Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma.

Multiple myeloma (MM) remains incurable due to drug resistance. Ribosomal protein S3 (RPS3) has been identified as a non-Rel subunit of NF-κB. However, the detailed biological roles of RPS3 remain unclear. Here, we report for the first time that RPS3 is necessary for MM survival and drug resistance. RPS3 was highly expressed in MM, and knockout of RPS3 in MM inhibited cell growth and induced cell apoptosis both in vitro and in vivo. Overexpression of RPS3 mediated the proteasome inhibitor resistance of MM and shortened the survival of MM tumor-bearing animals. Moreover, our present study found an interaction between RPS3 and the thyroid hormone receptor interactor 13 (TRIP13), an oncogene related to MM tumorigenesis and drug resistance. We demonstrated that the phosphorylation of RPS3 was mediated by TRIP13 via PKCδ, which played an important role in activating the canonical NF-κB signaling and inducing cell survival and drug resistance in MM. Notably, the inhibition of NF-κB signaling by the small-molecule inhibitor targeting TRIP13, DCZ0415, was capable of triggering synergistic cytotoxicity when combined with bortezomib in drug-resistant MM. This study identifies RPS3 as a novel biomarker and therapeutic target in MM.

Design and synthesis of cantharidin derivative DCZ5418 as a TRIP13 inhibitor with anti-multiple myeloma activity in vitro and in vivo.

Natural product cantharidin can inhibit multiple myeloma cell growth in vitro, while serious adverse effects limited its clinical application. Therefore, the structural modification of cantharidin is needed. Herein, inspired by the structural similarity of the aliphatic endocyclic moiety in cantharidin and TRIP13 inhibitor DCZ0415, we designed and synthesized DCZ5418 and its nineteen derivatives. The molecular docking study indicated that DCZ5418 had a similar binding mode to TRIP13 protein as DCZ0415 while with a stronger docking score. Moreover, the bioassay studies of the MM-cells viability inhibition, TRIP13 protein binding affinity and enzyme inhibiting activity showed that DCZ5418 had good anti-MM activity in vitro and definite interaction with TRIP13 protein. The acute toxicity test of DCZ5418 showed less toxicity in vivo than cantharidin. Furthermore, DCZ5418 showed good anti-MM effects in vivo with a lower dose administration than DCZ0415 (15 mg/kg vs 25 mg/kg) on the tumor xenograft models. Thus, we obtained a new TRIP13 inhibitor DCZ5418 with improved safety and good activity in vivo, which provides a new example of lead optimization by using the structural fragments of natural products.

The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13-MAPK-YWHAE signaling pathway.

BACKGROUND: Multiple myeloma (MM), an incurable disease owing to drug resistance, requires safe and effective therapies. Norcantharidin (NCTD), an active ingredient in traditional Chinese medicines, possesses activity against different cancers. However, its toxicity and narrow treatment window limit its clinical application. In this study, we synthesized a series of derivatives of NCTD to address this. Among these compounds, DCZ5417 demonstrated the greatest anti-MM effect and fewest side effects. Its anti-myeloma effects and  the mechanism were further tested. METHODS: Molecular docking, pull-down, surface plasmon resonance-binding, cellular thermal shift, and ATPase assays were used to study the targets of DCZ5417. Bioinformatic, genetic, and pharmacological approaches were used to elucidate the mechanisms associated with DCZ5417 activity. RESULTS: We confirmed a highly potent interaction between DCZ5417 and TRIP13. DCZ5417 inhibited the ATPase activity of TRIP13, and its anti-MM activity was found to depend on TRIP13. A mechanistic study verified that DCZ5417 suppressed cell proliferation by targeting TRIP13, disturbing the TRIP13/YWHAE complex and inhibiting the ERK/MAPK signaling axis. DCZ5417 also showed a combined lethal effect with traditional anti-MM drugs. Furthermore, the tumor growth-inhibitory effect of DCZ5417 was demonstrated using in vivo tumor xenograft models. CONCLUSIONS: DCZ5417 suppresses MM progression in vitro, in vivo, and in primary cells from drug-resistant patients, affecting cell proliferation by targeting TRIP13, destroying the TRIP13/YWHAE complex, and inhibiting ERK/MAPK signaling. These results imply a new and effective therapeutic strategy for MM treatment.

Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma.

BACKGROUND: Aberrant DNA repair pathways contribute to malignant transformation or disease progression and the acquisition of drug resistance in multiple myeloma (MM); therefore, these pathways could be therapeutically exploited. Ribonucleotide reductase (RNR) is the rate-limiting enzyme for the biosynthesis of deoxyribonucleotides (dNTPs), which are essential for DNA replication and DNA damage repair. In this study, we explored the efficacy of the novel RNR inhibitor, 4-hydroxysalicylanilide (HDS), in myeloma cells and xenograft model. In addition, we assessed the clinical activity and safety of HDS in patients with MM. METHODS: We applied bioinformatic, genetic, and pharmacological approaches to demonstrate that HDS was an RNR inhibitor that directly bound to RNR subunit M2 (RRM2). The activity of HDS alone or in synergy with standard treatments was evaluated in vitro and in vivo. We also initiated a phase I clinical trial of single-agent HDS in MM patients (ClinicalTrials.gov: NCT03670173) to assess safety and efficacy. RESULTS: HDS inhibited the activity of RNR by directly targeting RRM2. HDS decreased the RNR-mediated dNTP synthesis and concomitantly inhibited DNA damage repair, resulting in the accumulation of endogenous unrepaired DNA double-strand breaks (DSBs), thus inhibiting MM cell proliferation and inducing apoptosis. Moreover, HDS overcame the protective effects of IL-6, IGF-1 and bone marrow stromal cells (BMSCs) on MM cells. HDS prolonged survival in a MM xenograft model and induced synergistic anti-myeloma activity in combination with melphalan and bortezomib. HDS also showed a favorable safety profile and demonstrated clinical activity against MM. CONCLUSIONS: Our study provides a rationale for the clinical evaluation of HDS as an anti-myeloma agent, either alone or in combination with standard treatments for MM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03670173, Registered 12 September 2018.

Quercetin inhibits the proliferation of multiple myeloma cells by upregulating PTPRR expression.

Multiple myeloma (MM) is an incurable disease characterized by malignant plasma cell clonal expansion in the bone marrow; therefore, inhibiting the proliferation of plasma cells is an important approach to overcome the progression of MM. Quercetin (Que) is a promising flavonoid with broad-spectrum anti-tumor activity against various cancers, including MM; however, the underlying mechanism is not yet understood. The present study aimed to reveal the gene expression profile of Que-treated MM cells and clarify its potential mechanism. The 30% inhibitory concentration (IC30) of Que against MM cells was calculated, and the proliferation rate was significantly reduced after Que treatment. Next, 495 dysregulated genes were identified via RNA sequencing in Que-treated MM cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses indicated that the dysregulated genes were enriched in various apoptosis-related GO terms and amino acid metabolism-related pathways. qPCR validation showed that protein tyrosine phosphatase receptor-type R (PTPRR) had the highest verified log2 FC (abs) among the top 15 dysregulated genes. Overexpression of PTPRR increased the sensitivity of MM cells against Que, significantly inhibiting their proliferation and colony formation ability; silencing of PTPRR showed the opposite results. Furthermore, bioinformatics analyses and PPI network construction of PTPRR indicated that dephosphorylation of ERK might be the potential pathway for the PTPRR-induced inhibition of MM cell proliferation. In summary, our study identified the gene expression profile in Que-treated MM cells and demonstrated that the upregulation of PTPRR was one of the important mechanisms for the Que-induced inhibition of MM cell proliferation.

Resveratrol induces AMPK and mTOR signaling inhibition-mediated autophagy and apoptosis in multiple myeloma cells.

Resveratrol, a natural compound extracted from the skins of grapes, berries, or other fruits, has been shown to have anti-tumor effects against multiple myeloma (MM) via promoting apoptosis and inhibiting cell viability. In addition to apoptosis, autophagy also plays a significant role in anti-tumor effects. However, whether autophagy is involved in anti-MM activity of resveratrol remains unclear. In this study, human MM cell lines U266, RPMI-8226, and NCI-H929 were treated with resveratrol. Cell Counting Kit-8 assay and colony formation assay were used to measure cell viability. Western blot analysis was used to detect apoptosis- and autophagy-associated proteins. 3-Methyladenine (3-MA) was applied to inhibit autophagy. Results showed that resveratrol inhibited cell viability and colony formation via promoting apoptosis and autophagy in MM cell lines U266, RPMI-8226, and NCI-H929. Resveratrol promoted apoptosis-related proteins, Caspase-3 activating poly-ADP-ribose polymerase and Caspase-3 cleavage, and decreased the protein level of Survivin in a dose-dependent manner. Additionally, resveratrol upregulated the levels of LC3 and Beclin1 in a dose-dependent way, indicating that autophagy might be implicated in anti-MM effect of resveratrol. Furthermore, 3-MA relieved the cytotoxicity of resveratrol by blocking the autophagic flux. Resveratrol increased the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase and decreased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream substrates p70S6K and 4EBP1 in a dose-dependent manner, leading to autophagy. Therefore, our results suggest that resveratrol exerts anti-MM effects through apoptosis and autophagy, which can be used as a new therapeutic strategy for MM in clinic.

PKC inhibition of sotrastaurin has antitumor activity in diffuse large B-cell lymphoma via regulating the expression of MCT-1.

MCT-1 (multiple copies in T-cell lymphoma-1), a novel oncogene, was originally identified in T-cell lymphoma. A recent study has demonstrated that MCT-1 is highly expressed in 85% of diffuse large B-cell lymphomas (DLBCL). PKC (protein kinase C) plays an essential role in signal transduction for multiple biologically active substances for activating cellular functions and proliferation. In this study, we found that the mRNA and protein expression levels of MCT-1 were visibly decreased after knocking down PKC by siRNA in SUDHL-4 and OCI-LY8 DLBCL cell lines. A selective PKC inhibitor, sotrastaurin, effectively inhibited cell proliferation and induced cell apoptosis in a dose- and time-dependent manner. Meanwhile, we also observed that the cell cycle was arrested in the G1 phase in sotrastaurin-treated cells. In addition, MCT-1 was down-regulated in the sotrastaurin treatment group in vivo. Furthermore, we demonstrated that the PKC inhibitor sotrastaurin induced cell apoptosis and cell cycle arrest in DLBCL cells potentially through regulating the expression of MCT-1. Our data suggest that targeting PKC may be a potential therapeutic approach for lymphomas and related malignancies that exhibit high levels of MCT-1 protein.

Targeting the PI3K/Akt/mTOR signaling pathway by pterostilbene attenuates mantle cell lymphoma progression.

Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.

Neural Network Circuits for Bionic Associative Memory and Temporal Order Memory Based on DNA Strand Displacement.

Pavlovian associative memory plays an important role in our daily life and work. The realization of Pavlovian associative memory at the deoxyribonucleic acid (DNA) molecular level will promote the development of biological computing and broaden the application scenarios of neural networks. In this article, bionic associative memory and temporal order memory circuits are constructed by DNA strand displacement (DSD) reactions. First, a temporal logic gate is constructed on the basis of DSD circuit and extended to a three-input temporal logic gate. The output of temporal logic gate is used for the weight species of associative memory. Second, the forgetting module and output module based on the DSD circuit are constructed to realize some functions of associative memory, including associative memory with simultaneous stimulus, associative memory with interstimulus interval effect, and the facilitation by intermittent stimulus. In addition, the coding, storage, and retrieval modules are designed based on the analysis and memory capabilities of temporal logic gate for temporal information. The temporal order memory circuit is constructed, demonstrating the temporal order memory ability of DNA circuit. Finally, the reliability of the circuit is verified through Visual DSD software simulation. Our work provides ideas and inspiration to construct more complex DNA bionic circuits and intelligent circuits by using DSD technology.

Construction and analysis of protein-protein interaction network for esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor of the digestive tract. Clinical findings reveal that the five-year survival rate for mid-to late-stage ESCC patients is merely around 20 %, whereas those diagnosed at an early stage can achieve up to a 95 % survival rate. Consequently, early detection is paramount to improving ESCC patient survival. Protein markers are essential for diagnosing diseases, and the identification of new candidate proteins associated with ESCC through the protein-protein interaction (PPI) network is aimed for in this paper. The PPI network related to ESCC was constructed using protein data, comprising 2094 nodes and 19,660 edges. To assess the nodes' importance in the network, three metrics-degree centrality, betweenness centrality, and closeness centrality-were employed, leading to the identification of 81 key proteins. Subsequently, the biological significance of these proteins in the network was explored, combining biomedical knowledge from three perspectives: network, node, and cluster. The results demonstrated that 52 out of 81 key proteins were confirmed to be linked to ESCC. Among the remaining 29 unreported proteins, 18 displayed significant biological significance, indicating their potential as protein markers related to ESCC.

Hybrid Projective Synchronization via PI Controller Based on DNA Strand Displacement.

Classical three-variable chaotic system coupling synchronization has been implemented in previous work based on DNA strand displacement (DSD). Herein, by using DSD reactions as the foundation, a proportional integral (PI) controller for chaotic system is introduced to realize the hybrid projective synchronization for different four-variable chaotic systems. DSD-based chaotic systems are composed of catalysis modules, annihilation modules and degradation modules for realizing the construction of chaotic attractors. PI controllers are consist of catalysis, annihilation and adjust DSD modules that are easy to modify and can be added to chaotic system for achieving hybrid projective synchronization. Our work can be acted as the reference for the investigation of chaos synchronization.

PpPIF8, a DELLA2-interacting protein, regulates peach shoot elongation possibly through auxin signaling.

Rapid growth of branches in a peach tree restricts the light penetration and air ventilation within the orchard, which lowers fruit quality and promotes the occurrence of diseases and insects. Our previous works showed that PpDELLA1 and PpDELLA2 repress the rapid growth of annual shoots. Proteins that interact with DELLA are vital for its function. In this study, seven PpPIFs (PpPIF1, -2, -3, -4, -6, -7 and -8) were identified in the peach genome and contain a conserved bHLH domain. Among the seven PpPIFs, PpPIF8 interacted with PpDELLA2 through an unknown motif in the C-terminal and/or the bHLH domain. Overexpression of PpPIF8 in Arabidopsis promotes plant height and branch numbers. Hypocotyl elongation was significantly enhanced by PpPIF8 under weak light intensity. PpPIF8 overexpressed in Arabidopsis and transiently expressed in peach seedlings upregulated the transcription of YUCCA and SAUR19 and downregulated SHY1 and -2. Additionally, PpPIF4 and -8 were significantly induced by weak light. Phylogentic analysis and intron patterns of the bHLH domain strongly suggested that PIFs from six species could be divided into two groups of different evolutionary origins. These results lay a foundation for the further study of the repression of shoot growth by PpDELLA2 through protein interaction with PpPIF8 in peach.

DCZ0014, a novel compound in the therapy of diffuse large B-cell lymphoma via the B cell receptor signaling pathway.

Diffuse large B cell lymphoma (DLBCL) is a clinical and genetically heterogeneous lymphoid malignancy. Although R-CHOP (rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone) treatment can improve the survival rate of patients with DLBCL, more than 30% of patients exhibit treatment failure, relapse, or refractory disease. Therefore, novel drugs or targeted therapies are needed to improve the survival of patients with DLBCL. The compound DCZ0014 is a novel chemical similar to berberine. In this study, we found that DCZ0014 significantly inhibited the proliferation and activity of DLBCL cells, and induced cell apoptosis. Following treatment with DCZ0014, DLBCL cells accumulated in G0/G1-phase of the cell cycle and showed decreased mitochondrial membrane potential. Additionally, DCZ0014 inhibited DNA synthesis, enhanced DNA damage in DLBCL cells, as well as inhibited Lyn/Syk in B cell receptor signaling pathway. Further experiments demonstrated that DCZ0014 did not significantly affect peripheral blood mononuclear cells. Tumor xenograft model showed that DCZ0014 not only inhibited tumor growth but also extended the survival time of mice. Thus, DCZ0014 showed potential for clinical application in the treatment of patients with DLBCL.

Stability Based on PI Control of Three-Dimensional Chaotic Oscillatory System via DNA Chemical Reaction Networks.

The classical proportional integral (PI) controller of SISO linear system is realized by DNA chemical reaction networks (CRNs) in the previous work. Up to now, few works have been done to realize PI controller of chaotic system through DNA CRNs. In this paper, a three-dimensional chaotic oscillatory system and a PI controller of three-dimensional chaotic oscillatory system are proposed by DNA CRNs. The CRNs of chaotic oscillatory system are made up of catalysis modules, degradation module and annihilation module then chemical reaction equations can be compiled into three-dimensional chaotic oscillatory system by the law of mass action to generate chaotic oscillatory signals. The CRNs of PI controller are designed by an integral module, a proportion module and an addition module, which can be compiled into PI controller for stabilizing chaotic oscillatory signals. The simulations of Matlab and Visual DSD are given to show our design achieving the PI control of a three-variable chaotic oscillatory system.

A novel silicone derivative of natural osalmid (DCZ0858) exerts anti-multiple myeloma activity by promoting cell apoptosis and inhibiting cell cycle and mTOR signaling.

Multiple myeloma (MM) is a malignant disease characterized by abnormal proliferation of clonal plasma cells. Based on the organic drug osalmid, the novel small molecule compound DCZ0858 was designed and synthesized for treating MM. DCZ0858 inhibited the proliferation and activity of MM cells and reduced colony formation. It also promoted the apoptosis of primary cells from patients with MM and cultured MM cell lines but had little effect on peripheral blood mononuclear cells in healthy people. Simultaneously, DCZ0858 activated caspase family proteins, blocked MM cells in G0/G1 phase, and reduced the expression of related cyclins CDK4/6 and CyclinD1. Moreover, DCZ0858 overcame the protective effect of the bone marrow microenvironment and effectively inhibited the activity of mTORC1 and mTORC2. Further, xenograft model experiments in mice showed that DCZ0858 significantly inhibited the proliferation and growth of tumors, with low drug toxicity. These results indicate that DCZ0858 has marked anti-MM activity and little effect on normal cells and tissues, making it a new candidate clinical drug for the treatment of MM.

A novel silicone derivative of natural osalmid (DCZ0858) induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma via the JAK2/STAT3 pathway.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignant tumor characterized by diffuse growth. DCZ0858 is a novel small molecule with excellent antitumor effects in DLBCL. This study explored in depth the inhibitory effect of DCZ0858 on DLBCL cell lines. Cell Counting Kit-8 (CCK-8) and plate colony formation assays were used to evaluate cell proliferation levels. Flow cytometry was employed to analyze apoptosis and the cell cycle, and western blotting was used to quantify the expression of cell cycle regulators. The results indicated that DCZ0858 inhibited cell growth in a concentration-dependent and time-dependent manner while inducing no significant toxicity in normal cells. Moreover, DCZ0858 initiated cell apoptosis via both internal and external apoptotic pathways. DCZ0858 also induced cell cycle arrest in the G0/G1 phase, thereby controlling cell proliferation. Further investigation of the molecular mechanism showed that the JAK2/STAT3 pathway was involved in the DCZ0858-mediated antitumor effects and that JAK2 was the key target for DCZ0858 treatment. Knockdown of JAK2 partly weakened the DCZ0858-mediated antitumor effect in DLBCL cells, while JAK2 overexpression strengthened the effect of DCZ0858 in DLBCL cells. Moreover, a similar antitumor effect was observed for DCZ0858 and the JAK2 inhibitor ruxolitinib, and combining the two could significantly enhance cancer-suppressive signaling. Tumor xenograft models showed that DCZ0858 inhibited tumor growth in vivo and had low toxicity in important organs, findings that were consistent with the in vitro data. In summary, DCZ0858 is a promising drug for the treatment of DLBCL.

A novel phosphoramide compound, DCZ0847, displays in vitro and in vivo anti-myeloma activity, alone or in combination with bortezomib.

Multiple myeloma (MM) is an incurable hematological malignancy, for which novel effective therapies are urgently needed. We synthesized a novel phosphoramide compound, DCZ0847, showing a potent anti-myeloma activity both in vitro and in vivo. DCZ0847 showed high cytotoxicity towards primary MM cells but had no effect on normal cells and was well tolerated in vivo. The anti-myeloma activity of DCZ0847 was associated with inhibition of cell proliferation; promotion of cell apoptosis via mitochondrial transmembrane potential collapse and caspase-mediated extrinsic or intrinsic apoptotic pathways; and the induction of G2/M phase arrest via downregulation of CDC25C, CDK1, and cyclin B1. In particular, DCZ0847 induced DNA damage and triggered a DNA-damage response by enhancing the levels of γ-H2A.X, phosphorylated (p)-ATM, p-ATR, p-Chk1, and p-Chk2. Additionally, DCZ0847 was able to overcome the bone marrow stromal cells-induced proliferation of MM cells and blocked JAK2/STAT3 signaling. Importantly, DCZ0847 acted synergistically with bortezomib, with the combination exerting greater cytotoxic effects in vitro and in vivo. Together, our results indicate that DCZ0847, alone or in combination with bortezomib, may represent a potential new therapy for patients with MM.

A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe.

BACKGROUND: DCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown. METHODS: We generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models. RESULTS: DCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G2/M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933. CONCLUSIONS: Our study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.

A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression.

The AAA-ATPase TRIP13 drives multiple myeloma progression. Here, we present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 Å. A small-molecule inhibitor targeting TRIP13 was identified on the basis of the crystal structure. The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance-binding assays. DCZ0415 induced antimyeloma activity in vitro, in vivo, and in primary cells derived from drug-resistant patients with myeloma. The inhibitor impaired nonhomologous end joining repair and inhibited NF-κB activity. Moreover, combining DCZ0415 with the multiple myeloma chemotherapeutic melphalan or the HDAC inhibitor panobinostat induced synergistic antimyeloma activity. Therefore, targeting TRIP13 may be an effective therapeutic strategy for multiple myeloma, particularly refractory or relapsed multiple myeloma. SIGNIFICANCE: These findings identify TRIP13 as a potentially new therapeutic target in multiple myeloma.

Phase-change nanoclusters embedded in a memristor for simulating synaptic learning.

A type of memristor with a structure of Pd/Nb : AlNO/Pd was designed and fabricated in this work. Its filaments are embedded by phase-change NbO nanoclusters confirmed by the analysis of cross-sectional profiles. The resistive switching mechanism includes the contribution of oxygen vacancy (VO) migration and the structural evolution of phase-change nanoclusters. The system experiences two types of kinetics under external stimulations to replicate the critical dynamics in real synapses: VO migration corresponding to the dynamics of the Ca2+ flux and transmitter release at the pre-synapse, and the phase change of the NbO nanoclusters corresponding to the ionic flux modulated by the post-synaptic potential (current). It was found that the memristor can respond to a set of pulse stimulations in a pattern containing a slow linear increase term and a periodic oscillation term, suggesting that the output signals might be encoded. The simulation of long-term plasticity indicates that the memristor is suitable for diverse learning protocols, including spike-rate dependent plasticity and spike-timing-dependent plasticity. Our work proposes an elementary cell that closely approximates biological synapses and is usable for brain-like computing.