E2F2 modulates cell adhesion through the transcriptional regulation of PECAM1 in multiple myeloma.

Multiple myeloma (MM) is the second most common haematological malignancy. Despite the development of new drugs and treatments in recent years, the therapeutic outcomes of patients are not satisfactory. It is necessary to further investigate the molecular mechanism underlying MM progression. Herein, we found that high E2F2 expression was correlated with poor overall survival and advanced clinical stages in MM patients. Gain- and loss-of-function studies showed that E2F2 inhibited cell adhesion and consequently activated cell epithelial-to-mesenchymal transition (EMT) and migration. Further experiments revealed that E2F2 interacted with the PECAM1 promoter to suppress its transcriptional activity. The E2F2-knockdown-mediated promotion of cell adhesion was significantly reversed by the repression of PECAM1 expression. Finally, we observed that silencing E2F2 significantly inhibited viability and tumour progression in MM cell models and xenograft mouse models respectively. This study demonstrates that E2F2 plays a vital role as a tumour accelerator by inhibiting PECAM1-dependent cell adhesion and accelerating MM cell proliferation. Therefore, E2F2 may serve as a potential independent prognostic marker and therapeutic target for MM.

Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia.

The acute myeloid leukemia (AML) patients obtain limited benefits from current immune checkpoint blockades (ICBs), although immunotherapy have achieved encouraging success in numerous cancers. Here, we found that V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint, is highly expressed in primary AML cells and associated with poor prognosis of AML patients. Targeting VISTA by anti-VISTA mAb boosts T cell-mediated cytotoxicity to AML cells. Interestingly, high expression of VISTA is positively associated with hyperactive STAT3 in AML. Further evidence showed that STAT3 functions as a transcriptional regulator to modulate VISTA expression by directly binding to DNA response element of VISTA gene. We further develop a potent and selective STAT3 inhibitor W1046, which significantly suppresses AML proliferation and survival. W1046 remarkably enhances the efficacy of VISTA mAb by activating T cells via inhibition of STAT3 signaling and down-regulation of VISTA. Moreover, combination of W1046 and VISTA mAb achieves a significant anti-AML effect in vitro and in vivo. Overall, our findings confirm that VISTA is a potential target for AML therapy which transcriptionally regulated by STAT3 and provide a promising therapeutic strategy for immunotherapy of AML.

Cellular membrane-based vesicles displaying a reconstructed B cell maturation antigen for multiple myeloma therapy by dual targeting APRIL and BAFF.

Excessive secretion of cytokines (such as APRIL and BAFF) in the bone marrow microenvironment (BMM) plays an essential role in the formation of relapsed or refractory multiple myeloma (MM). Blocking the binding of excessive cytokines to their receptors is becoming a promising approach for MM therapy. Here, we proposed a strategy of engineering cell membrane-based nanovesicles (NVs) to reconstruct B cell maturation antigen (BCMA), a receptor of APRIL and BAFF, to capture excess APRIL/BAFF in BMM as a bait protein. Our results showed that reconstructed BCMA expressed on the membrane of NVs (Re-BCMA-NVs) retained the ability of binding to soluble and surface-bound APRIL/BAFF in BMM. Consequently, Re-BCMA-NVs blocked the activation of the NF-κB pathway, downregulating the expression of anti-apoptosis genes and cell cycle-related genes, and hence inhibiting MM cell survival. Importantly, Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomib (BTZ) in vitro and in vivo. Our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to BTZ-based therapy. STATEMENT OF SIGNIFICANCE: Excessive APRIL and BAFF is reported to promote the survival of MM cell and facilitate the formation of resistance to bortezomib therapy. In this study, we bioengineered cell membrane derived reconstructed BCMA nanovesicles (Re-BCMA-NVs) to capture both soluble and cell-surface APRIL and BAFF. These NVs inhibited the activation of NF-κB pathway and thus inhibit the survival of MM cells in 2D, 3D and subcutaneous mouse tumor models. Importantly, Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomib in vitro and in vivo. Taken together, our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to bortezomib-based therapy.

Prognostic significance of FSCN family in multiple myeloma.

Multiple myeloma (MM) is a hematologic tumor with monoclonal proliferation of malignant plasma cells in the bone marrow. Fascin (FSCN) is an actin-binding protein that plays a crucial role in cell migration and invasion, contributing to tumor metastasis. There are three members (FSCN1-3) in FSCN family. However, the prognostic role of FSCN family in MM remains unclear. In this study, we used four independent Gene Expression Omnibus (GEO) datasets to explore the relationships between FSCN1-3 expression profiles and patient survival in MM. We found that FSCN1 was dramatically down-regulated in MM compared to normal donors (p < 0.001) and monoclonal gammopathy of undetermined significance (MGUS) (p = 0.032). Patients with high expression of FSCN1 and FSCN2 had significantly longer OS (p = 0.023 and 0.028, respectively). Univariate and multivariate analysis showed that FSCN1 (p = 0.003, 0.002) and FSCN2 (p = 0.018, 0.013) were independent favorable prognostic factors for OS in MM. Moreover, the combination of high expression of FSCN1 and FSCN2 could effectively predict both longer EFS (p = 0.046) and OS (p = 0.015). Our study suggested that FSCN1 and FSCN2 can be used as favorable biomarkers for predicting clinical outcomes in MM.

Endocytic pathway inhibition attenuates extracellular vesicle-induced reduction of chemosensitivity to bortezomib in multiple myeloma cells.

Extracellular vesicles (EVs), including exosomes and microvesicles, derived from bone marrow stromal cells (BMSCs) have been demonstrated as key factors in the progression and drug resistance of multiple myeloma (MM). EV uptake involves a variety of mechanisms which largely depend on the vesicle origin and recipient cell type. The aim of the present study was to identify the mechanisms involved in the uptake of BMSC-derived small EVs (sEVs) by MM cells, and to evaluate the anti-MM effect of targeting this process. Methods: Human BMSC-derived sEVs were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. The effects of chemical inhibitors and shRNA-mediated knockdown of endocytosis-associated genes on sEV uptake and cell apoptosis were analyzed by flow cytometry. The anti-MM effect of blocking sEV uptake was evaluated in vitro and in a xenograft MM mouse model. Results: sEVs derived from BMSC were taken up by MM cells in a time- and dose-dependent manner, and subsequently promoted MM cell cycling and reduced their chemosensitivity to bortezomib. Chemical endocytosis inhibitors targeting heparin sulphate proteoglycans, actin, tyrosine kinase, dynamin-2, sodium/proton exchangers, or phosphoinositide 3-kinases significantly reduced MM cell internalization of BMSC-derived sEVs. Moreover, shRNA-mediated knockdown of endocytosis-associated proteins, including caveolin-1, flotillin-1, clathrin heavy chain, and dynamin-2 in MM cells suppressed sEV uptake. Furthermore, an endocytosis inhibitor targeting dynamin-2 preferentially suppressed the uptake of sEV by primary MM cells ex vivo and enhanced the anti-MM effects of bortezomib in vitro and in a mouse model. Conclusion: Clathrin- and caveolin-dependent endocytosis and macropinocytosis are the predominant routes of sEV-mediated communication between BMSCs and MM cells, and inhibiting endocytosis attenuates sEV-induced reduction of chemosensitivity to bortezomib, and thus enhances its anti-MM properties.

Methylation of the Promoter Region of the Tight Junction Protein-1 by DNMT1 Induces EMT-like Features in Multiple Myeloma.

The molecular alterations that initiate the development of multiple myeloma (MM) are not fully understood. Our results revealed that TJP1 was downregulated in MM and positively related to the overall survival of MM patients in The Cancer Genome Atlas (TCGA) database and patient samples. In parallel, cell adhesion capacity representing MM metastasis was decreased in MM patients compared with healthy samples, together with the significantly activated epithelial-to-mesenchymal transition (EMT) transcriptional-like patterns of MM cells. Further analyses demonstrated that TJP1 negatively regulated EMT and consequently positively regulated cell adhesion in MM from TCGA database and MM1s cells. Furthermore, the methylation level of each CpG site on the TJP1 promoter was negatively correlated with TJP1 expression levels. Quantitative real-time PCR and western blot assays demonstrated that methylase DNMT1 regulated the methylation of TJP1. Finally, treatment with a combination of the MM clinical medicine bortezomib, methylation inhibitor, or TJP1 overexpression significantly suppressed the viability and progression of tumor cells of MM orthotopic models. In summary, our results indicate that DNMT1 promotes the methylation of TJP1 promoter, thereby decreasing its expression and regulating the development of EMT-inhibited MM cell adhesion. Therefore, methylation of TJP1 is a potential therapeutic agent to prevent the progression of MM disease.

Identification of the immune checkpoint signature of multiple myeloma using mass cytometry-based single-cell analysis.

OBJECTIVES: New targets or strategies are needed to increase the success of immune checkpoint-based immunotherapy for multiple myeloma (MM). However, immune checkpoint signals in MM microenvironment have not been fully elucidated. Here, we aimed to have a broad overview of the different immune subsets and their immune checkpoint status, within the MM microenvironment, and to provide novel immunotherapeutic targets to treat MM patients. METHODS: We performed immune checkpoint profiling of bone marrow (BM) samples from MM patients and healthy controls using mass cytometry. With high-dimensional single-cell analysis of 30 immune proteins containing 10 pairs of immune checkpoint axes in 0.55 million of BM cells, an immune landscape of MM was mapped. RESULTS: We identified an abnormality of immune cell composition by demonstrating a significant increase in activated CD4 T, CD8 T, CD8+ natural killer T-like and NK cells in MM BM. Our data suggest a correlation between MM cells and immune checkpoint phenotypes and expand the view of MM immune signatures. Specifically, several critical immune checkpoints, such as programmed cell death 1 (PD-1)/PD ligand 2, galectin-9/T-cell immunoglobulin mucin-3, and inducible T-cell costimulator (ICOS)/ICOS ligand, on both MM and immune effector cells and a number of activated PD-1+ CD8 T cells lacking CD28 were distinguished in MM patients. CONCLUSION: A clear interaction between MM cells and the surrounding immune cells was established, leading to immune checkpoint dysregulation. The analysis of the immune landscape enhances our understanding of the MM immunological milieu and proposes novel targets for improving immune checkpoint blockade-based MM immunotherapy.

FDG PET/CT Imaging of Pancreatic Plasmacytoma.

A 56-year-old man underwent F-FDG PET/CT to evaluate possible pancreatic cancer, which was revealed by CT. The images showed a solid lesion with peripherally increased FDG activity in the tail of the pancreas, as well as hypermetabolic lesions in the lumbar spine and rib. Pathological examination following lumbar biopsy demonstrated multiple myeloma. Five months after chemotherapy, follow-up FDG PET/CT showed cystic change in the pancreatic lesion without elevated metabolism.

Exploration of the personalized immune checkpoint atlas of plasma cell dyscrasias patients using high­dimensional single­cell analysis.

Immune checkpoint blockade endows patients with unparalleled success in conquering cancer. Unfortunately, inter­individual heterogeneity causes failure in controlling tumors in many patients. Emerging mass cytometry technology is capable of revealing a multiscale onco­immune landscape that improves the efficacy of cancer immunotherapy. We introduced mass cytometry to determine the personalized immune checkpoint status in bone marrow and peripheral blood samples from 3 patients with multiple myeloma, amyloid light­chain amyloidosis, and solitary bone plasmacytoma and 1 non­hematologic malignancy patient. The expression of 18 immune regulatory receptors and ligands on 17 defined cell populations was simultaneously examined. By single­cell analyses, we identified the T cell clusters that serve as immunosuppressive signal source and revealed integrated immune checkpoint axes of individuals, thereby providing multiple potential immunotherapeutic targets, including programmed cell death protein 1 (PD­1), inducible co­stimulator (ICOS), and cluster of differentiation 28 (CD28), for each patient. Distinguishing the cell populations that function as providers and receivers of the immune checkpoint signals demonstrated a distinct cross­interaction network of immunomodulatory signals in individuals. These in­depth personalized data demonstrate mass cytometry as a powerful innovation to discover the systematical immune status in the primary and peripheral tumor microenvironment.

Enhanced osseointegration of double network hydrogels via calcium polyphosphate incorporation for bone regeneration.

To overcome the low mechanical strength and difficult bonding of hydrogels to bones which are the major limitations of hydrogels used in bone-regeneration, a new type of calcium polyphosphate incorporated into bioinspired alginate/polyacrylic acid (CPP/PAA-Alg) hybrid double network (DN) hydrogel with both high strength and enhanced osseointergration was prepared by a two-step polymerization with alginate and polyacrylic acid for bone regeneration. The morphology, mechanical properties, swelling, biocompatibility, osseointegration and osteogenic ability of this CPP/PAA-Alg DN hydrogel were investigated. The results show that CPP/PAA-Alg DN hydrogel with highly porous microstructure possesses high water absorption capacity and highly strength properties which meet the requirements of bone repairing. The results of in vitro studies revealed that the CPP/PAA-Alg DN hydrogels can support the spread of cells and promote the cell proliferation. Animal studies demonstrated that the CPP incorporated would enhance the osseointegration of DN hydrogel with host bone at an early stage after implantation to accelerate the regeneration of bone. This research may provide a new way to develop biocompatible biomaterials with high mechanical strength and good osseointegration to meet the needs of bone regeneration.

FDG PET/CT Findings of Unsuspected Pulmonary Epithelioid Angiosarcoma Manifested as a Brain Metastasis.

A 42-year-old man presented paroxysmal sharp pain in the right side of the head. Head CT showed a lesion in the right frontal lobe. MRI of the head suggested the possibility of metastasis. FDG PET/CT showed increased uptake corresponding to lesions in the right frontal lobe of the brain, the left upper lobe of lung, and the left adrenal gland, respectively. Cerebral and pulmonary lesions were both resected. Histopathology confirmed that both lesions are primary epithelioid angiosarcomas.

Human gingival tissue-derived MSC suppress osteoclastogenesis and bone erosion via CD39-adenosine signal pathway in autoimmune arthritis.

BACKGROUND: Bone destruction is one of many severe complications that occurs in patients with rheumatoid arthritis (RA) and current therapies are unable to cure this manifestation. This study here aims to determine whether GMSC can directly inhibit osteoclast formation and eventually attenuate osteoclastogenesis and bone erosion in an inflammatory milieu. METHOD: GMSC were co-cultured with osteoclast precursors with or without CD39 inhibitor, CD73 inhibitor or adenosine receptors inhibitors pretreatment and osteoclast formation were evaluated in vitro. 2×10^6 GMSC per mouse were transferred to CIA mice and pathology scores, the frequency of osteoclasts, bone erosion in joints were assessed in vivo. FINDING: GMSC but not control cells, markedly suppressed human or mice osteoclastogenesis in vitro. GMSC treatment also resulted in a dramatically decreased level of NF-κB p65/p50 in osteoclasts in vitro. Infusion of GMSC to CIA significantly attenuated the severity of arthritis, pathology scores, frequency of osteoclasts, particularly bone erosion, as well as a decreased expression of RANKL in synovial tissues in vivo. Blockade of CD39/CD73 or adenosine receptors has significantly abrogated the suppressive ability of GMSC in vitro and therapeutic effect of GMSC on bone erosion during CIA in vivo. INTERPRETATION: GMSC inhibit osteoclast formation in vitro and in vivo partially via CD39-CD73-adenosine signals. Manipulation of GMSC may have a therapeutic implication on rheumatoid arthritis and other bone erosion related diseases. FUND: This study was supported by grants from the National Key R&D Program of China (2017YFA0105801 to F.H); the Zhujiang Innovative and Entrepreneurial Talent Team Award of Guangdong Province (2016 ZT 06S 252 to F·H) and National Institutes of Health (R01 AR059103, R61 AR073409 and NIH Star Award to S.G.Z).

Multiscale modeling reveals angiogenesis-induced drug resistance in brain tumors and predicts a synergistic drug combination targeting EGFR and VEGFR pathways.

BACKGROUND: Experimental studies have demonstrated that both the extracellular vasculature or microenvironment and intracellular molecular network (e.g., epidermal growth factor receptor (EGFR) signaling pathway) are important for brain tumor growth. Additionally, some drugs have been developed to inhibit EGFR signaling pathways. However, how angiogenesis affects the response of tumor cells to drug treatment has rarely been mechanistically studied. Therefore, a multiscale model is required to investigate such complex biological systems that contain interactions and feedback among multiple levels. RESULTS: In this study, we developed a single cell-based multiscale spatiotemporal model to simulate vascular tumor growth and the drug response based on the vascular endothelial growth factor receptor (VEGFR) signaling pathway, the EGFR signaling pathway and the cell cycle as well as several microenvironmental factors that determine cell fate switches in a temporal and spatial context. By incorporating the EGFRI treatment effect, the model showed an interesting phenomenon in which the survival rate of tumor cells decreased in the early stage but rebounded in a later stage, revealing the emergence of drug resistance. Moreover, we revealed the critical role of angiogenesis in acquired drug resistance, since inhibiting blood vessel growth using a VEGFR inhibitor prevented the recovery of the survival rate of tumor cells in the later stage. We further investigated the optimal timing of combining VEGFR inhibition with EGFR inhibition and predicted that the drug combination targeting both the EGFR pathway and VEGFR pathway has a synergistic effect. The experimental data validated the prediction of drug synergy, confirming the effectiveness of our model. In addition, the combination of EGFR and VEGFR genes showed clinical relevance in glioma patients. CONCLUSIONS: The developed multiscale model revealed angiogenesis-induced drug resistance mechanisms of brain tumors to EGFRI treatment and predicted a synergistic drug combination targeting both EGFR and VEGFR pathways with optimal combination timing. This study explored the mechanistic and functional mechanisms of the angiogenesis underlying tumor growth and drug resistance, which advances our understanding of novel mechanisms of drug resistance and provides implications for designing more effective cancer therapies.

The role of a semi-automated NanoVelcro system in capturing circulating tumor cells and evaluating their prognostic value for gestational choriocarcinoma.

To investigate whether circulating tumor cells (CTCs) are detectable in patients with gestational choriocarcinoma (GC) and evaluate the prognostic value of CTC enumeration. In this multicenter study, the presence of CTCs was examined in 180 GC patients using a semi-automated NanoVelcro system, among whom 106 patients underwent CTC re-evaluation after one cycle of chemotherapy. Approximately 96% of the GC patients contained ≥2 CTCs in 7.5 mL of blood. The number of CTCs per 7.5 mL of blood was much higher in patients with distant metastases (n = 95; range, 0 to 104) than in patients without distant metastases (n = 85; range, 0 to 6). Applying a 90-patient training and 90-patient validation cohort, a cutoff value of ≥6 CTCs was defined as the prognostic threshold for progression-free survival (PFS) and overall survival (OS). The presence of ≥6 CTCs was significantly associated with worse PFS and OS (both P < 0.001). A multivariate analysis showed that the CTC number (≥6 CTCs) was the strongest predictor of OS (hazard ratio [HR], 15.8; 95% confidence interval [CI], 4.3-57.9; P < 0.001). The number of CTCs decreased after one cycle of chemotherapy; univariate analyses demonstrated that the CTC count after the first chemotherapy cycle was a strong predictor of OS (HR, 36.1; 95% CI, 4.8-271.5; P < 0.001). CTCs are a promising prognostic factor for GC. The absolute CTC count after one cycle of chemotherapy in the context of this disease is a strong predictor of chemotherapy response.

Inhibition of multiple myeloma­derived exosomes uptake suppresses the functional response in bone marrow stromal cell.

The communication between multiple myeloma (MM) cells and bone marrow stromal cells (BMSCs) serves a pivotal role in MM progression by supporting MM cell growth, proliferation and drug resistance. An exosomes­based endogenous transport system has been determined as a novel mechanism of this communication by revealing the capacity for exchange of functional components between cells. An exosomes transfer­mediated biological response in recipient cells is strongly determined by the detailed routes and mechanisms of exosomes internalization, which are diverse and can depend on surface molecules on the membrane of the vesicle and the recipient cell. Understanding the routes of exosomes uptake during MM cell­BMSC communication is of great importance for the development of blocking strategies beneficial for MM treatment. In the present study, fluorescently­labeled exosomes and pharmacological inhibitors, which are known to interfere with different internalization pathways, were used to characterize the cellular mechanisms involved in the uptake of MM cell­derived exosomes by BMSCs. MM cell­derived exosomes can promote BMSC viability and induce changes in multiple pro­survival and pro­proliferation pathways in BMSCs. As determined by flow cytometry and confocal microscopy, the uptake of MM cell­derived exosomes proceeded primarily through endocytosis, via special caveolin­dependent endocytosis, and partially through macropinocytosis and membrane fusion. Furthermore, treatment with endocytosis inhibitors suppressed the exosomes­induced changes in pathways in BMSCs. Collectively, these results indicate that endocytosis is the primary route of internalization of MM cell­derived exosomes by BMSCs and indicate that inhibition of exosomes uptake can interrupt the communication between MM cells and BMSCs and thus serve as a potential adjunctive strategy for MM treatment.

Whole Exome Sequencing Identified a Novel Heterozygous Mutation in HMBS Gene in a Chinese Patient With Acute Intermittent Porphyria With Rare Type of Mild Anemia.

Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease with an autosomal dominant mode of inheritance. Germline mutations of HMBS gene causes AIP. Mutation of HMBS gene results into the partial deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase. AIP is clinically manifested with abdominal pain, vomiting, and neurological complaints. Additionally, an extreme phenotypic heterogeneity has been reported in AIP patients with mutations in HMBS gene. Here, we investigated a Chinese patient with AIP. The proband is a 28-year-old Chinese male manifested with severe stomach ache, constipation, nausea and depression. Proband's father and mother is normal. Proband's blood sample was collected and genomic DNA was extracted. Whole exome sequencing and Sanger sequencing identified a heterozygous novel single nucleotide deletion (c.809delC) in exon 12 of HMBS gene in the proband. This mutation leads to frameshift followed by formation of a truncated (p.Ala270Valfs∗2) HMBS protein with 272 amino acids comparing with the wild type HMBS protein of 361 amino acids. This mutation has not been found in proband's unaffected parents as well as in 100 healthy normal control. According to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG), this variant is classified as "likely pathogenic" variant. Our findings expand the mutational spectra of HMBS gene related AIP which are significant for screening and genetic diagnosis for AIP.

Moracin M inhibits lipopolysaccharide-induced inflammatory responses in nucleus pulposus cells via regulating PI3K/Akt/mTOR phosphorylation.

Moracin M, a phenolic component obtained from Mori Cortex, has been reported to have anti-inflammatory activities. The present study was designed to investigate the effects and mechanisms of Moracin M on lipopolysaccharide (LPS)-treated nucleus pulposus cells (NPCs) in intervertebral disc. NPCs were treated with moracin M at different concentrations for 1 h and then stimulated with LPS (0.5 µg/mL) for 24 h. The result demonstrated that moracin M could significantly inhibit LPS-induced inflammation. The elevated levels of IL-1ß, TNF-α and IL-6 induced by LPS could be reversed by moracin M in NPCs. Moreover, moracin M increased the expressions of autophagy-related proteins and up-regulated the phosphorylation of PI3K/Akt/mTOR in LPS-treated NPCs. In conclusion, our data demonstrated that moracin M might inhibit LPS-induced PI3K and Akt phosphorylation, which leading to promote the autophagy and inhibit the inflammatory mediator production in NPCs.

A Spatio-Temporal Model of Macrophage-Mediated Drug Resistance in Glioma Immunotherapy.

The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment in driving the development of acquired drug resistance remain elusive, which significantly impedes effective clinical cancer treatment. Recent experimental studies have revealed a macrophage-mediated drug resistance mechanism in which the tumor microenvironment undergoes adaptation in response to macrophage-targeted colony-stimulating factor-1 receptor (CSF1R) inhibition therapy in gliomas. In this study, we developed a spatio-temporal model to quantitatively describe the interplay between glioma cells and CSF1R inhibitor-targeted macrophages through CSF1 and IGF1 pathways. Our model was used to investigate the evolutionary kinetics of the tumor regrowth and the associated dynamic adaptation of the tumor microenvironment in response to the CSF1R inhibitor treatment. The simulation result obtained using this model was in agreement with the experimental data. The sensitivity analysis revealed the key parameters involved in the model, and their potential impacts on the model behavior were examined. Moreover, we demonstrated that the drug resistance is dose-dependent. In addition, we quantitatively evaluated the effects of combined CSFR inhibition and IGF1 receptor (IGF1R) inhibition with the goal of designing more effective therapies for gliomas. Our study provides quantitative and mechanistic insights into the microenvironmental adaptation mechanisms that operate during macrophage-targeted immunotherapy and has implications for drug dose optimization and the design of more effective combination therapies. Mol Cancer Ther; 17(4); 814-24. ©2018 AACR.

Hybrid hydrogels with high strength and biocompatibility for bone regeneration.

The development of hydrogels for bone regeneration has highlighted the challenge that load-bearing hydrogels need to be biocompatible while achieving high strength. Several approaches have been reported to improve the toughness of hydrogels, but achieving high toughness and biocompatibility simultaneously remains a challenge. Here we report a polyacrylic acid/alginate/demineralized bone matrix (PAA/Alg/DBM) hybrid double network hydrogel, which was synthesized by a two-step sequential polymerization with embedded DBM, possessing both high strength and biocompatibility. With the persistence of DBM, it can promote the synthesis of VEGF and bFGF and the ALP activity of MG63 cells on hydrogel. All the results suggest that this hybrid double network hydrogel have potential for future application in bone regeneration.