Plasmin deficiency leads to fibrin accumulation and a compromised inflammatory response in the mouse brain.

BACKGROUND: Excess fibrin in blood vessels is cleared by plasmin, the key proteolytic enzyme in fibrinolysis. Neurological disorders and head trauma can result in the disruption of the neurovasculature and the entry of fibrin and other blood components into the brain, which may contribute to further neurological dysfunction. OBJECTIVES: While chronic fibrin deposition is often implicated in neurological disorders, the pathological contributions attributable specifically to fibrin have been difficult to ascertain. An animal model that spontaneously acquires fibrin deposits could allow researchers to better understand the impact of fibrin in neurological disorders. METHODS: Brains of plasminogen (plg)- and tissue plasminogen activator (tPA)-deficient mice were examined and characterized with regard to fibrin accumulation, vascular and neuronal health, and inflammation. Furthermore, the inflammatory response following intrahippocampal lipopolysaccharide (LPS) injection was compared between plg(-/-) and wild type (WT) mice. RESULTS AND CONCLUSIONS: Both plg(-/-) and tPA(-/-) mice exhibited brain parenchymal fibrin deposits that appear to result from reduced neurovascular integrity. Markers of neuronal health and inflammation were not significantly affected by proximity to the vascular lesions. A compromised neuroinflammatory response was also observed in plg(-/-) compared to WT mice following intrahippocampal LPS injection. These results demonstrate that fibrin does not affect neuronal health in the absence of inflammation and suggest that plasmin may be necessary for a normal neuroinflammatory response in the mouse CNS.

Decreased CCAAT/enhancer binding protein ß expression inhibits the growth of glioblastoma cells.

C/EBPß is a leucine-zipper transcription factor implicated in the control of metabolism, development, cell differentiation, and proliferation. However, it remains unclear its role in tumor development. Here, we show that down-regulation of C/EBPß by RNA interference inhibits proliferation in the GL261 murine glioblastoma cell line, induces an arrest of the cell cycle at the G0/G1 boundary, and diminishes their transformation capacity and migration. In addition, we show that C/EBPß regulates the expression of several DNA damage response- and invasion-related genes. Lastly, C/EBPß depletion significantly retards tumor onset and prolongs survival in a murine orthotopic brain tumor model. Immunohistochemical analysis revealed a significant diminution of proliferating cell nuclear antigen (PCNA) labeling in tumors derived from C/EBPß-depleted GL261 cells compared with that in controls. These results show, for the first time, the dependence of glioma cells on C/EBPß and suggest a potential role of this transcription factor in glioma development.

Fibrinogen, a possible key player in Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive loss of cognitive function and subsequent death. Since the first case of this disease was diagnosed one century ago, much effort has been dedicated to find a cure. However, even though progress has been made in the knowledge of the pathogenesis of this disease, an effective treatment has not been found. Therefore, new approaches are needed urgently. AD patients have an abnormal cerebral vasculature and brain hypoperfusion, and a large body of research, including some from our lab, implicates cerebrovascular dysfunction as a contributing factor to AD. Reducing fibrinogen, a circulating protein critical in hemostasis, provides a significant decrease in the neurovascular damage, blood-brain barrier permeability and neuroinflammation present in AD. These studies implicate fibrinogen as a possible contributor to AD.

Meningioma de la Vaina del Nervio Optico (MVNO). ¿La radioterapia es el actual patrón de cuidados? A propósito de un caso y revisión de la literatura / Optic nerve sheat meningioma (ONSM). Role of radiotherapy: a case report and literature review

El meningioma primario de la vaina del nervio óptico es un tumor raro, cuyo manejo diagnóstico yterapéutico ha variado de manera sustancial en los últimos años. La aparición y desarrollo de las técnicas dediagnóstico por imagen, como son la Tomografía Computerizada de Alta Resolución y la ResonanciaMagnética Nuclear, han permitido diagnósticos más precoces y precisos.La introducción de la Radioterapia Convencional (RT) a finales de los años 70, sola o en combinación conla cirugía, pero sobre todo la introducción de la Radioterapia Extereotáxica Fraccionada (RTEF) y laRadioterapia Conformacional Tridimensional (RTC3D), ha supuesto una alternativa terapéutica sumamenteeficaz y con una toxicidad relativamente baja.En este artículo revisamos en primer lugar el desarrollo embriológico, anatomía, la historia natural, eltratamiento quirúrgico, así como el papel de la RT en esta entidad, y su integración en el patrón de cuidadosactual. Analizamos las diferentes técnicas radioterápicas desde las más elementales como la RadioterapiaConvencional (RT), siguiendo con la Radioterapia Conformada 3 D (RTC3D), hasta las más sofisticadas comola Radioterapia Exterotáxica Fraccionada (RTEF), todo ello a propósito de nuestra experiencia en un caso

Primary optic nerve sheat meningioma (ONSM) is a rare tumor, whose diagnosis and therapeuticmanagement have varied in a substantial manner over the last few years. The appearance and development ofdiagnostic imaging techniques such as High Resolution Computerized Tomography and Nuclear MagneticResonance have allowed earlier and more precise diagnoses.The introduction of conventional radiation therapy in the late 1970s, alone or in combination with surgery,and above all the introduction of Fractionated Stereotactic Radiotherapy and Three-Dimensional ConformalIntensity-Modulated Radiotherapy (3DCRT) have provided very efficient alternative therapies with arelatively low toxicity.In this article we first review the embryological development, anatomy, natural history, and surgicaltreatment, and then describe the role of radiotherapy (RT) in the considered entity, indicating how it can beintegrated in the pattern of present day care.We analyse the different radiotherapy techniques, from the most elementary, such as conventional RT,followed by 3DCRT up to the most sophisticated such as Stereotactic Fractionated Radiotherapy, all based onour experience in one case

The peroxisome proliferator-activated receptor gamma is an inhibitor of ErbBs activity in human breast cancer cells.

One of the most interesting recent developments in the nuclear receptor field has been the identification of natural and synthetic agonists of the peroxisome proliferator-activated receptor (PPAR) family, coupled with a growing recognition that the gamma isoform (PPARgamma) affects pathways important in a variety of human diseases. Here we show that the activation of PPARgamma through the 15-deoxy-Delta-12,14-prostaglandin J(2) (PG-J(2)) ligand causes a dramatic inhibition of ErbB-2 and ErbB-3 tyrosine phosphorylation caused by neuregulin 1 (NRG1) and neuregulin 2 (NRG2) in MCF-7 cells. This effect is accompanied by a very efficient blocking of ErbBs effects upon proliferation, differentiation and cell death in these cells. Preincubation of MCF-7 cells with PG-J(2) before addition of NRG1 and NRG2 had a dramatic growth-suppressive effect accompanied by accumulation of cells in the G0/G1 compartment of the cell cycle, and a marked increase in apoptosis. NRG1 and NRG2 induce G1 progression, which was associated with stimulation of the phosphatidylinositol-3 kinase (PI 3-K) pathway, whereas survival was dependent on ERK1/ERK2 activation. Both pathways were inhibited by PG-J(2). Furthermore, PG-J(2) can abolish the NRG1 and NRG2-induced increase in anchorage-independent growth of these cells. PG-J(2) also blocks phosphorylation of other receptor tyrosine kinases, such as IGF-IR, in MCF-7 cells, and suppress proliferation of other breast cancer cell lines. In summary, our data show a specific inhibitory action of PG-J(2) on the activity of the ErbB receptors in breast cancer cells.

Involvement of the NGFI-A gene in the differentiation of neuroblastoma cells.

The transcription factor NGFI-A is an early response gene that has been implicated in the regulation of cell growth and differentiation and, more recently, in apoptosis. This gene is expressed in many tissues, and is very abundant in the brain. However, little is known about its functional role in the differentiation of this tissue. In the present work we investigated the role of NGFI-A in serum withdrawal-induced differentiation in N2A neuroblastoma cells. To do so, we studied the effect of NGFI-A antisense oligonucleotides and NGFI-A overexpression on this process. We show that neuroblastoma cells treated with an NGFI-A antisense oligonucleotide do not undergo normal morphological differentiation after serum withdrawal, whereas N2A cells overexpressing this gene extend long neurites, even in the presence of serum. We also show that NGFI-A overexpression is accompanied by an increase in the amount of phosphorylated microtubule-associated protein MAP1B, which has been associated with neurite outgrowth. Our results suggest that the NGFI-A gene plays an important role in neurite extension.

[Brachytherapy results in prostatic cancer]. / Resultados de la braquiterapia en el cáncer de próstata.

OBJECTIVE: To analyze the 15-year results of external irradiation combined with radioactive gold grain implantation (Au198) in the treatment of adenocarcinoma of the prostate and to discuss the therapeutic perspectives. METHODS: The present study was conducted on 23 patients with localized prostate carcinoma (17 stage B; 6 stage C) that had been diagnosed and treated at our department from February 1981 to October 1986. The mean patient follow-up was 90.96 months. Au198 implantation (mean dose 3347.6 cGy) was performed through the abdominal approach prior to external irradiation (mean dose 39 Gy) with Co-60 (19 patients) or the 18-MV photon linear accelerator (4 patients). The mean fractionated dose was 180.43 cGy/day. RESULTS: Overall the 15-year locoregional control rate was 61% and disease-free survival was 38%. The overall survival rate was 25%, regardless of the cause of death. The tumor control rate was 61% for stage B and 83% for stage C lesions at 15 years. The disease-free survival rate was 40% for stage B and 50% for stage C tumors. The local control and disease-free survival rates were worse for patients in whom the diagnosis had been made by TUR (p = not significant). CONCLUSIONS: The locoregional tumor control and disease-free survival rates for this group of 23 patients who received combined therapy with external irradiation and radioactive gold grain implantation (Au198) were slightly lower than those obtained in another group of 104 patients treated at our Service of Radiotherapeutic Oncology with radical external radiation therapy and can be ascribed mainly to poor patient selection and inadequate radiation dose.