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Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2 × 108–4 × 108 CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy.A new anti-CD19 CAR T cell therapy induces potent antitumor responses without causing severe cytokine-release syndrome or neurotoxicity in patients with lymphoma.

Prognosis is poor for patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) after failure of or who are ineligible for autologous stem cell transplant. We evaluated the efficacy and safety of tislelizumab, an investigational anti-PD-1 monoclonal antibody, in phase 2, single-arm study in Chinese patients with R/R cHL. The primary endpoint was overall response rate as assessed by an independent review committee, according to the Lugano 2014 Classification. Seventy patients were enrolled in the study and received at least one dose of tislelizumab. After median follow-up of 9.8 months, 61 (87.1%) patients achieved an objective response, with 44 (62.9%) achieving a complete response (CR). The estimated 9-month progression-free survival rate was 74.5%. Most common grade ≥3 adverse events (AEs) were upper respiratory tract infection and pneumonitis. Infusion-related reactions occurred in 27 (38.6%) patients, and 27 patients (38.6%) experienced an immune-related AE, the most common of which was thyroid dysfunction. Eleven (15.7%) patients experienced at least one treatment-emergent AE leading to dose interruption or delay. No deaths occurred due to AEs. Treatment of patients with R/R cHL with tislelizumab was generally well tolerated and resulted in high overall response and CR rates, potentially translating into more durable responses for these patients.

Mice are widely used as experimental models for gut microbiome (GM) studies, yet the majority of mouse GM members remain uncharacterized. Here, we report the construction of a mouse gut microbial biobank (mGMB) that contains 126 species, represented by 244 strains that have been deposited in the China General Microorganism Culture Collection. We sequence and phenotypically characterize 77 potential new species and propose their nomenclatures. The mGMB includes 22 and 17 species that are significantly enriched in ob/ob and wild-type C57BL/6J mouse cecal samples, respectively. The genomes of the 126 species in the mGMB cover 52% of the metagenomic nonredundant gene catalog (sequence identity ≥ 60%) and represent 93–95% of the KEGG-Orthology-annotated functions of the sampled mouse GMs. The microbial and genome data assembled in the mGMB enlarges the taxonomic characterization of mouse GMs and represents a useful resource for studies of host-microbe interactions and of GM functions associated with host health and diseases. Here, the authors established and characterized the mouse gut microbial biobank (mGMB), which includes 244 strains and 126 species that enlarges previous mouse intestinal bacterial collections and represents a resource for studies using mouse models to investigate microbiome-associated health and disease.

Enhancing farmers’ enthusiasm for grain cultivation is crucial for ensuring national food security. Based on survey data from the “Double Hundred and Double Thousand” farmers in Jiangxi Province, this study measures farmers’ enthusiasm for grain cultivation through their double-cropping rice cultivation behavior and employs Probit and Tobit models to empirically analyze the impact of farmers’ digital literacy on their enthusiasm for grain cultivation in traditional double-cropping rice production areas of Jiangxi, as well as its underlying mechanisms. The findings reveal: (1) Improving farmers’ digital literacy exerts a significantly positive influence on their enthusiasm for grain cultivation, promoting double-cropping rice adoption and expanding cultivation areas in traditional production regions. This conclusion remains robust after rigorous testing. (2) Mechanism analysis identifies three pathways: accelerating farmland transfer-in, facilitating the utilization of agricultural machinery socialization services, and promoting the adoption of green grain production technologies, through which enhanced digital literacy drives double-cropping rice cultivation and elevates cultivation enthusiasm. (3) Heterogeneity analysis demonstrates that the positive effect of digital literacy on double-cropping rice cultivation is more pronounced among farmers with higher educational attainment and the level of household part-time farming. Therefore, policies should prioritize elevating farmers’ overall digital literacy, narrowing digital capability gaps, refining land transfer procedures and mechanisms, leveraging the advantages of farmers’ cooperatives, and advancing the dissemination of agricultural machinery socialization services and green grain production technologies.

The coronavirus (COVID-19) expanded rapidly and affected almost the whole world since December 2019. COVID-19 has an unusual ability to spread quickly through airborne viruses and substances. Taking into account the disease’s natural progression, this study considers that viral spread is unpredictable rather than deterministic. The continuous time Markov chain (CTMC) stochastic model technique has been used to anticipate upcoming states using random variables. The suggested study focuses on a model with five distinct compartments. The first class contains Lévy noise-based infection rates (termed as vulnerable people), while the second class refers to the infectious compartment having similar perturbation incidence as the others. We demonstrate the existence and uniqueness of the positive solution of the model. Subsequently, we define a stochastic threshold as a requisite condition for the extinction and durability of the disease’s mean. By assuming that the threshold value R0D is smaller than one, it is demonstrated that the solution trajectories oscillate around the disease-free state (DFS) of the corresponding deterministic model. The solution curves of the SDE model fluctuate in the neighborhood of the endemic state of the base ODE system, when R0P>1 elucidates the definitive persistence theory of the suggested model. Ultimately, numerical simulations are provided to confirm our theoretical findings. Moreover, the results indicate that stochastic environmental disturbances might influence the propagation of infectious diseases. Significantly, increased noise levels could hinder the transmission of epidemics within the community.

Background Hematologic malignancies are one of the most common types of cancer. This study aims to assess the global burden of hematologic malignancies and analyze the global epidemiological trends. Methods Through the Global Burden of Disease Study 2021 (GBD 2021) and the Global Cancer Observatory (GLOBOCAN) 2022 project, we comprehensively evaluated the global prevalence, incidence, mortality, and disability-adjusted life-years (DALYs) of seven major hematologic malignancies, as well as their respective age-standardized rates (ASR) per 100,000 population. Regions were classified using the Socio-demographic Index (SDI) to evaluate the correlation between disease burden and economic level. In addition, we analyzed disease-related risk factors and predicted future trends up to 2040. Results From 1990 to 2021/2022, the number of global hematologic malignancy cases showed a continuously increasing trend, especially for non-Hodgkin lymphoma. However, the age-standardized death rates (ASDR) and age-standardized DALY rates (ASDALYR) of all types of hematologic malignancies tended to be stable or decline. For acute lymphoblastic leukemia, the number of death cases, ASDR, and ASDALYR decreased significantly. Nevertheless, the trends of hematologic malignancies varied by gender, age, and SDI. The burden of hematologic malignancies was generally higher in the elderly and male populations. Of course, acute lymphoblastic leukemia also imposed a huge burden on children, Hodgkin lymphoma also significantly burdened young people. Moreover, regions with a higher SDI had a higher incidence rate. Deaths related to smoking and high body mass index still played an important role in various regions, especially in regions with a higher SDI. It is predicted that the global age-standardized incidence rates (ASIR) and ASDALYR will show a slow downward trend by 2040. Conclusions Hematologic malignancies have remained a major global public health issue, with significant demographic and regional differences. The results of this study will provide a basis for analyzing the trends of the global disease burden of specific hematologic malignancies and offer a reference for health policymakers.

Aim: To investigate the effectiveness and safety of using chimeric antigen receptor (CAR) T cell therapies targeting CD19 in patients with diffuse large B-cell lymphoma (DLBCL). Methods: PubMed, Embase, and the Cochrane Library were searched for reports published from database inception up to July 2021. The present meta-analysis included clinical response outcomes, survival outcomes, and safety analyses. For qualitative analysis that could not be combined, the data were presented in a tabular form. Subgroup analyses were also performed according to the costimulatory domains, generic names, and study designs. Results: Twenty-seven studies (1,687 patients) were included. The pooled 12-months overall survival (OS) rate was 63% (95%CI: 56–70%). The pooled best overall response (BOR) was 74.0% (95%CI: 67–79%), with a best complete response (BCR) of 48% (95%CI: 42–54%) and a 3-months CR rate (CRR) of 41% (95%CI: 35–47%). The subgroup analyses by costimulatory domain suggested statistically significant differences in BOR and BCR, whereas not in the 12-months OS rate and 3-months CRR. Among the patients evaluable for safety, 78% (95%CI: 68–87%), 6% (95%CI: 3–10%), 41% (95%CI: 31–52%), and 16% (95%CI: 10–24%) experienced cytokine release syndrome (CRS), severe CRS, neurotoxicity, and severe neurotoxicity, respectively. Compared with the CD28 costimulatory domain, the 4-1BB-based products showed a better safety profile on any-grade CRS ( p < 0.01), severe CRS ( p = 0.04), any-grade neurotoxicity ( p < 0.01), and severe neurotoxicity ( p < 0.01). Conclusion: Anti-CD19 CAR-T cell immunotherapy has promising effectiveness and tolerable severe AE profile in DLBCL patients. 4-1BB-based CAR-T cells have a similar 12-months OS rate and 3-months CRR with CD28-based products but a better safety profile. The costimulatory domain might not affect the survival outcomes.

Although somatic mutations of DNA repair genes are frequent in mantle cell lymphoma (MCL), our understanding of their germline defects is limited. In a Chinese family with maternal Lynch syndrome and paternal B cell non-Hodgkin lymphoma, one sibling developed both Lynch syndrome and MCL. Lynch syndrome is caused by heterozygous mutations in mismatch repair (MMR) genes. To understand the genetic predispositions in the family, we performed exome sequencing and analyses of affected individuals and their tumor samples. A novel germline indel, MLH1 Gly101fsX1, was identified as the cause of Lynch syndrome, and unstable microsatellite loci and mutational signatures as evidence of defective MMR were revealed in the MCL sample. Furthermore, we included additional 15 MCL patients with early onset, and found by exome sequencing that 11 patients carried heterozygous germline variants of 20 DNA repair genes, including MSH2 in MMR. In the MCL with MSH2 Arg359fsX16, unstable microsatellite loci and defective MMR signatures were also found. In addition, five patients also had heterozygous germline variants of genes involved in B cell functions. Thus, our study found germline variants of genes in single-strand break repair, double-strand break repair, and Fanconi anemia pathway in early onset MCL; and for the first time we identified germline defects of MMR in two MCLs.

Background There is a dearth of accurate information about patterns of mortality of lymphoid neoplasms and temporal trends in China. In this nationwide mortality study, we aimed to assess the mortality of lymphoma and myeloma in 2017 and the changes in the trend from 2004 to 2016. Methods Death certificate data obtained from the Chinese Center for Disease Control and Prevention’s disease surveillance points system (CDC-DSP) and population data from the National Bureau of Statistics of China were used in this study. We described the mortality of lymphoma and myeloma in 2017 by age group, sex, residence, and region and evaluated the temporal trend from 2004 to 2016 using joinpoint regression. Results An estimated 52,000 deaths associated with lymphoma and myeloma occurred in 2017. The age-standardized mortality rate China (ASMRC) and age-standardized mortality rate worldwide (ASMRW) per 100,000 were 3.74 and 2.60, respectively. Males had higher ASMRC than females (4.54 vs. 2.91 per 100,000). The ASMRC in urban areas was significantly higher than that in rural areas (4.35 vs. 3.47 per 100,000). The age-specific mortality rate showed an upward trend with age and reached a maximum in the age group of over 85 years. In terms of regional variation, Eastern China had the highest mortality rate (3.43/100,000), followed by Central China (3.10/100,000) and Western China (3.02/100,000). The mortality rates of lymphoma and myeloma increased annually by 4.5% during the period 2004–2016, with a significant rapid upward trend in rural areas since 2007. Conclusions The mortality of lymphoma and myeloma increased in China from 2004 to 2017. The rapid increase in disease burden in rural areas highlights new challenges for disease prevention and control strategies.