Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(ß-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

Avidity-Based Method for the Efficient Generation of Monoubiquitinated Recombinant Proteins.

Monoubiquitination of proteins governs diverse physiological processes, and its dysregulation is implicated in multiple pathologies. The difficulty of preparing sufficient material often complicates the biophysical studies of monoubiquitinated recombinant proteins. Here we describe a robust avidity-based method that overcomes this problem. As a proof-of-concept, we produced milligram quantities of two monoubiquitinated targets, Parkinson's protein α-synuclein and ESCRT-protein ALIX, using NEDD4-family E3 ligases. Monoubiquitination hotspots were identified by quantitative chemical proteomics. Using FRAP and dye-binding assays, we uncovered strikingly opposite effects of monoubiquitination on the phase separation and fibrillization properties of these two amyloidogenic proteins, reflecting differences in their intermolecular interactions, thereby providing unique insights into the impact of monoubiquitination on protein aggregation.

Safety and efficacy of daratumumab in Chinese patients with relapsed or refractory multiple myeloma: a phase 1, dose-escalation study (MMY1003).

Daratumumab monotherapy demonstrated favorable safety and efficacy in relapsed/refractory multiple myeloma (RRMM) patients in the global phase 1/2 GEN501 and phase 2 SIRIUS studies. MMY1003 evaluated daratumumab monotherapy specifically in Chinese patients with RRMM. This 3-part, open-label, phase 1, dose-escalation study included patients with ≥ 2 prior lines of therapy. Part 3 included patients who had received a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and experienced disease progression on their last regimen. Patients received intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 and 16 mg/kg in parts 2 + 3. Primary endpoints were dose-limiting toxicity (DLT; part 1), pharmacokinetics (parts 1 + 2), and adverse events (AEs). Fifty patients enrolled. The first 3 patients in part 1 received daratumumab 8 mg/kg; remaining patients in parts 1-3 received daratumumab 16 mg/kg. In the daratumumab 16 mg/kg group (n = 47), patients received a median of 4 prior lines of therapy; 32% were refractory to a PI and IMiD, and 79% were refractory to their last prior therapy. No DLTs occurred. Thirty-six (77%) patients reported grade 3/4 treatment-emergent AEs. Thirteen (28%) patients experienced infusion-related reactions. At an 18.5-month median follow-up, overall response rate was 43%. Median progression-free survival (PFS) and overall survival (OS) were 6.7 months and not reached, respectively; 12-month PFS and OS rates were 35% and 70%. Pharmacokinetic results (n = 22) were consistent with other studies. Safety, pharmacokinetics, and efficacy of daratumumab monotherapy were confirmed in Chinese patients with RRMM. This trial is registered on ClinicalTrials.gov (NCT02852837).

Multi-Scale Attention 3D Convolutional Network for Multimodal Gesture Recognition.

Gesture recognition is an important direction in computer vision research. Information from the hands is crucial in this task. However, current methods consistently achieve attention on hand regions based on estimated keypoints, which will significantly increase both time and complexity, and may lose position information of the hand due to wrong keypoint estimations. Moreover, for dynamic gesture recognition, it is not enough to consider only the attention in the spatial dimension. This paper proposes a multi-scale attention 3D convolutional network for gesture recognition, with a fusion of multimodal data. The proposed network achieves attention mechanisms both locally and globally. The local attention leverages the hand information extracted by the hand detector to focus on the hand region, and reduces the interference of gesture-irrelevant factors. Global attention is achieved in both the human-posture context and the channel context through a dual spatiotemporal attention module. Furthermore, to make full use of the differences between different modalities of data, we designed a multimodal fusion scheme to fuse the features of RGB and depth data. The proposed method is evaluated using the Chalearn LAP Isolated Gesture Dataset and the Briareo Dataset. Experiments on these two datasets prove the effectiveness of our network and show it outperforms many state-of-the-art methods.

Co nanoparticle-embedded N,O-codoped porous carbon nanospheres as an efficient peroxymonosulfate activator: singlet oxygen dominated catalytic degradation of organic pollutants.

In this study, Co nanoparticle-embedded N,O-codoped porous carbon nanospheres (C@Co) with abundant N and O doping, high graphitization, large specific surface area (319 m2 g-1) and a well-developed mesoporous structure were synthesized and characterized thoroughly, and were applied to activate peroxymonosulfate (PMS) for the degradation of methylene blue (MB). Various influential factors affecting the catalytic performance including C@Co dosage, PMS dosage, MB concentration, initial pH, temperature, and co-existing common anions and humic acid (HA) on the MB degradation were systematically investigated. The increase of the C@Co dosage (15-60 mg), PMS dosage (25-100 mg) and reaction temperature (278-308 K) promoted the MB degradation in the C@Co/PMS system. The best performance of the C@Co/PMS system was observed under weakly acidic or nearly neutral conditions. Both the MB concentration (25-100 mg L-1) and Cl- (5-100 mM), NO3- (10-500 mM), CO32- (10-300 mM), HCO3- (1-30 mM) and HA (2-40 mg L-1) had an inhibitory effect on MB degradation, and the degree of decrease in MB degradation increased as their concentrations were enhanced. Interestingly, HPO42- (1-100 mM) had an overall inhibitory effect on the degradation process of MB; however, in comparison with lower concentrations (1-10 mM), an attenuation of the inhibitory effect at higher concentrations (50-100 mM) could be observed. Moreover, the C@Co/PMS system also exhibited general applicability in eliminating various organic pollutants from water such as methyl orange, malachite green, safranine T, Congo red, Rhodamine B, ofloxacin and tetracycline. Classical radical-quenching tests and EPR measurements showed that both the non-radical pathway (major route, involving 1O2) and radical pathway (minor route, involving ˙OH, ˙SO4- and ˙O2-) contribute to the MB degradation. DFT calculations disclosed that the combination of Co-C interactions with graphitic N doping brought in catalytically active sites in C@Co where the charge states of some C atoms were significantly increased. The degradation intermediates of MB during the catalytic reaction were also identified by HPLC-MS and the possible degradation pathway was proposed. Overall, the resultant C@Co can be developed as a novel and efficient heterogeneous catalyst for activating PMS to degrade organic pollutants, and has potential application in environmental remediation.

A Quantitative Chemical Proteomics Approach for Site-specific Stoichiometry Analysis of Ubiquitination.

Stoichiometric analysis of post-translational modifications is an emerging strategy for absolute quantification of the fractional abundance of the modification. Herein, a quantitative chemical proteomic workflow for stoichiometric analysis of ubiquitination is reported, named isotopically balanced quantification of ubiquitination (IBAQ-Ub). The strategy utilizes a new amine-reactive chemical tag (AcGG-NHS) that is structurally homologous to the GG remnant of ubiquitin on modified lysine after trypsin cleavage and therefore enables the generation of structurally identical peptides from ubiquitinated and unmodified lysine residues following trypsin digestion and secondary stable isotopic labeling. The strategy is highly robust, sensitive, and accurate with a wide dynamic range using either protein standards or complex cell lysates. Thus, this work provides an efficient chemical proteomics tool for quantitative stoichiometric analysis of ubiquitination signaling pathways.

Polypyrrole Whelk-Like Arrays toward Robust Controlling Manipulation of Organic Droplets Underwater.

Whelk-like polypyrrole (PPy) arrays film is successfully prepared by electropolymerization of pyrrole in the presence of low-surface-energy tetraethylammonium perfluorooctanesulfonate (TEAPFOS) as dopant. The underwater wettability of PPy whelk-like arrays can be successfully tuned by electrical doping/dedoping of PFOS ions. Interestingly, CCl4 droplets with microliter-size as a representative sample are gathered together to form a larger droplet underwater at the potential of +0.8 V (vs Ag/AgCl), because PPy is in its PFOS-doped states. Note that CCl4 droplet can climb uphill successfully on the inclined whelk-like arrays PPy film under the applied potential of -1.0 V (vs Ag/AgCl), which may be attributed to wettability gradient derived from different oxidation states of PPy induced by electrochemical potential. These results may provide a simple strategy for on-demand manipulation of organic droplets underwater at low voltage.

Rapid and sensitive detection of fipronil and its metabolites in edible oils by solid-phase extraction based on humic acid bonded silica combined with gas chromatography with electron capture detection.

Solid-phase extraction based on humic acid bonded silica followed by gas chromatography with electron capture detection was developed to determine fipronil and its metabolites in edible oil. To achieve the best extraction performance, we systematically investigated a series of solid-phase extraction parameters. Under the optimized conditions, the method was validated according to linearity, recovery, and precision. Good linearities were obtained with R(2) more than 0.9996 for all analytes. The limits of detection were between 0.3 and 0.5 ng/g, and the recoveries ranged from 83.1 to 104.0% at three spiked concentrations with intra- and interday relative standard deviation values less than 8.7%. Finally, the proposed method was applied to determine fipronil and its metabolites in 11 edible oil samples taken from Wuhan markets. Fipronil was detectable in four samples with concentrations ranging from 3.0 to 5.2 ng/g. In China, the maximum residue limits of fipronil in some vegetables and maize are 20 and 100 ng/g (GB/T 2763-2014), respectively. The residues of fipronil and its metabolites in commercial edible oils might exhibit some potential threat to human health as a result of high consumption of edible oil as part of daily intake.

A single nucleotide substitution in exon 5 generated the novel KIR2DL3*00112 allele.

The novel KIR2DL3*00112 allele differs from the closest allele KIR2DL3*00101 by a single same sense mutation.

Causal relationship between gut microbiota and Behçet's disease: a Mendelian randomization study.

Background: While observational epidemiological studies have suggested an association between gut microbiota and Behçet's disease (BD), the causal relationship between the two remains uncertain. Methods: Statistical data were obtained from gut microbiome Genome-Wide Association Studies (GWAS) published by the MiBioGen consortium, and genetic variation points were screened as instrumental variables (IV). Mendelian randomization (MR) study was performed using inverse variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods to evaluate the causal relationship between gut microbiota (18,340 individuals) and BD (317,252 individuals). IVW was the main method of analysis. The stability and reliability of the results were verified using the leave-one-out method, heterogeneity test, and horizontal genetic pleiotropy test. Finally, a reverse MR analysis was performed to explore reverse causality. Results: Inverse variance weighted (IVW) results showed that the genus Parasutterella (OR = 0.203, 95%CI 0.055-0.747, p = 0.016), Lachnospiraceae NC2004 group (OR = 0.101, 95%CI 0.015-0.666, p = 0.017), Turicibacter (OR = 0.043, 95%CI 0.007-0.273, p = 0.001), and Erysipelatoclostridium (OR = 0.194, 95%CI 0.040-0.926, p = 0.040) were protective factors against BD, while Intestinibacter (OR = 7.589, 95%CI 1.340-42.978, p = 0.022) might be a risk factor for BD. Conclusion: Our study revealed the causal relationship between gut microbiota and BD. The microbiota that related to BD may become new biomarkers; provide new potential indicators and targets for the prevention and treatment of BD.

Generation and Characterization of Induced Pluripotent Stem Cells Carrying An ASXL1 Mutation.

Additional sex combs-like 1 (ASXL1) is an epigenetic modulator frequently mutated in myeloid malignancies, generally associated with poor prognosis. Current models for ASXL1-mutated diseases are mainly based on the complete deletion of Asxl1 or overexpression of C-terminal truncations in mice models. However, these models cannot fully recapitulate the pathogenesis of myeloid malignancies. Patient-derived induced pluripotent stem cells (iPSCs) provide valuable disease models that allow us to understand disease-related molecular pathways and develop novel targeted therapies. Here, we generated iPSCs from a patient with myeloproliferative neoplasm carrying a heterozygous ASXL1 mutation. The iPSCs we generated exhibited the morphology of pluripotent cells, highly expressed pluripotent markers, excellent differentiation potency in vivo, and normal karyotype. Subsequently, iPSCs with or without ASXL1 mutation were induced to differentiate into hematopoietic stem/progenitor cells, and we found that ASXL1 mutation led to myeloid-biased output and impaired erythroid differentiation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that terms related to embryonic development, myeloid differentiation, and immune- and neural-related processes were most enriched in the differentially expressed genes. Western blot demonstrated that the global level of H2AK119ub was significantly decreased when mutant ASXL1 was present. Chromatin Immunoprecipitation Sequencing showed that most genes associated with stem cell maintenance were upregulated, whereas occupancies of H2AK119ub around these genes were significantly decreased. Thus, the iPSC model carrying ASXL1 mutation could serve as a potential tool to study the pathogenesis of myeloid malignancies and to screen targeted therapy for patients.

Seeking a Hierarchical Prototype for Multimodal Gesture Recognition.

Gesture recognition has drawn considerable attention from many researchers owing to its wide range of applications. Although significant progress has been made in this field, previous works always focus on how to distinguish between different gesture classes, ignoring the influence of inner-class divergence caused by gesture-irrelevant factors. Meanwhile, for multimodal gesture recognition, feature or score fusion in the final stage is a general choice to combine the information of different modalities. Consequently, the gesture-relevant features in different modalities may be redundant, whereas the complementarity of modalities is not exploited sufficiently. To handle these problems, we propose a hierarchical gesture prototype framework to highlight gesture-relevant features such as poses and motions in this article. This framework consists of a sample-level prototype and a modal-level prototype. The sample-level gesture prototype is established with the structure of a memory bank, which avoids the distraction of gesture-irrelevant factors in each sample, such as the illumination, background, and the performers' appearances. Then the modal-level prototype is obtained via a generative adversarial network (GAN)-based subnetwork, in which the modal-invariant features are extracted and pulled together. Meanwhile, the modal-specific attribute features are used to synthesize the feature of other modalities, and the circulation of modality information helps to leverage their complementarity. Extensive experiments on three widely used gesture datasets demonstrate that our method is effective to highlight gesture-relevant features and can outperform the state-of-the-art methods.

Semi-Supervised Domain Alignment Learning for Single Image Dehazing.

Convolutional neural networks (CNNs) have attracted much research attention and achieved great improvements in single-image dehazing. However, previous learning-based dehazing methods are mainly trained on synthetic data, which greatly degrades their generalization capability on natural hazy images. To address this issue, this article proposes a semi-supervised learning approach for single-image dehazing, where both synthetic and realistic images are leveraged during training. Considering the situation that it is hard to obtain the realistic pairs of hazy and haze-free images, how to utilize the realistic data is not a trivial work. In this article, a domain alignment module is introduced to narrow the distribution distance between synthetic data and realistic hazy images in a latent feature space. Meanwhile, a haze-aware attention module is designed to describe haze densities of different regions in the image, thus adaptively responds for different hazy areas. Furthermore, the dark channel prior is introduced to the framework to improve the quality of the unsupervised learning results by considering the statistical characters of haze-free images. Such a semi-supervised design can significantly address the domain shift issue between the synthetic and realistic data, and improve generalization performance in the real world. Experiments indicate that the proposed method obtains state-of-the-art performance on both public synthetic and realistic hazy images with better visual results.

Oxyhemoglobin-Based Nanophotosensitizer for Specific and Synergistic Photothermal and Photodynamic Therapies against Porphyromonas gingivalis Oral Infection.

Photothermal therapy (PTT) and photodynamic therapy (PDT) are emerging alternative antibacterial approaches. However, due to the lack of selectivity of photosensitizers for pathogenic bacteria, these methods often show more or less different degrees of in vivo toxicity. Moreover, it is difficult for PDT to exert effective antibacterial effects against anaerobic infections due to the oxygen deficiency. As one of the major anaerobic pathogens in oral infections, Porphyromonas gingivalis (P. gingivalis) acquires iron and porphyrin mainly from hemoglobin in the host. Hence, we developed a nanophotosensitizer named as oxyHb@IR820 through stable complexation between oxyhemoglobin and IR820, which is a photosensitizer possessing both PTT and PDT performance, for fighting P. gingivalis oral infection specifically and efficiently. Owing to hydrophobic interaction, oxyHb@IR820 had much stronger photoabsorption at 808 nm than free IR820, and thus exhibited significantly enhanced photothermal conversion efficiency. As an oxygen donor, oxyHb played an important role in enhancing the photodynamic efficiency of oxyHb@IR820. More importantly, oxyHb@IR820 showed efficient and specific uptake in P. gingivalis and exerted synergistic PTT/PDT performance against P. gingivalis and oral infection in golden hamsters. In summary, this study provides an efficient strategy for delivering photosensitizers specifically to P. gingivalis and augmenting antibacterial PDT against anaerobic infections.

Phosphorus doped molybdenum disulfide regulated by sodium chloride for advanced supercapacitor electrodes.

As a pseudocapacitor electrode material, molybdenum disulfide (MoS2) usually shows inferior capacity, rate capability and cyclability. Structural regulation and heteroatom doping are the available methods to ameliorate the electrochemical properties of MoS2. Herein, phosphorus doped molybdenum disulfide regulated by sodium chloride (SP-MoS2) is successfully synthesized using phosphomolybdate acid as a molybdenum source and an in situ dopant and sodium chloride (NaCl) as a structural regulator. Under the structural regulation of NaCl, the SP-MoS2 nanosheets exhibit an interweaved architecture with a large interlayer spacing of 0.68 nm. Owing to the in situ P doping and large specific surface area (21.0 m2 g-1), the SP-MoS2 electrode possesses a maximum capacity of 564.8 F g-1 at 1 A g-1 and retains 56.3% of the original capacity at 20 A g-1. Density functional theory (DFT) calculations indicate that SP-MoS2 displays a high K+ average adsorption energy of -3.636 eV. In addition, the fabricated SP-MoS2//AC asymmetric supercapacitor device displays an energy density of 22.8 W h kg-1 at 759 W kg-1.

Self-assembled molybdenum disulfide nanoflowers regulated by lithium sulfate for high performance supercapacitors.

Recently, molybdenum disulfide (MoS2) has been extensively investigated as a promising pseudocapacitor electrode material. However, MoS2 usually exhibits inferior rate capability and cyclability, which restrain its practical application in energy storage. In this work, MoS2 nanoflowers regulated by Li2SO4 (L-MoS2) are successfully fabricated via intercalating solvated Li ions. Via appropriate intercalation of Li2SO4, MoS2 nanosheets could self-assemble to form L-MoS2 nanoflowers with an interlayer spacing of 0.65 nm. Due to the large specific surface area (23.7 m2 g-1) and high 1T phase content (77.5%), L-MoS2 as supercapacitor electrode delivers a maximum specific capacitance of 356.7 F g-1 at 1 A g-1 and maintains 49.8% of capacitance retention at 20 A g-1. Moreover, the assembled L-MoS2 symmetric supercapacitor (SSC) device displays an energy density of 6.5 W h kg-1 and 79.6% of capacitance retention after 3000 cycles.

The miR-106b-25 cluster mediates drug resistance in myeloid leukaemias by inactivating multiple apoptotic genes.

Drug resistance is a major obstacle to the successful treatment of cancer. The role of the miR-106b-25 cluster in drug resistance of haematologic malignancies has not yet been elucidated. Here, we show that the miR-106b-25 cluster mediates resistance to therapeutic agents with structural and mechanistic dissimilarity in vitro and in vivo. RNA sequencing data revealed that overexpression of the miR-106b-25 cluster or its individual miRNAs resulted in downregulation of multiple key regulators of apoptotic pathways. Luciferase reporter assay identified TP73 as a direct target of miR-93 and miR-106b, BAK1 as a direct target of miR-25 and CASP7 as a direct target of all three miRNAs. We also showed that inhibitors of the miR-106b-25 cluster and BCL-2 exert synergistic effects on apoptosis induction in primary myeloid leukaemic cells. Thus, the members of the miR-106b-25 cluster may jointly contribute to myeloid leukaemia drug resistance by inactivating multiple apoptotic genes. Targeting this cluster could be a promising combination strategy in patients resistant to therapeutic agents that induce apoptosis.

CD11c regulates neutrophil maturation.

Sepsis continues to be associated with high morbidity and mortality. Currently, sepsis is managed only conservatively. In sepsis, a substantial number of neutrophils is required, leading to accelerated neutrophil production. Immature neutrophils are released into the circulation to meet a demand, despite their less effective functioning in microbial eradication. Although an intervention to provide more mature neutrophils may serve as a potential sepsis treatment, the mechanism of neutrophil differentiation and maturation remains poorly understood. We discovered that CD11c, traditionally known as a dendritic cell marker, was expressed in neutrophils and regulated neutrophil maturation and effector functions. In the absence of CD11c, neutrophil maturation was impaired in the bone marrow, concomitant with a significant increase in the proliferation and apoptosis of preneutrophils, associated with less effector functions. Under lipopolysaccharide challenge, inducing an emergent neutrophil production in the bone marrow, CD11c deficiency exaggerated the release of immature neutrophils into the circulation, associated with a significant proliferation and apoptosis of preneutrophils. In contrast, constitutively active CD11c knock-in mice showed accelerated neutrophil maturation associated with enhanced effector functions, which further supports the notion that CD11c regulates neutrophil maturation. Furthermore, the constitutively active CD11c knock-in mice offered enhanced bacterial eradication. Taken together, we discovered that CD11c was critical for the regulation of neutrophil maturation, and CD11c activation could serve as a potential target for sepsis treatment.

Non-Noble FeCrOx Bimetallic Nanoparticles for Efficient NH3 Decomposition.

Ammonia has the advantages of being easy to liquefy, easy to store, and having a high hydrogen content of 17.3 wt%, which can be produced without COx through an ammonia decomposition using an appropriate catalyst. In this paper, a series of FeCr bimetallic oxide nanocatalysts with a uniform morphology and regulated composition were synthesized by the urea two-step hydrolysis method, which exhibited the high-performance decomposition of ammonia. The effects of different FeCr metal ratios on the catalyst particle size, morphology, and crystal phase were investigated. The Fe0.75Cr0.25 sample exhibited the highest catalytic activity, with an ammonia conversion of nearly 100% at 650 °C. The dual metal catalysts clearly outperformed the single metal samples in terms of their catalytic performance. Besides XRD, XPS, and SEM being used as the means of the conventional characterization, the local structural changes of the FeCr metal oxide catalysts in the catalytic ammonia decomposition were investigated by XAFS. It was determined that the Fe metal and FeNx of the bcc structure were the active species of the ammonia-decomposing catalyst. The addition of Cr successfully prevented the Fe from sintering at high temperatures, which is more favorable for the formation of stable metal nitrides, promoting the continuous decomposition of ammonia and improving the decomposition activity of the ammonia. This work reveals the internal relationship between the phase and structural changes and their catalytic activity, identifies the active catalytic phase, thus guiding the design and synthesis of catalysts for ammonia decomposition, and excavates the application value of transition-metal-based nanocomposites in industrial catalysis.

Bortezomib, Melphalan, and Prednisone With or Without Daratumumab in Transplant-ineligible Asian Patients With Newly Diagnosed Multiple Myeloma: The Phase 3 OCTANS Study.

INTRODUCTION: In the global phase 3 ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) improved outcomes versus VMP in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Here, we report the primary analysis of the phase 3 OCTANS trial of D-VMP versus VMP in transplant-ineligible Asian NDMM patients. PATIENTS AND METHODS: In total, 220 patients were randomized (2:1) to receive 9 cycles of VMP (bortezomib 1.3 mg/m2 subcutaneously twice weekly in Cycle 1 and weekly in Cycles 2 to 9; melphalan 9 mg/m2 orally; and prednisone 60 mg/m2 orally on Days 1 to 4 of each cycle) ± daratumumab 16 mg/kg intravenously weekly in Cycle 1, every 3 weeks in Cycles 2 to 9, and every 4 weeks thereafter until disease progression. RESULTS: After a median follow-up of 12.3 months, very good partial response or better rates (primary endpoint) were 74.0% versus 43.2% with D-VMP versus VMP (odds ratio, 3.57; 95% confidence interval [CI], 1.99-6.43; P < .0001). Median progression-free survival (PFS) with D-VMP versus VMP was not reached versus 18.2 months (hazard ratio, .43; 95% CI, .24-.77; P = .0033); 12-month PFS rates were 84.2% versus 64.6%. The most frequent grade 3/4 treatment-emergent adverse events with D-VMP/VMP were thrombocytopenia (46.5%/45.1%), neutropenia (39.6%/50.7%), and leukopenia (31.3%/36.6%). CONCLUSION: D-VMP demonstrated a favorable benefit/risk profile in transplant-ineligible Asian NDMM patients. This trial was registered at www. CLINICALTRIALS: gov as #NCT03217812.