ERVs-TLR3-IRF axis is linked to myelodysplastic syndrome pathogenesis.

Toll-like receptors are mutated or overexpressed in up to 50% of patients with myelodysplastic syndrome (MDS). Endogenous retroviruses (ERV) trigger TLR3 leading to interferon regulatory genes (IRFs) activation. We evaluated if the ERVs-TLR3-IRF axis activation would be linked to MDS pathogenesis and we also conducted a detailed cancer analysis of the ERVs, TLR3 and IRFs gene expression in 30 cancer types using GEPIA database. Seventy-nine bone marrow samples from patients with MDS were evaluated for cytogenetics and quantitative real­time PCR of TLR3, ERVK6, ERVW-1, ERV3-1, IRF3 and IRF7. Patients with dyserythropoiesis showed higher TLR3 (p = 0.035), ERVK6 (p = 0.001), ERVW1 (p = 0.045) and ERV3-1 (p = 0.016) expression than patients without dyserythropoiesis. Upregulation of Interferon Regulatory Factors, IRF3 and IRF7, was associated with poor prognostic markers in MDS such as > 10% of blasts (p = 0.003-IRF3; p = 0.009-IRF7), low platelets count (< 50.000/mm3) (p = 0.001-IRF3; p = 0.021-IRF7), transfusion dependence (p = 0.014-IRF3) and chromosomal abnormalities (p = 0.036-IRF7). We found strong correlations between ERVK6-ERVW1 (r = 0.800; r2 = 0.640; p = 0.000), ERVW1-ERV3-1 (r = 0.715; r2 = 0.511; p = 0.000), and IRF7-IRF3 (r = 0.567; r2 = 0.321; p = 0.000) and moderate correlation between ERVK6-ERV3-1(r = 0.485; r2 = 0.235; p = 0.000), ERVW1-IRF7 (r = 0.389; r2 = 0.151; p = 0.001), ERVW1-IRF3 (r = 0.357; r2 = 0.127; p = 0.004), ERV3-1-IRF7 (r = 0.314; r2 = 0.098; p = 0.009), and ERV3-1-IRF3 (r = 0.324; r2 = 0.104; p = 0.007). Using GEPIA Database in 30 cancer types, we detected a typical pattern of upregulation as here presented in MDS. We suggest TLR3 activation by ERVs is linked to MDS pathogenesis leading to bone marrow failure. Abnormal double-stranded RNA (dsRNA) expression of Endogenous Retroviruses (ERV) triggers TLR3 hyperactivation. This induces IRF3, IRF7, and NF-kB to translocate to the nucleus and activate transcription of IFNα/ß which binds to the type I-IFN receptor promoting interferon response. Thus, just as TLR4 induces a crucial myeloid shift, the ERVs-TLR3 axis may play an important role in establishing one of the most striking characteristics in MDS, dyserythropoiesis.

Evaluation of cytopathological screening results and risk factors of women who underwent Papanicolaou test in a maternity school in Fortaleza, Ceará, Brazil.

INTRODUCTION: Papanicolaou test (Pap smear) is the standard screening test of pre-neoplastic lesions and cervical cancer. This study aimed to investigate cervical cancer screening results and risk factors such as age, reason for the examination, the epithelia detected in the sample, microbiota and signs of sexually transmitted infection (STIs) of women in a maternity school in Fortaleza, Ceará, Brazil. METHODS: In this cross-sectional study, data were retrieved of 353 women who underwent Pap smear between April 2016 and January 2017 at the Federal University of Ceará. RESULTS: Of all Pap smear samples retrieved, 54.1% (191/353) had glandular epithelium and 40.2% (142/353) had metaplastic epithelium. After statistical analyses adjusted for the final model, age ≥51 years (odds ratio = 3.47) and signs of STIs (odds ratio = 4.95) remained as risk factors. CONCLUSIONS: The diagnosis of high-grade lesions and carcinomas in patients older than 50 years indicates a deficiency in cervical screening. Women with signs and symptoms of STIs and candidiasis sought medical services more frequently than asymptomatic women, and presence of these signs and symptoms contributes to the diagnosis of cervical cancer. We highlight the importance of obtaining a correct smear sampling to allow prompt detection of all preneoplastic lesions; moreover, the implementation of human papillomavirus vaccination and an efficient routine Pap screening are necessary in low-resource settings.