Study protocol for investigating the clinical performance of an automated blood test for glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 blood concentrations in elderly patients with mild traumatic BRAIN Injury and reference values (BRAINI-2 Elderly European study): a prospective multicentre observational study.

INTRODUCTION: Two blood brain-derived biomarkers, glial fibrillar acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), can rule out intracranial lesions in patients with mild traumatic brain injury (mTBI) when assessed within the first 12 hours. Most elderly patients were excluded from previous studies due to comorbidities. Biomarker use in elderly population could be affected by increased basal levels. This study will assess the performance of an automated test for measuring serum GFAP and UCH-L1 in elderly patients to predict the absence of intracranial lesions on head CT scans after mTBI, and determine both biomarkers reference values in a non-TBI elderly population. METHODS AND ANALYSIS: This is a prospective multicentre observational study on elderly patients (≥65 years) that will be performed in Spain, France and Germany. Two patient groups will be included in two independent substudies. (1) A cohort of 2370 elderly patients (1185<80 years and 1185≥80 years; BRAINI2-ELDERLY DIAGNOSTIC AND PROGNOSTIC STUDY) with mTBI and a brain CT scan that will undergo blood sampling within 12 hours after mTBI. The primary outcome measure is the diagnostic performance of GFAP and UCH-L1 measured using an automated assay for discriminating between patients with positive and negative findings on brain CT scans. Secondary outcome measures include the performance of both biomarkers in predicting early (1 week) and midterm (3 months) neurological status and quality of life after trauma. (2) A cohort of 480 elderly reference participants (BRAINI2-ELDERLY REFERENCE STUDY) in whom reference values for GFAP and UCHL1 will be determined. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Institutional Review Boards of Hospital 12 de Octubre in Spain (Re#22/027) and Southeast VI (Clermont Ferrand Hospital) (Re# 22.01782.000095) in France. The study's results will be presented at scientific meetings and published in peer-review publications. TRIAL REGISTRATION NUMBER: NCT05425251.

TGF-ß Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma.

Glioma-initiating cells (GICs), also called glioma stem cells, are responsible for tumor initiation, relapse, and therapeutic resistance. Here, we show that TGF-ß inhibitors, currently under clinical development, target the GIC compartment in human glioblastoma (GBM) patients. Using patient-derived specimens, we have determined the gene responses to TGF-ß inhibition, which include inhibitors of DNA-binding protein (Id)-1 and -3 transcription factors. We have identified a cell population enriched for GICs that expresses high levels of CD44 and Id1 and tend to be located in a perivascular niche. The inhibition of the TGF-ß pathway decreases the CD44(high)/Id1(high) GIC population through the repression of Id1 and Id3 levels, therefore inhibiting the capacity of cells to initiate tumors. High CD44 and Id1 levels confer poor prognosis in GBM patients.

[Matrix metaloproteinases in neurological brain lesions: a new therapeutic target?]. / Metaloproteinasas de matriz en las lesiones neurológicas: ¿una nueva diana terapéutica?

INTRODUCTION: Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade the extracellular matrix and are found in a large amount of human tissues. Their main functions are to maintain the integrity of the extracellular matrix, to modulate the interaction of the cells during development, to contribute to tissue remodeling, to directly participate in angiogenesis and to facilitate cellular migration. Due to the importance of its maintaining extracellular matrix function, MMP expression is tightly regulated at transcriptional level, through proform activation and with the binding to tissular inhibitors. Despite this complex regulation system, MMP regulation can be altered, producing an overexpression of these proteolytic proteins that alter the tissular structure, possibly destroying the tissue, as observed in some neurologic pathologies such as multiple sclerosis, aneurism formation and cerebral ischemia. The role that MMP have in traumatic brain lesions is almost unknown and is derived mainly from in vivo and in vitro experimental studies, and only from three papers performed in humans. There are some experimental studies that relate the brain alterations produced after traumatic brain injury with an increase in the concentration of various MMP. AIM: To review the role of these proteases in human brain lesions, emphasizing on the function of these proteases in traumatic brain injury lesions and their possible therapeutic target. DEVELOPMENT: A bibliographic search was performed on Medline database. CONCLUSIONS: Some MMP could be related to blood-brain barrier alteration and postraumatic edema formation, turning them into promising therapeutic targets.

TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma.

Glioma-initiating cells (GICs) are responsible for the initiation and recurrence of gliomas. Here, we identify a molecular mechanism that regulates the self-renewal capacity of patient-derived GICs. We show that TGF-beta and LIF induce the self-renewal capacity and prevent the differentiation of GICs. TGF-beta induces the self-renewal capacity of GICs, but not of normal human neuroprogenitors, through the Smad-dependent induction of LIF and the subsequent activation of the JAK-STAT pathway. The effect of TGF-beta and LIF on GICs promotes oncogenesis in vivo. Some human gliomas express high levels of LIF that correlate with high expression of TGF-beta2 and neuroprogenitor cell markers. Our results show that TGF-beta and LIF have an essential role in the regulation of GICs in human glioblastoma.

Neuroprotection in malignant MCA infarction.

Massive unilateral hemispheric infarction often develops progressive postischemic edema that leads to a malignant course of stroke with mortality of up to 80% with conventional medical therapies. Hypothermia and decompressive hemicraniectomy have shown neuroprotective effects in several animal models of focal transient and permanent MCA occlusion by reducing infarct size and improving neurological outcome. Our aim in this paper was to review the possible mechanisms of both therapies as well as the optimal time window and duration of application of each treatment in animal model and in human malignant MCA infarction reported in the literature.