Publications by authors named "Ishtiaq Qadri"

71 Publications

Notch signalling pathway in development of cholangiocarcinoma.

World J Gastrointest Oncol 2020 Sep;12(9):957-974

Department of Gastrointestinal medicine, Croydon University Hospital, Croydon CR7 7YE, United Kingdom.

Cholangiocarcinoma (CCA) comprises of extra-hepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma cancers as a result of inflammation of epithelium cell lining of the bile duct. The incidence rate is increasing dramatically worldwide with highest rates in Eastern and South Asian regions. Major risk factors involve chronic damage and inflammation of bile duct epithelium from primary sclerosing cholangitis, chronic hepatitis virus infection, gallstones and liver fluke infection. Various genetic variants have also been identified and as CCA develops on the background of biliary inflammation, diverse range of molecular mechanisms are involved in its progression. Among these, the Notch signalling pathway acts as a major driver of cholangiocarcinogenesis and its components (receptors, ligands and downstream signalling molecules) represent a promising therapeutic targets. Gamma-Secretase Inhibitors have been recognized in inhibiting the Notch pathway efficiently. A comprehensive knowledge of the molecular pathways activated by the Notch signalling cascade as well as its functional crosstalk with other signalling pathways provide better approach in developing innovative therapies against CCA.
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http://dx.doi.org/10.4251/wjgo.v12.i9.957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509998PMC
September 2020

Seroprevalence of Dromedary Camel HEV in Domestic and Imported Camels from Saudi Arabia.

Viruses 2020 05 18;12(5). Epub 2020 May 18.

Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.

Hepatitis E Virus (HEV) imposes a major health concern in areas with very poor sanitation in Africa and Asia. The pathogen is transmitted mainly through ingesting contaminated water or food, coming into contact with affected people, and blood transfusions. Very few reports including old reports are available on the prevalence of HEV in Saudi Arabia in humans and no reports exist on HEV prevalence in camels. Dromedary camel trade and farming are increasing in Saudi Arabia with importation occurring unidirectionally from Africa to Saudi Arabia. DcHEV transmission to humans has been reported in one case from the United Arab Emeritus (UAE). This instigated us to perform this investigation of the seroprevalence of HEV in imported and domestic camels in Saudi Arabia. Serum samples were collected from imported and domestic camels. DcHEV-Abs were detected in collected sera using ELISA. The prevalence of DcHEV in the collected samples was 23.1% with slightly lower prevalence in imported camels than domestic camels (22.4% vs. 25.4%, value = 0.3). Gender was significantly associated with the prevalence of HEV in the collected camels ( value = 0.015) where males (31.6%) were more infected than females (13.4%). This study is the first study to investigate the prevalence of HEV in dromedary camels from Saudi Arabia. The high seroprevalence of DcHEV in dromedaries might indicate their role as a zoonotic reservoir for viral infection to humans. Future HEV seroprevalence studies in humans are needed to investigate the role of DcHEV in the Saudi human population.
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http://dx.doi.org/10.3390/v12050553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290434PMC
May 2020

Leaf Extracts and Their Quercetin Protect HepG2 Cell Lines Against CCL Induced Cytotoxicity.

Indian J Clin Biochem 2019 Jul 11;34(3):324-329. Epub 2018 Apr 11.

6Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu 641 046 India.

The present study was carried out to evaluate the in vitro cytoprotective effects of and their isolated quercetin fraction to reduce the CCl (carbon tetrachloride) induced toxicity in HepG2 cell lines (Hepatocellular carcinoma G2). Silymarin was used as a standard drug to compare the protective effects of plant extracts in infected cell lines. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay, cell viability assay, leakage parameters [Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Lactate dehydrogenase (LDH)], lipid peroxidation and reduced glutathione (GSH) levels were used to find out the protection of human derived HepG2 cells against CCl-induced damage. The levels of cytotoxicity, viability and GSH were reduced. While the activities of AST, ALT, LDH and lipid peroxidation was increased in CCl-treated groups. The treatment of and their isolated quercetin fractions (100, 200, 300 µg/mL) decreased the elevated levels of all these parameters. The results of the present study suggest that the ethanolic extract of leaf and their isolated quercetin fractions can able to reduce the CCl-induced cytotoxicity in HepG2 cell lines.
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http://dx.doi.org/10.1007/s12291-018-0752-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660539PMC
July 2019

Molecular docking analysis of netropsin and novobiocin with the viral protein targets HABD, MTD and RCD.

Bioinformation 2019 30;15(4):233-239. Epub 2019 Mar 30.

Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

Dengue, West Nile and Zika virus belongs to the family flaviviridae and genus flavivirus. It is of interest to design and develop inhibitors with improved activity against these diseases. We used the helicases target to screen for potential inhibitors against these viruses using molecular docking analysis. NS3 helicases of flavivirus family of viruses such as Dengue, West Nile and Zika are prime targets for drug development. The computer aided molecular docking analysis of netropsin and novobiocin with the viral protein targets HABD, MTD and RCD is reported for further consideration.
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http://dx.doi.org/10.6026/97320630015233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599439PMC
March 2019

Expression profile of MicroRNA: An Emerging Hallmark of Cancer.

Curr Pharm Des 2019 ;25(6):642-653

Biomedical Research Center, Qatar University, Doha, Qatar.

MicroRNA (miRNAs), a class of small, endogenous non-coding RNA molecules of about 21-24 nucleotides in length, have unraveled a new modulatory network of RNAs that form an additional level of posttranscriptional gene regulation by targeting messenger RNAs (mRNAs). These miRNAs possess the ability to regulate gene expression by modulating the stability of mRNAs, controlling their translation rates, and consequently regulating protein synthesis. Substantial experimental evidence established the involvement of miRNAs in most biological processes like growth, differentiation, development, and metabolism in mammals including humans. An aberrant expression of miRNAs has been implicated in several pathologies, including cancer. The association of miRNAs with tumor growth, development, and metastasis depicts their potential as effective diagnostic and prognostic biomarkers. Furthermore, exploitation of the role of different miRNAs as oncogenes or tumor suppressors has aided in designing several miRNA-based therapeutic approaches for treating cancer patients whose clinical trials are underway. In this review, we aim to summarize the biogenesis of miRNAs and the dysregulations in these pathways that result in various pathologies and in some cases, resistance to drug treatment. We provide a detailed review of the miRNA expression signatures in different cancers along with their diagnostic and prognostic utility. Furthermore, we elaborate on the potential employment of miRNAs to enhance cancer cell apoptosis, regress tumor progression and even overcome miRNA-induced drug resistance.
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http://dx.doi.org/10.2174/1386207322666190325122821DOI Listing
February 2020

Prevalence of Epstein–Barr Virus Genotypes in Pakistani Lymphoma Patients

Asian Pac J Cancer Prev 2018 Nov 29;19(11):3153-3159. Epub 2018 Nov 29.

Department of Biological Sciences, Gomal University, Dera Ismail Khan, Pakistan.

The Epstein-Barr virus (EBV) is a herpesvirus infecting more than 90% of the human population. The tropism of EBV for B lymphocytes is evidenced in its association with many lymphoproliferative disorders. Different types of EBV (EBV-1 and EBV-2), classified on the basis of EBV nuclear antigen-2 (EBNA-2) genotyping, have been reported in benign and malignant pathologies, but there is almost no information about their frequency in the Pakistani population. The aim of this study was to determine the frequency and distribution of EBNA-2-based EBV genotypes in lymphoma patients. Genomic DNA was extracted from formalin-fixed paraffin embedded (FFPE) tissue samples obtained from 73 EBV-DNA-positive lymphoma patients. The β-globin gene was amplified to assess the presence and quality of cellular DNA from all samples. EBER-1 DNA was detected by PCR to confirm EBV presence in tissue samples. EBNA-1 mRNA relative quantification done by quantitative PCR substantiated EBNA-1 mRNA overexpression in 43.8% of EBV-positive cases in comparison to EBV-positive control cell line. EBNA-2 genotyping was done by nested PCR. Among typable samples, EBV-1 was found in 90.7% of samples while EBV-2 was present in 9.3% cases. These results show that EBV-1 was the most prevalent type in the lymphoma population of Pakistan. This epidemiology of EBV in Pakistani lymphoma patients represents an important first step in using EBV for prognosis and monitoring treatment response.
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http://dx.doi.org/10.31557/APJCP.2018.19.11.3153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318387PMC
November 2018

The Dual Specificity Role of Transcription Factor FOXO in Type 2-diabetes and Cancer.

Curr Pharm Des 2018 ;24(24):2839-2848

Department of Biology, Faculty of Sciences, King AbdulAziz University, PO Box 80216 Jeddah 21589, Saudi Arabia.

The FOXO (Forkhead box O) transcription factors are implicated in several signaling pathways and play a vital role in various cellular and physiological processes include for instance, ROS (reactive oxygen species) response, cell proliferation, regulation of programmed cell death, longevity, metabolism and cancer and regulation of cell cycle. In humans, the four FOXO family members are responsible for resemblance in their structure, regulation and functions. FOXO1 gene is highly expressed in adipose tissues and it affects the regulation of glycogenolysis and gluconeogenesis through insulin signaling. The gene of FOXO3 is highly expressed in the kidney, heart, spleen and brain and is characterized as diverse forkhead DNA-binding domain of transcription factors. The FOXO3 is a tumor suppressor gene and found to interact with p53, the trigger for apoptosis through BCl2 family genes and a regulator of Notch signaling pathway for the self-renewal of stem cells. Therefore, FOXOs remains to be a fascinating and potential target to acquire novel therapeutic approaches to cure cancer. This review will provide a comprehensive overview about the biology of FOXO proteins, which can be utilized for developing current therapeutic approaches to treat cancer.
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http://dx.doi.org/10.2174/1381612824666180911114210DOI Listing
October 2019

Consequence of HIV and HCV co-infection on host immune response, persistence and current treatment options.

Virusdisease 2018 Mar 27;29(1):19-26. Epub 2018 Jan 27.

1Special Infectious Agents Unit (SIAU), King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589 Saudi Arabia.

Hepatitis C virus (HCV) is a common opportunistic pathogen especially among Human immunodeficiency virus (HIV) infected patients. Due to incongruous studies, the pathological effect of HCV on HIV induced disease are still not fully understood. While some studies have showed no effect of HCV on HIV infection, others reported a defined role of HCV in aggravating the rates of AIDS-related illnesses and mortality. The explanation of such variances may be due to the host immune response, viral genotypes, sub-type and quasi-species distribution. The factors that complicate the management of HIV/HCV patients are: (1) reduced HCV antibody production, (2) drug interactions, (3) liver disease and (4) different epidemiologic characteristics. However, it is abundantly clear that the morbidity and mortality caused by HCV have increased since the introduction of highly active antiretroviral therapy (HAART) against HIV. In this review, the consequence of HIV/HCV co-infection on host immune response, viral replication, disease progression, mortality and morbidity, viral load, persistence and current treatment options have been discussed. Based on the clinical studies, it is necessary to evaluate the effect of HCV therapy on HIV progression and to provide a fully active HCV treatment for patients receiving HIV treatment. In conclusion, it is recommended to provide fully active HAART therapy in combination with a known HCV therapy.
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http://dx.doi.org/10.1007/s13337-018-0424-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877845PMC
March 2018

Association of HCV mutated proteins and host SNPs in the development of hepatocellular carcinoma.

Infect Genet Evol 2018 06 1;60:160-172. Epub 2018 Mar 1.

Department of Biological Science, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:

Hepatitis C virus plays a significant role in the development of hepatocellular carcinoma (HCC) globally. The pathogenic mechanisms of hepatocellular carcinoma with HCV infection are generally linked with inflammation, cytokines, fibrosis, cellular signaling pathways, and liver cell proliferation modulating pathways. HCV encoded proteins (Core, NS3, NS4, NS5A) interact with a broad range of hepatocytes derived factors to modulate an array of activities such as cell signaling, DNA repair, transcription and translational regulation, cell propagation, apoptosis, membrane topology. These four viral proteins are also implicated to show a strong conversion potential in tissue culture. Furthermore, Core and NS5A also trigger the accretion of the β-catenin pathway as a common target to contribute viral induced transformation. There is a strong association between HCV variants within Core, NS4, and NS5A and host single nucleotide polymorphisms (SNPs) with the HCC pathogenesis. Identification of such viral mutants and host SNPs is very critical to determine the risk of HCC and response to antiviral therapy. In this review, we highlight the association of key variants, mutated proteins, and host SNPs in development of HCV induced HCC. How such viral mutants may modulate the interaction with cellular host machinery is also discussed.
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http://dx.doi.org/10.1016/j.meegid.2018.02.034DOI Listing
June 2018

Hepatitis C Virus-Associated Extrahepatic Manifestations in Lung and Heart and Antiviral Therapy-Related Cardiopulmonary Toxicity.

Viral Immunol 2017 11 27;30(9):633-641. Epub 2017 Sep 27.

2 Department of Biological Sciences, King Abdul Aziz University , Jeddah, Kingdom of Saudi Arabia.

Besides liver cirrhosis and hepatocellular carcinoma, chronic hepatitis C virus (HCV) infection is associated with many extrahepatic manifestations (EHMs). HCV exhibits lymphotropism that is responsible for various EHM. An important characteristic of HCV is escape from the immune system, which enables it to produce chronic infections and autoimmune disorders along with accumulation of circulating immune complexes. These EHMs have large spectrum, because they affect many organs such as heart, lungs, kidney, brain, thyroid, and skin. HCV-related cardiac and pulmonary manifestations include myocarditis, cardiomyopathies, cardiovascular diseases (i.e., Stroke, ischemic heart disease), chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, and interstitial lung diseases. This review discusses etiology and pathogenesis of HCV-associated cardiac and pulmonary manifestations and how different genes, immune system, indirectly linked factors (mixed cryoglobulinemia), liver cirrhosis, and antiviral treatment are involved in HCV-related heart and lung diseases, however, their exact mechanism is not clear.
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http://dx.doi.org/10.1089/vim.2017.0009DOI Listing
November 2017

Acoustic and hybrid 3D-printed electrochemical biosensors for the real-time immunodetection of liver cancer cells (HepG2).

Biosens Bioelectron 2017 Aug 21;94:500-506. Epub 2017 Mar 21.

Institute for Synthetic Bioarchitectures, Department of Nanobiotechnology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria.

This study presents an efficient acoustic and hybrid three-dimensional (3D)-printed electrochemical biosensors for the detection of liver cancer cells. The biosensors function by recognizing the highly expressed tumor marker CD133, which is located on the surface of liver cancer cells. Detection was achieved by recrystallizing a recombinant S-layer fusion protein (rSbpA/ZZ) on the surface of the sensors. The fused ZZ-domain enables immobilization of the anti-CD133 antibody in a defined manner. These highly accessible anti-CD133 antibodies were employed as a sensing layer, thereby enabling the efficient detection of liver cancer cells (HepG2). The recognition of HepG2 cells was investigated in situ using a quartz crystal microbalance with dissipation monitoring (QCM-D), which enabled the label-free, real-time detection of living cells on the modified sensor surface under controlled conditions. Furthermore, the hybrid 3D additive printing strategy for biosensors facilitates both rapid development and small-scale manufacturing. The hybrid strategy of combining 3D-printed parts and more traditionally fabricated parts enables the use of optimal materials: a ceramic substrate with noble metals for the sensing element and 3D-printed capillary channels to guide and constrain the clinical sample. Cyclic voltammetry (CV) measurements confirmed the efficiency of the fabricated sensors. Most importantly, these sensors offer low-cost and disposable detection platforms for real-world applications. Thus, as demonstrated in this study, both fabricated acoustic and electrochemical sensing platforms can detect cancer cells and therefore may have further potential in other clinical applications and drug-screening studies.
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http://dx.doi.org/10.1016/j.bios.2017.03.045DOI Listing
August 2017

HTLV-1 Associated Neurological Disorders.

Curr Top Med Chem 2017 ;17(12):1320-1330

King Fahd Medical Research Center, King Abdulaziz University, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770; Novel Global Community Educational Foundation. Australia.

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus which is endemic to certain regions of the world and infects around 10-20 million people. HTLV-1 is the etiologic agent of Adult T cell leukemia/lymphoma and HTLV-1 associated neurological disorders including mainly HTLV-1 associated myelopathy/Tropical spastic paraparesis. The involvement of the central nervous diseases occurs among: HTLV-1 infected patients from endemic areas, HIV positive individuals and drug users. The ability of HTLV-1 to cause associated neuropathies starts with the virus crossing the blood brain barrier (BBB), then entering and infecting the cells of the central nervous system. As a consequence, to the viral attack, HTLV-1 infected lymphocytes produce pro-inflammatory cytokines like tumor necrosis factor alpha, Interleukin 1 beta and interleukin 6 which further disrupts the BBB. Different serological tests have been used in the diagnosis of HTLV-1. These include: ELISA, Western Blotting (WB), Immunofluorescence, Particle Agglutination and Polymerase Chain Reaction which is used as a confirmatory test. Danazol, pentoxifylline, azathioprine and vitamin C have been used in the treatment of the HTLV-1 associated neurological disorders. Other antiviral drugs (lamivudine, zidovudine), monoclonal antibodies (Daclizumab) and therapeutic agents (valporic acid, interferons) have also been evaluated. No known drug, so far, has been shown to be efficacious. The aim of this review is to present the complexities of HTLV-1 associated neurological disorders and their current ongoing treatment. In addition to discussing future possible therapeutic strategies, by targeting HTVL-1 viral components and gene/s products, for the treatment of those neurological conditions.
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http://dx.doi.org/10.2174/1568026616666161222141318DOI Listing
July 2017

Role of Some Predominant Host Immunomodulators' Single Nucleotide Polymorphisms in Severity of Hepatitis B Virus and Hepatitis C Virus Infection.

Viral Immunol 2016 12 27;29(10):536-545. Epub 2016 Sep 27.

2 Department of Biological Sciences, King Abdul Aziz University , Jeddah, Kingdom of Saudi Arabia.

Hepatitis B and C infections can be either acute or chronic. The chronic infection can culminate in liver cirrhosis and hepatocellular carcinoma. Influence of the host genetic makeup on conversion of acute to chronic infection, development of cirrhosis, and hepatocellular carcinoma is an interesting area of research. Variability in different immune system genes may account for such differences in the outcome of infection. This article discusses single nucleotide polymorphisms in different host immunomodulator genes that have been frequently reported to influence the outcome of infection and severity of disease. The genetic variability could be utilized for the prediction of disease outcome and treatment responses.
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http://dx.doi.org/10.1089/vim.2016.0062DOI Listing
December 2016

Nanomaterial Induced Immune Responses and Cytotoxicity.

J Nanosci Nanotechnol 2016 Jan;16(1):40-57

Nanomaterials are utilized in a wide array of end user products such as pharmaceuticals, electronics, clothes and cosmetic products. Due to its size (< 100 nm), nanoparticles have the propensity to enter through the airway and skin, making its path perilous with the potential to cause damages of varying severity. Once within the body, these particles have unconstrained access to different tissues and organs including the brain, liver, and kidney. As a result, nanomaterials may cause the perturbation of the immune system eliciting an inflammatory response and cytotoxicity. This potential role is dependent on many factors such as the characteristics of the nanomaterials, presence or absence of diseases, and genetic predisposition. Cobalt and nickel nanoparticles, for example, were shown to have inflammogenic properties, while silver nanoparticles were shown to reduce allergic inflammation. Just as asbestos fibers, carbon nanotubes were shown to cause lungs damage. Some nanomaterials were shown, based on animal studies, to result in cell damage, leading to the formation of pre-cancerous lesions. This review highlights the impact of nanomaterials on immune system and its effect on human health with toxicity consideration. It recommends the development of suitable animal models to study the toxicity and bio-clearance of nanomaterials and propose safety guidelines.
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http://dx.doi.org/10.1166/jnn.2016.10885DOI Listing
January 2016

PCR-Based Molecular Diagnosis of Hepatitis Virus (HBV and HDV) in HCV Infected Patients and Their Biochemical Study.

J Pathog 2016 6;2016:3219793. Epub 2016 Jun 6.

King Fahd Medical Research Center, King Abdul Aziz University, Jeddah 21589, Saudi Arabia.

Seroprevalence of HCV indicates that HCV is found in more than 10% of HBV- or HDV-infected patients worldwide leading to liver disease. Here we show HBV and HDV coinfection association with HCV infected Pakistani patients, study of disease severity, and possible interpretation of associated risk factors in coinfected patients. A total of 730 liver diseased patients were included, out of which 501 were found positive for HCV infection via PCR. 5.1% of patients were coinfected with HBV while 1% were coinfected with HBV and HDV both. LFTs were significantly altered in dually and triply infected patients as compared to single HCV infection. Mean bilirubin, AST, and ALT levels were highest (3.25 mg/dL, 174 IU/L, and 348 IU/L) in patients with triple infection while dual infection LFTs (1.6 mg/dL, 61 IU/L, and 74 IU/L) were not high as in single infection (1.9 mg/dL, 76 IU/L, and 91 IU/L). The most prominent risk factor in case of single (22%) and dual infection (27%) group was "reuse of syringes" while in triple infection it was "intravenous drug users" (60%). It is concluded that HBV and HDV coinfections are strongly associated with HCV infected Pakistani patients and in case of severe liver disease the possibility of double and triple coinfection should be kept in consideration.
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http://dx.doi.org/10.1155/2016/3219793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913052PMC
July 2016

Hepatitis C virus and neurological damage.

World J Hepatol 2016 Apr;8(12):545-56

Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.
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http://dx.doi.org/10.4254/wjh.v8.i12.545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840160PMC
April 2016

Host nucleotide polymorphism in hepatitis B virus-associated hepatocellular carcinoma.

World J Hepatol 2016 Apr;8(10):485-98

Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia.

Hepatocellular carcinoma (HCC) is etiologically linked with hepatitis B virus (HBV) and is the leading cause of death amongst 80% of HBV patients. Among HBV affected patients, genetic factors are also involved in modifying the risk factors of HCC. However, the genetic factors that regulate progression to HCC still remain to be determined. In this review, we discuss several single nucleotide polymorphisms (SNPs) which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection such as cyclooxygenase (COX)-2 expression specifically at COX-2 -1195G/A in Chinese, Turkish and Egyptian populations, tumor necrosis factor α and the three most commonly studied SNPs: PAT-/+, Lys939Gln (A33512C, rs2228001) and Ala499Val (C21151T, rs2228000). In genome-wide association studies, strong associations have also been found at loci 1p36.22, 11q22.3, 6p21 (rs1419881, rs3997872, rs7453920 and rs7768538), 8p12 (rs2275959 and rs37821974) and 22q11.21. The genes implicated in these studies include HLA-DQB2, HLA-DQA1, TCF19, HLA-C, UBE2L3, LTL, FDX1, MICA, UBE4B and PG. The SNPs found to be associated with the above-mentioned genes still require validation in association studies in order to be considered good prognostic candidates for HCC. Screening of these polymorphisms is very beneficial in clinical experiments to stratify the higher or lower risk for HCC and may help in designing effective and efficient HCC surveillance programs for chronic HBV-infected patients if further genetic vulnerabilities are detected.
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http://dx.doi.org/10.4254/wjh.v8.i10.485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820640PMC
April 2016

Design, synthesis, structure information and biochemical activity of new floro substituted organotin(IV) carboxylates.

J Photochem Photobiol B 2016 Jan 17;154:99-107. Epub 2015 Oct 17.

Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.

Four new triorganotin(IV) complexes with general formula R3SnL (R=C4H9, C6H5, and L=3-[(fluorophenylamido)]propenoic acid, 3-[(fluorophenylamido)]propanoic acid) were synthesized and characterized by elemental analyses, FT-IR, NMR ((1)H, (13)C and (119)Sn), mass spectrometry and single crystal X-ray structural analysis. The disappearance of the OH peak of the carboxylic acid in the FT-IR and NMR spectra of the compounds conform the formation of the compound and suggests that the complexation occurs via oxygen atoms of the carboxylate moiety. FT-IR date shows the bidentate nature of the carboxylate moiety of the ligand as the Δν value in all complexes is less than 250. Crystallographic data for compound 2 showed that tin has distorted tetrahedral geometry with 433.42° angle around the central tin atom. The compounds (1-4) bind to DNA, resulting hypochromism shifts in UV-visible spectroscopy suggesting an intercalative mode of interactions. The compound-DNA interaction results (UV-visible and Viscometery) encourage using the compounds against HCV. The compounds (1-4) were screened for anti-HCV activity using Huh7.5 cell (human hepatoma cell) by the Gaussia Luciferase Assay and found to be biologically active. Based on Gaussia Luciferase Assay, compound 3 (Tributylstannic [3-(2-fluorophenylamido)propionate]) was taken for quantitative analysis by "QRT-PCR" using the serum of HCV patients and was found to have substantial anti-HCV activity. This work, demonstrated that compound 3 may be used as a potential anti-HCV agent in the future.
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http://dx.doi.org/10.1016/j.jphotobiol.2015.10.011DOI Listing
January 2016

Design, synthesis, and delivery studies of organotin(IV) based HCV inhibitor.

Infect Disord Drug Targets 2015 ;15(3):153-62

King Fahd Medical Research Center, King Abdul Aziz University, Saudi Arabia.

Tributylstannic[3-(3,5 -dimethylphenylamido)propionate] is synthesized and characterized by elemental analysis, FT-IR, multinuclear NMR ((1)H, (13)C and (119)Sn) and mass spectrometry. The organic anion was found to act as monodentate O-bound ligand in solution. The compound was screened for the anti-HCV potency by the Gaussia luciferase Assay using infected Huh 7.5 cells (human hepatocellular cell) and is found active against HCV with logIC50 1.2nM in the cell-based assay. Cationic surfactant cetyl N,N,N-trimethylammoniumbromide (CTAB) was used to study the interactions of the organotin(IV) complex with positively charged micelles of the surfactant acting as a model cell membrane. The thermodynamics parameters of complex- CTAB interaction concluded that the complex is located in the palisade layer of CTAB micelles. The increase in absorbance of visible spectra of the compound confirmed its solubilization into micelles. The two carbonyl oxygen's were found to be binding sites of the complex with CTAB.
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http://dx.doi.org/10.2174/1871526515666150903121956DOI Listing
August 2016

DNA Mediated Vaccines Delivery Through Nanoparticles.

J Nanosci Nanotechnol 2015 Jan;15(1):41-53

Vaccination has led to the eradication of those diseases which had once claimed millions of lives worldwide; however, it is accompanied with a number of dis-advantages especially safety issues until the entry of DNA vaccines. The DNA vaccines have been emerged as the best remedy for problematic diseases being capable of producing humoral and cellular immune responses as well as the safest vaccines so far. However, the magnitude of immune responses produced in primates is lower than that in experimental animals. There are several reasons described theoretically for this limited efficacy and a number of novel approaches have been applied to boost their immune responses, e.g., use of more efficient promoters and coding optimization, addition of traditional or genetic adjuvants, electroporation, intradermal delivery and various prime-boost strategies. One of these strategies is controlled antigen administration of plasmid DNA through microspheres and nanoparticles. This approach is accompanied with a number of advantages to overcome the limitations of traditional delivery systems in terms of stability, solubility and pharmacology. Furthermore, the surface structure of a virus highly resembles with a nanoparticle because of their geometrical regularities and nanoscale dimensions; therefore, the engineering of nanoparticles is based upon principles of natural virus attack which will be the best tool for vaccination. There is evidence that these immune responses can be augmented by properly structured nanosized particles (nanoparticles) that may avoid DNA degradation and facilitate targeted delivery to antigen presenting cells. Adsorption, formulation or encapsulation with particles has been found to stabilize DNA formulations. The use of nanoparticles for DNA vaccine delivery is a platform technology and has been applied for delivery of a variety of existing and potential vaccines successfully.
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http://dx.doi.org/10.1166/jnn.2015.9603DOI Listing
January 2015

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients.

Asian Pac J Trop Med 2015 Aug 29;8(8):618-23. Epub 2015 Jul 29.

King Fahd Medical Research Center, King Abdul Aziz University, Jeddah, Saudi Arabia.

Objective: To identify the differential expression of candidate gluconeogenic genes which may initiate hepatitis C virus (HCV) related metabolic disorder during early stages of disease.

Methods: Patients of diverse age and sex, with positive HCV genotype 3 (HCV-3) RNA in serum and with no history of other related infections, co-infections, alcoholism, diabetes or chemotherapeutic treatments were considered for this study. Semi-quantitative reverse transcriptase PCR analysis and quantitative fold change analysis of the fresh liver biopsies of eight chronically infected HCV-3 patients and six healthy individuals were evaluated for three potential biomarkers involved in glucose homeostasis induction, namely mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2), glucose-6-phosphatase catalytic subunit (G6PC) and associated forkhead box protein 01 (FOXO1).

Results: Symptomatic evaluation, clinical history and blood test were conducted according to general disease prognosis procedures and reported here. Significantly upregulated expression of PCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression of G6PC and FOXO1 were found.

Conclusions: PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients.
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http://dx.doi.org/10.1016/j.apjtm.2015.07.016DOI Listing
August 2015

In silico inhibition of GABARAP activity using antiepileptic medicinal derived compounds.

Bioinformation 2015 30;11(4):189-95. Epub 2015 Apr 30.

Medical Biotechnology and Translational Medicine Research, King Fahd Medical Research Center, King Abdul Aziz University, PO Box 80216 Jeddah 21589, Saudi Arabia.

Epilepsy is a neurological disorder affecting more than 50 million people worldwide. It can be controlled by antiepileptic drugs (AEDs) but more than 30% patients are still resistant to AEDs. To overcome this problem, researchers are trying to develop novel approaches to treat epilepsy including the use of herbal medicines. The γ-amino butyric acid type-A receptor associated protein (GABARAP) is ubiquitin-like modifier implicated in the intracellular trafficking of GABAAR. An in silico mutation was created at 116 amino acid position G116A, and an in silico study was carried out to identify the potential binding inhibitors (with antiepileptic properties) against the active sites of GABARAP. Five different plant derived compounds namely (a) Aconitine (b) Berberine (c) Montanine (d) Raubasine (e) Safranal were selected, and their quantitative structure-activity relationships (QSAR) have been conducted to search the inhibitory activity of the selected compounds. The results have shown maximum number of hydrogen bond (H-bond) interactions of Raubasine with highest interaction energy among all of the five compounds. So, Raubasine could be the best fit ligand of GABARAP but in vitro, and in vivo studies are necessary for further confirmation.
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http://dx.doi.org/10.6026/97320630011189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479051PMC
June 2015

Computational Docking Study of p7 Ion Channel from HCV Genotype 3 and Genotype 4 and Its Interaction with Natural Compounds.

PLoS One 2015 1;10(6):e0126510. Epub 2015 Jun 1.

King Fahd Medical Research Center, King Abdul Aziz University, Jeddah, Saudi Arabia.

Background: The current standard care therapy for hepatitis C virus (HCV) infection consists of two regimes, namely interferon-based and interferon-free treatments. The treatment through the combination of ribavirin and pegylated interferon is expensive, only mildly effective, and is associated with severe side effects. In 2011, two direct-acting antiviral (DAA) drugs, boceprevir and telaprevir, were licensed that have shown enhanced sustained virologic response (SVR) in phase III clinical trial, however, these interferon-free treatments are more sensitive to HCV genotype 1 infection. The variable nature of HCV, and the limited number of inhibitors developed thus aim in expanding the repertoire of available drug targets, resulting in targeting the virus assembly therapeutically.

Aim: We conducted this study to predict the 3D structure of the p7 protein from the HCV genotypes 3 and 4. Approximately 63 amino acid residues encoded in HCV render this channel sensitive to inhibitors, making p7 a promising target for novel therapies. HCV p7 protein forms a small membrane known as viroporin, and is essential for effective self-assembly of large channels that conduct cation assembly and discharge infectious virion particles.

Method: In this study, we screened drugs and flavonoids known to disrupt translation and production of HCV proteins, targeted against the active site of p7 residues of HCV genotype 3 (GT3) (isolatek3a) and HCV genotype 4a (GT4) (isolateED43). Furthermore, we conducted a quantitative structure-activity relationship and docking interaction study.

Results: The drug NB-DNJ formed the highest number of hydrogen bond interactions with both modeled p7 proteins with high interaction energy, followed by BIT225. A flavonoid screen demonstrated that Epigallocatechin gallate (EGCG), nobiletin, and quercetin, have more binding modes in GT3 than in GT4. Thus, the predicted p7 protein molecule of HCV from GT3 and GT4 provides a general avenue to target structure-based antiviral compounds.

Conclusions: We hypothesize that the inhibitors of viral p7 identified in this screen may be a new class of potent agents, but further confirmation in vitro and in vivo is essential. This structure-guided drug design for both GT3 and GT4 can lead to the identification of drug-like natural compounds, confirming p7 as a new target in the rapidly increasing era of HCV.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126510PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451521PMC
February 2016

Organotin(IV) based anti-HCV drugs: synthesis, characterization and biochemical activity.

Dalton Trans 2015 Jun;44(22):10467-78

Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.

Three new organotin(iv) carboxylates () of 3,5-dimethylbenzoate, have been synthesized and characterized by elemental analysis, FT-IR, multinuclear NMR ((1)H, (13)C and (119)Sn), mass spectrometry and single crystal X-ray structural analysis. Crystallographic data show that in compounds and , the geometry at the central Sn atom is skew-trapezoidal bipyramidal while compound displays a distorted trigonal bipyramidal coordination geometry. In the case of compounds and , the asymmetric chelating mode of the carboxylate groups is reflected in the unequal C-O bond distances, those observed for the O1 and O3 oxygen atoms being significantly longer than those found in the O2 and O4 atoms. In the case of compound , the carboxylate groups bridge asymmetrically adjacent tin atoms in an anti-syn mode generating polymeric zigzag chains running parallel to the crystallographic c-axis. The compounds were screened for anti-HCV (hepatitis C virus) potency by the Gaussia luciferase assay using infected Huh 7.5 cells (human hepatocellular cell). Structure-activity relationship studies led to the identification of dibutyltin(iv)bis(3,5-dimethylbenzoic acid) (compound ) as a potent HCV inhibitor, with log IC50 values equal to 0.69 nM in the cell-based assay. Compound was further subjected to quantitative analysis using real-time PCR assays and viral RNA count vs. drug concentration confirmed the Gaussia luciferase assay results. The HCV RNA targeting mode of the compounds () was confirmed by a compound-DNA interaction study. The compounds ()-DNA interactions were investigated by UV-vis spectroscopy and viscometry. The hypochromic effect in spectroscopy evidenced an intercalative mode of interaction with the binding affinity in the order of > > .
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http://dx.doi.org/10.1039/c5dt00862jDOI Listing
June 2015

Comparison of structural architecture of HCV NS3 genotype 1 versus Pakistani genotype 3a.

Biomed Res Int 2014 21;2014:749254. Epub 2014 Oct 21.

King Fahd Medical Research Center, King Abdul Aziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.

This study described the structural characterization of Pakistani HCV NS3 GT3a in parallel with genotypes 1a and 1b NS3. We investigated the role of amino acids and their interaction patterns in different HCV genotypes by crystallographic modeling. Different softwares were used to study the interaction pattern, for example, CLCBIO sequence viewer, MODELLER, NMRCLUST, ERRAT score, and MODELLER. Sixty models were produced and clustered into groups and the best model of PK-NCVI/Pk3a NS3 was selected and studied further to check the variability with other HCV NS3 genotypes. This study will help in future to understand the structural architecture of HCV genome variability and to further define the conserved targets for antiviral agents.
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http://dx.doi.org/10.1155/2014/749254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221965PMC
July 2015

Unraveling the complex relationship triad between lipids, obesity, and inflammation.

Mediators Inflamm 2014 28;2014:502749. Epub 2014 Aug 28.

Department of Medical Biotechnology, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.

Obesity today stands at the intersection between inflammation and metabolic disorders causing an aberration of immune activity, and resulting in increased risk for diabetes, atherosclerosis, fatty liver, and pulmonary inflammation to name a few. Increases in mortality and morbidity in obesity related inflammation have initiated studies to explore different lipid mediated molecular pathways of attempting resolution that uncover newer therapeutic opportunities of anti-inflammatory components. Majorly the thromboxanes, prostaglandins, leukotrienes, lipoxins, and so forth form the group of lipid mediators influencing inflammation. Of special mention are the omega-6 and omega-3 fatty acids that regulate inflammatory mediators of interest in hepatocytes and adipocytes via the cyclooxygenase and lipoxygenase pathways. They also exhibit profound effects on eicosanoid production. The inflammatory cyclooxygenase pathway arising from arachidonic acid is a critical step in the progression of inflammatory responses. New oxygenated products of omega-3 metabolism, namely, resolvins and protectins, behave as endogenous mediators exhibiting powerful anti-inflammatory and immune-regulatory actions via the peroxisome proliferator-activated receptors (PPARs) and G protein coupled receptors (GPCRs). In this review we attempt to discuss the complex pathways and links between obesity and inflammation particularly in relation to different lipid mediators.
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http://dx.doi.org/10.1155/2014/502749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166426PMC
June 2015

Potential mechanisms of hepatitis B virus induced liver injury.

World J Gastroenterol 2014 Sep;20(35):12462-72

Mohd Suhail, Ashraf Ali, Ghazi A Damanhouri, Adeel GA Chaudhary, Ishtiaq Qadri, King Fahd Medical Research Center, King Abdul Aziz University, Jeddah 21589, Saudi Arabia.

Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury.
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http://dx.doi.org/10.3748/wjg.v20.i35.12462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168079PMC
September 2014

Docking studies of Pakistani HCV NS3 helicase: a possible antiviral drug target.

PLoS One 2014 4;9(9):e106339. Epub 2014 Sep 4.

King Fahd Medical Research Center, King Abdul Aziz University, Jeddah, Saudi Arabia.

The nonstructural protein 3 (NS3) of hepatitis C virus (HCV) helicase is believed to be essential for viral replication and has become an attractive target for the development of antiviral drugs. The study of helicase is useful for elucidating its involvement in positive sense single-stranded RNA virus replication and to serve as templates for the design of novel antiviral drugs. In recent years, several models have been proposed on the conformational change leading to protein movement and RNA unwinding. Some compounds have been recently reported to inhibit the helicase and these include small molecules, RNA aptamers and antibodies. The current study is designed to help gain insights for the consideration of potential inhibitors for Pakistani HCV NS3 helicase protein. We have cloned, expressed and purified HCV NS3 helicase from Pakistani HCV serum samples and determined its 3D structure and employed it further in computational docking analysis to identify inhibitors against HCV genotype 3a (GT3a),including six antiviral key molecules such as quercetin, beta-carotene, resveratrol, catechins, lycopene and lutein. The conformation obtained after docking showed good hydrogen bond (HBond) interactions with best docking energy for quercetin and catechins followed by resveratrol and lutein. These anti-helicase key molecules will offer an alternative attraction to target the viral helicase, due to the current limitation with the interferon resistance treatment and presences of high rate of resistance in anti-protease inhibitor classes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106339PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154687PMC
May 2015

Hepatitis B virus, HBx mutants and their role in hepatocellular carcinoma.

World J Gastroenterol 2014 Aug;20(30):10238-48

Ashraf Ali, Mohd Suhail, Amany Al-Mars, Sultan Ahmad, Adeel Chaudhary, Ishtiaq Qadri, Department of Medical Biotechnology, King Fahad Medical Research Center, King Abdul Aziz University, PO Box 80216, Jeddah 21589, Saudi Arabia.

Hepatocellular carcinoma (HCC) is one of the leading causes of death induced by cancer in the modern world and majority of the cases are related to chronic hepatitis B virus (HBV) infection. HBV-encoded X protein (HBx) is known to play a pivotal role in the pathogenesis of viral induced HCC. HBx is a multifunctional protein of 17 kDa which modulates several cellular processes by direct or indirect interaction with a repertoire of host factors resulting in HCC. HBX might interfere with several cellular processes such as oxidative stress, DNA repair, signal transduction, transcription, protein degradation, cell cycle progression and apoptosis. A number of reports have indicated that HBx is one of the most common viral ORFs that is often integrated into the host genome and its sequence variants play a crucial role in HCC. By mutational or deletion analysis it was shown that carboxy terminal of HBx has a likely role in protein-protein interactions, transcriptional transactivation, DNA repair, cell, signaling and pathogenesis of HCC. The accumulated evidence thus far suggests that it is difficult to understand the mechanistic nature of HBx associated HCC, and HBx mediated transcriptional transactivation and signaling pathways may be a major determinant. This article addresses the role of HBx in the development of HCC with particular emphasis on HBx mutants and their putative targets.
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http://dx.doi.org/10.3748/wjg.v20.i30.10238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130832PMC
August 2014

Prevalence and genotyping of high risk human papillomavirus in cervical cancer samples from Punjab, Pakistan.

Viruses 2014 Jul 17;6(7):2762-77. Epub 2014 Jul 17.

School of Cancer Sciences, Cancer Research UK Birmingham Cancer Centre, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

Cervical cancer is the third most common cause of cancer-related death in women worldwide. Infection with high-risk human papillomavirus (HPV) is established as the cause of cervical carcinoma, therefore, high risk HPV detection may have prognostic significance for the women who are at increased risk of disease progression. The paucity of data on the incidence of cervical cancer in Pakistan makes it difficult to determine disease burden. Even less information is available regarding the prevalent HPV strains in cervical specimens collected from this region. Cervical cancer is a neglected disease in Pakistan in terms of screening, prevention, and vaccination. Identification and accurate genotyping of the virus burden in cancer specimens is important to inform intervention policies for future management of HPV associated disease and to potentially stratify patients dependent on HPV status. In this study, detection and genotyping of HPV types 16 and 18 from 77 cervical specimens were carried out. Consensus primers GP5+/GP6+, which detect 44 genital HPV types, and type specific primers (TS16 and TS18) were used in conjunction with newly designed type specific primers. Using a combination of these methods of detection, a total of 94.81% (95% CI ±4.95) of cervical lesions were positive for HPV. Single infections of HPV16 were detected in 24.68% (95% CI ±9.63) of total samples and HPV18 was found in 25.97% (95% CI ±9.79) samples. Interestingly, a high proportion of samples (40.26%, 95% CI ±10.95) was positive for both HPV16 and 18, indicating a higher incidence of co-infection than previously reported for similar ethnic regions. The HPV genotype of 3.90% of HPV positive samples remained undetected, although these samples were positive with the GP5+/GP6+ primer set indicating infection with an HPV type other than 16 or 18. These data indicate that the overall incidence of high risk HPV infection in cervical cancer and intraepithelial neoplasia specimens in Punjab, Pakistan is in line with the worldwide prevalence, but that the incidence of HPV16 and 18 co-infections in our cohort is higher than that previously reported.
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http://dx.doi.org/10.3390/v6072762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113792PMC
July 2014