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.

Expression of stem cell markers as predictors of therapeutic response in metastatic prostate cancer patients.

BACKGROUND: Cancer stem cells (CSCs) have been implicated in prostate cancer (PCA) progression and therapeutic resistance. This study aimed to compare the expression levels of CSC CD (CD 44, CD 133, and CD 24) markers in treatment-naive patients with metastatic PCA before and after treatment. METHODS: The study included 60 treatment-naïve patients with metastatic PCA who received androgen deprivation therapy (ADT) alone (n = 30) and ADT plus chemotherapy (n = 30). The level of CD44, CD133, and CD24 were obtained by flow cytometric analysis before and after treatment. Baseline characteristics were also assessed, including age, pretreatment testosterone levels, and pretreatment prostate-specific antigen (PSA) levels. RESULTS: The baseline characteristics analysis showed no significant difference in pre-treatment testosterone levels between the ADT+ chemotherapy and ADT-alone groups. In the flow cytometric analysis, no significant difference was observed in pre-treatment CD44+ and CD133+ levels between the 2 treatment groups, although a trend towards higher pretreatment CD24- levels was observed in the ADT+ chemotherapy group. After treatment, significant reductions in testosterone and PSA levels were observed in both treatment arms. The ADT+ chemotherapy group showed a greater reduction in CD44+ and CD133+ levels compared to the ADT-alone group. Bioinformatic analysis using the UALCAN TCGA database also showed a similar trend of CD 44, CD 24, and CD 133 gene expression patterns. CONCLUSION: Combination therapy involving chemotherapy and ADT appears to have a greater impact on suppressing CSCs compared to ADT alone. These findings highlight the potential of targeting CSCs as a prognostic and predictive marker therapeutic strategy in metastatic PCA.

Quantitative estimation of TNF-α and IL-3 by using ELISA from human lung tissue in fatal asphyxial deaths.

Asphyxia-related deaths have always been a challenging task in the specialty of forensic pathology. Apart from helpful macroscopical signs (e.g., strangulation marks, cyanosis, petechial haemorrhage, and lung edema), recent literature indicates that prolonged asphyxia is sufficient to induce an increase in mast cells (MC). Inflammatory cells migrate from the bone marrow to the lungs, aiding in the diagnosis of fatal asphyxial death. The present study analyzed human lung tissue samples from 90 medico-legal autopsy cases, including 45 asphyxial deaths and 45 controls (non-asphyxial deaths). The cases ranged from 2 to 68 years, with a mean age of 33.23 years. In 90 cases, 74 cases were of males, and 16 were of females. Human lung tissue samples were analyzed by using the sandwich ELISA method. The results indicated a statistically significant increase in TNF-α and IL-3 concentration in fatal asphyxial deaths, including those caused by hanging, drowning, and smothering. Mean ± SD in asphyxial and non-asphyxial cases for the TNF-α and IL-3 concentration statistically analysed. In asphyxial cases, the average IL-3 concentration (Conc.) was 1558.50 ± 350.53 pg/ml, and the average TNF-α concentration (Conc.) was 499.75 ± 479.41 pg/ml. In contrast, in non-asphyxial cases, the average IL-3 concentration (Conc.) was found to be 849.73 ± 484.99 pg/ml, and the average TNF-α concentration (Conc.) was 208.08 ± 81.23 pg/ml. The mean change in IL-3 and TNF-α (Conc.) values are found to significant (<0.01) in asphyxial cases as compared to non-asphyxial cases. The ROC (Receiver operating characteristic curve) analysis revealed that TNF-α (AUC = 0.89) and IL-3 (AUC = 0.87) concentration (conc.) were stronger predictors of asphyxial deaths with an optimal cut-off value of 455.20 pg/ml for TNF-alpha and 1700.62 pg/ml for IL-3 respectively. Our findings imply that mast cells (MC) are critical in fatal hypoxia-related mortality and that TNF-α and IL-3 can be reliable markers for detecting mast cells in asphyxial deaths. It could be very beneficial to forensic pathologists tasked with differentiating fatal asphyxial fatalities from other causes of death.

Deregulation of miR-10b and miR-21 Correlate with Cancer Stem Cells Expansion through the Apoptotic Pathway in Prostate Cancer.

BACKGROUND: MicroRNAs are small, non-coding RNA molecules that regulate important cellular processes such as tumorigenesis, cell proliferation, and apoptosis. Cancer stem cells are a subset of cells that control metastasis and cell proliferation. In this study, we focus on the roles of miR-10b, miR-21 and correlate with cancer stem cells through the apoptotic pathway in different stages of prostate cancer (PCa). METHODS: In total, 45 patients, each group with Benign prostatic hyperplasia (BPH), localised PCa, and metastatic PCa, were recruited. MicroRNA and gene expression were estimated through quantitative polymerase chain reaction. Flow cytometry was used to characterise prostate cancer stem cells (PCSCs), estimate reactive oxygen species (ROS), apoptosis and chemiluminescent immunoassay was used to estimate interleukin 6 (IL-6), tumour necrosis factor (TNF-α), prostate-specific antigen (PSA), and testosterone. RESULTS: The fold change mean expressions of miR-21, miR-10b, Cytochrome C, and B-cell lymphoma 2 (BCL-2) were significantly upregulated in localised and metastatic PCa compared with BPH. In contrast, the mean fold change expressions of Bcl-2-associated X protein (BAX), Caspase-3, Caspase-9, and Second mitochondria-derived activator of caspase (SMAC) were lower in localised and metastatic PCa compared to BPH. The levels of IL-6, TNF-α, ROS, PSA and testosterone also showed a significant increase while apoptosis was decreased in both localized PCa and metastatic PCa as compared with BPH. In bioinformatics analyses, we found a similar pattern of miRNAs and gene expression in PCa databases. Our study also found a high expression of CD44+/CD24- and CD44+/CD133+ in localised and metastatic PCa compared with BPH. CONCLUSION: Our findings suggest miR-10b and miR-21 promote PCSCs and may target apoptotic genes involved in PCa pathogenesis; these miRNAs could be used as diagnosis biomarkers of PCa. In PCa pathogenesis and PCSCs regulation, the interaction between these two players is crucial and will help develop new PCa therapeutic targets.

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.

Autonomic Correlates of Letter Cancelation Task: What the Attention Load May Evoke?

OBJECTIVE: Attention can be assessed through Letter cancelation tasks (LCT) that employ visuospatial selection and appropriate motor responses. We examined the performance in the LCT with increasing attention load, and determined the related autonomic changes. METHODS: Autonomic parameters were estimated in healthy males at baseline and during three different cognitive load conditions using the LCT. RESULTS: Results revealed a statistically significant difference (n = 30) in the percent accuracy (χ2(2) = 15.2, p < .001) and percent omission (χ2(2) = 13.3, p = 0.001) with the increasing challenge in the LCT. The vagally-mediated measures of heart rate variability were significantly decreased with the commencement of the task revealing a parasympathetic withdrawal. The respiratory sinus arrythmia was decreased, and the photoplethysmography amplitude was significantly reduced (χ2(3) = 14.2, p = 0.003) as the attention demand increased. CONCLUSION: The performance declined with the increasing attention load. LCT evokes autonomic perturbations though overall autonomic variability does not change remarkably.

Long Non Coding RNA in Triple Negative Breast Cancer: A Promising Biomarker in Tumorigenesis.

Globally, Triple-negative breast cancer (TNBC) is an unsurpassed variant of breast cancer (BC) with a very high fatality rate, and disease burden. Nevertheless, the deficit of diagnostic markers and focused treatment are major hurdles for potent therapeutics. They are also the reason for bad outcomes and causes of a worse prognosis and a high rate of flare up in patients with TNBC diagnosis. Long non-coding RNAs (lncRNA) are a new class of molecules that have recently gained interest in healthcare management due to their potential as biomarkers for human diseases especially cancers. The growing interest in lncRNA in clinical practice has created an unmet need for developing assays to test lncRNA quickly and accurately for early diagnostics. These lncRNA modulate multiple stages of tumor development, including growth, proliferation, invasion, angiogenesis, and metastases, by controlling several genes and changing metabolic networks. Highly invasive phenotype and chemo resistance are prominent characteristics of TNBC subtypes that require accurate diagnostic and prognostic instruments involving lncRNA. This review focusses on the evolving purpose and coalition of lncRNAs in TNBC and accentuates their capable effects in diagnosis and treatment of cancer. Moreover, the extensive literature analysis of our review creates an opportunity in the translational application concerning the TNBC lncRNAs described until now. The depiction of lncRNAs enrolled in TNBC is comprehensive, and sufficient substantiation studies are the need of the hour to authenticate the current outcomes and create imminent upcoming of elemental research setting into clinical practice.

Increased expression of serum IL-18 and IL-18R in newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disorder in which genetic, sedentary lifestyle, obesity, and environmental factors come together to produce insulin resistance in target tissues, leading to hyperglycemia. Evidence reveals that inflammation may play an essential role in the pathogenesis of T2DM. Interleukin-18 (IL-18), a proinflammatory cytokine, plays a crucial role in the acute and chronic inflammatory process. The association of IL-18 levels with IL-18R expression in T2DM has not been investigated so far. The aim of this study was to compare the peripheral changes in serum IL-18 levels and its receptor (IL18R) expression in newly diagnosed T2DM and healthy controls. METHODS: A total of 35 newly diagnosed type 2 diabetic cases and 35 non-diabetic controls were enrolled after obtaining informed consent. Venous whole blood was taken under aseptic conditions. Biochemical parameters were estimated in an auto-analyzer. Serum IL-18 levels were calculated using ELISA, whereas IL-18R expression was determined via RT-PCR. GAPDH was used as an internal control. RESULTS: When compared to non-diabetic controls, the serum IL-18 levels were significantly higher in T2DM patients (P=0.010) along with a significant upregulation of IL18R (P=0.0018). Serum IL-18 levels in T2DM and non-diabetic controls were 669.5 (445) and 498.3 (404.9) pg/mL respectively, and IL-18R showed a fold change of 10.33. CONCLUSIONS: Both serum IL-18 and its receptor IL-18R is significantly higher in newly diagnosed T2DM patients.

Explaining the Unexplained: Examining the Predictive Value of Semen Parameters, Sperm DNA Fragmentation and Metal Levels in Unexplained Infertility.

Background: There is ongoing research to find an optimum modality to predict male fertility potential. Aims: To compare the semen parameters, sperm DNA damage and seminal metal levels of Zinc, Lead and Aluminium among the male partners of couples with unexplained infertility and men with proven fertility. Settings and Design: Prospective case-control study at a tertiary level teaching hospital. Materials and Methods: One hundred male partners of couples with unexplained subfertility and 50 men with proven fertility were included in the study. Male partners of unexplained infertility couples and fertile men were compared for their semen parameters, sperm DNA Fragmentation Index (DFI) and seminal metal levels in semen. Statistical Analysis Used: Chi-square test, Student's t-test, sensitivity and specificity analysis, binomial logistic regression analysis. Results: Fertile men had statistically significantly higher mean progressive sperm motility than male partners of unexplained infertility (53.12 ± 9.89% vs. 44.81 ± 19.47%, P = 0.005). Semen volume and sperm concentration were comparable among the cases and control population. The mean sperm DFI was significantly lower among fertile men (10.83 ± 6.28 vs. 21.38 ± 10.28, P < 0.0001). Plotting the receiver-operating characteristic curve the threshold for discrimination was calculated to be 18% DFI. The sensitivity specificity and overall accuracy were 43%, 84% and 56.67%, respectively when the DFI cut-off was set at 18%. Zinc concentration in the semen had a strong positive correlation (Point Biserial correlation coefficient = 0.831) with fertility, whereas lead and aluminium had a moderate negative correlation. Conclusion: Conventional semen analysis had limited differentiating ability for unexplained infertility. The sperm DFI may be employed for explanatory purposes among couples with unexplained subfertility. A lower discriminatory threshold of DFI (18%) has better overall accuracy as opposed to a 30% cutpoint for unexplained subfertility. Among metals, Zinc was strongly correlated with fertility status.

Positive association of branched-chain amino acids with triglyceride and glycated haemoglobin in Indian patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: Over the past few years, branched-chain amino acids (BCAAs) are increasingly being linked to insulin resistance and type 2 diabetes mellitus (T2DM), but their relevance for metabolic dyslipidaemia in T2DM is unclear. This study aims to determine the plasma and urinary BCAAs and their association with insulin resistance, lipid profile and glycated haemoglobin in patients with T2DM among Indian adults. METHODS: In this analytical cross-sectional study, a total of eighty subjects were recruited, 40 T2DM cases and 40 healthy controls. Blood samples collected were subjected to fasting blood sugar (FBS), lipid profile, HbA1c, insulin and BCAAs analysis and urine samples were assessed for BCAAs. All associations were assessed using Spearman Rank Correlation. RESULTS: The plasma levels of BCAAs were significantly higher (p < 0.05) in subjects with T2DM than in control subjects. Spearman Rank Correlation analyses revealed a non-significant (p = 0.21) but positive association between BCAAs and homeostasis model assessment of insulin resistance (HOMA-IR) in patients with T2DM (Rho: 0.27). Among lipid profile parameters, only triglycerides had a significant positive correlation to plasma BCAAs in cases (Rho: 0.5971) but not in control subjects. Findings also revealed a significant positive (p < 0.05) association between plasma BCAAs and HbA1c in patients with T2DM (Rho: 0.5325). Urinary BCAAs levels had a non-significant increase in T2DM subjects and did not show any significant correlation with other parameters assessed. CONCLUSION: Elevated levels of plasma BCAAs are positively associated with triglyceride and HbA1c. They could serve as an effective marker for the assessment of metabolic dyslipidaemia in subjects with T2DM. Further, large scale studies are needed for confirmation of the same.

Recent scenario of long non-coding RNAs as a diagnostic and prognostic biomarkers of prostate cancer.

Prostate cancer (CaP) is a leading cause of cancer deaths in the worldwide with broad range of clinical manifestations ranging from relatively indolent to aggressive metastasis. Altered expression of many circulating long non-coding RNAs (lncRNAs), known to have role in tumorigenesis and metastasis, have already been reported in CaP patients. These lncRNAs modulate CaP pathogenesis by modulating multiple genes and thus altering metabolic pathways. Sustained androgen receptor (AR) signaling is one such key feature of castration-resistant prostate cancer, a CaP stage that has unmet need of accurate diagnostic and prognostic tools, that is affected by lncRNAs. In this review, we have discussed the emerging functions and associations of AR lncRNAs in CaP and highlighted their potential implications in cancer diagnostics and therapeutics. Further, extensive literature analysis in this article indicates that there is an immediate unmet need in the translational approach toward the hitherto identified AR lncRNAs. The characterization of AR lncRNAs involved in CaP is not exhaustive and adequate validation studies are still required to corroborate the present results that would be the impending future of basic research setting into clinical practice.

Japanese encephalitis virus: Associated immune response and recent progress in vaccine development.

Japanese encephalitis (JE) has emerged as one of the most important form of viral encephalitis, which accounts for an estimated 70,000 cases each year with approximately 10,000 fatalities. The clinical presentations and outcome of the infection is dependent upon both virulence of viral determinants and host immune responses. The causative pathogen of JE is a virus known as Japanese encephalitis virus (JEV), which penetrates into the CNS from blood and triggers rapid humoral and cell-mediated immune response. Humoral response is crucial for the control of dissemination of JEV infection and the cytokines produced by cell-mediated immunity during JEV infections serve as potent immune mediators. Till date, JE is only vaccine preventable and no complete antiviral treatment is available so far. Further, vaccine-mediated prevention also has certain limitations. Therefore, an understanding of the pathogenesis of JEV infection can enable the researchers to presume the depth of treatment regime. This review highlights the importance of understanding of the immune mechanisms that are operated in the host during JEV infection and would be helpful in improving future vaccination strategy against JEV.

Association of EGFR 1 Gene Alteration and their Association with Lung Adenocarcinoma Patients

Background: The epidermal growth factor receptor 1 (EGFR1) plays a significant role in cell proliferation and development. Its regulation in humans is very critical and incompletely understood in Non small cell lung cancer (NSCLC). Methods: 100 newly diagnosed NSCLC (lung adenocarcinoma) patients and 100 healthy controls were included and allele specific (AS) polymerase chain reaction (PCR) was used to genotype and expression was analyzed by quantitative real time PCR. Overall survival of patients was analyzed by Kaplan-Meier method and for prognostic significance ROC curve was plotted. Results: A statistically significant difference (p<0.0001) in CC, AA and CA genotypes distribution among patients and healthy controls was observed. Compared to the CC genotype as reference, OR was 30.40 (95%CI 1.75- 524.9, p=0.0002) and 3.97 (95%CI 1.49-10.52, p=0.003) for the homozygous AA and heterozygous CA genotypes respectively. Kaplan-Meier survival analysis was also performed to analyze the relationship of EGFR1 (-191C/A) genotypes with progression free median survival of NSCLC patients and the difference was found to be significantly (p=0.0002) associated with different genotypes. In the ROC curve with respect to TNM stage at optimal cut-off value of 9.88 fold increase in EGFR1 mRNA expression, sensitivity and specificity were 92.9%, 83.3% respectively (AUC=0.95, p<0.0001). ROC curve w.r.t. distant metastases at optimal cut-off value of 13.5 fold change EGFR1 mRNA expression, sensitivity and specificity were 68.2%, 71.4% respectively (AUC=0.81, p<0.0001). In ROC curve w.r.t to presence/ absence of pleural effusion at optimal cut-off value of 14.8 fold change EGFR1 mRNA expression sensitivity and specificity were 66.7%, 68.2% respectively (AUC=0.71, p=0.009). Conclusions: Study concluded EGFR1 promoter polymorphism could be a risk factor associated with disease and may be used as prognostic marker for patients' survival and predictor for disease worseness.

Recent scenario of microRNA as diagnostic and prognostic biomarkers of prostate cancer.

Prostate cancer (CaP) is a leading cause of cancer death and displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. Due to the alteration and incomplete characterization of the CaP genomic markers, the quest for novel cellular metabolic regulatory molecules like micro RNA (miRNA) as a biomarker could be considered for the prognosis and treatment of CaP in future. In this article, we review the existing literature pertaining to CaP. Study provides a comprehensive miRNA profile expressed in CaP. Beside the miRNA expressed in the tumor tissue, circulating miRNAs have been found highly stable and are both detectable and quantifiable in a range of accessible bio fluids; therefore, miRNA has the potential to be useful diagnostic, prognostic and predictive biomarker. Along with being an important molecule in modulation of CaP progression, the miRNA have certain limitations such as lack of stable expression of multiple target genes and often disrupt entire signaling networks of cellular metabolic pathways. We conclude that: The alteration of miRNA and their role played in cellular regulatory networks would be the next target of basic research in CaP. The miRNAs identified may be validated and modeled to understand their role in CaP, using bioinformatics. There is an immediate unmet need in the translational approach of identified miRNAs. The characterization of miRNAs involved in CaP is still incomplete: adequate validation studies are required to corroborate current results.

Association of Resistin with Insulin Resistance and Factors of Metabolic Syndrome in North Indians.

Metabolic syndrome (MetS) is a cluster of interrelated common clinical disorders. The role of resistin in insulin sensitivity and MetS is controversial till date. So, the aim of the present study was to investigate the relationship of plasma resistin levels with markers of the MetS in Indian subjects. In a case control study, total 528 subjects were selected for the study. 265 (194 male and 71 female) were cases (with MetS) and 263 (164 male and 99 female) were controls (without MetS). Required anthropometric measurements and calculations were carried out accordingly. All the Biochemical estimations were carried out according to standard protocol. Resistin level was measured by the standard protocol (By ELISA i.e. enzyme linked immunosorbent assay) as illustrated in the kit. Insulin level was also measured by the standard protocol as illustrated in the kit and insulin resistance was calculated by the standard procedures. Plasma resistin levels were significantly higher in cases compared with controls (male = 13.05 ± 4.31 vs. 7.04 ± 2.09 ng/ml; p ≤ 0.001 and female = 13.53 ± 4.14 vs. 7.42 ± 2.30 ng/ml; p ≤ 0.001). Plasma resistin levels were well correlated with waist circumference, glucose, triglycerides, waist/hip ratio, systolic and diastolic blood pressure, high density lipoprotein, total cholesterol, serum low density lipoprotein, serum very low density lipoprotein, insulin and insulin resistance. Plasma resistin levels were elevated in presence of the MetS and were associated with increased metabolic risk factors.

Blood Lead Level (BLL) in the Adult Population of Jodhpur: A Pilot Study.

Lead interferes with a variety of body processes and is toxic to many organs and tissues including the heart, bones, intestines, kidneys, and reproductive and nervous systems. Routes of exposure to lead include contaminated air, water, soil, food, and consumer products. The possibility of lead exposure in humans is therefore of great significance from health point of view. Occupational exposure is a common known cause of lead poisoning in adults but current status of adults exposed otherwise is not known. School teachers representing wide local population were selected and asked to furnish information regarding possible lead exposure. Blood lead level (BLL) was estimated using anodic stripping voltammetry. The mean BLL was 6.89 ± 9.5 µg/dl (<3.5->65 µg/dl) in representative adult population. Out of the total 16 % were found to be having BLL >10 µg/dl which has significantly decreased from leaded gasoline era. Those with increased BLL (>10 µg/dl) were found to have common determinants like usage of old metallic pipes for plumbing, water consumption without any purification system, usage of cosmetics and Ayurvedic/herbal medicines.

Nutlin-3a decreases male fertility via UQCRC2.

Ubiquinol-cytochrome-c reductase core protein 2 (UQCRC2) is a component of ubiquinol-cytochrome c reductase complex that is known to correlate with male fertility via spermatogenesis. Simultaneously, nutlin-3a is a small molecule antagonist of mouse double minute 2 repressor (MDM2), activate p53 and induce apoptosis responsible for spermatogenesis. To date, however there are no known effects of nutlin-3a on reproduction. Therefore, present study was designed to investigate the effect of nutlin-3a on male fertility via UQCRC2. In this in vitro trial with mice spermatozoa, we utilized CASA, CTC staining, ATP assay, western blotting, and IVF to measure the main study outcome. The short-term exposure of spermatozoa in nutlin-3a decreases sperm motion kinematics, intracellular ATP production, capacitation, the acrosome reaction, UQCRC2, and tyrosine phosphorylation (TYP) of sperm proteins in a dose-dependent manner. Notably, the decreased UQCRC2 and TYP were associated with reduced sperm kinematics, ATP production, and capacitation, which ultimately led to adverse effects on male fertility such as poor fertilization rates and embryo development. Thus, nutlin-3a may be considered as a potential male contraceptive agent due to its ability to decrease fertility secondary to changes in overall sperm physiology and embryonic development. However, the results of this preliminary study have to be confirmed by additional independent trial.

Significant association of TNFα and IL-6 gene with male infertility--an explorative study in Indian populations of Uttar Pradesh.

In this study were aimed to identify the association of SNPs candidate genes of TNF-α and IL-6 with hormones levels and sperm cells death in infertile subjects of Uttar Pradesh population in North India. The study population comprised, fertile donor (control group) and infertile group patients i.e. normozoospermic (idiopathic unexplained), oligozoospermic and asthenozoospermic groups, with 260 subjects in each group. Subjects were selected from the Departments of Urology, K.G's Medical University and Urology, SGPGIMS, Lucknow, India. The allele-specific polymerase chain reaction (PCR) and PCR-RFLP were used to investigate the substitution of the guanine (G)-to-adenosine (A) at position-308 and guanine (G)-to-cytosine (C) at position-174 in the promoter regions of the TNF-α and IL-6 genes, respectively. Further their relation to male fertility and sperm function were also investigated. It was found that the substitution levels from G to A and from G to C in the TNF-α and IL-6 genes, respectively, were significantly higher in the infertile subjects as compared to that of control group. The apoptosis and necrosis levels were also higher in oligozoospermic and asthenozoospermic infertile subjects. Further it was found to be associated with increased level of reactive oxygen species as observed in oligozoospermic and asthenozoospermic subjects. However, a significant decrease in testosterone and luteinizing hormone with increased prolactin and follicle stimulating hormones was observed in infertile subjects. The study populations indicating a strong association between TNF-α G-308A and IL-6 G-174C substitution with infertile men which is further supported by allele and genotype meta-analysis and thus established it as a risk factor.