IRF4-BLOC1S5: the first rearrangement gene identified in TEMPI syndrome.

Not available.

Indisulam synergizes with melphalan to inhibit Multiple Myeloma malignancy via targeting TOP2A.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an aryl sulfonamide, has a potent anti-myeloma activity in vitro and in vivo. This study aims to explore the new mechanism of indisulam and investigate its potential use in combination with melphalan. We examined DNA damage in MM cells through various methods such as western blotting (WB), immunofluorescence, and comet assay. We also identified the role of topoisomerase IIα (TOP2A) using bioinformatic analyses. The impact of indisulam on the RNA and protein levels of TOP2A was investigated through qPCR and WB. Cell proliferation and apoptosis were assessed using CCK-8 assays, Annexin V/PI assays and WB. We predicted the synergistic effect of the combination treatment based on calculations performed on a website, and further explored the effect of indisulam in combination with melphalan on MM cell lines and xenografts. RNA sequencing data and basic experiments indicated that indisulam caused DNA damage and inhibited TOP2A expression by decreasing transcription and promoting degradation via the proteasome pathway. Functional experiments revealed that silencing TOP2A inhibited cell proliferation and induced apoptosis and DNA damage. Finally, Indisulam/melphalan combination treatment demonstrated a strong synergistic anti-tumor effect compared to single-agent treatments in vitro and in vivo. These findings suggest that combination therapies incorporating indisulam and melphalan have the potential to enhance treatment outcomes for MM.

Causal relationship between physical activity and platelet traits: a Mendelian randomization study.

Introduction: The purpose of this study was to discuss the causal relationship between physical activity and platelet traits. Methods: A dataset from a large-scale European physical activity and platelet traits was collected by using Mendelian randomization of the study. For the analysis, the inverse variance weighting method, weighted median and MR-Egger were used to estimate causal effects. The sensitivity analyses were also performed using Cochran's Q test, funnel plots and Leave-one-out analysis. Results: Light DIY, other exercises, strenuous sports, walking for pleasure were significantly associated with a decrease in platelet crit. But none of the heavy /light DIY was associated with increase in platelet crit. Other exercises and strenuous sports were associated with decrease in platelet count. Conclusion: Some types of physical activity have a causal relationship with platelet crit and platelet count. However, the types of physical activity we studied have not supported a causal relationship with mean platelet volume and platelet distribution width.

Effects of diverse resistance training modalities on performance measures in athletes: a network meta-analysis.

Background: Jumping ability is one of the necessary qualities for athletes. Previous studies have shown that plyometric training and complex training including plyometrics can improve athletes' jumping ability. With the emergence of various types of complex training, there is uncertainty about which training method has the best effect. This study conducted a meta-analysis of randomized controlled trials of plyometric-related training on athletes' jumping ability, to provide some reference for coaches to design training plans. Methods: We systematically searched 3 databases (PubMed, Web of Science, and Scopus) up to July 2023 to identify randomized controlled trials investigating plyometrics related training in athletes. The two researchers conducted literature screening, extraction and quality assessment independently. We performed a network meta-analysis using Stata 16. Results: We analyzed 83 studies and found that complex training, which includes high-intensity intervals and plyometric exercises, was the most effective method for improving squat jumps (SURCA = 96%). In the case of countermovement jumps a combination of electrostimulation and plyometric training yielded the best results (SURCA = 97.6%). Weightlifting training proved to be the most effective for the standing long jump (SURCA = 81.4%), while strength training was found to be the most effective for the five bounces test (SURCA = 87.3%). Conclusion: Our current study shows that complex training performs more efficient overall in plyometric-related training. However, there are different individual differences in the effects of different training on different indicators (e.g., CMJ, SJ, SLJ, 5BT) of athletes. Therefore, in order to ensure that the most appropriate training is selected, it is crucial to accurately assess the physical condition of each athlete before implementation. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO/, Registration and protocol CRD42023456402.

Integrative analysis of an endoplasmic reticulum stress-related signature in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a malignancy in which plasma cells proliferate abnormally, and it remains incurable. The cells are characterized by high levels of endoplasmic reticulum stress (ERS) and depend on the ERS response for survival. Thus, we aim to find an ERS-related signature of MM and assess its diagnostic value. METHODS: We downloaded three datasets of MM from the Gene Expression Omnibus database. After identifying ERS-related differentially expressed genes (ERDEGs), we analyzed them using Gene Ontology enrichment analysis. A protein-protein interaction network, a transcription factor-mRNA network, a miRNA-mRNA network and a drug-mRNA network were constructed to explore the ERDEGs. The clinical application of these genes was identified by calculating the infiltration of immune cells and using receiver operating characteistic analyses. Finally, qPCR was performed to further confirm the roles of ERDEGs. RESULTS: We obtained nine ERDEGs of MM. Gene Ontology enrichment indicated that the ERDEGs played a role in the endoplasmic reticulum membrane. Additionally, the protein-protein interaction network showed interaction among the ERDEGs, and there were 20 proteins, 107 transcription factors, 42 drugs or molecular compounds and 51 miRNAs which were likely to interact with the nine genes. In addition, immune cell infiltration analyses showed that there was a strong correlation between the nine genes and immune cells, and these potential biomarkers exhibited good diagnostic values. Finally, the expression of ERDEGs in MM cells was different from that in healthy donor samples. CONCLUSION: The nine ERS-related genes, CR2, DHCR7, DNAJC3, KDELR2, LPL, OSBPL3, PINK1, VCAM1 and XBP1 are potential biomarkers of MM, and this supports further clinical development of the diagnosis and treatment of MM.

Research on the main methods of core strength training in sprinters / Pesquisa sobre os principais métodos de treino de força do core em velocistas / Investigación sobre los principales métodos de entrenamiento de fuerza del core en velocistas

ABSTRACT Introduction With the development of increasingly competitive sports, coaches began experimenting with new methods for training athletes. Although among the most explored training methods is core strength training, a set of muscle groups that stabilize the trunk and hips, there are few studies on the effectiveness of this training dedicated to sprinters. Objective This paper investigates the training method of sprinters based on core strength training, studying the method and its influence on athletes' performance. Methods Sixteen athletes with similar technical levels and physical fitness were selected, and professional coaches were invited to test the training samples. The athletes were randomly assigned to the experimental and control group (8 in each). The experimental group received core strength training for eight weeks, while the control group received general training. Results Off-core training affected the ankle joint angle of the support leg and the ankle joint angle of the swing leg (P < 0.01). After eight weeks of training, the performance of both groups improved without considerable differences. The high jump results of the athletes in the experimental group also improved compared to the previous training. Conclusion The physical function of athletes can be improved through core strength training to improve the sprinters' competitive level and technical ability. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução Com o desenvolvimento de esportes cada vez mais competitivos, os treinadores começaram a experimentar novos métodos para a formação de atletas. Embora entre os métodos de treinamento mais explorados encontra-se o treino do core, conjunto de grupos musculares estabilizadores do tronco e quadril, há poucos estudos sobre a efetividade desse treino dedicado a atletas velocistas. Objetivo Este artigo investiga o método de treino de velocistas baseado no treinamento de força do core, estudando o método e a influência no desempenho do atleta. Métodos Foram selecionados 16 atletas com nível técnico e aptidão física similares, treinadores profissionais foram convidados a testar as amostras de treino. Os atletas foram aleatoriamente designados para o grupo experimental e controle (8 em cada). O grupo experimental recebeu treinamento de força do core por 8 semanas, enquanto o grupo controle recebeu treinamento geral. Resultados O treinamento de fora do core teve um efeito no ângulo da articulação do tornozelo da perna de apoio e no ângulo da articulação do tornozelo da perna de balanço (P < 0,01). Após oito semanas de treinamento, o desempenho de ambos grupos melhoraram sem diferenças consideráveis. Os resultados do salto em altura dos atletas do grupo experimental também melhoraram em relação ao treinamento anterior. Conclusão A função física dos atletas pode ser aprimorada através do treinamento de força do core, de modo a melhorar ainda mais o nível competitivo e a capacidade técnica dos velocistas. Nível de evidência II; Estudos terapêuticos - investigação dos desfechos do tratamento.

RESUMEN Introducción Con el desarrollo de deportes cada vez más competitivos, los entrenadores comenzaron a experimentar nuevos métodos para el entrenamiento de los atletas. Aunque entre los métodos de entrenamiento más explorados se encuentra el entrenamiento del core, un conjunto de grupos musculares que estabilizan el tronco y las caderas, hay pocos estudios sobre la eficacia de este entrenamiento dedicado a los atletas velocistas. Objetivo Este artículo investiga el método de entrenamiento de los velocistas basado en el entrenamiento de la fuerza del core, estudiando el método y la influencia en el rendimiento del atleta. Métodos Se seleccionaron dieciséis atletas con un nivel técnico y una aptitud física similares, y se invitó a entrenadores profesionales a probar las muestras de entrenamiento. Los atletas fueron asignados aleatoriamente al grupo experimental y al de control (8 en cada uno). El grupo experimental recibió un entrenamiento del core durante 8 semanas, mientras que el grupo de control recibió un entrenamiento general. Resultados El entrenamiento fuera del core tuvo un efecto sobre el ángulo de la articulación del tobillo de la pierna de apoyo y el ángulo de la articulación del tobillo de la pierna de impulso (P < 0,01). Tras ocho semanas de entrenamiento, el rendimiento de ambos grupos mejoró sin diferencias considerables. Los resultados del salto de altura de los atletas del grupo experimental también mejoraron en relación con el entrenamiento anterior. Conclusión La función física de los atletas velocistas puede mejorarse mediante el entrenamiento del core, con el fin de mejorar aún más su nivel competitivo y su capacidad técnica. Nivel de evidencia II; Estudios terapéuticos: investigación de los resultados del tratamiento.

Effects of Chinese medical pricing reform on the structure of hospital revenue and healthcare expenditure in county hospital: an interrupted time series analysis.

BACKGROUND: China has initiated a medical pricing reform to combat the overuse of drugs and relieve the financial burden of patients. This paper aims to analyze the effect of medical pricing reform on revenue structure and healthcare expenditure of county public hospitals in Guangdong province. METHODS: Based on the monthly data from January 2013 to August 2019, we use interrupted time series design to evaluate the effects of medical pricing reform on healthcare expenditure in both outpatients and inpatients. A counterfactual is also established to examine the net effect of the policy. RESULTS: The proportion of drug revenue decreased from 35 % to 2015 to 29.7 % in 2019, and the revenue from medical services and inspection increased 3.2 and 3 % respectively. Meanwhile, the increasing trend of total expenditure and its main components is slowed down, especially the drug expense and medical consumable expense for inpatients after the Zero Mark-up Drug policy (coefficient = -18.76, p < 0.01; coefficient = -13.41, p < 0.01, respectively). However, the growth of inspection expense for outpatients continues to increase, while the healthcare expenditure for inpatients experiences an instant increase after the Zero Mark-up Medical Consumables policy. In terms of the net effect, most of healthcare expenditure in both outpatient and inpatient experienced a negative net growth from 2015 to 2019. CONCLUSIONS: The medical pricing reform is a valuable attempt in controlling the unreasonable increase of medical expenses. In the meantime, the unexpected increase in inspection expenditure and insufficient compensation from medical service adjustment should draw the attention of the policymakers.

FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia.

Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase-activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.