RESUMO
BACKGROUND: In most cases, lateral patellar dislocation (LPD) is accompanied by chondral injury and may initiate gradual degeneration of patellar cartilage, which might be detected with a T2 mapping, a well-established method for cartilage lesions assessment. PURPOSE: To examine short-term consequences of single first-time LPD in teenagers by T2 mapping of the patellar-cartilage state. STUDY TYPE: Prospective. POPULATION: 95 patients (mean age: 15.1 ± 2.3; male/female: 46/49) with first-time, complete, traumatic LPD and 51 healthy controls (mean age: 14.7 ± 2.2, male/female: 29/22). FIELD STRENGTH/SEQUENCE: 3.0 T; axial T2 mapping acquired using a 2D turbo spin-echo sequence. ASSESSMENT: MRI examination was conducted 2-4 months after first LPD. T2 values were calculated in manually segmented cartilage area via averaging over three middle level slices in six cartilage regions: deep, intermediate, superficial layers, and medial lateral parts. STATISTICAL TESTS: ANOVA analysis with Tukey's multiple comparison test, one-vs.-rest logistic regression analysis. The threshold of significance was set at P < 0.05. RESULTS: In lateral patellar cartilage, a significant increase in T2 values was found in deep and intermediate layers in both patient groups with mild (deep: 34.7 vs. 31.3 msec, intermediate: 38.7 vs. 34.6 msec, effect size = 0.55) and severe (34.8 vs. 31.3 msec, 39.1 vs. 34.6 msec, 0.55) LPD consequences as compared to controls. In the medial facet, only severe cartilage damage showed significant prolongation of T2 times in the deep layer (34.3 vs. 30.7 msec, 0.55). No significant changes in T2 values were found in the lateral superficial layer (P = 0.99), whereas mild chondromalacia resulted in a significant decrease of T2 in the medial superficial layer (41.0 vs. 43.8 msec, 0.55). DATA CONCLUSION: The study revealed substantial difference in T2 changes after LPD between medial and lateral areas of patellar cartilage. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 2.
Assuntos
Doenças das Cartilagens , Cartilagem Articular , Luxação Patelar , Adolescente , Humanos , Masculino , Feminino , Criança , Luxação Patelar/complicações , Luxação Patelar/diagnóstico , Luxação Patelar/patologia , Estudos Prospectivos , Patela , Imageamento por Ressonância Magnética/métodos , Cartilagem Articular/patologia , Doenças das Cartilagens/complicaçõesRESUMO
Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRASG12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.
Assuntos
Proteínas de Ciclo Celular/genética , GTP Fosfo-Hidrolases/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia Mielomonocítica Crônica/genética , Proteínas de Membrana/genética , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Animais , Proteínas de Ciclo Celular/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Leucêmica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Crônica/metabolismo , Leucemia Mielomonocítica Crônica/terapia , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/genética , Transplante de Células-Tronco/métodos , Transplante Homólogo , Sequenciamento do Exoma/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Quinase 1 Polo-LikeRESUMO
Oncolytic viruses, including live attenuated measles virus (MV) vaccine strains, have recently been shown as promising therapeutic agents against human malignancies. In this study, the oncolytic potential of the attenuated vaccine strain Leningrad-16 (L-16) of MV was evaluated in a panel of human metastatic melanoma cell lines. The L-16 measles virus was shown to replicate within melanoma cells mediating direct cell killing of tumor cells, although all melanoma cell lines varied in regard to their ability to respond to L-16 MV infection, as revealed by the different pattern of the Interferon Stimulated Gene expression, cytokine release and mechanisms of cell death. Furthermore, the statistically significant L-16 measles virus related tumor growth inhibition was demonstrated in a melanoma xenograft model. Therefore, L-16 MV represents an appealing oncolytic platform for target delivery of therapeutic genes along with other attenuated measles virus strains.