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1.  NLRP1 and NLRP3 polymorphisms in mesothelioma patients and asbestos exposed individuals a population-based autopsy study from North East Italy 
NRLP1 (rs12150220, rs9889625, rs9900356, rs6502867, rs2670660) and NLRP3 (rs35829419, rs10754558) polymorphisms have been analyzed in 69 subjects with documented asbestos exposure and death for malignant pleural mesothelioma and 59 patients with documented asbestos exposure but death for other causes, all from a North East Italy. No association was found between NLRP1 and NLRP3 polymorphisms and susceptibility to develop mesothelioma using the general, dominant or recessive models. Also haplotype analysis did not reveal any significant association with mesothelioma. Our findings, being controversial with respect to another study on Italian patients, do suggest the need of further studies to unravel the contribution of NLRP1 and NLRP3 in susceptibility to mesothelioma.
Electronic supplementary material
The online version of this article (doi:10.1186/s13027-015-0022-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13027-015-0022-0
PMCID: PMC4521353
Mesothelioma; Inflammasome; NLRP1 and NLRP3 polymorphisms; Asbestos exposure; Haplotypes
2.  Inhibitory effect of (−)-epigallocatechin-3-gallate and bleomycin on human pancreatic cancer MiaPaca-2 cell growth 
Background
Human pancreatic cancer is currently one of the deadliest cancers with high mortality rate. It has been previously shown that (−)-epigallocatechin-3-gallate (EGCG), the most abundant catechin found in green tea, has showed suppressive effects on human pancreatic cancer cells. Bleomycin, (BLM), an anti-cancer chemotherapeutic drug that induces DNA damage, has antitumor effects by induction of apoptosis in several cancer cell lines and also in pancreatic cancer cells. The present study investigated for the first time, the inhibitory effect of EGCG and BLM on pancreatic cancer cell growth.
Methods
Using the pancreatic cancer cell lines MIA PaCa-2 cells the efficacy and synergism of EGCG and BLM were evaluated by in vitro tests. Inhibition of cell proliferation was determined by MTT assay. Mitochondrial depolarization was performed with JC-1 probe. Viability and apoptosis were determined by Flow Cytometry with annexin V, propidium iodide staining and DNA fragmentation assay.
Results
Cell proliferation assay revealed significant additive inhibitory effects with combination of EGCG and BLM at 72 h in a dose dependent manner. The combination of EGCG and BLM induced cell cycle S-phase arrest and mitochondrial depolarization. Viability, apoptosis and DNA fragmentation assay indicated that the combination of EGCG and bleomycin potentiated apoptosis.
Conclusions
Our results indicate that EGCG and BLM have additive anti-proliferative effects in vitro by induction of apoptosis of MIA PaCa-2 cells. This combination could represent a new strategy with potential advantages for treatment of pancreatic cancer. To date, this is the first report published of the inhibitory effect of EGCG and BLM on human pancreatic cancer MIA Paca-2 cell growth.
doi:10.1186/s13027-015-0016-y
PMCID: PMC4518601
(−)-Epigallocatechin-3-gallate; Pancreatic cancer; Bleomycin; Cell proliferation; Apoptosis
3.  HCV infection-associated hepatocellular carcinoma in humanized mice 
Background and Aims
Hepatitis C virus (HCV) infection is a major risk factor for chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Our aim is to explore molecular changes that underlie HCV infection-associated HCC in a humanized mouse model, in order to identify markers of HCC progression.
Methods
Liver proteins from human hepatocyte-engrafted and HCV-infected MUP-uPA/SCID/Bg mice were compared with either uninfected controls or HCV-infected but HCC-negative mice by Western blotting. MicroRNA markers of HCC positive or uninfected mouse liver were analyzed by RT-PCR.
Results
We describe the depletion of tumor suppressor proteins and induction of oncoproteins and oncogenic microRNAs (oncomiRs) in HCV-infection associated HCC. Similar depletion of PTEN protein in both HCC-positive and HCV-infected but HCC-negative liver suggests that PTEN depletion is an early, precancerous marker of HCC. By contrast, induction of oncoprotein cMyc, oncomiRs (miR21, miR221 and miR141) and inflammatory response proteins correspond to HCC progression.
Conclusions
While the loss of PTEN is important for the initiation of HCV infection-associated HCC, PTEN depletion by itself is insufficient for tumor progression. Liver tumor progression requires induction of oncoproteins and oncomiRs. Overall, human hepatocyte-engrafted (MUP-uPA/SCID/Bg) mice provide a suitable small animal model for studying the effects of oncogenic changes that promote HCV infection associated HCC.
doi:10.1186/s13027-015-0018-9
PMCID: PMC4515941  PMID: 26217396
HCV Infection-associated HCC
4.  Prevalence of type-specific HPV among female university students from northern Brazil 
Background
Human papillomavirus (HPV) infection is associated with cervical cancer, the most frequent cancer in women from northern Brazil. Assessment of the short-term impact of HPV vaccination depends on the availability of data on the prevalence of type-specific HPV in young women in the pre-immunization period, although these data are currently unavailable for the study region. The aim of this study was to estimate the distribution of all mucosal HPV genotypes, including low- and high-risk HPV types, in unvaccinated college students from northern Brazil.
Findings
Specimens were collected from 265 university students during routine cervical cancer screening. The HPV DNA was assessed by Polymerase Chain Reaction and positive samples were genotyped by Restriction Fragment Length Polymorphism. Most students (85.7 %) had normal cytological results. The prevalence of HPV was 25.3 % (67/265), with a high frequency of multiple infections and non-vaccine high-risk HPV genotypes. The most prevalent type was HPV-61 (5.3 %), followed by types 82, 16, 59, and 6. Multiple infections were associated with high-risk and possibly high-risk HPVs.
Conclusions
We demonstrated a high prevalence of HPV infection in university students from northern Brazil. Vaccine high-risk types were relatively rare, emphasizing the predominance of carcinogenic genotypes that are not prevented by the currently available vaccines. Our study highlights the need to reinforce cytological screening in women from northern Brazil, and promote the early diagnosis and treatment of the precancerous lesions associated with cervical cancer.
doi:10.1186/s13027-015-0017-x
PMCID: PMC4511251  PMID: 26203300
Human papillomavirus; Prevalence; HPV vaccine impact; Genotype distribution
5.  Prevalence and risk factors for cancer of the uterine cervix among women living in Kinshasa, the Democratic Republic of the Congo: a cross-sectional study 
Background
Cancer of the uterine cervix is the leading cause of cancer-related death among women in Sub-Saharan Africa, but information from the Democratic Republic of the Congo (DRC) is scarce. The study objectives were to: 1/ assess prevalence of (pre)cancerous cervical lesions in adult women in Kinshasa, 2/ identify associated socio-demographic and behavioural factors and 3/ describe human papillomavirus (HPV) types in cervical lesions.
Methods
A cross-sectional study was conducted in Kinshasa. Between 2006 and 2013, four groups of women were recruited. The first two groups were included at HIV screening centres. Group 1 consisted of HIV-positive and group 2 of HIV-negative women. Group 3 was included in large hospitals and group 4 in primary health centres. Pap smears were studied by monolayer technique (Bethesda classification). Low- or high-grade squamous intraepithelial lesions or carcinoma were classified as LSIL+. HPV types were determined by INNO-LiPA®. Bivariate and multivariable analyses (logistic regression and generalised estimating equations (GEE)) were used to assess associations between explanatory variables and LSIL+.
Results
LSIL+ lesions were found in 76 out of 1018 participants. The prevalence was 31.3 % in group 1 (n = 131 HIV-positive women), 3.9 % in group 2 (n = 128 HIV-negative women), 3.9 % in group 3 (n = 539) and 4.1 % in group 4 (n = 220). The following variables were included in the GEE model but did not reach statistical significance: history of abortion, ≥3 sexual partners and use of chemical products for vaginal care. In groups 3 and 4 where this information was available, the use of plants for vaginal care was associated with LSIL+ (adjusted OR 2.70 (95 % confidence interval 1.04 – 7.01). The most common HPV types among HIV-positive women with ASCUS+ cytology (ASCUS or worse) were HPV68 (12 out of 50 samples tested), HPV35 (12/50), HPV52 (12/50) and HPV16 (10/50). Among women with negative/unknown HIV status, the most common types were HPV52 (10/40), HPV35, (6/40) and HPV18 (5/40).
Conclusion
LSIL+ lesions are frequent among women in Kinshasa. The use of plants for vaginal care deserves attention as a possible risk factor for LSIL+. In this setting, HPV16 is not the most frequent genotype in samples of LSIL+ lesions.
doi:10.1186/s13027-015-0015-z
PMCID: PMC4502934  PMID: 26180542
Cervical intraepithelial neoplasia; Human papillomavirus; Risk factors; Cross-sectional studies; Democratic Republic of the Congo
6.  Viral non-coding RNA inhibits HNF4α expression in HCV associated hepatocellular carcinoma 
Background
Hepatitis C virus (HCV) infection is an established cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC); however, it is unclear if the virus plays a direct role in the development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is critical determinant of epithelial architecture and hepatic development; depletion of HNF4α is correlated with oncogenic transformation. We explored the viral role in the inhibition of HNF4α expression, and consequent induction of tumor-promoting genes in HCV infection-associated HCC.
Methods
Western blot analysis was used to monitor the changes in expression levels of oncogenic proteins in liver tissues from HCV-infected humanized mice. The mechanism of HNF4α depletion was studied in HCV-infected human hepatocyte cultures in vitro. Targeting of HNF4α expression by viral non-coding RNA was examined by inhibition of Luciferase HNF4α 3’-UTR reporter. Modulation of invasive properties of HCV-infected cells was examined by Matrigel cell migration assay.
Results
Results show inhibition of HNF4α expression by targeting of HNF4α 3’-UTR by HCV-derived small non-coding RNA, vmr11. Vmr11 enhances the invasive properties of HCV-infected cells. Loss of HNF4α in HCV-infected liver tumors of humanized mice correlates with the induction of epithelial to mesenchymal transition (EMT) genes.
Conclusions
We show depletion of HNF4α in liver tumors of HCV-infected humanized mice by HCV derived small non-coding RNA (vmr11) and resultant induction of EMT genes, which are critical determinants of tumor progression. These results suggest a direct viral role in the development of hepatocellular carcinoma.
doi:10.1186/s13027-015-0014-0
PMCID: PMC4495692  PMID: 26157476
7.  A major shift of viral and nutritional risk factors affects the hepatocellular carcinoma risk among Ivorian patients: a preliminary report 
Hepatocellular carcinoma (HCC) is a major public health concern in Sub-Saharan Africa. Early research in Ivory Coast showed that chronic hepatitis B and aflatoxin B1 exposure were the two most important etiological agents of HCC in the country but, surprisingly, no survey analyzing HCC etiologies has been conducted since decades.
In a preliminary report, we characterized for hepatitis B and C markers 30 consecutive cases of HCC recruited from Abidjan hospitals between June 2011 and December 2012. Nutritional and lifestyle features of patients were analyzed as well. The mean age of the patients was 53 ± 15 years with a sex ratio (M:F = 2.7). HBsAg was the most frequent viral marker in the series (63 %). All HBV isolates belonged to genotype E. With regards to regional standard, anti-HCV reached a very high level (47 %) in the present series. Hepatitis C was more frequent among patients living outside Abidjan (83 vs 23 %, P = 0.009). Patients living in Abidjan were significantly younger than individual living elsewhere in the country (48 ± 14 vs 60 ± 16 years old, P = 0.038) reflecting a possible role for local environmental pollution in tumor progression. Finally, we observed that patients born in Mandé/Gur-speaking regions (North) were younger (48 ± 14 vs 59 ± 15, P = 0.05) and consumed maize more frequently (80 vs 26 %, P = 0.009) than other patients. Interestingly, maize consumption was associated with a trend for aminotransferases elevation (mean = 1.7-1.8 fold, P = 0.06) suggesting a direct hepatic toxicity of this staple food in Ivory Coast. In conclusion, our work indicates that HCC epidemiology underwent recently major drifts in Ivory Coast.
Electronic supplementary material
The online version of this article (doi:10.1186/s13027-015-0013-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13027-015-0013-1
PMCID: PMC4486136  PMID: 26131017
Aflatoxin B1; Ethnicity; Hepatocellular carcinoma; Hepatitis B virus; Hepatitis C virus; Maize
8.  Vaccines against human papillomavirus in low and middle income countries: a review of safety, immunogenicity and efficacy 
Currently, there is limited data on the immunogenicity and efficacy of human papillomavirus vaccines in Low and Middle income countries (LMIC). The review aims to summarize the current status from published HPV vaccine safety, immunogenicity and efficacy studies in low and middle income countries (LMIC). Electronic databases (PubMed/MEDLINE and HINARI) were searched for peer reviewed English language articles on HPV vaccination in LMIC that have so far been published from 1st January 2006 up to 30th January 2015. Eligible studies were included if they had used the bivalent (bHPV) or quadrivalent HPV (qHPV) vaccines in a LMIC and investigated safety, immunogenicity and/or efficacy. The main findings were extracted and summarized. A total of fourteen HPV vaccine studies assessing safety, Immunogenicity and efficacy of the bivalent or quadrivalent vaccines in LMIC were included. There are only ten published clinical trials where a LMIC has participated. There was no published study so far that assessed efficacy of the HPV vaccines in Sub-Saharan Africa. From these studies, vaccine induced immune response was comparable to that from results of HICs for all age groups. Studies assessing HPV vaccine efficacy of the bivalent or quadrivalent vaccine within LMIC were largely missing. Only three studies were found where a LMIC was part of a multi center clinical trial. In all the studies, there were no vaccine related serious adverse events. The findings from the only study that investigated less than three doses of the bivalent HPV-16/18 vaccine suggest that even with less than three doses, antibody levels were still comparable with older women where efficacy has been proven. The few studies from LMIC in this review had comparable safety, Immunogenicity and efficacy profiles like in HIC. Overall, the LMIC of Africa where immune compromising/modulating situations are prevalent, there is need for long term immunogenicity as well as surveillance studies for long term clinical effectiveness after two and three dose regimens.
doi:10.1186/s13027-015-0012-2
PMCID: PMC4465311  PMID: 26075018
Human papillomavirus vaccines; Immunogenicity; Safety; Efficacy; Low middle income countries
9.  Genetic variability in E6 and E7 oncogenes of human papillomavirus Type 16 from Congolese cervical cancer isolates 
Background
The molecular epidemiological studies showed that some variants of HPV-16, distributed geographically, would present a higher risk of causing cervical cancer. This study aimed to analyze nucleotide changes of HPV-16 E6 and E7 genomic regions from infected Southwestern Congolese women.
Methods
DNA of twenty HPV-16 isolates was analyzed by amplifying the E6 and E7 genes using type-specific primers PCR and direct sequencing. The sequences obtained were aligned with the HPV-16 GenBank reference sequences.
Results
Thirteen (65.0%) out of 20 DNA-samples were successfully amplified. Genetic analysis revealed 18 and 4 nucleotide changes in E6 and E7 genomic regions respectively. The most frequently observed nucleotide variations were the missense C143G, G145T and C335T in E6 (100%), leading to the non-synonymous amino acid variation Q14D and H78Y. E7 genomic region was found to be highly conserved with two most common T789C and T795G (100%) silent variations. All HPV-16 variants identified belonged to the African lineage: 7 (53.8%) belonged to Af-1 lineage and 6 (46.1%) to Af-2 lineage. The missense mutation G622A (D21N) in the E7 region seems to be described for the first time in this study.
Conclusion
This study reported for the first time the distribution of HPV-16 E6 and E7 genetic variants in infected women from southwest Congo. The findings confirmed almost ascendancy of the African lineage in our study population.
doi:10.1186/s13027-015-0010-4
PMCID: PMC4437748  PMID: 25991921
Human papillomavirus type 16; E6 and E7 genetic variants; Southwest Congo
10.  HPV prevalence and risk of pre-cancer and cancer in regular immigrants in Italy: results from HPV DNA test-based screening pilot programs 
Immigrants from low- and medium-income countries have a higher risk of cervical cancer due both to barriers in access to screening and to higher human papillomavirus (HPV) prevalence.
In the near future many screening programmes in industrialised countries will replace Pap test with HPV as primary test. In order to plan future interventions, it is essential to understand how the HPV screening performs in immigrant women.
Methods
We conducted a survey on the main performance indicators from some of the HPV DNA-based pilot programmes in Italy, comparing regular immigrant women, identified as women resident in Italy who were born abroad, with women who were born in Italy. All the programmes applied the same protocol, with HPV as stand-alone test starting for women of 25 or 35 to 64 years of age. Cytology triage is performed for positive women; those ASC-US or more severe are referred directly to colposcopy; negative women are referred to repeat HPV after one year.
Results
Overall, 162,829 women were invited, of whom 22,814 were born abroad. Participation was higher for Italy-born than born abroad (52.2% vs. 43.6%), particularly for women over 45 years. HPV positivity rate was higher in immigrants: 7.8% vs. 6.1%, age-adjusted Relative Risk (age-adj RR) 1.18, 95% confidence interval (95% CI) 1.13-1.22. The proportion of women with positive cytology triage was similar in the two groups (42%). Cervical Intraepithelial Neoplasia (CIN) grade 2 or more severe detection rate was higher for born abroad (age-adj RR 1.65, 95% CI 1.45-1.89). The difference was stronger when considering only CIN3 or more severe (age-adj RR 2.29, 95% CI 1.90-2.75). Both HPV positivity and CIN2 or more severe detection rate had a different age curve in born abroad compared with Italy-born: in the former, the risk was almost flat, while in the latter it declined rapidly with age.
Conclusion
Compliance with HPV screening is lower for migrant women, who are affected by higher HPV positivity and CIN3 cancer detection rates.
doi:10.1186/s13027-015-0009-x
PMCID: PMC4427984  PMID: 25969693
11.  Global availability of data on HPV genotype-distribution in cervical, vulvar and vaginal disease and genotype-specific prevalence and incidence of HPV infection in females 
Background
Country-level HPV genotyping data may be sought by decision-makers to gauge the genotype-specific burden of HPV-related diseases in their jurisdiction and assess the potential impact of HPV vaccines. We investigated, by country, the availability of published literature on HPV genotypes in cervical, vaginal and vulvar cancers and intraepithelial neoplasms (CINs, VaINs and VINs) and on prevalence and incidence of genital HPV infections among women without clinically manifest disease.
Findings
Primary sources of publications were the PubMed/Medline and EMBASE databases. Original studies or meta-analyses published from 2000, covering genotypes 16 and 18 and at least one of genotypes 31/33/45/52/58, were included. Key exclusion criteria were language not English, cervical lesions not histologically confirmed (cytology only), special populations (e.g., immunocompromised) and, for cervical studies, small population (<50). A total of 727 studies reporting HPV genotype-specific data were identified: 366 for cervical cancers and CINs, 43 for vulvar or vaginal cancers and VINs/VaINs, and 395 and 21 for infection prevalence and incidence, respectively, in general female population samples. A large proportion of studies originated from a small set of countries. Cervical cancer/CIN typing data was scarce for several regions with the highest cervical cancer burden, including Eastern, Middle and Western Africa, Central America, South-East Asia, South Asia, and Eastern Europe. Data for vulvar/vaginal disease was limited outside of Europe and North America.
Conclusions
Although a large body of published HPV genotype-specific data is currently available, data gaps exist for genotype-specific infection incidence and several world regions with the highest cervical cancer burden.
Electronic supplementary material
The online version of this article (doi:10.1186/s13027-015-0008-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13027-015-0008-y
PMCID: PMC4435914  PMID: 25987893
HPV; Genotype; Geographic region; Epidemiology; Genital infection; Cervical lesions; Cervical cancer
12.  A shifting paradigm in the aetiology of oral and pharyngeal cancer in Sri Lanka: a case-control study providing serologic evidence for the role of oncogenic HPV types 16 and 18 
Background
Oral and pharyngeal cancer (OPC) of multifactorial aetiology is a major health problem globally. Ranking first in all cancers, OPC poses a significant impact on the Sri Lankan male population. As Human Papillomavirus (HPV) high risk (HR) types are found to be significant risk factors for OPC globally, the current study was undertaken to examine the association between HR-HPV16 and 18 types with OPC in Sri Lanka.
Materials and methods
Serum samples of 78 OPC patients and 51 non-cancer controls were assayed for the presence of anti-HPV16 and anti-HPV18 IgG antibodies using in-house established Enzyme Linked Immunosorbent Assays (ELISAs). The association between OPC and its risk factors i.e. HPV, smoking, alcohol, betel quid, poor dentition, was established using Chi-square test. Logistic regression was used to calculate odds ratios (OR), adjusted for the influence of other risk factors.
Results
This prototype study in Sri Lanka showed a significant risk of 15 fold in developing OPC due to HPV16/18 seropositivity after removing variability due to other factors. Oncogenic HPV18 showed a higher rate of seropositivity being detected in 32% of OPC patients, and also in 2% of non-cancer control subjects. HR-HPV16 was detected in 23% of OPC patients and in 5.88% of controls. Moreover, seven OPC patients were detected with both anti-HPV16 and anti-HPV18 antibodies. According to the logistic regression models HPV18 seropositivity was associated with a 28 fold risk in developing OPC while that of HPV16 was associated with a 6 fold increase in risk for the development of OPC. A 5 fold risk of developing OPC was also pronounced among smokers while alcohol, betel and poor dentition was not significantly associated with OPC. Statistically significant differences with regard to age, gender, smoking, alcohol, betel use, poor dentition and site specificity of the tumour was not observed between HPV seropositive and seronegative OPC patients.
Conclusions
Both in-house developed ELISAs detected significant proportions of HPV seropositives within the OPC study population suggestive of HPV as a strong risk factor for oral and pharyngeal carcinogenesis in Sri Lanka.
doi:10.1186/s13027-015-0007-z
PMCID: PMC4407420  PMID: 25908938
Sri Lanka; Oral and pharyngeal cancer; Human papillomavirus (HPV); HPV16; HPV18; Enzyme-linked Immunosorbent assay; Risk factors; Smoking
13.  Hepatocellular carcinoma and liver metastases: clinical data on a new dual-lumen catheter kit for surgical sealant infusion to prevent perihepatic bleeding and dissemination of cancer cells following biopsy and loco-regional treatments 
Background
RFA is a safe and effective procedure for treating unresectable primary or secondary liver malignancies, but it is not without complications. The most common reported complications include abdominal hemorrhage, bile leakage, biloma formation, hepatic abscesses, and neoplastic seeding.
The aim of this study is to evaluate the feasibility of percutaneous use of surgical sealant with a new coaxial bilumen catheter, to prevent the perihepatic bleeding and dissemination of cancer cells through the needle-electrode (neoplastic seeding) or along the needle track.
Methods
We designed a novel dual-lumen catheter to facilitate the optimal application of fibrin sealant after diagnostic and therapeutic percutaneous procedures. Percutaneous RFA has been performed using mask ventilation or neuroleptanalgesia. The main aims of this study, after the ablation procedure, in the treatment of unresectable liver cancer were to prevent major adverse events: a) the perihepatic bleeding; b) dissemination of cancer cells through the needle-electrode and or needle track.
Results
A total of 181 patients were evaluated for this study at National Cancer Institute of Naples from January 2012 to January 2014. The association of blood loss (≤1 g/dl; ≥1 g/dl) with age, gender, histological diagnosis were analyzed. No statistical significance was observed between bleeding and age (p = 0.840), gender (p = 0.607) and histological diagnosis (p = 0,571), respectively.
Conclusions
This study demonstrated that fibrin sealant or other surgical sealant injection, after any locoregional procedure such as biopsy or ablation, could make adverse events even more rare.
doi:10.1186/s13027-015-0006-0
PMCID: PMC4403704  PMID: 25897320
Hepatocarcinoma; Liver metastases; Dual lumen catheter; Sealant; Locoregional treatments
14.  IL-10, IL-15, IL-17, and GMCSF levels in cervical cancer tissue of Tanzanian women infected with HPV16/18 vs. non-HPV16/18 genotypes 
Background
Despite comparable screening rates for precancerous lesions, higher incidence and mortality related to cervical cancer in minority women persists. Recent evidence suggests that minority women with precancerous cervical lesions harbor a wider range of human papillomavirus (HPV) genotypes, many of these distinct from HPV16/18, those most commonly found in Caucasian women. The goal of the analysis was to determine if inflammatory cytokines and chemokines varied by HPV 16/18 versus other genotypes in cervical cancer tissues from Tanzanian women.
Methods
HPV genotypes and concentrations of chemokines and cytokines were measured from homogenized fresh tumor tissue of thirty-one women with invasive cervical cancer (ICC). Risk factors for cervical cancer including age, parity, hormonal contraceptive use and cigarette smoking were obtained by questionnaire. Generalized linear models were used to evaluate differences between chemokines/cytokine levels in women infected with HPV16/18 and those infected with other HPV genotypes.
Results
After adjusting for age, parity and hormonal contraceptives, IL-17 was found significantly more frequently in invasive cervical cancer samples of women infected with HPV16/18 compared to women infected with other HPV genotypes (p = 0.033). In contrast, higher levels for granular macrophage colony-stimulating factor (p = 0.004), IL-10 (p = 0.037), and IL-15 (p = 0.041) were found in ICC tissues of women infected with genotypes other than HPV16/18 when compared to those of women infected with HPV16/18.
Conclusions
While the small sample size limits inference, our data suggest that infection with different HPV genotypes is associated with distinct pro-inflammatory cytokine expression profiles; whether this explains some of the racial differences observed in cervical cancer is still unclear. Future studies are needed to confirm these findings.
Electronic supplementary material
The online version of this article (doi:10.1186/s13027-015-0005-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13027-015-0005-1
PMCID: PMC4373111  PMID: 25810759
Invasive cervical cancer; Case-only; HPV infection; Cytokines; Race; Disparities
15.  An overview of loco-regional treatments in patients and mouse models for hepatocellular carcinoma 
Hepatocellular carcinoma is a highly aggressive malignancy and is the third leading cause of cancer-related deaths worldwide. Although surgery is currently considered the most effective curative treatment for this type of cancer, it is note that most of patients have a poor prognosis due to chemioresistence and tumor recurrence. Loco-regional therapies, including radiofrequency ablation, surgical resection and transcatheter arterial chemoembolization play a major role in the clinical management of hepatocellular carcinoma. In order to improve the treatment outcome of patients diagnosed with this disease, several in vivo studies by using different techniques on cancer mouse models have been performed. This review will focus on the latest papers on the efficacy of loco-regional therapy and combined treatments in patients and mouse models of hepatocellular carcinoma.
doi:10.1186/s13027-015-0004-2
PMCID: PMC4353675  PMID: 25755676
Loco-regional treatments; Hepatocellular carcinoma; Drug delivery; Safety; Efficacy
16.  Genotypic distribution of human papillomavirus (HPV) and cervical cytology findings in 5906 Thai women undergoing cervical cancer screening programs 
Background
Cervical cancer is the major cause of morbidity and mortality in Thai women. Nevertheless, the preventive strategy such as HPV vaccination program has not been implemented at the national level. This study explored the HPV prevalence and genotypic distribution in a large cohort of Thai women.
Methods
A hospital-based cervical cancer screening program at Chulabhorn Hospital, Bangkok and a population-based screening program at a rural Pathum Thani Province were conducted using liquid-based cytology and HPV genotyping.
Results
Of 5906 women aged 20–70 years, Pap smear was abnormal in 4.9% and the overall HPV prevalence was 15.1%, with 6.4% high-risk (HR), 3.5% probable high-risk (PR), and 8.4% low-risk (LR) HPV. The prevalence and genotypic distribution were not significantly different between the two cohorts. Among HR-HPV genotypes, HPV52 was the most frequent (1.6%), followed by HPV16 (1.4%), HPV51 (0.9%), HPV58 (0.8%), HPV18 (0.6%), and HPV39 (0.6%). Among LR-HPV genotypes, HPV72 and HPV62 were the most frequent while HPV6 and HPV11 were rare. HPV infection was found to be proportionately high in young women, aged 20–30 years (25%) and decreasing with age (11% in women aged >50). The more severe abnormal cytology results, the higher positivity of HR-HPV infection was observed.
Conclusions
In conclusion, HPV52, HPV16, and HPV51 were identified as the most common HR-HPV genotypes in Thai women. This study contributes genotypic evidence that should be essential for the development of appropriate HPV vaccination program as part of Thailand’s cervical cancer prevention strategies.
doi:10.1186/s13027-015-0001-5
PMCID: PMC4347911  PMID: 25737740
Cervical cancer; Cancer screening; HPV genotypes; Cervical cytology; Thailand
17.  NaCl pretreatment attenuates H.pylori-induced DNA damage and exacerbates proliferation of gastric epithelial cells (GES-1) 
Background
Both H. pylori infection and high salt (NaCl) diet are risks of gastric cancer, however, the interaction pattern of the two is not very clear. Our objective was to investigate the effects of NaCl-pretreated H. pylori on DNA damage and proliferation of gastric epithelial cell (GES-1).
Methods
GES-1 cells were co-cultured with H.pylori or NaCl-pretreated H. pylori (with 30% NaCl) for 24 h. The morphological changes of all cells were observed by inverted phase contrast microscopy and transmission electron microscopy. Oxidative DNA damage was examined by immunofluorescence. Alterations in mitochondrial membrane potential and apoptosis rate were detected by flow cytometry and western blot, and expression of Ki-67, PCNA and P21 were evaluated using the immunocytochemical staining.
Results
GES-1 cells co-cultured with NaCl-pretreated H.pylori exhibited morphological changes and oxidative DNA damage. Although no significant disruption of the mitochondrial membrane potential (ΔΨm) and apoptotic rate were observed compared with control groups, there were significant decreased in Bax and Caspase3 proteins and increased in Bcl-2 protein in GES-1 cells infected with H. pylori30 when compared with GES-1 cells cultured with H. pylori. In addition, we found a proliferative effect on GES-1 cells with an increased expression of Ki-67 and PCNA as well as a decreased p21 expression, through which the cells may acquire the potential for malignant transformation.
Conclusion
NaCl-pretreated H. pylori possessed the ability to cause cell injury and promote proliferation in gastric epithelial cells.
doi:10.1186/s13027-015-0003-3
PMCID: PMC4391598  PMID: 25859277
NaCl-pretreatment; H. pylori; Gastric epithelial cells; Apoptosis; Proliferation
18.  Molecular screening for Epstein Barr virus (EBV) among Sudanese patients with nasopharyngeal carcinoma (NPC) 
Objective
The aim of this study was to screen for the presence of Epstein Barr Virus (EBV) among Sudanese patients with Nasopharyngeal Carcinoma (NPC).
Methods
In this study, 150 tissue samples that were previously diagnosed as having NPC were screened for the presence of EBV using Polymerase Chain Reaction (PCR). PCR was performed to amplify two viral genes; EBV nuclear antigen-4 (EBNA-4) and latent membrane protein-1 (LMP1).
Results
EBV genes were detected in 92/150 (61.3%) tissue samples. Of the 92 infected samples, 58/92 (63%) were found among males and 34/92 (37%) were among females.
Conclusion
EBV is prevalent in the Sudan and responsible of the vast majority of cases of NPC.
doi:10.1186/s13027-015-0002-4
PMCID: PMC4335634  PMID: 25705250
Epstein barr virus; Nasopharyngeal carcinoma; Sudan
19.  Aberrant Epstein-Barr virus antibody patterns and chronic lymphocytic leukemia in a Spanish multicentric case-control study 
Background
Epstein-Barr virus (EBV)-related malignancies harbour distinct serological responses to EBV antigens. We hypothesized that EBV serological patterns can be useful to identify different stages of chronic lymphocytic leukemia.
Methods
Information on 150 cases with chronic lymphocytic leukemia and 157 frequency-matched (by age, sex and region) population-based controls from a Spanish multicentre case-control study was obtained. EBV immunoglobulin G serostatus was evaluated through a peptide-based ELISA and further by immunoblot analysis to EBV early antigens (EA), nuclear antigen (EBNA1), VCA-p18, VCA-p40 and Zebra. Two independent individuals categorized the serological patterns of the western blot analysis. Patients with very high response and diversity in EBV-specific polypeptides, in particular with clear responses to EA-associated proteins, were categorized as having an abnormal reactive pattern (ab_EBV). Adjusted odds ratios (OR) and 95% confidence interval (CI) were estimated using logistic regression models.
Results
Almost all subjects were EBV-IgG positive (>95% of cases and controls) whereas ab_EBV patterns were detected in 23% of cases (N = 34) and 11% of controls (N = 17; OR: 2.44, 95% CI, 1.29 to 4.62; P = 0.006), particularly in intermediate/high risk patients. Although based on small numbers, the association was modified by smoking with a gradual reduction of ab_EBV-related OR for all Rai stages from never smokers to current smokers.
Conclusions
Highly distinct EBV antibody diversity patterns revealed by immunoblot analysis were detected in cases compared to controls, detectable at very early stages of the disease and particularly among non smokers. This study provides further evidence of an abnormal immunological response against EBV in patients with chronic lymphocytic leukemia.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-9378-10-5) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-9378-10-5
PMCID: PMC4429596  PMID: 25972916
Chronic lymphocytic leukemia; Epstein-Barr virus; Serology; Case-control; Smoking
20.  HIV and cancer: a comparative retrospective study of Brazilian and U.S. clinical cohorts 
Background
With successful antiretroviral therapy, non-communicable diseases, including malignancies, are increasingly contributing to morbidity and mortality among HIV-infected persons. The epidemiology of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) in HIV-infected populations in Brazil has not been well described. It is not known if cancer trends in HIV-infected populations in Brazil are similar to those of other countries where antiretroviral therapy is also widely available.
Methods
We performed a retrospective analysis of clinical cohorts at Instituto Nacional de Infectologia Evandro Chagas (INI) in Rio de Janeiro and Vanderbilt Comprehensive Care Clinic (VCCC) in Nashville from 1998 to 2010. We used Poisson regression and standardized incidence ratios (SIRs) to examine incidence trends. Clinical and demographic predictors of ADCs and NADCs were examined using Cox proportional hazards models.
Results
This study included 2,925 patients at INI and 3,927 patients at VCCC. There were 57 ADCs at INI (65% Kaposi sarcoma), 47 at VCCC (40% Kaposi sarcoma), 45 NADCs at INI, and 82 at VCCC. From 1998 to 2004, incidence of ADCs remained statistically unchanged at both sites. From 2005 to 2010, ADC incidence decreased in both cohorts (INI incidence rate ratio per year = 0.74, p < 0.01; VCCC = 0.75, p < 0.01). Overall Kaposi sarcoma incidence was greater at INI than VCCC (3.0 vs. 1.2 cases per 1,000 person-years, p < 0.01). Incidence of NADCs remained constant throughout the study period (overall INI incidence 3.6 per 1,000 person-years and VCCC incidence 5.3 per 1,000 person-years). Compared to general populations, overall risk of NADCs was increased at both sites (INI SIR = 1.4 [95% CI 1.1-1.9] and VCCC SIR = 1.3 [1.0-1.7]). After non-melanoma skin cancers, the most frequent NADCs were anal cancer at INI (n = 7) and lung cancer at VCCC (n = 11). In multivariate models, risk of ADC was associated with male sex and immunosuppression. Risk of NADC was associated with increased age.
Conclusions
In both cohorts, ADCs have decreased over time, though incidence of KS was higher at INI than VCCC. Rates of NADCs remained constant over time at both sites.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-9378-10-4) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-9378-10-4
PMCID: PMC4327947  PMID: 25685180
HIV; Malignancy; Cancer; Brazil; Anal cancer; Kaposi sarcoma; Non-Hodgkin lymphoma; Lung cancer; Age; Sex
21.  Prevalence of human cytomegalovirus, polyomaviruses, and oncogenic viruses in glioblastoma among Japanese subjects 
Background
The association between human cytomegalovirus (HCMV) and glioblastoma multiforme (GBM) is becoming a new concept. However, information on the geographic variability of HCMV prevalence in GBM remains scarce. Moreover, the potential roles of various viruses, such as polyomaviruses and oncogenic viruses, in gliomagenesis remain unclear. Our aim was to investigate the prevalence of HCMV in GBM among Japanese patients. Furthermore, this was the first study that evaluated infection with four new human polyomaviruses in GBMs. This study also provided the first data on the detection of human papillomavirus (HPV) in GBM in the Eastern world.
Methods
We measured the number of various viral genomes in GBM samples from 39 Japanese patients using real-time quantitative PCR. The tested viruses included HCMV, Merkel cell polyomavirus, human polyomavirus (HPyV) 6, HPyV7, HPyV9, Epstein–Barr virus, human herpesvirus 8, and HPV. Our quantitative PCR analysis led to the detection of eight copies of the HCMV DNA mixed with DNA extracted from 104 HCMV-negative cells. The presence of HCMV and HPV genomes was also assessed by nested PCR. Immunohistochemical study was also carried out to detect HPV-derived protein in GBM tissues.
Results
The viral DNAs were not detectable, with the exception of HPV, which was present in eight out of 39 (21%) GBMs. All HPV-positive cases harbored high-risk-type HPV (HPV16 and HPV18). Moreover, the HPV major capsid protein was detected in GBM tumor cells.
Conclusions
In contrast with previous reports from Caucasian patients, we did not obtain direct evidence in support of the association between HCMV and GBM. However, high-risk-type HPV infection may play a potential etiological role in gliomagenesis in a subset of patients. These findings should prompt further worldwide epidemiological studies aimed at defining the pathogenicity of virus-associated GBM.
doi:10.1186/1750-9378-10-3
PMCID: PMC4328287  PMID: 25685179
Oncogenic viruses; HCMV; HPV; Polyomaviruses; Glioblastoma; Epidemiology
22.  Expression of bcl-2 and p53 in bovine cutaneous fibropapillomas 
Background
Bovine cutaneous fibropapillomas are benign hyperproliferative lesions induced by Bovine Papillomaviruses (BPVs). Bcl-2 is an important anti-apoptotic protein which is expressed in several cancer types. In contrary, p53 is a tumour suppressor protein that mediates cell cycle arrest, apoptosis and senescence in response to cellular stresses.
Findings
Here, we investigated immunohistochemically and biochemically, the expression of bcl-2 and p53 in a subset of BPV positive fibropapillomas and bovine normal skin. Normal skin samples showed a weak signal for both proteins in the cytoplasm of the basal cells. Nine out of twelve (75%) tumour samples stained positive for bcl-2 throughout basal and parabasal layers, with most of cells showing strong cytoplasmic immunoreactivity. Nine out of twelve (75%) fibropapillomas were found to be positive for p53 expression, showing a strong cytoplasmic and perinuclear staining of p53 protein mainly in the basal and parabasal layers.
Conclusions
Our data reveal an altered bcl-2 and p53 immunoreactivity in bovine cutaneous fibropapillomas, suggesting involvement of these two proteins in the cutaneous neoplastic transformation through an impaired apoptotic process.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-9378-10-2) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-9378-10-2
PMCID: PMC4298047  PMID: 25601891
Bovine papillomavirus; Cattle; Fibropapilloma
23.  The first case of human autochtonous subconjunctival dirofilariosis in Poland and MALT lymphoma as possible consequence of this parasitosis 
The first case of human dirofilarosis in Poland was recorded in 2007. Until that time our country was free of Dirofilaria repens. Recent studies show that 21,4- 60% of dogs in Warsaw region harbour microfilariae, therefore it is becoming a growing problem in Central Europe.
In April 2013 a subconjunctival D. repens was removed from the eye of 61-year-old woman. It was the twenty first case of this disease in Poland, the third case of eye dirofilaria and the fourth autochtonous case. The patient had never been abroad, so it was the first case of autochtonous human ocular dirofilariosis in Poland. Nine months after the D. repens had been removed, a MALT lymphoma was discovered. In the article we discuss whether a MALT lymphoma of the lacrimal gland of the eye, previously affected by the parasite, may be the consequence of the invasion.
doi:10.1186/1750-9378-10-1
PMCID: PMC4293813  PMID: 25589901
Dirofilaria repens; Human; Poland; Autochtonous species; MALT lymphoma; Wolbachia
24.  Disruption of Bcl-2 and Bcl-xL by viral proteins as a possible cause of cancer 
The Bcl proteins play a critical role in apoptosis, as mutations in family members interfere with normal programmed cell death. Such events can cause cell transformation, potentially leading to cancer. Recent discoveries indicate that some viral proteins interfere with Bcl proteins either directly or indirectly; however, these data have not been systematically described. Some viruses encode proteins that reprogramme host cellular signalling pathways controlling cell differentiation, proliferation, genomic integrity, cell death, and immune system recognition. This review analyses and summarises the existing data and discusses how viral proteins interfere with normal pro- and anti-apoptotic functions of Bcl-2 and Bcl-xL. Particularly, this article focuses on how viral proteins, such as Herpesviruses, HTLV-1, HPV and HCV, block apoptosis and how accumulation of such interference predisposes cancer development. Finally, we discuss possible ways to prevent and treat cancers using a combination of traditional therapies and antiviral preparations that are effective against these viruses.
doi:10.1186/1750-9378-9-44
PMCID: PMC4333878  PMID: 25699089
Bcl-2; Bcl-xL; Herpesviruses; Human T-lymphotropic virus 1; Human papillomavirus; Hepatitis C virus; Apoptosis; Signaling pathways; Tumor suppressor genes; Cancer
25.  Inhibitory effect of piperine on Helicobacter pylori growth and adhesion to gastric adenocarcinoma cells 
Background
Piperine is a compound comprising 5-9% of black pepper (Piper nigrum), which has a variety of biological roles related to anticancer activities. Helicobacter pylori has been classified as a gastric carcinogen, because it causes gastritis and gastric cancer by injecting the virulent toxin CagA and translocating VacA. The present study investigated the inhibitory action of piperine on H. pylori growth and adhesion.
Methods
Inhibition of H. pylori growth was determined by the broth macrodilution method, and adhesion to gastric adenocarcinoma cells validated by urease assay. Motility test was performed by motility agar and the expression of adhesion gene and flagellar gene in response to the piperine treatment was assessed by RT-PCR and immunoblotting.
Results
Administrated piperine suppressed the level of H. pylori adhesion to gastric adenocarcinoma cells in a dose dependent manner and the inhibition was statistically significant as determined by Student’s t-test. In addition, piperine treatment effects on the flagellar hook gene flgE and integral membrane component of the export apparatus gene flhA expression to be suppressed and piperine diminished the H. pylori motility.
Conclusions
flhA, encodes an integral membrane component of the export apparatus, which is also one of the regulatory protein in the class 2 genes expression and flgE is one of them that encodes hook part of the flagella. Suppression of both genes, leads to less motility results in the organism attracted less towards to the gastric epithelial cells might be the possible reason in the adhesion inhibition. To our knowledge, this is the first report published on the inhibitory effects of piperine against the adhesion of H. pylori to gastric adenocarcinoma cells.
doi:10.1186/1750-9378-9-43
PMCID: PMC4290101  PMID: 25584066
Piperine; Helicobacter pylori; Adhesion; Gastric cancer

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