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Secondary mutations in Fms-like tyrosine kinase 3-tyrosine kinase domain (FLT3-TKD) (e.g., D835Y and F691L) have become a major on-target resistance mechanism of FLT3 inhibitors, which present a significant clinical challenge. To date, no effective drugs have been approved to simultaneously overcome clinical resistance caused by these two mutants. Thus, a series of pyrazinamide macrocyclic compounds were first designed and evaluated to overcome the secondary mutations of FLT3. The representative 8v exhibited potent inhibitory activities against FLT3D835Y and FLT3D835Y/F691L with IC50 values of 1.5 and 9.7 nM, respectively. 8v also strongly suppressed the proliferation against Ba/F3 cells transfected with FLT3-ITD, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-D835Y-F691L, and MV4-11 acute myeloid leukemia (AML) cell lines with IC50 values of 12.2, 10.5, 24.6, 16.9, and 6.8 nM, respectively. Furthermore, 8v demonstrated ideal anticancer efficacy in a Ba/F3-FLT3-ITD-D835Y xenograft model. The results suggested that 8v can serve as a promising macrocycle-based FLT3 inhibitor for the treatment of AML.
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BACKGROUND: Children with acute lymphoblastic leukaemia (ALL) experience multiple symptoms that occur in complicated patterns and negatively affect patient outcomes. To date, no systematic review has been performed on the prevalence of symptoms in children with ALL. OBJECTIVE: The study aimed to report and analyse the prevalence of symptoms in children with ALL during treatment. METHODS: A systematic search was conducted in eight databases (PubMed, Ovid Embase, Web of Science, CINAHL, PsycINFO, China WanFang Database, China Science and Technology Journal Database, and China National Knowledge Infrastructure) for studies published between January 1, 2000, and August 12, 2023. The methodological quality of the included studies was evaluated and a meta-analysis was performed to pool the prevalence of symptoms. RESULTS: In total, 17 studies were included, from which 34 symptoms were identified. The symptom prevalence ranged between 1.5 and 91.0% and the most frequent symptoms observed were fatigue, lack of energy, dry mouth, lack of appetite, sweating, and feeling irritable, which occurred in at least 60% of the patients. CONCLUSIONS: Symptoms remain highly prevalent in paediatric patients with ALL, which provides support for the need for symptom assessment in the clinical setting. Specific intervention is urgently needed to mitigate the symptoms in children with ALL and help them cope with the symptom burden.
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Emociones , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Prevalencia , China/epidemiología , Fatiga/epidemiología , Fatiga/etiología , Fatiga/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologíaRESUMEN
PURPOSE: To investigate the level of fear of cancer recurrence (FCR) in spouses of patients with lymphoma and its relationship with patients' FCR, as well as the correlations between FCR, sense of spousal support (SSS), anxiety, and depression in the couples. METHODS: A cross-sectional study of 233 couples where one partner had lymphoma was conducted from May 2021 to February 2022. Participants provided demographic information and completed the Spouse Support Inventory and Hospital Anxiety and Depression Scale. The Fear of Progression Questionnaire (for patients) and Fear of Progression Questionnaire for Partners (for spouses) were used to measure FCR. Descriptive analyses, t-tests, variance analysis, Spearman's correlation analysis, and multiple linear regression analysis was performed. RESULTS: The prevalence of FCR, anxiety, and depression in patients was 37.7%, 68.7%, and 83.3%, respectively. The prevalence of FCR, anxiety, and depression in spouses was 56.2%, 78.1%, and 81.1%, respectively. Spouses' FCR scores were higher than those of patients, whereas patients' SSS and anxiety scores were higher than those of their spouses. Multiple linear regression analysis showed that patients' anxiety and SSS, as well as spouses' FCR were significantly associated with patients' FCR. Variables significantly associated with higher FCR among spouses were anxiety, per capita monthly household income, and patients' FCR. CONCLUSIONS: Patients with lymphoma and their spouses have a certain degree of FCR, anxiety, and depression. FCR levels in spouses are higher than in patients. IMPLICATIONS FOR CANCER SURVIVORS: Psychological support interventions for couples may be effective in reducing FCR and facilitating family adaptation to cancer.
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PURPOSE: This study aimed to understand and identify barriers to resilience in young and middle-aged patients with lymphoma in the context of Chinese culture. METHODS: A qualitative descriptive study was employed. Face-to-face, semi-structured, and in-depth individual interviews were conducted between May and July 2022. Purposive and differential sampling was used to select eligible participants. Conventional content analysis was used to analyze qualitative data and identify categories and subcategories. This study followed the COREQ checklist. RESULTS: Twenty patients aged 28-59 years completed the interviews. Three categories involving thirteen subcategories were identified from the interview data: (1) internal barriers-derived from individual cognitive, emotional, behavioral, spiritual, and physical distress, resulting in internal negative constructs, and reducing the motivation to overcome adversity; (2) unbalanced family functioning-families threatened by disease are incapable of maintaining normal functioning and fail to act effectively when facing crises; and (3) absent social support-insufficient or unavailable shielding protection from social support further inhibits resilience among patients with lymphoma. CONCLUSIONS: This study identified various barriers to the resilience of young and middle-aged patients with lymphoma in the context of Chinese culture. In addition to the patient's internal barriers of resilience, specific family and socio-cultural barriers should also be emphasized by healthcare professionals. Multidisciplinary and family-centered resilience intervention should be developed to help such patients cope with, adapt to the disease, and achieve good psychosocial returns.
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Linfoma , Resiliencia Psicológica , Apoyo Social , Humanos , Persona de Mediana Edad , Linfoma/terapia , Investigación Cualitativa , Adulto , Pueblos del Este de AsiaRESUMEN
PURPOSE: This study aimed to explore the positive experiences of dyadic coping between patients with acute leukemia and their spouses in China, and to highlight the target factors that could promote coping and adaptation. METHODS: A qualitative descriptive study was employed. This study was conducted at a tertiary hospital in China from September 2021 to February 2022. A purposive sampling method was used to select participants, and 17 patients diagnosed with acute leukemia and their spouses were interviewed. Qualitative data were analyzed using the content analysis method. This study followed the COREQ checklist. RESULTS: This study's data were categorized into five themes and twelve subthemes: (1) adapting to a new role-couples used role adjustments to adapt; (2) commitment to companionship-patients benefit from spousal commitment in word or in deed; (3) active communication-allows couples to get to know each other better; (4) white lies-shield partner from negative information; (5) seeking external support-outside of couple cohesion. In sum, positive dyadic coping experiences between couples follow the marital commitment of "never forsake." CONCLUSIONS: This study contributes new knowledge to the understanding of the dyadic coping experiences of patients with acute leukemia and their spouses within the Chinese social-cultural context and contributes to cross-cultural comparisons. The results can be used to design and implement couple-based intervention programs to support couples by enhancing their mutual support to cope with and adjust to acute leukemia effectively.
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Leucemia , Esposos , Humanos , Adaptación Psicológica , Relaciones Interpersonales , Estrés Psicológico , Leucemia/terapiaRESUMEN
Microglia are critical in neuroinflammation. M1/M2 polarization transitions of microglial phenotypes determine the states of neuroinflammation and are regulated by multiple pathways, including miRNAs and other epigenetic regulations. This study investigated the polarization transitions of microglia induced by high glucose and glucose fluctuations, and the role of miR-146a in regulating M1/M2 polarization transitions of microglia. BV-2 cells were cultured with 25 mmol/L glucose, 75 mmol/L glucose, and 25 mmol/L-75 mmol/L glucose fluctuation for 48 h. BV-2 cells overexpressing miR-146a were generated using a lentiviral vector. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure mRNA expression of miR-146a, CD11b, iNOS, Arg-1, IRAK1, TRAF6, and NF-κB. Immunofluorescence was used to measure CD11b expression. Western blot was used to measure protein expression of CD11b, iNOS, and Arg-1. Compared with those in the 25 mmol/L glucose control group, expression of CD11b, iNOS, TNF-α, and IL-6 in the 75 mmol/L glucose or glucose fluctuation groups of cultured BV-2 cells were significantly increased, while Arg-1 and IL-10 was significantly decreased. These effects were reversed by overexpression of miR-146a. Furthermore, expression of IRAK1, TRAF6, and NF-κB was significantly increased in the high glucose and glucose fluctuation groups; this was reduced after miR-146a overexpression. In sum, high glucose and glucose fluctuations induced polarization transitions from M1 to M2 phenotype in BV-2 cells. Overexpression of miR-146a might protect BV-2 cells from high glucose and glucose fluctuation associated with M1/M2 polarization transitions by downregulating the expression of IRAK1, TRAF6, and NF-κB.