RESUMEN
TCL1 oncogene is overexpressed in aggressive form of human chronic lymphocytic leukemia (CLL) and its dysregulation in mouse B cells causes a CD5-positive leukemia similar to the aggressive form of human CLLs. To identify oncogenes that cooperate with Tcl1, we performed genetic screen in Eµ-TCL1 mice using Sleeping Beauty transposon-mediated mutagenesis. Analysis of transposon common insertion sites identified 7 genes activated by transposon insertions. Overexpression of these genes in mouse CLL was confirmed by real time reverse transcription-polymerase chain reaction. Interestingly, the main known function of 4 of 7 genes (Nfkb1, Tab2, Map3K14, and Nfkbid) is participation in or activation of the nuclear factor-kB (NF-kB) pathway. In addition, activation of the NF-kB is 1 of main functions of Akt2, also identified in the screen. These findings demonstrate cooperation of Tcl1 and the NF-kB pathway in the pathogenesis of aggressive CLL. Identification cooperating cancer genes will result in the development of combinatorial therapies to treat CLL.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Subunidad p50 de NF-kappa B/genética , Subunidad p50 de NF-kappa B/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Modelos Animales de Enfermedad , Regulación Leucémica de la Expresión Génica/fisiología , Pruebas Genéticas/métodos , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/mortalidad , Ratones , Ratones Transgénicos , Mutagénesis Insercional/métodos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Transposasas/genética , Quinasa de Factor Nuclear kappa BRESUMEN
Pemphigus vulgaris is a rare autoimmune disorder characterized by the formation of intraepithelial blisters that clinically appear as erosions and flaccid bullae on the skin and mucus membranes. Herein, we report a case of pemphigus vulgaris in an elderly male. He was initially misdiagnosed by his primary care provider and given topical lidocaine and acetaminophen with hydrocodone, without improvement in symptoms. This delay in treatment caused a worsening of his condition. The patient presented to our dermatology office two months after his primary care visit and reported worsening blisters and pain. Clinically he presented with flaccid bullae, crusted erosions, and erythematous plaques on the chest, back, abdomen, arms, and legs, and a tender oral ulcer. Two punch biopsies were obtained and sent for direct immunofluorescence and routine histology. The biopsy results confirmed the diagnosis of pemphigus vulgaris. Our patient achieved clearance after four weeks of oral prednisone and maintained clearance after a slow prednisone taper and the addition of mycophenolate mofetil 1g twice daily. We aim to bring awareness of the clinical presentation and treatment regimen of pemphigus vulgaris to prevent misdiagnosis and delayed care.
RESUMEN
MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC). In most cases, metastatic disease is difficult to predict and to prevent with adequate therapies. The aim of our study was to identify a microRNA signature for metastatic CRC that could predict and differentiate metastatic target organ localization. Normal and cancer tissues of three different groups of CRC patients were analyzed. RNA microarray and TaqMan Array analysis were performed on 66 Italian patients with or without lymph nodes and/or liver recurrences. Data obtained with the two assays were analyzed separately and then intersected to identify a primary CRC metastatic signature. Five differentially expressed microRNAs (hsa-miR-21, -103, -93, -31 and -566) were validated by qRT-PCR on a second group of 16 American metastatic patients. In situ hybridization was performed on the 16 American patients as well as on three distinct commercial tissues microarray (TMA) containing normal adjacent colon, the primary adenocarcinoma, normal and metastatic lymph nodes and liver. Hsa-miRNA-21, -93, and -103 upregulation together with hsa-miR-566 downregulation defined the CRC metastatic signature, while in situ hybridization data identified a lymphonodal invasion profile. We provided the first microRNAs signature that could discriminate between colorectal recurrences to lymph nodes and liver and between colorectal liver metastasis and primary hepatic tumor.