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

Multiple primary lung cancer(MPLC)refers to patients with two or more primary lesions of lung cancer.It can be divided into synchronous MPLC(sMPLC)and metachronous MPLC(mMPLC)based on the timing of occurrence.In recent years,the detection rate of MPLC has gradually increased.However,considerable controversy exists in distinguishing MPLC from intrapulmonary metastasis(IM),especially when the histopathological types are identical.Given the significant differences in treatment strategies and prognosis in clinical practice currently,accurate diagnosis of MPLC is cru-cial for personalized precision therapy.Molecular genetics and sequencing technologies offer effective strategies for assessing the clonal origin of tumors.There have been reports of coexisting mutations in the epidermal growth factor receptor(EGFR)and anaplastic lymphoma kinase(ALK)fusion genes in non-small cell lung cancer,but case of EGFR mutation following an ALK mutation has not been mentioned.This article accurately diagnoses and retrospectively analyzes the clinical data of a case of ALK mutant adenocarcinoma in a male patient who developed an EGFR mutation with multiple metastases four years after surgery,and reviews the relevant literature.This paper aims to deepen the understanding of mMPLC and provide clinical refer-ences for the diagnosis and treatment of such patients.

Objective:To investigate the clinical outcome of biplanar botulinum toxin type A injection in alleviating platysmal bands.Methods:From November 2022 to May 2023, the clinical data of patients with platysmal bands treated by botulinum toxin type A injection in Department of Face and Neck Plastic Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, and Department of Plastic Surgery, Chengdu Badachu Cosmetic Hospital were retrospectively analyzed. The platysmal bands were marked, while patients were grinning, before injection. Using a 13 mm 30 G needle, 20 U/ml botulinum toxin was injected into the muscle layer along the bands from the clavicle direction. The dose was 1 U at a single point every 1.5 cm. Using a 3 mm 30 G needle, 10 U/ml botulinum toxin was injected into the deep surface of dermis along the bands with a single point dose of 0.5 U. Effects were evaluated by overall subjective satisfaction of patients, which were categorized into 4 grades: very satisfied, satisfied, dissatisfied, very dissatisfied. In addition, accessment by a third-party physician with global aesthetic improvement scale (GAIS) (1-5 points, the lower the score, the more significant the improvement is) and Geister platysmal band scale (0-4 points, the higher the score, the more severe the platysmal band is). Normal distribution data was represented by Mean±SD.Results:A total of 19 patients were included, including 3 males and 16 females, with the average age of 36.1 years. After a mean follow-up of 1.3 months (1-5 months), the overall subjective satisfaction was 100%(19/19). The GAIS score of third-party physicians was 1.12±0.33. 100%(19/19) of patients received a rating over moderate improvement(significant improvement in 17 cases and moderate improvement in 2 cases). The Geister platysmal band score decreased from preoperative 3.65 ± 0.33 to postoperative 0.76 ± 0.44. No serious complications were found except 5 cases of local congestion and 2 cases of injection pain, which were relieved in 1 week and 3 hours respectively. 2 cases felt mild neck weakness, but neck activity was not affected. The adverse symptoms all completely resolved spontaneously within 4 weeks. All patients have no mouth deviation, difficulty speaking, facial paralysis, allergies, or other noticeable complications.Conclusion:The injection of botulinum toxin type A in dual-plane of platysmal intramuscular layer and deep intradermal layer can effectively alleviate platysmal bands and achieve neck rejuvenation.

Objective:To investigate the clinical outcome of biplanar botulinum toxin type A injection in alleviating platysmal bands.Methods:From November 2022 to May 2023, the clinical data of patients with platysmal bands treated by botulinum toxin type A injection in Department of Face and Neck Plastic Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, and Department of Plastic Surgery, Chengdu Badachu Cosmetic Hospital were retrospectively analyzed. The platysmal bands were marked, while patients were grinning, before injection. Using a 13 mm 30 G needle, 20 U/ml botulinum toxin was injected into the muscle layer along the bands from the clavicle direction. The dose was 1 U at a single point every 1.5 cm. Using a 3 mm 30 G needle, 10 U/ml botulinum toxin was injected into the deep surface of dermis along the bands with a single point dose of 0.5 U. Effects were evaluated by overall subjective satisfaction of patients, which were categorized into 4 grades: very satisfied, satisfied, dissatisfied, very dissatisfied. In addition, accessment by a third-party physician with global aesthetic improvement scale (GAIS) (1-5 points, the lower the score, the more significant the improvement is) and Geister platysmal band scale (0-4 points, the higher the score, the more severe the platysmal band is). Normal distribution data was represented by Mean±SD.Results:A total of 19 patients were included, including 3 males and 16 females, with the average age of 36.1 years. After a mean follow-up of 1.3 months (1-5 months), the overall subjective satisfaction was 100%(19/19). The GAIS score of third-party physicians was 1.12±0.33. 100%(19/19) of patients received a rating over moderate improvement(significant improvement in 17 cases and moderate improvement in 2 cases). The Geister platysmal band score decreased from preoperative 3.65 ± 0.33 to postoperative 0.76 ± 0.44. No serious complications were found except 5 cases of local congestion and 2 cases of injection pain, which were relieved in 1 week and 3 hours respectively. 2 cases felt mild neck weakness, but neck activity was not affected. The adverse symptoms all completely resolved spontaneously within 4 weeks. All patients have no mouth deviation, difficulty speaking, facial paralysis, allergies, or other noticeable complications.Conclusion:The injection of botulinum toxin type A in dual-plane of platysmal intramuscular layer and deep intradermal layer can effectively alleviate platysmal bands and achieve neck rejuvenation.

Objective:To study and design one kind of flash radiotherapy(Flash-RT)equipment with ultra-high dose rate,which can be used in the mechanism research of Flash-RT with ultra-high dose rate.Methods:Based on the technique roadmap of high-power petal accelerator,the Flash-RT equipment can realize the requirement of Flash-RT for ultra-high dose rate and multiple irradiation angles.The corresponding design and research work were carried out on the basis of the overall design of the equipment,the main components and characteristics,the dynamics design of beam,the construction of movable and preliminary experimental platform,etc.Result:The dose rate of the designed equipment can reach to 100 Gy/s at a distance of 0.8 meters from the target point,which is easy to realize the radiotherapy method with multi angles.Conclusion:The designed X-ray equipment based on the technique roadmap of high-power petal accelerator can realize the research for the mechanism of medical Flash-RT equipment with ultra-high dose rate.

The establishment of an economic operating mechanisms for hospitals is a key factor in advancing the growth of public hospitals in the modern age.At present,the due value of key factors such as medical resources and labor value of medical personnel in public hospitals in China has not been fully reflected,which not only restricts the overall operation efficiency of hospitals,but also makes it difficult to realize the marginal value of hospital operation and management.The economic operating mechanisms of public hospitals is in urgent need of reform.Large public hospitals in Henan Province has established an economic operating mechanisms of public hospitals based on intelli-gent finance,comprehensive budget management as the core,and cost control and performance management as the major tools to realize the interconnection of various systems and promote the high-quality development of hospi-tals with the three major supports of industry and finance integration,financial integration and financial integration.

In this paper,a case of toxic epidermal necrolysis(TEN)after application of tigecycline in an elderly patient was analyzed,and was analyzed and discussed combined with domestic and foreign literature.According to the criteria for assessing the association of adverse drug reactions,the TEN present in this patient is likely to be related to tigecycline.It is suggested that clinicians and pharmacists should be vigilant and pay attention to TEN that may be caused by tigecycline in clinical work.

Objective:To analyze the efficacy and safety of integrase inhibitor-based single-tablet regimens bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) and lamivudine/dolutegravir (3TC/DTG) in the treatment-na?ve patients with acquired immunodeficiency syndrome (AIDS).Methods:This study was a retrospective cohort study. The clinical data of treatment-na?ve AIDS patients initiating anti-retroviral therapy (ART) with B/F/TAF or 3TC/DTG and on ART for greater than or equal to 24 weeks from October 2020 to July 2023 in Shanghai Public Health Clinical Center, Fudan University were collected. The baseline human immunodeficiency virus (HIV)-1 RNA, CD4 + T lymphocyte counts at baseline and 12 weeks of treatment, and the rates of virological suppression and virological failure at 24 weeks of treatment, and levels of total cholesterol, serum creatinine, uric acid before and after treatment were compared between the B/F/TAF group and 3TC/DTG group. Independent sample t test, corrected t test, Mann-Whitney U test, Wilcoxon signed rank test, chi-square test were used for statistical analysis. Results:Among 189 treatment-na?ve AIDS patients, 141 cases were in B/F/TAF group and 48 cases in 3TC/DTG group. The HIV-1 RNA level at baseline was 1.77(0.78, 4.52)×10 5 copies/mL in the B/F/TAF group and 0.97(0.24, 2.20)×10 5 copies/mL in the 3TC/DTG group. There was a statistically significant difference between the two groups ( U=2 221.00, P=0.006).There were 77.3%(109/141) patients on B/F/TAF achieved complete virological suppression with no virological failure at week 24, and 85.4%(41/48) on 3TC/DTG achieved complete virological suppression with one (2.1%) virological failure at week 24. At 12 weeks of treatment, 92.2%(130/141) of the patients in the B/F/TAF group and 85.4%(41/48) of the patients in the 3TC/DTG group had an increase in CD4 + T lymphocyte count by more than 30% compared with baseline. The proportion of CD4 + T lymphocyte count increased by more than 100/μL from baseline in the B/F/TAF group was 67.4%(95/141), and that in the 3TC/DTG group was 52.1%(25/48). There were no significant differences between the two groups ( χ2=1.91 and 3.61, respectively, P=0.167 and 0.733).The levels of total cholesterol ( W=2 036.00, t=-5.42, respectively), serum creatinine ( W=1 098.00, 234.00, respectively), uric acid ( W=2 188.00, 299.00, respectively) and the proportion of patients with mild to moderate renal insufficiency ( χ2=22.29, 8.22, respectively) in the B/F/TAF group and 3TC/DTG group after 24 weeks of treatment were significantly higher than those before treatment (all P<0.01). Conclusions:Both B/F/TAF and 3TC/DTG are effective in terms of virological suppression and immunological recovery and have good safety profiles in treatment-na?ve patients with AIDS.

Objective:To analyze the changes of pathogen spectrum of pulmonary infection in human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) patients before and during coronavirus disease 2019 (COVID-19) epidemic.Methods:The clinical data of hospitalized HIV infection/AIDS patients with pulmonary infection confirmed by etiology and/or imaging examinations in the Department of Infection and Immunity, Shanghai Public Health Clinical Center, Fudan University from January 2017 to December 2022 were collected, including the types of pathogens, the peripheral blood CD4 + T lymphocyte counts at admission due to pulmonary infection, and the treatment outcome of the patients at discharge. The changes of pathogen spectrum of pulmonary infection before COVID-19 epidemic (2017 to 2019) and during the epidemic (2020 to 2022) were analyzed, and their effects on adverse treatment outcomes (death during hospitalization or automatic discharge) were analyzed. Statistical analysis was performed using the chi-square test, trend chi-square test or Kruskal-Wallis test. Results:The proportion of patients with pulmonary infection during the epidemic was lower than that before the epidemic, the difference was statistically significant (23.01%(1 061/4 612) vs 28.68%(1 463/5 102), χ2=40.76, P<0.001). From 2017 to 2022, the proportion of hospitalized HIV infection/AIDS patients with pulmonary infection showed a downward trend ( χ2trend=8.81, P<0.001). Among the pathogens causing pulmonary infection from 2017 to 2022, bacteria, mycobacteria, and fungi were the three main pathogenic pathogens, accounting for 48.77%(1 231/2 524), 32.13%(811/2 524), and 14.34%(362/2 524), respectively. The proportion of bacterial infection decreased from 55.02%(805/1 463) before the epidemic to 40.15%(426/1 061) during the epidemic, and the proportion of fungal infection increased from 9.23%(135/1 463) to 21.39%(227/1 061), the differences were both statistically significant ( χ2=54.45 and 74.11, respectively, both P<0.001). There was no significant difference in the proportion of mycobacteria between before and during the epidemic ( P=0.169), but the proportion of Mycobacterium tuberculosis (MTB) infection decreased from 22.01%(322/1 463) before the epidemic to 15.08%(160/1 061) during the epidemic, while the proportion of nontuberculous mycobacterium (NTM) infection increased from 7.11%(104/463) to 11.78%(125/1 061), the differences were both statistically significant ( χ2=19.11 and 16.28, respectively, both P<0.001). There was a significant difference in the pathogen spectrum of pulmonary infection before and during the epidemic ( χ2=128.91, P<0.001). There was a significant difference in the peripheral blood CD4 + T lymphocyte counts of patients with MTB, NTM, Pnenmocystis, Talaromycosis marneffei and Cryptococcus infection ( H=71.92, P<0.001). There were 63.74%(109/171) of Pneumocystis infection and 67.65%(69/102) of Talaromycosis marneffei infection occurred in patients with CD4 + T lymphocyte count<50/μL. Among the patients with pulmonary infection, the proportion of patients with adverse treatment outcomes during the epidemic was higher than that before the epidemic, and the difference was statistically significant (13.29%(141/1 061) vs 10.39%(152/1 463), χ2=5.04, P=0.025). Among the patients with pulmonary infection who developed adverse treatment outcomes, the top three pathogens (from high to low) were bacteria (63.48%(186/293)), mycobacteria (27.65%(81/293)), and fungi (6.83%(20/293)). The proportion of adverse treatment outcomes caused by bacterial infection decreased during the epidemic compared with that of before the epidemic (71.71%(109/152) vs 54.61%(77/141), χ2=9.23, P=0.002), while the proportion of adverse treatment outcomes caused by fungal infection increased (2.63%(4/152) vs 11.35%(16/141), χ2=8.74, P=0.003), and the differences were both statistically significant. The proportion of adverse treatment outcomes caused by mycobacterial infection increased, but without statistically significant (23.03%(35/152) vs 32.62%(46/141), χ2=3.37, P=0.066), among which there was no difference in the proportion of adverse treatment outcomes caused by MTB infection (13.82%(21/152) vs 14.89%(21/141), χ2=0.07, P=0.793), while the proportion of adverse treatment outcomes caused by NTM infection increased (5.92%(9/152) vs 14.89%(21/141), χ2=6.41, P=0.011). There was a significant difference in the pathogen spectrum of pulmonary infection patients with adverse treatment outcomes before and during the epidemic ( χ2=12.22, P=0.007). Conclusions:Among the spectrum of pathogens causing pulmonary infection and adverse treatment outcomes of HIV infection/AIDS patients during the epidemic, compared with that before the epidemic, the proportion of bacterial decreases, while the proportion of fungi increases, and the proportion of mycobacteria remains stable with the proportion of NTM increasing. The proportion of MTB causing pulmonary infection decreases, while the proportion of MTB causing adverse treatment outcomes remains stable.