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Malignant brain tumors, such as glioblastoma multiforme (GBM) and brain metastases, continue to be an unmet medical challenge. Despite advances in cancer diagnostics and therapeutics, tumor cell colonization in the central nervous system renders most treatment options ineffective. This is primarily due to the selective permeability of the blood-brain barrier (BBB), which hinders the crossing of targeting agents into the brain. As such, repositioning medications that demonstrate anticancer effects and possess the ability to cross the BBB can be a promising option. Antidepressants, which are BBB-permeable, have been reported to exhibit cytotoxicity against tumor cells. Autophagy, specifically, has been identified as one of the common key mediators of antidepressant's antitumor effects. In this work, we provide a comprehensive overview of US Food and Drug Administration (FDA)-approved antidepressants with reported cytotoxic activities in different tumor models, where autophagy dysregulation was demonstrated to play the main part. As such, imipramine, maprotiline, fluoxetine and escitalopram were shown to induce autophagy, whereas nortriptyline, clomipramine and paroxetine were identified as autophagy inhibitors. Sertraline and desipramine, depending on the neoplastic context, were demonstrated to either induce or inhibit autophagy. Collectively, these medications were associated with favorable therapeutic outcomes in a variety of cancer cell models, including brain tumors.

Activators of MAPK signaling correlate to macrophage markers in human GBM patients. (A) Correlation of mRNA expression analysis of 161 GBM patients in TCGA library between ITGAM (CD11b) and MAPK13 (n=161). (B) Correlation between AIF1 (Iba1) and RRAS (n=161). (C) Correlation between AIF1 and MAPK13 (n=161). (D) Correlation between AIF1 and MAP3K8 (n=161). r and p values by Pearson correlation coefficient. Points represent individual GBM patients.

Purpose:Cancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intratumor heterogeneity characteristic of gliomas, we hypothesized that CD8+ T cells mediate immunoediting in these tumors.Experimental Design:We developed retrovirus-induced PDGF+Pten−/− murine gliomas and evaluated glioma progression and tumor immunogenicity in the absence of CD8+ T cells by depleting this immune cell population. Furthermore, we characterized the genomic alterations present in gliomas that developed in the presence and absence of CD8+ T cells.Results:Upon transplantation, gliomas that developed in the absence of CD8+ T cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8+ T-cell depletion. In contrast, gliomas that developed under pressure from CD8+ T cells were able to fully engraft in both CD8+ T-cell–depleted mice and immunocompetent mice. Remarkably, gliomas developed in the absence of CD8+ T cells exhibited increased aneuploidy, MAPK pathway signaling, gene fusions, and macrophage/microglial infiltration, and showed a proinflammatory phenotype. MAPK activation correlated with macrophage/microglia recruitment in this model and in the human disease.Conclusions:Our studies indicate that, in these tumor models, CD8+ T cells influence glioma oncogenic pathways, tumor genotype, and immunogenicity. This suggests immunoediting of immunogenic tumor clones through their negative selection by CD8+ T cells during glioma formation.

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Purpose: The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors. Experimental Design: To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes. Results: We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA. Conclusions: Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.

Purpose: Cancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intratumor heterogeneity characteristic of gliomas, we hypothesized that CD8+ T cells mediate immunoediting in these tumors. Experimental Design: We developed retrovirus-induced PDGF+Pten−/− murine gliomas and evaluated glioma progression and tumor immunogenicity in the absence of CD8+ T cells by depleting this immune cell population. Furthermore, we characterized the genomic alterations present in gliomas that developed in the presence and absence of CD8+ T cells. Results: Upon transplantation, gliomas that developed in the absence of CD8+ T cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8+ T-cell depletion. In contrast, gliomas that developed under pressure from CD8+ T cells were able to fully engraft in both CD8+ T-cell–depleted mice and immunocompetent mice. Remarkably, gliomas developed in the absence of CD8+ T cells exhibited increased aneuploidy, MAPK pathway signaling, gene fusions, and macrophage/microglial infiltration, and showed a proinflammatory phenotype. MAPK activation correlated with macrophage/microglia recruitment in this model and in the human disease. Conclusions: Our studies indicate that, in these tumor models, CD8+ T cells influence glioma oncogenic pathways, tumor genotype, and immunogenicity. This suggests immunoediting of immunogenic tumor clones through their negative selection by CD8+ T cells during glioma formation.

Glioblastomas (GBMs) are complex ecosystems composed of highly multifaceted tumor and myeloid cells capable of responding to different environmental pressures, including therapies. Recent studies have uncovered the diverse phenotypical identities of brain-populating myeloid cells. Differences in the immune proportions and phenotypes within tumors seem to be dictated by molecular features of glioma cells. Furthermore, increasing evidence underscores the significance of interactions between myeloid cells and glioma cells that allow them to evolve in a synergistic fashion to sustain tumor growth. In this review, we revisit the current understanding of glioma-infiltrating myeloid cells and their dialogue with tumor cells in consideration of their increasing recognition in response and resistance to immunotherapies as well as the immune impact of the current chemoradiotherapy used to treat gliomas.

El crecimiento poblacional de una ciudad genera un crecimiento del parque automotor y, a falta de una política de ordenamiento del sistema de transporte, zonas con mayor nivel de congestionamiento. Dicha situación sucede en la ciudad de Tacna. La avenida Bolognesi es un tramo altamente comercial que comprende una vía de subida y otra de bajada, divididas por una plataforma peatonal intermedia, donde se visualizan las famosas palmeras que caracterizan a la ciudad. Ante ello, la presente investigación tuvo como objetivo determinar el nivel de congestionamiento de las vías relacionadas con dicha zona comercial. En total se estudiaron 11 puntos en los turnos de mañana, tarde y noche, durante las denominadas “horas punta”, aplicando la metodología usada por Gardilci & otros (2014). Asimismo, se realizó una encuesta a transeúntes y conductores que transitaban por la zona para conocer el efecto del nivel de congestionamiento. Losresultados fueron los siguientes: En el turno mañana, 8 obtuvieron un nivel alto, 2 obtuvieron un nivel medio y 1 obtuvo un nivel bajo. En el turno tarde, 6 alcanzaron un alto nivel y 5 alcanzaron un nivel medio. En el turno noche, 7 obtuvieron un alto nivel y 4 alcanzaron un nivel medio. De las encuestas se recogió la información de malestar por parte de los conductores, quienes afirmaron perder tiempo y dinero. Por ello, se concluye que, generalmente en algunos puntos de la zona, el nivel de congestionamiento es alto, lo que conlleva al bloqueo de las líneas de cruce peatonal, así como el bloqueo de la demarcación de “no bloquear intersecciones”, especialmente en las intersecciones que no llevan dispositivos de control de tránsito.

International audience; In two cohorts of patients with glioblastoma who received anti-PD-1, Sonabend and colleagues show that ERK1/2 phosphorylation, detected by immunohistochemistry, provides a biomarker for MAPK/ERK pathway activity and better survival on this therapy. Only a subset of recurrent glioblastoma (rGBM) responds to anti-PD-1 immunotherapy. Previously, we reported enrichment of BRAF/PTPN11 mutations in 30% of rGBM that responded to PD-1 blockade. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in rGBM, including patients that do not harbor BRAF/PTPN11 mutations. Here we show that immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, is predictive of overall survival following adjuvant PD-1 blockade in two independent rGBM patient cohorts. Single-cell RNA-sequencing and multiplex immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and that high-p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. These findings indicate that ERK1/2 activation in rGBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.

Paclitaxel (PTX) is one the most potent and commonly used chemotherapies for breast and pancreatic cancer. Given the potency of this drug for glioblastomas (GBM) several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood-brain barrier for this disease. In spite of the efficacy of PTX, individual tumors exhibit variable susceptibility to this drug, with response rate in the range of 30%-60%. To identify predictive biomarkers for response to PTX, we performed a genome-wide CRISPR knock-out screen using human glioma cells. The most enriched genes in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort. This led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with response to PTX in breast cancer cells, glioma cells, in multiple intracranial glioma xenografts and in GBM patient derived explant cultures. Knockout of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. In gliomas, SSR3-mediated susceptibility to PTX relates to modulation of phosphorylation of ER stress sensor IRE1α. Thus, by using genome-wide screen combined with patient response data, we discovered a biomarker that demonstrates causal and correlative relationship with response to PTX in breast cancer and GBM. Prospective validation of this biomarker is warranted for its broad implementation for precision oncology.

Summary Background Malignant glioma is the most common and lethal primary brain tumour, with dismal survival rates and no effective treatment. We examined the safety and activity of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma. Methods This was a first-in-human, open-label, phase 1, dose-escalation trial done to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received a dose starting at 6·25 × 1010 viral particles administered by 5·00 × 107 NSCs, the second cohort a dose of 1·25 × 1011 viral particles administered by 1·00 × 108 NSCs, and the third cohort a dose of 1·875 × 1011 viral particles administered by 1·50 × 108 NSCs. No further dose escalation was planned. Within 10–14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov , NCT03072134 . Findings Between April 24, 2017, and Nov 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. The median follow-up was 18 months (IQR 14–22). One patient receiving 1·50 × 108 NSCs loading 1·875 × 1011 viral particles developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Otherwise, treatment was safe as no formal dose-limiting toxicity was reached, so 1·50 × 108 NSCs loading 1·875 × 1011 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5–not reached) and median overall survival was 18·4 months (15·7–not reached). Interpretation NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase 2/3 clinical trial. Funding US National Institutes of Health.

Neoadjuvant trials for early breast cancer have accelerated the identification of novel active agents, enabling streamlined conduct of registration trials with fewer subjects. Measurement of neoadjuvant drug effects has also enabled the identification of patients with high risk of distant recurrence and has justified development of additional adjuvant approaches to improve outcomes. Neoadjuvant evaluation of new drugs was significantly improved by the introduction of pathologic complete response (pCR) rate as a quantitative surrogate endpoint for distant disease-free survival (DDFS) and event free survival (EFS). The neoadjuvant phase 2 platform trial I-SPY 2 simultaneously tests multiple drugs across multiple breast cancer subtypes using Bayesian methods of adaptive randomization for assessment of drug efficacy. In addition to the pCR endpoint, the I-SPY 2 trial has demonstrated that the residual cancer burden (RCB) score measures gradations of tumor response that correlate with DDFS and EFS across treatments and subtypes. For HER2-positive and triple-negative breast cancers that have failed to attain pCR with neoadjuvant chemotherapy (NAC), effective modifications of adjuvant treatment have improved outcomes and changed the standard of care for these subtypes. Neoadjuvant therapy is therefore preferred for stage II and III, as well as some stage I, HER2-positive and triple-negative tumors. Neoadjuvant endocrine therapy (NET) strategies have also emerged from innovative trials for stage II and III estrogen receptor (ER)-positive/HER2-negative tumors, as in the ALTERNATE trial. From neoadjuvant trials, opportunities have emerged to de-escalate therapy on the basis of metrics of response to chemotherapy or hormonal therapy. Neoadjuvant therapy for early breast cancer is therefore emerging as a promising approach to accelerate new drug development, optimize treatment strategies, and (where appropriate) de-escalate neoadjuvant therapy.

Currently, glioblastomas remain incurable and are associated with a poor prognosis. Although the understanding of the biology of gliomas has been refined, little progress has been made in the therapeutic management of these tumors. Part of this failure is because the blood-brain barrier has prevented the inlet of new and standard therapeutics into the tumor territory and its vicinity. Therefore, effective strategies are needed to achieve good drug concentrations within tumors. This chapter addresses promising drug-delivery technologies such as convection-enhanced delivery and ultrasound, that have experienced an increasing use in preclinical and clinical research and have an enormous potential for implementation for the treatment of gliomas.

Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNg stimulation. BVaxmigrate to key secondary lymphoid organs and are proficient at antigen cross-presentation, which promotes both the survival and functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunologic memory that prevented the growth of new tumors upon subsequent re-injection in cured mice. GBM patient-derived BVax were successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. In addition to the role in activating CD8+ T cells, BVax produce tumor-specific antibodies able to control tumor growth via antibody-mediated cell cytotoxicity. In conclusion, BVax tackles GBM immunosurveillance escape by using both cellular (CD8+ T-cell activation) and humoral (anti-tumor antibody production) immunity. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

Objectives Breast cancer (BC) is the leading cause of morbidity and mortality. Neurological symptoms are highly feared because they are associated with central nervous system metastases (CNSm). So, we aimed to analyze the association of neurological symptoms with CNSm. Patients & Methods Patients with BC referred for a neuro-oncological evaluation at a cancer referral center from June 2012 to December 2017 were included. Demographic, oncological history, comorbidities, clinical symptoms and signs, and their correlation with CNSm were prospectively acquired during consultation in a computerized database. Analyses included descriptive observations, bivariate, and logistic linear regression tests that compared associations. Results A total of 857 patients with BC were referred for assessment. The most frequently occurring symptoms included headache, focal motor weakness, focal-sensitive complaints, and visual complaints. Of the 1029 neuro-oncology diagnoses made, the most common were CNSm, primary headache, and chemotherapy-induced neuropathy. The risk factors associated with CNSm in patients with neurological symptoms were HER2+, younger age at cancer diagnosis, presence of extracranial metastases, and >1 neurological symptom (mainly headache: hazard ratio (HR), 2.1 [95% confidence interval (CI), 1.5–2.7]; visual complaints: HR, 2.3 (95%CI, 1.2–4.2); and ataxia: HR, 2.1 (95%CI,1.04–4.3). Conclusions Clinical symptoms and cancer characteristics were correlated with the development of CNSm. Specific risk and protective factors were identified. Among BC patients with neurological symptoms, CNSm should always be considered, especially in patients with certain oncological and clinical features.

Cervical intramedullary schwannomas are extraordinarily rare. Gross total resection is the best therapeutic option for these types of tumors. Although rare, intramedullary schwannomas should be considered as a differential diagnosis of intramedullary lesions since a good prognosis can be guaranteed to the majority of these patients. We present a case of a cervical intramedullary schwannoma surgically treated in a 19-year-old male patient who initially presented with motor neuron disease.

PD-1 checkpoint inhibition has led to remarkable clinical responses in several cancer types. Whereas PD-1 blockade has not shown an overall survival (OS) benefit for glioblastoma (GBM) patients, a subset of them exhibit long-term responses to this immunotherapy. Previously, we reported an enrichment of BRAF/PTPN11 activating mutations in 30% of recurrent GBMs that responded to PD-1 blockade, but the molecular profile of the majority of responders remained elusive. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in recurrent GBM, including patients that do not harbor BRAF/PTPN11 mutations. Immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, was performed in a discovery cohort including pre-treatment specimens of 29 recurrent GBM patients treated with adjuvant PD-1 blockade, and 33 patients who did not undergo immunotherapy. p-ERK was predictive of response and OS following PD-1 blockade. Yet p-ERK was not associated with OS in patients not treated with immunotherapy. p-ERK was also associated with OS in a validation GBM cohort treated with adjuvant anti-PD-1 therapy. Single-cell RNA-seq and multiplex-immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and high p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. Thus, our findings indicate that ERK1/2 activation in recurrent GBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.

Purpose: Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across the blood–brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain. We investigated the distribution, toxicity, and efficacy of LIPU delivery of two different formulations of paclitaxel, albumin-bound paclitaxel (ABX) and paclitaxel dissolved in cremophor (CrEL-PTX), in preclinical glioma models. Experimental Design: The efficacy and biodistribution of ABX and CrEL-PTX were compared with and without LIPU delivery. Antiglioma activity was evaluated in nude mice bearing intracranial patient-derived glioma xenografts (PDX). Paclitaxel biodistribution was determined in sonicated and nonsonicated nude mice. Sonications were performed using a 1 MHz LIPU device (SonoCloud), and fluorescein was used to confirm and map BBB disruption. Toxicity of LIPU-delivered paclitaxel was assessed through clinical and histologic examination of treated mice. Results: Despite similar antiglioma activity in vitro, ABX extended survival over CrEL-PTX and untreated control mice with orthotropic PDX. Ultrasound-mediated BBB disruption enhanced paclitaxel brain concentration by 3- to 5-fold for both formulations and further augmented the therapeutic benefit of ABX. Repeated courses of LIPU-delivered CrEL-PTX and CrEL alone were lethal in 42% and 37.5% of mice, respectively, whereas similar delivery of ABX at an equivalent dose was well tolerated. Conclusions: Ultrasound delivery of paclitaxel across the BBB is a feasible and effective treatment for glioma. ABX is the preferred formulation for further investigation in the clinical setting due to its superior brain penetration and tolerability compared with CrEL-PTX.

PURPOSE: Cancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intra-tumor heterogeneity characteristic of gliomas, we hypothesized that CD8(+) T-cells mediate immunoediting in these tumors. EXPERIMENTAL DESIGN: We developed retrovirus-induced PDGF(+)Pten(−/−) murine gliomas and evaluated glioma progression and tumor immunogenicity in the absence of CD8(+) T-cells by depleting this immune cell population. Furthermore, we characterized the genomic alterations present in gliomas that developed in the presence and absence of CD8(+) T-cells. RESULTS: Upon transplantation, gliomas that developed in the absence of CD8(+) T-cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8(+) T-cell depletion. In contrast, gliomas that developed under pressure from CD8(+) T-cells were able to fully engraft in both CD8(+) T-cell-depleted mice and immunocompetent mice. Remarkably, gliomas developed in the absence of CD8(+) T-cells exhibited increased aneuploidy, MAPK pathway signaling, gene fusions, and macrophage/microglial infiltration, and showed a proinflammatory phenotype. MAPK activation correlated with macrophage/microglia recruitment in this model and in the human disease. CONCLUSIONS: Our studies indicate that, in these tumor models, CD8(+) T-cells influence glioma oncogenic pathways, tumor genotype, and immunogenicity. This suggests immunoediting of immunogenic tumor clones through their negative selection by CD8(+) T-cells during glioma formation.

Cancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intra-tumor heterogeneity intrinsic to gliomas, we hypothesized that CD8+ T-cells mediate immunoediting in these tumors. We evaluated glioma progression in the absence of CD8+ T-cells by depleting this immune cell population in transgenic murine gliomas. Upon transplantation, gliomas that developed in the absence of CD8+ T-cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8+ T-cell depletion. Gliomas developed in absence of CD8+ T-cells exhibited increased chromosomal instability, MAPK signaling, gene fusions, and macrophage/microglial infiltration. MAPK activation correlated with macrophage/microglial recruitment in this model and in the human disease. Our results indicate that CD8+ T-cells mediate immunoediting during gliomagenesis, influencing the genomic stability of glioma and its microenvironment, leading to immune evasion.SignificanceImmune evasion renders cancer resistant to anti-tumoral immunity. Therapeutic intervention often fails for gliomas because of the plasticity of tumor cell variants that resist immune surveillance. Our results demonstrate a mechanism of immune evasion in gliomas that derives from CD8+ T-cells during the development and progression of this disease.

Resumen: La lumbalgia y el sobrepeso-obesidad son patologías que se han constituido en tema de interés en salud pública, dado el incremento de incidencia y prevalencia de estas enfermedades en la población mundial. Investigaciones al respecto han sido realizadas especialmente en población anglosajona. Este artículo presenta un estudio analítico de corte transversal, en el que se incluyeron 100 pacientes escogidos con un muestreo por conveniencia, con diagnóstico de lumbalgia, y atendidos en la consulta externa institucional de Ortopedia-Columna del Hospital Militar Central, durante el periodo de abril-junio de 2015. Se analizaron variables sociodemográficas y relacionadas con severidad del dolor, sobrepeso-obesidad e imbalance muscular, variables que se consideraban factores asociados a la presentación y severidad de lumbalgia. De los pacientes analizados, el 52 % fueron mujeres y el 48 %, hombres. Se encontró que las mujeres con porcentaje de grasa corporal elevado tienen un riesgo mayor de padecer dolor lumbar severo, y los hombres con porcentaje de grasa corporal bajo tienen menos riesgo de presentar esta afección. El índice de masa corporal (IMC) para este estudio no pudo predecir la intensidad de dolor lumbar; sin embargo, se logró observar que ser hombre mayor de 50 años es un factor de riesgo para presentar lumbalgia severa. Abstract: Low back pain and overweight/obesity have become a topic of interest in public health, given the increased incidence and prevalence of these pathologies in the world population. Research in this regard has been carried out, especially in the Anglo-Saxon population. This article presents a cross-sectional analytical study, which included 100 patients chosen by convenience sampling, with a diagnosis of low back pain and attending the institutional Orthopedics-Column outpatient clinic of the Hospital Militar Central during April-June 2015. Sociodemographic variables related to pain severity, overweight/obesity, and muscular imbalance were analyzed, as they were considered factors associated with the occurrence and severity of low back pain. Of the patients analyzed, 52% were women and 48 % men. It was found that women with high fat percentage have a higher risk of severe low back pain, while men with low fat percentage have a lower risk of having this condition. Body mass index (BMI) for this study could not predict the intensity of low back pain; however, it was observed that being a man older than 50 is a risk factor for severe low back pain. Resumo: O lumbago e o sobrepeso-obesidade são patologias que se constituem em tema de interesse em saúde pública, tendo em vista o aumento de incidência e a prevalência dessas doenças na população em todo o mundo. Pesquisas sobre isso têm sido realizadas, em especial, com população anglo-sa-xã. Este artigo apresenta um estudo analitico, de corte transversal, do qual participaram 100 pacientes selecionados por conveniência, com diagnóstico de lumbago, e atendidos em consulta institucional de Ortopedia-Coluna do Hospital Militar Central, entre abril e junho de 2015. Foram analisadas variáveis sociodemográficas e relacionadas com severidade da dor, sobrepeso-obesidade e desequilíbrio muscular, variáveis consideradas fatores associados com a apresentação e a severidade de lumbago. Dos pacientes analisados, 52% eram mulheres e 48%, homens. Foi verificado que as mulheres com porcentagem de gordura elevada têm um risco maior de padecer dor lombar severa, e os homens com porcentagem de gordura baixa têm menos risco de apresentar essa condição. O indice de massa corporal para este estudo não pode predizer a intensidade de dor lombar; contudo, pôde-se observar que ser homem com mais de 50 anos é um fator de risco para apresentar lumbago grave.

Resumen Introduccion El traumatismo pelvico inveterado ocasiona graves secuelas ortopedicas en las extremidades, como dolor cronico, discrepancia de longitud, rotacion anormal, pseudoartrosis, consolidacion viciosa, ademas de otras neurologicas, como sindrome de cauda equina y plexopatias. Su tratamiento representa un reto por tratarse de una patologia infrecuente, lo cual genera poca experiencia profesional y la informacion en la bibliografia es, ademas, escasa. El objetivo del estudio es analizar la experiencia del manejo por estadios quirurgicos para los pacientes con traumatismo pelvico inveterado. Materiales y metodos Se realizo una serie de casos en que se incluyeron 15 pacientes que se trataron quirurgicamente en diferentes estadios quirurgicos (2004-2015), se analizaron variables sociodemograficas, clinicas y quirurgicas. El analisis de datos se realizo de forma uni y bivariada mediante Excel y se calcularon promedios o proporciones en funcion de la naturaleza de las variables. Resultados Se obtuvieron mejores resultados en los casos menos inveterados y/o con pseudoartrosis. En cambio, fueron peores los resultados y mayores las complicaciones en los casos mas inveterados o consolidados en posicion viciosa. Discusion Se recomienda la estrategia de tres estadios «prono-supino-prono» basados en la evidencia aunque la casuistica debe ser mucho mayor para definir una conducta con un nivel de evidencia adecuado. Nivel de evidencia clinica Nivel IV.

The relationship between anti-tumoral immunity and cancer progression is complex. Recently, immune editing has emerged as a model to explain the interplay between the immune system and the selection of genetic alterations in cancer. In this model, the immune system selects cancer cells that grow as these are fit to escape immune surveillance during tumor development. Gliomas and glioblastoma, the most aggressive and most common of all primary malignant brain tumors are genetically heterogeneous, are relatively less antigenic, and are less responsive to immunotherapy than other cancers. In this review, we provide an overview of the relationship between glioma´s immune suppressive features, anti-tumoral immunity and cancer genomics. In this context, we provide a critical discussion of evidence suggestive of immune editing in this disease and discuss possible alternative explanations for these findings.

El presente documento pretende contextualizar al lector sobre algunos de los mecanismos que existen para la transición de IPv4-IPv6 y evidencia algunos aspectos que se deben tener en cuenta al momento de evaluar e implementar algunos de ellos, específicamente en centros de computación de alto desempeño y en redes académicas para el apoyo de proyectos de investigación. También se pretende mostrar la implementación y soporte de IPv6 en plataformas tecnológicas e-learning This document aims to contextualize the reader about some of the mechanisms that currently exist for IPv4-IPv6 transition and evidence some aspects that must be taken into account when evaluating and implementing some of them, specifically in centers of high performance computing and academic networks to support research projects. It also aims to show the implementation and support of IPv6 in e-learning technology platforms.

Cancer immunoediting shapes tumor progression by the immunological selection of tumor cell variants that can evade immune recognition. Given the immune evasive cellular diversity of glioblastoma, we hypothesized that CD8+ T-cells mediate immunoediting in this tumor. We evaluated tumor progression in the absence of CD8+ T-cells by depleting this immune cell population in a transgenic murine glioma model. Tumors generated in the absence of CD8+ T-cells developed poorly in recipients with intact immunity, implying a more immunogenic profile. These tumors demonstrated increased chromosomal instability, gene fusions, MAPK signaling, and macrophage infiltration. These observations were stochastic, suggesting variability in the mode of tumor evolution in the absence of this immune effector. MAPK activation was correlated with macrophage recruitment in two transgenic murine models and the human disease. Our results indicate that CD8+ T-cells mediate a strong immunoediting selection in glioblastoma that protect against the hallmarks of cancer and drive immune evasion.

Introduction: Silencing of the human cytochrome P450 (CYP) monooxygenase enzyme CYP3A4 in the ER+ MCF-7 tumor cell line inhibits tumor growth in the mammary fat pad, but the relative roles of tumor cell intrinsic CYPs vs. vascular/microenvironment CYPs remain to be determined and a syngeneic animal model is needed to answer this question. The SSM2ucd ovarian dependent mouse mammary carcinoma cell line forms a transplantable estrogen-receptor positive (ER+) mouse mammary tumor in which growth dependence on cell intrinsic CYPs may be tested in vitro and in vivo. The SSM2ucd cell line is derived from 129SvJ: homozygous Stat1-null female mice, which develop ER+ mammary tumors (1,2). Expression profiling of spontaneously arising mouse mammary carcinomas in a TP53 KO model revealed that the CYP3A4 ortholog Cyp3a11 is up-regulated in these tumors. Methods: Cyp3a11 bactosomes were used to assay for NADPH dependent biosynthesis of EETs from arachidonic acid using an LC-MS/MS method. siRNA silencing and CRISPR/Cas9 knock out of the Cyp3a11 exons 2 and 3 was performed and the cell lines were characterized for EET dependence using an MTT assay. The highly potent inhibitor and chemical probe of CYP epoxygenase activity, hexyl-benzyl-biguanide (HBB), was used to test dependence of SSM2ucd cells on CYP epoxygenase activity. Total cellular EETs in SSM2ucd cells exposed to HBB at the IC50were measured by the LC-MS/MS method. Results: Cyp3a11 was shown to have robust NADPH dependent epoxygenase activity, while SSM2ucd cells were EET dependent for growth. Silencing of Cyp3a11 was demonstrated to inhibit proliferation of the SSM2ucd cell line, which was partly abrogated by EETs. CRISPR/Cas9 knock out of the Cyp3a11 in the SSM2ucd cell line was performed and exon 2 and exon 3 deleted cell lines were derived. SSM2ucd Cyp3a11 knock out cell lines were more sensitive to EET-induced proliferation under serum free condition than control lines. HBB potently inhibits the SSM2ucd cell line in vitro (IC50=25 uM) and reduces total cellular EET levels in this cell line at IC50. These results suggest that we may see inhibitory activity of HBB in a syngeneic 129/SvJ tumor transplantation model. Conclusions: The Cyp3a11 gene can be silenced in the SSM2ucd cell line, without disrupting cell viability, allowing further study of the roles of EETs in mouse mammary carcinoma proliferation, survival and clonogenicity. The Cyp3a11 gene has been knocked out in the SSM2 ucd cell line, allowing in vitro and in vivo studies of the roles of Cyp3a11 in the growth of ovarian dependent mouse mammary carcinoma. 1. Breast Cancer Res. 2012 Jan 20;14(1):R16 2. PLoS One. 2015 Jun 15;10(6):e0129895] Citation Format: Zhijun Guo, Patrick McGrarrah, Ted Bebi, Ashley Mooneyham, Alejandra Osorio, Cesar Herrera, Victor Arrieta, Sebastian Mohar, Irwin Hernandez, Robert Klink, Robert Cardiff, David A. Potter. Ovarian-dependent SSM2ucd mouse mammary carcinoma cells depend on Cyp3a11 epoxygenase activity for proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 963. doi:10.1158/1538-7445.AM2017-963