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• A high incidence of coagulation disorders was observed after chimeric antigen receptor (CAR)-T cell therapy infusion. • The changes of coagulation parameters were associated with cytokine release syndrome (CRS). • Disseminated intravascular coagulation was found in patients with severe CRS and indicated a poor prognosis. • Coagulation disorders are manageable in most patients after CAR-T cell infusion. Chimeric antigen receptor (CAR)-T cell therapy, a new immunotherapy for relapsed and refractory (R/R) hematologic malignancies, can be accompanied by adverse events, including coagulation disorders. Here, we performed a comprehensive analysis of coagulation parameters in 100 patients with R/R hematologic malignancies after receiving CAR-T cell therapy to illuminate the profiles of coagulation disorders and to facilitate the management of coagulation disorders. A high incidence of coagulation disorders was observed, including elevated D-dimer (50/100, 50%), increased fibrinogen degradation product (45/100, 45%), decreased fibrinogen (23/100, 23%), prolonged activated partial thromboplastin time (16/100, 16%), and prolonged prothrombin time (10/100, 10%). Coagulation disorders occurred mainly during day 6 to day 20 after CAR-T cell infusion. The changes in coagulation parameters were associated with high tumor burden in acute lymphoblastic leukemia, more lines of prior therapies, lower baseline platelet count, and especially cytokine release syndrome (CRS). Disseminated intravascular coagulation (DIC) was found in 7 patients with grade ≥3 CRS and indicated a poor prognosis. Our study suggests that coagulation disorders are manageable in most patients after CAR-T cell therapy. Coexistence of DIC and severe CRS is closely related to nonrelapsed deaths during the acute toxicity phase, and effective and timely treatment is the key to reduce nonrelapse mortality for patients with DIC and severe CRS. [ABSTRACT FROM AUTHOR]

The large ownership of direct-expansion (DX) air-conditioning (A/C) systems in small and medium-sized buildings brings with it the need to reduce their energy consumption without damaging the thermal comfort of the occupants. Model predictive control (MPC) is an effective method to optimally control the operation of air-conditioners. However, most existing MPC methods require the investment of additional equipment and labor-intensive work, which greatly increases the cost of MPC and hinders its practical application. To solve the problem, this paper presents an economical and practical MPC algorithm for DX A/C systems, capable of achieving a balance between thermal comfort and energy saving. The proposed algorithm was experimentally validated on both an experimental DX A/C system and a market available split-type air-conditioner. Experimental results on the experimental DX A/C system show that temperature and humidity set-points selected at α = 1 saved 23.3% of energy consumption compared to those selected at α = 0, while keeping indoor thermal comfort within acceptable range. And results on the split-type air-conditioner demonstrate energy savings of up to more than 32% compared to the baseline and proved that the algorithm can be practically applied on market available D/X air-conditioners. • A practical application-oriented model predictive control algorithm is developed for DX A/C systems. • A cooling capacity prediction ANN model of the DX A/C system is used to predict the cooling load. • An ANN model for predicting the operational status of the DX A/C system is developed without increasing the training data. • A cost function is used to balance indoor thermal comfort levels and energy consumption. • The algorithm has been validated in both an experimental DX A/C system and a market available split-type air-conditioner. [ABSTRACT FROM AUTHOR]

As a nonspecific alkylating antineoplastic agent, busulfan has been widely used in the treatment of patients with chronic myeloid leukemia. In vitro and in vivo studies demonstrated busulfan-induced cell apoptosis. Whether busulfan triggers platelet apoptosis remains unclear. This study aimed to evaluate the role of busulfan in platelet apoptosis. Isolated human platelets were incubated with busulfan followed by analysis of platelet apoptosis by flow cytometry or western blot, including mitochondrial depolarization, expression of Bcl-2, and Bax and caspase 3 activation. Meanwhile, platelet activation, expression of glycoprotein Ibα (GPIbα), glycoprotein VI (GPVI), and IIb3 and platelet aggregation in response to collagen and adenosine diphosphate (ADP) were measured. Additionally, busulfan was injected into mice with or without administration of caspase inhibitor QVD-Oph to investigate its effect on platelet lifespan. Our results showed that busulfan-treated platelets displayed increased mitochondrial membrane depolarization, decreased expression of Bcl-2, increased expression of Bax and caspase 3 activation in dose-dependent manner, which were inhibited by QVD-Oph. Platelet activation was not observed in busulfan-treated platelets as showed by no increased P-selectin expression and PAC-1 binding. However, busulfan reduced collagen- or ADP-induced platelet aggregation without affecting expression of GPIbα, GPVI, and IIb3. Furthermore, busulfan reduced circulating platelet lifespan which was ameliorated by QVD-Oph in mice. In conclusion, busulfan triggers mitochondrial-dependent platelet apoptosis and reduces platelet lifespan in mice. These data suggest targeting caspase activation might be beneficial in the prophylaxis of platelet apoptosis-associated thrombocytopenia after administration of busulfan. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mercury isotope ratios provide a new insight of the metal sources in Hg deposits. • The slight positive mercury odd-MIF values in Hg deposit are observed. • Mercury odd-MIF is a robust tracer to distinguish the metal sources. The genesis of the typical Hg-Au-Sb metallogenic district in the southwestern margin of the Yangtze Craton, Southwestern China, remains controversial. A systematic study of the mercury (Hg) concentrations and Hg isotopic compositions of the Hg deposit at Paiting was conducted to constrain the sources of metals. Mass-independent fractionation (MIF) of Hg isotopes with slight positive Δ199Hg (0.03‰ to 0.22‰) was observed in the Hg ore samples, indicating that Hg transported by the ore fluids was primarily derived from the Cambrian black shale as these rocks show similar Δ199Hg signatures (−0.02‰ to 0.08‰). Based on these newly obtained Hg isotope ratios, we propose that deep hydrothermal fluids promoted the mobilization of Hg in Hg-bearing strata (i.e., Cambrian Niutitang Formation black shale) in the paleo-basin sedimentary strata to form Hg-enriched fluids. The Hg-enriched fluids flowed and permeated from the lower to the upper strata during mineralization and were transported to the platform margin slope facies along faults, followed by Hg precipitation to form Hg deposits. Hg isotope ratios could be a robust tracer to distinguish the metal sources of hydrothermal Hg deposits. [ABSTRACT FROM AUTHOR]

Targeted inhibition of the Wnt pathway is a promising strategy for treating NSCLC. CDC2-like kinase 2 (CLK2), a dual-specificity kinase responsible for phosphorylating serine/arginine-rich (SR) proteins, can modulate Wnt signaling through the alternative splicing of Wnt target genes, making CLK2 an attractive therapeutic target for NSCLC. In this study, we report the synthesis, optimization, and evaluation of CLK2 inhibitors that effectively suppress the proliferation of NSCLC cells, with the identification of the lead compound LBM22. Notably, compound LBM22 demonstrated potent inhibition of CLK2 (IC 50  = 3.9 nM), leading to broad suppression of NSCLC cells proliferation and induction of apoptosis. Furthermore, LBM22 dose-dependently suppressed SR protein phosphorylation (pSRSF4, pSRSF5, and pSRSF6) in NSCLC cells, while downregulating the expression of Wnt pathway-related proteins (p-β-catenin, Axin 2, and c-Myc) as well as anti-apoptotic proteins (Bcl-2 and Mcl-1). Additionally, significant antiproliferative activity was observed for LBM22 in 3D cultured H1975OR cells. In conclusion, LBM22 emerges as a promising CLK2 inhibitor for the treatment of NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Some challenges still exist with single-target B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies due to variable or negative BCMA expression, although they have yielded remarkable efficacy in relapsed or refractory multiple myeloma. We developed anti-BCMA/GPRC5D bispecific CARs to mitigate the limitations and potentiate the functions of CAR T cells., Methods: This single-arm, phase 1 trial was conducted at the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China). The trial enrolled patients aged 18-75 years with relapsed or refractory multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-3. Anti-BCMA/GPRC5D bispecific CAR T cells were administered at 0·5 × 10 6 , 1·0 × 10 6 , 2·0 × 10 6 , and 4·0 × 10 6 CAR T cells per kg in the dose-escalation phase, with additional patients included at the dose selected for the dose-expansion phase. The primary endpoint was safety, which included dose-limiting toxicity and maximum tolerated dose. Activity was also evaluated as a secondary endpoint. The maximum tolerated dose was chosen for the dose-expansion phase. Safety and activity analyses were done in all patients who received anti-BCMA/GPRC5D bispecific CAR T cells as defined in the protocol. This trial is registered with ClinicalTrials.gov (NCT05509530) and is complete., Findings: Between Sept 1, 2022, and Nov 3, 2023, 24 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (two patients discontinued due to rapid disease progression and one patient was withdrawn because of failed manufacture of CAR T cells), so 21 patients were infused with anti-BCMA/GPRC5D bispecific CAR T cells. Median follow-up was 5·8 months (IQR 5·2-6·7). Median age was 62 years (IQR 56-67). Eight (38%) patients were male, and 13 (62%) female. All patients were Chinese. At the 4·0 × 10 6 CAR T cells per kg dose, two patients had dose-limiting toxicities, of whom one died of subarachnoid haemorrhage (which was not considered to be related to the study treatment). The maximum tolerated dose was identified as 2·0 × 10 6 CAR T cells per kg. The most common grade 3 or worse adverse events were haematological toxicities in 19 (90%) patients (except lymphopenia). 15 (71%) patients had cytokine release syndrome, of which all cases were grade 1 or 2. One case of grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in a patient who received 4·0 × 10 6 CAR T cells per kg. No ICANS or grade 3 or worse organ toxicities were observed in patients who received 0·5-2·0 × 10 6 CAR T cells per kg. The overall response rate was 86% (18 of 21 patients), with 13 (62%) patients having a complete response or better, and 17 (81%) patients having measurable residual disease negativity. Of the 12 patients who received 2·0 × 10 6 CAR T cells per kg (three in the dose-escalation phase and an addition nine in the dose-expansion phase), the overall response rate was 92% (11 of 12 patients) with nine (75%) patients having a complete response or better., Interpretation: Anti-BCMA/GPRC5D bispecific CAR T cells show a good safety profile and encouraging activity in patients with relapsed or refractory multiple myeloma., Funding: National Natural Science Foundation of China., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AHC is a founding member of Shanghai YaKe Biotechnology, a biotechnology company focusing on research and development of tumour cellular immunotherapy. YZ and SP are employed by Shanghai YaKe Biotechnology. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Peripheral T-cell lymphomas (PTCL) are an aggressive group of mature T-cell neoplasms, often associated with poor outcomes, in part, due to frequent relapsed/refractory disease. The objective of this study was to assess the prognostic impact of disease progression within 24 months (POD24) on overall survival (OS) for patients diagnosed with PTCL., Methods: A retrospective analysis was conducted on a cohort of patients with newly diagnosed PTCL who underwent chemotherapy at the Affiliated Hospital of Xuzhou Medical University between January 2010 and September 2021. Prognostic assessment was limited to patients who were evaluable for POD24., Results: Records were reviewed for 106 patients with PTCL, of whom 66 patients experienced POD24 (referred to as the POD24 group) and 40 patients did not experience POD24 (referred to as the no POD24 group). Significant differences were observed between the POD24 group and the no POD24 group in regard to clinical stage, Eastern Cooperative Oncology Group (ECOG) performance status (PS), International Prognostic Index (IPI) score, lactate dehydrogenase (LDH) levels, β2-microglobulin (β2-MG) levels, prealbumin and albumin levels. Patients in the POD24 group had a significant shorter median OS compared to the no POD24 group (11.9 months vs not reached, respectively; P  < 0.001). Non response (NR) to treatment and POD24 were identified as independent negative prognostic factors for survival in patients with PTCL., Conclusion: POD24 is a prognostic factor associated with unfavorable outcomes in patients with PTCL and can be used to identify high-risk patients and guide treatment decisions.

Relapsed/refractory multiple myeloma patients with extramedullary disease (EMD) have unfavorable prognosis and lack effective therapy. Chimeric antigen receptor (CAR) T-cell activities in EMD have yet to be determined; how EMD-specific microenvironment influences the clinical outcomes of CAR T-cell therapy remains of great interest. In this prospective cohort study, patients with histologically confirmed extra-osseous EMD were enrolled and treated with combined anti-BCMA and anti-CD19 CAR T-cell therapy from May 2017 to September 2023. Thirty-one patients were included in the study. Overall response occurred in 90.3% of medullary disease and 64.5% of EMD (p = .031). Discrepancies in treatment response were noted between medullary and extramedullary diseases, with EMD exhibiting suboptimal and delayed response, as well as shortened response duration. With a median follow-up of 25.3 months, the median progression-free and overall survival were 5.0 and 9.7 months, respectively. Landmark analysis demonstrated that progression within 6 months post-infusion is strongly associated with an increased risk of death (HR = 4.58; p = .029). Compared with non-EMD patients, patients with EMD showed inferior survival outcomes. Unique CAR-associated local toxicities at EMD were seen in 22.6% patients and correlated with the occurrence and severity of systemic cytokine release syndrome. To the cutoff date, 65% treated patients experienced EMD progression, primarily in the form of BCMA + progression. The pretherapy EMD immunosuppressive microenvironment, characterized by infiltration of exhausted CD8 + T cells, was associated with inferior clinical outcomes. CAR T cells have therapeutic activity in relapsed/refractory EMD, but the long-term survival benefits may be limited. EMD-specific microenvironment potentially impacts treatment. Further efforts are needed to extend EMD remission and improve long-term outcomes., (© 2024 Wiley Periodicals LLC.)

Background: Trailing parents, a distinct group emerging from China's rapid social change and urbanization, are experiencing migration in old age, posing challenges for their social adaptation. Existing research has mainly focused on the hardships faced by this group, but few studies have focused on how they cope with change and achieve some degree of successful social adaptation. This study aimed to understand the coping and social adaptation process of trailing parents in China., Methods: This study used a qualitative research approach. A total of 24 trailing parents were invited to participate in a semi-structured interview and share their experiences and efforts to cope with the many challenges. Kumpfer's resilience framework was used as the theoretical framework for the study design, data collection, and data analysis., Results: This study identified several intra-family and community stressors that trailing parents may face when moving to a new environment and uncovered five key resilience characteristics that may be triggered or fostered in the presence of these stressors, including physical fitness, psychological stability, open-mindedness, learning ability, and nurturing hobbies. Individuals with resilience traits have been observed to engage in positive cognitive processing and transform the new environment. Consistent with Kumpfer's resilience framework, this study revealed the dynamics of the stressors faced by trailing parents in the new environments, the role of resilience characteristics, and the critical influence of social support in shaping the interplay between the individual and the environment that enabled them to adapt positively., Conclusions: This study highlights the importance of fostering resilience traits and leveraging positive coping mechanisms to facilitate a smoother adaptation process for trailing parents. Meanwhile, there is an urgent need to focus on creating opportunities that strengthen their social support networks., (© 2024. The Author(s).)

Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM., (© 2024. The Author(s).)

As the electron transport layer in quantum dot light-emitting diodes (QLEDs), ZnO suffers from excessive electrons that lead to luminescence quenching of the quantum dots (QDs) and charge-imbalance in QLEDs. Therefore, the interplay between ZnO and QDs requires an in-depth understanding. In this study, DFT and COSMOSL simulations are employed to investigate the effect of sulfur atoms on ZnO. Based on the simulations, thiol ligands (specifically 2-hydroxy-1-ethanethiol) to modify the ZnO nanocrystals are adopted. This modification alleviates the excess electrons without causing any additional issues in the charge injection in QLEDs. This modification strategy proves to be effective in improving the performance of red-emitting QLEDs, achieving an external quantum efficiency of over 23% and a remarkably long lifetime T 95 of >12 000 h at 1000 cd m -2 . Importantly, the relationship between ZnO layers with different electronic properties and their effect on the adjacent QDs through a single QD measurement is investigated. These findings show that the ZnO surface defects and electronic properties can significantly impact the device performance, highlighting the importance of optimizing the ZnO-QD interface, and showcasing a promising ligand strategy for the development of highly efficient QLEDs., (© 2023 Wiley‐VCH GmbH.)

Maintaining animal gut health through modulating the gut microbiota is a constant need when antibiotics are not used in animal feed during the food animal production process. Prebiotics is regarded as one of the most promising antibiotic alternatives for such purpose. As an attractive prebiotic, the role and mechanisms of neoagarooligosaccharides (NAOS) in promoting animal growth and gut health have not been elucidated. In this study, we first cloned and expressed marine bacterial β-agarase in yeast to optimize the NAOS preparation and then investigated the role and the underlying mechanisms of the prepared NAOS in improving chicken gut health and function. The marine bacterial β-agarase PDE13B was expressed in Pichia pastoris GS115 and generated even-numbered NAOS. Dietary the prepared NAOS promoted chicken growth and improved intestinal morphology, its barrier, and digestion capabilities, and absorption function. Metagenomic analysis indicated that NAOS modulated the chicken gut microbiota structure and function, and microbial interactions, and promoted the growth of spermidine-producing bacteria especially Faecalibacterium. Through integration of gut metagenome, gut content metabolome, and gut tissue transcriptome, we established connections among NAOS, gut microbes, spermidine, and chicken gut gene expression. The spermidine regulation of genes related to autophagy, immunity, and inflammation was further confirmed in chicken embryo intestinal epithelium cells. We also verified that NAOS can be utilized by Faecalibacterium prausnitzii to grow and produce spermidine in in vitro experiments. Collectively, we provide a systematic investigation of the role of NAOS in regulating gut health and demonstrate the microbial spermidine-mediated mechanism involved in prebiotic effects of NAOS, which lays foundation for future use of NAOS as a new antibiotic alternative in animal production., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: The improvement of chicken growth performance is one of the major concerns for the poultry industry. Gut microbes are increasingly evidenced to be associated with chicken physiology and metabolism, thereby influencing chicken growth and development. Here, through integrated multi-omics analyses, we showed that chickens from the same line differing in their body weight were very different in their gut microbiota structure and host-microbiota crosstalk; microbes in high body weight (HBW) chickens contributed to chicken growth by regulating the gut function and homeostasis. We also verified that a specific bacterial consortium consisting of isolates from the HBW chickens has the potential to be used as chicken growth promoters. These findings provide new insights into the potential links between gut microbiota and chicken phenotypes, shedding light on future manipulation of chicken gut microbiota to improve chicken growth performance., Competing Interests: The authors declare no conflict of interest.

The development of hyperuricemia (HUA) and gout is associated with dysbiosis of the gut microbiota. Quercetin can reduce serum uric acid levels and thus alleviate HUA by modulating the gut microbiota. However, the detailed mechanisms involved in this process are not fully understood. Here, we showed that quercetin significantly reduced the serum uric acid level in a chicken HUA model by altering the chicken cecal microbiota structure and function and increasing the abundance of Lactobacillus aviarius. An L. aviarius strain, CML180, was isolated from the quercetin-treated chicken gut microbiota. Strain characterization indicated that quercetin promoted the growth of L. aviarius CML180 and increased its adhesion, hydrophobicity, and co-aggregation abilities. Gavage of live L. aviarius CML180 to a mouse model of HUA-established by adenosine and potassium oxonate-reduced the serum uric acid level and alleviated HUA. The ability of L. aviarius CML180 to decrease the level of uric acid was due to its degradation of purine nucleosides, which are the precursors for uric acid production. A nucleoside hydrolase gene, nhy69, was identified from the genome of L. aviarius CML180, and the resulting protein, Nhy69, exhibited strong purine nucleoside-hydrolyzing activity at mesophilic temperature and neutral pH conditions. These findings provide mechanistic insights into the potential of quercetin to treat HUA or gout diseases via a specific gut microbe., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Class I flextensional transducers cannot form broadband characteristics because of the deep valley between their first- and second-order response curves. This valley arises from the sound pressure cancellation produced by the vibration in different areas of the shell. This paper examines the cause of the deep valley by analyzing the three-dimensional equivalent radiated sound field of the transducer. By solving the three-dimensional vibration equation of the shell of revolution and reducing its dimensionality, it can be concluded that its vibration state is related to the positive and negative curvatures in both main directions. Therefore, a variable-curvature shell class I flextensional transducer is proposed, and the second-order vibration of the transducer is changed by the variable-curvature structure composed of positive and negative Gaussian curvature surfaces. The proposed transducer avoids sound pressure cancellation and achieves broadband characteristics. After optimization, a transducer prototype is fabricated, and a pool test is conducted. The test results show that the transducer couples the first three vibration modes, attaining broadband characteristics with an in-band fluctuation of less than 8 dB and a bandwidth of more than 5.4 kHz in the axial and circumferential directions., (© 2023 Acoustical Society of America.)

Artificial neural networks are prone to suffer from catastrophic forgetting. Networks trained on something new tend to rapidly forget what was learned previously, a common phenomenon within connectionist models. In this work, we propose an effective and efficient continual learning framework using random theory, together with Bayes' rule, to equip a single model with the ability to learn streaming data. The core idea of our framework is to preserve the performance of old tasks by guiding output weights to stay in a region of low error while encountering new tasks. In contrast to the existing continual learning approaches, our main contributions concern (1) closed-formed solutions with detailed theoretical analysis; (2) training continual learners by one-pass observation of samples; (3) remarkable advantages in terms of easy implementation, efficient parameters, fast convergence, and strong task-order robustness. Comprehensive experiments under popular image classification benchmarks, FashionMNIST, CIFAR-100, and ImageNet, demonstrate that our methods predominately outperform the extensive state-of-the-art methods on training speed while maintaining superior accuracy and the number of parameters, in the class incremental learning scenario. Code is available at https://github.com/toil2sweet/CRNet.

A new simple Pt(ii) terpyridyl salt that shows reversible response towards acetonitrile and irreversible response towards methanol has been reported, accompanied with the colorimetric/luminescent changing from red to yellow. Experimentally and theoretically, the spectroscopic change derives from the hydrogen bonds between crystal water in the Pt(ii) terpyridyl salt and external organic molecules, and the different strength of hydrogen bond leads either reversible or irreversible stimuli-response. Furthermore, this Pt(ii) terpyridyl salt has been on one hand applied as a probe for sensing acetonitrile in water solution, with high selectivity, good reversibility, proper sensitivity and fast response rate, and on the other hand as advanced anticounterfeiting materials. The current study provides a new approach to acquire and design either reversible or irreversible stimuli-responsive luminescent materials., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Background: Ginkgo biloba extract (GBE) is evidenced to be effective in the prevention and alleviation of metabolic disorders, including obesity, diabetes and fatty liver disease. However, the role of GBE in alleviating fatty liver hemorrhagic syndrome (FLHS) in laying hens and the underlying mechanisms remain to be elucidated. Here, we investigated the effects of GBE on relieving FLHS with an emphasis on the modulatory role of GBE in chicken gut microbiota., Results: The results showed that GBE treatment ameliorated biochemical blood indicators in high-fat diet (HFD)-induced FLHS laying hen model by decreasing the levels of TG, TC, ALT and ALP. The lipid accumulation and pathological score of liver were also relieved after GBE treatment. Moreover, GBE treatment enhanced the antioxidant activity of liver and serum by increasing GSH, SOD, T-AOC, GSH-PX and reducing MDA, and downregulated the expression of genes related to lipid synthesis (FAS, LXRα, GPAT1, PPARγ and ChREBP1) and inflammatory cytokines (TNF-α, IL-6, TLR4 and NF-κB) in the liver. Microbial profiling analysis revealed that GBE treatment reshaped the HFD-perturbed gut microbiota, particularly elevated the abundance of Megasphaera in the cecum. Meanwhile, targeted metabolomic analysis of SCFAs revealed that GBE treatment significantly promoted the production of total SCFAs, acetate and propionate, which were positively correlated with the GBE-enriched gut microbiota. Finally, we confirmed that the GBE-altered gut microbiota was sufficient to alleviate FLHS by fecal microbiota transplantation (FMT)., Conclusions: We provided evidence that GBE alleviated FLHS in HFD-induced laying hens through reshaping the composition of gut microbiota. Our findings shed light on mechanism underlying the anti-FLHS efficacy of GBE and lay foundations for future use of GBE as additive to prevent and control FLHS in laying hen industry., (© 2023. The Author(s).)

Despite surpassing lung cancer as the most frequently diagnosed cancer, female breast cancer (BC) still lacks rapid detection methods for screening that can be implemented on a large scale in practical clinical settings. However, urine is a readily available biofluid obtained non-invasively and contains numerous volatile organic metabolites (VOMs) that offer valuable metabolic information concerning the onset and progression of diseases. In this work, a rapid method for analysis of VOMs in urine by using high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS) coupled with dynamic purge injection. A simple pretreatment process of urine samples by adding acid and salt was employed for efficient VOM sampling, and the numbers of metabolites increased and the detection sensitivity was improved after the acid (HCl) and salt (NaCl) addition. The established mass spectrometry detection method was applied to analyze a set of training samples collected from a local hospital, including 24 breast cancer patients and 27 healthy controls. Statistical analysis techniques such as principal component analysis, partial least squares discriminant analysis, and the Mann-Whitney U test were used, and nine VOMs were identified as differential metabolites. Finally, acrolein, 2-pentanone, and methyl allyl sulfide were selected to build a metabolite combination model for distinguishing breast cancer patients from the healthy group, and the achieved sensitivity and specificity were 92.6% and 91.7%, respectively, according to the receiver operating characteristic curve analysis. The results demonstrate that this technology has potential to become a rapid screening tool for breast cancer, with significant room for further development.

The present study aimed to determine the clinical characteristics of cytopenia in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (B-NHL) who were treated with chimeric antigen receptor T-cell (CAR-T) therapy. Thus, a total of 63 patients with relapsed and refractory B-NHL who underwent CAR-T therapy between March 2017 and October 2021 were retrospectively selected for analysis. Neutropenia, anemia and thrombocytopenia at grade ≥3 occurred in 48 (76.19%), 16 (25.39%) and 15 (23.80%) cases, respectively. The results of a multivariate analysis demonstrated that the baseline absolute neutrophil count (ANC) and hemoglobin concentration were independent risk factors for grade ≥3 cytopenia. A total of 3 patients died early and were therefore excluded from the present study. Furthermore, cell recovery was examined at day +28 after infusion; 21 patients (35%) did not recover from cytopenia and 39 patients (65%) recovered. A multivariate analysis demonstrated that the baseline ANC <2.29×10 9 /l, baseline hemoglobin <114.50 g/l and baseline IL-6 >21.43 pg/l were independent risk factors affecting hemocyte recovery. In conclusion, patients with relapsed and refractory B-NHL exhibited an increased incidence of grade ≥3 hematologic toxicity following CAR-T cell therapy, while baseline blood cell and IL-6 levels are independent risk factors for hemocyte recovery., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023, Spandidos Publications.)

Purpose: G protein-coupled receptor, class C group 5 member D (GPRC5D) is considered to be a promising surface target for multiple myeloma (MM) immunotherapy. Here, we report the efficacy and safety of anti-GPRC5D chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory (R/R) MM., Methods: This phase Ⅱ, single-arm study enrolled patients (18-70 years) with R/R MM. Lymphodepletion was performed before patients received 2 × 10 6 /kg anti-GPRC5D CAR T cells. The primary end point was the proportion of patients who achieved an overall response. Safety was also evaluated in eligible patients., Results: From September 1, 2021, to March 23, 2022, 33 patients were infused with anti-GPRC5D CAR T cells. At a median follow-up of 5.2 months (range, 3.2-8.9), the overall response rate was 91% (95% CI, 76 to 98; 30 of 33 patients), including 11 (33%) stringent complete responses, 10 (30%) complete responses, four (12%) very good partial responses, and five (15%) partial responses. Partial responses or better were observed in nine (100%) of nine patients with previous anti-B-cell maturation antigen (BCMA) CAR T-cell therapy, including two patients who had received repeated anti-BCMA CAR T-cell infusions with no responses at the last time. Grade 3 or higher hematologic toxicities were neutropenia (33 [100%]), anemia (17 [52%]), and thrombocytopenia (15 [45%]). Cytokine release syndrome occurred in 25 (76%) of 33 patients (all were grade 1 or 2), and neurotoxicities in three patients (one grade 2 and one grade 3 ICANSs and one grade 3 headache)., Conclusion: Anti-GPRC5D CAR T-cell therapy showed an encouraging clinical efficacy and manageable safety profile in patients with R/R MM. For patients with MM that progressed after anti-BCMA CAR T-cell therapy or that is refractory to anti-BCMA CAR T cell, anti-GPRC5D CAR T-cell therapy might be a potential alternative option.

Introduction: Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented efficacy recently. However, the factors related to responses and durable remission are elusive. This study was to investigate the impact of pre-lymphodepletion (pre-LD) absolute lymphocyte count (ALC) on CAR T cell therapy outcomes., Methods: We conducted a retrospective study of 84 patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who underwent CAR T cell treatment at the Affiliated Hospital of Xuzhou Medical University between March 1,2016 and December 31, 2021. The enrolled patients were divided into high group and low group according to the optimal cutoff value of pre-LD ALC. The Kaplan-Meier analyses was used to calculate survival curves. The Cox proportional hazards model was used for univariate and multivariate analysis to assess the prognostic factors., Results: The ROC showed that the optimal cutoff value of pre-LD ALC was 1.05 x 10 9 /L. The overall response (defined as partial response or complete response) rate was significantly higher in patients with a high pre-LD ALC (75% versus 52.08%; P=0.032). Patients with a low pre-LD ALC had significantly inferior overall survival (OS) and progression-free survival (PFS) compared with those having a high pre-LD ALC (median OS, 9.6 months versus 45.17 months [P=0.008]; median PFS, 4.07 months versus 45.17 months [P= 0.030]). Meanwhile, low pre-LD ALC is an independent risk factor for PFS and OS., Discussion: The data suggested that pre-LD ALC may serve as a helpful indicator to predict the outcomes of CAR T cell therapy in patients with R/R DLBCL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lu, Zhu, Liu, Wang, Sun, Cheng, Yan, Cao, Sang, Zhu, Li, Sun, Zheng, Xu and Li.)

Background: Chimeric antigen receptor - T (CAR-T) cell therapy has shown remarkable efficacy in patients with relapsed/refractory multiple myeloma (R/R MM). However, a subset of patients still experienced progression or relapse, and the predictors of prognosis are little known. We analyzed the inflammatory markers before CAR-T cell infusion, to clarify their correlation with survival and toxicity., Methods: This study involved 109 R/R MM patients who received CAR-T therapy between June 2017 and July 2021. Inflammatory markers, including ferritin, c-reactive protein (CRP), and interleukin-6 (IL-6) before CAR-T cell infusion were detected and then categorized by quartiles. Adverse events and clinical outcomes were compared between patients with upper quartile of inflammatory markers and patients with lower three quartiles of inflammatory markers. An inflammatory prognostic index (InPI) based on these three inflammatory markers was developed in this study. Patients were divided into 3 groups according to the InPI score, progression-free survival (PFS) and overall survival (OS) were compared among the groups. In addition, we explored the correlation between cytokine release syndrome (CRS) and pre-infusion inflammatory markers., Results: We found that the pre-infusion high ferritin (hazard ratio [HR], 3.382; 95% confidence interval [CI], 1.667 to 6.863; P = .0007), high CRP (HR, 2.043; 95% CI, 1.019 to 4.097; P = .044), and high IL-6 (HR, 3.298; 95% CI, 1.598 to 6.808; P = .0013) were significantly associated with inferior OS. The formula of the InPI score was based on the HR value of these 3 variables. Three risk groups were formed: (good, 0 to 0.5 point; intermediate, 1 to 1.5 points; poor, 2 to 2.5 points). Median OS for patients with good, intermediate, and poor InPI was not reached, 24 months, and 4 months, respectively, and median PFS was 19.1 months, 12.3 months, and 2.9 months, respectively. In the cox proportional hazards model, poor InPI remained an independent prognostic factor for PFS and OS. Pre-infusion ferritin was negatively associated with CAR T-cell expansion normalized to baseline tumor burden. Spearman correlation analysis showed that pre-infusion ferritin and IL-6 levels positively correlated with the grade of CRS ( P = .0369 and P = .0117, respectively). The incidence of severe CRS was higher in patients with high IL-6 compared with patients with low IL-6 (26% vs . 9%, P = .0405). Pre-infusion ferritin, CRP and IL-6 were positively correlated with each peak values within the first month after infusion., Conclusions: Our results suggest that patients with elevated inflammation markers before CAR-T cell infusion are more likely to have poor prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Jie, Nian, Wang, Wang, Ma, Jiang, Wu, Qiao, Chen, Cao, Yan, Shi, Cheng, Zhu, Sang, Li, Chen, Xu and Li.)

Phytoremediation is considered an effective method for indoor air pollution control. The removal rate and mechanism of benzene in air by two plants, Tradescantia zebrina Bosse and Epipremnum aureum (Linden ex André) G. S. Bunting, were investigated through fumigation experiments under the condition of plant hydroponics culturing. Results showed that the plant removal rates increased with increase in benzene concentration in air. When the benzene concentration in air was set at 432.25-1314.75 mg·m -3 , the removal rates of T. zebrina and E. aureum ranged from 23.05 ± 3.07 to 57.42 ± 8.28 mg·kg -1 ·h -1 FW and from 18.82 ± 3.73 to 101.58 ± 21.20 mg·kg -1 ·h -1 FW, respectively. The removal capacity was positively related to the transpiration rate of plants, indicating that gas exchange rate could be a key factor for the evaluation of removal capacity. There existed fast reversible transport of benzene on air-shoot interface and root-solution interface. After shoot exposure to benzene for 1 h, downward transport was the dominant mechanism in the removal of benzene in air by T. zebrina, while in vivo fixation was the dominant mechanism at exposure time of 3 and 8 h. Within 1-8 h of shoot exposure time, in vivo fixation capacity was always the key factor affecting the removal rate of benzene in the air by E. aureum. Contribution ratio of in vivo fixation in the total benzene removal rate increased from 6.29 to 92.29% for T. zebrina and from 73.22 to 98.42% for E. aureum in the experimental conditions. Reactive oxygen species (ROS) burst induced by benzene exposure was responsible for the contribution ratio change of different mechanisms in the total removal rate, which also was verified by the change of activities of antioxidant enzymes (CAT, POD, and SOD). Transpiration rate and antioxidant enzyme activity could be considered parameters to evaluate the plant removal ability to benzene and to screen plants for establishment of plant-microbe combination technology., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In quantum dot light-emitting diodes (QLEDs), even seemingly with interfacial exciton quenching between quantum dots (QDs) and the electron transport layer (ETL) limiting the device efficiency, the internal quantum efficiency of such QLEDs approaches 100%. Therefore, it is a puzzle that QLEDs exhibit high performance although they suffer from interfacial exciton quenching. In this work, we solve this puzzle by identifying the cause of the interfacial exciton quenching. By analyzing the optical characteristics of pristine and encapsulated QD-ETL films, the interfacial exciton quenching in the pristine QD-ETL film is attributed to O 2 -induced charge transfer. We further investigate the charge transfer mechanism and its effect on the performance of QLEDs. Finally, we show the photodegradation of the pristine QD-ETL film under UV irradiation. Our work bridges interfacial exciton quenching and high performance in hybrid QLEDs and highlights the significance of encapsulation in QLEDs.

Type IV flextensional transducers do not have broadband characteristics due to the deep valley between their first- and second-order response curves arising from the sound pressure cancellation produced by the vibration in different areas of the shell. In this paper, the cause of the deep valley is examined by analyzing the equivalent radiated sound field of the transducer. Simplifying the three-dimensional vibration equation to a two-dimensional equation shows that the vibration state of the shell is related to the positive and negative curvature. Therefore, a variable-shell flextensional transducer with a negative curvature is proposed, which changes the second-order vibration of the transducer by introducing a negative curvature structure. The transducer avoids acoustic pressure cancellation, achieves broadband characteristics, and has continuous high efficiency in the frequency band. After optimization, a prototype of the transducer is fabricated and a pool test is completed. The test results show that the transducer realizes the coupling of the first three vibration mode, forming a broad band with an in-band fluctuation of less than 8 dB at 1200-5600 Hz, and the efficiencies of the first to third resonance peaks are 30.2 %, 16.6 %, and 9.4 %, respectively.

Encouraging response has been achieved in relapsed/refractory (R/R) B-cell lymphoma treated by chimeric antigen receptor T (CAR-T) cells. The efficacy and safety of CAR-T cells in central nervous system lymphoma (CNSL) are still elusive. Here, we retrospectively analyzed 15 patients with R/R secondary CNSL receiving CD19-specific CAR-T cell-based therapy. The patients were infused with CD19, CD19/CD20 or CD19/CD22 CAR-T cells following a conditioning regimen of cyclophosphamide and fludarabine. The overall response rate was 73.3% (11/15), including 9 (60%) with complete remission (CR) and 2 (13.3%) with partial remission (PR). During a median follow-up of 12 months, the median progression-free survival (PFS) was 4 months, and the median overall survival (OS) was 9 months. Of 12 patients with systemic tumor infiltration, 7 (58.3%) achieved CR in CNS, and 5 (41.7%) achieved CR both systemically and in CNS. Median DOR for CNS and systemic disease were 8 and 4 months, respectively. At the end point of observation, of the 7 patients achieved CNS disease CR, one was still alive with sustained CR of CNS disease and systemic disease. The other 6 died of systemic progression. Of the 15 patients, 11 (73.3%) experienced grades 1-2 CRS, and no patient had grades 3-4 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3 (20%) patients, including 1 (6.6%) with grade 4 ICANS. All the CRS or ICANS were manageable. The CD19-specific CAR-T cell-based therapy appeared to be a promising therapeutic approach in secondary CNSL, based on its antitumor effects and an acceptable side effect profile, meanwhile more strategies are needed to maintain the response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Yan, Wang, Qi, Hu, Li, Cao, Zhang, Xiao, Shi, Xia, Ma, Qiao, Li, Pan, Qi, Cheng, Sun, Zhu, Sang, Li, Li, Zheng, Zhao, Liang, Huang and Xu.)

Purpose: A combination of anti-B-cell maturation antigen (BCMA) and anti-CD19 chimeric antigen receptor (CAR) T cells induced high response rates in patients with relapsed or refractory (R/R) multiple myeloma (MM), but long-term outcomes have not been assessed yet., Patients and Methods: In this single-arm, phase II trial, patients with R/R MM received a combination of anti-BCMA CAR T cells and anti-CD19 CAR T cells at a dose of 1 × 10 6 cells/kg, after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics., Results: Of 69 enrolled patients, 62 received the combined infusion of anti-BCMA and anti-CD19 CAR T cells with a median follow-up of 21.3 months. The overall response rate was 92% (57/62), and complete response or better was observed in 37 patients (60%). Minimal residual disease-negativity was confirmed in 77% (43/56) of the patients with available minimal residual disease detection. The estimated median duration of response was 20.3 months (95% CI, 9.1 to 31.5). The median progression-free survival was 18.3 months (95% CI, 9.9 to 26.7), and the median overall survival was not reached. Patients with extramedullary disease had significantly inferior survival. Fifty-nine patients (95%) had cytokine release syndrome, with 10% grade 3 or higher. Neurotoxic events occurred in seven patients (11%), including 3% grade 3 or higher. Late adverse effects were rare, except for B-cell aplasia, hypogammaglobulinemia, and infections., Conclusion: The combination of anti-BCMA and anti-CD19 CAR T cells induced durable response in patients with R/R MM, with a median progression-free survival of 18.3 months and a manageable long-term safety profile.

Electrophoretic deposition (EPD) is a facile technique to deposit quantum dots (QDs) films, which can be used as the color conversion layers for display applications. To better understand the EPD process, researchers have built many models of the EPD process. However, most of these models lack solid experimental support. Here, by adopting simple yet effective solvent engineering and well-designed experiments, this study proves the Cordelair-Greil model on EPD processes. Moreover, some supplements about this model are made according to practical experiments. The experimental verification of the Cordelair-Greil model is a solid step toward revealing the dynamics of the EPD process. Furthermore, the formation of cracks in EPD deposited QD films is prevented through solvent engineering. This work proves that besides modifying the intrinsic properties of QDs, solvent engineering is also a simple, effective, and low-cost way to study the EPD process and improve the QD film qualities deposited., (© 2022 Wiley-VCH GmbH.)

Few studies have described chimeric antigen receptor (CAR) T-cell therapy for patients with B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system leukemia (CNSL) because of concerns regarding poor response and treatment-related neurotoxicity. Our study included 48 patients with relapsed/refractory B-ALL with CNSL to evaluate the efficacy and safety of CD19-specific CAR T cell-based therapy. The infusion resulted in an overall response rate of 87.5% (95% confidence interval [CI], 75.3-94.1) in bone marrow (BM) disease and remission rate of 85.4% (95% CI, 72.8-92.8) in CNSL. With a median follow-up of 11.5 months (range, 1.3-33.3), the median event-free survival was 8.7 months (95% CI, 3.7-18.8), and the median overall survival was 16.0 months (95% CI, 13.5-20.1). The cumulative incidences of relapse in BM and CNS diseases were 31.1% and 11.3%, respectively, at 12 months (P = .040). The treatment was generally well tolerated, with 9 patients (18.8%) experiencing grade ≥3 cytokine release syndrome. Grade 3 to 4 neurotoxic events, which developed in 11 patients (22.9%), were associated with a higher preinfusion disease burden in CNS and were effectively controlled under intensive management. Our results suggest that CD19-specific CAR T cell-based therapy can induce similar high response rates in both BM and CNS diseases. The duration of remission in CNSL was longer than that in BM disease. CD19 CAR T-cell therapy may provide a potential treatment option for previously excluded patients with CNSL, with manageable neurotoxicity. The clinical trials were registered at www.clinicaltrials.gov as #NCT02782351 and www.chictr.org.cn as #ChiCTR-OPN-16008526., (© 2022 by The American Society of Hematology.)

In chickens, the effect of host genetics on the gut microbiota is not fully understood, and the extent to which the heritable gut microbes affect chicken metabolism and physiology is still an open question. Here, we explored the interactions among chicken genetics, the cecal microbiota and metabolites in breast muscle from ten chicken breeds in China. We found that different chicken breeds displayed distinct cecal microbial community structures and functions, and 15 amplicon sequence variants (ASVs) were significantly associated with host genetics through different genetic loci, such as those related to the intestinal barrier function. We identified five heritable ASVs significantly associated with 53 chicken muscle metabolites, among which the Megamonas probably affected lipid metabolism through the production of propionate. Our study revealed that the chicken genetically associated cecal microbes may have the potential to affect the bird's physiology and metabolism., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

This work demonstrated color-conversion layers of red and green quantum dots color filter for full-color display arrays. Ligands exchange using (3-glycidyloxypropyl) trimethoxysilane with epoxy functional groups to treat QDs in the liquid phase was performed for photolithography use. The combination of ligands of QDs with photo-initiator played a protective role on QDs. Moreover, the pixel size of green QDCF can be reduced to 50 μm, and a high optical density (OD) of 1.2 is realized.

Anti-CD30 CAR-T is a potent candidate therapy for relapsed/refractory (r/r) CD30+ lymphomas with therapy limitations, and the efficacy needed to be further improved. Herein a multi-center phase II clinical trial (NCT03196830) of anti-CD30 CAR-T treatment combined with PD-1 inhibitor in r/r CD30+ lymphoma was conducted. After a lymphocyte-depleting chemotherapy with fludarabine and cyclophosphamide, 4 patients in cohort 1 and 3 patients in cohort 2 received 10 6 /kg and 10 7 /kg CAR-T cells, respectively, and 5 patients in cohort 3 received 10 7 /kg CAR-T cells combined with anti-PD-1 antibody. The safety and the efficacy of CAR-T cell therapy were analyzed. Cytokine release syndrome (CRS) was observed in 4 of 12 patients, and only 1 patient (patient 9) experienced grade 3 CRS and was treated with glucocorticoid and tocilizumab. No CAR-T-related encephalopathy syndrome was observed. Only two patients in cohorts 2 and 3 experienced obviously high plasma levels of IL-6 and ferritin after CD30 CAR-T cell infusion. The overall response rate (ORR) was 91.7% (11/12), with 6 patients achieving complete remission (CR) (50%). In cohorts 1 and 2, 6 patients got a response (85.7%), with 2 patients achieving CR (28.6%). In cohort 3, 100% ORR and 80% CR were obtained in 5 patients without ≥3 grade CRS. With a median follow-up of 21.5 months (range: 3 - 50 months), the progression-free survival and the overall survival rates were 45 and 70%, respectively. Of the 11 patients who got a response after CAR-T therapy, 7 patients (63.6%) maintained their response until the end of follow-up. Three patients died last because of disease progression. Taken together, the combination of anti-PD-1 antibody showed an enhancement effect on CD30 CAR-T therapy in r/r CD30+ lymphoma patients with minimal toxicities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sang, Wang, Geng, Li, Li, Zhang, Zhou, Song, Sun, Yan, Li, Li, Li and Xu.)

Systematic and dynamic humoral immune reconstitution is little-known for patients with relapsed/refractory (R/R) multiple myeloma (MM) who received anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy. We investigated the kinetics of B-cell, normal plasma cell, and immunoglobulin recovery in 40 patients who achieved ongoing response after anti-BCMA CAR T-cell therapy. All patients developed B-cell aplasia and the median duration of B-cell aplasia was 70 days (range, 23-270). The B-cell count reached its nadir on median day 7 and returned to baseline level on median day 97. BCMA+ cells in bone marrow turned undetectable on median day 28 (13-159) in 94.87% (37 of 39) of patients. Normal plasma cells in bone marrow were first redetected on median day 212. All patients developed a significant decrease in serum IgG, IgA, and IgM on median day 60. At year 1, recovery of serum IgG, IgM, and IgA was observed in 53.33% (8 of 15; non-IgG MM), 73.08% (19 of 26; non-IgM MM), and 23.81% (5 of 21;non-IgA MM) of the patients, respectively. Median time to IgG, IgM, and IgA recovery were days 386, 254, and not reached during follow-up, respectively. Virus-specific IgG levels decreased with loss of protection. Twenty-three of 40 (57.5%) patients had a total of 44 infection events. There were no infection-related deaths. These results reveal a 7-month aplasia of bone marrow normal plasma cells and longer period of hypogammaglobulinemia, suggesting a profound and lasting humoral immune deficiency after anti-BCMA CAR T-cell therapy, especially for IgA., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The formaldehyde dehydrogenase (FADH) activity in plants is essential to the removal of airborne formaldehyde (FA) by plants. A rapid and efficient method was established to assess the FADH activity in plants by analyzing the efficiencies of the extracts of fresh and enzyme-inactivated leaves to degrade FA, with the enzyme-inactivated leaves prepared by freezing with liquid nitrogen. The efficiencies of airborne FA dissipated by different plants were evaluated through the FA fumigation experiments using four selected plants, with the results analyzed against the calculated leaf FADH activities. Fresh and enzyme-inactivated leaf extracts degraded FA to different extents. The degradative efficiencies of leaf extracts were positively related to the initial FA test levels at 6-18 mg l -1 . The relative plant-leaf FADH activities formed the order of Chenopodium album L. > Atenia cordifolia > Plantain > Aloe, which was in line with the observed FA dissipating efficiencies of the plants exposed to 0.72 mg m -3 airborne FA for 24 h. Other dominant degrading mechanisms in plant leaves resulted in higher dissipating efficiencies of Plantain over that of Atenia cordifolia when exposed to 1.56 mg m -3 FA for 24 h. The established method could be applied to estimate the FADH activity in plants for assessment of the plant remediation efficiency of FA in air at lower concentrations.

Objective: To investigate the effect of up-regulation of Rap1GAP on the invasion ability of leukemic HL-60 cells in vitro, and to establish leukemia mouse model to verify the effects in vivo., Methods: Quantitative RT-PCR and Western blot methods were used to detect the expression of Rap1GAP in Venus/HL-60 (vehicle control) and Rap1GAP/HL-60 cells (R1 andR2). Transwell method was used to examine the invasion ability in vitro. Quantitative RT-PCR and gelatin zymograph were used to study the expression of MMP-2 and MMP-9. Four-week-old BALB/c nu/nu mice were pre-treated and inoculated with leukemic cells from different groups, several index including survival time were then monitored., Results: Rap1GAP mRNA level of R1 and R2 increased about 16-17 folds as compared to the control cells. The invasion rate of R1 and R2 are (55 ± 5)% and (59 ± 4)%, which are significantly higher than (14 ± 4)% of the control cells. The mRNA level of MMP-9 was up-regulated about 12.0 folds in R1 and R2 cells compared to the corresponding control cells. The median survival times of R1 and R2 mice are (32.00 ± 1.85) d and (33.37 ± 2.50) d, respectively, which are shorter than (43.62 ± 2.32) d of the control group. Three mice of R1 and R2 groups showed leukemic cells infiltration in meninges tissue, and the genes of Rap1GAP and MMP-9 were amplified by PCR method., Conclusion: Up-regulated expression of Rap1GAP increased the invasion ability of HL-60 cells accompanied with enhancement of MMP-9 expression in vitro, and the experiment in mouse model also confirmed that Rap1GAP enhanced the invasion of HL-60 cells in vivo.

Objective: To investigate the sensitivity of imatinib (IM) on Sup-B15 Ph+ acute lmphoblastic leukemia (ALL) cells indused by stromal cells OP9, and to further explore its mechanism., Methods: The study is divided into two group, Sup-B15 cells group and co-cultured with OP9 cells group (Sup-B15/OP9 group). The inhibitory effects of IM on leukemia cells were measured by CCK-8 test, and the apoptosis by Annexin Ⅴ/7-AAD dyeing and the percentage of CD 34+CD38- leukemia cells were determined by flow cytometry. ALDH1, CD144, and β-catenin mRNA were detected by real-time RT-PCR, protein levels by Western blot. Inmunoprecipitation was used to detect the level of β-catenin connected to CD144., Results: IM presented inhibitory effects on Sup-B15 and Sup-B15/OP9 cells at multiple concentrations from 10 μmol/L to 45 μmol/L. The IC50 of IM on Sup-B15/OP and Sup-B15 cells were 35.8 μmol/L and 6.3 μmol/L, respectively (P<0.05). After 24 h of 30 μmol/L IM treatment, the percentages of apoptosis cells in Sup-B15/OP9 and Sup-B 15 cell were (14.24 ± 2.11)% and (3.45 ± 0.68)%, respectively (P<0.05). The percentage of CD34+CD38- cells in Sup-B15/OP9 group was significantly higher than that in Sup-B15 group [(3.42 ± 0.28)% vs (0.16 ± 0.15)%, P<0.05]. As compared to Sup-B15 cells, the transcription of ALDH1 in Sup-B15/OP9 group was remarkably upregulated (0.097 ± 0.012 vs 0.046 ± 0.010, P<0.05), and the CD133 protein level was also upregulated in Sup-B15/OP9 group. The transcription of CD144 in Sup-B15/OP9 group was remarkably upregulated compared with Sup-B15 group (0.103 ± 0.015 vs 0.010±0.003, P<0.05), as well as the CD144 protein. β-catenin mRNA transcription has no obvious changes between Sup-B15 group and Sup-B15/OP9 group (P>0.05), while the whole β-catenin protein and the cell nucleus β-catenin significantly increased, as well as the β-catenin protein combined with CD144., Conclusion: Co-cultured with OP9 cells, Sup-B15 cells show less sensitivity to imatinib. The raising activity of CD144 and CD144/β-catenin signaling may work in this procession.

The effect of infusion of lentiviral vector‑mediated, genetically engineered dendritic cells (DCs) following allogeneic bone marrow transplantation (allo‑BMT) on graft‑versus‑host disease (GVHD) and graft‑versus‑leukemia (GVL) was investigated in a mouse model. Lentivirus‑mediated expression of soluble tumor necrosis factor receptor 1 (sTNFR1) converted immature DCs (imDCs) from BABL/c mice into engineered DCs in vitro. An EL4 leukemia allo‑BMT model of BABL/c to C57BL/6 mice was established. Engineered DCs with donor bone marrow cells and splenocytes were subsequently transplanted into myeloablatively irradiated recipients. The average survival duration in the sTNFR1‑ and pXZ9‑imDC groups was significantly prolonged compared with that of the allo‑BMT group (P<0.05). Mild histological changes in GVHD or leukemia were observed in the recipients in the sTNFR1‑imDC group and clinical GVHD scores in this group were significantly decreased compared with those of the transplantation and pXZ9‑imDC groups. Serum interferon‑γ levels were decreased in the pXZ9‑imDC and sTNFR1‑imDC groups compared with those in the allo‑BMT group (P<0.05), with the reduction being more significant in the sTNFR1‑imDC group (P<0.05). Serum interleukin‑4 expression levels were decreased in the allo‑BMT group, but gradually increased in the pXZ9‑imDC and sTNFR1‑imDC groups (P<0.05). Co‑injection of donor genetically‑engineered imDCs was able to efficiently protect recipient mice from lethal GVHD while preserving GVL effects during allo‑BMT.

Objective: To observe the efficacy of high-dose dexamethasone in combination with low-dose rituximab as a second-line treatment for patients with immune thrombocytopenia (ITP)., Methods: 65 patients with ITP, previously by conventional dose of glucocorticoids, received high-dose dexamethasone in combination with low-dose rituximab (dexamethasone 40 mg/d for 4 days, rituximab 100 mg, d 7, 14, 21, 28 intravenous infusion). Treatment response, regulatory T cells (Treg), cytokines levels and treatment-related adverse effects were observed., Results: Total response rate 1 month after treatment was achieved in 81.5% (53/65) of patients, and complete response at 3,6 and 12 months was 72.3% (47/65), 66.2%(43/65), 63.1%(41/65). The higher efficiency and complete response rate was achieved in preexisting glucocorticoid-dependent patients. For patients with complete response, Treg cells continued to show a high level state [(3.01 ± 0.95)% vs (1.69 ± 0.35)%, P=0.032], cytokines of BAFF [(648.03 ± 79.63) ng/L vs (972.35 ± 93.64) ng/L, P=0.001], IL-2 [(2.84 ± 0.32) ng/L vs (4.18 ± 0.46) ng/L, P=0.012], sCD40L[(4.55 ± 0.66) ng/L vs (7.73 ± 1.04) ng/L, P=0.006] significantly lower than that before treatment. The level of IL-10 was increased, but without significance compared with that before treatment (P=0.136). All patients completed the protocol with no serious adverse reactions., Conclusion: The data show high-dose dexamethasone in combination with low-dose rituximab still has a satisfactory outcomes for patients previously with conventional dose of glucocorticoid.

Objective: To explore the expression and significance of miRNAs and Th17 related cytokines in patients with multiple myeloma (MM)., Methods: A total of 27 MM patients and 8 health controls were enrolled in this study. The expression of miR-15a/16,miR-34a,miR-194-2-192 cluster and miR-181a/b in bone marrow were detected by real-time quantitative PCR (qRT-PCR). Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of Th17 related cytokines interleukin-17 (IL-17), IL-21, IL-22, IL-23 and IL-27 in peripheral blood plasma. The role of miRNAs and Th17 related cytokines was analyzed in the development of MM., Results: The expression of miR-15a/16,miR-34a,miR-194-2-192 cluster in MM patients were significantly lower than those of the health controls, while miR-181a/b were exactly the reverse (P<0.05). The levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to health controls while IL-22 was down-regulated (P<0.05). There was no significant difference of IL-23 between the two groups. The levels of miRNAs and Th17 related cytokines had associated with ISS but not with some clinical parameters (such as gender, age, disease classification). Higher expression of IL-17, IL-21, IL-23, IL-27, miR-181a/b and lower expression of miR-15a/16,miR-34a,miR-194 and IL-22 were observed in the end stage than the early stage of MM patients (P<0.05). There was a significant correlation between miRNAs and Th17 related cytokines., Conclusion: Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease.