more susceptible to infection. Infections attributable to biofilm-producing microbes can be managed by adjuvant therapy with vitamin D because of its immunomodulatory role, particularly because of the ability of vitamin D-pathway to induce the antimicrobial peptides like cathelicidin and decrease proinflammatory cytokines. AREAS COVERED: This narrative review covers biofilm formation, infections associated with biofilm due to vitamin D deficiency, putative role of vitamin D in host protection and the effect of vitamin D supplementation in biofilm-associated infections. A comprehensive literature search in PubMed and Google Scholar utilizing suitable keywords at multiple time points extracted relevant articles. EXPERT OPINION: Although vitamin D deficiency has been associated with infections by biofilm producing microbes, comprehensive clinical trials in various ethnicities are required to understand the likely relationships between vitamin D receptor gene expression, cathelicidin levels, and infection outcome. Current evidence hypothesizes that maintaining normal vitamin D level can help prevent and treat these infections.

Psychosis susceptibility zinc finger protein 804A (ZNF804A) gene polymorphism in schizophrenia patients treated with olanzapine in North Indian population.

PURPOSE: The Zinc finger protein 804A (ZNF804A) is a potential schizophrenia candidate gene that has emerged from genome-wide association studies. The aim of the study is to investigate whether this gene variant influences the response of positive or negative symptoms to antipsychotic drug olanzapine in North Indian schizophrenia patients. MATERIALS AND METHODS: Our study involved 184 unrelated schizophrenia cases (114 males and 70 females; mean age: 52.8 ± 11.6 years) and 300 normal controls (168 males and 132 females; mean age: 54.9 ± 6.9 years). At the start of treatment and after four weeks, we assessed the response of positive and negative symptoms by positive and negative syndrome scale (PANSS). Olanzapine drug level was estimated using HPLC Method and Genotyping was performed using PCR-Snap Shot technique. RESULTS: Significant differences were observed in the genotype distribution (χ2 = 6.10, d.f. = 2, p = 0.04) and allele frequencies (χ2 = 5.14, d.f. = 1, p = 0.02; odds ratio = 0.57, 95% confidence interval =1.09-3.48) between schizophrenia patients and controls group. The improvement of positive and negative schizophrenia symptoms after 4 weeks of treatment with olanzapine was assessed. Patients homozygous for the ZNF804A risk allele for AA show poorer improvement of positive symptoms compared to patients with a protective allele. CONCLUSIONS: Our findings indicate that ZNF804A gene polymorphism plays a significant role in the treatment of schizophrenia, suggesting that ZNF804A may be an effective marker for schizophrenia treatment.

A comparative analysis of molecular genotypes of Mycobacterium tuberculosis isolates from HIV-positive and HIV-negative patients.

Setting: Tuberculosis Research Laboratory, Division of Clinical Microbiology and Molecular Medicine, Department of Laboratory Medicine, All India Institute of Medical Sciences, and the National Institute of Tuberculosis and Respiratory Diseases (NITRD), both situated in New Delhi. Objectives: We aimed to identify the distribution of various genotypes of M. tuberculosis among HIV-positive and HIV-negative patients suspected of having Tuberculosis, seen at the National Institute of Tuberculosis and Respiratory Diseases, New Delhi, which is a tertiary care dedicated TB hospital. Patients and methods: Genotyping by Spoligotyping and 24 loci MIRU-VNTR was performed and analyzed using SITVITWEB and MIRU-VNTRplus. Drug susceptibility patterns were also analyzed. Results: A total of 503 subjects who were PTB/EPTB suspected were recruited and 287 were culture positive. Among them, 276 had growth of Mycobacterium tuberculosis (MTB) and in 11 patients non-tuberculous mycobacteria (NTM) were grown. The isolation rate of NTM was predominantly from HIV positive [10 of 130 (7.6%)] patients. Of the total isolates of MTB, 156 (56.5%) were from HIV negative patients and 120 (43.5%) were from HIV positive patients. All 276 M. tuberculosis isolates were genotyped and tested for drug susceptibility patterns. The CAS genotype was most predominant [153 (55.4%)], followed by Beijing lineage [44 (15.9%)], East African India [25 (9.1%)] and others [54 (19.6%)]. Beijing genotype was significantly more common in HIV positive patients (22.5%) than in HIV negative patients (10.9%). In MIRU-VNTR analysis, clustering was found to be more frequent in CAS strains irrespective of HIV status. In the HIV positive group, spoligotyping could differentiate various genotypes in 90% of isolates and MIRU-VNTR analysis in 84.2% of isolates. The clustering of various MTB strains was more associated with drug resistance. Conclusion: The Beijing lineage was predominant in HIV-TB coinfected cases, even though the Central Asian Strain (CAS) was overall more predominant in the region.

Procalcitonin as a predictive marker in COVID-19: A systematic review and meta-analysis.

BACKGROUND: Coronavirus disease 2019 has emerged as a global pandemic causing millions of critical cases and deaths. Early identification of at-risk patients is crucial for planning triage and treatment strategies. METHODS AND FINDINGS: We performed this systematic review and meta-analysis to determine the pooled prognostic significance of procalcitonin in predicting mortality and severity in patients with COVID-19 using a robust methodology and clear clinical implications. DESIGN: We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Handbook for Systematic Reviews of Interventions guidelines. We included thirty-two prospective and retrospective cohort studies involving 13,154 patients. RESULTS: The diagnostic odds ratio of procalcitonin for predicting mortality were estimated to be 11 (95% CI: 7 to 17) with sensitivity, specificity, and summary area under the curveof 0.83 (95% CI: 0.70 to 0.91), 0.69 (95% CI: 0.58 to 0.79), and 0.83 (95% CI: 0.79 to 0.86) respectively. While for identifying severe cases of COVID-19, the odds ratio was 8.0 (95% CI 5.0 to 12.0) with sensitivity, specificity, and summary area under the curve of 0.73 (95% CI 0.67 to 0.78), 0.74 (0.66 to 0.81), and 0.78 (95% CI 0.74 to 0.82) respectively. CONCLUSION: Procalcitonin has good discriminatory power for predicting mortality and disease severity in COVID-19 patients. Therefore, procalcitonin measurement may help identify potentially severe cases and thus decrease mortality by offering early aggressive treatment.

Vitamin D receptor gene polymorphism and vitamin D supplementation on clinical/ treatment outcome in tuberculosis: current and future perspectives.

INTRODUCTION: Tuberculosis (TB) is a transnational public health concern, which requires more precise treatment strategies than the existing approaches. Vitamin D modulates the inflammatory and immune response to the disease. Robust evidence shows that vitamin D deficiency and its receptor gene polymorphism influence the susceptibility to TB and the outcome of the anti-tubercular treatment (ATT). However, in the different populations, these findings were inconsistent and even contradictory. AREAS COVERED: The current review focuses on the association between vitamin D receptor (VDR) gene polymorphism with the risk of development of TB disease and response to the ATT. Additionally, it reviews various systematic reviews and meta-analyses on the impact of vitamin D supplements on both clinical and treatment outcomes in TB patients. EXPERT OPINION: Although the majority of the findings rule out the benefits of the supplementation, sufficient evidence is available to warrant larger epidemiological research that should be aimed to generate possible interaction among the VDR polymorphism, vitamin D status, and the outcome in TB. We conclude that establishing such an association in different ethnic populations will help design nutrigenomics- or pharmacogenomics-based vitamin D supplementation to develop a personalized medicine approach to flatten the curve of TB disease.

Signet ring cell cancer of stomach and gastro-esophageal junction: molecular alterations, stage-stratified treatment approaches, and future challenges.

PURPOSE: There has been an increase in the incidence of signet ring cell cancer (SRCC) of the stomach and gastro-esophageal junction (GEJ). The multistage carcinogenesis involving genetic and epigenetic aberrations may have a major role in the increasing incidence of SRCC. Although there are numerous studies on the prognostic value of SRCC, they are markedly inconsistent in their results, making it impossible to draw any meaningful conclusions. We aimed to examine the available evidences on molecular alterations and stage-stratified treatment approaches in SRCC of the stomach and GEJ. METHODS: A systematic search was carried out in PubMed. Studies available in English related to SRCC of stomach and gastro-esophageal junction were identified and evaluated. RESULTS: This study reviewed the current evidence and provided an insight into the molecular alterations, stage-stratified treatment approaches, and future challenges in the management of SRCC of the stomach and GEJ. Specific therapeutic strategies and personalized multimodal treatment have been recommended based on the tumor characteristics of SRCC. CONCLUSION: Multistage carcinogenesis involving genetic and epigenetic aberrations in SRCC is interlinked with stage-dependent prognosis. Specific therapeutic strategy and personalized multimodal treatment should be followed based on the tumor characteristics of SRCC. Endoscopic resection, radical surgery, and perioperative chemotherapy should be offered in carefully selected patients based on stage and prognostic stratification. Future studies in genetic and molecular analysis, histopathological classification, and options of multimodality treatment will improve the prognosis and oncological outcomes in SRCC of gastric and GEJ.

Pharmacogenomics and Personalized Medicine in Type 2 Diabetes Mellitus: Potential Implications for Clinical Practice.

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, and is rising in incidence with widespread prevalence. Multiple gene variants are associated with glucose homeostasis, complex T2DM pathogenesis, and its complications. Exploring more effective therapeutic strategies for patients with diabetes is crucial. Pharmacogenomics has made precision medicine possible by allowing for individualized drug therapy based on a patient's genetic and genomic information. T2DM is treated with various classes of oral hypoglycemic agents, such as biguanides, sulfonylureas, thiazolidinediones, meglitinides, DPP4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, and GLP1 analogues, which exhibit various pharmacogenetic variants. Although genomic interventions in monogenic diabetes have been implemented in clinical practice, they are still in the early stages for complex polygenic disorders, such as T2DM. Precision DM medicine has the potential to be effective in personalized therapy for those suffering from various forms of DM, such as T2DM. With recent developments in genetic techniques, the application of candidate-gene studies, large-scale genotyping investigations, genome-wide association studies, and "multiomics" studies has begun to produce results that may lead to changes in clinical practice. Enhanced knowledge of the genetic architecture of T2DM presents a bigger translational potential. This review summarizes the genetics and pathophysiology of T2DM, candidate-gene approaches, genome-wide association studies, personalized medicine, clinical relevance of pharmacogenetic variants associated with oral hypoglycemic agents, and paths toward personalized diabetology.

Prediction of potential drug interactions between repurposed COVID-19 and antitubercular drugs: an integrational approach of drug information software and computational techniques data.

INTRODUCTION: Tuberculosis is a major respiratory disease globally with a higher prevalence in Asian and African countries than rest of the world. With a larger population of tuberculosis patients anticipated to be co-infected with COVID-19 infection, an ongoing pandemic, identifying, preventing and managing drug-drug interactions is inevitable for maximizing patient benefits for the current repurposed COVID-19 and antitubercular drugs. METHODS: We assessed the potential drug-drug interactions between repurposed COVID-19 drugs and antitubercular drugs using the drug interaction checker of IBM Micromedex®. Extensive computational studies were performed at a molecular level to validate and understand the drug-drug interactions found from the Micromedex drug interaction checker database at a molecular level. The integrated knowledge derived from Micromedex and computational data was collated and curated for predicting potential drug-drug interactions between repurposed COVID-19 and antitubercular drugs. RESULTS: A total of 91 potential drug-drug interactions along with their severity and level of documentation were identified from Micromedex between repurposed COVID-19 drugs and antitubercular drugs. We identified 47 pharmacodynamic, 42 pharmacokinetic and 2 unknown DDIs. The majority of our molecular modelling results were in line with drug-drug interaction data obtained from the drug information software. QT prolongation was identified as the most common type of pharmacodynamic drug-drug interaction, whereas drug-drug interactions associated with cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) inhibition and induction were identified as the frequent pharmacokinetic drug-drug interactions. The results suggest antitubercular drugs, particularly rifampin and second-line agents, warrant high alert and monitoring while prescribing with the repurposed COVID-19 drugs. CONCLUSION: Predicting these potential drug-drug interactions, particularly related to CYP3A4, P-gp and the human Ether-à-go-go-Related Gene proteins, could be used in clinical settings for screening and management of drug-drug interactions for delivering safer chemotherapeutic tuberculosis and COVID-19 care. The current study provides an initial propulsion for further well-designed pharmacokinetic-pharmacodynamic-based drug-drug interaction studies. PLAIN LANGUAGE SUMMARY: Introduction:: Tuberculosis is a major respiratory disease globally with a higher prevalence in Asian and African countries than rest of the world. With a larger population of tuberculosis patients predicted to be infected with COVID-19 during this period, there is a higher risk for the occurrence of medication interactions between the medicines used for COVID-19 and tuberculosis. Hence, identifying and managing these interactions is vital to ensure the safety of patients undergoing COVID-19 and tuberculosis treatment simultaneously.Methods:: We studied the major medication interactions that could likely happen between the various medicines that are currently given for COVID-19 and tuberculosis treatment using the medication interaction checker of a drug information software (Micromedex®). In addition, thorough molecular modelling was done to confirm and understand the interactions found from the medication interaction checker database using specific docking software. Molecular docking is a method that predicts the preferred orientation of one medicine molecule to a second molecule, when bound to each other to form a stable complex. Knowledge of the preferred orientation may be used to determine the strength of association or binding affinity between two medicines using scoring functions to determine the extent of the interactions between medicines. The combined knowledge from Micromedex and molecular modelling data was used to properly predict the potential medicine interactions between currently used COVID-19 and antitubercular medicines.Results:: We found a total of 91 medication interactions from Micromedex. Majority of our molecular modelling findings matched with the interaction information obtained from the drug information software. QT prolongation, an abnormal heartbeat, was identified as one of the most common interactions. Our findings suggest that antitubercular medicines, mainly rifampin and second-line agents, suggest high alert and scrutiny while prescribing with the repurposed COVID-19 medicines.Conclusion:: Our current study highlights the need for further well-designed studies confirming the current information for recommending safe prescribing in patients with both infections.

Biomarkers for Antiplatelet Therapies in Acute Ischemic Stroke: A Clinical Review.

Stroke is one of the world's leading causes of disability and death. Antiplatelet agents are administered to acute ischemic stroke patients as secondary prevention. Clopidogrel involves biotransformation by cytochrome P450 (CYP) enzymes into an active metabolite, and single nucleotide polymorphisms (SNPs) can influence the efficacy of this biotransformation. Despite the therapeutic advantages of aspirin, there is significant inter-individual heterogeneity in response to this antiplatelet drug. In this clinical review, the recent advances in the biomarkers of antiplatelet agents in acute ischemic stroke are discussed. The studies reviewed herein highlight the clinical relevance of antiplatelet resistance, pharmacotherapy of antiplatelet agents predicting drug response, strategies for identifying aspirin resistance, pharmacogenetic variants of antiplatelet agents, miRNAs, and extracellular vesicles (EVs) as biomarkers toward the personalized approach in the management of acute ischemic stroke. The precise pathways contributing to antiplatelet resistance are not very well known but are presumably multi-factorial. It is essential to understand the clinical relevance of clopidogrel and aspirin-related single nucleotide polymorphism (SNPs) as potential predictive and prognostic biomarkers. Prasugrel is a next-generation antiplatelet agent that prevents ADP-platelet activation by binding irreversibly to P2Y12 receptor. There are sporadic reports of prasugrel resistance and polymorphisms in the Platelet endothelial aggregation receptor-1 (PEAR1) that may contribute to a change in the pharmacodynamics response. Ticagrelor, a direct-acting P2Y12-receptor antagonist, is easily absorbed and partly metabolized to major AR-C124910XX metabolite (ARC). Ticagrelor's primary active metabolite, ARC124910XX (ARC), is formed via the most abundant hepatic cytochrome P450 (CYP) enzyme, CYP3A4, and CYP3A5. The integration of specific biomarkers, genotype as well as phenotype-related data in antiplatelet therapy stratification in patients with acute ischemic stroke will be of great clinical significance and could be used as a guiding tool for more effective, personalized therapy.

Pharmacogenetics of ATP binding cassette transporter MDR1(1236C>T) gene polymorphism with glioma patients receiving Temozolomide-based chemoradiation therapy in Indian population.

Temozolomide (TMZ), an alkylating agent with a broad-spectrum antitumor activity, ability to cross blood-brain barrier (BBB), shown to be effective against malignant glioma. This study aims to investigate the effect of 1236C>T (rs1128503) single-nucleotide gene polymorphisms of ABCB1 (MDR1) in north-Indian patients diagnosed with glioma undergoing TMZ-based chemoradiotherapy. Genotyping was performed in 100 patients diagnosed with malignant glioma (50 anaplastic astrocytoma (AA) patients and 50 glioblastoma multiforme (GBM) patients) and 150 age and sex-matched controls by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method, followed by sanger sequencing. TMZ plasma levels were analyzed by reverse phase HPLC method. Glioma patient's survival time was analyzed by Kaplan-Meier's curve. Results of MDR1 gene 1236C>T polymorphism showed significant allelic and genotypic frequency association between glioma patients and controls. The plasma TMZ levels between metabolizers group in Grade III and Grade IV were found to be statistically significant (p < 0.05). The mutant genotype (TT) has less survival benefit compared with other genotypes (CT/CC) and the survival difference between AA and GBM was found to be statistically significant (p < 0.05). Though CT and TT polymorphisms have significant association with lower TMZ levels in both Grade III (AA) and IV (GBM) tumors, the survival difference seems to be mainly among patients with Grade III tumors. Our findings suggest that the MDR1 gene polymorphism plays a role in plasma TMZ levels and in survival time of glioma patients and, hence, TMZ therapy in malignant glioma can be predicted by genotyping MDR1 (1236C>T) gene polymorphism.

Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions.

Ubiquitination is a key enzymatic post-translational modification that influences p53 stability and function. p53 protein regulates the expression of MDM2 (mouse double-minute 2 protein) E3 ligase and MDMX (double-minute 4 protein), through proteasome-based degradation. Exploration of targeting the ubiquitination pathway offers a potentially promising strategy for precision therapy in a variety of cancers. The p53-MDM2-MDMX pathway provides multiple molecular targets for small molecule screening as potential therapies for wild-type p53. As a result of its effect on molecular carcinogenesis, a personalized therapeutic approach based on the wild-type and mutant p53 protein is desirable. We highlighted the implications of p53 mutations in cancer, p53 ubiquitination mechanistic details, targeting p53-MDM2/MDMX interactions, significant discoveries related to MDM2 inhibitor drug development, MDM2 and MDMX dual target inhibitors, and clinical trials with p53-MDM2/MDMX-targeted drugs. We also investigated potential therapeutic repurposing of selective estrogen receptor modulators (SERMs) in targeting p53-MDM2/MDMX interactions. Molecular docking studies of SERMs were performed utilizing the solved structures of the p53/MDM2/MDMX proteins. These studies identified ormeloxifene as a potential dual inhibitor of p53/MDM2/MDMX interaction, suggesting that repurposing SERMs for dual targeting of p53/MDM2 and p53/MDMX interactions is an attractive strategy for targeting wild-type p53 tumors and warrants further preclinical research.

Vitamin D Supplementation in Diabetic Foot Ulcers: A Current Perspective.

INTRODUCTION: Diabetic foot ulcer (DFU) is a major complication of diabetes mellitus, as it can physically and emotionally impact the person. Its management can be challenging and expensive, depending on the severity of the wound and the presence of infection. BACKGROUND: The fat-soluble molecule, vitamin D, has gained great importance ever since its pleiotropism has been recognized. Its efficacy could be attributed to the presence of vitamin D receptors in most of the body tissues. Vitamin D plays a significant role in cell proliferation, differentiation, and immune modulation. It modulates the T and B cells resulting in the suppression of the immunoglobulins, autoimmunity, and inflammation. METHODS: We performed a literature search with the objective to highlight the role of vitamin D in peripheral vascular disease and peripheral neuropathy, which are the major risk factors for DFU, as well as evidences of its role in wound healing and management of DFU. RESULTS: Preclinical and clinical studies have shown that vitamin D influences multiple phases of wound healing and thereby accelerates the process. It modulates various cells involved in proliferation and remodelling phases. Vitamin D also enhances the expression of antimicrobial peptides that help to eliminate the microbes, as well as suppress the proinflammatory responses while enhancing the anti-inflammatory responses. CONCLUSION: This review concludes vitamin D to have a protective role in the immune and vascular system, improve glycaemic outcomes, and wound healing. Therefore, vitamin D could be a preferred adjuvant in the management of DFU.

Liquid biopsy approaches for pleural effusion in lung cancer patients.

Genomic profiling of tumors has become the mainstay for diagnosis, treatment monitoring and a guide to precision medicine. However, in clinical practice, the detection of driver mutations in tumors has several procedural limitations owing to progressive disease and tumor heterogeneity. The current era of liquid biopsy promises a better solution. This diagnostic utility of liquid biopsy has been demonstrated by numerous studies for the detection of cell-free DNA (cfDNA) in plasma for disease diagnosis, prognosis, and prediction. However, cfDNAs are limited in blood circulation and still hurdles to achieve promising precision medicine. Malignant pleural effusion (MPE) is usually detected in advanced lung malignancy, which is rich in tumor cells. Extracellular vesicles and cfDNAs are the two major targets currently explored using MPE. Therefore, MPE can be used as a source of biomarkers in liquid biopsy for investigating tumor mutations. This review focuses on the liquid biopsy approaches for pleural effusion which may be explored as an alternative source for liquid biopsy in lung cancer patients to diagnose early disease progression.

Histone Demethylase KDM5B as a Therapeutic Target for Cancer Therapy.

Lysine-specific demethylase 5B (KDM5B/PLU1/JARID1B) is found to be overexpressed in numerous malignancies, including breast, lung, skin, liver, and prostate cancer. Identification of molecules targeting the KDM5B enzyme could be a potential lead in cancer research. Although many KDM5B inhibitors with promising outcomes have been developed so far, its further application in clinical practice is limited due to toxicity and lack of target specificity. Here, we summarize the significance of targeting KDM5B in anticancer therapy and report the molecular docking studies of some known anti-viral agents, decitabine, entecavir, abacavir, penciclovir, and 3-deazaneplanocin A in the catalytic domain JmjC of KDM5B. These studies show the repurposing potential of identified anti-viral agents in cancer therapy.

Cannabinoids as an Alternative Option for Conventional Analgesics in Cancer Pain Management: A Pharmacogenomics Perspective.

The global cancer burden is significantly increasing at an alarming rate affecting patients, relatives, communities, and health-care system. Cancer patients require adequate pain relief and palliative care throughout the life course, especially in terminal illness. Although opioid treatment is successful in majority of patients, around 40% do not achieve enough analgesia or are prone to serious side effects and toxicity. The treatment of medical conditions with cannabis and cannabinoid compounds is constantly expanding. This review organizes the current knowledge in the context of SNPs associated with opioids and nonopioids and its clinical consequences in pain management and pharmacogenetic targets of cannabinoids, for use in clinical practice.