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A recent study showed that antlers have evolved a high rate of growth due to the expression of proto-oncogenes and that they have also evolved to express several tumour suppressor genes to control the risk of cancer. This may explain why deer antler velvet (DAV) extract shows anti-tumour activity. The fast growth of antler innervation through the velvet in close association to blood vessels provides a unique environment to study the fast but non-cancerous proliferation of heterogeneous cell populations. We set out to study the anti-cancer effect of DAV in glioblastoma (GB) cell lines in comparison with temozolomide, a chemotherapeutic drug used to treat high-grade brain tumours. Here we report, for the first time, that DAV extract from the tip, but not from mid-parts of the antler, exhibits an anti-tumour effect in GB cell lines (T98G and A172) while being non-toxic in non-cancerous cell lines (HEK293 and HACAT). In T98G cells, DAV treatment showed reduced proliferation (37.5%) and colony-formation capacity (84%), inhibited migration (39%), induced changes in cell cycle progression, and promoted apoptosis. The anticancer activity of DAV extract as demonstrated by these results may provide a new therapeutic strategy for GB treatment.

Chemotherapy for high-grade astrocytic tumors is mainly based on the use of temozolomide (TMZ), whose efficacy is limited by resistance mechanisms. Despite many investigations pointing to O 6-methylguanine-DNA-methyltransferase (MGMT) as being responsible for tumor chemo-resistance, its expression does not predict an accurate response in most gliomas, suggesting that MGMT is not the only determinant of response to treatment. In this sense, several reports indicate that N -methylpurine-DNA-glycosylase (MPG) may be involved in that resistance. With that in mind, we evaluated for the first time the degree of resistance to TMZ treatment in 18 patient-derived glioma cells and its association with MGMT and MPG mRNA levels. Viability cell assays showed that TMZ treatment hardly caused growth inhibition in the patient-derived cells, even in high concentrations, indicating that all primary cultures were chemo-resistant. mRNA expression analyses showed that the TMZ-resistant phenotype displayed by cells is associated with an elevated expression of MPG to a greater extent than it is with transcript levels of MGMT. Our findings suggest that not only is MGMT implicated in resistance to TMZ but MPG, the first enzyme in base excision repair processing, is also involved, supporting its potential role as a target in anti-resistance chemotherapy for astrocytoma and glioblastoma.

Uric acid is an antioxidant with neuroprotective effects in experimental models of stroke. We assessed whether uric acid therapy would improve functional outcomes at 90 days in patients with acute ischaemic stroke. URICO-ICTUS was a randomised, double-blind, placebo-controlled, phase 2b/3 trial that recruited patients with acute ischaemic stroke admitted to ten Spanish stroke centres. Patients were included if they were aged 18 years or older, had received alteplase within 4·5 h of symptom onset, and had an eligible National Institutes of Health Stroke Scale (NIHSS) score (>6 and ≤25) and premorbid (assessed by anamnesis) modified Rankin Scale (mRS) score (≤2). Patients were randomly allocated (1:1) to receive uric acid 1000 mg or placebo (both infused intravenously in 90 min during the infusion of alteplase), stratified by centre and baseline stroke severity. The primary outcome was the proportion of patients with excellent outcome (ie, an mRS score of 0–1, or 2 if premorbid score was 2) at 90 days, analysed in the target population (all randomly assigned patients who had been correctly diagnosed with ischaemic stroke and had begun study medication). The study is registered with ClinicalTrials.gov, number NCT00860366. Between July 1, 2011, and April 30, 2013, we randomly assigned 421 patients, of whom 411 (98%) were included in the target population (211 received uric acid and 200 received placebo). 83 (39%) patients who received uric acid and 66 (33%) patients who received placebo had an excellent outcome (adjusted risk ratio 1·23 [95% CI 0·96–1·56]; p=0·099). No clinically relevant or statistically significant differences were reported between groups with respect to death (28 [13%] patients who received uric acid vs 31 [16%] who received placebo), symptomatic intracerebral haemorrhage (nine [4%] vs six [3%]), and gouty arthritis (one [<1%] vs four [2%]). 516 adverse events occurred in the uric acid group and 532 in the placebo group, of which 61 (12%) and 67 (13%), respectively, were serious adverse events (p=0·703). The addition of uric acid to thrombolytic therapy did not increase the proportion of patients who achieved excellent outcome after stroke compared with placebo, but it did not lead to any safety concerns. Institute of Health Carlos III of the Spanish Ministry of Health and Fundación Doctor Melchor Colet.

Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86–1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events. Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke. Ferrer Grupo.

The irruption of SARS-CoV-2 during 2020 has been of pandemic proportions due to its rapid spread and virulence. COVID-19 patients experience respiratory, digestive and neurological symptoms. Distinctive symptom as anosmia, suggests a potential neurotropism of this virus. Amongst the several pathways of entry to the nervous system, we propose an alternative pathway from the infection of the gut, involving Toll-like receptor 4 (TLR4), zonulin, protease-activated receptor 2 (PAR2) and zonulin brain receptor. Possible use of zonulin antagonists could be investigated to attenuate neurological manifestations caused by SARS-CoV-19 infection.

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative motor neuron disease. Although an early diagnosis is crucial to provide adequate care and improve survival, patients with ALS experience a significant diagnostic delay. This study aimed to use real-world data to describe the clinical profile and timing between symptom onset, diagnosis, and relevant outcomes in ALS. Retrospective and multicenter study in 5 representative hospitals and Primary Care services in the SESCAM Healthcare Network (Castilla-La Mancha, Spain). Using Natural Language Processing (NLP), the clinical information in electronic health records of all patients with ALS was extracted between January 2014 and December 2018. From a source population of all individuals attended in the participating hospitals, 250 ALS patients were identified (61.6% male, mean age 64.7 years). Of these, 64% had spinal and 36% bulbar ALS. For most defining symptoms, including dyspnea, dysarthria, dysphagia and fasciculations, the overall diagnostic delay from symptom onset was 11 (6–18) months. Prior to diagnosis, only 38.8% of patients had visited the neurologist. In a median post-diagnosis follow-up of 25 months, 52% underwent gastrostomy, 64% non-invasive ventilation, 16.4% tracheostomy, and 87.6% riluzole treatment; these were more commonly reported (all Ps < 0.05) and showed greater probability of occurrence (all Ps < 0.03) in bulbar ALS. Our results highlight the diagnostic delay in ALS and revealed differences in the clinical characteristics and occurrence of major disease-specific events across ALS subtypes. NLP holds great promise for its application in the wider context of rare neurological diseases.

ObjectiveThere has been limited systematic evaluation of outcomes and drivers of inappropriate non-vitamin K antagonist oral anticoagulants (NOACs) dosing among patients with atrial fibrillation (AF). This review identified and systematically evaluated literature on clinical and economic outcomes of inappropriate NOAC dosing and associated patient characteristics.MethodsMEDLINE, Embase, Cochrane Library, International Pharmaceutical Abstracts, Econlit, PubMed and NHS EEDs databases were searched for English language observational studies from all geographies published between 2008 and 2020, examining outcomes of, or factors associated with, inappropriate NOAC dosing in adult patients with AF.ResultsOne hundred and six studies were included in the analysis. Meta-analysis showed that compared with recommended NOAC dosing, off-label underdosing was associated with a null effect on stroke outcomes (ischaemic stroke and stroke/transient ischaemic attack (TIA), stroke/systemic embolism (SE) and stroke/SE/TIA). Meta-analysis of 15 studies examining clinical outcomes of inappropriate NOAC dosing found a null effect of underdosing on bleeding outcomes (major bleeding HR=1.04, 95% CI 0.90 to 1.19; p=0.625) but an increased risk of all-cause mortality (HR=1.28, 95% CI 1.10 to 1.49; p=0.006). Overdosing was associated with an increased risk of major bleeding (HR=1.41, 95% CI 1.07 to 1.85; p=0.013). No studies were found examining economic outcomes of inappropriate NOAC dosing. Narrative synthesis of 12 studies examining drivers of inappropriate NOAC dosing found that increased age, history of minor bleeds, hypertension, congestive heart failure and low creatine clearance (CrCl) were associated with an increased risk of underdosing. There was insufficient evidence to assess drivers of overdosing.ConclusionsOur analysis suggests that off-label underdosing of NOACs does not reduce bleeding outcomes. Patients prescribed off-label NOAC doses are at an increased risk of all-cause mortality. These data underscore the importance of prescriber adherence to NOAC dosing guidelines to achieve optimal clinical outcomes for patients with AF.PROSPERO registration numberCRD42020219844.

The mechanisms by which tumor-associated macrophages, key components of the glioblastoma (GBM) microenvironment, impair chemotherapy efficacy remain poorly understood. Resistance to temozolomide (TMZ), the standard chemotherapeutic agent for GBM, is associated with poor prognosis due to efficient DNA repair mechanisms. While low expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) has been linked to improved TMZ response, our previous findings suggest that N-methylpurine-DNA glycosylase (MPG) may also contribute to chemoresistance in GBM. Here, we report for the first time that conditioned medium from pro-inflammatory macrophages (CM-M1) enhances TMZ cytotoxicity by suppressing STAT3 phosphorylation, resulting in decreased MGMT and MPG expression in GBM cells. Proteomic profiling of CM-M1 revealed a unique, cytokine-rich secretome that may promote STAT1 activation, thereby inhibiting pSTAT3 and reducing DNA repair enzymes levels. Clinically, elevated MGMT and MPG protein levels were associated with increased pSTAT3 in our GBM patient cohort, and analysis of the TCGA database further showed that their combined overexpression correlates with significantly reduced progression-free survival. Gene silencing experiments confirmed the contribution of both enzymes to TMZ resistance, with dual knockdown producing a synergistic sensitizing effect. These findings uncover a novel mechanism of macrophage secretome–mediated chemoresistance and support the development of M1-based strategies to improve TMZ efficacy in GBM.

Accurate etiological diagnosis ensures appropriate secondary prevention of ischemic stroke (IS) patients. However, about 25–40% of IS cases remain of undetermined origin (referred to as ESUS if an unknown embolic source is suspected), highlighting the need to improve diagnostic precision. To identify potential biomarkers of IS etiologies, we analyzed the transcriptomic content of extracellular vesicles (EVs) from thrombi obtained after thrombectomy, including patients with cardioembolic (CE, n  = 10), atherothrombotic (AT, n  = 10) and ESUS ( n  = 10) IS (discovery cohort). mRNA levels of those differentially expressed genes in thrombus EVs were determined in microvascular brain endothelial cells after stimulation, revealing PECAM-1, as the most promising candidate. Next, PECAM-1 levels were determined in thrombi ( n  = 65) and serum samples ( n  = 95) of an independent validation cohort of IS patients, using immunohistochemistry and ELISA respectively. The transcriptome profiling and bioinformatics analysis revealed 1,514 gene transcripts in thrombus EVs, of which 114 were differentially expressed in AT vs CE etiologies. The genes upregulated in EVs from CE thrombi were enriched in pathways related to cell surface interactions at the vascular wall, leukocyte migration and neutrophil degranulation. Consistent with the increased PECAM-1 expression in thrombus EVs from CE vs AT etiologies, the endothelial expression of PECAM-1 increased after thrombin exposure and diminished upon atherogenic stimulation (oxLDL and TNFα). Moreover, thrombus expression of PECAM-1 was localized predominantly in platelet rich areas containing or surrounded by inflammatory cells and fibrin, and was higher in CE stroke thrombi. Serum levels of PECAM-1 were associated [OR (95%CI) 1.52 (1.14–2.03), p  = 0.004] with the severity of stroke at Hospital admission. These findings collectively suggest that the transcriptional study of thrombus EVs may be useful to unravel the molecular pathways behind thrombus formation, and to explore local biological differences between IS etiologies. Specifically, PECAM-1, an adhesion molecule implicated in immuno-inflammatory processes, was increased in thrombi EVs and thrombi of patients with CE IS. Regarding the use of PECAM-1 as systemic biomarker, it did not discriminate IS etiologies, but was positively correlated with worse neurological outcome, suggesting a possible role of PECAM-1 in processes leading to brain injury post-IS.

Despite the efficacy and safety of SARS-CoV-2 vaccines, inflammatory and/or thrombotic episodes have been reported. Since the impact of COVID-19 vaccines on the endothelium remains uncertain, our objective was to assess endothelial activation status before and 90 days after the third dose of the BNT162b2 mRNA COVID-19 vaccine. A prospective longitudinal study was conducted at University General Hospital of Albacete, involving 38 healthy health-care workers. Serum levels of endothelial markers (endocan and sVCAM-1) and spike S1-specific IgG antibodies were determined before and at 7, 15, 24 and 90days following vaccination. To analyze each participant´s individual response, we calculated relative increases/decreases (delta values) in endothelial markers and antibodies concentrations compared to their pre-vaccination levels. We identified two significantly distinct profiles of endothelial markers response, characterized by either increased or decreased serum levels of endocan and sVCAM. Incremental and decremental response groups did not differ in terms of age, sex, cardiovascular risk factors, previous SARS-CoV-2 infection and influenza vaccine co-administration. However, these responses were significantly associated with the relative spike-specific antibody production. Specifically, the greatest relative increase in antibodies was found in the decremental responders. Additionally, the higher delta antibody production was observed in non-previously infected individuals. Administration of the BNT162b2 booster vaccine triggered a non-homogenous response of endothelial function markers among the study participants. Our findings improve the understanding of individual responses to the mRNA COVID-19 booster vaccine, which could be useful in assessing the need for booster doses, particularly in population at risk of vascular complications.