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1.
Diagn Pathol ; 16(1): 53, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127009

RESUMO

BACKGROUND: Malignancy after transplantation is a leading cause of death among kidney transplant recipients. However, donor-derived malignancies are rare. We report a case of a high grade papillary urothelial carcinoma arising in a transplanted kidney. CASE PRESENTATION: A 62-year-old female who received a kidney transplantation more than 30 years ago presented with urinary tract infection, acute renal failure, and hydronephrosis of the transplant kidney. Anterograde nephrostogram showed a large filling defect in the lower pole of the transplant kidney and in the proximal 3-4 cm of the ureter. A biopsy from the renal pelvic mass showed a high grade urothelial carcinoma. She underwent an anterior exenteration, resection of both transplant and native kidneys and bilateral pelvic lymph node dissection. Pathologic examination showed a high grade papillary urothelial carcinoma which appeared to arise in the pelvis of the graft kidney, involve the graft ureter and native urinary bladder. The tumor had metastasized to one left obturator lymph node but spared the two native kidneys and ureters. Short tandem repeat (STR) analysis confirmed the tumor to be of donor origin. Next-generation sequencing identified amplification of TERT and loss of CDKN2A/CDKN2B in the primary tumor. CONCLUSION: While it is known that transplant recipients have an increased risk of urothelial carcinoma compared to the general population, the lack of the well-documented risk factors, such as older age at transplantation, BK polyomavirus infection, and prolonged post-transplantation history and dissemination of the tumor in this case shed light on the de novo tumorigenesis of the graft kidney within the host microenvironment. Amplification of Telomerase reverse transcriptase (TERT) and loss of cyclin dependent kinase inhibitor 2A/2B (CDKN2A/CDKN2B) detected in the tumor by next gene sequencing suggests that they may play an important role in this case.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Papilar/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Amplificação de Genes , Neoplasias Renais/genética , Transplante de Rim/efeitos adversos , Telomerase/genética , Biomarcadores Tumorais/deficiência , Carcinoma Papilar/etiologia , Carcinoma Papilar/secundário , Carcinoma Papilar/terapia , Inibidor de Quinase Dependente de Ciclina p15/deficiência , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Renais/etiologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Pessoa de Meia-Idade , Gradação de Tumores , Fenótipo , Resultado do Tratamento , Urotélio/patologia
2.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-20099960

RESUMO

BACKGROUNDSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe, disproportionately affecting New York City. A comprehensive, integrative autopsy series that advances the mechanistic discussion surrounding this disease process is still lacking. METHODSAutopsies were performed at the Mount Sinai Hospital on 67 COVID-19 positive patients and data from the clinical records were obtained from the Mount Sinai Data Warehouse. The experimental design included a comprehensive microscopic examination carried out by a team of expert pathologists, along with transmission electron microscopy, immunohistochemistry, RNA in situ hybridization, as well as immunology and serology assays. RESULTSLaboratory results of our COVID-19 cohort show elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8 and TNF. Autopsies revealed large pulmonary emboli in four cases. We report microthrombi in multiple organ systems including the brain, as well as conspicuous hemophagocytosis and a secondary hemophagocytic lymphohistiocytosis-like syndrome in many of our patients. We provide electron microscopic, immunofluorescent and immunohistochemical evidence of the presence of the virus and the ACE2 receptor in our samples. CONCLUSIONSWe report a comprehensive autopsy series of 67 COVID-19 positive patients revealing that this disease, so far conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction, a hypercoagulable state, and an imbalance of both the innate and adaptive immune responses. Novel findings reported here include an endothelial phenotype of ACE2 in selected organs, which correlates with clotting abnormalities and thrombotic microangiopathy, addressing the prominent coagulopathy and neuropsychiatric symptoms. Another original observation is that of macrophage activation syndrome, with hemophagocytosis and a hemophagocytic lymphohistiocytosis-like disorder, underlying the microangiopathy and excessive cytokine release. We discuss the involvement of critical regulatory pathways.

3.
Arthritis Rheumatol ; 67(12): 3146-57, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26315890

RESUMO

OBJECTIVE: Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing rheumatoid arthritis (RA). This study was undertaken to determine the role of IRF5 in a mouse model of arthritis development. METHODS: K/BxN serum-transfer arthritis was induced in mice deficient in IRF5, or lacking IRF5 only in myeloid cells, and arthritis severity was evaluated. K/BxN arthritis was also induced in mice deficient in TRIF, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR7 to determine the pathways through which IRF5 might promote arthritis. In vitro studies were performed to determine the role of IRF5 in interleukin-1 (IL-1) receptor and TLR signaling. RESULTS: Arthritis severity was reduced in IRF5-deficient, TRIF-deficient, TLR3-deficient, and TLR7-deficient mice. The expression of multiple genes regulating neutrophil recruitment or function and bioactive IL-1ß formation was reduced in the joints during active arthritis in IRF5-deficient mice. In vitro studies showed that TLR7 and the TRIF-dependent TLR3 pathway induce proinflammatory cytokine production in disease-relevant cell types in an IRF5-dependent manner. CONCLUSION: Our findings indicate that IRF5 contributes to disease pathogenesis in inflammatory arthritis. This is likely due at least in part to the role of IRF5 in mediating proinflammatory cytokine production downstream of TLR7 and TLR3. Since TLR7 and TLR3 are both RNA-sensing TLRs, this suggests that endogenous RNA ligands present in the inflamed joint promote arthritis development. These findings may be relevant to human RA, since RNA capable of activating TLR7 and TLR3 is present in synovial fluid and TLR7 and TLR3 are up-regulated in the joints of RA patients.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Artrite Experimental/genética , Artrite Reumatoide/genética , Fatores Reguladores de Interferon/genética , Glicoproteínas de Membrana/genética , Células Mieloides/metabolismo , Receptor 3 Toll-Like/genética , Receptor 7 Toll-Like/genética , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Animais , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Técnicas In Vitro , Fatores Reguladores de Interferon/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Índice de Gravidade de Doença , Transdução de Sinais , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 3 Toll-Like/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Receptor 7 Toll-Like/imunologia
4.
Rheumatology (Oxford) ; 48(7): 734-40, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19439502

RESUMO

OBJECTIVE: SSc is characterized by microvascular abnormalities and leucocyte infiltration. Previous studies have suggested a proadhesive phenotype in SSc skin, but the functional consequences of this phenotype are not fully understood. Molecules known to mediate leucocyte adhesion include those present at intracellular junctions, such as junctional adhesion molecule-B (JAM-B), JAM-C and CD99, as well as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). The aim of this study was to examine adhesive interactions in SSc skin. METHODS: The expression of JAM-B, JAM-C, CD99, ICAM-1 and VCAM-1 in SSc skin was determined by immunohistology and cell surface ELISA. Myeloid U937 cell-SSc dermal fibroblast adhesion assays or in situ adhesion assays to SSc skin were performed. RESULTS: JAM-C and CD99 expression on endothelial cells (ECs) in SSc skin was decreased compared with expression on normal ECs. CD99 was overexpressed on mononuclear cells in SSc skin and on SSc dermal fibroblasts. Neutralizing ICAM-1 inhibited the binding of U937 cells to SSc dermal fibroblasts. In addition, blocking both ICAM-1 and VCAM-1 inhibited U937 cell adhesion to either proximal (less involved) or distal (more involved) SSc skin. CONCLUSIONS: These studies show that JAM-C and CD99 are aberrantly expressed in SSc skin. However, these adhesion molecules do not mediate myeloid cell-SSc skin adhesion. In contrast, we demonstrate an important role for ICAM-1 and VCAM-1 in the retention of myeloid cells in SSc skin, suggesting that targeting these molecules may be useful SSc therapies.


Assuntos
Molécula 1 de Adesão Intercelular/metabolismo , Células Mieloides/patologia , Escleroderma Sistêmico/patologia , Pele/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Antígeno 12E7 , Animais , Antígenos CD/análise , Antígenos CD/metabolismo , Estudos de Casos e Controles , Adesão Celular , Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/metabolismo , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular/análise , Camundongos , Células U937 , Molécula 1 de Adesão de Célula Vascular/análise
5.
Arthritis Rheum ; 43(6): 1266-77, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10857785

RESUMO

OBJECTIVE: To examine cytokine and chemokine production during the evolution of rat adjuvant-induced arthritis (AIA), a model of rheumatoid arthritis. METHODS: Clinical and laboratory assessment of the course of AIA was performed over a 47-day period. Levels of the cytokines tumor necrosis factor a (TNFalpha), interleukin-1beta (IL-1beta), and IL-6, as well as levels of the chemokines macrophage inflammatory protein 1alpha (MIP-1alpha) and JE, the murine homolog of monocyte chemoattractant protein 1, were determined by enzyme-linked immunosorbent assay in the sera and joints of AIA and control rats. Synovia from AIA rats were (immuno)histochemically analyzed. Results of cytokine and chemokine measurements were correlated with clinical and laboratory markers of inflammation and histology. RESULTS: Early (before day 14 post adjuvant injection) and later phases of AIA could be distinguished. Cytokine and chemokine production was increased in AIA versus control rats. The production of TNFalpha, IL-1beta, MIP-1alpha, and, as determined earlier, epithelial neutrophil-activating peptide 78-like protein was abundant prior to and during the course of AIA, while that of IL-6 and JE was elevated in the late phase of AIA. Cytokine and chemokine levels were correlated with the clinical symptoms of arthritis and blood neutrophil counts. Joint levels of IL-1beta showed correlation with synovial lining proliferation and neutrophil ingress into AIA synovium. CONCLUSION: Cytokines and chemokines are involved in the clinical, laboratory, and histologic changes underlying AIA. The production of these mediators may be temporally and spatially regulated. These findings may be important for the optimal timing of cytokine and chemokine targeting.


Assuntos
Artrite Experimental/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Animais , Artrite Experimental/sangue , Quimiocinas/sangue , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Mediadores da Inflamação/sangue , Articulações/metabolismo , Cinética , Ratos , Ratos Endogâmicos Lew , Valores de Referência , Sinovite/metabolismo , Sinovite/patologia , Fatores de Tempo
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