Lung microbiome in lung cancer: A new horizon in cancer study.

Lung cancer (LC) is the second most prevalent cancer worldwide and a leading cause of cancer-related deaths. Recent technological advancements have revealed that the lung microbiome, previously thought to be sterile, is host to various microorganisms. The association between the lung microbiome and LC initiation, progression, and metastasis is complex and contradictory. However, disruption in the homeostasis of microbiome compositions correlated with the increased risk of LC. This review summarises current knowledge on the most recent developments and trends in lung cancer-related microbiota or microbial components. This manuscript aims to provide information on this rapidly evolving field while giving context to the general role of the lung microbiome in LC. In addition, this review briefly discussed the causative association of lung microbiome with LC. We will review the mechanisms of how lung microbiota influences carcinogenesis, focusing on microbiota dysbiosis. Moreover, we will also discuss the host-microbiome interaction as host-microbiota plays a crucial role in stimulating and regulating the immune response. Finally, we provide information on the diagnostic role of the microbiome in LC. It aims to offer an overview of the lung microbiome as a predictive and diagnostic biomarker in LC.

Promises of Protein Kinase Inhibitors in Recalcitrant Small-Cell Lung Cancer: Recent Scenario and Future Possibilities.

SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs.

Epigenetics regulation of prostate cancer: Biomarker and therapeutic potential.

Prostate cancer (CaP) is the second leading cause of cancer death and displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. The etiology of most cases of CaP is not understood completely, which makes it imperative to search for the molecular basis of CaP and markers for early diagnosis. Epigenetic modifications, including changes in DNA methylation patterns, histone modifications, miRNAs, and lncRNAs are key drivers of prostate tumorigenesis. These epigenetic defects might be due to deregulated expression of the epigenetic machinery, affecting the expression of several important genes like GSTP1, RASSF1, CDKN2, RARRES1, IGFBP3, RARB, TMPRSS2-ERG, ITGB4, AOX1, HHEX, WT1, HSPE, PLAU, FOXA1, ASC, GPX3, EZH2, LSD1, etc. In this review, we highlighted the most important epigenetic gene alterations and their variations as a diagnostic marker and target for therapeutic intervention of CaP in the future. Characterization of epigenetic changes involved in CaP is obscure and adequate validation studies are still required to corroborate the present results that would be the impending future of transforming basic research settings into clinical practice.

Development and Challenges of Diclofenac-Based Novel Therapeutics: Targeting Cancer and Complex Diseases.

Diclofenac is a highly prescribed non-steroidal anti-inflammatory drug (NSAID) that relieves inflammation, pain, fever, and aches, used at different doses depending on clinical conditions. This drug inhibits cyclooxygenase-1 and cyclooxygenase-2 enzymes, which are responsible for the generation of prostaglandin synthesis. To improve current diclofenac-based therapies, we require new molecular systematic therapeutic approaches to reduce complex multifactorial effects. However, the critical challenge that appears with diclofenac and other drugs of the same class is their side effects, such as signs of stomach injuries, kidney problems, cardiovascular issues, hepatic issues, and diarrhea. In this article, we discuss why defining diclofenac-based mechanisms, pharmacological features, and its medicinal properties are needed to direct future drug development against neurodegeneration and imperfect ageing and to improve cancer therapy. In addition, we describe various advance molecular mechanisms and fundamental aspects linked with diclofenac which can strengthen and enable the better designing of new derivatives of diclofenac to overcome critical challenges and improve their applications.

Racially Disparate Expression of mTOR/ERK-1/2 Allied Proteins in Cancer.

Recent studies revealed that ethnic differences in mechanistic target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK-1/2) signaling pathways might be associated with the development and progression of different human malignancies. The African American (AA) population has an increased rate of cancer incidence and mortality compared to the Caucasian American (CA) population. Although the socioeconomic differences across different ethnic groups contribute to the disparity in developing different cancers, recent scientific evidence indicates the association of molecular and genetic variations in racial disparities of different human malignancies. The mTOR and ERK-1/2 signaling pathways are one of the well-known oncogenic signaling mechanisms that regulate diverse molecular and phenotypic aspects of normal as well as cancer cells in response to different external or internal stimuli. To date, very few studies have been carried out to explore the significance of racial disparity with abnormal mTOR and ERK-1/2 kinase signaling pathways, which may contribute to the development of aggressive human cancers. In this review, we discuss the differential regulation of mTOR and ERK-1/2 kinase signaling pathways across different ethnic groups, especially between AA and CA populations. Notably, we observed that key signaling proteins associated with mTOR and ERK-1/2 pathway including transforming growth factor-beta (TGF-ß), Akt, and VEGFR showed racially disparate expression in cancer patients. Overall, this review article encompasses the significance of racially disparate signaling molecules related to mTOR/ERK1/2 and their potential in developing tailor-made anti-cancer therapies.

BCG response prediction with cytokine gene variants and bladder cancer: where we are?

PURPOSE: Bladder cancer (BC) is one of the most widespread cancers afflicting men and women and also has major philosophical impact on health care worldwide. Despite elaborate characterization of the risk factors and treatment options, BC is still a major epidemiological problem worldwide and its incidence lingers to upswing each year. Over the last three decades, intravesical immunotherapy with the biological response modifier Mycobacterium bovis-Bacillus Calmette Guerin (BCG) has been established as the most effective adjuvant treatment for averting local recurrences and tumor progression following transurethral resection of non-muscle-invasive bladder cancer. DESIGN AND METHODS: PUBMED database was searched for articles, and manuscripts were selected that provided data regarding the correlation of BCG therapy and its response with different cytokine gene variants. RESULTS: It is not clear how Bacillus Calmette-Guerin (BCG) works to treat BC. It may stimulate an immune response or cause inflammation of the bladder wall that destroys cancer cells within the bladder. Lot of reports indicated the correlation of various cytokines with respect to BCG therapy in BC, but the exact mechanism is under debate. CONCLUSION: Research continues to establish the most effectual strain of BCG and the best dosage schedule for the treatment for bladder cancer but, on the other hand, a very critical part of this therapy to find out the correlation of different cytokine with BCG therapy, which will give a better insights not only the mechanism but also a better therapeutic options.

IL-8 -251 T > A polymorphism is associated with bladder cancer susceptibility and outcome after BCG immunotherapy in a northern Indian cohort.

BACKGROUND AND AIMS: Chemokines and transcription factor NF-kappaB play a pivotal role in development of carcinoma of the bladder (CaB). The present study was conducted to analyze the association of chemokines IL-8 -251 T>A and +678 C>T and NF-kappaB -94 (ATTG) insertion/deletion polymorphisms with the risk of CaB and outcome after bacillus Calmette-Guerin (BCG) immunotherapy in a cohort of northern India. METHODS: Histologically confirmed 205 CaB cases and 270 controls were included. Of these, 71 patients were treated with BCG immunotherapy. Genotyping was done using allele-specific PCR methodology. RESULTS: The variant genotype (AA) of IL-8 -251 polymorphism was associated with more than 2-fold risk of CaB (OR 2.12; p = 0.003; 95% CI 1.28-3.52). None of the other genotypes showed association with CaB risk. Subsequently, the diplotype -251A/+678T demonstrated a 1.8-fold increased risk for CaB (OR 1.84, 95% CI 1.37-2.47). Furthermore, -251 AA genotypes reduced the risk of recurrence after BCG immunotherapy (AA; HR 0.12; 95% CI 0.04-0.41). Subsequently, improved recurrence-free survival (mean recurrence-free survival for GG, GA and AA genotypes was 24, 39 and 53 months respectively). Similarly, NF-kappaB ATTG Ins/Ins genotype was at reduced risk of recurrence after BCG treatment compared to Del/Del genotype, which exhibited a 2.5-fold increased risk of recurrence in patients treated with BCG immunotherapy (HR, 2.53; 95% CI 1.00-6.36). Subsequently, mean recurrence-free survival (Ins/Ins, 41; Ins/Del, 44 and Del/Del, 10 months; log rank, 0.030). CONCLUSIONS: Our results suggested that the IL-8 -251 T>A polymorphism may be a relevant host susceptibility factor for bladder carcinoma development and may influence outcome after BCG immunotherapy. Similarly, NF-kappaB ATTG polymorphism may also modify risk-free survival of BCG-treated patients.

IL-10 -1082 G>A: a risk for prostate cancer but may be protective against progression of prostate cancer in North Indian cohort.

BACKGROUND: Chronic intraprostatic inflammation is suspected to play a major role in the pathogenesis of prostate cancer (PCa). Polymorphisms in interleukin-10 (IL-10), a key anti-inflammatory cytokine gene can influence immune response and immune evasion of tumor cells. Its role as an anti-metastatic molecule is also well documented. METHODS: Gene promoter polymorphisms in IL-10 (-1082 G>A and -819 C>T) was analyzed in 159 PCa patients and 259 healthy controls to investigate their potential association with susceptibility for PCa. RESULTS: Our results indicated that the heterozygous (GA) and homozygous mutant (AA) genotypes of IL-10 -1082 to be more prevalent among PCa patients in comparison to controls (GA: OR - 2.8, p = 0.011; AA: OR - 2.3, p = 0.037). More patients (92.5%) than controls (82.7%) were positive for the A allele (GA + AA: OR - 2.6, p = 0.015). We observed lower frequency of T(-819)-G(-1082) haplotype in patients without bone metastasis (4.4%, OR - 0.30, p = 0.019) in comparison to PCa patients with bone metastasis (12.6%). CONCLUSION: Our results support the emerging hypothesis that genetically determined immune activity may play a role in the pathophysiology of PCa. Our findings of high producer of IL-10 -1082 variants suggest initiation of PCa. Future studies in large cohort of different ethnicity PCa groups are warranted to establish definite associations with other cytokine gene polymorphisms.

Association between -174 G/C promoter polymorphism of the interleukin-6 gene and progression of prostate cancer in North Indian population.

The cellular alterations that give rise to cancer initiate changes in cytokine expression. Though IL-6 is known to play a major role in proliferation of tumor cells, IL-4 upregulates androgen receptors and prostate-specific antigen (PSA). The present study was undertaken to evaluate the association of IL-4 and IL-6 gene polymorphisms for the susceptibility to prostate cancer (PCa) risk. Our study included 200 controls and 200 histologically confirmed cases of PCa. Polymorphisms in IL-4 (intron 3, by VNTR analysis) and IL-6 (-174 G/C, by amplification refractory mutation system, i.e., ARMS-PCR) were genotyped in all the subjects. There was no significant association of IL-4 and IL-6 gene polymorphisms with the risk of PCa. Nevertheless, twofold risk with progression to bone metastasis (odds ratio = 2.09; 95% confidence interval = 1.16-3.75; p = 0.014) in PCa patients was observed. No association with other confounding factors such as PSA level, Gleason score, and lifestyle-associated risk factors like tobacco chewing and cigarette smoking was seen. Our study suggests that an IL-6 gene variant may be associated with prostate progression and bone metastasis.