Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

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Low blood folate concentrations have been associated with cardiovascular disease, neural tube defects and selected cancers, but little is known about folate status in Chinese adults. In a cross-sectional study we measured the plasma and red blood cell folate concentrations in 2422 Chinese men and women aged 35 to 64 y, living in the North and South of China, who provided blood samples either in March or September of 2001. The geometric mean concentrations of plasma and red blood cell folate were lower among Northerners than Southerners (adjusted geometric means, 8.4 and 502, and 16.7 and 811 nmol/L, respectively) controlling for age, gender, season (spring and fall), area (urban and rural), BMI, multivitamin use, alcohol intake and current smoking status. We estimated that approximately 40% of the Northerners and approximately 6% of the Southerners had plasma folate concentrations lower than the 6.8 nmol/L (3 microg/L), and approximately 30% of the Northerners and approximately 4% of the Southerners had red blood cell folate concentrations lower than the 363 nmol/L (160 microg/L), levels used to define folate deficiency. Within each region, men had lower plasma folate concentrations than women (6.9 versus 9.8 nmol/L in the North, and 14.5 versus 19.6 nmol/L in the South). In men, current smokers had a higher risk of folate deficiency compared with nonsmokers [adjusted odds ratios, 1.9 (95% CI, 1.4-2.6) for plasma folate deficiency and 2.5 (95% CI, 1.7-3.6) for red blood cell folate deficiency (P < 0.001)]. Our findings suggest that a large proportion of Chinese adults have a low folate status, especially those living in northern China where 60% of the men are plasma folate deficient in the spring. Further studies are needed to elucidate the factors that influence folate concentrations among middle-aged Chinese and to evaluate possible intervention strategies.

B cell maturation antigen- (BCMA) specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed, refractory multiple myeloma (RRMM). Since the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase I trial. Eighteen consecutive RRMM patients, including four patients with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate (ORR) was 100%, with 72.2% of the patients achieving complete response or stringent complete response (sCR). For the four murine BCMA CAR-exposed patients, three achieved sCR, and one achieved a very good partial response. At one year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events. 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell-associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only one patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in RRMM patients and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. (Chinese Clinical Trial Registry ChiCTR1800018137)

Background Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) presents anti-inflammatory properties by modulating microglia and macrophages; however, our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 days after MCAO, and the gene expression levels of inflammatory cytokines were analyzed via qRT-PCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment inhibited M1 polarization of microglia and pro-inflammatory cytokine expression through its actions on FGF receptor 1 (FGFR1) by suppressing nuclear factor-kappa B (NF-κB) and upregulating peroxisome proliferator-activated receptor-γ (PPAR-γ). Conclusions rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment.

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Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy.

Purpose To examine insomnia disorder and its association with sociodemographic factors and poor mental health in 2019 novel coronavirus (COVID-19) inpatients in Wuhan, China. Design and Methods: A total of 484 COVID-19 inpatients in Wuhan Tongji Hospital were selected and interviewed with standardized assessment tools. Insomnia disorder was measured by the Chinese version of the Insomnia Severity Index (ISI-7), a total score of 8 or more was accepted as the threshold for diagnosing insomnia disorder. Results The prevalence of insomnia disorder in the whole sample was 42.8%. Binary logistic regression analysis revealed that female gender, younger age, and higher fatigue and anxiety severity were more likely to experience insomnia disorder. Conclusion Given the high rate of insomnia disorder status among COVID-19 inpatients in Wuhan, China, and its negative effects, follow-up assessments and appropriate psychological interventions for insomnia disorder are needed in this population.