RESUMO
BACKGROUND: Patients with advanced-stage epithelial ovarian cancer (EOC) receive treatment with a poly-ADP ribose-polymerase (PARP) inhibitor (PARPi) as maintenance therapy after surgery and chemotherapy. Unfortunately, many patients experience disease progression because of acquired therapy resistance. This study aims to characterize epigenetic and genomic changes in cell-free DNA (cfDNA) associated with PARPi resistance. MATERIALS AND METHODS: Blood was taken from 31 EOC patients receiving PARPi therapy before treatment and at disease progression during/after treatment. Resistance was defined as disease progression within 6 months after starting PARPi and was seen in fifteen patients, while sixteen patients responded for 6 to 42 months. Blood cfDNA was evaluated via Modified Fast Aneuploidy Screening Test-Sequencing System (mFast-SeqS to detect aneuploidy, via Methylated DNA Sequencing (MeD-seq) to find differentially methylated regions (DMRs), and via shallow whole-genome and -exome sequencing (shWGS, exome-seq) to define tumor fractions and mutational signatures. RESULTS: Aneuploid cfDNA was undetectable pre-treatment but observed in six patients post-treatment, in five resistant and one responding patient. Post-treatment ichorCNA analyses demonstrated in shWGS and exome-seq higher median tumor fractions in resistant (7% and 9%) than in sensitive patients (7% and 5%). SigMiner analyses detected predominantly mutational signatures linked to mismatch repair and chemotherapy. DeSeq2 analyses of MeD-seq data revealed three methylation signatures and more tumor-specific DMRs in resistant than in responding patients in both pre- and post-treatment samples (274 vs. 30 DMRs, 190 vs. 57 DMRs, Χ2-test p < 0.001). CONCLUSION: Our genome-wide Next-Generation Sequencing (NGS) analyses in PARPi-resistant patients identified epigenetic differences in blood before treatment, whereas genomic alterations were more frequently observed after progression. The epigenetic differences at baseline are especially interesting for further exploration as putative predictive biomarkers for PARPi resistance.
Assuntos
Carcinoma Epitelial do Ovário , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Resistencia a Medicamentos Antineoplásicos/genética , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Idoso , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Adulto , Aneuploidia , Genômica/métodosRESUMO
BACKGROUND: Knowledge of quality-of-life after cytoreductive surgery is important to counsel patients with advanced-stage epithelial ovarian cancer prior to surgery. The aim of this study was to determine whether the use of the PlasmaJet Surgical device during cytoreductive surgery has an effect on the quality-of-life of patients with advanced epithelial ovarian cancer. METHODS: Data included in this prospective observational study were derived from the PlaComOv study, in which patients with advanced epithelial ovarian cancer were randomly assigned to have cytoreductive surgery with or without adjuvant use of the PlasmaJet. Quality-of-life was measured before surgery and one, six, 12, and 24 months after surgery with three questionnaires: the EORTC QLQ-C30, QLQ-OV28, and EQ-5D-5L. RESULTS: Between 2018 and 2020, 326 patients were enrolled in the trial. The overall response rate was high, with the lowest response rate at 24 months of 77%. At 6 months, quality-of-life was higher in the intervention group (95%CI 0.009; 0.081, p = 0.045). At 12 months, quality-of-life was higher in the intervention group with fewer symptoms of fatigue, appetite loss, and diarrhea (95%CI 0.6; 10,0, p = 0.027); similarly, patients in the intervention group reported a better body image (95%CI -14.2; -3.0, p = 0.003) and a higher score on the visual analog scale (95%CI 1.99; 11.15, p = 0.005). At 24 months postoperatively, no further difference was found between the two groups except for pain (95%CI -12.9; -0.8, p = 0.027) and body image (95%CI -13.808; -0.733, p = 0.029). A higher quality-of-life in the intervention group was partially explained by the mediator 'surgery outcome'. CONCLUSIONS: This study demonstrated knowledge of patients' quality-of-life until two years after cytoreductive surgery. The use of the PlasmaJet Surgical device during cytoreductive surgery leads to a higher quality-of-life than conventional surgery with electrocoagulation alone. Even after adjustment for the mediator of surgical outcome, a higher quality-of-life was seen in patients who had surgery with the use of the PlasmaJet device.
RESUMO
Background: Improved Pregnancy Outcomes via Early Detection (IMPROvED) is a multi-centre, European phase IIa clinical study. The primary aim of IMPROvED is to enable the assessment and refinement of innovative prototype preeclampsia risk assessment tests based on emerging biomarker technologies. Here we describe IMPROvED's profile and invite researchers to collaborate. Methods: A total of 4,038 low-risk nulliparous singleton pregnancies were recruited from maternity units in Ireland (N=1,501), United Kingdom (N=1,108), The Netherlands (N=810), and Sweden (N=619) between November 2013 to August 2017. Participants were interviewed by a research midwife at ~11 weeks (optional visit), ~15 weeks, ~20 weeks, ~34 weeks' gestation (optional visit), and postpartum (within 72-hours following delivery). Findings to date: Clinical data included information on maternal sociodemographic, medical history, and lifestyle factors collected at ~15 weeks' gestation, and maternal measurements, collected at each study visit. Biobank samples included blood, urine, and hair collected at each study visit throughout pregnancy in all units plus umbilical cord/blood samples collected at birth in Ireland and Sweden. A total of 74.0% (N=2,922) had an uncomplicated pregnancy, 3.1% (N=122) developed preeclampsia, 3.6% (N=143) had a spontaneous preterm birth, and 10.5% (N=416) had a small for gestational age baby. We evaluated a panel of metabolite biomarkers and a panel of protein biomarkers at 15 weeks and 20 weeks' gestation for preeclampsia risk assessment. Their translation into tests with clinical application, as conducted by commercial entities, was hampered by technical issues and changes in test requirements. Work on the panel of proteins was abandoned, while work on the use of metabolite biomarkers for preeclampsia risk assessment is ongoing. Future plans: In accordance with the original goals of the IMPROvED study, the data and biobank are now available for international collaboration to conduct high quality research into the cause and prevention of adverse pregnancy outcomes.
RESUMO
The current COVID-19 pandemic has affected societies across the world while its economic impact has cut deeper than any recession since the Second World War. Climate change is potentially an even more disruptive and complex global challenge. Climate change could cause social and economic damage far larger than that caused by COVID-19. The current pandemic has highlighted the extent to which societies need to prepare for disruptive global environmental crises. Although the dynamics of combating COVID-19 and climate change are different, the priorities for action are the same: behavioral change, international cooperation to manage shared challenges, and technology's role in advancing solutions. For a sustainable recovery from the COVID-19 crisis to be durable and resilient, a return to 'business as usual' and the subsequent often environmentally destructive economic activities must be avoided as they have significantly contributed to climate change. To avoid this, we draw lessons from the experiences of the waves of the COVID-19 pandemic and beyond to advance sustainable development.
RESUMO
Preeclampsia is a pregnancy-specific multiorgan disorder in which impaired placental functioning and excessive oxidative stress play an important role. We previously showed distinct differences between cerebrospinal fluid proteins in patients with preeclampsia and normotensive pregnant women. An additional group of nonpregnant women was included to study the presence of pregnancy-related proteins in normotensive and preeclamptic pregnancies and whether pregnancy-related proteins were associated with preeclampsia. Cerebrospinal fluid samples were tryptically digested and subsequently measured with a nano-LC-tribrid Orbitrap mass spectrometry system. Proteins were identified by shotgun proteomic analysis based on a data-dependent acquisition method. Proteins identified in preeclampsia, normotensive pregnant controls, and nonpregnant groups were compared to the Progenesis method according to the criteria as previously described and with a secondary analysis using a Scaffold method including Benjamini-Hochberg correction for multiple testing. For preeclampsia, the Progenesis and the Scaffold method together identified 15 (eight proteins for both analyses with one overlap) proteins that were significantly different compared to normotensive control pregnancies. Three of these 15 proteins, which were elevated in cerebrospinal fluid of preeclamptic women, were described to be pregnancy proteins with a calcium-binding function. Using two analysis methods (Progenesis and Scaffold), four out of 15 differential proteins were associated with pregnancy, as described in the literature. Three out of the four pregnancy-related proteins were elevated in preeclampsia. Furthermore, the contribution of elevated (n = 4/15) and downregulated (n = 2/15) calcium-binding proteins in preeclampsia is remarkably high (40%) and needs to be elucidated further.
RESUMO
PURPOSE: The objective of present study is to determine serum levels and placental distribution of two interacting proteins calcyclin and heat shock protein 90 in preeclampsia. EXPERIMENTAL DESIGN: Maternal serum levels of calcyclin and heat shock protein 90 are compared throughout pregnancy from the first trimester till term among women with preeclampsia (n = 43) and age-matched normotensive pregnant controls (n = 46). A serum-based 2D LC-MS assay using Parallel Reaction Monitoring is applied to quantify both calcyclin and heat shock protein 90. RESULTS: Serum levels of calcyclin are significantly lower in patients with preeclampsia in the second trimester of pregnancy as compared to controls (p < 0.05). Serum levels of heat shock protein 90 are significantly higher in patients with preeclampsia in the third trimester as compared to controls (p < 0.001). CONCLUSION AND CLINICAL RELEVANCE: Both interacting proteins calcyclin and heat shock protein 90 are notably changed in preeclamptic patients compared to controls. Calcyclin is already decreased before the onset of preeclampsia in the second trimester and HSP90 is strongly increased in the third trimester. This suggests that these proteins may play a role in the pathogenesis of preeclampsia and ought to be investigated in large cohort studies as molecular biomarkers.
Assuntos
Proteínas de Choque Térmico HSP90/sangue , Placenta/metabolismo , Pré-Eclâmpsia/sangue , Proteína A6 Ligante de Cálcio S100/sangue , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Espectrometria de Massas , Pré-Eclâmpsia/patologia , Gravidez , Proteômica , Trofoblastos/metabolismoRESUMO
OBJECTIVE: Preeclampsia is a severe hypertensive disorder of pregnancy which may lead to brain complications such as eclampsia. Visual symptoms are present in â¼25% of preeclamptic women suggesting the visual cortex to be altered during preeclampsia. Visual evoked potentials (VEPs) measure the functional neuronal integrity of the visual pathway from retina to the occipital cortex of the brain. The objective of this study was to compare neurophysiological changes in women with preeclampsia and other hypertensive disorders of pregnancy, using VEPs. We hypothesized that women with preeclampsia and other hypertensive disorders of pregnancy develop abnormal latency and amplitude of VEPs as compared with normotensive pregnant women. METHODS: We performed a prospective observational study in 15 women with mild preeclampsia, 33 with severe preeclampsia (sPE), eight women with chronic hypertension, nine with pregnancy-induced hypertension, and 29 normotensive pregnant women. VEP measurements were made at four different time points of gestation (12-14 weeks, 26-28 weeks, 32-34 weeks, 36-40 weeks) and 6-8 weeks postpartum. RESULTS: We defined reference values for normotensive pregnant women. Normotensive pregnant women had a shorter latency during pregnancy compared to their postpartum value (Pâ=â0.005). Women with sPE had a prolonged latency of VEPs compared with normotensive pregnant women (Pâ=â0.006), a difference that disappeared postpartum. CONCLUSION: Our study showed neurophysiological adaptation to pregnancy of the visual cortex in normotensive pregnant women, that seemed to be absent in women with sPE. The study groups of women with chronic hypertension and pregnancy-induced hypertension were to small to draw any conslusions from.
Assuntos
Potenciais Evocados Visuais , Hipertensão/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Adulto , Pressão Sanguínea , Estudos de Casos e Controles , Feminino , Idade Gestacional , Humanos , Período Pós-Parto , Gravidez , Estudos Prospectivos , Valores de Referência , Adulto JovemRESUMO
PURPOSE: To investigate the cerebrospinal fluid (CSF) proteome of patients with preeclampsia (PE) and normotensive pregnant women, in order to provide a better understanding of brain involvement in PE. EXPERIMENTAL DESIGN: Ninety-eight CSF samples (43 women with PE and 55 normotensive controls) were analyzed by LC-MS/MS proteome profiling. CSF was obtained during the spinal puncture before caesarean delivery. RESULTS: Eight proteins were higher abundant and 17 proteins were lower abundant in patients with PE. The most significantly differentially abundant protein was protein AMBP (alpha-1-microglobulin/bikunin precursor). This finding was validated by performing an ELISA experiment (p = 0.002). CONCLUSIONS AND CLINICAL RELEVANCE: The current study showed a clear difference between the protein profiles of CSF from patients with PE and normotensive pregnant women. Protein AMBP is a precursor of a heme-binding protein that counteracts the damaging effects of free hemoglobin, which may be related to the presence of free hemoglobin in CSF. Protein levels showed correlations with clinical symptoms during pregnancy and postpartum. To our knowledge, this is the first LC-MS/MS proteome profiling study on a unique set of CSF samples from (severe) preeclamptic patients and normotensive pregnant women.
Assuntos
alfa-Globulinas/líquido cefalorraquidiano , Pré-Eclâmpsia/patologia , Adulto , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pré-Eclâmpsia/metabolismo , Gravidez , Proteoma/análise , Espectrometria de Massas em TandemRESUMO
Pre-eclampsia (PE) complicates 2%-8% of all pregnancies and is an important cause of perinatal morbidity and mortality worldwide. In order to reduce these complications and to develop possible treatment modalities, it is important to identify women at risk of developing PE. The use of biomarkers in early pregnancy would allow appropriate stratification into high and low risk pregnancies for the purpose of defining surveillance in pregnancy and to administer interventions. We used formal methods for a systematic review and meta-analyses to assess the accuracy of all biomarkers that have been evaluated so far during the first and early second trimester of pregnancy to predict PE. We found low predictive values using individual biomarkers which included a disintegrin and metalloprotease 12 (ADAM-12), inhibin-A, pregnancy associated plasma protein A (PAPP-A), placental growth factor (PlGF) and placental protein 13 (PP-13). The pooled sensitivity of all single biomarkers was 0.40 (95% CI 0.39-0.41) at a false positive rate of 10%. The area under the Summary of Receiver Operating Characteristics Curve (SROC) was 0.786 (SE 0.02). When a combination model was used, the predictive value improved to an area under the SROC of 0.893 (SE 0.03). In conclusion, although there are multiple potential biomarkers for PE their efficacy has been inconsistent and comparisons are difficult because of heterogeneity between different studies. Therefore, there is an urgent need for high quality, large-scale multicentre research in biomarkers for PE so that the best predictive marker(s) can be identified in order to improve the management of women destined to develop PE.
Assuntos
Pré-Eclâmpsia/diagnóstico , Proteínas ADAM/análise , Proteína ADAM12 , Biomarcadores/análise , Feminino , Galectinas/análise , Humanos , Inibinas/análise , Proteínas de Membrana/análise , Fator de Crescimento Placentário , Gravidez , Proteínas da Gravidez/análise , Proteína Plasmática A Associada à Gravidez/análiseRESUMO
Os autores fazem uma revisão bibliográfica sobre disfonias neurológica, suas definições incidência, fisiopatologia, manifestações clinicas, diagnostico e tratamento.
Assuntos
Humanos , Distúrbios da Voz/classificação , Distúrbios da Voz/diagnóstico , Distúrbios da Voz/etnologia , Distúrbios da Voz/terapiaRESUMO
This study assessed the safety and efficacy of early discharge after percutaneous coronary intervention (PCI) using 5Fr guiding catheters with a femoral approach in 100 patients undergoing elective coronary stenting. Patients were treated with aspirin and thienopyridines for 72 hours before PCI, and unfractionated heparin 70 IU/kg (< or = 5,000 IU) intravenously after arterial puncture. PCI was performed by femoral access using 5Fr guiding catheters and immediate postprocedural arterial sheath removal. Patients were discharged within 8 to 12 hours. No closure devices were used. Early discharge using 5Fr catheters was successful in 97% of cases. No deaths, myocardial infarction, or vascular complications occurred at 24 hours and 30 days.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Angioplastia Coronária com Balão/métodos , Tempo de Internação , Alta do Paciente , Stents , Idoso , Aspirina/administração & dosagem , Estudos de Viabilidade , Feminino , Heparina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Estudos Prospectivos , Piridinas/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
A ototoxicidade secundária ao uso de medicações é um acontecimento presente na prática médica diária e que deve ser evitada. Para tal, torna-se imprescindível o conhecimento das drogas potencialmente tóxicas à orelha interna, bem como a detecção precoce dos danos por elas provocados. Este artigo tem como objetivo destacar os fármacos de maior impacto no desenvolvimento de ototoxicidade, bem como sugerir medidas para sua prevenção
Assuntos
Masculino , Feminino , Humanos , Orelha Interna , Orelha Interna/lesões , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Doenças do Labirinto/induzido quimicamente , Doenças do Labirinto/tratamento farmacológico , Otopatias/induzido quimicamente , Otopatias/tratamento farmacológicoRESUMO
O artigo tem por objetivo revisar os diferentes métodos para o diagnóstico de infecção urogenital por Chlamydia trachomatis. O método utilizado foi à revisão de literatura médica especializada e concluiu-se que na escolha do método diagnóstico deve-se considerar a sensibilidade e especificidade da técnica pretendida, a individualidade do caso e a adequação aos recursos disponíveis. O exame cultural para Chlamydia trachomati constitui-se no teste padrão, por apresentar a melhor especificidade na detecção da infecção. Entretanto, estudos recentes sugerem que as técnicas de amplificação de ácido nucléico têm demonstrado maior sensibilidade e especificidade semelhante ao teste cultural.
Assuntos
Humanos , Masculino , Feminino , Técnicas de Laboratório Clínico , Chlamydia trachomatis , Infecções por Chlamydia , Sistema UrogenitalRESUMO
O objetivo deste artigo é determinar o perfil da paciente atendida na Sala de Admissão do Hospital São Lucas da PUCRS (HSL). Sugerir rotinas de atendimento em nosso serviço a fim de dinamizar a atuação dos profissionais envolvidos no mesmo. O método utilizado foi o estudo de casos, retrospectivo, de 1065 pacientes atendidas na Sala de Admissão do Centro Obstétrico (CO) do HSL, entre os meses de Setembro e Outubro do ano 2001. Entre as 1065 pacientes estudadas, 86 eram gestantes. No total, 25,4 eram procedentes de Viamão, 69,8 de POA e 4,9 de outras procedências. A raça predominantes foi a branca, com 73,1 dos atendimentos. A média de idade foi de 24,82 anos. Da amostra estudada 82,1 mão apresentaram indicações para internação hospitalar, e 9,9 internaram por trabalho de parto, 3 por ruptura prematura das membranas, 0,5 para indução eletiva do parto, 1,2 por patologia materna, 0,3 por morte fetal e 3,1 por outras causas. O perfil desenhado acima nos fornece uma visão da realidade do nosso serviço, porém é preciso uma continuidade na coleta e armazenamento computadorizado dos dados e na sua análise, a fim de que rotinas elaboradas com maior precisão possam ser sugeridas para melhorar a dinâmica dos profissionais envolvidos no atendimento das gestantes.