Human Papillomavirus-Associated Cancers.

Human Papillomavirus (HPV) is the causative agent in the majority of anal, head and neck, oral, oropharyngeal, penile, vaginal, vulvar, and cervical cancers. Cervical cancer is the fourth most common cancer among women worldwide. Of all diagnosed human malignant neoplasms, approximately 4.5% are attributable to HPV, including cervical, anal cancers, vaginal, vulvar, penile, and oropharyngeal cancers. Over 182 HPV types have been identified and sequenced to date however, only certain types of HPV are more frequent in malignant lesions and considered to be a major risk factor in the development of some cancers. Because most HPV infections are transient, and an individual's immunocompetent may clear the infection, HPV infection has received little attention from clinicians, the general public, or policy makers. This lack of attention may underpin a deadly and increasing problem because each newly acquired infection has the potential to persist and become an incurable, lifelong affliction. In addition, no successful treatment of HPV infection currently exists despite the great strides toward understanding the mechanisms underlying HPV pathogenesis. Moreover, ample research has proven that the use of prophylactic vaccines, such as Gardasil and Cervarix, have led to documented progress in decreasing the burden of HPV infection, however not all countries introduced a government-funded National HPV Vaccination Program to protect young men and women. This chapter summarizes the HPV infection, detection and prevention. We also shed light on non-cervical HPV-related cancers, which is rapidly increasing in more developed countries toward cervical cancer.

Genetic diversity of carbapenem-resistant Klebsiella Pneumoniae causing neonatal sepsis in intensive care unit, Cairo, Egypt.

Neonatal sepsis is a great challenge for clinicians and infection control practitioners, especially in facilities with limited resources. Carbapenem-resistant Klebsiella pneumoniae (CRKP) is rapidly increasing and carriages a major threat to neonates. We aimed to examine phenotypes causing neonatal late onset sepsis (NLOS) in comparison with neonatal early onset sepsis (NEOS) with further investigations of genotypes, and genetic relatedness of CRKP in neonatal late-onset sepsis. Our study included 88 neonates diagnosed with sepsis: 58 with (NLOS) and 30 with (NEOS) from November 2015 to April 2016, at neonatal intensive care unit (NICU) of Cairo University Hospital. K. pneumoniae was the most common encountered pathogen in the NLOS group (37.9%) with a mean sepsis score of 6.39 when compared to the NEOS group (p < 0.05). In Klebsiella group, C-reactive protein and interleukin-6 levels were significantly high (p ˂ 0.001) and 56.5% of the isolates were meropenem resistant. The most prevalent carbapenemase gene was OXA-48 which was identified in 14/23 (60.8%) followed by NDM-1 which was identified in 12/23 (52.2%) as detected by multiplex PCR. Coexistence of both carbapenemases was found in 52.2% (12/23). The blaKPC, blaIMP, and blaVIM genes were not harbored in the isolates. By investigating the genetic relatedness of CRKP by pulsed-field gel electrophoresis, 23 isolates of K. pneumoniae revealed various pulsed-field gel electrophoresis (PFGE) patterns, demonstrating that the isolates were non-clonal. Awareness of the existing phenotypes and genotypes is important for proper treatment and infection control practices.

Interleukin-22 Polymorphisms in Plasmodium falciparum-Infected Malaria Patients.

Background and Objectives. Malaria infection, caused by Plasmodium falciparum, is the most lethal and frequently culminates in severe clinical complications. Interleukin-22 (IL-22) has been implicated in several diseases including malaria. The objective of this study was to investigate the role of IL-22 gene polymorphisms in P. falciparum infection. Material and Methods. Ten single-nucleotide polymorphisms (SNPs), rs976748, rs1179246, rs2046068, rs1182844, rs2227508, rs2227513, rs2227478, rs2227481, rs2227491, and rs2227483, of IL-22 gene were genotyped through PCR-based assays of 250 P. falciparum infection. IL-22 gene promoter activity. RESULTS: We found that the rs2227481 TT genotype (odds ratio 0.254, confidence interval = 0.097-0.663, P. P. falciparum infection. P. P. P. P. CONCLUSION: The study suggests that IL-22 polymorphisms in rs2227481 and rs2227483 could contribute to protection against P. falciparum infection. IL-22 gene promoter activity.

Deletion and Functional Analysis of Hepatitis B Virus X Protein: Evidence for an Effect on Cell Cycle Regulators.

BACKGROUND/AIMS: The hepatitis B virus X protein (HBx) is a viral trans-activator that plays a crucial role in pathogenesis of hepatocellular carcinoma (HCC) via an unknown mechanism. The role of HBx in modulating cell proliferation and programmed cell death is replete with controversies. Thus, the goal of this study was to elucidate the effect of HBx and its deletion mutants on cell cycle progression in human hepatoma cells. METHODS: Huh7 cells transfected with either full-length or truncated HBx were tested for their mitogenic potential based on their effect on the expression of key cell cycle-related proteins (p27, cyclin D1, p21, and p53) and pro-apoptotic proteins such as cleaved poly (ADP-ribose) polymerase (PARP) and Bax. Western blotting and immunofluorescence techniques were applied to detect changes in the expression levels and intracellular localization, respectively, of the investigated proteins. Also, Quantitative real-time PCR (qRT-PCR) was used to detect changes in RNA levels. RESULTS: An increased anchorage-independent growth of cells transfected with HBx-WT and its deletion mutants was observed. The cell cycle regulatory molecules were differentially modulated by full-length HBx (1-154) and its different N- and C-terminal truncated forms (HBx (31-154), HBx (61-154), HBx (1-94), and HBx (61-124)). An enhanced modulation of p27, p21, and cyclin D1 was associated with HBx (1-154), whereas p53 expression was significantly inhibited by HBx (61-124). Similarly, the expression of cleaved PARP and Bax was efficiently suppressed by HBx (1-94) and HBx (61-154). CONCLUSION: The HBx-WT and its mutants play a critical role in the pathogenesis and progression of HCC by modulating cell cycle regulatory proteins.

Molecular epidemiology of vancomycin resistant enterococci in a tertiary care hospital in Saudi Arabia.

AIM: Vancomycin-resistant enterococci (VRE) are a major cause of nosocomial infections with high mortality and morbidity. There is limited data on the molecular characterization of VRE in Saudi Arabia. This study was carried out to investigate the premise that a shift in VRE epidemiology is occurring in our setting. METHODS: Enterococcus species identification and susceptibility testing plus VRE phenotypic confirmation by vancomycin and teicoplanin E-test were carried out. Vancomycin resistance genes were detected by PCR. Strain typing was conducted using PFGE. RESULTS: Among the strains of Enterococcus spp. investigated in this study, 17 (4.5%) were VRE. With the exception of one isolate from rectal swab, all others were clinical specimens with blood being the commonest source (n = 11; 64.7%), followed by urine (n = 3; 17.6%). The 17 VRE isolates were Enterococcus faecium (n/N = 13/17) and Enterococcus gallinarum (n/N = 4/17). Among E. faecium isolates, vanA(+)/vanB(+) (n/N = 8/13; 62%) exhibiting VanB phenotype were predominant. One of the five vanA(+)E. faecium isolates exhibited a VanB phenotype indicative of vanA genotype-VanB phenotype incongruence. E. gallinarum isolates exhibited a Van C phenotype although two were vanA(+)/vanC1(+). PFGE revealed a polyclonal distribution with eight pulsotypes. CONCLUSION: These findings indicate an evolving VRE epidemiology with vanA(+)/vanB(+) isolates and vanA genotype-VanB phenotype incongruence isolates, which were previously described as colonizers, are now causing clinical infection.

PARK2 polymorphisms predict disease progression in patients infected with hepatitis C virus.

 Background. The protein encoded by PARK2 gene is a component of the ubiquitin-proteasome system that mediates targeting of proteins for the degradation pathway. Genetic variations at PARK2 gene were linked to various diseases including leprosy, typhoid and cancer. The present study investigated the association of single nucleotide polymorphisms (SNPs) in the PARK2 gene with the development of hepatitis C virus (HCV) infection and its progression to severe liver diseases. MATERIAL AND METHODS: A total of 800 subjects, including 400 normal healthy subjects and 400 HCV-infected patients, were analyzed in this study. The patients were classified as chronic HCV patients (group I), patients with cirrhosis (group II) and patients with hepatocellular carcinoma (HCC) in the context of cirrhosis (group III). DNA was extracted and was genotyped for the SNPs rs10945859, rs2803085, rs2276201 and rs1931223. RESULTS: Among these SNPs, CT genotype of rs10945859 was found to have a significant association towards the clinical progression of chronic HCV infection to cirrhosis alone (OR = 1.850; 95% C. I. 1.115-3.069; p = 0.016) or cirrhosis and HCC (OR = 1.768; 95% C. I. 1.090-2.867; p value = 0.020). CONCLUSION: SNP rs10945859 in the PARK2 gene could prove useful in predicting the clinical outcome in HCV-infected patients.

The transferability of blaOXA-23 gene in multidrug-resistant Acinetobacter baumannii isolates from Saudi Arabia and Egypt.

Carbapenem-resistant Acinetobacter spp. have been increasingly reported worldwide including Saudi Arabia and Egypt. We examined 64, non-repetitive, Acinetobacter baumannii isolates collected in 2013 and 2014 from four different medical centres (two from Saudi Arabia and two from Egypt). All the isolates were resistant to ceftazidime and ciprofloxacin. The intI1 harbouring blaGES-11 and aac-6'-1b was detected in 19% (n=12) of the isolates. ISAba1 over-expression of blaADC gene was observed in 65% (n=42) of isolates. Of all the isolates 19% (n=12) had ISAba1 upstream of the blaOXA-51-like gene, 69% (n=44) carried the blaOXA-23 gene within the Tn2006 structure, 8% (n=5) had blaOXA-24-like gene and 9% (n=6) harboured either blaVIM-2 or blaNDM-1 gene. Eighty nine percent (n=57) of isolates were resistant to imipenem and had an MIC of ≥8mg/L. Pulsed-field gel electrophoresis (PFGE) typing revealed the presence of 23 different PFGE. Three PFGE types were very widespread, ST236 (CC104) (PFGE type 1, n=15), ST208 (CC92) (PFGE type 2, n=10), ST884 (CC unassigned) (PFGE type 3, n=7) in and across all four medical centres. The blaOXA-23 gene was found to be present on a 60kb transferable plasmid in both PFGE type 1 and 2 but was absent in PFGE type 3. This is the first study to report on the emergence of ST236 in Saudi Arabia and Egypt, and spread of distinct carbapenem resistant A. baumannii clones belonging to ST884, ST945 and ST1096 in Saudi Arabia.

Detection and genotyping of torque teno virus (TTV) in healthy blood donors and patients infected with HBV or HCV in Qatar.

Torque Teno virus (TTV) has been associated with non A-G hepatitis. The goal of this study was to estimate the infection rates and genotypic characteristics of TTV in the State of Qatar. A total of 644 blood samples representing different nationalities: (i) Qatari (118) and (ii) non-Qatari (526) nationals (mostly from Arab and South Eeast Asia countries) were tested for the presence of TTV DNA by nested PCR. The majority (573) of the blood samples belonged to healthy blood donors, whereas 54 and 53 of the blood samples belonged to patients infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. The results obtained showed that the TTV infection rates in the healthy blood donors, and those infected with HBV or HCV patients were 81.4, 90.75 and 84.9%, respectively. Significant association between TTV viremia and age, or nationality was observed. Sequence analysis of PCR fragments amplified from the 5'-untranslated region (5'-UTR) of all (531) TTV positive samples showed that 65.5% (348/531) of the PCR fragment sequences were classified into main genogroup 3, followed by main genogroups 5 (24%), 2 (5.8%), and 1 (4.7%). Genogroup 4 was not detected among the our studied subjects. Phylogenetic and pairwise analyses using sequences from TTV viremic samples also showed an overall close similarity to the main genogroup 3. In conclusion, there was no significant difference in the rates of TTV detection among Qataris and non-Qataris and several genotypes, mainly genotype 3, were isolated.

Genetic variability of the core protein in hepatitis C virus genotype 4 in Saudi Arabian patients and its implication on pegylated interferon and ribavirin therapy.

BACKGROUND: Hepatitis C virus (HCV) shows a remarkable genetic diversity, contributing to its high persistence and varied susceptibilities to antiviral treatment. Previous studies have reported that the substitution of amino acids in the HCV subgenotype 1b core protein in infected patients is associated with a poor response to pegylated interferon and ribavirin (PEG-IFN/RBV) combined therapy. OBJECTIVES: Because the role of the core protein in HCV genotype 4 infections is unclear, we aimed in this study to compare the full-length core protein sequences of HCV genotype 4 between Saudi patients who responded (SVR) and did not respond (non-SVR) to PEG-IFN/RBV therapy. STUDY DESIGN: Direct sequencing of the full-length core protein and bioinformatics sequence analysis were utilized. RESULTS: Our data revealed that there is a significant association between core protein mutations, particularly at position 70 (Arg70Gln), and treatment outcome in HCV subgenotype 4d patients. However, HCV subgenotype 4a showed no significant association between core protein mutations and treatment outcome. In addition, amino acid residue at position 91 was well-conserved among studied patients where Cys91 is the dominant amino acid residue. CONCLUSIONS: These findings provide a new insight into HCV genotype 4 among affected Saudi population where the knowledge of HCV core gene polymorphisms is inadequate.

Genetic variation in interleukin 28B and correlation with chronic hepatitis B virus infection in Saudi Arabian patients.

BACKGROUND & AIMS: Several genome-wide association studies have shown that genetic variations in the chromosomal region containing interleukin-28B (IL28B) gene are associated with response to treatment in hepatitis C virus (HCV) infection. This study was conducted to examine the role of genetic variations in IL28B on disease progression in Saudi Arabian patients chronically infected with hepatitis B virus (HBV). METHODS: The study included 1128 subjects divided into four categories; 304 clearance subjects, 518 inactive carriers, 212 active carriers and 94 cirrhosis/HCC. RESULTS: Three single nucleotide polymorphisms (SNPs), rs12979860 (OR=1.307; 95% CI 1.046-1.634, χ2=5.57 and P=0.0183), rs12980275 (OR=0.642; CI 0.517-0.798, χ2=16.17 and P=0.0001) and rs8105790 (OR=0.746; CI 0.592-0.941, χ2=6.12 and P=0.0133), were found to be strongly associated with HBV clearance. The frequency of the G allele of rs12980275 and the C allele of rs8105790 were found to be more in clearance group than in patients and could contribute to protection against the disease. On the other hand, only rs12979860 showed significant difference in distribution when inactive group was compared to other groups (OR=1.285; CI 1.030-1.603, χ2=4.95, P=0.0261). No significant association was evident for any of the variants when active carriers were compared to cirrhosis/HCC patients. Haplotype analysis showed that a combination of A-T-T-G of rs12980275, rs8105790, rs8099917, and rs7248668, respectively, was associated with clearance of the virus (frequency=67.5% and P=0.015). CONCLUSION: genetic variations in IL28B gene region may influence the clearance of HBV infection.