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Introduction: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m2 in the avacopan group and 4.1 ml/min per 1.73 m2 in the prednisone group (P = 0.029) at week 52. This new analysis examines the results in the patient subgroup with severe renal insufficiency at enrollment into the trial, i.e., eGFR ≤20 ml/min per 1.73 m2. Methods: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups. Results: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR ≤20 ml/min per 1.73 m2. At week 52, eGFR increased on average 16.1 and 7.7 ml/min per 1.73 m2 in the avacopan and prednisone groups, respectively (P = 0.003). The last eGFR value measured during the 52-week treatment period was ≥2-fold higher than baseline in 41% of patients in the avacopan group compared to 13% in the prednisone group (P = 0.030). More patients in the avacopan group versus prednisone group had increases in eGFR above 20, 30, and 45 ml/min per 1.73 m2, respectively. Serious adverse events occurred in 13 of 27 patients (48%) in the avacopan group and 16 of 23 patients (70%) in the prednisone group. Conclusion: Among patients with baseline eGFR ≤20 ml/min per 1.73 m2 in the ADVOCATE trial, eGFR improved more in the avacopan group than in the prednisone group.

This study conducted an analysis of muons, protons, and charged pions emitted from $\nu_{\mu}$ charged-current interactions on iron using a nuclear emulsion detector. The emulsion detector with a 65$\,$kg iron target was exposed to a neutrino beam corresponding to 4.0$\times$10$^{19}$ protons on target with a mean neutrino energy of 1.49$\,$GeV. The measurements were performed at a momentum threshold of 200 (50)$\,$MeV/$c$ for protons (pions), which are the lowest momentum thresholds attempted up to now. The measured quantities are the multiplicities, emission angles, and momenta of the muons, protons, and charged pions. In addition to these inclusive measurements, exclusive measurements such as the muon-proton emission-angle correlations of specific channels and the opening angle between the protons of CC0$\pi$2$p$ events were performed. The data were compared to Monte Carlo (MC) predictions and some significant differences were observed. The results of the study demonstrate the capability of detailed measurements of neutrino-nucleus interactions using a nuclear emulsion detector to improve neutrino interaction models., Comment: 21 pages, 25 figures

This study conducted an analysis of muons, protons, and charged pions emitted from $\nu_{\mu}$ charged-current interactions on iron using a nuclear emulsion detector. The emulsion detector with a 65$\,$kg iron target was exposed to a neutrino beam corresponding to 4.0$\times$10$^{19}$ protons on target with a mean neutrino energy of 1.49$\,$GeV. The measurements were performed at a momentum threshold of 200 (50)$\,$MeV/$c$ for protons (pions), which are the lowest momentum thresholds attempted up to now. The measured quantities are the multiplicities, emission angles, and momenta of the muons, protons, and charged pions. In addition to these inclusive measurements, exclusive measurements such as the muon-proton emission-angle correlations of specific channels and the opening angle between the protons of CC0$\pi$2$p$ events were performed. The data were compared to Monte Carlo (MC) predictions and some significant differences were observed. The results of the study demonstrate the capability of detailed measurements of neutrino-nucleus interactions using a nuclear emulsion detector to improve neutrino interaction models., Comment: 21 pages, 25 figures

OBJECTIVE: The absent in melanoma 2 (AIM2) cytosolic pattern recognition receptor and DNA sensor promotes the pathogenesis of autoimmune and chronic inflammatory diseases via caspase-1-containing inflammasome complexes. However, the role of AIM2 in cancer is ill-defined. DESIGN: The expression of AIM2 and its clinical significance was assessed in human gastric cancer (GC) patient cohorts. Genetic or therapeutic manipulation of AIM2 expression and activity was performed in the genetically engineered gp130F/F spontaneous GC mouse model, as well as human GC cell line xenografts. The biological role and mechanism of action of AIM2 in gastric tumourigenesis, including its involvement in inflammasome activity and functional interaction with microtubule-associated end-binding protein 1 (EB1), was determined in vitro and in vivo. RESULT(S): AIM2 expression is upregulated by interleukin-11 cytokine-mediated activation of the oncogenic latent transcription factor STAT3 in the tumour epithelium of GC mouse models and patients with GC. Genetic and therapeutic targeting of AIM2 in gp130F/F mice suppressed tumourigenesis. Conversely, AIM2 overexpression augmented the tumour load of human GC cell line xenografts. The protumourigenic function of AIM2 was independent of inflammasome activity and inflammation. Rather, in vivo and in vitro AIM2 physically interacted with EB1 to promote epithelial cell migration and tumourigenesis. Furthermore, upregulated expression of AIM2 and EB1 in the tumour epithelium of patients with GC was independently associated with poor patient survival. CONCLUSION(S): AIM2 can play a driver role in epithelial carcinogenesis by linking cytokine-STAT3 signalling, innate immunity and epithelial cell migration, independent of inflammasome activation.Copyright © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

We have studied the validity of the double-probe method in recombining plasmas. Electron temperature (Te) measured with a double probe was quantitatively evaluated by taking into account the influences of plasma potential fluctuation, plasma resistivity, and electron density fluctuation on the current–voltage characteristics. Differential potential fluctuation and plasma resistivity between two electrodes have a minor effect on Te especially when the inter-distance is small (typically 1 mm). Scattering of measured Te due to the density fluctuation was sufficiently suppressed by making the data acquisition time long (typically 4 s) and taking the average. There is a good agreement between Te measured with the optimized double-probe method and that with laser Thomson scattering diagnostics., source:https://doi.org/10.1002/ctpp.201800088, identifier:0000-0001-6090-5010

We have carried out $\nu_{\mu}$ charged-current interaction measurement on iron using an emulsion detector exposed to the T2K neutrino beam in the J-PARC neutrino facility. The data samples correspond to 4.0$\times$10$^{19}$ protons on target, and the neutrino mean energy is 1.49$\,$GeV. The emulsion detector is suitable for precision measurements of charged particles produced in neutrino-iron interactions with a low momentum threshold thanks to thin-layered structure and sub-$\mu$m spatial resolution. The charged particles are successfully detected, and their multiplicities are measured using the emulsion detector. The cross section was measured to be $\sigma^{\mathrm{Fe}}_{\mathrm{CC}} = (1.28 \pm 0.11({\mathrm{stat.}})^{+0.12}_{-0.11}({\mathrm{syst.}})) \times 10^{-38} \, {\mathrm{cm}}^{2}/{\mathrm{nucleon}}$. The cross section in a limited kinematic phase space of induced muons, $\theta_{\mu} < 45^{\circ}$ and $p_{\mu} > 400 \, {\rm MeV}/c$, on iron was $\sigma^{\mathrm{Fe}}_{\mathrm{CC \hspace{1mm} phase \hspace{0.5mm} space}} = (0.84 \pm 0.07({\mathrm{stat.}})^{+0.07}_{-0.06}({\mathrm{syst.}})) \times 10^{-38} \, {\mathrm{cm}}^{2}/{\mathrm{nucleon}}$. The cross-section results are consistent with previous values obtained via different techniques using the same beamline, and they are well reproduced by current neutrino interaction models. These results demonstrate the capability of the detector towards the detailed measurements of the neutrino-nucleus interactions around the 1$\,$GeV energy region., Comment: 27 pages, 17 figures

We have carried out $\nu_{\mu}$ charged-current interaction measurement on iron using an emulsion detector exposed to the T2K neutrino beam in the J-PARC neutrino facility. The data samples correspond to 4.0$\times$10$^{19}$ protons on target, and the neutrino mean energy is 1.49$\,$GeV. The emulsion detector is suitable for precision measurements of charged particles produced in neutrino-iron interactions with a low momentum threshold thanks to thin-layered structure and sub-$\mu$m spatial resolution. The charged particles are successfully detected, and their multiplicities are measured using the emulsion detector. The cross section was measured to be $\sigma^{\mathrm{Fe}}_{\mathrm{CC}} = (1.28 \pm 0.11({\mathrm{stat.}})^{+0.12}_{-0.11}({\mathrm{syst.}})) \times 10^{-38} \, {\mathrm{cm}}^{2}/{\mathrm{nucleon}}$. The cross section in a limited kinematic phase space of induced muons, $\theta_{\mu} < 45^{\circ}$ and $p_{\mu} > 400 \, {\rm MeV}/c$, on iron was $\sigma^{\mathrm{Fe}}_{\mathrm{CC \hspace{1mm} phase \hspace{0.5mm} space}} = (0.84 \pm 0.07({\mathrm{stat.}})^{+0.07}_{-0.06}({\mathrm{syst.}})) \times 10^{-38} \, {\mathrm{cm}}^{2}/{\mathrm{nucleon}}$. The cross-section results are consistent with previous values obtained via different techniques using the same beamline, and they are well reproduced by current neutrino interaction models. These results demonstrate the capability of the detector towards the detailed measurements of the neutrino-nucleus interactions around the 1$\,$GeV energy region., Comment: 27 pages, 17 figures

This paper reports the track multiplicity and kinematics of muons, charged pions, and protons from charged-current inclusive $\bar{\nu}_{\mu}$ and $\nu_{\mu}$ interactions on a water target, measured using a nuclear emulsion detector in the NINJA experiment. A 3-kg water target was exposed to the T2K antineutrino-enhanced beam with a mean energy of 1.3 GeV. Owing to the high-granularity of the nuclear emulsion, protons with momenta down to 200 MeV/$c$ from the neutrino-water interactions were detected. We find good agreement between the observed data and model predictions for all kinematic distributions other than the number of charged pions. These results demonstrate the capability of measurements with nuclear emulsion to improve neutrino interaction models., Comment: 22 pages, 20 figures

Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation-associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour-associated TLSs remain ill-defined. Here, we observed tumour-associated TLSs in a preclinical mouse model (gp130F/F) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL-6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell-rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130-driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3-dependent, but independent of the cytokine IL-17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour-associated TLSs were also observed in patients with intestinal-type gastric cancer, and a gene signature linked with TLS development in gp130F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130-STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis.Copyright © 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf o

Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation-associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour-associated TLSs remain ill-defined. Here, we observed tumour-associated TLSs in a preclinical mouse model (gp130F/F) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL-6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell-rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130-driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3-dependent, but independent of the cytokine IL-17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour-associated TLSs were also observed in patients with intestinal-type gastric cancer, and a gene signature linked with TLS development in gp130F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130-STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis.Copyright © 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf o

Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation-associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour-associated TLSs remain ill-defined. Here, we observed tumour-associated TLSs in a preclinical mouse model (gp130F/F ) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL-6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell-rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130-driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3-dependent, but independent of the cytokine IL-17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour-associated TLSs were also observed in patients with intestinal-type gastric cancer, and a gene signature linked with TLS development in gp130F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130-STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis.

Precise neutrino--nucleus interaction measurements in the sub-multi GeV region are important to reduce the systematic uncertainty in future neutrino oscillation experiments. Furthermore, the excess of ${\nu_e}$ interactions, as a possible interpretation of the existence of a sterile neutrino has been observed in such an energy region. The nuclear emulsion technique can measure all the final state particles with low energy threshold for a variety of targets (Fe, C, H${_2}$O, and so on). Its sub-$\mu$m position resolution allows measurements of the ${\nu_e}$ cross-section with good electron/gamma separation capability. We started a new experiment at J-PARC to study sub-multi GeV neutrino interactions by introducing the nuclear emulsion technique. The J-PARC T60 experiment has been implemented as a first step of such a project. Systematic neutrino event analysis with full scanning data in the nuclear emulsion detector was performed for the first time. The first neutrino event detection and its analysis is described in this paper., Comment: 26 pages, 29 figures, 4 table, prepared for submission to PTEP

Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC. © 2012 Elsevier Inc.

Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC. © 2012 Elsevier Inc.

Injectable biomaterials have been recently investigated as a therapeutic approach for cardiac repair. Porcine-derived small intestinal submucosa (SIS) material is currently used in the clinic to promote accelerated wound healing for a variety of disorders. In this study, we hypothesized that gels derived from SIS extracellular matrix would be advantageous as an injectable material for cardiac repair. We evaluated 2 forms of SIS gel, types B (SIS-B) and C (SIS-C), for their ability to provide a therapeutic effect when injected directly into ischemic myocardium using a murine model of an acute myocardial infarction. Echocardiography analysis at both 2 and 6 weeks after infarction demonstrated preservation of end-systolic left ventricular geometry and improvement of cardiac contractility in the hearts injected with SIS-B when compared with control hearts injected with saline. However, the SIS-C gel provided no functional efficacy in comparison with control. Histological analysis revealed that SIS-B reduced infarct size and induced angiogenesis relative to control, whereas injection of SIS-C had minimal effect on these histological parameters. Characterization of both gels revealed differential growth factor content with SIS-B exhibiting higher levels of basic fibroblast growth factor than SIS-C, which may explain, at least in part, the differential histological and functional results. This study suggests that SIS gel offers therapeutic potential as an injectable material for the repair of ischemic myocardium. Further understanding of SIS gel characteristics, such as biological and physical properties, that are critical determinants of efficacy would be important for optimization of this biomaterial for cardiac repair. © 2010 Elsevier Ltd.

Injectable biomaterials have been recently investigated as a therapeutic approach for cardiac repair. Porcine-derived small intestinal submucosa (SIS) material is currently used in the clinic to promote accelerated wound healing for a variety of disorders. In this study, we hypothesized that gels derived from SIS extracellular matrix would be advantageous as an injectable material for cardiac repair. We evaluated 2 forms of SIS gel, types B (SIS-B) and C (SIS-C), for their ability to provide a therapeutic effect when injected directly into ischemic myocardium using a murine model of an acute myocardial infarction. Echocardiography analysis at both 2 and 6 weeks after infarction demonstrated preservation of end-systolic left ventricular geometry and improvement of cardiac contractility in the hearts injected with SIS-B when compared with control hearts injected with saline. However, the SIS-C gel provided no functional efficacy in comparison with control. Histological analysis revealed that SIS-B reduced infarct size and induced angiogenesis relative to control, whereas injection of SIS-C had minimal effect on these histological parameters. Characterization of both gels revealed differential growth factor content with SIS-B exhibiting higher levels of basic fibroblast growth factor than SIS-C, which may explain, at least in part, the differential histological and functional results. This study suggests that SIS gel offers therapeutic potential as an injectable material for the repair of ischemic myocardium. Further understanding of SIS gel characteristics, such as biological and physical properties, that are critical determinants of efficacy would be important for optimization of this biomaterial for cardiac repair. © 2010 Elsevier Ltd.

We have previously shown that populations of skeletal muscle-derived stem cells (MDSCs) exhibit sexbased differences for skeletal muscle and bone repair, with female cells demonstrating superior engrafting abilities to males in skeletal muscle while male cells differentiating more robustly toward the osteogenic and chondrogenic lineages. In this study, we tested the hypothesis that the therapeutic capacity of MDSCs transplanted into myocardium is influenced by sex of donor MDSCs or recipient. Male and female MDSCs isolated from the skeletal muscle of 3-week-old mice were transplanted into recipient male or female dystrophin-deficient (mdx) hearts or into the hearts of male SCID mice following acute myocardial infarction. In the mdx model, no difference was seen in engraftment or blood vessel formation based on donor cell or recipient sex. In the infarction model, MDSC-transplanted hearts showed higher postinfarction angiogenesis, less myocardial scar formation, and improved cardiac function compared to vehicle controls. However, sex of donor MDSCs had no significant effects on engraftment, angiogenesis, and cardiac function. VEGF expression, a potent angiogenic factor, was similar between male and female MDSCs. Our results suggest that donor MDSC or recipient sex has no significant effect on the efficiency of MDSC-triggered myocardial engraftment or regeneration following cardiac injury. The ability of the MDSCs to improve cardiac regeneration and repair through promotion of angiogenesis without differentiation into the cardiac lineage may have contributed to the lack of sex difference observed in these models. Copyright © 2009 Cognizant Comm. Corp.

We have previously shown that populations of skeletal muscle-derived stem cells (MDSCs) exhibit sexbased differences for skeletal muscle and bone repair, with female cells demonstrating superior engrafting abilities to males in skeletal muscle while male cells differentiating more robustly toward the osteogenic and chondrogenic lineages. In this study, we tested the hypothesis that the therapeutic capacity of MDSCs transplanted into myocardium is influenced by sex of donor MDSCs or recipient. Male and female MDSCs isolated from the skeletal muscle of 3-week-old mice were transplanted into recipient male or female dystrophin-deficient (mdx) hearts or into the hearts of male SCID mice following acute myocardial infarction. In the mdx model, no difference was seen in engraftment or blood vessel formation based on donor cell or recipient sex. In the infarction model, MDSC-transplanted hearts showed higher postinfarction angiogenesis, less myocardial scar formation, and improved cardiac function compared to vehicle controls. However, sex of donor MDSCs had no significant effects on engraftment, angiogenesis, and cardiac function. VEGF expression, a potent angiogenic factor, was similar between male and female MDSCs. Our results suggest that donor MDSC or recipient sex has no significant effect on the efficiency of MDSC-triggered myocardial engraftment or regeneration following cardiac injury. The ability of the MDSCs to improve cardiac regeneration and repair through promotion of angiogenesis without differentiation into the cardiac lineage may have contributed to the lack of sex difference observed in these models. Copyright © 2009 Cognizant Comm. Corp.

Objectives: The aim of this study was to evaluate the therapeutic potential of human skeletal muscle-derived myoendothelial cells for myocardial infarct repair. Background: We have recently identified and purified a novel population of myoendothelial cells from human skeletal muscle. These cells coexpress myogenic and endothelial cell markers and produce robust muscle regeneration when injected into cardiotoxin-injured skeletal muscle. Methods: Myoendothelial cells were isolated from biopsies of human skeletal muscle using a fluorescence-activated cell sorter along with populations of regular myoblasts and endothelial cells. Acute myocardial infarction was induced in male immune-deficient mice, and cells were directly injected into the ischemic area. Cardiac function was assessed by echocardiography, and donor cell engraftment, angiogenesis, scar tissue, endogenous cardiomyocyte proliferation, and apoptosis were all evaluated by immunohistochemistry. Results: A greater improvement in left ventricular function was observed after intramyocardial injection of myoendothelial cells when compared with that seen in hearts injected with myoblast or endothelial cells. Transplanted myoendothelial cells generated robust engraftments within the infarcted myocardium, and also stimulated angiogenesis, attenuation of scar tissue, and proliferation and survival of endogenous cardiomyocytes more effectively than transplanted myoblasts or endothelial cells. Conclusions: Our findings suggest that myoendothelial cells represent a novel cell population from human skeletal muscle that may hold promise for cardiac repair. © 2008 American College of Cardiology Foundation.

Objectives: The aim of this study was to evaluate the therapeutic potential of human skeletal muscle-derived myoendothelial cells for myocardial infarct repair. Background: We have recently identified and purified a novel population of myoendothelial cells from human skeletal muscle. These cells coexpress myogenic and endothelial cell markers and produce robust muscle regeneration when injected into cardiotoxin-injured skeletal muscle. Methods: Myoendothelial cells were isolated from biopsies of human skeletal muscle using a fluorescence-activated cell sorter along with populations of regular myoblasts and endothelial cells. Acute myocardial infarction was induced in male immune-deficient mice, and cells were directly injected into the ischemic area. Cardiac function was assessed by echocardiography, and donor cell engraftment, angiogenesis, scar tissue, endogenous cardiomyocyte proliferation, and apoptosis were all evaluated by immunohistochemistry. Results: A greater improvement in left ventricular function was observed after intramyocardial injection of myoendothelial cells when compared with that seen in hearts injected with myoblast or endothelial cells. Transplanted myoendothelial cells generated robust engraftments within the infarcted myocardium, and also stimulated angiogenesis, attenuation of scar tissue, and proliferation and survival of endogenous cardiomyocytes more effectively than transplanted myoblasts or endothelial cells. Conclusions: Our findings suggest that myoendothelial cells represent a novel cell population from human skeletal muscle that may hold promise for cardiac repair. © 2008 American College of Cardiology Foundation.

Objectives: We investigated whether vascular endothelial growth factor (VEGF) was associated with the angiogenic and therapeutic effects induced after transplantation of skeletal muscle-derived stem cells (MDSCs) into a myocardial infarction (MI). Background: Because very few MDSCs were found to differentiate into new blood vessels when injected into the heart, the mechanism underlying the occurrence of angiogenesis after MDSC transplantation is currently unknown. In the present study, we used a gain- or loss-of-VEGF function approach with skeletal MDSCs engineered to express VEGF or soluble Flt1, a VEGF-specific antagonist, to identify the involvement of VEGF in MDSC transplantation-induced neoangiogenesis. Methods: Vascular endothelial growth factor- and soluble Flt1-engineered MDSCs were injected into an acute MI. Angiogenesis and cardiac function were evaluated by immunohistochemistry and echocardiography. Results: Both control and VEGF-overexpressing MDSCs induced angiogenesis, prevented adverse cardiac remodeling, and improved function compared with saline-injected hearts. However, these therapeutic effects were diminished in hearts transplanted with MDSCs expressing soluble Flt1 despite successful cell engraftment. In vitro experiments demonstrated that MDSCs increased secretion of VEGF in response to hypoxia and cyclic stretch (likely conditions in ischemic hearts), suggesting that transplanted MDSCs release VEGF in vivo. Conclusions: Our findings suggest that VEGF is essential for the induction of angiogenesis and functional improvements observed after MDSC transplantation for infarct repair. © 2007 American College of Cardiology Foundation.

Objectives: We investigated whether vascular endothelial growth factor (VEGF) was associated with the angiogenic and therapeutic effects induced after transplantation of skeletal muscle-derived stem cells (MDSCs) into a myocardial infarction (MI). Background: Because very few MDSCs were found to differentiate into new blood vessels when injected into the heart, the mechanism underlying the occurrence of angiogenesis after MDSC transplantation is currently unknown. In the present study, we used a gain- or loss-of-VEGF function approach with skeletal MDSCs engineered to express VEGF or soluble Flt1, a VEGF-specific antagonist, to identify the involvement of VEGF in MDSC transplantation-induced neoangiogenesis. Methods: Vascular endothelial growth factor- and soluble Flt1-engineered MDSCs were injected into an acute MI. Angiogenesis and cardiac function were evaluated by immunohistochemistry and echocardiography. Results: Both control and VEGF-overexpressing MDSCs induced angiogenesis, prevented adverse cardiac remodeling, and improved function compared with saline-injected hearts. However, these therapeutic effects were diminished in hearts transplanted with MDSCs expressing soluble Flt1 despite successful cell engraftment. In vitro experiments demonstrated that MDSCs increased secretion of VEGF in response to hypoxia and cyclic stretch (likely conditions in ischemic hearts), suggesting that transplanted MDSCs release VEGF in vivo. Conclusions: Our findings suggest that VEGF is essential for the induction of angiogenesis and functional improvements observed after MDSC transplantation for infarct repair. © 2007 American College of Cardiology Foundation.