Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attrac...Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.展开更多
Gradual distraction with an external fixator is a widely used treatment for severe postburn ankle contracture(SPAC).However,application of external fixators is complex,and conventional two-dimensional(2D)imaging-based...Gradual distraction with an external fixator is a widely used treatment for severe postburn ankle contracture(SPAC).However,application of external fixators is complex,and conventional two-dimensional(2D)imaging-based surgical planning is not particularly helpful due to a lack of spatial geometry.The purpose of this study was to evaluate the surgical planning process for this procedure with patient-specific three-dimension-printed models(3DPMs).In this study,patients coming from two centers were divided into two cohorts(3DPM group vs.control group)depending on whether a 3DPM was used for preoperative surgical planning.Operation duration,improvement in metatarsal-tibial angle(MTA),range of motion(ROM),the American Orthopedic Foot and Ankle Society(AOFAS)scores,complications,and patient-reported satisfaction were compared between two groups.The 3DPM group had significantly shorter operation duration than the control group((2.0±0.3)h vs.(3.2±0.3)h,P<0.01).MTA,ROM,and AOFAS scores between the two groups showed no significant differences pre-operation,after the removal of the external fixator,or at follow-up.Plantigrade feet were achieved and gait was substantially improved in all patients at the final follow-up.Pin-tract infections occurred in two patients(one in each group)during distraction and were treated with wound care and oral antibiotics.Patients in the 3DPM group reported higher satisfaction than those in the control group,owing to better patient-surgeon communication.Surgical planning using patient-specific 3DPMs significantly reduced operation duration and increased patient satisfaction,while providing similar improvements in ankle movement and function compared to traditional surgical planning for the correction of SPAC with external fixators.展开更多
Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment.We developed porcine stomach musculofascial flap matrix(PDSF)comprising extracellular matrix(ECM)and ...Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment.We developed porcine stomach musculofascial flap matrix(PDSF)comprising extracellular matrix(ECM)and intact vasculature.PDSF had a dominant vascular pedicle,microcirculatory vessels,a nerve network,well-retained 3-dimensional(3D)nanofibrous ECM structures,and no allo-or xenoantigenicity.In-depth proteomic analysis demonstrated that PDSF was composed of core matrisome proteins(e.g.,collagens,glycoproteins,proteoglycans,and ECM regulators)that,as shown by Gene Ontology term enrichment analysis,are functionally related to musculofascial biological processes.Moreover,PDSFhuman adipose-derived stem cell(hASC)synergy not only induced monocytes towards IL-10producing M2 macrophage polarization through the enhancement of hASCs’paracrine effect but also promoted the proliferation and interconnection of both human skeletal muscle myoblasts(HSMMs)and human umbilical vein endothelial cells(HUVECs)in static triculture conditions.Furthermore,PDSF was successfully prevascularized through a dynamic perfusion coculture of hASCs and HUVECs,which integrated with PDSF and induced the maturation of vascular networks in vitro.In a xenotransplantation model,PDSF demonstrated myoconductive and immunomodulatory properties associated with the predominance of M2 macrophages and regulatory T cells.In a volumetric muscle loss(VML)model,prevascularized PDSF augmented neovascularization and constructive remodeling,which was characterized by the predominant infiltration of M2 macrophages and significant musculofascial tissue formation.These results indicate that hASCs’integration with PDSF enhances the cells’dual function in immunomodulation and angiogenesis.Owing in part to this PDSF-hASC synergy,our platform shows promise for vascularized muscle flap engineering for VML reconstruction.展开更多
基金the National Natural Science Foundation of China(Grant No.:51803120).
文摘Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.
文摘Gradual distraction with an external fixator is a widely used treatment for severe postburn ankle contracture(SPAC).However,application of external fixators is complex,and conventional two-dimensional(2D)imaging-based surgical planning is not particularly helpful due to a lack of spatial geometry.The purpose of this study was to evaluate the surgical planning process for this procedure with patient-specific three-dimension-printed models(3DPMs).In this study,patients coming from two centers were divided into two cohorts(3DPM group vs.control group)depending on whether a 3DPM was used for preoperative surgical planning.Operation duration,improvement in metatarsal-tibial angle(MTA),range of motion(ROM),the American Orthopedic Foot and Ankle Society(AOFAS)scores,complications,and patient-reported satisfaction were compared between two groups.The 3DPM group had significantly shorter operation duration than the control group((2.0±0.3)h vs.(3.2±0.3)h,P<0.01).MTA,ROM,and AOFAS scores between the two groups showed no significant differences pre-operation,after the removal of the external fixator,or at follow-up.Plantigrade feet were achieved and gait was substantially improved in all patients at the final follow-up.Pin-tract infections occurred in two patients(one in each group)during distraction and were treated with wound care and oral antibiotics.Patients in the 3DPM group reported higher satisfaction than those in the control group,owing to better patient-surgeon communication.Surgical planning using patient-specific 3DPMs significantly reduced operation duration and increased patient satisfaction,while providing similar improvements in ankle movement and function compared to traditional surgical planning for the correction of SPAC with external fixators.
基金This work was supported by a grant from The Plastic Surgery Foundation(PSF312406,to Q.Zhang)by the Kyte Fund through MD Anderson’s Department of Plastic Surgery+1 种基金This research was also supported by the NIH through MD Anderson’s Cancer Center Support Grant(P30CA016672)used MD Anderson’s High Resolution Electron Microscopy Facility,Flow Cytometry and Cellular Imaging Core Facility,and Proteomics and Metabolomics Core Facility.
文摘Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment.We developed porcine stomach musculofascial flap matrix(PDSF)comprising extracellular matrix(ECM)and intact vasculature.PDSF had a dominant vascular pedicle,microcirculatory vessels,a nerve network,well-retained 3-dimensional(3D)nanofibrous ECM structures,and no allo-or xenoantigenicity.In-depth proteomic analysis demonstrated that PDSF was composed of core matrisome proteins(e.g.,collagens,glycoproteins,proteoglycans,and ECM regulators)that,as shown by Gene Ontology term enrichment analysis,are functionally related to musculofascial biological processes.Moreover,PDSFhuman adipose-derived stem cell(hASC)synergy not only induced monocytes towards IL-10producing M2 macrophage polarization through the enhancement of hASCs’paracrine effect but also promoted the proliferation and interconnection of both human skeletal muscle myoblasts(HSMMs)and human umbilical vein endothelial cells(HUVECs)in static triculture conditions.Furthermore,PDSF was successfully prevascularized through a dynamic perfusion coculture of hASCs and HUVECs,which integrated with PDSF and induced the maturation of vascular networks in vitro.In a xenotransplantation model,PDSF demonstrated myoconductive and immunomodulatory properties associated with the predominance of M2 macrophages and regulatory T cells.In a volumetric muscle loss(VML)model,prevascularized PDSF augmented neovascularization and constructive remodeling,which was characterized by the predominant infiltration of M2 macrophages and significant musculofascial tissue formation.These results indicate that hASCs’integration with PDSF enhances the cells’dual function in immunomodulation and angiogenesis.Owing in part to this PDSF-hASC synergy,our platform shows promise for vascularized muscle flap engineering for VML reconstruction.
