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 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.
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.
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.
The permanent magnet (PM) flux-switching linear motor, which is developed from the PM flux-switching rotary machine, possesses similar advantages such as high power density and simple structure. ...Furthermore, the PM flux-switching linear motor has a potential for mass production at low cost, since the expensive coils and magnets are both set on the short mover. However, the detent force which is induced by both slot-effect and end-effect deteriorates the motor performance. Some methods to reduce detent force which are effective in PM linear synchronous motors do not work in PM flux-switching linear motors, due to their special structure. This paper describes a new method to reduce the detent force by fixing assistant teeth on the mover ends. Finite element analysis shows some interesting results which will be detailed in this paper.
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 breaking of time reversal symmetry in topological insulators may create previously unknown quantum effects. We observed a magnetic quantum phase transition in Cr-doped Bi₂(Se x Te₁₋ x )₃ ...topological insulator films grown by means of molecular beam epitaxy. Across the critical point, a topological quantum phase transition is revealed through both angle-resolved photoemission measurements and density functional theory calculations. We present strong evidence that the bulk band topology is the fundamental driving force for the magnetic quantum phase transition. The tunable topological and magnetic properties in this system are well suited for realizing the exotic topological quantum phenomena in magnetic topological insulators.
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 safe and efficient storage and release of hydrogen are widely recognized as the main challenges for the establishment of a fuel‐cell‐based hydrogen economy. Formic acid (FA) has great potential ...as a safe and convenient source of hydrogen for fuel cells. Despite tremendous efforts, the development of heterogeneous catalysts with high activity and relatively low cost remains a major challenge. The synthesis of AuPd–MnOx nanocomposite immobilized on ZIF‐8–reduced‐graphene‐oxide (ZIF‐8–rGO) bi‐support by a wet‐chemical method is reported here. Interestingly, the resultant AuPd–MnOx/ZIF‐8–rGO shows excellent catalytic activity for the generation of hydrogen from FA, and the initial turnover frequency (TOF) reaches a highest value of 382.1 mol H2 mol catalyst−1 h−1 without any additive at 298 K. This good performance of AuPd–MnOx/ZIF‐8–rGO results from the modified electronic structure of Pd in the AuPd–MnOx/ZIF‐8–rGO composite, the small size and high dispersion of the AuPd–MnOx nanocomposite, and also the strong metal‐support interaction between the AuPd–MnOx and ZIF‐8–rGO bi‐support.
AuPd–MnOx/ZIF‐8–rGO composites are synthesized using a facile wet‐chemical method and show good catalytic performance for formic acid dehydrogenation at room temperature. The excellent catalytic performance can be attributed to the electronically enriched Pd surface, the strong metal–support interaction, as well as the ultrafine and high distribution of the AuPd–MnOx nanocomposite on the unique ZIF‐8–rGO bi‐supportZIF‐8–rGO.
Chemotherapy represents an important treatment option for colorectal cancer (CRC), but only half of the patients benefit from these regimens. We explored the potential predicting value and mechanism ...of PIK3CA mutation in CRC chemotherapy. CRC specimens from 440 patients were retrospectively collected and examined with a fluorescence PCR-based method. The correlation of first-line chemotherapy response and PIK3CA mutation was evaluated according to follow-up and medical records. The underlying mechanism of PIK3CA mutation in chemotherapy resistance was assessed with CRC tumors and primary cells. The mutation frequency of the PIK3CA gene in CRC patients was 9.55%, which was correlated with late TNM staging and lower histological grade. The CRC patients with PIK3A mutation showed worse response to first-line chemotherapy than those without PIK3CA mutation. PIK3A mutation tumor cells showed poor sensitivity to first-line chemotherapy in vitro and in vivo. PIK3CA mutation induced PI3K/Akt signaling activation to increase LGR5
CRC stem cells survival and proliferation, from which lead to chemotherapy resistance. Furthermore, PIK3CA
/LGR5
expression was an independent detrimental factor for CRC patients. Our findings indicated that PIK3CA mutation induced PI3K/Akt activation contributed to CRC stem cells survival and proliferation, from which cells further resistance to chemotherapy. PIK3CA
/LGR5
expression was a potential biomarker for monitoring chemotherapy resistance in CRC.
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