Oncolytic adenovirus coding for shedding-resistant MICA enhances immune responses against tumors.

Cancer immunotherapies strive to overcome tumor-induced immune suppression and activate antitumor immune responses. Although cytotoxic T lymphocytes (CTLs) play a pivotal role in this process, natural killer (NK) cells have also demonstrated remarkable tumor-killing abilities, given their ability to discriminate tumor cells from normal cells and mediate specific antitumoral cytotoxicity. NK cells activation depends on a balance between activation and inhibition signals from several ligands/receptors. Among them, MICA/NKG2D axis is a master regulator of NK activation. MHC class I chain-related polypeptide A (MICA) expression is upregulated by many tumor cell lines and primary tumors and serves as a ligand for the activating NK group 2D (NKG2D) receptor on NK cells and subpopulations of T cells. However, cancer cells can cleave MICA, making it soluble and de-targeting tumor cells from NK cells, leading to tumor immune escape.In this study, we present ICOVIR15KK-MICAMut, an oncolytic adenovirus (OAdv) armed with a transgene encoding a non-cleavable MICA to promote NK-mediated cell-killing capacity and activate the immune response against cancer cells. We first demonstrated the correct MICA overexpression from infected cells. Moreover, our MICA-expressing OAdv promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells. Finally, OAdv-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control.In summary, this study highlights the significance of NK cells in cancer immunotherapy and presents an innovative approach using a modified oncolytic virus to enhance NK cell activation and antitumor immune response. These findings suggest promising potential for future research and clinical applications.

Política industrial farmacéutica, un requisito clave para la autonomía sanitaria de Colombia

Colombia depende de la importación de medicamentos, así como de gran parte de los materiales (principios activos y excipientes) requeridos para su elaboración; problemática que genera consecuencias sanitarias y macroeconómicas, las cuales se agudizan en el contexto de desindustrialización nacional y de disrupción tecnológica. De esta manera, se acepta que la disponibilidad y acceso a medicamentos y otras tecnologías sanitarias esenciales son un requisito fundamental para alcanzar la autonomía sanitaria de un país. Por lo tanto, resulta imprescindible coordinar esfuerzos entre diversos sectores sociales para desarrollar una agenda pública enfocada a la creación de condiciones que fortalezcan las capacidades científicas y tecnológicas de la industria farmacéutica local, y con ello, mejorar el suministro farmacéutico del país. En el presente documento se presentan conceptos teóricos y prácticos que deberían ser considerados en la definición y materialización de una política pública encaminada a fortalecer la industria farmacéutica y favorecer la autonomía sanitaria de Colombia.

Colombia has a notorious dependency on the importation of medicines, as well as a large part of the materials (active ingredients and excipients) required for their manufacture. This problem generates health and macroeconomic consequences, which are exacerbated in the context of national deindustrialization and technological disruption. In this way, it is accepted that the availability and access to medicines and other essential health technologies are a fundamental requirement to achieve the health autonomy of a country. Therefore, it is crucial to coordinate efforts between several social sectors to develop a public agenda focused on creating conditions that allow strengthening the scientific and technological capabilities of the local pharmaceutical industry, thereby, improving the country's pharmaceutical supply. This document presents conceptual and practical topics that should be considered to defining and materializing a public policy aimed at strengthening the local pharmaceutical industry and favoring Colombia's sanitary autonomy.

Empiema subdural y su relación con hematomas subdurales: experiencia local y revisión de la literatura / Subdural empyema and its relationship to subdural hematomas: local experience and literature review

RESUMEN: Los empiemas subdurales, tanto los de aparición espontánea o como complicación en la evolución de un hematoma subdural (HSD), son infrecuentes y de los cuales existen pocas publicaciones en la literatura(1). En este trabajo se revisa una serie de 15 casos operados en el Hospital de Urgencia Asistencia Pública (HUAP) en un período de 15 años. Se observó que en general tienen buena evolución con el tratamiento instaurado en forma oportuna y que son larvados en su presentación, pudiendo llegar a ser diagnosticados incluso en el intraoperatorio. No se observó diferencia en su evolución cuando se operaron a través de una craniectomía o de una craneotomía (plaqueta)(2). No se encontró tampoco diferencia cuando se trataron con o sin drenaje. Como consenso general, deben ser tratados con antibioticoterapia prolongada de al menos 3-4 semanas para controlar el foco infeccioso(2). Ninguno de los casos revisados requirió de reintervención.

ABSTRACT Subdural empyemas, both spontaneous or as a complication in the evolution of subdural hematomas, are an uncommon fact of which there are few publications in literature. In this review we analyze a retrospective serie of 15 cases operated in HUAP in a period of 15 years. In general we don't observed differences in the outcome using different surgical techniques, both in those treated by craniectomy as those treated by craniotomy. Also we don't observed differences in those treated with or without drainage. In the same way is clear that the optimal period of antibiotic treatment must be 3-4 weeks to fully cover them. None of the cases treated, needed reintervention.

Time Series Transcriptomic Analysis of Bronchoalveolar Lavage Cells from Piglets Infected with Virulent or Low-Virulent Porcine Reproductive and Respiratory Syndrome Virus 1.

Porcine reproductive and respiratory syndrome virus (PRRSV) has evolved to escape the immune surveillance for a survival advantage leading to a strong modulation of host's immune responses and favoring secondary bacterial infections. However, limited data are available on how the immunological and transcriptional responses elicited by virulent and low-virulent PRRSV-1 strains are comparable and how they are conserved during the infection. To explore the kinetic transcriptional signature associated with the modulation of host immune response at lung level, a time-series transcriptomic analysis was performed in bronchoalveolar lavage cells upon experimental in vivo infection with two PRRSV-1 strains of different virulence, virulent subtype 3 Lena strain or the low-virulent subtype 1 3249 strain. The time-series analysis revealed overlapping patterns of dysregulated genes enriched in T-cell signaling pathways among both virulent and low-virulent strains, highlighting an upregulation of co-stimulatory and co-inhibitory immune checkpoints that were disclosed as Hub genes. On the other hand, virulent Lena infection induced an early and more marked "negative regulation of immune system process" with an overexpression of co-inhibitory receptors genes related to T-cell and NK cell functions, in association with more severe lung lesion, lung viral load, and BAL cell kinetics. These results underline a complex network of molecular mechanisms governing PRRSV-1 immunopathogenesis at lung level, revealing a pivotal role of co-inhibitory and co-stimulatory immune checkpoints in the pulmonary disease, which may have an impact on T-cell activation and related pathways. These immune checkpoints, together with the regulation of cytokine-signaling pathways, modulated in a virulence-dependent fashion, orchestrate an interplay among pro- and anti-inflammatory responses. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the major threats to swine health and global production, causing substantial economic losses. We explore the mechanisms involved in the modulation of host immune response at lung level performing a time-series transcriptomic analysis upon experimental infection with two PRRSV-1 strains of different virulence. A complex network of molecular mechanisms was revealed to control the immunopathogenesis of PRRSV-1 infection, highlighting an interplay among pro- and anti-inflammatory responses as a potential mechanism to restrict inflammation-induced lung injury. Moreover, a pivotal role of co-inhibitory and co-stimulatory immune checkpoints was evidenced, which may lead to progressive dysfunction of T cells, impairing viral clearance and leading to persistent infection, favoring as well secondary bacterial infections or viral rebound. However, further studies should be conducted to evaluate the functional role of immune checkpoints in advanced stages of PRRSV infection and explore a possible T-cell exhaustion state.

Capillary malformation-arteriovenous malformation syndrome: a multicentre study.

BACKGROUND: Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a rare syndrome with characteristic skin lesions that are associated with fast-flow vascular malformations (FFVMs) in one-third of patients. Few case series have been described, and none in Spain. AIM: To identify the prevalence of dermatological parameters, FFVMs and associated features in a large series of patients with CM-AVM. METHODS: We conducted an observational study of patients with CM-AVM syndrome diagnosed in 15 Spanish hospitals over 3 years. The main clinical, radiological, genetic findings and associated diseases were analysed. RESULTS: In total, 64 patients were assessed. In 26.5% of cases, the diagnosis was incidental. In 75% of patients, there was one significantly larger macule, which we termed the 'herald patch'. FFVMs were detected in 34% of the patients, with 30% located on the skin, 7.8% in the brain and in 1.5% in the spine. There was a positive family history in 65% of the 64 patients. Genetic analysis was performed for RASA1 mutations in 57 patients, of whom 42 (73%) had a positive result. All 4 patients tested for EPHB4 mutations had a positive result. No tumour lesions were detected in the series, except for five infantile haemangiomas. CONCLUSIONS: Our data on clinical lesions, associated FFVM, family history and genetics are similar to those previously published in the literature. An extensive data analysis failed to demonstrate any statistically significant association between the presence of an FFVM and any clinical, familial or genetic parameter that could predict its onset, although a link between the presence of a herald patch on the midline face and the presence of a brain FFVM was observed. We did not detect any genotype-phenotype correlation.

Histopathological hallmarks of cutaneous lesions of capillary malformation-arteriovenous malformation syndrome.

IMPORTANCE: Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a recently described syndrome with distinctive cutaneous lesions. Very little is known about the histopathology of these lesions. OBJECTIVE: The purpose of the study was to evaluate the histopathological characteristics of the pink macules of the CM-AVM syndrome and to investigate if these pink macules could be classified as capillary malformations or arteriovenous malformations based on their histopathological features. DESIGN-SETTINGS-PARTICIPANTS: We conducted a retrospective multicenter study involving eight hospitals in Spain. Fifteen biopsies from pink macules of the CM-AVM syndrome were analysed and compared with five biopsies of diverse capillary malformations and three stage I arteriovenous malformations. RESULTS: Pink macules' biopsies of the CM-AVM syndrome showed similar features including a high vascular density encompassing capillaries and numerous thick-walled arterioles mainly located in the superficial dermis, a predominance of elongated over round vessels, scarce or absent erythrocytes within the lumina and discrete perivascular inflammation. CMs were characterized by an increased number of capillary-type vessels mostly rounded and located in the upper dermis. AVMs were composed by highly increased numbers of vessels with a branching pattern involving the full thickness of the dermis, without erythrocytes within the lumina. Wilms tumour 1 protein was positive in the endothelial cells both in pink macules of the CM-AVM and in arteriovenous malformations. CONCLUSIONS AND RELEVANCE: Pink macules of the CM-AVM syndrome seem to be different from capillary malformations. Our results suggest that histologically and immunohistochemically they are closer to incipient arteriovenous malformations than to capillary malformations. A deepened knowledge about the nature of these skin lesions will contribute to the better understanding of capillary malformation-arteriovenous malformation syndrome, and will open the possibility of new and more specific treatments in the future.

Caracterización molecular y detección de genes blaCTX-M grupos 1 y 9 en Klebsiella pneumoniae resistentes a ceftazidima, en un hospital de San José de Cúcuta, Colombia / Molecular characterization and detection of genes blaCTX-M groups 1 and 9 in Klebsiella pneumoniae resistant to ceftazidime, in a hospital in San José de Cúcuta, Colombia

Resumen Introducción: La expresión de β-lactamasas CTX-M pertenecientes a los grupos 1 y 9 en Klebsiella pneumoniae produce grados altos de resistencia a ceftazidima, y presentan una amplia distribución mundial. Objetivo: Identificar y caracterizar los genes blaCTX-M-Grupo1 y blaCTX-M-Grupo9 en aislados de K. pneumoniae resistentes a ceftazidima en un hospital de San José de Cúcuta, Colombia. Material y Método: Se diseñaron partidores para la identificación de K. pneumoniae y los genes blaCTX-M mediante reacción de polimerasa en cadena (RPC). Posteriormente se realizó el análisis de la relación genética de estos aislados por medio de la RPC basada en secuencias repetitivas (RPC-REP). Resultados: Treinta y ocho por ciento de los 24 aislados identificados por RPC como K. pneumoniae presentaron los genes blaCTX-M-3, blaCTX-M-15 y blaCTX-M-32 (Grupo CTX-M-1) y 42% los genes blaCTX-M14, blaCTX-M-24 y blaCTX-M-27 (Grupo CTX-M-9). El análisis filogenético agrupó los aislados de K. pneumoniae en cuatro clusters, mostrando correlación en los clusters I, II y IV, al comparar los perfiles genéticos con el tipo de muestra y grupo de genes. Discusión: Se encontró una frecuencia similar de los genes blaCTX-M-Grupo1 y blaCTX-M-Grupo 9 en aislados de K. pneumoniae resistentes a ceftazidima. La correlación entre la RPC-REP con los grupos de CTX-M y el tipo de muestra reveló la presencia de tres patrones clonales.

Background: The expression of CTX-M β-lactamases belonging to groups 1 and 9 in Klebsiella pneumoniae produces high levels of resistance to ceftazidime, and they have a wide distribution worldwide. Aim: To identify and characterize the blaCTX-M-Group1 and blaCTX-M-Group9 genes in K. pneumoniae isolates resistant to ceftazidime in a hospital in San José de Cúcuta, Colombia. Material and Methods: Primers were designed for the identification of K. pneumoniae and blaCTX-M genes by PCR. Subsequently, the genetic relationship of these isolates was analyzed by REP-PCR. Results: A 38% of the 24 isolates identified by PCR as K. pneumoniae showed blaCTX-M-3. blaCTX-M-15 y blaCTX-M-32 genes (Group CTX-M-1) and 42% blaCTX-M14. blaCTX-M-24 y blaCTX-M-27 genes (Group CTX-M-9). The phylogenetic analysis grouped the K. pneumoniae isolates into 4 clusters, showing correlation in clusters I, II and IV, when comparing the genetic profiles with the type of sample and group of genes. Discussion: We found a similar frequency of blaCTX-M-Group 1 and blaCTX-M-Group 9 genes in isolates of K. pneumoniae resistant to ceftazidime. The correlation between the REP-PCR with the CTX-M groups and the type of sample revealed the presence of three clonal patterns.

Frecuencia cardiaca y actividad física en niños con obesidad del Sur de Sonora / Heart rate and physical activity among obese children in south Sonora / Frequência cardíaca e atividade física em crianças com obesidade do Sul de Sonora

Introducción La obesidad infantil provoca una alteración en la modulación autonómica cardiaca. Se ha señalado que la reducción de la acción protectora del sistema nervioso parasimpático cardiaco, manifestada en una frecuencia cardiaca más acelerada tras la actividad física en este grupo de pacientes, podría representar un dato temprano de disfunción cardiovascular. Objetivo Determinar diferencias en la Frecuencia cardiaca en reposo y tras actividad física en escolares con y sin obesidad, adscritos al servicio de pediatría de un Hospital de Segundo Nivel de Atención. Material y método Bajo un diseño transversal, y un muestreo no probabilístico; se estudiaron niños en edad escolar que asistían a consulta externa de pediatría, se categorizó estado nutricional mediante score Z de IMC e índice cintura-estatura, se midió frecuencia cardiaca en tres momentos: reposo, posterior a actividad y en reposo tras actividad. Se realizó análisis descriptivo de las variables, coeficiente de correlación de Pearson, Kruskal Wallis y U de Mann Whitney, para medir asociación y diferencia de frecuencias cardiacas entre los grupos estudiados. Resultados Se estudiaron 106 niños en edad escolar, el 53% presentaba obesidad abdominal y el 66% sobrepeso/obesidad. Se encontraron diferencias de medias estadísticamente significativas en las frecuencias cardiacas post actividad y tras reposo post actividad, entre pacientes con y sin obesidad. Discusión y Conclusiones Los niños con sobrepeso y obesidad deberían tener un seguimiento estrecho, ya que el marcado aumento de la FC después de la actividad física, debe ser tomado en cuenta como signo de alarma temprano de disfunción cardiovascular.

Introduction Childhood obesity provokes alterations in the cardiac autonomic modulation; and it has been pointed that disturbances to cardiac parasympathetic system, manifested as faster heart rate after physical activity, in this group of patients, could represent an early sign of cardiovascular disfunction. Objective To determine differences in heart rate at rest and after physical activity among school children, with and without obesity, attending to a pediatric service in a Second Level of Attention Hospital. Materials and method Under a transversal study design, and non-probabilistic sampling, school children attending to pediatric service were studied. The nutritional status was assessed through BMI Z scores, and a waist/height index. Heart rate were measured at three times: rest, after some physical activity, and at rest after such physical activity. A descriptive analysis was performed, and Pearson correlation coefficient, and Kruskal-Wallis, and Mann-Whitney tests were calculated to assess cardiac-related associations and differences between the two groups. Results 106 school children were studied. 53% showed abdominal obesity and 66% overweight/obesity. Statistically significant mean differences were found in the cardiac frequencies post activity and at rest post activity between the patients with and without obesity. Discussion and conclusion Considering the notorious increases in cardiac frequencies after physical activity, children with overweight and obesity should to be closely monitored for possible signs of cardiovascular disfunction.

Introdução A obesidade infantil provoca uma alteração na modulação autonómica cardíaca. Foi apontado que a redução da ação protetora do sistema nervoso parassimpático cardíaco, manifestada em uma fre quência cardíaca mais acelerada após a atividade física neste grupo de pacientes, poderia representar um dado precoce de disfunção cardiovascular neles. Objetivo Determinar diferenças na Frequência cardíaca em repouso e após da atividade física em estu dantes com e sem obesidade, vinculados ao serviço de pediatria de um Hospital de Segundo Nível de Atenção. Material e método Sob um desenho transversal, e uma amostra não probabilística; estudaram-se crianças em idade escolar que assistiam a consulta externa de pediatria, categorizou-se estado nutricional mediante score Z de IMC e índice cinto-estatura, mediu-se frequência cardíaca em três momentos: repouso, posterior à atividade e em repouso após a atividade. Realizou-se análise descritiva das variáveis, coeficiente de correlação de Pearson, Kruskal Wallis e U de Mann Whitney, para medir associação e diferença de frequências cardíacas entre os grupos estudados. Resultados Estudaram-se 106 crianças em idade escolar, o 53% apresentava obesidade abdominal e o 66% sobrepeso/obesidade. Encontraram-se diferenças de médias estatisticamente significativas nas frequên cias cardíacas post atividade e após repouso post atividade, entre os pacientes com e sem obesidade. Discussão e Conclusões As crianças com sobrepeso e obesidade deveriam ter um acompanhamento maior, já que o marcado aumento da FC depois da atividade física é um signo de alarme, que deve ser tomado em conta como signo precoce de disfunção cardiovascular.

[The effect of age on the prognosis of patients with traumatic brain injury who undergo a craniotomy: analysis of a surgical series]. / Efecto de la edad en el pronostico de pacientes con traumatismo craneoencefalico sometidos a craneotomia: analisis de una serie quirurgica.

INTRODUCTION: In our setting, the ageing of the population has led to management of traumatic brain injury (TBI) in the later stages of life becoming an increasingly frequent problem. AIM: To evaluate the association between age and the functional and survival prognosis of patients who have undergone surgery due to TBI. PATIENTS AND METHODS: We performed a retrospective analysis of a series of 404 patients submitted to surgery between the years 2000 and 2015: 144 youngsters (12-44 years), 77 adults (45-64 years), 148 geriatric patients (65-79 years) and 26 'super geriatric' patients (> 80 years). We reviewed the demographic and nosological characteristics of the population, the survival and functional prognosis (Glasgow Outcome Scale, GOS) on discharge and at six months. RESULTS: Age presents a positive linear association with both intra-hospital mortality and the proportion of patients with an unfavourable prognosis (GOS 1-3) on hospital discharge and at six months (p < 0.001). Taking the population of youngsters as a reference, the relative risk for an unfavourable prognosis at six months was 1.5 (95% CI: 1.04-2.19) for adults; 2.37 (95% CI: 1.77-3.17) for the geriatric patients; and 3.5 (95% CI: 2.63-4.7) for the 'super geriatric' patients. These latter present a mortality rate while in hospital of 77.78% and a percentage of poor functional prognosis at six months of 94.44%. CONCLUSION: Increased age is a major negative determining factor in the prognosis of patients who undergo a craniotomy due to TBI. More precise knowledge of these outcomes and an adequate pre-operative discussion with the family will be an invaluable aid in the decision-making process.

TITLE: Efecto de la edad en el pronostico de pacientes con traumatismo craneoencefalico sometidos a craneotomia: analisis de una serie quirurgica.Introduccion. En nuestro entorno, el envejecimiento poblacional ha convertido el manejo del traumatismo craneoencefalico (TCE) en etapas avanzadas de la vida en un problema de frecuencia creciente. Objetivo. Valorar la asociacion entre la edad y el pronostico vital y funcional de pacientes intervenidos por TCE. Pacientes y metodos. Analizamos retrospectivamente una serie de 404 pacientes intervenidos en nuestro centro entre los años 2000 y 2015: 144 jovenes (12-44 años), 77 adultos (45-64 años), 148 pacientes geriatricos (65-79 años) y 26 supergeriatricos (> 80 años). Revisamos las caracteristicas demograficas y nosologicas de la poblacion, y el pronostico vital y funcional (escala pronostica de Glasgow, GOS) en el momento del alta y a los seis meses. Resultados. La edad presenta asociacion lineal positiva tanto con la mortalidad intrahospitalaria como con la proporcion de pacientes con pronostico desfavorable (GOS 1-3) en el alta y a los seis meses (p < 0,001). Tomando como referencia la poblacion de jovenes, el riesgo relativo para pronostico desfavorable a los seis meses fue de 1,5 (IC 95%: 1,04-2,19) para los adultos, 2,37 (IC 95%: 1,77-3,17) para los geriatricos y 3,5 (IC 95%: 2,63-4,70) para los supergeriatricos. Estos ultimos presentan una mortalidad durante el ingreso del 77,78% y un porcentaje de mal pronostico funcional a los seis meses del 94,44%. Conclusion. El aumento de la edad es un factor determinante negativo mayor en el pronostico de pacientes sometidos a craneotomia por TCE. Un conocimiento preciso de estos resultados y una adecuada discusion preoperatoria con la familia resultaran de gran ayuda en el proceso de toma de decisiones.

Postoperative management of radical cystectomy. Review of the evidence on the prevention and treatment of urological complications. / Manejo postoperatorio de cistectomía radical. Revisión de la evidencia sobre la prevención y el tratamiento de las complicaciones urológicas.

INTRODUCTION AND OBJECTIVES: This review article focuses on the prevention and management of the most common postoperative urological complications of radical cystectomy. We reviewed the current literature and conducted an analysis of frequency, prevention and treatment of complications. ACQUISITION OF EVIDENCE: We conducted a search on Medline to identify original articles, literature reviews and editorials focusing on the urological complications of radical cystectomy during the first 90 days after surgery. We identified those series that included more than 100 patients. SYNTHESIS OF THE EVIDENCE: The literature regarding the prevention and treatment of complications after cystectomy is in general retrospective and nonstandardised. The level of evidence is generally low, and it is difficult to make evidence-based recommendations. CONCLUSIONS: Progress has been made in recent years in reducing mortality and preventing the complications of cystectomy. The most common complications are gastrointestinal, for which significant efforts have been made to implement ERAS and Fast Track protocols. The complications that can most significantly change patients' quality of life are urinary stoma.

Human Menstrual Blood-Derived Mesenchymal Stem Cells as Potential Cell Carriers for Oncolytic Adenovirus.

Antitumor efficacy of systemically administered oncolytic adenoviruses (OAdv) is limited due to diverse factors such as liver sequestration, neutralizing interactions in blood, elimination by the immune system, and physical barriers in tumors. It is therefore of clinical relevance to improve OAdv bioavailability and tumor delivery. Among the variety of tumor-targeting strategies, the use of stem cells and specifically bone marrow-derived mesenchymal stem cells (BM-MSCs) is of particular interest due to their tumor tropism and immunomodulatory properties. Nonetheless, the invasive methods to obtain these cells, the low number of MSCs present in the bone marrow, and their restricted in vitro expansion represent major obstacles for their use in cancer treatments, pointing out the necessity to identify an alternative source of MSCs. Here, we have evaluated the use of menstrual blood-derived mesenchymal stem cells (MenSCs) as cell carriers for regional delivery of an OAdv in the tumor. Our results indicate that MenSCs can be isolated without invasive methods, they have an increased proliferation rate compared to BM-MSCs, and they can be efficiently infected with different serotype 5-based capsid-modified adenoviruses, leading to viral replication and release. In addition, our in vivo studies confirmed the tumor-homing properties of MenSCs after regional administration.

Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses.

Homeodomain interacting protein kinase-2 (HIPK2) is a member of the HIPK family of stress-responsive kinases that modulates cell growth, apoptosis, proliferation and development. HIPK2 has several well-characterised tumour suppressor roles, but recent studies suggest it can also contribute to tumour progression, although the underlying mechanisms are unknown. Herein, we have identified novel crosstalk between HIPK2 and the cytoprotective transcription factor NRF2. We show that HIPK2 is a direct transcriptional target of NRF2, identifying a functional NRF2 binding site in the HIPK2 gene locus and demonstrating for the first time a transcriptional mode of regulation for this kinase. In addition, HIPK2 is required for robust NRF2 responsiveness in cells and in vivo. By using both gain-of-function and loss-of-function approaches, we demonstrate that HIPK2 can elicit a cytoprotective response in cancer cells via NRF2. Our results have uncovered a new downstream effector of HIPK2, NRF2, which is frequently activated in human tumours correlating with chemoresistance and poor prognosis. Furthermore, our results suggest that modulation of either HIPK2 levels or activity could be exploited to impair NRF2-mediated signalling in cancer cells, and thus sensitise them to chemotherapeutic drugs.

Endovascular treatment of idiopathic intracranial hypertension: retrospective analysis of immediate and long-term results in 51 patients.

PURPOSE: Idiopathic intracranial hypertension (IIH) is a disorder of increased intracranial pressure in the absence of any known causative factor. Sinus stenosis is common in these patients. Stenting of stenotic dural sinuses has gained popularity as a treatment option, since these stenoses may contribute to an obstruction of the venous return, and, thereby may contribute to IIH via an increase in venous sinus pressure. We evaluated the safety and efficacy of endovascular treatment in IIH with venous sinus stenosis. METHODS: Fifty-one patients with IIH underwent stenting. Median age was 40 years. Clinical manifestation was headache in 74.5% of the patients and visual obscurations in 78.5%. Papilledema was present in 50/51 patients (98%), and lumbar puncture documented elevated CSF opening pressure in all but one patient (98%). Sinus stenoses were observed in all patients. RESULTS: Endovascular treatment was successfully performed in all patients. There were no major complications encountered (i.e., live threatening or causing a deterioration of a patient's condition equivalent to mRS 3-6). Improvement or resolution of papilledema was observed in 88% of the patients, and 84% reported improvement or resolution of the headache. Follow-up angiographies were performed in 48 patients at a median interval of 49 months and demonstrated in stent-stenosis or a de novo stenosis in 12 patients, eight of them needed re-treatment. CONCLUSION: Venous sinus stenting is a safe and effective alternative to other invasive treatments (e.g., optic nerve sheath fenestration, CSF diversion) in patients with IIH. The majority of patients have a persistent clinical benefit.

Use of the pCONus as an adjunct to coil embolization of acutely ruptured aneurysms.

INTRODUCTION: Coil embolization of ruptured aneurysms has become the standard treatment in many situations. However, certain aneurysm morphologies pose technical difficulties and may require the use of adjunctive devices. OBJECTIVE: To present our experience with the pCONus, a new neck bridging device, as an adjunct to coil embolization for acutely ruptured aneurysms and discuss the technical success, angiographic and clinical outcomes. METHODS: We conducted a retrospective review of our database of prospectively collected data to identify all patients who presented with acute subarachnoid hemorrhage that required adjunctive treatment with the pCONus in the acute stage. We searched the database between April 2011 and April 2016. RESULTS: 21 patients were identified (13 male, 8 female) with an average age of 54.6 years (range 31-73). 8 aneurysms were located at the basilar artery tip, 7 at the anterior communicating artery, 4 at the middle cerebral artery bifurcation, 1 pericallosal, and 1 basilar fenestration. 61.8% patients achieved modified Raymond-Roy classification I or II at immediate angiography, with 75% of patients having completely occluded aneurysms or stable appearance at initial follow-up. There were no repeat aneurysmal ruptures and two device-related complications (no permanent morbidity). Four patients in our cohort died. CONCLUSIONS: Use of the pCONus is safe and effective in patients with acutely ruptured aneurysms and carries a high rate of technical success.

Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment.

CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.

Use of flow diverters in the treatment of unruptured saccular aneurysms of the anterior cerebral artery.

BACKGROUND: Few publications have dealt exclusively with the use of flow diverter stents for the treatment of aneurysms of the anterior cerebral artery (ACA). OBJECTIVE: To determine the efficacy of flow-diverting stents in the treatment of small, unruptured aneurysms of the ACA. METHODS: We retrospectively reviewed our database of prospectively collected information for all patients treated with flow diversion for an unruptured saccular aneurysm of the ACA between September 2009 and July 2016. The aneurysm fundus size, neck size, number and type of flow-diverting stent (FDS), complications, and follow-up data were recorded. RESULTS: In total 26 patients, with 27 aneurysms were identified that matched our inclusion criteria (11 male and 15 female). The average age of the patients was 59.3 years (range 27-77 years). All patients, except one, had a single aneurysm affecting the ACA. Fourteen aneurysms were located on the left (51.9%). The average aneurysm fundus size was 2.9 mm (range 2-6 mm). Twenty patients had follow-up angiographic studies. In total, 16 aneurysms were completely excluded, 1 aneurysm showed a very small remnant, and no follow-up angiographic data are available for the remaining patients. One patient had a treatment-related complication. CONCLUSIONS: Treatment of aneurysms arising from the ACA with flow diverters is technically feasible and carries a high degree of success with low complication rate.

Tumor gigante de vaina neural / Giant tumor from the nerve sheath

Resumen: El schwannoma es un tumor benigno derivado de la vaina neural de las células de Schwann. Habitualmente suele ser pequeño y solitario, siendo más frecuente en los pares craneales y en la médula espinal, aunque menos frecuente en las extremidades. Se han descrito casos de aparición en las extremidades (principalmente superiores). Son muy raros los casos de schwannomas de gran tamaño sin relación con la neurofibromatosis. Presentamos a una paciente de 25 años de edad, con un schwannoma gigante que invadía desde la región isquiática al tríceps sural.

Abstract: A schwannoma is a benign nerve sheath tumor derived from Schwann cells. They are usually small and solitary tumors more frequently localized in cranial nerves and the spinal cord and rarely in the limbs. Some cases have been reported involving extremities (mainly the upper ones) but with a small size. Cases of big size schwannomas unrelated to a neurofibromatosis are very rare. We report the case of a 25 year old patient, with a giant schwannoma which invaded the ischiatic region reaching the triceps surae.

Familial Hemiplegic Migraine with Severe Attacks: A New Report with ATP1A2 Mutation.

Introduction. Familial hemiplegic migraine (FHM) is a rare disorder characterized by migraine attacks with motor weakness during the aura phase. Mutations in CACNA1A, ATP1A2, SCN1A, and PRRT2 genes have been described. Methods. To describe a mutation in ATP1A2 gene in a FHM case with especially severe and prolonged symptomatology. Results. 22-year-old woman was admitted due to migraine-type headache and sudden onset of right-sided weakness and aphasia; she had similar episodes in her childhood. Her mother was diagnosed with hemiplegic migraine without genetic confirmation. She presented with fever, decreased consciousness, left gaze preference, mixed aphasia, right facial palsy, right hemiplegia, and left crural paresis. Computed tomography (CT) showed no lesion and CT perfusion study evidenced oligohemia in left hemisphere. A normal brain magnetic resonance (MR) was obtained. Impaired consciousness and dysphasia began to improve three days after admission and mild dysphasia and right hemiparesis lasted for 10 days. No recurrences were reported during a follow-up of two years. We identified a variant in heterozygous state in ATP1A2 gene (p.Thr364Met), pathogenic according to different prediction algorithms (SIFT, PolyPhen2, MutationTaster, and Condel). Conclusion. Prolonged and severe attacks with diffuse hypoperfusion in a FHM seemed to be specially related to ATP1A2 mutations, and p.T364M should be considered.