TT Patients Research Articles

Meta‐analysis: the impact of IL28B polymorphisms on rapid and sustained virological response in HCV‐2 and ‐3 patients

Recent studies suggested that IL28B polymorphisms may affect rapid and sustained virological response rates in HCV patients infected with genotype 2 or 3. To assess the role of IL28B polymorphisms on the virological response in HCV-2 and -3 patients. We performed meta-analysis of studies evaluating the impact of rs12979860 and rs8099917 polymorphisms on rapid and sustained virological response in HCV-2 or -3 patients. Twenty-three studies involving 3042 patients were included. The first meta-analysis evaluated the impact of rs12979860 polymorphism and included 1963 patients. When compared with rs12979860 CT/TT patients, CC patients had a higher rapid virological response rate (mean difference: 12.9%, 95% CI: 6.5-19.4%, P<0.001) and a higher sustained virological response rate (mean difference: 4.9%, 95% CI: 0.1-9.8%, P=0.046). The second meta-analysis evaluated the impact of rs8099917 polymorphism and included 2246 patients. When compared with rs8099917 TG/GG patients, TT patients had a higher rapid virological response rate (mean difference: 14.8%, 95% CI: 7.2-22.4%, P<0.001) and a higher sustained virological response rate (mean difference: 5.5%, 95% CI: 0.4-10.6%, P=0.033). When considering only patients treated for 24weeks, results were unchanged. No potential sources of between-study heterogeneity were identified. Favourable IL28B polymorphisms are associated with higher rapid and sustained virological response rates in HCV-2 and -3 patients. However, as the impact on a sustained response is very limited, it is unlikely that IL28B polymorphisms provide additional predictive value when considering other predictors of a sustained response.

IL28B CC Genotype Is Associated with Higher All-Cause Mortality in Antiretroviral-Treated HIV-Infected Patients

Il28B single nucleotide polymorphisms were found to influence interferon λ expression, resulting in changes in hepatitis C virus (HCV)-RNA serum levels as well as the HIV-RNA set point prior to combined antiretroviral therapy (cART). To date, there is limited information on the influence of this polymorphism on survival in HIV-infected, treatment-naïve, and antiretroviral-treated patients. Longitudinal data from 484 patients diagnosed with HIV infection (including 406 on cART) were analyzed to investigate the association between Il28B rs 1979860 variants and all-cause mortality. Kaplan-Meyer and Cox models were used to calculate the hazard ratio associated with IL28B genotypes predictive of a greater likelihood of survival for patients prior to the introduction of cART and for patients on cART. The IL28B genotype frequencies were 41.7% (n=202) for CC, 46.5% (n=225) for CT, and 11.7% (n=57) for TT patients. The CC variant was associated with higher mortality (46 cases, 22.8%) compared to other genotypes [n=31 (13.8%) and n=7 (12.3%) for CT and TT, respectively, p=0.02]. IL28 genotypes did not influence the survival probability prior to treatment initiation (HR 1.04, 95% CI: 0.84-1.24, p=0.68). In antiretroviral-treated patients, after adjustment for gender, baseline CD4 count, CDC category at HIV diagnosis, and age (multivariate HR 1.75, 95% CI: 1.20-2.30, p=0.047), the CC genotype was associated with a decreased probability of survival when compared to the non-CC genotype (univariate HR 1.8, 95% CI: 1.28-2.34, p=0.029). IL28B rs12979860 genotypes influence mortality risk in HIV-infected, antiretroviral-treated patients. The effect may be related to higher baseline plasma HIV viremia and possibly altered immune reconstitution associated with interferon λ expression.

The single-nucleotide polymorphism T&gt;C rs4353229 in CASP7 gene and mir-224 as new biomarkers of oxaliplatin-induced neurotoxicity in advanced colorectal cancer.

513 Background: Oxaliplatin represents a central component of colorectal (CCR) cancer treatment. It is known that the ways in which oxaliplatin is neurotoxic include not only DNA damage, but also the modulation of specific molecules, such as caspases 3 and 7, involved in regulating the cellular equilibrium between apoptotic death and the cell cycle. MiRNAs are non-coding RNAs that can block mRNA traslation. Recent evidences indicate that variations in miRNA binding sites may contribute to the susceptibility to CCR. However, the effect of these SNPs on miRNA-target interaction remains to be determined. The SNP T&gt;C rs4353229 in CASP7 gene is binding site of miR-224. We hypothesize that miR-224 and the SNP T&gt;C rs4353229 could be new predictive biomarkers of oxaliplatin-induced neurotoxicity in advanced colorectal cancer. Methods: We examined the SNP T&gt;C rs4353229 in CASP7 gene in 62 patients with advanced CCR. All patients had received first line of chemotherapy based in fluoropirimidines plus oxaliplatin. The Oxaliplatin-Specific Neurotoxicity Scale was utilized to assess oxaliplatin-related symptoms. Time to progresion (TTP) and objetive response rate (ORR) were calculated. Genomic DNA was extracted from peripheral blood and genotyped by allelic discrimination. We explored the possible correlation of rs4353229 with neurotoxicity, DCR and TTP using and Chi-cuadrado test and Kaplan-Meier model (log rank) respectively. Results: SNP distribution was 3,2% (ancestral homozygous CC), 46,7% (variant homocygous TT) and 43,7% (heterocygous CT). Median TTP was 10 months (IC95%: 7,4-12,5); regarding CASP7 polymorphism, there were not differences (p=0,41; log rank). ORR was 64,5% and there are not differences between CC, CT and TT patients (p=0,50). Fifteen patients experienced neurotoxicity grade III/IV (24,19%) and it was correlated significantly with ancestral homoygous CC patients (p=0,003). Conclusions: The SNP T&gt;C rs4353229 in CASP7 gene and miR-224 may be new candidates predictor of oxaliplatin-induced neurotoxicity. Further characterization of CASP7 SNPs and miR-224 may open new avenues for the study of cancer and therapeutic interventions.

ENOS [Glu298Asp] polymorphism, erectile function and ocular pressure in type 2 diabetes

Imbalance in nitric oxide (NO), an atheroprotective vasodilator, is associated with endothelial dysfunction, cardiovascular diseases (CVD) and diabetic complications. Various endothelial NO synthase (eNOS) polymorphisms may affect NO bioavailability, thereby promoting adverse cardiovascular milieu. To analyze glucose homeostasis, cardiometabolic phenotype, and micro- and macroangiopathies associated with eNOS G894T gene polymorphism in type 2 diabetes (T2DM). 210 T2DM outpatients (mean age (1SD) 70 (12); diabetes duration 19 (9) years; males:females 64:36%; metabolic syndrome 87%) had insulin sensitivity and b-cell function modelled with HOMA, alongside routine laboratory and endothelin measurements. GG, GT and TT genotypes represented 48% (n = 100), 39% (n = 83) and 13% (n = 27). Overall microangiopathy (retinopathy, neuropathy and/or nephropathy) was present in 74%, and overall macroangiopathy (CAD, PAD and/or TIA/stroke) in 45%. The TT genotype did not translate into a more severe vascular phenotype, as TT patients carrying the proposed risk genotype did not suffer a higher rate of micro- and macrovascular complications. On the other hand, erectile dysfunction, present in 60% of males (n = 135), was much more prevalent in TT males: 57% [GG & GT] vs. 93% in TT (p 0.0088). Ocular hypertension/glaucoma frequency (18% of the whole group) was also markedly different, albeit in opposing directions, between eNOS G894T gene polymorphism subgroups: 21% [GG & GT] vs. 0% prevalence (TT; p 0.0057). eNOS G894T gene polymorphism in homozygous TT carriers translates into opposing effects on erectile function (detrimental) and ocular hypertension/glaucoma (protective) in T2DM, without affecting glucose homeostasis determinants or the presence of micro- and macrovascular complications.

IL28B Polymorphism, Explanation for Different Responses to Therapy in Hepatitis C Patients

: Implication for health policy/practice/research/medical education:This article focuses on impact of IL28B polymorphisms on hepatitis C outcomes. This study is recommended to clinicians and researchers in the field of viral hepatitis. Please cite this paper as:Sharafi H, Alavian SM. IL28B polymorphism, explanation for Different Responses to Therapy in Hepatitis C patients. HepatMon. 2011; 11(12):958-9. DoI: 10.5812/kowsar.1735143X.794

Anti-cyclic citrullinated peptide antibodies and rheumatoid factor sera titers in leprosy patients from Mexico

Leprosy offers a broad spectrum of altered immunological sceneries, ranging from strong cell-mediated immune responses seen in tuberculoid leprosy (TT), through borderline leprosy (BB), to the virtual absence of T cell responses characteristic in lepromatous leprosy (LL). The exact mechanism of autoantibodies production remains unknown in leprosy and other chronic inflammatory diseases and also the contribution of these antibodies to the pathogenesis of the disease. The aim of this study is to evaluate the frequency and profiles of serum anti-cyclic citrullinated peptide antibodies (a-CCP), rheumatoid factor (RF) and its relationship with leprosy spectrum. Serum samples from 67 leprosy patients (54 LL, 5 TT and 8 BB) and 46 clinically healthy subjects (CHS) from the same endemic region were investigated. The clinical chart and questionnaire were used to obtain clinical information. Anti-cyclic citrullinated peptide antibodies (a-CCP) were measured by enzyme-linked immunosorbent assay, whereas the rheumatoid factor (RF) levels were measured by nephelometric method. The mean age of patients was 51.5 ± 13 years. Sera levels of a-CCP where higher in leprosy patients than in CHS (5.9 ± 11.6 vs. 0.3 ± 0.29) (P < 0.0001); the same pattern was found for RF sera titers without reaching statistical significance (16.8 ± 22.5 vs. 9.9 ± 3) (P = NS). We did not find a correlation between a-CCP and RF Rho =0.02786 (IC 95%) P = 0.8229. However, LL patients had higher a-CCP and RF levels than TT patients. Although an absence in correlation was observed, the serum levels of a-CCP antibodies and RF appeared to be useful in distinguishing LL from TT patients with a limited significance in detecting reactional leprosy patients.

Endothelial Nitric Oxide Synthase T(–786)C Polymorphism in Children and Adolescents with Type 1 Diabetes and Impaired Endothelium-Dependent Dilatation

Background/Aims: This study aimed to investigate the association of endothelial nitric oxide synthase (eNOS) polymorphisms with impaired endothelium-dependent dilatation (EDD) in a cohort of children and adolescents with type 1 diabetes. Methods: Ninety-seven children and adolescents with type 1 diabetes underwent ultrasound assessment of EDD. The association of various factors with EDD was analyzed with multivariate linear regression analysis. Genotypes were determined for the eNOS T(–786)C and 4ab polymorphisms, and their association with EDD was tested with logistic regression analysis. Results: Thirty-three percent of children had impaired EDD. EDD was independently associated with A1c (p = 0.0005) and inversely correlated with A1c (p = 0.0037, OR = 2.14) using logistic regression analysis. The presence of any C allele at eNOS (–786) was significantly more frequent in patients with impaired EDD (OR = 2.97, 95% CI = 1.08–8.87, p = 0.03). Logistic regression analysis revealed OR of 3.09 for impaired EDD for patients with any C allele as compared to TT patients when controlling for all other covariates (p = 0.048). Conclusion:A third of children and adolescents with type 1 diabetes had impaired EDD independently associated with A1c. The presence of any C at (–786) of the eNOS gene conveyed a significantly increased independent risk for impaired EDD.

OP12 Similar Svr Rates In Il28b Cc, Ct Or Tt prior relapser, partial- or null-responder patients treated with telaprevir/peginterferon/ribavirin: retrospective analysis of the Realize Study

IntroductionIL28B polymorphisms are linked to differences in SVR rates in HCV treatment-naÔve patients treated with pegylated interferon (P) and ribavirin (R). REALIZE is a Phase 3 study that compared the...

Osteoradionecrosis and Trismus Following Radiotherapy Is Genotype Dependent

Osteoradionecrosis and Trismus Following Radiotherapy Is Genotype Dependent

Osteoradionecrosis in Head-and-Neck Cancer Has a Distinct Genotype-Dependent Cause

We performed a case-control study to establish whether the development of osteoradionecrosis (ORN) was related to a variant allele substituting T for C at -509 of the transforming growth factor-β1 gene (TGF-β1). A total of 140 patients, 39 with and 101 without ORN, who underwent radiotherapy for head-and-neck cancer with a minimum of 2 years follow-up, were studied. None of the patients had clinical evidence of recurrence at this time. DNA extracted from blood was genotyped for the -509 C-T variant allele of the TGF-β1 gene. There were no significant differences in patient, cancer treatment, or tumor characteristics between the two groups. Of the 39 patients who developed ORN, 9 were homozygous for the common CC allele, 19 were heterozygous, and 11 were homozygous for the rare TT genotype. Of the 101 patients without ORN, the distribution was 56 (CC), 33 (CT), and 12 (TT). The difference in distribution was significant, giving an increased risk of ORN of 5.7 (95% CI, 1.7-19.2) for homozygote TT patients (p= 0.001) and 3.6 (95% CI, 1.3-10.0) for heterozygotes (p= 0.004) when compared with patients with the CC genotype. Postradiotherapy dentoalveolar surgery preceding the development of ORN was associated with the CC genotype (p= 0.02). Our findings support the postulate that the development of ORN is related to the presence of the T variant allele at -509 within the TGF-β1 gene.

Similar SVR Rates in IL28B CC, CT or TT Prior Relapser, Partial- or Null-Responder Patients Treated With Telaprevir/Peginterferon/Ribavirin: Retrospective Analysis of the Realize Study

Introduction IL28B polymorphisms are linked to differences in SVR rates in HCV treatment-naOve patients treated with pegylated interferon (P) and ribavirin (R). REALIZE is a Phase 3 study that compared the efficacy, safety and tolerability of telaprevir (T), with or without a Lead-in (LI), in combination with PR against PR alone in prior treatment-failure patients including relapsers, partial responders and null responders (NR). Both T/PR arms were superior to control in all three patient categories. The relationship between IL28B genotype and SVR was investigated retrospectively. Method 527/662 (80%) patients enrolled in REALIZE consented to genetic testing. This represented 72%, 76% and 98% of the total relapsers, partial responders, and NR, respectively. Genotype rs12979860 was determined using a TaqMan allelic discrimination assay validated against Sanger sequencing on 50 independent samples. This was a retrospective study based on patients who consented to genetic testing prior to the discovery of IL28B, thus, sample size was not based on formal statistical considerations. Results Overall, 94% were Caucasian and 4% were Black. 18% of patients were IL28B CC, 61% CT and 21% TT. By prior response category, the highest proportion of IL28B TT patients was among prior NR (28%) while the highest frequency of CC patients occurred among prior relapsers (27%). The observed IL28B genotype frequencies indicate that the population was not in Hardy–Weinberg equilibrium (χ 2 =28, p Conclusion Differences in SVR rates among IL28B CC, CT and TT patients were only evident when the three patient subpopulations were pooled, however, SVR among CT and TT patients were still high. In this retrospective analysis, IL28B genotype did not contribute to outcome prediction in prior treatment-experienced patients treated with a telaprevir-based regimen and thus, may be of limited utility in this setting.

Involvement of p53 R72P polymorphism in the association of MDM2-SNP309 with breast cancer

The allelic variant MDM2-SNP309 (T>G) has been suggested to influence cancer development, but the clinical correlation between the risk allele and breast cancer remains controversial. The genetic background and the ethnicity of selected subgroups may influence the power of these risk genotypes. In this study, we investigated whether MDM2-SNP309 is associated with p53 R72P genetic polymorphism for the risk of breast cancer development in Asian Taiwanese, which has not been well-studied in this regard. Two hundred and fifty-five patients and 324 cancer-free controls were included, and we found that the MDM2-SNP309 TG and GG genotypes displayed marginally increased risks of breast cancer (GG vs. TT: OR = 1.7, 95% CI = 0.93 to 3.09; TG + TT vs. TT: OR = 1.57, 95% CI = 0.98 to 2.56). The breast cancer risk associated with MDM2-SNP309 was enhanced after stratification for the homozygous GG genotype at p53 codon 72 representing the Arg form of this genotype (GG vs. TT: OR = 3.7, 95% CI = 1.144 to 12.02; TG + GG vs. TT: OR = 2.7, 95% CI = 1.027 to 6.895). Also, the median age at diagnosis of patients with MDM2-SNP309 GG increased from 4 years earlier to 9 years earlier than TT patients after stratification for the GG genotype at p53 codon 72. Moreover, the G-allele of MDM2-SNP309 exhibited a stronger capacity than the T-allele to drive the full-length P2 promoter of the MDM2 gene in several human cell lines, suggesting that the association between MDM2-SNP309 and breast cancer is likely multifactorial rather than due to inconsistent gene expression in different cancer sources.

14 PIOGLITAZONE IS ANTI-INFLAMMATORY IN HUMAN LIVER AND REDUCES STELLATE CELL ACTIVATION AND PROLIFERATION

Results: Overall, 94% were Caucasian and 4% were Black. 18% of patients were IL28B CC, 61% CT and 21% TT. By prior response category, the highest proportion of IL28B TT patients was among prior NR (28%) while the highest frequency of CC patients occurred among prior relapsers (27%). The observed IL28B genotype frequencies indicate that the population was not in HardyWeinberg equilibrium (Chi=28, P < 0.0001). IL28B genotypes were well balanced across all arms with exception of a higher frequency of TTs in the placebo arm. Since no differences were observed between the two T arms, a pooled analysis is presented.

The GNAS1 T393C single nucleotide polymorphism predicts the natural postoperative course of complete resected esophageal cancer

Genetic variations in cancer patients may serve as important prognostic indicators of clinical outcome. The GNAS1 T393C single nucleotide polymorphism (SNP) diversely correlates with the clinical outcome in cancer. The aim of this study was to evaluate the potential prognostic value of T393C-SNP in complete resected only surgically treated esophageal cancer (EC). Genomic DNA was extracted from peripheral blood leucocytes of 190 patients who underwent only complete surgical resection for EC. T393C-SNP was correlated with clinic-pathological parameters, tumor cell dissemination in bone marrow (DTC) and clinical outcome. T-allele carriers had more advanced disease due to presence of lymph node metastasis (P < 0.0001) and DTC (P = 0.01) and higher recurrence rate (P = 0.01) compared to CC genotype. The disease-free (P < 0.001) and overall survival (P < 0.001) was better in CC compared to TT and TC patients. In the multivariate Cox regression disease-stage adjusted analysis the T393C-SNP was identified as a strong independent prognostic factor for recurrence (hazard ratio 1.8, P = 0.01) and survival (hazard ratio 2.5, P < 0.001) in EC patients. Determination of T393C-SNP preoperatively will allow allocation of EC patients into different risk profiles which may help to stratify patients eligible for neoadjuvant and or adjuvant therapy.

Cytokine gene polymorphisms are associated with markers of disease severity and prognosis in patients with idiopathic dilated cardiomyopathy

AimsTo identify potential genetic associations of five cytokine gene polymorphisms with disease severity and prognosis in patients with idiopathic dilated cardiomyopathy (DCM). Methods and resultsEighty patients with DCM were genotyped for transforming growth factor beta1 (TGF-β1)+869 T/C (codon10 Leu→Pro), TGF-β1+915 G/C (codon25 Arg→Pro), interleukin (IL)-6 −174G/C, tumor necrosis factor-alpha (TNF-α) −308A/G, interferon-gamma (IFN-γ)+874T/A, IL-10 −1082A/G, IL-10 −819T/C and IL-10 −592A/C gene polymorphisms. In homozygous TT patients for TGF-β1 +869 T/C polymorphism mean VO2 max was significantly higher than in CC homozygous patients (25.67±6.73ml/kg/min vs. 20.29±6.35ml/kg/min, p=0.046), which remained significant only for patients younger than 39years old after adjusting for age and sex (p=0.009). C carriers of TGF-β1 +915 G/C polymorphism are 4.2 times more likely to be in a worse NYHA stage (III–IV) than non C carriers [OR: 4.25, 95% CI (1.53–11.80), p=0.006]. Patients GG homozygous for IL-6 −174G/C polymorphism presented greater left ventricle end-systolic (p=0.018) and end-diastolic (p=0.04) diameters in comparison to the CC homozygous. The AA homozygote for IFN-γ+874T/A polymorphism (p=0.02) and the combination of the TGF-β1+869 T/C and TGF-β1+915 G/C genotypes were associated with adverse outcome (p=0.014). ConclusionSpecific cytokine gene polymorphisms seem to be associated with worse prognosis as well as with measures of disease severity in DCM.

The genetic association of CYP2C19 allele with clopidogrel treatment in myocardial infarction

Background: Major adverse cardiac events, including thrombosis and cardiac stroke, represent life-threatening conditions that need to be analyzed from every perspective including: life-style and genetic background. There is growing evidence that such ischemic events are more prone to arise in populations with a certain genetic background. With appropriate treatment and significant improvements in technology, genetics analysis of many diseases has become readily available and are easier to perform. In this paper we studies the genetic association of CYP2C19 allelic variants *2,*5 and *17 polymorphisms on the response to clopidogrel antipla telet treatment in post-myocardial infarction patients. Method: 5 ml of blood was drawn from 42 cardiac patients on antiplatelet therapy. For the detection of the CYP2C19*5, CYP2C19*17, CYP2C19*2, extracted DNA was carried out by the 5’ nuclease assay using TaqMan MGB probe by means of an ABI 7900 [Applied Biosystems). Results: Results have shown that there is significant association between CYP2C19*17 mutation and clinical outcome in TT patients carrying the mutant allele (p=0.048). As for CYP2C19*5 (p=0.917) and CYP2C19*2(p=0.09) mutations results have shown no significant association between CYP2C19*5 and *2 response to plavix, although CT/TT and GA/AA mutations have shown more recurrent ischemic events and death than wild type genotypes. Conclusion: Mutations in CYP2C19*17 has an effect on clopidogrel response, while CYP2C19*2 and *5 are not significantly associated with such low response. Further studies are needed with a larger sample size.

Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma

Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC. Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels. Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure. The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.

IL28 variation affects expression of interferon stimulated genes and peg-interferon and ribavirin therapy

Common genetic variation within the IL28 locus has been found to influence the effect of peg-interferon and ribavirin combination therapy against chronic hepatitis C virus (HCV) infection. Expression of IL28 in peripheral blood cells has been reported to be higher in patients with IL28 SNP genotypes associated with favorable response. We analyzed 52 liver and 114 blood samples obtained from patients with HCV genotype 1b. We used reverse transcription-real time polymerase chain reaction to analyze expression levels of IL28 and several interferon stimulated genes (ISGs), including MxA, double stranded RNA dependent protein kinase (PKR), 2'-5' oligo-nucleotide synthetase (OAS1), ISG15, and SOCS1. Interestingly, expression of IL28 was significantly lower in patients with the response-favorable rs8099917 TT genotype compared to those with TG or GG genotypes (p<0.005). In hepatic cells, expression of MxA, PKR, OAS1, and ISG15 were also significantly lower in rs8099917 TT patients (p<0.001, p=0.005, p=0.001, p<0.001, respectively), whereas in peripheral blood mononuclear cells ISG expression levels did not differ significantly. Among patients treated with peg-interferon plus ribavirin therapy, liver mRNA levels of IL28, MxA, PKR, OAS1, and ISG15 were significantly or marginally lower in responders who became negative for HCV RNA (p=0.001, 0.004, 0.014, 0.051, and 0.015, respectively). Expression levels of ISGs are differentially regulated in the liver and peripheral blood. The mechanism underlying the expression levels of IL28 and ISGs and the correlation with the effect of the therapy should be further investigated.

Influence of methylenetetrahydrofolate reductase polymorphisms in oral cancer patients

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Two common polymorphisms associated with MTHFR gene - C677T and A1298C - influence the thermolabile nature and activity of the enzyme. This study aimed to investigate the role of MTHFR polymorphisms on oral cancer susceptibility and its potential impact on the prognostic outcome. Oral cancer cases and controls were genotyped using PCR-RFLP technique for MTHFR C677T and A1298C polymorphisms. Disease susceptibility analysed using regression analysis. The association between clinical outcomes and the polymorphisms were analysed using univariate and multivariate model. The 677CT+TT genotype showed a significant three-fold reduction in oral cancer risk (RR-0.35, p-0.009). 1298CC genotype showed decreased cancer risk when compared to AA+AC genotype (RR-0.55, p-0.062). When prognostic significance of MTHFR polymorphism was evaluated, 677CT+TT patients showed improved survival than the CC individuals (RR = 0.56, P = 0.378). The 1298 CC and AC+CC showed an increased risk for treatment failure and poor survival when compared with the wild AA genotype (HR = 4.27, P = 0.001). Here we observed MTHFR C677T to influence oral cancer susceptibility, while A1298C polymorphism associated with patient prognosis. Our data support MTHFR polymorphism to be an independent prognostic marker in oral carcinoma.

Circulating CD4+ CD25highFoxP3+ T cells vary in different clinical forms of leprosy

CD4(+) CD25(high) FoxP3(+) regulatory T cells (T-regs) were reported to increase in chronic infections. We aimed at studying their frequency in leprosy to investigate their role during Mycobacterium leprae infection. Using flow cytometry, the frequency and FoxP3 expression of circulating T-regs was assessed in 38 leprosy patients and 38 healthy controls. Patients were divided into; group I tuberculoid (TT), group II borderline cases [borderline tuberculoid (BT), borderline (BB), and borderline lepromatous (BL)], group III lepromatous (LL), and group IV erythema nodosum leprosum (ENL). Mean T-regs% and FoxP3 expression were significantly elevated in patients (particularly TT) compared to controls (3.8 ± 2.5% vs. 2.5 ± 0.8% and 78.8 ± 56.2% vs. 55.8 ± 15.7%, respectively) (P < 0.05). Comparing the four disease groups, T-regs% was significantly different (median 5.3% in group I, 3.4% in group II, 2.8% in group III, and 1.2% in group IV; P = 0.005). FoxP3% on T-regs was not significantly different between them [median 71.5% in TT, 62.3% in borderline categories, 67.75% in LL, and 85.75% in ENL; P = 0.149). Notably FoxP3 expression was significantly higher in ENL than controls (P = 0.011). The frequency and suppressive marker of circulating T-regs are elevated in TT patients. Patients with LL and ENL express significantly lower frequency of T-regs and higher FoxP3 expression (in ENL), consistent with disease progression and immune hyper-activation in these disease categories. Thus, rather than being detrimental to immunity, intact T-regs activity may be beneficial to leprosy patients.