BACKGROUND： Studies of several animal models of central nervous system diseases have shown that neural progenitor cells （NPCs） can migrate to injured tissues. Stromal cell-derived factor 1 alpha （SDF-la）, and its...BACKGROUND： Studies of several animal models of central nervous system diseases have shown that neural progenitor cells （NPCs） can migrate to injured tissues. Stromal cell-derived factor 1 alpha （SDF-la）, and its primary physiological receptor CXCR4, have been shown to contribute to this process. OBJECTIVE： To investigate migration efficacy of human NPCs toward a SDF-1α gradient, and the regulatory roles of tumor necrosis factor-α （TNF-α） and interleukin-8 （IL-8） in SDF-1α/CXCR4 axis-induced migration of NPCs. DESIGN, TIME AND SETTING： An in vitro, randomized, controlled, cellular and molecular biology study was performed at the Laboratory of Department of Cell Biology, Medical College of Soochow University between October 2005 and November 2007. MATERIALS： SDF-1α and mouse anti-human CXCR4 fusion antibody were purchased from R＆D Systems, USA. TNF-αwas purchased from Biomyx Technology, USA and IL-8 was kindly provided by the Biotechnology Research Institute of Soochow University. METHODS： NPCs isolated from forebrain tissue of 9 to 10-week-old human fetuses were cultured in vitro. The cells were incubated with 0, 20, and 40 ng/mL TNF-α, or 0, 20, and 40 ng/mL IL-8, for 48 hours prior to migration assay. For antibody-blocking experiments, cells were further pretreated with 0, 20, and 40 μg/mL mouse anti-human CXCR4 fusion antibody for 2 hours. Subsequently, the transwell assay and CXCR4 blockade experiments were performed to evaluate migration of human NPCs toward a SDF-1α gradient. Serum-free culture medium without SDF-1α served as the negative control. MAIN OUTCOME MEASURES： The transwell assay was performed to evaluate migration of human NPCs toward a SDF-1α gradient, which was blocked by fusion antibody against CXCR4. In addition, CXCR4 expression in human NPCs stimulated by TNF-α and IL-8 was measured by flow cytometry. RESULTS： Results from the transwell assay demonstrated that SDF-1α was a strong chemoattractant for human NPCs （P 〈 0.01）, and 20 ng/mL produced the highest levels of migration. Anti-human CXCR4 fusion antibody significantly blocked the chemotactic effect （P 〈 0.05）. Flow cytometry results showed that treatment with TNF-α and IL-8 resulted in increased CXCR4 expression and greater chemotaxis efficiency of NPCs towards SDF-1α（P 〈 0.01）. CONCLUSION： These results demonstrated that SDF-la significantly attracted NPCs in vitro, and neutralizing anti-CXCR4 antibody could block part of this chemotactic function. TNF-α and IL-8 increased chemotaxis efficiency of NPCs towards the SDF-1αgradient by upregulating CXCR4 expression in NPCs.展开更多
Atypical fibroxanthomas (AFX) are rare skin tumors. These generally are superficial tumors, usually <3 cm red, fleshy, ulcerated skin lesions, that characteristically occur on sun-damaged skin, sometimes in immunoc...Atypical fibroxanthomas (AFX) are rare skin tumors. These generally are superficial tumors, usually <3 cm red, fleshy, ulcerated skin lesions, that characteristically occur on sun-damaged skin, sometimes in immunocompromised or previously irradiated patients. These are part of a spectrum of more aggressive fibro-histiocytic neoplasms. In the older literature, these have been termed aggressive or metastatic AFX, but currently these have been reclassified as pleomorphic dermal sarcomas (PDS) and systemic undifferentiated pleomorphic sarcoma (UPS, formerly malignant fibrohistiocytic sarcoma, MFH). We present the case of a 64-year old woman who developed a deeply invasive PDS on the vertex of her scalp invading to the galea, with in-transit scalp metastases. Very little information is available about optimal treatment of metastatic PDS lesions. The patient was initially treated with 2 cycles of epirubicin/ifosfamide chemotherapy, resulting in life-threatening complications. A pretreatment peripheral blood sample was sent for CTC-derived colony assay. This sample grew 8 colonies from 10 ml blood. The tumor failed to respond to epirubicin and ifosfamide, and after several months of hospitalization, a second peripheral blood CTC-derived colony assay grew >376 colonies. The patient could not tolerate additional chemotherapy. She was therefore treated with the oral targeted agent pazopanib. The patient developed a dramatic biopsy-confirmed complete response. After 11 months of pazopanib treatment, a repeat CTC-derived culture sample grew only 8 colonies/10 ml blood. The complete response to pazopanib is still ongoing at over 41 months. To our knowledge, this is the first demonstration of clinical complete response of a PDS tumor following targeted therapy. An additional novel feature was the demonstration that CTC-derived colonies could be grown from the blood of a PDS patient. The number of colonies appeared to correlate with the clinical treatment response and seemed to function as a potential prognostic marker.展开更多
AIM:To evaluate differences in microparticle profiles in vitreous samples between diabetic and non-diabetic eyes undergoing vitrectomy.METHODS:Un-masked cross-sectional series of 34 eyes undergoing vitrectomy.Vitreous...AIM:To evaluate differences in microparticle profiles in vitreous samples between diabetic and non-diabetic eyes undergoing vitrectomy.METHODS:Un-masked cross-sectional series of 34 eyes undergoing vitrectomy.Vitreous specimens were collected and processed to evaluate for membrane integrity(DAPI),apoptosis(Annexin-V),and endothelial-cell origin(V-Cadherin).A BD LSR II flow cytometer was used for analysis and standardized sub-micron-sized beads were used for size comparison.RESULTS:Thirty-four specimens underwent analysis.Greater levels of Annexin-V were found on microparticles from specimens in which blood had entered the vitreous(n=12)compared to those without blood(n=22;52.3%±30.7%vs 19.6%±27.2%,P=0.002).Patients with diabetes having surgery with hemorrhage(n=7)had greater expression of Annexin-V than those without hemorrhage(n=8;62.1%±31.7%vs 18.9%±20.9%,P=0.009).However,in patients with non-diabetic vitreous hemorrhage,the level of Annexin-V expression was not significantly different compared to other disease processes(38.6%±25.7%,n=5 vs 20.0%±30.9%,n=14,P=0.087).CONCLUSION:Increased expression of the apoptotic marker,Annexin-V is detected on vitreous microparticles in diabetes-related vitreous hemorrhage.When evaluating vitreous hemorrhage in patients without diabetes,the apoptotic signal is not significantly different.Vitrectomy in patients with diabetes,and improvement in visual outcomes,may be related to the removal of a serumderived,pro-apoptotic vitreous.Further investigation is warranted in order to identify the molecular characteristics of microparticles that regulate disease.展开更多
Immunotherapy has great promise in improving malignant tumor treatment.However,the efficacy of existing strategies is often limited by the immunosuppressive environment.Here,we demonstrate an in situ bionic immunoacti...Immunotherapy has great promise in improving malignant tumor treatment.However,the efficacy of existing strategies is often limited by the immunosuppressive environment.Here,we demonstrate an in situ bionic immunoactivator,PLT-Bec1/DTA-1,with possessed natural advantages of platelets for tumor recruitment and activation,on which DTA-1(CD357 monoclonal antibody)and Bec1 were tethered as combined immune boosters.PLT-Bec1/DTA-1,as a self-triggered release repository,can deliver the pre-tethered Bec1 and DTA-1 deeply through the secretion of platelet microparticles(PMPs),thereby cooperate tacitly and exhibit superiority in immune activation of dendritic cells(DCs)and T cells via autophagy inducibility,coupled with glucocorticoid-induced tumor necrosis factor receptor(GITR)-triggered T_(Reg) suppression,remodeled the immunosuppressive network of tumor microenvironment.PLT-Bec1/DTA-1 promoted antigen presentation and T cell proliferation,and alleviated the low activity state of bone marrow-derived dendritic cells(BMDCs)in tumor suppressive environment.PLT-Bec1/DTA-1 inhibited tumor recurrence(5-and 13-fold lower of control group in tumor volume)and CD8^(+)T/T_(Reg) ratio(6.3-and 8.8-fold vs.control group)in mouse tumor model after intravenous or subcutaneous administration.Also,PLT-Bec1/DTA-1 prevented tumor colonization in lung through in situ immune activation,and was slightly superior to the combined of Bec1 and PD-L1.Our findings highlight the promise of delivering immunostimulatory payloads via bionic carriers,eliciting automatic in situ activation of effector immune cells in tumor microenvironment for tumor eradication.All these results provide promising prospects into the application of immunoactivator in improving cancer synergistic immunotherapy to overcome the bottlenecks in clinic.展开更多
Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Ac...Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Academy of Medical Sciences Initiative for Innovative Medicine on Tumor Immunology held in Beijing, China, on May 12, 2017, a number of speakers reported new findings and ongoing studies on immune-related diseases such as cancer, fibrotic disease, diabetes, and others. A considerably insightful overview was provided on cancer immunity, tumor microenvironments,and new immunotherapy for cancer. In addition, chronic inflammatory diseases were discussed. These findings may offer new insights into targeted immunotherapy.展开更多
基金the National Natural Science Foundation of China,No.30671041the National Basic Research Program of China(973 Program),No. 2005CB623902
文摘BACKGROUND： Studies of several animal models of central nervous system diseases have shown that neural progenitor cells （NPCs） can migrate to injured tissues. Stromal cell-derived factor 1 alpha （SDF-la）, and its primary physiological receptor CXCR4, have been shown to contribute to this process. OBJECTIVE： To investigate migration efficacy of human NPCs toward a SDF-1α gradient, and the regulatory roles of tumor necrosis factor-α （TNF-α） and interleukin-8 （IL-8） in SDF-1α/CXCR4 axis-induced migration of NPCs. DESIGN, TIME AND SETTING： An in vitro, randomized, controlled, cellular and molecular biology study was performed at the Laboratory of Department of Cell Biology, Medical College of Soochow University between October 2005 and November 2007. MATERIALS： SDF-1α and mouse anti-human CXCR4 fusion antibody were purchased from R＆D Systems, USA. TNF-αwas purchased from Biomyx Technology, USA and IL-8 was kindly provided by the Biotechnology Research Institute of Soochow University. METHODS： NPCs isolated from forebrain tissue of 9 to 10-week-old human fetuses were cultured in vitro. The cells were incubated with 0, 20, and 40 ng/mL TNF-α, or 0, 20, and 40 ng/mL IL-8, for 48 hours prior to migration assay. For antibody-blocking experiments, cells were further pretreated with 0, 20, and 40 μg/mL mouse anti-human CXCR4 fusion antibody for 2 hours. Subsequently, the transwell assay and CXCR4 blockade experiments were performed to evaluate migration of human NPCs toward a SDF-1α gradient. Serum-free culture medium without SDF-1α served as the negative control. MAIN OUTCOME MEASURES： The transwell assay was performed to evaluate migration of human NPCs toward a SDF-1α gradient, which was blocked by fusion antibody against CXCR4. In addition, CXCR4 expression in human NPCs stimulated by TNF-α and IL-8 was measured by flow cytometry. RESULTS： Results from the transwell assay demonstrated that SDF-1α was a strong chemoattractant for human NPCs （P 〈 0.01）, and 20 ng/mL produced the highest levels of migration. Anti-human CXCR4 fusion antibody significantly blocked the chemotactic effect （P 〈 0.05）. Flow cytometry results showed that treatment with TNF-α and IL-8 resulted in increased CXCR4 expression and greater chemotaxis efficiency of NPCs towards SDF-1α（P 〈 0.01）. CONCLUSION： These results demonstrated that SDF-la significantly attracted NPCs in vitro, and neutralizing anti-CXCR4 antibody could block part of this chemotactic function. TNF-α and IL-8 increased chemotaxis efficiency of NPCs towards the SDF-1αgradient by upregulating CXCR4 expression in NPCs.
文摘Atypical fibroxanthomas (AFX) are rare skin tumors. These generally are superficial tumors, usually <3 cm red, fleshy, ulcerated skin lesions, that characteristically occur on sun-damaged skin, sometimes in immunocompromised or previously irradiated patients. These are part of a spectrum of more aggressive fibro-histiocytic neoplasms. In the older literature, these have been termed aggressive or metastatic AFX, but currently these have been reclassified as pleomorphic dermal sarcomas (PDS) and systemic undifferentiated pleomorphic sarcoma (UPS, formerly malignant fibrohistiocytic sarcoma, MFH). We present the case of a 64-year old woman who developed a deeply invasive PDS on the vertex of her scalp invading to the galea, with in-transit scalp metastases. Very little information is available about optimal treatment of metastatic PDS lesions. The patient was initially treated with 2 cycles of epirubicin/ifosfamide chemotherapy, resulting in life-threatening complications. A pretreatment peripheral blood sample was sent for CTC-derived colony assay. This sample grew 8 colonies from 10 ml blood. The tumor failed to respond to epirubicin and ifosfamide, and after several months of hospitalization, a second peripheral blood CTC-derived colony assay grew >376 colonies. The patient could not tolerate additional chemotherapy. She was therefore treated with the oral targeted agent pazopanib. The patient developed a dramatic biopsy-confirmed complete response. After 11 months of pazopanib treatment, a repeat CTC-derived culture sample grew only 8 colonies/10 ml blood. The complete response to pazopanib is still ongoing at over 41 months. To our knowledge, this is the first demonstration of clinical complete response of a PDS tumor following targeted therapy. An additional novel feature was the demonstration that CTC-derived colonies could be grown from the blood of a PDS patient. The number of colonies appeared to correlate with the clinical treatment response and seemed to function as a potential prognostic marker.
基金Supported by an unrestricted grant to Washington University by Research to Prevent Blindness Inc.,New York,NY。
文摘AIM:To evaluate differences in microparticle profiles in vitreous samples between diabetic and non-diabetic eyes undergoing vitrectomy.METHODS:Un-masked cross-sectional series of 34 eyes undergoing vitrectomy.Vitreous specimens were collected and processed to evaluate for membrane integrity(DAPI),apoptosis(Annexin-V),and endothelial-cell origin(V-Cadherin).A BD LSR II flow cytometer was used for analysis and standardized sub-micron-sized beads were used for size comparison.RESULTS:Thirty-four specimens underwent analysis.Greater levels of Annexin-V were found on microparticles from specimens in which blood had entered the vitreous(n=12)compared to those without blood(n=22;52.3%±30.7%vs 19.6%±27.2%,P=0.002).Patients with diabetes having surgery with hemorrhage(n=7)had greater expression of Annexin-V than those without hemorrhage(n=8;62.1%±31.7%vs 18.9%±20.9%,P=0.009).However,in patients with non-diabetic vitreous hemorrhage,the level of Annexin-V expression was not significantly different compared to other disease processes(38.6%±25.7%,n=5 vs 20.0%±30.9%,n=14,P=0.087).CONCLUSION:Increased expression of the apoptotic marker,Annexin-V is detected on vitreous microparticles in diabetes-related vitreous hemorrhage.When evaluating vitreous hemorrhage in patients without diabetes,the apoptotic signal is not significantly different.Vitrectomy in patients with diabetes,and improvement in visual outcomes,may be related to the removal of a serumderived,pro-apoptotic vitreous.Further investigation is warranted in order to identify the molecular characteristics of microparticles that regulate disease.
基金We would like to thank the National Natural Science Foundation of China(No.81973258)the Beijing Natural Science Foundation(Nos.L202044,7202092)for funding this work.
文摘Immunotherapy has great promise in improving malignant tumor treatment.However,the efficacy of existing strategies is often limited by the immunosuppressive environment.Here,we demonstrate an in situ bionic immunoactivator,PLT-Bec1/DTA-1,with possessed natural advantages of platelets for tumor recruitment and activation,on which DTA-1(CD357 monoclonal antibody)and Bec1 were tethered as combined immune boosters.PLT-Bec1/DTA-1,as a self-triggered release repository,can deliver the pre-tethered Bec1 and DTA-1 deeply through the secretion of platelet microparticles(PMPs),thereby cooperate tacitly and exhibit superiority in immune activation of dendritic cells(DCs)and T cells via autophagy inducibility,coupled with glucocorticoid-induced tumor necrosis factor receptor(GITR)-triggered T_(Reg) suppression,remodeled the immunosuppressive network of tumor microenvironment.PLT-Bec1/DTA-1 promoted antigen presentation and T cell proliferation,and alleviated the low activity state of bone marrow-derived dendritic cells(BMDCs)in tumor suppressive environment.PLT-Bec1/DTA-1 inhibited tumor recurrence(5-and 13-fold lower of control group in tumor volume)and CD8^(+)T/T_(Reg) ratio(6.3-and 8.8-fold vs.control group)in mouse tumor model after intravenous or subcutaneous administration.Also,PLT-Bec1/DTA-1 prevented tumor colonization in lung through in situ immune activation,and was slightly superior to the combined of Bec1 and PD-L1.Our findings highlight the promise of delivering immunostimulatory payloads via bionic carriers,eliciting automatic in situ activation of effector immune cells in tumor microenvironment for tumor eradication.All these results provide promising prospects into the application of immunoactivator in improving cancer synergistic immunotherapy to overcome the bottlenecks in clinic.
基金supported by grants of 81530093 from the National Natural Science Foundation of China81661128007, 81472653 and 81530080 from National Natural Science Foundation of China+26 种基金supported by grants of 31390431 from the National Natural Science Foundation of Chinasupported by grants of Natural Sciences Foundation of China(31301007 and 81272525)supported by grants of 81622010 from the National Natural Science Foundation of Chinasupported by grants of 81472717 and 81673474 from the National Natural Science Foundation of China81661128007, 81472653 and 81530080 from National Natural Science Foundation of Chinasupported by grants of 81400286 and 81530093 from the National Natural Science Foundation of Chinasupported by grants of 81400140 from the National Natural Science Foundation of Chinasupported by grants of 81503128 from the National Natural Science Foundation of China2016I2M-1-008 from Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciencessupported by grants of 2014CB542103 from National Basic Research Program of China81502473 from National Natural Science Fund for Young Scholars of Chinasupported by US National Institutes of Health grants (CA217510, CA123088, CA099985, CA193136 and CA152470)supported by grants from the Canadian Institutes of Health Research(FRN 123516 and 152954)the Ontario Institute for Cancer Research(ORBiT)supported by NIH grant GM072744Ministry of Science and Technology of China grant 2016YFA0101100the Fundamental Research Fund for the Central University(No. 2017KFQWJX002) from Huazhong University of Science and TechnologyCore fund (Wang2016) for Development of Cell and Gene Therapy Centre of Academy of Medical Sciences,Zhengzhou UniversityThe MRC (MR/M015696/1)2017YFA0205400 from Ministry of Science and Technology of China2016ZX310190 and 2016ZX320014 from Central Public-interest Scientific Institution Basal Research Fund7162133 from Beijing Natural Science Foundation2016-I2M-4-001 from CAMS Innovation Fund for Medical Sciences2016-I2M-1-007 from the CAMS Innovation Fund for Medical Sciences2016-I2M-1010 from the CAMS Innovation Fund for Medical Sciences2016-I2M-1011 from the CAMS Innovation Fund for Medical Sciences2016-I2M-1008 from CAMS Innovation Fund for Medical Sciences
文摘Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Academy of Medical Sciences Initiative for Innovative Medicine on Tumor Immunology held in Beijing, China, on May 12, 2017, a number of speakers reported new findings and ongoing studies on immune-related diseases such as cancer, fibrotic disease, diabetes, and others. A considerably insightful overview was provided on cancer immunity, tumor microenvironments,and new immunotherapy for cancer. In addition, chronic inflammatory diseases were discussed. These findings may offer new insights into targeted immunotherapy.
