Showing papers in "Infectious Agents and Cancer in 2012"
TL;DR: The addition of HPV 31/33/45/52/58 to HPV types included in current vaccines could prevent almost 90% of ICC cases worldwide and if the nine-valent vaccine achieves the same degree of efficacy than previous vaccines, world incidence rates could be substantially reduced.
Abstract: Information on human papillomavirus (HPV) type distribution is necessary to evaluate the potential impact of current and future HPV vaccines. We estimated the relative contribution (RC) to invasive cervical cancer (ICC) and precancerous cervical lesions of the nine HPV types (HPV 6/11/16/18/31/33/45/52/58) included in an HPV vaccine currently under development. Estimations on ICC were based on an international study of 8,977 HPV positive cases and estimations on precancerous cervical lesions were extracted from a published meta-analysis including 115,789 HPV positive women. Globocan 2008 and 2010 World Population Prospects were used to estimate current and future projections of new ICC cases. RC of the 9 HPV types in ICC was 89.4%, with 18.5% of cases positive for HPV 31/33/45/52/58. Regional variations were observed. RCs varied by histology, ranging between 89.1% in squamous cell carcinomas (SCC) and 95.5% in adenocarcinomas (ADC). HPV 16/18/45 were detected in 94.2% of ADC. RC of the 9 types altogether decreased with age (trend test p < 0.0001), driven by the decrease in older ages of HPV 16/18/45. In contrast, the RC of HPV 31/33/52/58 increased with age. Due to population growth alone, projected estimates of ICC cases attributable to the 9 types are expected to rise from 493,770 new cases in 2012 to 560,887 new cases in 2025. The RCs of individual high risk HPV types varied by cytological and histological grades of HPV-positive precancerous cervical lesions, and there was an under representation of HPV 18 and 45 compared to ICC. The addition of HPV 31/33/45/52/58 to HPV types included in current vaccines could prevent almost 90% of ICC cases worldwide. If the nine-valent vaccine achieves the same degree of efficacy than previous vaccines, world incidence rates could be substantially reduced.
257 citations
TL;DR: This study clearly demonstrated that the p16-IHC test is not satisfactory when used exclusively as the only HPV detecting method, and quantitative E6 DNA PCR has proven to have very high level of accuracy but lesser prognostic association with clinical outcome than the HPV E6 oncoprotein RNA PCR.
Abstract: Recent emerging evidences identify Human Papillomavirus (HPV) related Head and Neck squamous cell carcinomas (HN-SCCs) as a separate subgroup among Head and Neck Cancers with different epidemiology, histopathological characteristics, therapeutic response to chemo-radiation treatment and clinical outcome. However, there is not a worldwide consensus on the methods to be used in clinical practice. The endpoint of this study was to demonstrate the reliability of a triple method which combines evaluation of: 1. p16 protein expression by immunohistochemistry (p16-IHC); 2. HPV-DNA genotyping by consensus HPV-DNA PCR methods (Consensus PCR); and 3 viral integration into the host by in situ hybridization method (ISH). This triple method has been applied to HN-SCC originated from oral cavity (OSCC) and oropharynx (OPSCC), the two anatomical sites in which high risk (HR) HPVs have been clearly implicated as etiologic factors. Methylation-Specific PCR (MSP) was performed to study inactivation of p16-CDKN2a locus by epigenetic events. Reliability of multiple methods was measured by Kappa statistics. All the HN-SCCs confirmed HPV positive by PCR and/or ISH were also p16 positive by IHC, with the latter showing a very high level of sensitivity as single test (100% in both OSCC and OPSCC) but lower specificity level (74% in OSCC and 93% in OPSCC). Concordance analysis between ISH and Consensus PCR showed a faint agreement in OPSCC (κ = 0.38) and a moderate agreement in OSCC (κ = 0.44). Furthermore, the addition of double positive score (ISHpositive and Consensus PCR positive) increased significantly the specificity of HR-HPV detection on formalin-fixed paraffin embedded (FFPE) samples (100% in OSCC and 78.5% in OPSCC), but reduced the sensitivity (33% in OSCC and 60% in OPSCC). The significant reduction of sensitivity by the double method was compensated by a very high sensitivity of p16-IHC detection in the triple approach. Although HR-HPVs detection is of utmost importance in clinical settings for the Head and Neck Cancer patients, there is no consensus on which to consider the 'golden standard' among the numerous detection methods available either as single test or combinations. Until recently, quantitative E6 RNA PCR has been considered the 'golden standard' since it was demonstrated to have very high accuracy level and very high statistical significance associated with prognostic parameters. In contrast, quantitative E6 DNA PCR has proven to have very high level of accuracy but lesser prognostic association with clinical outcome than the HPV E6 oncoprotein RNA PCR. However, although it is theoretically possible to perform quantitative PCR detection methods also on FFPE samples, they reach the maximum of accuracy on fresh frozen tissue. Furthermore, worldwide diagnostic laboratories have not all the same ability to analyze simultaneously both FFPE and fresh tissues with these quantitative molecular detection methods. Therefore, in the current clinical practice a p16-IHC test is considered as sufficient for HPV diagnostic in accordance with the recently published Head and Neck Cancer international guidelines. Although p16-IHC may serve as a good prognostic indicator, our study clearly demonstrated that it is not satisfactory when used exclusively as the only HPV detecting method. Adding ISH, although known as less sensitive than PCR-based detection methods, has the advantage to preserve the morphological context of HPV-DNA signals in FFPE samples and, thus increase the overall specificity of p16/Consensus PCR combination tests.
115 citations
TL;DR: The use of antibiotic-therapy in specific cases, although with conflicting results, could improve the treatment of ocular adnexa MALT lymphomas and underlining specific biological characteristics mainly related to the potential role of Chlamydia psittaci in lymphomagenesis.
Abstract: Ocular adnexa MALT-lymphomas represent approximatively 5-15% of all extranodal lymphomas. Almost 75% of OAMLs are localized in orbital fat, while 25% of cases involves conjunctive. MALT-lymphomas often recognize specific environmental factors responsible of lymphoma development and progression. In particular as Helicobacter pylori in gastric MALT lymphomas, other bacterial infections have been recognized related to MALT lymphomas in specific site. Recently Chlamydia psittaci has been identified in Ocular Adnexa MALT lymphomas, with variable frequence dependently from geographic areas. Thus bacterial infection is responsible of clonal selection on induced MALT with subsequent lymphoma development. Moreover Chlamydia psittaci could promote chromosomal aberration either through genetic instability as a consequence of induced proliferation and probably through DNA oxidative damage. The most common translocation described in MALT lymphomas affects NF-kB pathway with a substantial antiapoptotic effect. Several therapeutic approaches are now available, but the use of antibiotic-therapy in specific cases, although with conflicting results, could improve the treatment of ocular adnexa MALT lymphomas. In this review we analyse the most relevant features of Ocular adnexa MALT lymphomas, underlining specific biological characteristics mainly related to the potential role of Chlamydia psittaci in lymphomagenesis.
55 citations
TL;DR: This study shows how modern molecular technology applied to archival fixed tissues yields novel insights into viral oncogenesis that could be useful in managing affected patients.
Abstract: Background: EBV DNA is found within the malignant cells of 10% of gastric cancers. Modern molecular technology facilitates identification of virus-related biochemical effects that could assist in early diagnosis and disease management. Methods: In this study, RNA expression profiling was performed on 326 macrodissected paraffin-embedded tissues including 204 cancers and, when available, adjacent non-malignant mucosa. Nanostring nCounter probes targeted 96 RNAs (20 viral, 73 human, and 3 spiked RNAs). Results: In 182 tissues with adequate housekeeper RNAs, distinct profiles were found in infected versus uninfected cancers, and in malignant versus adjacent benign mucosa. EBV-infected gastric cancers expressed nearly all of the 18 latent and lytic EBV RNAs in the test panel. Levels of EBER1 and EBER2 RNA were highest and were proportional to the quantity of EBV genomes as measured by Q-PCR. Among protein coding EBV RNAs, EBNA1 from the Q promoter and BRLF1 were highly expressed while EBNA2 levels were low positive in only 6/14 infected cancers. Concomitant upregulation of cellular factors implies that virus is not an innocent bystander but rather is linked to NFKB signaling (FCER2, TRAF1) and immune response (TNFSF9, CXCL11, IFITM1, FCRL3, MS4A1 and PLUNC), with PPARG expression implicating altered cellular metabolism. Compared to adjacent non-malignant mucosa, gastric cancers consistently expressed INHBA, SPP1, THY1, SERPINH1, CXCL1, FSCN1, PTGS2 (COX2), BBC3, ICAM1, TNFSF9, SULF1, SLC2A1, TYMS, three collagens, the cell proliferation markers MYC and PCNA, and EBV BLLF1 while they lacked CDH1 (E-cadherin), CLDN18, PTEN, SDC1 (CD138), GAST (gastrin) and its downstream effector CHGA (chromogranin). Compared to lymphoepithelioma-like carcinoma of the uterine cervix, gastric cancers expressed CLDN18, EPCAM, REG4, BBC3, OLFM4, PPARG, and CDH17 while they had diminished levels of IFITM1 and HIF1A. The druggable targets ERBB2 (Her2), MET, and the HIF pathway, as well as several other potential pharmacogenetic indicators (including EBV infection itself, as well as SPARC, TYMS, FCGR2B and REG4) were identified in some tumor specimens. Conclusion: This study shows how modern molecular technology applied to archival fixed tissues yields novel insights into viral oncogenesis that could be useful in managing affected patients.
54 citations
TL;DR: This review summarizes the data on the effects of antivirals and antibiotics on cancer treatment and describes their mechanisms.
Abstract: Recent clinical and pre-clinical data demonstrate that adjuvant antimicrobial therapy is beneficial in cancer treatment There could be several reasons for this effect, which include treating cancer associated bacteria and viruses, prophylaxis of post-chemotherapy infections due to immunosuppression, and antiproliferative effect of certain antimicrobials Targeting cancer associated viruses and bacteria with antimicrobial agents is currently used for gastric, cervical, hematopoietic, liver and brain cancer However this treatment is effective only in combination with conventional therapies Antimicrobials can also have a direct antiproliferative and cytotoxic effect, and can cause apoptosis Moreover, some antimicrobials are known to be helpful in overcoming side effects of drugs commonly used in cancer treatment Chemotherapy related bacteremia and neutropenia can be overcome by the appropriately timed use of antimicrobials This review summarizes the data on the effects of antivirals and antibiotics on cancer treatment and describes their mechanisms
54 citations
TL;DR: P-MAPA acted as TLR ligand in vitro and improved the immunological status in BC, increasing TLR2 and TLR4 protein levels and showing significantly greater antitumor activity than BCG.
Abstract: Compounds that can act as agonists for toll-like receptors (TLRs) may be promising candidates for the development of drugs against infectious diseases and cancer. The present study aimed to characterize the immunomodulatory effects of P-MAPA on TLRs in vitro and in vivo, as well as to investigate its potential as adjuvant therapy in infectious diseases and cancer. For these purposes, the activity of P-MAPA on TLRs was assayed in vitro through NF-κB activation in HEK293 cells expressing a given TLR, and using an in vivo animal model for bladder cancer (BC). The antimicrobial activity of P-MAPA was tested against Mycobacterium tuberculosis (TB) in vitro in an MIC assay, and in vivo using an aerosol infection model of murine tuberculosis. Antitumor effects of P-MAPA were tested in an animal model with experimentally induced BC. Moxifloxacin (MXF) and Bacillus Calmette-Guerin (BCG) were used as positive controls in the animal models. The results showed that P-MAPA, administered alone or in combination with MXF, induced significant responses in vivo against TB. In contrast, the compound did not show antimicrobial activity in vitro. P-MAPA showed a significant stimulatory effect on human TLR2 and TLR4 in vitro. In BC, TLR2, TLR4 and p53 protein levels were significantly higher in the P-MAPA group than in the BCG group. The most common histopathological changes in each group were papillary carcinoma in BC group, low-grade intraepithelial neoplasia in BCG group and simple hyperplasia in P-MAPA group. Concerning the toxicological analysis performed during BC treatment, P-MAPA did not show evidence for hepatotoxicity and nephrotoxicity. In conclusion, P-MAPA acted as TLR ligand in vitro and improved the immunological status in BC, increasing TLR2 and TLR4 protein levels. P-MAPA immunotherapy was more effective in restoring p53 and TLRs reactivities and showed significantly greater antitumor activity than BCG. The activation of TLRs and p53 may provide a hypothetical mechanism for the therapeutic effects in both cancer and infectious diseases. Taken together data obtained will encourage the further investigation of P-MAPA as a potential candidate for the treatment of cancer and infectious diseases.
46 citations
TL;DR: The −592 polymorphism is associated with increased risk of S ICL and can serve as a marker of genetic susceptibility to SICL among Mexican women.
Abstract: Women with Human Papilloma Virus (HPV) persistence are characterized by high levels of IL-10 at cervix. We have determined whether polymorphisms of IL-10 gene promoter might be associated with increased risk of squamous intraepithelial cervical lesions (SICL) and whether exist significative differences of IL-10 mRNA expression at cervix and systemic and serum IL-10 protein between SICL cases and non-Cervical Lesions (NCL). Peripheral blood samples from SICL (n = 204) and NCL (n = 166) were used to detect IL-10 promoter polymorphisms at loci -592A/C (rs1800872), -819C/T (rs1800871), -1082A/G (rs1800896), -1352A/G (rs1800893), by allelic discrimination and to evaluate serum IL-10 protein. Cervical epithelial scrapings from NCL and biopsies from SICLs were used for HPV-typing and to evaluate IL-10 mRNA expression level. The systemic and local IL-10 mRNA expression levels were measured by real time-PCR. Genotypic and allelic frequencies of the selected polymorphisms were analyzed by logistic regression, adjusting by age and HPV-genotype, to determine the association with SICL. No significant differences were found between genotype frequencies at loci −819, -1082, and −1352. Individuals carrying at least one copy of risk allele A of polymorphism −592 had a two-fold increased risk of developing SICL [adjusted odds ratio (OR), 2.02 (95% CI, 1.26-3.25), p = 0.003], compared to NCL. The IL-10 mRNA expression and serum IL-10 protein, were significantly higher in SICL cases (p < 0.01), being higher in patients carrying the risk allele A. The −592 polymorphism is associated with increased risk of SICL and can serve as a marker of genetic susceptibility to SICL among Mexican women. According to IL-10 levels found in SICL, IL-10 can be relevant factor for viral persistence and progression disease.
46 citations
TL;DR: Taken together, genotypes 58 and 31 (10%) are more common than type 18 in CC, and inclusion of these two genotypes in a second-generation vaccine would provide optimal prevention of CC in Mexico.
Abstract: Human Papillomavirus (HPV) in cervical epithelium has been identified as the main etiological factor in the developing of Cervical Cancer (CC), which has recently become a public health problem in Mexico. This finding has allowed for the development of vaccines that help prevent this infection. In the present study, we aimed to determine the prevalence and HPV type-distribution in Mexican women with CC, high-grade squamous intraepithelial lesion (HSIL), low-grade squamous intraepithelial lesion (LSIL), and Normal cytology (N) to estimate the impact of the HPV vaccines. The PubMed database was used to identify and review all articles that reported data on HPV prevalence in CC, precursor lesions, and normal cytology of Mexican women. A total of 8,706 samples of the tissues of Mexican women were stratified according to diagnosis as follows: 499 for CC; 364 for HSIL; 1,425 for LSIL, and 6,418 for N. According to the results, the most prevalent genotypes are the following: HPV16 (63.1%), -18 (8.6%), -58, and −31 (5%) for CC; HPV-16 (28.3%), 58 (12.6%), 18 (7.4%), and 33 (6.5%) for HSIL; HPV-16 (13.1%), 33 (7.4%), 18 (4.2%), and 58 (2.6%) for LSIL, and HPV-16 (3.4%), 33 (2.1%), 18, and 58 (1.2%) for N. Taken together, genotypes 58 and 31 (10%) are more common than type 18 (8.6%) in CC. Therefore, the inclusion of these two genotypes in a second-generation vaccine would provide optimal prevention of CC in Mexico.
40 citations
TL;DR: A greater understanding of the role of infectious agents could aid the identification of novel methods of urogenital cancer treatment, and a significant volume of data collected to date show an association between infectious agents andUrogenital cancers.
Abstract: Since the late 1990s, infectious agents have been thought to play a role in the pathogenesis of approximately 15% of cancers. It is now widely accepted that infection of stomach tissue with the bacteria Helicobacter pylori is an important cause of stomach adenocarcinoma. In addition, oncogenic viruses, such as papilloma viruses, herpes viruses, and hepadnaviruses are strongly associated with increased risk of cervical cancer, lymphomas, liver cancer, amongst others. However, in the scientific community the percentage of cancers caused by pathogens is believed to be far higher than 15%. A significant volume of data collected to date show an association between infectious agents and urogenital cancers. These agents include Chlamydia trachomatis, Neisseria gonorrhoea, Mycoplasma genitalium and certain viruses that have been implicated in ovarian cancer. Other pathogens include the hepatitis C and Epstein-Barr viruses, which are potentially involved in kidney cancer. In addition, infections with Schistosoma haematobium, the human papillomavirus, and human polyomaviruses are strongly associated with an increased risk of urinary bladder cancer. This article reviews publications available to date on the role of infectious agents in urogenital cancers. A greater understanding of the role of such agents could aid the identification of novel methods of urogenital cancer treatment.
38 citations
TL;DR: Findings suggested that urinary bladder infection by E. coli may play a major additive and synergistic role during bladder carcinogenesis.
Abstract: Bladder cancer is a common malignancy in Egypt A history of urinary tract infection can be considered as a risk factor for bladder cancer Escherichia coli (E coli) infection is responsible for 70% of urinary tract infection This study aimed to evaluate the role of chronic E coli infection during bladder carcinogenesis In order to achieve this aim, we investigated the histopathological changes in bladder tissue and measured the level of nuclear factor kappa p65 (NF-κBp65), Bcl-2 and interleukin 6 (IL-6) in four groups each consisting of 25 male albino rats except of control group consisting of 20 rats The first group was normal control group, the second group was infected with E coli, the third group was administered nitrosamine precursor, and the forth group was infected with E coli and administered nitrosamine precursor The histopathological examination revealed that E coli infected group was able alone to produce some histopathological changes in bladder tissue and that nitrosamine precursor plus E coli group showed highest incidences of urinary bladder lesions than the nitrosamine precursor group NF-κBp65, Bcl-2 and IL-6 levels were significantly higher in nitrosamine precursor plus E coli group than the other groups These findings suggested that urinary bladder infection by E coli may play a major additive and synergistic role during bladder carcinogenesis
35 citations
TL;DR: Although NLRP3 SNPs was not involved in mesothelioma predisposition, these data proposed NLRP1 as a novel factor possibly involved in the development of mesotelioma.
Abstract: Background: An increasing incidence of malignant mesothelioma (MM) cases in patients with low levels of asbestos exposure suggests the interference of alternative cofactors. SV40 infection was detected, as co-morbidity factor, only in 22% of asbestos-MM patients from a North-Eastern Italy area. An additional mechanism of injury related to asbestos exposure in MM development has been recently associated to inflammatory responses, principally driven by interleukin (IL)-1 beta (s) activated within the inflammasome complex. NLRP3 inflammosome has been described as the intracellular sensor for asbestos able to induce inflammasome activation and IL-1s secretion while NLRP1 is expressed in lung epithelial cells and alveolar macrophages and contributes to the immune response and to survival/apoptosis balance. This study proposes to evaluate the impact of known NLRP3 and NLRP1 polymorphisms in the individual susceptibility to asbestos-induced mesothelioma in subjects from a hyperendemic area for MM. Methods: 134 Italian patients with diagnosis of mesothelioma due (MMAE, n=69) or not (MMAF, n=65) to asbestos, 256 healthy Italian blood donors and 101 Italian healthy subjects exposed to asbestos (HCAE) were genotyped for NLRP1 (rs2670660 and rs12150220) and NLRP3 (rs35829419 and rs10754558) polymorphisms. Results: While NLRP3 SNPs were not associated to mesothelioma, the NLRP1 rs12150220 allele T was significantly more frequent in MMAE (0.55) than in HCAE (0.41) (p=0.011; OR=1.79) suggesting a predisponent effect of this allele on the development of mesothelioma. This effect was amplified when the NLRP1 rs2670660 allele was combined with the NLRP1 rs12150220 allele (p=0.004; OR=0.52). Conclusion: Although NLRP3 SNPs was not involved in mesothelioma predisposition, these data proposed NLRP1 as a novel factor possibly involved in the development of mesothelioma.
TL;DR: This Review illustrates viral and host factors which induce Oxidative stress, steatosis and leads toward HCC and expresses Molecular cascade which leads oxidative stress and ste atosis to HCC.
Abstract: Hepatitis C virus causes acute and chronic hepatitis and can lead to permanent liver damage and hepatocellular carcinoma (HCC) in a significant number of patients via oxidative stress, insulin resistance (IR), fibrosis, liver cirrhosis and HCV induced steatosis. HCV induced steatosis and oxidative stress causes steato-hepatitis and these pathways lead to liver injury or HCC in chronic HCV infection. Steatosis and oxidative stress crosstalk play an important role in liver damage in HCV infection. This Review illustrates viral and host factors which induce Oxidative stress, steatosis and leads toward HCC. It also expresses Molecular cascade which leads oxidative stress and steatosis to HCC.
TL;DR: One of the new monoclonal antibodies produced, 1G3, demonstrated very good sensitivity and specificity when used for immunohistochemistry and could confirm the intense and constant expression of galectin-9 by Epstein-Barr virus positive malignant cells from nasopharyngeal carcinomas.
Abstract: Galectin-9 is a mammalian lectin which possesses immunosuppressive properties. Excessive production of galectin-9 has been reported in two types of human virus-associated diseases chronic hepatitis C and nasopharyngeal carcinoma associated to the Epstein-Barr virus. The objective of this study was to produce new monoclonal antibodies targeting galectin-9 in order to improve its detection in clinical samples, especially on tissue sections analysed by immunohistochemistry. Hybridomas were produced through immunization of mice with the recombinant c-terminus part of galectin-9 (residues 191 to 355 of the long isoform) and semi-solid fusion of spleen cells with Sp2/0 cells. Monoclonal antibodies were characterized using ELISA, epitope mapping, western blot and immunohistochemistry. We selected seven hybridomas producing antibodies reacting with our recombinant c-terminus galectin-9 in ELISA. Five of them reacted with the epitope “TPAIPPMMYPHPA” (common to all isoforms, residues 210 to 222 of the long isoform) and stained all three isoforms of galectin-9 analysed by western blot. One of them, 1G3,demonstrated very good sensitivity and specificity when used for immunohistochemistry. Using 1G3, we could confirm the intense and constant expression of galectin-9 by Epstein-Barr virus positive malignant cells from nasopharyngeal carcinomas. In most samples, specific staining was detected in both cytoplasm and nuclei. Galectin-9 was also detected in liver biopsies from patients infected by the human hepatitis C or B viruses with expression not only in inflammatory leucocytes and Kupffer cells, but also in hepatocytes. In contrast, galectin-9 was virtually absent in non-infected liver specimens. The 1G3 monoclonal antibody will be a powerful tool to assess galectin-9 expression and distribution especially in diseases related to oncogenic viruses.
TL;DR: The impact of HPV 16/18 vaccine on cervical cancer will be greater for early onset cancers, and in vaccinated women, screening could be started at an older age without reducing protection.
Abstract: Objective
The aim of this study is to describe the prevalence of HPV types in invasive cervical cancers in Italy from 1996 to 2008.
TL;DR: A nonspecific inflammatory response triggered by activation of NK cells upon KIR-HLA interaction could be associated with the pathogenesis of KS.
Abstract: Classic Kaposi's Sarcoma (cKS) is a rare vascular tumor associated with Human Herpesvirus 8 (KSHV) infection, nevertheless not all KSHV-infected individuals have cKS. We investigated whether particular KIR/HLA receptor/ligand genotypes would be preferentially present in KSHV-infected and uninfected individuals who have or have not developed cKS. KIR/HLA genotypes were analyzed by molecular genotyping in 50 KSHV-infected individuals who did or did not have cKS and in 33 age-and sex-matched KSHV seronegative individuals. There was no association of individual KIR, HLA or receptor ligand combinations with KSHV infection. However, activating KIR and KIR/HLA genotypes were significantly more frequent in cKS cases, specifically KIR3DS1, KIR2DS1, and KIR2DS1 with its HLA-C2 ligand. A nonspecific inflammatory response triggered by activation of NK cells upon KIR-HLA interaction could be associated with the pathogenesis of KS.
TL;DR: The existing political commitment, community support for immunization and the favorable laws and policy environment all provide an opportunity that should not be missed to introduce this much needed vaccine to the young adolescent girls.
Abstract: This article reviews the existing realities in Uganda to identify opportunities and potential obstacles of providing universal routine HPV vaccination to young adolescent girls. Cervical cancer is a public health priority in Uganda where it contributes to about 50–60% of all female malignancies. It is associated with a dismal 5-year relative survival of approximately 20%. With adequate financial resources, primary prevention through vaccination is feasible using existing education and health infrastructure. Cost-effectiveness studies show that at a cost of US$2 per dose, the current vaccines would be cost effective. With optimal (≥70%) coverage of the target population, the lifetime risk of cervical cancer could be reduced by >50%. Uganda fulfils 4 out of the 5 criteria set by the WHO for the introduction of routine HPV vaccination to young adolescent girls. The existing political commitment, community support for immunization and the favorable laws and policy environment all provide an opportunity that should not be missed to introduce this much needed vaccine to the young adolescent girls. However, sustainable financing by the government without external assistances remains a major obstacle. Also, the existing health delivery systems would require strengthening to cope with the delivery of HPV vaccine to a population that is normally not targeted for routine vaccination. Given the high incidence of cervical cancer and in the absence of a national screening program, universal HPV vaccination of Ugandan adolescent girls is critical for cervical cancer prevention.
TL;DR: These data confirm that TLR3 expression is a factor of vulnerability for NPC cells and suggest that in some specific pathological and pharmacological contexts, it might be worth to use Smac-mimetics at very low doses, allowing a better management of secondary effects.
Abstract: Background: Nasopharyngeal carcinomas (NPC) are consistently associated with the Epstein-Barr virus (EBV). Though NPCs are more radiosensitive and chemosensitive than other tumors of the upper aero-digestive tract, many therapeutic challenges remain. In a previous report, we have presented data supporting a possible therapeutic strategy based on artificial TLR3 stimulation combined to the inhibition of the IAP protein family (Inhibitor of Apoptosis Proteins). The present study was designed to progress towards practical applications of this strategy pursuing 2 main objectives: 1) to formally demonstrate expression of the TLR3 protein by malignant NPC cells; 2) to investigate the effect of poly(A:U) as a novel TLR3-agonist more specific than poly(I:C) which was used in our previous study. Methods: TLR3 expression was investigated in a series of NPC cell lines and clinical specimens by Western blot analysis and immunohistochemistry, respectively. The effects on NPC cells growth of the TLR3 ligand poly(A:U) used either alone or in combination with RMT5265, an IAP inhibitor based on Smac-mimicry, were assessed using MTT assays and clonogenic assays. Results: TLR3 was detected at a high level in all NPC cell lines and clinical specimens. Low concentrations of poly(A: U) were applied to several types of NPC cells including cells from the C17 xenograft which for the first time have been adapted to permanent propagation in vitro. As a single agent, poly(A:U) had no significant effects on cell growth and cell survival. In contrast, dramatic effects were obtained when it was combined with the IAP inhibitor RMT5265. These effects were obtained using concentrations as low as 0.5 μg/ml (poly(A:U)) and 50 nM (RMT5265). Conclusion: These data confirm that TLR3 expression is a factor of vulnerability for NPC cells. They suggest that in some specific pathological and pharmacological contexts, it might be worth to use Smac-mimetics at very low doses, allowing a better management of secondary effects. In light of our observations, combined use of both types of compounds should be considered for treatment of nasopharyngeal carcinomas.
TL;DR: Clinico-pathological evidence suggests that the authors are dealing with virally-induced cancers, and that HPV should not be a relevant candidate for OSCC, and a systematic search of HPV in OSCC has no real relevance in current clinical practice.
Abstract: Head & Neck Cancer (HNC) is one of the most common malignancies worldwide and among oral neoplasias about 90-92% are squamous cell carcinomas (OSCC) Alcohol and tobacco consumption have been recognized as the main risk factors for development of OSCC However, 10 to 20% of patients suffering from OSCC have no history of use of these substances Clinico-pathological evidence suggests that we are dealing with virally-induced cancers, and that HPV should not be a relevant candidate A systematic search of HPV in OSCC has no real relevance in current clinical practice even although it is still relevant in organized research protocols Further studies are ongoing, with the aim of identifying other infectious agents, including viruses, in OSCC
TL;DR: This review focuses on host-cell interactions that facilitate primary mechanisms of tumorigenesis and provides new insights into novel GI cancer treatments.
Abstract: The regulation of cancerous tumor development is converged upon by multiple pathways and factors. Besides environmental factors, gastrointestinal (GI) tract cancer can be caused by chronic inflammation, which is generally induced by bacteria, viruses, and parasites. The role of these inducers in cancer development, cell differentiation and transformation, cell cycle deregulation, and in the expression of tumor-associated genes cannot be ignored. Although Helicobacter pylori activates many oncogenic pathways, particularly those in gastric and colorectal cancers, the role of viruses in tumor development is also significant. Viruses possess significant oncogenic potential to interfere with normal cell cycle control and genome stability, stimulating the growth of deregulated cells. An increasing amount of recent data also implies the association of GI cancers with bacterial colonization and viruses. This review focuses on host-cell interactions that facilitate primary mechanisms of tumorigenesis and provides new insights into novel GI cancer treatments.
TL;DR: Together, Hedgehog pathway inhibitors serve as exciting new prospects, with a bright future, both alone or as an adjuvant to the more traditional anti-cancer drugs.
Abstract: The Hedgehog (Hh) proteins comprise a group of secreted proteins that regulate cell growth, differentiation and survival. Inappropriate activation of the Hh signaling pathway has been implicated in the development of a variety of cancers. Hedgehog pathway inhibitors are a relatively new class of therapeutic agents that act by targeting the proteins involved in the regulation of Hh pathway (PTCH, SMO and Gli). Together, they serve as exciting new prospects, with a bright future, both alone or as an adjuvant to the more traditional anti-cancer drugs.
TL;DR: The frequency of SIL and carcinoma appeared to be higher among HIV-infected women on HAART compared to seronegative controls and as expected increased with age, suggesting a role of HIV in altering the natural history of HPV infection and cervical lesions.
Abstract: Tanzania is among Sub-Saharan countries mostly affected by the HIV and AIDS pandemic, females being more vulnerable than males. HIV infected women appear to have a higher rate of persistent infection by high risk types of human papillomavirus (HPV) strongly associated with high-grade squamous intraepithelial lesions (HSIL) and invasive cervical carcinoma. Furthermore, although HIV infection and cervical cancer are major public health problems, the frequency and HIV/HPV association of cervical cancer and HSIL is not well documented in Tanzania, thus limiting the development of preventive and therapeutic strategies. A prospective unmatched, case-control study of HIV-seropositive, ≥ 18 years of age and consenting non-pregnant patients attending the care and treatment center (CTC) at Muhimbili National Hoospital (MNH) as cases was done between 2005 and 2006. HIV seronegative, non-pregnant and consenting women recruited from the Cervical Cancer Screening unit (CCSU) at ORCI were used as controls while those who did not consent to study participation and/or individuals under < 18 years were excluded. Pap smears were collected for routine cytodiagnosis and P53 immunohistochemistry (IHC). Cervical lesions were classified according to the Modified Bethesda System. A total of 170 participants from the two centers were recruited including 50 HIV-seronegative controls were from the CCSU. Ages ranged from 20-66 years (mean 40.5 years) for cases and 20-69 years (mean 41.6 years) for controls. The age group 36-45 years was the most affected by HIV (39.2%, n = 47). Cervicitis, squamous intraepithelial lesions (SIL) and carcinoma constituted 28.3% (n = 34), 38.3% (n = 46) and 5.8% (n = 7) respectively among cases, and 28% (n = 14), 34% (n = 17) and 2% (n = 1) for controls, although this was not statistically significant (P-value = 0.61). IHC showed that p53 was not detectable in HPV + Pap smears and cell blocks indicating possible degradation. The frequency of SIL and carcinoma appeared to be higher among HIV-infected women on HAART compared to seronegative controls and as expected increased with age. HIV seropositive patients appeared to present earlier with SIL compared to those HIV seronegative suggesting a role of HIV in altering the natural history of HPV infection and cervical lesions. The absence of p53 immunoreactivity in HPV + lesions is indicative of the ability of HPV E6 proteins to interact with the tumor suppressor gene and pave way for viral-induced oncogenesis in the studied Tanzanian women.
TL;DR: Recent findings on the interaction between HCV infection and innate immune response whose final effect is the downstream inefficient development of antigen-specific adaptive immunity, thereby contributing to virus persistence are summarized.
Abstract: Hepatitis C virus (HCV) induces a chronic infection in more than two-thirds of HCV infected subjects. The inefficient innate and adaptive immune responses have been shown to play a major pathogenetic role in the development and persistence of HCV chronic infection. Several aspects of the interactions between the virus and the host immune system have been clarified and, in particular, mechanisms have been identified which underlie the ability of HCV to seize and subvert innate as well as adaptive immune responses. The present review summarizes recent findings on the interaction between HCV infection and innate immune response whose final effect is the downstream inefficient development of antigen-specific adaptive immunity, thereby contributing to virus persistence.
TL;DR: Author(s): Amerson, Erin; Buziba, Nathan; Wabinga, Henry; Wenger, Megan; Bwana, Mwebesa; Muyindike, Winnie; Kyakwera, Catherine; Laker, Miriam; Mbidde, Edward; Yiannoutsos, Constantin; Wools-Kaloustian, Kara; Musick, Beverly; LeBoit, Philip; McCalmont, Tim; Ruben, Beth; Vol
Abstract: Author(s): Amerson, Erin; Buziba, Nathan; Wabinga, Henry; Wenger, Megan; Bwana, Mwebesa; Muyindike, Winnie; Kyakwera, Catherine; Laker, Miriam; Mbidde, Edward; Yiannoutsos, Constantin; Wools-Kaloustian, Kara; Musick, Beverly; LeBoit, Philip; McCalmont, Tim; Ruben, Beth; Volberding, Paul; Maurer, Toby; Martin, Jeffrey
TL;DR: The frequency of infection with HR-HPV subtypes 16 and 18 is high among Sudanese women with cervical lesions and suggests a role of HR- HPV in the development of cervical cancer in Sudan.
Abstract: This study examined whether there is a positive correlation existed between cervical and oral High Risk-Human Papilloma Viruses (HR-HPV) types 16, 18 infections in patients with clinically confirmed cervical lesions. In this study 50 participants were included (40 were cases and 10 were controls). One hundred DNA materials (50 were cervical and 50 were oral epithelial tissues) were analyzed using HR-HPV subtypes 16 and 18 specific PCR probes. Of the 40 cases, HR-HPV 16, 18 were identified in 16/40 (40%), of the cervical tissues of whom 8/16 (50%) were positive for HPV 16; 6/16 (37.5%) were identified with HR-HPV 18, and 2/16 (12.5%) were detected with both HR-HPV subtypes. All of the clinically healthy cases were found negative. Only one oral tissue sample (case) was 1/40 (2.5%) was found positive for HPV subtype16. The frequency of infection with HR-HPV subtypes 16 and 18 is high among Sudanese women with cervical lesions and suggests a role of HR-HPV in the development of cervical cancer in Sudan. No correlation between cervical and oral HPV infection was noted. Further study with screening of large number of patients with cervical cancer is recommended for further clarification of these findings.
TL;DR: In this paper, a new wave of clinical trials has commenced using a second generation of mTORC1 and mTORc2 inhibitors, which are derivatives of rapamycin, temsirolimus and everolimus.
Abstract: Mammalian Target of Rapamycin (mTOR) is a serine/threonine protein kinase that acts as a master switch between anabolic and catabolic functions of the human body in pathways stimulated by insulin, growth factors and mitogen [1]. mTOR functions as a central controller of growth, proliferation, metabolism and angiogenesis, but its signaling is dysregulated in various human diseases especially certain cancers like renal cell carcinoma and breast cancer [2]. In cancer, mTOR is frequently hyperactivated which promotes cancer development and progression. In certain cancers, resistance to antineoplastic agents such as topoisomerase 1, topoisomerase 2 inhibitors and methotrexate can be overcome with a synergistic combination with mTOR inhibitors [3,4]. Furthermore, mTOR activates the degradation of cyclin dependent kinases such as CDK1 which increases synthesis of dihydrofolate reductases. By decreasing this enzyme, mTOR inhibitors like sirolimus and temsirolimus, promote tumour sensitivity to agents such as methotrexate [4].
Recent development has made cancer treatment move on from conventional cytotoxic drugs to agents that target specific proteins like mTOR called mTOR inhibitors. A very common mTOR inhibitor, rapamycin, is a bacterial product that inhibits mTOR by associating with its intracellular receptor [5]. [Currently, two mTOR inhibitors, temsirolimus and everolimuswhich are derivatives of rapamycin, temsirolimus(Torisel: Wyeth-Ayerst, Charlotte, NC, U.S.A.) and everolimus(Certican: Novartis Pharmaceuticals, St. Louis, MO, U.S.A.) ] are approved for the treatment of patients with advanced renal cell carcinoma (RCC) and mantle cell lymphoma, effectively translating this paradigm into the clinical setting [6].
mTOR inhibitors (like other drugs) have an adverse effect profile. Clinical trials have had mixed opinions regarding drug efficacy [7]. Examples of the neoplasias with promising results include pancreatic neuroendocrine tumors, follicular lymphoma, renal cell carcinoma and mantle cell lymphoma while the ones with negative results include glioblastoma multiforme and small cell carcinoma of lung. Although relatively safe, these drugs are associated with some unique adverse side effects, such as hyperlipidemia, hyperglycemia, and pneumonitis, which require monitoring and may require clinical intervention [6]. Clinical utility of mTOR inhibitors depends on appropriate selection of patients and type of cancer. Mutations in the mTOR pathway of cancer cells may result in resistance to mTOR inhibition and prevent any action of the mTOR inhibitors. Examples include mutations of FKBP-12 proteins, mammalian 14-3-3 proteins ATM (ataxia telangiectasia, mutated) cells, all responsible for growth of cancer cells.
A new wave of clinical trials has commenced using a second generation of mTORC1 and mTORC2 inhibitors. First generation of mTOR inhibitors like rapamycin, showed certain limitations by blocking only C1 isoform, inducing feedback activation of Akt and showing resistance to mTORC2 [8]. The newer agents can inhibit both mTORC1 and mTORC2 by targeting kinase domains as an effective means with a high degree of selectivity [9]. For example, Agent OSI-027 (OSI Pharmaceuticals, Melville, NY, U.S.A.) is currently in phase 1 of trial and being evaluated on patients with lymphoma or solid tumors [9]. XL765 (Exelixis, San Francisco, CA, U.S.A.) is also in phase 1 of clinical trial and being assessed in combination therapies [9].
In contrast to the older mTOR inhibitors like rapamycin which blocked only C1 isoform, the newer agents can inhibit both mTORC1 and 2 with high degree of selectivity [10]. Further clinical trials are necessitated to determine the therapeutic uses, predictive biomarkers and clinical efficacy for this novel class of anti-cancer agents.
TL;DR: This study confirms the absence of role of HHV-6 in the genesis of acute leukemia but the virus was reactivated after chemotherapy treatment.
Abstract: Infectious etiology in lymphoproliferative diseases has always been suspected. The pathogenic roles of human herpesvirus-6 (HHV-6) in acute leukemia have been of great interest. Discordant results to establish a link between HHV-6 activation and the genesis of acute leukemia have been observed. The objective of this study was to evaluate a possible association between HHV-6 infection and acute leukemia in children and adults, with a longitudinal follow-up at diagnosis, aplasia, remission and relapse. HHV-6 load was quantified by a quantitative real-time PCR in the blood and bone marrow samples from 37 children and 36 adults with acute leukemia: 33 B acute lymphoblastic leukemia (B-ALL), 6 T acute lymphoblastic leukemia (T-ALL), 34 acute myeloid leukemia (AML). HHV-6 was detected in 15%, 8%, 30% and 28% of the blood samples at diagnosis, aplasia, remission and relapse, respectively. The median viral loads were 138, 244, 112 and 78 copies/million cells at diagnosis, aplasia, remission and relapse, respectively. In the bone marrow samples, HHV-6 was detected in 5%, 20% and 23% of the samples at diagnosis, remission and relapse, respectively. The median viral loads were 34, 109 and 32 copies/million cells at diagnosis, remission and relapse, respectively. According to the type of leukemia at diagnosis, HHV-6 was detected in 19% of the blood samples and in 7% of the bone marrow samples (with median viral loads at 206 and 79 copies/million cells, respectively) from patients with B-ALL. For patients with AML, HHV-6 was present in 8% of the blood samples and in 4% of the bone marrow samples (with median viral loads at 68 and 12 copies/million cells, respectively). HHV-6 was more prevalent in the blood samples from children than from adults (25% and 9%, respectively) and for the bone marrow (11% and 0%, respectively). All typable HHV-6 were HHV-6B species. No link was shown between neither the clinical symptoms nor the abnormal karyotype and HHV-6 activation. A case of HHV-6 chromosomal integration was shown in one patient with AML. This study confirms the absence of role of HHV-6 in the genesis of acute leukemia but the virus was reactivated after chemotherapy treatment.
TL;DR: It is proposed that the different roles of HBx displayed in different subcellular locations might be regulated by an evolutionarily conserved mechanism of posttranslational modification, via phosphorylation.
Abstract: Hepatitis B virus (HBV) encodes an oncogenic factor, HBx, which is a multifunctional protein that can induce dysfunctional regulation of signaling pathways, transcription, and cell cycle progression, among other processes, through interactions with target host factors. The subcellular localization of HBx is both cytoplasmic and nuclear. This dynamic distribution of HBx could be essential to the multiple roles of the protein at different stages during HBV infection. Transactivational functions of HBx may be exerted both in the nucleus, via interaction with host DNA-binding proteins, and in the cytoplasm, via signaling pathways. Although there have been many studies describing different pathways altered by HBx, and its innumerable binding partners, the molecular mechanism that regulates its different roles has been difficult to elucidate. In the current study, we took a bioinformatics approach to investigate whether the viral protein HBx might be regulated via phosphorylation by an evolutionarily conserved mechanism. We found that the phylogenetically conserved residues Ser25 and Ser41 (both within the negative regulatory domain), and Thr81 (in the transactivation domain) are predicted to be phosphorylated. By molecular 3D modeling of HBx, we further show these residues are all predicted to be exposed on the surface of the protein, making them easily accesible to these types of modifications. Furthermore, we have also identified Yin Yang sites that might have the potential to be phosphorylated and O-β-GlcNAc interplay at the same residues. Thus, we propose that the different roles of HBx displayed in different subcellular locations might be regulated by an evolutionarily conserved mechanism of posttranslational modification, via phosphorylation.
TL;DR: HPV-genotype analyses can identify women who significantly increase their chance of regression by consistent condom use, andeterogeneity among hr HPV genotypes excists is identified.
Abstract: The major cause of cervical intraepithelial neoplasia (CIN) is persistent infection with human papillomavirus (HPV). Most CIN grade 2 and 3 lesions are treated with cone excision, although a substantial proportion (6-50%) of CIN2-3 lesions will regresses spontaneously. Predictors for regression of CIN2-3 are desirable in order to reduce this overtreatment. In this prospective cohort study, 145 consecutive women with first-time onset CIN2-3 in colposcopy-directed biopsies and standardized biopsy-cone excision interval were included. The genotype of the high-risk human papillomaviruses (=hr HPV) and clinical factors including sexual behaviour, parity, contraception and smoking were assessed. Patients were divided into two groups according to lesions containing HPV16 (hr HPV16+) and high-risk non-HPV16 (hr HPV16-) genotypes. Women whose partners consistently used condoms showed a significantly higher regression rate than women using other types of contraception (53% versus 13%, p<0.0001). However, this effect was only seen in hr HPV16- patients (73% regression rate versus 13%, p<0.0001). Hr HPV16+ patients had a significantly higher number of sexual partners and more current smokers compared to hr HPV16- patients. The regression rate was not significantly different in CIN2-3 lesions containing HPV16 (hr HPV16+) versus hr HPV16- genotypes. Heterogeneity among hr HPV genotypes excists. HPV-genotype analyses can identify women who significantly increase their chance of regression by consistent condom use.
TL;DR: The number of positive results was not a lot in this study, but it was in contrast with previous studies which could not find any HP tracks in benign laryngeal lesions by in house PCR, the most sensitive method for detecting the genome tracks.
Abstract: Background: Although Helicobacter Pylori (HP) was detected in some cases of chronic laryngitis, the results were not confirmed by polymerase chain reaction (PCR). By this time, it has not been found in laryngeal lesions by in house PCR, the most sensitive method for detecting the genome tracks. Regarding the previous results and also few numbers of studies about the presence of HP in benign laryngeal lesions, specifically by PCR, we aimed to investigate the presence of HP in benign laryngeal lesions by in-house PCR. Methods: The samples were taken from 55 patients with benign laryngeal lesions and frozen in �20°C. One milliliter (ml) of lysis buffer was added to 100 mg (mg) of each sample and the tube was placed in 56°C overnight. Then DNA extraction was carried out. Results: To find HP DNA, in-house PCR was performed that revealed 5 positive results among 55 patients with benign laryngeal lesions. Of them, 3 were polyp, 1 was nodule and 1 was papilloma. Conclusion: Although the number of positive results was not a lot in this study, it was in contrast with previous studies which could not find any HP tracks in benign laryngeal lesions by other methods. More studies about the prevalence of HP in benign laryngeal lesions improve judging about the effect of this infection on benign laryngeal lesions.
TL;DR: The findings of poor knowledge of cancer among PLHIV in Nigeria indicate the need for health care providers and the government to intervene by developing primary cancer prevention strategies for this population.
Abstract: The epidemic of HIV in sub-Saharan Africa varies significantly across countries in the region with high prevalence in Southern Africa and Nigeria. Cancer is increasingly identified as a complication of HIV infection with higher incidence and mortality in this group than in the general population. Without cancer prevention strategies, improved cancer treatment alone would be an insufficient response to this increasing burden among people living with HIV (PLHIV). Although previous studies have noted low levels of awareness of cancers in sub-Saharan Africa none has examined the knowledge and perceptions of cancer among people living with HIV/AIDS. Focus group discussions (FGD) and Key Informant Interviews (KII) were carried out in 4 high volume tertiary care institutions that offer HIV care and treatment in Nigeria. FGD and KII assessed participants’ knowledge of cancer, attitudes towards cancer risk and cancer screening practices. The mean age (SD) of the FGD participants was 38 (2.8) years. Most participants had heard about cancer and considered it a fatal disease but displayed poor knowledge of the causes of cancer in general and of AIDs associated cancers in particular. PLHIV in Nigeria expressed fear, denial and disbelief about their perceived cancer risk. Some of the participants had heard about cancer screening but very few participants had ever been screened. Our findings of poor knowledge of cancer among PLHIV in Nigeria indicate the need for health care providers and the government to intervene by developing primary cancer prevention strategies for this population.