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1.
J Am Heart Assoc ; 9(15): e016715, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32750292

RESUMO

Background Current methods for aortic dissection risk assessment are inadequate for patients with ascending aortic aneurysms associated with either bicuspid aortic valves (BAVs) or tricuspid aortic valves (TAVs). Biomechanical testing of aortic tissue may provide novel insights and biomarkers. Methods and Results From March 2017 to August 2019, aneurysmal ascending aortas (BAV=23, TAV=23) were collected from elective aortic surgery, normal aortas from transplant donors (n=9), and dissected aortas from surgery for aortic dissection (n=7). These aortas underwent delamination testing in simulation of aortic dissection. Biaxial tensile testing was performed to determine modulus of elasticity (aortic stiffness), and energy loss (a measure of efficiency in performing the Windkessel function). Delamination strength (Sd) was lowest in dissected aortas (18±6 mN/mm) and highest in normal aortas (58±16 mN/mm), and aneurysms fell in between, with greater Sd in the BAV group (37±10 mN/mm) than the TAV group (27±10 mN/mm) (P<0.001). Bicuspid aortopathy was associated with greater stiffness (P<0.001), while aneurysms with TAV demonstrated greater energy loss (P<0.001). Sd decreased by 7.8±1.2 mmol/L per mm per decade of life (r2=0.45, P<0.001), and it was significantly lower for patients with hypertension (P=0.001). Sd decreased by 6.1±2.1 mmol/L per mm with each centimeter increase in aortic diameter (r2=0.15, P=0.007). Increased energy loss was associated with decreased Sd (r2=0.41), whereas there was no relationship between Sd and aortic stiffness. Conclusions Aneurysms with BAV had higher Sd than those with TAV, suggesting that BAV was protective. Energy loss was lower in aneurysms with BAV, and inversely associated with Sd, representing a potential novel biomarker.

2.
J Card Surg ; 35(5): 1132-1134, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32237173

RESUMO

BACKGROUND AND AIM: Lipomatous hypertrophy of the interatrial septum (LHIS), a fatty tumor, is usually diagnosed on both echo and CT/MRI imaging. Cases of LHIS located outside of the interatrial septum are extremely rare and rarer still are these cases large enough to cause symptoms. The clinical literature demonstrates a misunderstanding that fatty tumors outside the intra-atrial area represent lipomas. However, pathologic understanding of these fatty tumors is clear and is based on microscopic findings. METHODS: The tumor was removed by diving the base of attachment at the left ventricular apex via a median sternotomy on cardiopulmonary bypass. RESULTS: The patient made an uneventful recovery and remains well at 6 months postoperatively. CONCLUSIONS: On rare occasions, LHIS can arise from outside the interatrial septum. An LHIS can be differentiated from a lipoma by the presence of entrapped cardiac myocytes in LHIS, making it a pathological, rather than an anatomic, diagnosis.


Assuntos
Septo Interatrial/patologia , Átrios do Coração/patologia , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/patologia , Septos Cardíacos/patologia , Lipoma/diagnóstico , Lipoma/patologia , Adulto , Procedimentos Cirúrgicos Cardíacos , Ponte Cardiopulmonar , Neoplasias Cardíacas/cirurgia , Humanos , Hipertrofia , Lipoma/cirurgia , Imagem por Ressonância Magnética , Masculino , Esternotomia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
3.
Artigo em Inglês | MEDLINE | ID: mdl-32243080

RESUMO

OBJECTIVE: To create an experimental chronic total occlusion (CTO) model with calcification by dietary modification (cholesterol, calcium carbonate, vitamin D) and local injection of pro-calcification factors (dipotassium phosphate, calcium chloride, and bone morphogenetic protein-2 [BMP-2]). BACKGROUND: Percutaneous revascularization of CTOs frequently fails in heavily calcified occlusions. Development of novel approaches requires a reproducible preclinical model of calcified CTO. METHODS: CTOs were created in 18 femoral arteries of 9 New Zealand White rabbits using the thrombin injection model. Dietary interventions included a high cholesterol diet (0.5% or 0.25%), calcium carbonate (150 mg × 3-5 days/week), and vitamin D (50,000 U × 3-5 days/week). In selected animals, BMP-2 (1-4 µg), dipotassium phosphate, and calcium chloride were injected locally at the time of CTO creation. Animals were sacrificed at 2 weeks (n = 4 arteries), 6 weeks (n = 4 arteries), and 10-12 weeks (n = 14 arteries). RESULTS: CTOs showed evidence of chronic lipid feeding (foam cells) and chronic inflammation (intimal/medial fibrosis and microvessels, inflammatory cells, internal elastic lamina disruption). In calcium/vitamin D supplemented rabbits, mineralization (calcification and/or ossification) was evident as early as 2 weeks post CTO creation, and in 78% of the overall arteries. Mineralization changes were not present in the absence of calcium/vitamin D dietary supplements. Mineralization occurred in 85% of BMP-treated arteries and 60% of arteries without BMP. CONCLUSIONS: Complex mineralization occurs in preclinical CTO models with dietary supplementation of cholesterol with vitamin D and calcium.

4.
Curr Opin Cardiol ; 35(2): 123-132, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31972604

RESUMO

PURPOSE OF REVIEW: A thorough understanding of the modes of bioprosthetic valve failure is critical as clinicians will be facing an increasing number of patients presenting with failed bioprostheses in coming years. The purpose of this article is to review modes of bioprosthestic valve degeneration, their management, and identify gaps for future research. RECENT FINDINGS: Guidelines recommend monitoring hemodynamic performance of prosthetic valves using serial echocardiograms to determine valve function and presence of valve degeneration. Modes of bioprosthetic valve failure may be categorized as structural degeneration (calcification, tears, fibrosis, flail), nonstructural degeneration (pannus), thrombosis, and endocarditis. Calcification is the most common form of structural valve degeneration. Predictors of bioprosthetic valve failure include valves implanted in the mitral position, younger age, and type of valve (porcine versus bovine pericardial). Failed bioprosthetic valves are managed with either redo surgical replacement or transcatheter valve-in-valve implantation. SUMMARY: Several modes of bioprosthetic valve failure exist, which vary based on patient, implant position, and valve characteristics. Further research is required to characterize factors associated with early failure to delay structural valve degeneration and improve patient prognosis.


Assuntos
Bioprótese/efeitos adversos , Calcinose , Endocardite , Implante de Prótese de Valva Cardíaca/efeitos adversos , Próteses Valvulares Cardíacas/efeitos adversos , Animais , Valva Aórtica/cirurgia , Bovinos , Humanos , Falha de Prótese , Suínos
6.
J Card Surg ; 35(2): 454-456, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31730722

RESUMO

A 58-year-old man was admitted for reoperation for severe aortic stenosis in a previously preserved bicuspid aortic valve (BAV). He had undergone valve-sparing root replacement (VSSR) for dilated aortic root 6 years ago. Transesophageal echocardiography following VSSR showed good valve function with no aortic incompetence. However, the BAV became stenotic causing shortness of breath. At reoperation, the preserved BAV was noted to be fibrotic and calcified and had a fixed rigid small orifice. It was replaced with a biological valve plus root enlargement. Macroscopic finding showed thickening of the cusps and nodular calcification. Microscopic examination revealed severe nodular calcification.


Assuntos
Estenose da Valva Aórtica/cirurgia , Valva Aórtica/anormalidades , Valva Aórtica/patologia , Valva Aórtica/cirurgia , Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca/métodos , Tratamentos com Preservação do Órgão/métodos , Valva Aórtica/diagnóstico por imagem , Calcinose/cirurgia , Ecocardiografia Transesofagiana , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Reoperação , Índice de Gravidade de Doença
7.
Am J Transplant ; 20(5): 1262-1271, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31769924

RESUMO

Ischemia-reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post-heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species-mediated NF-κB activation. We hypothesized that Nrf2 inhibits NF-κB activation post-Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild-type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline-treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2-KO showed significantly less SOD1/2 activity compared with WT. Nrf2-KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF-κB-mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase-3 activity were significantly higher in Nrf2-KO. In the allograft studies, graft beating score was significantly weaker in Nrf2-KO compared with WT. Nrf2-KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF-κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.

8.
Appl Immunohistochem Mol Morphol ; 27(10): 699-714, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31584451

RESUMO

Since 2014, programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors have been approved by various regulatory agencies for the treatment of multiple cancers including melanoma, lung cancer, urothelial carcinoma, renal cell carcinoma, head and neck cancer, classical Hodgkin lymphoma, colorectal cancer, gastroesophageal cancer, hepatocellular cancer, and other solid tumors. Of these approved drug/disease combinations, a subset also has regulatory agency-approved, commercially available companion/complementary diagnostic assays that were clinically validated using data from their corresponding clinical trials. The objective of this document is to provide evidence-based guidance to assist clinical laboratories in establishing fit-for-purpose PD-L1 biomarker assays that can accurately identify patients with specific tumor types who may respond to specific approved immuno-oncology therapies targeting the PD-1/PD-L1 checkpoint. These recommendations are issued as 38 Guideline Statements that address (i) assay development for surgical pathology and cytopathology specimens, (ii) reporting elements, and (iii) quality assurance (including validation/verification, internal quality assurance, and external quality assurance). The intent of this work is to provide recommendations that are relevant to any tumor type, are universally applicable and can be implemented by any clinical immunohistochemistry laboratory performing predictive PD-L1 immunohistochemistry testing.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores/metabolismo , Imunoterapia/métodos , Neoplasias/terapia , Antígeno B7-H1/antagonistas & inibidores , Canadá , Técnicas de Laboratório Clínico , Medicina Baseada em Evidências , Humanos , Imuno-Histoquímica , Neoplasias/diagnóstico , Neoplasias/imunologia , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Prognóstico , Garantia da Qualidade dos Cuidados de Saúde
9.
J Clin Pathol ; 72(10): 689-695, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31262953

RESUMO

AIMS: Rapid procurement of a wide variety of metastatic and primary cancers and normal tissues after death through rapid autopsy opens largely unexplored avenues in cancer research. We describe a high-volume rapid research autopsy programme at a large academic medical centre. METHODS: Advanced-stage cancer patients, most commonly inpatients in palliative care facilities, were approached to participate in a cancer research autopsy programme with the goal of acquiring multidimensionally annotated tissue for cancer research. On death of an enrolled patient, a predetermined notification plan was enacted, with the medical oncologist/clinical research coordinator informing a team of pathologists, researchers and allied staff. Quality assurance metrics were measured. Thereafter, tissues were annotated in a tissue bioinformatics database and linked to electronic patient records. All banked tissues were reviewed for tumour integrity, including DNA and RNA quality. RESULTS: Over 100 rapid research autopsies from diverse cancer sites were performed, and specimens were procured and annotated with detailed clinical information, including treatment and response. Tissues were successfully enabling studies of tumour immunology, xenografts, genomics and proteomics. CONCLUSIONS: Large-scale rapid procurement and biobanking of cancer tissues from a rapid autopsy programme is feasible. Multidisciplinary integration between health and administrative staff from medical oncology, palliative care, pathology and biospecimen sciences is critical for the success of this challenging endeavour.


Assuntos
Oncologia , Neoplasias/patologia , Patologia Cirúrgica , Bancos de Tecidos , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/cirurgia , Cuidados Paliativos , Proteômica , Adulto Jovem
10.
J Mol Cell Cardiol ; 132: 71-83, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31047984

RESUMO

Bicuspid aortic valve (BAV) disease is a congenital abnormality that is associated with ascending aortic aneurysm yet many of the molecular mechanisms remain unknown. To identify novel molecular mechanisms of aneurysm formation we completed microarray analysis of the proximal (severely dilated) and distal (less dilated) regions of the ascending aorta from five patients with BAV. We identified 180 differentially expressed genes, 40 of which were validated by RT-qPCR. Most genes had roles in inflammation and endothelial cell function including cytokines and growth factors, cell surface receptors and the Activator Protein 1 (AP-1) transcription factor family (FOS, FOSB and JUN) which was chosen for further study. AP-1 was differentially expressed within paired BAV aneurysmal samples (n = 8) but not Marfan patients (n = 5). FOS protein was significantly enriched in BAV aortas compared to normal aortas but unexpectedly, ERK1/2 activity, an upstream regulator of FOS was reduced. ERK1/2 activity was restored when BAV smooth muscle cells were cultured in vitro. An mRNA-miRNA network within paired patient samples identified AP-1 as a central hub of miRNA regulation. FOS knockdown in BAV SMCs increased expression of miR-27a, a stretch responsive miRNA. AP-1 and miR-27a were also dysregulated in a mouse model of aortic constriction. In summary, this study identified a central role for AP-1 signaling in BAV aortic dilatation by using paired mRNA-miRNA patient sample. Upstream analysis of AP-1 regulation showed that the ERK1/2 signaling pathway is dysregulated and thus represents a novel chain of mediators of aortic dilatation in BAV which should be considered in future studies.


Assuntos
Aneurisma Aórtico/patologia , Doenças da Aorta/patologia , Valva Aórtica/anormalidades , Biomarcadores/metabolismo , Dilatação Patológica/patologia , Doenças das Valvas Cardíacas/patologia , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/metabolismo , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Valva Aórtica/fisiopatologia , Dilatação Patológica/genética , Dilatação Patológica/metabolismo , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Transdução de Sinais
11.
J Rheumatol ; 46(4): 391-396, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30323009

RESUMO

OBJECTIVE: Antimalarials (AM) are recommended for all systemic lupus erythematosus (SLE) patients without specific contraindications. Their main adverse effect is retinal damage; however, heart disease has been described in isolated cases. The aim of our study is to describe 8 patients with AM-induced cardiomyopathy (AMIC) in a defined SLE cohort. METHODS: Patients attending the Toronto Lupus Clinic and diagnosed with definite (based on endomyocardial biopsy; EMB) and possible AMIC were included [based on cardiac magnetic resonance imaging (cMRI) and other investigations]. RESULTS: Eight female patients (median age 62.5 yrs, disease duration 35 yrs, AM use duration 22 yrs) were diagnosed with AMIC in the past 2 years. Diagnosis was based on EMB in 3 (extensive cardiomyocyte vacuolation, intracytoplasmic myelinoid, and curvilinear bodies). In 4 patients, cMRI was highly suggestive of AMIC (ventricular hypertrophy and/or atrial enlargement and late gadolinium enhancement in a nonvascular pattern). Another patient was diagnosed with complete atrioventricular block, left ventricular and septal hypertrophy, along with concomitant ocular toxicity. All patients had abnormal cardiac troponin I (cTnI) and brain natriuretic peptide (BNP), whereas 7/8 also had chronically elevated creatine phosphokinase. During followup, 1 patient died from refractory heart failure. In the remaining patients, hypertrophy regression and a steady decrease of heart biomarkers were observed after AM cessation. CONCLUSION: Once considered extremely rare, AMIC seems to be underrecognized, probably because of the false attribution of heart failure or hypertrophy to other causes. Certain biomarkers (cTnI, BNP) and imaging findings may lead to early diagnosis and enhance survival.


Assuntos
Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Doenças Raras/induzido quimicamente , Doenças Raras/diagnóstico por imagem , Idoso , Biomarcadores/sangue , Biópsia , Canadá , Cardiomiopatias/patologia , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Doenças Raras/patologia , Troponina I/sangue , Suspensão de Tratamento
12.
Cancer Med ; 8(1): 104-110, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30575309

RESUMO

BACKGROUND: Primary cardiac sarcoma (PCS) is a rare but often fatal disease. The current study aimed to analyze the impact of baseline demographics, local and systemic therapies in a contemporary cohort. METHODS: Clinical records of PCS across six institutions in three continents were reviewed. Kaplan-Meier method was used to estimate survival. Cox proportional hazard model was used to determine variables impacting progression-free survival (PFS) or overall survival (OS). RESULTS: Sixty-one patients with PCS (1996-2016) were identified. The median age at diagnosis was 46 (range 18-79); 36% (n = 22) presented with metastatic disease. The most common histology was angiosarcoma (n = 24, 39%). A total of 46 patients received surgery (75%) but only 5 (8%) patients achieved R0 resection. Multi-modality treatment to the primary tumor was given to 28 patients (46%; localized disease 23/39 (59%); metastatic disease 5/22 (23%)). The median OS for the entire cohort was 17.5 months (95% CI 9.5-20.6), with seven (11%) patients surviving longer than 36 months. On multi-variate analysis, age <65 (P = 0.01) was the only significant favorable prognostic factor. For first-line palliative chemotherapy, the median PFS was 4.4 months (95% CI 2.9-7.7 months). The best response for first-line chemotherapy was 32% (CR = 1, PR = 9). No significant improvement in OS was identified in patients presenting throughout the 20-year period of this review. CONCLUSION: Younger age at diagnosis was associated with improved outcome although the prognosis of PCS remains poor. Given the lack of improvement in survival, further dedicated research is required.


Assuntos
Neoplasias Cardíacas , Sarcoma , Adolescente , Adulto , Idoso , Feminino , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/epidemiologia , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Sarcoma/patologia , Sarcoma/terapia , Análise de Sobrevida , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
13.
Interact Cardiovasc Thorac Surg ; 28(4): 645-646, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496422

RESUMO

Only a handful of congenital aneurysms of the right atrium have been reported in the literature. They are most commonly found in the third decade of life, and the differential diagnosis depends on the patient's age profile. They are associated with 5% risk of sudden cardiac death. Once diagnosed, they should be surgically removed even in the absence of symptoms.


Assuntos
Aneurisma Coronário/diagnóstico , Aneurisma Coronário/cirurgia , Idoso , Diagnóstico Diferencial , Átrios do Coração , Humanos , Masculino
15.
J Card Surg ; 33(8): 432-437, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29992619

RESUMO

BACKGROUND: Primary cardiac adipose tumors are rare. There are two distinct pathologically defined entities that represent this tumor type: lipoma and lipomatous hypertrophy of the interatrial septum (LHIS). We present a single-center experience with these tumors and demonstrate that the location may not correspond to the pathologic diagnosis. METHODS: A retrospective review of a prospectively collected cardiac surgery database from January 1990 to July 2016 identified 254 cases of surgically treated primary cardiac tumors at our Institution. Of these, 06/254 (2%) were primary adipose tumors. RESULTS: In 3/6 (50%) cases, patients were asymptomatic or had symptoms referable to other known intracardiac lesions. Five patients (83%) had preserved ventricular function. In 4/6 cases (67%), the tumor was identified preoperatively. All patients presented in New York Heart Association functional class ≤2. Pathologic diagnosis of LHIS was made in 5/6 cases (83%), with 2/5 LHIS (40%) located in the interatrial septum. A bovine pericardial patch was utilized for reconstruction following tumor resection in 3/6 cases (50%). Mean cardiopulmonary bypass time was 88 ± 43 min. All the patients tolerated the procedure well without any postoperative complications. CONCLUSIONS: Primary cardiac adipose tumors are responsible for a small portion of all primary heart tumors. Surgical resection provided excellent outcomes, and did not affect cardiac performance, in spite of the need for extensive resections. LHIS was identified in locations other than the interatrial septum and was usually symptomatic.


Assuntos
Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/patologia , Lipoma/diagnóstico , Lipoma/patologia , Idoso , Procedimentos Cirúrgicos Cardíacos/métodos , Feminino , Neoplasias Cardíacas/epidemiologia , Neoplasias Cardíacas/cirurgia , Septos Cardíacos , Humanos , Lipoma/epidemiologia , Lipoma/cirurgia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
16.
Endocrinology ; 159(4): 1570-1584, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29444223

RESUMO

Glucagonlike peptide-1 receptor (GLP-1R) agonists, which are used to treat type 2 diabetes and obesity, reduce the rates of myocardial infarction and cardiovascular death. GLP-1R has been localized to the human sinoatrial node; however, its expression in ventricular tissue remains uncertain. Here we studied GLP-1R expression in the human heart using GLP-1R-directed antisera, quantitative polymerase chain reaction (PCR), reverse transcription PCR to detect full-length messenger RNA (mRNA) transcripts, and in situ hybridization (ISH). GLP1R mRNA transcripts, encompassing the entire open reading frame, were detected in all four cardiac chambers from 15 hearts at levels approximating those detected in human pancreas. In contrast, cardiac GLP2R expression was relatively lower, and cardiac GCGR expression was sporadic and not detected in the left ventricle. GLP1R mRNA transcripts were not detected in RNA from human cardiac fibroblasts, coronary artery endothelial, or vascular smooth muscle cells. Human Brunner glands and pancreatic islets exhibited GLP-1R immunopositivity and abundant expression of GLP1R mRNA transcripts by ISH. GLP1R transcripts were also detected by ISH in human cardiac sinoatrial node tissue. However, definitive cellular localization of GLP1R mRNA transcripts or immunoreactive GLP-1R protein within human cardiomyocytes or cardiac blood vessels remained elusive. Moreover, validated GLP-1R antisera lacked sufficient sensitivity to detect expression of the endogenous islet or cardiac GLP-1R by Western blotting. Hence, although human cardiac ventricles express the GLP1R, the identity of one or more ventricular cell type(s) that express a translated GLP1R protein requires further clarification with highly sensitive methods of detection.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 2/metabolismo , Miocárdio/metabolismo , Animais , Linhagem Celular , Cricetinae , Feminino , Fibroblastos/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Humanos , Ilhotas Pancreáticas/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo
18.
Endocr Pathol ; 29(1): 15-20, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28718084

RESUMO

The objective of the study is to report a rare case of pancreatic neuroendocrine tumor (pNET) producing insulin and vasopressin. We describe the clinical presentation and management of a metastatic pNET with refractory hypoglycemia and progressive severe hyponatremia. A 52-year-old patient had abdominal pain leading to the diagnosis of a tumor that was initially presumed to be splenic in origin. Investigations ultimately identified a pancreatic mass that on biopsy proved to be a pNET. Eventually, he developed extensive liver metastases, and with tumor progression, he manifested hypoglycemia and severe hyponatremia. He was managed with multiple therapies including somatostatin analogue, peptide-receptor-radionuclide-therapy (PRRT), diazoxide, and everolimus; none of these therapeutic modalities was successful in controlling functional and structural progression of the tumor. Ultimately, the pNET proved fatal and autopsy confirmed widely metastatic disease that stained strongly and diffusely for vasopressin, a feature not seen in the previous liver biopsy. This case illustrates the challenges of diagnosis and management of aggressive insulin-producing pNETs and highlights the potential concomitant ectopic production of vasopressin leading to refractory hyponatremia.


Assuntos
Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Humanos , Síndrome de Secreção Inadequada de HAD/etiologia , Insulina/biossíntese , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/metabolismo , Neurofisinas/biossíntese , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/metabolismo , Precursores de Proteínas/biossíntese , Vasopressinas/biossíntese
20.
Cell Cycle ; 16(17): 1585-1600, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28745540

RESUMO

Defining the roadblocks responsible for cell cycle arrest in adult cardiomyocytes lies at the core of developing cardiac regenerative therapies. p53 and Mdm2 are crucial mediators of cell cycle arrest in proliferative cell types, however, little is known about their function in regulating homeostasis and proliferation in terminally differentiated cell types, like cardiomyocytes. To explore this, we generated a cardiac-specific conditional deletion of p53 and Mdm2 (DKO) in adult mice. Herein we describe the development of a dilated cardiomyopathy, in the absence of cardiac hypertrophy. In addition, DKO hearts exhibited a significant increase in cardiomyocyte proliferation. Further evaluation showed that proliferation was mediated by a significant increase in Cdk2 and cyclin E with downregulation of p21Cip1 and p27Kip1. Comparison of miRNA expression profiles from DKO mouse hearts and controls revealed 11 miRNAs that were downregulated in the DKO hearts and enriched for mRNA targets involved in cell cycle regulation. Knockdown of these miRNAs in neonatal rat cardiomyocytes significantly increased cytokinesis with an upregulation in the expression of crucial cell cycle regulators. These results illustrate the importance of the cooperative activities of p53 and Mdm2 in a network of miRNAs that function to impose a barrier against aberrant cardiomyocyte cell cycle re-entry to maintain cardiac homeostasis.


Assuntos
Pontos de Checagem do Ciclo Celular , Homeostase , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Envelhecimento , Animais , Cardiomiopatias/genética , Cardiomiopatias/patologia , Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/genética , Ciclina E/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação para Baixo/genética , Deleção de Genes , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , MicroRNAs/genética , Ratos Wistar
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