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BACKGROUND: Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited. METHODS: In a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: A total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P = 0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively. CONCLUSIONS: In this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.).
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Fibrinolíticos , Accidente Cerebrovascular Isquémico , Tenecteplasa , Activador de Tejido Plasminógeno , Humanos , Tenecteplasa/uso terapéutico , Tenecteplasa/efectos adversos , Fibrinolíticos/uso terapéutico , Fibrinolíticos/efectos adversos , Fibrinolíticos/administración & dosificación , Masculino , Persona de Mediana Edad , Activador de Tejido Plasminógeno/uso terapéutico , Activador de Tejido Plasminógeno/efectos adversos , Femenino , Anciano , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/cirugía , Trombectomía , Tiempo de Tratamiento , Hemorragias Intracraneales/etiología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/cirugíaRESUMEN
BACKGROUND: Cancer-associated fibroblast (CAF)-cancer cell crosstalk (CCCT) plays an important role in tumor microenvironment shaping and immunotherapy response. Current prognostic indexes are insufficient to accurately assess immunotherapy response in patients with head and neck squamous cell carcinoma (HNSCC). This study aimed to develop a CCCT-related gene prognostic index (CCRGPI) for assessing the prognosis and response to immune checkpoint inhibitor (ICI) therapy of HNSCC patients. METHODS: Two cellular models, the fibroblast-cancer cell indirect coculture (FCICC) model, and the fibroblast-cancer cell organoid (FC-organoid) model, were constructed to visualize the crosstalk between fibroblasts and cancer cells. Based on a HNSCC scRNA-seq dataset, the R package CellChat was used to perform cell communication analysis to identify gene pairs involved in CCCT. Least absolute shrinkage and selection operator (LASSO) regression was then applied to further refine the selection of these gene pairs. The selected gene pairs were subsequently subjected to stepwise regression to develop CCRGPI. We further performed a comprehensive analysis to determine the molecular and immune characteristics, and prognosis associated with ICI therapy in different CCRGPI subgroups. Finally, the connectivity map (CMap) analysis and molecular docking were used to screen potential therapeutic drugs. RESULTS: FCICC and FC-organoid models showed that cancer cells promoted the activation of fibroblasts into CAFs, that CAFs enhanced the invasion of cancer cells, and that CCCT was somewhat heterogeneous. The CCRGPI was developed based on 4 gene pairs: IGF1-IGF1R, LGALS9-CD44, SEMA5A-PLXNA1, and TNXB-SDC1. Furthermore, a high CCRGPI score was identified as an adverse prognostic factor for overall survival (OS). Additionally, a high CCRGPI was positively correlated with the activation of the P53 pathway, a high TP53 mutation rate, and decreased benefit from ICI therapy but was inversely associated with the abundance of various immune cells, such as CD4+ T cells, CD8+ T cells, and B cells. Moreover, Ganetespib was identified as a potential drug for HNSCC combination therapy. CONCLUSIONS: The CCRGPI is reliable for predicting the prognosis and immunotherapy response of HSNCC patients and may be useful for guiding the individualized treatment of HNSCC patients.
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Fibroblastos Asociados al Cáncer , Neoplasias de Cabeza y Cuello , Aprendizaje Automático , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Pronóstico , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral/genética , Comunicación Celular/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Masculino , Resultado del Tratamiento , Línea Celular Tumoral , FemeninoRESUMEN
GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.
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ADN Helicasas , ARN Helicasas , Humanos , Proteínas de Unión a Poli-ADP-Ribosa , Proteínas con Motivos de Reconocimiento de ARN , Regiones no Traducidas 5' , Cuerpos de Inclusión Intranucleares , Ribosomas , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
BACKGROUND AND AIMS: Observational studies have suggested a relationship between leptin and risk of stroke. However, evidence for the association remains inconsistent, and whether the association reflects a causal relationship remains to be established. To clarify this relationship, we adopted a two-sample Mendelian randomization (MR) analysis to investigate whether leptin plays a causal role in the risk of stroke and its subtypes. METHODS AND RESULTS: Five independent single-nucleotide polymorphisms (SNPs) associated with the leptin level from genome-wide association studies (GWASs) of European individuals were selected. We performed an MR analysis using the inverse-variance-weighted (IVW) as primary method to examine the causal effects of leptin on ischemic stroke (IS). Moreover, MR-Egger intercept and Cochran's Q statistic were also performed to detect the pleiotropy or heterogeneity of our MR results. Genetically predicted circulating leptin level was not associated with ischemic stroke [odds ratio (OR): 1.48, 95% confidence interval (CI): 0.78-2.8, P = 0.22], large artery stroke (OR: 1.44, 95% CI: 0.39-5.25, P = 0.57), cardioembolic stroke (OR:1.33, 95% CI: 0.55-3.22, P = 0.52), and small vessel stroke (OR: 1.48, 95% CI: 0.39-5.63, P = 0.56) using the IVW method. Likewise, there is no convincing evidence for the associations between leptin levels and cardiovascular diseases (CVD) risk factors. CONCLUSIONS: This study did not provide evidence that leptin levels are associated with increased risk of stroke and its subtypes.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Estudio de Asociación del Genoma Completo , Leptina/genética , Análisis de la Aleatorización Mendeliana , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genéticaRESUMEN
P-stereogenic phosphines, renowned for their utility as ligands and catalysts, have been instrumental in the field of asymmetric catalysis. However, the catalytic asymmetric synthesis of chiral ligands possessing both axial and phosphine chirality remains a significant challenge. Here, we present the successful demonstration of a Cu-catalyzed asymmetric C-P construction using in situ generated secondary phosphine and heteroaryl chloride. By introducing a chiral NHC ligand and an achiral diphosphine auxiliary ligand, we effectively alleviated the poisoning effect caused by phosphine(III) compounds and suppressed the nonenantioselective background reaction. The reaction exhibited excellent enantioselectivity, with up to 96% ee, and good diastereoselectivity, with up to 14:1 dr, when employing less sterically hindered secondary phosphines. This particular substrate poses a significant challenge due to its strong poisoning effect in copper catalysis.
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Cerebral small vessel disease (CSVD) causes 20%-25% of stroke and contributes to 45% of dementia cases worldwide. However, since its early symptoms are inconclusive in addition to the complexity of the pathological basis, there is a rather limited effective therapies and interventions. Recently, accumulating evidence suggested that various brain-waste-clearance dysfunctions are closely related to the pathogenesis and prognosis of CSVD, and after a comprehensive and systematic review we classified them into two broad categories: trans-barrier transport and lymphatic drainage. The former includes blood brain barrier and blood-cerebrospinal fluid barrier, and the latter, glymphatic-meningeal lymphatic system and intramural periarterial drainage pathway. We summarized the concepts and potential mechanisms of these clearance systems, proposing a relatively complete framework for elucidating their interactions with CSVD. In addition, we also discussed recent advances in therapeutic strategies targeting clearance dysfunction, which may be an important area for future CSVD research.
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Enfermedades de los Pequeños Vasos Cerebrales , Sistema Glinfático , Accidente Cerebrovascular , Humanos , Barrera Hematoencefálica/metabolismo , Meninges , Encéfalo/metabolismoRESUMEN
The Golgi apparatus is vital for protein modification and molecular trafficking. It is essential for nerve development and activity, and damage thereof is implicated in many neurological diseases. Primary familial brain calcification (PFBC) is a rare inherited neurodegenerative disease characterized by multiple brain calcifications. SLC20A2, which encodes the inorganic phosphate transporter 2 (PiT-2) protein, is the main pathogenic gene in PFBC. The PiT-2 protein is a sodium-dependent phosphate type III transporter, and dysfunction leads to a deficit in the cellular intake of inorganic phosphate (Pi) and calcium deposits. Whether the impaired Golgi apparatus is involved in the PFBC procession requires elucidation. In this study, we constructed induced pluripotent stem cells (iPSCs) derived from two PFBC patients with different SLC20A2 gene mutations (c.613G > A or del exon10) and two healthy volunteers as dependable cell models for research on pathogenic mechanism. To study the mechanism, we differentiated iPSCs into neurons and astrocytes in vitro. Our study found disruptive Golgi structure and damaged autophagy in PFBC neurons with increased activity of mTOR. We also found damaged mitochondria and increased apoptosis in the PFBC dopaminergic neurons and astrocytes. In this study, we prove that dysfunctional PiT-2 leads to an imbalance of cellular Pi, which may disrupt the Golgi apparatus with impaired autophagy, mitochondria and apoptosis in PFBC. Our study provides a new avenue for understanding nerve damage and pathogenic mechanism in brain calcifications.
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Calcinosis , Enfermedades Neurodegenerativas , Humanos , Enfermedades Neurodegenerativas/metabolismo , Proteínas de Transporte de Fosfato/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/metabolismo , Fosfatos/metabolismo , Calcinosis/metabolismo , Aparato de Golgi/metabolismo , Mutación , Encéfalo/metabolismoRESUMEN
The meninges, membranes surrounding the central nervous system (CNS) boundary, harbor a diverse array of immunocompetent immune cells, and therefore, serve as an immunologically active site. Meningeal immunity has emerged as a key factor in modulating proper brain function and social behavior, performing constant immune surveillance of the CNS, and participating in several neurological diseases. However, it remains to be determined how meningeal immunity contributes to CNS physiology and pathophysiology. With the advances in single-cell omics, new approaches, such as single-cell technologies, unveiled the details of cellular and molecular mechanisms underlying meningeal immunity in CNS homeostasis and dysfunction. These new findings contradict some previous dogmas and shed new light on new possible therapeutic targets. In this review, we focus on the complicated multi-components, powerful meningeal immunosurveillance capability, and its crucial involvement in physiological and neuropathological conditions, as recently revealed by single-cell technologies.
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Meninges , Enfermedades del Sistema Nervioso , Humanos , Sistema Nervioso CentralRESUMEN
BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are three nervous system diseases that partially overlap clinically and genetically. However, bulk RNA-sequencing did not accurately detect the core pathogenic molecules in them. The availability of high-quality single cell RNA-sequencing data of post-mortem brain collections permits the generation of a large-scale gene expression in different cells in human brain, focusing on the molecular features and relationships between diseases and genes. We integrated single-nucleus RNA-sequencing (snRNA-seq) datasets of human brains with AD, PD, and MS to identify transcriptomic commonalities and distinctions among them. METHODS: The snRNA-seq datasets were downloaded from Gene Expression Omnibus (GEO) database. The Seurat package was used for snRNA-seq data processing. The uniform manifold approximation and projection (UMAP) were utilized for cluster identification. The FindMarker function in Seurat was used to identify the differently expressed genes. Functional enrichment analysis was carried out using the Gene Set Enrichment Analysis (GSEA) and Gene ontology (GO). The protein-protein interaction (PPI) analysis of differentially expressed genes (DEGs) was analyzed using STRING database ( http://string-db.org ). SCENIC analysis was performed using utilizing pySCENIC (v0.10.0) based on the hg19-tss-centered-10 kb-10species databases. The analysis of potential therapeutic drugs was analyzed on Connectivity Map ( https://clue.io ). RESULTS: The gene regulatory network analysis identified several hub genes regulated in AD, PD, and MS, in which HSPB1 and HSPA1A were key molecules. These upregulated HSP family genes interact with ribosome genes in AD and MS, and with immunomodulatory genes in PD. We further identified several transcriptional regulators (SPI1, CEBPA, TFE3, GRHPR, and TP53) of the hub genes, which has important implications for uncovering the molecular crosstalk among AD, PD, and MS. Arctigenin was identified as a potential therapeutic drug for AD, PD, and MS. CONCLUSIONS: Together, the integrated snRNA-seq data and findings have significant implications for unraveling the shared and unique molecular crosstalk among AD, PD, and MS. HSPB1 and HSPA1A as promising targets involved in the pathological mechanisms of neurodegenerative diseases. Additionally, the identification of arctigenin as a potential therapeutic drug for AD, PD, and MS further highlights its potential in treating these neurological disorders. These discoveries lay the groundwork for future research and interventions to enhance our understanding and treatment of AD, PD, and MS.
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Enfermedad de Alzheimer , Esclerosis Múltiple , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Esclerosis Múltiple/genética , Enfermedad de Alzheimer/genética , ARNRESUMEN
OBJECTIVE: CGG/GGC repeat expansion in FMR1 and NOTCH2NLC is reportedly associated with movement disorders; therefore, we hypothesized that the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1, which was previously identified in myopathy, might also be associated with movement-disorder phenotypes. Here, we investigated whether CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 presents in a cohort of patients with movement disorders. METHODS: We screened for the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 in 1,346 movement-disorder patients and 1,451 matched healthy controls. RESULTS: No patients or controls harbored expanded CGG repeats in LRP12 or NUTM2B-AS1, whereas 16 patients harbored >40 CGG repeats in GIPC1, with 11 of these patients harboring >60 CGG repeats. One control individual harbored an expanded GIPC1 allele (83 CGG units), suggesting that approximately 1% of patients affected by movement disorders in our population might harbor GIPC1 CGG repeat expansion, with this likely extremely rare in healthy controls (<0.001). The clinical phenotypes of the GIPC1 CGG repeat-positive patients strongly resembled those in patients displaying NOTCH2NLC GGC repeat-positive movement disorders. Additionally, the GIPC1 CGG repeat-positive patients presented white-matter hyperintensities but without typical NOTCH2NLC-related high-intensity signals in the corticomedullary junction. Furthermore, 44% of the GIPC1 CGG repeat-positive patients showed a cognitive deficit, and skin biopsies in 2 patients revealed deposition of intranuclear inclusions. INTERPRETATION: The CGG repeat expansion in GIPC1 might be associated with movement-disorder phenotypes and lead to diseases related to intranuclear inclusions. ANN NEUROL 2022;91:704-715.
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Trastornos del Movimiento , Distrofias Musculares , Proteínas Adaptadoras Transductoras de Señales/genética , Estudios de Cohortes , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Humanos , Cuerpos de Inclusión Intranucleares/patología , Trastornos del Movimiento/genética , Distrofias Musculares/genética , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
Cerebral amyloid-ß (Aß) accumulation due to impaired Aß clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aß is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aß and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aß42 and 8.9% of Aß40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aß receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aß levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aß clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aß burden and cognitive deficits, while enhancing hepatic Aß clearance via LRP-1 overexpression attenuated cerebral Aß deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aß and regulates brain Aß levels, suggesting that a decline of hepatic Aß clearance during aging could be involved in AD development, and hepatic Aß clearance is a novel therapeutic approach for AD.
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Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Hígado/metabolismo , Hígado/patología , Ratones Transgénicos , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood. OBJECTIVE: The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci. METHODS: We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed. RESULTS: MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.
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Estudio de Asociación del Genoma Completo , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Predisposición Genética a la Enfermedad/genética , Fenotipo , Encéfalo/diagnóstico por imagen , Polimorfismo de Nucleótido Simple/genética , Sitios GenéticosRESUMEN
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant cerebellar ataxia accompanied by extracerebellar signs and other neurological disorders. It is caused by an expansion of the ATTCT pentanucleotide repeat in intron 9 of ATXN10. Cases of SCA10, formerly confined to America, have been reported in Europe and Asia. In the present study, we aim to report an atypical SCA10 family in China and provide a reference for the diagnosis of SCA10 in Asia by comparing their clinical and genetic features with former SCA10 pedigrees. Genomic DNA was extracted from patients and subjected to RP-PCR (repeat-primed PCR), Southern blotting, and haplotype analysis to determine the genetic pathogenesis. Patients with SCA10 in this pedigree demonstrated atypical SCA10 manifestations, including the absence of seizures and ocular abnormalities. Magnetic resonance imaging (MRI) showed cerebellar atrophy in five patients with available data. RP-PCR and Southern blotting revealed abnormal expansion. Analysis of single nucleotide polymorphisms (SNPs) surrounding the SCA10 locus in the proband and other affected family members revealed the "C-expansion-G-G-C" haplotype, consistent with former studies. These findings imply that the SCA10 mutation may have occurred before the Amerindian migration from East Asia to North America. It also suggested that SCA10 should be taken into account during differential diagnosis in patients of Asian ancestry, even if they do not present with typical features such as epilepsy.
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Pueblos del Este de Asia , Ataxias Espinocerebelosas , Humanos , Expansión de las Repeticiones de ADN , Mutación , Ataxias Espinocerebelosas/genéticaRESUMEN
OBJECTIVES: Lymph node (LN) metastasis is a common cause of recurrence in oral cancer; however, the accuracy of distinguishing positive and negative LNs is not ideal. Here, we aimed to develop a deep learning model that can identify, locate, and distinguish LNs in contrast-enhanced CT (CECT) images with a higher accuracy. METHODS: The preoperative CECT images and corresponding postoperative pathological diagnoses of 1466 patients with oral cancer from our hospital were retrospectively collected. In stage I, full-layer images (five common anatomical structures) were labeled; in stage II, negative and positive LNs were separately labeled. The stage I model was innovatively employed for stage II training to improve accuracy with the idea of transfer learning (TL). The Mask R-CNN instance segmentation framework was selected for model construction and training. The accuracy of the model was compared with that of human observers. RESULTS: A total of 5412 images and 5601 images were labeled in stage I and II, respectively. The stage I model achieved an excellent segmentation effect in the test set (AP50-0.7249). The positive LN accuracy of the stage II TL model was similar to that of the radiologist and much higher than that of the surgeons and students (0.7042 vs. 0.7647 (p = 0.243), 0.4216 (p < 0.001), and 0.3629 (p < 0.001)). The clinical accuracy of the model was highest (0.8509 vs. 0.8000, 0.5500, 0.4500, and 0.6658 of the Radiology Department). CONCLUSIONS: The model was constructed using a deep neural network and had high accuracy in LN localization and metastasis discrimination, which could contribute to accurate diagnosis and customized treatment planning. KEY POINTS: ⢠Lymph node metastasis is not well recognized with modern medical imaging tools. ⢠Transfer learning can improve the accuracy of deep learning model prediction. ⢠Deep learning can aid the accurate identification of lymph node metastasis.
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Aprendizaje Profundo , Neoplasias de la Boca , Humanos , Estudios Retrospectivos , Metástasis Linfática/diagnóstico por imagen , Neoplasias de la Boca/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Ganglios Linfáticos/diagnóstico por imagenRESUMEN
BACKGROUND: Imaging indicators of early neurological deterioration (END) in patients with acute isolated pontine infarctions (AIPI) remained ambiguous. We aimed to find more specific neuroimaging markers for the development of END in patients with AIPI. METHODS: Patients with AIPI within 72 h of stroke onset were screened from a stroke database from January 2018 to July 2021 in the First Affiliated Hospital of Zhengzhou University. Clinical characteristics, laboratory tests, and imaging parameters were collected. The layers having the largest infarct area on diffusion-weighted imaging (DWI) and T2 sequences were chosen. On the transverse plane of DWI and sagittal plane of T2-Flair images, the maximum length (a, m) and maximum width (b, n) vertical to the length of the infarcted lesions were measured respectively. On the sagittal plane of T2-Flair image, the maximum ventrodorsal length (f) and rostrocaudal thickness (h) were measured. On the sagittal plane, lesions were evenly split into upper, middle, and lower types based on the lesion's location in the pons. The ventral and dorsal types of location were separated based on whether the ventral borders of the pons were involved on transvers plane. END was defined as a ≥2 point increase in the National Institutes of Health Stroke Scale (NIHSS) total score or a ≥1 point increase in the motor items within 72 h after admission. Multivariate logistic regression analyses were used to explore risk factors associated with END. The receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) was performed to estimate the discriminative power and determine the optimal cut-off points of imaging parameters on the prediction of END. RESULTS: A total of 218 patients with AIPI were included in the final analysis. END occurred in 61 cases (28.0%). Multivariate logistic regression analysis showed that the ventral type of lesion location was associated with END in all models adjusted. In addition, in Model 1, b (odds ratio (OR) 1.145, 95% confidence interval (95% CI), 1.007-1.301) and n (OR 1.163, 95% CI 1.012-1.336); in Model 2, b*n (OR 1.010, 95% CI 1.002-1.018); in Model 3, n (OR 1.179, 95% CI, 1.028-1.353); and in Model 4, b (OR 1.143, 95% CI 1.006-1.298) and n (OR 1.167, 95% CI 1.016-1.341) were found to be associated with END respectively after different adjustments. ROC curve analysis with END showed that the AUC, the optimal cut-off value, and its sensitivity and specificity were 0.743 (0.671-0.815), 9.850 mm, and 68.9% and 79.0% for b; 0.724 (0.648-0.801), 10.800 mm, and 57.4% and 80.9% for n; and 0.772 (0.701-0.842), 108.274 mm2, and 62.3% and 85.4% for b*n, respectively (b*n vs b: P =0.213; b*n vs n: P =0.037; b vs n: P =0.645). CONCLUSIONS: Our study revealed that besides the ventral type of lesion location, the maximum width of lesion on the transverse plane of DWI and sagittal plane of T2 image (b, n) may be imaging markers for the development of END in AIPI patients, and the product of the two (b*n) showed a better prediction value on the risks of END.
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Infartos del Tronco Encefálico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/diagnóstico por imagen , Infartos del Tronco Encefálico/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética , Sensibilidad y Especificidad , Neuroimagen , Estudios RetrospectivosRESUMEN
BACKGROUND: The discovery of skin intranuclear inclusions and GGC repeat expansion of NOTCH2NLC has greatly promoted the diagnosis of neuronal intranuclear inclusion disease (NIID). With highly heterogeneous clinical manifestations, NIID patients tend to be underdiagnosed at early stages. METHODS: This study comprehensively studied clinical manifestations, magnetic resonance imaging (MRI), and peripheral nerve conduction in 24 NIID and 166 other neurodegenerative disease (ND) subjects. The nomogram was plotted using the "rms" package, and the t-distributed stochastic neighbor embedding algorithm was performed. Associations between skin intranuclear inclusions and NOTCH2NLC GGC repeats were further analyzed. RESULTS: The clinical, MRI, and peripheral nerve conduction features seriously overlapped in NIID and ND patients; they were assigned variables according to their frequency and specificity in NIID patients. A nomogram that could distinguish NIID from ND was constructed according to the assigned variables and cutoff values of the above features. The occurrence of skin intranuclear inclusions and NOTCH2NLC GGC repeats ≥ 60 showed 100% consistency, and intranuclear inclusion frequency positively correlated with NOTCH2NLC GGC repeats. A hierarchical diagnostic flowchart for definite NIID was further established. CONCLUSION: We provide a novel nomogram with the potential to realize early identification and update the diagnostic flowchart for definitive diagnosis. Moreover, this is the first study to define the association between skin pathology and NOTCH2NLC genetics in NIID.
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Enfermedades Neurodegenerativas , Humanos , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/genética , Cuerpos de Inclusión Intranucleares/genética , Cuerpos de Inclusión Intranucleares/patología , Imagen por Resonancia Magnética , PielRESUMEN
GGC repeat expansion in the 5' untranslated region of NOTCH2NLC is the most common causative factor in neuronal intranuclear inclusion disease (NIID) in Asians. Such expanded GGC repeats have been identified in patients with leukoencephalopathy, essential tremor (ET), multiple system atrophy, Parkinson's disease (PD), amyotrophic lateral sclerosis and oculopharyngodistal myopathy (OPDM). Herein, we review the recently reported NOTCH2NLC-related disorders and potential disease-causing mechanisms. We found that visual abnormalities may be NOTCH2NLC-specific and should be investigated in other patients with NOTCH2NLC mutations. NOTCH2NLC GGC repeat expansion was rarely identified in patients of European ancestry, whereas the actual prevalence of the expansion in European patients may be potentially higher than reported, and the CGG repeats in LRP12/GIPC1 are suggested to be screened in European patients with NIID. The repeat size and interruptions in NOTCH2NLC GGC expansion confer pleiotropic effects on clinical phenotype, a pure and stable ET phenotype may be an early symptom of NIID, and GGC repeats in NOTCH2NLC possibly give rise to ET. An association may also exist between intermediate-length NOTCH2NLC GGC repeat expansion and patients affected by PD and ET. NOTCH2NLC-OPDM highly resembles NOTCH2NLC-NIID, the two disorders may be the variations of a single neurodegenerative disease, and there may be a disease-causing upper limit in size of GGC repeats in NOTCH2NLC, repeats over which may be non-pathogenic. The haploinsufficiency of NOTCH2NLC may not be primarily involved in NOTCH2NLC-related disorders and a toxic gain-of-function mechanism possibly drives the pathogenesis of neurodegeneration in patients with NOTCH2NLC-associated disorders.
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Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas del Tejido Nervioso/genética , Enfermedades Neurodegenerativas/metabolismo , Expansión de Repetición de Trinucleótido , Pueblo Asiatico/genética , Estudios de Asociación Genética , Humanos , Cuerpos de Inclusión Intranucleares/genética , Cuerpos de Inclusión Intranucleares/metabolismo , Enfermedades Neurodegenerativas/genéticaRESUMEN
BACKGROUND: While previous genome-wide association studies (GWAS) have identified multiple risk variants for migraine, there is a lack of evidence about how these variants contribute to the development of migraine. We employed an integrative pipeline to efficiently transform genetic associations to identify causal genes for migraine. METHODS: We conducted a proteome-wide association study (PWAS) by combining data from the migraine GWAS data with proteomic data from the human brain and plasma to identify proteins that may play a role in the risk of developing migraine. We also combined data from GWAS of migraine with a novel joint-tissue imputation (JTI) prediction model of 17 migraine-related human tissues to conduct transcriptome-wide association studies (TWAS) together with the fine mapping method FOCUS to identify disease-associated genes. RESULTS: We identified 13 genes in the human brain and plasma proteome that modulate migraine risk by regulating protein abundance. In addition, 62 associated genes not reported in previous migraine TWAS studies were identified by our analysis of migraine using TWAS and fine mapping. Five genes including ICA1L, TREX1, STAT6, UFL1, and B3GNT8 showed significant associations with migraine at both the proteome and transcriptome, these genes are mainly expressed in ependymal cells, neurons, and glial cells, and are potential target genes for prevention of neuronal signaling and inflammatory responses in the pathogenesis of migraine. CONCLUSIONS: Our proteomic and transcriptome findings have identified disease-associated genes that may give new insights into the pathogenesis and potential therapeutic targets for migraine.
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Trastornos Migrañosos , Proteoma , Humanos , Proteoma/genética , Estudio de Asociación del Genoma Completo , Proteómica , Transcriptoma , Trastornos Migrañosos/genéticaRESUMEN
BACKGROUND: A loss-of-function mutation in ATPase phospholipid transporting 11-B (putative) (ATP11B) gene causing cerebral small vessel disease (SVD) in vivo, and a single intronic nucleotide polymorphism in ATP11B: rs148771930 that was associated with white matter hyperintensities burden in European patients with SVD, was recently identified. Our results suggest that ATP11B may not play an essential role in SVD in the Chinese population. RESULTS: We performed target region sequencing including ATP11B gene in 182 patients with sporadic SVD, and identified five rare variants and two novel variants of ATP11B. A case-control study was then performed in 524 patients and matched 550 controls to investigate the relationship between ATP11B and sporadic SVD in the Chinese Han population. Although none of these variants were significantly associated with SVD in our samples, it is important to mention that we identified a novel variant, p. G238W, which was predicted to be pathogenic in silico. This variant was present in our cohort of patients with an extremely low frequency and was absent in the controls. CONCLUSION: Our results suggest that ATP11B may not play an essential role in SVD in the Chinese population.
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Adenosina Trifosfatasas , Enfermedades de los Pequeños Vasos Cerebrales , Pueblos del Este de Asia , Humanos , Estudios de Casos y Controles , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/patología , Polimorfismo de Nucleótido Simple , Adenosina Trifosfatasas/genéticaRESUMEN
BACKGROUND: Angiogenesis is a key rate-limiting step in the process of tumour progression. Cancer-associated fibroblasts (CAFs), the most abundant component OSCC stroma, play important roles in pro-angiogenesis. Recently, the stroma "reverse Warburg effect" was proposed, and PFKFB3 has been brought to the forefront as a metabolic enzyme regulating glycometabolism. However, it remains unclear whether glycometabolism reprogramming is involved in promoting the angiogenesis of CAFs. METHODS: CAFs and paracancerous fibroblasts (PFs) were isolated from OSCC and adjacent tissues. We detected the pro-angiogenesis and glycometabolism phenotype of three pairs of fibroblasts. Targeted blockage of PFKFB3 or activation of PGC-1α signal was used to investigate the effect of glycolysis on regulating angiogenesis of CAFs in vitro and vivo. RESULTS: CAFs exhibited metabolic reprogramming and enhanced proangiogenic phenotype compared with PFs. Inhibition of PFKFB3-dependent glycolysis impaired proangiogenic factors (VEGF-A, PDGF-C and MMP9) expression in CAFs. Furthermore, CAFs proangiogenic phenotype was regulated by glycometabolism through the PGC-1α/PFKFB3 axis. Consistently, PGC-1α overexpression or PFKFB3 knockdown in CAFs slowed down tumour development by reducing tumour angiogenesis in the xenograft model. CONCLUSION: CAFs of OSCC are characterised with glycometabolic reprogramming and enhanced proangiogenic phenotypes. Our findings suggest that activating PGC-1α signalling impairs proangiogenic phenotype of CAFs by blocking PFKFB3-driven glycolysis.