The diacylglycerol kinase α/Atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness

Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5β1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of β1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and β1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - β1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells

Epidemiología de la Urgencia Psiquiátrica en el Instituto Psiquiátrico "Dr. José Horwitz": Un nuevo estudio comparativo

Indexación: ScieloUna urgencia psiquiátrica es cualquier alteración del afecto, conducta o pensamiento que puede producir daños a terceros o al consultante. La consulta de urgencia ido en aumento en los últimos años. Objetivos: Determinar laprevalencia de las distintas patologías, describir su distribución según sexo, edad, sector de residencia, estado civil, ocupación, previsión y derivación en las consultas de urgencia psiquiátrica en el Hospital Psiquiátrico "Dr. JoséHorwitz" de Santiago y comparar estos resultados con publicaciones previas de estudios en el mismo centro. Material y Método: Muestra representativa de 1999 casos, escogidos aleatoriamente de las consultas realizadas entre el Io de julio de 2005 y el 30 de junio de 2006. Se agruparon los diagnósticos de acuerdo a la nomenclatura CIÉ-10. Resultados: 48,7% de las consultas fueron realizadas por pacientes de sexo masculino. La media de edad fue 39 años. 76,7% de las consultas fueron realizadas en horario diurno. El 48,3% de los pacientes no tiene ocupación. 48% eran solteros. Abuso de sustancias y alcohol, trastornos esquizoides, afectivos y neuróticos congregan el 73,9% de las consultas. La más prevalente fue la de trastornos asociados al abuso de sustancias y alcohol con un 19,7% del total. Conductas autoagresivas (74%) y trastornos afectivos (74%) se asoció más a mujeres, en cambio el abuso de sustancias y alcohol más con hombres (76%). Discusión: Las consultas por trastornos esquizoides han disminuido a lo largo de los años. En cambio las consultas por el abuso de sustancias y alcohol y los trastornos afectivos han aumentado. Se hacen sugerencias para enfrentar el nuevo perfil epidemiológico.A psychiatric emergency is any alteration of affection, thought or behavior that may cause harm to others or to the same consultant. These consultations have increased over the last years. Objectives: Determine the prevalence of the various pathologies, describing their distribution according to sex, age, area of residence, marital status, occupation, health insurance, and referral in psychiatric emergency consultations at "Dr. José Horwitz" Hospital of Santiago, and to compare these results with previously published studies in the same center. Material and Method: We used a representative sample of 1999 cases, chosen randomly from consultations held between July 1,2005 and June 30,2006. Diagnoses were grouped according to the nomenclature of the ICD-10. Results: 48.7% of the consultations were carried out by male patients and. Average age of consultation was 39. 76.7% of consultations were carried out in daytime. The 48.3% of people who consulted didn't have any occupation. 48% were singles. Abuse of substances and alcohol, schizoid, afective and neurotic disorders congregate 73.9% of total consultations. The most prevalent were the disorders associated with abuse of substances and alcohols with a 19.7% overall. Autoagressive behaviors (74%) and affective disorders (74%) were associated with females, while abuse of substances and alcohol was associated with males (76%). Discussion: Schizoid disorders have proportionally declined in importance over the years. In contrast, abuse of substances and alcohol, and affective disorders have increased their frecuency. Suggestions are made to FACE the new epidemiological profile.http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-92272010000400002&nrm=is

HGF-Induced PKCζ Activation Increases Functional CXCR4 Expression in Human Breast Cancer Cells

The chemokine receptor CXCR4 and its ligand CXCL12 have been shown to mediate the metastasis of many malignant tumors including breast carcinoma. Interaction between hepatocyte growth factor (HGF) and the Met receptor tyrosine kinase mediates development and progression of cancers. HGF is able to induce CXCR4 expression and contributes to tumor cell invasiveness in breast carcinoma. However, the mechanism of the CXCR4 expression modulated by c-Met-HGF axis to enhance the metastatic behavior of breast cancer cells is still unclear. In this study, we found that HGF induced functional CXCR4 receptor expression in breast cancer cells. The effect of HGF was specifically mediated by PKCζ activity. After transfection with PKCζ-siRNA, the phosphorylation of PKCζ and CXCR4 was abrogated in breast cancer cells. Interference with the activation of Rac1, a downstream target of HGF, prevented the HGF-induced increase in PKCζ activity and CXCR4 levels. The HGF-induced, LY294002-sensitive translocation of PKCζ from cytosol to plasma membrane indicated that HGF was capable of activating PKCζ, probably via phosphoinositide (PI) 3-kinases. HGF treatment also increased MT1-MMP secretion. Inhibition of PKCζ, Rac-1 and phosphatidylinositol 3-kinase may attenuate MT1-MMP expression in cells exposed to HGF. Functional manifestation of the effects of HGF revealed an increased ability for migration, chemotaxis and metastasis in MDA-MB-436 cells in vitro and in vivo. Our findings thus provided evidence that the process of HGF-induced functional CXCR4 expression may involve PI 3-kinase and atypical PKCζ. Moreover, HGF may promote the invasiveness and metastasis of breast tumor xenografts in BALB/c-nu mice via the PKCζ-mediated pathway, while suppression of PKCζ by RNA interference may abrogate cancer cell spreading

Sustained seizure freedom with adjunctive brivaracetam in patients with focal onset seizures

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32–56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12 months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy

Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST)

Background: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Objective: This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice. Methods: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure‐freedom, seizure response (≥ 50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed. Results: A total of 1029 patients with a median age of 45 years (33–56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p < 0.001); the corresponding values for ≥ 50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p < 0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%; p = 0.341) and seizure response (39.7% vs. 26.9%; p = 0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p = 0.017). Conclusion: The BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations

Spatial Memory of Heterozygous Staggerer (Rora(+)/Rora(sg)) Versus Normal (Rora(+)/Rora(+)) Mice During Aging.

Heterozygous staggerer mice (Rora+/Rorasg) and control mice (Rora+/Rora+) of the same C57BL/6J strain background were tested in a spontaneous alternation task at 3 to 24 months old. The results demonstrated a decrement in long-term working memory as early as 6 months in Rora+/Rora+ mice and at 3 months in Rora+/Rorasg mice. Previous studies showed that in both cases, neuronal number in the cerebellar cortex was normal (Doulazmi et al. [1999]). This suggests that age-dependent decrease in long-term working memory would be due to fine structural or biochemical changes preceding neuronal death in the cerebellum. Such subtle changes would occur more precociously in Rora+/Rorasg than in Rora+/Rora+ mice. Also, short-term working memory was preserved in Rora+/Rora+ mice as old as 24 months, but was impaired in 6-month-old Rora+/Rorasg mice

Effect of training on motor abilities of heterozygous staggerer mutant (Rora ' /Rora sg ) mice during aging

International audienceHeterozygous cerebellar mutant (Rora ' /Rora sg) mice and control (Rora ' /Rora ') mice of the same C57Bl6/J strain, 3 Á/24 months old, were subjected to motor training on a rotorod for 10 days. Falling latency and percentage of time spent walking were measured. A good correlation was found between falling latency and walking time: the mice which maintained equilibrium for a long time were those which were walking, and the mice which fell early were those which were gripping suggesting that walking is obviously the most adapted strategy to keep balance on the rotorod. In Rora ' /Rora ' mice, scores before training were altered very precociously (from 6 months of age). Moreover, scores of Rora ' /Rora sg mice were lower than those of Rora ' /Rora ' mice from the age of 3 months, while neuronal number in the cerebellar cortex of these mutants was quite normal and similar to that of Rora ' / Rora ' mice. This suggests that the motor skill disability would be due to fine structural and/or biochemical changes preceding neuronal death. Such subtle changes would begin several months earlier in Rora ' /Rora sg than in Rora ' /Rora ' mice. Training on the rotorod resulted in increased scores in both genotypes at all ages. Motor learning abilities were therefore preserved in animals with a moderate neuronal loss in the cerebellum. It may be that motor learning is partly compensated by the striatum, which is known to play a major role in learning of motor skills