MRI-Guided Tumor Therapy Based on Synergy of Ferroptosis, Immunosuppression Reversal and Disulfidptosis.

Triple negative breast cancer (TNBC) cells have a high demand for oxygen and glucose to fuel their growth and spread, shaping the tumor microenvironment (TME) that can lead to a weakened immune system by hypoxia and increased risk of metastasis. To disrupt this vicious circle and improve cancer therapeutic efficacy, a strategy is proposed with the synergy of ferroptosis, immunosuppression reversal and disulfidptosis. An intelligent nanomedicine GOx-IA@HMON@IO is successfully developed to realize this strategy. The Fe release behaviors indicate the glutathione (GSH)-responsive degradation of HMON. The results of titanium sulfate assay, electron spin resonance (ESR) spectra, 5,5'-Dithiobis-(2-nitrobenzoic acid (DTNB) assay and T1-weighted magnetic resonance imaging (MRI) demonstrate the mechanism of the intelligent iron atom (IA)-based cascade reactions for GOx-IA@HMON@IO, generating robust reactive oxygen species (ROS). The results on cells and mice reinforce the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis triggered by the GOx-IA@HMON@IO with the following steps: 1) GSH peroxidase 4 (GPX4) depletion by disulfidptosis; 2) IA-based cascade reactions; 3) tumor hypoxia reversal; 4) immunosuppression reversal; 5) GPX4 depletion by immunotherapy. Based on the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis, the intelligent nanomedicine GOx-IA@HMON@IO can be used for MRI-guided tumor therapy with excellent biocompatibility and safety.

A mesoporous superparamagnetic iron oxide nanoparticle as a generic drug delivery system for tumor ferroptosis therapy.

As a famous drug delivery system (DDS), mesoporous organosilica nanoparticles (MON) are degraded slowly in vivo and the degraded components are not useful for cell nutrition or cancer theranostics, and superparamagnetic iron oxide nanoparticles (SPION) are not mesoporous with low drug loading content (DLC). To overcome the problems of MON and SPION, we developed mesoporous SPIONs (MSPIONs) with an average diameter of 70 nm and pore size of 3.9 nm. Sorafenib (SFN) and/or brequinar (BQR) were loaded into the mesopores of MSPION, generating SFN@MSPION, BQR@MSPION and SFN/BQR@MSPION with high DLC of 11.5% (SFN), 10.1% (BQR) and 10.0% (SNF + BQR), demonstrating that our MSPION is a generic DDS. SFN/BQR@MSPION can be used for high performance ferroptosis therapy of tumors because: (1) the released Fe2+/3+ in tumor microenvironment (TME) can produce •OH via Fenton reaction; (2) the released SFN in TME can inhibit the cystine/glutamate reverse transporter, decrease the intracellular glutathione (GSH) and GSH peroxidase 4 levels, and thus enhance reactive oxygen species and lipid peroxide levels; (3) the released BQR in TME can further enhance the intracellular oxidative stress via dihydroorotate dehydrogenase inhibition. The ferroptosis therapeutic mechanism, efficacy and biosafety of MSPION-based DDS were verified on tumor cells and tumor-bearing mice.

Hollow mesoporous calcium peroxide nanoparticles for drug-free tumor calcicoptosis therapy.

Calcium ions (Ca2+) participate in the regulation of cellular apoptosis as a second messenger. Calcium overload, which refers to the abnormal elevation of intracellular Ca2+ concentration, is a factor that can lead to cell death. Here, based on the unique biological effects of Ca2+, hollow mesoporous calcium peroxide nanoparticles (HMCPN) were developed by a facile hydrolysis-precipitation method for drug-free tumor calcicoptosis therapy. The average pore size of the optimized HMCPN17 is 6.4 nm, and the surface area is 81.3 m2/g, which enables HMCPN17 with high drug loading capability. The Ca2+ release from HMCPN17 is much faster at pH 6.8 than that at pH 7.4, which can be ascribed to the acid-triggered conversion of HMCPN17 to Ca2+ and H2O2, indicating a pH-responsive decomposition behavior of HMCPN17. The high drug loading contents of doxorubicin (DOX) and/or sorafenib (SFN) indicate that HMCPN17 can be employed as a generic drug delivery system (DDS). The in vitro and in vivo results reinforce the high calcicoptosis therapeutic efficacy of tumors by our HMCPN17 without drug loading, which can be attributed to the efficient accumulation in tumors and the ability of H2O2 and Ca2+ production at acidic TME. Our HMCPN17 has broad application prospect for construction of multi-drug-loaded composite nanomaterials with diversified functions for the treatment of tumors. STATEMENT OF SIGNIFICANCE: The combination of hollow mesoporous nanomaterials and calcium peroxide nanoparticles has a wide range of applications in the synergistic treatment of tumors. In this study, hollow mesoporous calcium peroxide nanoparticles (HMCPN) were developed based on a simple hydrolysis-precipitation method for tumor calcicoptosis therapy without drug loading. The high drug loading contents of DOX and/or SFN indicate that our HMCPN can serve as a generic DDS. The experimental results demonstrated the high calcicoptosis therapeutic efficacy of HMCPN on tumors even without drug loading.

Double-Layered Hollow Mesoporous Cuprous Oxide Nanoparticles for Double Drug Sequential Therapy of Tumors.

Cancer stem cells (CSCs) are one of the determinants of tumor heterogeneity and are characterized by self-renewal, high tumorigenicity, invasiveness, and resistance to various therapies. To overcome the resistance of traditional tumor therapies resulting from CSCs, a strategy of double drug sequential therapy (DDST) for CSC-enriched tumors is proposed in this study and is realized utilizing the developed double-layered hollow mesoporous cuprous oxide nanoparticles (DL-HMCONs). The high drug-loading contents of camptothecin (CPT) and all-trans retinoic acid (ATRA) demonstrate that the DL-HMCON can be used as a generic drug delivery system. ATRA and CPT can be sequentially loaded in and released from CPT3@ATRA3@DL-HMCON@HA. The DDST mechanisms of CPT3@ATRA3@DL-HMCON@HA for CSC-containing tumors are demonstrated as follows: 1) the first release of ATRA from the outer layer induces differentiation from CSCs with high drug resistance to non-CSCs with low drug resistance; 2) the second release of CPT from the inner layer causes apoptosis of non-CSCs; and 3) the third release of Cu+ from DL-HMCON itself triggers the Fenton-like reaction and glutathione depletion, resulting in ferroptosis of non-CSCs. This CPT3@ATRA3@DL-HMCON@HA is verified to possess high DDST efficacy for CSC-enriched tumors with high biosafety.

Cyclic catalysis of intratumor Fe3+/2+ initiated by a hollow mesoporous iron sesquioxide nanoparticle for ferroptosis therapy of large tumors.

Numerous nanoparticles have been utilized to deliver Fe2+ for tumor ferroptosis therapy, which can be readily converted to Fe3+via Fenton reactions to generate hydroxyl radical (•OH). However, the ferroptosis therapeutic efficacy of large tumors is limited due to the slow conversion of Fe3+ to Fe2+via Fenton reactions. Herein, a strategy of intratumor Fe3+/2+ cyclic catalysis is proposed for ferroptosis therapy of large tumors, which was realized based on our newly developed hollow mesoporous iron sesquioxide nanoparticle (HMISN). Cisplatin (CDDP) and Gd-poly(acrylic acid) macrochelates (GP) were loaded into the hollow core of HMISN, whose surface was modified by laccase (LAC). Fe3+, CDDP, GP, and LAC can be gradually released from CDDP@GP@HMISN@LAC in the acidic tumor microenvironment. The intratumor O2 can be catalyzed into superoxide anion (O2•-) by LAC, and the intratumor NADPH oxidases can be activated by CDDP to generate O2•-. The O2•- can react with Fe3+ to generate Fe2+, and raise H2O2 level via the superoxide dismutase. The generated Fe2+ and H2O2 can be fast converted into Fe3+ and •OH via Fenton reactions. The cyclic catalysis of intratumor Fe3+/2+ initiated by CDDP@GP@HMISN@LAC can be used for ferroptosis therapy of large tumors.

A strategy of "adding fuel to the flames" enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy.

Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of "adding fuel to the flames" for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) (i.e., DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H2S, Cu2+, and Fe2+ in the acidic tumor microenvironment (TME). The hydrogen peroxide (H2O2) levels and acidity within tumor cells enhanced by the released H2S induce acceleration of Fenton (Fe2+) and Fenton-like (Cu2+) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of "fuel", intensifying catalytic effect ("flame") in tumor cells through the sustainable Fenton chemistry (i.e., "add fuel to the flames"). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe-S) proteins, and elevates intracellular oxidative stress by releasing free Fe3+. These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.

Expression and significance of cyclin D1, cyclin-dependent kinase 4 and cyclin-dependent kinase inhibitor P27 in patients with non-neoplastic epithelial disorders of the vulva.

Non-neoplastic epithelial disorders of the vulva (NNEDV) are prevalent and refractory gynecological diseases. However, the underlying pathogenesis of these diseases remain unclear. The present study aimed to investigate the expression and significance of cyclin D1, cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase inhibitor P27 (P27) in patients with NNEDV and provide a reference for clinical diagnosis and treatment. Normal vulvar skin samples from patients with perineum repair (control group, n=20) and skin samples from the vulvar lesions of patients with NNEDV (NNEDV group, n=36) were collected. Expression levels of cyclin D1, CDK4 and P27 were assessed in the samples using immunohistochemistry. The expression of each protein was evaluated based on the mean optical density (MOD). The MODs of cyclin D1 and CDK4 were significantly higher in samples of the three pathological types of NNEDV, namely squamous hyperplasia (SH), lichen sclerosus (LS) and mixed SH and LS lesions, compared with those of the control group. The MOD of P27 was lower in samples of the three pathological types of NNEDV than in the control group, although the difference was not statistically significant. No significant differences in the MOD of cyclin D1, CDK4 and P27 were detected among the three pathological types of NNEDV. The ratios of the MOD of cyclin D1 and CDK4 in the prickle cell layer to those in the basal cell layer were significantly higher in the NNEDV group than in the control group. However, the ratio of the MOD of P27 in the prickle cell layer to that in the basal cell layer exhibited no significant difference between the NNEDV and control groups. NNEDV has the potential for malignant transformation. The occurrence and development of NNEDV may be associated with the acceleration of cell proliferation, in which cyclin D1, CDK4 and P27 contribute to regulation of the cell cycle. Therefore, cyclin D1, CDK4 and P27 may be potential targets in the development of new clinical therapeutic drugs for patients with NNEDV.

Improved cancer immunotherapy strategies by nanomedicine.

Cancer immunotherapy agents fight cancer via immune system stimulation and have made significant advances in minimizing side effects and prolonging the survival of patients with solid tumors. However, major limitations still exist in cancer immunotherapy, including the inefficiency of immune response stimulation in specific cancer types, therapy resistance caused by the tumor microenvironment (TME), toxicities by the immune imbalance, and short lifetime of stimulator of interferon genes (STING) agonist. Recent advances in nanomedicine have shown significant potential in overcoming the obstacles of cancer immunotherapy. Several nanoscale agents have been reported for cancer immunotherapy, including nanoscale cancer vaccines impacting the STING pathway, nanomaterials reprogramming TME, nano-agents triggering immune response with immune checkpoint inhibitor synergy, ferroptosis-mediated and indoleamine-2,3-dioxygenase immunosuppression-mediated cancer immunotherapy, and nanomedicine-meditated chimeric antigen receptor-T-cell therapy. Herein, we summarize the major advances and innovations in nanomedicine-based cancer immunotherapy, and outline the opportunities and challenges to integrate more advanced nanomaterials into cancer immunotherapy. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Synergistic Functional Nanomedicine Enhances Ferroptosis Therapy for Breast Tumors by a Blocking Defensive Redox System.

The upregulation of dihydroorotate dehydrogenase (DHODH) redox systems inside tumor cells provides a powerful shelter against lipid peroxidation (LPO), impeding ferroptosis-induced antitumor responses. To solve this issue, we report a strategy to block redox systems and enhance ferroptotic cancer cell death based on a layered double hydroxide (LDH) nanoplatform (siR/IONs@LDH) co-loaded with ferroptosis agent iron oxide nanoparticles (IONs) and the DHODH inhibitor (siR). siR/IONs@LDH is able to simultaneously release IONs and siR in a pH-responsive manner, efficiently generate toxic reactive oxygen species (ROS) via an Fe2+-mediated Fenton reaction, and synergistically induce cancer cell death upon the acceleration of LPO accumulation. In vivo therapeutic evaluations demonstrate that this nanomedicine has excellent performance for tumor growth inhibition without any detectable side effects. This work thus provides a new insight into nanomaterial-mediated tumor ferroptosis therapy.

A STING pathway-activatable contrast agent for MRI-guided tumor immunoferroptosis synergistic therapy.

The immunotherapy efficiency of stimulator of interferon genes (STING)-activatable drugs (e.g., 7-ethyl-10-hydroxycamptothecin, SN38) is limited by their non-specificity to tumor cells and the slow excretion of the DNA-containing exosomes from the treated cancer cells. The efficacy of tumor ferroptosis therapy is always limited by the elimination of lipid peroxides (LPO) by the pathways of glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH) and ferroptosis suppressor protein 1(FSP1). To solve these problems, in this study, we developed a STING pathway-activatable contrast agent (i.e., FeGd-HN@TA-Fe2+-SN38 nanoparticles) for magnetic resonance imaging (MRI)-guided tumor immunoferroptosis synergistic therapy. The remarkable in vivo MRI performance of FeGd-HN@TA-Fe2+-SN38 is attributed to its high accumulation at tumor location, the high relaxivities of FeGd-HN core, and the pH-sensitive TA-Fe2+-SN38 layer. The effectiveness and biosafety of the immunoferroptosis synergistic therapy induced by FeGd-HN@TA-Fe2+-SN38 are demonstrated by the in vivo investigations on the 4T1 tumor-bearing mice. The mechanisms of in vivo immunoferroptosis synergistic therapy by FeGd-HN@TA-Fe2+-SN38 are demonstrated by measurements of in vivo ROS, LPO, GPX4 and SLC7A11 levels, the intratumor matured DCs and CD8+ T cells, the protein expresion of STING and IRF-3, and the secretion of IFN-ß and IFN-γ.

An AND Logic Gate for Magnetic-Resonance-Imaging-Guided Ferroptosis Therapy of Tumors.

To improve the magnetic resonance imaging (MRI) efficiency and ferroptosis therapy efficacy of exceedingly small magnetic iron oxide nanoparticles (IO, <5 nm) for tumors via enhancing the sensitivity of tumor microenvironment (TME) responsiveness, inspired by molecular logic gates, a self-assembled IO with an AND logic gate function is designed and constructed. Typically, cystamine (CA) is conjugated onto the end of poly(2-methylthio-ethanol methacrylate) (PMEMA) to generate PMEMA-CA. The PMEMA-CA is grafted onto the surface of brequinar (BQR)-loaded IO to form IO-BQR@PMEMA. The self-assembled IO-BQR@PMEMA (SA-IO-BQR@PMEMA) is obtained due to the hydrophobicity of PMEMA. The carbon-sulfur single bond of PMEMA-CA can be oxidized by reactive oxygen species (ROS) in the TME to a thio-oxygen double bond, resulting in the conversion from being hydrophobic to hydrophilic. The disulfide bond of PMEMA-CA can be broken by the glutathione (GSH) in the TME, leading to the shedding of PMEMA from the IO surface. Under the dual actions of ROS and GSH in TME (i.e., AND logic gate), SA-IO-BQR@PMEMA can be disassembled to release IO, Fe2+/3+ , and BQR. In vitro and in vivo results demonstrate the AND logic gate function and mechanism, the high T1 MRI performance and exceptional ferroptosis therapy efficacy for tumors, and the excellent biosafety of SA-IO-BQR@PMEMA.

Altered Effective Connectivity of Resting-State Networks by Tai Chi Chuan in Chronic Fatigue Syndrome Patients: A Multivariate Granger Causality Study.

Numerous evidence has shown that patients with chronic fatigue syndrome (CFS) have changes in resting brain functional connectivity, but there is no study on the brain network effect of Tai Chi Chuan intervention in CFS. To explore the influence of Tai Chi Chuan exercise on the causal relationship between brain functional networks in patients with CFS, 21 patients with CFS and 19 healthy controls were recruited for resting-state functional magnetic resonance imaging (rs-fMRI) scanning and 36-item Short-Form Health Survey (SF-36) scale assessment before and after 1month-long training in Tai Chi Chuan. We extracted the resting brain networks using the independent component analysis (ICA) method, analyzed the changes of FC in these networks, conducted Granger causality analysis (GCA) on it, and analyzed the correlation between the difference causality value and the SF-36 scale. Compared to the healthy control group, the SF-36 scale scores of patients with CFS were lower at baseline. Meanwhile, the causal relationship between sensorimotor network (SMN) and default mode network (DMN) was weakened. The above abnormalities could be improved by Tai Chi Chuan training for 1 month. In addition, the correlation analyses showed that the causal relationship between SMN and DMN was positively correlated with the scores of Role Physical (RP) and Bodily Pain (BP) in CFS patients, and the change of causal relationship between SMN and DMN before and after training was positively correlated with the change of BP score. The findings suggest that Tai Chi Chuan is helpful to improve the quality of life for patients with CFS. The change of Granger causality between SMN and DMN may be a readout parameter of CFS. Tai Chi Chuan may promote the functional plasticity of brain networks in patients with CFS by regulating the information transmission between them.

Tai Chi postural training for dyskinesia rehabilitation: a study protocol for a randomised controlled trial in convalescent ischaemic stroke patients.

INTRODUCTION: Acute ischaemic stroke (AIS) is not only seriously damaging to the physical and mental health of patients, but also has become a major social public health problem. Effective dyskinesia rehabilitation treatment in convalescence is of great significance for AIS patients' prognosis and quality of life. Tai Chi (TC) shows great potential in improving motor function. This trial aims to evaluate the clinical efficacy of modified TC postural training (TPT), and to explore the related central-peripheral neurotransmitter mechanisms. METHODS/DESIGN: The proposed study will be a multicentre randomised controlled trial. The trial will randomise 120 eligible AIS patients in a 1:1 ratio to receive TPT or Bobath rehabilitation training. Each training session will last 40 min and will be implemented once a day and five times per week (from Monday to Friday) in a duration of 4 weeks. After finishing the 4-week treatment, another 3-month follow-up period will be seen. Root mean square generated from the surface electromyogram (sEMG) will be the primary outcome. Other sEMG time-domain parameters and frequency-domain parameters and clinical scales assessment will be the secondary outcomes. Peripheral blood samples will be collected at baseline and at the end of 4-week treatment, which will be used to explore the related therapeutic mechanisms. Intention-to-treat analysis and per-protocol analysis will both be implemented in this trial. ETHICS AND DISSEMINATION: The study has been approved by Ethics Committee of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, being granted approval numbers DZMEC-KY-2020-22. The research results will be disseminated through (open access) peer-reviewed publications and presentations at conferences. TRIAL REGISTRATION NUMBER: ChiCTR2000032999.

Peony and licorice decoction fumigation treatment for strephenopodia after stroke: Study protocol for a randomized controlled pilot trial.

BACKGROUND: As one of the most common functional disabilities in stroke patients with hemiplegia, poststroke strephenopodia (PSS) seriously affects the life quality of patients, and causes mental and emotional disorders. Some studies have suggested that the traditional Chinese medicine fumigation therapy could be an effective intervention method for patients with PSS. This study aims to investigate the biomechanical effect of the classic prescription peony and licorice decoction (PLD) fumigation treatment for PSS. METHODS/DESIGN: This study is a multicenter, randomized, placebo-controlled, double blind trial. A total of 190 patients with PSS according to the inclusion criteria will be recruited in 3 centers and randomly distributed to either the intervention group or the control group in a 1:1 ratio. The intervention group will receive PLD fumigation treatment, while the control group will receive placebo fumigation treatment. All patients will receive standardized modern rehabilitation treatment according to the "Chinese Guidelines for Stroke Rehabilitation" (2011 version). The primary outcome measure is medial plantar area (Metatarsal 1+ Metatarsal 2 + Heel Medial) generating from the RSSCAN gait system. The secondary outcome measures contain the scores of clinical scales including Berg Balance Scale, Fugl-Meyer Assessment, Modified Ashworth Scale, Barthel Index, and Stroke-Specific Quality of Life Scale. All assessments will be implemented at baseline, 4 weeks after intervention and at the end of 3 months' follow-up. Intention-to-treat analysis and per-protocol analysis will be applied in this trial. DISCUSSION: The results of this study are expected to verify the clinical effect of PLD fumigation treatment for strephenopodia after stroke, and to explore the related biomechanical mechanisms by objective evaluation parameter. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000032433. Registered on 28 April 2020. http://www.chictr.org.cn/showprojen.aspx?proj=52644.

The effect and biomechanical mechanisms of intradermal needle for post-stroke hemiplegia recovery: Study protocol for a randomized controlled pilot trial.

The incidence of stroke has increased significantly in recent years. Post-stroke hemiplegia is a common stroke complication with long-term negative consequences. Several studies have suggested that acupuncture could be an effective intervention for the rehabilitation of post-stroke hemiplegia. Intradermal needling is a kind of acupuncture which is widely used in clinical settings. This study attempts to investigate the biomechanical effects of intradermal needle for post-stroke hemiplegia recovery.This proposed study is a single-centered, prospective, single-blinded (patient-assessor-blinded), randomized clinical pilot trial involving 40 patients with post-stroke hemiplegia. Patients will be randomized to an experimental group or control group in a 1:1 ratio. All of them will receive conventional rehabilitation therapies. Patients in the experimental group will be treated with intradermal needle, whereas patients in the control group will receive sham intradermal needle. The primary outcome measures will be biomechanically validated from the parameters of RSSCAN gait system: plantar pressure distribution, step length, and stride. The scores of clinical scales such as National Institutes of Health Stroke Scale, Fugl-Meyer Assessment, Berg Balance Scale, Barthel Index, and Stroke-specific Quality of Life Scale will be assessed as secondary outcome measures. All assessments will be conducted at baseline, 4 weeks after intervention and at the end of 3 months' follow-up.The purpose of this study is to explore the potential effect and biomechanical mechanisms of intradermal needle for post-stroke hemiplegia recovery, as well as to provide a basis for future larger clinical studies.

Effect of Tai Chi for post-stroke mental disorders and sleep disorders: A protocol for systematic review and meta-analysis.

BACKGROUND: Post-stroke mental disorders (PSMDs) and post-stroke sleep disorders (PSSDs) are very common in stroke patients. Recently, Tai Chi (TC) as a form of Chinese traditional mind-body exercise has been gradually applied to stroke rehabilitation although its efficacy for PSMD and PSSD varies across different studies. The aim of this study is to explore the therapeutic effect of TC training for PSMD and PSSD. METHODS: This review will only include randomized controlled trials (RCTs). Search strategy will be performed in 3 English databases, 4 Chinese databases, and the WHO International Clinical Trials Registry Platform. All English or Chinese RCTs, published from inception to February 28, 2019, will be sought. Two reviewers will screen, select studies, extract data, and assess quality independently. Primary outcomes are clinical scales, mainly including "Hamilton depression scale," "Hamilton anxiety scale," and "Pittsburgh sleep quality index." The methodological quality including the risk of bias of the included studies will be evaluated using a modified assessment form, which is based on Cochrane assessment tool and Physiotherapy Evidence Database scale. Review Manager Software (Revman5.3) will be used for heterogeneity assessment, generating funnel-plots, data synthesis, subgroup analysis, and sensitivity analysis. We will use GRADE system to evaluate the quality of our evidence. RESULTS: We will provide some more practical and targeted results investigating the effect of TC exercise for PSMD and PSSD in the current meta-analysis. Meanwhile, we will ascertain study progress of TC for PSMD and PSSD and find out defects or inadequacies of previous studies, so that future researchers could get beneficial guidance for more rigorous study. CONCLUSION: The stronger evidence about TC's rehabilitative effect and safety for PSMD and PSSD will be provided for clinicians and policymakers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018106608. ETHICS AND DISSEMINATION: We do not apply for formal ethical approval from ethics committee because all of the study data in our review will be obtained in an anonymous way. Findings of this study are projected to be disseminated through peer-review publications.

Tai Chi for Stroke Rehabilitation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Stroke is a major cause of poor health and has numerous complications. Tai Chi (TC) may have positive effects on the rehabilitation of stroke survivors, but recent clinical findings have not been included in previously published reviews. Objectives: We conducted this systematic review and meta-analysis to determine the effectiveness of all types of TC vs. conventional rehabilitation therapy for all aspects of stroke survivors' rehabilitation that have been studied. Method: We searched seven electronic literature databases (three in English, four in Chinese) and one clinical registry platform using established strategies to identify randomized controlled trials performed up to October 2017. Screening, quality assessment, and data collection were performed by two researchers separately, using the same standard. The results were analyzed using RevMan 5.3.0. The quality of evidence was evaluated with GRADEpro. Results: A total of 21 studies with 1,293 stroke survivors met inclusion criteria; 14 were included in the quantitative synthesis to evaluate four aspects and five outcomes. Nine studies indicated that TC was able to improve independent activities of daily living (ADL), especially TC vs. conventional rehabilitation therapy [mean difference (MD) [95% confidence interval (CI)] = 9.92 [6.82, 13.02], P < 0.00001]. Five studies reported significant effects of TC plus conventional rehabilitation therapy in increasing scores on the Fugl-Meyer Assessment for the upper limb [MD (95%CI) = 8.27 [4.69, 11.84], P < 0.0001], lower limb [MD (95%CI) = 2.75 [0.95, 4.56], P = 0.003], and overall [MD (95%CI) = 4.49 [1.92, 7.06], P = 0.0006]. The Berg Balance Scale revealed significant improvements according to pooled estimates for TC vs. conventional rehabilitation therapy [MD (95%CI) = 5.23 [3.42, 7.05], P < 0.00001]. TC plus conventional rehabilitation therapy also improved walking ability as measured by the Holden scale [MD (95%CI) = 0.61 [0.38, 0.85], P < 0.00001] and up-and-go time [MD (95%CI) = 2.59 [1.76, 3.43], P < 0.00001]. Conclusion: TC has an overall beneficial effect on ADL, balance, limb motor function, and walking ability among stroke survivors, based on very low-quality evidence, and may also improve sleep quality, mood, mental health, and other motor function. Well-designed, higher-quality trials with longer-term follow-up periods are needed to develop better-quality evidence.

Fabricating 3D Macroscopic Graphene-Based Architectures with Outstanding Flexibility by the Novel Liquid Drop/Colloid Flocculation Approach for Energy Storage Applications.

Inspired by "water ripples" in nature and the flocculation phenomenon in colloid chemistry, a novel liquid drop/colloid flocculation approach is developed to fabricate an extremely flexible and compressible 3D macroscopic graphene-based architecture (hydrogels or aerogels), via a new coagulation-induced self-assembly mechanism. This facile and universal technique can be achieved in a neutral, acidic, or basic coagulation bath, producing microsized hydrogels with various structures, such as mushroom, circle, disc shapes, etc. The method also allows us to introduce various guest materials in the graphene matrix using transition metal salts as the coagulating bath. A mushroom-shaped NiCo oxide/GS hybrid aerogel (diameter: 3 mm) is prepared as an example, with ultrathin NiCo oxide nanosheets in situ grown onto the surface of graphene. By employing as binder-free electrodes, these hybrid aerogels exhibit a specific capacitance of 858.3 F g-1 at 2 A g-1, as well as a good rate capability and cyclic stability. The asymmetric supercapacitor, assembling with the hybrid aerogels as cathode and graphene hydrogels as anode materials, could deliver an energy density of 21 Wh kg-1 at power density of 4500 W kg-1. The ease of synthesis and the feasibility of obtaining highly flexible aerogels with varied morphologies and compositions make this method a promising one for use in the field of biotechnology, electrochemistry, flexible electronics, and environment applications.

[Clinical research of effect of Yishen Yangnao capsule on vascular dementia].

OBJECTIVE: To find a good way to diagnose VD, value the effect of Yishen Yangnao capsule on VD and try to find some rules of changes in Chinese medicine syndromes. METHOD: Patients were randomly divided into treating group and western medicine comparison group. It's the phase III clinical research of Rishen Yangnao capsule curing VD, judging the validity and security of it, using dukexi slice as comparison drug. Some of the patients did the examination of P300. RESULT: The total validity of Yishen Yangnao capsule is 56.3% (contract team is 60.0%). The improve rate of ADL is 0.1069% (contract team is 0.1134%). The scores of Chinese medicine syndrome descend. CONCLUSION: Yishen Yangnao capsule has the same effect as dukexi slice in curing VD at the side of intelligence situation and life ability.

Tai Chi for stroke rehabilitation: protocol for a systematic review.

INTRODUCTION: Stroke is a major cause of death and disability, and imposes a huge burden and significant workload for patients, their families and society. As a special form of physical activity, Tai Chi is may be useful for stroke rehabilitation. The objective of this review is to systematically evaluate the efficacy and safety of Tai Chi for rehabilitation in stroke patients. METHODS AND ANALYSIS: We will conduct a systematic search of the following electronic databases from their inception to 31 October 2015: MEDLINE, EMBASE, the Cochrane Library, the Chinese BioMedical Literature Database (CBM), the Chinese National Knowledge Infrastructure (CNKI), the Chinese Science and Technology Periodical Database (VIP), Wanfang and the Chinese Dissertation Database. All relevant randomised controlled trials (RCTs) in English and Chinese will be included. The main outcomes will be changes in the neurological function of patients and in independence in activities of daily living. Adverse events, adherence, costs and the cost effectiveness of Tai Chi will also be assessed. Two independent reviewers will select studies, extract data and assess quality. Review Manager 5.3 will be used for assessment of risk of bias, data synthesis and subgroup analysis. ETHICS AND DISSEMINATION: This systematic review does not require formal ethical approval because all data will be analysed anonymously. Results will provide a general overview and evidence concerning the efficacy and safety of Tai Chi for stroke rehabilitation. Findings will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: CRD42015026999.