Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

RASSF1A hypermethylation in pretreatment serum DNA of neuroblastoma patients: a prognostic marker

The tumour suppressor gene RASSF1A is known to be frequently silenced by promoter hypermethylation in neuroblastoma tumours. Here we explored the possible prognostic significance of aberrant promoter hypermethylation of RASSF1A in serum DNA samples of patients with neuroblastoma as a surrogate marker for circulating tumour cells. We analysed the methylation status of the RASSF1A gene in matched tumour and pretreatment serum DNA obtained from 68 neuroblastoma patients. Hypermethylation of RASSF1A in tumour samples was found in 64 patients (94%). In contrast, serum methylation of RASSF1A was observed in 17 patients (25%). Serum methylation of RASSF1A was found to be statistically associated with age ⩾12 months at diagnosis (P=0.002), stage 4 (P<0.001) and MYCN amplification (P<0.001). The influence of serum RASSF1A methylation on prognosis was found to be comparable with that of the currently most reliable marker, MYCN amplification on univariate analysis (hazard ratio, 9.2; 95% confidence interval (CI), 2.8–30.1; P<0.001). In multivariate analysis of survival, methylation of RASSF1A in serum had a hazard ratio of 2.4 (95% CI, 0.6–9.2), although this association did not reach statistical significance (P=0.194). These findings show that the methylation status of RASSF1A in the serum of patients with neuroblastoma has the potential to become a prognostic predictor of outcome

The ubiquitin proteasome system in neuropathology

The ubiquitin proteasome system (UPS) orchestrates the turnover of innumerable cellular proteins. In the process of ubiquitination the small protein ubiquitin is attached to a target protein by a peptide bond. The ubiquitinated target protein is subsequently shuttled to a protease complex known as the 26S proteasome and subjected to degradative proteolysis. The UPS facilitates the turnover of proteins in several settings. It targets oxidized, mutant or misfolded proteins for general proteolytic destruction, and allows for the tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. In neuropathology, alteration of the UPS, or mutations in UPS target proteins may result in signaling abnormalities leading to the initiation or progression of tumors such as astrocytomas, hemangioblastomas, craniopharyngiomas, pituitary adenomas, and medulloblastomas. Dysregulation of the UPS may also contribute to tumor progression by perturbation of DNA replication and mitotic control mechanisms, leading to genomic instability. In neurodegenerative diseases caused by the expression of mutant proteins, the cellular accumulation of these proteins may overload the UPS, indirectly contributing to the disease process, e.g., sporadic Parkinsonism and prion diseases. In other cases, mutation of UPS components may directly cause pathological accumulation of proteins, e.g., autosomal recessive Parkinsonism and spinocerebellar ataxias. Defects or dysfunction of the UPS may also underlie cognitive disorders such as Angelman syndrome, Rett syndrome and autism, and muscle and nerve diseases, e.g., inclusion body myopathy and giant axon neuropathy. This paper describes the basic biochemical mechanisms comprising the UPS and reviews both its theoretical and proven involvement in neuropathological diseases. The potential for the UPS as a target of pharmacological therapy is also discussed

A Novel ATM/TP53/p21-Mediated Checkpoint Only Activated by Chronic γ-Irradiation

Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decision remain elusive. Here we exposed cultured cells and mice to different doses and dose rates of γ-irradiation, which revealed cell-type-specific sensitivities to chronic, but not acute, γ-irradiation. Among tested cell types, human fibroblasts were associated with the highest levels of growth inhibition in response to chronic γ-irradiation. In this context, fibroblasts exhibited a reversible G1 cell-cycle arrest or an irreversible senescence-like growth arrest, depending on the irradiation dose rate or the rate of DNA damage. Remarkably, when the same dose of γ-irradiation was delivered chronically or acutely, chronic delivery induced considerably more cellular senescence. A similar effect was observed with primary cells isolated from irradiated mice. We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate. Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells. Together these results provide insights into the mechanisms governing cell-fate determination in response to different rates of DNA damage

LINFOMA DE CÉLULAS T HELPER FOLICULAR NODAL EM PACIENTE PEDIÁTRICO: RELATO DE CASO

Introdução: Os linfomas de células T são incomuns em crianças e adolescentes, e aqueles oriundos de células precursoras, como linfoma T linfoblástico, são os mais prevalentes. Os linfomas de células T periféricas, que perfazem 15% dos linfomas não-Hodgkin em adultos, são muito raros em pacientes pediátricos, representando cerca de 1% das neoplasias de células T nessa população. Assim, são um desafio diagnóstico e terapêutico na hematologia pediátrica, e o reconhecimento dessa entidade clínica é essencial para o manejo das neoplasias linfoides nessa faixa etária. Objetivo: Relatar um caso de linfoma T helper folicular nodal em idade pediátrica. Relato do caso: Menino, 11 anos, interna no Hospital de Clínicas de Porto Alegre em janeiro de 2024 por febre intermitente há 11 dias, associada a perda ponderal e sudorese noturna. Ao exame, emagrecido, com hepatoesplenomegalia. Hemograma com pancitopenia (hemoglobina 8,8 g/dL, leucócitos 1060/μL com 400 neutrófilos/μL, e plaquetas 59.000/μL) sem células jovens e LDH 289 U/L. Tomografias de tórax e abdome mostraram linfonodomegalias mediastinais e hilares confluentes (a maior sendo paratraqueal direita – 5,3 x 3,0 cm) além de retroperitoneais, principalmente em hilo esplênico. Havia esplenomegalia importante (baço de 18,9 x 13,9 x 6,2 cm, com imagens hipovasculares). Biópsia de linfonodo paratraqueal descreveu arquitetura linfonodal alterada pela proliferação de linfócitos pequenos e intermediários; análise imunohistoquímica foi positiva para CD5, CD7, CD4 e negativa para CD8, BCL6, CD10 e CD30, firmando o diagnóstico de linfoma de células T helper folicular nodal sem especificação, com índice proliferativo Ki67 de 30%. Avaliação medular negativa. Após 4 ciclos de CHOEP (ciclofosfamida-daunorrubicina-vincristina-etoposídeo-prednisona), paciente apresentava doença estável, com escore de Lugano 5 em PET-CT e infiltração de medula óssea por células do mesmo fenótipo daquelas encontradas no linfonodo ao diagnóstico. Iniciado protocolo ICE (ifosfamida-carboplatina-etoposídeo) e, em PET-CT após o segundo ciclo, paciente apresentou escore de Lugano 4 (resposta parcial). Discussão: Por sua raridade, os linfomas de células T periféricas são um diagnóstico diferencial desafiador em crianças e adolescentes – grupo com alta prevalência de doenças virais que mimetizam sintomas B, como infecção por vírus Epstein-Barr e citomegalovírus. Assim, a correlação clínica, patológica e imunohistoquímica é crucial. Quanto ao tratamento – amplamente baseado em regimes de quimioterapia citotóxica como o CHOEP, pensados para adultos – mostra-se fundamental a busca por terapias-alvo, almejando melhor sobrevida na população pediátrica. Em adultos, o uso de brentuximab vedotina (BV) em pacientes CD30-positivos, associado a ciclofosfamida, daunorrubicina e prednisona (CHP), demonstra maior sobrevida livre de progressão e sobrevida global. Conclusão: O diagnóstico preciso de linfomas de célula T, na era das terapias-alvo, tem implicação prognóstica e terapêutica. No cenário pediátrico, os linfomas de células T maduras, ainda que raros, apresentam desfechos pouco melhores do que em adultos. Ademais, recaída e refratariedade são comuns, e o melhor regime de tratamento nesses casos ainda não é definido. A preferência do transplante autólogo de células hematopoiéticas em relação ao alogênico se dá por melhor perfil de toxicidade e pela relação risco-benefício

AVALIAÇÃO DE CUSTO-EFETIVIDADE DO BLINATUMOMABE VERSUS QUIMIOTERAPIA CONVENCIONAL EM CRIANÇAS COM LEUCEMIA LINFOBLÁSTICA AGUDA RECIDIVANTE

Objetivos: Avaliar, com dados de mundo real, o custo-efetividade do Blinatumomabe em crianças com Leucemia Linfoblástica Aguda (LLA) B recidivante em comparação com a quimioterapia padrão. Este estudo visa fornecer dados comparáveis sobre a melhor alocação de recursos na ausência de informações sobre vantagem farmacoeconômica com dados de vida real e QALY do tratamento em crianças com LLA recidivante e imunoterapia no Brasil. Material e métodos: Estudo com amostra de conveniência de coorte retrospectivo com controle histórico desenvolvido no Hospital de Clínicas de Porto Alegre com dados de vida real. Critérios de inclusão: crianças (> 28 dias e < 18 anos) diagnosticadas com LLA B de alto risco em primeira recaída, tratadas de acordo com o protocolo IntReALL que incluiu indução e duas consolidações, seguidas de quimioterapia ou blinatumomabe. Os pacientes foram identificados através de banco de dados de pacientes da unidade de hematologia pediátrica. Foram incluídas 13 crianças, sendo 7 no braço intervenção (Blinatumomabe) e 6 no braço controle (quimioterapia) tratados na instituição. A análise farmacoeconômica foi baseada na eficiência, com a inclusão dos cálculos de custo. Para isso, utilizamos o modelo MARKOV com o uso do programa de computador TREEAGE. As variáveis analisadas foram os custos referentes a diária do paciente internado no hospital, os exames realizados, os medicamentos administrados, hemoterapia e insumos. Resultados: O Blinatumomabe mostrou-se mais eficaz que a quimioterapia em termos de QALY, com um ganho incremental de 3,22 anos de vida ajustados pela qualidade. Embora o Blinatumomabe tenha custo incremental de R$340.490,07, a análise de custo-efetividade indica que o Blinatumomabe é custo-efetivo em comparação à quimioterapia, com custo por QALY de R$ 105.742,26, valor abaixo do limite de custo-efetividade para o Brasil (R$ 126.742,56). Discussão: Apesar do custo mais elevado, o Blinatumomabe proporciona benefícios substanciais em anos de vida e qualidade de vida ajustada. A Razão de Custo-Efetividade Incremental e a Razão de Custo-Utilidade Incremental indicam que o Blinatumomabe é uma opção custo-efetiva, sendo uma preferível para pacientes que podem se beneficiar de anos adicionais de vida com melhor qualidade. Conclusão: Este estudo sugere que o tratamento com Blinatumomabe, apesar de ter custo imediato superior a quimioterapia convencional, proporciona benefícios significativos em termos de anos de vida adicionais e qualidade de vida ajustada. As razões de custo-efetividade incremental e custo-utilidade incremental destacam que o Blinatumomabe é uma opção custo-efetiva para o tratamento. Decisores de políticas de saúde podem considerar esses resultados para cálculo de impacto orçamentário e melhorias de médio e longo prazo na saúde pública

GENETIC POLYMORPHISMS RELATED TO PEG-ASPARAGINASE HYPERSENSITIVITY IN THE BRAZILIAN PEDIATRIC POPULATION

Introduction/Objective: PEG-Asparaginase (PEG-ASNase) is critical in treating pediatric acute lymphoblastic leukemia (ALL). However, hypersensitivity reactions and inactivations associated with ASNase are major patient challenges. The detection of single nucleotide polymorphisms (SNPs), which recognize, in advance, patients who will develop hypersensitivity to ASNase, would help to optimize treatment. To describe pharmacogenetic variations influencing hypersensitivity to PEG-ASNase and their correlation with our patient population. Material and methods: We conducted a prospective multicenter study involving ALL patients under 18 years old receiving PEG-ASNase. Genotyping was carried out for 6 SNPs, which are more frequently related to hypersensitivity in other populations, including GRIA1 rs4958351, NFACT2 rs6021191, MYBBP1A rs3809849, CNOT3 rs73062673, GR1A1 rs6890057 and HLA-DQB1 rs1694129. The tests were performed using custom TaqMan® SNP genotyping assays. Results: A total of 305 patients were included, with 10.8% experiencing clinical allergic reactions and (14.1%) patients with inactivation (ASNase activity 0.01). Discussion: Our analysis characterized the pharmacogenetic polymorphisms in our population, reflecting diversity similar to the general population. Despite the lack of correlation between the studied SNPs and allergic reactions observed in our sample, we encourage further exploration to identify additional SNPs associated with hypersensitivity. Conclusion: These findings lay the groundwork for future research to uncover new genetic predictors of hypersensitivity, which could contribute to the development of personalized treatment approaches and the prevention of allergic reactions