scholarly journals Microvasculopathy, Luminal Calcification and Premature Aging in Fetuin-A Deficient Mice

2019 ◽  
Author(s):  
Marietta Herrmann ◽  
Anne Babler ◽  
Irina Moshkova ◽  
Felix Gremse ◽  
Fabian Kiessling ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Early Stage ◽  
Analytical Electron Microscopy ◽  
Premature Aging ◽  
Fetuin A ◽  
Genome Wide ◽  
Ectopic Mineralization ◽  
Brown Adipose ◽  
Calciprotein Particles ◽  
Deficient Mice

AbstractObjectiveThe plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP) – rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore ectopic mineralization (calcification). The mutant mouse strain D2,Ahsg-/- combines fetuin-A deficiency with the mineralization-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue mineralization. Here we studied mechanisms leading to soft tissue mineralization, organ damage and premature aging in these mice.Approach and ResultsWe analyzed mice longitudinally by echocardiography, X-ray-computed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/- mice.Fetuin-A deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature aging. Importantly, early stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genome-wide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the ectopic mineralization was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis.ConclusionsCollectively, these results demonstrate that pathological mineralization can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of mineralized matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.

scholarly journals Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium

2019 ◽  
Author(s):  
Anne Babler ◽  
Carlo Schmitz ◽  
Andrea Büscher ◽  
Marietta Herrmann ◽  
Felix Gremse ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Molecular Genetic ◽  
Extracellular Fluid ◽  
Molecular Genetic Analysis ◽  
Ectopic Calcification ◽  
Special Importance ◽  
Soft Tissue Calcification ◽  
Fetuin A ◽  
Tissue Calcification ◽  
Deficient Mice

AbstractObjectiveCalcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic target that could be influenced by dietary of parenteral supplementation.Approach and ResultsWe studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the TRPM6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with dietary phosphate restriction, magnesium supplementation, or by parenteral administration of fetuin-A or pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement.ConclusionsWe show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, pyrophosphate, and magnesium. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, pyrophosphate and magnesium levels.Subject CodesAnimal Models of Human Disease, Fibrosis, Inflammation, Proteomics, Peripheral Vascular Disease

Surgery alone is adequate treatment for early stage soft tissue sarcoma of the extremity

2010 ◽  
Vol 97 (5) ◽  
pp. 707-713 ◽  
Author(s):  
W. B. Al-Refaie ◽  
E. B. Habermann ◽  
E. H. Jensen ◽  
T. M. Tuttle ◽  
P. W. T. Pisters ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Early Stage ◽  
Adequate Treatment

scholarly journals Genome-Wide Analysis of Survival in Early-Stage Non–Small-Cell Lung Cancer

2009 ◽  
Vol 27 (16) ◽  
pp. 2660-2667 ◽  
Author(s):  
Yen-Tsung Huang ◽  
Rebecca S. Heist ◽  
Lucian R. Chirieac ◽  
Xihong Lin ◽  
Vidar Skaug ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Massachusetts General Hospital ◽  
Early Stage ◽  
The United States ◽  
Small Cell ◽  
Genome Wide Analysis ◽  
Early Stage Nsclc ◽  
Genome Wide ◽  
Nsclc Patients

Purpose Lung cancer, of which 85% is non–small-cell (NSCLC), is the leading cause of cancer-related death in the United States. We used genome-wide analysis of tumor tissue to investigate whether single nucleotide polymorphisms (SNPs) in tumors are prognostic factors in early-stage NSCLC. Patients and Methods One hundred early-stage NSCLC patients from Massachusetts General Hospital (MGH) were used as a discovery set and 89 NSCLC patients collected by the National Institute of Occupational Health, Norway, were used as a validation set. DNA was extracted from flash-frozen lung tissue with at least 70% tumor cellularity. Genome-wide genotyping was done using the high-density SNP chip. Copy numbers were inferred using median smoothing after intensity normalization. Cox models were used to screen and validate significant SNPs associated with the overall survival. Results Copy number gains in chromosomes 3q, 5p, and 8q were observed in both MGH and Norwegian cohorts. The top 50 SNPs associated with overall survival in the MGH cohort (P ≤ 2.5 × 10−4) were selected and examined using the Norwegian cohort. Five of the top 50 SNPs were validated in the Norwegian cohort with false discovery rate lower than 0.05 (P < .016) and all five were located in known genes: STK39, PCDH7, A2BP1, and EYA2. The numbers of risk alleles of the five SNPs showed a cumulative effect on overall survival (Ptrend = 3.80 × 10−12 and 2.48 × 10−7 for MGH and Norwegian cohorts, respectively). Conclusion Five SNPs were identified that may be prognostic of overall survival in early-stage NSCLC.

scholarly journals Fetuin-A-Containing Calciprotein Particles Reduce Mineral Stress in the Macrophage

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e60904 ◽  
Author(s):  
Edward R. Smith ◽  
Eric Hanssen ◽  
Lawrence P. McMahon ◽  
Stephen G. Holt
Keyword(s):  
Fetuin A ◽  
Calciprotein Particles ◽  
Mineral Stress

scholarly journals Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Claire Angebault ◽  
Mathieu Panel ◽  
Mathilde Lacôte ◽  
Jennifer Rieusset ◽  
Alain Lacampagne ◽  
...  
Keyword(s):  
Complex I ◽  
Early Stage ◽  
Intrinsic Activity ◽  
Proximity Ligation Assay ◽  
Proximity Ligation ◽  
Skeletal Muscle Dysfunction ◽  
Species Production ◽  
Therapeutic Perspective ◽  
Deficient Mice

Besides skeletal muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibits a progressive cardiomyopathy characterized by an impaired calcium (Ca2+) homeostasis and a mitochondrial dysfunction. Here we aimed to determine whether sarco-endoplasmic reticulum (SR/ER)–mitochondria interactions and mitochondrial function were impaired in dystrophic heart at the early stage of the pathology. For this purpose, ventricular cardiomyocytes and mitochondria were isolated from 3-month-old dystrophin-deficient mice (mdx mice). The number of contacts points between the SR/ER Ca2+ release channels (IP3R1) and the porine of the outer membrane of the mitochondria, VDAC1, measured using in situ proximity ligation assay, was greater in mdx cardiomyocytes. Expression levels of IP3R1 as well as the mitochondrial Ca2+ uniporter (MCU) and its regulated subunit, MICU1, were also increased in mdx heart. MICU2 expression was however unchanged. Furthermore, the mitochondrial Ca2+ uptake kinetics and the mitochondrial Ca2+ content were significantly increased. Meanwhile, the Ca2+-dependent pyruvate dehydrogenase phosphorylation was reduced, and its activity significantly increased. In Ca2+-free conditions, pyruvate-driven complex I respiration was decreased whereas in the presence of Ca2+, complex I-mediated respiration was boosted. Further, impaired complex I-mediated respiration was independent of its intrinsic activity or expression, which remains unchanged but is accompanied by an increase in mitochondrial reactive oxygen species production. Finally, mdx mice were treated with the complex I modulator metformin for 1 month. Metformin normalized the SR/ER-mitochondria interaction, decreased MICU1 expression and mitochondrial Ca2+ content, and enhanced complex I-driven respiration. In summary, before any sign of dilated cardiomyopathy, the DMD heart displays an aberrant SR/ER-mitochondria coupling with an increase mitochondrial Ca2+ homeostasis and a complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.

scholarly journals Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Matthieu Roulleaux Dugage ◽  
Elise F. Nassif ◽  
Antoine Italiano ◽  
Rastislav Bahleda
Keyword(s):  
Soft Tissue ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Soft Tissue Sarcomas ◽  
Oncolytic Viruses ◽  
Cellular Therapies ◽  
M1 Macrophage ◽  
Synovial Sarcomas

Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.

scholarly journals Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD

2012 ◽  
Vol 27 (5) ◽  
pp. 1957-1966 ◽  
Author(s):  
Edward R. Smith ◽  
Martin L. Ford ◽  
Laurie A. Tomlinson ◽  
Chakravarthi Rajkumar ◽  
Lawrence P. McMahon ◽  
...  
Keyword(s):  
Aortic Stiffness ◽  
Fetuin A ◽  
Calciprotein Particles
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