International treaties have mostly failed to produce their intended effects.

There are over 250,000 international treaties that aim to foster global cooperation. But are treaties actually helpful for addressing global challenges? This systematic field-wide evidence synthesis of 224 primary studies and meta-analysis of the higher-quality 82 studies finds treaties have mostly failed to produce their intended effects. The only exceptions are treaties governing international trade and finance, which consistently produced intended effects. We also found evidence that impactful treaties achieve their effects through socialization and normative processes rather than longer-term legal processes and that enforcement mechanisms are the only modifiable treaty design choice with the potential to improve the effectiveness of treaties governing environmental, human rights, humanitarian, maritime, and security policy domains. This evidence synthesis raises doubts about the value of international treaties that neither regulate trade or finance nor contain enforcement mechanisms.

Characterizing the Copy Number Variation of Non-Coding RNAs Reveals Potential Therapeutic Targets and Prognostic Markers of LUSC.

Lung squamous cell carcinoma (LUSC) has a poor clinical prognosis and a lack of available targeted therapies. Therefore, there is an urgent need to identify novel prognostic markers and therapeutic targets to assist in the diagnosis and treatment of LUSC. With the development of high-throughput sequencing technology, integrated analysis of multi-omics data will provide annotation of pathogenic non-coding variants and the role of non-coding sequence variants in cancers. Here, we integrated RNA-seq profiles and copy number variation (CNV) data to study the effects of non-coding variations on gene regulatory network. Furthermore, the 372 long non-coding RNAs (lncRNA) regulated by CNV were used as candidate genes, which could be used as biomarkers for clinical application. Nine lncRNAs including LINC00896, MCM8-AS1, LINC01251, LNX1-AS1, GPRC5D-AS1, CTD-2350J17.1, LINC01133, LINC01121, and AC073130.1 were recognized as prognostic markers for LUSC. By exploring the association of the prognosis-related lncRNAs (pr-lncRNAs) with immune cell infiltration, GPRC5D-AS1 and LINC01133 were highlighted as markers of the immunosuppressive microenvironment. Additionally, the cascade response of pr-lncRNA-CNV-mRNA-physiological functions was revealed. Taken together, the identification of prognostic markers and carcinogenic regulatory mechanisms will contribute to the individualized treatment for LUSC and promote the development of precision medicine.

Correction: In vivo migration of Fe3O4@polydopamine nanoparticle-labeled mesenchymal stem cells to burn injury sites and their therapeutic effects in a rat model.

Correction for 'In vivo migration of Fe3O4@polydopamine nanoparticle-labeled mesenchymal stem cells to burn injury sites and their therapeutic effects in a rat model' by Xiuying Li et al., Biomater. Sci., 2019, 7, 2861-2872, DOI: 10.1039/C9BM00242A.

Magnetic targeting enhances the cutaneous wound healing effects of human mesenchymal stem cell-derived iron oxide exosomes.

Human mesenchymal stem cell (MSC)-derived exosomes (Exos) are a promising therapeutic agent for cell-free regenerative medicine. However, their poor organ-targeting ability and therapeutic efficacy have been found to critically limit their clinical applications. In the present study, we fabricated iron oxide nanoparticle (NP)-labeled exosomes (Exo + NPs) from NP-treated MSCs and evaluated their therapeutic efficacy in a clinically relevant model of skin injury. We found that the Exos could be readily internalized by human umbilical vein endothelial cells (HUVECs), and could significantly promote their proliferation, migration, and angiogenesis both in vitro and in vivo. Moreover, the protein expression of proliferative markers (Cyclin D1 and Cyclin A2), growth factors (VEGFA), and migration-related chemokines (CXCL12) was significantly upregulated after Exo treatment. Unlike the Exos prepared from untreated MSCs, the Exo + NPs contained NPs that acted as a magnet-guided navigation tool. The in vivo systemic injection of Exo + NPs with magnetic guidance significantly increased the number of Exo + NPs that accumulated at the injury site. Furthermore, these accumulated Exo + NPs significantly enhanced endothelial cell proliferation, migration, and angiogenic tubule formation in vivo; moreover, they reduced scar formation and increased CK19, PCNA, and collagen expression in vivo. Collectively, these findings confirm the development of therapeutically efficacious extracellular nanovesicles and demonstrate their feasibility in cutaneous wound repair.

Magnetic Targeting of HU-MSCs in the Treatment of Glucocorticoid-Associated Osteonecrosis of the Femoral Head Through Akt/Bcl2/Bad/Caspase-3 Pathway.

PURPOSE: Osteonecrosis of the femoral head (ONFH) is a chronic and irreversible disease that eventually develops into a joint collapse and results in joint dysfunction. Early intervention and treatment are essential for preserving the joints and avoiding hip replacement. In this study, a system of human umbilical mesenchymal stem cells-supermagnetic iron oxide nanoparticles (NPs) @polydopamine (SCIOPs) was constructed. The magnetic targeting system gathers in the lesion area, inhibits the apoptosis of bone cells, enhances osteogenic effect, and effectively treats ONFH under external magnetic field. MATERIALS AND METHODS: The supermagnetic iron oxide NPs @polydopamine (SPION@PDA NPs) were characterized by transmission electron microscopy and zeta potential, respectively. The effects of SPION@PDA NPs on the viability, proliferation, and differentiation of stem cells were detected by the CCK8 method, flow cytometry, and staining, respectively. The serum inflammatory indicators were detected by Luminex method. The bone mass of the femoral head was analyzed by micro computed tomography. The expression of apoptosis and osteoblast-related cytokines was detected by Western blotting. The osteogenesis of the femoral head was detected by histological and immunohistochemical sections. RESULTS: The SCIOPs decreased the pro-inflammatory factors, and the micro CT showed that the bone repair of the femoral head was enhanced after treatment. The hematoxylin and eosin sections also showed an increase in the osteogenesis in the femoral head. Western blotting results showed and increased expression of anti-apoptotic proteins Akt and Bcl-2, decreased expression of apoptotic proteins caspase-3 and Bad, and increased expression of osteogenic proteins Runx-2 and Osterix in the femoral head. CONCLUSION: Under the effect of magnetic field and homing ability of stem cells, SCIOPs inhibited the apoptosis of osteoblasts, improved the proliferation ability of osteoblasts, and promoted bone repair in the femoral head through the Akt/Bcl-2/Bad/caspase-3 signaling pathway, thereby optimizing the tissue repair ability.

Growth and elongation of axons through mechanical tension mediated by fluorescent-magnetic bifunctional Fe3O4·Rhodamine 6G@PDA superparticles.

BACKGROUND: The primary strategy to repair peripheral nerve injuries is to bridge the lesions by promoting axon regeneration. Thus, the ability to direct and manipulate neuronal cell axon regeneration has been one of the top priorities in the field of neuroscience. A recent innovative approach for remotely guiding neuronal regeneration is to incorporate magnetic nanoparticles (MNPs) into cells and transfer the resulting MNP-loaded cells into a magnetically sensitive environment to respond to an external magnetic field. To realize this intention, the synthesis and preparation of ideal MNPs is an important challenge to overcome. RESULTS: In this study, we designed and prepared novel fluorescent-magnetic bifunctional Fe3O4·Rhodamine 6G@polydopamine superparticles (FMSPs) as neural regeneration therapeutics. With the help of their excellent biocompatibility and ability to interact with neural cells, our in-house fabricated FMSPs can be endocytosed into cells, transported along the axons, and then aggregated in the growth cones. As a result, the mechanical forces generated by FMSPs can promote the growth and elongation of axons and stimulate gene expression associated with neuron growth under external magnetic fields. CONCLUSIONS: Our work demonstrates that FMSPs can be used as a novel stimulator to promote noninvasive neural regeneration through cell magnetic actuation.

Targeted multifunctional nanomaterials with MRI, chemotherapy and photothermal therapy for the diagnosis and treatment of bladder cancer.

Bladder cancer is a common urinary tract tumor in clinic, and its morbidity and mortality are always high. Surgical treatment is operator dependent, residual tumor cells often lead to tumor recurrence, and chemotherapy after surgery causes high side effects. So, it is urgent to develop new methods for the theranostics of bladder cancer. Among them, functional nanomaterials have shown good application in tumor theranostics, but they are rarely used in bladder cancer. In our work, we demonstrate the fabrication of folate-modified vincristine-loaded polydopamine-coated Fe3O4 superparticles (Fe3O4@PDA-VCR-FA SPs), and applied them in the theranostics of bladder cancer. The PDA shell not only improves the colloidal stability and biocompatibility, but also enhances the photothermal effect and prolongs the blood circulation half-life. The half-life of Fe3O4@PDA-VCR-FA SPs in blood is calculated as 2.83 h, and the tumor retention rate is 5.96 %ID g-1, these data are significantly higher than those before folic acid modification. The superparamagnetism of Fe3O4 and loading of vincristine endow Fe3O4@PDA-VCR-FA SPs with magnetic resonance imaging and chemotherapy capabilities. Further by employing NIR laser-triggered photothermal therapy, bladder tumors were ablated completely, and no recurrence was observed. Blood and histological tests of the major organs confirm that Fe3O4@PDA-VCR-FA SPs show good biosafety.

In vivo migration of Fe3O4@polydopamine nanoparticle-labeled mesenchymal stem cells to burn injury sites and their therapeutic effects in a rat model.

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising therapeutic strategy for tissue regeneration and repair. However, efficient targeted delivery to specific tissues remains an open challenge. Here, we non-invasively monitored the migration of MSCs labeled with Fe3O4@polydopamine nanoparticles (Fe3O4@PDA NPs) toward laser burn injury sites in a living rat model and evaluated the effects of the labeled MSCs at the injury site. The Fe3O4@PDA NPs could be effectively incorporated into the MSCs without any negative effects on stem cell properties. Furthermore, they enhanced the migration ability of the MSCs by up-regulating the expression level of C-X-C chemokine receptor type 4 (CXCR4). They also increased the secretion of some cytokines and the expression of healing-related genes in comparison with unlabeled MSCs. Labeled MSCs were intravenously administered into injured rats, and live imaging was performed to monitor MSC migration. Fluorescent signals of the labeled MSCs appeared at burn injury lesions 1 day after injection and then gradually increased up to 7 days. After 7 days, the group injected with the labeled MSCs showed less inflammation compared with those injected with the unlabeled MSCs. Additionally, the labeled MSC group showed increased cytokines and reduced pro-inflammatory factors compared with the unlabeled MSC group. The Fe3O4@PDA NPs enhanced stromal cell-derived factor-1/CXCR4-mediated MSC migration in vivo. Thus, we demonstrated the safety, feasibility, and potential efficacy of using the Fe3O4@PDA NPs for optimizing MSC-based therapeutic strategies for burn wound healing.

Photothermal-Activatable Fe3O4 Superparticle Nanodrug Carriers with PD-L1 Immune Checkpoint Blockade for Anti-metastatic Cancer Immunotherapy.

Checkpoint blockade immunotherapy has shown great potential in clinical cancer therapy, but the body's systemic immune must be fully activated and generates a positive tumor-specific immune cell response. In this work, we demonstrate the design of the immune-adjuvant nanodrug carriers on the basis of poly(ethylene glycol)- block-poly(lactic- co-glycolic acid) copolymer-encapsulated Fe3O4 superparticles (SPs), in which imiquimod (R837), a kind of Toll-like receptor 7 agonist, is loaded. The nanodrug carriers are defined as Fe3O4-R837 SPs. The multitasking Fe3O4-R837 SPs can destroy the 4T1 breast tumor by photothermal therapy (PTT) under near-infrared laser irradiation to generate the tumor-associated antigens because of the high efficiency of tumor magnetic attraction ability and photothermal effect. The PTT also triggers the release of R837 as the adjuvant to trigger a strong antitumor immune response. By further combining with the checkpoint blockade adjusted by programmed death ligand 1 (PD-L1) antibody, the Fe3O4-R837 SP-involved PTT cannot only eliminate the primary tumors but also prevent tumor metastasis to lungs/liver. Meanwhile, this synergistic therapy also shows abscopal effects by completely inhibiting the growth of untreated distant tumors through effectively triggering the tumors infiltrated by CD45+ leukocytes. Such findings suggest that Fe3O4-R837 SP-involved PTT can significantly potentiate the systemic therapeutic efficiency of PD-L1 checkpoint blockade therapy by activating both innate and adaptive immune systems in the body.