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1.
Am J Surg Pathol ; 48(8): 991-1004, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39016330

RESUMO

Recently, FN1 fusions to receptor tyrosine kinase genes have been identified in soft tissue tumors with calcified chondroid matrix named calcifying chondroid mesenchymal neoplasms (CCMNs). We collected 33 cases of CCMN from the French network for soft tissue and bone tumors. We performed whole-exome RNA sequencing, expression analysis, and genome-wide DNA methylation profiling in 33, 30, and 20 cases of CCMN compared with a control group of tumors, including noncalcified tenosynovial giant cell tumor (TGCT). Among them, 15 cases showed morphologic overlap with soft tissue chondroma, 8 cases with tophaceous pseudogout, and 10 cases with chondroid TGCT. RNA-sequencing revealed a fusion of FN1 in 76% of cases (25/33) with different 5' partners, including most frequently FGFR2 (14 cases), TEK or FGFR1. Among CCMN associated with FGFR1 fusions, 2 cases had overexpression of FGF23 without tumor-induced osteomalacia. Four CCMN had PDGFRA::USP8 fusions; 3 of which had histologic features of TGCT and were located in the hip, foot, and temporomandibular joint (TMJ). All cases with FN1::TEK fusion were located at TMJ and had histologic features of TGCT with or without chondroid matrix. They formed a distinct cluster on unsupervised clustering analyses based on whole transcriptome and genome-wide methylome data. Our study confirms the high prevalence of FN1 fusions in CCMN. In addition, through transcriptome and methylome analyses, we have identified a novel subgroup of tumors located at the TMJ, exhibiting TGCT-like features and FN1::TEK fusions.


Assuntos
Biomarcadores Tumorais , Calcinose , Fator de Crescimento de Fibroblastos 23 , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Calcinose/genética , Calcinose/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Adulto Jovem , Metilação de DNA , Adolescente , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Fibronectinas/genética , Sequenciamento do Exoma , Criança , Idoso de 80 Anos ou mais , França , Fenótipo
2.
Artigo em Inglês | MEDLINE | ID: mdl-38946295

RESUMO

BACKGROUND: Microcalcifications are acknowledged as a malignancy risk factor in multiple cancers. However, the prevalence and association of intrathoracic lymph node (ILN) calcifications with malignancy remain unexplored. METHODS: In this cross-sectional study, we enrolled patients with known/suspected malignancy and an indication for endosonography for diagnosis or ILN staging. We assessed the prevalence and pattern of calcified ILNs and the prevalence of malignancy in ILNs with and without calcifications. In addition, we evaluated the genomic profile and PD-L1 expression in lung cancer patients, stratifying them based on the presence or absence of ILN calcifications. RESULTS: A total of 571 ILNs were sampled in 352 patients. Calcifications were detected in 85 (24.1%) patients and in 94 (16.5%) ILNs, with microcalcifications (78/94, 83%) being the predominant type. Compared with ILNs without calcifications (214/477, 44.9%), the prevalence of malignancy was higher in ILNs with microcalcifications (73/78, 93.6%; P<0.0001) but not in those with macrocalcifications (7/16, 43.7%; P=0.93). In patients with lung cancer, the high prevalence of metastatic involvement in ILNs displaying microcalcifications was independent of lymph node size (< or >1 cm) and the clinical stage (advanced disease; cN2/N3 disease; cN0/N1 disease). The anaplastic lymphoma kinase (ALK) rearrangement was significantly more prevalent in patients with than in those without calcified ILNs (17.4% vs. 1.7%, P<0.001), and all of them exhibited microcalcifications. CONCLUSION: ILN microcalcifications are common in patients undergoing endosonography for suspected malignancy, and they are associated with a high prevalence of metastatic involvement and ALK rearrangement.


Assuntos
Quinase do Linfoma Anaplásico , Calcinose , Neoplasias Pulmonares , Linfonodos , Humanos , Masculino , Feminino , Quinase do Linfoma Anaplásico/genética , Estudos Transversais , Pessoa de Meia-Idade , Calcinose/diagnóstico por imagem , Calcinose/patologia , Calcinose/genética , Calcinose/epidemiologia , Prevalência , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/diagnóstico por imagem , Idoso , Linfonodos/patologia , Linfonodos/diagnóstico por imagem , Endossonografia , Adulto , Rearranjo Gênico
3.
BMC Pulm Med ; 24(1): 343, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014333

RESUMO

BACKGROUND: Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disease characterized by recurrent respiratory infections. In clinical manifestations, DNAH5 (NM_001361.3) is one of the recessive pathogenic genes. Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcification in the basal ganglia and other brain regions. PFBC can be inherited in an autosomal dominant or recessive manner. A family with PCD caused by a DNAH5 compound heterozygous variant and PFBC caused by a MYORG homozygous variant was analyzed. METHODS: In this study, we recruited three generations of Han families with primary ciliary dyskinesia combined with primary familial brain calcification. Their clinical phenotype data were collected, next-generation sequencing was performed to screen suspected pathogenic mutations in the proband and segregation analysis of families was carried out by Sanger sequencing. The mutant and wild-type plasmids were constructed and transfected into HEK293T cells instantaneously, and splicing patterns were detected by Minigene splicing assay. The structure and function of mutations were analyzed by bioinformatics analysis. RESULTS: The clinical phenotypes of the proband (II10) and his sister (II8) were bronchiectasis, recurrent pulmonary infection, multiple symmetric calcifications of bilateral globus pallidus and cerebellar dentate nucleus, paranasal sinusitis in the whole group, and electron microscopy of bronchial mucosa showed that the ciliary axoneme was defective. There was also total visceral inversion in II10 but not in II8. A novel splice variant C.13,338 + 5G > C and a frameshift variant C.4314delT (p. Asn1438lysfs *10) were found in the DNAH5 gene in proband (II10) and II8. c.347_348dupCTGGCCTTCCGC homozygous insertion variation was found in the MYORG of the proband. The two pathogenic genes were co-segregated in the family. Minigene showed that DNAH5 c.13,338 + 5G > C has two abnormal splicing modes: One is that part of the intron bases where the mutation site located is translated, resulting in early translation termination of DNAH5; The other is the mutation resulting in the deletion of exon76. CONCLUSIONS: The newly identified DNAH5 splicing mutation c.13,338 + 5G > C is involved in the pathogenesis of PCD in the family, and forms a compound heterozygote with the pathogenic variant DNAH5 c.4314delT lead to the pathogenesis of PCD.


Assuntos
Calcinose , Mutação , Linhagem , Humanos , Masculino , Calcinose/genética , Calcinose/patologia , Feminino , Dineínas do Axonema/genética , Adulto , Transtornos da Motilidade Ciliar/genética , Encefalopatias/genética , Fenótipo , Células HEK293 , China , Splicing de RNA/genética , Pessoa de Meia-Idade , Glicosídeo Hidrolases
4.
Head Neck Pathol ; 18(1): 46, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38884770

RESUMO

Phleboliths are reported as calcifications that occur in vascular malformations, associated with changes in blood flow dynamics, thrombus formation and subsequent calcifications. Radiological examination, such as cone beam computed tomography (CBCT) could help in demonstrating the presence of a calcifiied mass. A 45-year-old male was referred to our service with an asymptomatic nodular purplish lesion located on the ventrolateral tongue. Within the lesion, a stony mass was also evident on palpation. A digital dental radiograph demonstrated two circumscribed radiopaque structures. Phleboliths associated with vascular malformation was the main diagnostic hypothesis. The patient underwent a sclerotherapy protocol allowing surgical accessibility to the area. Phlebolyts were surgically removed using electrocoagulation. Histopathological examination revealed phleboliths in the context of a vascular malformation with intense fibrosis.


Assuntos
Calcinose , Humanos , Masculino , Pessoa de Meia-Idade , Calcinose/patologia , Malformações Vasculares/patologia , Doenças da Língua/patologia
5.
Arch Dermatol Res ; 316(7): 390, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38878086

RESUMO

Calcinosis cutis is a condition that is commonly associated with autoimmune connective tissue diseases. It is characterized by the deposition of insoluble calcium salts in the skin and subcutaneous tissue, which can cause pain, impair function, and have significant impacts on quality of life. Calcinosis cutis is difficult to manage because there is no generally accepted treatment: evidence supporting treatments is mostly comprised of case reports and case series, sometimes yielding mixed findings. Both pharmacologic and procedural interventions have been proposed to improve calcinosis cutis, and each may be suited to different clinical scenarios. This review summarizes current treatment options for calcinosis cutis, with discussion of recommendations based on patient-specific factors and disease severity.


Assuntos
Doenças Autoimunes , Calcinose , Doenças do Tecido Conjuntivo , Dermatopatias , Humanos , Calcinose/diagnóstico , Calcinose/terapia , Calcinose/etiologia , Calcinose/patologia , Calcinose/imunologia , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Dermatopatias/etiologia , Dermatopatias/terapia , Dermatopatias/diagnóstico , Dermatopatias/imunologia , Doenças Autoimunes/terapia , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Qualidade de Vida , Pele/patologia , Pele/imunologia , Calcinose Cutânea
6.
Genes Chromosomes Cancer ; 63(6): e23249, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38884173

RESUMO

The widespread use of advanced molecular techniques has led to the identification of several tumor types with PLAG1 gene fusions some of which also affect the skin and soft tissues. Herein, we present a 38-year-old female with a subcutaneous tumor affecting her forearm, which does not seem to fit into any currently recognized entity. It was a well-circumscribed tumor measuring 6 × 4,5 × 4 cm. It had a thick capsule composed of bland spindle cells forming palisades and Verocay body-like structures within a myxocollagenous background. Scattered calcifications were dispersed throughout the lesion. No cytological atypia, mitotic activity, or necrosis were present. Targeted NGS revealed a SOX10::PLAG1 fusion and fluorescent in situ hybridization confirmed the presence of PLAG1 gene rearrangement. The neoplastic cells showed a diffuse immunohistochemical expression of S100, SOX10, and PLAG1, as well as patchy desmin and CD34 positivity. The methylation profile of this tumor did not match any other entity covered by the DKFZ sarcoma classifier and apart from the gain of chromosome 12, the copy number profile was normal. The tumor was completely excised, and the patient has been free of disease for 4 years since the excision. While more cases are needed to confirm this tumor as a distinct entity, we propose a provisional name "SOX10::PLAG1-rearranged calcifying spindle cell tumor."


Assuntos
Proteínas de Ligação a DNA , Fatores de Transcrição SOXE , Neoplasias de Tecidos Moles , Humanos , Feminino , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Adulto , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Calcinose/genética , Calcinose/patologia , Calcinose/metabolismo , Sarcoma/genética , Sarcoma/patologia , Sarcoma/metabolismo
7.
Sci Rep ; 14(1): 13351, 2024 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858542

RESUMO

To explore the clinicopathological characteristics and prognostic significance of casting-type calcification (CC) in patients with breast cancer presenting with microcalcification on mammography. Data on patients with invasive breast cancer who had mammographic calcification was retrospectively analyzed. The chi-square test was utilized to assess the clinicopathological characteristics of two forms of CC-related breast cancer. The examination of prognostic variables was conducted using Kaplan-Meier and Cox regression analyses. A total of 427 eligible patients were included in this study. Chi-square analysis indicated that the presence of CC was associated with estrogen receptor (ER) negativity (P = 0.005), progesterone receptor (PR) negativity (P < 0.001), and epidermal growth factor receptor 2 (HER-2) positivity (P < 0.001); among these, the association was stronger with the CC-predominant type. After a median follow-up of 82 months, those with CC had a worse 5-year recurrence-free survival (RFS) (77.1% vs. 86.9%, p = 0.036; hazard ratio [HR], 1.86; 95% confidence interval [CI] 1.04-3.31) and overall survival (OS) (84.0% vs. 94.4%, p = 0.007; HR, 2.99; 95% CI 1.34-6.65) rates. In COX regression analysis, such differences were still observed in HER-2 positive subgroups (RFS: HR: 2.45, 95% CI 1-5.97, P = 0.049; OS: HR: 4.53, 95% CI 1.17-17.52, P = 0.029). In patients with invasive breast cancer exhibiting calcifications on mammography, the presence of CC, especially the CC-predominant type, is linked to a higher frequency of hormone receptor negativity and HER-2 positivity. The presence of CC is associated with an unfavorable 5-year RFS and OS rates.


Assuntos
Neoplasias da Mama , Calcinose , Mamografia , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/complicações , Neoplasias da Mama/mortalidade , Feminino , Calcinose/patologia , Calcinose/diagnóstico por imagem , Pessoa de Meia-Idade , Prognóstico , Mamografia/métodos , Idoso , Estudos Retrospectivos , Adulto , Invasividade Neoplásica , Receptor ErbB-2/metabolismo , Estimativa de Kaplan-Meier , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Intervalo Livre de Doença
8.
JACC Cardiovasc Interv ; 17(11): 1340-1351, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38866457

RESUMO

BACKGROUND: The etiology of transcatheter aortic valve (TAV) degeneration is poorly understood, particularly noncalcific mechanisms. OBJECTIVES: The authors sought to investigate noncalcific and calcific mechanisms of TAV degeneration and evaluate their impact on leaflet function by bench testing, imaging, and histology. METHODS: TAV explants were obtained from the EXPLANT THV registry and clinical institutions. Hydrodynamic assessment was performed using a heart valve pulse duplicator system under physiological conditions. Micro-computed tomography, high-resolution photography, high speed video, and hematoxylin and eosin staining were used to evaluate the morphological appearance, leaflet kinematics, and calcium burden of TAVs. RESULTS: A total of 14 explants were evaluated: 10 self-expanding CoreValve/Evolut TAVs (Medtronic), 3 balloon-expandable SAPIEN 3 TAVs (Edwards Lifesciences), and 1 mechanically expandable Lotus TAV (Boston Scientific). The median patient age at explantation was 73.0 years (Q1-Q3: 64.5-80.0 years), with a time to explantation of 4 years 1 month (1 year 5 months to 4 years 11 months). Six TAV explants were found to have leaflet calcification (162.4 mm3; 58.8-603.0 mm3), and 8 had no calcification detectable by micro-computed tomography and histology. All samples had impaired leaflet kinematics. There was no significant difference in the hydrodynamic mean gradient between calcified (47.2 mm Hg; 26.6-74.1 mm Hg) and noncalcified (27.6 mm Hg; 15.2-36.7 mm Hg; P = 0.28) TAVs. Leaflet calcification had a weak but nonsignificant association with the hydrodynamic mean gradient (r = 0.42; P = 0.14). CONCLUSIONS: TAV function can be severely impacted by noncalcific and calcific mechanisms of tissue degeneration. Importantly, functional stenosis can occur in TAVs in the absence of obvious and significant calcification.


Assuntos
Valva Aórtica , Calcinose , Próteses Valvulares Cardíacas , Hidrodinâmica , Desenho de Prótese , Falha de Prótese , Sistema de Registros , Substituição da Valva Aórtica Transcateter , Microtomografia por Raio-X , Humanos , Idoso , Valva Aórtica/fisiopatologia , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Valva Aórtica/patologia , Calcinose/fisiopatologia , Calcinose/diagnóstico por imagem , Calcinose/patologia , Calcinose/cirurgia , Feminino , Idoso de 80 Anos ou mais , Masculino , Substituição da Valva Aórtica Transcateter/instrumentação , Substituição da Valva Aórtica Transcateter/efeitos adversos , Pessoa de Meia-Idade , Fatores de Tempo , Remoção de Dispositivo , Estenose da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Hemodinâmica , Fenômenos Biomecânicos , Teste de Materiais , Gravação em Vídeo
9.
Mol Med ; 30(1): 76, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840067

RESUMO

BACKGROUND: Advanced glycation end product-modified low-density lipoprotein (AGE-LDL) is related to inflammation and the development of atherosclerosis. Additionally, it has been demonstrated that receptor for advanced glycation end products (RAGE) has a role in the condition known as calcific aortic valve disease (CAVD). Here, we hypothesized that the AGE-LDL/RAGE axis could also be involved in the pathophysiological mechanism of CAVD. METHODS: Human aortic valve interstitial cells (HAVICs) were stimulated with AGE-LDL following pre-treatment with or without interleukin 37 (IL-37). Low-density lipoprotein receptor deletion (Ldlr-/-) hamsters were randomly allocated to chow diet (CD) group and high carbohydrate and high fat diet (HCHFD) group. RESULTS: AGE-LDL levels were significantly elevated in patients with CAVD and in a hamster model of aortic valve calcification. Our in vitro data further demonstrated that AGE-LDL augmented the expression of intercellular cell adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and alkaline phosphatase (ALP) in a dose-dependent manner through NF-κB activation, which was attenuated by nuclear factor kappa-B (NF-κB) inhibitor Bay11-7082. The expression of RAGE was augmented in calcified aortic valves, and knockdown of RAGE in HAVICs attenuated the AGE-LDL-induced inflammatory and osteogenic responses as well as NF-κB activation. IL-37 suppressed inflammatory and osteogenic responses and NF-κB activation in HAVICs. The vivo experiment also demonstrate that supplementation with IL-37 inhibited valvular inflammatory response and thereby suppressed valvular osteogenic activities. CONCLUSIONS: AGE-LDL promoted inflammatory responses and osteogenic differentiation through RAGE/NF-κB pathway in vitro and aortic valve lesions in vivo. IL-37 suppressed the AGE-LDL-induced inflammatory and osteogenic responses in vitro and attenuated aortic valve lesions in a hamster model of CAVD.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Produtos Finais de Glicação Avançada , Lipoproteínas LDL , NF-kappa B , Osteogênese , Receptor para Produtos Finais de Glicação Avançada , Transdução de Sinais , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Produtos Finais de Glicação Avançada/metabolismo , NF-kappa B/metabolismo , Humanos , Calcinose/metabolismo , Calcinose/patologia , Calcinose/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor para Produtos Finais de Glicação Avançada/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/etiologia , Estenose da Valva Aórtica/patologia , Cricetinae , Osteogênese/efeitos dos fármacos , Masculino , Lipoproteínas LDL/metabolismo , Modelos Animais de Doenças , Feminino , Pessoa de Meia-Idade , Proteínas Glicadas
10.
Adv Exp Med Biol ; 1441: 761-775, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38884747

RESUMO

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.


Assuntos
Aorta Torácica , Valva Aórtica , Humanos , Aorta Torácica/anormalidades , Aorta Torácica/patologia , Valva Aórtica/anormalidades , Valva Aórtica/patologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Doença da Válvula Aórtica Bicúspide/genética , Estenose da Valva Pulmonar/genética , Mutação , Receptor Notch1/genética , Valvopatia Aórtica/genética , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/patologia , Calcinose/genética , Calcinose/patologia , Doenças Hematológicas/genética , Doenças Hematológicas/patologia , Doenças Vestibulares/genética , Doenças Vestibulares/patologia
11.
Stomatologiia (Mosk) ; 103(3): 56-58, 2024.
Artigo em Russo | MEDLINE | ID: mdl-38904561

RESUMO

This article discusses a rare clinical case of differential diagnosis between salivary stone disease and calcinosis, which developed against the background of autoimmune pathology. Diagnosis of these pathologies causes difficulties for practitioners, and treatment methods have fundamental differences. In this regard, the description of this case is relevant and significant. The algorithm of the main and additional research methods to confirm the diagnosis is described.


Assuntos
Calcinose , Glândula Parótida , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Calcinose/patologia , Calcinose/diagnóstico , Calcinose/etiologia , Feminino , Diagnóstico Diferencial , Glândula Parótida/patologia , Pessoa de Meia-Idade
12.
J Mol Neurosci ; 74(2): 54, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760510

RESUMO

This article discusses a rare case of coexistent meningiomas and Primary familial brain calcification (PFBC). PFBC is a neurodegenerative disease characterized by brain calcifications and a variety of neuropsychiatric symptoms and signs, with pathogenic variants in specific genes. The study explores the potential link between PFBC and meningiomas, highlighting shared features like intralesional calcifications and common genes such as MEA6. The article also revisits PFBC patients developing other brain tumors, particularly gliomas, emphasizing the intersection of oncogenes like PDGFB and PDGFRB in both calcifications and tumor progression. In recent investigations, attention has extended beyond brain tumors to breast cancer metastasis, unveiling a noteworthy connection. These findings suggest a broader connection between brain calcifications and tumors, encouraging a reevaluation of therapeutic approaches for PFBC.


Assuntos
Neoplasias Encefálicas , Calcinose , Meningioma , Humanos , Calcinose/genética , Calcinose/patologia , Meningioma/genética , Meningioma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Feminino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Encefalopatias/genética , Encefalopatias/patologia , Encefalopatias/metabolismo
13.
Lab Invest ; 104(7): 102086, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38797343

RESUMO

Retinoschisin (RS1) is a secretory protein specifically localized to the extracellular domains in both the lateral retina and the pineal gland (PG). However, the functions of RS1 in the pineal body are poorly understood. To address this knowledge gap, in this study, we undertook histochemical, ultrastructural, and Western blotting analyses of the PG in rats and RS1-knock-in transgenic. We found that RS1 plays a key role in pineal gland calcification (PGC) in mice through both extracellular and intracellular pathways. RS1 was clustered around the cell membrane or intracellularly in pinealocytes, actively participating in the exchange of calcium and thereby mediating PGC. Additionally, RS1 deposition is essential for maintaining PGC architecture in the intercellular space of the adult PG. In RS1-knock-in mice with a nonsense mutation (p.Y65X) in the Rs1-domain of RS1, the Rs1-domain is chaotically dispersed in pinealocytes and the intercellular region of the PG. This prevents RS1 from binding calcified spots and forming calcified nodules, ultimately leading to the accumulation of calcareous lamellae in microvesicles. Additionally, RS1 was observed to colocalize with connexin-36, thereby modulating intercellular communication in the PG of both rats and mice. Our study revealed for the first time that RS1 is essential for maintaining PGC architecture and that it colocalizes with connexin 36 to modulate intercellular communication in the PG. These findings provide novel insights into the function of the RS1 gene in the PG.


Assuntos
Comunicação Celular , Glândula Pineal , Animais , Glândula Pineal/metabolismo , Ratos , Camundongos , Proteínas do Olho/metabolismo , Proteínas do Olho/genética , Calcinose/metabolismo , Calcinose/patologia , Masculino , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Ratos Sprague-Dawley
14.
Redox Biol ; 73: 103215, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38810422

RESUMO

The prevalence of calcific aortic valve disease (CAVD) remains substantial while there is currently no medical therapy available. Forkhead box O1 (FOXO1) is known to be involved in the pathogenesis of cardiovascular diseases, including vascular calcification and atherosclerosis; however, its specific role in calcific aortic valve disease remains to be elucidated. In this study, we identified FOXO1 significantly down-regulated in the aortic valve interstitial cells (VICs) of calcified aortic valves by investigating clinical specimens and GEO database analysis. FOXO1 silencing or inhibition promoted VICs osteogenic differentiation in vitro and aortic valve calcification in Apoe-/- mice, respectively. We identified that FOXO1 facilitated the ubiquitination and degradation of RUNX2, which process was mainly mediated by SMAD-specific E3 ubiquitin ligase 2 (SMURF2). Our discoveries unveil a heretofore unacknowledged mechanism involving the FOXO1/SMURF2/RUNX2 axis in CAVD, thereby proposing the potential therapeutic utility of FOXO1 or SMURF2 as viable strategies to impede the progression of CAVD.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Subunidade alfa 1 de Fator de Ligação ao Core , Proteína Forkhead Box O1 , Ubiquitina-Proteína Ligases , Ubiquitinação , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Camundongos , Humanos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Calcinose/metabolismo , Calcinose/patologia , Calcinose/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/genética , Masculino , Osteogênese/genética , Modelos Animais de Doenças , Diferenciação Celular
15.
Arthritis Res Ther ; 26(1): 102, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38778407

RESUMO

BACKGROUND: To perform a detailed morphological analysis of the inorganic portion of two different clinical presentations of calcium-based deposits retrieved from subjects with SSc and identify a chemical dissolution of these deposits suitable for clinical use. METHODS: Chemical analysis using Fourier Transform IR spectroscopy ('FTIR'), Raman microscopy, Powder X-Ray Diffraction ('PXRD'), and Transmission Electron Microscopy ('TEM') was undertaken of two distinct types of calcinosis deposits: paste and stone. Calcinosis sample titration with ethylenediaminetetraacetic acid ('EDTA') assessed the concentration at which the EDTA dissolved the calcinosis deposits in vitro. RESULTS: FTIR spectra of the samples displayed peaks characteristic of hydroxyapatite, where signals attributable to the phosphate and carbonate ions were all identified. Polymorph characterization using Raman spectra were identical to a hydroxyapatite reference while the PXRD and electron diffraction patterns conclusively identified the mineral present as hydroxyapatite. TEM analysis showed differences of morphology between the samples. Rounded particles from stone samples were up to a few micron in size, while needle-like crystals from paste samples reached up to 0.5 µm in length. Calcium phosphate deposits were effectively dissolved with 3% aqueous solutions of EDTA, in vitro. Complete dissolution of both types of deposit was achieved in approximately 30 min using a molar ratio of EDTA/HAp of ≈ 300. CONCLUSIONS: Stone and paste calcium-based deposits both comprise hydroxyapatite, but the constituent crystals vary in size and morphology. Hydroxyapatite is the only crystalline polymorph present in the SSc-related calcinosis deposits. Hydroxyapatite can be dissolved in vitro using a dosage of EDTA considered safe for clinical application. Further research is required to establish the optimal medium to develop the medical product, determine the protocol for clinical application, and to assess the effectiveness of EDTA for local treatment of dystrophic calcinosis.


Assuntos
Calcinose , Ácido Edético , Ácido Edético/química , Humanos , Calcinose/tratamento farmacológico , Calcinose/patologia , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Microscopia Eletrônica de Transmissão/métodos , Difração de Raios X/métodos , Análise Espectral Raman/métodos , Feminino , Durapatita/química , Pessoa de Meia-Idade , Masculino , Quelantes de Cálcio/química
16.
Circulation ; 149(25): 1938-1948, 2024 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-38804148

RESUMO

BACKGROUND: Ascending aorta dilation and aortic valve degeneration are common complications in patients with bicuspid aortic valve. Several retrospective studies have suggested the benefit of statins in reducing these complications. This study aimed to determine whether atorvastatin treatment is effective in reducing the growth of aortic diameters in bicuspid aortic valve and if it slows the progression of valve calcification. METHODS: In a randomized clinical trial, 220 patients with bicuspid aortic valve (43 women; 46±13 years of age) were included and treated with either 20 mg of atorvastatin per day or placebo for 3 years. Inclusion criteria were ≥18 years of age, nonsevere valvular dysfunction, nonsevere valve calcification, and ascending aorta diameter ≤50 mm. Computed tomography and echocardiography studies were performed at baseline and after 3 years of treatment. RESULTS: During follow-up, 28 patients (12.7%) discontinued medical treatment (15 on atorvastatin and 13 taking placebo). Thus, 192 patients completed the 36 months of treatment. Low-density lipoprotein cholesterol levels decreased significantly in the atorvastatin group (median [interquartile range], -30 mg/dL [-51.65 to -1.75 mg/dL] versus 6 mg/dL [-4, 22.5 mg/dL]; P<0.001). The maximum ascending aorta diameter increased with no differences between groups: 0.65 mm (95% CI, 0.45-0.85) in the atorvastatin group and 0.74 mm (95% CI, 0.45-1.04) in the placebo group (P=0.613). Similarly, no significant differences were found for the progression of the aortic valve calcium score (P=0.167) or valvular dysfunction. CONCLUSIONS: Among patients with bicuspid aortic valve without severe valvular dysfunction, atorvastatin treatment was not effective in reducing the progression of ascending aorta dilation and aortic valve calcification during 3 years of treatment despite a significant reduction in low-density lipoprotein cholesterol levels. REGISTRATION: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001808-57. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02679261.


Assuntos
Valva Aórtica , Atorvastatina , Doença da Válvula Aórtica Bicúspide , Calcinose , Progressão da Doença , Doenças das Valvas Cardíacas , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Atorvastatina/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Valva Aórtica/anormalidades , Valva Aórtica/efeitos dos fármacos , Calcinose/tratamento farmacológico , Calcinose/diagnóstico por imagem , Calcinose/patologia , Doença da Válvula Aórtica Bicúspide/diagnóstico por imagem , Doença da Válvula Aórtica Bicúspide/tratamento farmacológico , Doenças das Valvas Cardíacas/tratamento farmacológico , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/patologia , Adulto , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Dilatação Patológica/tratamento farmacológico , Seguimentos , Método Duplo-Cego , Resultado do Tratamento , Aorta/diagnóstico por imagem , Aorta/patologia , Aorta/efeitos dos fármacos , Valvopatia Aórtica/tratamento farmacológico , Estenose da Valva Aórtica
17.
Commun Biol ; 7(1): 577, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38755434

RESUMO

Pseudoxanthoma elasticum (PXE) is a rare disease characterized by ectopic calcification, however, despite the widely spread effect of pro/anti-calcifying systemic factors associated with this genetic metabolic condition, it is not known why elastic fibers in the same patient are mainly fragmented or highly mineralized in clinically unaffected (CUS) and affected (CAS) skin, respectively. Cellular morphology and secretome are investigated in vitro in CUS and CAS fibroblasts. Here we show that, compared to CUS, CAS fibroblasts exhibit: a) differently distributed and organized focal adhesions and stress fibers; b) modified cell-matrix interactions (i.e., collagen gel retraction); c) imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases; d) differentially expressed pro- and anti-calcifying proteoglycans and elastic-fibers associated glycoproteins. These data emphasize that in the development of pathologic mineral deposition fibroblasts play an active role altering the stability of elastic fibers and of the extracellular matrix milieu creating a local microenvironment guiding the level of matrix remodeling at an extent that may lead to degradation (in CUS) or to degradation and calcification (in CAS) of the elastic component. In conclusion, this study contributes to a better understanding of the mechanisms of the mineral deposition that can be also associated with several inherited or age-related diseases (e.g., diabetes, atherosclerosis, chronic kidney diseases).


Assuntos
Calcinose , Elastina , Fibroblastos , Pseudoxantoma Elástico , Pseudoxantoma Elástico/metabolismo , Pseudoxantoma Elástico/patologia , Pseudoxantoma Elástico/genética , Humanos , Elastina/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Calcinose/metabolismo , Calcinose/patologia , Derme/metabolismo , Derme/patologia , Pessoa de Meia-Idade , Feminino , Masculino , Adulto , Células Cultivadas , Matriz Extracelular/metabolismo , Tecido Elástico/metabolismo , Tecido Elástico/patologia
19.
Scand Cardiovasc J ; 58(1): 2353070, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38757904

RESUMO

Objectives: The role of diabetes mellitus as a risk factor for the development of calcific aortic valve disease has not been fully clarified. Aortic valve interstitial cells (VICs) have been suggested to be crucial for calcification of the valve. Induced calcification in cultured VICs is a good in vitro model for aortic valve calcification. The purpose of this study was to investigate whether increased glucose levels increase experimentally induced calcification in cultured human VICs. Design: VICs were isolated from explanted calcified aortic valves after valve replacement. Osteogenic medium induced calcification of cultured VICs at different glucose levels (5, 15, and 25 mM). Calcium deposits were visualized using Alizarin Red staining and measured spectrophotometrically. Results: The higher the glucose concentration, the lower the level of calcification. High glucose (25 mM) reduced calcification by 52% compared with calcification at a physiological (5 mM) glucose concentration (correlation and regression analysis: r = -0.55, p = .025 with increased concentration of glucose). Conclusions: In vitro hyperglycemia-like conditions attenuated calcification in VICs. High glucose levels may trigger a series of events that secondarily stimulate calcification of VICs in vivo.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Glucose , Hiperglicemia , Humanos , Valva Aórtica/patologia , Valva Aórtica/metabolismo , Valva Aórtica/cirurgia , Calcinose/patologia , Calcinose/metabolismo , Células Cultivadas , Glucose/metabolismo , Hiperglicemia/metabolismo , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/cirurgia , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Relação Dose-Resposta a Droga , Osteogênese/efeitos dos fármacos
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