Microstructure, Mechanical Properties and Wear Behaviors of Ultrafine-Grain WC-Based Cermets with Different Binder Phases Fabricated by Spark Plasma Sintering.

In this work, to explore potential substitutions for the Co binder phase, ultrafine-grain WC-based cermets with various binder phases of Co, Ni and AlCoCrNiFeCu HEA were prepared using the SPS method. Based on SPS, WC-based cermets were fabricated at higher speed, showing fine carbide particles less than 410 µm. The microstructure, mechanical properties and wear properties were systematically evaluated. By comparison, the grain size of WC was the lowest for WC-10Co, while WC-10 HEA cermet held the coarsest WC particles. The hardness and fracture toughness of WC-10 HEA were the best among all three samples, with values of 93.2 HRA and 11.3 MP·m1/2. However, the bending strength of WC-10HEA was about 56.1% lower than that of WC-10Co, with a value of 1349.6 MPa. The reduction in bending strength is attributed to the lower density, formation of a newly Cr-Al rich phase and coarser WC grains. In dry sliding wear conditions, WC-10 HEA showed the lowest wear rate (0.98 × 10-6 mm3/(N·m)) and coefficient of friction (0.19), indicating the best wear resistance performance. This reveals that WC-based cermet with a HEA binder phase has superior wear performance due to the higher hardness and good self-lubricating effect of the wear products.

Novel CAR T-cell therapies for relapsed/refractory B-cell malignancies: latest updates from 2023 ASH annual meeting.

Chimeric antigen receptors (CAR) are engineered fusion proteins that target T-cells to specific surface antigens of tumor cells to generate effective anti-tumor responses. CAR T-cell therapy is playing an increasingly important role in the treatment of relapsed/refractory B-cell malignancies (R/R BCM). Attempting to make CAR T-cells safer and more effective in treating R/R BCM, various novel engineered CAR T-cell agents are currently in the research and development or clinical trial stages. We have summarized here the latest reports on the novel CAR T-cell therapies for R/R BCM presented at the 2023 ASH Annual Meeting as well as the latest updates in related clinical trials.

Social capital, depressive symptomatology, and frailty among older adults in the western areas of China.

We aimed to explore the relationship between social capital (SC) and frailty, and the mediation role of depressive symptoms in this relationship. A cross-sectional study among 2,591 older adults aged ≥60 years old was conducted from September 2020 to May 2021. SC, depressive symptoms, and frailty were measured using the social capital scale, the 9-item patient health questionnaire, and the FRAIL scale, respectively. The mediation model was tested by Bootstrap PROCESS. After controlling for socio-demographical covariates, the SC was negatively correlated with frailty (r = -0.07, P = 0.001), and depressive symptomatology (r = -0.08, P<0.001); while the depressive symptomatology was positively correlated with frailty (r = 0.33, P<0.001). Logistic regression results showed that SC was associated with a lower risk of frailty (OR = 0.94; 95% CI: 0.92-0.97; P<0.001). Depressive symptomatology partially mediated (explained 36.4% of the total variance) the association between SC and frailty. Those findings suggest that SC may protect older adults from frailty by reducing depressive symptoms. Prevention and intervention implications were also discussed.

A Novel Identified Necroptosis-Related Risk Signature for Prognosis Prediction and Immune Infiltration Indication in Acute Myeloid Leukemia Patients.

AML ranks second in the most common types of leukemia diagnosed in both adults and children. Necroptosis is a programmed inflammatory cell death form reported to be an innate immune effector against microbial and viral pathogens and recently has been found to play an eventful role in the oncogenesis, progression, and metastasis of cancer. This study is designed to explore the potential value of necroptosis in predicting prognostic and optimizing the current therapeutic strategies for AML patients. We collected transcriptome and clinical data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases and selected necroptosis-related genes with both differential significance and prognostic value. Six genes (YBX3, ZBP1, CDC37, ALK, BRAF, and BNIP3) were incorporated to generate a risk model with the implementation of multivariate Cox regression. The signature was proven to be an independent prognostic predictor in both training and validation cohorts with hazard ratios (HRs) of 1.51 (95% CI: 1.33-1.72) and 1.57 (95% CI: 1.16-2.12), respectively. Moreover, receiver operating characteristic (ROC) curve was utilized to quantify the predictive performance of the signature and satisfying results were shown with the area under the curve (AUC) up to 0.801 (3-year) and 0.619 (3-year), respectively. In addition, the subtyping of AML patients based on the risk signature demonstrated a significant correlation with the immune cell infiltration and response to immunotherapy. Finally, we incorporated risk signature with the classical clinical features to establish a nomogram which may contribute to the improvement of clinical management. To conclude, this study identified a necroptosis-related signature as a novel biomarker to improve the risk stratification, to inform the immunotherapy efficacy, and to indicate the therapeutic option of targeted therapy.

Targeting matrix metallopeptidase 2 by hydroxyurea selectively kills acute myeloid mixed-lineage leukemia.

Oncogene-induced tumorigenesis results in the variation of epigenetic modifications, and in addition to promoting cell immortalization, cancer cells undergo more intense cellular stress than normal cells and depend on other support genes for survival. Chromosomal translocations of mixed-lineage leukemia (MLL) induce aggressive leukemias with an inferior prognosis. Unfortunately, most MLL-rearranged (MLL-r) leukemias are resistant to conventional chemotherapies. Here, we showed that hydroxyurea (HU) could kill MLL-r acute myeloid leukemia (AML) cells through the necroptosis process. HU target these cells by matrix metallopeptidase 2 (MMP2) deficiency rather than subordinate ribonucleotide reductase regulatory subunit M2 (RRM2) inhibition, where MLL directly regulates MMP2 expression and is decreased in most MLL-r AMLs. Moreover, iron chelation of HU is also indispensable for inducing cell stress, and MMP2 is the support factor to protect cells from death. Our preliminary study indicates that MMP2 might play a role in the nonsense-mediated mRNA decay pathway that prevents activation of unfolding protein response under innocuous endoplasmic reticulum stress. Hence, these results reveal a possible strategy of HU application in MLL-r AML treatment and shed new light upon HU repurposing.

Tumor-intrinsic CD21 expression impacts the response of B-cell malignancy cells to CD19-CAR-T cells.

CD19-chimeric antigen receptor (CAR)-based T-cell therapy has produced promising clinical responses in patients with relapsed or refractory B-cell malignancies. However, a significant portion of patients with mature B cell-derived malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), do not respond to CD19-CAR-T cell therapy. Whether any characteristics and biomarkers intrinsic to cancer cells themselves can predict the CD19-CAR-T cell therapeutic response remains largely unknown. Surprisingly, by using experimental models, we show here that malignant B cells bearing CD21, a mature B cell marker, could not be efficiently killed by CD19-CAR-T cells. CD19, CD21, and CD81, together with CD225, form the B cell coreceptor complex that enhances B cell-mediated signaling. Our results indicated that CD21 affected the recognition of CD19-positive tumor cells by CD19-CAR-T cells and impaired the antitumor capacities of these effector cells. We have not only uncovered a mechanism underlying the impairment of CD19-CAR-T cells in mature B cell-derived CLL and NHL, but also proposed a pretreatment biomarker that may predict CD19-CAR-T cell therapeutic response, thus preventing foreseeable therapy failure and suggesting optimal personized therapies.

A T-cell independent universal cellular therapy strategy through antigen depletion.

Rationale: T cell therapeutic strategy using CD19-targeting chimeric antigen receptor (CAR) is a revolutionary, novel, and successful treatment for B-cell malignancies. However, the dependency on T-cell mediated cytotoxicity restricts CAR-T therapy as a patient-specific individualized therapy with severe side effects, such as cytokine release syndrome (CRS). Whether a non-T-cell based universal cellular therapy can substitute CAR-T therapy is largely unknown. Methods: Various artificial antigen-recognizing cells were prepared to determine whether non-T-cell-derived CD19-scFv bearing effector cells could cause target cell death. A universal strategy for CRS-free cellular therapeutics was proposed, utilizing artificial antigen-recognizing cells (AARC), which can be manufactured universally and routinely as "off-the-shelf" mesenchymal stromal cells (MSCs) or other types of non-autologous cells expressing anergic CARs. Results: We demonstrated that T-lymphocytic and non-lymphocytic cells could cause CD19 internalization and subsequent depletion when armed with a CD19-recognizing moiety. This CD19 antigen depletion could efficiently induce T-cell independent apoptosis in target cancer cells whose survival depends on CD19 expression, suggesting that CD19 antigen depletion constitutes a crucial tumor destroying mechanism for CD19-CAR-T, especially for its long-term efficacy. Conclusion: Our results uncovered an unrecognized CAR-T cytotoxicity and antigen loss mechanism and provided new insights into a shift from unique patient-specific autologous therapeutics to universal and standardized allogeneic treatment.

Deubiquitinating enzyme inhibitor alleviates cyclin A1-mediated proteasome inhibitor tolerance in mixed-lineage leukemia.

Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug-tolerant cancer cells, which offer therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively, however the ways by which drug-tolerant cancer cells orchestrate their adaptive responses to drug challenges remain largely unknown. Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells. This adaptive process involved reversible downregulation of cyclin A1, which promoted PI resistance through cell-cycle arrest. PI-tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL-mediated histone H3 lysine 4 methylation. These results reveal the importance of cyclin A1-engaged cell-cycle regulation in PI resistance in MLL cells, and suggest that cell-cycle re-entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.

Achieving Superior Energy Storage Properties and Ultrafast Discharge Speed in Environment-Friendly Niobate-Based Glass Ceramics.

Glass ceramics composed of Na2O-BaO-Bi2O3-Nb2O5-Al2O3-SiO2 (NBBN-AS) were modified by rare-earth doping and prepared via the melt-quenching process accompanied by controlled crystallization. High-resolution transmission electron microscopy displayed the glassy matrix closely encompassing the nanosized NaNbO3, Ba2NaNb5O15, BaAl2Si2O8, and AlNbO4 crystalline grains. With rare-earth doping, the NBBN-AS glass ceramics' theoretical energy storage density can reach 22.48 J/cm3. This excellent energy storage property is credited with increasing breakdown strength, and numerical simulation was applied to reveal the intrinsic mechanism for increased breakdown strength by rare-earth doping. The charge-discharge results indicated a giant power density of 220 MW/cm3 as well as an ultrafast discharge speed of 11 ns. The results indicate that the glass ceramic can be used in advanced capacitor applications.

mTORC1-mediated amino acid signaling is critical for cell fate determination under transplant-induced stress.

Transplantation of in vitro-manipulated cells is widely used in hematology. While transplantation is well recognized to impose severe stress on transplanted cells, the nature of transplant-induced stress remains elusive. Here, we propose that the lack of amino acids in serum is the major cause of transplant-induced stress. Mechanistically, amino acid deficiency decreases protein synthesis and nutrient consummation. However, in cells with overactive AKT and ERK, mTORC1 is not inhibited and protein synthesis remains relatively high. This impaired signaling causes nutrient depletion, cell cycle block, and eventually autophagy and cell death, which can be inhibited by cycloheximide or mTORC1 inhibitors. Thus, mTORC1-mediated amino acid signaling is critical in cell fate determination under transplant-induced stress, and protein synthesis inhibition can improve transplantation efficiency.