Microvascularized tumor assembloids model for drug delivery evaluation in colorectal cancer-derived peritoneal metastasis.

Peritoneal metastasis (PM) is a fatal state of colorectal cancer, and only a few patients may benefit from systemic chemotherapy. Although hyperthermic intraperitoneal chemotherapy (HIPEC) brings hope for affected patients, the drug development and preclinical evaluation of HIPEC are seriously lagging behind, mainly due to the lack of an ideal in vitro PM model that makes drug development over-reliant on expensive and inefficient animal experiments. This study developed an in vitro colorectal cancer PM model [microvascularized tumor assembloids (vTA)] based on an assembly strategy of endothelialized microvessels and tumor spheroids. Our data showed that the in vitro perfusion cultured vTA could maintain a similar gene expression pattern to their parental xenografts. Also, the drug penetration pattern of the in vitro HIPEC in vTA could mimic the drug delivery behavior in tumor nodules during in vivo HIPEC. More importantly, we further confirmed the feasibility of constructing a tumor burden-controlled PM animal model using vTA. In conclusion, we propose a simple and effective strategy to construct physiologically simulated PM models in vitro, thus providing a basis for PM-related drug development and preclinical evaluation of locoregional therapies. STATEMENT OF SIGNIFICANCE: This study developed an in vitro colorectal cancer peritoneal metastasis (PM) model based on microvascularized tumor assembloids (vTA) for drug evaluation. With perfusion culture, vTA could maintain a similar gene expression pattern and tumor heterogeneity to their parental xenografts. And the drug penetration pattern in vTA was similar to the drug delivery behavior in tumor nodules under in vivo treatment. Moreover, vTA was more conducive to construct PM animal models with controllable tumor burden. In conclusion, the construction of vTA could provide a new strategy for the PM-related drug development and preclinical evaluation of locoregional therapies.

Lycopene-loaded emulsions stabilized by whey protein covalently modified with pectin or/and chlorogenic acid: Enhanced physicochemical stability and reduced bio-accessibility.

Lycopene-loaded emulsions were formulated with whey protein isolate (WPI) covalently modified with high methoxylated pectin (HMP) or/and chlorogenic acid (CA) prepared by dry heating or/and alkali grafting. Covalent WPI products were confirmed by SDS-PAGE and degree of graft/CA binding equivalent values. The α-helix and ß-sheet percentage, surface hydrophobicity and fluorescence intensity of WPI decreased significantly (p < 0.05) upon binding. Both binary and ternary complexes enhanced the stability of the emulsions, and lycopene retained more after UV irradiation, thermal treatment, storage, compared with emulsions stabilized by WPI, with the best protection by both ternary complexes. In vitro simulated digestion results showed that free fatty acids were released in the order of WPI > WPI-HMP > WPI-CA > WPI-HMP-CA ≈ WPI-CA-HMP. Bio-accessibility analysis showed the same trend as the fatty acid release rate. These results may provide a theoretical basis for applications of conjugating protein with polysaccharide or/and polyphenol emulsions.

Surface programmed bacteria as photo-controlled NO generator for tumor immunological and gas therapy.

The use of bacteria as living vehicles has attracted increasing attentions in tumor therapy field. The combination of functional materials with bacteria dramatically facilitates the antitumor effect. Here, we presented a rationally designed living system formed by programmed Escherichia Coli MG1655 cells (Ec) and black phosphorus (BP) nanoparticles (NPs). The bacteria were genetically engineered to express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), via an outer membrane YiaT protein (Ec-T). The Ec-T cells were associated with BP NPs on their surface to acquire BP@Ec-T. The designed living system could transfer the photoelectrons produced by BP NPs after laser irradiation and triggered the reductive metabolism of nitrate to nitric oxide for the in situ release at tumor sites, facilitating the therapeutic efficacy and the polarization of tumor associated macrophages to M1 phenotype. Meanwhile, the generation of reactive oxygen species induced the immunogenic cell death to further improve the antitumor efficacy. Additionally, the living system enhanced the immunological effect by promoting the apoptosis of tumor cells, activating the effect of T lymphocytes and releasing the pro-inflammatory cytokines. The integration of BP NPs, MG1655 cells and TRAIL led to an effective tumor therapy. Our work established an approach for the multifunctional antitumor living therapy.

Effects of Acupuncture Combined with Biofeedback Therapy on Limb Motor Rehabilitation in Patients with Acute Stroke: Systematic Review and Meta-Analysis.

Objective: The purpose of the systematic review is to verify the effect of biofeedback therapy on limb motor rehabilitation in patients with acute stroke and to provide evidence-based medicine for the promotion and use of biofeedback therapy. Methods: The randomized controlled trials (RCT) of biofeedback therapy in the treatment of cerebral palsy were searched in PubMed, EMBASE, ScienceDirect, Cochrane Library, China National Knowledge Infrastructure (CNKI), China VIP Database, Wanfang Database, and Chinese Biomedical Literature Database (CBM). The starting time and ending time of this study are from the time of building the database of the number of pieces to October 31, 2018. The data included in this study were extracted by two independent researchers and evaluated the bias risk of all the literature included in the study according to the Cochrane manual 5.1.0 criteria. RevMan5.4 statistical software was used to analyze the collected data by meta. Results: This systematic review included 9 RCT studies with a total of 1410 patients. The results of meta-analysis showed that there were significant differences in the improvement of lower limb muscle tension, comprehensive spasm scale score, EMG score, and passive range of motion of ankle joint between biofeedback therapy and routine rehabilitation therapy. Conclusion: Biofeedback therapy can improve lower limb muscle tension, spasticity, EMG integral value, and passive range of motion of ankle joint in children with cerebral palsy and provide better conditions for improving the motor ability of lower extremities in children with cerebral palsy. However, more studies and follow-up with higher methodological quality and longer intervention time are needed to further verify.

Injectable Black Phosphorus Nanosheets for Wireless Nongenetic Neural Stimulation.

Neurons can be modified to express light-sensitive proteins for enabling stimulation with a high spatial and temporal resolution, but such techniques require gene transfection and systematical implantation. Here, a black phosphorus nanosheet-based injectable strategy is described for wireless neural stimulation both in vitro and in vivo without cell modifications. These nanosheets, with minimal invasiveness, high biocompatibility, and biodegradability, are anchored on cell membranes as miniature near-infrared (NIR) light transducers to create local heating for neural activity excitation. Based on cultured multielectrode-array recording, in vivo electrophysiology analysis, and open field behavioral tests, it is demonstrated that remotely applied NIR illumination can reliably trigger spiking activity in cultured neurons and rat brains. Excitingly, reliable regulation of brain function to control animal behaviors is also described. Moreover, this approach has shown its potential for future clinical use by successful high-frequency stimulation in cells and animals in this proof-of-concept study. It is believed that this new method will offer a powerful alternative to other neural stimulation solutions and potentially be of independent value to the healthcare system.

A MXene-Based Bionic Cascaded-Enzyme Nanoreactor for Tumor Phototherapy/Enzyme Dynamic Therapy and Hypoxia-Activated Chemotherapy.

The enzyme-mediated elevation of reactive oxygen species (ROS) at the tumor sites has become an emerging strategy for regulating intracellular redox status for anticancer treatment. Herein, we proposed a camouflaged bionic cascaded-enzyme nanoreactor based on Ti3C2 nanosheets for combined tumor enzyme dynamic therapy (EDT), phototherapy and deoxygenation-activated chemotherapy. Briefly, glucose oxidase (GOX) and chloroperoxidase (CPO) were chemically conjugated onto Ti3C2 nanosheets, where the deoxygenation-activated drug tirapazamine (TPZ) was also loaded, and the Ti3C2-GOX-CPO/TPZ (TGCT) was embedded into nanosized cancer cell-derived membrane vesicles with high-expressed CD47 (meTGCT). Due to biomimetic membrane camouflage and CD47 overexpression, meTGCT exhibited superior immune escape and homologous targeting capacities, which could effectively enhance the tumor preferential targeting and internalization. Once internalized into tumor cells, the cascade reaction of GOX and CPO could generate HClO for efficient EDT. Simultaneously, additional laser irradiation could accelerate the enzymic-catalytic reaction rate and increase the generation of singlet oxygen (1O2). Furthermore, local hypoxia environment with the oxygen depletion by EDT would activate deoxygenation-sensitive prodrug for additional chemotherapy. Consequently, meTGCT exhibits amplified synergistic therapeutic effects of tumor phototherapy, EDT and chemotherapy for efficient tumor inhibition. This intelligent cascaded-enzyme nanoreactor provides a promising approach to achieve concurrent and significant antitumor therapy.

Multifunctional FeS2@SRF@BSA nanoplatform for chemo-combined photothermal enhanced photodynamic/chemodynamic combination therapy.

Combination therapy has been widely studied due to its promising applications in tumor therapy. However, a sophisticated nanoplatform and sequential irradiation with different laser sources for phototherapy complicate the treatment process. Unlike the integration of therapeutic agents, we report a FeS2@SRF@BSA nanoplatform for the combination of chemo-combined photothermal therapy (PTT) enhanced photodynamic therapy (PDT) and chemodynamic therapy (CDT) to achieve an "all-in-one" therapeutic agent. Ultrasmall FeS2 nanoparticles (NPs) with a size of 7 nm exhibited higher Fenton reaction rates due to their large specific surface areas. A photodynamic reaction could be triggered and could generate 1O2 to achieve PDT under 808 nm irradiation. FeS2 NPs also exhibited the desired photothermal properties under the same wavelength of the laser. The Fenton reaction and photodynamic reaction were both significantly improved to accumulate more reactive oxygen species (ROS) with an increase of temperature under laser irradiation. Besides, loading of the chemotherapeutic drug sorafenib (SRF) further improved the efficacy of tumor treatment. To realize long blood circulation, bovine serum albumin (BSA) was used as a carrier to encapsulate FeS2 NPs and SRF, remarkably improving the biocompatibility and tumor enrichment ability of the nanomaterials. Additionally, the tumors on mice treated with FeS2@SRF@BSA almost disappeared under 808 nm irradiation. To sum up, FeS2@SRF@BSA NPs possess good biocompatibility, stability, and sufficient therapeutic efficacy in combination therapy for cancer treatment. Our study pointed out a smart design of the nanoplatform as a multifunctional therapeutic agent for combination cancer therapy in the near future.

Functionalized 2D Nb2C nanosheets for primary and recurrent cancer photothermal/immune-therapy in the NIR-II biowindow.

Near-infrared-II (NIR-II) cancer photothermal therapy (PTT) has become more and more attractive as the NIR-II light shows a higher tissue penetrating depth, which leads to better anti-cancer effects. Recently, the members of the MXene family have been reported as NIR-II photothermal agents, possessing a high specific surface area and a fascinating light-to-heat conversion rate at the same time. Herein, we reported a combination of NIR-II photothermal therapy and immune therapy based on the MXene family member niobium carbide (Nb2C). First, Nb2C nanosheets (NSs) under 50 nm were prepared. They showed a high photothermal conversion efficiency under a 1064-nm laser, and the NIR-II light showed a deeper tissue penetration depth. Then, a nanoplatform with high R837 stability and a high loading rate was obtained after modification with a polydopamine (PDA) layer on the surface of Nb2C. With the R837 modification, the percentage of mature dendritic cells (DCs) increased and the immune response enhanced, compared with the immune response caused by PTT only. Finally, a red blood cell (RBC) membrane was applied as a coat over the nanoplatform in order to avoid excessive blood clearance. During in vivo experiments, blood circulation of Nb2C@PDA-R837@RBC nanoparticles (NPs) was prolonged, and all primary tumors were eliminated. Secondary tumors were also inhibited effectively due to the strengthened immune response, proving that Nb2C@PDA-R837@RBC NPs could inhibit tumor recurrence. All the results above indicated Nb2C@PDA-R837@RBC NPs as a potential RBC camouflaged nanoplatform for the combination of effective PTT and immune therapy towards tumor treatment.

Icariin ameliorates the cognitive function in an epilepsy neonatal rat model by blocking the GluR2/ERK I/II pathway.

The present study was performed to evaluate the protective effects of icariin on cognitive function in a hypoxia-induced neonatal epilepsy rat model. Neonatal epilepsy was induced in rat pups on postnatal day (PD) 20 by induction of hypoxia for 15 minutes. Rats were treated intraperitoneally with icariin at 75 mg/kg 1 hour before the induction of hypoxia. The effects of icariin were examined by estimating seizure stage, cognitive function and parameters of electroencephalography (EEG) in this neonatal epilepsy rat model. Parameters of oxidative stress and expression of proteins were examined in the brain tissue of the neonatal epilepsy rat model by histopathological study and Western blotting analysis, respectively. The results of this study suggest that treatment with icariin ameliorates the changes in seizure stage, number of seizures and parameters of EEG in hypoxia-induced neonatal epilepsy rats. Oxidative stress and apoptosis were decreased in the brain tissue of the icariin treatment group compared to the hypoxia group. Moreover, treatment with icariin ameliorated the altered expression of glutamate ionotropic receptor AMPA type subunit 2 (GluR2) and extracellular receptor kinase (ERK I/II) proteins in the brain tissue of hypoxia-induced epilepsy rats. Histopathological study also showed that icariin treatment improved the histopathology of brain tissue of hypoxia-induced epilepsy rats. In conclusion, the results of the present study suggest that icariin protects against neuronal injury and improves cognitive function in hypoxia-induced neonatal epilepsy rats by modulating the GluR2/ERK I/II pathway.

A stepwise control strategy for glutathione synthesis in Saccharomyces cerevisiae based on oxidative stress and energy metabolism.

A stepwise control strategy for enhancing glutathione (GSH) synthesis in yeast based on oxidative stress and energy metabolism was investigated. First, molasses and corn steep liquor were selected and fed as carbon source mixture at a flow rate of 1.5 g/L/h and 0.4 g/L/h, respectively, for increasing cell density in a 10 L fermenter. When the biomass reached 90 g/L, the KMnO4 sustained-release particles, composed of 1.5% KMnO4, 3% stearic acid, 2% polyethylene glycol and 3% agar powder, were prepared and added to the fermentation broth for maintaining the oxidative stress. The results showed that the maximum GSH accumulation of the group fed KMnO4 sustained-release particles was 39.0% higher than that of KMnO4-fed group. In addition to the improved average GSH productivity and average specific production rate, the activities of GSH peroxidase, γ-glutamylcysteine synthetase and GSH reductase, enzymes taking part in GSH metabolism, were also significantly enhanced by KMnO4 sustained-release particles feeding. Finally, 6 g/L sodium citrate fed as an energy adjuvant elevated the intracellular ATP level for further enhancing GSH production. Through the above stepwise strategy, the GSH accumulation reached 5.76 g/L, which was 2.84-fold higher than that of the control group. The stepwise control strategy based on oxidative stress and energy metabolism significantly improved GSH accumulation in yeast.

NIR light-induced tumor phototherapy using photo-stable ICG delivery system based on inorganic hybrid.

NIR responsive inorganic hybrid (Ti@GO) was synthesized. It could absorb NIR light and convert it into local hyperthermia and ROS synchronously. Ti@GO was firstly developed as a photosensitizer and a photothermal agent to realize tumor PTT and PDT. For anti-tumor application, HA was grafted on Ti@GO simultaneously as water solubility improver and tumor targeting moiety. ICG was chosen as a model drug. Results demonstrated that HA-Ti@GO could remarkably improve ICG stability and drug accumulation in 4T1 cells, enhance tumor phototherapy efficiency and reduce light-associated side effects. HA-Ti@GO/ICG under NIR laser irradiation showed a significant decreased cell viability of 20.7±2.6% and a high DNA damage degree of 82.4±8.3%. Moreover, in vivo results showed that HA-Ti@GO/ICG plus NIR laser achieved almost complete tumor regression on 4T1 tumor-bearing mice, with a tumor volume of 67.0 mm3. Taken together, our study provided a promising strategy to realize synergistic PTT/PDT tumor therapy with a single NIR light.

In vitro and in vivo chemo-phototherapy of magnetic TiO2 drug delivery system formed by pH-sensitive coordination bond.

To achieve tumor-specific delivery of doxorubicin, TiO2@Fe3O4/PEI/delivery of doxorubicin conjugates were designed and synthesized. Fe3O4 could act as magnetically responsive carriers and enhance the visible light photodynamic activities of TiO2 Delivery of doxorubicin was conjugated via coordination bond. The drug release rate at pH 5.2 was much faster than that at pH 7.4, due to pH-sensitive coordination bond. Besides, TiO2@Fe3O4/PEI/delivery of doxorubicin showed high antitumor efficacy combining with phototherapy, good bio-safety, higher cellular uptake with an external magnetic field, and less toxicity in vitro and in vivo. These results suggested that TiO2@Fe3O4/PEI/delivery of doxorubicin may be promising for high tumor treatment efficacy with minimal side effects in future.

A multi-functional nanoplatform for tumor synergistic phototherapy.

Phototherapy, which mainly includes photothermal treatment (PTT) and photodynamic treatment (PDT), is a photo-initiated, noninvasive and effective approach for cancer treatment. The high accumulation of photosensitizers (PSs) in a targeted tumor is still a major challenge for efficient light conversion, to generate reactive oxygen species (ROS) and local hyperthermia. In this study, a simple and efficient hyaluronic acid (HA)-modified nanoplatform (HA-TiO2@MWCNTs) with high tumor-targeting ability, excellent phototherapy efficiency, low light-associated side effects and good water solubility was developed. It could be an effective carrier to load hematoporphyrin monomethyl ether (HMME), owing to the tubular conjugate structure. Apart from this, the as-prepared TiO2@MWCNTs nanocomposites could also be used as PSs for tumor PTT and PDT. Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly better than those of single treatment manner. In addition, this drug delivery system could realize high ratio of drug loading, sustained drug release, prolonged circulation in vivo and active targeted accumulation in tumor. These results suggest that HA-TiO2@MWCNTs/HMME has high potential for tumor synergistic phototherapy as a smart theranostic nanoplatform.

An improved Physarum polycephalum algorithm for the shortest path problem.

Shortest path is among classical problems of computer science. The problems are solved by hundreds of algorithms, silicon computing architectures and novel substrate, unconventional, computing devices. Acellular slime mould P. polycephalum is originally famous as a computing biological substrate due to its alleged ability to approximate shortest path from its inoculation site to a source of nutrients. Several algorithms were designed based on properties of the slime mould. Many of the Physarum-inspired algorithms suffer from a low converge speed. To accelerate the search of a solution and reduce a number of iterations we combined an original model of Physarum-inspired path solver with a new a parameter, called energy. We undertook a series of computational experiments on approximating shortest paths in networks with different topologies, and number of nodes varying from 15 to 2000. We found that the improved Physarum algorithm matches well with existing Physarum-inspired approaches yet outperforms them in number of iterations executed and a total running time. We also compare our algorithm with other existing algorithms, including the ant colony optimization algorithm and Dijkstra algorithm.

Literature study on clinical treatment of facial paralysis in the last 20 years using Web of Science: Comparison between rehabilitation, physiotherapy and acupuncture.

BACKGROUND: Facial paralysis is defined as severe or complete loss of facial muscle motor function. OBJECTIVE: The study was undertaken to explore a bibliometric approach to quantitatively assess the research on clinical treatment of facial paralysis using rehabilitation, physiotherapy and acupuncture using Web of Science from 1992 to 2011. DESIGN: Bibliometric approach. DATA RETRIEVAL: A bibliometric analysis based on the publications on Web of Science was performed using key words such as "facial paralysis", "rehabilitation", "physiotherapy" and "acupuncture". INCLUSIVE CRITERIA: (1) Research articles on the clinical treatment of facial paralysis using acupuncture or physiotherapy (e.g. exercise, electro-stimulation) and other rehabilitation methods; (2) researches on human and animal fundamentals, clinical trials and case reports; (3) Article types: article, review, proceedings paper, note, letter, editorial material, discussion, book chapter. (4) Publication year: 1992-2011 inclusive. EXCLUSION CRITERIA: (1) Articles on the causes and diagnosis on facial paralysis; (2) Type of articles: correction; (3) Articles from following databases: all databases related to social science and chemical databases in Web of Science. MAIN OUTCOME MEASURES: (1) Overall number of publications; (2) number of publications annually; (3) number of citations received annually; (4) top cited paper; (5) subject categories of publication; (6) the number of countries in which the article is published; (7) distribution of output in journals. RESULTS: Overall population stands at 3 543 research articles addressing the clinical treatment of facial paralysis in Web of Science during the study period. There is also a markedly increase in the number of publications on the subject "facial paralysis treatments using rehabilitation" during the first decade of the 21(st) century, except in 2004 and 2006 when there are perceptible drops in the number of articles published. The only other year during the study period saw such a drop is 1993. Specifically, there are 192 published articles on facial paralysis treated by rehabilitation in the past two decades, far more than the output of physiotherapy treatment. Physiotherapy treatment scored only 25 articles including acupuncture treatment, with over 80% of these written by Chinese researchers and clinicians. Ranked by regions, USA is by far the most productive country in terms of the number of publications on facial paralysis rehabilitation and physiotherapy research. Seeing from another angle, the journals that focus on otolaryngology published the most number of articles in rehabilitation and physiotherapy studies, whereas most acupuncture studies on facial paralysis were published in the alternative and complementary medicine journals. CONCLUSION: Study of facial paralysis remains an area of active investigation and innovation. Further clinical studies in humans addressing the use of growth factors or stem cells continue to successful facial nerve regeneration.