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An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby [CD8.sup.+] T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research., Introduction Despite the significant impact that checkpoint inhibitor immunotherapies have generated in clinical oncology, the majority of patients with cancer still do not benefit from this treatment modality (1). It [...]

Antimony sulfide (Sb2S3) solar cells have attracted extensive attention in silicon‐based tandem solar cells. The performance of Sb2S3 devices fabricated by the vacuum method is limited by sulfur vacancies (VS) and surface oxide defects during high‐temperature processes. Herein, amorphous Sb2S3 film based on low‐temperature rapid thermal evaporation (RTE) technique is fabricated to overcome S loss. Moreover, a sulfur‐atmosphere recrystallization strategy is further developed to obtain high‐quality absorbers from the amorphous film. The element content of Sb2S3 film is completely in accord with the stoichiometric ratio (2:3), and the surface oxides are effectively suppressed, enhancing VOC and fill factor. Compared to the control directly crystallized film, the defect concentrations of the S‐recrystallized Sb2S3 film are reduced by 61%, exhibiting better uniformity and higher PN junction quality. Ultimately, the full‐inorganic Sb2S3 solar cells (FTO/TiO2/Sb2S3/Au) achieve an efficiency of 6.25%. The S‐atmosphere recrystallization process can effectively passivate bulk defects (VS and Sb2O3) and suppress recombination to improve device performance, which will provide new prospects for vacuum method‐based Sb2S3 thin film solar cells. [ABSTRACT FROM AUTHOR]

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]

This article discusses a rare case of coinciding kappa AL amyloidosis and kappa light chain deposition disease (LCDD) in the lung. Amyloidosis is characterized by the accumulation of insoluble protein aggregates, while LCDD involves the deposition of monoclonal immunoglobulin light chains in tissues. The case study highlights the diagnostic challenge of encountering amyloid-like material that fails to stain positively with Congo red. The article also mentions the association of these diseases with underlying hematolymphoid neoplasms and Sjögren syndrome. Further research is needed to understand the clinical significance of this coexistence. [Extracted from the article]

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]

Antimonide-based ternary III–V nanowires (NWs) provide a tunable bandgap over a wide range, and the GaAsSb material system has prospective applications in the 1.3–1.55 μm spectral range of optical communications. In this paper, GaAs/Ga(As)Sb/GaAs single quantum well (SQW) NWs were grown on Si(111) substrates by molecular beam epitaxy (MBE). In addition, the morphologies and tunable wavelengths of the GaAs/Ga(As)Sb/GaAs SQWs were adjusted by interrupting the Ga droplets and changing the growth temperatures and V/III ratios. The four morphologies of the GaAs/Ga(As)Sb/GaAs SQW NWs were observed by scanning electron microscopy (SEM). The microscale lattice structure related to the incorporation of Sb in GaAs/Ga(As)Sb/GaAs SQWs was studied by Raman spectroscopy. The crystal quality of the GaAs/Ga(As)Sb/GaAs SQW NWs was researched by X-ray diffraction (XRD) and transmission electron microscopy (TEM). In addition, the optical properties of the GaAs/Ga(As)Sb/GaAs SQWs were investigated by photoluminescence (PL) spectroscopy. The PL spectra showed the peak emission wavelength range of ∼818 nm (GaAs) to ∼1628 nm (GaSb) at 10 K. This study provides an approach to enhance the effective control of the morphology, structure and wavelength of quantum well or core–shell NWs. [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]

Myeloid-derived suppressor cells (MDSCs) are a hetero geneous group of cells, which can suppress the immune response, promote tumor progression and impair the efficacy of immunotherapies. Consequently, the pharmacological targeting of MDSC is emerging as a new immunotherapeutic strategy to stimulate the natural anti-tumor immune response and potentiate the efficacy of immunotherapies. Herein, we leveraged genetically modified models and a small molecule inhibitor to validate Calcium-Calmodulin Kinase Kinase 2 (CaMKK2) as a druggable target to control MDSC accumulation in tumor-bearing mice. The results indicated that deletion of CaMKK2 in the host attenuated the growth of engrafted tumor cells, and this phenomenon was associated with increased antitumor T cell response and decreased accumulation of MDSC. The adoptive transfer of MDSC was sufficient to restore the ability of the tumor to grow in Camkk2-/- mice, confirming the key role of MDSC in the mechanism of tumor rejection. In vitro studies indicated that blocking of CaMKK2 is sufficient to impair the yield of MDSC. Surprisingly, MDSC generated from Camkk2-/- bone marrow cells also showed a higher ability to terminally differentiate toward more immunogenic cell types (e.g inflammatory macrophages and dendritic cells) compared to wild type (WT). Higher intracellular levels of reactive oxygen species (ROS) accumulated in Camkk2-/- MDSC, increasing their susceptibility to apoptosis and promoting their terminal differentiation toward more mature myeloid cells. Mechanistic studies indicated that AMP-activated protein kinase (AMPK), which is a known CaMKK2 proximal target controlling the oxidative stress response, fine-tunes ROS accumulation in MDSC. Accordingly, failure to activate the CaMKK2-AMPK axis can account for the elevated ROS levels in Camkk2-/- MDSC. These results highlight CaMKK2 as an important regulator of the MDSC lifecycle, identifying this kinase as a new druggable target to restrain MDSC expansion and enhance the efficacy of anti-tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract Peripheral neuropathy (PN) is one of the most common side effects of bortezomib therapy. The majority of bortezomib-related PN is a sensory neuropathy of mild to moderate degree, and is reversible after dose reduction or discontinuation. However, occasionally bortezomib-induced neuropathy can be severe and affects motor and/or autonomic nerves, and may be mediated by immune process. The role of immune modulation therapy in the management of bortezomib-induced PN was not well established. Here, we reported a case of bortezomib-induced severe PN that responded well to plasma exchange and steroid treatment.

We determined the impact of bone marrow fibrosis (BMF) on the clinical outcomes of newly diagnosed multiple myeloma (NDMM) patients in the current era of myeloma therapy. A total of 393 MM patients were included in the final analysis. The median followup was 83 months (range: 3.9 to 212 months). BMF was noted in 122 (48.2%) evaluable patients. Median progression free survival (PFS) in patients without BMF was 30.2 (95% CI: 24.7‐38.0) months, and 21.1 (95% CI: 18.8‐27.5) months in patients with BMF present (P =.024). Median overall survival (OS) was 61.2 (95% CI: 51.5‐81.2) months in patients without BMF, and 45.1 (95% CI: 38.7‐57.0) months in patients with BMF (P =.0048). A subset of 99 patients had their bone marrow biopsies stained for JAK1 and JAK2 by immunohistochemistry. Of these samples 67 (67.7%) patients had detectable JAK2 expression predominantly noted on bone marrow megakaryocytes. JAK2 expression correlated with myeloma disease stage (P =.0071). Our study represents the largest dataset to date examining the association of BMF with prognosis in the era of novel therapies and widespread use of hematopoietic stem cell transplant (HSCT). Our data suggest that MM patients with BMF (particularly those with extensive BMF) have a poorer prognosis even when treated with immunomodulatory agents and proteasome inhibitors. [ABSTRACT FROM AUTHOR]

PURPOSE We performed a retrospective chart review on 393 patients with multiple myeloma (MM) to determine the utility of the gamma gap (GG). METHODS We calculated the difference between a patient’s total serum protein and albumin as a point-of-care test for assessing disease status in MM. RESULTS GG is highly correlated with the level of M-spike, and the change in GG correlates with myeloma treatment response. In addition, fitted linear models were established that allow for the calculation of M-protein level from the GG within hours from blood draw. CONCLUSION Our study has important implications in the care of MM, particularly in countries/areas with limited resources. [ABSTRACT FROM AUTHOR]

The roles of mitochondrial dysfunction in carcinogenesis remain largely unknown. The effects of PTEN‐induced putative kinase 1 (PINK1)‐dependent mitophagy on the pathogenesis of multiple myeloma (MM) are determined. The levels of the PINK1‐dependent mitophagy markers PINK1 and parkin RBR E3 ubiquitin protein ligase (PARK2) in CD138+ plasma cells are reduced in patients with MM and correlate with clinical outcomes in myeloma patients. Moreover, the induction of PINK1‐dependent mitophagy with carbonylcyanide‐m‐chlorophenylhydrazone (CCCP) or salinomycin, or overexpression of PINK1 leads to inhibition of transwell migration, suppression of myeloma cell homing to calvarium, and decreased osteolytic bone lesions. Furthermore, genetic deletion of pink1 accelerates myeloma development in a spontaneous X‐box binding protein‐1 spliced isoform (XBP‐1s) transgenic myeloma mouse model and in VK*MYC transplantable myeloma recipient mice. Additionally, treatment with salinomycin shows significant antimyeloma activities in vivo in murine myeloma xenograft models. Finally, the effects of PINK1‐dependent mitophagy on myeloma pathogenesis are driven by the activation of the Mps one binder kinase activator (MOB1B)‐mediated Hippo pathway and the subsequent downregulation of Yes‐associated protein (YAP)/transcriptional co‐activator with PDZ‐binding motif (TAZ) expression. These data provide direct evidence that PINK1‐dependent mitophagy plays a critical role in the pathogenesis of MM and is a potential therapeutic target. [ABSTRACT FROM AUTHOR]

GaAsSb-Based QW structure nanowires play an important role in the field of nano-optoelectronics. In this manuscript, we report the epitaxial growth of GaAs/GaAs0.75Sb0.25/GaAs single quantum well (SQW) nanowires on a Si (111) substrate by solid source molecular beam epitaxy (SS-MBE) and study the morphology, structure and optical properties of the nanowires. Two morphologies of SQW nanowires are observed, essentially caused by Ga droplets at the top of a small number of nanowires which were not completely consumed. The structure of GaAs/GaAsSb/GaAs SQW nanowires was characterized by transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDXS). The results show that the nanowires have a zinc blende crystal structure. The photoluminescence (PL) spectrum of GaAs/GaAs0.75Sb0.25/GaAs SQW nanowires shows a peak emission wavelength of ∼1.2 μm at room temperature. Finally, the controllable growth of nanowires was explored by changing the Ga interruption time. This work would have a positive influence on the development of optoelectronic devices based on GaAs/GaAsSb/GaAs quantum well nanowires. [ABSTRACT FROM AUTHOR]

The GaAsSb-based quantum well plays a very important role in optoelectronic devices due to its excellent wavelength tunability. When the dimension reduces, the quantum confinement effect will take place and the quantum well in nanowires will show many interesting characteristics. GaAsSb-based quantum-well nanowires are of contemporary interest. However, the properties of the quasi-type-II structure in a single quantum well nanowire have been rarely investigated. Here, we grow GaAs/GaAs0.92Sb0.08/GaAs coaxial single quantum-well nanowires and discussed their power-dependent and temperature-dependent photoluminescence. We find that due to the small band offset of conduction bands, both type-I like and type-II like emission exist in our nanowires. When electrons obtain enough thermal energy through collisions or surrounding environment, they will overcome the barrier and diffuse to the GaAs conduction band, which contributes to the type-II like recombination. These results show the optical property of the quasi-type-II quantum well in nanowires, which can pave the way toward future nanoscale quantum well devices. [ABSTRACT FROM AUTHOR]

Abstract: Multiple myeloma (MM) remains an incurable disease in need of the development of novel therapeutic agents and drug combinations. ABT‐199 is a specific Bcl‐2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co‐expression of Mcl‐1 and Bcl‐xL. These limitations preclude its use in a broader patient population. We have recently found that a sphingosine kinase 2‐specific inhibitor (ABC294640) induces apoptosis in primary human CD138+ cells and MM cell lines. ABC294640 is currently in phase I/II clinical trials for myeloma (clinicaltrials.gov: #NCT01410981). Interestingly, ABC294640 down‐regulates c‐Myc and Mcl‐1, but does not have any effects on Bcl‐2. We first evaluated the combinatorial anti‐myeloma effect of ABC294640 and ABT‐199 in vitro in 7 MM cell lines, all of which harbor no t(11;14) translocation. Combination index calculation demonstrated a synergistic anti‐myeloma effect of the combination of ABC294640 and ABT‐199. This synergistic anti‐myeloma effect was maintained even in the presence of bone marrow (BM) stromal cells. The combination of ABC294640 and ABT‐199 led to enhanced cleavage of PARP and caspase‐3/9 and increased Annexin‐V expression, consistent with the induction of apoptosis by the combination treatment. In addition, the combination of ABC294640 and ABT‐199 resulted in the down‐regulation of the anti‐apoptotic proteins Mcl‐1, Bcl‐2, and Bcl‐xL and the cleavage of Bax and Bid. The combination induced both the mitochondrial mediated‐ and caspase‐mediated apoptosis pathways. Finally, the combination of ABC294640 and ABT‐199 resulted in augmented anti‐myeloma effect in vivo in a mouse xenograft model. These findings demonstrate that the co‐administration of ABC294640 and ABT‐199 exhibits synergistic anti‐myeloma activity in vitro and in vivo, providing justification for a clinical study of this novel combination in patients with relapsed/refractory multiple myeloma. [ABSTRACT FROM AUTHOR]

Etched stainless steel plates were prepared using electrolytic oxidation while varying the applied voltage and reaction time. The morphology of the surfaces of the etched stainless steel plates was investigated using scanning electron microscopy. A hierarchical pore network with multiple pore sizes was observed on the etched surface. It is thought that these structures on the metal surface contributed to an improvement in metal-ceramic adhesion by linking with ceramic particles. Citratoperoxotitanate(IV) is a typical titanium complexing ion containing carboxyl groups. Therefore, this complex ion was expected to readily form organic-inorganic hybrid chemical bonds on the metal surface. Water-soluble citratoperoxotitanate(IV) was synthesized via a ‘peroxotitanate’ intermediate. The titanium complexing solution was mixed with a catalyst solution and the product was used to coat the stainless steel plates. The complexing ion formed chemical bonds, such as Fe-COO-Ti, on the steel surface. Improved adhesion was observed between the metal and ceramic particles, attributed to the organic-inorganic chemical bonds. [ABSTRACT FROM AUTHOR]