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1.
Nucleic Acids Res ; 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38860430

RESUMEN

The abnormal GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause the fatal neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. The transcribed RNA HREs, short for r(G4C2)n, can form toxic RNA foci which sequestrate RNA binding proteins and impair RNA processing, ultimately leading to neurodegeneration. Here, we determined the crystal structure of r(G4C2)2, which folds into a parallel tetrameric G-quadruplex composed of two four-layer dimeric G-quadruplex via 5'-to-5' stacking in coordination with a K+ ion. Notably, the two C bases locate at 3'- end stack on the outer G-tetrad with the assistance of two additional K+ ions. The high-resolution structure reported here lays a foundation in understanding the mechanism of neurological toxicity of RNA HREs. Furthermore, the atomic details provide a structural basis for the development of potential therapeutic agents against the fatal neurodegenerative diseases ALS/FTD.

2.
Stroke Vasc Neurol ; 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38889918

RESUMEN

BACKGROUND: Hypertension is widely acknowledged as a significant contributory factor to the heightened risk of intracranial aneurysm rupture. Nevertheless, the impact of hypertension management on the outcomes subsequent to aneurysmal subarachnoid haemorrhage (aSAH), particularly concerning the severity of aSAH, remains an underexplored area. METHODS: We conducted a retrospective analysis using data from a prospectively multicentre cohort of 4545 patients with aSAH in China. Premorbid hypertension status and the utilisation of antihypertensive medications prior to admission were set as key exposure factors. The primary outcomes encompassed unfavourable clinical grading scales observed on admission. Employing multivariable logistic regression, we explored the association between premorbid hypertension status, preadmission use of renin-angiotensin-aldosterone system (RAAS) inhibitors and unfavourable clinical grading scales. RESULTS: In comparison to patients with normal blood pressure, only uncontrolled hypertension demonstrated a significant and independent association with an elevated risk of poor outcomes on the Hunt-Hess scale (OR=1.799, 95% CI 1.413 to 2.291, p<0.001) and the World Federation of Neurological Surgeons (WFNS) scale (OR=1.721, 95% CI 1.425 to 2.079, p<0.001). Furthermore, the antecedent use of RAAS inhibitors before admission was markedly and independently linked to a diminished risk of adverse outcomes on the Hunt-Hess scale (OR=0.653, 95% CI 0.430 to 0.992, p=0.046) and the WFNS scale (OR=0.656, 95% CI 0.469 to 0.918, p=0.014). CONCLUSIONS: Uncontrolled hypertension markedly elevates the risk of adverse clinical outcomes following an aSAH. Conversely, the preadmission utilisation of RAAS inhibitors demonstrates a noteworthy association with a favourable clinical outcome after aSAH.

3.
Signal Transduct Target Ther ; 9(1): 142, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38825657

RESUMEN

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Endopeptidasas/genética , Células 3T3 NIH , Radiofármacos/uso terapéutico , Serina Endopeptidasas/genética , Serina Endopeptidasas/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Inmunoterapia , Gelatinasas/genética , Gelatinasas/inmunología , Lutecio/farmacología , Línea Celular Tumoral
4.
iScience ; 27(6): 110006, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38868202

RESUMEN

Apolipoprotein E (apoE) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Microglia exhibit a substantial upregulation of apoE in AD-associated circumstances, despite astrocytes being the primary source of apoE expression and secretion in the brain. Although the role of astrocytic apoE in the brain has been extensively investigated, it remains unclear that whether and how apoE particles generated from astrocytes and microglia differ in biological characteristic and function. Here, we demonstrate the differences in size between apoE particles generated from microglia and astrocytes. Microglial apoE particles impair neurite growth and synapses, and promote neuronal senescence, whereas depletion of GPNMB (glycoprotein non-metastatic melanoma protein B) in microglial apoE particles mitigated these deleterious effects. In addition, human APOE4-expressing microglia are more neurotoxic than APOE3-bearing microglia. For the first time, these results offer concrete evidence that apoE particles produced by microglia are involved in neuronal senescence and toxicity.

5.
ACS Biomater Sci Eng ; 10(5): 3069-3085, 2024 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-38578110

RESUMEN

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Drug delivery to the brain through the blood-brain barrier (BBB) is a significant challenge in PD treatment. Exosomes, which can efficiently traverse the BBB, which many drugs cannot penetrate, are ideal natural carriers for drug delivery. In this study, the BBB shuttle peptide was modified on the exosome surfaces. Three types of exosomes were constructed, each modified with a distinct peptide (RVG29, TAT, or Ang2) and loaded with miR-133b. The safety and brain-targeting capabilities of these peptide-modified exosomes were then evaluated. Finally, the mechanism by which RVG29-Exo-133b regulates the RhoA-ROCK signaling pathway was investigated. The findings indicate that the three peptide-modified exosomes were adequately tolerated, safe, and effectively assimilated in vivo and ex vivo, with RVG29 exhibiting superior targeting to the brain. Furthermore, RVG29-Exo-133b decreased the phosphorylation level of the Tau protein by targeting the RhoA-ROCK signaling pathway. It also enhanced the motor function in mice with PD, thereby reducing the degree of depression, improving dopaminergic neuron function, and attenuating 6-OHDA-induced nerve damage. In this study, we developed a stable drug delivery mechanism that targets the intracerebral region using exosomes. Furthermore, a novel strategy was developed to manage PD and can potentially serve as a preclinical basis for utilizing exosomes in the diagnosis and treatment of neurodegenerative conditions.


Asunto(s)
Exosomas , MicroARNs , Enfermedad de Parkinson , Transducción de Señal , Quinasas Asociadas a rho , Proteína de Unión al GTP rhoA , Exosomas/metabolismo , Animales , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/genética , MicroARNs/metabolismo , MicroARNs/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Proteína de Unión al GTP rhoA/metabolismo , Proteína de Unión al GTP rhoA/genética , Ratones , Masculino , Ratones Endogámicos C57BL , Humanos , Péptidos/metabolismo , Barrera Hematoencefálica/metabolismo
6.
EPMA J ; 15(1): 53-66, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38463627

RESUMEN

Background/aims: The reciprocal promotion of cancer and stroke occurs due to changes in shared risk factors, such as metabolic pathways and molecular targets, creating a "vicious cycle." Cancer plays a direct or indirect role in the pathogenesis of ischemic stroke (IS), along with the reactive medical approach used in the treatment and clinical management of IS patients, resulting in clinical challenges associated with occult cancer in these patients. The lack of reliable and simple tools hinders the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) approach. Therefore, we conducted a multicenter study that focused on multiparametric analysis to facilitate early diagnosis of occult cancer and personalized treatment for stroke associated with cancer. Methods: Admission routine clinical examination indicators of IS patients were retrospectively collated from the electronic medical records. The training dataset comprised 136 IS patients with concurrent cancer, matched at a 1:1 ratio with a control group. The risk of occult cancer in IS patients was assessed through logistic regression and five alternative machine-learning models. Subsequently, select the model with the highest predictive efficacy to create a nomogram, which is a quantitative tool for predicting diagnosis in clinical practice. Internal validation employed a ten-fold cross-validation, while external validation involved 239 IS patients from six centers. Validation encompassed receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and comparison with models from prior research. Results: The ultimate prediction model was based on logistic regression and incorporated the following variables: regions of ischemic lesions, multiple vascular territories, hypertension, D-dimer, fibrinogen (FIB), and hemoglobin (Hb). The area under the ROC curve (AUC) for the nomogram was 0.871 in the training dataset and 0.834 in the external test dataset. Both calibration curves and DCA underscored the nomogram's strong performance. Conclusions: The nomogram enables early occult cancer diagnosis in hospitalized IS patients and helps to accurately identify the cause of IS, while the promotion of IS stratification makes personalized treatment feasible. The online nomogram based on routine clinical examination indicators of IS patients offered a cost-effective platform for secondary care in the framework of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00354-8.

7.
JMIR Pediatr Parent ; 7: e46813, 2024 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-38526553

RESUMEN

BACKGROUND: After the implementation of 2- and 3-child policies, the rising proportion of high-age and high-risk pregnancies put enormous pressure on maternal and child health (MCH) services for China. This populous nation with an increasing population flow imperatively required the support of large-scale information systems for management. Municipal MCH information systems were commonly applied in developed cities of eastern provinces in China. However, implementation of provincial MCH information systems in relatively low-income areas is lacking. In 2020, the implementation of a regional maternal and child information system (RMCIS) in Inner Mongolia filled this gap. OBJECTIVE: This paper aimed to demonstrate the construction process and evaluate the implementation effect of an RMCIS in improving the regional MCH in Inner Mongolia. METHODS: We conducted a descriptive study for the implementation of an RMCIS in Inner Mongolia. Based on the role analysis and information reporting process, the system architecture design had 10 modules, supporting basic health care services, special case management, health support, and administration and supervision. Five-color management was applied for pregnancy risk stratification. We collected data on the construction cost, key characteristics of patients, and use count of the main services from January 1, 2020, to October 31, 2022, in Inner Mongolia. Descriptive analysis was used to demonstrate the implementation effects of the RMCIS. RESULTS: The construction and implementation of the RMCIS cost CNY 8 million (US $1.1 million), with a duration of 13 months. Between 2020 and 2022, the system recorded 221,772 registered pregnant women, with a 44.75% early pregnancy registry rate and 147,264 newborns, covering 278 hospitals and 225 community health care centers in 12 cities. Five-color management of high-risk pregnancies resulted in 76,975 (45.45%) pregnancies stratified as yellow (general risk), 36,627 (21.63%) as orange (relatively high risk), 156 (0.09%) as red (high risk), and 3888 (2.30%) as purple (infectious disease). A scarred uterus (n=28,159, 36.58%), BMI≥28 (n=14,164, 38.67%), aggressive placenta praevia (n=32, 20.51%), and viral hepatitis (n=1787, 45.96%) were the top factors of high-risk pregnancies (yellow, orange, red, and purple). In addition, 132,079 pregnancies, including 65,018 (49.23%) high-risk pregnancies, were registered in 2022 compared to 32,466 pregnancies, including 21,849 (67.30%) high-risk pregnancies, registered in 2020. CONCLUSIONS: The implementation of an RMCIS in Inner Mongolia achieved the provincial MCH data interconnection for basic services and obtained both social and economic benefits, which could provide valuable experience to medical administration departments, practitioners, and medical informatics constructors worldwide.

8.
Int J Surg ; 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38445521

RESUMEN

BACKGROUND: Early assessment and management of cerebral edema and hematoma following aneurysmal subarachnoid hemorrhage (a-SAH) can significantly impact clinical cognitive outcomes. However, current clinical practices lack predictive models to identify early structural brain abnormalities affecting cognition. To address this gap, we propose the development of a predictive model termed the a-SAH Early Brain Edema/Hematoma Compression Neural (Structural Brain) Networks Score System (SEBE-HCNNSS). METHODS: In this study, 202 consecutive patients with spontaneous a-SAH underwent initial computed tomography (CT) or magnetic resonance imaging (MRI) scans within 24 hours of ictus with follow-up 2 months after discharge. Using logistic regression analysis (univariate and multivariate), we evaluated the association of clinically relevant factors and various traditional scale ratings with cognitive impairment (CI). Risk factors with the highest area under the curve (AUC) values were included in the multivariate analysis and least absolute shrinkage and selection operator (LASSO) analysis or Cox regression analysis. RESULTS: A total of 177 patients were enrolled in the study, and 43 patients were classified with a high SEBE-HCNNSS grade (3 to 5). After a mean follow-up of 2 months, 121 individuals (68.36%) with a-SAH and 3 control subjects developed incident CI. The CT inter-observer reliability of the SEBE-HCNNSS scale was high, with a Kappa value of 1. Furthermore, ROC analysis identified the SEBE-HCNNSS scale (OR 3.322, 95% CI 2.312-7.237, P=0.00025) as an independent predictor of edema, CI, and unfavorable prognosis. These results were also replicated in a validation cohort. CONCLUSION: Overall, the SEBE-HCNNSS scale represents a simple assessment tool with promising predictive value for CI and clinical outcomes post-a-SAH. Our findings indicate its practical utility as a prognostic instrument for risk evaluation after a-SAH, potentially facilitating early intervention and treatment.

9.
Cell Rep ; 43(4): 113980, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38520693

RESUMEN

In the brain, the role of matrilin-3, an extracellular matrix component in cartilage, is unknown. Here, we identify that matrilin-3 decreased in reactive astrocytes but was unchanged in neurons after ischemic stroke in animals. Importantly, it declined in serum of patients with acute ischemic stroke. Genetic or pharmacological inhibition or supplementation of matrilin-3 aggravates or reduces brain injury, astrocytic cell death, and glial scar, respectively, but has no direct effect on neuronal cell death. RNA sequencing demonstrates that Matn3-/- mice display an increased inflammatory response profile in the ischemic brain, including the nuclear factor κB (NF-κB) signaling pathway. Both endogenous and exogenous matrilin-3 reduce inflammatory mediators. Mechanistically, extracellular matrilin-3 enters astrocytes via caveolin-1-mediated endocytosis. Cytoplasmic matrilin-3 translocates into the nucleus by binding to NF-κB p65, suppressing inflammatory cytokine transcription. Extracellular matrilin-3 binds to BMP-2, blocking the BMP-2/Smads pathway. Thus, matrilin-3 is required for astrocytes to exert neuroprotection, at least partially, by suppressing astrocyte-mediated neuroinflammation.


Asunto(s)
Astrocitos , Accidente Cerebrovascular Isquémico , Proteínas Matrilinas , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias , Neuroprotección , Animales , Humanos , Masculino , Ratones , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Proteínas Matrilinas/metabolismo , Ratones Noqueados , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Neuroprotección/efectos de los fármacos , FN-kappa B/metabolismo , Transducción de Señal
10.
Neuron ; 112(10): 1676-1693.e12, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38513667

RESUMEN

Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration.


Asunto(s)
Enfermedad de Alzheimer , Anticuerpos Monoclonales , Tauopatías , Proteínas tau , Anciano , Anciano de 80 o más Años , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/tratamiento farmacológico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/administración & dosificación , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Inmunoterapia/métodos , Ratones Transgénicos , Degeneración Nerviosa/patología , Degeneración Nerviosa/tratamiento farmacológico , Fosforilación , Proteínas tau/metabolismo , Tauopatías/tratamiento farmacológico
11.
Science ; 383(6685): eadd6371, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38386758

RESUMEN

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9on-off). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9on-on Cadherin6pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.


Asunto(s)
Lesión Renal Aguda , Túbulos Renales Proximales , Riñón , Insuficiencia Renal Crónica , Factor de Transcripción SOX9 , Animales , Humanos , Ratones , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Células Epiteliales , Fibrosis , Riñón/patología , Regeneración , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Factor de Transcripción SOX9/genética , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/metabolismo
12.
Int J Biol Macromol ; 260(Pt 1): 129487, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38237821

RESUMEN

Guanine (G)-rich nucleic acid sequences can form diverse G-quadruplex structures located in functionally significant genome regions, exerting regulatory control over essential biological processes, including DNA replication in vivo. During the initiation of DNA replication, Cdc6 is recruited by the origin recognition complex (ORC) to target specific chromosomal DNA sequences. This study reveals that human Cdc6 interacts with G-quadruplex structure through a distinct region within the N-terminal intrinsically disordered region (IDR), encompassing residues 7-20. The binding region assumes a hook-type conformation, as elucidated by the NMR solution structure in complex with htel21T18. Significantly, mutagenesis and in vivo investigations confirm the highly specific nature of Cdc6's recognition of G-quadruplex. This research enhances our understanding of the fundamental mechanism governing the interaction between G-quadruplex and the N-terminal IDR region of Cdc6, shedding light on the intricate regulation of DNA replication processes.


Asunto(s)
ADN , G-Cuádruplex , Humanos , ADN/química , Replicación del ADN , Complejo de Reconocimiento del Origen/química , Complejo de Reconocimiento del Origen/genética , Complejo de Reconocimiento del Origen/metabolismo , Secuencia de Bases
13.
Diabetes Metab ; 50(2): 101518, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38272255

RESUMEN

AIM: We aimed to explore the relationship between type 2 diabetes mellitus (T2DM) and the incidence rate of migraine in a Chinese population, and analyze the clinical characteristics of migraine patients with T2DM. METHODS: Data on the study cohort of 9873 individuals were obtained from the China Health and Retirement Longitudinal Study (CHARLS). The incidence rate of migraine from 2015 to 2018 was assessed. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for the relationship between T2DM and the incidence of migraine. In addition, a cross-sectional study including 168 migraine patients was conducted in Xiamen, China. Migraine patients were grouped according to their T2DM status. Multivariable linear regression models were used to estimate ßs and their 95% CIs for the relationship between migraine characteristics and T2DM. RESULTS: The cumulative incidence rate of migraine from 2015 to 2018 in the T2DM group and control group was 7.26% [6.04%.8.65%] and 8.91% [8.27%.9.58%], respectively. The risk of migraine in patients with T2DM was reduced by 21% (HR 0.79 [0.65;0.95]) compared to patients with no T2DM after adjustment for confounders. The cross-sectional study showed that the presence of T2DM significantly reduced migraine frequency and relieved migraine intensity. CONCLUSION: This was the first study to validate that T2DM reduced the risk of migraine in a Chinese population cohort. Patients with migraine and T2DM may experience significant relief from their headache symptoms. Carrying out relevant mechanistic research may help to identify new targets for migraine treatment and contribute to further understanding the impact of T2DM or related metabolic disorders on an individual's health.


Asunto(s)
Diabetes Mellitus Tipo 2 , Trastornos Migrañosos , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/diagnóstico , Estudios Longitudinales , Estudios Transversales , Estudios Prospectivos , China/epidemiología , Trastornos Migrañosos/epidemiología , Incidencia , Factores de Riesgo
14.
Comput Biol Med ; 168: 107776, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38056214

RESUMEN

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and lethal neurodegenerative disease. Several studies have suggested the involvement of cuproptosis in its pathogenesis. In this research, we intend to explore the cuproptosis-related molecular clusters in ALS and develop a novel cuproptosis-related genes prediction model. METHODS: The peripheral blood gene expression data was downloaded from the Gene Expression Omnibus (GEO) online database. Based on the GSE112681 dataset, we investigated the critical cuproptosis-related genes (CuRGs) and pathological clustering of ALS. The immune microenvironment features of the peripheral blood in ALS patients were also examined using the CIBERSORT algorithm. Cluster-specific hub genes were determined by the WGCNA. The most accurate prediction model was selected by comparing the performance of four machine learning techniques. ROC curves and two independent datasets were applied to validate the prediction accuracy. The available compounds targeting these hub genes were filtered to investigate their efficacy in treating ALS. RESULTS: We successfully determined four critical cuproptosis-related genes and two pathological clusters with various immune profiles and biological characteristics in ALS. Functional analysis showed that genes in Cluster1 were primarily enriched in pathways closely associated with immunity. The Support Vector Machine (SVM) model exhibited the best discrimination properties with a large area under the curve (AUC = 0.862). Five hub prediction genes (BAP1, SMG1, BCLAF1, DHX15, EIF4G2) were selected to establish a nomogram model, suggesting significant risk prediction potential for ALS. The accuracy of this model in predicting ALS incidence was also demonstrated through calibration curves, nomograms, and decision curve analysis. Finally, three drugs targeting BAP1 were determined through drug-gene interactions. CONCLUSION: This study elucidated the complex associations between cuproptosis and ALS and constructed a satisfactory predictive model to explore the pathological characteristics of different clusters in ALS patients.


Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Humanos , Esclerosis Amiotrófica Lateral/genética , Algoritmos , Calibración , Análisis por Conglomerados , Apoptosis
15.
World Neurosurg ; 181: e713-e721, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37898277

RESUMEN

OBJECTIVE: To conduct a quantitative analysis of published studies on hematoma enlargement after intracerebral hemorrhage. METHODS: Studies on hematoma enlargement after cerebral hemorrhage were retrieved from the Web of Science database on June 30, 2023. Microsoft Excel, VOSviewer, and CiteSpace software were used for bibliometric analysis and visualization, focusing on the quantitative characteristics of the literature. RESULTS: A total of 444 articles were published in 161 journals, with 2161 authors from 41 countries and 717 institutions. The most published authors, countries, and institutions were Goldstein, the USA, and Massachusetts General Hospital. Stroke published the most studies, but the average citation number per year of Lancet Neurology far exceeded that of other journals. The research field of hematoma enlargement is mainly divided into 3 focuses, including mechanisms, identification (computed tomography signs, predictive models), and treatment (hemostasis, antihypertensive therapy). Most bursts in publication number have been since 2010, where the highest burst was from research on spot signs, and the latest burst focused on tranexamic acid. Treatment using tranexamic acid based on different computed tomography signs is a focus of current research, but the effectiveness still requires further exploration. CONCLUSIONS: This bibliometric analysis analyzed the research framework and hotspots on hematoma enlargement after cerebral hemorrhage, which can help researchers better understand this field and provide potential suggestions for collaborations and research.


Asunto(s)
Accidente Cerebrovascular , Ácido Tranexámico , Humanos , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico por imagen , Bibliometría , Hematoma/diagnóstico por imagen , Hipertrofia
16.
Neurol Ther ; 13(1): 107-125, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38019380

RESUMEN

INTRODUCTION: Cognitive impairment (CI) is a common comorbidity in patients with late-onset epilepsy of unknown origin (LOEU). However, limited data are available on effective screening methods for CI at an early stage. We aimed to develop and internally validate a nomogram for identifying patients with LOEU at risk of CI and investigate the potential moderating effect of education on the relationship between periventricular white matter hyperintensities (PVHs) and cognitive function. METHODS: We retrospectively reviewed the clinical data of 61 patients aged ≥ 55 years diagnosed with LOEU. The main outcome was CI, reflected as an adjusted Montreal Cognition Assessment score of < 26 points. A nomogram based on a multivariable logistic regression model was constructed. Its discriminative ability, calibration, and clinical applicability were tested using calibration plots, the area under the curve (AUC), and decision curves. Internal model validation was conducted using the bootstrap method. The moderating effect of education on the relationship between PVH and cognitive function was examined using hierarchical linear regression. RESULTS: Forty-four of 61 (72.1%) patients had CI. A nomogram incorporating seizure type, total cerebral small vessel disease burden score, and PVH score was built to identify the risk factors for CI. The AUC of the model was 0.881 (95% confidence interval: 0.771-0.994) and 0.78 (95% confidence interval: 0.75-0.8) after internal validation. Higher educational levels blunted the negative impact of PVH on cognitive function. CONCLUSION: Our nomogram provides a convenient tool for identifying patients with LOEU who are at risk of CI. Moreover, our findings demonstrate the importance of education for these patients.

17.
J Headache Pain ; 24(1): 149, 2023 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-37932721

RESUMEN

PURPOSE: Serum neurofilament light chain (sNfL) can reflect nerve damage. Whether migraine can cause neurological damage remain unclear. This study assesses sNfL levels in migraine patients and explores whether there is nerve damage in migraine. METHODS: A case-control study was conducted in Xiamen, China. A total of 138 migraine patients and 70 healthy controls were recruited. sNfL (pg/mL) was measured on the single-molecule array platform. Univariate, Pearson correlation and linear regression analysis were used to assess the relationship between migraine and sNfL levels, with further subgroup analysis by migraine characteristics. RESULTS: Overall, 85.10% of the 208 subjects were female, with a median age of 36 years. sNfL levels were higher in the migraine group than in the control group (4.85 (3.49, 6.62) vs. 4.11 (3.22, 5.59)), but the difference was not significant (P = 0.133). The two groups showed an almost consistent trend in which sNfL levels increased significantly with age. Subgroup analysis showed a significant increase in sNfL levels in patients with a migraine course ≥ 10 years (ß = 0.693 (0.168, 1.220), P = 0.010). Regression analysis results show that age and migraine course are independent risk factors for elevated sNfL levels, and there is an interaction between the two factors. Patients aged < 45 years and with a migraine course ≥ 10 years have significantly increased sNfL levels. CONCLUSIONS: This is the first study to evaluate sNfL levels in migraine patients. The sNfL levels significantly increased in patients with a migraine course ≥ 10 years. More attention to nerve damage in young patients with a long course of migraine is required.


Asunto(s)
Filamentos Intermedios , Trastornos Migrañosos , Humanos , Femenino , Adulto , Masculino , Estudios de Casos y Controles , Biomarcadores , China
18.
BMC Pregnancy Childbirth ; 23(1): 633, 2023 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-37660016

RESUMEN

PURPOSE: The impact of body mass index (BMI) on in vitro fertilization (IVF) has been well acknowledged; however, the reported conclusions are still incongruent. This study aimed to investigate the effect of BMI on IVF embryos and fresh transfer clinical outcomes. METHODS: This retrospective cohort analysis included patients who underwent IVF/ICSI treatment and fresh embryo transfer from 2014 to March 2022. Patients were divided into the underweight group: BMI < 18.5 kg/m2; normal group: 18.5 ≤ BMI < 24 kg/m2; overweight group: 24 ≤ BMI < 28 kg/m2; and obesity group: BMI ≥ 28 kg/m2. A generalized linear model was used to analyze the impact of BMI on each IVF outcome used as a continuous variable. RESULTS: A total of 3465 IVF/ICSI cycles in the embryo part; and 1698 fresh embryo transplanted cycles from the clinical part were included. Available embryos rate (61.59% vs. 57.32%, p = 0.007) and blastocyst development rates (77.98% vs. 66.27%, p < 0.001) were higher in the obesity group compared to the normal BMI group. Also, the fertilization rate of IVF cycles in the obesity group was significantly decreased vs. normal BMI group (normal: 62.95% vs. 66.63% p = 0.006; abnormal: 5.43% vs. 7.04%, p = 0.037), while there was no difference in ICSI cycles. The clinical outcomes of overweight and obesity groups were comparable to the normal group. The gestational age of the obesity group was lower compared to the normal group (38.08 ± 1.95 vs. 38.95 ± 1.55, p = 0.011). The adjusted OR (AOR) of BMI for the preterm birth rate of singletons was 1.134 [(95% CI 1.037-1.240), p = 0.006]. BMI was significantly associated with live birth rate after excluded the PCOS patients [AOR: 1.042 (95% CI 1.007-1.078), p = 0.018]. In young age (≤ 35 years), clinical pregnancy rate and live birth rate were positively correlated with BMI, AOR was 1.038 [95% CI (1.001-1.076), p = 0.045] and 1.037 [95% CI (1.002-1.074) p = 0.038] respectively. CONCLUSION: Being overweight and obese was not associated with poor IVF outcomes but could affect blastocyst formation. ICSI could help to avoid low fertilization in obese patients. Also, obesity was associated with increased rates of premature singleton births.


Asunto(s)
Sobrepeso , Nacimiento Prematuro , Recién Nacido , Femenino , Embarazo , Humanos , Adulto , Sobrepeso/complicaciones , Sobrepeso/epidemiología , Estudios Retrospectivos , Obesidad/complicaciones , Obesidad/epidemiología , Fertilización In Vitro
19.
J Mol Cell Biol ; 2023 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-37771073

RESUMEN

ELP3, the catalytic subunit of Elongator complex, is an acetyltransferase and associated with tumor progression. However, the detail of ELP3 oncogenic function remains largely unclear. Here, we found that ELP3 stabilizes c-Myc to promote tumorigenesis in an acetyltransferase-independent manner. Mechanically, ELP3 competes with the E3-ligase FBXW7ß for c-Myc binding, resulting in the inhibition of FBXW7ß-mediated ubiquitination and proteasomal degradation of c-Myc. ELP3-knockdown diminishes glycolysis and glutaminolysis and dramatically retards cell proliferation and xenograft growth by downregulating c-Myc, and such effects are rescued by reconstitution of c-Myc expression. Moreover, ELP3 and c-Myc were overexpressed with a positive correlation in colorectal cancer and hepatocellular carcinoma. Taken together, we elucidate a new function of ELP3 in promoting tumorigenesis by stabilizing c-Myc, suggesting that inhibition of ELP3 is a potential strategy for the therapy of c-Myc-driven carcinomas.

20.
Front Neurol ; 14: 1178404, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37693759

RESUMEN

Background: Studies have shown that longer leukocyte telomere length (LTL) is significantly associated with increased risk of meningioma. However, there is limited evidence concerning the causal association of LTL with benign and malignant meningiomas or with the location of benign tumors. Methods: We used three LTL datasets from different sources, designated by name and sample size as LTL-78592, LTL-9190, and LTL-472174. The linkage disequilibrium score (LDSC) was used to explore the association between LTL and meningioma. We utilized two-sample bidirectional Mendelian randomization (TSMR) to evaluate whether LTL is causally related to meningioma risk. We adjusted for confounders by conducting multivariable Mendelian randomization (MVMR). Results: In the LTL-78592, longer LTL was significantly associated with increased risk of malignant [odds ratio (OR) = 5.14, p = 1.04 × 10-5], benign (OR = 4.81, p < 0.05), benign cerebral (OR = 5.36, p < 0.05), and benign unspecified meningioma (OR = 8.26, p < 0.05). The same results were obtained for the LTL-9190. In the LTL-472174, longer LTL was significantly associated with increased risk of malignant (OR = 4.94, p < 0.05), benign (OR = 3.14, p < 0.05), and benign cerebral meningioma (OR = 3.59, p < 0.05). Similar results were obtained in the MVMR. In contrast, only benign cerebral meningioma displayed a possible association with longer LTL (OR = 1.01, p < 0.05). No heterogeneity or horizontal pleiotropy was detected. Conclusion: In brief, genetically predicted longer LTL may increase the risk of benign, malignant, and benign cerebral meningiomas, regardless of the LTL measure, in European populations.

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