In vivo CRISPR/Cas9 targeting of fusion oncogenes for selective elimination of cancer cells.

Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells.

Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI.

BACKGROUND AND PURPOSE: Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression. MATERIALS AND METHODS: Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%-75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression. RESULTS: Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non-true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from nonpseudoprogression (true progression and mixed) with an area under the curve of 0.807. CONCLUSIONS: DTI and DSC perfusion imaging can improve accuracy in assessing treatment response and may aid in individualized treatment of patients with glioblastomas.

Hidatidosis muscular primaria / Primary muscle hydatidosis

No disponible

Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis.

OBJECTIVES: Most patients with anti-NMDA receptor (NMDAR) encephalitis have intrathecal synthesis of antibodies, which cause a decrease of cell surface and synaptic NMDAR. Antibodies are immunoglobulin G (IgG)1 and IgG3 subtypes and can potentially activate complement. We examined whether complement immunoreactivity and antibody-secreting cells (plasma cells/plasmablasts) are present in the brain of these patients. METHODS: Cultured rat hippocampal neurons were used in an immunocytochemical assay to test whether patients' antibodies can fix complement. Using the same reagents (antibodies to C9neo, C(5b-9), C3), complement immunoreactivity was determined in the brain of 5 patients, the teratoma of 21 patients, and appropriate control tissues. A set of markers for B (CD20), T (CD3, CD4, CD8) and antibody-secreting cells (plasma cells/plasmablasts, CD138) were used to examine the brain inflammatory infiltrates. RESULTS: Patients' antibodies were able to bind complement in vitro, but deposits of complement were not detected in patients' brain. Parallel experiments with teratomas showed that in contrast to the brain, the neural tissue of the tumors contained complement. Analysis of the inflammatory infiltrates in brain samples from autopsy or biopsy performed 3-4 weeks after symptom presentation demonstrated numerous antibody-secreting cells (CD138+) in perivascular, interstitial, and Virchow-Robin spaces, and B and T cells predominantly located in perivascular regions. CONCLUSIONS: Complement-mediated mechanisms do not appear to play a substantial pathogenic role in anti-NMDAR encephalitis. In contrast, there are copious infiltrates of antibody-secreting cells (plasma cells/plasmablasts) in the CNS of these patients. The demonstration of these cells provides an explanation for the intrathecal synthesis of antibodies and has implications for treatment.

[Brain photon emission tomography. Value of the corticocerebellar index and gammagraphic patterns in Alzheimer's disease and other diseases]. / Tomografía de emisión de fotones cerebral. Valor del índice corticocerebeloso y patrones gammagráficos en la enfermedad de Alzheimer y otras afecciones.

Brain single photon emission computed tomography (SPECT) with 99mTc-HMPAO is a diagnostic tool for evaluating regional cerebral blood flow. Recently, the diagnostic possibilities of the method are being investigated in some neurologic disorders, such as cerebrovascular accidents, seizures and dementia. This work has been carried out with 54 subjects, 9 healthy volunteers and 45 patients (31 dementia and 14 epileptics), in order to evaluate gammagraphic patterns and the utility of cortico/cerebellar activity indexes. An interesting diagnostic finding is a significant decrease (p less than 0.001) in perfusion of temporoparietal regions in the patients with Alzheimer's disease in relation with the healthy volunteers' group. We have not found significant changes in perfusion in the group of epileptic patients during the interictal phase. We conclude emphasizing the interest of the SPECT in the differential diagnosis of dementia.

Intra-arterial and intravenous chemotherapy for the treatment of malignant glioma. Preliminary results.

Twenty-one patients with malignant glioma were treated with cis-diamminedichloroplatinum II (CDDP II) 60-90 mg/m2 intra-arterial (I.A.) bolus on day 1 and Carmustine (BCNU) 100 mg/m2 intravenously (I.V.) on days 1 and 2. Three patients received additional Aziridinylbenzoquinone (AZQ) 7 mg/m2 (I.V.) on days 1 and 2. At the time of this treatment, seven patients had local recurrence after previous surgery and radiotherapy. Nine patients had subtotal tumor resection or biopsy, one patient had macroscopic tumor resection, and four patients had no previous surgery because of medical contraindication. Six patients received five or more courses of I.A. and I.V. chemotherapy. Five of these patients showed complete remission (CR) and one had a partial remission (PR) by brain computerized tomography (CT scan). Another 15 patients treated with two to four courses of I.A., and I.V. chemotherapy showed eight partial responses (PR), and seven showed no changes (NC) by brain CT scan. Five patients died with disease. Patients who achieved CR also received radical radiotherapy for remission consolidation. Sixteen patients are still alive; five patients are off treatment, four of these with no evidence of disease (NED), one alive with disease (AWD); and the remaining 11 patients are still on treatment. Toxicity, symptomatic neurological recovery, disease stabilization, and causes of death will be discussed.