Tumor-targeted self-assembled micelles reducing PD-L1 expression combined with ICIs to enhance chemo-immunotherapy of TNBC

Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.

Novel hybrid biocomposites for tendon grafts:The addition of silk to polydioxanone and poly(lactide-co-caprolactone)enhances material properties,in vitro and in vivo biocompatibility

Biopolymers play a critical role as scaffolds used in tendon and ligament(TL)regeneration.Although advanced biopolymer materials have been proposed with optimised mechanical properties,biocompatibility,degradation,and processability,it is still challenging to find the right balance between these properties.Here,we aim to develop novel hybrid biocomposites based on poly(p-dioxanone)(PDO),poly(lactide-co-caprolactone)(LCL)and silk to produce high-performance grafts suitable for TL tissue repair.Biocomposites containing 1-15%of silk were studied through a range of characterisation techniques.We then explored biocompatibility through in vitro and in vivo studies using a mouse model.We found that adding up to 5%silk increases the tensile properties,degradation rate and miscibility between PDO and LCL phases without agglomeration of silk inside the composites.Furthermore,addition of silk increases surface roughness and hydrophilicity.In vitro experiments show that the silk improved attachment of tendon-derived stem cells and proliferation over 72 h,while in vivo studies indicate that the silk can reduce the expression of pro-inflammatory cytokines after six weeks of implantation.Finally,we selected a promising biocomposite and created a prototype TL graft based on extruded fibres.We found that the tensile properties of both individual fibres and braided grafts could be suitable for anterior cruciate ligament(ACL)repair applications.

Natural,synthetic and commercially-available biopolymers used to regenerate tendons and ligaments

Tendon and ligament(TL)injuries affect millions of people annually.Biopolymers play a significant role in TL tissue repair,whether the treatment relies on tissue engineering strategies or using artificial tendon grafts.The biopolymer governs the mechanical properties,biocompatibility,degradation,and fabrication method of the TL scaffold.Many natural,synthetic and hybrid biopolymers have been studied in TL regeneration,often combined with therapeutic agents and minerals to engineer novel scaffold systems.However,most of the advanced biopolymers have not advanced to clinical use yet.Here,we aim to review recent biopolymers and discuss their features for TL tissue engineering.After introducing the properties of the native tissue,we discuss different types of natural,synthetic and hybrid biopolymers used in TL tissue engineering.Then,we review biopolymers used in commercial absorbable and non-absorbable TL grafts.Finally,we explain the challenges and future directions for the development of novel biopolymers in TL regenerative treatment.

State-owned Enterprises in China as Macroeconomic Stabilizers: Their Special Function in Times of Economic Policy Uncertainty

China has many state-owned enterprises(SOEs)and they have accounted for a large proportion of China's GDP over the last four decades.China's rapid growth contradicts literature that focuses on the inefficiency of SOEs.This study shows that,in periods of economic policy uncertainty(EPU),SOEs have performed a special function as"macroeconomic stabilizers."Using Chinese listed firm data from 2008 to 2019,we investigate five aspects of SOEs'unique functions as macroeconomic stabilizers:employment,investment,growth,financial operation,and expectations.When EPU increased,SOEs had more employment,higher investment expenditure,lower performance volatility,more robust financial structures,and more stable expectations than private firms.We employ the US-China trade war as an exogenous shock on EPU to conduct a difference-in-difference-in-differences approach to mitigate the problem of potentially omitted variables.The findings of this study provide a new perspective to better explain the functions of SOEs in the 21st century.

Systematic evaluation of three porcine-derived collagen membranes for guided bone regeneration

Guided bone regeneration is one of the most common surgical treatment modalities performed when an additional alveolar bone is required to stabilize dental implants in partially and fully edentulous patients.The addition of a barrier membrane prevents non-osteogenic tissue invasion into the bone cavity,which is key to the success of guided bone regeneration.Barrier membranes can be broadly classified as non-resorbable or resorbable.In contrast to non-resorbable membranes,resorbable barrier membranes do not require a second surgical procedure for membrane removal.Commercially available resorbable barrier membranes are either synthetically manufactured or derived from xenogeneic collagen.Although collagen barrier membranes have become increasingly popular amongst clinicians,largely due to their superior handling qualities compared to other commercially available barrier membranes,there have been no studies to date that have compared commercially available porcine-derived collagen membranes with respect to surface topography,collagen fibril structure,physical barrier property,and immunogenic composition.This study evaluated three commercially available non-crosslinked porcine-derived collagen membranes(Striate+TM,Bio-Gide®and CreosTM Xenoprotect).Scanning electron microscopy revealed similar collagen fibril distribution on both the rough and smooth sides of the membranes as well as the similar diameters of collagen fibrils.However,D-periodicity of the fibrillar collagen is significantly different among the membranes,with Striate+TM membrane having the closest D-periodicity to native collagen I.This suggests that there is less deformation of collagen during manufacturing process.All collagen membranes showed superior barrier property evidenced by blocking 0.2–16.4µm beads passing through the membranes.To examine the immunogenic agents in these membranes,we examined the membranes for the presence of DNA and alpha-gal by immunohistochemistry.No alpha-gal or DNA was detected in any membranes.However,using a more sensitive detection method(real-time polymerase chain reaction),a relatively strong DNA signal was detected in Bio-Gide®membrane,but not Striate+TM and CreosTM Xenoprotect membranes.Our study concluded that these membranes are similar but not identical,probably due to the different ages and sources of porcine tissues,as well as different manufacturing processes.We recommend further studies to understand the clinical implications of these findings.