Hydrogen Therapy Reverses Cancer-Associated Fibroblasts Phenotypes and Remodels Stromal Microenvironment to Stimulate Systematic Anti-Tumor Immunity.

Tumor microenvironment (TME) plays an important role in the tumor progression. Among TME components, cancer-associated fibroblasts (CAFs) show multiple tumor-promoting effects and can induce tumor immune evasion and drug-resistance. Regulating CAFs can be a potential strategy to augment systemic anti-tumor immunity. Here, the study observes that hydrogen treatment can alleviate intracellular reactive oxygen species of CAFs and reshape CAFs' tumor-promoting and immune-suppressive phenotypes. Accordingly, a controllable and TME-responsive hydrogen therapy based on a CaCO3 nanoparticles-coated magnesium system (Mg-CaCO3) is developed. The hydrogen therapy by Mg-CaCO3 can not only directly kill tumor cells, but also inhibit pro-tumor and immune suppressive factors in CAFs, and thus augment immune activities of CD4+ T cells. As implanted in situ, Mg-CaCO3 can significantly suppress tumor growth, turn the "cold" primary tumor into "hot", and stimulate systematic anti-tumor immunity, which is confirmed by the bilateral tumor transplantation models of "cold tumor" (4T1 cells) and "hot tumor" (MC38 cells). This hydrogen therapy system reverses immune suppressive phenotypes of CAFs, thus providing a systematic anti-tumor immune stimulating strategy by remodeling tumor stromal microenvironment.

Suit the Remedy to the Case-The Effectiveness of COVID-19 Nonpharmaceutical Prevention and Control Policies Based on Individual Going-Out Behavior.

Nonpharmaceutical policies for epidemic prevention and control have been extensively used since the outbreak of COVID-19. Policies ultimately work by limiting individual behavior. The aim of this paper is to evaluate the effectiveness of policies by combining macro nonpharmaceutical policies with micro-individual going-out behavior. For different going out scenarios triggered by individual physiological safety needs, friendship needs, and family needs, this paper categorizes policies with significant differences in intensity, parameterizes the key contents of the policies, and simulates and analyzes the effectiveness of the policies in different going-out scenarios with simulation methods. The empirical results show that enhancing policy intensity can effectively improve policy effectiveness. Among different types of policies, restricting the times of going out is more effective. Further, the effect of controlling going out based on physiological safety needs is better than other needs. We also evaluate the policy effectiveness of 26 global countries or regions. The results show that the policy effectiveness varies among 26 countries or regions. The quantifiable reference provided by this study facilitates decision makers to establish policy and practices for epidemic prevention and control.

A Social Media Infodemic-Based Prediction Model for the Number of Severe and Critical COVID-19 Patients in the Lockdown Area.

Accurately predicting the number of severe and critical COVID-19 patients is critical for the treatment and control of the epidemic. Social media data have gained great popularity and widespread application in various research domains. The viral-related infodemic outbreaks have occurred alongside the COVID-19 outbreak. This paper aims to discover trustworthy sources of social media data to improve the prediction performance of severe and critical COVID-19 patients. The innovation of this paper lies in three aspects. First, it builds an improved prediction model based on machine learning. This model helps predict the number of severe and critical COVID-19 patients on a specific urban or regional scale. The effectiveness of the prediction model, shown as accuracy and satisfactory robustness, is verified by a case study of the lockdown in Hubei Province. Second, it finds the transition path of the impact of social media data for predicting the number of severe and critical COVID-19 patients. Third, this paper provides a promising and powerful model for COVID-19 prevention and control. The prediction model can help medical organizations to realize a prediction of COVID-19 severe and critical patients in multi-stage with lead time in specific areas. This model can guide the Centers for Disease Control and Prevention and other clinic institutions to expand the monitoring channels and research methods concerning COVID-19 by using web-based social media data. The model can also facilitate optimal scheduling of medical resources as well as prevention and control policy formulation.

Photogenerated reactive oxygen species and hyperthermia by Cu3SnS4 nanoflakes for advanced photocatalytic and photothermal antibacterial therapy.

BACKGROUND: The rapid spread of infectious bacteria has brought great challenges to public health. It is imperative to explore effective and environment-friendly antibacterial modality to defeat antibiotic-resistant bacteria with high biosafety and broad-spectrum antibacterial property. RESULTS: Herein, biocompatible Cu3SnS4 nanoflakes (NFs) were prepared by a facile and low-cost fabrication procedure. These Cu3SnS4 NFs could be activated by visible light, leading to visible light-mediated photocatalytic generation of a myriad of reactive oxygen species (ROS). Besides, the plasmonic Cu3SnS4 NFs exhibit strong near infrared (NIR) absorption and a high photothermal conversion efficiency of 55.7%. The ROS mediated cellular oxidative damage and the NIR mediated photothermal disruption of bacterial membranes collaboratively contributed to the advanced antibacterial therapy, which has been validated by the efficient eradication of both Gram-negative Escherichia coli and Gram-positive methicillin-resistant Staphylococcus aureus strains in vitro and in vivo. Meanwhile, the exogenous copper ions metabolism from the Cu3SnS4 NFs facilitated the endothelial cell angiogenesis and collagen deposition, thus expediting the wound healing. Importantly, the inherent localized surface plasmon resonance effect of Cu3SnS4 NFs empowered them as an active substrate for surface-enhanced Raman scattering (SERS) imaging and SERS-labeled bacteria detection. CONCLUSIONS: The low cost and biocompatibility together with the solar-driven broad-spectrum photocatalytic/photothermal antibacterial property of Cu3SnS4 NFs make them a candidate for sensitive bacteria detection and effective antibacterial treatment.

Prussian Blue Nanoparticles Stabilize SOD1 from Ubiquitination-Proteasome Degradation to Rescue Intervertebral Disc Degeneration.

Discography often destroys the hypoxic environment in the intervertebral disc and accelerates intervertebral disc degeneration (IVDD). Therefore, it often fails to meet the requirements for application in clinical practice. This technology mainly increases the reactive oxygen species (ROS) in the IVD. As so, it is particularly critical to develop strategies to avoid this degeneration mechanism. Prussian blue nanoparticles (PBNPs) are found to enhance development under magnetic resonance T1 and have antioxidant enzyme activity. The key results of the present study confirm that PBNPs alleviate intracellular oxidative stress and increase the intracellular activities of antioxidant enzymes, such as superoxide dismutase 1 (SOD1). PBNPs can rescue nucleus pulposus cell degeneration by increasing oxidoreductase system-related mRNA and proteins, especially by stabilizing SOD1 from ubiquitination-proteasome degradation, thus improving the mitochondrial structure to increase antioxidation ability, and finally rescuing ROS-induced IVDD in a rat model. Therefore, it is considered that PBNPs can be a potential antioxidation-protective discography contrast agent.

Additively manufactured biodegradable porous magnesium implants for elimination of implant-related infections: An in vitro and in vivo study.

Magnesium (Mg) alloys that have both antibacterial and osteogenic properties are suitable candidates for orthopedic implants. However, the fabrication of ideal Mg implants suitable for bone repair remains challenging because it requires implants with interconnected pore structures and personalized geometric shapes. In this study, we fabricated a porous 3D-printed Mg-Nd-Zn-Zr (denoted as JDBM) implant with suitable mechanical properties using selective laser melting technology. The 3D-printed JDBM implant exhibited cytocompatibility in MC3T3-E1 and RAW267.4 cells and excellent osteoinductivity in vitro. Furthermore, the implant demonstrated excellent antibacterial ratios of 90.0% and 92.1% for methicillin-resistant S. aureus (MRSA) and Escherichia coli, respectively. The 3D-printed JDBM implant prevented MRSA-induced implant-related infection in a rabbit model and showed good in vivo biocompatibility based on the results of histological evaluation, blood tests, and Mg2+ deposition detection. In addition, enhanced inflammatory response and TNF-α secretion were observed at the bone-implant interface of the 3D-printed JDBM implants during the early implantation stage. The high Mg2+ environment produced by the degradation of 3D-printed JDBM implants could promote M1 phenotype of macrophages (Tnf, iNOS, Ccl3, Ccl4, Ccl5, Cxcl10, and Cxcl2), and enhance the phagocytic ability of macrophages. The enhanced immunoregulatory effect generated by relatively fast Mg2+ release and implant degradation during the early implantation stage is a potential antibacterial mechanism of Mg-based implant. Our findings indicate that 3D-printed porous JDBM implants, having both antibacterial property and osteoinductivity, hold potential for future orthopedic applications.

Effectiveness and safety of biodegradable Mg-Nd-Zn-Zr alloy screws for the treatment of medial malleolar fractures.

BACKGROUND: /Objective: This study aimed to evaluate the effectiveness and safety of treating medial malleolar fractures using our patented Mg-Nd-Zn-Zr alloy (abbr. JDBM) screws with Ca-P coating, in order to provide a solid basis for their further clinical translation. METHODS: Nine patients with medial malleolar fractures were treated using coated JDBM screws. All patients had closed injuries, and none had open fractures. Postoperative radiography was performed to evaluate fracture healing and degradation of the JDBM screws. The visual analogue scale (VAS) was used to evaluate the degree of postoperative pain perceived by the patients, and the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot scoring system was used to evaluate their postoperative ankle function. Postoperative complications, including infection, failure of internal fixation, and malunion, were carefully recorded during follow-up. RESULTS: The mean follow-up time was 12.2 â€‹± â€‹4.9 months. After the operation, all patients achieved good medial malleolar fracture alignment, and none of them experienced breakage of the JDBM screws before fracture healing. Postoperative radiography indicated JDBM screws gradually degradated with implantation time, and obvious degradation could be observed 12 months, postoperatively. At the final follow-up, the patients' mean VAS score was 2.3 â€‹± â€‹1.9. The mean AOFAS score was 90.4 â€‹± â€‹8.9, with excellent or good rates of 88.9%. None of the patients experienced infection, failure of internal fixation, malunion, or other complications. CONCLUSION: Coated biodegradable JDBM screws are effective for the treatment of medial malleolar fractures, and have good prospects for further clinical translation in the future. TRANSLATIONAL POTENTIAL STATEMENT: The results of this study indicates coated biodegradable JDBM screw is an alternative internal fixation instrument for fracture treatment and has excellent prospects for clinical translation.

Activatable nanomedicine for overcoming hypoxia-induced resistance to chemotherapy and inhibiting tumor growth by inducing collaborative apoptosis and ferroptosis in solid tumors.

Hypoxia has been firmly correlated to the drug resistance of solid tumors. Alleviation of hypoxia by tumor reoxygenation is expected to sensitize the chemotherapy toward solid tumors. Alternatively, ferroptosis provides a therapeutic strategy to overcome apoptotic resistance and multidrug resistance of solid tumors, collaboratively strengthening the chemotherapy toward hypoxic tumors. Herein, an ultrasound (US)-activatable nanomedicine was developed for overcoming hypoxia-induced resistance to chemotherapy and efficiently inhibiting tumor growth by inducing sensitized apoptosis and collaborative ferroptosis of tumor cells. This nanomedicine was constructed by integrating ferrate and doxorubicin into biocompatible hollow mesoporous silica nanoplatforms, followed by assembling a solid-liquid phase-change material of n-heneicosane. The US-induced mild hyperthermia initiates the phase change of n-heneicosane, enabling US-activated co-release of ferrate and doxorubicin. Results reveal that the released ferrate effectively reacts with water as well as the over-expressed hydrogen peroxide and glutathione in tumor cells, achieving tumor-microenvironment-independent reoxygenation and glutathione-depletion in tumors. The reoxygenation down-regulates expressions of hypoxia-inducible factor 1α and multidrug resistance gene/transporter P-glycoprotein in tumor cells, sensitizing the apoptosis-based doxorubicin chemotherapy. More importantly, exogenous iron metabolism from the nanomedicine initiates intracellular Fenton reactions, leading to reactive oxygen species overproduction and iron-dependent ferroptotic death of tumor cells. Furthermore, the glutathione-depletion inactivates the glutathione peroxidase 4 (GPX4, a critical regulatory target in ferroptosis), inhibiting the reduction of lipid peroxides and reinforcing the ferroptotic cell death. The sensitized chemotherapy together with the iron-dependent ferroptosis of tumor cells play a synergistic role in boosting the growth suppression of hypoxic osteosarcoma in vivo. Additionally, the nanomedicine acts as a nanoprobe for in vivo photoacoustic imaging and glutathione tracking, showing great potential as theranostic agents for hypoxic solid tumors treatment.

Fabrication and Biological Activity of 3D-Printed Polycaprolactone/Magnesium Porous Scaffolds for Critical Size Bone Defect Repair.

Polycaprolactone (PCL) is widely used in bone tissue engineering due to its biocompatibility and mechanical strength. However, PCL is not biologically active and shows poor hydrophilicity, making it difficult for new bones to bind tightly to its surface. Magnesium (Mg), an important component of natural bone, exhibits good osteo-inductivity and biological activity. Therefore, porous PCL/Mg scaffolds, including pure PCL, PCL/5%Mg, PCL/10%Mg, and PCL/15%Mg, were prepared to elucidate whether the porous structure of scaffolds and the bioactivity of PCL may be enhanced via 3D printing and incorporation of Mg powder. Compared with the control group (pure PCL only), the hydrophilicity of composite PCL/Mg scaffolds was greatly increased, resulting in the scaffolds having decreased water contact angles. Tests for adhesion and proliferation of rat bone marrow mesenchymal stem cells (rBMSCs) indicated that the PCL/10%Mg scaffold showed superior compatibility. Furthermore, as indicated by alkaline phosphatase (ALP) activity and semiquantitative analysis of alizarin red staining, PCL/10%Mg scaffolds exhibited significantly stronger osteogenic activity than the other scaffolds. Animal experiments demonstrated that PCL/10%Mg scaffolds displayed pro-osteogenic effects at an early stage (4 weeks) and produced more new bone mass 8-12 weeks following implantation, compared with the control group. Visceral and blood parameter analyses indicated that PCL/10%Mg scaffolds did not exert any noticeable toxic effects. PCL/10%Mg composite scaffolds were found to promote bone defect repair at an early stage with good cytocompatibility. This finding revealed a new concept in designing bone tissue materials, which showed potential as a clinical treatment for bone defects.

Partially Melted Ti6Al4V Particles Increase Bacterial Adhesion and Inhibit Osteogenic Activity on 3D-printed Implants: An In Vitro Study.

BACKGROUND: A porous Ti6Al4V implant that is manufactured using selective laser melting (SLM) has broad potential applications in the field of orthopaedic implants. The pore structure of the SLM porous Ti6Al4V implant allows for cell migration and osteogenic differentiation, which is favorable for bone ingrowth and osseointegration. However, it is unclear whether the pore structure and partially melted Ti6Al4V particles on a SLM porous Ti6Al4V implant will increase bacterial adhesion and, perhaps, the risk of implant-related infection. QUESTIONS/PURPOSES: (1) Is there more bacterial adhesion and colonization on SLM porous Ti6Al4V implants than on polished orthopaedic implants? (2) Do partially melted Ti6Al4V particles on SLM porous Ti6Al4V implants reduce human bone mesenchymal stem cells (hBMSCs) adhesion, viability, and activity? METHODS: To determine bacterial adhesion and biofilm formation, we incubated five different Ti6Al4V discs (polished, grit-blasted, plasma-sprayed, particle SLM porous, and nonparticle SLM porous discs) with methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli. Bacterial coverage on the surface of the five different Ti6Al4V discs were evaluated based on scanning electron microscopy (SEM) images quantitatively. In addition, a spread-plate method was used to quantitatively evaluate the bacterial adhesion on those implants. The biofilm formation was stained with crystal violet and semi-quantitatively determined with a microplate reader. The morphology and adhesion of hBMSCs on the five Ti6Al4V discs were observed with SEM. The cell viability was quantitatively evaluated with a Cell Counting Kit-8 assay. In addition, the osteogenic activity was determined in vitro with a quantitatively alkaline phosphatase activity assay and alizarin-red staining. For semiquantitative analysis, the alizarin-red stained mineralized nodules were dissolved and determined with a microplate reader. RESULTS: The polished discs had the lowest MRSA adhesion (8.3% ± 2.6%) compared with grit-blasted (19.1% ± 3.9%; p = 0.006), plasma-sprayed (38.5% ± 5.3%; p < 0.001), particle (23.1% ± 2.8%; p < 0.001), and nonparticle discs (15.7% ± 2.5%; p = 0.003). Additionally, when comparing the two SLM discs, we found that particle discs had higher bacterial coverage than nonparticle discs (23.1% ± 2.8% versus 15.7% ± 2.5%; p = 0.020). An E. coli analysis showed similar results, with the higher adhesion to particle SLM discs than to nonparticle discs (20.7% ± 4.2% versus 14.4% ± 3.6%; p = 0.011). In addition, on particle SLM porous discs, bacterial colonies were localized around the partially melted Ti6Al4V particles, based on SEM images. After a 7-day incubation period, the cell viability in the particle group (optical density value 0.72 ± 0.05) was lower than that in the nonparticle groups (optical density value: 0.87 ± 0.08; p = 0.003). Alkaline phosphatase activity, as a marker of osteogenic differentiation, was lower in the particle group than in the nonparticle group (1.32 ± 0.12 U/mL versus 1.58 ± 0.09 U/mL; p = 0.012). CONCLUSION: Higher bacterial adhesion was observed on SLM porous discs than on polished discs. The partially melted Ti6Al4V particles on SLM porous discs not only enhanced bacterial adhesion but also inhibited the osteogenic activity of hBMSCs. Postprocessing treatment is necessary to remove partially melted Ti6Al4V particles on an SLM implant before further use. Additional studies are needed to determine whether an SLM porous Ti6Al4V implant increases the risk of implant-related infection in vivo. CLINICAL RELEVANCE: As implants with porous Ti6Al4V made using SLM are being designed, our preliminary findings suggest that postprocessing treatment is needed to remove partially melted Ti6Al4V particles before further use. In addition, the depth of the porous structure of the SLM implant should not exceed the maximum depth of bone ingrowth because the host immune defense cannot prevent bacterial adhesion without integration.

Study of Bone Regeneration and Osteointegration Effect of a Novel Selective Laser-Melted Titanium-Tantalum-Niobium-Zirconium Alloy Scaffold.

Titanium-tantalum-niobium-zirconium (Ti-Ta-Nb-Zr) alloy is a novel material currently available for orthopedic applications. However, these scaffolds, manufactured using traditional methods, present disadvantages such as irregular pore size, unsuitable mechanical features, and poor connectivity between pores. In this study, porous Ti-Ta-Nb-Zr (60% Ti, 2% Ta, 36% Nb, and 2% Zr) scaffolds were printed by selective laser melting (SLM) with a controllable pore size of 300-400 µm. The mechanical properties of the SLM-manufactured scaffolds were evaluated, as well as its osteogenesis in vitro and osteointegration in vivo. Porous Ti-Ta-Nb-Zr scaffolds yielded superior cell proliferation and cell adhesion results with human bone mesenchymal stem cells (hBMSCs) compared with porous Ti6Al4V scaffolds. The osteogenic differentiation experiment demonstrated enhanced osteogenic differentiation of hBMSCs in the Ti-Ta-Nb-Zr group than in the Ti6Al4V group. After the porous Ti-Ta-Nb-Zr or control scaffolds were implanted into a cylindrical bone defect in the rabbit lateral femoral condyle, the initial radiological results confirmed the excellent osteogenic activity of the novel 3D-printed scaffolds. Histological analysis further indicated that the Ti-Ta-Nb-Zr scaffolds promoted bone regeneration and osteointegration more effectively than Ti6Al4V scaffolds. Our findings demonstrate that the SLM-manufactured porous Ti-Ta-Nb-Zr scaffold has considerable potential for clinical orthopedic application.

A Multiorgan Segmentation Model for CT Volumes via Full Convolution-Deconvolution Network.

We propose a model with two-stage process for abdominal segmentation on CT volumes. First, in order to capture the details of organs, a full convolution-deconvolution network (FCN-DecNet) is constructed with multiple new unpooling, deconvolutional, and fusion layers. Then, we optimize the coarse segmentation results of FCN-DecNet by multiscale weights probabilistic atlas (MS-PA), which uses spatial and intensity characteristic of atlases. Our coarse-fine model takes advantage of intersubject variability, spatial location, and gray information of CT volumes to minimize the error of segmentation. Finally, using our model, we extract liver, spleen, and kidney with Dice index of 90.1 ± 1%, 89.0 ± 1.6%, and 89.0 ± 1.3%, respectively.