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Mismatch repair genes (hMLH1, hPMS1, hPMS2, GTBP/hMSH6,HMSH2) in the pathogenesis of hepatocellular carcinoma

World Journal of Gastroenterology 2005年第20期11卷 3020-3026页

作者： abdel-rahman N. zekri Gelane M. Sabry Abeer A. Bahnassy Kamal A. Shalaby Sabrin A.abdel-Wahabh Serag Zakaria Virology and Immunology Unit Cancer Biology Department National Cancer Institute Cairo University Egypt Biochemistry Department Faculty of Science Ain Shams University Egypt Pathology Department National Cancer Institute Cairo University Egypt Tropical Medicine Department El-Kaser Al-Aini School of Medicine Cairo University Egypt

AIM: DMA mismatch repair (MMR) is an important mechanism for maintaining fidelity of genomic DNA. Abnormalities in one or more MMR genes are implicated in the development of many cancers. We investigated the role of expression of MMR genes (hMLH1, hPMS1, hPMS2, GTBP/hMSH6, hMSH2) in hepatocellular carcinogenesis. METHODS: We evaluated the expression level of MMR genes in 33 hepatocellular carcinoma (HCC) cases using the multiplex reverse transcription (RT) PCR assays, as well as in 16 cases of normal adjacent hepatic tissues. β-actin gene was used as an internal control and calibrator for quantification of gene expression. RESULTS: Out of the 33 studied cases, 25 were HCV positive and 30 (90.9%) showed reduced expression in one or more of the studied MMR genes. Reduced expression was found in hMSH2(71.9%), hMLH1 (53.3%), GTBP(51.1%), hPMS2 (33.3%) and hPMS1 (6%). A significant correlation was found between reduced expression of hPMS2(P= 0.0069) and GTBP(P= 0.0034), hPMS2 and non-cirrhosis (P= 0.0197), hMLH1 and high grade. On the other hand, 57.1%, 50%, 20%, 18.8%, and 6% of the normal tissues distant to tumors showed reduced expression of hMSH2, hMLH1, GTBP, hPMS2, and hPMS1 respectively. Multivariate analysis revealed a significant correlation between the expression level of hMSH2(P= 0.008), hMLH1 (P= 0.001) and GTBP (P= 0.032) and HCC, between hPMS2, GTBP and HCV-associated HCC (P<0.001, 0.002). CONCLUSION: Reduced expression of MMR genes seems to play an important role in HCV-associated HCC. hPMS2 is likely involved at an early stage of hepatocarcinogenesis since it was detected in normal adjacent tissues. Reduced expression of hPMS2 provides a growth advantage and stimulates proliferation which encourages malignant transformation in non-cirrhotic HCV-infected patients via acquisition of more genetic damages.

关键词： Hepatocellular carcinoma Mismatch repair Normal distant hepatic tissue

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Cytokine profile in Egyptian hepatitis C virus genotype-4 in relation to liver disease progression

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World Journal of Gastroenterology 2005年第42期11卷 6624-6630页

作者： abdel-rahman N zekri Mohammed S El-Din Ashour Ahmed Hassan Hanaa M Alam El-Din Amal MR El-Shehaby Maha A Abu-Shady Virology and Immunology Unit Cancer Biology Department National Cancer Institute Cairo University Egypt Microbiology Department Faculty of Pharmacy Azhar University Egypt Microbiology and Immunology Department Sohag Faculty of Medicine South Valley University Egypt Virology and Immunology Unit Cancer Biology Department National Cancer Institute Cairo University Egypt Biochemistry Department El-Kaser El-Aini School of Medicine Cairo University Egypt

AIM： To observe the imbalance between T helper cell Th1 and Th2 cytokines in several chronic hepatitis disease at different stages of disease progression. METHODS： We measured the cytokine levels of Thl （IL-2 and IL-2R）, Th2 （IL-10） and the pro-inflammatory cytokines （IL-6 and IL-6R and TNF and TNF-RI and II） by the ELISA technique in the sera of 33 hepatocellular carcinoma （HCC） patients and 20 chronic liver disease （CLD） patients. In addition, 20 asymptomatic hepatitis C virus carriers and 20 healthy subjects negative for hepatitis C virus（HCV） markers served as controls. RESULTS： Anti-HCV antibodies were found to be positive in 94% of HCC cases and 75% of CLD cases. On the other hand, HCV viremia was detected using RT- PCR in 67% of HCC cases and 65% of CLD cases. HBsAg was positive in 9% of HCC cases and 30% of CLD cases. Also bilharziaI-Ab was positive in 55% of HCC cases, 65% of CLD cases and in 70% of asymptomatic carriers （ASC）. HCC patients had significantly higher values of IL- 2R, TNF-RII （P〈0.001）, and TNF-RI （P〉0.05）, but lower TNFα （P〈0.001） and IL-6 （P = 0.032） in comparison to ASC. But, in comparison to non-cancer controls, HCC patients had higher values of IL-2R, IL-6R, TNF-RI and TNF-RII, but lower TNF-α （P〈0.001）. CLD patients had higher IL-2R, TNF-RI, and TNF-RII （P〈0.001） than ASC. But, in comparison to non-cancer controls, CLD patients had higher values of IL-2R, TNF-RI and TNF-RII, but lower TNF-α （P〈0.001）. IL-10 was higher （though not significantly） in HCC and CLD patients than in symptomatic carriers and non-cancer controls. CONCLUSION： Liver disease progression from CLD to HCC due to HCV genotype-4 infection is associated with an imbalance between Th1 and Th2 cytokines. IL-2R, TNF-RI, and TNF-RII could be used as potential markers.

关键词： Cytokine HCV Genotype-4 Liver disease

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Autologous CD34^+ and CD133^+ stem cells transplantation in patients with end stage liver disease

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World Journal of Gastroenterology 2010年第42期16卷 5297-5305页

作者： Hosny Salama abdel-rahman N zekri Abeer A Bahnassy Eman Medhat Hanan A Halim Ola S Ahmed Ghada Mohamed Sheren A Al Alim Ghada M Sherif Tropical Medicine Department El-Kasr Al-Aini School of MedicineKasr Al-Aini st.Kasr AlAini11977 CairoEgypt Virology and Immunology Unit Cancer Biology DepartmentNational Cancer InstituteCairo UniversityKasr Al-Aini st.Fom El-Khaleeg11976 CairoEgypt Pathology Department National Cancer InstituteCairo UniversityKasr Al-Aini st.Fom El-Khaleg11976 CairoEgypt Biostatistics and Epidemiology Department National Cancer InstituteCairo University11976 CairoEgypt

AIM:To assess the utility of an autologous CD34 + and CD133 + stem cells infusion as a possible therapeutic modality in patients with end-stage liver ***:One hundred and forty patients with endstage liver diseases were randomized into two *** 1,comprising 90 patients,received granulocyte colony stimulating factor for five days followed by autologous CD34 + and CD133 + stem cell infusion in the portal *** 2,comprising 50 patients,received regular liver treatment only and served as a control ***:Near normalization of liver enzymes and improvement in synthetic function were observed in 54.5% of the group 1 patients;13.6% of the patients showed stable states in the infused *** of the patients in the control group showed *** adverse effects were ***:Our data showed that a CD34 + and CD133 + stem cells infusion can be used as supportive treatment for end-stage liver disease with satisfactory tolerability.

关键词： CD34 CD133 Stem cell Liver Hepatitis C virus

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Circulating tumor and cancer stem cells in hepatitis C virusassociated liver disease

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World Journal of Gastroenterology 2014年第48期20卷 18240-18248页

作者： Abeer A Bahnassy abdel-rahman N zekri Ahmed El-Bastawisy Amal Fawzy Marwa Shetta Nehal Hussein Dalia Omran Abdallah A S Ahmed Samir S El-Labbody Molecular Pathology Unit Pathology Department National Cancer Institute Cairo University Cairo 11796 Egypt Virology and Immunology Unit Cancer Biology Department National Cancer Institute Cairo University Cairo 11796 Egypt Medical Oncology Department National Cancer Institute Cairo University Cairo 11796 Egypt Clinical Pathology Department National Cancer Institute Cairo University Cairo 11796 Egypt Clinical Pathology Kasr Al-Aini Cairo university Cairo 11782 Egypt Tropical Medicine Department Faculty of Medicine Cairo University Cairo 11796 Egypt Microbiology Department El-Azhar University Cairo 11964 Egypt

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

关键词： Cancer stem cells Circulating tumor cells Hepatitis C virus genotype-4 Hepatocellular carcinoma

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Positional effect of mutations in 5'UTR of hepatitis C virus 4a on patients' response to therapy

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World Journal of Gastroenterology 2009年第12期15卷 1480-1486页

作者： Mostafa K El Awady Hassan M Azzazy Ahmed M Fahmy Sherif M Shawky Noha G Badreldin Samar S Yossef Moataza H Omran abdel rahman N zekri Said A Goueli Department of Biomedical Technology National Research CenterDokkiCairo 12622Egypt Department of Chemistry and Yousef Jameel Science and Technology Research Center the American University in CairoCairo 11511Egypt Structural biology department Free University of AmsterdamDe Boelelaan 10851081 HV AmsterdamThe Netherlands National Cancer Institute Cairo 11796Egypt Department of Pathology and Laboratory Medicine University of WisconsinMadisonWI 53711United States

AIM： To investigate the effects of mutations in domain Ⅲ of the hepatitis C virus （HCV） internal ribosome entry sequences （IRES） on the response of chronic HCV genotype 4a patients to interferon therapy.METHODS： HCV RNA was extracted from 19 chronic HCV 4a patients receiving interferon/ribavirin therapy who showed dramatic differences in their response to combination therapy after initial viral clearance. IRES domain Ⅲ was cloned and 15 clones for each patient were sequenced. The obtained sequences were aligned with genotype 4a prototype using the ClustaIW program and mutations scored. Prediction of stem-loop secondary structure and thermodynamic stability of the major quasispecies in each patient was performed using the MFOLD 3.2 program with Turner energies and selected constraints on base pairing.RESULTS： Analysis of RNA secondary structure revealed that insertions in domain Ⅲ altered WatsonCrick base pairing of stems and reduced molecular stability of RNA, which may ultimately reduce binding affinity to ribosomal proteins. Insertion mutations in domain - were statistically more prevalent in sustained viral response patients （SVR, n = 14） as compared to breakthrough （BT, n = 5） patients.CONCLUSION： The influence of mutations within domain Ⅲ on the response of HCV patients to combination therapy depends primarily on the position, but not the frequency, of these mutations within IRES domain Ⅲ.

关键词： Hepatitis C virus Internal ribosome entrysequences Domain Ⅲ Genotype 4a Ribosomal sub-unit Interferon therapy RNA folding

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Early detection of hepatocellular carcinoma co-occurring with hepatitis C virus infection: A mathematical model

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World Journal of Gastroenterology 2016年第16期22卷 4168-4182页

作者： abdel-rahman Nabawy zekri Amira Salah El-Din Youssef Yasser Mabrouk Bakr Reham Mohamed Gabr Ola Sayed Ahmed Mostafa Hamed Elberry Ahmed Mahmoud Mayla Mohamed Abouelhoda Abeer A Bahnassy Molecular Virology and Immunology Unit Cancer Biology Department National Cancer Institute Cairo University Systems and Biomedical Engineering Department Faculty of Engineering Cairo University Center for Informatics Sciences Nile University Sheikh Zayed City Pathology Department National Cancer Institute Cairo University

AIM: To develop a mathematical model for the early detection of hepatocellular carcinoma (HCC) with a panel of serum proteins in combination with α-fetoprotein (AFP).METHODS: Serum levels of interleukin (IL)-8, soluble intercellular adhesion molecule-1 (sICAM-1), soluble tumor necrosis factor receptor II (sTNF-RII), proteasome, and β-catenin were measured in 479 subjects categorized into four groups: (1) HCC concurrent with hepatitis C virus (HCV) infection (n = 192); (2) HCV related liver cirrhosis (LC) (n = 96); (3) Chronic hepatitis C (CHC) (n = 96); and (4) Healthy controls (n = 95). The R package and different modules for binary and multi-class classifiers based on generalized linear models were used to model the data. Predictive power was used to evaluate the performance of the model. Receiver operating characteristic curve analysis over pairs of groups was used to identify the best cutoffs differentiating the different ***: We revealed mathematical models, based on a binary classifier, made up of a unique panel of serum proteins that improved the individual performance of AFP in discriminating HCC patients from patients with chronic liver disease either with or without cirrhosis. We discriminated the HCC group from the cirrhotic liver group using a mathematical model (-11.3 + 7.38 × Prot + 0.00108 × sICAM + 0.2574 × β-catenin + 0.01597 × AFP) with a cutoff of 0.6552, which achieved 98.8% specificity and 89.1% sensitivity. For the discrimination of the HCC group from the CHC group, we used a mathematical model [-10.40 + 1.416 × proteasome + 0.002024 × IL + 0.004096 × sICAM-1 + (4.251 × 10-4) × sTNF + 0.02567 × β-catenin + 0.02442 × AFP] with a cutoff 0.744 and achieved 96.8% specificity and 89.7% sensitivity. Additionally, we derived an algorithm, based on a binary classifier, for resolving the multi-class classification

关键词： Mathematical model Hepatocellular carcinoma α -fetoprotein Soluble intercellular adhesion molecule-1 β -catenin Interleukin-8 Soluble tumor necrosis factor receptor II Proteasome

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Role of relevant immune-modulators and cytokines in hepatocellular carcinoma and premalignant hepatic lesions

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World Journal of Gastroenterology 2018年第11期24卷 1228-1238页

作者： abdel-rahman N zekri Somaya El Deeb Abeer A Bahnassy Abeer M Badr Mona S abdellateif Gamal Esmat Hosny Salama Marwa Mohanad Ahmed Esam El-dien Shimaa Rabah Assmaa Abd Elkader Molecular Virology and Immunology Unit Department of Cancer BiologyNational Cancer InstituteCairo University Department of Zoology Faculty of ScienceCairo University Department of Pathology National Cancer InstituteCairo University Medical Biochemistry and Molecular Biology Department of Cancer BiologyNational Cancer InstituteCairo University Department of Hepatology and Tropical Medicine Faculty of MedicineCairo University Department of Biochemistry Misr University for Science and Technology

AIM To assess the levels of different immune modulators in patients with hepatocellular carcinoma(HCC),in relation to other hepatic *** Eighty-eight patients were included in the current study and represented patients with HCC(20),liver cirrhosis(28) and chronic hepatitis(CH;25),and normal controls(NC;15).Peripheral blood was isolated for immunophenotyping of active myeloid dendritic cells(m DCs;CD1 c and CD40),mature inactive myeloid cells(CD1 c and HLA),active plasmacytoid cells(p DCs;CD303 and CD40),mature inactive p DCs(CD30 and HLA),active natural killer(NK) cells(CD56 and CD161),active NK cells(CD56 and CD314) and inactive NK cells(CD56 and CD158) was done by flow *** levels of interleukin(IL)-2,IL-10,IL-12,IL-1β,interferon(IFN)-α,IFN-γ and tumor necrosis factor(TNF)-αR2 were assessed by *** Active m DCs(CD1 C+/CD40+) and inactive m DCs(CD1 c+/HLA+) were significantly decreased in HCC patients in relation to NC(P < 0.001).CD40+ expression on active p DCs was decreased in HCC patients(P < 0.001),and its level was not significantly changed among other *** p DCs(CD303+/HLA+),inactive NKs(CD56+/CD158+) and active NKs(CD56+/CD161+) were not statistically changed among the four groups studied;however,the latter was increased in CH(P < 0.05).NKG2 D was statistically decreased in HCC,CH and cirrhosis(P < 0.001),and it was not expressed in 63%(12/20) of HCC *** was significant decrease of IL-2,IFN-α and IFN-γ(P < 0.001),and a significant increase in IL-10,IL-1β,and TNF-αR2(P <0.01,P < 0.001 and P < 0.001;respectively) in HCC *** was inverted correlation between IL-12 and IL-1β in HCC(r =-0.565,P < 0.01),with a strong correlation between p DCs(CD303+/CD40+) and NKs(CD56+/CD161+;r = 0.512,P < 0.05) as well as inactive m DCs(CD1 c+/HLA+) and inactive NK cells(CD56+/CD158+;r = 0.945,P < 0.001).CONCLUSION NKG2 D,CD40,IL-2 and IL-10 are important modulators in the development and progression of HCC.

关键词： Hepatocellular carcinoma Hepatitis C virus NKG2D CD40 interleukin-2 interleukin-10 myeloid dendritic cells plasmacytoid cells natural killer cell Cytokines

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miR-34a: Multiple Opposing Targets and One Destiny in Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2016年第4期4卷 300-305页

作者： Radwa Alaa Yacoub Injie Omar Fawzy Reem Amr Assal Karim Adel Hosny abdel-rahman Nabawy zekri Gamal Esmat Hend Mohamed El Tayebi Ahmed Ihab abdelaziz Pharmaceutical Biology Department Faculty of Pharmacy and Biotechnology German University in Cairo Cairo Egypt pharmacology and Toxicology Department Faculty of Pharmacy and Biotechnology German University in Cairo Cairo Egypt Department of General Surgery Faculty of Medicine Cairo University Cairo Egypt Virology and Immunology Cancer Biology Department National Cancer Institute Cairo University Cairo Egypt Department of Endemic Medicine and Hepatology Cairo University Cairo Egypt pharmacology and Toxicology Department Faculty of Pharmacy and Biotechnology German University in Cairo Cairo Egypt School of Medicine New Giza University Cairo Egypt

Background and Aims:The role of miR-34a in hepatocellular carcinoma (HCC) is controversial and several unresolved issues remain,including its expression pattern and relevance to tumor etiology,tumor stage and prognosis,and finally,its impact on ***:miR-34a expression was assessed in hepatitis C virus (HCV)-induced non-metastatic HCC tissues by ***-7 cells were transfected with miR-34a mimics and the impact of miR-34a was examined on 84 pro-apoptotic/anti-apoptotic genes using PCR array;its net effect was tested on cell viability via ***:miR-34a expression was up-regulated in HCC ***,miR-34a induced a large set of pro-apoptotic/anti-apoptotic genes,with a net result of triggering apoptosis and repressing cell ***:HCC-related differential expression of miR-34a could be etiology-based or stage-specific,and low expression of miR-34a may predict poor *** study's findings also emphasize the role of miR-34a in apoptosis.

关键词： MicroRNA Hepatocellular carcinoma Apoptosis PCR array.

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The Antiviral Efficacy of Withania somnifera(Ashwagandha) against Hepatitis C Virus Activity: In Vitroand in SilicoStudy

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Advances in Microbiology 2020年第9期10卷 463-477页

作者： Dina Mofed Wafaa Ahmed abdel-rahman zekri Ola Said Mohamed Rahouma Ahmed Hassan Ibrahim Faraag Biochemistry and Molecular Biology Unit Department of Cancer Biology National Cancer Institute Cairo University Cairo Egypt Immunity and Virology Unit Department of Cancer Biology National Cancer Institute Cairo University Cairo Egypt Department of Surgical Oncology National Cancer Institute Cairo University Cairo Egypt Department of Botany and Microbiology Faculty of Science Helwan University Cairo Egypt

Objective: Evaluation antiviral effects of Withania somnifera (Ashwagandha) leaf extract against HCV. Methods: cell proliferation was assessed using MTT assay after isolation of lymphocyte cells and treated with Ashwagandha water extract (ASH-WX) (6.25 mg/ml - 100 mg/ml). Assessment of quantitative Real-time PCR, Colony forming assay, TNF-α and molecular docking studies after infection of normal lymphocyte cells with 1 ml (1.5 × 106 HCV) serum then incubated with ASH-WX at concentration 25 mg/ml & 50 mg/ml. Results: MTT assay revealed a significant increase (p α significantly decreased following ASH-WX treatment compared with control untreated infected cells (p 3 IU/mL. Colony formation assay test revealed colony formation reduction compared to positive untreated control. Molecular docking analysis revealed good prediction of binding between Ashwagandha and NS5B and PKN2 compared to Sovaldi. Conclusion: ASH-WX may be a powerful antiviral against HCV infection.

关键词： Antiviral Ashwagandha Hepatitis C Virus Docking Lymphocyte

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Hydrological and economic feasibility of mitigating a stressed coastal aquifer using managed aquifer recharge: a case study of Jamma aquifer, Oman

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Journal of Arid Land 2019年第1期11卷 148-159页

作者： Mustafa EL-RAWY Ali AL-MAKTOUMI Slim zekri Osman ABDALLA Rashid AL-ABRI Sultan Qaboos University Civil Engineering Department Faculty of Engineering Shaqra University Department of Civil Engineering Faculty of Engineering Minia University Ministry of Regional Municipality and Water Resources Oman Water Society

This study explored the hydrological and economic feasibility of managed aquifer recharge(MAR) using tertiary treated wastewater(TWW) to mitigate salinity in the coastal aquifer of Jamma, Oman. A steady-state groundwater flow and transport model, using MODFLOW software, was developed and calibrated. Different managerial scenarios were simulated and the results reveal that the Jamma aquifer will be further deteriorated in the next 20 a if it remains unmanaged. The groundwater table will decline further by more than 3 m on average; and the iso-concentration salinity line of 1500 mg/L will advance 2.7 km inland, which will severely affect the farming activities in the area. However, MAR using TWW when integrated with the management of groundwater abstraction(e.g., using modern irrigation systems to reduce the abstraction rate) becomes hydrologically feasible to augment the aquifer storage and control seawater intrusion, and hence improves the farming activities. The results indicate that:(1) injecting TWW in the vicinity of irrigation wells(Scenario A2);(2) investing in smart water meters and online control of pumping from the wells to reduce the abstraction rate by 25%(Scenario B); and(3) a combination of both(Scenario B2) are feasible scenarios with positive net present values. Recharge in upstream areas is found not economically feasible because of the very high investment cost of the installation of pipes to transport the TWW over a distance of 12.5 km. Because of securing funds are challenging, Scenario B would be the best option and the second-best option is Scenario A2. Scenario B2 has the lowest net benefit investment ratio and is very attractive because it entails integrated demand and supply management of groundwater. It is required to reduce pumping and to invest in injecting TWW to improve groundwater quality in the vicinity of irrigation wells and to form a hydrological barrier to control seawater intrusion in the long run.

关键词： managed aquifer recharge treated wastewater salinity line coastal aquifer Oman

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