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

The research on the cardiovascular toxicity of air pollutants is in urgent need of collaborative innovation across multiple models. This paper systematically reviewed the advantages and limitations of four principal research models of cardiotoxicity, including epidemiological model, mammalian model, zebrafish model, and in vitro model. Epidemiological models have been used to demonstrate a significant correlation between exposure to PM_2.5 and both the incidence and mortality of cardiovascular diseases within populations; however, these models face challenges in establishing causal inferences and interpreting individual mechanisms. Mammalian models have been applied to elucidate the pathogenic mechanisms of PM_2.5 at both the systemic and organ-specific levels, yet they encounter difficulties related to interspecies differences and throughput constraints. Zebrafish models, with their transparent embryos and observable development, offer a distinctive opportunity for high-throughput screening and mechanistic investigation of PM_2.5-induced cardiac developmental toxicity. Nonetheless, their cardiac physiological structure diverges from that of mammals, limiting their capacity to accurately model chronic conditions such as coronary heart disease. In vitro models, particularly human heart organoids and chip technologies, have provided profound insights into the direct toxic mechanisms of PM_2.5, including disruptions in calcium homeostasis, cellular senescence, and electrophysiological irregularities at the cellular and molecular levels. Despite these advancements, the complexity and developmental maturity of these models present challenges to their broader application. This paper proposed that the key to overcoming the bottlenecks of single models lies in the construction of an integrated evaluation system that combines “epidemiological studies, mammalian models, zebrafish models, and in vitro models”. By focusing on three aspects, namely model integration, technological convergence, and policy support, it is intended to collaboratively address issues such as standardization of multi-model data, simulation of complex exposure scenarios and susceptible life stages, and transformation pathways. This will provide innovative methodological support for the analysis of the cardiotoxic mechanisms of air pollutants, the assessment of environmental health impacts, and the formulation of precise prevention and control strategies.

Objective To grasp the main environmental factors affecting the growth of Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao;To predict the distribution of suitable areas of Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao in Shanxi Province;To provide references for the rational distribution of the resources in Shanxi Province.Methods This study utilized the sample point longitude and latitude information collected in the"Fourth Survey of Chinese Materia Medica Resources"database in Shanxi Province.The data were supplemented by searching the China Digital Herbarium and retrieving related literature records.347 sample points distribution data and environmental factors were added to the MaxEnt model.The main environmental factors and contribution rates affecting the geographical distribution of Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao were screened out.The ArcGIS software was used to divide the ecological suitable area of Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao in Shanxi Province.Results The area under the ROC curve of the established MaxEnt model was 0.909,indicating that the model prediction results were accurate.The model screened 19 environmental factors.Among them,climate factor was the most important environmental factor,followed by biological factor and topographic factor,and soil factor had the least influence.The potential suitable areas of Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao in Shanxi Province were mainly distributed in the northern mountainous areas,presenting a trend of gradually decreasing suitability levels from north to south.Under the current climate conditions,the most suitable area for Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao in Shanxi Province was 15 424 km2,the suitable area was 19 856 km2,the sub suitable area was 59 436 km2,and the unsuitable area was 61 894 km2.Conclusion Based on MaxEnt model and ArcGIS software,this study predicts the distribution of suitable areas of Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao in Shanxi Province,which has certain reference value for the protection and rational distribution of Astragalus membranaceus(Fisch.)Bge.var.mongholicus(Bge.)Hsiao resources in Shanxi Province.

Objective:To analyze clinical efficacy, failure mode and prognostic factors of nasopharyngeal carcinoma (NPC) patients undergoing intensity modulated radiation therapy (IMRT).Methods:Clinical data of 951 locally advanced NPC patients who were newly-treated with IMRT in Hunan Cancer Hospital from January 2018 to January 2019 were retrospectively analyzed. The patients' general data, overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), local recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) were analyzed. Comparison among different groups was performed by one-way ANOVA. Survival rate was calculated by Kaplan-Meier method. Survival difference was compared by log-rank test. Univariate and multivariate analyses were performed by Cox regression model.Results:The median follow-up time was 62.0 months (IQR, 58.0-65.0 months). The 5-year OS, LRFS, RRFS, LRRFS, DMFS, and PFS were 85.4%, 94.0%, 97.7%, 92.6%, 85.7% and 76.9%, respectively. According to the 8th edition staging of American Joint Committee on Cancer (AJCC), there were 10 cases (1.1%) of stage I, 76 cases (8.0%) of stage II, 445 cases (46.8%) of stage III, and 420 cases (44.2%) of stage IVA, respectively. Among them, the OS rates of stage I, II, III and IVA patients were 100%, 97.2%, 88.8% and 79.2%, respectively ( P<0.001); LRRFS rates were 100%, 90.4%, 94.7% and 90.4%, respectively( P=0.104); DMFS rates were 90.0%, 95.9%, 88.0% and 81.1%, respectively ( P<0.001); PFS rates were 90.0%, 89.1%, 80.9% and 70.1% respectively ( P<0.001). There were 183 cases of treatment failure, including 52 cases (5.5%) of local failure, 19 cases (2.0%) of regional failure, 130 cases (13.7%) of distant metastasis, 16 cases of local combined with regional failure (1.7%), 16 cases (1.7%) of local failure combined with distant metastasis, 13 cases (1.4%) of regional failure combined with distant metastasis, and 9 cases (0.9%) of local regional failure combined with distant metastasis, respectively. Multivariate regression analysis suggested that EB virus DNA copy number before treatment, T stage and N stage were the independent prognostic factors affecting OS, DMFS and PFS. Conclusions:Compared with two-dimensional radiotherapy, IMRT has improved the overall therapeutic effect for NPC, especially the local control rate. Distant metastasis is still the main failure mode. Clinical staging, prognostic risk stratification and prognostic biomarkers can be combined to deliver stratified and precise treatment, which may further improve clinical efficacy and reduce treatment-related side effects.

Objective: To propose updates and amendments for the nitroglycerin tablets quality in the Chinese pharmacopoeia 2020 due to the failure of effective separation of 4 known impurities and nonseparation of free nitrate ion and excipients.
Methods: Related substances were analyzed using gradient elution by HPLC, and free nitrate ion was determined on SAX column by different HPLC method.
Results: Using the improved method to test the related substances and free nitrate ion of nitroglycerin tablets,the content of the maximum individual impurity were not more than 0.5%, the total content was not more than 2.4% and the content of free nitrate ion was not more than 6.3%.
Conclusion: The improved method is accurate and feasible. It provided a reference for the updates and amendments of the quality standard of nitroglycerin tablets in the Chinese Pharmacopoeia 2020.

The anterior cruciate ligament (ACL), anterolateral complex (ALC) and lateral meniscus (LM) maintain the anterolateral rotatory stability of the knee and control the internal rotation of the tibia. Anterolateral rotatory instability (ALRI) of the knee is not uncommon in clinic, and its main injury mechanism is non-contact injury. A pivot shift test or a tibial internal rotation test can indicate ALRI while X-ray, CT, MRI and ultrasound can assist in its diagnosis and differential diagnosis. For acute ALRI, good technique of ACL reconstruction is the basis to avoid postoperative residual ALRI, and anterolateral ligament reconstruction and extra-articular tenodesis are optional as appropriate. For chronic cases, however, both anterolateral ligament reconstruction and extra-articular tenodesis are effective. This article reviews the progress in research on the diagnosis and treatment of ALRI of the knee, hoping to provide references for its clinical diagnosis and treatment.

Objective To explore the correlation between lumbar spine bone mineral density and the occurrence of large rotator cuff tears. Methods A total of 109 patients with arthroscopic shoulder surgery in the Department of Arthroplasty Surgery in Kunshan Hospital of Traditional Chinese Medicine from January 2018 to October 2023 were selected and divided into large rotator cuff tear group (n=27) and small rotator cuff tear group (n=82) according to the severity of the rotator cuff tears. General materials of patients were collected, and multivariate Logistic regression analysis was used to investigate the correlation between lumbar spine bone mineral density and the occurrence of large rotator cuff tears. Results The large rotator cuff tear group had significant higher age and higher proportion of patients with a history of trauma compared to the small rotator cuff tear group (P < 0.05); additionally, the levels of total cholesterol, albumin, serum magnesium, total hip bone mineral density, and lumbar spine bone mineral density were significantly lower in the large rotator cuff tear group (P < 0.05). The results of multivariate Logistic regression analysis indicated that lumbar spine bone mineral density was associated with the occurrence of large rotator cuff tears. The prevalence of large rotator cuff tears across the four quartile intervals of lumbar spine bone mineral density named as Q1 (< 0.870 g/cm²), Q2 (0.870~ < 0.991 g/cm²), Q3 (0.991~1.137 g/cm²), and Q4 (>1.137 g/cm²) were 48.15%, 29.63%, 18.52% and 3.70% respectively, showing a gradual decreasing trend with significant differences (P < 0.05). Conclusion There is a correlation between lumbar spine bone mineral density and large rotator cuff tears. The lower the bone density of the lumbar spine is, the higher the risk of large rotator cuff tears will be.

Objective:To explore the incidence, clinical characteristics, imaging features, clinical outcome and prognosis of indeterminate pulmonary nodules (IPN) in patients with osteosarcoma.Methods:A total of 69 patients of osteosarcoma with IPN in lung treated in the Bone tumor Center of Eastern Theater General Hospital from January 2011 to January 2021 were collected retrospectively, there were 47 males and 22 females, with a median age of 19 years old (range 7-60 years old). The clinical characteristics including disease-free interval, the chemotherapy response, with recurrence/non-pulmonary, IPN presence before / during / after chemotherapy and imaging features of IPN including number of IPN, location of IPN, density of IPN, boundary clarity of IPN and outcome. The patients were divided into the metastasis pulmonary nodules group and the benign nodules group according to the final outcome of IPN. Further, χ 2 test was performed for comparison of the clinical and imaging characteristics between the two groups. The survival of patients was counted and the correlation between single factor and survival was compared by Kaplan-Meier test, and multivariate survival analyses were performed using Cox proportional hazards regression models. Results:Sixty-nine cases occurred IPN in 211 patients with osteosarcoma, with an incidence of 32.7%. Of the 69 patients, 45 patients (65.2%) with IPN were diagnosed as metastases, and 24 patients (34.8%) with IPN were diagnosed as benign nodules. Follow-up length ranged from 1 to 124 months, with the median follow up time 43 months. To the end of follow-up, 41 patients (59.4%) remained alive and 28 patients (40.6%) had died. The median survival time was 41.0 (20.0, 65.0) months and the median survival time after diagnosis of IPN was 25.0 (10.0, 43.0) months. There were significant differences in lung nodule density ( P<0.001), boundary ( P=0.002), history of recurrence/extra-pulmonary metastasis ( P=0.023) and chemotherapeutic effect ( P<0.001) between the metastasis pulmonary nodules group and the benign nodules group. Multivariate survival analysis showed that chemotherapeutic effect was an independent factor affecting the overall survival of patients [ HR=0.048, 95% CI (0.01, 0.26)]. Boundary definition [ HR=0.12, 95% CI (0.02, 0.93)] and chemotherapeutic effect [ HR=0.06, 95% CI (0.01, 0.29)] were independent factors influencing survival after diagnosis of IPN. Conclusion:Osteosarcoma patients with IPN have a poor prognosis. The poor effect of chemotherapy is an independent risk factor for the overall survival time of those patients and the survival time after diagnosis of IPN. The boundary definition of IPN is an independent risk factor for the survival time after diagnosis of IPN.

Objective:To evaluate the efficacy and safety of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of pseudomyxoma peritonei (PMP).Methods:In this descriptive case series study, we retrospective analyzed the records of PMP patients treated with CRS and HIPEC between January 2013 and June 2023 at Affiliated Cancer Hospital and Institute of Guangzhou Medical University. The inclusion criteria were as follows: (1) Aged 18 to 75 years and nonpregnant women. (2) Histologically confirmed diagnosis of pseudomyxoma peritonei. (3) Karnofsky Performance Scale (KPS)>70. (4) The functions of major organs such as the heart, liver, lungs, and kidneys can tolerate major surgery for long periods of time. (5) No evidence of extra-abdominal metastasis. Patients with extensive intra-abdominal adhesions or severe infectious diseases were excluded. The main outcomes were overall survival (OS) and postoperative major complications. The postoperative major complications were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). We used the peritoneal cancer index (PCI) score to quantitatively assess the peritoneal metastases and the completeness of cytoreduction (CCR) score at the end of surgery (CCR-0 and CCR-1 considered to be complete CRS).Results:A total of the 186 PMP patients with a median age of 56 (interquartile range extremes (IQRE), 48-64) years were included, 65 (34.9%) males and 121 (65.1%) females. The median peritoneal cancer index (PCI) score was 28 (20-34). Appendiceal origin accounted for 91.4%. Histological types were low grade in 99 patients (53.2%), high grade in 57 patients (30.6%), and 55 patients (29.6%) received complete cytoreduction (CCR-0/1). The median operative duration was 300 (211-430) minutes for all patients. Treatment-related 30-day mortality was 2.7%; 90-day mortality 4.3%; reoperation 1.6%; and severe morbidity 43.0%. Within the entire series, anemia(27.4%), electrolyte disturbance(11.6%), and hypoalbuminemia(7.5%) were the most frequent major complications (grade 3-4). The incidences of gastrointestinal anastomotic leakage, abdominal bleeding, and abdominal infection were 2.2%, 2.2%, and 4.3%, respectively. After a median follow-up of 38.1 (95%CI:31.2-45.1) months, the 5-year OS was 50.3% (95%CI: 40.7%-59.9%) with a median survival time of 66.1 (95%CI: 43.1-89.1) months. The survival analysis showed that patients with pathological low grade, low PCI, and low CCR score had better survival with statistically significant differences (all P<0.05). Further stratified into complete and incomplete CRS subgroups, the 5-year OS of the CCR-0 and CCR-1 subgroups was 88.9% (95%CI: 68.3%-100.0%) and 77.6% (95%CI: 62.7%-92.5%), respectively; and 42.0% (95%CI: 29.5%-54.5%) in the CCR-2/3 subgroup. Conclusions:CRS and HIPEC may result in a long-term survival benefit for PMP patients with acceptable perioperative morbidity and mortality. This strategy, when complete CRS is possible, could significantly prolong survival for strictly selected patients at experienced centers.

Objective:To evaluate the efficacy and safety of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of pseudomyxoma peritonei (PMP).Methods:In this descriptive case series study, we retrospective analyzed the records of PMP patients treated with CRS and HIPEC between January 2013 and June 2023 at Affiliated Cancer Hospital and Institute of Guangzhou Medical University. The inclusion criteria were as follows: (1) Aged 18 to 75 years and nonpregnant women. (2) Histologically confirmed diagnosis of pseudomyxoma peritonei. (3) Karnofsky Performance Scale (KPS)>70. (4) The functions of major organs such as the heart, liver, lungs, and kidneys can tolerate major surgery for long periods of time. (5) No evidence of extra-abdominal metastasis. Patients with extensive intra-abdominal adhesions or severe infectious diseases were excluded. The main outcomes were overall survival (OS) and postoperative major complications. The postoperative major complications were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). We used the peritoneal cancer index (PCI) score to quantitatively assess the peritoneal metastases and the completeness of cytoreduction (CCR) score at the end of surgery (CCR-0 and CCR-1 considered to be complete CRS).Results:A total of the 186 PMP patients with a median age of 56 (interquartile range extremes (IQRE), 48-64) years were included, 65 (34.9%) males and 121 (65.1%) females. The median peritoneal cancer index (PCI) score was 28 (20-34). Appendiceal origin accounted for 91.4%. Histological types were low grade in 99 patients (53.2%), high grade in 57 patients (30.6%), and 55 patients (29.6%) received complete cytoreduction (CCR-0/1). The median operative duration was 300 (211-430) minutes for all patients. Treatment-related 30-day mortality was 2.7%; 90-day mortality 4.3%; reoperation 1.6%; and severe morbidity 43.0%. Within the entire series, anemia(27.4%), electrolyte disturbance(11.6%), and hypoalbuminemia(7.5%) were the most frequent major complications (grade 3-4). The incidences of gastrointestinal anastomotic leakage, abdominal bleeding, and abdominal infection were 2.2%, 2.2%, and 4.3%, respectively. After a median follow-up of 38.1 (95%CI:31.2-45.1) months, the 5-year OS was 50.3% (95%CI: 40.7%-59.9%) with a median survival time of 66.1 (95%CI: 43.1-89.1) months. The survival analysis showed that patients with pathological low grade, low PCI, and low CCR score had better survival with statistically significant differences (all P<0.05). Further stratified into complete and incomplete CRS subgroups, the 5-year OS of the CCR-0 and CCR-1 subgroups was 88.9% (95%CI: 68.3%-100.0%) and 77.6% (95%CI: 62.7%-92.5%), respectively; and 42.0% (95%CI: 29.5%-54.5%) in the CCR-2/3 subgroup. Conclusions:CRS and HIPEC may result in a long-term survival benefit for PMP patients with acceptable perioperative morbidity and mortality. This strategy, when complete CRS is possible, could significantly prolong survival for strictly selected patients at experienced centers.