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Archives of Pathology & Laboratory... Oct 2019Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal... (Review)
Review
Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal purpura fulminans, a life-threatening disorder. Hereditary PC deficiency is caused by mutation in the PC () gene located on chromosome 2q14.3. Heterozygous and acquired PC deficiencies are more common than homozygous deficiency. The recommended initial laboratory test measures PC activity using either clot-based or chromogenic methods. There are numerous potential interferences in PC activity testing that may result in either false-positive (falsely low activity) or false-negative (falsely normal or elevated activity) results. In the present review, we discuss common clinical presentations; laboratory testing, with a focus on potential assay interferences; treatment options; and prognosis in patients with PC deficiency.
Topics: Blood Coagulation Tests; Humans; Mutation; Protein C Deficiency; Purpura Fulminans; Thrombophilia; Venous Thromboembolism
PubMed: 30702334
DOI: 10.5858/arpa.2017-0403-RS -
International Journal of Molecular... Feb 2022Severe inherited thrombophilia includes rare deficiencies of natural anticoagulants (antithrombin and proteins C and S) and homozygous or combined factor V Leiden and... (Review)
Review
Severe inherited thrombophilia includes rare deficiencies of natural anticoagulants (antithrombin and proteins C and S) and homozygous or combined factor V Leiden and FII G20210A variants. They are associated with a high thrombosis risk and can impact the duration of anticoagulation therapy for patients with a venous thromboembolism (VTE) event. Therefore, it is important to diagnose thrombophilia and to use adapted anticoagulant therapy. The widespread use of direct anticoagulants (DOACs) for VTE has raised new issues concerning inherited thrombophilia. Concerning inherited thrombophilia diagnosis, DOACs are directed toward either FIIa or FXa and can therefore interfere with coagulation assays. This paper reports DOAC interference in several thrombophilia tests, including the assessment of antithrombin, protein S, and protein C activities. Antithrombin activity and clot-based assays used for proteins C and S can be overestimated, with a risk of missing a deficiency. The use of a device to remove DOACs should be considered to minimize the risk of false-negative results. The place of DOACs in the treatment of VTE in thrombophilia patients is also discussed. Available data are encouraging, but given the variability in thrombosis risk within natural anticoagulant deficiencies, evidence in patients with well-characterized thrombophilia would be useful.
Topics: Administration, Oral; Anticoagulants; Antithrombins; Humans; Protein C; Risk Factors; Thrombophilia; Thrombosis; Venous Thromboembolism
PubMed: 35163742
DOI: 10.3390/ijms23031821 -
The Journal of Clinical Investigation Oct 2020Epithelial cell dysfunction has emerged as a central component of the pathophysiology of diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF).... (Review)
Review
Epithelial cell dysfunction has emerged as a central component of the pathophysiology of diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF). Alveolar type 2 (AT2) cells represent a metabolically active lung cell population important for surfactant biosynthesis and alveolar homeostasis. AT2 cells and other distal lung epithelia, like all eukaryotic cells, contain an elegant quality control network to respond to intrinsic metabolic and biosynthetic challenges imparted by mutant protein conformers, dysfunctional subcellular organelles, and dysregulated telomeres. Failed AT2 quality control components (the ubiquitin-proteasome system, unfolded protein response, macroautophagy, mitophagy, and telomere maintenance) result in diverse cellular endophenotypes and molecular signatures including ER stress, defective autophagy, mitochondrial dysfunction, apoptosis, inflammatory cell recruitment, profibrotic signaling, and altered progenitor function that ultimately converge to drive downstream fibrotic remodeling in the IPF lung. As this complex network becomes increasingly better understood, opportunities will emerge to identify targets and therapeutic strategies for IPF.
Topics: Alveolar Epithelial Cells; Animals; Autophagy; Cell Lineage; Humans; Idiopathic Pulmonary Fibrosis; Mitophagy; Models, Biological; Mutation; Proteasome Endopeptidase Complex; Proteostasis; Pulmonary Surfactant-Associated Protein C; Signal Transduction; Telomere Homeostasis; Ubiquitin; Unfolded Protein Response
PubMed: 32870817
DOI: 10.1172/JCI139519 -
Pathology Oncology Research : POR Oct 2020Ewing sarcoma is a rare tumor developed in bone and soft tissues of children and teenagers. This entity is biologically led by a chromosomal translocation, typically... (Review)
Review
Ewing sarcoma is a rare tumor developed in bone and soft tissues of children and teenagers. This entity is biologically led by a chromosomal translocation, typically including EWS and FLI1 genes. Little is known about Ewing sarcoma predisposition, although the role of environmental factors, ethnicity and certain polymorphisms on Ewing sarcoma susceptibility has been studied during the last few years. Its prevalence among cancer predisposition syndromes has also been thoroughly examined. This review summarizes the available evidence on predisposing factors involved in Ewing sarcoma susceptibility. On the basis of these data, an integrated approach of the most influential factors on Ewing sarcoma predisposition is proposed.
Topics: Bone Neoplasms; Genetic Predisposition to Disease; Humans; Polymorphism, Single Nucleotide; Proto-Oncogene Protein c-fli-1; RNA-Binding Protein EWS; Sarcoma, Ewing
PubMed: 31656020
DOI: 10.1007/s12253-019-00765-3 -
Cell Mar 2020It has generally proven challenging to produce functional β cells in vitro. Here, we describe a previously unidentified protein C receptor positive (Procr) cell...
It has generally proven challenging to produce functional β cells in vitro. Here, we describe a previously unidentified protein C receptor positive (Procr) cell population in adult mouse pancreas through single-cell RNA sequencing (scRNA-seq). The cells reside in islets, do not express differentiation markers, and feature epithelial-to-mesenchymal transition characteristics. By genetic lineage tracing, Procr islet cells undergo clonal expansion and generate all four endocrine cell types during adult homeostasis. Sorted Procr cells, representing ∼1% of islet cells, can robustly form islet-like organoids when cultured at clonal density. Exponential expansion can be maintained over long periods by serial passaging, while differentiation can be induced at any time point in culture. β cells dominate in differentiated islet organoids, while α, δ, and PP cells occur at lower frequencies. The organoids are glucose-responsive and insulin-secreting. Upon transplantation in diabetic mice, these organoids reverse disease. These findings demonstrate that the adult mouse pancreatic islet contains a population of Procr endocrine progenitors.
Topics: Animals; Cell Culture Techniques; Cell Differentiation; Cell Line; Cells, Cultured; Diabetes Mellitus, Experimental; Endothelial Protein C Receptor; Epithelial-Mesenchymal Transition; Female; Glucose; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Nude; Organoids; Pancreas; Protein C; Stem Cells
PubMed: 32200801
DOI: 10.1016/j.cell.2020.02.048 -
Frontiers in Cardiovascular Medicine 2022
PubMed: 36211582
DOI: 10.3389/fcvm.2022.1021626 -
Blood May 2022
Topics: Animals; Anticoagulants; Arthritis; Hemarthrosis; Hematologic Diseases; Hemophilia A; Mice; Protein C
PubMed: 35511191
DOI: 10.1182/blood.2022015776 -
Revue Neurologique May 2024Biallelic intronic expansions (AAGGG) in intron 2 of the RFC1 gene have been shown to be a common cause of late-onset ataxia. Since their first description, the... (Review)
Review
Biallelic intronic expansions (AAGGG) in intron 2 of the RFC1 gene have been shown to be a common cause of late-onset ataxia. Since their first description, the phenotypes, neurological damage, and pathogenic variants associated with the RFC1 gene have been frequently updated. Here, we review the various motifs, genetic variants, and phenotypes associated with the RFC1 gene. We searched PubMed for scientific articles published between March 1st, 2019, and January 15th, 2024. The motifs and phenotypes associated with the RFC1 gene are highly heterogeneous, making molecular diagnosis and clinical screening and investigation challenging. In this review we will provide clues to give a better understanding of RFC1 disease. We briefly discuss new methods for molecular diagnosis, the origin of cough in RFC1 disease, and research perspectives.
Topics: Humans; Phenotype; Replication Protein C; Ataxia; Introns
PubMed: 38627134
DOI: 10.1016/j.neurol.2024.03.006