Evaluation of MCM-2 Expression in TMA Cervical Specimens

Background:Minichromosome maintenance proteins (MCM) are highly expressed in actively replicating cells. The need for biological markers for cervical carcinoma and its precursor lesions is emerging. Our main aim was to determine the immunohistochemical expression of MCM-2 in HIV-positive and -negative dysplastic cervical specimens. Methods:Immunohistochemical analysis of MCM-2 was performed in a total of 352 cervical TMA specimens of normal control, low-grade CIN, high-grade CIN and invasive tumor. 38 specimens were from HIV-positive women. A receiver operating characteristic (ROC) curve was constructed to determine the best cutoff to diagnose high-grade CIN and invasive cervical cancer. Results:In the progression from normal epithelium to high-grade CIN and invasive tumor we found significant differences in the MCM-2 expression (p,0.05). Based on the ROC curve of 80% with an area under the curve (AUC) of 0.78, expression of MCM-2 to diagnose high-grade CIN and invasive tumor resulted in sensitivity of 81%, specificity of 66%, a positive predictive value (PPV) of 86% and a negative predictive value (NPV) of 57%. HIV-positive cervices revealed a decreasing expression of MCM-2 in both LGCIN and HGCIN compared with HIV-negative specimens (p,0.0001). Conclusions:The present study suggests that immunohistochemical MCM-2 may not be a promising biomarker for diagnosing high-grade CIN and invasive cance

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The role of p16 as putative biomarker for cervical neoplasia: A controversial issue?

Submitted by Sandra Infurna ([email protected]) on 2018-03-01T16:15:43Z No. of bitstreams: 1 alcinaf_nicol_etal_IOC_2017.pdf: 282043 bytes, checksum: a766894a85bdf3650c4e0d6878e5ecff (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-03-01T16:30:15Z (GMT) No. of bitstreams: 1 alcinaf_nicol_etal_IOC_2017.pdf: 282043 bytes, checksum: a766894a85bdf3650c4e0d6878e5ecff (MD5)Made available in DSpace on 2018-03-01T16:30:15Z (GMT). No. of bitstreams: 1 alcinaf_nicol_etal_IOC_2017.pdf: 282043 bytes, checksum: a766894a85bdf3650c4e0d6878e5ecff (MD5) Previous issue date: 2017Instituto Brasileiro de Medicina e Reabilitação. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Nacional da Saúde da Mulher, Criança e Adolescente Fernandes Figueira. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional da Saúde da Mulher, Criança e Adolescente Fernandes Figueira. Rio de Janeiro, RJ, Brasil.State University Comprehensive Cancer Center. Columbus, OH, USA.Instituto Nacional de Câncer. Divisão de Genética. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil.INTRODUCTION: Protein p16 has been extensively studied as a potential biomarker for precursor lesions to distinguish cervical Intraepithelial neoplasia (CIN) from their mimics. However, the use of p16 as prognostic biomarker for diagnosis of cervical cancer and precancer is controversial. This study focuses on the assessment of peer-reviewed scientific data related to the use of p16 to predict disease severity and its controversies. METHODS: We reviewed publications in MEDLINE/PubMed assessing the clinical, diagnostic and prognostic significance of p16 in CIN and cervical cancer; we included publications from 2009 to June 2017. RESULTS: The use of p16 as a prognostic marker is still unreliable, although it could be a useful tool for diagnosis of Cervical Intraepithelial Neoplasia lesions with undetermined morphology. Moreover, p16 appears to be a specific marker of high-risk oncogenic HPV infection. CONCLUSION: This review shows the potential utility and drawbacks of p16 for clinical practice and the diagnosis of cervical cancer. Further studies are required to substantiate the role of p16 in conjunction with other more sensitive and specific biomarkers for diagnosing CIN and predicting its progression

In situ FoxP3+ and IL-10 over-expression is associated with high grade anal lesions in HIV infected patients

Submitted by Alcina Frederica Nicol ([email protected]) on 2017-11-12T20:43:42Z No. of bitstreams: 1 FOX-ijcep0019868.pdf: 1341261 bytes, checksum: 188a212005045eeaaae4280385a30d59 (MD5)Approved for entry into archive by Raphael Rodrigues ([email protected]) on 2017-11-13T14:43:39Z (GMT) No. of bitstreams: 1 FOX-ijcep0019868.pdf: 1341261 bytes, checksum: 188a212005045eeaaae4280385a30d59 (MD5)Made available in DSpace on 2017-11-13T14:43:39Z (GMT). No. of bitstreams: 1 FOX-ijcep0019868.pdf: 1341261 bytes, checksum: 188a212005045eeaaae4280385a30d59 (MD5) Previous issue date: 2016Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira. Departamento de Patologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ. Brasil.Universidade Estácio de Sá. Departamento de Endodontia. Programa de pós graduação em odontologia. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil.Instituto Nacional do Cancer. Divisão de Genética. Rio de Janeiro, RJ. Brasil.Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil.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

An evaluation of p16INK4a expression in cervical intraepithelial neoplasia specimens, including women with HIV-1

Although several studies have evaluated the role of p16INK4a as a diagnostic marker of cervical intraepithelial neoplasia (CIN) and its association with disease progression, studies regarding the role of p16INK4a in human immunodeficiency virus (HIV)-infected patients remain scarce. The present study was designed to determine the potential utility of p16INK4a as a diagnostic marker for CIN and invasive cervical cancer in HIV-positive and negative cervical specimens. An immunohistochemical analysis of p16INK4a was performed in 326 cervical tissue microarray specimens. Performance indicators were calculated and compared using receiving operating characteristics curve (ROC)/area under the curve. In HIV-1-negative women, the percentage of cells that was positive for p16INK4a expression was significantly correlated with the severity of CIN (p < 0.0001). A ROC curve with a cut-off value of 55.28% resulted in a sensitivity of 89%, a specificity of 81%, a positive predictive value of 91% and a negative predictive value of 78%. HIV-seropositive women exhibited decreased expression of p16INK4a in CIN2-3 specimens compared with HIV-negative specimens (p = 0.031). The ROC data underscore the potential utility of p16INK4a under defined conditions as a diagnostic marker for CIN 2-3 staging and invasive cervical cancer. HIV-1 infection, however, is associated with relatively reduced p16INK4a expression in CIN 2-3

Association between the patient information with the tissue morphology and the FIGO stage.

<p>Association between the patient information with the tissue morphology and the FIGO stage.</p

Crude table showing the % of stained cells in the cervical epithelium.

*<p>Dunn's test for multiple comparisons: revealed significant differences among normal controls compared with low CIN, High grade CIN and invasive tumor; and between low CIN compared to invasive tumor.</p><p>Moreover significant differences were found among Invasive tumor and control, High grade CIN and control. Low grade CIN and control, invasive tumor and low grade CIN and between invasive tumor and high grade CIN.</p