Human Papillomavirus 16 Lineage A Variants Associated With Persistent Genital Infections in Men: The HPV Infection in Men (HIM) Study.

BACKGROUND: Human papillomavirus (HPV) 16 non-A lineage variants have higher carcinogenic potential for cervical cancer. HPV-16 variants natural history among males is not established. We evaluated HPV-16 variants prevalence and persistence in the external genitalia of men enrolled in the prospective HPV Infection in Men (HIM) Study. METHODS: The HIM Study included men from the United States, Brazil, and Mexico. HPV-16 variants were distinguished using polymerase chain reaction sequencing. The prevalence of HPV-16 variants was assessed, and associations with infection persistence were estimated. RESULTS: We characterized the HPV-16 variants for 1700 genital swab samples from 753 men and 22 external genital lesions in 17 men. The prevalence of HPV-16 lineages differed by country and marital status (P < .001). Overall, 90.9% of participants harbored lineage A variants. The prevalence of non-A lineages was heterogenous among countries. HPV-16 lineage A variants were associated with a 2.69-fold increased risk of long-term persistent infections compared with non-A lineages. All high-grade penile intraepithelial neoplasia harbored lineage A variants and occurred in the context of long-term persistent infections with the same variants. CONCLUSIONS: The prevalence and persistence of HPV-16 variants observed at the male external genitalia suggest differences in the natural history of these variants between men and women, which may be associated with intrinsic differences in the infected genital epithelia.

Altered Expression of CYSLTR1 is Associated With Adverse Clinical Outcome in Triple Negative Breast Tumors: An In Silico Approach.

Objective: Triple negative breast cancer (TNBC) has high relapse rates due to dysregulated inflammatory signaling pathways and significant changes in the tumor microenvironment, probably influencing the failure of several therapies. The Cysteinyl Leukotriene Receptor 1 (CYSLTR1), a leukotriene modulator of inflammation, has been shown to play an important role in cancer pathogenesis and survival but few studies have been reported on its role in breast cancer. Materials and Methods: The present work was conducted using publicly available platforms that have omics data to assess the clinical potential of CYSLTR1 expression and its prognostic validation in large cohorts of samples from breast cancer patients. Web platforms containing clinical information, RNA-seq and protein data were selected to perform in silico analyses of the potential marker CYLSTR1. Added together, the platforms included modules for correlation, expression, prognosis, drug interactions, and construction of gene networks. Results: Kaplan-Meier curves revealed that reduced levels of CYSLTR1 corresponded to an unfavorable outcome for overall survival (p<0.005) as well as relapse-free survival (p<0.001) in the basal subtype. Additionally, CYSLTR1 was downregulated in breast tumor samples compared to adjacent healthy tissue (p<0.01) and the basal subtype exhibited the lowest expression of CYSLTR1 relative to the other subtypes (p<0.0001). Furthermore, gene networking analysis showed strong associations of CYSLTR1 with two protein-coding genes (P2RY10 and XCR1) when tested on a TNBC dataset. Conclusion: Our data highlighted the relevance of CYSLTR1 since it may play an important role in TNBC therapy. However, further in vitro and in vivo studies should be directed towards validating our findings in an effort to improve our understanding of TNBC pathology.

Prevalence and persistence of HPV-16 molecular variants in the anal canal of men: The HIM study.

BACKGROUND: HPV-16 causes approximately 90% of anal canal (AC) cancers worldwide. This study aimed to evaluate the prevalence and persistence of HPV-16 genetic variants in the AC of men from three different countries (Brazil, Mexico and United States) and to further identify sociodemographic and behavioral factors associated with these infections. METHODS: Participants from the multinational prospective HPV Infection in Men (HIM) Study who had at least one HPV-16 positive AC swab were included. Characterization into HPV-16 genetic variants was successfully performed by PCR-sequencing in 95.6% (217/227) samples and these were classified into HPV-16 lineages and sublineages. RESULTS: We observed higher prevalence of lineage A variants, mainly from A1 sublineage, in all countries. Non-A lineage variants were mostly detected in men from Brazil, where higher diversity of sublineage variants was detected during follow-up. Compare to men detected with Non-A HPV-16 lineage variants, men infected with lineage A reported a higher lifetime number of female sexual partners. Finally, a significantly higher prevalence of Non-A lineage variants was observed among men who have sex with men (MSM) with a transient HPV-16 AC infection (p = 0.033), but no significant differences regarding variants lineages and persistence status were observed when stratified by country, self-reported ethnicity or age. CONCLUSIONS: Our data extend previous reports which indicate that globally HPV-16 variants are unevenly distributed, and contribute further to studies of the natural history of AC HPV infections in men.

Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro.

Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.

Genetic variants of HPV-16 and their geographical and anatomical distribution in men: A systematic review with meta-analysis.

BACKGROUND: The prevalence of Human Papillomavirus type 16 (HPV-16) variants in men and the association with tumor development has not been fully investigated. We estimated the prevalence of genital, anal, and oral HPV-16 infections in men through a systematic review and meta-analysis. METHODS: Seven databases were searched and included studies that identified HPV-16 positive males, HPV-16 variants (lineages/sublineages), and indicated the sample's anatomical origin. This protocol is registered in PROSPERO (CRD42020178013). RESULTS: The database searches yielded 14 studies including 445 HPV-16 positive samples classified as lineage A (n = 390), lineage D (n = 43), lineage B (n = 10), and lineage C (n = 2) variants. Lineage A variants predominated among the anatomical sites and the diverse geographical regions. CONCLUSIONS: HPV-16 lineages vary according to anatomical and geographical region. According to this preliminary evaluation of the current literature, we hypothesize that, similar to women, specific HPV-16 variants may also be associated to increased cancer risk in men.

Influence of Lipoxygenase Inhibition on Glioblastoma Cell Biology.

BACKGROUND: The relationship between glioblastoma (GBM) and fatty acid metabolism could be the key to elucidate more effective therapeutic targets. 15-lipoxygenase-1 (15-LOX), a linolenic acid and arachidonic acid metabolizing enzyme, induces both pro- and antitumorigenic effects in different cancer types. Its role in glioma activity has not yet been clearly described. The objective of this study was to identify the influence of 15-LOX and its metabolites on glioblastoma cell activity. METHODS: GBM cell lines were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to identify 15-LOX metabolites. GBM cells treated with 15-LOX metabolites, 13-hydroxyoctadecadeinoic acid (HODE) and 9-HODE, and two 15-LOX inhibitors (luteolin and nordihydroguaiaretic acid) were also examined. Dose response/viability curves, RT-PCRs, flow cytometry, migration assays, and zymograms were performed to analyze GBM growth, migration, and invasion. RESULTS: Higher quantities of 13-HODE were observed in five GBM cell lines compared to other lipids analyzed. Both 13-HODE and 9-HODE increased cell count in U87MG. 15-LOX inhibition decreased migration and increased cell cycle arrest in the G2/M phase. CONCLUSION: 15-LOX and its linoleic acid (LA)-derived metabolites exercise a protumorigenic influence on GBM cells in vitro. Elevated endogenous levels of 13-HODE called attention to the relationship between linoleic acid metabolism and GBM cell activity.

Opposing roles of PGD2 in GBM.

BACKGROUND: The World Health Organization classifies glioblastoma (GBM) as a grade IV astrocytoma. Despite the advances in chemotherapy, surgery, and radiation treatments that improve a patient's length of survival, the overall trajectory of the disease remains unchanged. GBM cells produce significant levels of various types of bioactive lipids. Prostaglandin D2 (PGD2) influences both pro- and anti-tumorigenic activities in the cell; however, its role in GBM is unclear. Therefore, this study aimed to identify the impact of PGD2 on GBM cell activities in vitro. METHODS: First we looked to identify the presence of the PGD2 synthesis pathway through RT-PCR, immunohistochemistry, and HPLC-MS/MS in three GBM cell lines. Then, to observe PGD2's effects on cell count and apoptosis/mitosis (Hoechst 33342 stain), and migration (Transwell Assay), the cells were treated in vitro with physiological (<1µM) and/or supraphysiological (>1µM) concentrations of PGD2 over 72h. HPLC-MS/MS was used to identify the lipid composition of patients with either Grade II/III gliomas or GBM. RESULTS: We identified the presence of endogenous PGD2 with its corresponding enzymes and receptors. Exogenous PGD2 both increased cell count (<1µM) and decreased cell count (10µM) in a concentration-dependent manner. There were no significant effects on apoptosis. A significant decrease in mitotic activity was seen only in U251MG, and a significant increase was seen in migration with 5µM PGD2 treatments. A very significant increase of PGD2 was seen from Grade II/III gliomas to GBM. CONCLUSIONS: Our study demonstrates that prostaglandin D2 possesses a dynamic, concentration-dependent effect in GBM cell activities. The increase of PGD2 production in GBM patients suggests a pro-tumorigenic role of PGD2 in glioma growth and invasion. Therefore, prostaglandin signaling in GBM requires further investigation to identify new targets for more effective therapies.

[Is plasma selenium correlated to transthyretin levels in critically ill patients?]

BACKGROUND: Selenium is an essential trace element, but critically ill patients using total parenteral nutrition (PN) do not receive selenium because this mineral is not commonly offered. Threfore, the eval uation of plasma selenium levels is very important for treating or preventing this deficiency. Recent studies have shown that transthyretin may reflect the selenium intake and could be considered a biomarker. However, this issue is still little explored in the literature. OBJECTIVE: This study aims to investigate the correlation of transthyretin with the plasma selenium of critically ill patients receiving PN. METHOD: This was a prospective cohort study with 44 patients using PN without selenium. Blood samples were carried out in 3 stages: initial, 7th and 14th day of PN. In order to evaluate the clinical condition and the inflammatory process, albumin, C-reactive protein (CRP), transthyretin, creatinine and HDL cholesterol levels were observed. To assess the selenium status, plasma selenium and glutathione peroxidase (GPx) in whole blood were measured. Descriptive analyses were performed and the ANOVA, Mann-Whitney and Spearman's coefficient tests were conducted; we assumed a significance level of 5%. RESULTS: A positive correlation of selenium with the GPx levels (r = 0.46; p = 0.03) was identified. During two weeks, there was a positive correlation of transthyretin with plasma selenium (r = 0.71; p = 0.05) regardless of the CRP values. CONCLUSION: Transthyretin may have reflected plasma selenium, mainly because the correlation was verified after the acute phase.