Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells' productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.
Humans ; Receptors, Chimeric Antigen/therapeutic use* ; Immunotherapy, Adoptive ; Hematologic Neoplasms/therapy* ; Treatment Outcome

Hepatocellular carcinoma is one of the common causes of tumor-related death, and it has high morbidity and mortality rates in China. Recent studies have shown that platelets are closely associated with the development of hepatocellular carcinoma. Literature review shows that platelets not only participate in hemostasis, but also act on liver cells and tumor microenvironment, promote the formation of new blood vessels, and participate in the development and progression of hepatocellular carcinoma as a cell mediator through immune response and other pathways. In addition, platelets and their derivatives can be used as potential therapeutic targets for hepatocellular carcinoma. Therefore, antiplatelet therapy is expected to become a new adjuvant strategy for the treatment of hepatocellular carcinoma, which has important clinical significance.

Objective Drug resistance is the main cause of chemotherapy failure in hepatocellular carcinoma (HCC), and thioredoxin reductase 1 (TXNRD1), as a major influencing factor for reactive oxygen species (ROS) metabolism, has been proven to be associated with the poor prognosis of patients with HCC. This study aims to explore the role of TXNRD1 in the mechanism of multidrug resistance in HCC. Methods BEL/FU cells in BEL-7402 cell line were selected as the multidrug-resistant cell line. The siRNA was used for the intervention of TXNRD1 expression; quantitative real-time PCR and Western blotting were used to measure the expression of TXNRD1; CCK-8 assay and flow cytometry were used to evaluate the effect of TXNRD1 on hepatocyte ROS accumulation, resistance to 5-fluorouracil (5-Fu) and doxorubicin (DOX), and apoptosis in vitro; a xenograft tumor model was established to investigate the effect of auranofin (AUR) on drug resistance in vivo. The two-independent-samples t test was used for comparison of continuous data between two groups. Results As a multidrug-resistant HCC cell line, BEL/Fu showed high mRNA and protein expression levels of TXNRD1 (both P < 0.05). Compared with 5-Fu or DOX treatment alone, the TXNRD1 inhibitor AUR combined with 5-Fu or DOX had had a significant reduction in the number of colony formation ( P < 0.01) and a significant increase in apoptosis ratio ( P < 0.001). The ROS scavenger N-acetylcysteine (NAC) significantly weakened the effect of TXNRD1 knockdown by siRNA on the drug resistance of BEL/Fu cells, and the application of NAC effectively reduced the apoptosis ratio of cells after siRNA interference ( P < 0.001). Animal experiments also confirmed that compared with the nude mice treated with 5-Fu alone, the nude mice treated with 5-Fu and AUR had a significantly lower tumor mass ( P < 0.001) and a significantly smaller tumor volume ( P < 0.001). Conclusion TXNRD1 plays an important role in the drug resistance of HCC, and inhibition of its level in cells can effectively improve drug resistance. As a TXNRD1 inhibitor, AUR has great application prospects in the multimodality therapy for HCC.

The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized three-dimensional (3D) chromatin architecture and dynamics remains poorly understood. Here by combining imaging and sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to detachment of lamina-associated domains (LADs) from the nuclear periphery accompanied with global chromatin redistribution and decompaction. Consequently, the inter-chromosomal as well as inter-compartment interactions are increased, but the structure of topologically associating domains (TADs) is not affected. Using live-cell genomic loci tracking, we further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nucleoplasm. Taken together, our data suggest that lamin B1 and chromatin interactions at the nuclear periphery promote LAD maintenance, chromatin compaction, genomic compartmentalization into chromosome territories and A/B compartments and confine chromatin dynamics, supporting their crucial roles in chromatin higher-order structure and chromatin dynamics.
Chromatin ; Chromosomes ; Genome ; Humans ; Lamin Type B/genetics*

Objective:To investigate the influencing factors of hospitalization for pregnant women with influenza A.Methods:From December 2018 to February 2019, 261 pregnant women with influenza A were admitted to Beijing Ditan Hospital, Capital Medical University. The clinical data of age, gestational period, underlying diseases, time from onset to treatment, white blood cell count and lymphocyte count of these patients were collected. Data of out-patients were compared with those of inpatients. Chi-square test and multivariate logistic regression were used to analyze the influencing factors of hospitalization in pregnant women with influenza A.Results:Among the 261 cases of pregnancy with influenza A, 36 cases (13.79%) were hospitalized, of which 10 (27.78%) were hospitalized due to severe influenza complications, the other 26 cases (72.22%) were hospitalized due to pregnancy related adverse events. The proportions of hospitalized patients with age ≥30 years old, gestational period ≥28 weeks, combined with underlying diseases and lymphocyte count <1×10 9/L were 75.00%(27/36), 83.33%(30/36), 16.67%(6/36) and 50.00%(18/36), respectively, which were significantly higher than those of out-patients (47.11%(106/225), 35.56%(80/225), 0.89%(2/225) and 13.22%(16/121), respectively; χ2=9.66, 29.05, 26.00 and 22.12, respectively, all P<0.05). The proportions of inpatients and out-patients with white blood cell count ≥4×10 9/L were 97.22%(35/36) and 97.52%(118/121), respectively, and there was no significant difference ( χ2=0.01, P=0.921). Multivariate logistic regression analysis showed that age ≥30 years (odds ratio ( OR)=5.181, 95% confidence interval ( CI) 1.628-16.489, P=0.005), gestational period ≥28 weeks ( OR=11.054, 95% CI 3.233-37.796, P<0.01), lymphocyte count <1×10 9/L ( OR=6.864, 95% CI 2.237-20.729, P=0.001), and time from onset to treatment <24 h ( OR=0.076, 95% CI 0.012-0.468, P=0.005) were the influencing factors for hospitalization of pregnant women with influenza A. Conclusion:Age ≥30 years old, gestational period ≥28 weeks, lymphocyte count <1×10 9/L and time from onset to treatment <24 h are the influencing factors for hospitalization of pregnant women with influenza A.

Objective:To explore the consistency of peripheral whole blood and venous serum procalcitonin (PCT) levels, and the value of peripheral whole blood PCT in evaluating pediatric bacterial infection.Methods:This multicenter cross-sectional parallel control study was conducted in 11 children′s hospital. All the 1 898 patients older than 28 days admitted to these hospitals from March 2018 to February 2019 had their peripheral whole blood and venous serum PCT detected simultaneously with unified equipment, reagent and method. According to the venous serum PCT level, the patients were stratified to subgroups. Analysis of variance and chi-square test were used to compare the demographic characteristics among groups. And the correlation between the peripheral blood and venous serum PCT level was investigated by quantitative Pearson correlation analysis.The PCT resultes were also converted into ranked data to further test the consistency between the two sampling methods by Spearman′s rank correlation test. Furthermore, the ranked data were converted into binary data to evaluate the consistency and investigate the best cut-off of peripheral blood PCT level in predicting bacterial infection.Results:A total of 1 898 valid samples were included (1 098 males, 800 females),age 27.4(12.2,56.7) months. There was a good correlation between PCT values of peripheral whole blood and venous serum ( r=0.97 , P<0.01). The linear regression equation was PCT?venous serum=0.135+0.929×PCT peripheral whole blood. However, when stratified to 5 levels, PCT results showed diverse and unsatisfied consistency between the two sampling methods ( r=0.51-0.92, all P<0.01). But after PCT was converted to ordinal categorical variables, the stratified analysis showed that the coincidence rate of the measured values by the two sampling methods in each boundary area was 84.9%-97.1%. The dichotomous variables also showed a good consistency (coincidence rate 96.8%-99.3%, Youden index 0.82-0.89). According to the severity of disease, the serum PCT value was classified into 4 intervals（<0.5、0.5-<2.0、2.0-<10.0、≥10.0 μg/L）, and the peripheral blood PCT value also showed a good predictive value (AUC value was 0.991 2-0.997 9). The optimal cut points of peripheral whole blood PCT value 0.5、1.0、2.0、10.0 μg/L corresponding to venous serum PCT values were 0.395, 0.595, 1.175 and 3.545 μg/L, respectively. Conclusions:There is a good correlation between peripheral whole blood PCT value and the venous serum PCT value, which means that the peripheral whole blood PCT could facilitate the identification of infection and clinical severity. Besides, the sampling of peripheral whole blood is simple and easy to repeat.

Objective:To analyze the epidemiological and clinical characteristics of patients with imported corona virus disease 2019 (COVID-19) in Beijing City.Methods:A case-control study was performed to retrospectively analyze 69 cases of imported COVID-19 from abroad and 147 cases of domestic confirmed COVID-19 from China as a control group from January 20 to March 20, 2020 admitted to Beijing Ditan Hospital, Capital Medical University.The epidemiological and clinical characteristics were compared.Statistical analysis were performed by t test, Mann-Whitney U test, chi-square test and Fisher exact test. Results:The main sources of the cases in the import group were from the United Kingdom, Italy, Spain and other European countries, with 44.9%(31/69) of the overseas students entering the country by air. The age of the imported group (27(21, 40) years) was lower than the domestic group (43 (32, 59)years), the difference between the two groups was statistically significant ( U=2 828.500, P<0.01). Compared with the domestic group, the proportion of cases with contact history of confirmed cases in the imported group was lower (30.4%(21/69) vs 68.0%(100/147)), the interval between onset and admission ≤seven days was higher (81.2%(56/69) vs 66.0%(97/147)), the proportion of cases with underlying diseases was lower (21.7%(15/69) vs 44.2%(65/147)). The differences between the two groups were all statistically significant ( χ2=26.935, 5.233 and 10.175, respectively, all P<0.05). The proportion of mild cases in the imported group was higher than that in the domestic group (42.0%(29/69) vs 10.9%(16/147)). Seventeen cases with olfactory abnormality and 12 cases with taste abnormality were found in the imported group, while no olfactory and taste abnormality was found in the domestic group. The proportions of fever, weakness, muscle soreness and dyspnea were all lower than those of the domestic group, the differences between the two groups were all statistically significant ( χ2=13.851, 8.118, 9.730 and 16.255, respectively, all P<0.01). The proportions of cases with decreased lymphocyte absolute numbers (37.7%(26/69) vs 67.3%(99/147)) and increased C reactive protein level (15.9%(11/69) vs 51.8%(72/139)) were both lower than the domestic group, and the differences between the two groups were both statistically significant ( χ2=18.015 and 24.722, respectively, both P<0.01). The proportions of cases with ground glass shadow and consolidation of chest computed tomography were lower than those of the domestic group and the differences between the two groups were all statistically significant ( χ2=11.961 and 5.099, respectively, all P<0.05). In terms of complications, the proportions of cases with acute respiratory distress syndrome and acute myocardial injury were lower (2.9%(2/69) vs 10.9%(16/147) and 4.3%(3/69) vs 14.0%(16/114), respectively), and there were statistically significant differences between the two groups ( χ2=4.017 and 4.335, respectively, both P<0.05). There were no cases received mechanical ventilation and extracorporeal membrane oxygenation in the imported group, and the proportions of patients received oxygen therapy and antibiotic treatment were significantly lower than those in the domestic group (13.0%(9/69) vs 26.5%(39/147) and 13.0%(9/69) vs 39.5%(58/147), respectively) and the differences between the two groups were statistically significant ( χ2=4.942 and 15.797, respectively, both P<0.05). Conclusions:The majority of imported COVID-19 cases are mainly from European countries, mostly young and middle-aged, and mostly mild and ordinary types.The symptoms of olfactory and taste abnormality are found for the first time.

Mantle cell lymphoma (MCL) is a distinct histological type of B-cell lymphoma with a poor prognosis. Several agents, such as proteasome inhibitors, immunomodulatory drugs, and inhibitors of B cell lymphoma-2 and Bruton's tyrosine kinase have shown efficacy for relapsed or refractory (r/r) MCL but often have short-term responses. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin's lymphoma. However, long-term safety and tolerability associated with CAR T-cell therapy are not defined well, especially in MCL. In this report, we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy. CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient. This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL, who are generally elderly and have comorbid conditions.
Adult ; Aged ; Cell- and Tissue-Based Therapy ; Humans ; Immunotherapy, Adoptive ; Lymphoma, Mantle-Cell/therapy* ; Neoplasm Recurrence, Local ; Receptors, Chimeric Antigen

Objective:To explore a method of improving the nursing service ability after total hip arthroplasty (THA) among nurses in villages and towns medical health institutions under the county medical community model and to evaluate its effects.Methods:From June 1 2018 to September 30 2019, we took Department of Orthopedics, Dazhu County People's Hospital of Dazhou of Sichuan Province, as the core, and united with county medical community built by villages and towns medical health institutions with the country in organizing the nursing theoretical knowledge and specialist service ability training after THA for 140 nurses of villages and towns medical health institutions within county medical community. Before and after training, we carried out the theoretical test and practice ability test in trainers, and implemented the consistency analysis in scores of nursing assessment scales for specialist service so as to evaluate the subjective training effect. We also compared the incidence of postoperative complications, functional recovery of hip joint as well as the satisfaction among 30 THA patients before (October 2017 to September 2018) and after (October 2018 to September 2019) training so as to explore the clinical effect.Results:Before and after training, scores of theoretical achievements of nurses of villages and towns medical health institutions were 60 (56, 62) and 82 (79, 85) respectively, and scores of practice ability were 52 (47, 62) and 86 (81, 91) respectively with statistical differences ( P<0.01) . After training, the incidence of postoperative complications was lower than that before training (6.67% vs. 26.67%) ; the postoperative satisfaction, scores of Harris Hip Score (HHS) one month and three months after surgery were higher than those before training [90.00% vs. 66.67%, (73.1±6.00) vs. (57.6±6.67) , (86.6±4.49) vs. (74.5±6.20) ]among 30 THA patients with statistical differences ( P<0.05) . Conclusions:Training with the county medical community model can improve the nursing service ability of nurses in villages and towns medical health institutions among THA patients, postoperative function of hip joint of THA patients as well as patient satisfaction.

Objective To explore the functional properties of the brain's resting state networks in neonates with hypoxic ischemic encephalopathy.Methods Use the methods of functional MRI probabilistic tractography and graph theory to compare the global and local functional properties of the brain's resting state network between 12 cases of children with mild HIE and 14 cases of children with moderate/severe HIE.Results In terms of global topological properties,both the mild and moderate/severe group showed small-world properties.The γ and λ in the mild group were 2.450± 1.642 and 1.542±0.564 and in the moderate/severe group were 2.331± 1.554 and 1.353±0.672,respectively,which were in line with the characteristics of small-world properties (γ＞ 1 and λ ≈ 1).As far as local topological properties were concerned,the distribution of hub regions in the functional networks had smaller number of nodes in the moderate/severe group (8 nodes) than the mild group (14 nodes).The comparison of nodal efficiencies showed that the moderate/severe group had significantly reduced nodal efficiency in the left insula opercula,left supramarginal gyrus,left and right temporal pole and right middle temporal gyrus(the nodal efficiencies of the moderate/severe group:0.4089±0.0865,0.3377±0.1223,0.3842±0.0898,0.3508±0.1295,0.3564±0.0843;the nodal efficiencies of the mild group:0.4801±0.0762,0.4465±0.0898,0.4655 ±0.0812,0.4640±0.0690,0.4271±0.0636,all P＜0.05).Conclusion The topological structure of resting state functional network in children with moderate and severe hypoxic-ischemic encephalopathy is obviously backward than that in children with mild hypoxic-ischemic encephalopathy,which may be related to abnormal language,movement and cognitive function in the late stage.