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1.
Harefuah ; 160(9): 576-581, 2021 Sep.
Artigo em Hebraico | MEDLINE | ID: mdl-34482669

RESUMO

INTRODUCTION: Transrectal ultrasound is utilized as an auxiliary tool when performing a prostate biopsy, but its sensitivity and specificity are low. Performing prostate multiparametric magnetic resonance imaging (mp-MRI) before prostate biopsy can increase the probability to detect aggressive prostate cancer while decreasing the probability to detect indolent prostate cancer, thereby assisting in the selection of patients before the biopsy. The Israel Basket of Health Services does not include prostate mpMRI prior to the first prostate biopsy. Our objective was to examine the significance of performing mpMRI before prostate biopsy. METHODS: We retrospectively evaluated the demographic, clinical, and pathological data from men who underwent transrectal biopsy of the prostate in the last 30 months in our institute. In all men with suspicious findings on mpMRI, targeted biopsies were taken in addition to systematic biopsies. We considered cancer as clinically significant if the Gleason sum was 7 or above. Fisher's Exact test was performed for categorical variables and student t-test for continuous variables. RESULTS: Five hundred and sixteen men underwent prostate biopsy; 163(32%) performed prostate mpMRI before the biopsy; 101(25%) performed mpMRI before the first prostate biopsy and 62(59%) before the second or more prostate biopsies. Prostate cancer was detected in 46% of all men (61% in men after mpMRI versus 38% in men without, p<0.0001). In men for whom this was the first prostate biopsy, prostate cancer was detected in 47% (73% in men after mpMRI versus 39% in men without, p<0.0001); and after second or more biopsies 38% (42% in men after mpMRI versus 33% in men without, p=0.4147). Also, there was a statistically significant difference in the detection of clinically significant prostate cancer with mpMRI versus without. CONCLUSIONS: Performing prostate mpMRI before prostate biopsy significantly increases the detection rate of prostate cancer and clinically significant prostate cancer. It should be recommended to perform mpMRI before any prostate biopsy in accordance with the European and American Urology Association, and NCCN guidelines.


Assuntos
Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias da Próstata , Biópsia , Humanos , Biópsia Guiada por Imagem , Israel , Imageamento por Ressonância Magnética , Masculino , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico , Estudos Retrospectivos
2.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361736

RESUMO

We recently developed a molecule (GT-73) that blocked leukocyte transendothelial migration from blood to the peripheral tissues, supposedly by affecting the platelet endothelial cell adhesion molecule (PECAM-1) function. GT-73 was tested in an LPS-induced acute respiratory distress syndrome (ARDS) mouse model. The rationale for this is based on the finding that the mortality of COVID-19 patients is partly caused by ARDS induced by a massive migration of leukocytes to the lungs. In addition, the role of tert-butyl and methyl ester moieties in the biological effect of GT-73 was investigated. A human leukocyte, transendothelial migration assay was applied to validate the blocking effect of GT-73 derivatives. Finally, a mouse model of LPS-induced ARDS was used to evaluate the histological and biochemical effects of GT-73. The obtained results showed that GT-73 has a unique structure that is responsible for its biological activity; two of its chemical moieties (tert-butyl and a methyl ester) are critical for this effect. GT-73 is a prodrug, and its lipophilic tail covalently binds to PECAM-1 via Lys536. GT-73 significantly decreased the number of infiltrating leukocytes in the lungs and reduced the inflammation level. Finally, GT-73 reduced the levels of IL-1ß, IL-6, and MCP-1 in bronchoalveolar lavage fluid (BALF). In summary, we concluded that GT-73, a blocker of white blood cell transendothelial migration, has a favorable profile as a drug candidate for the treatment of ARDS in COVID-19 patients.


Assuntos
COVID-19/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/antagonistas & inibidores , Pirimidinas/farmacologia , Síndrome do Desconforto Respiratório/tratamento farmacológico , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Animais , COVID-19/patologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Movimento Celular/efeitos dos fármacos , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Leucócitos/imunologia , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Pirimidinas/química , Síndrome do Desconforto Respiratório/induzido quimicamente , SARS-CoV-2
3.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803648

RESUMO

Free fatty acids are essential structural components of the cell, and their intracellular distribution and effects on membrane organelles have crucial roles in regulating the metabolism, development, and cell cycle of most cell types. Here we engineered novel fluorescent, polarity-sensitive fatty acid derivatives, with the fatty acid aliphatic chain of increasing length (from 12 to 18 carbons). As in the laurdan probe, the lipophilic acyl tail is connected to the environmentally sensitive dimethylaminonaphthalene moiety. The fluorescence lifetime imaging analysis allowed us to monitor the intracellular distribution of the free fatty acids within the cell, and to simultaneously examine how the fluidity and the microviscosity of the membrane environment influence their localization. Each of these probes can thus be used to investigate the membrane fluidity regulation of the correspondent fatty acid intracellular distribution. We observed that, in PC-12 cells, fluorescent sensitive fatty acid derivatives with increased chain length compartmentalize more preferentially in the fluid regions, characterized by a low microviscosity. Moreover, fatty acid derivatives with the longest chain compartmentalize in lipid droplets and lysosomes with characteristic lifetimes, thus making these probes a promising tool for monitoring lipophagy and related events.


Assuntos
Ácidos Graxos/metabolismo , Corantes Fluorescentes/metabolismo , Espaço Intracelular/metabolismo , Fluidez de Membrana , 2-Naftilamina/análogos & derivados , 2-Naftilamina/química , Animais , Fluorescência , Lauratos/química , Lisossomos/metabolismo , Células PC12 , Ratos , Solventes , Viscosidade
4.
Bioorg Chem ; 92: 103250, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31580982

RESUMO

Leukocyte transendothelial migration is one of the most important step in launching an inflammatory immune response and chronic inflammation can lead to devastating diseases. Leukocyte migration inhibitors are considered as promising and potentially effective therapeutic agents to treat inflammatory and auto-immune disorders. In this study, based on previous trioxotetrahydropyrimidin based integrin inhibitors that suboptimally blocked leukocyte adhesion, twelve molecules with a modified scaffold were designed, synthesized, and tested in vitro for their capacity to block the transendothelial migration of immune cells. One of the molecules, namely, methyl 4-((2-(tert-butyl)-6-((2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene) methyl) phenoxy) methyl) benzoate, (compound 12), completely blocked leukocyte transendothelial migration, without any toxic effects on immune or endothelial cells (IC50 = 2.4 µM). In vivo, compound 12 exhibited significant therapeutic effects in inflammatory bowel disease (IBD)/Crohn's disease, multiple sclerosis, fatty liver disease, and rheumatoid arthritis models. A detailed acute and chronic toxicity profile of the lead compound in vivo did not reveal any toxic effects. Such a type of molecule might therefore provide a unique starting point for designing a novel class of leukocyte transmigration blocking agents with broad therapeutic applications in inflammatory and auto-immune pathologies.


Assuntos
Linfócitos B/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Pirimidinas/síntese química , Linfócitos T/efeitos dos fármacos , Migração Transcelular de Célula/efeitos dos fármacos , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Linfócitos B/imunologia , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação , Estrutura Molecular , Monócitos/imunologia , Mucoproteínas/imunologia , Pirimidinas/química , Pirimidinas/farmacologia , Linfócitos T/imunologia , Molécula 1 de Adesão de Célula Vascular/imunologia
5.
Urol Oncol ; 36(12): 531.e9-531.e17, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30337218

RESUMO

OBJECTIVES: High-grade nonmuscle-invasive urothelial tumors of the bladder that fail intravesical Bacillus Calmette-Guérin (BCG) immunotherapy are at the highest risk of progression. Initial evidence links heat shock protein expression levels and outcome of bladder cancer after BCG treatment. We aimed to determine the association between HSP60, 70, and 90 expression levels and long-term outcomes of T1 high-grade (T1HG) urothelial bladder tumors treated with BCG immunotherapy. MATERIALS AND METHODS: Data of 54 consecutive patients with primary T1HG bladder tumors who underwent transurethral resection between 2002 and 2008 and received at least an induction course of BCG were reviewed. Immunohistochemical staining for heat shock protein (HSP)60, 70, and 90 were performed on resected specimens. Study outcomes included disease recurrence and progression. The association between HSP expression levels and outcomes were evaluated with univariable and multivariable Cox proportional hazards models. RESULTS: During a median follow-up of 9.6 years, 25 patients had a disease recurrence and 14 patients a disease progression. Estimated 5-year recurrence and progression-free survival were 59% and 81%, respectively. On multivariable analyses, HSP60 staining >65% was associated with a higher risk for progression (hazard ratio [HR] = 3.96, 95% confidence interval [CI] 1.35-11.58, P = 0.012), and HSP70 staining >5% was associated with a decreased risk for progression (HR = 0.33, 95% CI 0.11-0.98, P = 0.045), and recurrence (HR = 0.29, 95% CI 0.13-0.65, P = 0.003). HSP90 expression was not associated with disease recurrence or progression. Five patients had both a HSP60 staining >65% and a HSP70 staining ≤5% all of whom recurred at a median time of 6 months (interquartile range 3, 16) and 80% of whom progressed at a median time of 26 months (interquartile range 5, 60). CONCLUSIONS: HSP60 and 70 cellular expression levels are associated with long-term outcome following BCG treatment of T1HG urothelial bladder tumors. These findings, if further validated, may be used to better stratify the risk of disease recurrence and progression in this group of patients.


Assuntos
Vacina BCG/administração & dosagem , Biomarcadores Tumorais/metabolismo , Chaperonina 60/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas Mitocondriais/metabolismo , Recidiva Local de Neoplasia/mortalidade , Neoplasias Urológicas/mortalidade , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Taxa de Sobrevida , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/patologia , Neoplasias Urológicas/terapia
6.
Mod Pathol ; 31(1): 62-67, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28799535

RESUMO

The use of hygroscopic sonographically detectable clips (HSDCs) has dramatically increased during the last years, especially in breast cancer patients who undergo neoadjuvant chemotherapy. The aims of this study are to define the appearance of HSDC sites in histopathological specimens, and to enable pathologists to recognize these sites and differentiate them from other lesions. We examined 124 breast cancer specimens in which the application of HSDCs was documented, 88 breast tissues and 36 lymph nodes, and analyzed the appearance of the clip site in these tissues. The clip site was clearly detected histologically in 79/88 (90%) of the breast specimens and in 29/36 (81%) of lymph node specimens. In most of the specimens, the HSDC site had a specific characteristic appearance of a pseudocyst, lined by layers of epithelioid histiocytes, sometimes with pseudopapillary formation, and with minimal or no fibrosis. This was the appearance in 69 of the breast specimens and in 23 of the lymph node specimens. In other specimens, scarring, scattered foamy macrophages and abundant siderophages were the predominant findings, as usually found in sites of other clips. As non-palpable breast lesions become more frequent, clips play a major role in the treatment of breast cancer, making them an important component of the communication among radiologists, surgeons, pathologists, and oncologists. HSDCs in tissues have a characteristic appearance with an epithelioid component. Pathologists should be able to recognize this finding, differentiate it from other breast lesions and include it in the pathology report.


Assuntos
Mama/diagnóstico por imagem , Cistos/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Instrumentos Cirúrgicos , Adulto , Idoso , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Cistos/etiologia , Cistos/patologia , Feminino , Humanos , Linfonodos/patologia , Pessoa de Meia-Idade
7.
Oncoscience ; 1(4): 250-261, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25594017

RESUMO

Fyn kinase is implicated in prostate cancer. We illustrate the role of miR-125a-3p in cellular pathways accounted for motility and migration of prostate cancer cells, probably through its regulation on Fyn expression and Fyn-downstream proteins. Prostate cancer PC3 cells were transiently transfected with empty miR-Vec (control) or with miR-125a-3p. Overexpression of miR-125a-3p reduced migration of PC3 cells and increased apoptosis. Live cell confocal imaging indicated that overexpression of miR-125a-3p reduced the cells' track speed and length and impaired phenotype. Fyn, FAK and paxillin, displayed reduced activity following miR-125a-3p overexpression. Accordingly, actin rearrangement and cells' protrusion formation were impaired. An inverse correlation between miR-125a-3p and Gleason score was observed in human prostate cancer tissues. Our study demonstrated that miR-125a-3p may regulate migration of prostate cancer cells.

8.
Mol Oncol ; 7(3): 732-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23587442

RESUMO

Renal cancers account for more than 3% of adult malignancies and cause more than 13,000 deaths per year in the US alone. The four most common types of kidney tumors include the malignant renal cell carcinomas; clear cell, papillary, chromophobe and the benign oncocytoma. These histological subtypes vary in their clinical course and prognosis, and different clinical strategies have been developed for their management. In some kidney tumor cases it can be very difficult for the pathologist to distinguish between tumor types on the basis of morphology and immunohistochemistry (IHC). In this publication we present the development and validation of a microRNA-based assay for classifying primary kidney tumors. The assay, which classifies the four main kidney tumor types, was developed based on the expression of a set of 24 microRNAs. A validation set of 201 independent samples was classified using the assay and analyzed blindly. The assay produced results for 92% of the samples with an accuracy of 95%.


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Rim/patologia , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adulto , Carcinoma de Células Renais/patologia , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Rim/metabolismo , Neoplasias Renais/patologia , Patologia Molecular/métodos , Reprodutibilidade dos Testes
10.
J Oncol ; 2010: 969084, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19680458

RESUMO

The detection of breast carcinoma cells in effusions is associated with rapidly fatal outcome, but these cells are poorly characterized at the molecular level. This study compared the gene array signatures of breast carcinoma cells in primary carcinomas and effusions. The genetic signature of 10 primary tumors and 10 effusions was analyzed using the Array-Ready Oligo set for the Human Genome platform. Results for selected genes were validated using PCR, Western blotting, and immunohistochemistry. Array analysis identified 255 significantly downregulated and 96 upregulated genes in the effusion samples. The majority of differentially expressed genes were part of pathways involved in focal adhesion, extracellular matrix-cell interaction, and the regulation of the actin cytoskeleton. Genes that were upregulated in effusions included KRT8, BCAR1, CLDN4, VIL2, while DCN, CLDN19, ITGA7, and ITGA5 were downregulated at this anatomic site. PCR, Western blotting, and immunohistochemistry confirmed the array findings for BCAR1, CLDN4, VIL2, and DCN. Our data show that breast carcinoma cells in primary carcinomas and effusions have different gene expression signatures, and differentially express a large number of molecules related to adhesion, motility, and metastasis. These differences may have a critical role in designing therapy and in prognostication for patients with metastatic disease localized to the serosal cavities.

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