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 To investigate the expression changes of T-cell exhaustion-related genes in multiple myeloma(MM)and their potential causal relationships.Methods A bidirectional summary-level Mendelian randomization(MR)analysis was used to explore the causal relationship between T-cell exhaustion and MM.The eQTL data and genome-wide association study(GWAS)were used to summarize data,and corresponding single nucleotide polymorphisms(SNPs)were extracted as instru-mental variables.Four methods,namely inverse variance weighted(IVW)method,MR Egger,weighted median,and weighted mode were used to assess the reliability of the causal relationship.The robustness of the results was validated using Cochran's Q heterogeneity test and pleiotropy test.In cel-lular models,RNA interference was used to silence key target genes,and phenotypic changes such as myeloma cell viability,colony-forming ability,and apoptosis were observed to experimentally confirm the causal effects revealed by MR.Results The genes PRDM1,ENTPD1,PTPN11,and HLA-B were involved in the T-cell exhaustion process in MM.The presence of the PRDM1 gene(OR=0.998 5,95％CI,0.997 1 to 0.999 8,P=0.024 6)may reduce the risk of MM,whereas ENTPD1(OR=1.000 4,95％CI,1.000 1 to 1.000 7,P=0.015 8),HLA-B(OR=1.000 4,95％CI,1.000 1 to 1.000 8,P=0.012 4),and PTPN11(OR=1.002 5,95％CI,1.001 0 to 1.003 9,P=0.001 2)were associated with an increased risk of MM.Real-time quantitative polymerase chain reaction showed overexpression of PTPN11 in MM cell lines and patients' samples.By assessing cell viabili-ty,colony formation and detecting apoptosis,it was found that inhibiting PTPN11 promoted apopto-sis in MM cell lines.Conclusion A causal relationship exists between T-cell exhaustion and MM.Targeted interventions against specific T-cell exhaustion-related genes may help reduce the incidence of MM.

Objective:To understand the psychological experience of tumor radiotherapy patients after participating in acceptance and commitment therapy (ACT), and to provide reference and supplement for the development of ACT psychological intervention plans for tumor radiotherapy patients.Methods:This study was a qualitative study. Using the purposive sampling method, a total of 17 tumor radiotherapy patients treated at Shanghai Proton and Heavy Ion Center from January to March 2023 were selected as the research objects. Phenomenological research method was used to conduct semi-structured in-depth interviews with patients, and the interview data were analyzed by Colaizzi 7-step analysis method.Results:Three themes were extracted, namely, positive physical and mental experience (including improving physical symptoms, relieving negative emotions and cooperating with particle therapy), gaining personal growth (including learning flexible and varied psychological coping strategies, gaining mutual help and friendship, feeling valuable family affection and drawing a better future life) and recommendations for optimizing the ACT intervention program (including building teams according to the patients' conditions, increasing the frequency of activities, trying to experience relief exercises outdoors and increasing the continuity of the intervention program) .Conclusions:ACT can help cancer radiotherapy patients improve their physical and mental health, cope with psychological problems, so that patients can face the disease, treatment and life more positively.

Objective:To evaluate the effects of different types of psychological interventions on the fear of cancer recurrence through a network Meta-analysis.Methods:Randomized controlled trials on the effects of different types of psychological interventions on the fear of cancer recurrence were retrieved from PubMed, PsycINFO, Web of Science, The Cochrane Library, Embase, EBSCO, China Biomedical Literature Database, CNKI, Wanfang Database and Vip Database. The retrieval period was from the establishment of the database to December, 31 2022. Two researchers conducted literature screening, extraction and quality evaluation, and used Stata14.0 software to conduct network Meta-analysis.Results:A total of 29 pieces of research involving 3 068 cancer patients and 11 psychological intervention measures. The results of network Meta-analysis showed that narrative therapy, PERMA(Positive, Engagement, Relationship, Meaning, Accomplishment) happiness theory model, acceptance and commitment therapy and cognitive behavior therapy had statistically significant differences in the intervention effect on the fear of cancer recurrence compared with conventional nursing ( SMD values were -1.93--0.83, all P<0.05); there was no significant difference among narrative therapy, PERMA happiness model, acceptance and commitment therapy and gratitude-expansion behavior theory (all P>0.05). The results of the cumulative probability map showed the best intervention was narrative therapy. Conclusions:The results of this study suggest that narrative therapy, acceptance and commitment therapy, and cognitive behavior therapy may be effective psychological intervention measures to improve the fear of cancer recurrence. However, more studies are still needed for further verification.

Objective:To explore the effectiveness of positive cognitive therapy in improving anxiety and depression, psychological distress, positive awareness, and quality of life in cancer patients, with a view to providing an experience for practical clinical application.Methods:This study was a quasi experimental study, in which 96 patients with cancer radiotherapy attending Shanghai Proton Heavy Ion Center from April 2019 to January 2021 were selected as study subjects by convenience sampling, and were divided into 47 cases in the intervention group and 49 cases in the control group according to the district group randomization method. The control group was given conventional psychological care and health education, and instructed to learn the audio and video of positive cognitive therapy at the end of the study; the intervention group was given 8 sessions of positive cognitive therapy over a period of 4 weeks. At the end of the intervention, the Pdistress Thermometer, the Generalized Anxiety Inventory, the Patient Health Questionnaire Depression Inventory, the Brief Version of the Five Factor Positive Thinking Inventory, and the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire C30 were used to compare the psychological distress, anxiety and depression, positive cognitive awareness and quality of life of the two groups.Results:After the implementation of the positive cognitive therapy intervention, the incidence rate of anxiety and depression in the intervention group was 12.8% (6/47) and 14.9% (7/47), respectively, both of which were significantly lower than the 30.6% (15/49) and 32.7% (16/49) in the control group, with statistically significant differences ( χ2=3.80, 3.89, both P<0.05); after intervention the scores on the observation, description and perceived action dimensions of the Brief Version of the Five Factor Positive Thinking Scale were (23.8 ± 6.5), (28.6 ± 5.4) and (31.3 ± 5.3) respectively, all significantly higher than those of the control group (20.0 ± 5.1), (23.7 ± 5.5) and (26.9±6.2), the differences were statistically significant ( t=2.79, 3.59, 3.21, all P<0.05); the post-intervention score on the Emotional Functioning dimension of the European Organization for Research and Treatment of Cancer Quality of Life Scale (94.3 ± 7.4) was significantly higher than that of the control group (88.8 ± 11.4), with a statistically significant difference ( t=-2.28, P<0.05). Conclusions:Positive cognitive therapy is effective in relieving anxiety and depression, increasing positive awareness, and improving emotional distress in cancer patients. It can be incorporated into the daily psychological care process of tumor patients, giving them appropriate guidance and support to help improve their psychological and quality of life.

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 compare outcomes between standardized and misdiagnosis and mistreatment of osteosarcoma.Methods:A retrospective analysis of patients with high-grade osteosarcoma who received appropriate surgical treatment and chemotherapy (299 cases, control group) and those who were misdiagnosed (benign or infective) and received mistreatment (23 cases, study group) between January 2009 and December 2021. Gender, age, first operation mode, recurrence time, recurrence interval, metastasis time, metastasis interval, total survival time (months), survival status in the two group and tumor site reoperation mode in the study group were statistically analyzed. Further, chi-square test was performed for comparison of the clinical between two groups. The survival analysis was performed using Kaplan-Meier test and Log-rank test.Results:All the 322 patients were followed up. In the control group, the average follow-up time was 42 months (1-137 months), the average age was 24 years (3-80 years), male 184 cases, female 115 cases, and limb salvage rate was 85.3% (255/299). Seven patients underwent amputation, and the amputation rate was 17.7% (44/299). The recurrence rate was 8.4% (25/299), the average recurrence interval was 22.8 months (7-36 months), and the metastasis rate was 28.1% (85/299), the average metastasis time was 32.7 months (0-58 months). In the study group, the average of follow-up time was 30 months (9-117 months), the average age was 36 years (5-67 years), 17 males and 6 females. Among them, eleven patients were treated with limb salvage in the second stage, and the limb salvage rate was 47.8% (11/23). Seven patients underwent amputation, and the amputation rate was 30.4% (7/23). The recurrence rate was 26.1% (6/23), the average recurrence interval was 11 months (1-42 months), and the metastasis rate was 43.4% (10/23), the average metastasis time was 20.3 months (1-44 months). The 5-year survival rate was 50.7% in the study group and 56.1% in the control group. There was no significant difference between the two groups (χ 2=0.09, P=0.760). Conclusion:The overall prognosis of patients with high-grade osteosarcoma who receive active treatment after mistreatment is similar to that of patients with standardized treatment, but the recurrence and metastasis rate is higher, the recurrence time is earlier, and the amputation rate is higher.

Objective:To explore the mediating effect of self-management efficacy between social support and self-management behavior in cancer patients treated with proton-heavy ions.Methods:From April 2020 to April 2021, convenience sampling was used to select 674 cancer patients in Shanghai Proton and Heavy Ion Center as the research subject. The patients were investigated with the General Information Questionnaire, Chronic Disease Self-Management Study Measures (CDSMS) , Chinese-version Strategies Used by People to Promote Health (C-SUPPH) , and Medical Outcome Study Social Support Survey (MOS-SSS) . Statistical analysis was performed using SPSS 24.0 and AMOS 24.0 software. Pearson correlation was used to calculate the correlation between variables, and a structural equation model was constructed to test the relationship between variables. A total of 674 questionnaires were distributed, 610 valid questionnaires were recovered, and the valid recovery rate was 90.5% (610/674) .Results:The total scores of self-management behavior, self-management efficacy, and social support in 610 cancer patients treated with proton heavy ions were (18.38±7.64) , (94.30±22.72) and (73.97±13.94) , respectively. Pearson correlation analysis showed that except for the dimension of life support with dimension of exercise, all the other dimension scores and the total score of patients' social support were positively correlated with all the dimension scores and the total score of self-management behaviors ( P<0.05) ; the dimension scores and the total score of patients' social support were positively correlated with the dimension scores and the total score of self-management efficacy ( P<0.05) ; the dimension scores and the total score of patients' self-management efficacy were positively correlated with the dimension scores and the total score of self-management behavior ( P<0.05) . Self-management efficacy had a partial mediating effect between social support and medical staff communication behavior, with an effect value of 23.4% ( P<0.05) . Conclusions:Cancer patients treated with proton-heavy ions have poor levels of self-management behavior. Nurses can improve the patients' self-efficacy and enhance the impact of social support on the patients' self-management behavior, so as to promote the precise realization and timely completion of proton heavy ion therapy.

Objective:To explore the effect of sandplay therapy on distress and quality of life in patients with tumor during radiotherapy.Method:A total of 49 patients with tumor during radiotherapy admitted to Shanghai Proton and Heavy Ion Center from January 2019 to December 2019 were enrolled, and divided into experimental group (21 cases) and control group (28 cases) by stratified random method. Both groups received routine nursing, and extra sandplay therapy was given to the experimental group. The degree of psychological distress and quality of life of the two groups before and after the intervention were compared by using the Distress Thermometer and the five functional dimensions of the life quality core scale of European Organization for Research and Treatment of Cancer.Results:After the intervention, the Distress Thermometer scores of both groups were lower than those before the intervention, and the score of the experimental group was lower than that of the control group. The difference was statistically significant ( P<0.01) . Before and after the intervention, the decrease of dimension scores (physical function, role function, cognitive function, emotional function, social function) in the experimental group were less than those in the control group. The differences were statistically significant ( P< 0.01) . Conclusions:Sandplay therapy can reduce the distress and improve the quality of life for patients with tumor during radiotherapy.

Objective: To define the connotation of village doctors′ vulnerability. Methods: On the basis of document analysis, Delphic method was used to consult and argument the connotation of village doctors′ vulnerability from October 2015 to November 2015. Results: Twenty and 16 specialists were consulted in two rounds of the consulting. According to these consultations, the acceptance rate of the specialists for the seven consulting units increased from 74.29% to 93.16%. Conclusions The vulnerability of village doctors was identified, as a status in which their self-ability and support against their exterior environment could not to cope with the disturbances they faced, while the vulnerability was co-determined by disturbance and response ability of village doctors.