Search

To date, almost all studies regarding chimeric antigen receptor (CAR)-T cell therapy for B-cell acute lymphoblastic leukemia (B-ALL) were performed in refractory/relapsed (r/r) or minimal residual disease-positive patients. CAR-T therapy in remission patients has not been reported.To observe the treatment outcome of CAR-T cells for remission B-ALL patients with poor prognosis.CAR-T treatment was applied to two B-ALL patients in remission status who had poor prognostic factors and refused transplantation, and one case was unable to accept standard chemotherapy owing to multiple complications. The procedure of CAR-T therapy in these two remission patients was the same as that in r/r B-ALL patients. Lentiviral vectors encoding second generation CARs composed of CD3ζ and 4-1BB were used to produce CAR-T cells. Lymphodepleting agents fludarabine and cyclophosphamide were administered prior to cell infusion. Grade I cytokine release syndrome occurred after each T-cell infusion and there was no neurotoxicity. CAR-T treatment followed by non-intensive maintenance chemotherapy and targeted drugs allowed both patients to obtain a long-term event-free survival of more than three and a half years without transplantation.CAR-T therapy could be used in high-risk B-ALL patients as a consolidation to avoid transplantation, the combination of CAR-T and following maintenance therapy may be better than CAR-T alone for durable remission.

Background For CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To overcome this immunogenicity, we applied humanized CD19 (hCD19) CAR-T cells to treat r/r B-ALL patients with prior mCD19 CAR-T therapy. Methods Nineteen pediatric and adult patients were included, 16 relapsed after and 3 were primarily resistant to mCD19 CAR-T. All patients presented with more than 5% blasts in bone marrow and/or extramedullary disease, and still showed CD19 antigen expression. Humanized CD19-CARs were lentiviral vectors carrying a second generation CAR with 4–1-BB co-stimulatory and CD3ζ signaling domains. Patient-derived cells were collected for producing CAR-T cells, the median dose of infused hCD19 CAR-T cells was 2.4 × 105/kg (range, 1.0–18.0 × 105/kg). Results hCD19 CAR-T resulted in a complete remission (CR) rate of 68% (13/19). Among 13 remission patients, 11 underwent allogeneic hematopoietic cell transplantation (allo-HCT) (3 were second HCT) and 10 remained in CR; the event-free survival rates at 12–18 months were 91% in 11 patients received following allo-HCT and 69% in all CR patients. Six cases had no response to hCD19 CAR-T, 3 died of disease progression; another 3 received salvage second transplantation, of them, 2 relapsed again (one died). Cytokine release syndrome (CRS) occurred in 95% (18/19) of patients, most CRS events were grade 1 and grade 2 (n = 17), there was only one grade 4 CRS. Two cases experienced grade 1 neurotoxicity. Conclusions Humanized CD19 CAR-T cell therapy could be a treatment option for CD19-positive B-ALL patients who relapsed after or resisted prior murine CD19 CAR-T, hCD19 CAR-T followed by allo-HCT provided a longer remission in CR patients. Nevertheless, the prognosis of non-responders to hCD19 CAR-T remained dismal. Trial registration Chinese Clinical Trial Registry/WHO International Clinical Trial Registry (ChiCTR1900024456, URL: www.chictr.org.cn); registered on July 12, 2019.

The COVID-19 infections have profoundly and negatively impacted the whole world. Hence, we have modeled the dynamic spread of global COVID-19 infections with the connectedness approach based on the TVP-VAR model, using the data of confirmed COVID-19 cases during the period of March 23rd, 2020 to September 10th, 2021 in 18 countries. The results imply that, (i) the United States, the United Kingdom and Indonesia are global epidemic centers, among which the United States has the highest degree of the contagion of the COVID-19 infections, which is stable. South Korea, France and Italy are the main receiver of the contagion of the COVID-19 infections, and South Korea has been the most severely affected by the overseas epidemic; (ii) there is a negative correlation between the timeliness, effectiveness and mandatory nature of government policies and the risk of the associated countries COVID-19 epidemic affecting, as well as the magnitude of the net contagion of domestic COVID-19; (iii) the severity of domestic COVID-19 epidemics in the United States and Canada, Canada and Mexico, Indonesia and Canada is almost equivalent, especially for the United States, Canada and Mexico, whose domestic epidemics are with the same tendency; (iv) the COVID-19 epidemic has spread though not only the central divergence manner and chain mode of transmission, but also the way of feedback loop. Thus, more efforts should be made by the governments to enhance the pertinence and compulsion of their epidemic prevention policies and establish a systematic and efficient risk assessment mechanism for public health emergencies.

This paper constructs a partial equilibrium model under public health emergency shocks based on economic growth theory, and investigates the relationship between government intervention and virus transmission and economic growth path. We found that both close contacts tracing measures and isolation measures are beneficial to human capital stock and economic output per capita, and the effect of close contact tracing measures is better than that of isolation measures. For infectious diseases of different intensities, economic growth pathways differed across interventions. For low contagious public health emergencies, the focus should be on the coordination of isolation and tracing measures. For highly contagious public health emergencies, strict isolation, and tracing measures have limited effect in repairing the negative economic impact of the outbreak. The theoretical model provides a basic paradigm for the future researches to study economic growth under health emergencies, with good scalability and robustness.

Background Mental disorders have become an important public health issue and evidence is lacking on the impact of childhood experience on adulthood mental health in regions of low and middle income. Using national representative data from the China Health and Retirement Longitudinal Study, we aimed to explore the impact of childhood familial environment on adulthood depression. Methods A total of 19 485 subjects were interviewed. The survey collected information on demographic variables, variables of childhood familial environment and potential pathway variables, including childhood health status, adulthood physical health status, adulthood social support and adulthood socio-economic status (SES). Depressive symptoms were measured by the 10-item version of the Center for Epidemiological Studies Depression Scale. Results Parents’ physical and mental health during the subjects’ childhood were significantly associated with adulthood mental health. Mothers’ smoking, unfair treatment and low family SES were associated with higher depressive symptoms in adulthood. Childhood physical and mental health status, adulthood physical health and adulthood SES might be important mediators in the pathways of childhood familial environment affecting adulthood depressive symptoms. Conclusions This study is the first to explore the relationship of childhood familial environment and adulthood depression in China. The results indicate that parents’ physical and mental health, health behaviour and treatment equity among children a important predictors for adult depression.

The prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic transplantation is dismal when treated with conventional approaches. While single-target CD19 or CD22 chimeric antigen receptor (CAR) T-cell therapy has achieved high complete remission (CR) rates in refractory/relapsed B-ALL, it could not maintain a durable remission in most patients. To prolong relapse-free survival, we sequentially combined CD19 and CD22 CAR-T cells to treat post-transplant relapsed B-ALL patients with both CD19/CD22 antigen expression on lymphoblasts. Patient-derived donor cells were collected to produce CAR-T cells that were transfected by lentiviral vectors encoding second generation CARs composed of CD3ζ and 4-1BB. The second T-cell infusion was scheduled at least 1 month, and usually within 6 months after the first CAR-T treatment. Twenty-seven adult and pediatric patients, including 11 (41%) with extramedullary diseases (EMD), received the first CD19 CAR-T and 23 (85%) achieved CR. Subsequently, 21 out of 27 patients received the second CD22 CAR-T and were followed-up for a median of 19.7 (range, 5.6-27.3) months; 14 cases remained in CR, seven relapsed and two of them died from disease progression; Kaplan-Meier survival analysis showed overall survival and event-free survival rates of 88.5% and 67.5%, respectively, at both 12 months and 18 months. CAR-T associated graft-versus-host disease (GVHD) occurred in 23% of patients, with 8% new-onset acute GVHD and 15% persistent or worsened pre-existing cGVHD before CAR-T. This combination strategy of sequential CD19 and CD22 CAR-T therapy significantly improved the long-term survival in B-ALL patients who relapsed after transplantation.

Coxsackievirus B1 (CVB1) is a major pathogen that causes viral myocarditis and aseptic meningitis and is implicated as a cause of type 1 diabetes mellitus. The rapid detection of neutralizing antibodies can help in the prevention and diagnosis of viral infection. The traditional cytopathic effect (CPE)-based neutralization assay (Nt-CPE) is time-consuming and labor-intensive. In this study, an efficient neutralization test based on an enzyme-linked immunospot assay and a monoclonal antibody 2E6 against CVB1 (Nt-Elispot) was developed. In this optimal Nt-Elispot, a multiplicity of infection (MOI) of 1 per well was set as the infection dose, and an incubation time of 18 hours was selected as the checkpoint. Compared with Nt-CPE, Nt-Elispot significantly shortened the detection period and displayed a good correlation with it. This established CVB1 Nt-Elispot could be applied to efficiently screen neutralizing antibodies and evaluate the level of NAb against CVB1 in large cohorts.

Coxsackievirus A10 (CVA10) recently has become one of the major pathogens of hand, foot, and mouth disease (HFMD) in children worldwide, but no cure or vaccine against CVA10 is available yet. Serological evaluation of herd immunity to CVA10 will promote the development of vaccine. The traditional neutralization assay based on inhibition of cytopathic effect (Nt-CPE) is a common method for measuring neutralizing antibody titer against CVA10, which is time-consuming and labor-intensive. In this study, an efficient neutralization test based on a monoclonal antibody (mAb) 3D1 against CVA10, called Elispot-based neutralization test (Nt-Elispot), was developed. In the Nt-Elispot, the mAb 3D1 labeled with horseradish peroxidase (HRP) was used to detect the CVA10-infected RD cells at a 1:4000 dilution and the optimal infectious dose of CVA10 was set at 105 TCID50/well when combined with a fixed incubation time of 14 h. Compared with the Nt-CPE, the Nt-Elispot method effectively shortened the detection period and presented a good correlativity with it. Using the Nt-Elispot, a total of 123 sera from healthy children were tested for neutralizing antibody against CVA10, demonstrating that the overall seroprevalence was 49.3% (54/123) and the geometric mean titer (GMT) had been calculated as 574.2. Furthermore, 2 anti-CVA10 neutralizing mAbs were obtained by screening via the Nt-Elispot. Overall, the established Nt-Elispot could be used as an efficient and high-throughput method for evaluating immunity to CVA10 and screening the neutralizing antibodies.

Enterovirus D68 (EV-D68) undergoes structural transformation between mature, cell-entry intermediate (A-particle) and empty forms throughout its life cycle. Structural information for the various forms and antibody-bound capsids will facilitate the development of effective vaccines and therapeutics against EV-D68 infection, which causes childhood respiratory and paralytic diseases worldwide. Here, we report the structures of three EV-D68 capsid states representing the virus at major phases. We further describe two original monoclonal antibodies (15C5 and 11G1) with distinct structurally defined mechanisms for virus neutralization. 15C5 and 11G1 engage the capsid loci at icosahedral three-fold and five-fold axes, respectively. To block viral attachment, 15C5 binds three forms of capsids, and triggers mature virions to transform into A-particles, mimicking engagement by the functional receptor ICAM-5, whereas 11G1 exclusively recognizes the A-particle. Our data provide a structural and molecular explanation for the transition of picornavirus capsid conformations and demonstrate distinct mechanisms for antibody-mediated neutralization.

Hand-foot-and-mouth disease is a common childhood illness primarily caused by coxsackievirus A16 (CVA16), for which there are no current vaccines or treatments. We identify three CVA16-specific neutralizing monoclonal antibodies (nAbs) with therapeutic potential, 18A7, 14B10, and NA9D7. We present atomic structures of these nAbs bound to all three viral particle forms --the mature virion, A-particle and empty particle-- and show that each Fab can simultaneously occupy the mature virion. Additionally, 14B10 or NA9D7 provide 100% protection against lethal CVA16 infection in a neonatal mouse model. 18A7 binds to a non-conserved epitope present in all three particles, whereas 14B10 and NA9D7 recognize broad protective epitopes but only bind the mature virion. NA9D7 targets an immunodominant site, which may overlap the receptor binding site. These findings indicate that CVA16 vaccines should be based on mature virions and that these antibodies could be used to discriminate optimal virion-based immunogens.

Despite worldwide promising clinical outcome of CD19 CAR-T therapy, relapse after this therapy is associated with poor prognosis and has become an urgent problem to be solved. We conducted a CD22 CAR T-cell therapy in 34 relapsed or refractory (r/r) B-ALL pediatric and adult patients who failed from previous CD19 CAR T-cell therapy. Complete remission (CR) or CR with incomplete count recovery (CRi) was achieved in 24 of 30 patients (80%) that could be evaluated on day 30 after infusion, which accounted for 70.5% of all 34 enrolled patients. Most patients only experienced mild cytokine-release syndrome and neurotoxicity. Seven CR patients received no further treatment, and 3 of them remained in remission at 6, 6.6, and 14 months after infusion. Eleven CR patients were promptly bridged to transplantation, and 8 of them remained in remission at 4.6 to 13.3 months after transplantation, resulted in 1-year leukemia-free survival rate of 71.6% (95% CI, 44.2-99.0). CD22 antigen loss or mutation was not observed to be associated with relapsed patients. Our study demonstrated that our CD22 CAR T-cells was highly effective in inducing remission in r/r B-ALL patients, and also provided a precious window for subsequent transplantation to achieve durable remission.

Copyright © 2018 The Authors. Coxsackievirus A10 (CVA10) recently emerged as a major pathogen of hand, foot, and mouth disease and herpangina in children worldwide, and lack of a vaccine or a cure against CVA10 infections has made therapeutic antibody identification a public health priority. By targeting a local isolate, CVA10-FJ-01, we obtained a potent antibody, 2G8, against all three capsid forms of CVA10. We show that 2G8 exhibited both 100% preventive and 100% therapeutic efficacy against CVA10 infection in mice. Comparisons of the near-atomic cryo-electron microscopy structures of the three forms of CVA10 capsid and their complexes with 2G8 Fab reveal that a single Fab binds a border region across the three capsid proteins (VP1 to VP3) and explain 2G8's remarkable cross-reactivities against all three capsid forms. The atomic structures of this first neutralizing antibody of CVA10 should inform strategies for designing vaccines and therapeutics against CVA10 infections.

Human enteroviruses (EVs) are the most common causative agents infecting human, causing many harmful diseases, such as hand, foot, and mouth disease (HFMD), herpangina (HA), myocarditis, encephalitis, and aseptic meningitis. EV-related diseases pose a serious worldwide threat to public health. To gain comprehensive insight into the seroepidemiology of major prevalent EVs in humans, we firstly performed a serological survey for neutralizing antibodies (nAbs) against Enterovirus A71 (EV-A71), Coxsackie virus A16 (CV-A16), Coxsackie virus A6 (CV-A6), Coxsackie virus A10 (CV-A10), Coxsackie virus B3 (CV-B3), Coxsackie virus B5 (CV-B5), Echovirus 25 (ECHO25), and Echovirus 30 (ECHO30) among the healthy population in Xiamen City in 2016, using micro-neutralization assay. A total of 515 subjects aged 5 months to 83 years were recruited by stratified random sampling. Most major human EVs are widely circulated in Xiamen City and usually infect infants and children. The overall seroprevalence of these eight EVs were ranged from 14.4% to 42.7%, and most of them increased with age and subsequently reached a plateau. The co-existence of nAbs against various EVs are common among people ≥ 7 years of age, due to the alternate infections or co-infections with different serotypes of EVs, while most children were negative for nAb against EVs, especially those

Depression is a common mental disorder due to high risk of the adolescence development stage. Few studies discussed the association between family socioeconomic status (SES) and depression and its mechanism. We aimed to provide a national view of depressive symptoms among Chinese adolescents to explore the relationship between family SES and depressive symptoms. We used the data from the Chinese Family Panel Studies (CFPS). Family SES include family income and parents' educational attainment. Depressive symptoms were measured by the Center for Epidemiological Study Depression. Family SES was found to be significantly associated with adolescents' depressive symptoms. The study indicated that adolescents were more likely to have depressive symptoms when family income decreased. Poor self-confidence, mathematics performance, and physical health were associated with high risk for depressive symptoms. The presence of these factors greatly weakened the association between family SES and depressive symptoms. Therefore, adolescents’ mental health is vulnerable and connected to family SES. Physical health, school performance, and self-confidence might be important mediators in the pathways of family SES affecting depressive symptoms. Prevention and intervention programs are important and necessary to improve the mental health of Chinese adolescents, and the effect of family SES should be considered in these programs.

Indoleamine 2,3-dioxygenase (IDO, subsequently named IDO1) can degrade the level of essential amino acid tryptophan in mammals, and catalyze the initial and rate-limiting step through the kynurenine pathway. Broad evidence implies that IDO is overexpressed in both tumor cells and antigen-presenting cells, facilitating the escape of malignant tumors from immune surveillance. In the past decades, the inhibition of IDO has been one of the most promising areas in cancer immunotherapy and many potential inhibitors of IDO have been designed, synthesized and evaluated, among which d-1-methyl-tryptophan and INCB24360 have advanced to clinical trial stage. This review aims to give an overview of the rationale for IDO as a therapeutic target as well as the research progress of IDO inhibitors.