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Amaro-Filho S.M.,Laboratory of Interdisciplinary Medical Research LIPMED | Nuovo G.J.,Ohio State University | Levi J.E.,University of Sao Paulo | Villa L.L.,Ludwig Institute for Cancer Research | And 5 more authors.
PLoS ONE | Year: 2013

Cell cycle protein expression plays an important role in the pathophysiology of cervical cancer. However, few studies have attempted to correlate the use of these biomarkers with the clinical progression of the tumor. Objectives: 1) To analyze the expression of Ki-67, p53 and p16INK4a in cervical cancer, 2) to correlate the relative expression of these proteins as well as clinical parameters with the stage of disease, and 3) to determine the HPV DNA prevalence and subtype distribution. Methods: Tissue Micro-Arrays (TMA) from patients with invasive cervical cancer (ICC) and controls were analyzed. HPV DNA detection was done by PCR and in situ hybridization. Ki-67, p53 and p16INK4a were analyzed by immunohistochemistry; clinical data was derived from the chart review. Results: Advanced tumor stage (III and IV) was strongly associated (p<0.005) with advanced age (>55 years old), with more than four pregnancies and with the lack of formal education. HPV DNA was found in 94.3% of cases with the most prevalent types being HPV16 (67.5%), followed by HPV33 (12.0%) and HPV35 (3.6%). High expression of Ki-67 and p16 was more common in the advanced FIGO stages (p = 0.023). Women with HPV16 tended to be younger (50.9 years; SE 1.9) compared to women with other types (59.9 years; SE 2.8). Conclusion: We found that Ki-67 and p16 expression were independently associated with the tumor stage. We also noted that about 1/3 of the cervical cancers in this Brazilian cohort were not associated with HPV types directly targeted by the current HPV vaccines. © 2013 Amaro-Filho et al.

Oliveira N.S.,Laboratory of Interdisciplinary Medical Research LIPMED | Andrade C.V.,Fernandes Figueira Institute Fiocruz | Grinsztejn B.,National Institute of Infectology INI FIOCRUZ | Friedman R.K.,National Institute of Infectology INI FIOCRUZ | And 10 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2016

Human papillomavirus (HPV) is the main etiologic agent of lower genital tract cancers. The natural history of HPV infection and the immune response to HIV/HPV co-infection, particularly in the anal mucosa, is poorly understood. The aim was evaluate the in situ immune response in anorectal biopsies from HIV-infected patients. A total of 114 biopsies were analyzed by Tissue Micro-Array: 15 were from HIV-negative individuals with normal squamous epithelium and 99 from HIV-positive individuals (21 normal squamous epithelium, 39 with anal intra-epithelial lesion grade 1 and 39 with anal intra-epithelial lesion grade 2/3). PCR and sequencing were used to identify HPV DNA. Staining for CD4, CD8, Foxp3+, T-bet and IL-10 were analyzed via immunohistochemistry. HIV-positive patients with AIN 2/3 showed a lower number of CD4+ cells (< 50 cells/mm3) compared to HIV negative subjects (P = 0.01). HIV infected individuals showed a higher expression of FoxP3+ and IL-10 that correlated with the severity of the lesion (P = 0.002). A positive coefficient correlation was found between FoxP3+ and IL-10 (r = 0.34; P = 0.027). HPV DNA was detected in 93.4% (101/107) of the samples and the most common types were HPV 16 (26.9%), followed by HPV 6 (15.7%), HPV 59 (13%) and HPV 18 (10.2%). Our results showed a strong association between the increased T-reg cells and IL-10 expression in HIV-positive patients with AIN 2/3. HPV 16 was the most prevalent type. Our study suggests that the immune regulatory in situ profile may favor HPV persistence in HIV-positive individuals. Further in situ studies should be done in order to elucidate the development of anal cancer in HPV/HIV co-infected individuals.

Filho S.M.A.,Laboratory of Interdisciplinary Medical Research LIPMED | Filho S.M.A.,Brazilian National Cancer Institute INCA | Nuovo G.J.,Ohio State University | Pereira L.O.R.,Laboratory of Interdisciplinary Medical Research LIPMED | And 4 more authors.
International Journal of Biological Markers | Year: 2014

The highly conserved mini-chromosome maintenance proteins (MCM) are important in the initiation of DNA replication. Few studies have correlated MCM expression with the progression of cancer. Objectives: (i) To analyze the expression of MCM2 in cervical cancer; (ii) to correlate MCM2 expression with the clinical tumor staging according to FIGO classification, and (iii) to relate HPV type to MCM2 expression.Methods: Tissue micro-arrays (TMA) from patients with invasive cervical cancer and controls were analyzed. Human papillomavirus (HPV) DNA detection and HPV types were determined by in situ hybridization, PCR, and sequencing. MCM2 expression was analyzed by immunohistochemistry.Results: The most prevalent HPV types found in invasive cancer were HPV 16 (66.6%), followed by HPV 33 (11.8%), and HPV 35 (3.6%). An increased (p<05) expression of MCM2 was found in invasive cervical cancers compared to controls. Moreover, a strong correlation was found between the MCM2-positive cells and the presence of HPV DNA detected by in situ hybridization. No statistically significant difference was observed between MCM2 expression and FIGO stage.Conclusions: The present study shows that HPV-infected cells strongly express MCM2; nevertheless, our data suggests that MCM2 is not a good biomarker when comparing the different clinical stages of cervical cancer. © 2014 Wichtig Publishing.

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