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The optimal strategy estimation of random evolutionary Boolean games (REBGs) is discussed in this article. First, using the minimum mean square error criterion, the optimal strategy estimator is proposed for REBGs. Then, a matrix approach is developed to calculate the optimal strategy estimator by the aid of a semitensor product of matrices, which includes the prediction matrix, updating distribution, and strategy iterative formula. Finally, an elucidative example is included to show the obtained results are valid.

Objective: The current study aims to assess the reporting quality and its correlation with randomized controlled trials (RCTs) on acupuncture associated with other treatments for facial paralysis. Methods: Original articles were retrieved from the China National Knowledge Infrastructure (CNKI), the China Science and Technology Journal Database (VIP), the Wanfang Database (WF), SinoMed, PubMed, and the Web of Science (WOS). The literature was published between 2020 and 2021 in Chinese and English. Results: A total of 22 articles were included, and the reporting rate of CONSORT items for 22 RCTs ranged from 16.22% to 40.54%. There were 23 entries with a reporting rate below 10%. Additionally, the reporting rate of STRICTA entries for the 22 RCTs ranged from 41.18% to 94.12%. Of all the STRICTA entries, five entries reported rates below or equal to 50%. No literature complies with the CONSORT statement, and none satisfies the STRICTA standard. Conclusion: The quality of randomized controlled trials of acupuncture combined with other treatments for facial paralysis was generally low. The future trial design of acupuncture and other methods for facial paralysis should be standardized to improve the reporting quality based on the CONSORT statement and the STRICTA standard.

This meta-analysis aimed to assess the impact of nursing interventions (e.g., educational and empathic interviewing, motor exercise, therapeutic play interventions) on the perioperative outcome of children with congenital heart disease (CHD).We searched PubMed, Embase, Web of Science, Scopus, Cochrane, EBSCO, The Chinese National Knowledge Infrastructure, Wan Fang Data and the VIP Chinese Journal Service platform from the date of database creation to August 2021. Our study adhered to the recommendations of the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RevMan 5.4 and Stata 16.0 were used to complete the meta-analysis.This meta-analysis showed that comprehensive nursing intervention reduced both the length of hospital stay (weighted mean difference [WMD] = -1.982, 95%CI [-2.329, -1.634], P .001) and the related risk of post-operative complications [OR = 0.345, 95%CI (0.225, 0.528), P .001]. In addition, nursing intervention increased parental satisfaction with the care provided [OR = 0.308, 95%CI (1.923, 6.863), P .001]. Nursing interventions have also had a positive impact in reducing preoperative anxiety [WMD = -6.721, 95% CI (-7.194, -6.249), P .001] and postoperative pain [WMD = -7.103, 95% CI (-7.103, -7.663), P .001] in children.This meta-analysis confirms the beneficial effects of comprehensive nursing interventions in terms of reduced complication rates and shorter hospital stays. The effectiveness of comprehensive nursing in reducing anxiety and pain levels was also demonstrated. The findings support the implementation of comprehensive care interventions in the perioperative period for children with CHD to improve clinical outcomes.

The standard regimens for graft-versus-host disease (GvHD) prophylaxis in matched unrelated donor (MUD) transplantation were based on antithymocyte globulin (ATG) in combination with calcineurin inhibitors (CNIs). To improve the efficiency of GvHD prophylaxis in MUD peripheral blood stem cell transplantation (MUD-PBSCT), 51 patients with hematological malignancies received a novel regimen for GvHD prophylaxis, which is composed of low dose of ATG (5 mg/kg) plus low-dose posttransplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy) combined with cyclosporine A (CsA) and mycophenolate mofetil (MMF). The cumulative incidences (CIs) of grades I–IV and II–IV acute GvHD (aGvHD) were 14.5% (95% CI, 9.4–19.6%) and 6.2% (95% CI, 2.8–9.6%) within 100 days after transplantation, respectively. The CI of mild-to-moderate chronic GvHD (cGvHD) within 1 year was 11.5% (95% CI, 6.6–16.4%). The 1-year probabilities of GvHD and relapse-free survival, relapse-free survival, and over survival were 70.6% (95% CI, 64.2–77.0%), 76.5% (95% CI, 70.6–82.4%), and 82.0% (95% CI, 76.5–87.5%), respectively. The CIs of CMV and EBV reactivation by day 180 were 10.4% (95% CI, 1.5–19.4%) and 8.3% (95% CI, 0.2–16.4%), respectively. The results suggested that low-dose ATG/PTCy combined with CsA/MMF as GvHD prophylaxis in MUD-PBSCT had promising activity.

This brief investigates the finite-time time-variant state feedback stabilization of $k$ -valued logical control networks (KVLCNs) with Markov jump disturbances via the algebraic state space representation (ASSR) method. Firstly, an equivalent Markov jump system is established for the considered KVLCNs with Markov jump disturbances by using ASSR. Secondly, a sequence of reachable sets is defined, based on which, a control design procedure is established for the time-variant state feedback stabilization of KVLCNs with Markov jump disturbances. Finally, the obtained result is applied to lac operon in the bacterium Escherichia coli.

Diabetic cardiomyopathy (DCM) is a vital cause of fatalities in diabetic patients. The programmed death of cardiomyocytes and inflammation critically contribute to cardiac hypertrophy and fibrosis in DCM. Furthermore, circular RNA (circRNA) is a key regulator of various diseases. However, the role of circRNAs in DCM remains to be elucidated. Our previous study found that pyroptosis was markedly activated in the cardiomyocytes subjected to high-glucose conditions, and miR-214-3p regulated the expression of caspase-1. The aim of this study was to elucidate whether circRNA is involved in DCM pyroptosis via the miR-214-3p/caspase-1 pathway. Herein, we identified that hsa_circ_0076631, named caspase-1-associated circRNA (CACR), was increased both in high-glucose-treated cardiomyocytes and in the serum of diabetic patients. CACR also sponged an endogenous miR-214-3p to sequester and inhibit its expression. CACR knockdown in cardiomyocytes counteracted high-glucose-induced caspase-1 activation. Conversely, miR-214-3p knockdown partially abolished the beneficial effects of CACR silencing on pyroptosis in cardiomyocytes. Therefore, this study elucidated that CACR might be a novel therapeutic target via the CACR/miR-214-3p/caspase-1 pathway in DCM. Keywords: circular RNA, miR-214-3p, caspase-1, diabetic cardiomyopathy, pyroptosis

Using the semi-tensor product method, this paper studies the set stability of Boolean networks (BNs) with stochastic function perturbations. First, the definition of one-column function perturbation for BNs is defined, and two kinds of stochastic function perturbations are formulated. Second, by constructing a state transition matrix, a new criterion is proposed for the set stability of BNs with probabilistic function perturbation. Third, the set stability of BNs with Markov jump function perturbation is studied by calculating the state probability distribution. Finally, the obtained results are applied to D. melanogaster segmentation polarity gene network.

Narcolepsy is a sleep disorder with the main manifestations of excessive daytime sleepiness, cataplexy, sleep paralysis, sleep hallucinations, and nighttime sleep disturbance. It is still not fully recognized by clinicians, and many patients are often misdiagnosed with epilepsy, syncope, or mental disorders. In the present study, we report the first case of narcolepsy diagnosed at the district, with a complete medical history, objective examinations, and cerebrospinal fluid and hematological tests, but no cataplexy. Mutiple sleep latentcy test (MSLT) showed that the average sleep latency was 3.1 min, and abnormal REM sleep episodes were detected in 4 naps. The average REM latency was 1.3 min. We review the knowledge and researches on this disease in Mainland China in the past 10 years. Data from China in 2014 showed a significant increase in the incidence of narcolepsy in 2011 after the H1N1 epidemic in China in 2009. Despite the low incidence rate, diagnosis of narcolepsy is still confusing and needs clinicians' attention. Whether the incidence of narcolepsy may increase after covid19 remains to be observed. So far, there is no clear evidence to support immunotherapy. In conclusion, further studies are needed to verify more treatments and improve the patient's life quality.

Outlier detection is a key field of machine learning for identifying abnormal data objects. Due to the high expense of acquiring ground truth, unsupervised models are often chosen in practice. To compensate for the unstable nature of unsupervised algorithms, practitioners from high-stakes fields like finance, health, and security, prefer to build a large number of models for further combination and analysis. However, this poses scalability challenges in high-dimensional large datasets. In this study, we propose a three-module acceleration framework called SUOD to expedite the training and prediction with a large number of unsupervised detection models. SUOD's Random Projection module can generate lower subspaces for high-dimensional datasets while reserving their distance relationship. Balanced Parallel Scheduling module can forecast the training and prediction cost of models with high confidence---so the task scheduler could assign nearly equal amount of taskload among workers for efficient parallelization. SUOD also comes with a Pseudo-supervised Approximation module, which can approximate fitted unsupervised models by lower time complexity supervised regressors for fast prediction on unseen data. It may be considered as an unsupervised model knowledge distillation process. Notably, all three modules are independent with great flexibility to "mix and match"; a combination of modules can be chosen based on use cases. Extensive experiments on more than 30 benchmark datasets have shown the efficacy of SUOD, and a comprehensive future development plan is also presented., Comment: In AAAI-20 Workshop on Artificial Intelligence for Cyber Security (AICS)

Maternal and collateral donors were associated with a higher incidence of graft- versus-host disease (GvHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). A more effective regimen for GvHD prophylaxis after haplo-HSCT with maternal/collateral donors needed to be explored. A retrospective study was performed on 62 patients after haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with maternal/collateral donors, which included 35 patients with low-dose antithymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide-based (low-dose ATG/PTCy-based) and 27 with ATG-based regimens for GvHD prophylaxis. The 180-day cumulative incidences (CIs) of grades II-IV and III-IV acute GvHD (aGvHD) were 17.7% and 6.8% in low-dose ATG/PTCy-based group, which were significantly lower than that in ATG-based group (55.4% and 31.9%) ( P = 0.003 for grade II-IV and P = 0.007 for III-IV aGvHD). In low-dose ATG/PTCy-based group, the 1-year overall survival (OS) and relapse-free survival (RFS) were 80.0%and 80.4%, which were higher than that in ATG-based group with OS of 59.4% and RFS of 62.0%. In multivariate analysis, the low-dose ATG/PTCy-based regimen significantly reduced the risk of grade II-IV (HR = 0.357; P = 0.049) and grade III-IV aGvHD (HR = 0.190; P = 0.046) as an independent risk factor. The results suggested that the low-dose ATG/PTCy-based regimen could effectively prevent the occurrence of aGvHD after haplo-PBSCT with maternal/collateral donors compared with the ATG-based regimen.

This study studies the stochastic set stabilisation of an n-person random evolutionary Boolean game (REBG). Firstly, the definition of stochastic set stabilisation has been proposed, and the n-person REBG is converted to an equivalent algebraic form by using the semi-tensor product of matrices. Secondly, by defining a series of stochastic reachable sets, a necessary and sufficient condition is presented for the state feedback stochastic set stabilisation of n-person REBG. Thirdly, based on the concept of uniformly one-step reachability with probability one, a constructive procedure is proposed for the calculation of stochastic reachable sets. Finally, as two applications of stochastic set stabilisation, the output tracking control and the strategy consensus of n-person REBG are investigated, respectively, and two necessary and sufficient conditions are presented.

Model combination, often regarded as a key sub-field of ensemble learning, has been widely used in both academic research and industry applications. To facilitate this process, we propose and implement an easy-to-use Python toolkit, combo, to aggregate models and scores under various scenarios, including classification, clustering, and anomaly detection. In a nutshell, combo provides a unified and consistent way to combine both raw and pretrained models from popular machine learning libraries, e.g., scikit-learn, XGBoost, and LightGBM. With accessibility and robustness in mind, combo is designed with detailed documentation, interactive examples, continuous integration, code coverage, and maintainability check; it can be installed easily through Python Package Index (PyPI) or https://github.com/yzhao062/combo., In Proceedings of Thirty-Fourth AAAI Conference on Artificial Intelligence (AAAI 2020)

Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin αvβ3. Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy.

Additional file 1: Figure S1. THP-1 monocyte differentiation induced by PMA. (A) Quantitative analysis expression of CD11b and A15 in THP-1 monocytes and differentiated macrophages for different treated concentration of PMA. (B) a)Flow cytometry analysis of A15 expression in THP-1 cells treated with PMA (50 ng/mL) for different times; b) mean fluorescence intensity of A15 expression in THP-1 cells treated with PMA (50 ng/mL) for different times. Figure S2. Confocal laser-scanning microscopy (CLSM) images of MDA-MB-231 and MCF-7 incubated with PKH7 labled Exo or A15-Exo at 37 °C for 4 h. Figure S3. Wound healing assay of MDA-MB-231 cells incubated with Co-A15-Exo displayed arrested healing/closing of the scratch. (representative pictures from 3 repeated experiments) Scale bar: 100 μm. Figure S4. The migratory ability of MDA-MB-231 receiving different treatments was further confirmed by the transwell assay and quantitative analysis of the migrated cells. n = 3 per group. Scale bar, 100 μm.

// Baoyue Ding 1, 2, 3, * , Wei Zhang 4, * , Xin Wu 5, * , Jeffrey Wang 3 , Chen Xie 3 , Xuan Huang 1 , Shuyu Zhan 1 , Yongxia Zheng 1 , Yueyan Huang 1 , Ningyin Xu 1 , Xueying Ding 5 , Shen Gao 2 1 Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing, PR China 2 Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, PR China 3 Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, USA 4 Department of Pharmaceutics, Shanghai Pulmonary Hospital, Tongji University, Shanghai, PR China 5 Department of Pharmaceutics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, PR China * These authors have contributed equally to this work Correspondence to: Shen Gao, email: liullk@126.com Xueying Ding, email: dingxueying@126.com Baoyue Ding, email: lena_310@163.com Keywords: malignant melanoma, DR5 monoclonal antibodies, dacarbazine, chemoimmunotherapy, active targeting nanoparticles Received: April 25, 2016 Accepted: July 19, 2016 Published: August 2, 2016 ABSTRACT We combined chemo- and immunotherapies by constructing dual therapeutic function immuno-nanoparticles (NPs) consisting of death receptor 5 monoclonal antibody (DR5 mAb)-conjugated nanoparticles loaded with dacarbazine (DTIC) (DTIC-NPs-DR5 mAb). We determined the in vivo targeting specificity of DTIC-NPs-DR5 mAb by evaluating distribution in tumor-bearing nude mice using a real-time imaging system. Therapeutic efficacy was assessed in terms of its effect on tumor volume, survival time, histomorphology, microvessel density (MVD), and apoptotic index (AI). Systemic toxicity was evaluated by measuring white blood cells (WBC) counts, alanine aminotransferase (ALT) levels, and creatinine clearance (CR). In vivo and ex vivo imaging indicates that DR5 mAb modification enhanced the accumulation of NPs within the xenograft tumor. DTIC-NPs-DR5 mAb inhibited tumor growth more effectively than DTIC or DR5 mAb alone, indicating that combining DTIC and DR5 mAb through pharmaceutical engineering achieves a better therapeutic effect. Moreover, the toxicity of DTIC-NPs-DR5 mAb was much lower than that of DTIC, implying that DR5 mAb targeting reduces nonspecific uptake of DTIC into normal tissue and thus decreases toxic side effects. These results demonstrate that DTIC-NPs-DR5 mAb is a safe and effective nanoparticle formulation with the potential to improve the efficacy and specificity of melanoma treatment.

Aims: Within the past few years, there has been tremendous growth in clinical trials of chimeric antigen receptor (CAR) T-cell therapies. Unlike those of many small-molecule pharmaceuticals, CAR T-cell therapy clinical trials are fraught with risks due to the use of live cell products. The aim of this study is to reach a consensus with experts on the most relevant set of risks that practically occur in CAR T-cell therapy clinical trials. Methods: A Delphi method of consensus development was used to identify the risks in CAR T-cell therapy clinical trials, comprising three survey rounds. The expert panel consisted of principal investigators, clinical research physicians, members of institutional ethics committees, and Good Clinical Practice managers. Results: Of the 24 experts invited to participate in this Delphi study, 20 participants completed Round 1, Round 2, and Round 3. Finally, consensus (defined as >80% agreement) was achieved for 54 risks relating to CAR T-cell clinical trials. Effective interventions related to these risks are needed to ensure the proper protection of subject health and safety. Conclusion: The Delphi method was successful in gaining a consensus on risks relevant to CAR T-cell clinical trials in a geographically diverse expert association. It is hoped that this work can benefit future risk-based quality management in clinical trials and can potentially promote the better development of CAR T-cell therapy products.

This paper studies the leader–follower consensus of multiagent systems with time delays and switching topology over finite fields. First, an equivalent algebraic form is established for leader–follower multiagent systems with time delays over finite fields. Second, based on the algebraic form, a necessary and sufficient condition is presented for the finite-field leader–follower consensus with time delays. Third, the switching topology case is considered, and a new criterion is presented for the finite-field leader–follower consensus with time delays and switching topology. Finally, an example is worked out to illustrate the obtained results.

Background Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein reported as an anti-inflammatory adipocytokine. Evidences from clinical and experimental studies revealed that brain inflammation plays important roles in epileptogenesis and seizure. Interestingly, closely relationship between ZAG and many important inflammatory mediators has been proven. Our previous study identified ZAG in neurons and found that ZAG is decreased in epilepsy and interacts with TGFβ and ERK. This study aimed to investigate the role of ZAG in seizure and explore its effect on seizure-related neuroinflammation. Methods We overexpressed AZGP1 in the hippocampus of rats via adeno-associated virus vector injection and observed their seizure behavior and EEG after pentylenetetrazol (PTZ) kindling. The level of typical inflammation mediators including TNFα, IL-6, TGFβ, ERK, and ERK phosphorylation were determined. Results The overexpression of AZGP1 reduced the seizure severity, prolonged the latency of kindling, and alleviated epileptiform discharges in EEG changes induced by PTZ. Overexpression of AZGP1 also suppressed the expression of TNFα, IL-6, TGFβ, and ERK phosphorylaton in PTZ-kindled rats. Conclusions ZAG may inhibit TGFβ-mediated ERK phosphorylation and inhibit neuroinflammation mediated by TNFα and IL-6, suggesting ZAG may suppress seizure via inhibiting neuroinflammation. ZAG may be a potential and novel therapeutic target for epilepsy.

Using the algebraic state space representation, this paper studies the robust consensus of networked evolutionary games (NEGs) with attackers and forbidden profiles. Firstly, an algebraic form is established for NEGs with attackers and forbidden profiles. Secondly, based on the algebraic form, a necessary and sufficient condition is presented for the robust constrained reachability of NEGs. Thirdly, a series of robust reachable sets is constructed by using the robust constrained reachability, based on which a constructive procedure is proposed to design state feedback controls for the robust consensus of NEGs with attackers and forbidden profiles. Finally, an illustrative example is given to show that the main results are effective.

Xin Wu,1,2,* Zongguang Tai,1,* Quangang Zhu,3,* Wei Fan,4 Baoyue Ding,5 Wei Zhang,1,6 Lijuan Zhang,1 Chong Yao,1 Xiaoyu Wang,1 Xueying Ding,2 Qin Li,2 Xiaoyu Li,2 Gaolin Liu,2 Jiyong Liu,1 Shen Gao1 1Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, 2Department of Pharmaceutics, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, 3Department of Pharmaceutics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Department of Pharmaceutics, The 425th Hospital of PLA, Sanya, People’s Republic of China; 5Department ofPharmaceutics, Medical College of Jiaxing University, Jiaxing, People’s Republic of China; 6Department ofPharmaceutics, The 522nd Hospital of PLA, Luoyang, People’s Republic of China *These authors contributed equally tothis work Abstract: Ligand-mediated prostate cancer (PCa)-targeting gene delivery is one of the focuses of research in recent years. Our previous study reported the successful preparation of aptamer-modified nanoparticles (APT-NPs) in our laboratory and demonstrated their PCa-targeting ability in vitro. However, the mechanism underlying this PCa-targeting effect and their anticancer ability in vivo have not yet been elucidated. The objective of this study was to assess the feasibility of using APT-NPs to deliver micro RNA (miRNA) systemically to PCa cells, to testify their tumor-targeting efficiency, and to observe their biodistribution after systemic administration to a xenograft mouse model of PCa. In addition, the effect of APT depletion and endocytosis inhibitors on cellular uptake was also evaluated quantitatively in LNCaP cells to explore the internalization mechanism of APT-NPs. Finally, blood chemistry, and renal and liver function parameters were measured in the xenograft mouse model of PCa to see whether APT-NPs had any demonstrable toxicity in mice in vivo. The results showed that APT-NPs prolonged the survival duration of the PCa tumor-bearing mice as compared with the unmodified NPs. In addition, they had a potential PCa-targeting effect in vivo. In conclusion, this research provides a prototype for the safe and efficient delivery of miRNA expression vectors to PCa cells, which may prove useful for preclinical and clinical studies on the treatment of PCa. Keywords: miRNA, aptamer, polyamidoamine, prostate-specific membrane antigen, targeted delivery, prostate cancer

Introduction Prolonged postoperative analgesia cannot be achieved by a single injection of local anesthetic solution. The objective of this study was to optimize the formulation of a ropivacaine hydrochloride (Ropi-HCl) loaded in situ forming implant (ISI) by addition of different co-solvents, and evaluate the in vitro release of Ropi-HCl, and the analgesic effect and toxicity of the optimized formulation in rats.

Dacarbazine (DTIC) loaded or blank methoxy poly (ethylene glycol)-poly (lactide) (MPEG-PLA) nanoparticles (NPs) were prepared by modified w/o/w double emulsion-solvent evaporation method through ultrasonic processor without any additional additives. The hemolytic test and cytotoxicity test of blank MPEG-PLA NPs demonstrated that the obtained drug delivery system is safety. Its particle size distribution, morphology, drug loading, drug release proi¬le and anticancer activity in vitro were studied in detail. The small sized nanoparticles (NPs) with a particle size of 144.2±7.8 nm in diameter and drug encapsulation efficiency of 70.1±2.3% are easy to be dispersed in water and suitable for vascular administration. The drug release pattern was biphasic with a fast release rate followed by a slow one. The in vitro and in vivo study results demonstrated that compared with free DTIC, DTIC loaded MPEG-PLA NPs could induce more apoptosis of cancer cell and showed enhanced antitumor activity. The described DTIC loaded MPEG-PLA nanoparticle in this paper might be a novel potential formulation for metastatic melanoma therapy. Key words: Malignant melanoma, dacarbazine, methoxy poly (ethylene glycol)-poly (lactide), double emulsion and solvent evaporation method, nanoparticles, anticancer activity.

Baoyue Ding1,2, Xin Wu1, Wei Fan1,3, Zhaoyong Wu4, Jing Gao5, Wei Zhang1, Lulu Ma5, Wang Xiang1, Quangang Zhu1, Jiyong Liu1, Xueying Ding5, Shen Gao11Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, 2Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing, 3The 425th Hospital of PLA, Department of Pharmacy, Sanya, 4Department of Pharmaceutics, Jiaxing Maternal and Childcare Hospital, Jiaxing, 5Department of Pharmaceutics, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China The first three authors contributed equally to this work. Background: The increased incidence of malignant melanoma in recent decades, along with its high mortality rate and pronounced resistance to therapy pose an enormous challenge. Novel therapeutic strategies, such as immunotherapy and targeted therapy, are urgently needed for melanoma. In this study, a new active targeting drug delivery system was constructed to combine chemotherapy and active specifc immunotherapy. Methods: The chemotherapeutic drug, dacarbazine (DTIC), that induces apoptosis through the intrinsic pathway which typically responds to severe DNA damage, was used as a model drug to prepare DTIC-loaded polylactic acid (PLA) nanoparticles (DTIC-NPs), which were covalently conjugated to a highly specific targeting functional TRAIL-receptor 2 (DR5) monoclonal antibody (mAb) that can contribute directly to cancer cell apoptosis or growth inhibition through the extrinsic pathway. Results: Our in vitro experiments demonstrated that DTIC-PLA-DR5 mAb nanoparticles (DTIC-NPs-DR5 mAb) are an active targeting drug delivery system which can specifcally target DR5-overexpressing malignant melanoma cells and become efficiently internalized. Most strikingly, compared with conventional DTIC-NPs, DTIC-NPs-DR5 mAb showed significantly enhanced cytotoxicity and increased cell apoptosis in DR5-positive malignant melanoma cells. Conclusion: The DTIC-NPs-DR5 mAb described in this paper might be a potential formulation for targeting chemotherapy and immunotherapy to DR5-overexpressing metastatic melanoma.Keywords: malignant melanoma, DR5 monoclonal antibodies, dacarbazine, apoptosis, chemoimmunotherapy, active targeting nanoparticles