Up-regulation of 14-3-3sigma (Stratifin) is associated with high-grade CIN and high-risk human papillomavirus (HPV) at baseline but does not predict outcomes of HR-HPV infections or incident CIN in the LAMS study

To assess whether the potentially high-risk (HR) human papillomavirus (HPV)-related up-regulation of 14-3-3sigma (stratifin) has implications in the outcome of HPV infections or cervical intraepithelial neoplasia (CIN) lesions, cervical biopsy specimens from 225 women in the Latin American Screening Study were analyzed for 14-3-3sigma expression using immunohistochemical analysis. We assessed its associations with CIN grade and HR HPV at baseline and value in predicting outcomes of HR-HPV infections and the development of incident CIN 1+ and CIN 2+. Expression of 14-3-3sigma increased in parallel with the lesion grade. Up-regulation was also significantly related to HR-HPV detection (P = .004; odds ratio, 2.71; 95% confidence interval, 1.37-5.35) and showed a linear relationship to HR-HPV loads (P = .003). 14-3-3sigma expression was of no value in predicting the outcomes (incident, persistent, clearance) of HR-HPV infections or incident CIN 1+ and CIN 2+. 14-3-3sigma is not inactivated in cervical carcinoma and CIN but is up-regulated on transition from CIN 2 to CIN 3. Its normal functions in controlling G(1)/S and G(2)/M checkpoints are being bypassed by HR HPV.LAMS, Latin American Screening Study, funded by European Commission, INCO-DEV contract ICA4-CT-2001-10013

Hormonal contraceptives and the length of their use are not independent risk factors for high-risk HPV infections or high-grade CIN

AIMS: To evaluate the role of hormonal contraceptives as a risk factor of high-risk human papillomavirus (HR-HPV), cervical intraepithelial lesions (CIN) and cervical cancer in our multi-center population-based LAMS (Latin American Screening) study. METHODS: A cohort study with >12,000 women from Brazil and Argentina using logistic regression to analyze the covariates of hormonal contraception (HOC - oral, injections, patches, implants, vaginal ring and progesterone intrauterine system) use followed by multivariate modeling for predictors of HR-HPV and CIN2+. RESULTS: HR-HPV infection was a consistent risk factor of high-grade CIN in all three groups of women. The length of HOC use was not significantly related to high-grade squamous intraepithelial lesions (HSIL)+ Pap (p = 0.069), LSIL+ Pap (p = 0.781) or ASCUS+ (p = 0.231). The same was true with the length of HOC use and histology CIN3+ (p = 0.115) and CIN2+ (p = 0.515). Frequently, HOC users have previously shown more HPV-related lesions, as well as lower HPV prevalence if they were current smokers. But HOC use and time of usage were not independent risk factors of either HR-HPV infection or high-grade CIN using multiple logistic regressions. CONCLUSIONS: No evidence was found for an association between the use of HOC with an increased risk for HR-HPV infection or high-grade CIN in this cohort.This study is a part of the ongoing LAMS (Latin American Screening) study, entitled: Improving Health Systems Towards Equality-Based Control of Cervical Cancer in Latin America, and is supported by the INCO-DEV Program of the European Commission (Project No. ICA4-CT-2001-10013). The generous contribution of Digene Corporation (USA) who donated the HCII tests at our disposal is gratefully acknowledged

Up-Regulation of Plasminogen Activator Inhibitor-2 Is Associated With High-Risk HPV and Grade of Cervical Lesion at Baseline but Does Not Predict Outcomes of High-Risk HPV Infections or Incident CIN

n/

Association between age at first sexual intercourse and subsequent human papillomavirus infection: results of a Brazilian screening program

Objetivo: descrever a idade de início da atividade sexual (sexarca) e a sua associação com a idade das mulheres com a infecção por papilomavírus humano (HPV) e com as alterações citológicas no exame de papanicolaou. Métodos: mulheres da população geral foram recrutadas para participar de um estudo de rastreamento de câncer cervical e lesões pré-malignas. Após a aplicação de questionário comportamental, foram submetidas ao rastreamento com gia cervical e teste para DNA de HPV de alto risco, por meio de Captura Híbrida 2. Este projeto faz parte do Latin American Screening Study, que envolve mulheres do Brasil e da Argentina, e os dados aqui apresentados referem-se aos centros brasileiros nas cidades de Porto Alegre, São Paulo e Campinas. Resultados: de 8.649 mulheres entrevistadas, 8.641 relataram atividade sexual prévia e foram incluídas na análise. A média de idade no momento da entrevista foi de 38,1±11,04 anos, com início da atividade sexual em média aos 18,5±4,0 anos. Identificamos que a idade do início da atividade sexual aumenta de acordo com o aumento da faixa etária no momento da entrevista, isto é, mulheres mais novas relataram sexarca mais precoce que mulheres mais velhas (p<0,001). Em relação à infecção por HPV de alto risco, do total de mulheres que haviam iniciado as relações sexuais, 3.463 foram testadas, com 17,3% de positividade para HPV. Notadamente, em todos os centros, as mulheres com idade ao início da atividade sexual abaixo da média da população entrevistada apresentaram positividade maior para HPV (20,2%) do que as mulheres com sexarca em idade acima da média (12,5%) – Odds Ratio (OR)=1,8 (IC95%=1,5-2,2; p<0,001). Em relação à citologia, mulheres com sexarca abaixo da média de idade apresentaram também maior percentual de citologia alterada ≥ ASC-US (6,7%) do que mulheres com sexarca em idade maior que a média (4,3%) – OR=1,6 (IC95%=1,3-2,0; p<0,001). Conclusões: a infecção por HPV e a presença de alterações citológicas identificadas no rastreio de lesões cervicais em uma população assintomática estiveram significativamente associadas à idade mais precoce no início das relações sexuais. Ademais, identificamos também que as mulheres desta amostra apresentaram diminuição da idade ao início da atividade sexual, nas últimas décadas, sugerindo importante causa para o acréscimo da prevalência de HPV e as lesões decorrentes desta infecção.Purpose: to investigate women’s age at their first sexual intercourse and its correlation with their present age, human papillomavirus (HPV) infection and cytological abnormalities at Pap smear. Methods: women from the general population were invited to be screened for cervical cancer and pre-malignant lesions. After answering a behavior questionnaire, they were submitted to screening with cervical cytology and high-risk HPV testing with Hybrid Capture 2 (HC2). This report is part of the Latin American Screening (LAMS) study, that comprises centers from Brazil and Argentina, and the data presented herein refer to the Brazilian women evaluated at the cities of Porto Alegre, São Paulo and Campinas. Results: from 8,649 women that answered the questionnaire, 8,641 reported previous sexual activity and were included in this analysis. The mean age at the interview was 38.1±11.0 years and the mean age at the first sexual intercourse was 18.5±4.0 years. The age at the first sexual intercourse increased along with the age at the interview, i.e., younger women reported they had begun their sexual life earlier than older women (p<0.001). From the total of women who had already begun having sexual intercourse, 3,643 patients were tested for high-risk HPV infection and 17.3% of them had positive results. In all the centers, it became clear that the women with the first sexual intercourse at ages below the mean age of all the population interviewed presented higher rates of HPV infection (20.2%) than the women with the first sexual intercourse at ages above the mean (12.5%) – Odds Ratio (OR) 1.8 (IC95% 1.5-2.2;p<0,001). According to the cytology, the women with first sexual intercourse at ages under the mean, presented higher percentage of abnormal cytology ≥ ASC-US (6.7%) than the women with the first sexual intercourse at ages above the mean (4.3%) – OR 1.6 (IC95% 1.3-2.;p<0.001). ConclusionS: the high-risk HPV infection and cytological abnormalities identified during the asymptomatic population screening were significantly associated to the women’s age at the first sexual intercourse. Additionally, we have also identified that the women’s age at the first sexual intercourse has decreased during the last decades, suggesting an important contribution to the increase of HPV infection and the subsequent cervical lesions.Comissão Europeia - programa INCO-DEV (International Cooperation Development) Contrato #ICA4-2001-10013

Safety of screening with Human papillomavirus testing for cervical cancer at three-year intervals in a high-risk population: experience from the LAMS study

To assess whether human papillomavirus (HPV) testing is a safe enough approach to warrant extension of the screening intervals of baseline Papanicolaou (Pap)-/HPV- women in low-income settings.European Commission, INCO-DEV Programme (Contract # ICA4-CT-2001-10013). The generous contribution from DIGENE Inc. (USA) donating the HC 2 test

Evaluation of visual inspection with acetic acid (VIA), Lugol’s iodine (VILI), cervical cytology and HPV testing as cervical screening tools in Latin America

Objectives: To assess the performance indicators of visual inspection with acetic acid (VIA) and visual inspection with Lugol’s iodine (VILI) in four Latin American centres participating in the ongoing Latin AMerican Screening (LAMS) study, in settings with moderate incidence of cervical disease and with poorly to moderately well-organized cervical cancer screening. Setting: Three Brazilian centres (São Paulo, Campinas and Porto Alegre) and one Argentine centre (Buenos Aires) recruited a total of 11,834 healthy women to undergo VIA, VILI, conventional Pap smear and Hybrid Capture II (HCII). Methods: Women who had a positive result from any of these tests were subjected to colposcopy and biopsies (if necessary), and women with high-grade cervical intraepithelial neoplasia (CIN) were properly treated. To control for verification bias, 5% of women with normal tests were referred for colposcopy, as were 20% of HCII-negative women. Results: Data on VIA (n = 11,834), VILI (n = 2994), conventional Pap smear (n = 10,138) and HCII (n = 4195) were available for test comparisons, calculating sensitivity, specificity, and positive and negative predictive values. Overall test positivity was 11.6% for VIA, 23.0% for VILI, 2.2% for Pap smear (LSIL threshold), 1.1% for Pap smear (HSIL threshold) and 17.1% for HCII. VIA was positive in 61.8% of the women with CIN 1, 57.0% of those with CIN 2, 35.0% of women with CIN 3 and in 21 of 28 (75%) of women with cancer. Approximately 10% of women with no detectable disease had an abnormal VIA. Regarding VILI, 83.3% of women diagnosed with CIN 1 and 62.5% of those with CIN 3 had an abnormal test. VILI failed to detect one of three cases of cancer. Both the sensitivity, specificity and positive predictive value of VIA and VILI in detecting CIN 2 or CIN 3 could be significantly improved depending on the combination with Pap smear or HCII (sensitivity up to 100.0% and specificity up to 99.8%). Conclusions: The LAMS study failed to reproduce the performance figures obtained with VIA and VILI (as stand-alone tests) in some other settings, where the prevalence of cervical disease was higher. However, a combined use of VIA or VILI with the Pap test or HCII allowed specific detection of cervical abnormalities.European Union (EU) - INCO-DEV Programme - Contract# ICA4-CT-2001-10013

Human papillomavirus testing as an optional screening tool in low-resource settings of Latin America: experience from the Latin American Screening study

Hybrid capture II (HC II) test for oncogenic human papillomaviruses (HPV) was carried out in a cohort of 4284 women at their first clinical visit. Overall prevalence of HPV was 17.1%, decreasing with age from 33.9% among women below 20 years to only 11.0% among those older than 41 years. HPV prevalence was significantly higher among current smokers (odds ratio [OR] ¼ 1.31; 95% CI 1.1–1.6), in women with two or more lifetime sexual partners (OR ¼ 1.9; 95% CI 1.6–2.4), and those women with two or more sexual partners during the past 12 months prior to examination (OR ¼ 1.6; 95% CI 1.2–2.2). HPV detection increased in parallel with increasing cytologic abnormality, being highest in women with high-grade squamous intraepithelial lesion (P ¼ 0.001). Specificity of the HPV test in detecting histologically confirmed cervical disease was 85% (95% CI 83.9–86.1). Sensitivity of the HPV test in detecting histologic abnormalities increased in parallel with disease severity, ranging from 51.5% for cervical intraepithelial neoplasia (CIN) 1 to 96.5% for CIN 3 and 100.0% for cancer, with respective decline of positive predictive value. These data suggest that HPV testing with HC II assay might be a viable screening tool among this population with relatively high prevalence of cervical disease

Copy number alterations associated with clinical features in an underrepresented population with breast cancer

As the most incident tumor among women worldwide, breast cancer is a heterogeneous disease. Tremendous efforts have been made to understand how tumor characteristics as histological type, molecular subtype, and tumor microenvironment collectively influence disease diagnosis to treatment, which impact outcomes. Differences between populations and environmental and cultural factors have impacts on the origin and evolution of the disease, as well as the therapeutic challenges that arise due to these factors. We, then, compared copy number variations (CNVs) in mucinous and nonmucinous luminal breast tumors from a Brazilian cohort to investigate major CNV imbalances in mucinous tumors versus non‐mucinous luminal tumors, taking into account their clinical and pathological features.48 breast tumor samples and 48 matched control blood samples from Brazilian women were assessed for CNVs by chromosome microarray. Logistic regression and random forest models were used in order to assess CNVs in chromosomal regions from tumors.CNVs that were identified in chromosomes 1, 5, 8, 17, 19, and 21 classify tumors according to their histological type, ethnicity, disease stage, and familial history.Copy number alterations described in this study provide a better understanding of the landscape of genomic aberrations in mucinous breast cancers that are associated with clinical features.77FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo2013/25683-3; 2015/18830-

Puntos de inflexión en los gradientes de composición de las comunidades de plantas acuáticas de diferentes continentes

Sección: SIBECOL-AIL Meeting in Aveiro-2022[EN] Unravelling patterns and mechanisms of biogeographical transitions is crucial if we are to understand compositional gradients at large spatial extents, but no studies have thus far examined breakpoints in community composition of freshwater plants across continents. Using a dataset of almost 500 observations of lake plant community composition from six continents, we examined, for the first time, if such breakpoints in geographical space exist for freshwater plants and how well a suite of ecological factors (including climatic and local environmental variables) can explain transitions in community composition from the subtropics to the poles. Our combination of multivariate regression tree (MRT) analysis and k-means partitioning suggests that the most abrupt breakpoint exists between temperate to boreal regions on the one hand and freshwater plant communities harbouring mainly subtropical or Mediterranean assemblages on the other. The spatially structured variation in current climatic conditions is the most likely candidate for controlling these latitudinal patterns, although one cannot rule out joint effects of eco-evolutionary constraints in the harsher high-latitude environments and post-glacial migration lags after Pleistocene Ice Ages. Overall, our study supports the foundations of global regionalisation for freshwater plants and anticipates further biogeographical research on freshwater plant communities once datasets have been harmonised for conducting large-scale spatial analyses[ES] Desentrañar los patrones y mecanismos que subyacen a las transiciones biogeográficas es un requisito fundamental a la hora de comprender los gradientes de composición de las comunidades ecológicas a grandes extensiones espaciales, si bien ningún estudio ha examinado explícitamente estos puntos de inflexión para comunidades de plantas acuáticas de diferentes continentes. Utilizando una completa base de datos que condensa un total de casi 500 observaciones individuales sobre las comunidades florísticas lacustres de seis continentes, este trabajo pretende delinear las transiciones biogeográficas en plantas acuáticas a escala global, así como valorar el papel que desempeñan diversos mecanismos ecológicos (a saber, las condiciones climáticas y las características locales del hábitat) sobre estos puntos de inflexión en el espacio geográfico comprendido entre las latitudes subtropicales y los polos. Nuestros resultados obtenidos mediante la ejecución simultánea de árboles de regresión multivariante (MRT) y algoritmos de agrupación por k-medias demuestran la existencia de un punto de inflexión entre las regiones templadas y boreales y los lagos localizados en las bandas subtropicales y en las inmediaciones del Mediterráneo. La estructura espacial que subyace a la distribución de los condicionantes climáticos en nuestro planeta parece ser el principal mecanismo de control de dichas transiciones biogeográficas, si bien estos patrones latitudinales también podrían explicarse en base a constricciones eco-evolutivas en las regiones más septentrionales y a la colonización diferencial de los territorios norteños antaño cubiertos por el hielo durante el Último Máximo Glacial. En síntesis, nuestro estudio proporciona una base teórica preliminar para futuras investigaciones encaminadas a delimitar las unidades geográficas de los principales componentes de la flora acuática contemporánea y también anticipa un creciente interés por los estudios de carácter fitogeográfico en las aguas continentales, si bien los análisis venideros deberán prestar especial atención a la armonización de datos biológicos potencialmente heterogéneos en naturaleza y con orígenes disparesSIJGG was funded by the European Union Next Generation EU/PRTR (grant no. AG325). Academy of Finland supported JH, JGG (grant no. 331957), and JA (grant no. 322652). CFL appreciates financial support from the Spanish Ministry of Science and Technology (grant no. CL2017- 84176R). BAL was supported by National Research, Development, and Innovation Office (grant no. NKFIH, OTKA FK127939) and by the Bolyai János Research Scholarship of the Hungarian Academy of Sciences. SK was supportedby NWO Vidi (grant no. 203098). LR was funded by MESRSI (Ministry of Higher Education, Scientific Research and Innovation of Morocco) as part of the BiodivRestore Program (RESPOND Project) and by the Tour du Valat Foundation. Sampling of the Brazilian coastal lakes was financed by NWO (grant no. W84-549), the National Geographic Society (grant no. 7864-5), and CNPq (grants no. 480122, 490409, 311427