TNF-α promoter variant (G-308A) is associated with susceptibility to P. falciparum infection and severe malaria: a meta-analysis and trial sequential analysis.

Tumor necrosis factor-alpha (TNF-α) plays an essential role in Plasmodium falciparum infection, with lower levels associated with susceptibility to infection and higher levels linked with organ failure in severe malaria. Genetic polymorphisms in the promoter region of the TNF-α gene (G-308A and G-238A) affect plasma TNF-α levels. Numerous case-control studies have been conducted to determine the possible association between TNF-α polymorphisms and susceptibility to malaria infection and clinical severity; however, the results are inconsistent. Various databases such as Google Scholar, Science Direct, PubMed, and Scopus were searched for relevant articles for the present meta-analysis. Data were extracted from the eligible studies based on inclusion and exclusion criteria. Meta-analysis was carried out with CMA v.3.3.070 software, and combined odds ratio, 95% confidence interval, and p values were calculated. Further, a trial sequential analysis was also performed to test whether enough number of case and controls have been enrolled to date to draw a valid conclusion. Allele (OR = 9.757, p value=.049) and heterozygous (OR = 8.98, p value=.016) comparison model revealed the TNF-α G-308A variant as a susceptible genetic factor for P. falciparum infection. Similarly, a significant association of TNF-α G-308A polymorphism with P. falciparum malarial severity was also observed (A versus G: OR = 1.761, p value = .000; and GG + GA versus GG: OR = 1.769, p value = .000). However, no association of TNF-α (G-238A) polymorphism was observed with infection and severity of P. falciparum or Plasmodium vivax malaria. TNF-α G-308A variant is associated with susceptibility to P. falciparum infection and clinical severity. However, further studies on different populations are required.

Polymorphisms and haplotypes of TLR-4/9 associated with bacterial infection, gingival inflammation/recession and oral cancer.

BACKGROUND: The expression and SNPs of innate immunity genes TLR-4/9 for bacterial infection, gingival inflammation/gingival recession (GIGR), and oral squamous cell carcinoma (OSCC) are largely unknown. PATIENTS AND METHOD: 235 specimens (120 OSCC cases, among which 85 cases with either Porphyromonas gingivalis, Fusobacterium nucleatum or Treponema denticola infection and GIGR) and 115 healthy controls were used to know the expression and polymorphisms (TLR-4: N1:rs10759931, N2:rs11536889, N3:rs1927911, N4:rs4986790; TLR-9: N5:rs5743836, N6:rs352140, N7:rs187084 and N8:rs352139) of TLR-4/9 by western blot, RT-PCR, and allele-specific (AS)-PCR followed by sequencing. RESULTS: Increased TLR-4/9 mRNA/protein expression, bacterial infection (BI) and GIGR were associated with OSCC incidence. One of the three BI and GIGR was observed in 70.83% of OSCC cases, whereas all the HC used were free from any of these three BI/GIGR. The N3: CT-genotype (Odds Ratio hereafter as O.R.=1.811, p = 0.0338), TT-genotype (O.R.=3.094, p = 0.0124), 'T'-allele (O.R.=1.821, p = 0.003), N4: AG-genotype (O.R.=2.015, p = 0.0222) and 'G'-allele (O.R.=1.86, p = 0.018) of TLR-4 as well as the N5: CC-genotype (O.R.=3.939, p = 0.0017), 'C'-allele (O.R.=1.839, p = 0.0042), N6: AA-genotype (O.R.=2.195, p = 0.0234), 'A'-allele (O.R.=1.569, p = 0.0163), N7: TC-genotype (O.R.=2.083, p = 0.0136), CC-genotype (O.R.=2.984, p = 0.003) and 'C'-allele (O.R.=1.885, p = 0.0008) of TLR-9 were associated with increased OSCC risk. Similarly, the N2:'C'-allele (O.R.=1.615, p = 0.0382), N3: TT-genotype (O.R.=2.829, p = 0.0336), 'T'-allele (O.R.=1.742, p = 0.0115), N4: AG-genotype (O.R.=2.221, p = 0.0147) and 'G'-allele (O.R.=1.890, p = 0.0238) of TLR-4 as well as the N5: CC-genotype (O.R.=2.830, p = 0.031), N6: AA-genotype (O.R.=2.6, p = 0.0122) and 'A'-allele (O.R.=1.746, p = 0.0064), N7:CC-genotype (O.R.2.706, p = 0.0111) and 'C'-allele (O.R. 1.774, p = 0.0055) of TLR-9 were correlated with GIGR and BI. TLR-4 (N1-N2-N3-N4: A-C-T-A (O.R.=2.1, p = 0.0069) and TLR-9 (N5-N6-N7-N8: T-A-C-A (O.R.=2.019, p = 0.0263); C-A-C-A (O.R.=6.0, p = 0.0084); C-A-C-G (O.R.=4.957, p = 0.0452) haplotypes were linked with OSCC vulnerability, while the TLR-4 (N1-N2-N3-N4: G-C-C-A (O.R.=0.5752, p = 0.0131) and TLR-9 (N5-N6-N7-N8: T-G-T-A (O.R.=0.5438, p = 0.0314); T-G-T-G (O.R.=0.5241, p = 0.036) haplotypes offered protection. CONCLUSION: TLR-4/9 expression, polymorphisms, and BI-induced GIGR could increase OSCC risk. This may be used in pathogenesis and oral cancer prediction.

The role of MBL, PCT, CRP, neutrophil-lymphocyte ratio, and platelet lymphocyte ratio in differentiating infections from flares in lupus.

BACKGROUND: The distinction between infection and flare in systemic lupus erythematosus (SLE) has always been a dilemma for clinicians as the clinical and biochemical profiles overlap. The present study evaluated affordable biomarkers to distinguish infection from flare in an SLE cohort in a tertiary care center in eastern India. METHODS: One hundred and fifty-two SLE patients were clinically evaluated and enrolled in the present study. Hematological, immunological, and biochemical profiles and various biomarkers such as C reactive protein (CRP), procalcitonin (PCT), and Mannose-binding lectin (MBL) were quantified. RESULTS: One hundred and fifty-two patients (152) were enrolled in the present study and all had SLEDAI scores of more than 4. From which 70 had infection, and the common infections were urinary tract infection (34.28%) followed by pneumonia (27.14%). Neutrophil-lymphocyte ratio (NLR) and C-reactive protein (CRP) were significantly elevated in SLE with infections (NLR: 5.84 ± 2.47; CRP: 30.56 ± 41.63) than those with flare (NLR: 3.87 ± 2.62; CRP: 8.73 ± 9.53). The receiver operating characteristic curve (ROC) analysis revealed CRP, PLR, and NLR as important markers for predicting infections (CRP: AUC = 0.682, p = 0.0001; PLR: AUC = 0.668, p = 0.0008; NLR: AUC = 0.742, p < 0.0001). The MBL and PCT levels were comparable among SLE flare and those with infections. CONCLUSIONS: NLR and CRP levels are affordable biomarkers to distinguish infections from flares in SLE. MBL and PCT could not differentiate flare from an infection. Key Points • Biomarkers for the differentiation of infection and flare in SLE are limited. • NLR, PLR, and CRP are promising biomarkers to enable differentiation. • PCT and MBL are not ideal biomarkers to differentiate infection from flare.

Role of interleukin-6 and interferon-α in systemic lupus erythematosus: A case-control study and meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting various organ systems with unknown etiology. Interleukin-6 (IL-6) and interferon-alpha (IFN-α) have been shown to have a major role in disease pathogenesis, and they correlate with SLE disease activity, but reports in the literature are conflicting. The present study aims to investigate the significance of IL-6 and IFN-α levels in SLE pathogenesis in an eastern Indian cohort. MATERIAL AND METHODS: 70 SLE patients fulfilled SLICC 2012 criteria, and 40 age- and gender-matched healthy controls (HC) were enrolled. Baseline characteristics along with disease activity were recorded for all patients. Levels of IL-6 and IFN-α were measured by using ELISA. For the meta-analysis, published articles were searched through different databases. Two independent researchers extracted data, and the meta-analysis was performed with CMA v3.1. RESULTS: The plasma levels of IL-6 and IFN-α in SLE patients were significantly elevated compared to HC (IL-6: p < .0001, IFN-α: p = 0.01). SLEDAI score correlated positively with plasma IL-6 (p < .0001, r = 0.46) and IFN-α levels (p < .0001; r = 0.47). Meta-analysis of previous reports, including our case-control data, revealed higher IL-6 (p < .0001) and IFN-α (p = .005) in SLE patients compared to HC. Furthermore, IL-6 (p < .0001, r = 0.526) and IFN-α (p < .0001; r = 0.371) levels positively correlated with the disease activity. CONCLUSION: IL-6 and IFN-α levels are elevated in SLE and they correlate with disease activity. Further studies with a larger sample size in different populations are required to validate our findings.

Polymorphisms and haplotypes of TLR4, TLR9 and CYP1A1 genes possibly interfere with high-risk human papillomavirus infection and cervical cancer susceptibility in Jharkhand, India.

BACKGROUND: Expression and single nucleotide polymorphisms (SNPs) of TLR4/9 and CYP1A1 genes are vital for cervical squamous cell carcinoma (CSCC) but considerably vary in different populations. METHODS: A total of 255-subjects from Jharkhand (130-cases, 125-controls) were utilized to obtain the expression/SNP status of TLR4/9, CYP1A1, and E6 (HPV16/18) by RT-PCR, WB, and allele-specific-PCR followed by sequencing. RESULTS: Over-expression of TLR4/9 and high infection of HPV16/18(78.5%) were found to be associated with CSCC. Among the seven SNPs(p1-p7) tested, the CT-genotype (p3:rs1927911; OR = 2.142; p = 0.004) and 'T'-allele (p3; OR = 1.694; p = 0.0061) of TLR4; CC-genotype (p4:rs5743836; OR = 3.307; p = 0.0018), 'C'-allele (p4; OR = 1.895; p = 0.0009), GA-genotype (p5:rs352140; OR = 2.064; p = 0.0172), AA-genotype (p5; OR = 2.602; p = 0.0021) and 'A'-allele (p5; OR = 1.939; p = 0.0002) of TLR9; and the TC-genotype (p6:rs4646903; OR = 1.967; p = 0.0452) and GG-genotype (p7:rs1048943; OR = 2.336; p = 0.0287) and 'G'-allele (p7; OR = 1.685; p = 0.0082) of CYP1A1 were associated with an increased-risk of CSCC. Similarly, the p3:CT-genotype (OR = 1.993; p = 0.0134); p4:CC-genotype (OR = 3.071; p = 0.0057) and 'C'-allele (OR = 1.838; p = 0.0029); p5:AA-genotype (OR = 2.231; p = 0.0147) and 'A'-allele (OR = 1.756; p = 0.0032); p6:TC-genotype (OR = 2.370; p = 0.02); and the p7:GG-genotype (OR = 2.255; p = 0.0488) and 'G'-allele (OR = 1.691; p = 0.0118) showed an association with HPV16/18 infection. Conversely, TLR4 (p1-p2-p3:A-G-T; OR = 3.361; p = 0.029), TLR9 (p4-p5:C-A; OR = 1.786; p = 0.032) and CYP1A1 (p6-p7:C-G; OR = 1.783; p = 0.033) haplotypes with CSCC susceptibility was observed, whereas the TLR4 (p1-p2-p3:A-C-C; OR = 0.4675; p = 8.E-3) and TLR9 (p4-p5:T-G; OR = 0.3937; p = 0.00) haplotypes showed protection against the development of CSCC. Further, though p1:rs10759931 and p2:rs11536889 were found to be insignificant, the p3:CT-genotype, p5:GA/AA-genotype, and p7:GG-genotype were associated with elevated protein; the p4:CC-genotype and p6:TC-genotype were associated with increased mRNA compared to their respective-wild-type-groups. CONCLUSION: The present study revealed an association between TLR4/9 and CYP1A1 polymorphisms with increased HPV16/18 infection susceptibility and CSCC risk among the women of Jharkhand state.

Association of TGF-ß1 Polymorphisms with Breast Cancer Risk: A Meta-Analysis of Case-Control Studies †.

Reports on the association of TGF-ß1 polymorphisms with breast cancer (BC) have been conflicting, inconsistent, inconclusive, and controversial. PubMed, EMBASE, and Google Scholar were used to identify studies on TGF-ß1 polymorphisms and BC risk. Data were extracted independently, and of the initial 3043 studies, 39 case-control studies were eligible for inclusion in the meta-analysis. Information from these studies was extracted, and the overall associations of three TGF-ß1 polymorphisms (TGF-ß1 29>T/C, TGF-ß1-509 C/T, and TGF-ß1*6A) with BC risk were analyzed using overall allele, homozygous, heterozygous, recessive, and dominant models. None of the three TGF-ß1 polymorphisms studied had a significant influence on the development of BC. However, stratified analysis revealed a positive correlation between the TGF-ß1 29T>C polymorphism and BC risk according to a heterozygous model of the Asian population (odds ratio (OR) = 1.115, 95% confidence interval (CI) = 1.006-1.237, p = 0.039). Interestingly, this polymorphism was associated with lower odds of BC according to a heterozygous model of the Middle Eastern population (OR = 0.602, 95% CI = 0.375-0.966, p = 0.035). Thus, our analysis of large datasets indicates that the TGF-ß1 29T>C polymorphism is significantly associated with BC risk in the Asian population. In contrast, the TGF-ß1*6A and TGF-ß1-509 C/T polymorphisms failed to show an association with BC.

TNF-α promoter polymorphisms (G-238A and G-308A) are associated with susceptibility to Systemic Lupus Erythematosus (SLE) and P. falciparum malaria: a study in malaria endemic area.

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine associated with autoimmune and infectious diseases. Importance of TNF-α in P. falciparum malaria and systemic lupus erythematosus (SLE) have been demonstrated. However, association of functional promoter variants with SLE and malaria is lacking in malaria endemic population. A total of 204 female SLE patients and 224 age and sex matched healthy controls were enrolled in the study. Three hundred fourteen P. falciparum infected patients with different clinical phenotypes were included. TNF-α polymorphisms (G-238A & G-308A) were genotyped by PCR-RFLP. Plasma levels of TNF-α was quantified by ELISA. Heterozygous mutants and minor alleles of TNF-α (G-238A and G-308A) polymorphisms were significantly higher in SLE patients compared to healthy controls and associated with development of lupus nephritis. In addition, both promoter variants were associated with severe P. falciparum malaria. SLE patients demonstrated higher levels of plasma TNF-α compared to healthy controls. TNF-α (G-238A and G-308A) variants were associated with higher plasma TNF-α. In conclusion, TNF-α (G-238A & G-308A) variants are associated with higher plasma TNF-α levels in SLE patients residing in malaria endemic areas and could be a contributing factor in the development of SLE and susceptibility to severe P. falciparum malaria.

A trial sequential meta-analysis of TNF-α -308G>A (rs800629) gene polymorphism and susceptibility to colorectal cancer.

PURPOSE: Tumor necrosis factor-α (TNF-α), secreted by the activated macrophages, may participate in the onset and progression of colorectal cancer (CRC). The association of TNF-α -308 G>A (rs1800629) single-nucleotide polymorphism (SNP) with CRC risk has been investigated by many studies but the results are inconclusive. A trial sequential meta-analysis was performed for precise estimation of the relationship between TNF-α -308 G>A gene polymorphism with CRC risk. METHODS: Medline (PubMed), EMBASE (Excerpta-Medica) and Google Scholar were mined for relevant articles. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the significance of association. RESULTS: The pooled analysis indicated no risk associated with TNF-α -308 G>A SNP and overall CRC risk in five genetic comparison models, i.e. allelic (A vs. G: P = 0.524; OR = 1.074, 95% CI = 0.863-1.335), homozygous (AA vs. GG: P = 0.489; OR = 1.227, 95% CI = 0.688-2.188), heterozygous (AG vs. GG: P = 0.811; OR = 1.024, 95% CI = 0.843-1.244), dominant (AA+AG vs. GG: P = 0.630; OR = 1.055, 95% CI = 0.849-1.311) and recessive (AA vs. AG+GG: P = 0.549; OR = 1.181, 95% CI = 0.686-2.033). Subgroup analysis revealed that TNF-α -308 G>A SNP is associated with reduced risk of CRC in Asian ethnicity. The study showed no publication bias. CONCLUSIONS: No association of TNF-α -308 G>A SNP with overall CRC risk was found. This SNP is likely to be protective against CRC in Asian population when compared with Caucasian population. Larger prospective-epidemiological studies are warranted to elucidate the roles of TNF-α -308 G>A SNP in the etiology of CRC and to endorse the present findings.

Role and regulation of proapoptotic Bax in oral squamous cell carcinoma and drug resistance.

BACKGROUND: Bax, a proapoptotic protein but its regulation during oral cancer progression and resistance remains elusive. METHODS: A total of 127 samples including adjacent normal, primary tumor, and resistance to chemoradiation therapy (RCRT) samples from oral squamous cell carcinoma (OSCC) patients were used. The status of Bax was analyzed at DNA/mRNA/protein levels and the results were correlated with p53 and Akt expression in tissue samples/cisplatin-resistant oral tongue SCC (SCC9/SCC4-CisR) cell line. RESULTS: Frequent progressive decrease of Bax expression with infrequent promoter methylation, polymorphisms G(-248)A, and mutations was observed in OSCC progression/resistance. Furthermore, by targeting Akt pathway, induction of Bax-dependent cell death was observed and this was further enhanced with nimbolide treatment in SCC9/SCC4-CisR cells. CONCLUSION: Hence, the Bax gene alteration and its deregulation through p53/Akt pathway are important for OSCC progression and drug resistance. Akt Inhibitor VIII and nimbolide synergistically induce Bax, and it is therefore beneficial for chemosensitizing cisplatin-resistant human OSCC.

Her2 Ile655Val polymorphism and its association with breast cancer risk: an updated meta-analysis of case-control studies.

Breast cancer (BC) is one of the most common types of cancer in women worldwide. Several factors including genetic and environmental have been linked with susceptibility to development of BC. Her2 is a transmembrane protein with tyrosine kinase activity, overexpressed in several cancers including BC. Various studies in different populations have shown association of Her2 variants with susceptibility to BC, however these results were inconsistent, inconclusive and controversial. To obtain a common conclusive finding, we performed meta-analysis of 35 case-control studies reported earlier including 19, 220 cases and 22, 306 controls. We observed significant association of Her2 Ile655Val polymorphism with susceptibility to development of breast cancer (Overall allele Val vs Ile: OR = 1.130, 95% CI = 1.051-1.216, p = 0.001; Ile-Val vs Ile-Ile: OR = 1.100, 95% CI = 1.016-1.192, p = 0.019; Val-Val+Ile-Val vs Ile-Ile: OR = 1.127, 95% CI = 1.038-1.223, p = 0.004). Subgroup analysis indicated a significant association with susceptibility to breast cancer in African and Asian populations. However, such association was not observed in other ethnic groups. Our findings suggested that Her2 Ile655Val polymorphism is associated with breast cancer risk in overall, Asian and African populations, and can be used as diagnostic marker for BC.

Impact of LMP7 (rs2071543) gene polymorphism in increasing cancer risk: evidence from a meta-analysis and trial sequential analysis.

Genetic variant LMP7 (low molecular weight polypeptide 7) -145 C > A may influence the function of immune surveillance of an individual and lead to cancer development. Various studies have investigated the relevance of LMP7 -145 C > A gene polymorphism with cancer risk; but, their results are conflicting and inconsistent. To obtain a comprehensive conclusion, a meta-analysis was performed by including eight eligible published studies retrieved from PubMed (Medline), EMBASE and Google Scholar web search until December 2016. Individuals with AA genotype (AA vs CC: p = 0.001; OR = 2.602, 95% CI = 1.780 to 3.803) of LMP7 -145 C > A were found to have 2 folds higher risk of cancer than those with CC genotype. The recessive genetic model (AA vs AC + CC) also indicated that individuals with AA genotype have 2 folds higher cancer risk than AC and CC genotypes (p = 0.001; OR = 2.216, 95% CI = 1.525 to 3.221). Also, significant increased cancer risk was observed in Asians but not in Caucasians. No publication bias was observed during the analysis. Trial sequential analysis also strengthened our current findings. These results suggest that genetic variant LMP7-145 C > A has significant role in increasing cancer risk in overall and Asian population, and could be useful as a prognostic marker for early cancer predisposition.

Impact of TNF -308 G>A (rs1800629) gene polymorphism in modulation of leprosy risk: a reappraise meta-analysis of 14 case-control studies.

PURPOSE: Earlier studies have shown that tumor necrosis factor (TNF) -308 G>A (rs1800629) gene polymorphism is implicated in the susceptibility to leprosy, but results were inconsistent. METHODS: A meta-analysis of 14 studies involving 3327 leprosy cases and 3203 controls was performed to appraise the association of TNF -308 G>A polymorphism with leprosy using MEDLINE (PUBMED), EMBASE, and Google Scholar web databases. RESULTS: Overall, no significant association was observed in allelic (A vs. G: P=0.068; OR = 0.836, 95% CI = 0.689-1.013), homozygous (AA vs. GG: P=0.394; OR = 0.810, 95% CI = 0.499-1.315), heterozygous (GA vs. GG: P=0.059; OR = 0.780, 95% CI = 0.603-1.010), dominant (AA + GA vs. GG: P=0.067; OR = 0.797, 95% CI = 0.625-1.016), and recessive (AA vs. GG + GA: P=0.594; OR = 0.877, 95% CI = 0.542- 1.420) genetic models. Subgroup analysis showed no association in Asians. Whereas, reduced risk was found in allelic contrast (A vs. G: P=0.014; OR = 0.832, 95% CI = 0.718-0.963) and dominant models (AA + GA vs. GG: P=0.004; OR = 0.790, 95% CI = 0.673-0.928) of the mixed population. CONCLUSIONS: TNF -308 G>A polymorphism is not associated with leprosy risk in the overall population. However, subgroup analysis demonstrated protective effect of the said polymorphism in leprosy risk in the Latin American population, but showed no association in the Asians.

Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: A case-control study and meta-analysis.

The association of interleukin-6 (IL-6)-174G > C (rs1800795) single nucleotide polymorphism (SNP) with the risk of acquiring rheumatoid arthritis (RA) is a relevant issue because of conflicting and consensus lacking reports published in literature. We investigated IL-6-174G > C promoter polymorphism in 34 RA patients, attending a tertiary care hospital in north India. We also performed a meta-analysis, of the previously published studies reporting this genetic relationship, in overall population, and independently in Asian and Caucasian ethnicities to further elucidate this association. A total of 13 studies, including the current one, involving 3291 RA cases and 3812 controls were analyzed. Out of the 13 studies, 6 were from Asian, 6 from Caucasian and 1 from a mixed population. Our case-control study showed significant association of IL-6-174G > C SNP with increased RA risk: allelic (OR = 3.750, 95% CI = 1.800-7.813, p < 0.001); dominant (OR = 2.800, 95% CI = 1.167-6.721, p = 0.021); and recessive (OR = 36.72, 95% CI = 2.004-672.7, p = 0.015). The meta-analysis revealed the increased RA risk associated with IL-6-174G > C SNP in overall population: allelic (OR = 1.650, 95% CI = 1.169-2.329, p = 0.004); homozygous (OR = 1.380, 95% CI = 0.906-2.101, p = 0.133); heterozygous (OR = 1.559, 95% CI = 1.001-2.428, p = 0.049); dominant (OR = 1.663, 95% CI = 1.078-2.567, p = 0.022); and recessive (OR = 1.366, 95% CI = 0.964-1.935, p = 0.079). Subgroup analysis also showed this polymorphism to be associated with increased RA risk in Asian population: allelic (OR = 3.724, 95% CI = 1.361-10.190, p = 0.010); dominant (OR = 3.823, 95% CI = 1.320-11.074, p = 0.013); and recessive (OR = 4.357, 95% CI = 1.634-11.623, p = 0.003), but not in Caucasian population. This meta-analysis shows that IL-6-174G > C SNP is significantly associated with increased RA risk in overall, and specifically in Asian population.

Reversion-inducing cysteine-rich protein with Kazal motifs and its regulation by glycogen synthase kinase 3 signaling in oral cancer.

The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and glycogen synthase kinase (GSK3) are novel tumor suppressors, and emerging evidence has suggested their active role in oral cancer pathogenesis. In the present study, 112 human samples, including 55 fresh samples of 14 adjacent normal tissues, 25 noninvasive oral tumors, and 18 invasive tumors, were included. The messenger RNA (mRNA) expression, protein expression, and promoter methylation of the RECK gene, as well as the expression of GSK3ß, phospho/total ß-catenin, and c-myc, were measured by RT-PCR, bisulphate modification-PCR, immunohistochemistry, and Western blot analysis. Additionally, ectopic expression of in/active GSK3ß was performed in cell culture experiments. This study provided information on the progressive silencing of RECK gene expression at the protein and mRNA levels paralleled with promoter hypermethylation at various stages of oral tumor invasion. RECK expression and the hypermethylation of the RECK gene promoter were negatively and positively correlated with pS9GSK3ß/c-myc expression, respectively. Further, a negative trend of RECK protein expression with nuclear ß-catenin expression was observed. Induced expression of active GSK3ß reversed the RECK silencing in SCC9 cells. Collectively, our results demonstrated that the silencing of the RECK gene, possibly regulated by the GSK3ß pathway, is an important event in oral cancer invasion and this pathway could be exploited for therapeutic interventions.

TNF-α -308 G > A (rs1800629) Polymorphism is Associated with Celiac Disease: A Meta-analysis of 11 Case-Control Studies.

Celiac disease (CD) remains one of the most significant autoimmune diseases worldwide. The pathogenesis of CD is not clearly understood and is probably attributed to genomic variations and host genetic make-up. Case-control and cohort studies of the association between the TNF-α -308 G > A (rs1800629) polymorphism and CD susceptibility have yielded inconsistent results. In this study, PubMed, EMBASE, and Google Scholar web-databases were searched for pertinent reports showing association of TNF-α -308 G > A gene with CD risk. A total of eleven reports involving 1774 controls and 1147 CD cases were included. Significant associations in four genetic models, viz. variant allele (A vs. G: p = 0.001; OR = 2.051, 95% CI = 1.452-2.895), variant homozygous (AA vs. GG: p = 0.001; OR = 6.626, 95% CI = 3.569-12.300), recessive (AA vs. GG + AG: p = 0.001; OR = 4.766, 95% CI = 3.177-7.152) and dominant (AA + AG vs. GG: p = 0.008; OR = 1.910, 95% CI = 1.181-3.088) were found in comparison with wild type homozygous GG genotype. However, heterozygous genetic model did not show any association. Sensitivity analysis revealed stable and statistically robust results. Our results suggest that TNF-α -308 G > A gene polymorphism significantly contributes to CD susceptibility.

Heterozygous mutants of TIRAP (S180L) polymorphism protect adult patients with Plasmodium falciparum infection against severe disease and mortality.

Toll-interleukin-1 receptor domain containing adapter protein (TIRAP) plays a crucial role in TLR2 and TLR4 signaling pathways. Glycosylphospatidylinositol (GPI), considered a toxin molecule of Plasmodium falciparum, interacts with TLR2 and 4 to induce an immune inflammatory response. A single nucleotide polymorphism at coding region of TIRAP (S180L) has been reported to influence TLRs signaling. In the present study, we investigated the association of TIRAP (S180L) polymorphism with susceptibility/resistance to severe P. falciparum malaria in a cohort of adult patients from India. TIRAP S180L polymorphism was typed in 347 cases of severe malaria (SM), 232 uncomplicated malaria and 150 healthy controls. Plasma levels of TNF-α was quantified by ELISA. Heterozygous mutation (S/L) conferred significant protection against MOD (multi organ dysfunction), NCSM (non-cerebral severe malaria) as well as mortality. Interestingly, homozygous mutants (L/L) had 16 fold higher susceptibility to death. TIRAP mutants (S/L and L/L) were associated with significantly higher plasma TNF-α levels compared to wild type (S/S). The results of the present study demonstrate that TIRAP S180L heterozygous mutation may protect patients against severe malaria and mortality.

G894T and 4a/b polymorphisms of NOS3 gene are not associated with cancer risk: a meta-analysis.

Endothelial nitric oxide synthase (eNOS or NOS3) produces nitric oxide and genetic polymorphisms of NOS3 gene play significant roles in various processes of carcinogenesis. The results from published studies on the association between NOS3 G894T and NOS3 intron 4 (4a/b) polymorphisms and cancer risk are conflicting and inconclusive. However, i n order to assess this relationship more precisely, a meta-analysis was performed with PubMed (Medline), EMBASE and Google web searches until February 2014 to select all published case- control and cohort studies. Genotype distribution data were collected to calculate the pooled odd ratios (ORs) and 95% confidence intervals (CIs) to evaluate the strength of association. A total of 10,546 cancer cases and 10,550 controls were included from twenty four case-control studies for the NOS3 G894T polymorphism. The results indicated no significant association with cancer risk as observed in allelic (T vs G: OR=1.024, 95%CI=0.954 to 1.099, p=0.508), homozygous (TT vs GG: OR=1.137, 95%CI=0.944 to 1.370, p=0.176), heterozygous (GT vs GG: OR=0.993, 95%CI=0.932 to 1.059, p=0.835), recessive (TT vs GG+GT: OR=1.100, 95%CI=0.936 to 1.293, p=0.249) and dominant (TT+GT vs GG: OR=1.012, 95%CI=0.927 to 1.105, p=0.789) genetic models. Similarly, a total of 3,449 cancer cases and 3,691 controls were recruited from fourteen case-control studies for NOS3 4a/b polymorphism. Pooled results indicated no significant association under allelic (A vs B: OR=0.981, 95%CI=0.725 to 1.329, p=0.902), homozygous (AA vs BB: OR=1.166, 95%CI=0.524 to 2.593, p=0.707), heterozygous (BA vs BB: OR=1.129, 95%CI=0.896 to 1.422, p=0.305), dominant (AA+BA vs BB: OR=1.046, 95%CI=0.779 to 1.405, p=0.763) and recessive (AA vs BB+BA: OR=1.196, 95%CI=0.587 to 2.439, p=0.622) genetic contrast models. This meta-analysis suggests that G894T and 4a/b polymorphisms of NOS3 gene are not associated with increased or decreased risk of overall cancer.