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Yi-Yen Lee,1,2,* Aliaksandr A Yarmishyn,3,4,* Mong-Lien Wang,3,4 Hsiao-Yun Chen,4,5 Shih-Hwa Chiou,3–5 Yi-Ping Yang,4,5 Chun-Fu Lin,1,2 Pin-I Huang,2,6 Yi-Wei Chen,2,6 Hsin-I Ma,7 Ming-Teh Chen1,2 1Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, 2Faculty of Medicine, National Yang-Ming University, 3Institute of Pharmacology, National Yang-Ming University, 4Department of Medical Research, Taipei Veterans General Hospital, 5Institute of Clinical Medicine, National Yang Ming University, 6Cancer Center, Radiation Oncology Division, Taipei Veterans General Hospital, 7Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan *These authors contributed equally to this work Background: Glioblastoma multiforme (GBM) is the most malignant brain tumor, and there is no effective treatment strategy. Patients with GBM have a median overall survival of only 14.6 months. Current treatment consists of safe and maximal surgical excision, followed by concurrent chemoradiotherapy and maintenance chemotherapy. There are several obstacles that hinder the effectiveness of this aggressive treatment. Temozolomide (TMZ) is an oral alkylating drug that acts through alkylating the O6 position of guanine in DNA that leads to cell death. However, the expression and enzymatic activity of the DNA repair protein MGMT limits the therapeutic benefit from treatment with TMZ. MGMT reduces the efficacy of alkylating drugs by removing the methyl or alkyl group from damaged O6-methylguanine. Expression levels of MGMT play an important role in the outcome of GBM patients. miRNAs are a group of small regulatory RNAs that control target gene expression by binding to mRNAs. miR-142-3p has been found to be an important factor in the development and maintenance of the oncogenic state. Results: In this study, we sought to investigate whether miR-142-3p can regulate MGMT gene expression in GBM cells. Here, we show that miR-142-3p downregulates MGMT expression through binding to the 3′-UTR of MGMT mRNA, thus affecting protein translation. Responsiveness to TMZ was significantly enhanced after transfection with miR-142-3p. Overexpression of miR-142-3p also sensitized GBM cells to alkylating drugs. Conclusion: Above all, our findings demonstrate that miR-142-3p plays a critical role in regulating MGMT expression, has great potential for future clinical applications, and acts as a new diagnostic marker for this intractable disease. Keywords: glioblastoma, O6-methylguanine-DNA methyltransferase, miR-142-3p, carmustine, temozolomide

Introduction: To provide competent care to patients with autism spectrum disorder (ASD) or intellectual developmental disorder (IDD), healthcare professionals must recognize the needs of neurodivergent populations and adapt their clinical approach. We assessed the perceived preparedness of medical students to adapt care delivery for patients with ASD/IDD, as well as their perceptions on neurodiversity education. Methods: We conducted a sequential explanatory mixed-methods study on undergraduate medical students at McGill University during the academic year 2020-2021. We administered an online survey, followed by semi-structured interviews. We analyzed data using descriptive statistics and thematic analysis. We integrated findings at the interpretation level. Results: We included two-hundred-ten survey responses (~29% of class), and 12 interviews. Few students felt prepared to adjust care for patients with ASD/IDD despite most indicating doing so was important. Ninety-seven percent desired more training regarding care accommodation for neurodivergent patients. Thematic analysis unveiled the perception of current insufficient education, and the value of experiential learning. Discussion/Conclusions: This study highlights low perceived preparedness of medical students to accommodate care for neurodivergent patients, and a desire for more instruction. Incorporating interactive training in medical school curricula regarding modifying care delivery for neurodivergent individuals may improve the perceived preparedness of medical trainees to work with these patients and care quality.

Objetivo: Investigar as implicações da expressão gênica de PAX5, IKZF1, CXCR4 na patogênese da leucemia linfoide aguda (LLA) infanto-juvenil, avaliando a expressão gênica de PAX5, IKZF1, CXCR4 em amostras de sangue periférico de pacientes com LLA de diferentes subtipos e as possíveis associações com os parâmetros, na busca por marcadores de relevância clínica . Materiais e métodos: Projeto sob o CAAE nº 17123113.4.0000.5231. Tratou-se de um estudo quantitativo experimental retrospectivo. Foram incluídos pacientes do Hospital do Câncer de Londrina (HCL) com diagnóstico de leucemia linfoblástica aguda de ambos os sexos com idade entre 3 meses e 19 anos. As amostras de RNA foram obtidas a partir do sangue periférico de pacientes. A expressão de CXCR4 foi analisada em 59 amostras, já o IKZF1 e o PAX5 foram analisados em 40 amostras. Foram selecionados 31 indivíduos controle sem neoplasias, provenientes do Hospital Universitário da Universidade Estadual de Londrina (HU-UEL). Os parâmetros avaliados foram: sexo, risco de recidiva, recidiva e fase do tratamento no momento da coleta da amostra. Avaliou-se a expressão gênica por meio de PCR Quantitativo em Tempo Real (qRT-PCR) e fez-se coleta das informações clínicas através de prontuário médico. Os resultados estatísticos foram obtidos pelo programa SPSS Statistics 24.0. Resultados: Observou-se que o PAX5 tinha mais expresso em pacientes com LLA-B e menos expresso em pacientes que foram a óbito. A LLA-T era mais frequente em crianças mais velhas e associou-se ao pior prognóstico. O óbito mais frequente ocorreu em pacientes com recidiva. A expressão do PAX5 apresentou correlação inversamente proporcional significativa com a expressão do CXCR4 (p < 0,05). Discussão: Os dados obtidos sobre incidência da LLA em relação à gênero, à idade e ao subtipo corroboram com a literatura. Os resultados confirmam que a LLA do subtipo B é mais frequente que do subtipo T. E, a correlação entre o diagnóstico em crianças mais velhas e pior prognóstico é mais frequente na LLA-T. Pacientes com mais recidivas apresentavam taxas de sobrevida menores. A explicação seria que a expansão dos danos cromossômicos, durante a recidiva da doença, tem impacto na resposta às terapias convencionais. A relação inversamente proporcional de PAX5 com CXCR4 pode ser corroborada, posto que o PAX5 é um fator sinalizador de anormalidades celulares e, na existência de quantidades aberrantes de CXCR4, o PAX5 provavelmente se encontra inibido ou pouco expresso. Incapaz de realizar sua função de reparo, permitindo a expansão de células neoplásicas. A correlação entre a LLA B e a respectiva expressão do PAX5, em detrimento da LLA T, é explicada pela função primordial que esse gene realiza na maturação dos linfócitos B, modulando a linhagem celular. Conclusão: A expressão gênica do CXCR4, IKZF1 e PAX5 parece influenciar aspectos clínicos e de prognóstico da LLA infantojuvenil. A análise da expressão destes genes na evolução da doença pode elucidar outros mecanismos envolvidos na leucemogênese não compreendidos neste estudo.

Abstract Background Miliary tuberculosis (TB) is an uncommon cause of acute respiratory distress syndrome (ARDS) with a high mortality. The aim of the present study was to evaluate the clinical characteristics, predictors and outcome of patients with ARDS caused by miliary TB. Methods A retrospective study was conducted among patients with a diagnosis of ARDS with miliary TB in four hospitals from 2006 to 2010. Medical records and laboratory examinations of these patients were taken during the first 24 h of admission. Results Eighty-five patients with miliary TB developed ARDS, 45 of whom survived (52.9%). The median age was 36.6 ± 12.5 years with 38 males (44.7%). Diabetes mellitus (DM) was the most common underlying disease (18.8%).ICU mortality was 47.1%. The time from admission to anti-tuberculosis therapy was 4.5 ± 2.0 days. Mean duration of mechanical ventilation was 8.5 ± 3.0 days in all patients. Duration of time to diagnosis, time from diagnosis to mechanical ventilation, and time to anti-tuberculosis therapy were significantly shorter in survivors than those in non-survivors. Diabetes mellitus (OR 5.431, 95%CI 1.471-20.049; P = 0.005), ALT (70-100U/L, OR 10.029, 95%CI 2.764-36.389; P = 0.001), AST (>94U/L,OR 8.034, 95%CI 2.200-29.341; P = 0.002), D-dimer (>1.6mg/L, OR 3.167, 95%CI 0.896-11.187; P = 0.042), hemoglobin ( Conclusions Accurate diagnosis, early initiation of anti-tuberculosis therapy and mechanical ventilation are important for the outcome of patients with ARDS caused by miliary TB. DM, ALT, AST, D-dimer, hemoglobin, and albumin are independent predictors of ARDS development in patients with miliary TB.