Is elevated gastric tissue NOX2 associated with lymphoma of mucosa-associated lymphoid tissue?

Abstract Helicobacter pylori infection plays a crucial role in the pathogenesis of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). However, the host response to this infection is also important in the development of the disease. In particular, NADPH oxidases (NOXs) which generate reactive oxygen species are known to induce cell damage possibly leading to carcinogenesis. We analyze for the first time NOX expression in a series of well characterized gastric MALT lymphoma (GML) patients in comparison with controls. Our observation leads to the hypothesis that NOX2 expression is significantly associated with GML.     

Do neutralizing antibody responses generated by human papillomavirus infections favor a better outcome of low‐grade cervical lesions?

To determine the role of neutralizing antibody generated by human papillomavirus (HPV) infections, baseline levels of serum neutralizing antibodies directed against HPV 16 and cervical HPV DNA were determined in 242 unvaccinated women with low‐grade cervical abnormalities, who were then monitored by cytology and colposcopy every 4 months. In women infected with HPV 16 (n = 42), abnormal cytology persisted longer in those positive for HPV 16‐specific neutralizing antibodies at baseline (median time to cytological regression: 23.8 vs. 7.2 months). Progression to cervical precancer (cervical intraepithelial neoplasia grade 3) within 5 years occurred only among women carrying HPV 16‐specific neutralizing antibodies (P = 0.03, log‐rank test). In women infected with types other than HPV 16 (n = 200), detection of HPV 16‐specific neutralizing antibodies was not correlated with disease outcome. In conclusion, development of specific neutralizing antibodies following natural HPV 16 infection did not favor a better outcome of low‐grade cervical lesions induced by HPV 16 or by other types; rather, detection of neutralizing antibodies generated by current infection may reflect viral persistence and thus help identify those who are at high risk of disease progression. J. Med. Virol. 84: 1128–1134, 2012. © 2012 Wiley Periodicals, Inc.     

Can carcinogenic potency be predicted from in vivo genotoxicity data? a meta‐analysis of historical data

Genotoxicity is generally a parameter used for hazard identification, however, the applicability of using in vivo genotoxicity tests for hazard characterization has never been thoroughly investigated in a quantitative manner. Genotoxicity assays could be useful for the determination of cancer potency parameters given that genotoxicty tests measure mutations and/or chromosomal aberrations which are strongly associated with carcinogenesis. A detailed literature survey was performed in search for dose-response data in various in vivo genotoxicity and carcinogenicity studies. The benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST. Dose-response data were available from 18 compounds in the micronucleus assay (MN), the in vivo transgenic rodent mutation assay (TG) and the comet assay, and their BMD(10) values were compared to the BMD(10) from carcinogenicity studies in mice. Of the 18 compounds, 15 had acceptable dose-response data from the MN and the TG, but only 4 from the comet assay. A major limitation in our analysis was the lack of proper dose-response studies using the recommended protocols. Nevertheless, our findings are promising because even with these suboptimal studies, a positive correlation was observed when the lowest BMD(10) from the genotoxicity tests (MN and TG) was compared to the tissue-matched carcinogenicity BMD(10) . It is evident that more compounds need to be analyzed with proper dose-response schemes to further validate our initial findings. Experimental designs of genotoxicity assays need to shift from focusing only on hazard identification where positive and negative results are reported, to a more quantitative, dose-response assessment.     

Upregulation of Soluble HLA‐G5 and HLA‐G6 Isoforms in the Milder Histopathological Stages of Helicobacter pylori Infection: A Role for Subverting Immune Responses?

The subversion mechanisms employed by Helicobacter pylori (H. pylori) to escape from immune surveillance and to establish persistent infection are poorly understood. Growing evidence indicates that expression of HLA‐G, a non‐classical major histocompatibility complex molecule, negatively regulates immune responses in pathological conditions, including infectious diseases. In this context, we aimed to evaluate HLA‐G expression in the gastric microenvironment of individuals harbouring H. pylori and to correlate it with histological variables. Fifty‐four gastric specimens from patients harbouring H. pylori infection were evaluated by immunohistochemistry using anti‐HLA‐G monoclonal antibody. As a result, HLA‐G expression was detected in 43 of 54 specimens harbouring H. pylori. The presence of HLA‐G was significantly associated with milder colonization by H. pylori (P < 0.02), milder inflammatory activity (P < 0.02) and bacterium histological location in the gastric antrum. This study is the first to explore HLA‐G expression in the context of bacterial infection. Whether the biological role of HLA‐G during H. pylori infection is beneficial or hazardous for patients remains to be defined.     

Can interferon‐γ and interleukin‐10 balance be associated with severity of human Leishmania (Viannia) braziliensis infection?

Suitable levels of interferon (IFN)-gamma and interleukin (IL)-10 seem to favour the outcome of cutaneous leishmaniasis (CL), while high IFN-gamma and low IL-10 production are associated with severity of mucosal leishmaniasis (ML). Considering that cytokine balance is important for the maintenance of protective responses in leishmaniasis, our aim was to investigate leishmanial antigens-induced IFN-gamma and IL-10 levels maintained in healed individuals who had different clinical outcomes of Leishmania infection. Thirty-three individuals who recovered from L. braziliensis infection were studied: cured CL (CCL), cured ML (CML), spontaneous healing of CL (SH) or asymptomatic individuals (ASY). Cytokines were quantified by enzyme-linked immunosorbent assay (ELISA) in culture supernatants of L. braziliensis-stimulated peripheral blood mononuclear cells (PBMC). IFN-gamma levels were higher in CML (7593 +/- 5994 pg/ml) in comparison to SH (3163 +/- 1526 pg/ml), ASY (1313 +/- 1048 pg/ml) or CCL (1897 +/- 2087 pg/ml). Moreover, cured ML cases maintained significantly lower production of IL-10 (127 +/- 57.8 pg/ml) in comparison to SH (1373 +/- 244 pg/ml), ASY (734 +/- 233 pg/ml) or CCL (542 +/- 375 pg/ml). Thus, a high IFN-gamma/IL-10 ratio observed in CML can indicate unfavourable cytokine balance. On the other hand, no significant difference in the IFN-gamma/IL-10 ratio was observed when CCL individuals were compared to SH or ASY subjects. In conclusion, even after clinical healing, ML patients maintained a high IFN-gamma/IL-10 secretion profile in response to leishmanial antigens. This finding can explain a delayed down-modulation of exacerbated inflammatory responses, which can be related in turn to the necessity of prolonged therapy in ML management. Conversely, lower IFN-gamma/IL-10 balance observed in CCL, SH and ASY individuals can represent a better-modulated immune response associated with a favourable prognosis.     

Molecular epidemiology of human papillomavirus genotype in women with high‐grade squamous intraepithelial lesion and cervical cancer: Will a quadrivalent vaccine be necessary in Thailand?

This study was designed to investigate the distribution of human papillomavirus (HPV) genotypes among a group of patients with high-grade squamous intraepithelial lesion (HSIL) or worse cytology. Consequently, the genotype-specific HPV infection in a group of HSIL and invasive cervical cancer (ICC) samples was described. Specimens were collected prospectively from 132 women referred for colposcopic examination. All the women underwent Papanicolaou (Pap) smears and colposcopies and some also underwent cervical excision procedure biopsy. The HPV genotype was determined using the INNO-LiPA assay. Among the 132 genotyped samples, 90.91% (120/132) were diagnosed HSIL, whereas 9.09% (12/132) were ICC. From the overall prevalence of HPV in the patients, 77.27% (102/132) and 22.72% (30/132) of cases had single and multiple genotype infections, respectively. The most common cases with statistical significance were high-risk HPV (HR-HPV) infections in 128 samples (96.97%), whereas, four individuals (3.03%) barely were low-risk HPV (LR-HPV) infected, P < 0.0001, χ(2). The most prevalent genotypes were frequently HPV-16 (65/167; 38.92%, followed by HPV-58 (25/167; 14.97%), HPV-18 (18/167; 10.78%), HPV-33 (13/167; 7.19%), and HPV-68 (11/167; 6.59%). In addition, HPV-11 (2/132; 1.51%) and HPV-6 (1/132; 0.76%) also were observed in this study, which confirmed the high distribution of HR-HPV among women with HSIL and ICC. HPV-58; a unique high-risk HPV, is prevalent in a group of HSIL and ICC cases. These data also contribute evidence that HPV-16, -18, -58, -33, and -68 genotypes are high-risk and high distribution among women with HSIL and ICC. Therefore, HPV-58, HPV-33, and HPV-68 should be considered for development of the next vaccine generation in Thailand.     

Two years outcome of women infected with high risk HPV having normal colposcopy following low‐grade or equivocal cytological abnormalities: Are HPV16 and 18 viral load clinically useful predictive markers?

Management of patients infected with high-risk HPV (hrHPV) despite normal colposcopy following abnormal cytology remains a clinical challenge. The aim of this study was to evaluate if, in that specific population, initial HPV 16 and HPV 18 viral loads are predictive of infection clearance over a 24-month follow-up. A total of 67 women infected with hrHPV having normal colposcopy following equivocal or low-grade cytological abnormalities were recruited and attended regular follow-ups based on repeat colposcopies and HPV testing. HPV16 and HPV18 infection were diagnosed in 36 (53.7%) and 7 (10.4%) cases, respectively. Viral load was quantified using the quantitative duplex real-time PCR method. Although this was not observed for HPV 18, initial HPV 16 viral load was highly associated to HPV 16 infection outcome (receiver operating characteristic curve analysis, area under curve: 0.90). Thus, women who had cleared their HPV 16 infection had significantly lower median initial HPV 16 viral load than those with persistent HPV 16 infection: 1.5 × 10(3) copies per million cells (CPMC) versus 3.8 × 10(6) CPMC, respectively (P = 0.006). The best prediction of HPV 16 clearance was obtained with an initial HPV 16 viral load of <7.5 × 10(4) CPMC: 86.7% specificity and 85.7% sensitivity. Finally, six patients were diagnosed with grade 2 or 3 cervical or vaginal intraepithelial neoplasia. Although all had a persistent hrHPV infection, neither HPV 16 nor 18 viral loads were found to be predictive of the risk of cervical or vaginal intraepithelial neoplasia. HPV16 viral load quantitation could represent a clinically useful marker in that very specific population.