Altered expression of cytokines, chemokines, growth factors, and soluble receptors in patients with colorectal cancer, and correlation with treatment outcome.

Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors, and soluble receptors in patients with CRC and cancer-free controls as possible CRC signatures. Serum levels of 65 analytes were measured in patients with CRC and age- and sex-matched cancer-free controls using the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Of the 65 tested analytes, 8 cytokines (CSF-3, IFN-γ, IL-12p70, IL-18, IL-20, MIF, TNF-α and TSLP), 8 chemokines (fractalkine, MIP-1ß, BLC, Eotaxin-1, Eotaxin-2, IP-10, MIP-1a, MIP-3a), 2 growth factors (FGF-2, MMP-1), and 4 soluble receptors (APRIL, CD30, TNFRII, and TWEAK), were differentially expressed in CRC. ROC analysis confirmed the high association of TNF-α, BLC, Eotaxin-1, APRIL, and Tweak with AUC > 0.70, suggesting theranostic application. The expression of IFN-γ, IL-18, MIF, BLC, Eotaxin-1, Eotaxin-2, IP-10, and MMP1 was lower in metastatic compared to non-metastatic CRC; only AUC of MIF and MIP-1ß were > 0.7. Moreover, MDC, IL-7, MIF, IL-21, and TNF-α are positively associated with tolerance to CRC chemotherapy (CT) (AUC > 0.7), whereas IL-31, Fractalkine, Eotaxin-1, and Eotaxin-2 were positively associated with resistance to CT. TNF-α, BLC, Eotaxin-1, APRIL, and Tweak may be used as first-line early detection of CRC. The variable levels of MIF and MIP-1ß between metastatic and non-metastatic cases assign prognostic nature to these factors in CRC progression. Regarding tolerance to CT, MDC, IL-7, MIF, IL-21, and TNF-α are key when down-regulated or resistant to treatment is observed.

Mir-21 and Mir-125b as theranostic biomarkers for epithelial ovarian cancer in Tunisian women.

Background: Ovarian cancer (OC) is the third most common cancer in women and the leading cause of death associated with gynecologic tumors. Because this disease is asymptomatic in the early stages, most patients are not diagnosed until the late stages. This highlights the need for the development of diagnostic biomarkers. MicroRNAs (miRNAs), small non-coding RNAs, are currently being explored as potential biomarkers for the early detection of various malignancies in humans. However, their expression and diagnostic value in OC have not been well studied. Materials and Methods: the plasma levels of miR-21, miR-200a, miR-200b, miR-200c, miR-205 and miR-125b were determined in epithelial ovarian cancer (EOC) patients and healthy controls by Reverse Transcription Quantitative Realtime Polymerase Chain Reaction (RT-qPCR). The expression levels of the deregulated microRNAs were analysed according to clinical characteristics. Results: It was found that miR-21 and miR-125b were upregulated in EOC compared with healthy controls. Moreover, decreased miR-125b was associated with resistance to platinum-based chemotherapy. Conclusions: Our data suggest that miR-21 and miR-125b in plasma may serve as potential circulating biomarkers for the early detection of EOC. MiR-125b may also be useful for predicting chemosensitivity in EOC patients.

HLA DRB1/DQB1 alleles and DRB1-DQB1 haplotypes and the risk of rheumatoid arthritis in Tunisians: a population-based case-control study.

Rheumatoid arthritis (RA) is an inflammatory disease, which affects synovial joints, and is influenced by environmental and genetic factors, in particular the human leucocyte antigen (HLA) system. In our study, we investigated the association of HLA class II DRB1 and DQB1 alleles and DRB1-DQB1 haplotypes with RA susceptibility in Tunisian subjects. Therefore, HLA class II low-resolution genotyping was done in 110 RA patients and 116 controls, with a HLA-DRB1*04 high-resolution typing. Our results showed a strong association between HLA-DRB1*04/DRB1*04:05 alleles and RA presence, which persisted after correcting for multiple comparisons (Pc < 10-3, Pc = 0.020, respectively), in contrast to the protective effect of HLA-DRB1*04:03 allele (Pc = 15.2 × 10-4). However, increased frequency of DQB1*05 (Pc = 0.020) and decreased frequency of DRB1*04:03 subtype (Pc = 0.032) were seen in RF+ patients than controls. Moreover, when RA patients were compared to controls, DRB1*04-DQB1*03 haplotype was associated with RA susceptibility in Tunisians (Pc = 16.8 × 10-5), independently of RF status. Conversely, DRB1*01 allele and DRB1*01-DQB1*05 haplotype was highly present in RF+ vs RF- groups (Pc < 10-3, Pc = 5.6 × 10-3, respectively) and seems to be linked to seropositivity. Investigation of HLA class II alleles and haplotypes association with RA susceptibility with secondary Sjögren's syndrome (sSS) showed a predisposing effect of DRB1*04 (Pc < 10-3) and DRB1*04-DQB1*03 haplotype when RA with sSS/without sSS groups were compared to healthy controls. Our results confirms the association of HLA-DRB1*04, specifically HLA-DRB1*04:05 subtype, and DRB1*04-DQB1*03 haplotype with RA susceptibility in Tunisians, independently of seropositivity or the sSS presence.

Interleukin-1ß, Interleukin1-Ra, Interleukin-10, and tumor necrosis factor-α polymorphisms in Tunisian patients with rheumatoid arthritis.

OBJECTIVES: The aim of this study was to investigate the role of IL-1ß (-511C>T), TNFα (-308 G>A), IL-10 (-1082 G>A) and IL-1RN VNTR polymorphisms in the susceptibility to rheumatoid arthritis (RA) in Tunisians. PATIENTS AND METHODS: Using PCR-based methods, 104 RA patients and 150 healthy controls were investigated. We compared allele and genotype frequencies in RA patients versus controls and analyzed their correlations with erosive form (EF). RESULTS: IL1-RN VNTR A1A3 genotype is associated with higher risk of RA (P=0.012, OR=4.31). Among the cases, males who carry this genotype were more exposed to RA (P=0.044, OR=8, 47). For IL1- ß gene, a significantly higher frequency of the -511C/C genotype was observed in RA patients in comparison to controls (P=0.013, OR=2.45). This higher frequency was especially observed in women (P=0,003, OR=3.42). In contrast, IL10-1082G/G genotype was less common in patients (P=0.046, OR=0.46). According to EF, men carrying IL1-RN VNTR A1A3 (P=0.005 OR=5.28) and IL1-ß-511C/C (P=0.015 OR=2.61) genotypes develop non EF of RA. Moreover, TNFα-308 A allele (P=0.024, OR=1.84) and A/A genotype (P=0.033, OR=3.1) were positively associated to EF of RA. However, G allele (P=0.024, OR=0.31) and GG genotype (P=0.31, OR=0.031) of the TNFα-308 were protectors. CONCLUSION: Our results indicated that IL-1RN VNTR, IL-1ß (-511C>T) and IL-10 (-1082 G>A) are associated with susceptibility to RA, and that IL-1RN VNTR, IL-1ß (-511C>T) and TNFα (-308 G>A) are associated with severity of RA.

Germline HVR-II mitochondrial polymorphisms associated with breast cancer in Tunisian women.

A high incidence of somatic mtDNA polymorphisms has been reported in a wide variety of human cancers; some of them have been proposed as markers for the early detection of breast cancer. However, little attention has been paid to the potential of germline mitochondrial sequence variations as genetic risk factors for cancer. We performed a case-control study of 70 unrelated Tunisian women with breast cancer and 80 healthy age- and gender-matched blood donors, taking into account clinicopathological data, to evaluate germline polymorphism of mitochondrial HVR-II region as a genetic risk factor for breast cancer. Through direct sequencing, we detected 351 polymorphisms in controls and 248 variants in patients, with 47 and 39 segregating sites, respectively. In both groups, more than 50% of the polymorphisms were due to four variants: 315 ins C, 309 ins C, 263 A>G, and 73 A>G. The HVR-II sequences were also classified into haplotypes on the basis of the polymorphisms. Fifty-nine different haplotypes were found, 20 of them shared between patients and controls. Both groups had specific haplotypes, 18 in breast cancer patients and 21 in controls. Statistical analysis revealed a weak protective effect against breast cancer risk for two mitochondrial polymorphisms - 152 T>C (odds ratio (OR) = 0.33, 95% confidence interval (CI) = 0.12-0.91) and 263 A>G (OR = 0.17, 95%CI = 0.06-0.47). In contrast, an increased risk of breast cancer was detected for the 315+C haplotype (OR = 11.66, 95%CI = 1.44-252.23). We conclude that mitochondrial variants can affect breast cancer risk. More extensive studies, involving different types of cancer and patients with different genetic makeup, will be required to improve our understanding of the effects of germline mtDNA polymorphisms on carcinogenesis.

Y chromosome microsatellite variation in three populations of Jerba Island (Tunisia).

Six Y-chromosome linked microsatellites were typed in a sample of 135 unrelated males representing three different ethnic groups: Arabs, Berbers and Blacks of Jerba Island (Tunisia). Analysis of variation at the six Y chromosome STRs showed significant differences in allele distributions between the Black group and the two other Islander groups. The Black group revealed the highest level of genetic diversity as compared to Arabs and Berbers, while the latter group was the most homogeneous. Allele frequencies obtained for the three islander groups analysed were compared to data available for some European, Mediterranean and African populations. Principal-coordinate analyses showed genetic differentiation between the three geographically closed groups of Jerba. The absence of the YAP insertion marker and the position of Arabs and Jerban Blacks near the European cluster would suggest their relative 'admixture' with European populations.

[Mitochondrial DNA polymorphism reveals a genetic differentiation between ethnic groups in the population of Jerba]. / Le polymorphisme de l'ADN mitochondrial revèle une différenciation génétique entre certains groupes ethniques de la population de Jerba.

Jerba is an island situated in the South-East of Tunisia were some ethnic groups (Arabs, Berbers, Blacks, Jewishs and others) cohabit for centuries. The religion and cultural differences have represented an obstacle to a mixture between these groups. In order to evaluate the genetic differentiation between the muslim groups (Arabs, Berbers and Blacks), we have analysed the polymorphism of a mitochondrial DNA coding region. The cytochrome oxydase coding region (COII) was amplified by PCR in 57 Arabs, 42 Berbers and 16 Blacks. The amplified products were analysed by Restriction Fragment Length Polymorphism (RFLP). Genetic distances were calculated by using the AMOVA program. The values of these distances were significantly different between Arabs and Blacks, and between Berbers and Blacks but not between Arabs and Berbers. So That, to refine the evaluation of genetic diversity between Arabs and Berbers, we have analysed the polymorphism of a second mitochondrial coding region which encodes for the fifth unit of NADH deshydrogenase (ND5). Eleven haplotypes were defined from the resulting data of mitochondrial COII and ND5 polymorphism and a significant genetic distance between Arabs and Berbers was computed.