The role of cyclins and cyclin dependent kinases in development and progression of hepatitis C virus-genotype 4-associated hepatitis and hepatocellular carcinoma., Bahnassy, Abeer A., Zekri Abdel-Rahman N., Loutfy Samah A., Mohamed Waleed S., Moneim Amrallah Abdel, Salem Salem E., Sheta Marwa M., Omar Ashraf, and Al-Zawahry Heba , Experimental and molecular pathology, 2011 Oct, Volume 91, Issue 2, p.643-52, (2011) Abstract

UNLABELLED: Altered cell cycle regulatory genes expression contributes to HCV-associated liver disease. We sought to assess the role of cyclins and cyclin dependent kinases (CDKs) in HCV-associated CH and HCC. Aberrant expression of cyclins A, E, D1, CDK2 and CDK4 was assessed by immunohistochemistry and differential PCR in HCV-associated CH and HCC with pericarcinomatous foci (PCF). S phase fraction (SPF) was determined by flow cytometry. Results were correlated with overall survival (OS) in HCC patients. In HCC, cyclins A, E, D1, CDK2 and CDK4 protein overexpression was detected in 52.8%, 52.8%, 69%, 47% and 58% compared to 36.1%, 33%, 56%, 27.8%, 55.6% for CH and 36.1%, 27%, 30.6%, 27%, 50% for PCF. Gene amplification was detected in 38.9%, 33% 66%, 33%, 44% of HCC compared to 27.8%, 25%, 44%, 27.8%, 36% in CH and 25%, 22.2%, 38.9%, 27%, 33% in PCF. A significant difference was reported between HCC, CH, NHT regarding cyclins A, E, D1, CDK2 (p=0.007, p=0.002, p=0.047, p=0.002) protein expression (ADD) and cyclin D1 amplification (p=0.009). Cyclins A, E, CDK2 expression was associated with fibrosis in CH (p=0.004, p=0.02, p=0.012). Reduced OS was (ADD) associated with cyclin D1 and cyclin A, grade, stage and metastasis (p=0.001, p=0.02, p=0.018, p=0.01, p=0.001).

CONCLUSIONS: Increased cyclins A, E, D1, CDK2 and CDK4 expression is important for HCV-associated CH and HCC. Cyclin D1 and cyclin A are prognostic biomarkers associated with reduced OS in HCC. Cyclin D1 aberration could identify high risk groups of CH patients prone to develop HCC.

Aberrant expression of cancer stem cell markers (CD44, CD90, and CD133) contributes to disease progression and reduced survival in hepatoblastoma patients: 4-year survival data., Bahnassy, Abeer A., FAWZY MOHAMED, El-Wakil Mohamed, Zekri Abdel-Rahman N., Abdel-Sayed Ahmed, and Sheta Marwa , Translational research : the journal of laboratory and clinical medicine, 2015 Mar, Volume 165, Issue 3, p.396-406, (2015) Abstract

Hepatoblastoma (HB) is an embryonal tumor of the liver in children. Prognosis and response to treatment in HB are highly variable. Cancer stem cells (CSCs) constitute a population of cells, which contribute to the development and progression of many tumors. However, their role in HB is not well defined yet. We assessed the prognostic and predictive values of some CSC markers in HB patients. Protein and messenger RNA expressions of the CSC markers CD133, CD90, and CD44 were assessed in 43 HB patients and 20 normal hepatic tissues using immunohistochemistry and quantitative real-time polymerase chain reaction. The expression levels of these markers were correlated to standard prognostic factors, patients' response to treatment, overall survival (OS), and disease-free survival (DFS). CD44, CD90, and CD133 proteins were detected in 48.8%, 32.6%, and 48.8% compared with 46.5%, 41.7%, and 58.1% RNA, respectively (concordance, 77.8%-96%). None of the normal tissue samples was positive for any of the markers. Significant correlations were reported between α-fetoprotein and both CD44 and CD133 (P = 0.02) as well as between tumor types CD90 and CD133 (P = 0.009). Reduced OS correlated with CD44, CD90, and CD133 expressions (P < 0.001), advanced stage (P < 0.001), response to treatment (P < 0.001), and total excision of the tumor. Reduced DFS correlated with CD44 and CD133 expressions (P < 0.001) only. In conclusion, CD133, CD44, and CD90 could be used as prognostic and predictive markers in HB. High expression of these markers is significantly associated with poor response to treatment and reduced survival. Moreover, complete surgical resection and systemic chemotherapy are essential to achieve good response and prolonged survival, especially in early stage patients.

Evidence of association of interleukin-23 receptor gene polymorphisms with Egyptian rheumatoid arthritis patients., Hamdy, Gehan, Darweesh Hanan, Khattab Enas A., Fawzy Samar, Fawzy Esmat, and Sheta Marwa , Human immunology, 2015 Jun, Volume 76, Issue 6, p.417-20, (2015) Abstract

BACKGROUND: The identification of additional genetic risk factor is an on-going process that will aid in the understanding of rheumatoid arthritis (RA) aetiology. A genome-wide association scan in Crohn's (CD) disease highlighted the interleukin-23 receptor (IL23R) gene as a susceptibility factor. Since the IL-23/IL-17 pathway is known to associate with other autoimmune disease, including rheumatoid arthritis and systemic sclerosis, we hypothesised that IL23R could be a shared susceptibility gene. The rare allele of IL23R single nucleotide polymorphism (SNP) rs11209026 (Arg381Gln) confers strong protection against CD. Our aim was to analyse IL23R SNP (rs11209026, rs2201841, and rs10889677) and to detect its association with RA in Egyptian patients.

METHODS: A group of Egyptian patients with RA (n=120) and apparently healthy persons as controls (n=120) was genotyped for rs11209026, rs2201841 and rs10889677 by real time/polymerase chain reaction (real-time/PCR) for the first SNP and restriction fragment length polymorphism/PCR (RFLP/PCR) in the last two SNPs.

RESULTS: Our data emphasise that the AA genotype of rs11209026 (Arg381Gln) was significantly associated with RA patients compared to the controls (P value=0.001).We did not find any significant association between either rs2201841 or rs10889677 and the development of rheumatoid arthritis (P value=1.000 & 0.562 respectively).

CONCLUSION: Our results suggest that IL23 receptor AA genotype variant of rs11209026 would contribute to RA aetiology; consequently, it might be a genetic marker for RA. We need to address the subgroup of patients who will benefit from the selective suppression of the IL23 signalling which would represent new perspectives toward a personalized therapy of RA patients by further studies.

Circulating tumor and cancer stem cells in hepatitis C virus-associated liver disease., Bahnassy, Abeer A., Zekri Abdel-Rahman N., El-Bastawisy Ahmed, Fawzy Amal, Shetta Marwa, Hussein Nehal, Omran Dalia, Ahmed Abdallah A. S., and El-Labbody Samir S. , World journal of gastroenterology, 2014 Dec 28, Volume 20, Issue 48, p.18240-8, (2014) Abstract

AIM: To assess the role of circulating tumor cells (CTCs) and cancer stem cells (CSCs) in hepatitis C virus (HCV)-associated liver disease.

METHODS: Blood and/or tissue samples were obtained from HCV (genotype 4)-associated hepatocellular carcinoma patients (HCC; n = 120), chronic hepatitis C patients (CH; n = 30) and 33 normal control subjects (n = 33). Serum levels of alpha-fetoprotein (AFP), alkaline phosphatase, and alanine and aspartate aminotransferases were measured. Cytokeratin 19 (CK19) monoclonal antibody was used to enumerate CTCs, and CD133 and CD90 were used to enumerate CSCs by flow cytometry. The expression levels of the CSCs markers (CD133 and CD90) as well as telomerase, melanoma antigen encoding gene 1 (MAGE1) and MAGE3 were assessed by RT-PCR and quantitative real-time polymerase chain reactions. The number of CTCs and/or the expression levels of CK19, CD133, telomerase, MAGE1 and MAGE3 were correlated to the standard clinicopathologic prognostic factors and disease progression.

RESULTS: Levels of AFP, alkaline phosphatase and aspartate aminotransferase were significantly different among the HCC, CH and control groups (P < 0.001), whereas alanine aminotransferase differed significantly between patient (HCC and CH) and control groups (P < 0.001). At the specified cutoff values determine by flow cytometry, CK19 (49.8), CD90 (400) and CD133 (73) were significantly higher in the blood of HCC patients compared to those in the CH and control groups (P < 0.001). On the other hand, CD133 at a 69.5 cutoff was significantly higher in the CH compared to the control group (P ≤ 0.001). Telomerase, MAGE1 and MAGE3 RNA were expressed in 55.71%, 60.00% and 62.86% of the HCC patients, respectively, but were not detected in patients in the CH or control groups, which were statistically significant (Ps < 0.001). The expression levels of telomerase, CD90, MAGE3, CD133 and CK19 were all significantly associated with high tumor grade and advanced stage in HCC patients (all Ps < 0.05).

CONCLUSION: CTC counts and AFP, CK19, telomerase, and MAGE1/MAGE3 expression predict disease progression in patients with HCV, whereas telomerase, MAGE3, CD90, CD133 and CK19 are prognostic markers in HCC.

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