Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

OBJECTIVES: To investigate the genomic characteristics and prognostic factors of juvenile myelomonocytic leukemia (JMML) with RAS mutations. METHODS: A retrospective analysis was conducted on the clinical data of JMML children with RAS mutations treated at the Hematology Hospital of Chinese Academy of Medical Sciences, from January 2008 to November 2022. RESULTS: A total of 34 children were included, with 17 cases (50%) having isolated NRAS mutations, 9 cases (27%) having isolated KRAS mutations, and 8 cases (24%) having compound mutations. Compared to children with isolated NRAS mutations, those with NRAS compound mutations showed statistically significant differences in age at onset, platelet count, and fetal hemoglobin proportion (P<0.05). Cox proportional hazards regression model analysis revealed that hematopoietic stem cell transplantation (HSCT) and hepatomegaly (≥2 cm below the costal margin) were factors affecting the survival rate of JMML children with RAS mutations (P<0.05); hepatomegaly was a factor affecting survival in the non-HSCT group (P<0.05). CONCLUSIONS Children with NRAS compound mutations have a later onset age compared to those with isolated NRAS mutations. At initial diagnosis, children with NRAS compound mutations have poorer peripheral platelet and fetal hemoglobin levels than those with isolated NRAS mutations. Liver size at initial diagnosis is related to the prognosis of JMML children with RAS mutations. HSCT can improve the prognosis of JMML children with RAS mutations.
Humans ; Leukemia, Myelomonocytic, Juvenile/therapy* ; Mutation ; Male ; Female ; Child, Preschool ; Retrospective Studies ; Child ; Infant ; GTP Phosphohydrolases/genetics* ; Membrane Proteins/genetics* ; Adolescent ; Hematopoietic Stem Cell Transplantation ; Proportional Hazards Models ; Proto-Oncogene Proteins p21(ras)/genetics* ; Prognosis

OBJECTIVES: To evaluate the efficacy and safety of avatrombopag in promoting platelet engraftment after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children, compared with recombinant human thrombopoietin (rhTPO). METHODS: A retrospective analysis was conducted on 53 pediatric patients who underwent allo-HSCT at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences from April 2023 to August 2024. Based on medications used during the periengraftment period, patients were divided into two groups: the avatrombopag group (n=15) and the rhTPO group (n=38). RESULTS: At days 14, 30, and 60 post-transplant, platelet engraftment was achieved in 20% (3/15), 60% (9/15), and 93% (14/15) of patients in the avatrombopag group, and in 39% (15/38), 82% (31/38), and 97% (37/38) in the rhTPO group, respectively. There were no significant differences between the two groups in platelet engraftment rates at each time point, cumulative incidence of platelet engraftment, overall survival, and relapse-free survival (all P>0.05). Multivariable Cox proportional hazards analysis indicated that acute graft-versus-host disease was an independent risk factor for delayed platelet engraftment (P=0.043). CONCLUSIONS In children undergoing allo-HSCT, avatrombopag effectively promotes platelet engraftment, with efficacy and safety comparable to rhTPO, and represents a viable therapeutic option.
Humans ; Retrospective Studies ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Male ; Female ; Child ; Child, Preschool ; Infant ; Adolescent ; Transplantation, Homologous ; Blood Platelets/drug effects* ; Thiazoles/therapeutic use* ; Thrombopoietin/therapeutic use* ; Thiophenes

OBJECTIVE: To evaluate the clinical effect and safety of acupuncture manipulation on treatment of intractable facial paralysis (IFP), and verify the practicality and precision of the Anzhong Facial Paralysis Precision Scale (Eyelid Closure Grading Scale, AFPPS-ECGS). METHODS: A multicentre, single-blind, randomized controlled trial was conducted from October 2022 to June 2024. Eighty-nine IFP participants were randomly assigned to an ordinary acupuncture group (OAG, 45 cases) and a characteristic acupuncture group (CAG, 44 cases) using a random number table method. The main acupoints selected included Yangbai (GB 14), Quanliao (SI 18), Yingxiang (LI 20), Shuigou (GV 26), Dicang (ST 4), Chengjiang (CV 24), Taiyang (EX-HN 5), Jiache (ST 6), Fengchi (GB 20), and Hegu (LI 4). The OAG patients received ordinary acupuncture manipulation, while the CAG received characteristic acupuncture manipulation. Both groups received acupuncture treatment 3 times a week, with 10 times per course, lasting for 10 weeks. Facial recovery was assessed at baseline and after the 1st, 2nd and 3rd treatment course by AFPPS-ECGS and the House-Brackmann (H-B) Grading Scale. Infrared thermography technology was used to observe the temperature difference between healthy and affected sides in various facial regions. Adverse events and laboratory test abnormalities were recorded. The correlation between the scores of the two scales was analyzed using Pearson correlation coefficient. RESULTS: After the 2nd treatment course, the two groups showed statistically significant differences in AFPPS-ECGS scores (P<0.05), with even greater significance after the 3rd course (P<0.01). Similarly, H-B Grading Scale scores demonstrated significant differences between groups following the 3rd treatment course (P<0.05). Regarding temperature measurements, significant differences in temperatures of frontal and ocular areas were observed after the 2nd course (P<0.05), becoming more pronounced after the 3rd course (P<0.01). Additionally, mouth corner temperature differences reached statistical significance by the 3rd course (P<0.05). No safety-related incidents were observed during the study. Correlation analysis revealed that the AFPPS-ECGS and the H-B Grading Scale were strongly correlated (r=0.86, 0.91, 0.93, and 0.91 at baseline, and after 1st, 2nd, and 3rd treatment course, respectively, all P<0.01). CONCLUSIONS Acupuncture is an effective treatment for IFP, and the characteristic acupuncture manipulation enhances the therapeutic effect. The use of the AFPPS-ECGS can more accurately reflect the recovery status of patients with IFP. (Trial registration No. ChiCTR2200065442).
Humans ; Acupuncture Therapy/methods* ; Facial Paralysis/therapy* ; Female ; Male ; Middle Aged ; Adult ; Treatment Outcome ; Acupuncture Points ; Aged

Abdominal aortic aneurysm (AAA) is a deadly condition of the aorta, carrying a significant risk of death upon rupture. Currently, there is a dearth of efficacious pharmaceutical interventions to impede the advancement of AAA and avert it from rupturing. Here, we investigated dihydromyricetin (DHM), one of the predominant bioactive flavonoids in Ampelopsis grossedentata (A. grossedentata), as a potential agent for inhibiting AAA. DHM effectively blocked the formation of AAA in angiotensin II-infused apolipoprotein E-deficient (ApoE^-/-) mice. A combination of network pharmacology and whole transcriptome sequencing analysis revealed that DHM's anti-AAA action is linked to heme oxygenase (HO)-1 (Hmox-1 for the rodent gene) and hypoxia-inducible factor (HIF)-1α in vascular smooth muscle cells (VSMCs). Remarkably, DHM caused a robust rise (∼10-fold) of HO-1 protein expression in VSMCs, thereby suppressing VSMC inflammation and oxidative stress and preserving the VSMC contractile phenotype. Intriguingly, the therapeutic effect of DHM on AAA was largely abrogated by VSMC-specific Hmox1 knockdown in mice. Mechanistically, on one hand, DHM increased the transcription of Hmox-1 by triggering the nuclear translocation and activation of HIF-1α, but not nuclear factor erythroid 2-related factor 2 (NRF2). On the other hand, molecular docking, combined with cellular thermal shift assay (CETSA), isothermal titration calorimetry (ITC), drug affinity responsive target stability (DARTS), co-immunoprecipitation (Co-IP), and site mutant experiments revealed that DHM bonded to HO-1 at Lys243 and prevented its degradation, thereby resulting in considerable HO-1 buildup. In summary, our findings suggest that naturally derived DHM has the capacity to markedly enhance HO-1 expression in VSMCs, which may hold promise as a therapeutic strategy for AAA.

The application of pesticides(mostly insecticides and fungicides)during the tea-planting process will undoubtedly increase the dietary risk associated with drinking tea.Thus,it is necessary to ascertain whether pesticide residues in tea products exceed the maximum residue limits.However,the complex matrices present in tea samples comprise a major challenge in the analytical detection of pesticide residues.In this study,nine types of lateral flow immunochromatographic strips(LFICSs)were developed to detect the pesticides of interest(fenpropathrin,chlorpyrifos,imidacloprid,thiamethoxam,acet-amiprid,carbendazim,chlorothalonil,pyraclostrobin,and iprodione).To reduce the interference of tea substrates on the assay sensitivity,the pretreatment conditions for tea samples,including the extraction solvent,extraction time,and purification agent,were optimized for the simultaneous detection of these pesticides.The entire testing procedure(including pretreatment and detection)could be completed within 30 min.The detected results of authentic tea samples were confirmed by ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS),which suggest that the LFICS coupled with sample rapid pretreatment can be used for on-site rapid screening of the target pesticide in tea products prior to their market release.

Further evidence is needed to explore the impact of high-altitude environments on the neurologic function of neonates.Non-invasive techniques such as cerebral near-infrared spectroscopy and amplitude-integrated electroencephalography can provide data on cerebral oxygenation and brain electrical activity.This study will conduct multiple cerebral near-infrared spectroscopy and amplitude-integrated electroencephalography monitoring sessions at various time points within the first 3 days postpartum for healthy full-term neonates at different altitudes.The obtained data on cerebral oxygenation and brain electrical activity will be compared between different altitudes,and corresponding reference ranges will be established.The study involves 6 participating centers in the Chinese High Altitude Neonatal Medicine Alliance,with altitude gradients divided into 4 categories:800 m,1 900 m,2 400 m,and 3 500 m,with an anticipated sample size of 170 neonates per altitude gradient.This multicenter prospective cohort study aims to provide evidence supporting the impact of high-altitude environments on early brain function and metabolism in neonates.[Chinese Journal of Contemporary Pediatrics,2024,26(4):403-409]

Objective To investigate the nutritional status of children with Crohn's Disease (CD) at diagnosis and its association with clinical characteristics. Methods A retrospective analysis was performed for the clinical data and nutritional status of 118 children with CD who were admitted to Beijing Children's Hospital,Capital Medical University,from January 2016 to January 2024. A multivariate logistic regression analysis was used to investigate the risk factors for malnutrition. Results A total of 118 children with CD were included,among whom there were 68 boys (57.6％) and 50 girls (42.4％),with a mean age of (11±4) years. Clinical symptoms mainly included recurrent abdominal pain (73.7％,87/118),diarrhea (37.3％,44/118),and hematochezia (32.2％,38/118),and 63.6％ (75/118) of the children had weight loss at diagnosis. The incidence rate of malnutrition was 63.6％ (75/118),and the children with moderate or severe malnutrition accounted for 67％ (50/75). There were 50 children (42.4％) with emaciation,8 (6.8％) with growth retardation,and 9 (7.6％) with overweight or obesity. Measurement of nutritional indices showed a reduction in serum albumin in 83 children (70.3％),anemia in 74 children (62.7％),and a reduction in 25 hydroxyvitamin D in 15 children (60％,15/25). The children with malnutrition had significantly higher disease activity,proportion of children with intestinal stenosis,and erythrocyte sedimentation rate and a significant reduction in serum albumin (P<0.05). The multivariate logistic regression analysis showed that intestinal stenosis was an independent risk factor for malnutrition in children with CD (OR=4.416,P<0.05). Conclusions There is a high incidence rate of malnutrition in children with CD at diagnosis,which is associated with disease activity and disease behavior. The nutritional status of children with CD should be closely monitored.

Objective:To explore potential predictors of refractory Mycoplasma pneumoniae pneumonia (RMPP) in early stage. Methods:The prospective multicenter study was conducted in Zhejiang, China from May 1 st, 2019 to January 31 st, 2020. A total of 1 428 patients with fever >48 hours to <120 hours were studied. Their clinical data and oral pharyngeal swab samples were collected; Mycoplasma pneumoniae DNA in pharyngeal swab specimens was detected. Patients with positive Mycoplasma pneumoniae DNA results underwent a series of tests, including chest X-ray, complete blood count, C-reactive protein, lactate dehydrogenase (LDH), and procalcitonin. According to the occurrence of RMPP, the patients were divided into two groups, RMPP group and general Mycoplasma pneumoniae pneumonia (GMPP) group. Measurement data between the 2 groups were compared using Mann-Whitney U test. Logistic regression analyses were used to examine the associations between clinical data and RMPP. Receiver operating characteristic (ROC) curves were used to analyse the power of the markers for predicting RMPP. Results:A total of 1 428 patients finished the study, with 801 boys and 627 girls, aged 4.3 (2.7, 6.3) years. Mycoplasma pneumoniae DNA was positive in 534 cases (37.4%), of whom 446 cases (83.5%) were diagnosed with Mycoplasma pneumoniae pneumonia, including 251 boys and 195 girls, aged 5.2 (3.3, 6.9) years. Macrolides-resistant variation was positive in 410 cases (91.9%). Fifty-five cases were with RMPP, 391 cases with GMPP. The peak body temperature before the first visit and LDH levels in RMPP patients were higher than that in GMPP patients (39.6 (39.1, 40.0) vs. 39.2 (38.9, 39.7) ℃, 333 (279, 392) vs. 311 (259, 359) U/L, both P<0.05). Logistic regression showed the prediction probability π=exp (-29.7+0.667×Peak body temperature (℃)+0.004×LDH (U/L))/(1+exp (-29.7+0.667×Peak body temperature (℃)+0.004 × LDH (U/L))), the cut-off value to predict RMPP was 0.12, with a consensus of probability forecast of 0.89, sensitivity of 0.89, and specificity of 0.67; and the area under ROC curve was 0.682 (95% CI 0.593-0.771, P<0.01). Conclusion:In MPP patients with fever over 48 to <120 hours, a prediction probability π of RMPP can be calculated based on the peak body temperature and LDH level before the first visit, which can facilitate early identification of RMPP.