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Objetivo: Os microRNAs (miRNAs) são pequenos RNAs que não codificam proteínas e desempenham diversas funções na regulação gênica e têm sido extensivamente estudados em diversos tipos de câncer, incluindo leucemia linfoblástica aguda (LLA) e leucemia mieloide aguda (LMA). Assim, o presente estudo objetivou caracterizar 5 famílias de miRNAs, quanto aos níveis de expressão, genes alvos, funções e impactos associados a LLA e LMA. Materiais e métodos: Utilizou-se softwares de bioinformática, incluindo miRbase, para verificar a expressão dos miRNAs e a sua influência nas leucemias estudadas. ENCORI e Targetscan Human foram empregadas para identificação dos genes alvos dos miRNAs a fim de identificar sua relação com as fusões gênicas. Além disso, foi realizada uma busca na literatura para validar os dados de bioinformática. Resultados: As famílias miR-128, let-7, miR-223, miR-155, miR-203 estão relacionadas com LLA e LMA. Dessa forma, os genes parceiros escolhidos relacionados à leucemia linfoblástica aguda foram: ETV6::RUNX1; BCR::ABL1; TCF3::PBX1; KMT2A::AFF1 e os de Leucemia Mieloide Aguda: PML::RARA; RUNX1::RUNX1T1;CBFB::MYH11. Os miRNAs miR-128 e miR-203 apresentaram superexpressão em LLA, enquanto let-7, miR-223 e miR-155 foram superexpressos em LMA. Na investigação dos genes-alvo relacionadas com LLA foi verificado que RUNX1 é regulado por (miR-128-3p, miR-128-1-5p, miR-98-3p); ABL1 por (miR-98-3p, miR-203a-5p, miR-203a-3p.2); PBX1 por (let-7f-1-3p, miR-223-5p, miR-203b-3p); e AFF4/AFF1 por (miR-218-3p, let-7a-3p, miR-223-5p, miR-203a-3p.2, miR-203a-3p.1). Quanto aos genes-alvo relacionados à LMA, foi constatado que RARA é regulado por miR-128-3p, MYH11 por (miR-128-1-5p e miR-203b-3p); RUNX1T1 por (miR-98-5p, miR-223-5p, miR-155-3p, miR-203a-3p.1, miR-203a-3p.2). Esses dados foram validados na literatura, logo, ressalta-se quemiR-223-3p e o miR-155 regulam o gene RASA1, cuja a expressão está aumentada em casos de LMA FLT3::IDT+. Discussão: A desregulação dos miRNAs influencia diretamente no desenvolvimento e progressão do câncer. miR-128, expresso na LLA, inibe o crescimento, migração e metástase. Já miR-155, expresso na LMA, amplifica a população mieloide, sendo um biomarcador potencial para diagnóstico precoce de LMA em crianças. Ressalta-se ainda que miR-203, regulado positivamente na LLA, está ligado à fusão BCR::ABL1, característica da LMC e de alguns casos de LLA progenitora B com prognóstico ruim. O silenciamento de miR-203 leva à alta expressão de ABL1 ou BCR::ABL1, e sua restauração suprime a proliferação tumoral. Conclusão: O presente estudo evidencia a importância de explorar a influência dos miRNAs em LLA e LMA, em especial miR-128, miR-155 e miR-203, uma vez que essas biomoléculas, estão relacionadas no fusões gênicas, como BCR::ABL1 e apresentam funções oncogênicas e supressoras de tumor, sendo potenciais biomarcadores e alvos terapêuticos. Destaca-se ainda a importância de mais estudos acerca da relação dos miRNAs com as fusões gênicas a fim de elucidar seus mecanismos de ação.

Objetivo: A Leucemia Linfoblástica Aguda (LLA) é a neoplasia mais prevalente na infância, representando aproximadamente 80% das leucemias agudas, sendo assim uma doença complexa. Na maioria dos casos de LLA, a busca por alterações no conjunto cromossômico e pela presença de genes de fusões, nos centros oncológicos, torna-se o caminho mais assertivo para diagnosticar e entender as leucemias agudas. Diante disso, este estudo buscou realizar um levantamento epidemiológico e molecular das fusões mais recorrentes na LLA tipo B (LLA-B) e anormalidades cromossômicas (hiperdiploidia e hipodiploidia) entre os continentes. Materiais e métodos: Foram selecionados relatos de casos e revisões bibliográficas dos últimos 20 anos para o levantamento da incidência das fusões ETV6::RUNX1, BCR::ABL, TCF3::PBX1 e KMT2A::AFF1. Um total de 16.221 pacientes LLA-B foram selecionados e foi realizada a separação por continentes conforme o país de cada trabalho. A frequência das fusões em cada continente e a mediana entre os pacientes foram calculadas. Foi realizado o teste de Kruskal-Wallis para a diferença entre os continentes, com p-valor ≤ 0,05. Resultados: : A Ásia apresentou maior frequência das fusões BCR::ABL (58,6%), TCF3::PBX1 (47,1%) e ETV6::RUNX1 (46,4%) e América do Norte apresentou a maior ocorrência da fusão KMT2A::AFF1, 67,2%, enquanto a África a menor, 0,72%. O teste Kruskal-Wallis evidenciou uma diferença na incidência da fusão BCR::ABL1 entre a Ásia e a América do Norte (p = 0.0155). Em relação às anormalidades cromossômicas, foi observado um maior número de casos de hiperdiploidia na América do Norte (31,97%) e de hipodiploidia na Eurásia -Rússia e Turquia- (30,66%). Discussão: A Ásia foi o continente com maior frequência da maioria das fusões gênicas, isto ocorre devido a um número maior de registros, porém, também pode ter origem em fatores étnicos e/ou ambientais que influenciam na ocorrência das fusões. A fusão BCR::ABL1 foi encontrada em vários grupos étnicos, porém estudos sugerem variação na frequência entre as populações, sendo maior em populações asiáticas em relação às ocidentais. A fusão KMT2A::AFF1 foi mais comum em crianças lactentes e está associada a LLA-B em bebês independentemente do grupo étnico. Em estudos feitos em centros de tratamento dos Estados Unidos, foi relatado que a ocorrência da fusão KMT2::AFF1 e de anormalidades cromossômicas são menores em pacientes com etniahispânica. Conclusão: Como resultado, este estudo demonstrou que o continente asiático apresentou maior frequência das fusões ETV6::RUNX1, BCR::ABL e TCF3::PBX1, enquanto KMT2A::AFF1 foi mais frequente na América do Norte. Além disso, a incidência da fusão BCR::ABL apresentou uma diferença estatisticamente significativa entre Ásia e América do Norte. Por fim, hiperdiploidia e hipodiploidia tiveram suas maiores frequências na América do Norte e Eurásia, respectivamente.

Objetivo: O objetivo da revisão é sintetizar a literatura existente sobre a avaliação prognóstica de hipodiploidia e hiperdiploidia na Leucemia Linfoblástica de células B (LLA-B) pediátrica. Metodologia: A construção da pesquisa se deu pela busca de artigos publicados nos bancos de dados JANE, Scielo, BVS e PubMed. A coleta foi norteada pela busca combinada nos idiomas português e inglês dos seguintes termos de busca: Cruzamento (CR): CR1: Leucemia Linfoblástica Aguda (LLA); Hipodiplóide; Hiperdiplóide. CR2: Prognóstico; alterações cromossômicas. CR3: Acute Lymphoblastic Leukemia (ALL); Hypodiploid; Hyperdiploid. CR4: Prognosis; Chromosomal changes. Resultado: Foram identificados 268 artigos. Destes, foram excluídos os artigos duplicados, estudos com apenas adultos, revisões e artigos fora do escopo, identificados através da leitura dos títulos e resumos. Após aplicados os critérios, 196 estudos foram descartados, 6 artigos foram selecionados e considerados para o desenvolvimento da discussão. Os artigos incluídos nesta revisão foram publicados no período de 2014 a 2024. Discussão: O estudo de Kerketta et al. (2017) sobre LLA-B revelou que 54% dos pacientes estudados apresentavam anormalidades citogenéticas, sendo a hiperdiploidia a mais comum. Isso corrobora com a pesquisa de Paulsson (2015), a qual aponta tal anormalidade citogenética como a mais frequente na LLA-B, ocorrendo de 25% a 30% dos casos. Essa condição envolve a presença de 51 a 67 cromossomos, com mais de 70% dos casos afetando especificamente os cromossomos X, 4, 6, 10, 14, 17, 18 e 21. A análise por matriz de 11 casos hipodiploides feita por Safavi et al. (2015), revelou a perda completa de heterozigosidade (LOH) em vários cromossomos, indicando duplicação de clones hipodiploides mascarados. Por outro lado, Shetty et al. (2020) conduziram um estudo com 11 pacientes com LLA-B hipodiploide. Nove desses pacientes eram mosaicos, com cinco casos quase haploides e três casos hipodiploides baixos. A análise por citometria de fluxo (CF) identificou endoreduplicação (ED) em 57%, e mutações missense em TP53 e JAK3. No estudo de Carroll et al. (2019), de 7.013 pacientes com LLA-B, 121 (1,72%) foram classificados como hipodiploides com ≤ 43 cromossomos. A maioria das anormalidades cromossômicas era numérica, envolvendo perda de cromossomos inteiros. Ao avaliar 20 casos de LLA-B com ED usando métodos de CF e citogenética, Chaturvedi et al. (2022) revelaram dois picos distintos de ploidia: um pico de hipodiploidia com mediana de índice de DNA (DI) de 0,82; e outro de hiperdiploidia (mediana DI = 1,53). Conclusão: A hiperdiploidia é uma anomalia citogenética frequente na LLA-B e está associada a um aumento da expressão gênica. Em comparação, a hipodiploidia é menos comum, mas está ligada a um pior prognóstico e associa-se a mutações gênicas críticas. Ambas as alterações apresentam desafios únicos e complexidades que requerem mais investigações para melhor compreensão de seus papéis. Sendo assim, o uso de técnicas como a citogenética e a CF permitem identificar variações cromossômicas envolvidas na fisiopatologia da LLA-B.

Objetivo: Analisar in silico as atividades biológicas de compostos químicos da própolis com potencial anticancerígenas. Metodologia: Através da plataformas PubChem foi realizado a busca dos compostos químicos específicos da própolis e direcionados ao Pass Online, para obter dados sobre atividades biológicas e farmacológicas. Os compostos selecionados e coletados pelo SMILES canônicos (estrutura de uma molécula) foram classificados de acordo com PA (Probabilidade de atividade) e PI (Probabilidade de inatividade), com PA > 0,7 sendo os compostos: 7-Hidroxiflavanona, Pinocembrina, Pinostrobina e Pinobanksin. Resultado: Efeitos dos compostos de ser bioativas: 7-Hidroxiflavanona:Membrane integrity agonist (PA = 0,955 e PI = 0,003) e Antimutagenic (PA = 0,809 e PI = 0,004); Pinocembrina: Membrane integrity agonist (PA = 0,962 e PI = 0,003), Antimutagenic(PA = 0,842 e PI = 0,003), TP53 expression enhancer (PA = 0,816 e PI = 0,009), Antioxidant (PA = 0,793 e PI = 0,003), Apoptosis agonist (PA = 0,752 e PI = 0,011), Antineoplastic (PA = 0,746 e PI = 0,019) e Anticarcinogenic (PA = 0,721 e PI = 0,008); Pinostrobina: Membrane integrity agonist (PA = 0,953 e PI = 0,003), Antimutagenic (PA = 0,817 e PI = 0,004), TP53 expression enhancer (PA = 0,799 e PI = 0,011), Apoptosis agonist (PA = 0,730 e PI = 0,012), Antineoplastic (PA = 0,730 e PI = 0,021 e Anticarcinogenic (PA = 0,705 e PI = 0,008); Pinobanksin: Membrane integrity agonist (PA = 0,973 e PI = 0,002), TP53 expression enhancer (PA = 0,962 e PI = 0,003), Antioxidant (PA = 0,940 e PI = 0,002), Antimutagenic (PA = 0,883e PI = 0,002), Anticarcinogenic (PA = 0,780 e PI = 0,006), Apoptosis agonist (PA = 0,756 e PI = 0,010), Antiinflammatory (PA = 0,712 e PI = 0,014) e Antineoplastic (PA = 0,706 e PI = 0,025). Discussão: No estudo conduzido por Moghadari Masoud et al. (2022), foi explorado o potencial antitumoral da própolis de Kerman como tratamento das células NALM-6 com concentrações variáveis de própolis de Kerman e doxorrubicina durante 72 horas. Os resultados demonstraram que tanto a própolis de Kerman quanto a doxorrubicina induziram a morte celular por apoptose de forma dose-dependente, com uma regulação significativa da razão Bax/Bcl-2, sugerindo um efeito pró-apoptótico. O que endossa os estudo dirigido por Franchi Jr. et al. (2011), em que investigaram o efeito dos extratos etanólicos de própolis grupo 12 (G12) e própolis grupo 13 (G13) em células de leucemia humana, em que os valores de IC50 para os extratos de própolis vermelha (G13) e verde (G12) variaram significativamente entre diferentes linhagens de células de leucemia. A própolis vermelha demonstrou ser mais potente em termos citotóxicos, especialmente nas células K562 e HL60, e apresentou menor dispersão nos valores de IC50. Além disso, ao comparar o efeito da própolis vermelha com os fármacos clínicos Gleevec e citarabina, foi identificada uma diferença marcante nas células K562 e Nalm16, com a G12 mostrando um efeito citotóxico mais significativo. Conclusão: A composição química da própolis pode ser útil para linhagem de leucemia linfoblástica aguda (NALM-6), o que envolve principalmente compostos que possuem atividades anticancerígenas. Esses compostos podem interferir no ciclo celular, induzir apoptose e reduzir o estresse oxidativo nas células cancerígenas com potencial para afetar as células NALM-6.

Objective: Acute Lymphoblastic Leukemia (ALL) is classified according to its genetic abnormalities, which are associated with the clinical and biological characteristics of the disease. The detection of gene fusions assists in diagnosis, risk stratification, and targeted therapy. This study aims to evaluate the status of gene fusions in pediatric ALL patients from the Brazilian Amazon and their association with known hematological parameters. Materials and methods: The research was approved by the ethics committee under number 4.040.805 and included a total of 160 patients diagnosed with ALL at the Octávio Lobo Children's Oncology Hospital during the period from 2017 to 2023. Clinical data (leukometry, platelets, and hemoglobin) and epidemiological data (gender and age) were collected from the hospital's database system. For the analysis of gene fusions, c-DNA was obtained for the detection of molecular biomarkers by PCR using specific primers. Agarose gel electrophoresis was performed to visualize the PCR products. Finally, Sanger Sequencing was carried out to confirm the PCR results. For qualitative variables, descriptive statistics were used, determining absolute and percentage frequencies. For quantitative variables, median and standard deviation values were calculated according to the variables under study. The Kruskal-Wallis test was performed to test the association of the presence of one of the gene fusions (BCR::ABL, TCF3::PBX1, KMT2A::AFF1, ETV6::RUNX1 and SIL::TAL) with the clinical data, adopting a p-value ≤ 0.05 as significant. Statistical analyses were performed using RStudio 12.1 software. Results: Regarding gene fusions, 21% of patients had the TCF3::PBX1 fusion, 19% ETV6::RUNX1, 11% BCR::ABL, 3% KMT2A::AFF1, 2% SIL::TAL, and 44% had none of the studied fusions. 61% of the patients were male and 39% female, with a median age of 6 years. Regarding clinical data, the patients had a median white blood cell (WBC) count of 13,150/mm3; a median platelet count of 36,000/mm3; and a median hemoglobin level of 8 g/dL. The Kruskal-Wallis test revealed a significant statistical difference between gene fusions and white blood cell count (p-value = 0.0024), and Dunn's post-test showed that in TCF3::PBX1, the WBC count is significantly higher mainly compared to ETV6::RUNX1 (p-value = 0.007). Discussion: Studies have reported ETV6::RUNX1 as the most frequent fusion, but this work found TCF3::PBX1 as the most frequent find, which may be explained by the highly mixed population of the Amazon, supporting the existence of ethnic differences. Other studies found significant statistical differences in white blood cell count between the TCF3::PBX1 fusion and others, which corroborates the findings of this study, indicating that this molecular biomarker has a poor prognosis and is characterized by a white blood cell count above 50,000/mm3, which was found in about 35% of the patients in this study. Conclusion: In the study, the frequency of the TCF3::PBX1 fusion was observed to be relatively higher than what is reported in the literature. The TCF3::PBX1 fusion leads to the activation of genes encoding proteins with malignant potential, and that the fusion showed a statistical difference between groups regarding white blood cell count, which is used as a risk classification according to the National Cancer Institute.

Objetivo: A leucemia linfoblástica aguda (LLA) é uma doença hematológica caracterizada pela rápida proliferação de células imaturas da linhagem linfoide. Modificações na expressão de genes condutores dos processos biológicos das células tronco hematopoiéticas podem está diretamente relacionada ao desenvolvimento dessa doença. A identificação dos mecanismos acerca da gênese e da progressão da LLA e crucial para entendimento de como intervir de forma significativa para o combate da LLA. Esse estudo tem como principal objetivo realizar um levantamento das frequências da variação no numero de copias dos genes condutores da leucemia linfoblástica aguda pediátrica. Materiais e métodos: Nesse estudo, foram analisadas amostras de pacientes pediátricos diagnosticado com Leucemia linfoblástica aguda, atendidos no Hospital Ophir Loyola situado no Estado do Para. A coleta das amostras foi realizada no período de 2017 a 2019. Este estudo, foi submetido e aprovado pelo comitê de ética (CAAE 0905812.1.0000.0018). As analises partiram da coleta de 2ml de sangue ais quais foram submetidas aos processos de extração e quantificação de DNA e obtivemos 16 amostras aptas ao ensaio de hibridização genômica comparativa em seguida foi seguida as etapas que culminaram na identificação dos genes condutores que continham o número de copias alteradas. Resultados: Esse estudo analisou as frequências e identificou o tipo de variação no número de cópias em genes condutores da LLA. Foi constado variações do número de copias em 6 genes dos 21 estudados, dentro de uma frequência igual ou superior a 25% das amostras analisadas. O tipo de alteração mais frequente nas amostras foi por amplificação: onde o gene, mas alterado foi o KDM6A, seguido por RUNX1, ERG, USPX e RB1. A perda de heterozigose foi registrada nos genes: CDKN2A, USP9X, RB1 e KDM6A. E por fim a perda de números de copias ocorreram nos genes: RB1 e CDKN2A. Discursão: As alterações genéticas estão ligadas a os processos que conduzem a LLA, atuando como fatores que medeiam de forma direta o indiretamente, agindo em vias regulatórias, acelerando ou retirando as travas que limitam a progressão das leucemias. Sendo assim, os genes ligados aos processos biológicos celulares que estão com variações no número de copias alterados, podem está diretamente associados com a progressão da LLA. Conclusão: Apesar da etiologia da leucemia ainda ser pouco conhecida, estudos sobre alterações genéticas recorrentes em pacientes leucêmicos, como as pesquisas de alterações nos números de copias, podem vim a ser de extrema contribuição, para um dia encontrarmos mais evidencias que associem os fatores genéticos com possíveis causas para a manifestação clínica da LLA. Portanto e necessário aja mais pesquisas voltadas para a compreensão acerca dos fatores que medeiam alterações dos genes condutores da leucemia linfoblástica aguda para que se tenham um vasto conhecimento da atuação de cada uma dessas alterações e suas consequências dentro da LLA.

Objective: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the proliferation of myeloid lineage progenitor cells, increasing the circulating cells of the granulocytic lineage. The aim of this study is to evaluate the status of the BCR-ABL gene fusion transcript (P210) in cases of CML in patients from the Brazilian Amazon in relation to frequency and association with known prognostic laboratory data. Materials and methods: The research was approved by the ethics committee number 20528519.8.0000.5550 and included a total of 161 patients detectable for one of the BCR-ABL gene transcripts between 2015 and 2024. Clinical data (leukocyte count, blast count, platelets, and hemoglobin levels) and epidemiological data (sex and age) were collected from secondary data from the LABMASTER database system of the HEMOPA Foundation. For the analysis of fusion transcripts, c-DNA was obtained to detect the presence of molecular biomarkers by Real-Time PCR (RT-qPCR) using specific Taqman probes on the Rotor Gene equipment. Descriptive statistics were used for qualitative variables, determining absolute and percentage frequencies of the qualitative variables. For quantitative variables, median values and standard deviation were calculated according to the variables under study. The Kruskal-Wallis test was used to test the association of the presence of one of the P210 transcripts (B2A2, B3A2, and/or Both) with the clinical data, adopting a p-value ≤ 0.05 as significant. Statistical analyses were performed using SPSS software version 29.0. Results: Regarding the BCR-ABL gene, 39% (63/161) presented the B2A2 transcript, 30% (50/161) presented B3A2, and 31% (48/161) presented Both. Of the patients, 57% (92/161) were male and 43% (69/161) were female, with a median age of 44.5 years. In terms of white cell count, patients had a median of 164,200/mm3; regarding blast count, the median was 6,816/mm3; for platelet count, the median was 401,250/mm3; and for hemoglobin levels, the median was 11 g/dL. The Kruskal-Wallis test revealed no statistical difference between the types of P210 gene fusion transcripts and the analyzed clinical laboratory data. Discussion: Studies conducted by other researchers on CML and the BCR-ABL gene found a higher prevalence in male patients, which is consistent with the findings of this study. However, the median age of patients is about 10 years lower than reported in the literature. Studies in Latin American (Argentina, Colombia and Ecuador) presented the B2A2 transcript as the most frequent, which corroborates the findings of this study, while in European countries (Bulgaria, Italy, and Serbia), the B3A2 transcript was the most prevalent. These differences can be explained by different ethnicities, but deeper studies are needed to understand the impact of genetic ancestry and the presence of the fusion transcript. Conclusion: In the present study, the B2A2 transcript was observed as the most prevalent in patients with CML and this type of transcript had a higher median leukocyte compared to the other groups, and patients with the B3A2 transcript had a higher median platelet compared to the others. However, no significant difference was found between the groups. The transcript impacts the disease development process, so it is worthwhile to study the P210 pathways and find new treatment strategies.

Objetivo: Devido à ausência de estudos sobre o melhor gene de referência para a análise de pacientes com leucemia aguda, o objetivo deste estudo foi realizar uma validação e uma normalização dos ensaios de expressão com amostras de sangue periférico e medula óssea desses pacientes. Metodologia: Um painel de genes comumente utilizados como endógenos foi selecionado da literatura para análise da estabilidade: GAPDH, ABL, HPRT1, RPLP0, ACTB e TBP. O estudo incluiu amostras de medula óssea e sangue periférico de 50 pacientes adultos (25 com diagnóstico de Leucemia Linfoblástica Aguda- LLA e 25 com Leucemia Mieloide Aguda- LMA) e amostras de sangue periférico de 25 pacientes pediátricos com LLA. Além disso, amostras de sangue periférico de 15 voluntários saudáveis foram usadas como controles. Este estudo foi aprovado pelos Comitês de Ética do Hospital Ophir Loyola (nº2.798.615) e do Hospital Geral de Fortaleza (nº4.798.575). Reações em cadeia da polimerase foram utilizadas para identificar diferentes expressões endógenas. A estabilidade dos genes de referência candidatos foi analisada de acordo com três métodos estatísticos de avaliação: NormFinder, GeNorm e R software. Resultados: A análise realizada neste estudo mostrou que os genes GAPDH e HPRT não podem ser classificados como bons genes de referência, uma vez que apresentaram alto desvio padrão e grande variabilidade entre os grupos, indicando baixa estabilidade. Além disso, foi possível identificar que o conjunto endógeno composto por ACTB, ABL, TBP e RPLPO apresentou, em geral, bons desempenhos e expressões estáveis entre os grupos analisados. Os níveis de expressão de muitos desses genes apresentam certa variabilidade não apenas dentro dos conjuntos de dados, mas também em relação à origem das amostras analisadas. Discussão: Apesar dos genes de referência mais utilizados para estudos de expressão gênica em geral serem os genes B-actina (ACTB), gliceraldeído-3-fosfato desidrogenase (GAPDH) e hipoxantina-guanina fosforibosiltransferase 1 (HPRT1), os resultados de estudos de validação de endógenos são conflitantes. Os achados deste estudo concordam com vários outros estudos que examinaram a estabilidade dos genes de referência GAPDH e HPRT1, demonstrando que eles devem ser utilizados com cautela, devido à considerável variação das expressões. O gene de referência ACTB está diferencialmente expresso em diversos tipos de câncer, o que sugere que sua utilização em estudos de análise de expressão pode ser inadequada. Entretanto, os achados desse trabalho demonstraram que a ACTB foi um dos genes de referência pesquisados com maiores taxas de estabilidade e melhor desempenho de forma geral. Porém os níveis de estabilidades observados nos genes de referência ABL, TBP e RPLPO também foram muito satisfatórios, especialmente quando ambos os tipos de amostra eram analisados de forma conjunta. Conclusão: Diante desses achados, este estudo sugere que o principal conjunto endógeno para uso como controle/referência em análises de expressão gênica em amostras de sangue periférico e medula óssea de pacientes com leucemias agudas, é composto pelos genes ACTB, ABL, TBP e RPLPO. Além disso, é extremamente necessária a validação de genes de referência para qualquer estudo de expressão gênica, considerando que o endógeno utilizado influencia na confiabilidade e acurácia desses estudos.

This study addresses competences of the Open Scholar. It draws on a theoretical framework reaching out to sustainability education, responsibility and activity theory to describe competences. Competences of the Open Scholar are understood within the context of Higher Education institutions' three missions: teaching, research and service to the community. The systematic literature review of three key concepts, Open Educator, Open Researcher and Open Scholar performed on a total of 811 articles between 2011 and 2023 as well as the content analysis performed on 10 competence frameworks highlight a dearth in epistemic competences. To fill this gap, the study raises awareness of the importance of initiating the development of scholars' capabilities in areas that can enable them to ask questions at the level of purpose and paradigm. Capabilities to address these deeper levels are presented as a way of enhancing the responsibility of scholars. Responsibility is framed in-line with its Latin root, "respondere," i.e., providing a response and drawing on a semantics of care, respect and concern (instead of the foregrounded framing of responsibility in terms of subjectivity, power and causality). Furthermore, identifying "not-yetness" and addressing uncertainty are presented as key competences of the Open Scholar.

The marketing of heated tobacco products (HTPs), like IQOS, influences consumers' perceptions. This mixed-methods study analyzed (i) survey data (2021) of 2222 US and Israeli adults comparing perceptions of 7 IQOS attributes (design, technology, colors, customization, flavors, cost and maintenance) and 10 marketing messages (e.g. 'Go smoke-free…') across tobacco use subgroups and (ii) qualitative interviews (n = 84) regarding IQOS perceptions. In initial bivariate analyses, those never using HTPs (86.2%) reported the least overall appeal; those currently using HTPs (7.7%) reported the greatest appeal. Notably, almost all (94.8%) currently using HTPs also currently used cigarettes (82.0%) and/or e-cigarettes (64.0%). Thus, multivariable linear regression accounted for current cigarette/e-cigarette use subgroup and HTP use separately; compared to neither cigarette/e-cigarette use (62.8%), cigarette/no e-cigarette use (17.1%) and e-cigarette/no cigarette use (6.5%), those with dual use (13.5%) indicated greater overall IQOS appeal (per composite index score); current HTP use was not associated. Qualitative data indicated varied perceptions regarding advantages (e.g. harm, addiction and complexity) of IQOS versus cigarettes and e-cigarettes, and perceived target markets included young people, those looking for cigarette alternatives and females. Given the perceived target markets and particular appeal to dual cigarette/e-cigarette use groups, IQOS marketing and population impact warrant ongoing monitoring to inform regulation.

Abstract Aims Central sleep apnoea (CSA) is present in 20–40% of heart failure (HF) patients and is associated with poor clinical outcomes and health status. Transvenous phrenic nerve stimulation (TPNS) is an available treatment for CSA in HF patients. The impact on HF outcomes is incompletely understood. The win ratio (WR) allows inclusion of multiple endpoint components, considers the relative severity of each component, and permits assessment of recurrent events in evaluation of clinical benefit. Methods and results A WR hierarchy was pre‐defined for analysis of the HF subgroup of the remedē® System Pivotal Trial. The analysis used three hierarchical components to compare all treated to all control subjects: longest survival, lowest HF hospitalization rate, and ≥2‐category difference in Patient Global Assessment at 6 months. Sensitivity analyses were performed substituting Epworth Sleepiness Scale and 4% oxygen desaturation index for the third component, and a 4‐component WR hierarchy was also evaluated. Ninety‐one HF subjects, 43 receiving TPNS and 48 in the control group, provided 2064 pairwise comparisons. More patients treated with TPNS experienced clinical benefit compared with control (WR 4.92, 95% confidence interval 2.27–10.63, P

Nasogastric tube placement is frequently performed in various medical settings. While generally deemed safe in patients without risk factors, complications may occur due to malposition, justifying the need of systematic confirmation of position with chest radiographs. We present the case of a critically ill male adult patient for whom the tube position was initially deemed very unusual on postinsertion radiographs, prompting further workup which ultimately confirmed an oropharyngeal perforation with a left parapharyngeal, left visceral, retrotracheal, and right retrodiaphragmatic course, and resulting in a recurrent pneumothorax and empyema treated by surgical decortication.

Abstract Background Miners exposed to silica dust are susceptible to silicotuberculosis (STB) outcome – the development of tuberculosis (TB) in miners with silicosis. STB is an important occupational and public health issue in the twenty-first century. This scoping review aimed to map the risk factors associated with STB. Methods A literature search was carried out to identify the available international literature on STB risk factors from four databases: MEDLINE, EMBASE, CINAHL, and COCHRANE LIBRARY. Various grey literature sources such as Google Scholar, Science.gov, and WHO Global Index Medicus were also searched. The main study outcome is STB; the selection criteria also included studies assessing TB and silicosis as comorbidities leading to STB. Results The final review included 22 studies. Findings identified various STB risk factors including demographic factors such as age and sex, lifestyle factors including smoking and alcohol intake, clinical factors such as history of TB, grades of silicosis, and human immunodeficiency virus (HIV), in addition to occupational factors encompassing silica exposure, duration of employment, and type of work setting. Conclusion The findings of this scoping review highlight the research gaps in the reviewed literature, including the dearth of longitudinal studies focusing on the directionality of the two comorbidities (TB and silicosis) that lead to STB, lack of gender considerations in research on this topic, and an absence of articles on vulnerable populations including children. The findings of this review may help guide future research and inform occupational health and safety policies addressing STB outcomes among miners.

Abstract Cisplatin is a chemotherapeutic drug, which exhibits undesirable side effects. Chitosan nanoparticles are promising for drug delivery. The aim of this study was to determine the effect of the brown alga Turbinaria triquetra ethyl acetate fraction and polysaccharides, either loaded on chitosan nanoparticles or free, against podocyturia and cisplatin nephrotoxicity in rats. Sixty-six male rats were distributed into 11 equal groups: untreated control, chitosan (CSNPs), ethyl acetate fraction (EAE), polysaccharide (PS), EAE loaded on chitosan nanoparticles (EAE-CSNPs), PS loaded on chitosan nanoparticles (PS-CSNPs), Cisplatin or cis-diamminedichloroplatinum(II) (CDDP), CDDP + EAE, CDDP + PS, CDDP + EAE-CSNPs, and CDDP + PS-CSNPs. Serum urea, creatinine, creatinine clearance, renal malondialdehyde, nitric oxide, paraoxonase 1, renal nephrin, and podocin, and their renal mRNA gene expressions, as well as urinary nephrin and podocin were determined. The results indicated that the ethyl acetate fraction and polysaccharides, either free or loaded, efficiently attenuated podocyturia and cisplatin nephrotoxicity compared to the Cis group. However, the improvement was higher in the nephrotoxic groups treated with EAE-CSNPs and PS-CSNPs. The current study revealed that chitosan nanoencapsulation showed ameliorative effects against podocyturia and cisplatin nephrotoxicity in rats compared to free extracts, offering a new therapeutic strategy for attenuating podocyturia and CDDP-induced nephrotoxicity.

Author(s): Hasan M. Al-Dorzi (corresponding author) [1]; Sadeem Atham [2]; Faten Khayat [2]; Jullanar Alkhunein [2]; Bushra T. Alharbi [2]; Norah Alageel [2]; Mohamed Tlayjeh [3]; Haytham Tlayjeh [1]; Yaseen [...], RATIONALE: The prognosis of patients with lung cancer admitted to the intensive care unit (ICU) is often perceived as poor. We described the characteristics, management, and outcomes of critically ill patients with lung cancer and determined the predictors of mortality. METHODS: We retrospectively studied patients with lung cancer who were admitted to the ICU of a tertiary care hospital between 1999 and 2021 for the reasons other than routine postoperative care. We noted their characteristics, ICU management, and outcomes. We performed the multivariable logistic regression analysis to determine the predictors of hospital mortality. RESULTS: In the 23-year period, 306 patients with lung cancer were admitted to the ICU (median age = 63.0 years, 68.3 males, 45.6 with moderate/severe functional disability, most had advanced lung cancer, and median Acute Physiology and Chronic Health Evaluation II score = 24.0). Life support measures included invasive mechanical ventilation (47.1), vasopressors (34.0), and new renal replacement therapy (8.8). Do-Not-Resuscitate orders were implemented during ICU stay in 30.1. The hospital mortality was 43.8 with a significantly lower rate in patients admitted after 2015 (28.0). The predictors of mortality were moderate/severe baseline disability (odds ratio [OR] 2.65, 95 confidence interval [CI] 1.22, 5.78), advanced lung cancer (OR 8.36, 95 CI 1.81, 38.58), lactate level (OR 1.45, 95 CI 1.12, 1.88, invasive mechanical ventilation (OR 10.92, 95 CI 4.98, 23.95), and admission period after 2015 (OR 0.37, 95 CI 0.16, 0.85). CONCLUSIONS: The mortality rates in patients with lung cancer admitted to the ICU during a 23-year period decreased after 2015. Functional disability, advanced lung cancer stage, vasopressor use, and invasive mechanical ventilation predicted mortality. Keywords: Goals of care, intensive care, lung cancer, mechanical ventilation, mortality

In recent decades, thermal-fluid specialists have made considerable efforts to investigate the boiling heat transfer process. Pool boiling of pure liquids and nanofluids has been widely studied in the last decade, but the existing knowledge on modeling of nanofluids pool boiling process is still limited. The boiling of fluids containing tinny solid particles is very complicated due to the interaction between the existing phases, their interface, and the heating surface. Some new research shows that many factors are effective in pool boiling of nanofluids. Among these factors, we can mention particle size, concentration, the structure of the boiling surface, and the dynamics of bubbles. In this research, the film pool boiling process of pure ethanol was numerically simulated. Then, the film pool boiling of nanofluids including two types of nanoparticles 〖Al〗_2 O_3 و SiO_2 and ethanol base fluid with two volumetric concentrations of 0.1% and 0.3% have been simulated. The results show that the presence of nanoparticles in film boiling in the base fluid has increased the heat transfer coefficient. The highest value coefficient for alumina and silica nanofluids with a volumetric concentration of 0.3% was obtained, respectively 0.32 (kW/m2°C) and 0.3 (kW/m2°C). In addition, the presence of nanoparticles in the boiling process has significantly increased the minimum heat flux. According to the results of numerical simulation, the minimum heat flux value in boiling of pure ethanol is 28.99 (kW/m2), in boiling of alumina-ethanol nanofluid with volumetric concentrations of 0.1% and 0.3%, is 37.11 (kW/m2) and 38.84 (kW/m2), respectively and in boiling of silica-ethanol nanofluid with volumetric concentrations of 0.1% and 0.3%, is 35.81 (kW/m2) and 38.31 (kW/m2), respectively. The highest heat transfer coefficient is achieved by alumina nanofluid with 0.3% concentration, while the highest minimum heat flux is achieved by silica nanofluid with 0.3% concentration. The numerical results are in good agreement with the experimental results. By comparing these values with the experimental results, there is a good consistency between the results.

In the field of implantology, peri-implantitis is still a common complication of implant failure. Similar to periodontal disease, this kind of pathological condition is characterized by inflammation of the tissues surrounding dental implants or fillings. The sources of infection have been shown to be chronic periodontitis and poor maintenance of the communion. A thorough examination of the intricate components of peri-implantitis was sought in this review in order to identify common characteristics of the disease with regard to bacteria, biofilm formation, host immunological responses, diagnostic tools, and therapeutic treatments. The aim of this study was to provide a detailed overview of the different bacterial species associated with peri-implantitis, a clinical condition similar to periodontitis, characterized by a higher prevalence of staphylococci and enteric bacteria. The study underscores the importance of employing sophisticated diagnostic methods like cone beam computed tomography. It covers a range of therapeutic approaches including surgical and non-surgical techniques as well as strategies stressing host-modification and photodynamic treatment. The study was conducted using pertinent publications from scientific databases, including Scopus, Google Scholar, PubMed, and Web of Science. We searched these databases using the following terms: periodontitis, microbial, dental implants, peri-implantitis, and biofilm formation.

Abstract Background and aim Promoting ethical medical practices and preserving human rights principles require an understanding of patient rights. Studies show varying awareness levels among patients regarding their rights. This study aims to assess the level of awareness among patients in Palestine about their rights and the compliance of healthcare professionals. Methods A cross-sectional study was conducted between November 2023 and January 2024 in the Northern West Bank cities. Data collection was conducted by three trained medical students utilizing an interviewer-administered questionnaire. The association between participant characteristics and awareness was assessed using the Chi-square test, followed by a multivariate regression analysis to control for confounding variables. Results Of 400 patients surveyed, 47.0% had good awareness of their rights. Multivariate analysis showed that awareness was associated with patients in the age group of 18–30 years and 46–60 years, having private insurance, more prior hospitalizations, non-governmental settings, and prior charter awareness. Awareness was highest for respectful care and lowest for staff introductions. Non-governmental facilities performed better than governmental on explaining procedures, alternatives, and costs, though both settings scored highly on non-discrimination and consent. Conclusions Our findings underscore global gaps in ensuring adequate patients’ rights awareness and implementation, with over half exhibiting inadequate knowledge. Significant deficiencies exist in involving patients in decision-making, informing about procedures/costs, and providing accessible complaint mechanisms, particularly in governmental facilities. Comprehensive, culturally-appropriate initiatives involving multisectoral collaborations are crucial to drive substantive reforms translating patient-centered care principles into consistent practice worldwide.

BACKGROUND: Central sleep apnea (CSA) is associated with increased mortality and morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Treatment of CSA with a certain type of adaptive servo-ventilation (ASV) device that targets minute ventilation (ASVmv) was found to be harmful in these patients. A newer generation of ASV devices that target peak flow (ASVpf) is presumed to have different effects on ventilation and airway patency. We analyzed our registry of patients with HFrEF-CSA to examine the effect of exposure to ASV and role of each type of ASV device on mortality. METHODS: This is a retrospective cohort study in patients with HFrEF and CSA who were treated with ASV devices between 2008 and 2015 at a single institution. Mortality data were collected through the institutional data honest broker. Usage data were obtained from vendors and manufacturers servers. Median follow-up was 64 months. RESULTS: The registry included 90 patients with HFrEF-CSA who were prescribed ASV devices. Applying a 3-h-per-night usage cutoff, we found a survival advantage at 64 months for those who used the ASV device above the cutoff (n = 59; survival 76%) compared to those who did not (n = 31; survival 49%; hazard ratio 0.44; CI 95%, 0.20 to 0.97; P = 0.04). The majority (n = 77) of patients received ASVpf devices with automatically adjusting end-expiratory pressure (EPAP) and the remainder (n = 13) received ASVmv devices mostly with fixed EPAP (n = 12). There was a trend towards a negative correlation between ASVmv with fixed EPAP and survival. CONCLUSION: In this population of patients with HFrEF and CSA, there was no evidence that usage of ASV devices was associated with increased mortality. However, there was evidence of differential effects of type of ASV technology on mortality.

BACKGROUND: The impact of sleep disordered breathing (SDB) on heart failure (HF) is increasingly recognized. However, limited data exist in support of quantification of the clinical and financial impact of SDB on HF hospitalizations. METHODS: A sleep-heart registry included all patients who underwent inpatient sleep testing during hospitalization for HF at a single cardiac center. Readmission data and actual costs of readmissions were obtained from the institutional honest broker. Patients were classified based on the inpatient sleep study as having no SDB, obstructive sleep apnea (OSA), or central sleep apnea (CSA). Cumulative cardiac readmission rates and costs through 3 and 6 months post-discharge were calculated. Unadjusted and adjusted (age, sex, body mass index, and left ventricular ejection fraction) modeling of cost was performed. RESULTS: The cohort consisted of 1547 patients, 393 (25%) had no SDB, 438 (28%) had CSA, and 716 (46%) had OSA. Within 6 months of discharge, 195 CSA patients (45%), 264 OSA patients (37%), and 109 no SDB patients (28%) required cardiovascular readmissions. Similarly, 3- and 6-month mortality rates were higher in both SDB groups than those with no SDB. Both unadjusted and adjusted readmission costs were higher in the OSA and CSA groups compared to no SDB group at 3 and 6 months post-discharge with the CSA and OSA group costs nearly double (~ $16,000) the no SDB group (~ $9000) through 6 months. INTERPRETATION: Previously undiagnosed OSA and CSA are common in patients hospitalized with HF and are associated with increased readmissions rate and mortality.

The purpose of the study is to evaluate the impact of varying salinity levels on bacterial communities that influence the maturation of the biofloc technology (BFT) system in Penaeus vannamei culture. The experiment involved four water treatments with different salinities: seawater from the Arabian Gulf with 44 ppt (M44), seawater diluted to 22 ppt (M22), well water with 22 ppt (W22), and seawater diluted to 11 ppt (M11). The study was conducted in triplicate using a completely randomized design, with a stocking density of 240 shrimps m−3 for 45 days until BFT reached a mature state. Water quality parameters were monitored daily, and the bacterial communities in the biofloc system were evaluated every 15 days. The results showed that salinity impacts both the water parameters and the nutritional composition of the biofloc culture. Bacteria that convert ammonia to nitrite matured more rapidly at low salinity (11 ppt), while bacteria that convert nitrite to nitrate matured faster at high salinity (44 ppt). Additionally, this study shows that microbial communities can shift significantly through the maturation process depending on competitive dynamics and the metabolic requirements of bacteria. This study indicates the crucial role of salinity in affecting the microbial community and maturation functionality of the BFT. The results further highlight the significance of preserving a varied and well-balanced bacterial community in biofloc aquaculture systems to optimize nitrification and water quality control.

This study aimed to investigate the effects of social isolation stress during pregnancy on maternal behavior and associated neurochemical changes in the hippocampus of rats.Twenty female Sprague-Dawley rats were randomly assigned to either a group housing (two rats per cage: control group) or a social isolation stress group (one rat per cage: SI group) during pregnancy. At the end of the study, we assessed the levels of BDNF, corticosterone, and GABAARα1 in the hippocampus of the maternal brain, along with evaluating the endurance, integration, and emotional aspects of maternal behavior. Results indicated that social isolation stress significantly decreased maternal endurance, integration, and emotionality (self-calming) of maternal behavior. Concurrently, blood and the hippocampal corticosterone concentration significantly increased, while BDNF concentration significantly decreased in the SI stress group compared to controls. Moreover, GABAARα1 mRNA expression was significantly decreased in the hippocampus of socially isolated rats. These findings demonstrate that social isolation stress during pregnancy profoundly impacts maternal behaviors in rats, including endurance, integration, and self-soothing. The altered concentration of corticosterone and BDNF, and GABAARα1 mRNA expression in the hippocampus of social isolation group suggests disruptions in stress response regulation and synaptic plasticity during pregnancy to form normal maternal behavior.

In oil-rich regions, the increasing risk of oil spills on soil is largely attributed to intensified extraction and transportation activities. This situation necessitates a focus on the short-term and long-term strength of contaminated soils. While existing literature primarily evaluates the oil-contaminated soils over short-term periods, typically up to 28 days, it is essential to investigate their long-term performance, extending the evaluation period to 365 days. This study addresses the critical gap in understanding the long-term performance of soils contaminated with 4 %, 7 %, and 10 % oil by evaluating the effectiveness of lime stabilization over a one-year period. Laboratory tests were conducted on soils treated with varying lime contents (0 %, 3 %, 6 %, and 9 %) and cured for 1, 14, 28, and 365 days. Key performance indicators, including unconfined compressive strength (UCS), California Bearing Ratio (CBR), and durability under wet-dry cycles, were measured. The results demonstrate that a 6 % lime content significantly improves long-term UCS, with strength gains ranging from 16.6 % to 24.5 % while enhancing resilience to wet-dry cycles. Microstructural analyses confirmed the formation of calcium-aluminum-silicate-hydrate (C-A-S-H) phases, contributing to the observed strength and durability improvements. This research underscores the potential of lime stabilization as a sustainable solution for managing oil-contaminated soils, reducing reliance on raw materials, and promoting more sustainable infrastructure development.