Phytoconstituents from Vernonia glaberrima Welw. Ex O. Hoffm. leaves and their cytotoxic activities on a panel of human cancer cell lines

Vernonia glaberrima is a medicinal plant that is used in African traditional medicine for the treatment of skin cancer. The aim of this study was to investigate the anticancer activity of V. glaberrima leaves and isolate its bioactive constituents. Crude methanolic leaves extract of V. glaberrima showing significant cytotoxic activity against cancer cell lines was subjected to chromatographic separation, purification and hydrolysis to yield four compounds namely, nonacosanoic acid, lupeol, 5-methylcoumarin-4-β-glucoside and 4-hydroxy-5-methylcoumarin. Three of the isolated compounds showed significant cytotoxic activity against human malignant melanoma (A375) cell line (IC50: 59.18 ± 2.70 to 139.53 ± 10.79 μg/mL) and human caucasian colon adenocarcinoma (HT-29) cell line (IC50: 4.22 ± 0.13 to 20.0 ± 1.91 μg/mL) while only lupeol displayed significant activity against human breast adenocarcinoma (MCF7) (IC50: 34.15 ± 2.32 μg/mL) cell line. CDK2 receptor and CAIX were identified through molecular docking as potential targets for the bioactive compounds. The findings of this study have revealed the therapeutic potential of V. glaberrima against breast cancer, skin cancer and colorectal carcinoma, respectively and further support its traditional uses in the treatment of skin cancer. Keywords: Vernonia glaberrima; Anticancer activity; 5-Methylcoumarin-4-β-glucoside; Molecular docking; Carbonic anhydrase I

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

Thermostable phycocyanin from the red microalga Cyanidioschyzon merolae, a new natural blue food colorant

The demand for natural food colorants is growing as consumers question the use of artificial colorants more and more. The phycobiliprotein C-phycocyanin of Arthospira platensis is used as a natural blue colorant in certain food products. The thermoacidophilic red microalga Cyanidioschyzon merolae might provide an alternative source of phycocyanin. Cyanidioschyzon merolae belongs to the order Cyanidiophyceae of the phylum Rhodophyta. Its natural habitat are sulfuric hot springs and geysers found near volcanic areas in, e.g., Yellowstone National Park in the USA and in Java, Indonesia. It grows optimally at a pH between 0.5 and 3.0 and at temperatures up to 56 A degrees C. The low pH at which C. merolae grows minimizes the risk of microbial contamination and could limit production loss. As C. merolae lacks a cell wall, phycocyanin with a high purity number of 9.9 could be extracted by an osmotic shock using a simple ultrapure water extraction followed by centrifugation. The denaturation midpoint at pH 5 was 83 A degrees C, being considerably higher than the A. platensis phycocyanin (65 A degrees C). The C. merolae phycocyanin was relatively stable at pH 4 and 5 up to 80 A degrees C. The high thermostability at slightly acidic pH makes the C. merolae phycocyanin an interesting alternative to A. platensis phycocyanin as a natural blue food colorant

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-

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

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

A Statin-Loaded Reconstituted High-Density Lipoprotein Nanoparticle Inhibits Atherosclerotic Plaque Inflammation

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show this effect is mediated through inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show they accumulate in atherosclerotic lesions where they directly affect plaque macrophages. Finally we demonstrate that a three-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a one-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation

Development of a Ki-67-based clinical trial assay for neoadjuvant endocrine therapy response monitoring in breast cancer.

Purpose The recent publication of the ACOSOG Z1031 trial results demonstrated that Ki-67 proliferation marker-based neoadjuvant endocrine therapy response monitoring could be used for tailoring the use of adjuvant chemotherapy in ER+HER2-negative breast cancer patients. In this paper, we describe the development of the Ki-67 clinical trial assay used for this study.Methods Ki-67 assay assessment focused on reproducing a 2.7% Ki-67 cut-point (CP) required for calculating the Preoperative Endocrine Prognostic Index and a 10% CP for poor endocrine therapy response identification within the first month of neoadjuvant endocrine treatment. Image analysis was assessed to increase the efficiency of the scoring process. Clinical outcome concordance for two independent Ki-67 scores was the primary performance metric.Results Discordant scores led to a triage approach where cases with complex histological features that software algorithms could not resolve were flagged for visual point counting (17%). The final Ki-67 scoring approach was run on T1/2 N0 cases from the P024 and POL trials (N = 58). The percent positive agreement for the 2.7% CP was 87.5% (95% CI 61.7-98.5%); percent negative agreement 88.9% (95% CI: 65.3-98.6%). Minor discordance did not affect the ability to predict similar relapse-free outcomes (Log-Rank P = 0.044 and P = 0.055). The data for the 10% early triage CP in the POL trial were similar (N = 66), the percentage positive agreement was 100%, and percent negative agreement 93.55% (95% CI: 78.58-99.21%). The independent survival predictions were concordant (Log-rank P = 0.0001 and P = 0.01).Conclusions We have developed an efficient and reproducible Ki-67 scoring system that was approved by the Clinical Trials Evaluation Program for NCI-supported neoadjuvant endocrine therapy trials. Using the methodology described here, investigators are able to identify a subgroup of patients with ER+HER2-negative breast cancer that can be safely managed without the need of adjuvant chemotherapy

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