Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell ...therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m
. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 10
cells/kg range, 0.07 to 2.1 × 10
) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.
At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval CI, 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.
LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.
ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered.
Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), ...a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+), but not CD4(+) T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.
The quantum anomalous Hall (QAH) effect, which has been realized in magnetic topological insulators (TIs), is the key to applications of dissipationless quantum Hall edge states in electronic ...devices. However, investigations and utilizations of the QAH effect are limited by the ultralow temperatures needed to reach full quantization—usually below 100 mK in either Cr‐ or V‐doped (Bi,Sb)2Te3 of the two experimentally confirmed QAH materials. Here it is shown that by codoping Cr and V magnetic elements in (Bi,Sb)2Te3 TI, the temperature of the QAH effect can be significantly increased such that full quantization is achieved at 300 mK, and zero‐field Hall resistance of 0.97 h/e2 is observed at 1.5 K. A systematic transport study of the codoped (Bi,Sb)2Te3 films with varied Cr/V ratios reveals that magnetic codoping improves the homogeneity of ferromagnetism and modulates the surface band structure. This work demonstrates magnetic codoping to be an effective strategy for achieving high‐temperature QAH effect in TIs.
In Cr and V codoped (Bi,Sb)2Te3 topological insulator films, the quantum anomalous Hall (QAH) effect is achieved at 300 mK, about one order of magnitude higher than that for singly Cr‐ or V‐doped ones, and the energy scale of QAH state reaches 1.4 K. The transport study of the codoped films with varied Cr/V ratios reveals the origins of enhancement.
Less noble: The Co0.30Au0.35Pd0.35 nanoalloy supported on carbon is reported as a stable, low‐cost, and highly efficient catalyst for the CO‐free hydrogen generation from formic acid dehydrogenation ...at room temperature (see picture). The method may strongly encourage the practical application of formic acid as a hydrogen storage material for fuel cells.
The quantized version of the anomalous Hall effect has been predicted to occur in magnetic topological insulators, but the experimental realization has been challenging. Here, we report the ...observation of the quantum anomalous Hall (QAH) effect in thin films of chromium-doped (Bi, Sb)₂ Te₃, a magnetic topological insulator. At zero magnetic field, the gate-tuned anomalous Hall resistance reaches the predicted quantized value of h/e², accompanied by a considerable drop in the longitudinal resistance. Under a strong magnetic field, the longitudinal resistance vanishes, whereas the Hall resistance remains at the quantized value. The realization of the QAH effect may lead to the development of low-power-consumption electronics.
Cardiac patch is considered a promising strategy for enhancing stem cell therapy of myocardial infarction (MI). However, the underlying mechanisms for cardiac patch repairing infarcted myocardium ...remain unclear. In this study, we investigated the mechanisms of PCL/gelatin patch loaded with MSCs on activating endogenous cardiac repair. PCL/gelatin patch was fabricated by electrospun. The patch enhanced the survival of the seeded MSCs and their HIF‐1α, Tβ4, VEGF and SDF‐1 expression and decreased CXCL14 expression in hypoxic and serum‐deprived conditions. In murine MI models, the survival and distribution of the engrafted MSCs and the activation of the epicardium were examined, respectively. At 4 weeks after transplantation of the cell patch, the cardiac functions were significantly improved. The engrafted MSCs migrated across the epicardium and into the myocardium. Tendency of HIF‐1α, Tβ4, VEGF, SDF‐1 and CXCL14 expression in the infarcted myocardium was similar with expression in vitro. The epicardium was activated and epicardial‐derived cells (EPDCs) migrated into deep tissue. The EPDCs differentiated into endothelial cells and smooth muscle cells, and some of EPDCs showed to have differentiated into cardiomyocytes. Density of blood and lymphatic capillaries increased significantly. More c‐kit+ cells were recruited into the infarcted myocardium after transplantation of the cell patch. The results suggest that epicardial transplantation of the cell patch promotes repair of the infarcted myocardium and improves cardiac functions by enhancing the survival of the transplanted cells, accelerating locality paracrine, and then activating the epicardium and recruiting endogenous c‐kit+ cells. Epicardial transplantation of the cell patch may be applied as a novel effective MI therapy.
Tumor cells with stemness (stem‐cell) features contribute to initiation and progression of hepatocellular carcinoma (HCC), but involvement of long noncoding RNAs (lncRNAs) remains largely unclear. ...Genome‐wide analyses were applied to identify tumor‐associated lncRNA‐DANCR. DANCR expression level and prognostic values of DANCR were assayed in two HCC cohorts (China and Korea, n = 135 and 223). Artificial modulation of DANCR (down‐ and overexpression) was done to explore the role of DANCR in tumorigenesis and colonization, and tumor‐bearing mice were used to determine therapeutic effects. We found that lncRNA‐DANCR is overexpressed in stem‐like HCC cells, and this can serve as a prognostic biomarker for HCC patients. Experiments showed that DANCR markedly increased stemness features of HCC cells to promote tumorigenesis and intra‐/extrahepatic tumor colonization. Conversely, DANCR knockdown attenuated the stem‐cell properties and in vivo interference with DANCR action led to decreased tumor cell vitality, tumor shrinkage, and improved mouse survival. Additionally, we found that the role of DANCR relied largely on an association with, and regulation of, CTNNB1. Association of DANCR with CTNNB1 blocked the repressing effect of microRNA (miR)−214, miR‐320a, and miR‐199a on CTNNB1. This observation was confirmed in vivo, suggesting a novel mechanism of tumorigenesis involving lncRNAs, messenger RNAs, and microRNAs. Conclusions: These studies reveal a significance and mechanism of DANCR action in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HCC. (Hepatology 2016;63:499–511)
The primary objective of this work is to give the reader an understanding of stress wave behaviour while taking into account the dynamic constitutive equations of elastic-plastic solids. The author ...has combined a 'materials characteristics' approach with a 'singularity surface' approach in this work, which readers will find to be a novel and unique route to solving their problems.* Helps engineers understand the effects and behavior of stress waves in various materials* Aids in the process of engineering design, testing, and evaluation.
In recent years, many studies have been done to identify the factors that affect teacher emotions at schools. However, the empirical evidence on how teachers' emotions influence students' outcomes ...and performance is not extensive. Against this background, this study explored the correlation between teacher EI and student academic achievement and possible mechanisms may lie in this relationship. A sample of 365 Chinese teachers from 25 public middle schools participated in this study by completing measurements of teacher EI, teacher work engagement, and teacher self-efficacy. The student academic achievement was assessed by the grades of the previous term (February to June 2020) reported by the students. The results indicated that teacher work engagement partially mediated the path from teacher EI and student academic achievement. Moderated mediation further showed that teachers with high self-efficacy had a more significant positive impact on the relationship between teacher work engagement and student academic achievement than teachers with low self-efficacy. The limitations of this study were also discussed.
PDF
