Truncating the i-leader open reading frame enhances release of human adenovirus type 5 in glioma cells

Background: The survival of glioma patients with the current treatments is poor. Early clinical trails with replicating adenoviruses demonstrated the feasibility and safety of the use of adenoviruses as oncolytic agents. Antitumor efficacy has been moderate due to inefficient virus replication and spread. Previous studies have shown that truncation of the adenovirus i-leader open reading frame enhanced cytopathic activity of HAdV-5 in several tumor cell lines. Here we report the effect of an i-leader mutation on the cytopathic activity in glioma cell lines and in primary high-grade glioma

Idh1-mutated transgenic zebrafish lines: An in-vivo model for drug screening and functional analysis

Introduction The gene encoding isocitrate dehydrogenase 1 (IDH1) is frequently mutated in several tumor types including gliomas. The most prevalent mutation in gliomas is a missense mutation leading to a substitution of arginine with histidine at the residue 132 (R132H). Wild type IDH1 catalyzes oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) whereas mutant IDH1 converts α-KG into D2-hydroxyglutarate (D2HG). Unfortunately, there are few in vivo model systems for IDH-mutated tumors to study the effects of IDH1 mutations in tumor development. We have therefore created transgenic zebrafish lines that express various IDH1 mutants. Materials and methods IDH1 mutations (IDH1R132H, IDH1R132C and loss-of-function mutation IDH1G70D), IDH1wildtype or eGFP were cloned into constructs with several brain-specific promoters (Nestin, Gfap or Gata2). These constructs were injected into fertilized zebrafish eggs at the one-cell stage. Results In total more than ten transgenic zebrafish lines expressing various brain-specific IDH1 mutations were created. A significant increase in the level of D2HG was observed in all transgenic lines expressing IDH1R132C or IDH1R132H, but not in any of the lines expressing IDH1wildtype, IDH1G70D or eGFP. No differences in 5-hydroxymethyl cytosine and mature collagen IV levels were observed between wildtype and mutant IDH1 transgenic fish. To our surprise, we failed to identify any strong phenotype, despite increased levels of the oncome-tabolite D2HG. No tumors were observed, even when backcrossing with tp53-mutant fish which suggests that additional transforming events are required for tumor formation. Elevated D2HG levels could be lowered by treatment of the transgenic zebrafish with an inhibitor of mutant IDH1 activity. Conclusions We have generated a transgenic zebrafish model system for mutations in IDH1 that can be used for functional analysis and drug screening. Our model systems help understand the biology of IDH1 mutations and its role in tumor formation

Peptides from the variable region of specific antibodies are shared among lung cancer patients

Late diagnosis of lung cancer is still the main reason for high mortality rates in lung cancer. Lung cancer is a heterogeneous disease which induces an immune response to different tumor antigens. Several methods for searching autoantibodies have been described that are based on known purified antigen panels. The aim of our study is to find evidence that parts of the antigen-binding-domain of antibodies are shared among lung cancer patients. This was investigated by a novel approach based on sequencing antigen-binding- fragments (Fab) of immunoglobulins using proteomic techniques without the need of previously known antigen panels. From serum of 93 participants of the NELSON trial IgG was isolated and subsequently digested into Fab and Fc. Fab was purified from the digested mixture by SDS-PAGE. The Fab containing gel-bands were excised, tryptic digested and measured on a nano-LC-Orbitrap-Mass- spectrometry system. Multivariate analysis of the mass spectrometry data by linear canonical discriminant analysis combined with stepwise logistic regression resulted in a 12-antibody-peptide model which was able to distinguish lung cancer patients from controls in a high risk population with a sensitivity of 84% and specificity of 90%. With our Fab-purification combined Orbitrap-mass-spectrometry approach, we found peptides from the variable-parts of antibodies which are shared among lung cancer patients

Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score

Objective: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. Methods: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. Results: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2–18)

Autonomic Dysfunction : a conceptual model, the effects of a physical therapeutic manipulation targeting the T3-T4 segment on the autonomic nervous system

Purpose: This study will identify that patients with chronic neck pain have an altered autonomic functioning compared to a control group, and that manipulation might directly influence the autonomic nervous system as measured by using a fully automated pupillometry system. Subjects: 100 chronic pain patients and 50 control subjects participated in this study to achieve a power of 0.80, effect size of 0.5, and a type I error rate of 0.05 for two-tailed hypothesis testing. Method: A quasi-experimental design was be used. The ANOVA and Chi square test were used to establish homogeneity of baseline characteristics. The Mann-Whitney U test was performed to compare the pre-intervention pupil diameter amongst the groups. The Friedman\u27s test was used to determine the pupil diameter change during the three measurements. The Wilcoxen Signed-ranks test was used to analyze the difference in pupil size between the pre- and post-intervention measures and to determine if there was a difference in pupil diameter between the two groups undergoing the thoracic manipulation. The Kruskal-Wallis test was used to compare the pupil diameter change to the presence of joint sounds. And the Fisher\u27s Exact test was used to determine the relationship between the number of pops and the VAS change score \u3e 13mm. Results: This study demonstrated that the chronic pain group had a statistically significant smaller pupil diameter than the healthy control group (P=0.022). Manipulation resulted in a relative increase in pupil diameter following the manipulation, however this was not statistical significant. There was a statistical significant decrease in pupil diameter in the placebo group (pConclusions: It appears that a T3-T4 manipulation results in a relative non-specific increase in sympathetic activity. Recommendations: Manipulation may be used by physical therapists to affect the autonomic nervous system. Visual pupil assessment may become part of the evaluation process to identify patients that might present with autonomic dysfunction and to determine the effect of treatment modalities

Anatomy and clinical relevance of sub occipital soft tissue connections with the dura mater in the upper cervical spine

Background The upper cervical region is a complex anatomical structure. Myodural bridges between posterior suboccipital muscles and the dura might be important explaining conditions associated with the upper cervical spine dysfunction such as cervicogenic headache. This cadaver study explored the upper cervical spine and evaluated the myodural bridges along with position of spinal cord in response to passive motion of upper cervical spine. Methods A total of seven adult cadavers were used in this exploratory study. The suboccipital muscles and nuchal ligament were exposed. Connections between the Rectus Capitis Posterior major/minor and the Obliquus Capitis minor, the nuchal ligament, posterior aspect of the cervical spine, flavum ligament and the dura were explored and confirmed with histology. The position of the spinal cord was evaluated with passive motions of the upper cervical spine. Outcomes In all cadavers connective tissues attaching the Rectus Capitis Posterior Major to the posterior atlanto-occipital membrane were identified. In the sagittal dissection we observed connection between the nuchal ligament and the dura. Histology revealed that the connection is collagenous in nature. The spinal cord moves within the spinal canal during passive movement. Discussion The presence of tissue connections between ligament, bone and muscles in the suboccipital region was confirmed. The nuchal ligament was continuous with the menigiovertebral ligament and the dura. Passive upper cervical motion results in spinal cord motion within the canal and possible tensioning of nerve and ligamentous connections

Can mindfulness practice improve short-term retention in a science course?

Integrating mindfulness into learning has shown to improve short-term retention of factual knowledge. Our research project integrated mindful breathing exercises into teaching sessions in Anatomy & Physiology classes. Half of our labs session stopped for 5-minute guided breathing exercises every 30-35 minutes during frontal teaching, the other half did not incorporate these sessions into the class. Students in all classes completed short quizzes that related to the material taught at the end of the lab session. Our hypothesis was that integrating mindfulness exercises would increase retention of the learned material

Neuromodulation of the Autonomic Nervous System in Chronic Low Back Pain: A Randomized, Controlled, Crossover Clinical Trial

Chronic pain is a societal concern influencing the autonomic nervous system. This system can be captured with automated pupillometry. The direct connection between the epidermal cells and the brain is presented as part of the central nervous system, reflecting the modulation of the autonomic system. This study's aim was to investigate if tape containing magnetic particles (TCMP) has an immediate effect on the autonomic nervous system (ANS) and influences chronic low back pain. Twenty-three subjects completed this study. Subjects were randomized to either receive the control tape (CT) or TCMP first. Each subject underwent a pain provocative pressure test on the spinous process, followed by the skin pinch test and automated pupillometry. Next, the TCMP/control tape was applied. After tape removal, a second provocative spinous process pressure test and skin pinch test were performed. Subjects returned for a second testing day to receive the other tape application. The results demonstrate that TCMP had an immediate significant effect on the autonomic nervous system and resulted in decreased chronic lower back pain. We postulate that this modulation by TCMP s has an immediate effect on the autonomic system and reducing perceived pain, opening a large field of future research.Sin financiación4.7 Q1 JCR 20220.897 Q1 SJR 2022No data IDR 2022UECUE