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Jouni Uitto - One of the best experts on this subject based on the ideXlab platform.
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etidronate prevents but does not reverse Ectopic mineralization in a mouse model of pseudoxanthoma elasticum abcc6
Oncotarget, 2014Co-Authors: Joshua Kingman, John P Sundberg, Michael A Levine, Jouni UittoAbstract:// Qiaoli Li 1 , Joshua Kingman 1 , John P. Sundberg 2 , Michael A. Levine 3 , Jouni Uitto 1 1 Department of Dermatology and Cutaneous Biology, The Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA 2 The Jackson Laboratory, Bar Harbor, ME, USA 3 Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA Correspondence to: Qiaoli Li, email: Qiaoli.Li@jefferson.edu Keywords: pseudoxanthoma elasticum, Ectopic mineralization, etidronate treatment, bisphosphonates, mouse model Received: March 03, 2016 Accepted: June 09, 2016 Published: July 20, 2016 ABSTRACT Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are heritable disorders manifesting with Ectopic Tissue mineralization. Most cases of PXE and some cases of GACI are caused by mutations in the ABCC6 gene, resulting in reduced plasma pyrophosphate (PPi) levels. There is no effective treatment for these disorders. It has been suggested that administration of bisphosphonates, stable and non-hydrolyzable PPi analogs, could counteract Ectopic mineralization in these disorders. In this study we tested the potential efficacy of etidronate, a first generation bisphosphonate, on Ectopic mineralization in the muzzle skin of Abcc6 -/- mice, a model of PXE. The Abcc6 -/- mice received subcutaneous injections of etidronate, 0.283 and 3.40 mg/kg per injection (0.01× and 0.12×), twice a week, in both prevention and reversal studies. Ectopic mineralization in the dermal sheath of vibrissae in muzzle skin was determined by histopathologic analysis and by direct chemical assay for calcium content. Subcutaneous injection of etidronate prevented Ectopic mineralization but did not reverse existing mineralization. The effect of etidronate was accompanied by alterations in the trabecular bone microarchitecture, determined by micro-computed tomography. The results suggest that etidronate may offer a potential treatment modality for PXE and GACI caused by ABCC6 mutations. Etidronate therapy should be initiated in PXE patients as soon as the diagnosis is made, with careful monitoring of potential side effects.
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juxta articular joint capsule mineralization in cd73 deficient mice similarities to patients with nt5e mutations
Cell Cycle, 2014Co-Authors: Thea P Price, John P Sundberg, Jouni UittoAbstract:Arterial calcification due to CD73 deficiency (ACDC), an autosomal recessive disorder, manifests with extensive mineralization of the lower-extremity arteries as well as of hand and foot joint-capsules. This disease is caused by mutations in the NT5E gene which encodes CD73, a membrane-bound ecto-5′-nucleotidase hydrolyzing 5′-AMP into adenosine and Pi. To gain insight into the pathophysiologic details of ACDC, we have characterized a Nt5e−/− knock out mouse (Nt5etm1Jgsc) deficient in CD73. These mice, when maintained on appropriate strain background, demonstrated stiffening of the joints and micro CT revealed distinct changes in the thoracic skeletal structure with evidence of mineralization at the costochondral junctions. Mineralization was also noted in the juxta-articular spaces of the lower extremities as well as of ligaments and capsules adjacent to the bony structures. No evidence of vascular mineralization was noted either by CT or by microdissection of arteries in the thoracic area or in lower extremities. The Nt5e−/− mutant mice demonstrated significantly increased Pi levels in the serum and significantly reduced PPi concentration in the heparinized plasma, resulting in markedly increased Pi/PPi ratio, thus creating a pro-mineralization environment. In conclusion, the Nt5e−/− targeted mutant mice recapitulate some, but not all, features of ACDC and serve as a model system to study pharmacologic interventions for Ectopic mineralization. Collectively, this mouse model deficient in CD73, with other targeted mutant mice with vascular mineralization, attests to the presence of a complex pro-mineralization/anti-mineralization network that under physiologic homeostatic conditions prevents Ectopic Tissue mineralization.
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Mutations in the ABCC6 Gene as a Cause of Generalized Arterial Calcification of Infancy: Genotypic Overlap with Pseudoxanthoma Elasticum
The Journal of investigative dermatology, 2013Co-Authors: Jill L. Brodsky, Leon J Schurgers, Laura K. Conlin, Bruce R. Pawel, Andrew C. Glatz, Rachel I. Gafni, Jouni Uitto, Hakon Hakonarson, Matthew A. DeardorffAbstract:Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder characterized by congenital calcification of large- and medium-sized arteries, associated with early myocardial infarction, heart failure, and stroke, and premature death. Most cases of GACI are caused by mutations in the ENPP1 gene. We first studied two siblings with GACI from a non-consanguineous family without mutations in the ENPP1 gene. To search for disease-causing mutations, we identified genomic regions shared between the two affected siblings but not their unaffected parents or brother. The ABCC6 gene, which is mutated in pseudoxanthoma elasticum (PXE), resided within a small region of homozygosity shared by the affected siblings. Sequence analysis of ABCC6 revealed that the two affected siblings were homozygous for the missense mutation p.R1314W. Subsequently, ABCC6 mutations were identified in five additional GACI families with normal ENPP1 sequences. Genetic mutations in ABCC6 in patients with PXE are associated with Ectopic Tissue mineralization in the skin and arterial blood vessels. Thus, our findings provide additional evidence that the ABCC6 gene product inhibits calcification under physiologic conditions and confirm a second locus for GACI. In addition, our study emphasizes the potential utility of shared homozygosity mapping to identify genetic causes of inherited disorders.
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warfarin accelerates Ectopic mineralization in abcc6 mice clinical relevance to pseudoxanthoma elasticum
American Journal of Pathology, 2013Co-Authors: Haitao Guo, Leon J Schurgers, David W Chou, Dominic J Harrington, Sharon F Terry, Jouni UittoAbstract:Pseudoxanthoma elasticum (PXE) is a multisystem Ectopic mineralization disorder caused by mutations in the ABCC6 gene. Warfarin, a commonly used anticoagulant, is associated with increased mineralization of the arterial blood vessels and cardiac valves. We hypothesized that warfarin may accelerate Ectopic Tissue mineralization in PXE, with clinical consequences. To test this hypothesis, we developed a model in which Abcc6−/− mice, which recapitulate features of PXE, were fed a diet supplemented with warfarin and vitamin K1. Warfarin action was confirmed by significantly increased serum levels of oxidized vitamin K. For mice placed on a warfarin-containing diet, quantitative chemical and morphometric analyses revealed massive accumulation of mineral deposits in a number of Tissues. Mice fed a warfarin-containing diet were also shown to have abundant uncarboxylated form of matrix Gla protein, which allowed progressive Tissue mineralization to ensue. To explore the clinical relevance of these findings, 1747 patients with PXE from the approximately 4000 patients in the PXE International database were surveyed about the use of warfarin. Of the 539 respondents, 2.6% reported past or present use of warfarin. Based on the prevalence of PXE (approximately 1:50,000), thousands of patients with PXE worldwide may be at risk for worsening of PXE as a result of warfarin therapy.
Mariacarla Moleti - One of the best experts on this subject based on the ideXlab platform.
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thyroid cancer in lingual thyroid and thyroglossal duct cyst
Endocrinología Diabetes y Nutrición, 2017Co-Authors: Giacomo Sturniolo, Francesco Vermiglio, Mariacarla MoletiAbstract:Ectopy is the most common embryogenetic defect of the thyroid gland, representing between 48 and 61% of all thyroid dysgeneses. Persistence of thyroid Tissue in the context of a thyroglossal duct remnant and lingual thyroid Tissue are the most common defects. Although most cases of Ectopic thyroid are asymptomatic, any disease affecting the thyroid may potentially involve the Ectopic Tissue, including malignancies. The prevalence of differentiated thyroid carcinoma in lingual thyroid and thyroglossal duct cyst is around 1% of patients affected with the above thyroid ectopies. We here review the current literature concerning primary thyroid carcinomas originating from thyroid Tissue on thyroglossal duct cysts and lingual thyroid.
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Differentiated thyroid carcinoma in lingual thyroid
Endocrine, 2016Co-Authors: Giacomo Sturniolo, Maria Antonia Violi, Bruno Galletti, Sergio Baldari, Alfredo Campennì, Francesco Vermiglio, Mariacarla MoletiAbstract:The lingual thyroid is the most common form of thyroid ectopy. The Ectopic Tissue may display any disease affecting the thyroid, including malignancies, which have an estimated incidence of less than 1 %. To date only 51 cases of lingual thyroid cancer were reported. Analogously to what observed in orthotopic thyroid, papillary carcinoma is the predominant histotype in lingual thyroid carcinoma. The higher frequency of lingual follicular thyroid carcinoma previously reported is possibly related to histological misclassification in some early reports, prior to the standardization of histological typing of differentiated thyroid carcinomas. Nonetheless, the frequency of the follicular histotype is not negligible, accounting for about one-third of the reported cases. Both natural history and prognosis of lingual thyroid carcinoma are poorly known, likely because of the rarity of the disease and the heterogeneity in the therapeutic approach. However, among the cases more recently reported, surgical excision of the mass, either alone or followed by radioiodine ablation, is the first-line approach, with only two cases treated by radioiodine alone. The nonsignificant rate of neoplastic transformation in lingual thyroid should encourage efforts to obtain a widely accepted consensus for the management of this rare condition, along with standardization of either diagnostic or therapeutic handling of malignancies arising in Ectopic thyroid.
Robert Lanza - One of the best experts on this subject based on the ideXlab platform.
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Treatment of Macular Degeneration Using Embryonic Stem Cell-Derived Retinal Pigment Epithelium: Preliminary Results in Asian Patients
Stem Cell Reports, 2015Co-Authors: Won kyung Song, Jae ho Lee, So young Chong, Sung han Shim, Lucian v. Del priore, Kyung Mi Park, Jinjung Choi, Hyun-ju Kim, Robert LanzaAbstract:Embryonic stem cells hold great promise for various diseases because of their unlimited capacity for self-renewal and ability to differentiate into any cell type in the body. However, despite over 3 decades of research, there have been no reports on the safety and potential efficacy of pluripotent stem cell progeny in Asian patients with any disease. Here, we report the safety and tolerability of subretinal transplantation of human embryonic-stem-cell (hESC)-derived retinal pigment epithelium in four Asian patients: two with dry age-related macular degeneration and two with Stargardt macular dystrophy. They were followed for 1 year. There was no evidence of adverse proliferation, tumorigenicity, Ectopic Tissue formation, or other serious safety issues related to the transplanted cells. Visual acuity improved 9-19 letters in three patients and remained stable (+1 letter) in one patient. The results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine.
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embryonic stem cell trials for macular degeneration a preliminary report
The Lancet, 2012Co-Authors: Steven D Schwartz, Jeanpierre Hubschman, Gad Heilwell, Valentina Francocardenas, Carolyn K Pan, Rosaleen Ostrick, Edmund Mickunas, Irina Klimanskaya, Robert LanzaAbstract:Summary Background It has been 13 years since the discovery of human embryonic stem cells (hESCs). Our report provides the first description of hESC-derived cells transplanted into human patients. Methods We started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium (RPE) in patients with Stargardt's macular dystrophy and dry age-related macular degeneration—the leading cause of blindness in the developed world. Preoperative and postoperative ophthalmic examinations included visual acuity, fluorescein angiography, optical coherence tomography, and visual field testing. These studies are registered with ClinicalTrials.gov, numbers NCT01345006 and NCT01344993. Findings Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt's macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28). Interpretation The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, Ectopic Tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue. Funding Advanced Cell Technology.
Le K Blanc - One of the best experts on this subject based on the ideXlab platform.
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analysis of Tissues following mesenchymal stromal cell therapy in humans indicates limited long term engraftment and no Ectopic Tissue formation
Stem Cells, 2012Co-Authors: L Von Bahr, I Batsis, Guido Moll, M Hagg, A Szakos, B Sundberg, Mehmet Uzunel, O Ringden, Le K BlancAbstract:Mesenchymal stromal cells (MSCs) are explored as a novel treatment for a variety of medical conditions. Their fate after infusion is unclear, and long-term safety regarding malignant transformation and Ectopic Tissue formation has not been addressed in patients. We examined autopsy material from 18 patients who had received human leukocyte antigen (HLA)-mismatched MSCs, and 108 Tissue samples from 15 patients were examined by PCR. No signs of Ectopic Tissue formation or malignant tumors of MSC-donor origin were found on macroscopic or histological examination. MSC donor DNA was detected in one or several Tissues including lungs, lymph nodes, and intestine in eight patients at levels from 1/100 to <1/1,000. Detection of MSC donor DNA was negatively correlated with time from infusion to sample collection, as DNA was detected from nine of 13 MSC infusions given within 50 days before sampling but from only two of eight infusions given earlier. There was no correlation between MSC engraftment and treatment response. We conclude that MSCs appear to mediate their function through a "hit and run" mechanism. The lack of sustained engraftment limits the long-term risks of MSC therapy.
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mesenchymal stem cells for treatment of acute and chronic graft versus host disease Tissue toxicity and hemorrhages
Best Practice & Research Clinical Haematology, 2011Co-Authors: Olle Ringden, Le K BlancAbstract:Mesenchymal stem cells (MSCs) have immunomodulatory effects and low immunogenicity. MSCs inhibit T-cell alloreactivity in vitro . Immune inhibition is caused by soluble factors. MSCs affect almost all cells of the immune system. They are safe to infuse in humans with no acute toxicity and no Ectopic Tissue formation. We treated patients with life-threatening acute graft-versus-host disease (GVHD) not responding to conventional immunosuppressive therapy with MSCs. Approximately half of the patients responded. HLA-identical or third party MSCs were equally effective. Children tended to have a better response compared to adults. MSCs have also been used for chronic GVHD with positive effects. MSCs also reversed Tissue toxicity such as hemorrhagic cystitis, pneumomediastinum and colon perforation with peritonitis. A patient with extensive hemorrhages was successfully treated with repeated doses of MSCs pooled from two donors. This may indicate that MSCs apart from wound healing may stimulate clotting and vasoconstriction. To conclude, MSCs is a novel treatment that may be used for GVHD, Tissue toxicity and hemorrhages because of its immune inhibitory and anti-inflammatory effects.
Murphy, Mary J. - One of the best experts on this subject based on the ideXlab platform.
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A novel high-throughput screening platform identifies itaconate derivatives from marine Penicillium antarcticum as inhibitors of mesenchymal stem cell differentiation
MDPI, 2020Co-Authors: Marchese Pietro, Mahajan Nipun, O’connell Enda, Fearnhead Howard, Tuohy Maria, Krawczyk Janusz, Thomas, Olivier P., Barry Frank, Murphy, Mary J.Abstract:Worldwide diffused diseases such as osteoarthritis, atherosclerosis or chronic kidney disease are associated with a Tissue calcification process which may involve unexpected local stem cell differentiation. Current pharmacological treatments for such musculoskeletal conditions are weakly effective, sometimes extremely expensive and often absent. The potential to develop new therapies is represented by the discovery of small molecules modulating resident progenitor cell differentiation to prevent aberrant Tissue calcification. The marine environment is a rich reserve of compounds with pharmaceutical potential and many novel molecules are isolated from macro and microorganisms annually. The potential of small molecules synthetized by marine filamentous fungi to influence the osteogenic and chondrogenic differentiation of human mesenchymal stem/stromal cells (hMSCs) was investigated using a novel, high-throughput automated screening platform. Metabolites synthetized by the marine-derived fungus Penicillium antarcticum were evaluated on the platform. Itaconic acid derivatives were identified as inhibitors of calcium elaboration into the matrix of osteogenically differentiated hMSCs and also inhibited hMSC chondrogenic differentiation, highlighting their capacity to impair Ectopic calcification. Bioactive small molecule discovery is critical to address Ectopic Tissue calcification and the use of biologically relevant assays to identify naturally occurring metabolites from marine sources represents a strategy that can contribute to this effort.Funding: This research was funded by Science Foundation Ireland Strategic Research Cluster, grant number 09/SRC/B1794. The Genomics and Screening Core facility at the National University of Ireland Galway is funded by NUIG and the Irish Government’s Programme for Research in Third Level Institutions, Cycles 4 and 5, National Development Plan 2007-2013. This research was partly funded by the Marine Institute under the Marine Research Program by the Irish Government, grant number PBA/MB/16/01.The APC was funded by Irish Research Council through Postgraduate Scholarship GOIPG/2016/1113. Acknowledgments: Pietro Marchese was supported by Irish Research Council through a Postgraduate Scholarship GOIPG/2016/1113 as well as the College of Medicine Nursing and Health Sciences at NUI Galway. We acknowledge Prof. Moustapha Kassem from University of Copenhagen for providing hTERT-MSC used
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A novel high-throughput screening platform identifies itaconate derivatives from marine Penicillium antarcticum as inhibitors of mesenchymal stem cell differentiation
'MDPI AG', 2020Co-Authors: Marchese Pietro, Mahajan Nipun, O’connell Enda, Fearnhead Howard, Tuohy Maria, Krawczyk Janusz, Thomas, Olivier P., Barry Frank, Murphy, Mary J.Abstract:Worldwide diffused diseases such as osteoarthritis, atherosclerosis or chronic kidney disease are associated with a Tissue calcification process which may involve unexpected local stem cell differentiation. Current pharmacological treatments for such musculoskeletal conditions are weakly effective, sometimes extremely expensive and often absent. The potential to develop new therapies is represented by the discovery of small molecules modulating resident progenitor cell differentiation to prevent aberrant Tissue calcification. The marine environment is a rich reserve of compounds with pharmaceutical potential and many novel molecules are isolated from macro and microorganisms annually. The potential of small molecules synthetized by marine filamentous fungi to influence the osteogenic and chondrogenic differentiation of human mesenchymal stem/stromal cells (hMSCs) was investigated using a novel, high-throughput automated screening platform. Metabolites synthetized by the marine-derived fungus Penicillium antarcticum were evaluated on the platform. Itaconic acid derivatives were identified as inhibitors of calcium elaboration into the matrix of osteogenically differentiated hMSCs and also inhibited hMSC chondrogenic differentiation, highlighting their capacity to impair Ectopic calcification. Bioactive small molecule discovery is critical to address Ectopic Tissue calcification and the use of biologically relevant assays to identify naturally occurring metabolites from marine sources represents a strategy that can contribute to this effort.Funding: This research was funded by Science Foundation Ireland Strategic Research Cluster, grant number 09/SRC/B1794. The Genomics and Screening Core facility at the National University of Ireland Galway is funded by NUIG and the Irish Government’s Programme for Research in Third Level Institutions, Cycles 4 and 5, National Development Plan 2007-2013. This research was partly funded by the Marine Institute under the Marine Research Program by the Irish Government, grant number PBA/MB/16/01.The APC was funded by Irish Research Council through Postgraduate Scholarship GOIPG/2016/1113. Acknowledgments: Pietro Marchese was supported by Irish Research Council through a Postgraduate Scholarship GOIPG/2016/1113 as well as the College of Medicine Nursing and Health Sciences at NUI Galway. We acknowledge Prof. Moustapha Kassem from University of Copenhagen for providing hTERT-MSC used.peer-reviewe
