OBJECTIVE: To retrospectively analyze the clinical data of newly diagnosed acute myeloid leukemia (AML) patients treated with venetoclax combined with azacitidine (Ven/Aza) or standard "3+7" regimen and similar regimens, collect real-world study data, compare the treatment response and adverse events between the two regimens, as well as perform survival analysis. METHODS: To retrospectively analyze the efficacy, survival, and adverse reactions of newly diagnosed AML patients treated with Ven/Aza (24 cases) and "3+7" regimens (117 cases ) in our hospital from September 2009 to March 2023, as well as factors influencing outcomes. A propensity score matching (PSM) was performed on age and Eastern Cooperative Oncology Group performance status (ECOG PS) to obtain a 1:1 matched cohort of 20 pairs, and the efficacy and survival before and after the matching were compared. RESULTS: The median age of patients in the Ven/Aza group was 69 years, while that in the "3+7" group was 56 years (P <0.001). Objective remission rate (ORR) was 62.5% in Ven/Aza group and 74.8% in "3+7" group (P >0.05). The median overall survival (OS) in the Ven/Aza group was 522 days, while that in the "3+7" group was 1 002 days (P >0.05). After controlling the two variables of age and ECOG PS, a PSM cohort of 20 pairs was obtained, in which the ORR was 65% in Ven/Aza group and 60% in "3+7" group (P >0.05). The median OS was 522 days and 629 days, and median progression-free survival (PFS) was 531 days and 198 days between the two groups, respectively. There were no statistically significant differences in OS and PFS between the two groups (both P >0.05). Additionally, the incidence of adverse events in the Ven/Aza group was significantly reduced. CONCLUSION The overall cohort shows that the "3+7" regimen has advantages in efficacy and survival, but Ven/Aza regimen is relatively safer. After performing PSM on age and ECOG PS, the Ven/Aza group showed improved efficacy, and a longer median PFS compared to "3+7" group.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Retrospective Studies ; Sulfonamides/administration & dosage* ; Azacitidine/administration & dosage* ; Bridged Bicyclo Compounds, Heterocyclic/administration & dosage* ; Aged ; Middle Aged ; Male ; Female ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Treatment Outcome

Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

ObjectiveTo study the effect of Bufei Tongbi decoction on pulmonary fibrosis in diabetic rats via the transforming growth factor-β₁ （TGF-β₁）/phosphorylated Smad family member 3 （p-Smad3） signaling pathway. MethodsStreptozotocin （60 mg·kg^-1） and bleomycin （24.80 U·kg^-1） were used to prepare the rat model of diabetes with pulmonary fibrosis by intratracheal injection. Sixty rats were randomly assigned into blank， model， low-， medium-， and high-dose （3.98， 7.95， and 15.90 g·kg^-1， respectively） Bufei Tongbi decoction， and pirfenidone （0.36 mg·kg^-1） groups （n=10）. The successfully modeled rats in each group were administrated with corresponding agents once per day for four consecutive weeks. After drug administration， fasting blood glucose and lung function indicators were measured. Chemical immunoassay was employed to determine the serum levels of hydroxyproline （Hyp）， hyaluronic acid （HA）， and laminin （LN）. The lung index was determined by the wet and dry methods. The pathological changes in the lung tissue were observed by hematoxylin-eosin （HE） staining， and the degree of fibrosis was detected by Masson staining. The mRNA and protein levels of TGF-β₁， p-Smad3， Smad3， α-smooth muscle actin （α-SMA）， collagen type Ⅰ alpha 1 （Col1A1）， and fibronectin were determined by PCR and Western blotting， respectively. ResultsCompared with the blank group， the model group showed alveolar septa thickening， obvious thickening of the basement membrane of pulmonary blood vessels， severe destruction of the alveolar structure， structural disarrangement of the lung parenchyma， and an increase in the proportion of inflammatory cell infiltration in the lung tissue， together with a large amount of blue collagen deposition and a large amount of collagen fibroplasia in the bronchial wall， vessel wall， interstitium， and alveolar wall， which indicated severe fibrosis. Bufei Tongbi decoction groups and the pirfenidone group showed lower fasting blood glucose level （P<0.05） and higher forced vital capacity （FVC）， cytoplasmic dynein （Cydn）， FEV_0.3/FEV ratio， and lung index （P<0.05） than the model group. Moreover， these groups demonstrated alleviated lung fibrosis， elevated Hyp， HA， and LN levels， down-regulated mRNA levels of α-SMA， Col1A1， and fibronectin， and down-regulated protein levels of TGF-β₁， Smad3， p-Smad3， α-SMA， Col1A1， and fibronectin （P<0.05）. ConclusionBufei Tongbi decoction can inhibit pulmonary fibrosis in diabetic rats by inhibiting the TGF-β₁/p-Smad3 signaling pathway.

Objective To explore the correlation between the rs7296288 single nucleotide polymorphism(SNP)of the DHH gene and the onset of depression.Methods From March 2018 to December 2019,480 patients with depression in Sichuan Provincial People's Hospital,Jining Mental Hospital,Yunnan Mental Health Center were collected as the case group,and 329 patients without depression were collected as the control group.Peripheral blood samples were collected and DNA was extracted.After multiple amplification and high-throughput sequencing,statistical software was used to analyze the relevant data.Results The rs7296288 polymorphism of the DHH gene,the AA genotype was 32.9％in the control group and 36.7％in the case group,with no statistical difference;the AC genotype was 52.8％in the control group and 47.7％in the case group,with no statistical difference;the CC genotype was 14.3％in the control group and 15.6％in the case group,with no statistical difference.The co-dominant,dominant,and recessive statistical models were not statistically significant.Subgroup analysis of the degree of depressive episodes,suicide attempts,and first-episode patients did not find an association between the rs7296288 SNP locus of the DHH gene and the clinical features of depression,that is,the SNP rs7296288 of the DHH gene had no significant correlation with depression.Conclusion The rs7296288 polymorphism of DHH gene is not correlated with the pathogenesis of depression.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective Advances in synthetic DNA technology have made it much easier to fake human DNA samples.There are literature reports that fake human DNA can be synthesized by different methods and implanted in the field to confuse the investigation or mislead the trial.Therefore,distinguishing authentic human DNA from synthetic DNA and performing individual identification has become a critical scientific challenge.Methods We define a novel composite genetic marker(methylation-microhaplotype)by combining CpG sites stably hypermethylated or hypomethylated in natural human DNA and nearby immediately adjacent microhaplotype sites.A total of 19 locis were obtained according to the screening criteria,and a composite detection system for methylation-microhaplotypes was established using MPS technology.Random volunteer DNA samples were extracted and synthetic DNA samples were prepared based on whole genome amplification techniques.Population DNA samples were analyzed to evaluate forensic parameters and methylation variability of the methylation-microhaplotype markers.Comparative analyses of human and synthetic DNA were conducted to assess the markers'ability to discriminate between the two and to detect/type both components in mixed mixed samples.Results The composite detection system composed of 19 locis demonstrated high individual identification ability,achieving a cumulative individual identification probability of 0.999 999 999 996 86.12 hypermethylated locis and 7 hypomethylated locis had relatively stable methylation levels in 57 human DNA samples.According to the allele methylation rate(Ram)value,the system can effectively identify natural and synthetic DNA samples.Meanwhile,for mixed DNA samples,the presence of human and synthetic DNA samples can be found and genotyped.Conclusion Methylation-microhaplotype genetic markers,which can discover human DNA and synthetic DNA and can detect the presence and genotyping of them from mixed samples,is a potential useful tool for forensic DNA analysis.

Objective Advances in synthetic DNA technology have made it much easier to fake human DNA samples.There are literature reports that fake human DNA can be synthesized by different methods and implanted in the field to confuse the investigation or mislead the trial.Therefore,distinguishing authentic human DNA from synthetic DNA and performing individual identification has become a critical scientific challenge.Methods We define a novel composite genetic marker(methylation-microhaplotype)by combining CpG sites stably hypermethylated or hypomethylated in natural human DNA and nearby immediately adjacent microhaplotype sites.A total of 19 locis were obtained according to the screening criteria,and a composite detection system for methylation-microhaplotypes was established using MPS technology.Random volunteer DNA samples were extracted and synthetic DNA samples were prepared based on whole genome amplification techniques.Population DNA samples were analyzed to evaluate forensic parameters and methylation variability of the methylation-microhaplotype markers.Comparative analyses of human and synthetic DNA were conducted to assess the markers'ability to discriminate between the two and to detect/type both components in mixed mixed samples.Results The composite detection system composed of 19 locis demonstrated high individual identification ability,achieving a cumulative individual identification probability of 0.999 999 999 996 86.12 hypermethylated locis and 7 hypomethylated locis had relatively stable methylation levels in 57 human DNA samples.According to the allele methylation rate(Ram)value,the system can effectively identify natural and synthetic DNA samples.Meanwhile,for mixed DNA samples,the presence of human and synthetic DNA samples can be found and genotyped.Conclusion Methylation-microhaplotype genetic markers,which can discover human DNA and synthetic DNA and can detect the presence and genotyping of them from mixed samples,is a potential useful tool for forensic DNA analysis.

Objective To investigate the nutritional status of children with cystic fibrosis(CF)and understand the correlation between malnutrition and clinical characteristics as well as lung function.Methods A retrospective analysis was performed on clinical data of CF children admitted from January 2016 to June 2023.Clinical characteristics of CF children with different nutritional statuses were compared,and the correlation between malnutrition and lung function was analyzed.Results A total of 52 CF children were included,comprising 25 boys(48％)and 27 girls(52％),aged between 7 months and 17 years.Respiratory symptoms were the predominant clinical manifestations(96％,50/52).The prevalence of malnutrition was 65％(34/52),with moderate/severe malnutrition being the most common(65％,22/34).The malnutrition group had a longer duration of illness,higher proportion of digestive system symptoms,and lower levels of serum albumin(P＜0.05).Pulmonary function parameters,including forced expiratory volume in one second as a percentage of the predicted value,ratio of forced expiratory volume in one second to forced vital capacity,forced expiratory flow at 25％of forced vital capacity exhaled,forced expiratory flow at 50％of forced vital capacity exhaled,forced expiratory flow at 75％of forced vital capacity exhaled,and maximum mid-expiratory flow as a percentage of the predicted value,were lower in the malnutrition group compared to the normal nutrition group(P＜0.05).Correlation analysis showed body mass index Z-score was positively correlated with the above six pulmonary function parameters(P＜0.05).Conclusions The prevalence of malnutrition is high in CF children and is associated with decreased lung function.CF children with higher body mass index have better lung function.Therefore,screening and evaluation of nutritional status as well as appropriate nutritional intervention should be emphasized in CF children.[Chinese Journal of Contemporary Pediatrics,2024,26(3):275-281]

OBJECTIVE: To establish the dynamic treatment strategy of Chinese medicine (CM) for metastatic colorectal cancer (mCRC) by machine learning algorithm, in order to provide a reference for the selection of CM treatment strategies for mCRC. METHODS: From the outpatient cases of mCRC in the Department of Oncology at Xiyuan Hospital, China Academy of Chinese Medical Sciences, 197 cases that met the inclusion criteria were screened. According to different CM intervention strategies, the patients were divided into 3 groups: CM treatment alone, equal emphasis on Chinese and Western medicine treatment (CM combined with local treatment of tumors, oral chemotherapy, or targeted drugs), and CM assisted Western medicine treatment (CM combined with intravenous regimen of Western medicine). The survival time of patients undergoing CM intervention was taken as the final evaluation index. Factors affecting the choice of CM intervention scheme were screened as decision variables. The dynamic CM intervention and treatment strategy for mCRC was explored based on the cost-sensitive classification learning algorithm for survival (CSCLSurv). Patients' survival was estimated using the Kaplan-Meier method, and the survival time of patients who received the model-recommended treatment plan were compared with those who received actual treatment plan. RESULTS: Using the survival time of patients undergoing CM intervention as the evaluation index, a dynamic CM intervention therapy strategy for mCRC was established based on CSCLSurv. Different CM intervention strategies for mCRC can be selected according to dynamic decision variables, such as gender, age, Eastern Cooperative Oncology Group score, tumor site, metastatic site, genotyping, and the stage of Western medicine treatment at the patient's first visit. The median survival time of patients who received the model-recommended treatment plan was 35 months, while those who receive the actual treatment plan was 26.0 months (P=0.06). CONCLUSIONS The dynamic treatment strategy of CM, based on CSCLSurv for mCRC, plays a certain role in providing clinical hints in CM. It can be further improved in future prospective studies with larger sample sizes.
Humans ; Colorectal Neoplasms/therapy* ; Machine Learning ; Female ; Male ; Middle Aged ; Neoplasm Metastasis ; Algorithms ; Medicine, Chinese Traditional/methods* ; Aged ; Adult ; Kaplan-Meier Estimate