Effectiveness of exosome mediated miR-126 and miR-146a delivery on cardiac tissue regeneration.

Despite advances in the treatment of acute myocardial infarction, due to the non-proliferative nature of adult cardiomyocytes, the injured myocardium is mainly replaced by fibrotic tissue, which ultimately causes heart failure. To prevent heart failure, particularly after myocardial infarction, exosome-based therapy has emerged as one of the most promising strategies to regenerate cardiac function. Exosomes can carry microRNAs in support of neovascularization, anti-inflammatory, and endogenous cardiac regeneration. This study demonstrated that animal rat models' combination treatment with microRNA-126 and microRNA-146a mimics in exosomes is desirable for cardiac regeneration after myocardial infarction. The exosomes isolated from stem cells and loaded with microRNAs were characterized their impacts in cell migration, tube formation, and vascular endothelial growth factor degree. In the following, the usefulness of loaded microRNAs in exosomes and their encapsulation within alginate derivative hydrogel was analyzed in myocardial infarction for an animal model. Exosomes isolated and loaded with microRNAs showed the synergetic impact on cell migration, tube formation, and promoted vascular endothelial growth factor folding. Moreover, microRNAs loaded exosomes and encapsulated them in alginate hydrogel could help in reducing infarct size and improving angiogenesis in myocardial infarction. The angiogenesis markers including CD31 and connexion 43 upregulated for myocardial infarction models treated with alginate-based hydrogels loaded with exosomes and microRNAs-exosomes. Histological analysis indicated that myocardial infarction model rats treated with alginate hydrogel loaded with microRNAs-exosomes possessed lower and higher degrees of fibrosis and collagen fiber, respectively. These findings have important therapeutic implications for a myocardial infarction model through angiogenesis and vascular integrity regulation.

Improvement of sciatic nerve regeneration by multichannel nanofibrous membrane-embedded electro-conductive conduits functionalized with laminin.

Multichannel structures in the design of nerve conduits offer potential advantages for regeneration of damaged nerves. However, lack of biochemical cues and electrical stimulation could hamper satisfactory nerve regeneration. The aim of this study was to simultaneously evaluate the effects of topographical, biological, and electrical cues on sciatic nerve regeneration. Accordingly, a series of multichannel nerve conduit was made using longitudinally-aligned laminin-coated poly (lactic-co-glycolic acid) (PLGA)/carbon nanotubes (CNT) nanofibers (NF, mean diameter: 455 ± 362 nm) in the lumen and randomly-oriented polycaprolactone (PCL) NF (mean diameter: 340 ± 200 nm) on the outer surface. In vitro studies revealed that the materials were nontoxic and able to promote cell attachment and proliferation on nanofibers and on fibrin gel. To determine the influence of laminin as biological and CNT as electrical cues on nerve regeneration, either of hollow PCL conduits, PLGA NF-embedded, PLGA/CNT NF-embedded or laminin-coated PLGA/CNT NF-embedded PCL conduits were implanted in rats. A new surgery method was utilized and results were compared with an autograft. The results of motor and sensory tests in addition to histopathological examination of the regenerated nerves demonstrated the formation of nerve fibers in laminin-coated PLGA/CNT NF-embedded PCL conduits. Results suggested that these conduits have the potential to improve sciatic nerve regeneration. Graphical abstract.

Microphase Arrangement of Smart Superhydrophilic Segmented Polyurethanes at Their Interface with Water.

Smart coatings have aroused a growing interest because of the performance of predefined surface functions upon reacting to external stimuli. Among them, responsive polymer coatings to water, which often benefit from the presence of a mobile hydrophilic material, are of great interest. Polyurethanes (PUs) are versatile materials with respect to the structure-property relationship. Therefore, the incorporation of hydrophilic segments in PUs is a rational way to produce water-sensitive smart coatings; however, having a considerable amount of hydrophilic material deteriorates the physical properties because of a large amount of water uptake. In this study, we have analyzed previously synthesized smart PUs, based on hydrophobic polycarbonate (PC) and hydrophilic polyethylene glycol (PEG) soft segments, in which only a limited amount of PEG is used. These coatings maintain, more or less, zero water contact angle, whereas the water uptake remains below 15 wt %. The combination of experimental analysis and coarse-grained molecular dynamics (CG MD) simulations reveals that PEG segments migrate to the coating/water interface and partially cover the surface, whereas the hydrophobic nature of the PC keeps the bulk of the coating intact when the coating is covered with water. Moreover, our CG MD simulations and experimental analysis suggest a reversible phase arrangement under wet/dry cycles on molecular and macroscopic scales.

Nanofiber-acellular dermal matrix as a bilayer scaffold containing mesenchymal stem cell for healing of full-thickness skin wounds.

Full-thickness skin defect is one of the main clinical problems, which cannot be repaired spontaneously. The aim of this study was to evaluate the feasibility of combining nanofibers with ADM as a bilayer scaffold for treatment of full-thickness skin wounds in a single-step procedure. The nanofibrous polycaprolactone/fibrinogen scaffolds were fabricated by electrospinning. Subsequently, mesenchymal stem cells were isolated from rat adipose tissues and characterized by flow cytometry. Cell adhesion, proliferation, and the epidermal differentiation potential of adipose-derived stem cells (ADSCs) on nanofibrous scaffolds were investigated by scanning electron microscopy (SEM), alamarBlue, and real-time PCR, respectively. In animal studies, full-thickness excisional wounds were created on the back of rats and treated with following groups: ADM, ADM-ADSCs, nanofiber, nanofiber-ADSCs, bilayer, and bilayer-ADSCs. In all groups, wounds were harvested on days 14 and 21 after treatment to evaluate re-epithelialization, blood vessel density, and collagen content. The results indicated that ADSCs seeded on ADM, nanofiber, and bilayer scaffolds can promote re-epithelialization, angiogenesis, and collagen remodeling in comparison with cell-free scaffolds. In conclusion, nanofiber-ADSCs showed the best results for re-epithelialization (according to histological scoring), average blood vessel density (92.7 ± 6.8), and collagen density (87.4 ± 4.9%) when compared to the control and other experimental groups.

Monitoring, mapping and health risk assessment of fluoride in drinking water supplies in rural areas of Maku and Poldasht, Iran.

The aim of this study was to investigate and determine fluoride concentrations in drinking water supplies in rural areas of Maku and Poldasht in West Azerbaijan Province, the northwest of Iran. Fluorosis risk assessment and characterization was also investigated. Fluoride concentrations mapping was accomplished by using the GIS system. Totally, 356 water samples, including one sample in each season, were collected from 89 water supplies providing water for 95 and 61 rural areas of Maku and Poldasht, respectively. According to the results, in Maku and Poldasht, 25 and 30 rural areas had contaminated water sources, respectively. Average annual fluoride concentrations ranged from 3.04 to 7.31 mg/l in the contaminated villages of Maku, which is about 2-4.8 times higher than the maximum standard level of the Iranian drinking water standard, and 4.52-8.21 mg/l in the contaminated areas of Poldasht, which is about 3-5.47 times higher than the maximum standard level. The maximum fluoride level was determined 11.12 mg/l and 10.98 mg/l in one of villages of Maku and Poldasht Counties in summer, respectively. Neither in Maku nor in Poldasht, water resources showed dental cavity risk, while dental fluorosis risk and skeletal fluorosis risk were very significant in some villages of both cities. Children were at most risk of fluorosis. New alternative water supplies for the contaminated villages if possible, consumption of bottled water and application of reverse osmosis are recommended as remedial actions in the contaminated areas.

Will Nanotechnology Bring New Hope for Stem Cell Therapy?

The potential of stem cell therapy has been shown in preclinical trials for the treatment of damage and replacement of organs and degenerative diseases. After many years of research, its clinical application is limited. Currently there is not a single stem cell therapy product or procedure. Nanotechnology is an emerging field in medicine and has huge potential due to its unique characteristics such as its size, surface effects, tunnel effects, and quantum size effect. The importance of application of nanotechnology in stem cell technology and cell-based therapies has been recognized. In particular, the effects of nanotopography on stem cell differentiation, proliferation, and adhesion have become an area of intense research in tissue engineering and regenerative medicine. Despite the many opportunities that nanotechnology can create to change the fate of stem cell technology and cell therapies, it poses several risks since some nanomaterials are cytotoxic and can affect the differentiation program of stem cells and their viability. Here we review some of the advances and the prospects of nanotechnology in stem cell research and cell-based therapies and discuss the issues, obstacles, applications, and approaches with the aim of opening new avenues for further research.

Novel electro-conductive nanocomposites based on electrospun PLGA/CNT for biomedical applications.

Electro-conductive nanocomposites have several applications in biomedical field. Development of a biocompatible electro-conductive polymeric materials is therefore of prime importance. In this study, electro-conductive nanofibrous mats of PLGA/CNT were fabricated through different methods including blend electrospinning, simultaneous PLGA electrospinning and CNT electrospraying and ultrasound-induced adsorption of CNTs on the electrospun PLGA nanofibers. The morphology and diameter of fibers were characterized by SEM and TEM, showing the lowest average diameters of 477 ± 136 nm for PLGA/MWCNT blend nanocomposites. MWCNT-sprayed PLGA specimens showed significant lower water contact angle (83°), electrical resistance (3.0 × 104 Ω) and higher mechanical properties (UTS: 5.50 ± 0.46 MPa) compared to the untreated PLGA scaffolds. Also, results of PC12 cell study demonstrated highest viability percentage on the MWCNT-sprayed PLGA nanofibers. We propose that the conductive nanocomposites have capability to use as tool for the neural regeneration and biosensors.

Fluorescent multi-responsive cross-linked P(N-isopropylacrylamide)-based nanocomposites for cisplatin delivery.

Magnetic, pH and temperature-sensitive, poly(N-isopropylacrylamide) (PNIPAM)-based nanocomposites with fluorescent properties were synthesized by free radical copolymerization-cross linking of NIPAM, N,N-dimethylaminoethyl methacrylate (DMAEMA) and 4-acrylamidofluorescein (AFA). The model anti-cancer drug, cisplatin (CDDP), was loaded into the resulted nanogel. For the production of CDDP-loaded nanocomposite, Fe3O4 magnetic nanoparticles (MNPs) and CDDP were loaded into the nanogel. Field-emission scanning electron microscopy (FE-SEM) indicated that the size of nanogel and CDDP-loaded nanocomposite were about 90 and 160 nm, respectively. The encapsulation efficiency of CCDP was found up to 65%. The loaded CCDP showed sustained thermal and pH-responsive drug release. A high level of drug release was observed under the conditions of low pH and high temperature. The lower critical solution temperature (LCST) of synthesized nanogel was about 40 °C. CDDP-loaded nanocomposite showed a volume phase transition from 282 to 128 nm at its LCST. Accordingly, in this study, the synthesized nanocomposite can be employed as a stimuli-responsive anti-cancer drug delivery system and the pH and temperature of solution have the potential to monitor the drug release.

Optimization of Self-Assembled Chitosan/Streptokinase Nanoparticles and Evaluation of Their Cytotoxicity and Thrombolytic Activity.

In this study, the enzyme streptokinase (thrombolysis agent) and chitosan (Cs) nanoparticles were prepared by self-assembly. Using experimental design, chitosan concentration, solution pH and stirring time were studied as independent variables to identify their effects on size, polydispersity index (PDI) and loading efficiency of nanoparticles. Results showed that pH and concentration have a direct effect on size. Additionally, minimum PDI was observed at lowest values of concentration and highest values of stirring time. pH-5.6 was also necessary to obtain the smallest PDI and highest loading efficiency values. The model predicted that to obtain maximum loading efficiency and minimum size along with low PDI, optimum values are 0.5 mg/mL, 5.18 and 30 min for the Cs concentration, solution pH and stirring time, respectively. The corresponding mean ± SD values for experimentally prepared nanoparticles were 43 ± 10%, 526 ± 121 nm, 0.3 ± 0.2, respectively. MTT and euglobulin clot lysis assays on the optimized nanoparticles showed that chitosan/streptokinase nanoparticles have slightly toxic effect on human fetal lung fibroblast cells (Mrc-5), compared with chitosan and streptokinase alone as a control. Also, thrombolytic activity of encapsulated streptokinase in nanoparticles is decreased slightly in comparison with free streptokinase. However, the preparation keeps a good potency for use as a thrombolytic agent in vivo.

Preparation of a nanoemulsion containing active ingredients of cannabis extract and its application for glioblastoma: in vitro and in vivo studies.

Recently, the anti-tumor effects of cannabis extract on various cancers have attracted the attention of researchers. Here, we report a nanoemulsion (NE) composition designed to enhance the delivery of two active components in cannabis extracts (∆9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)) in an animal model of glioblastoma. The efficacy of the NE containing the two drugs (NED) was compared with the bulk drugs and carrier (NE without the drugs) using the C6 tumor model in rats. Hemocompatibility factors (RBC, MCV, MCH, MCHC, RDW, PPP, PT and PTT) were studied to determine the potential in vivo toxicity of NED. The optimized NED with mean ± SD diameter 29 ± 6 nm was obtained. It was shown that by administering the drugs in the form of NED, the hemocompatibility increased. Cytotoxicity studies indicated that the NE without the active components (i.e. mixture of surfactants and oil) was the most cytotoxic group, while the bulk group had no toxicity. From the in vivo MRI and survival studies, the NED group had maximum efficacy (with ~4 times smaller tumor volume on day 7 of treatment, compared with the control. Also, survival time of the control, bulk drug, NE and NED were 9, 4, 12.5 and 51 days, respectively) with no important adverse effects. In conclusion, the NE containing cannabis extract could be introduced as an effective treatment in reducing brain glioblastoma tumor progression.

Comparison of the efficiency of ultrafiltration, precipitation, and ultracentrifugation methods for exosome isolation.

Extracellular vesicles (EVs) are enclosed by a lipid-bilayer membrane and secreted by all types of cells. They are classified into three groups: apoptotic bodies, microvesicles, and exosomes. Exosomes play a number of important roles in the intercellular communication and crosstalk between tissues in the body. In this study, we use three common methods based on different principles for exosome isolation, namely ultrafiltration, precipitation, and ultracentrifugation. We use field emission scanning electron microscopy (FESEM) and dynamic light scattering (DLS) analyses for characterization of exosomes. The functionality and effect of isolated exosomes on the viability of hypoxic cells was investigated by alamarBlue and Flow-cytometry. The results of the FESEM study show that the ultrafiltration method isolates vesicles with higher variability of shapes and sizes when compared to the precipitation and ultracentrifugation methods. DLS results show that mean size of exosomes isolated by ultrafiltration, precipitation, and ultracentrifugation methods are 122, 89, and 60 nm respectively. AlamarBlue analysis show that isolated exosomes increase the viability of damaged cells by 11%, 15%, and 22%, respectively. Flow-cytometry analysis of damaged cells also show that these vesicles increase the content of live cells by 9%, 15%, and 20%, respectively. This study shows that exosomes isolated by the ultracentrifugation method are characterized by smaller size and narrow size distribution. Furthermore, more homogenous particles isolated by this method show increased efficiency of the protection of hypoxic cells in comparison with the exosomes isolated by the two other methods.

Oxidative stress and neurodegenerative disorders.

Living cells continually generate reactive oxygen species (ROS) through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious. The central nervous system (CNS) is particularly vulnerable to oxidative stress due to its high oxygen consumption, weakly antioxidative systems and the terminal-differentiation characteristic of neurons. Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and peripheral nervous system (PNS) of cancer patients, and a growing body of evidence demonstrates the involvement of ROS in drug-induced neurotoxicities as well. Therefore, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy. In this review, we summarize the source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS. We ultimately assess the value for antioxidants as neuroprotective drugs and provide our comments on the unmet needs.

Evaluating the antioxidant potential of resveratrol-gold nanoparticles in preventing oxidative stress in endothelium on a chip.

Vascular endothelial cells play a vital role in the health and maintenance of vascular homeostasis, but hyperglycemia disrupts their function by increasing cellular oxidative stress. Resveratrol, a plant polyphenol, possesses antioxidant properties that can mitigate oxidative stress. Addressing the challenges of its limited solubility and stability, gold nanoparticles (GNps) were utilized as carriers. A microfluidic chip (MFC) with dynamic flow conditions was designed to simulate body vessels and to investigate the antioxidant properties of resveratrol gold nanoparticles (RGNps), citrate gold nanoparticles (CGNps), and free Resveratrol on human umbilical vein endothelial cells (HUVEC). The 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay was employed to measure the extracellular antioxidant potential, and cell viability was determined using the Alamar Blue test. For assessing intracellular oxidative stress, the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay was conducted, and results from both the cell culture plate and MFC were compared. Free Resveratrol demonstrated peak DPPH scavenging activity but had a cell viability of about 24-35%. RGNPs, both 3.0 ± 0.5 nm and 20.2 ± 4.7 nm, consistently showed high cell viability (more than about 90%) across tested concentrations. Notably, RGNPs (20 nm) exhibited antioxidative properties through DPPH scavenging activity (%) in the range of approximately 38-86% which was greater than that of CGNps at about 21-32%. In the MFC,the DCFH-DA analysis indicated that RGNPs (20 nm) reduced cellular oxidative stress by 57-82%, surpassing both CGNps and free Resveratrol. Morphologically, cells in the MFC presented superior structure compared to those in traditional cell culture plates, and the induction of hyperglycemia successfully led to the formation of multinucleated variant endothelial cells (MVECs). The MFC provides a distinct advantage in observing cell morphology and inducing endothelial cell dysfunction. RGNps have demonstrated significant potential in alleviating oxidative stress and preventing endothelial cell disorders.

Tissue-engineered heart valve: future of cardiac surgery.

BACKGROUND: Heart valve disease is currently a growing problem, and demand for heart valve replacement is predicted to increase significantly in the future. Existing "gold standard" mechanical and biological prosthesis offers survival at a cost of significantly increased risks of complications. Mechanical valves may cause hemorrhage and thromboembolism, whereas biologic valves are prone to fibrosis, calcification, degeneration, and immunogenic complications. METHODS: A literature search was performed to identify all relevant studies relating to tissue-engineered heart valve in life sciences using the PubMed and ISI Web of Knowledge databases. DISCUSSION: Tissue engineering is a new, emerging alternative, which is reviewed in this paper. To produce a fully functional heart valve using tissue engineering, an appropriate scaffold needs to be seeded using carefully selected cells and proliferated under conditions that resemble the environment of a natural human heart valve. Bioscaffold, synthetic materials, and preseeded composites are three common approaches of scaffold formation. All available evidence suggests that synthetic scaffolds are the most suitable material for valve scaffold formation. Different cell sources of stem cells were used with variable results. Mesenchymal stem cells, fibroblasts, myofibroblasts, and umbilical blood stem cells are used in vitro tissue engineering of heart valve. Alternatively scaffold may be implanted and then autoseeded in vivo by circulating endothelial progenitor cells or primitive circulating cells from patient's blood. For that purpose, synthetic heart valves were developed. CONCLUSIONS: Tissue engineering is currently the only technology in the field with the potential for the creation of tissues analogous to a native human heart valve, with longer sustainability, and fever side effects. Although there is still a long way to go, tissue-engineered heart valves have the capability to revolutionize cardiac surgery of the future.

Evaluation of drug-eluting nanoparticle coating on magnesium alloy for development of next generation bioabsorbable cardiovascular stents.

Since the introduction of bioabsorbable magnesium alloys into cardiovascular stent technology, many researches have been conducted to improve these metallic scaffolds. Various coatings and different coating techniques, super plastic deformation techniques and synthesizing different Mg-based alloy are examples of such efforts. In this study, a magnesium based alloy (WE43) was coated with dexamethasone loaded polymeric nanoparticles via electrospraying method. Drug release behavior, drug inhibitory effects, surface properties and cell responses to the surface were evaluated. Drug release profile was investigated and compared to drug-loaded nanoparticle on stainless steel as a control. The inhibitory effects of the drug-loaded nanoparticle coatings on smooth muscle cells was evaluated via MTT assay. Endothelial cells response to the surface was investigated by SEM. The results showed that contact angle and roughness of the surface were 131° and 600-800 nm, respectively. Drug release studies showed a burst release less than 30% after 24 h which followed by nearly zero order release kinetic. MTT assay showed that SMCs viability decreased to 60% and 25% after 24 and 72 h, respectively. SEM images indicated proper adhesion and proliferation of endothelial cells on the surface. The findings suggest that nanoparticle-coated surfaces could effectively inhibit SMC proliferation meanwhile provide desirable surface features for adhesion and proliferation of endothelial cell on magnesium alloy based stents.

Green synthesis of oxidized starch with a novel catalyst based on Fe3O4 nanoparticles and H2O2 reagent to form thermoplastic as a stable gel coating on the cardiovascular stents.

Oxidation of starch is one of the most commonly used approaches to improve its properties in the thermoplastic (TP) reactions. Iron oxide nanoparticle (IONP) (8.2 ± 1.5 nm) was used as a novel catalyst for this reaction. The functional groups of the carbonyl (COH) and the carboxyl (COOH) were obtained about of 7-12.2 % and 0.03-0.3 %. TP reaction and then electrospray technique of oxidized starch were used for the thin-film coating. The swelling ratio of the gelled thermoplastic structure with IONP (198 ± 9 % at 180 min) was lower than the sample without NP (193 ± 8 % at 90 min). The results from fourier transform infrared spectroscopy (FTIR), hydrogen nuclear magnetic resonance (HNMR), X-ray diffraction (XRD), and transmission electron microscopy (TEM) reveal desirable chemical and crystalline changes. Scanning electron microscopy (SEM) analysis was used to determine the thickness of the thin film (1.4 ± 0.2 µm) and the size of the electrosprayed droplets (172 ± 45 nm). Cytotoxicity studies of HUVEC and L929 cell lines against the extracts have shown appropriate biocompatibility. The blood compatibility analysis demonstrated proper results for (nanocomposite) NC. The results show that NC coated on metal surfaces can be used in medical approaches with drug delivery capability.

Hybrid PCL/chitosan-PEO nanofibrous scaffolds incorporated with A. euchroma extract for skin tissue engineering application.

Skin tissue engineering is an advanced method to repair and regenerate skin injuries. Recent research is focused on the development of scaffolds that are safe, bioactive, and cytocompatible. In this work, a new hybrid nanofibrous scaffold composed of polycaprolactone/chitosan-polyethylene oxide (PCL/Cs-PEO) incorporated with Arnebia euchroma (A. euchroma) extract were synthesized by the two-nozzle electrospinning method. Then the synthesized scaffold was characterized for morphology, sustainability, chemical structure and properties. Moreover, to verify their potential in the burn wound healing process, biodegradation rate, contact angle, swelling properties, water vapor permeability, mechanical properties, antibacterial activity and drug release profile were measured. Furthermore, cytotoxicity and biocompatibility tests were performed on human dermal fibroblasts cell line via XTT and LDH assay. It is shown that the scaffold improved and increased proliferation during in-vitro studies. Thus, results confirm the efficacy and potential of the hybrid nanofibrous scaffold for skin tissue engineering.

Adaptive antitumor immune response stimulated by bio-nanoparticle based vaccine and checkpoint blockade.

BACKGROUND: Interactions between tumor and microenvironment determine individual response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors (ICIs). Aspartate ß-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. METHODS: Subcutaneous HCC and orthotopic TNBC murine models were established in immunocompetent BALB/c mice with injection of BNL-T3 and 4 T1 cells, respectively. Immunohistochemistry, immunofluorescence, H&E, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. RESULTS: The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based λ phage vaccine targeting ASPH was administrated to mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In control, autocrine chemokine ligand 13 (CXCL13)-C-X-C chemokine receptor type 5 (CXCR5) axis promoted tumor development and progression in HCC and TNBC. Interactions between PD-L1+ cancer cells and PD-1+ T cells resulted in T cell exhaustion and apoptosis, causing immune evasion of cancer cells. In contrast, combination therapy (Vaccine+PD-1 inhibitor) significantly suppressed primary hepatic or mammary tumor growth (with distant pulmonary metastases in TNBC). Adaptive immune responses were attributed to expansion of activated CD4+ T helper type 1 (Th1)/CD8+ cytotoxic T cells (CTLs) that displayed enhanced effector functions, and maturation of plasma cells that secreted high titers of ASPH-specific antibody. Combination therapy significantly reduced tumor infiltration of immunosuppressive CD4+/CD25+/FOXP3+ Tregs. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH+ cancer cells recruited CXCR5+/CD8+ T lymphocytes to tertiary lymphoid structures (TLSs), comprising effector and memory CTLs, T follicular helper cells, B cell germinal center, and follicular dendritic cells. TLSs facilitate activation and maturation of DCs and actively recruit immune subsets to tumor microenvironment. These CTLs secreted CXCL13 to recruit more CXCR5+ immune cells and to lyse CXCR5+ cancer cells. Upon combination treatment, formation of TLSs predicts sensitivity to ICI blockade. Combination therapy substantially prolonged overall survival of mice with HCC or TNBC. CONCLUSIONS: Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH, an ideal TAA, combined with ICIs, inhibits tumor growth and progression of TNBC and HCC.

A nanocage for nanomedicine: polyhedral oligomeric silsesquioxane (POSS).

Ground-breaking advances in nanomedicine (defined as the application of nanotechnology in medicine) have proposed novel therapeutics and diagnostics, which can potentially revolutionize current medical practice. Polyhedral oligomeric silsesquioxane (POSS) with a distinctive nanocage structure consisting of an inner inorganic framework of silicon and oxygen atoms, and an outer shell of organic functional groups is one of the most promising nanomaterials for medical applications. Enhanced biocompatibility and physicochemical (material bulk and surface) properties have resulted in the development of a wide range of nanocomposite POSS copolymers for biomedical applications, such as the development of biomedical devices, tissue engineering scaffolds, drug delivery systems, dental applications, and biological sensors. The application of POSS nanocomposites in combination with other nanostructures has also been investigated including silver nanoparticles and quantum dot nanocrystals. Chemical functionalization confers antimicrobial efficacy to POSS, and the use of polymer nanocomposites provides a biocompatible surface coating for quantum dot nanocrystals to enhance the efficacy of the materials for different biomedical and biotechnological applications. Interestingly, a family of POSS-containing nanocomposite materials can be engineered either as completely non-biodegradable materials or as biodegradable materials with tuneable degradation rates required for tissue engineering applications. These highly versatile POSS derivatives have created new horizons for the field of biomaterials research and beyond. Currently, the application of POSS-containing polymers in various fields of nanomedicine is under intensive investigation with expectedly encouraging outcomes.

Remote ischaemic preconditioning versus no remote ischaemic preconditioning for vascular and endovascular surgical procedures.

BACKGROUND: Despite advances in perioperative care, elective major vascular surgical procedures carry a significant risk of morbidity and mortality. Remote ischaemic preconditioning is initiated by brief, non-lethal periods of ischaemia in a vascular bed different from the one which will be subjected to ischaemic insult during surgery. It has the potential to provide local tissue protection from further prolonged periods of ischaemia. OBJECTIVES: The aim of this review was to compare the outcomes from vascular and endovascular surgical procedures with and without the use of remote ischaemic preconditioning. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (June 2011) and CENTRAL (2011, Issue 2). The authors searched MEDLINE via PubMed (July 2011), EMBASE (June 2011), and Science Citation Index Expanded (July 2011). SELECTION CRITERIA: We considered for inclusion all randomised controlled trials that evaluated the role of remote ischaemic preconditioning in reducing mortality and systemic injury in patients undergoing open vascular or endovascular surgery. DATA COLLECTION AND ANALYSIS: We collected the data on characteristics of the trial, methodological quality, the remote ischaemic preconditioning stimulus used, mortality, morbidity, operating time and hospital stay from each trial. We analysed the data with both the fixed-effect and the random-effects models using RevMan analysis. For each outcome we calculated the risk ratio (RR) or mean difference with 95% confidence interval (CI) based on an intention-to-treat analysis. MAIN RESULTS: We included four studies with a total of 115 patients randomised to undergo a vascular procedure with remote ischaemic preconditioning and 117 patients randomised to have the procedure without remote ischaemic preconditioning. None of the trials were of low risk of bias. There was no significant difference in mortality between the two groups (RR 1.70, 95% CI 0.51 to 5.72). Similarly, there was no statistically significant difference between the two groups for all other outcomes except reduced risk of myocardial infarction in the remote ischaemic preconditioning group, which was significant by the fixed-effect model (RR 0.31, 95% CI 0.10 to 0.90) but not by the random-effects model (RR 0.34, 95% CI 0.11 to 1.08). This positive effect was from the results of only one trial and was not consistently observed. Furthermore, it was noted that there was an observed trend of high incidence of unplanned critical care admission in the remote ischaemic preconditioning group, although this was not statistically significant (RR 2.15, 95% CI 0.87 to 5.33). AUTHORS' CONCLUSIONS: Based on current evidence from small pilot trials, there are too few data to be able to say whether remote ischaemic preconditioning has any beneficial or harmful effects. The safety of this technique needs to be confirmed in adequately powered trials. Therefore, further randomised trials on this technique are required.