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Un test delle urine per il cancro alla prostata potrebbe essere utilizzato a casa
I ricercatori dell’University of Vanderbilt e dell’University of Michigan hanno […]
Giornata mondiale contro il cancro, 12 tipi legati all'obesità
Oncologi,ma meno del 50% cittadini riceve consigli su stili vita
Chronic Migraine in Adults
This JAMA Insights explores the prevalence of episodic and chronic migraine in adults and acute and preventive treatments for migraine, such as novel calcitonin gene-related peptide receptor antagonists.
In Italia oltre 3,7 milioni di persone vivono con un tumore
Esperti, corretta comunicazione determinante in lotta al cancro. Si chiude la seconda edizione del corso di perfezionamento universitario promosso dall’Università Politecnica delle Marche
Systematic Review, Meta-Analysis, and Population Study to Determine the Biologic Sex Ratio in Dilated Cardiomyopathy
Circulation, Ahead of Print. BACKGROUND:Dilated cardiomyopathy (DCM) appears to be diagnosed twice as often in male than in female patients. This could be attributed to underdiagnosis in female patients or sex differences in susceptibility. Up to 30% of cases have an autosomal dominant monogenic cause, where equal sex prevalence would be expected. The aim of this systematic review, meta-analysis, and population study was to assess the sex ratio in patients with DCM, stratified by genetic status, and evaluate whether this is influenced by diagnostic bias.METHODS:A literature search identified DCM patient cohorts with discernible sex ratios. Exclusion criteria were studies with a small (n
Cell and Gene Therapies — Improving Access and Outcomes for Medicare and Medicaid Beneficiaries
New England Journal of Medicine, Ahead of Print.
Protocol for a randomised 'screen-and-treat Helicobacter pylori eradication trial in 14-18-years-old adolescents residing in three regions of Chile: effectiveness and microbiological host implications
Introduction
Gastric cancer is a major global health concern, being the final stage of a long-term process, primarily associated with Helicobacter pylori (H. pylori) infection. Early childhood acquisition of H. pylori with low spontaneous eradication rates underscores the need for preventive measures. Our previous pilot treatment study revealed high eradication rates, favourable tolerance profile and a decline in serum biomarkers indicative of gastric damage in asymptomatic school-aged children. The purpose of this study is to determine the potential benefit of a ‘screen-and-treat’ strategy targeting persistently infected, asymptomatic adolescents. Specific aims are to assess eradication efficacy, its clinical and molecular outcomes and potential clinical and microbiological side effects.
Methods and analysis
The screening phase will involve testing 500–1000 asymptomatic adolescents aged 14–18 from three cities in Chile using the urea breath test (UBT) to identify 210 participants with persistent infection. They will proceed to a randomised, non-blinded, controlled trial, receiving either a sequential eradication scheme for H. pylori or no treatment. Follow-up will span up to 24 months post-treatment, involving UBT, gastroenterological assessments and blood and stool sample collections. Concurrently, a subset of 60 uninfected adolescents will undergo matched follow-up. Enzyme-linked immunosorbent assay (ELISA) commercial kits will evaluate gastric damage biomarkers in serum (pepsinogen I and II, gastrin-17, VCAM-1, CXCL13). Stool samples will be employed for Escherichia coli and Enterococcus spp—culture, assessing AMR via the disk diffusion method. H. pylori clarithromycin resistance will be determined by molecular method from stool samples. The gut microbiome will be characterised by amplifying and sequencing the 16S rRNA gene from stool samples, followed by bioinformatics analysis.
Ethics and dissemination
Approved by the Human Research Ethics Committee at the Faculty of Medicine, University of Chile (073–2022). Findings will be disseminated in peer-reviewed journals and scientific meetings to guide future practices.
Trial registration number
NCT05926804.
Abstract TP307: Circulating immune cell landscape in ischemic stroke patients with early neurological deterioration
Stroke, Volume 56, Issue Suppl_1, Page ATP307-ATP307, February 1, 2025. Introduction:In this study, we investigated peripheral blood mononuclear cells (PBMCs) transcriptomics of patients who had a stroke using single-cell RNA sequencing (scRNA-seq) to understand peripheral immune response after Early neurological deterioration (END) based on the gene expression in an unbiased way.Methods:Transcriptomes of PBMCs from 5 patients who had END within 24 hours after stroke onset were compared with 5 race-matched/age- matched/gender-matched controls. Based on whether the patient experienced END and the timing before and after the occurrence of END, the samples were divided into four groups: END_T0, END_T1, Non-END_T0, and Non-END_T1.Results:A total of 20 peripheral blood PBMC samples were collected from patients with acute ischemic stroke before and after the occurrence of END. Compared with Non-END, the proportion of mononuclear macrophages in the peripheral blood of patients with END and the number of differential genes have significantly increased (P< 0.05). Further heterogeneity analysis of mononuclear macrophages revealed a cell subset C1Q+Mono that highly expresses C1QA. The proportion of this subset significantly increased before and after the occurrence of END (P< 0.05). Pseudotime analysis showed that its differentiation trajectory is different from that of classical mononuclear macrophages, and functional enrichment suggests it is related to the activation of inflammatory cells and the coagulation system.Conclusion:For the first time, our study constructed a peripheral blood immune landscape of acute ischemic stroke before and after the occurrence of END, as well as in Non-END cases, based on scRNA-seq. our study also identified a novel monocyte subpopulation, providing new insights into the immune regulation of END
Abstract TP301: Prevalence and In-Hospital Characteristics of Patients with Acute Ischemic Stroke and CADASIL
Stroke, Volume 56, Issue Suppl_1, Page ATP301-ATP301, February 1, 2025. Background:Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common hereditary stroke disorder due to pathogenic variants in the NOTCH3 gene on chromosome 19. Characteristics of CADASIL patients hospitalized with acute ischemic stroke (AIS) have not been widely reported.Methods:We identified all adult hospitalizations in the National Inpatient Sample (NIS) from 2018-2020 with diagnosis codes for acute ischemic stroke (ICD-10 I63) and the newly available code as of October 2018 for CADASIL (I67.850) using weighted sampling. Descriptive statistics evaluated demographic and clinical characteristics among AIS patients with and without CADASIL.Results:Of a total 1,918,920 weighted AIS hospitalizations, there were 300 patients with CADASIL. The prevalence of CADASIL among AIS patients increased from 0.2% in 2018 to 2.8% in 2020. AIS patients with CADASIL were similar in sex and more likely to be younger (55.8 ± 25.2 vs 69.7 ± 31.4 years, p
Abstract WMP111: Progranulin Enhances the Engraftment of Transplanted Human induced Pluripotent Stem Cell-derived Cerebral Neurons in Cell Replacement Therapy
Stroke, Volume 56, Issue Suppl_1, Page AWMP111-AWMP111, February 1, 2025. Background:Stroke or traumatic brain injury (TBI), due to damage to the cerebral motor cortex, often results in significant motor dysfunction and disabilities. Cell replacement therapy emerges as a prospective alternative treatment, promising to restore the impaired neural circuits and facilitate functional recovery. The current study aimed to systemically identify new factors capable of enhancing the efficacy of cell transplantation with human-induced pluripotent stem cell-derived cerebral organoids (hiPSC-COs). Earlier research demonstrated the effectiveness of delaying the transplantation procedure by 1 week and we hypothesized in this study that brain tissues 1 week after brain damage possess a more favorable environment for cell transplantation when compared to immediately after injury.Methods and Results:Using rodent models, we made a transcriptomic comparison to differentiate gene expression between these two temporal states in order to discern novel factors that could potentiate the therapeutic impact of cell transplantation. Ultimately, 7 candidate genes coding for secreted and extracellular proteins (apolipoprotein D, cathepsin D, cathepsin S, lysozyme 2, secreted phosphoprotein 1, granulin, and secreted protein acidic and cysteine rich) were selected through the transcriptome analysis. In controlled in vitro conditions, recombinant human progranulin (rhPGRN) bolstered the survival rate of dissociated neurons sourced from hiPSC-COs by approximately 25% under oxidative stress. Further experiments revealed that this increase in viability was attributable to a reduction in apoptosis via Akt phosphorylation. In addition, rhPGRN pretreatment before in vivo transplantation experiments augmented the number of engrafted cells about 3.3 times compared to the control group and facilitated neurite elongation along the host brain’s corticospinal tracts in rodent models. Subsequent histological assessments at 3 months post-transplantation revealed an elevated presence of graft-derived subcerebral projection neurons—crucial elements for reconstituting neural circuits—in the rhPGRN-treated group.Conclusion:Our data highlight the potential of PGRN as a neurotrophic factor suitable for incorporation into hiPSC-CO-based cell therapies for stroke or TBI.
Abstract 95: LILRB4 Inhibition Alleviates Ischemic Brain Injury by Reducing Microglial Necroptosis
Stroke, Volume 56, Issue Suppl_1, Page A95-A95, February 1, 2025. Objective:Microglia, the central nervous system’s immune cells, are crucial in neuroinflammation after ischemic brain injury. Previous single-cell and spatial transcriptomics showed that LILRB4 was upregulated in microglia after MCAO in C57BL/B6J mice, but its role is unclear. This study investigates LILRB4’s function and mechanism in ischemic injury.Methods:In C57BL/B6J mice, LILRB4 expression was analyzed at various time points post-MCAO using Q-PCR, Western blot, and flow cytometry. A microglia-specific LILRB4 knockout mouse model (LILRB4-cKO) and control mice (LILRB4fl/fl) were established, and MCAO was induced. Infarct volume and behavioral changes were assessed by MAP2 staining, mNSS scoring, grip strength, gait, and rotarod tests. qPCR and Western blot were used to detect brain inflammatory factors and DAMPs, while microglial morphology, cell counts, and RIPK3 levels were analyzed by immunofluorescence and flow cytometry. In vitro, LILRB4 expression changes post-OGD were validated, and LILRB4 knockdown BV2 cells (sh-LILRB4 BV2) were constructed. Necroptosis was induced using RIPK3 inhibitor and OGD, and necroptosis markers were detected. The JASPAR database was used to identify ATF2 as a potential RIPK3 transcription factor, and its role in gene regulation was validated by transfecting ATF2 plasmid into sh-LILRB4 BV2 cells.Results:LILRB4 expression in microglia was upregulated after MCAO, peaking at day 3. LILRB4-cKO mice showed larger infarct volumes, greater neurological deficits, and higher pro-inflammatory cytokines (TNF, IL-6, IL-1β) than LILRB4fl/flmice. Microglia from LILRB4-cKO mice had larger cell bodies, shorter processes, reduced numbers, and more RIPK3+necroptotic cells. In primary microglia and sh-LILRB4 BV2 cells, OGD increased LILRB4, RIPK3, MLKL, and cytokines, which were suppressed by GSK-872. The JASPAR database identified ATF-2 as a potential RIPK3 transcription factor, and its role in promoting RIPK3 transcription was confirmed. The JASPAR database identified ATF-2 as a potential RIPK3 transcription factor, and its role in promoting RIPK3 transcription was confirmed. Knockdown of ATF-2 reduced the elevated levels of inflammatory cytokines, DAMPs, and necroptosis markers induced by LILRB4 deletion.Conclusion:LILRB4 inhibits microglial necroptosis through the ATF2/RIPK3 pathway, reducing neuroinflammation and offering neuroprotection. Therefore, LILRB4 may serve as a potential therapeutic target for ischemic brain injury
Abstract TMP71: Delineating the Evolution of the Immune Response in Peripheral Blood, Hematoma and Peri-hematomal Brain of Intracerebral Hemorrhage Patients
Stroke, Volume 56, Issue Suppl_1, Page ATMP71-ATMP71, February 1, 2025. Background:Intracerebral hemorrhage (ICH) is the second most prevalent type of stroke, but carries the greatest degree of mortality and morbidity. In addition to the primary injury due to mechanical stress and mass effect on adjacent brain regions, uncontrolled inflammation in the peri-hematomal area constitutes a secondary insult that can exacerbate tissue damage, leading to cerebral edema, neuronal death, and thus worse clinical outcomes. Prior efforts at controlling ICH-related inflammation reported mixed outcomes, likely reflecting our poor understanding of the evolving inflammatory cascade following ICH. In this investigation we sought to better characterize the cellular immune response in the acute period following ICH.Methods:Surgical candidates for minimally invasive hematoma evacuation were approached for participation in this study. We collected evacuated clots, and small biopsies from peri-hematomal brain, and matched peripheral blood immediately preceding surgical evacuation, and on days 1, 3, and 5-7 post-surgery. We then isolated all immune cells from each compartment and performed transcriptomic profiling by single cell RNA-sequencing, from 6 patients operated on at time points ranging from 4 to 29 hours after time of last known well.Results:Data from 5 male and 1 female patient 46-79 years old are reported. Our data analyses showed an evolving inflammatory cascade consisting primarily of neutrophils and macrophages that is very similar in the blood and clot compartments. Importantly, the time elapsed between ICH incidence and surgical evacuation is positively correlated with the emergence of an inflammatory osteopontin-expressing macrophage population in the blood clot, and a unique microglial signature in the peri-hematomal brain. We also found that the presence of a fibrin-laden blood clot in the brain initiates an early and evolving gene signature in neutrophils and microglia in the brain parenchyma, that is distinct from the inflammatory responses identified in peripheral blood.Conclusions:Our findings show that rapid surgical evacuation of the hematoma within the first 4-5 hours limits the inflammatory insult, and highlight key immune cell populations involved in the inflammatory response post-ICH. We also identified key pathways driving these inflammatory responses, thereby providing novel potential therapeutic targets for patients with ICH.
Abstract TMP88: Clinical Utility of Genetic Testing in Pediatric and Young Adult Hemorrhagic Stroke and Cerebrovascular Malformations
Stroke, Volume 56, Issue Suppl_1, Page ATMP88-ATMP88, February 1, 2025. Introduction:Pediatric and young adult cerebrovascular disease is more commonly associated with genetic conditions compared to in adults. This pilot study aims to characterize utility of genetic testing in a pediatric and young adult neurovascular clinic.Methods:This was a single center cohort study of pediatric and young adult patients (age
Abstract TP336: Neuropathological changes in the chronic phase of ischemic stroke are marked by persistent alteration of microglial function and neurodegenerative phenotypes
Stroke, Volume 56, Issue Suppl_1, Page ATP336-ATP336, February 1, 2025. Improvements in acute stroke treatment, including EVT and critical care management, have increased survival rates post-stroke. However, many stroke survivors have significant post-stroke disability and cognitive impairment. Despite this, the chronic progression and long-term sequelae of ischemic stroke pathology remains understudied.Methods:We examined the chronicity of neurobehavioral recovery and progressive neuropathology in young male (3 month) and middle-aged male and female (14 month) C57Bl/6 mice at 3 and 6 months after a 60-minute transient middle cerebral artery occlusion (tMCAO) or sham surgery (n = 10-20/group). Behavioral testing included NORT, fear conditioning (FC), and tail suspension. Immunohistochemistry (IHC) was performed on mouse brains, as well as post-mortem human brain samples from patients with a chronic infarct (n = 6/group), to assess demyelination (MBP), neuronal apoptosis (TUNEL/NeuN), and amyloid burden (Aβ-42). Flow cytometry was performed on the ipsilateral mouse brain hemisphere. RNA isolated from the ipsilateral hemisphere was sent for gene profiling.Results:In both young and middle-aged mice, depressive-like behavior persisted for 6 months post-stroke (PS) (p=
Abstract TMP51: Association between genetic variation and acute stroke characteristics
Stroke, Volume 56, Issue Suppl_1, Page ATMP51-ATMP51, February 1, 2025. Introduction:Strokes lead to acute deficits with wide-ranging severity. Genetic variation may explain some of these inter-subject differences. The current report examined the relationship that candidate genetic variants have with acute injury and acute behavioral deficits. We hypothesized that variants known to be associated with poorer stroke recovery would also be associated with more a severe acute presentation.Methods:Infarcts were outlined on clinical scans acquired during acute stroke admission as part of the STRONG (“Stroke, sTress, RehabilitatiON, and Genetics”) study and resampled to MNI152 brain standard space. Multivariable linear regression modeling was used to examine association with genetic measures known to be related to stroke outcome: 3 single nucleotide polymorphisms (SNPs): BDNF (rs6265), ACE (rs4291), and FAAH (rs324420), plus ApoE e4 and ApoE e2; a dopamine polygene score was also explored. Acute injury (infarct volume) and acute deficits (NIHSS score, grip strength, and acute stress disorder inventory (ASDI)) were each examined as the dependent measure in separate models that used age, gender, and ancestry as covariates. To understand where in the brain these relationships occurred, voxel lesion symptom mapping (VLSM) was used to test for associations between acute injury and each genetic measure.Results:In 448 subjects (age 63.4±14.4 yr (mean±SD), 43.1% females), lesion volume ranged from 0.46 to 535.13 cc and involved cortical grey matter in 63% of patients. Larger lesion volume was associated with presence of the ACE SNP (β=8.77, p=0.03); lower NIHSS score, with ApoE e4 (β=-1.69, p=0.04); greater grip strength, with ApoE e2 SNPs (β=6.78, p=0.03); and higher ASDI, with the ACE SNP (β=0.56, p=0.05). VLSM revealed that acute injury to the postcentral gyrus was significantly more likely in the presence of the ACE SNP (z=-3.5), and that acute injury to the calcarine fissure was significantly more likely in the presence of the BDNF SNP (z=-2.53).Conclusions:Genetic variants known to be associated with differences in stroke recovery are also related to acute stroke deficits and injury. In particular, a common variant in the gene for ACE was associated with differences in lesion volume and location, findings that may suggest a personalized medicine approach to acute therapy. Measures of genetic variability may be useful to understand inter-subject differences in acute injury and symptom severity, and may have therapeutic implications.