Cenk Celik, A. Franco-Obregón, E. Lee, J. Hui, Zheng Yang
Mesenchymal stem cell (MSC) chondrogenesis is modulated by diverse biophysical cues. We have previously shown that brief, low-amplitude pulsed electromagnetic fields (PEMFs) differentially enhance MSC chondrogenesis in scaffold-free pellet cultures versus conventional tissue culture plastic (TCP), indicating an interplay between magnetism and micromechanical environment. Here, we examined the influence of PEMF directionality over the chondrogenic differentiation of MSCs laden on electrospun fibrous scaffolds of either random (RND) or aligned (ALN) orientations. Correlating MSCs' chondrogenic outcome to pFAK activation and YAP localisation, MSCs on the RND scaffolds experienced the least amount of resting mechanical stress and underwent greatest chondrogenic differentiation in response to brief PEMF exposure (10 min at 1 mT) perpendicular to the dominant plane of the scaffolds (Z-directed). By contrast, in MSC-impregnated RND scaffold, greatest mitochondrial respiration resulted from X-directed PEMF exposure (parallel to the scaffold plane) and was associated with curtailed chondrogenesis. MSCs on TCP or the ALN scaffolds exhibited greater resting mechanical stress and accordingly, were unresponsive, or negatively responsive, to PEMF exposure from all directions. The efficacy of PEMF-induced MSC chondrogenesis is hence regulated in a multifaceted manner involving focal adhesion dynamics, as well as mitochondrial responses, culminating in a final cellular response. The combined contributions of micromechanical environment and magnetic field orientation hence will need to be considered when designing magnetic exposure paradigms.
{"title":"Directionalities of Magnetic Fields and Topographic Scaffolds Synergise to Enhance MSC Chondrogenesis","authors":"Cenk Celik, A. Franco-Obregón, E. Lee, J. Hui, Zheng Yang","doi":"10.2139/ssrn.3686389","DOIUrl":"https://doi.org/10.2139/ssrn.3686389","url":null,"abstract":"Mesenchymal stem cell (MSC) chondrogenesis is modulated by diverse biophysical cues. We have previously shown that brief, low-amplitude pulsed electromagnetic fields (PEMFs) differentially enhance MSC chondrogenesis in scaffold-free pellet cultures versus conventional tissue culture plastic (TCP), indicating an interplay between magnetism and micromechanical environment. Here, we examined the influence of PEMF directionality over the chondrogenic differentiation of MSCs laden on electrospun fibrous scaffolds of either random (RND) or aligned (ALN) orientations. Correlating MSCs' chondrogenic outcome to pFAK activation and YAP localisation, MSCs on the RND scaffolds experienced the least amount of resting mechanical stress and underwent greatest chondrogenic differentiation in response to brief PEMF exposure (10 min at 1 mT) perpendicular to the dominant plane of the scaffolds (Z-directed). By contrast, in MSC-impregnated RND scaffold, greatest mitochondrial respiration resulted from X-directed PEMF exposure (parallel to the scaffold plane) and was associated with curtailed chondrogenesis. MSCs on TCP or the ALN scaffolds exhibited greater resting mechanical stress and accordingly, were unresponsive, or negatively responsive, to PEMF exposure from all directions. The efficacy of PEMF-induced MSC chondrogenesis is hence regulated in a multifaceted manner involving focal adhesion dynamics, as well as mitochondrial responses, culminating in a final cellular response. The combined contributions of micromechanical environment and magnetic field orientation hence will need to be considered when designing magnetic exposure paradigms.","PeriodicalId":346455,"journal":{"name":"Pharmacology eJournal","volume":"156 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115315399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The synergistic efficacy and clinical application of light-responsive polymeric co-delivery are severely restricted by the uncertain drug ratio and the potential adverse effects from light-responsive molecules and extra contrast agents. Here, we report the design of a dual prodrug polymer (DPP) for light-activatable precise synergistic chemotherapy guided by drug-mediated computed tomography imaging without the introduction of any extra light-responsive molecule and contrast agent. The self-assembled nanoparticle (DPP NP) was capable of triggering bioactive Pt(II) release by visible light in cancer cells/tumor, further inducing acid hydrolysis of DMC. Notably, the synergistic cancer cell killing ratio of Pt(II) and DMC in DPP NP was fixed at an optimal value even after cellular uptake, resulting in enhanced synergistic antitumor efficacy in vitro and in vivo. Due to the high content of heavy metal Pt in the polymer chain, the spatial/temporal dynamic bio-distribution as well as metabolism of DPP NP in tumor can be monitored via Pt drug-mediated computed tomography (DMCT) imaging to guide the illumination parameters for optimized light-activatable synergistic chemotherapy. Guided by Pt DMCT imaging, DPP NP showed an excellent light-activatable antitumor efficacy and low toxicity with 75% fully cured tumors. The light-activatable dual drug polymer system could be potential for precise theranostic nanomedicine.
{"title":"Light-Activatable Precise Synergistic Chemotherapy Through a Dual Prodrug Polymer Guided by Drug-Mediated Computed Tomography Imaging","authors":"Zigui Wang, Gaizhen Kuang, Zhiqiang Yu, Aimin Li, Dongfang Zhou, Yubin Huang","doi":"10.2139/ssrn.3330019","DOIUrl":"https://doi.org/10.2139/ssrn.3330019","url":null,"abstract":"The synergistic efficacy and clinical application of light-responsive polymeric co-delivery are severely restricted by the uncertain drug ratio and the potential adverse effects from light-responsive molecules and extra contrast agents. Here, we report the design of a dual prodrug polymer (DPP) for light-activatable precise synergistic chemotherapy guided by drug-mediated computed tomography imaging without the introduction of any extra light-responsive molecule and contrast agent. The self-assembled nanoparticle (DPP NP) was capable of triggering bioactive Pt(II) release by visible light in cancer cells/tumor, further inducing acid hydrolysis of DMC. Notably, the synergistic cancer cell killing ratio of Pt(II) and DMC in DPP NP was fixed at an optimal value even after cellular uptake, resulting in enhanced synergistic antitumor efficacy in vitro and in vivo. Due to the high content of heavy metal Pt in the polymer chain, the spatial/temporal dynamic bio-distribution as well as metabolism of DPP NP in tumor can be monitored via Pt drug-mediated computed tomography (DMCT) imaging to guide the illumination parameters for optimized light-activatable synergistic chemotherapy. Guided by Pt DMCT imaging, DPP NP showed an excellent light-activatable antitumor efficacy and low toxicity with 75% fully cured tumors. The light-activatable dual drug polymer system could be potential for precise theranostic nanomedicine.","PeriodicalId":346455,"journal":{"name":"Pharmacology eJournal","volume":"36 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130934701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
H. Grabowski, Zoya Marriott, P. Kovacheva, A. Elzinga
In September 2015, the first biosimilar drug, Zarxio, was launched on the U.S. market. While the impact of generic entry on the small molecule branded market in the U.S. is well-understood, the impact of biosimilar entry on the large molecule biologic market has only been studied in Europe and results suggest that the nature of competition depends greatly on country-specific features of the health care market. In this article, we examine Zarxio’s performance in the first year since its launch and evaluate to what extent that performance can be informative of future biologic-biosimilar competition in the U.S. Since many of the market mechanisms driving fast penetration of small molecule generic drugs in the U.S. are absent in the case of biosimilar drugs, biosimilar penetration is expected to be slower. Indeed, the penetration for Zarxio has so far been much more modest than the average for small molecule drugs: 22% by the end of the first year compared to 88% for small molecule generic drugs. We identify several reasons why Zarxio’s performance may understate the rigor of future U.S. biologic-biosimilar competition.
{"title":"One Year after the Launch of the First U.S. Biosimilar Drug: Lessons for the Future?","authors":"H. Grabowski, Zoya Marriott, P. Kovacheva, A. Elzinga","doi":"10.2139/SSRN.3016138","DOIUrl":"https://doi.org/10.2139/SSRN.3016138","url":null,"abstract":"In September 2015, the first biosimilar drug, Zarxio, was launched on the U.S. market. While the impact of generic entry on the small molecule branded market in the U.S. is well-understood, the impact of biosimilar entry on the large molecule biologic market has only been studied in Europe and results suggest that the nature of competition depends greatly on country-specific features of the health care market. In this article, we examine Zarxio’s performance in the first year since its launch and evaluate to what extent that performance can be informative of future biologic-biosimilar competition in the U.S. Since many of the market mechanisms driving fast penetration of small molecule generic drugs in the U.S. are absent in the case of biosimilar drugs, biosimilar penetration is expected to be slower. Indeed, the penetration for Zarxio has so far been much more modest than the average for small molecule drugs: 22% by the end of the first year compared to 88% for small molecule generic drugs. We identify several reasons why Zarxio’s performance may understate the rigor of future U.S. biologic-biosimilar competition.","PeriodicalId":346455,"journal":{"name":"Pharmacology eJournal","volume":"06 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2017-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116217535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Spanish Abstract: Artículo corto en el que se revisa la legislación vigente con respecto al uso del cannabis en Ecuador y el mundo, y alguna evidencia acerca de los efectos de esta sustancia en los seres humanos. Se sugieren algunas consideraciones a ser tomadas en cuenta en futuras legislaciones sobre el uso medicinal del cannabis.
English Abstract: Short paper that reviews the available Ecuadorian legislation on cannabis, and surveys evidence about the effects of cannabis on human beings. The paper makes some suggestions to be incorpored in future legislations about medical use of cannabis.
{"title":"Legalización del uso terapéutico del cannabis (About Legalizing Medical Use of Cannabis)","authors":"Diego Fernando Ramos Flor","doi":"10.2139/ssrn.3451236","DOIUrl":"https://doi.org/10.2139/ssrn.3451236","url":null,"abstract":"<b>Spanish Abstract:</b> Artículo corto en el que se revisa la legislación vigente con respecto al uso del cannabis en Ecuador y el mundo, y alguna evidencia acerca de los efectos de esta sustancia en los seres humanos. Se sugieren algunas consideraciones a ser tomadas en cuenta en futuras legislaciones sobre el uso medicinal del cannabis.<br><br><b>English Abstract:</b> Short paper that reviews the available Ecuadorian legislation on cannabis, and surveys evidence about the effects of cannabis on human beings. The paper makes some suggestions to be incorpored in future legislations about medical use of cannabis.","PeriodicalId":346455,"journal":{"name":"Pharmacology eJournal","volume":"21 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2016-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129794025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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