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Highlights CD73 is the key ectoenzyme involved in the generation of AMP-derived adenosine, which contributes to immunosuppression in the MM BM milieu. Blocking CD73 activity with a potent, selective, orally bioavailable CD73 inhibitor ORIC-533 decreases adenosine generation, overcomes immune suppression, and restores immune cell-mediated MM cell lysis. Based on these preclinical studies, a multi-center clinical trial of ORIC-533 has been initiated in patients with relapsed refractory MM (NCT05227144).

This study investigated the use of smartphones by family caregivers for hospitalized patients with chronic heart failure (CHF). In total, 120 patients and their unpaid family caregivers participated in this study. The caregivers were divided into two groups based on the perceived importance of smartphones in patient care. Both groups completed the General Demographic Information Survey, Problematic Mobile Phone Use Questionnaire, Barthel Index Scale, Modified Early Warning Score (MEWS), Johns Hopkins Fall Risk Assessment Tool (JH-FRAT), and Family Burden Scale of Diseases Survey. Moreover, left ventricular ejection fraction (LVEF) and stroke volume (SV) were measured in all participants. The age of hospitalized patients with CHF was correlated with the Barthel Index Scale, MEWS, and JH-FRAT, whereas LVEF and SV were correlated with MEWS. The important group had a much higher financial burden than the nonimportant group. Linear regression analysis revealed that financial burden and mental health had a remarkable impact on the content of mobile calls about treatment. Furthermore, the economic status of family caregivers determined the importance of smartphone calls in the care of patients with CHF during hospitalization.

Multiple myeloma (MM) remains an incurable hematological malignancy. Despite tremendous advances in the treatment, about 10% of patients still have very poor outcomes with median overall survival less than 24 months. Our study aimed to underscore the critical mechanisms pertaining to the rapid disease progression and provide novel therapeutic selection for these ultra-high-risk patients. We utilized single-cell transcriptomic sequencing to dissect the characteristic bone marrow niche of patients with survival of less than two years (EM24). Notably, an enrichment of LILRB4high pre-matured plasma-cell cluster was observed in the patients in EM24 compared to patients with durable remission. This cluster exhibited aggressive proliferation and drug-resistance phenotype. High-level LILRB4 promoted MM clonogenicity and progression. Clinically, high expression of LILRB4 was correlated with poor prognosis in both newly diagnosed MM patients and relapsed/refractory MM patients. The ATAC-seq analysis identified that high chromosomal accessibility caused the elevation of LILRB4 on MM cells. CRISPR-Cas9 deletion of LILRB4 alleviated the growth of MM cells, inhibited the immunosuppressive function of MDSCs, and further rescued T cell dysfunction in MM microenvironment. The more infiltration of myeloid-derived suppressive cells (MDSCs) was observed in EM24 patients as well. Therefore, we innovatively generated a TCR-based chimeric antigen receptor (CAR) T cell, LILRB4-STAR-T. Cytotoxicity experiment demonstrated that LILRB4-STAR-T cells efficaciously eliminated tumor cells and impeded MDSCs function. In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T cell immunotherapy is promising against tumor cells and immunosuppressive tumor microenvironment in MM.

Summary: Background: Multiple myeloma (MM) is an incurable hematological malignancy of the plasma cells. The maintenance of protein homeostasis is critical for MM cell survival. Elevated levels of paraproteins in MM cells are cleared by proteasomes or lysosomes, which are independent but inter-connected with each other. Proteasome inhibitors (PIs) work as a backbone agent and successfully improved the outcome of patients; however, the increasing activity of autophagy suppresses the sensitivity to PIs treatment. Methods: The transcription levels of CRIP1 were explored in plasma cells obtained from healthy donors, patients with newly diagnosed multiple myeloma (NDMM), and relapsed/refractory multiple myeloma (RRMM) using Gene expression omnibus datasets. Doxycycline-inducible CRIP1-shRNA and CRIP1 overexpressed MM cell lines were constructed to explore the role of CRIP1 in MM pathogenesis. Proliferation, invasion, migration, proteasome activity and autophagy were examined in MM cells with different CRIP1 levels. Co-immunoprecipitation (Co-IP) with Tandem affinity purification/Mass spectrum (TAP/MS) was performed to identify the binding proteins of CRIP1. The mouse xenograft model was used to determine the role of CRIP1 in the proliferation and drug-resistance of MM cells. Findings: High CRIP1 expression was associated with unfavorable clinical outcomes in patients with MM and served as a biomarker for RRMM with shorter overall survival. In vitro and in vivo studies showed that CRIP1 plays a critical role in protein homeostasis via the dual regulation of the activities of proteasome and autophagy in MM cells. A combined analysis of RNA-seq, Co-IP and TAP/MS demonstrated that CRIP1 promotes proteasome inhibitors resistance in MM cells by simultaneously binding to de-ubiquitinase USP7 and proteasome coactivator PA200. CRIP1 promoted proteasome activity and autophagosome maturation by facilitating the dequbiquitination and stabilization of PA200. Interpretation: Our findings clarified the pivotal roles of the CRIP1/USP7/PA200 complex in ubiquitin-dependent proteasome degradation and autophagy maturation involved in the pathogenesis of MM. Funding: A full list of funding sources can be found in the acknowledgements section.

MicroRNAs (MiRNAs) carried by exosomes play pivotal roles in the crosstalk between cell components in the tumor microenvironment. Our study aimed at identifying the expression profile of exosomal miRNAs (exo-miRNAs) in the serum of multiple myeloma (MM) patients and investigating the regulation networks and their potential functions by integrated bioinformatics analysis. Exosomes in serum from 19 newly diagnosed MM patients and 9 healthy donors were isolated and the miRNA profile was investigated by small RNA sequencing. Differential expression of exo-miRNAs was calculated and target genes of miRNAs were predicted. CytoHubba was applied to identify the hub miRNAs and core target genes. The LASSO Cox regression model was used to develop the prognostic model, and the ESTIMATE immune score was calculated to investigate the correlation between the model and immune status in MM patients. The top six hub differentially expressed serum exo-miRNAs were identified. 513 target genes of the six hub exo-miRNAs were confirmed to be differentially expressed in MM cells in the Zhan Myeloma microarray dataset. Functional enrichment analysis indicated that these target genes were mainly involved in mRNA splicing, cellular response to stress, and deubiquitination. 13 core exo-miRNA target genes were applied to create a novel prognostic signature to provide risk stratification for MM patients, which is associated with the immune microenvironment of MM patients. Our study comprehensively investigated the exo-miRNA profiles in MM patients. A novel prognostic signature was constructed to facilitate the risk stratification of MM patients with distinct outcomes.

Ovarian cancer is the second leading cause of death in women with gynecological malignancy in China. Circular RNAs are a class of noncoding regulatory RNAs reported to be involved in cancer development and progression. Previous studies, including our own, have indicated that hsa_circ_0007444 is downregulated in ovarian cancer tissues. This study aims to elucidate the function and mechanism of hsa_circ_0007444 in ovarian cancer progression. The expression of hsa_circ_0007444 is determined by quantitative real-time PCR (qRT-PCR). Cell proliferation, invasion, migration and apoptosis are examined by cell counting-kit 8 (CCK-8), transwell and flow cytometry assays. Tumor growth and metastasis are assessed in vivo using Balb/c nude mouse xenograft model and tail vein injection model. And the mechanism of action of hsa_circ_0007444 is analysed by RNA-binding protein immunoprecipitation (RIP), luciferase reporter and rescue assays. hsa_circ_0007444 is downregulated in ovarian cancer tissues and cell lines compared with that in normal ovarian tissues and normal epithelial cell line. Gain- and loss-of-function results indicate that hsa_circ_0007444 inhibits cell proliferation, invasion, migration and increases cell apoptosis of ovarian cancer cells in vitro, and inhibits tumor growth and lung metastasis in vivo. Mechanistically, hsa_circ_0007444 can interact with AGO2 and sponge miR-23a-3p, thereby upregulating DICER1 expression, which is an important tumor suppressor in ovarian cancer. And miR-23a-3p mimics can rescue the inhibitory effect of hsa_circ_0007444 on ovarian cancer cell proliferation, invasion and migration. Therefore, hsa_circ_0007444 can inhibit ovarian cancer progression through the hsa_circ_0007444/miR-23a-3p/DICER1 axis.

Abstract Background Waldenström macroglobulinemia (WM) is a rare and incurable indolent B-cell malignancy. The molecular pathogenesis and the role of immunosuppressive microenvironment in WM development are still incompletely understood. Methods The multicellular ecosystem in bone marrow (BM) of WM were delineated by single-cell RNA-sequencing (scRNA-seq) and investigated the underlying molecular characteristics. Results Our data uncovered the heterogeneity of malignant cells in WM, and investigated the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. Two novel subpopulations of malignant cells, CD19+CD3+ and CD138+CD3+, co-expressing T-cell marker genes were identified at single-cell resolution. Pseudotime-ordered analysis elucidated that CD19+CD3+ malignant cells presented at an early stage of WM-B cell differentiation. Colony formation assay further identified that CD19+CD3+ malignant cells acted as potential WM precursors. Based on the findings of T cell marker aberrant expressed on WM tumor cells, we speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. Therefore, our study further investigated the possible molecular mechanism of immune cell dysfunction. A precursor exhausted CD8-T cells and functional deletion of NK cells were identified in WM, and CD47 would be a potential therapeutic target to reverse the dysfunction of immune cells. Conclusions Our study facilitates further understanding of the biological heterogeneity of tumor cells and immunosuppressive microenvironment in WM. These data may have implications for the development of novel immunotherapies, such as targeting pre-exhausted CD8-T cells in WM.

Summary: Background: Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in majority of newly diagnosed patients with myeloma. However, drug resistance remains the major obstacle causing treatment failure in clinical practice. Here, we investigated the effects of Indirubin-3’-monoxime (I3MO), one of the derivatives of Indirubin, in the treatment of MM. Methods: MM patient primary samples and human cell lines were examined. I3MO effects on myeloma treatment and the underling molecular mechanisms were investigated via in vivo and in vitro study. Findings: Our results demonstrated the anti-MM activity of I3MO in both drug- sensitive and -resistance MM cells. I3MO sensitizes MM cells to bortezomib-induced apoptosis. Mechanistically, I3MO acts as a multifaceted regulator of cell death, which induced DNA damage, cell cycle arrest, and abrogates NF-κB activation. I3MO efficiently down-regulated USP7 expression, promoted NEK2 degradation, and suppressed NF-κB signaling in MM. Our study reported that I3MO directly bound with and caused the down-regulation of PA28γ (PSME3), and PA200 (PSME4), the proteasome activators. Knockdown of PSME3 or PSME4 caused the inhibition of proteasome capacity and the overload of paraprotein, which sensitizes MM cells to bortezomib-mediated growth arrest. Clinical data demonstrated that PSME3 and PSME4 are over-expressed in relapsed/refractory MM (RRMM) and associated with inferior outcome. Interpretation: Altogether, our study indicates that I3MO is agent triggering proteasome inhibition and represents a promising therapeutic strategy to improve patient outcome in MM. Fundings: A full list of funding can be found in the acknowledgements.

(Bi,Sb)2(Te,Se)3 alloys are widely used commercial thermoelectric (TE) materials for solid-state refrigeration around room temperature. The composition-induced structural phase transition could be realized by varying the compositions in these alloys, which may largely alter the electronic structure and phonon dispersion. Among them, the Se-alloyed Sb2Te3 accompanied with structural transition is seldom reported. Herein, the interrelations of Se-alloying induced changes in structural phase transition, band structure and TE properties of p-type zone-melted Sb2Te3-xSex (x = 1.5–2.4) alloys near phase transition boundary are systematically investigated. The results demonstrate that Sb2Te3-xSex shows a structural transition from a rhombohedral phase to mixed structure at x = 2.0. The carrier concentration and bandgap at room temperature of Sb2Te3-xSex (x = 1.5–2.4) constantly decrease with increasing Se contents x. The zT peak of the Sb2TeSe2 matrix is improved and shifted to higher temperature by optimizing carrier concentration via Ag doping. A maximum zT of ∼0.4 is obtained at 680 K in Sb1.97Ag0.03TeSe2 alloy, about 100% enhancement compared with the undoped sample. Keywords: Thermoelectric materials, Zone melting, Structural transition, Doping, Thermoelectric properties

Abstract p‐Type elemental tellurium (Te) has been found to be a promising thermoelectric (TE) material due to its high band degeneracy near the valence band maximum, and has exhibited a high zT ≈ 1.0 above 600 K. However, when forming Te1−xSex solid solutions, the maximal zTs are reduced because of the severely decreased carrier concentration. It is demonstrated that Se alloying is beneficial for enhancing TE performance of elemental Te provided the carrier concentration is optimized. Through Se alloying, the lattice thermal conductivity is remarkably suppressed by the induced large mass and strain field fluctuation, while the power factor can be maintained at a relatively high value as a result of the moderate alloying scattering potential, the unchanged density‐of‐state effective mass, and the optimized carrier concentration in Te1−xSex alloys. Notably, a positive temperature dependence of carrier mobility is observed near room temperature in Te1−xSex, which is proven to be caused by grain boundary scattering. A maximal zT ≈ 1.05 at 625 K is realized in Te0.93Se0.04As0.03 alloys, about 9% higher than the Se‐free Te. The conversion efficiency between 300 and 625 K is also improved ≈18% via Se alloying.

The continental crust is strongly depleted in copper compared with its building blocks-primary arc magmas-and this depletion is intrinsically associated with continental crust formation. However, the process by which Cu removal occurs remains enigmatic. Here we show, using Cu isotopes, that subduction-zone processes and mantle melting produce limited fractionation of Cu isotopes in arc magmas, and, instead, the heterogeneous Cu isotopic compositions of lower crustal rocks, which negatively correlate with Cu contents, suggest segregation or accumulation of isotopically light sulfides during intracrustal differentiation of arc magmas. This is supported by the extremely light Cu isotopic compositions of lower crustal mafic cumulates and heavy Cu isotopic compositions of differentiated magmas in thick continental arcs. Intracrustal differentiation of mantle-derived magmas and subsequent foundering of sulfide-rich mafic cumulates preferentially removes isotopically light Cu, leaving a Cu-depleted and isotopically heavy continental crust.

Future climates are likely to include extreme events, which in turn have great impacts on ecological systems. In this study, we investigated possible effects that could mitigate stem breakage caused by a rare and extreme ice storm in a Chinese subtropical forest across a gradient of forest diversity. We used Bayesian modeling to correct stem breakage for tree size and variance components analysis to quantify the influence of taxon, leaf and wood functional traits, and stand level properties on the probability of stem breakage. We show that the taxon explained four times more variance in individual stem breakage than did stand level properties; trees with higher specific leaf area (SLA) were less susceptible to breakage. However, a large part of the variation at the taxon scale remained unexplained, implying that unmeasured or undefined traits could be used to predict damage caused by ice storms. When aggregated at the plot level, functional diversity and wood density increased after the ice storm. We suggest that for the adaption of forest management to climate change, much can still be learned from looking at functional traits at the taxon level.

This study investigated the use of smartphones by family caregivers for hospitalized patients with chronic heart failure (CHF). In total, 120 patients and their unpaid family caregivers participated in this study. The caregivers were divided into two groups based on the perceived importance of smartphones in patient care. Both groups completed the General Demographic Information Survey, Problematic Mobile Phone Use Questionnaire, Barthel Index Scale, Modified Early Warning Score (MEWS), Johns Hopkins Fall Risk Assessment Tool (JH-FRAT), and Family Burden Scale of Diseases Survey. Moreover, left ventricular ejection fraction (LVEF) and stroke volume (SV) were measured in all participants. The age of hospitalized patients with CHF was correlated with the Barthel Index Scale, MEWS, and JH-FRAT, whereas LVEF and SV were correlated with MEWS. The important group had a much higher financial burden than the nonimportant group. Linear regression analysis revealed that financial burden and mental health had a remarkable impact on the content of mobile calls about treatment. Furthermore, the economic status of family caregivers determined the importance of smartphone calls in the care of patients with CHF during hospitalization. [ABSTRACT FROM AUTHOR]