RESUMO
DNA repair protein RAD51 is a key player in the homologous recombination pathway. Upon DNA damage, RAD51 is transported into the nucleus by BRCA2, where it can repair DNA double-strand breaks. Due to the structural complexity and dynamics, researchers have not yet clarified the mechanistic details of every step of RAD51 recruitment and DNA repair. RAD51 possesses an intrinsic tendency to form oligomeric structures, which make it challenging to conduct biochemical and biophysical investigations. Here, for the first time, we report on the isolation and characterization of a human monomeric RAD51 recombinant form, obtained through a double mutation, which preserves the protein's integrity and functionality. We investigated different buffers to identify the most suitable condition needed to definitively stabilize the monomer. The monomer of human RAD51 provides the community with a unique biological tool for investigating RAD51-mediated homologous recombination, and paves the way for more reliable structural, mechanistic, and drug discovery studies.
Assuntos
Recombinação Homóloga , Neoplasias , Rad51 Recombinase , Proteínas Recombinantes , Humanos , Dano ao DNA , Reparo do DNA , Neoplasias/genética , Rad51 Recombinase/química , Rad51 Recombinase/genética , Rad51 Recombinase/isolamento & purificação , Mutação , Estabilidade Proteica , Domínios Proteicos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificaçãoRESUMO
In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. Todalam binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells in G2/M, induces cell death, and synergizes with vinblastine. The compound destabilizes microtubules by acting as a molecular plug that sterically inhibits the curved-to-straight conformational switch in the α-tubulin subunit, and by sequestering tubulin dimers into assembly incompetent oligomers. Our results describe for the first time the generation of a fully rationally designed small molecule tubulin inhibitor from a fragment, which displays a unique molecular mechanism of action. They thus demonstrate the usefulness of tubulin-binding fragments as valuable starting points for innovative antitubulin drug and chemical probe discovery campaigns.
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Moduladores de Tubulina , Tubulina (Proteína) , Morte Celular , Microtúbulos/metabolismo , Ligação Proteica , Tubulina (Proteína)/química , Moduladores de Tubulina/químicaRESUMO
To analyze the modifications of CD4 T cell, CD4/CD8 ratio, and serum levels of soluble CD14 (sCD14) in HIV/HCV-coinfected patients after treatment with direct anti-HCV antiviral agents. Consecutive cases of HIV/HCV-coinfected patients, attended at the University Hospital, who achieved sustained virological responses with interferon-free hepatitis C antiviral drugs, were analyzed. Thirty-five percent of patients (n = 39) had been diagnosed with liver cirrhosis. The evaluation criteria were changes in CD4 T-cell counts and percentages and inflammation (measured by serum sCD14 levels) or immune activation indexes (determined by CD4/CD8 ratio) from beginning anti-HCV therapy to 12 months later. One hundred twelve patients were included (87% male; median age, 54 years; median time from the infection diagnosis, 22 years; previous drug users, 87%). Significant increases in CD4 T cell count and percentage were detected only in individuals without liver cirrhosis. No significant differences in CD4/CD8 ratios or sCD14 levels were observed in patients with or without cirrhosis. The proportion of patients with less than 500 CD4 T cell/mm3 before therapy who achieved more than 500 CD4 T cell/mm3 after it increased only in the group without liver cirrhosis. The finding that CD4 T cell count and percentage were improved only in patients without liver cirrhosis supports the idea that treatment against HCV in HIV/HCV-coinfected patients is needed in the early phases of liver disease.
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Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Coinfecção/imunologia , Coinfecção/virologia , Infecções por HIV/virologia , Hepacivirus/imunologia , Receptores de Lipopolissacarídeos/sangue , Cirrose Hepática/imunologia , Contagem de Linfócito CD4/estatística & dados numéricos , Coinfecção/tratamento farmacológico , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Resposta Viral SustentadaRESUMO
Mexican Lake Chapala is used as water supply for human consumption. Consequently, water quality of this lake is of paramount importance for the lake's wellbeing. The contribution presented in this paper investigates monitoring and assessment of lake water quality using water quality index (WQI), metal chemical speciation, and multivariate statistical techniques. Descriptive statistics shows total metal concentrations undetected conferring the lake a healthy status. Dissolved Cd and Pb exceed criterion continuous concentration limit, whereas Zn is below this limit indicating that water quality is satisfactory for aquatic life. However, WQI indicates poor water quality attributed to failure of conductivity, total solids, nitrogen, and phosphates, due to industrial and agro-industrial effluents. Metal speciations indicate that the presence of low concentrations of dissolved metals reflect interactions with gills of fish through metal-biotic ligand complexes affecting water quality. Positive correlations are obtained between conductivity and nitrates, indicating that agricultural activities and fertilizer runoffs increase the conductivity and that the environmental state of lake is being altered by human activities. Factors F1 (31%), F2 (19%), and F3 (11%) represent 61% of variability; F1 and F2 corroborate the pressure exerted by pollutants related with fertilizers and agrochemicals; F3 contains Zn and Pb with positive loads attributed to influx of tourist visitors. Sites S4, S5, S6, and S9 are identified as the most environmentally affected by COD, Alk*, pH, Cl-, nitrites, phosphates, and TS. Multivariate techniques permit to conclude that environmental stress of Lake Chapala is caused by variables pertaining to agrochemical, fertilizers and municipal wastes.
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Metais Pesados , Poluentes Químicos da Água , Animais , Monitoramento Ambiental , Humanos , Lagos , Metais Pesados/análise , México , Poluentes Químicos da Água/análise , Qualidade da ÁguaRESUMO
AIMS: To assess the prevalence of urinary incontinence (UI) in a cohort of women attended in primary care gynecological and estimate the incidence and remission rates of UI symptoms at 1 year. METHODS: We performed a multicenter prospective cohort study of women attending eight primary care gynecological practices. Consecutive women attended for gynecological issues different from UI were invited to participate in the study by answering the International Consultation on Incontinence questionnaire-Short Form (ICIQ-UI-SF). Patients receiving treatment for UI, during pregnant, and postpartum were excluded. All women with UI symptoms (ICIQ-UI-SF > 0) wishing treatment were studied and treated following routine clinical practice. All women were invited to answer the same questionnaire by phone 1 year after inclusion. RESULTS: A total of 2,840 women answered the questionnaire; 1,188 (41.8%) had UI symptoms (ICIQ-UI-SF > 0). Accordingly, nearly half (44.9%) had mild UI symptoms. Treatment was requested by only 551/1,188 incontinent women (46.38%), being related to the severity of UI. At 1 year, 2,443 patients/2,840 (86.0%) were found and again responded to the ICIQ-UI-SF. At 1 year the incidence of UI was 5.3% (77 new cases of UI out of 1,652 with the initial ICIQ-UI-SF = 0) while the remission rate of UI among untreated women was 27.9% (144 with ICIQ-UI-SF = 0). CONCLUSIONS: Almost one half of women attended in primary care general gynecology practices have UI symptoms, with less than 50% requesting treatment. In these women, UI is a dynamic process with an incidence of 5.3% and a remission rate of 27.9% at 1 year. Neurourol. Urodynam. 36:1081-1085, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Ginecologia/estatística & dados numéricos , Remissão Espontânea , Incontinência Urinária/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Espanha/epidemiologia , Adulto JovemRESUMO
We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed anticancer efficacy in vivo. Here, we describe a second class of CDC42 inhibitors with favorable drug-like properties. Out of the 25 compounds here reported, compound 15 (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development.
Assuntos
Antineoplásicos , Proteína cdc42 de Ligação ao GTP , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/química , Humanos , Camundongos , Proteína cdc42 de Ligação ao GTP/antagonistas & inibidores , Proteína cdc42 de Ligação ao GTP/metabolismo , Linhagem Celular Tumoral , Descoberta de Drogas , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , FemininoRESUMO
OBJECTIVES: To evaluate the appropriateness of antimicrobial treatment and the risk factors for mortality in patients with negative blood cultures (BC), in order to evaluate whether this population would be a suitable target for antimicrobial stewardship (AMS) interventions. METHODS: A multicentre prospective cohort study of patients with negative BC in three Spanish hospitals between October 2018 and July 2019 was performed. The main endpoints were the appropriateness of antimicrobial treatment (evaluated by two investigators according to local guidelines) and 30-day mortality. Cox-regression was performed to estimate the association between variables and 30-day mortality. RESULTS: Of 1011 patients in whom BC was obtained, these were negative in 803 (79%) and were included; 30-day mortality was 9% (70 patients); antibiotic treatment was considered inappropriate in 299 (40%) of 747 patients evaluated at day 2, and in 266 (46%) of 573 at day 5-7. The variables independently associated with increased risk of 30-day mortality were higher age (HR 1.05; 95% CI 1.03-1.07), neoplasia (HR 2.73; 95% CI 1.64-4.56), antibiotic treatment in the 48 h prior to BC extraction (HR 2.06; 95% CI 1.23-3.43) and insufficient antibiotic coverage at day 2 after BC obtainment (HR 2.35; 95% CI 1.39-4.00). Urinary, catheter and biliary sources of infection were associated with lower risk (HR 0.40; 95% CI 0.20-0.81). CONCLUSIONS: Antimicrobial treatment is frequently inappropriate among patients with negative BC; insufficient antibiotic coverage at day 2 was associated with mortality. These results suggest that patients with negative BC are a suitable population for AS interventions. SUMMARY: Antimicrobial treatment in patients with negative blood culture was frequently inappropriate, and inappropriate coverage at day 2 was associated with increased risk of death. These data support the consideration of this population as a potential target for antimicrobial stewardship interventions.
Assuntos
Antibacterianos , Gestão de Antimicrobianos , Humanos , Antibacterianos/uso terapêutico , Estudos Prospectivos , Hemocultura , AntibioticoprofilaxiaRESUMO
The objective of the systematic review is to analyze the efficacy of direct-acting oral anticoagulants (DOAC) in the prophylaxis of thrombosis in antiphospholipid syndrome (APS). We searched for clinical trials, cohort studies and meta-analyses published from January 1, 2012 to September 30, 2022. Articles that analyzed the efficacy of DOAC in the prevention of thrombosis recurrence, with or without comparison with antivitamin K (VKA) drugs, were selected. DOACs, specifically rivaroxaban and apixaban, were significantly less effective than VKAs in preventing recurrence of thrombosis in patients with APS and prior arterial thrombosis or the concomitant presence of two or three different antiphospholipid antibodies. The proportion of patients with severe bleeding as side effect are similar in those treated with DOAC and with VKA. The results argue against the use of DOAC in the treatment of patients with thrombotic APS.
Assuntos
Síndrome Antifosfolipídica , Trombose , Humanos , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/tratamento farmacológico , Anticoagulantes/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Varfarina/uso terapêutico , Trombose/prevenção & controle , Trombose/complicações , Administração OralRESUMO
CDC42 GTPases (RHOJ, CDC42, and RHOQ) are overexpressed in multiple tumor types and activate pathways critical for tumor growth, angiogenesis, and metastasis. Recently, we reported the discovery of a novel lead compound, ARN22089, which blocks the interaction of CDC42 GTPases with specific downstream effectors. ARN22089 blocks tumor growth in BRAF mutant mouse melanoma models and patient-derived xenografts (PDXs) in vivo. ARN22089 also inhibits tumor angiogenesis in three-dimensional vascularized microtumor models in vitro. Notably, ARN22089 belongs to a novel class of trisubstituted pyrimidines. Based on these results, we describe an extensive structure-activity relationship of â¼30 compounds centered on ARN22089. We discovered and optimized two novel inhibitors (27, ARN25062, and 28, ARN24928), which are optimal back-up/follow-up leads with favorable drug-like properties and in vivo efficacy in PDX tumors. These findings further demonstrate the potential of this class of CDC42/RHOJ inhibitors for cancer treatment, with lead candidates ready for advanced preclinical studies.
Assuntos
Neoplasias , Proteínas rho de Ligação ao GTP , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Neovascularização Patológica , Quinases Ativadas por p21/metabolismo , Ligação ProteicaRESUMO
RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of N-acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 N-acylhydrazones. Screening against the RAD51-BRCA2 protein-protein interaction via ELISA assay afforded 10 inhibitors in the micromolar range. Further 19F NMR experiments revealed that 7 could bind RAD51 and be displaced by BRC4, suggesting an interaction in the same binding pocket of BRCA2. These results proved not only that ptDCC could be successfully applied on full-length oligomeric RAD51, but also that it could address the need of alternative strategies toward the identification of small-molecule PPI inhibitors.
RESUMO
Microtubules (MTs) are dynamic filaments of the cytoskeleton, which are formed by the polymerization of their building block tubulin. Perturbation of MT dynamics by MT-targeting agents (MTAs) leads to cell cycle arrest or cell death, a strategy that is pursued in chemotherapy. We recently performed a combined computational and crystallographic fragment screening approach and identified several tubulin-binding fragments. Here, we sought to capitalize on this study with the aim to demonstrate that low affinity tubulin-binding fragments can indeed be used as valuable starting points for the development of active, lead-like antitubulin small molecules. To this end, we report on a new, rationally designed series of 2-aminobenzimidazole derivatives that destabilize MTs by binding tubulin at the colchicine-binding site (CBS). We applied a fragment growing strategy by combining X-ray crystallography and computer-aided drug design. Preliminary structure-activity-relationship studies afforded compound 18 that inhibits HeLa cell viability with a submicromolar activity (IC50 of 0.9 µM). X-ray crystallography confirmed the compound pose in the CBS, while immunostaining experiments suggested a molecular mechanism of action alike classical CBS ligands with antimitotic and antitumor activity associated with MTs destabilization. This promising outcome underpins that our previously performed combined computational and crystallographic fragment screening approach provides promising starting points for developing new MTAs binding to the CBS of tubulin and, eventually, to further tubulin pockets.
Assuntos
Antineoplásicos , Colchicina , Antineoplásicos/química , Sítios de Ligação , Proliferação de Células , Colchicina/metabolismo , Células HeLa , Humanos , Microtúbulos/metabolismo , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/químicaRESUMO
Antibiotic stewardship programs (ASP) have already demonstrated clinical benefits. We aimed to describe the Point Prevalence Surveys (PPS) methodology implemented in our hospital as an efficient tool to guide ASP strategies. Annually repeated PPS were conducted from 2012 to 2019 at a 750-bed university hospital in South Spain. Key quality indicators and inappropriateness of antimicrobial treatment, defined strictly according to local guidelines, were described. Variables associated with inappropriate treatment were identified by bi/multivariable analysis. A total of 1,600 patients were included. We found that 49% of the prescriptions were inappropriate due to unnecessary treatment (14%), not first line drug recommended (14%), inadequate drug according to microbiological results (9%), unsuitable doses (8%), route (3%) or duration (7%). Samples collection presented a significant protective effect together with sepsis presentation at onset and intensive care unit admission. However, age, receiving an empirical treatment and an unknown or urinary source of the infections treated were independent risk factors for inappropriateness. Site and severity of infection were documented in medical charts by prescribers (75 and 61% respectively). PPS may allow identifying the main risk factors for inappropriateness. This simple methodology may be useful for ASP to select modifiable factors to be prioritized for targeted interventions.
RESUMO
Inhibition of intracellular N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity is a promising approach to manage the inflammatory response under disabling conditions. In fact, NAAA inhibition preserves endogenous palmitoylethanolamide (PEA) from degradation, thus increasing and prolonging its anti-inflammatory and analgesic efficacy at the inflamed site. In the present work, we report the identification of a potent, systemically available, novel class of NAAA inhibitors, featuring a pyrazole azabicyclo[3.2.1]octane structural core. After an initial screening campaign, a careful structure-activity relationship study led to the discovery of endo-ethoxymethyl-pyrazinyloxy-8-azabicyclo[3.2.1]octane-pyrazole sulfonamide 50 (ARN19689), which was found to inhibit human NAAA in the low nanomolar range (IC50 = 0.042 µM) with a non-covalent mechanism of action. In light of its favorable biochemical, in vitro and in vivo drug-like profile, sulfonamide 50 could be regarded as a promising pharmacological tool to be further investigated in the field of inflammatory conditions.
Assuntos
Amidoidrolases/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Tropanos/farmacologia , Amidoidrolases/metabolismo , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tropanos/síntese química , Tropanos/metabolismo , Tropanos/farmacocinéticaRESUMO
Personalized medicine and therapies represent the goal of modern medicine, as drug discovery strives to move away from one-cure-for-all and makes use of the various targets and biomarkers within differing disease areas. This approach, especially in oncology, is often undermined when the cells make use of alternative survival pathways. As such, acquired resistance is unfortunately common. In order to combat this phenomenon, synthetic lethality is being investigated, making use of existing genetic fragilities within the cancer cell. This Perspective highlights exciting targets within synthetic lethality, (PARP, ATR, ATM, DNA-PKcs, WEE1, CDK12, RAD51, RAD52, and PD-1) and discusses the medicinal chemistry programs being used to interrogate them, the challenges these programs face, and what the future holds for this promising field.
Assuntos
Mutações Sintéticas Letais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Genes BRCA2 , Humanos , Neoplasias/genética , Neoplasias/terapia , Poli(ADP-Ribose) Polimerases/genética , Medicina de Precisão , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Rad51 Recombinase/genéticaRESUMO
Aberrant expression ratio of Cl- transporters, NKCC1 and KCC2, is implicated in several brain conditions. NKCC1 inhibition by the FDA-approved diuretic drug, bumetanide, rescues core symptoms in rodent models and/or clinical trials with patients. However, bumetanide has a strong diuretic effect due to inhibition of the kidney Cl- transporter NKCC2, creating critical drug compliance issues and health concerns. Here, we report the discovery of a new chemical class of selective NKCC1 inhibitors and the lead drug candidate ARN23746. ARN23746 restores the physiological intracellular Cl- in murine Down syndrome neuronal cultures, has excellent solubility and metabolic stability, and displays no issues with off-target activity in vitro. ARN23746 recovers core symptoms in mouse models of Down syndrome and autism, with no diuretic effect, nor overt toxicity upon chronic treatment in adulthood. ARN23746 is ready for advanced preclinical/manufacturing studies toward the first sustainable therapeutics for the neurological conditions characterized by impaired Cl- homeostasis.
RESUMO
We disclose a novel class of 6-amino-tetrahydroquinazoline derivatives that inhibit human topoisomerase II (topoII), a validated target of anticancer drugs. In contrast to topoII-targeted drugs currently in clinical use, these compounds do not act as topoII poisons that enhance enzyme-mediated DNA cleavage, a mechanism that is linked to the development of secondary leukemias. Instead, these tetrahydroquinazolines block the topoII function with no evidence of DNA intercalation. We identified a potent lead compound [compound 14 (ARN-21934) IC50 = 2 µM for inhibition of DNA relaxation, as compared to an IC50 = 120 µM for the anticancer drug etoposide] with excellent metabolic stability and solubility. This new compound also shows ~100-fold selectivity for topoIIα over topoß, a broad antiproliferative activity toward cultured human cancer cells, a favorable in vivo pharmacokinetic profile, and the ability to penetrate the blood-brain barrier. Thus, ARN-21934 is a highly promising lead for the development of novel and potentially safer topoII-targeted anticancer drugs.
Assuntos
DNA Topoisomerases Tipo II/química , Quinidina/análogos & derivados , Inibidores da Topoisomerase II/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/química , DNA/metabolismo , Clivagem do DNA , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Meia-Vida , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Quinidina/química , Quinidina/metabolismo , Quinidina/farmacologia , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/farmacologiaRESUMO
Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Proteína BRCA2/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Rad51 Recombinase/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antineoplásicos/química , Proteína BRCA2/genética , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Descoberta de Drogas , Sinergismo Farmacológico , Recombinação Homóloga/efeitos dos fármacos , Humanos , Modelos Moleculares , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ftalazinas/química , Piperazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Mutações Sintéticas Letais/efeitos dos fármacosRESUMO
INTRODUCTION: Demographic and Health Surveys, widely used for estimation of fertility and reproductive health indicators in developing countries, remain underutilized for the study of pregnancy termination. This is partly due to most surveys not reporting the type of pregnancy termination, whether spontaneous or induced. Reproductive calendar data makes it possible to examine termination patterns according to contraceptive use at the time of pregnancy. Contraceptive failure is expected to increase the likelihood of induced abortion helping in the interpretation of reported termination patterns. MATERIALS AND METHODS: We use individual-level calendar data regarding 623,966 pregnancies to analyze levels and differentials in reported patterns of pregnancy termination by age, union status, and contraceptive use in 107 DHS surveys from 50 countries. From the estimates of the probability of pregnancy termination, we compute derived reproductive health indicators providing an assessment of what is driving the differences by comparison to the few surveys reporting the type of pregnancy termination. RESULTS: From our estimates, 10.9% of pregnancies do not end in live-birth and 63.7% of them are spontaneous terminations. Reported pregnancy termination is higher among women using contraceptives, consistent with expectations. Very low levels of reported PT in some countries, particularly in sub-Saharan Africa, suggests possible underreporting. Differential patterns emerging from cluster analysis and regional rates indicate high rates of pregnancy termination driven by induced abortion in countries from the Former Soviet Union and Asian countries with liberal laws. Most countries with restrictive abortion laws have low levels of reported termination. While the probabilities of pregnancy termination are higher at older ages, termination rates generally peak at younger ages due to higher conception rates. DISCUSSION: This is the first large comparative study of the patterns of reported pregnancy termination in DHS surveys. While we have explored the extent to which differences arise from spontaneous terminations or induced abortion, more research is needed regarding the determinants of reported pregnancy termination.
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Aborto Induzido/estatística & dados numéricos , Demografia/estatística & dados numéricos , Países em Desenvolvimento/estatística & dados numéricos , Saúde Global/estatística & dados numéricos , Aborto Induzido/tendências , Adolescente , Adulto , África Subsaariana , Ásia , Análise por Conglomerados , Comportamento Contraceptivo/estatística & dados numéricos , Serviços de Planejamento Familiar/estatística & dados numéricos , Feminino , Saúde Global/tendências , Humanos , Pessoa de Meia-Idade , Gravidez , U.R.S.S. , Adulto JovemRESUMO
In this paper intergenerational dimensions of reproductive behavior are studied within the context of the experience of a mid-sized Spanish town just before and during the demographic transition. Different indicators of reproduction are used in bivariate and multivariate approaches. Fertility shows a small, often statistically significant intergenerational dimension, with stronger effects working through women and their mothers than those stemming from the families of their husbands. These effects are materialized mainly through duration-related fertility variables, are singularly absent for variables such as age at first birth or birth intervals, and are much stronger in the case of firstborn daughters than with later siblings. There is a substantial increase in the strength of intergenerational effects during the course of the demographic transition, most visible in age at last birth and duration of reproduction (between women and their mothers), as well as in the effects working through the families of their husbands. These results underscore the on-going importance of biological dimensions of reproduction as well as the way attitudes toward reproduction are taught within the family. The changes identified in this study suggest that the transmission of values and attitudes became more important for reproductive outcomes during this period of demographic modernization.
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We used a pharmacophore hybridization strategy to combine key structural elements of merbarone and etoposide and generated new type II topoisomerase (topoII) poisons. This first set of hybrid topoII poisons shows promising antiproliferative activity on human cancer cells, endorsing their further exploration for anticancer drug discovery.