RESUMO
Prolyl hydroxylase domain (PHD) proteins are oxygen sensors that use intracellular oxygen as a substrate to hydroxylate hypoxia-inducible factor (HIF) α proteins, routing them for polyubiquitylation and proteasomal degradation. Typically, HIFα accumulation in hypoxic or PHD-deficient tissues leads to upregulated angiogenesis. Here, we report unexpected retinal phenotypes associated with endothelial cell (EC)-specific gene targeting of Phd2 (Egln1) and Hif2alpha (Epas1). EC-specific Phd2 disruption suppressed retinal angiogenesis, despite HIFα accumulation and VEGFA upregulation. Suppressed retinal angiogenesis was observed both in development and in the oxygen-induced retinopathy (OIR) model. On the other hand, EC-specific deletion of Hif1alpha (Hif1a), Hif2alpha, or both did not affect retinal vascular morphogenesis. Strikingly, retinal angiogenesis appeared normal in mice double-deficient for endothelial PHD2 and HIF2α. In PHD2-deficient retinal vasculature, delta-like 4 (DLL4, a NOTCH ligand) and HEY2 (a NOTCH target) were upregulated by HIF2α-dependent mechanisms. Inhibition of NOTCH signaling by a chemical inhibitor or DLL4 antibody partially rescued retinal angiogenesis. Taken together, our data demonstrate that HIF2α accumulation in retinal ECs inhibits rather than stimulates retinal angiogenesis, in part by upregulating DLL4 expression and NOTCH signaling.
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Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Células Endoteliais , Prolina Dioxigenases do Fator Induzível por Hipóxia , Receptores Notch , Neovascularização Retiniana , Transdução de Sinais , Regulação para Cima , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Camundongos , Receptores Notch/metabolismo , Receptores Notch/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/genética , Neovascularização Retiniana/patologia , Células Endoteliais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Retina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Vasos Retinianos/metabolismo , AngiogêneseRESUMO
Under normoxia, hypoxia inducible factor (HIF) α subunits are hydroxylated by PHDs (prolyl hydroxylase domain proteins) and subsequently undergo polyubiquitylation and degradation. Normal embryogenesis occurs under hypoxia, which suppresses PHD activities and allows HIFα to stabilize and regulate development. In this Primer, we explain molecular mechanisms of the oxygen-sensing pathway, summarize HIF-regulated downstream events, discuss loss-of-function phenotypes primarily in mouse development, and highlight clinical relevance to angiogenesis and tissue repair.
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Embrião de Mamíferos/embriologia , Desenvolvimento Embrionário , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Oxigênio/metabolismo , Ubiquitinação , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , CamundongosRESUMO
The translocation t(8;9) produces the fusion gene PCM1-JAK2, resulting in the continuous activation of the JAK2 tyrosine kinase. Myelodysplastic/myeloproliferative neoplasms are the most common disease with t(8;9)/PCM1-JAK2. Individuals with this abnormality have similar features, and JAK2 kinase inhibitor (ruxolitinib) is an effective treatment of the condition. The long-term remission results of ruxolitinib are varied. It is important to determine the response to ruxolitinib. Here, we describe a patient who has been diagnosed with eosinophilia-associated myeloproliferative neoplasm with t(8;9)(p21;p24). This patient has achieved sustained response for >1 year since the administration of ruxolitinib.
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Eosinofilia , Transtornos Mieloproliferativos , Neoplasias , Humanos , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Janus Quinase 2/genética , Nitrilas , Translocação Genética , Eosinofilia/tratamento farmacológico , Eosinofilia/genéticaRESUMO
Vascular pruning is crucial for normal development, but its underlying mechanisms are poorly understood. Here, we report that retinal vascular pruning is controlled by the oxygen-sensing mechanism in local astrocytes. Oxygen sensing is mediated by prolyl hydroxylase domain proteins (PHDs), which use O2 as a substrate to hydroxylate specific prolyl residues on hypoxia inducible factor (HIF)-α proteins, labeling them for polyubiquitylation and proteasomal degradation. In neonatal mice, astrocytic PHD2 deficiency led to elevated HIF-2α protein levels, expanded retinal astrocyte population and defective vascular pruning. Although astrocytic VEGF-A was also increased, anti-VEGF failed to rescue vascular pruning. However, stimulation of retinal astrocytic growth by intravitreal delivery of PDGF-A was sufficient to block retinal vascular pruning in wild-type mice. We propose that in normal development, oxygen from nascent retinal vasculature triggers PHD2-dependent HIF-2α degradation in nearby astrocytic precursors, thus limiting their further growth by driving them to differentiate into non-proliferative mature astrocytes. The physiological limit of retinal capillary density may be set by astrocytes available to support their survival, with excess capillaries destined for regression.This article has an associated 'The people behind the papers' interview.
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Astrócitos/citologia , Astrócitos/metabolismo , Oxigênio/metabolismo , Retina/citologia , Retina/metabolismo , Animais , Apoptose/fisiologia , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Camundongos , Pseudópodes/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
We quantified the serum levels of 34 cytokines/chemokines in 30 patients with SARS-CoV-2 infection. Elevated levels of IP-10 and IL-7 were detected in the acute and convalescent stages of the infection and were highly associated with disease severity.
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COVID-19/sangue , Quimiocina CXCL10/sangue , Interleucina-7/sangue , SARS-CoV-2/metabolismo , Índice de Gravidade de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The study aims to investigate the factors causing the difference of stroke patients' in-hospital cost and study these factors on health outcome in terms of mortality. METHODS: Eight hundred and sixty-two in-patients with stroke in a tertiary hospital in China from 2017 to 2019 were included in the database. Descriptive statistics indexes were used to describe patients' in-hospital cost and mortality. Based on Elixhauser coding algorithms, multiple linear regression and logistic regressions (LRs) were used to evaluate the impact of factors identified from univariate analysis on in-hospital cost and mortality, respectively. In addition to LRs, a comparison study was then carried out with random forest, gradient boosting decision tree and artificial neural network. RESULTS: Factors affecting both cost and mortality are age, discharged day-of-week, length of stay, stroke subtype, other neurological disorders, renal failure, fluid and electrolyte disorders and total number of comorbidities. CONCLUSION: With the increase of age, the mortality rate of in-patients (except for the juvenile) with stroke increases and the cost of hospitalization decreases. Intracerebral haemorrhage is the most devastating stroke for its highest mortality in short length of stay. Medical services should focus on these specific comorbidities.
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Custos Hospitalares , Acidente Vascular Cerebral , Mortalidade Hospitalar , Hospitalização , Humanos , Tempo de Internação , Centros de Atenção TerciáriaRESUMO
In this paper, a two-layer network is built to simulate the mechanism of visual selection and shifting based on the mapping dynamic model for instantaneous frequency. Unlike the differential equation model using limit cycle to simulate neuron oscillation, we build an instantaneous frequency mapping dynamic model to describe the change of the neuron frequency to avoid the difficulty of generating limit cycle. The activity of the neuron is rebuilt based on the instantaneous frequency and in this work, we use the first layer of neurons to implement image segmentation and the second layer of neurons to act as visual selector. The frequency of the second neuron (central neuron) is always changing, while central neuron resonates with the neurons corresponding to an object, the object is selected, then with the central neuron frequency changing, the selected object loses attention, the process goes on.
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Atenção , Redes Neurais de Computação , Percepção Visual , Atenção/fisiologia , Córtex Cerebral/fisiologia , Neurônios/fisiologia , Periodicidade , Retina/fisiologia , Percepção Visual/fisiologiaRESUMO
Deficiencies in prolyl hydroxylase domain proteins (PHDs) may lead to the accumulation of hypoxia-inducible factor-α proteins, the latter of which activate local angiogenic responses by paracrine mechanisms. Here, we investigate whether a keratinocyte-specific PHD deficiency may promote vascular survival and growth in a distantly located ischemic tissue by a remote signaling mechanism. We generated mice that carry a keratinocyte-specific Phd2 knockout (kPhd2KO) and performed femoral artery ligation. Relative to wild-type controls, kPhd2KO mice displayed improved vascular survival and arteriogenesis in ischemic hind limbs, leading to the accelerated recovery of hindlimb perfusion and superior muscle regeneration. Similar protective effects were also seen in type 1 and type 2 diabetic mice. Molecularly, both abundance of hypoxia-inducible factor-1α protein and expression of vascular endothelial growth factor-A were increased in epidermal tissues of kPhd2KO mice, accompanied by increased plasma concentration of vascular endothelial growth factor-A. Contrary to kPhd2KO mice, which are PHD2 deficient in all skin tissues, localized kPhd2KO in hindlimb skin tissues did not have similar effects, excluding paracrine signaling as a major mechanism. Confirming the existence of remote effects, hepatocyte-specific Phd2 knockout also protected hind limbs from ischemia injury. These data indicate that vascular survival and growth in ischemia-injured tissue may be stimulated by suppressing PHD2 in a remotely located tissue and may provide highly effective angiogenesis therapies without the need for directly accessing target tissues.
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Diabetes Mellitus Experimental/fisiopatologia , Membro Posterior/irrigação sanguínea , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Isquemia/fisiopatologia , Transdução de Sinais , Animais , Modelos Animais de Doenças , Artéria Femoral/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Knockout , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Prolyl hydroxylase domain (PHD) proteins catalyze oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor 1α and 2α, tagging them for pVHL-dependent polyubiquitination and proteasomal degradation. In this study, albumin Cre (Alb(Cre))-mediated, hepatocyte-specific triple disruption of Phd1, Phd2, and Phd3 (Phd(1/2/3)hKO) promoted liver erythropoietin (EPO) expression 1246-fold, whereas renal EPO was down-regulated to 6.7% of normal levels. In Phd(1/2/3)hKO mice, hematocrit levels reached 82.4%, accompanied by severe vascular malformation and steatosis in the liver. In mice double-deficient for hepatic PHD2 and PHD3 (Phd(2/3)hKO), liver EPO increase and renal EPO loss both occurred but were much less dramatic than in Phd(1/2/3)hKO mice. Hematocrit levels, vascular organization, and liver lipid contents all appeared normal in Phd(2/3)hKO mice. In a chronic renal failure model, Phd(2/3)hKO mice maintained normal hematocrit levels throughout the 8-week time course, whereas floxed controls developed severe anemia. Maintenance of normal hematocrit levels in Phd(2/3)hKO mice was accomplished by sensitized induction of liver EPO expression. Consistent with such a mechanism, liver HIF-2α accumulated to higher levels in Phd(2/3)hKO mice in response to conditions causing modest systemic hypoxia. Besides promoting erythropoiesis, EPO is also known to modulate retinal vascular integrity and neovascularization. In Phd(1/2/3)hKO mice, however, neonatal retinas remained sensitive to oxygen-induced retinopathy, suggesting that local EPO may be more important than hepatic and/or renal EPO in mediating protective effects in the retina.
Assuntos
Anemia/metabolismo , Eritropoetina/metabolismo , Falência Renal Crônica/metabolismo , Fígado/enzimologia , Prolil Hidroxilases/deficiência , Doenças Retinianas/metabolismo , Anemia/patologia , Animais , Western Blotting , Modelos Animais de Doenças , Falência Renal Crônica/patologia , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Doenças Retinianas/patologiaRESUMO
Voluntary motor performance is the result of cortical commands driving muscle actions. Corticomuscular coherence can be used to examine the functional coupling or communication between human brain and muscles. To investigate the effects of grip force level on corticomuscular coherence in an accessory muscle, this study proposed an expanded support vector regression (ESVR) algorithm to quantify the coherence between electroencephalogram (EEG) from sensorimotor cortex and surface electromyogram (EMG) from brachioradialis in upper limb. A measure called coherence proportion was introduced to compare the corticomuscular coherence in the alpha (7-15Hz), beta (15-30Hz) and gamma (30-45Hz) band at 25 % maximum grip force (MGF) and 75 % MGF. Results show that ESVR could reduce the influence of deflected signals and summarize the overall behavior of multiple coherence curves. Coherence proportion is more sensitive to grip force level than coherence area. The significantly higher corticomuscular coherence occurred in the alpha (p < 0.01) and beta band (p < 0.01) during 75 % MGF, but in the gamma band (p < 0.01) during 25 % MGF. The results suggest that sensorimotor cortex might control the activity of an accessory muscle for hand grip with increased grip intensity by changing functional corticomuscular coupling at certain frequency bands (alpha, beta and gamma bands).
Assuntos
Força da Mão/fisiologia , Modelos Neurológicos , Córtex Motor/fisiologia , Músculo Esquelético/fisiologia , Desempenho Psicomotor/fisiologia , Algoritmos , Eletroencefalografia , Eletromiografia , Humanos , Masculino , Máquina de Vetores de Suporte , Adulto JovemRESUMO
BACKGROUND: Experiencing a major natural disaster is a stressful event that challenges survival and sense of self. Adolescents are undergoing rapid developmental change in self-concept, and their sense of self is particularly susceptible to such stressful events. Although many studies have investigated adolescent self-concept, few have examined self-concept in relation to experiencing a natural disaster. OBJECTIVES: Following the Great Wenchuan Earthquake in Sichuan Province, China, in 2008, this study aimed to (a) describe disaster experiences; (b) describe social support, coping, and self-support; and (c) identify disaster experiences, social support, and coping factors associated with self-concept of adolescent survivors 3 months after the earthquake. METHODS: This was a large-scale cross-sectional study. A total of 1,976 adolescents living where the earthquake caused the most severe damage took part. The Tennessee Self-Concept Scale; Coping Styles Scale; and Internality, Powerful Others, and Chance Scales were used to assess self-concept, coping strategy, and locus of control, respectively. Sociodemographic characteristics, earthquake experiences, and social support were also obtained by self-report. RESULTS: Three months after the disaster, adolescent self-concept was generally positive. Locus of control centered on powerful others was the strongest predictor of total self-concept. The negative coping strategy, "abreacting," was a positive predictor of negative self-concept (self-criticism). DISCUSSION: Close attention to adolescents who use negative coping strategies and who tend to lack a sense of control is needed after major disaster events. Studies that examine long-term relationships between earthquake and other major disaster experiences and self-concept of adolescent survivors are needed.
Assuntos
Comportamento do Adolescente/psicologia , Desastres , Terremotos , Autoimagem , Transtornos de Estresse Pós-Traumáticos/psicologia , Sobreviventes/psicologia , Adaptação Psicológica , Adolescente , China , Estudos Transversais , Feminino , Humanos , Acontecimentos que Mudam a Vida , Masculino , Apoio Social , Fatores SocioeconômicosRESUMO
The quest for effective epilepsy treatments has spotlighted natural alkaloids due to their broad neuropharmacological effects. This review provides a comprehensive analysis of the antiseizure properties of various natural compounds, with an emphasis on their mechanisms of action and potential therapeutic benefits. Our findings reveal that bioactive substances such as indole, quinoline, terpenoid, and pyridine alkaloids confer medicinal benefits by modulating synaptic interactions, restoring neuronal balance, and mitigating neuroinflammation-key factors in managing epileptic seizures. Notably, these compounds enhance GABAergic neurotransmission, diminish excitatory glutamatergic activities, particularly at NMDA receptors, and suppress proinflammatory pathways. A significant focus is placed on the strategic use of nanoparticle delivery systems to improve the solubility, stability, and bioavailability of these alkaloids, which helps overcome the challenges associated with crossing the blood-brain barrier (BBB). The review concludes with a prospective outlook on integrating these bioactive substances into epilepsy treatment regimes, advocating for extensive research to confirm their efficacy and safety. Advancing the bioavailability of alkaloids and rigorously assessing their toxicological profiles are essential to fully leverage the therapeutic potential of these compounds in clinical settings.
RESUMO
Epilepsy is a chronic brain disease caused by excessive discharge of brain neurons. Long-term recurrent seizures bring a lot of trouble to patients and their families. Prediction of different stages of epilepsy is of great significance. We extract pearson correlation coefficients (PCC) between channels in different frequency bands as features of EEG signals for epilepsy stages prediction. However, the features are of large feature dimension and serious multi-collinearity. To eliminate these adverse influence, the combination of traditional dimension reduction method principal component analysis (PCA) and logistic regression method with regularization term is proposed to avoid over-fitting and achieve the feature sparsity. The experiments are conducted on the widely used CHB-MIT dataset using different regularization terms L1 and L2, respectively. The proposed method identifies various stages of epilepsy quickly and efficiently, and it presents the best average accuracy of 94.86%, average precision of 96.71%, average recall of 93.48%, average kappa value of 0.90 and average Matthews correlation coefficient (MCC) value of 0.90 for all patients.
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Insomnia is the most common sleep disorder linked with adverse long-term medical and psychiatric outcomes. Automatic sleep staging plays a crucial role in aiding doctors to diagnose insomnia disorder. Only a few studies have been conducted to develop automatic sleep staging methods for insomniacs, and most of them have utilized transfer learning methods, which involve pre-training models on healthy individuals and then fine-tuning them on insomniacs. Unfortunately, significant differences in feature distribution between the two subject groups impede the transfer performance, highlighting the need to effectively integrate the features of healthy subjects and insomniacs. In this paper, we propose a dual-teacher cross-domain knowledge transfer method based on the feature-based knowledge distillation to improve the performance of sleep staging for insomniacs. Specifically, the insomnia teacher directly learns from insomniacs and feeds the corresponding domain-specific features into the student network, while the health domain teacher guide the student network to learn domain-generic features. During the training process, we adopt the OFD (Overhaul of Feature Distillation) method to build the health domain teacher. We conducted the experiments to validate the proposed method, using the Sleep-EDF database as the source domain and the CAP-Database as the target domain. The results demonstrate that our method surpasses advanced techniques, achieving an average sleep staging accuracy of 80.56% on the CAP-Database. Furthermore, our method exhibits promising performance on the private dataset.
Assuntos
Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Sono , Bases de Dados Factuais , Nível de Saúde , Aprendizado de MáquinaRESUMO
BACKGROUND: Palliative care is mainly used to improve the quality of life of patients with chronic diseases by addressing their medical conditions and psychological problems. End-stage Parkinson's disease (PD) is also a progressive disease like cancer and could be managed by palliative care. This study was conducted at a single center in China and aimed to compare the quality of nurse-led palliative care with standard medical care during six months in 405 patients with Parkinson's disease (PPD) and their caregivers using the Chinese version of the 39-item Parkinson's Disease Questionnaire (PDQ-39) and the Chinese Zarit Burden Interview (ZBI) scale. METHODS: PPD (stage 2-5) received nurse-led palliative care (NP cohort, 103 patients; 103 caregivers) or neurologist-led standard care (NS cohort, 134 patients; 134 caregivers), or primary care practitioner-led usual care (PS cohort, 168 patients; 168 caregivers) for six months. RESULTS: Before the health professional-led care (BN), the PDQ-39 score of PPD was 68 (71-64) and their caregivers had 54.86 ± 7.64 a ZBI scale. After 6-months of the health professional-led care (AN), the PDQ-39 score of PPD and a ZBI scale of their caregivers decreased for the NP cohort as compared to those of BN condition and those of patients in the NS and PS cohorts at AN condition (p < 0.001 for all). CONCLUSIONS: The quality of life of PPD must be improved and the burden on their caregivers must be relieved. Nurse-led palliative care successfully improved the quality of life of PPD and reduced their caregiver burden.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Doença de Parkinson/psicologia , Qualidade de Vida/psicologia , Cuidadores/psicologia , Cuidados Paliativos , Estudos Retrospectivos , Papel do Profissional de EnfermagemRESUMO
In this study, dielectric barrier discharge (DBD) plasma combined with titanium dioxide/reduced graphene oxide/copper oxide (TiO2/rGO/Cu2O) composites for simultaneous removal of hexavalent chromium (Cr(â ¥)) and tetracycline (TC) from wastewater were explored systematically. The TiO2/rGO/Cu2O composites were successfully prepared to improve the specific surface area and charge carrier separation rate. When Cr(â ¥) and TC coexist, the two pollutants have better removal efficiency without changing the initial pH. Moreover, the removal efficiency of Cr(â ¥) and TC could be further improved in the DBD-TiO2/rGO/Cu2O system, indicating that the TiO2/rGO/Cu2O composites also exhibited good synergistic effects with the DBD plasma. The mechanism exploration showed that the TiO2/rGO/Cu2O composite catalyst could be activated in DBD system to produce various active species by photocatalytic reaction, among which photo-generated electrons and â¢O2- could significantly enhance Cr(â ¥) reduction, while photo-generated holes and â¢OH could improve TC degradation. More importantly, the intermediate products obtained from TC degradation can be oxidized to â¢CO2- by photo-generated holes, which can also facilitate the reduction of Cr(â ¥). This study shows that DBD combined with TiO2/rGO/Cu2O composites are capable of simultaneous Cr(â ¥) reduction and TC degradation, which would provide novel ideas for practical wastewater remediation.
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Grafite , Compostos Heterocíclicos , Águas Residuárias , Cobre , Tetraciclina , Titânio , Antibacterianos , CatáliseRESUMO
Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive malignancy, and timely diagnosis of ESCC contributes to an increased cancer survival rate. However, current detection methods for ESCC mainly rely on endoscopic examination, limited by a relatively low participation rate. Herein, ferric-particle-enhanced laser desorption/ionization mass spectrometry (FPELDI MS) is utilized to record the serum metabolic fingerprints (SMFs) from a retrospective cohort (523 non-ESCC participants and 462 ESCC patients) to build diagnostic models toward ESCC. The PFELDI MS achieved high speed (≈30 s per sample), desirable reproducibility (coefficients of variation < 15%), and high throughput (985 samples with ≈124â¯200 data points for each spectrum). Desirable diagnostic performance with area-under-the-curves (AUCs) of 0.925-0.966 is obtained through machine learning of SMFs. Further, a metabolic biomarker panel is constructed, exhibiting superior diagnostic sensitivity (72.2-79.4%, p < 0.05) as compared with clinical protein biomarker tests (4.3-22.9%). Notably, the biomarker panel afforded an AUC of 0.844 (95% confidence interval [CI]: 0.806-0.880) toward early ESCC diagnosis. This work highlighted the potential of metabolic analysis for accurate screening and early detection of ESCC and offered insights into the metabolic characterization of diseases including but not limited to ESCC.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Reprodutibilidade dos Testes , Biomarcadores TumoraisRESUMO
BACKGROUND: Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is a potential therapeutic target for cardiovascular diseases, but its role in angiogenesis remains controversial. Whereas germline Vegfr-1(-/-) embryos die of abnormal vascular development in association with excessive endothelial differentiation, mice lacking only the kinase domain appear healthy. METHODS AND RESULTS: We performed Cre-loxP-mediated knockout to abrogate the expression of all known VEGFR-1 functional domains in neonatal and adult mice and analyzed developmental, pathophysiological, and molecular consequences. VEGFR-1 deficiency promoted tip cell formation and endothelial cell proliferation and facilitated angiogenesis of blood vessels that matured and perfused properly. Vascular permeability was normal at the basal level but elevated in response to high doses of exogenous VEGF-A. In the postinfarct ischemic cardiomyopathy model, VEGFR-1 deficiency supported robust angiogenesis and protected against myocardial infarction. VEGFR-1 knockout led to abundant accumulation of VEGFR-2 at the protein level, increased VEGFR-2 tyrosine phosphorylation transiently, and enhanced serine phosphorylation of Akt and ERK. Interestingly, increased angiogenesis, tip cell formation, vascular permeability, VEGFR-2 accumulation, and Akt phosphorylation could be partially rescued or suppressed by one or more of the following manipulations, including injection of the VEGFR-2 selective inhibitor SU1498, anti-VEGF-A, or introduction of Vegfr-2(+/-) heterozygosity into Vegfr-1 somatic knockout mice. CONCLUSIONS: Upregulation of VEGFR-2 abundance at the protein level contributes in part to increased angiogenesis in VEGFR-1-deficient mice.
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Neovascularização Fisiológica/genética , Regulação para Cima , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Regulação para Cima/genética , Regulação para Cima/fisiologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologiaRESUMO
Tailless (TLX, an orphan nuclear receptor) and hypoxia inducible factor-2α (HIF2α) are both essential for retinal astrocyte and vascular development. Tlx-/- mutation and astrocyte specific Hif2α disruption in Hif2αf/f/GFAPCre mice are known to cause defective astrocyte development and block vascular development in neonatal retinas. Here we report that TLX and HIF2α support retinal angiogenesis by cooperatively maintaining retinal astrocytes in their proangiogenic states. While Tlx+/- and Hif2αf/+/GFAPCre mice are phenotypically normal, Tlx+/-/Hif2αf/+/GFAPCre mice display precocious retinal astrocyte differentiation towards non-angiogenic states, along with significantly reduced retinal angiogenesis. In wild-type mice, TLX and HIF2α coexist in the same protein complex, suggesting a cooperative function under physiological conditions. Furthermore, astrocyte specific disruption of Phd2 (prolyl hydroxylase domain protein 2), a manipulation previously shown to cause HIF2α accumulation, did not rescue retinal angiogenesis in Tlx-/- background, which suggests functional dependence of HIF2α on TLX. Finally, the expression of fibronectin and VEGF-A is significantly reduced in retinal astrocytes of neonatal Tlx+/-/Hif2αf/+/GFAPCre mice. Overall, these data indicate that TLX and HIF2α cooperatively support retinal angiogenesis by maintaining angiogenic potential of retinal astrocytes.