Pd2Spermine as an Alternative Therapeutics for Cisplatin-Resistant Triple-Negative Breast Cancer.

Cisplatin (cDDP) resistance is a matter of concern in triple-negative breast cancer therapeutics. We measured the metabolic response of cDDP-sensitive (S) and -resistant (R) MDA-MB-231 cells to Pd2Spermine(Spm) (a possible alternative to cDDP) compared to cDDP to investigate (i) intrinsic response/resistance mechanisms and (ii) the potential cytotoxic role of Pd2Spm. Cell extracts were analyzed by untargeted nuclear magnetic resonance metabolomics, and cell media were analyzed for particular metabolites. CDDP-exposed S cells experienced enhanced antioxidant protection and small deviations in the tricarboxylic acid cycle (TCA), pyrimidine metabolism, and lipid oxidation (proposed cytotoxicity signature). R cells responded more strongly to cDDP, suggesting a resistance signature of activated TCA cycle, altered AMP/ADP/ATP and adenine/uracil fingerprints, and phospholipid biosynthesis (without significant antioxidant protection). Pd2Spm impacted more markedly on R/S cell metabolisms, inducing similarities to cDDP/S cells (probably reflecting high cytotoxicity) and strong additional effects indicative of amino acid depletion, membrane degradation, energy/nucleotide adaptations, and a possible beneficial intracellular γ-aminobutyrate/glutathione-mediated antioxidant mechanism.

Disclosing a metabolic signature of cisplatin resistance in MDA-MB-231 triple-negative breast cancer cells by NMR metabolomics.

This work compared the metabolic profile of a parental MDA-MB-231 cisplatin-sensitive triple negative breast cancer (TNBC) cell line with that of a derived cisplatin-resistant line, to characterize inherent metabolic adaptations to resistance, as a means for marker and new TNBC therapies discovery. Supported by cytotoxic, microscopic and biochemical characterization of both lines, Nuclear Magnetic Resonance (NMR) metabolomics was employed to characterize cell polar extracts for the two cell lines, as a function of time (0, 24 and 48 h), and identify statistically relevant differences both between sensitive and resistant cells and their time course behavior. Biochemical results revealed a slight increase in activation of the NF-κB pathway and a marked decrease of the ERK signaling pathway in resistant cells. This was accompanied by lower glycolytic and glutaminolytic activities, possibly linked to glutamine being required to increase stemness capacity and, hence, higher survival to cisplatin. The TCA cycle dynamics seemed to be time-dependent, with an apparent activation at 48 h preferentially supported by anaplerotic aromatic amino acids, leucine and lysine. A distinct behavior of leucine, compared to the other branched-chain-amino-acids, suggested the importance of the recognized relationship between leucine and in mTOR-mediated autophagy to increase resistance. Suggested markers of MDA-MB-231 TNBC cisplatin-resistance included higher phosphocreatine/creatine ratios, hypotaurine/taurine-mediated antioxidant protective mechanisms, a generalized marked depletion in nucleotides/nucleosides, and a distinctive pattern of choline compounds. Although the putative hypotheses generated here require biological demonstration, they pave the way to the use of metabolites as markers of cisplatin-resistance in TNBC and as guidance to develop therapies.

Analysis of the quality of prenatal data of pregnant women attended at Healthcare Services in the city of São Paulo between 2012 and 2020.

OBJECTIVE: To analyze the quality of data collected during prenatal care recorded in the Integrated Health Care Management System (SIGA) of the Municipal Department of Health of São Paulo from 2012 to 2020. METHODS: Descriptive study using SIGA data and the variables: maternal height (cm), weight (kg) measured throughout pregnancy, gestational age at prenatal consultation, systolic (SBP) and diastolic (DBP) blood pressure (in mmHg), and body mass index (BMI) at the beginning of pregnancy (up to 8 weeks). Quality analysis was carried out by calculating the indicators: percentage of incompleteness and zero values of all variables studied, percentage of implausible values for height, weight, BMI; preference for terminal digit of weight and height, and normality of distributions. RESULTS: The database of pregnant women made available for analysis included 8,046,608 records and 1,174,115 women. The percentage of incompleteness and zero values was low (<1%) in all original variables of the system. There are more records at the end of pregnancy. For the four original variables of interest in the database (weight, height, SBP, DBP), there is a clear preference for the terminal digit. The variables of interest did not present an approximately normal distribution during the evaluated period. CONCLUSION: The quality analysis showed the need for improving the standardization of information collection and recording, the rounding of measurements and the need for encouraging pregnant women to start prenatal care as soon as possible, in such a way that it is important to invest in data quality, through educational resources for professionals who work in health care.

Achievement of appropriate cesarean rates using Robson's 10-Group classification system in Brazilian private practice.

BACKGROUND: Increasing cesarean section (CS) rates are a global concern because they are related to higher maternal and neonatal complication rates and do not provide positive childbirth experiences. In 2019, Brazil ranked second globally, given its overall CS rate of 57%. According to the World Health Organization (WHO), populational CS rates of 10-15% are associated with decreased maternal, neonatal, and infant mortality rates. This study aimed to investigate whether multidisciplinary care following evidence-based protocols associated with a high motivation of both women and professionals for a vaginal birth leads to less overuse of CS in a Brazilian private practice (PP). METHODS: This cross-sectional study evaluated CS rates by Robson group for women who sought vaginal birth in a private practice in Brazil comparing with Swedish data. Collaborative care of midwives and obstetricians who adopted evidence-based guidelines was offered. CS rates, overall and by Robson group, contribution of each Robson group to the overall CS rate, clinical and nonclinical interventions, vaginal birth, pre-labor CS, and intrapartum CS proportions were estimated. The expected CS rate was calculated using the World Health Organization C-model tool. The analysis used Microsoft Excel and R Studio (version 1.2.1335. 2009-2019). RESULTS: The PP overall CS rate was 15.1% (95%CI, 13.4-17.1%) versus the 19.8% (95%CI, 14.8-24.7%) rate expected by the WHO C-model tool. The population included 43.7% women in Robson Group 1 (nulliparous, single, cephalic, at term, spontaneous labor), 11.4% in Group 2 (nulliparous, single, cephalic, at term, induced labor or CS before labor), and 14.9% in Group 5 (multiparous women with previous CS), the greatest contributors to higher CS rates (75.4% of them). The Swedish overall CS rate was 17.9% (95%CI, 17.6-18.1%) in a population of 27% women in Robson Group 1, 10.7% in Group 2, and 9.2% in Group 5. CONCLUSIONS: Multidisciplinary care following evidence-based protocols, associated with high motivation of both women and professionals for vaginal birth, may lead to a significant and safe reduction of CS rates even in contexts such as Brazil, with high medicalization of obstetric care and excess CS.

Pd(II) and Pt(II) Trinuclear Chelates with Spermidine: Selective Anticancer Activity towards TNBC-Sensitive and -Resistant to Cisplatin.

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and constitutes 10-20% of all breast cancer cases. Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug resistance often hamper their clinical use. Hence, novel drug entities with improved tolerability and selectivity profiles, as well as the ability to surpass resistance, are needed. The current study focuses on Pd(II) and Pt(II) trinuclear chelates with spermidine (Pd3Spd2 and Pt3Spd2) for evaluating their antineoplastic activity having been assessed towards (i) cisplatin-resistant TNBC cells (MDA-MB-231/R), (ii) cisplatin-sensitive TNBC cells (MDA-MB-231) and (iii) non-cancerous human breast cells (MCF-12A, to assess the cancer selectivity/selectivity index). Additionally, the complexes' ability to overcome acquired resistance (resistance index) was determined. This study revealed that Pd3Spd2 activity greatly exceeds that displayed by its Pt analog. In addition, Pd3Spd2 evidenced a similar antiproliferative activity in both sensitive and resistant TNBC cells (IC50 values 4.65-8.99 µM and 9.24-13.34 µM, respectively), with a resistance index lower than 2.3. Moreover, this Pd compound showed a promising selectivity index ratio: >6.28 for MDA-MB-231 cells and >4.59 for MDA-MB-231/R cells. Altogether, the data presently gathered reveal Pd3Spd2 as a new, promising metal-based anticancer agent, which should be further explored for the treatment of TNBC and its cisplatin-resistant forms.

Gestational age: comparing estimation methods and live births' profile.

OBJECTIVE: To identify factors associated with the definition of the gestational age (GA) estimation method recorded in the live birth certificate (LBC), and to compare the results obtained according to the method in the city of São Paulo (CSP), between 2012 and 2019. METHODS: Cross-sectional population-based study using the Live Birth Information System. Descriptive and comparative analysis was performed according to the GA estimation method, followed by a univariate and multivariate logistic regression model to identify the predictor variables of the method used. RESULTS: The estimation of GA by the date of the last menstrual period (LMP) (39.9%) was lower than that obtained by other methods (OM) (60.1%) - physical examination and ultrasound, between 2012-2019. LMP registration in the LBC increased with the mother's age, it was higher among women who were white, more educated and with partners, in cesarean sections and with private funding. In the logistic regression, public funding was 2.33 times more likely than private funding to use OM. The proportion of preterm infants (<37 weeks) with GA by LMP was 26.5% higher than that obtained by OM. Median birth weight was higher among preterm infants with GA estimated by LMP. CONCLUSION: Prematurity was higher with the GA estimated by LMP in the CSP, which may indicate overestimation by this method. The source of funding was the most explanatory variable for defining the GA estimator method at the LBC. The results point to the need for caution when comparing the GA obtained by different methods.

Intra-urban spatial variability of breast and cervical cancer mortality in the city of São Paulo: analysis of associated factors. / Variabilidade espacial intraurbana da mortalidade por câncer de mama e do colo do útero no município de São Paulo: análise dos fatores associados.

OBJECTIVE: To identify spatial variability of mortality from breast and cervical cancer and to assess factors associated in the city of São Paulo. METHODS: Between 2009 and 2016, 10,124 deaths from breast cancer and 2,116 deaths from cervical cancer were recorded in the Mortality Information System among women aged 20 years and over. The records were geocoded by address of residence and grouped according to Primary Health Care coverage areas. A spatial regression modeling was put together using the Bayesian approach with a Besag-York-Mollié structure to verify the association of deaths with selected indicators. RESULTS: Mortality rates from these types of cancer showed inverse spatial patterns. These variables were associated with breast cancer mortality: travel time between one and two hours to work (RR - relative risk: 0.97; 95%CI - credible interval: 0.93-1.00); women being the head of the household (RR 0.97; 95%CI 0.94-0.99) and deaths from breast cancer in private health institutions (RR 1.04; 95%CI 1.00-1.07). The following variables were associated with mortality from cervical cancer: travel time to work between half an hour and one hour (RR 0.92; 95%CI 0.87-0.98); per capita household income of up to 3 minimum wages (RR 1.27; 95%CI 1.18-1.37) and ratio of children under one year of age related to the female population aged 15 to 49 years (RR 1.09; 95%CI 1.01-1.18). CONCLUSION: The predicted RR for mortality from these cancers were calculated and associated with the socioeconomic conditions of the areas covered.

OBJETIVO: Identificar a variabilidade espacial da mortalidade por câncer de mama e colo do útero e avaliar fatores associados à mortalidade por esses cânceres no município de São Paulo. MÉTODOS: Entre 2009 e 2016 foram registrados, no Sistema de Informações sobre Mortalidade, 10.124 óbitos por câncer de mama e 2.116 óbitos por câncer do colo do útero em mulheres com 20 anos e mais. Os registros foram geocodificados por endereço de residência e agregados segundo território adstrito. Foram realizadas modelagens de regressão espacial utilizando-se a abordagem bayesiana com estrutura de Besag-York-Mollié para verificar a associação dos óbitos com indicadores selecionados. RESULTADOS: As taxas de mortalidade por esses cânceres apresentaram padrões espaciais inversos. As variáveis associadas à mortalidade por câncer de mama foram: tempo de deslocamento para o trabalho entre uma e duas horas (risco relativo ­ RR 0,97; intervalo de credibilidade ­ IC95% 0,93­1,00); mulheres responsáveis pelo domicílio (RR 0,97; IC95% 0,94­0,99) e óbitos por câncer de mama ocorridos em estabelecimentos privados (RR 1,04; IC95% 1,00­1,07). À mortalidade por câncer do colo do útero, estiveram associados: tempo de deslocamento para o trabalho entre meia e uma hora (RR 0,92; IC95% 0,87­0,98); rendimento domiciliar até três salários-mínimos (RR 1,27; IC95% 1,18­1,37); e razão de menores de um ano em relação à população feminina de 15 a 49 anos (RR 1,09; IC95% 1,01­1,18). CONCLUSÃO: Foram calculados os RR preditos para a mortalidade por esses cânceres, que estiveram associados às condições socioeconômicas das áreas de abrangência.

Gestational age: comparing estimation methods and live births' profile / Gestational age: comparing estimation methods and live births' profile

ABSTRACT Objective: To identify factors associated with the definition of the gestational age (GA) estimation method recorded in the live birth certificate (LBC), and to compare the results obtained according to the method in the city of São Paulo (CSP), between 2012 and 2019. Methods: Cross-sectional population-based study using the Live Birth Information System. Descriptive and comparative analysis was performed according to the GA estimation method, followed by a univariate and multivariate logistic regression model to identify the predictor variables of the method used. Results: The estimation of GA by the date of the last menstrual period (LMP) (39.9%) was lower than that obtained by other methods (OM) (60.1%) — physical examination and ultrasound, between 2012-2019. LMP registration in the LBC increased with the mother's age, it was higher among women who were white, more educated and with partners, in cesarean sections and with private funding. In the logistic regression, public funding was 2.33 times more likely than private funding to use OM. The proportion of preterm infants (<37 weeks) with GA by LMP was 26.5% higher than that obtained by OM. Median birth weight was higher among preterm infants with GA estimated by LMP. Conclusion: Prematurity was higher with the GA estimated by LMP in the CSP, which may indicate overestimation by this method. The source of funding was the most explanatory variable for defining the GA estimator method at the LBC. The results point to the need for caution when comparing the GA obtained by different methods.

RESUMO Objetivo: Identificar fatores associados à definição do método estimador da idade gestacional (IG) registrado na declaração de nascido vivo (DNV) e comparar os resultados obtidos segundo método no município de São Paulo, entre 2012 e 2019. Métodos: Estudo transversal de base populacional utilizando o Sistema de Informações sobre Nascidos Vivos. Realizou-se análise descritiva e comparativa segundo método de estimativa da IG, seguida de modelo de regressão logística uni e multivariada para identificar as variáveis preditoras do método utilizado. Resultados: A estimativa da IG pela data da última menstruação (DUM) (39,9%) foi inferior à obtida por outros métodos (OM) (60,1%) — exame físico e ultrassonografia, entre 2012-2019. O registro da DUM na DNV aumentou com a idade da mãe, foi maior entre as brancas, mais escolarizadas e com companheiro, nas cesarianas e nos partos realizados com financiamento privado. Na regressão logística, o financiamento público apresentou chance 2,33 vezes maior que o privado para uso de OM. A proporção de prematuros (<37 semanas) com IG pela DUM foi 26,5% maior do que a obtida por OM. A mediana de peso ao nascer foi maior entre prematuros com IG estimada pela DUM. Conclusão: A prematuridade foi mais elevada com a IG estimada pela DUM no MSP, o que pode indicar superestimação por este método. A fonte de financiamento foi a variável mais explicativa para definição do método estimador da IG na DNV. Os resultados apontam a necessidade de cautela ao comparar a IG obtida por métodos diferentes.

Variabilidade espacial intraurbana da mortalidade por câncer de mama e do colo do útero no município de São Paulo: análise dos fatores associados / Intra-urban spatial variability of breast and cervical cancer mortality in the city of São Paulo: analysis of associated factors

RESUMO Objetivo: Identificar a variabilidade espacial da mortalidade por câncer de mama e colo do útero e avaliar fatores associados à mortalidade por esses cânceres no município de São Paulo. Métodos: Entre 2009 e 2016 foram registrados, no Sistema de Informações sobre Mortalidade, 10.124 óbitos por câncer de mama e 2.116 óbitos por câncer do colo do útero em mulheres com 20 anos e mais. Os registros foram geocodificados por endereço de residência e agregados segundo território adstrito. Foram realizadas modelagens de regressão espacial utilizando-se a abordagem bayesiana com estrutura de Besag-York-Mollié para verificar a associação dos óbitos com indicadores selecionados. Resultados: As taxas de mortalidade por esses cânceres apresentaram padrões espaciais inversos. As variáveis associadas à mortalidade por câncer de mama foram: tempo de deslocamento para o trabalho entre uma e duas horas (risco relativo — RR 0,97; intervalo de credibilidade — IC95% 0,93-1,00); mulheres responsáveis pelo domicílio (RR 0,97; IC95% 0,94-0,99) e óbitos por câncer de mama ocorridos em estabelecimentos privados (RR 1,04; IC95% 1,00-1,07). À mortalidade por câncer do colo do útero, estiveram associados: tempo de deslocamento para o trabalho entre meia e uma hora (RR 0,92; IC95% 0,87-0,98); rendimento domiciliar até três salários-mínimos (RR 1,27; IC95% 1,18-1,37); e razão de menores de um ano em relação à população feminina de 15 a 49 anos (RR 1,09; IC95% 1,01-1,18). Conclusão: Foram calculados os RR preditos para a mortalidade por esses cânceres, que estiveram associados às condições socioeconômicas das áreas de abrangência.

ABSTRACT Objective: To identify spatial variability of mortality from breast and cervical cancer and to assess factors associated in the city of São Paulo. Methods: Between 2009 and 2016, 10,124 deaths from breast cancer and 2,116 deaths from cervical cancer were recorded in the Mortality Information System among women aged 20 years and over. The records were geocoded by address of residence and grouped according to Primary Health Care coverage areas. A spatial regression modeling was put together using the Bayesian approach with a Besag-York-Mollié structure to verify the association of deaths with selected indicators. Results: Mortality rates from these types of cancer showed inverse spatial patterns. These variables were associated with breast cancer mortality: travel time between one and two hours to work (RR - relative risk: 0.97; 95%CI - credible interval: 0.93-1.00); women being the head of the household (RR 0.97; 95%CI 0.94-0.99) and deaths from breast cancer in private health institutions (RR 1.04; 95%CI 1.00-1.07). The following variables were associated with mortality from cervical cancer: travel time to work between half an hour and one hour (RR 0.92; 95%CI 0.87-0.98); per capita household income of up to 3 minimum wages (RR 1.27; 95%CI 1.18-1.37) and ratio of children under one year of age related to the female population aged 15 to 49 years (RR 1.09; 95%CI 1.01-1.18). Conclusion: The predicted RR for mortality from these cancers were calculated and associated with the socioeconomic conditions of the areas covered.

Analysis of the quality of prenatal data of pregnant women attended at Healthcare Services in the city of São Paulo between 2012 and 2020 / Análise da qualidade dos dados de pré-natal de gestantes atendidas em Unidades Básicas de Saúde do município de São Paulo entre 2012 e 2020

ABSTRACT Objective: To analyze the quality of data collected during prenatal care recorded in the Integrated Health Care Management System (SIGA) of the Municipal Department of Health of São Paulo from 2012 to 2020. Methods: Descriptive study using SIGA data and the variables: maternal height (cm), weight (kg) measured throughout pregnancy, gestational age at prenatal consultation, systolic (SBP) and diastolic (DBP) blood pressure (in mmHg), and body mass index (BMI) at the beginning of pregnancy (up to 8 weeks). Quality analysis was carried out by calculating the indicators: percentage of incompleteness and zero values of all variables studied, percentage of implausible values for height, weight, BMI; preference for terminal digit of weight and height, and normality of distributions. Results: The database of pregnant women made available for analysis included 8,046,608 records and 1,174,115 women. The percentage of incompleteness and zero values was low (<1%) in all original variables of the system. There are more records at the end of pregnancy. For the four original variables of interest in the database (weight, height, SBP, DBP), there is a clear preference for the terminal digit. The variables of interest did not present an approximately normal distribution during the evaluated period. Conclusion: The quality analysis showed the need for improving the standardization of information collection and recording, the rounding of measurements and the need for encouraging pregnant women to start prenatal care as soon as possible, in such a way that it is important to invest in data quality, through educational resources for professionals who work in health care.

RESUMO Objetivo: Analisar a qualidade dos dados coletados no acompanhamento pré-natal registrados no Sistema Integrado de Gestão da Assistência à Saúde (SIGA) da Secretaria Municipal de Saúde de São Paulo de 2012 a 2020. Métodos: Estudo descritivo utilizando dados do SIGA e as variáveis: altura materna (cm), peso (kg) medido ao longo da gestação, idade gestacional na consulta pré-natal, pressão arterial (em mmHg) sistólica (PAS) e diastólica (PAD), e índice de massa corporal (IMC) no início da gestação (até 8 semanas). A análise da qualidade foi realizada por meio do cálculo dos indicadores: percentual de incompletude e valores zero de todas as variáveis estudadas, percentual de valores implausíveis de estatura, peso, IMC; preferência por dígito terminal do peso e estatura, e normalidade das distribuições. Resultados: Base de dados de gestantes disponibilizada para análise incluía 8.046.608 registros e 1.174.115 mulheres. O percentual de incompletude e valores zeros foi baixo (<1%) em todas as variáveis originais do sistema. Existe maior número de registros ao final da gestação. Para as quatro variáveis de interesse originais do banco de dados (peso, altura, PAS, PAD), existe clara preferência por dígito terminal. As variáveis de interesse não apresentaram distribuição aproximadamente normal durante o período avaliado. Conclusão: A análise da qualidade mostrou necessidade de melhoria na padronização da coleta e do registro das informações, no arredondamento das medidas e na necessidade de incentivar as gestantes a iniciar o pré-natal o quanto antes; por isso, é importante investir na qualidade do dado, por meio de recursos educativos para profissionais que atuam na assistência.

Neonatal mortality by gestational age in days in infants born at term: A cohort study in Sao Paulo city, Brazil.

Birth at term comprises a period with heterogeneous neonatal outcomes that tend to be worse for infants born earlier. However, few studies have analyzed this period, in which each day can make a difference. Therefore, we aim to assess neonatal mortality (NM) according to gestational age (GA) at birth measured in days in term liveborn infants born in 2012-2017 in São Paulo, the largest city in Latin America. This population-based cohort study assessed term liveborn infants followed until the end of the neonatal period. We analyzed 7 models for NM according to GA in days: crude NM adjusted for maternal and prenatal variables, NM additionally adjusted for type of birth and type of hospital, and adjusted NM stratified by type of birth (cesarean and vaginal) and by type of hospital (public and private). We included 440,119 live infants born at 259-293 days of gestation. The median GA at birth was 274 days. In all models, NM was higher for infants born early term, decreasing in infants born full term and rising again in infants born late term. In the unadjusted model, hazard ratios of NM changed daily, decreasing from 3.34 to 1.00 on day 278 and increasing again thereafter. In the stratified analysis according to type of hospital, being born in a public hospital was associated with a reduced risk of NM for infants born at 278-283 days of pregnancy. There was a decrease in GA related to obstetric interventions, especially cesarean sections, which increased NM. The loss of days of pregnancy was larger in private hospitals. Increasing the granularity of GA to days is feasible and has the potential to drive public policies. To the best of our knowledge, this is the first Brazilian study on GA in days using a national live births database.

Effect of Pd2Spermine on Mice Brain-Liver Axis Metabolism Assessed by NMR Metabolomics.

Cisplatin (cDDP)-based chemotherapy is often limited by severe deleterious effects (nephrotoxicity, hepatotoxicity and neurotoxicity). The polynuclear palladium(II) compound Pd2Spermine (Pd2Spm) has emerged as a potential alternative drug, with favorable pharmacokinetic/pharmacodynamic properties. This paper reports on a Nuclear Magnetic Resonance metabolomics study to (i) characterize the response of mice brain and liver to Pd2Spm, compared to cDDP, and (ii) correlate brain-liver metabolic variations. Multivariate and correlation analysis of the spectra of polar and lipophilic brain and liver extracts from an MDA-MB-231 cell-derived mouse model revealed a stronger impact of Pd2Spm on brain metabolome, compared to cDDP. This was expressed by changes in amino acids, inosine, cholate, pantothenate, fatty acids, phospholipids, among other compounds. Liver was less affected than brain, with cDDP inducing more metabolite changes. Results suggest that neither drug induces neuronal damage or inflammation, and that Pd2Spm seems to lead to enhanced brain anti-inflammatory and antioxidant mechanisms, regulation of brain bioactive metabolite pools and adaptability of cell membrane characteristics. The cDDP appears to induce higher extension of liver damage and an enhanced need for liver regeneration processes. This work demonstrates the usefulness of untargeted metabolomics in evaluating drug impact on multiple organs, while confirming Pd2Spm as a promising replacement of cDDP.

Unravelling Potential Health-Beneficial Properties of Corema album Phenolic Compounds: A Systematic Review.

Corema (C.) album belongs to the family Ericaceae and can be found in the Iberian Peninsula, especially on the coastal areas facing the Atlantic coast. C. album berries have been used for centuries in traditional medicine. Recent studies have revealed that not only the berries but also the leaves have relevant antioxidant, antiproliferative, and anti-inflammatory properties, bringing this plant to the forefront of discussion. A systematic review of the literature was carried out to summarize the phenolic compounds and bioactive properties identified in C. album berries and leaves and to search for research gaps on this topic. The search was conducted in three electronic databases (PubMed, SCOPUS, and Web of Science) using PRISMA methodology. The inclusion criteria were the chemical compositions of the berries, leaves, or their extracts and their bioactive properties. The exclusion criteria were agronomic and archaeological research. The number of studies concerning phenolic compounds' composition and the bioactive properties of C. album berries and leaves is still limited (11 articles). However, the variety of polyphenolic compounds identified make it possible to infer new insights into their putative mechanism of action towards the suppression of NF-kB transcription factor activation, the modulation of inflammatory mediators/enzymes, the induction of apoptosis, the modulation of mitogen activated protein kinase, cell cycle arrest, and the reduction of oxidative stress. These factors can be of major relevance concerning the future use of C. album as nutraceuticals, food supplements, or medicines. Nevertheless, more scientific evidence concerning C. album's bioactivity is required.

Protein Hydrolysates from Brewing By-Products as Natural Alternatives to ACE-Inhibitory Drugs for Hypertension Management.

The treatment of hypertension is of major importance to reduce the risk of cardiovascular disease, the leading cause of death worldwide. Angiotensin-converting enzyme (ACE) inhibitors are anti-hypertensive drugs associated with several side effects. Natural products, namely bioactive peptides from brewing by-products, brewers' spent grain (BSG), and yeast (BSY), are promising alternatives since they can inhibit ACE in vitro. However, the oral intake of these peptides may modify their expected inhibitory effect owing to possible changes in active peptides' bioavailability, which have not been assessed so far. The goal of this study was to simulate oral administration to evaluate BSG/BSY peptides' effectiveness by submitting protein hydrolysates sequentially to simulated gastrointestinal digestion, intestinal absorption (Caco-2 cells), and liver metabolism (HepG2 cells). MTT assay was used to assess BSG/BSY protein hydrolysates safeness. The ACE-inhibitory potential of initial and final protein hydrolysates (BSY, BSG, and a new product, MIX) were tested using a fluorometric assay and compared with captopril (1 µM, an ACE-inhibitory drug). Simulation of oral administration greatly increased BSY and MIX protein hydrolysates' ACE-inhibitory capacity, though final MIX and BSG revealed greater ACE-inhibitory potential than captopril. Notwithstanding, all final protein hydrolysates presented ACE-inhibitory capacity, thus being promising compounds to manage hypertension.

Elevated Vascular Sympathetic Neurotransmission and Remodelling Is a Common Feature in a Rat Model of Foetal Programming of Hypertension and SHR.

Hypertension is of unknown aetiology, with sympathetic nervous system hyperactivation being one of the possible contributors. Hypertension may have a developmental origin, owing to the exposure to adverse factors during the intrauterine period. Our hypothesis is that sympathetic hyperinnervation may be implicated in hypertension of developmental origins, being this is a common feature with essential hypertension. Two-animal models were used: spontaneously hypertensive rats (SHR-model of essential hypertension) and offspring from dams exposed to undernutrition (MUN-model of developmental hypertension), with their respective controls. In adult males, we assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), sympathetic nerve function (3H-tritium release), sympathetic innervation (immunohistochemistry) and vascular remodelling (histology). MUN showed higher SBP/DBP, but not HR, while SHR exhibited higher SBP/DBP/HR. Regarding the mesenteric arteries, MUN and SHR showed reduced lumen, increased media and adventitial thickness and increased wall/lumen and connective tissue compared to respective controls. Regarding sympathetic nerve activation, MUN and SHR showed higher tritium release compared to controls. Total tritium tissue/tyrosine hydroxylase detection was higher in SHR and MUN adventitia arteries compared to respective controls. In conclusion, sympathetic hyperinnervation may be one of the contributors to vascular remodelling and hypertension in rats exposed to undernutrition during intrauterine life, which is a common feature with spontaneous hypertension.

Corema album Leaves Mediate DNA Damage in Triple-Negative Breast Cancer Cells.

Corema (C.) album is a shrub endemic to the Atlantic coast and has been described as yielding beneficial effects for human health. Nevertheless, studies concerning the bioactivity of C. album leaves are scarce. This study aims at investigating the anticancer potential and mode of action, of an hydroethanolic extract of C. album leaves (ECAL) on triple-negative breast cancer. This is a poor survival breast cancer subtype, owing to its high risk of distant reappearance, metastasis rates and the probability of relapse. The ECAL ability to prevent tumor progression through (i) the inhibition of cell proliferation (cell viability); (ii) the induction of apoptosis (morphological changes, TUNEL assay, caspase-3 cleaved) and (iii) the induction of DNA damage (PARP1 and γH2AX) with (iv) the involvement of NF-κB and of ERK1/2 pathways (AlphaScreen assay) was evaluated. ECAL activated the apoptotic pathway (through caspase-3) along with the inhibition of ERK and NF-κB pathways causing DNA damage and cell death. The large polyphenolic content of ECAL was presumed to be accountable for these effects. The extract of C. album leaves can target multiple pathways and, thus, can block more than one possible means of disease progression, evidencing the anticancer therapeutic potential from a plant source.

Measuring harm-free care in childbirth: a pilot application of the maternity safety thermometer in Brazil

Introduction: In Brazil, interventions during labor and childbirth are harmful and, for the most part, unnecessary. In addition, there is a high prevalence of abuse and disrespect for women and babies during this period. Objective: To describe the prevalence of maternal and neonatal harm and harm-free care in a Brazilian maternity setting. Methods: Pilot application of the Portuguese version of Maternal Safety Thermometer (MST) by a cross-sectional study in a public setting. Data collection was made at two timepoints. Results: 140 women were included. Over 84% of women had a postpartum sutured wound, resulting from a caesarean section, an episiotomy, or a perineal trauma. Puerperal infection, especially on a caesarean wound, was the most frequent physical harm. Women's perception of safety, including being left alone in labour, and feeling their safety concerns were not taken seriously, decreased from 80.6% to 43.3% in the second timepoint. Using the MST helped to improve the quality of medical records since critical information about a patient's health status was not properly recorded, or even absent. Conclusion: MST is a concise tool and includes indicators related to harm-free care in a short time range. However, this study suggests that the MST can underestimate harm if it is used alone to assess harm-free care in maternities with excessive levels of intervention, and poor reporting of harms (i.e., blood loss), as in most Brazilian settings.

Introdução: No Brasil, as intervenções durante o parto e o nascimento são prejudiciais e, em sua maioria, desnecessárias. Além disso, é alta a prevalência de abusos e desrespeito à mulher e ao bebê neste período. Objetivo: Descrever a prevalência dos danos maternos e neonatais, e do cuidado livre de danos em uma maternidade brasileira. Método: Estudo transversal, com aplicação piloto, em português, do Termômetro de Segurança da Maternidade (TSM) em uma instituição pública. A coleta de dados foi realizada em dois momentos. Resultados: 140 mulheres foram incluídas. Mais de 84% delas deixaram a maternidade com algum tipo de ferida suturada, resultante de cesariana, episiotomia ou outro trauma perineal. Infecção puerperal, principalmente na incisão da cesariana, foi o dano físico mais frequente. A percepção de segurança das mulheres ­ incluindo ficar sozinha no trabalho de parto e sentir que suas preocupações com relação à segurança não foram consideradas ­ diminuiu de 80,6% para 43,3% no segundo momento. O uso do TSM ajudou a melhorar a qualidade dos registros em prontuário, dado que, informações importantes sobre a condição das pacientes não eram registradas adequadamente ou estiveram ausentes. Conclusão: O TSM é uma ferramenta concisa que possibilita descrever o cuidado livre de danos rapidamente. No entanto, este estudo sugere que, se usado isoladamente, o TSM pode subestimar danos em serviços com níveis excessivos de intervenção e com registros inadequados de danos (exemplo, perda sanguínea), como é o caso da maioria das maternidades brasileiras.

Metabolic Impact of Anticancer Drugs Pd2Spermine and Cisplatin on the Brain of Healthy Mice.

The new palladium agent Pd2Spermine (Spm) has been reported to exhibit promising cytotoxic properties, while potentially circumventing the known disadvantages associated to cisplatin therapeutics, namely acquired resistance and high toxicity. This work presents a nuclear magnetic resonance (NMR) metabolomics study of brain extracts obtained from healthy mice, to assess the metabolic impacts of the new Pd2Spm complex in comparison to that of cisplatin. The proton NMR spectra of both polar and nonpolar brain extracts were analyzed by multivariate and univariate statistics, unveiling several metabolite variations during the time course of exposition to each drug (1-48 h). The distinct time-course dependence of such changes revealed useful information on the drug-induced dynamics of metabolic disturbances and recovery periods, namely regarding amino acids, nucleotides, fatty acids, and membrane precursors and phospholipids. Putative biochemical explanations were proposed, based on existing pharmacokinetics data and previously reported metabolic responses elicited by the same metal complexes in the liver of the same animals. Generally, results suggest a more effective response of brain metabolism towards the possible detrimental effects of Pd2Spm, with more rapid recovery back to metabolites' control levels and, thus, indicating that the palladium drug may exert a more beneficial role than cDDP in relation to brain toxicity.

Fetal Undernutrition Modifies Vascular RAS Balance Enhancing Oxidative Damage and Contributing to Remodeling.

Fetal stress is known to increase susceptibility to cardiometabolic diseases and hypertension in adult age in a process known as fetal programming. This study investigated the relationship between vascular RAS, oxidative damage and remodeling in fetal programming. Six-month old Sprague-Dawley offspring from mothers that were fed ad libitum (CONTROL) or with 50% intake during the second half of gestation (maternal undernutrition, MUN) were used. qPCR or immunohistochemistry were used to obtain the expression of receptors and enzymes. Plasma levels of carbonyls were measured by spectrophotometry. In mesenteric arteries from MUN rats we detected an upregulation of ACE, ACE2, AT1 receptors and NADPH oxidase, and lower expression of AT2, Mas and MrgD receptors compared to CONTROL. Systolic and diastolic blood pressure and plasma levels of carbonyls were higher in MUN than in CONTROL. Vascular morphology evidenced an increased media/lumen ratio and adventitia/lumen ratio, and more connective tissue in MUN compared to CONTROL. In conclusion, fetal undernutrition indices RAS alterations and oxidative damage which may contribute to the remodeling of mesenteric arteries, and increase the risk of adverse cardiovascular events and hypertension.

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice.

Pd2Spm is a dinuclear palladium(II)-spermine chelate with promising anticancer properties against triple-negative breast cancer (TNBC), a breast carcinoma subset with poor prognosis and limited treatment options. The present study evaluated the in vitro and in vivo anticancer effects of Pd2Spm compared to the reference metal-based drug cisplatin. Triple-negative breast cancer MDA-MB-231 cells, non-cancerous MCF-12A breast cells and chorioallantoic membrane (CAM) assay were used for antiproliferative, antimigratory and antiangiogenic studies. For an in vivo efficacy study, female CBA nude mice with subcutaneously implanted MDA-MB-231 breast tumors were treated with Pd2Spm (5 mg/kg/day) or cisplatin (2 mg/kg/day) administered intraperitoneally during 5 consecutive days. Promising selective antiproliferative activity of Pd2Spm was observed in MDA-MB-231 cells (IC50 values of 7.3-8.3 µM), with at least 10-fold lower activity in MCF-12A cells (IC50 values of 89.5-228.9 µM). Pd2Spm inhibited the migration of MDA-MB-231 cells, suppressed angiogenesis in CAM and decreased VEGF secretion from MDA-MB-231 cells with similar potency as cisplatin. Pd2Spm-treated mice showed a significant reduction in tumor growth progression, and tumors evidenced a reduction in the Ki-67 proliferation index and number of mitotic figures, as well as increased DNA damage, similar to cisplatin-treated animals. Encouragingly, systemic toxicity (hematotoxicity and weight loss) observed in cisplatin-treated animals was not observed in Pd2Spm-treated mice. The present study reports, for the first time, promising cancer selectivity, in vivo antitumor activity towards TNBC and a low systemic toxicity of Pd2Spm. Thus, this agent may be viewed as a promising Pd(II) drug candidate for the treatment of this type of low-prognosis neoplasia.