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Multiple myeloma (MM) is a common hematological malignancy that has fostered several new therapeutic approaches to combat newly diagnosed or relapsed MM. While the field has advanced over the past 2 decades, the majority of patients will develop resistance to these treatments, causing the need for new therapeutic targets. SLAMF7 is an attractive therapeutic target in multiple myeloma, and a monoclonal antibody that targets SLAMF7 has shown consistent beneficial outcomes in clinical trials to date. In this review, we will focus on the structure and regulation of SLAMF7 and its mechanism of action. The most recent clinical trials will be reviewed to further understand the clinical implications and improve the prognosis of MM. Furthermore, the efficacy of anti-SLAMF7 monoclonal antibodies combined with standard therapies and possible resistance mechanisms will be discussed. This review aimed to provide a detailed summary of the role of SLAMF7 in the pathogenesis of patients with MM and the rationale for further investigation into SLAMF7-mediated molecular pathways associated with MM development. [ABSTRACT FROM AUTHOR]

Retinoid X receptor (RXR) heterodimerizes with the PPAR nuclear hormone receptor and regulates its downstream events. We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide's anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. Genetic overexpression and CRISPR/Cas9 knockout experiments were conducted in multiple myeloma (MM) cell lines and Jurkat T cell lines to determine the roles of CRBN in RXR-agonist mediated effects. A xenograft mouse model of MM was established to determine the combination effect of LG100754 and lenalidomide. The combination of RXR agonists and lenalidomide demonstrated synergistic activity in increasing CRBN expression and killing myeloma cells. Mechanistically, the RXR agonists reduced the binding of PPARs to the CRBN promoter, thereby relieving the repressor effect of PPARs on CRBN transcription. RXR agonists downregulated the exhaustion markers and increased the activation markers of Jurkat T cells and primary human T cells. Co-administration of LG100754 and lenalidomide showed enhanced anti-tumor activity in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma. [ABSTRACT FROM AUTHOR]

GaAsSb semiconductor material, a ternary alloy, has long been recognized as a crucial semiconductor in the near infrared range due to its ability to finely adjust the wavelength through controlling the Sb component. In this work, we report on the pattern of orientation variation in self-catalyzed grown GaAsSb nanowires (NWs). Utilizing solid-source molecular-beam epitaxy (MBE), self-catalyzed GaAs and GaAsSb nanowires (NWs) were grown on Si (111) substrates. The influence of various Sb components on the growth direction of the nanowires in the ternary GaAsSb alloy was examined using scanning electron microscopy (SEM). The inclusion of Sb components was discovered to alter the growth direction of the nanowires, transitioning them from a vertical and inclined orientation to a configuration that encompassed vertical, inclined, and parallel orientations with respect to the Si (111) substrate. As the Sb component in GaAsSb increased, there was an increased likelihood of the nanowires growing parallel to the surface of the Si (111) substrate. A combination of X-ray diffraction (XRD) and Raman spectroscopy validated the presence of Sb components and indicated a high crystalline quality. Additionally, XRD confirmed that the Sb components aligned with the intended structure. These findings establish a solid material foundation for the development of high-performance GaAsSb-based devices. [ABSTRACT FROM AUTHOR]

Mitophagy plays an important role in maintaining mitochondrial homeostasis by clearing damaged mitochondria. Sphingosine kinase 2 (SK2), a type of sphingosine kinase, is an important metabolic enzyme involved in generating sphingosine-1-phosphate. Its expression level is elevated in many cancers and is associated with poor clinical outcomes. However, the relationship between SK2 and mitochondrial dysfunction remains unclear. We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines. We showed that mitophagy correlates with apoptosis induction and likely occurs through the SET/PP2AC/PARK2 pathway, where inhibiting PP2AC activity may rescue this process. Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein–protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma. [ABSTRACT FROM AUTHOR]

Simple Summary: Cereblon (CRBN) is a direct binding target of immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma (MM). Many patients with MM have comorbidities, including diabetes and/or dyslipidemia, and are treated with peroxisome proliferator-activated receptor (PPAR) agonists. This study aimed to further analyze the effects and mechanisms underlying the drug-to-drug interactions between IMiDs and PPAR agonists in MM. We found that PPAR agonists reduced CRBN expression by inducing DNA methylation and increasing protein degradation. PPAR agonists and IMiDs showed opposing metabolic effects in MM cells. Our retrospective study suggested an inferior response and outcome when PPARs and IMiDs were concurrently administered. Our study has important implications for the care of patients with MM and provides a foundation for exploring novel compounds or PPAR partial agonists/antagonists that can increase CRBN expression while retaining their lipid-lowering or insulin-sensitizing functions. Our previous study demonstrated that peroxisome proliferator-activated receptor (PPAR) agonists downregulated cereblon (CRBN) expression and reduced the anti-myeloma activity of lenalidomide in vitro and in vivo. We aimed to determine whether DNA methylation and protein degradation contribute to the effects of PPAR agonists. CRBN promoter methylation status was detected using methylation-specific polymerase chain reaction. The CRBN protein degradation rate was measured using a cycloheximide chase assay. Metabolomic analysis was performed in multiple myeloma (MM) cells treated with PPAR agonists and/or lenalidomide. Our retrospective study determined the effect of co-administration of PPAR agonists with immunomodulatory drugs on the outcomes of patients with MM. CpG islands of the CRBN promoter region became highly methylated upon treatment with PPAR agonists, whereas treatment with PPAR antagonists resulted in unmethylation. The CRBN protein was rapidly degraded after treatment with PPAR agonists. Lenalidomide and fenofibrate showed opposite effects on acylcarnitines and amino acids. Co-administration of immunomodulatory drugs and PPAR agonists was associated with inferior treatment responses and poor survival. Our study provides the first evidence that PPAR agonists reduce CRBN expression through various mechanisms including inducing methylation of CRBN promoter CpG island, enhancing CRBN protein degradation, and affecting metabolomics of MM cells. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effects of the addition of Bi and Zn on the mechanical properties of Sn-Ag-Cu lead-free alloy frequently used as a soldering material in the semiconductor packaging process. To reduce the Ag content of the commercial alloy SAC305 (Sn-3Ag-0.5Cu) by 1 wt.%, Bi and Zn were admixed in different ratios and the changes in mechanical and electrical properties were analyzed. Compared to the SAC305 alloy, electrical conductivity and elongation at break decreased while tensile strength increased following the addition of the two elements. In particular, upon the addition of 1 wt.% Bi, the tensile strength increased to a maximum of 43.7 MPa, whereas the tensile strength was 31.9 MPa in the alloy with 1 wt.% Zn. Differential thermal analysis and scanning electron microscopy revealed that the changes in physical properties can be ascribed to a reduction in the activation energy required for formation intermetallic compound when Bi was added, and the refinement of the structure due to a decrease in undercooling degree when Zn was added. When Bi and Zn were added at the same time, each characteristic for the change in the microstructure was applied in a complex manner, but the effect on the change of the physical properties worked independently. [ABSTRACT FROM AUTHOR]

The United States is undergoing a demographic shift towards an older population with profound economic, social, and healthcare implications. The number of Americans aged 65 and older will reach 80 million by 2040. The shift will be even more dramatic in the extremes of age, with a projected 400% increase in the population over 85 years old in the next two decades. Understanding the molecular and cellular mechanisms of ageing is crucial to reduce ageing-associated disease and to improve the quality of life for the elderly. In this review, we summarized the changes associated with the ageing of hematopoietic stem cells (HSCs) and what is known about some of the key underlying cellular and molecular pathways. We focus here on the effects of reactive oxygen species and the thioredoxin redox homeostasis system on ageing biology in HSCs and the HSC microenvironment. We present additional data from our lab demonstrating the key role of thioredoxin-1 in regulating HSC ageing. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma is the second most common hematologic malignancy in the United States. Eventually, all myeloma patients will relapse and develop resistance to currently available agents. There is an unmet medical need to identify novel therapeutic targets. PIM kinases play an important role in myeloma pathogenesis and disease relapse. We herein provided a comprehensive review on the roles of PIM kinases in myeloma cell survival and proliferation and in the bone marrow microenvironment that supports myeloma growth. The development and testing of novel PIM kinase inhibitors were summarized. Finally, the preclinical studies of the combinatorial effects of PIM kinase inhibitors and other anti-myeloma agents were presented. Multiple myeloma (MM) remains an incurable disease and novel therapeutic agents/approaches are urgently needed. The PIM (Proviral insertion in murine malignancies) serine/threonine kinases have 3 isoforms: PIM1, PIM2, and PIM3. PIM kinases are engaged with an expansive scope of biological activities including cell growth, apoptosis, drug resistance, and immune response. An assortment of molecules and pathways that are critical to myeloma tumorigenesis has been recognized as the downstream targets of PIM kinases. The inhibition of PIM kinases has become an emerging scientific interest for the treatment of multiple myeloma and several PIM kinase inhibitors, such as SGI-1776, AZD1208, and PIM447 (formerly LGH447), have been developed and are under different phases of clinical trials. Current research has been focused on the development of a new generation of potent PIM kinase inhibitors with appropriate pharmacological profiles reasonable for human malignancy treatment. Combination therapy of PIM kinase inhibitors with chemotherapeutic appears to create an additive cytotoxic impact in cancer cells. Notwithstanding, the mechanisms by which PIM kinases modulate the immune microenvironment and synergize with the immunomodulatory agents such as lenalidomide have not been deliberately depicted. This review provides a comprehensive overview of the PIM kinase pathways and the current research status of the development of PIM kinase inhibitors for the treatment of MM. Additionally, the combinatorial effects of the PIM kinase inhibitors with other targeted agents and the promising strategies to exploit PIM as a therapeutic target in malignancy are highlighted. [ABSTRACT FROM AUTHOR]

In the current investigation, we synthesize zeolite using two different waste streams, such as aluminum dross and waste glass powder, for its potential application in indium and tin recovery from the leach liquor of waste liquid crystal display (LCD) glass. The aluminum dross (Al resource) and waste glass powder (Si resource) were used as raw materials for the synthesis of zeolite. Zeolite was synthesized using different weight ratios of Al dross and waste LCD glass by hydrothermal synthesis route using NaOH. The weight ratio variations of Al dross and waste LCD glass in this study are 0.3:1, 0.5:1, 1:1, 2:1, 3:1, and 4:1 using 2 M NaOH hydroxide by the hydrothermal technique. The synthesized zeolite was analyzed by X-ray diffraction spectroscopy (XRD), scanning electron microscopy (SEM), and Brunauer–Emmett–Teller (BET) followed by the possible application for recovery/extraction of indium and tin from leach liquor of waste LCD glasses. The indium extraction of average 93.66%, and tin extraction of 93.10% could be achieved from mixed solution indium and tin chloride. The significant achievement of the current investigation is that it can address two environment problems simultaneously, i.e., waste LCD glass and Al dross, and can be used for value recovery from waste LCD, LCD etching waste like secondary resources. [ABSTRACT FROM AUTHOR]