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We present the Topology Transformation Equivariant Representation learning, a general paradigm of self-supervised learning for node representations of graph data to enable the wide applicability of Graph Convolutional Neural Networks (GCNNs). We formalize the proposed model from an information-theoretic perspective, by maximizing the mutual information between topology transformations and node representations before and after the transformations. We derive that maximizing such mutual information can be relaxed to minimizing the cross entropy between the applied topology transformation and its estimation from node representations. In particular, we seek to sample a subset of node pairs from the original graph and flip the edge connectivity between each pair to transform the graph topology. Then, we self-train a representation encoder to learn node representations by reconstructing the topology transformations from the feature representations of the original and transformed graphs. In experiments, we apply the proposed model to the downstream node classification, graph classification and link prediction tasks, and results show that the proposed method outperforms the state-of-the-art unsupervised approaches., Comment: Accepted to IEEE Transactions on Knowledge and Data Engineering (TKDE)

Identification of host determinants of coronavirus infection informs mechanisms of viral pathogenesis and can provide new drug targets. Here we demonstrate that mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) chromatin remodeling complexes, specifically canonical BRG1/BRM-associated factor (cBAF) complexes, promote severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and represent host-directed therapeutic targets. The catalytic activity of SMARCA4 is required for mSWI/SNF-driven chromatin accessibility at the ACE2 locus, ACE2 expression and virus susceptibility. The transcription factors HNF1A/B interact with and recruit mSWI/SNF complexes to ACE2 enhancers, which contain high HNF1A motif density. Notably, small-molecule mSWI/SNF ATPase inhibitors or degraders abrogate angiotensin-converting enzyme 2 (ACE2) expression and confer resistance to SARS-CoV-2 variants and a remdesivir-resistant virus in three cell lines and three primary human cell types, including airway epithelial cells, by up to 5 logs. These data highlight the role of mSWI/SNF complex activities in conferring SARS-CoV-2 susceptibility and identify a potential class of broad-acting antivirals to combat emerging coronaviruses and drug-resistant variants.

Purpose: BRD9 is a defining component of the noncanonical SWI/SNF complex, which regulates gene expression by controlling chromatin dynamics. Although recent studies have found an oncogenic role for BRD9 in multiple cancer types including multiple myeloma, its clinical significance and oncogenic mechanism have not yet been elucidated. Here, we sought to identify the clinical and biological impact of BRD9 in multiple myeloma, which may contribute to the development of novel therapeutic strategies. Experimental Design: We performed integrated analyses of BRD9 in vitro and in vivo using multiple myeloma cell lines and primary multiple myeloma cells in established preclinical models, which identified the molecular functions of BRD9 contributing to multiple myeloma cell survival. Results: We found that high BRD9 expression was a poor prognostic factor in multiple myeloma. Depleting BRD9 by genetic (shRNA) and pharmacologic (dBRD9-A; proteolysis-targeting chimera; BRD9 degrader) approaches downregulated ribosome biogenesis genes, decreased the expression of the master regulator MYC, and disrupted the protein-synthesis maintenance machinery, thereby inhibiting multiple myeloma cell growth in vitro and in vivo in preclinical models. Importantly, we identified that the expression of ribosome biogenesis genes was associated with the disease progression and prognosis of patients with multiple myeloma. Our results suggest that BRD9 promotes gene expression by predominantly occupying the promoter regions of ribosome biogenesis genes and cooperating with BRD4 to enhance the transcriptional function of MYC. Conclusions: Our study identifies and validates BRD9 as a novel therapeutic target in preclinical models of multiple myeloma, which provides the framework for the clinical evaluation of BRD9 degraders to improve patient outcome.

Exosomes containing various biological cargoes have potential to be novel diagnostic biomarkers for metabolic diseases. In this study, retinol-binding protein 4 (RBP4) was found to be enriched in serum exosomes, and its increased levels could be considered as an independent risk factor for the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Exosomal RBP4 (exo-RBP4), primarily derived from hepatocytes, significantly enhanced the M1-like polarization of Kupffer cells (KCs) via promoting the activation of NOX2 and NF-κB and reactive oxygen species (ROS) accumulation, resulting in the over-production of inflammatory cytokines including TNF-α. Subsequently, those excess cytokines remarkably increased the levels of intracellular free fatty acid uptake and lipogenesis-related genes (FAS and SREBP-1c) but decreased fatty acid degradation-related genes (CPT-1 and PPARα) in palmitic acid-treated LO2 cells. More notably, TNF-α significantly elevated RBP4 transcription by activating STAT3 in hepatocytes, playing a positive role in NAFLD development. Intravenous injection with RBP4 (50 μg/kg) potentiated hepatic lipid accumulation, M1-type KC proportion, and serum pro-inflammatory cytokine levels in the hepatic tissues of high-fat-diet-fed mice. Collectively, these data indicated that exo-RBP4 converted KCs to M1 subtype by mediating the NOX2/ROS/NF-κB pathway, subsequently promoting de novo lipogenesis in hepatocytes by TNF-α secretion to activate the JAK2/STAT3 signaling pathway. Therefore, this study uncovered a novel intercellular communication between the inflammatory microenvironment and lipid metabolism for fostering NAFLD progression and found the potential of exo-RBP4 as a novel diagnostic biomarker and therapeutic target for NAFLD.

The amorphous IrOx layer as formed by a dynamic dissolution–reprecipitation process is probed to serve as a protective layer for the catalyst during the OER.

The Yangtze River Economic Belt, an inland economic zone with global influence, has shown a trend of prosperous economic development in recent years. Economic development, water pollution, resource depletion, and other environmental problems continue to emerge. The steady state of the water ecological environment is an important aspect of ecological security. To investigate the regional water ecological security state, this study constructs a comprehensive evaluation indicator system within the framework of "driving force-carrying source-state-management" (DCSM). The entropy weight method was used to determine the weight of each indicator, and the weighted rank sum ratio model was introduced to classify the water ecological environment of the Yangtze River Economic Belt from 2010 to 2019. Finally, an adversarial interpretative structure model is used to refine the ranking of each region. The results show that the bearing state and driving force subsystems are closely related to the water ecological environment. The top three indicators are wastewater discharge of industrial added value of 10,000 yuan, water consumption per 10,000 yuan of industrial gross product, and water consumption per 10,000 yuan of tertiary gross domestic product. In addition, there are clear differences in the water ecological environment of the Yangtze River Economic Belt. The classification results show that Zhejiang and Jiangsu are rated as "excellent''; Yunnan, Guizhou, Anhui, and Jiangxi are in the "good" level; and Sichuan, Hunan, Chongqing, and Hubei are in the "medium" level. Shanghai is "poor." As a whole, the downstream is superior, the upstream is second, and the midstream is poor in an asymmetric "U"-shaped distribution. During the study period, the overall state of water ecology in the Yangtze River Economic Belt was at a medium level and has not yet reached a safe and steady state. The performance of areas with traditional industrialization as the main development path was poor. Therefore, it is necessary to pay attention to the overall water ecological security in the basin in the future, strengthen the regulatory role of the government's water ecological management, promote reform of traditional industries and resource-based regions, and achieve the sustainable development of the water ecological environment.

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. Significance: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.

Selective C-F bond cleavage of polyfluoroarenes has attracted tremendous interest due to its promising applications in introducing fluorinated building blocks into organic molecules. However, it remains a challenge to achieve highly site-selective C-F bond cleavage because of the intrinsic inertness of the C-F bond and the difficulty in distinguishing specific C-F bonds on the aromatic ring. Herein we report an efficient nucleophilic aromatic substitution (S

An innovative shoe bolt connection for precast concrete (PC) structures that features resilience is proposed in this study. In this connection, a steel washer plate that could be easily replaced after an earthquake serves as the “fuse” element, and the bolt passing through the horizontal joints serves as the self-centring element. To validate the reliability of the proposed connection, quasi-static tests were conducted on two PC shear wall specimens. One specimen was designed with a conventional wall shoe bolt connection (S-1). The other specimen was designed with the proposed connection (S-2). The crack pattern, failure mode, hysteresis curve, skeleton curve, ductility and energy dissipation capacity of the specimens were studied. Furthermore, finite element (FE) analysis was conducted to reproduce the test and facilitate an in-depth understanding on the mechanism of the specimens. The test and analysis results indicated that S-1 exhibited brittle failure, while the failure of S-2 was governed by concrete crushing and fuse plate yielding and reflected a remarkable self-centring capacity; only minor shear slips of the horizontal joints occurred, even for the specimen S-1 with a smaller axial load ratio, indicating that the joints had enough shear resistance; the proposed three-dimensional FE model could predict the skeleton curve and the failure mode of the specimens with acceptable accuracy; for the specimen with proposed connection, the failure mode was significantly influenced by the thickness of the fuse plate.

Mass spectrometry-based proteomics and glycomics reveal post-translational modifications providing significant biological insights beyond the scope of genomic sequencing.To characterize the N-linked glycoproteomic profile in esophageal squamous cell carcinoma (ESCC)Using tandem multilectin affinity chromatography for enrichment of N-linked glycoproteins, we performed N-linked glycoproteomic profiling in ESCC tissues by two-dimensional gel electrophoresis (2-DE)-based and isobaric tags for relative and absolute quantification (iTRAQ) labeling-based mass spectrometry quantitation in parallel, followed by validation of candidate glycoprotein biomarkers by Western blot.2-DE-based and iTRAQ labeling-based quantitation identified 24 and 402 differentially expressed N-linked glycoproteins, respectively, with 15 in common, demonstrating the outperformance of iTRAQ labeling-based quantitation over 2-DE and complementarity of these two approaches. Proteomaps showed the distinct compositions of functional categories between proteins and glycoproteins with differential expression associated with ESCC. Western blot analysis validated the up-regulation of total procathepsin D and high-mannose procathepsin D, and the down-regulation of total haptoglobin, high-mannose clusterin, and GlcNAc/sialic acid-containing fraction of 14-3-3ζ in ESCC tissues. The serum levels of glycosylated fractions of clusterin, proline-arginine-rich end leucine-rich repeat protein, and haptoglobin in patients with ESCC were remarkably higher than those in healthy controls.Our study provides insights into the aberrant N-linked glycoproteome associated with ESCC, which will be a valuable resource for future investigations.

There are currently few large-scale studies describing the clinical characteristics of these histological variants of prostate cancer (PCa) and the prognostic results of these patients. Thus, we used the Surveillance, Epidemiology, and End Results (SEER) database to achieve a more comprehensive understanding of the current prevalence and prognosis of these histological variants. A total of 780 (3.3%) patients with histological variants and 235834 patients with typical adenocarcinoma were included in the present study. The variants group presented with a more advanced stage than the typical adenocarcinoma group. The results also showed that patients with neuroendocrine (NE) PCa were more likely to have visceral metastases. In prognostic comparison, we found that variants, except for mucinous, had a worse prognosis than typical adenocarcinoma. Moreover, among these variants, we also discovered that NEPCa patients with low prostate-specific antigen level had the worst survival. In contrast, mucinous PCa had similar overall survival to typical adenocarcinoma. PATIENT SUMMARY: We reported follow-up results for prostate cancer (PCa) patients from the Surveillance, Epidemiology, and End Results database (2004-2016). We focused on the prognosis of PCa with different histological variants and evaluated the risk factors that were significant in predicting poor prognosis. We suggested that neuroendocrine PCa patients should receive active treatment as soon as possible to improve their prognosis. We still need further studies to identify the role of mucinous PCa in patients' prognosis compared with typical adenocarcinoma.

Bromodomain and extraterminal domain (BET) proteins are important regulators of gene transcription and chromatin remodeling. BET family members BRD4 and BRDT are validated targets for cancer and male contraceptive drug development, respectively. Due to the high structural similarity of the acetyl-lysine binding sites, most reported inhibitors lack intra-BET selectivity. We surmised that protein-protein interactions induced by bivalent inhibitors may differ between BRD4 and BRDT, conferring an altered selectivity profile. Starting from nonselective monovalent inhibitors, we developed cell-active bivalent BET inhibitors with increased activity and selectivity for BRDT. X-ray crystallographic and solution studies revealed unique structural states of BRDT and BRD4 upon interaction with bivalent inhibitors. Varying spacer lengths and symmetric vs unsymmetric connections resulted in the same dimeric states, whereas different chemotypes induced different dimers. The findings indicate that the increased intra-BET selectivity of bivalent inhibitors is due to the differential plasticity of BET bromodomains upon inhibitor-induced dimerization.

Our aim was to evaluate the renal response rate of patients with lupus nephritis (LN) undergoing standard treatment during a 2-year follow-up and to investigate its predictive factors.A prospective cohort study that enrolled 56 clinically diagnosed LN patients with urinary protein positivity was carried out. All patients underwent standard treatment. All patients were followed up at 6-month intervals for 2 years. Data on renal response and clinical characteristics were collected and analyzed.Among 56 patients, 27 (48.2%) and 13 (23.2%) patients achieved complete renal response (CR) and partial renal response (PR) at 6 months after induction therapy, respectively, and 42 (75.0%) and 4 (7.1%) patients developed CR and PR at 2 years. Among patients who achieved PR at 6 months, 90.0% achieved CR at 24 months, while only 37.5% of the patients who were unresponsive at 6 months achieved CR. In the multivariable Cox proportional-hazards model, female (OR 6.51, 95% CI 1.23-34.52, p = 0.028), disease duration (OR 0.84, 95% CI 0.73-0.98, p = 0.021), achieving PR within 6 months (OR 8.09, 95% CI 2.06-31.73, p = 0.003), and urine protein/creatinine ratio (UPCR) (OR 0.998, 95% CI 0.996-1.000, p = 0.025) were found to be predictive factors of CR.A total of 48.2% of patients achieved CR at 6 months of induction therapy, and the response rates gradually increased to 60.7%, 64.3%, and 75.0% at 12, 18, and 24 months. Besides, female, disease duration, partial response within 6 months, and UPCR were predictive factors for a complete renal response. Key Points • We evaluate the renal response rates in Chinese patients with lupus nephritis in the real world for 2 years. • A total of 48.2% and 75.0% of patients achieved a complete response after standard treatment for 6 months and 2 years. • Female, disease duration, partial response within 6 months, and UPCR are predictors of complete renal response.

Stochastic point location deals with the problem of finding a target point on a real line through a learning mechanism (LM) with the stochastic environment (SE) offering directional information. The SE can be further categorized into an informative or deceptive one, according to whether p is above 0.5 or not, where p is the probability of providing a correct suggestion of a direction to LM. Several attempts have been made for LM to work in both types of environments, but none of them considers a dynamically changing environment where p varies with time. A dynamic dual environment involves fierce changes that frequently cause its environment to switch from an informative one to a deceptive one, or vice versa. This article presents a novel weak estimator-based adaptive step search solution, to enable LM to track the target in a dynamic dual environment, with the help of a weak estimator. The experimental results show that the proposed solution is feasible and efficient.

This study investigated the seismic performance of an innovative semi-precast concrete sandwich shear wall (SCSSW) system. The system consists of two precast reinforced concrete (RC) wythes, a core cast-in-place RC wythe, a core thermal insulation layer, the fiber reinforced polymer connectors and the steel trusses. A total of three RC shear wall specimens were fabricated and tested under in-plane cyclic load. They consists of one conventional cast-in-place RC shear wall, one structural wythe of SCSSW (i.e., the assemble of a precast and a cast-in-place RC wythe), and one typical SCSSW. The failure mode, hysteretic curve, ductility and energy dissipation of the three specimens were studied and compared. Furthermore, numerical simulation based on multi-layer shell element was conducted to reproduce the test, and parametric analysis was conducted to facilitate a better understanding on the SCSSW. It was concluded that the SCSSW presented a ductile failure behavior; the seismic performance of the SCSSW including hysteretic curves, skeleton curves, stiffness degradation and the energy dissipation was similar to that of the cast-in-place RC shear wall, while the ductility of the SCSSW was slightly lower; and the facade precast RC wythe contributed few effect on the seismic performance of the SCSSW.

Qi Chen,1,&ast; Jingqiu Liang,2,&ast; Ling Liang,2 Zhongli Liao,2 Bin Yang,3 Jun Qi2 1Department of Anesthesiology, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 2Chongqing Cancer Multi-Omics Big Data Application Engineering Research Center, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 3Department of Anesthesiology, the First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Yang, Department of Anesthesiology, the First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China, Email yangbin4332@outlook.com Jun Qi, Chongqing Cancer Multi-Omics Big Data Application Engineering Research Center, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China, Email qqyc2005@163.comPurpose: The neutrophil-to-lymphocyte ratio (NLR) is a useful prognostic marker for various diseases and surgery-induced immunosuppression. While opioids are important in general anesthesia, the association between immediate perioperative immune monitoring and opioid consumption for postoperative analgesia after video-assisted thoracoscopic surgery (VATS) is unknown. We aimed to investigate the effect of analgesic techniques on opioid-induced immune perturbation, and the feasibility of NLR as an indicator of opioid-induced immune changes.Patients and Methods: Patients were randomly assigned to two groups: Group P (n=40) or Group C (n=40). Patients in group P received ultrasound-guided paravertebral block (PVB) before surgery, and followed by sufentanil patient-controlled intravenous analgesia (PCIA) after surgery, and group C received sufentanil PCIA only. The total and differential white blood cell counts, including CD4+ T lymphocyte counts, CD8+ T lymphocyte were recorded before surgery and at 24 and 72 hours after surgery. NLR was determined using the frequencies of lymphocyte subpopulations. The cumulative dose of sufentanil were recorded at 24 and 24h after surgery while the 40-item quality of recovery questionnaire (QoR-40) score were assessed at 48h after the surgery.Results: At 24 and 48 hours after surgery, a lower sufentanil consumption, and higher QoR-40 recovery scores were found in group P than in group C (P< 0.05). In biochemical analyses, the values of NLR were lower in group P compared to group C (p< 0.0001) and ratio of CD4/CD8 were higher in group P compared to group C (p< 0.05) on day three after surgery. NLR showed excellent predictive capability for immunosuppression, with an area under the curve (AUC) of 0.92 [95% confidence interval (CI), 0.86– 0.98, P < 0.0001].Conclusion: Opioid-sparing pain management strategies may affect postoperative immunosuppression and NLR could be a reliable indicator of opioid-related immunosuppression. Moreover, opioid-sparing pain management strategies could improve patient’s satisfaction in VATS.Keywords: neutrophil-to-lymphocyte ratio, immunosuppression, paravertebral block, opioid, analgesia

Supplementary Materials

BRD9 occupies promoter regions of target gene.

Purpose:BRD9 is a defining component of the noncanonical SWI/SNF complex, which regulates gene expression by controlling chromatin dynamics. Although recent studies have found an oncogenic role for BRD9 in multiple cancer types including multiple myeloma, its clinical significance and oncogenic mechanism have not yet been elucidated. Here, we sought to identify the clinical and biological impact of BRD9 in multiple myeloma, which may contribute to the development of novel therapeutic strategies.Experimental Design:We performed integrated analyses of BRD9 in vitro and in vivo using multiple myeloma cell lines and primary multiple myeloma cells in established preclinical models, which identified the molecular functions of BRD9 contributing to multiple myeloma cell survival.Results:We found that high BRD9 expression was a poor prognostic factor in multiple myeloma. Depleting BRD9 by genetic (shRNA) and pharmacologic (dBRD9-A; proteolysis-targeting chimera; BRD9 degrader) approaches downregulated ribosome biogenesis genes, decreased the expression of the master regulator MYC, and disrupted the protein-synthesis maintenance machinery, thereby inhibiting multiple myeloma cell growth in vitro and in vivo in preclinical models. Importantly, we identified that the expression of ribosome biogenesis genes was associated with the disease progression and prognosis of patients with multiple myeloma. Our results suggest that BRD9 promotes gene expression by predominantly occupying the promoter regions of ribosome biogenesis genes and cooperating with BRD4 to enhance the transcriptional function of MYC.Conclusions:Our study identifies and validates BRD9 as a novel therapeutic target in preclinical models of multiple myeloma, which provides the framework for the clinical evaluation of BRD9 degraders to improve patient outcome.

GSEA_RNAseq (GOBP)

Objectives To evaluate the ovarian reserve (OR) in women with systemic lupus erythematosus (SLE)-antiphospholipid syndrome (APS), and to determine the association between OR and clinical and laboratory parameters.Methods We compared the antral follicle count (AFC) and blood parameters of patients who were diagnosed with APS or SLE but had not yet been treated. We compared the presence of anticardiolipin antibody, and concentrations of anti-Müllerian hormone (AMH), inhibin B (INHB), follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), testosterone (T), and estradiol (E2) among patients with primary APS(PAPS), SLE-associated APS, and SLE who were treated at Jinhua Central Hospital between 2017 and 2020. We also conducted correlations and logistic regression analyses to identify the risk factors of OR failure in women with APS.Results Serum AMH levels were positively correlated with AFC and INHB levels in APS patients, and low AMH and high LH were independent risk factor for OR decline in APS patients. The receiver operating characteristic (ROC) curve also showed a high accuracy for AMH in the prediction of OR failure. Compared to healthy subjects (HS), patients with PAPS, SLE-APS, and SLE exhibited lower serum AMH, AFC, INHB, and E2 levels and higher FSH and LH levels (P P Conclusions APS and SLE patients showed lower indications of OR, including AFC, AMH and LH, compared to HS. SLE-APS patients also appeared to have a lower OR than either SLE or PAPS patients. We noted that the low E2 levels in APS and SLE patients on day 3 of the menstrual cycle were not able to inhibit FSH release.

Combination chemotherapy is crucial for achieving durable cancer cures, however, developing safe and effective drug combinations has been a significant challenge. To improve this process, we conducted large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics. We prioritized neuroblastoma, the most common pediatric solid tumor, where 50% of high-risk patients do not survive. Our screen examined all druggable gene knockouts in 18 cell lines (10 neuroblastoma, 8 others) treated with 8 widely used drugs, resulting in 94,320 unique combination-cell line perturbations, which is comparable to the largest drug combination screens ever reported. Remarkably, using dense drug-drug rescreening, we found that the top CRISPR-nominated drug combinations were far more synergistic than standard-of-care combinations, suggesting existing combinations could be improved. As proof of principle, we discovered that inhibition of PRKDC, a component of the non-homologous end-joining pathway, sensitizes high-risk neuroblastoma cells to the standard-of-care drug doxorubicinin vitroandin vivousing PDX models. Our findings provide a valuable resource for the development of improved chemotherapeutic strategies and demonstrate the feasibility of using targeted CRISPR knockout to discover new combinations with common chemotherapeutics, a methodology with application across all cancers.

Supplementary Figure S2 shows the selectivity of JQKD82 against KDM5 in biochemical assay and in MM cells

Supplementary Figure S3 shows that JQKD82 have good activities against KDM5 in MM cells and in animal models.