Dynamic Single-Cell RNA-Seq reveals mechanism of Selinexor-Resistance in Chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a type of hematologic malignancies caused by BCR-ABL chimeric oncogene. Resistance to tyrosine kinase inhibitors (TKIs) leads to the progression of CML into advanced stages. Selinexor is a small molecule inhibitor that targets a nuclear transporter called Exportin 1. Combined with imatinib, selinexor has been shown to disrupt nuclear-cytoplasmic transport signal of leukemia stem cells, resulting in cell death. The objective of this study was to investigate the mechanism of drug resistance to selinexor in CML. We established K562 cell line resistant to selinexor and conducted single cell dynamic transcriptome sequencing to analyze the heterogeneity within the parental and selinexor resistant cell populations. We identified specific gene expression changes associated with resistance to selinexor. Our results revealed differential expression patterns in genes such as MT2A, TFPI, MTND3, and HMGCS1 in the total RNA, as well as MT-TW, DNAJB1, and HSPB1 in the newly synthesized RNA, between the parental and drug-resistant groups. By applying pseudo-time analysis, we discovered that a specific cluster of cells exhibited characteristics of tumor stem cells. Furthermore, we observed a gradual decrease in the expression of ferroptosis-related molecules as drug resistance developed. In vitro experiments confirmed that the combination of a ferroptosis inducer called RSL3 effectively overcame drug resistance. In conclusion, this study revealed the resistance mechanism of selinexor in CML. In conclusion, we identified a subgroup of CML cells with tumor stem cell properties and demonstrated that ferroptosis inducer improved the efficacy of selinexor in overcoming drug resistance.

Sprayable self-assembly multifunctional bioactive poly(ferulic acid) hydrogel for rapid MRSA infected wound repair.

The repair of methicillin-resistant staphylococcus aureus (MRSA) infected wounds remains a serious challenge. Development of multifunctional bioactive hydrogels has shown promising potential in treating MRSA wound. Ferulic acid has special bioactivities including antioxidant antiinflammation antibacterial capacities but limited in lack of engineering strategy for efficient treatment of MRSA infected wound. Herein, we developed a multifunctional bioactive poly(ferulic acid) copolymer (FPFA) for treating MRSA infected wound. FPFA could be self-assembled into hydrogel under body temperature and demonstrated the injectable, sprayable, self-healing, anti-inflammatory, antioxidant, and angiogenic activity. FPFA hydrogel also showed the good cytocompatibility, efficiently enhanced the endothelial cell migration, scavenged intracellular reactive oxygen species (ROS), inhibited the expression of inflammatory factors and enhanced the in vitro angiogenesis. The MRSA-infected wound model showed that FPFA could significantly inhibit the MRSA infection and excess inflammation, reinforce the angiogenesis, accelerate wound healing and skin tissue regeneration.

SOX10 deficiency-mediated LAMB3 upregulation determines the invasiveness of MAPKi-resistant melanoma.

Melanoma that develops adaptive resistance to MAPK inhibitors (MAPKi) through transcriptional reprograming-mediated phenotype switching is associated with enhanced metastatic potential, yet the underlying mechanism of this improved invasiveness has not been fully elucidated. In this study, we show that MAPKi-resistant melanoma cells are more motile and invasive than the parental cells. We further show that LAMB3, a ß subunit of the extracellular matrix protein laminin-332 is upregulated in MAPKi-resistant melanoma cells and that the LAMB3-Integrin α3/α6 signaling mediates the motile and invasive phenotype of resistant cells. In addition, we demonstrate that SOX10 deficiency in MAPKi-resistant melanoma cells drives LAMB3 upregulation through TGF-ß signaling. Transcriptome profiling and functional studies further reveal a FAK/MMPs axis mediates the pro-invasiveness effect of LAMB3. Using a mouse lung metastasis model, we demonstrate LAMB3 depletion inhibits the metastatic potential of MAPKi-resistant cells in vivo. In summary, this study identifies a SOX10low/TGF-ß/LAMB3/FAK/MMPs signaling pathway that determines the migration and invasion properties of MAPKi-resistant melanoma cells and provide rationales for co-targeting LAMB3 to curb the metastasis of melanoma cells in targeted therapy.

Ultrathin heteroatom-doped CeO2 nanosheet assemblies for durable oxygen evolution: Oxygen vacancy engineering to trigger deprotonation.

The manipulation of oxygen vacancies (OVs) in metal oxides has progressively emerged as a versatile strategy for improving their catalytic performance. In this study, we aim to enhance the oxygen evolution reaction (OER) performance of cerium oxide (CeO2) by doping heteroatoms (Fe, Co, Ni) to generate additional OVs. We systematically analyzed both the morphology and electronic structure of the obtained CeO2 catalysts. The experimental results revealed the self-assembly of two-dimensional (2D) CeO2 nanosheets, with an approximate thickness of ∼1.7 nm, into 2D nanosheet assemblies (NSAs). Moreover, the incorporation of heteroatoms into the CeO2 matrix promoted the formation of OVs, resulting in a significant enhancement of the OER performance of CeO2. Among them, the Co-doped CeO2 NSAs sample displayed the highest activity and durability, with almost negligible activity loss during extended operating periods. The roles of heteroatom doping in improving OER activity were explored by DFT calculations. The produced OVs improve the adsorption of hydroxyl groups (OH-), promote the deprotonation process, and increase more active sites. These findings suggest that doping CeO2 with heteroatoms is a promising strategy for improving electrocatalytic OER activity, with great potential for the development of clean energy technologies, including but not limited to water splitting and fuel cells.

Nurses' Colleague Solidarity and Job Performance: Mediating Effect of Positive Emotion and Turnover Intention.

Background: Job performance is known as an essential reflection of nursing quality. Colleague solidarity, positive emotion, and turnover intention play effective roles in a clinical working environment, but their impacts on job performance are unclear. Investigating the association between nurses' colleague solidarity and job performance may be valuable, both directly and through the mediating roles of positive emotion and turnover intention. Methods: In this cross-sectional study, a total of 324 Chinese nurses were recruited by convenience sampling method from July 2016 to January 2017. Descriptive analysis, Spearman's correlation analysis, and the structural equation model were applied for analysis by SPSS 26.0 and AMOS 24.0. Results: A total of 49.69% of participants were under 30 years old, and 90.12% of participants were female. Colleague solidarity and positive emotion were positively connected with job performance. The results indicated the mediating effects of positive emotion and turnover intention in this relationship, respectively, as well as the chain mediating effect of positive emotion and turnover intention. Conclusions: In conclusion, dynamic and multiple supportive strategies are needed for nurse managers to ameliorate nursing job performance by improving colleague solidarity and positive emotion and decreasing turnover intention based on the job demand-resource model.

Liquid extramedullary disease in multiple myeloma strongly predicts a poor prognosis and is associated with bortezomib resistance gene upregulation.

BACKGROUND-AIM: Patients with multiple myeloma (MM) relapse with extramedullary disease (EMD) exhibits an aggressive disease course and poor prognostic features. Myelomatous effusion (ME) is a rare subtype of EMD. METHODS: In this retrospective study, we analyzed the baseline characteristics and therapies of 14 EMD patients relapse with ME and 21 EMD patients relapse without ME. RESULTS: Patients with ME relapse demonstrated higher concentrations of serum lactate dehydrogenase, a higher fraction in the International Staging System stage III, and poorer event-free survival (EFS) (9.3 vs. 36.57 months; P = 0.0013) and overall survival (OS) (12.06 vs. 42.64 months; P < 0.001). The multivariate analysis showed that the presence of ME (hazard ratio [HR] 12.57; P = 0.003) and lack of autologous hematopoietic stem cell transplantation therapy (HR 4.382; P = 0.014) were predictive factors for poor OS. Using single-cell RNA sequencing, we discovered several bortezomib resistance genes were highly expressed in extramedullary malignant plasma cells. CONCLUSIONS: The presence of ME strongly predicts a poor prognosis in patients with MM relapse with EMD, and bortezomib resistance genes are highly expressed in extramedullary malignant plasma cells.

Identification of evolutionary mechanisms of myelomatous effusion by single-cell RNA sequencing.

Myelomatous effusion (ME) is a rare manifestation of extramedullary multiple myeloma (MM) with limited therapeutic options and poor outcomes. The molecular mechanisms underlying ME are incompletely understood. We profiled transcriptomes of bone marrow, peripheral blood (PB), and pleural effusion/ascites from 3 patients with ME using single-cell RNA sequencing analysis. We found that ME contained a higher percentage of cytotoxic T cells, whereas PB contained a higher proportion of naive T cells. Malignant cells varied within and between sites and patients in their expression of signatures. We identified a gene module highly expressed in intramedullary and extramedullary plasma cell clusters and defined cell clusters expressing this gene set as extramedullary-initiating cells (EMICs). This gene set was associated with increased cellular proliferation, involved in p53 signaling, and related to poor prognosis in MM. The transcriptional regulators E2F1, YY1, and SMAD1 were activated in EMICs. Leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) was upregulated in extramedullary EMICs. We confirmed that LILRB4 promoted MM cell migration in vitro. This study provided insight into the evolutionary mechanisms of ME and defined EMICs and LILRB4 associated with extramedullary development.

Fine particulate matter exposure disturbs autophagy, redox balance and mitochondrial homeostasis via JNK activation to inhibit proliferation and promote EMT in human alveolar epithelial A549 cells.

Epidemiologic studies have demonstrated a direct correlation between fine particulate matter (FPM) exposure and the high risk of respiratory diseases. FPM can penetrate deep into the lung and deposit in the alveoli with breath, where it directly interacts with alveolar epithelial cell (APC). However, we know little about the effects nor mechanisms of FPM on APC. Here, using human APC A549 cells, we found that FPM resulted in blockade of autophagic flux, redox imbalance and oxidative stress, mitochondrial fragmentation, increased mitophagy and impaired mitochondrial respiration. Further we showed that activation of JNK signaling (c-Jun N-terminal kinase) and excessive ROS (reactive oxygen species) release contribute to these adverse effects, with the former being upstream of the latter. More importantly, we found that scavenging ROS or inhibiting JNK activation could restore those effects as well as ameliorate FPM-induced inhibition of cell proliferation, and epithelial-mesenchymal transformation (EMT) in A549 cells. Taken together, our findings indicate that FPM leads to toxicity in alveolar type II cells via JNK activation, and JNK-targeting or antioxidant strategies might be beneficial for prevention or treatment of FPM-related pulmonary diseases.

[The Risk and Survival Analysis of Multiple Malignancies in Hematologic Malignancy Patients: A Single Chinese Center Retrospective Study, 2009 through 2017].

OBJECTIVE: To explore the risk and location of multiple malignancies in patients with hematologic malignancies who were followed up for 9 years in Jiangsu Province Hospital and to evaluate the impact of the second primary malignancy on survival of patients. METHODS: The incidence and survival of multiple malignancies in 7 921 patients with hematologic malignancies from 2009 to 2017 were analyzed retrospectively. RESULTS: A total of 180 (2.3%, 180/7 921) patients developed second malignancy, of whom 58 patients were diagnosed with hematologic malignancies as the first primary malignancy, and 98 patients developed hematologic malignancies as second primary malignancy, and the other 24 cases were diagnosed with the second malignancy within 6 months after the first primary malignancy was diagnosed, which was difined as multiple malignancies occurring simultaneously. In 180 patients, 18 cases developed two hematologic malignancies successively, and 11 patients developed more than 3 primary cancers (among them, 2 female patients were diagnosed with 4 primary cancers). Patients with lymphoma and multiple myeloma (MM) as the second primary malignancy had poorer survival than patients with lymphoma and MM as the first primary malignancy. Patients with chronic myeloid leukemia as the second primary malignancy were also associated with inferior overall survival. CONCLUSION: In this study, 2.3% of hematologic malignancy patients had multiple mali-gnancies, lymphoma and MM as the second primary malignancy had poor survival.

Photoactivated MXene Nanosheets for Integrated Bone-Soft Tissue Therapy: Effect and Potential Mechanism.

The bone defects caused by trauma are inevitably accompanied by soft tissue damage. The development of multifunctional bioactive biomaterials with integrated bone and soft tissue regeneration is necessary and needed urgently in orthopedics. In this work, we found that the photoactivated MXene (Ti3C2Tx) nanosheet showed positive effects on promoting both bone and soft tissue regeneration. We further investigated the detailed effect and potential mechanism of photoactivated MXene on tissue regeneration. Photoactivated MXene shows a good thermal effect and robust antibacterial activity to inhibit the expression of inflammation factors and methicillin-resistant Staphylococcus aureus (MRSA) infection and induces the expression of pro-angiogenic factors and soft tissue wound repair. Photoactivated MXene can also regulate the osteogenic differentiation of adipose-derived stem cells (ADSCs) through the ERK signaling pathway by activating the heat shock protein 70 (HSP70) and enhancing the repair of bone tissue. This work sheds light on the development of bioactive MXene with photothermal activation as an efficient strategy for bone and soft tissue regeneration simultaneously.

A bionic "Trojan horse"-like gene delivery system hybridized with tumor and macrophage cell membrane for cancer therapy.

MiRNA-based gene therapy as a novel targeted therapy has yielded promising results in experimental cancer treatment, however, the inefficient delivery of miRNA to target tissues has limited its application in vivo. Here a unique dual-membrane-camouflaged miRNA21 antagomir delivery nanoplatform (M@NPs/miR21) with immune escape and homologous targeting properties was constructed by cancer cell membrane and macrophage membrane. Different from the single-cell membrane camouflage strategy, the dual-membrane camouflage miRNA21 antagomir delivery nanoplatform based on modification of CD47 protein with immune escape signal and galectin-3 protein with tumor cell aggregation enables efficient, safe and targeted therapy for colon cancer and lung metastases. Camouflaged with the dual-cell membrane, the "Trojan horse" like "pseudo-tumor cell" and/or "pseudo-macrophage" (M@NPs/miR21) carried the target gene miR21 antagomir to the tumor site and showed significant anti-tumor properties at the periphery and the core of subcutaneous tumor tissues. In addition, M@NPs/miR21 was more likely to penetrate dense tumor tissues and function within the tumor mass than NPs/miR21 without membrane coating. M@NPs/miR21 can deliver miR21 antagomir into MC38 cancer cells and tumor tissues, promote tumor apoptosis, and regulate the expression of Bcl2 and Ki67. Moreover, the M@NPs/miR21 gene delivery system not only can effectively inhibit the progression of subcutaneous tumors and lung metastases, but also showed minimal toxicity and good biosafety, making this delivery system particularly attractive for future translational research.

Differences in clinical characteristics and chest CT findings between severe and critical H1N1 pneumonia.

INTRODUCTION: Critical H1N1 pneumonia patients usually have one of the symptoms such as respiratory failure, septic shock, multiple organ dysfunction, or other need for intensive care management, which are associated with high risk of mortality. It is essential to differentiate the severity of H1N1 pneumonia and take corresponding target treatments. OBJECTIVES: We aim to investigate the differences in clinical characteristics and chest computed tomography (CT) findings between severe and critical patients with H1N1 pneumonia. METHODS: A total of 27 patients diagnosed with H1N1 pneumonia from October 2018 to March 2019 were retrospectively analyzed, and the differences in clinical manifestations, laboratory tests, and chest CT findings between the severe group (15 patients) and the critical group (12 patients) were compared. RESULTS: Frequency of dyspnea at rest was higher in critical group than that in severe group (P = 0.019). The neutrophil percentage was higher (P = 0.014) and the lymphocyte percentage was lower (P = 0.025) in critical compared with severe group. Bilateral lung involvement was the predominant pattern in both severe and critical patients, whereas the number of involved lobes in critical patients was more than that in severe patients (P = 0.024). Peripheral distribution was the predominant pattern in severe patients (40%), whereas more diffuse involvement of the lungs was observed in critical patients (83.30%). Ground-glass opacities and consolidation were the main CT findings in both groups, and prevalence of consolidation was higher in critical relative to severe group (83.30%). CONCLUSION: Compared with severe patients, those with critical H1N1 pneumonia were more likely to present with dyspnea at rest and decreased lymphocyte percentage. Chest CT showed that diffuse bilateral involvement and higher prevalence of consolidation are associated with critical outcomes.

Engineering Multifunctional Polyether Ether Ketone Implant: Mechanics-Adaptability, Biominerialization, Immunoregulation, Anti-Infection, Osteointegration, and Osteogenesis.

Polyether ether ketone (PEEK) has become one of the most promising polymer implants in bone orthopedics, due to the biocompatibility, good processability, and radiation resistance. However, the poor mechanics-adaptability/osteointegration/osteogenesis/antiinfection limits the long-term in vivo applications of PEEK implants. Herein, a multifunctional PEEK implant (PEEK-PDA-BGNs) is constructed through in situ surface deposition of polydopamine-bioactive glass nanoparticles (PDA-BGNs). PEEK-PDA-BGNs exhibit good performance on osteointegration and osteogenesis in vitro and in vivo, due to their multifunctional properties including mechanics-adaptability, biominerialization, immunoregulation, anti-infection, and osteoinductive activity. PEEK-PDA-BGNs can show the bone tissue-adaptable mechanic surface and induce the rapid biomineralization (apatite formation) under a simulated body solution. Additionally, PEEK-PDA-BGNs can induce the M2 phenotype polarization of macrophages, reduce the expression of inflammatory factors, promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), and improve the osseointegration and osteogenesis ability of the PEEK implant. PEEK-PDA-BGNs also show good photothermal antibacterial activity and can kill 99% of Escherichia coli (E. coli) and Methicillin-resistant Staphylococcus aureus (MRSA), suggesting their potential antiinfection ability. This work suggests that PDA-BGNs coating is probably a facile strategy to construct multifunctional (biomineralization, antibacterial, immunoregulation) implants for bone tissue replacement.

Identification of long noncoding RNA NEAT1 as a key gene involved in the extramedullary disease of multiple myeloma by bioinformatics analysis.

OBJECTIVE: Long non-coding RNAs (lncRNAs) are involved in tumorigenesis and play a key role in cancer progression. To determine whether lncRNAs are involved in extramedullary disease of multiple myeloma (EMD), we analyzed the expression profile of lncRNAs in EMD. METHODS: Three pairs of EMD patients and their intramedullary MM cells were screened by microarray first. We extracted data from gene chips and made an identification of lncRNAs and mRNAs with significant differences between EMD group and non EMD group. WGCNA confirmed the EMD related gene module and drew a heat map to further determine the key gene lncRNA-NEAT1. In the meantime, bone marrow and extramedullary samples (hydrothorax and ascites) were collected from 2 MM patients and subjected to single-cell RNA-seq. Single cell Transcriptome analysis was conducted to verify the gene expression difference of malignant plasma cells derived from intramedullary and extramedullary. Then we verified high expression level of lncRNA-NEAT1 in EMD patients by using quantitative real-time PCR (qRT-PCR) and analyzed the correlation between expression patterns and survival and molecular genetics analysis of the LncRNA (NEAT1) involved in MM patients. At last, cell experiments were conducted to observe the effects of down-regulation of NEAT1on the proliferation, cell cycle and PTEN pathway related proteins of multiple myeloma cell lines U266 and RPMI8226. RESULTS: We identified one of the EMD related key gene is lncRNA-NEAT1. Compared with patients without extramedullary lesions, intramedullary MM cells in EMD patients expressed NEAT1 highly. The outcome of parallel single-cell RNA sequencing (RNA-seq) revealed NEAT1 level of plasma cells came from pleural effusion /ascites increased significantly compared with myeloma-stricken bone marrow. By survival and molecular genetic analysis, NEAT1 gene expression was not associated with OS and PFS in MM patients. However, the expression of NEAT1 is related to adverse therapeutic reactions and the progression of MM. We found that the expressions of NEAT1 were negatively associated with albumin levels and were positively associated with gain of chromosome 1q, IGH-CCND1, IGH@-FGFR3/WHSC1,and IGH-MAF gene fusion, respectively. At the level of cell experiment, CCK-8, soft agar clone formation experiment and CFSE staining showed that down regulating NEAT1 could inhibit the proliferation of U266 and RPMI8226 cells; Cell cycle detection showed that down-regulation of NEAT1 would interfere with the cell cycle process, and RPMI 8226 cells were blocked in G1 phase. Western blot analysis showed that when the expression of NEAT1 was down regulated in U266 and RPMI 8226 cells, the expression of PTEN and p-PTEN (phosphorylated phosphatase and tensin homologue) was up-regulated, and the expression of PI3K, p-PI3K (human phosphorylated inositol 3 kinase), Akt, p-Akt (phosphorylated protein kinase B). DISCUCCION AND CONCLUSION: This study provides novel insights into the lncRNA-NEAT1 and reveals that NEAT1 maybe a potential lncRNA biomarkers in EMD.

Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma.

BACKGROUND: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy showed remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). This phase 1 dose-escalation and expansion study developed C-CAR088, a novel second-generation humanized anti-BCMA CAR T-cell therapy, and assessed the safety and efficacy of three dosages of C-CAR088 in patients with RRMM. METHODS: Patients received lymphodepletion with three doses of cyclophosphamide (300 mg/m2) and three doses of fludarabine (30 mg/m2) on days -5, -4, and -3, followed by an infusion of C-CAR088 on day 0. Doses of 1.0×106, 3.0×106, and 6.0×106 CAR T cells/kg (±20%) were tested in the dose-escalation cohorts and expansion cohorts. The primary endpoint was treatment safety, including the rate of treatment-emergent adverse events after cell infusion. Secondary endpoints were the overall response rate and progression-free survival. The exploratory endpoints were the quantification of C-CAR088 CAR T cells, selection of cytokines and chemokines in blood, and measurement of tumor BCMA expression. RESULTS: As of July 2, 2021, 31 patients had been infused with C-CAR088. Any grade cytokine release syndrome (CRS) occurred in 29 patients (93.5%), and grade 3 CRS occurred in 3 patients (9.7%). One patient from the high-dose group (4.5-6.0×106 CAR T cells/kg) developed grade 1 neurotoxicity. No dose-limiting toxicities were observed in any dose group, and all adverse events were reversible after proper management. The overall response, stringent complete response, complete response (CR), and very good partial response rates were 96.4%, 46.4%, 10.7%, and 32.1%, respectively. The CR rate in the medium-dose (3.0×106 CAR T cells/kg) and high-dose (4.5-6.0×106 CAR T cells/kg) groups was 54.5% and 71.4%, respectively. In the CR group, 15 (93.7%) patients achieved minimal residual disease (MRD) negativity (test sensitivity >1/10-5). All seven patients with double-hit or triple-hit multiple myeloma achieved MRD-negative CR. CONCLUSIONS: The present study demonstrated that C-CAR088 had a good safety profile and high antitumor activity in patients with RRMM, constituting a promising treatment option for RRMM. TRIAL REGISTRATION NUMBER: NCT03815383, NCT03751293, NCT04295018, and NCT04322292.

MiR-365-3p is a negative regulator in IL-17-mediated asthmatic inflammation.

Background: Interleukin-17, the major proinflammatory cytokine secreted by Th17 cells, makes essential contribution to pathogenesis of severe asthma, while the detailed mechanisms, especially the involvement of microRNAs which are also important participants in asthma progression, remains largely unclear. Methods: In this study, we established a house dust mite (HDM) extract-induced murine asthmatic models and the miRNA expression in the lung tissues of mice were profiled by miRNA microarray assay. The effect of miR-365-3p on IL-17-mediated inflammation was examined by qRT-PCR and immunoblotting analysis. The involvement of ARRB2 as target gene of miR-365-3p was verified by overexpression or RNA interference. Results: HDM extract-induced asthmatic inflammation was proved to be IL17-mediated and miR-365-3p was screened out to be the only miRNA exclusively responsive to IL-17. miR-365-3p, whose expression was significantly downregulated upon IL-17 stimulation, was demonstrated to exert remarkable anti-inflammatory effect to decrease IL-17-provoked inflammatory cytokines (KC/IL-8 and IL-6) in both airway epithelial cells and macrophages of murine and human origins, verifying its universal antagonizing activity against IL-17-initiated inflammation across the two species. ARRB2 was characterized as the key target of miR-365-3p to negate IL-17-induced inflammatory cytokines. Conclusion: Taken together, our data supported the notion that miR-365-3p, which was diminished by IL-17 in murine and human asthmatic pathogenesis, functioned as an essential negative mediator in IL-17-stimuated inflammatory response by targeting ARRB2, which would shed new light to the understanding and therapeutics thereof of asthmatic inflammation.

[Clinical Characteristics of Multiple Myeloma Patients with Early Relapse].

OBJECTIVE: To analyze the clinical characteristics of multiple myeloma(MM) patients with early relapse. METHODS: A total of 50 MM patients with early relapse (≤12 months) and 50 matched controls with late relapse (>12 months) were selected. The time from diagnosis to relapse and related clinical data of the 100 patients were retrospectively analyzed, and the factors associated with early relapse were identified. Kaplan-Meier curve was used to analyze the overall survival (OS) time of the whole cohort. Area under the curve (AUC) was used to evaluate the effect of circulating plasma cells on early recurrence of the patients. RESULTS: The results showed that high-risk cytogenetics (FISH) (P=0.005), and ISS stage III (P=0.008) were associated with early recurrence of the patients. For patients with early relapse, high-risk FISH showed poor survival. Compared with the patients with late relapse, most of the chromosome karyotype of patients with early relapse showed quantitative and structural abnormalities. The expression of circulating plasma cells was significantly increased in patients with early recurrence group (P=0.0318). The response to initial treatment was poor in the early recurrence group (P=0.001), and the prognosis was significantly worse than those in the late recurrence group (median OS: 38 vs 81 months, P=0.002). CONCLUSION: Early relapse is a marker poor prognostic in MM patients, and such patients should be focused on the improving their prognosis.

Bioactive anti-inflammatory antibacterial metformin-contained hydrogel dressing accelerating wound healing.

Highly efficient wound healing and skin regeneration remain a challenge. Long-term inflammation and bacterial infection can inhibit the healing process and lead to the scar formation. Here, we report a hydrogel (FEM) formed by self-assembly of ε-poly-l-lysine-F127-ε-poly-l-lysine (EPL-F127-EPL) and metformin for wound repair. Especially, the role of metformin-based antibacterial hydrogel in wound healing and repair was investigated for the first time. FEM has inherent multifunctional properties, including controlled metformin release, anti-inflammatory and antibacterial activity, temperature responsiveness, injectable and self-healing capabilities. The in vivo results showed that FEM dressings accelerated the wound healing by stimulating the angiogenesis process of the wound tissue and anti-inflammation. This study shows that the multifunctional metformin-contained hydrogel scaffolds could enhance the wound repair through the anti-inflammation and accelerated angiogenesis, which could also expand the biomedical applications of metformin-based biomaterials.

Advances in the treatment of extramedullary disease in multiple myeloma.

Extramedullary disease (EMD) is characterized by plasma cells outside of bone marrow in multiple myeloma (MM) patients, which results in an adverse prognosis. The cornerstone of treatment consists of combination therapy including proteasome inhibitors, immunomodulatory agents, steroids, followed by consolidative autologous hematopoietic stem cell transplantation in eligible patients. This review summarized the recent advances in the treatment of EMD. Bortezomib based therapy showed efficacy and was recommended to treat EMD. Marizomib had advantages in the treatment of central nervous system-multiple myeloma (CNS-MM) because of its good central nervous system penetrability. Immunomodulatory drugs such as lenalidomide and pomalidomide have been reported to be effective. Isatuximab and selinexor were also active. Based on the treatment experience of EMD in our department, we summarized treatment approach for EMD. However, the benefits of patients with EMD from the new era of novel drugs were limited. Novel drugs combination, monoclonal antibody, molecular targeted therapy, cellular immunotherapy and autologous stem cell transplantation (ASCT) are under investigation. Therapeutic studies and clinical trials specifically target EMD should be conducted. Hopefully, these treatment options for EMD will be demonstrated efficacy in the future.

Bioactive cytomembrane@poly(citrate-peptide)-miRNA365 nanoplatform with immune escape and homologous targeting for colon cancer therapy.

Colon cancer is one of the most common gastrointestinal tumors in the world. Currently, the commonly used methods such as radiotherapy, chemotherapy and drug treatments are often ineffective and have significant side effects. Here we developed a safe and efficient biomaterials based anti-tumor nanoplatform (M@NPs/miR365), which was formed with poly (citrate-peptide) (PCP), miRNA365 mimic and MC38 cancer cell membrane (M). PCP could efficiently deliver miR365 mimic into MC38 cancer cells, promote the apoptosis of MC38 tumor cells and regulate the expression of Bcl2 and Ki67 in vitro. Tumor cell membranes were prepared by a fast and convenient sonication method. This tumor cell membrane-coated drug delivery system M@NPs can effectively reduce macrophage uptake and increase the stability of NPs. And the MC38 tumor model mice experiment showed that M@NPs/miR365 via caudal vein injection effectively inhibit tumor development. Based on the immune escape and homologous targeting of cancer cells and efficient gene transfection ability of NPs, this "Trojan horse" like "Pseudotumor cell" carries the target gene miR365 mimic to the tumor site and realizes cancer therapy. Noteworthy, the drug delivery system has good biocompatibility. Thus, this safe drug delivery strategy mediated by cancer cell membrane and gene therapy may have a certain significance for reducing the gap between nanoplatform and tumor clinical treatment.