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Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
Assuntos
Progressão da Doença , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteogenômica , Fumar/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinógenos/toxicidade , Estudos de Coortes , Citosina Desaminase/metabolismo , Ásia Oriental , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Genoma Humano , Humanos , Metaloproteinases da Matriz/metabolismo , Mutação/genética , Análise de Componente PrincipalRESUMO
Protein post-translational modifications (PTMs) are crucial in plant cellular processes, particularly in protein folding and signal transduction. N-glycosylation and phosphorylation are notably significant PTMs, playing essential roles in regulating plant responses to environmental stimuli. However, current sequential enrichment methods for simultaneous analysis of phosphoproteome and N-glycoproteome are labor-intensive and time-consuming, limiting their throughput. Addressing this challenge, this study introduces a novel tandem S-Trap-IMAC-HILIC (S-Trap: suspension trapping; IMAC: immobilized metal ion affinity chromatography; HILIC: hydrophilic interaction chromatography) strategy, termed TIMAHAC, for simultaneous analysis of plant phosphoproteomics and N-glycoproteomics. This approach integrates IMAC and HILIC into a tandem tip format, streamlining the enrichment process of phosphopeptides and N-glycopeptides. The key innovation lies in the use of a unified buffer system and an optimized enrichment sequence to enhance efficiency and reproducibility. The applicability of TIMAHAC was demonstrated by analyzing the Arabidopsis phosphoproteome and N-glycoproteome in response to abscisic acid (ABA) treatment. Up to 1954 N-glycopeptides and 11,255 phosphopeptides were identified from Arabidopsis, indicating its scalability for plant tissues. Notably, distinct perturbation patterns were observed in the phosphoproteome and N-glycoproteome, suggesting their unique contributions to ABA response. Our results reveal that TIMAHAC offers a comprehensive approach to studying complex regulatory mechanisms and PTM interplay in plant biology, paving the way for in-depth investigations into plant signaling networks.
Assuntos
Arabidopsis , Cromatografia de Afinidade , Fosfoproteínas , Proteômica , Fluxo de Trabalho , Proteômica/métodos , Arabidopsis/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/análise , Cromatografia de Afinidade/métodos , Proteínas de Arabidopsis/metabolismo , Glicopeptídeos/metabolismo , Glicopeptídeos/análise , Interações Hidrofóbicas e Hidrofílicas , Processamento de Proteína Pós-Traducional , Proteoma/metabolismo , Fosforilação , Fosfopeptídeos/metabolismo , Fosfopeptídeos/análise , Espectrometria de Massas em Tandem , Proteínas de Plantas/metabolismoRESUMO
Osmotic stress significantly hampers plant growth and crop yields, emphasizing the need for a thorough comprehension of the underlying molecular responses. Previous research has demonstrated that osmotic stress rapidly induces calcium influx and signaling, along with the activation of a specific subset of protein kinases, notably the Raf-like protein (RAF)-sucrose nonfermenting-1-related protein kinase 2 (SnRK2) kinase cascades within minutes. However, the intricate interplay between calcium signaling and the activation of RAF-SnRK2 kinase cascades remains elusive. Here, in this study, we discovered that Raf-like protein (RAF) kinases undergo hyperphosphorylation in response to osmotic shocks. Intriguingly, treatment with the calcium chelator EGTA robustly activates RAF-SnRK2 cascades, mirroring the effects of osmotic treatment. Utilizing high-throughput data-independent acquisition-based phosphoproteomics, we unveiled the global impact of EGTA on protein phosphorylation. Beyond the activation of RAFs and SnRK2s, EGTA treatment also activates mitogen-activated protein kinase cascades, Calcium-dependent protein kinases, and receptor-like protein kinases, etc. Through overlapping assays, we identified potential roles of mitogen-activated protein kinase kinase kinase kinases and receptor-like protein kinases in the osmotic stress-induced activation of RAF-SnRK2 cascades. Our findings illuminate the regulation of phosphorylation and cellular events by Ca2+ signaling, offering insights into the (exocellular) Ca2+ deprivation during early hyperosmolality sensing and signaling.
RESUMO
α- and ß-neurexins are extensively alternatively spliced, presynaptic cell-adhesion molecules that are thought to organize synapse assembly. However, recent data revealed that, in the hippocampus in vivo, the deletion of one neurexin isoform, Nrxn2, surprisingly increased excitatory synapse numbers and enhanced their presynaptic release probability, suggesting that Nrxn2 restricts, instead of enabling, synapse assembly. To delineate the synaptic function and mechanism of action of Nrxn2, we examined cultured hippocampal neurons as a reduced system. In heterologous synapse formation assays, different alternatively spliced Nrxn2ß isoforms robustly promoted synapse assembly similar to Nrxn1ß and Nrxn3ß, consistent with a general synaptogenic function of neurexins. Deletion of Nrxn2 from cultured hippocampal neurons, however, caused a significant increase in synapse density and release probability, replicating the in vivo data that suggested a synapse-restricting function. Rescue experiments revealed that two of the four Nrxn2ß splice variants (Nrxn2ß-SS4+/SS5- and Nrxn2ß-SS4+/SS5+) reversed the increase in synapse density in Nrxn2-deficient neurons, whereas only one of the four Nrxn2ß splice variants (Nrxn2ß-SS4+/SS5+) normalized the increase in release probability in Nrxn2-deficient neurons. Thus, a subset of Nrxn2 splice variants restricts synapse numbers and restrains their release probability in cultured neurons.
Assuntos
Processamento Alternativo , Sinapses , Sinapses/metabolismo , Hipocampo/metabolismo , Moléculas de Adesão Celular/metabolismo , Neurônios/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/metabolismoRESUMO
Secondary mutation, T790M, conferring tyrosine kinase inhibitors (TKIs) resistance beyond oncogenic epidermal growth factor receptor (EGFR) mutations presents a challenging unmet need. Although TKI-resistant mechanisms are intensively investigated, the underlying responses of cancer cells adapting drug perturbation are largely unknown. To illuminate the molecular basis linking acquired mutation to TKI resistance, affinity purification coupled mass spectrometry was adopted to dissect EGFR interactome in TKI-sensitive and TKI-resistant non-small cell lung cancer cells. The analysis revealed TKI-resistant EGFR-mutant interactome allocated in diverse subcellular distribution and enriched in endocytic trafficking, in which gefitinib intervention activated autophagy-mediated EGFR degradation and thus autophagy inhibition elevated gefitinib susceptibility. Alternatively, gefitinib prompted TKI-sensitive EGFR translocating toward cell periphery through Rab7 ubiquitination which may favor efficacy to TKIs suppression. This study revealed that T790M mutation rewired EGFR interactome that guided EGFR to autophagy-mediated degradation to escape treatment, suggesting that combination therapy with TKI and autophagy inhibitor may overcome acquired resistance in non-small cell lung cancer.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Gefitinibe/farmacologia , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular TumoralRESUMO
Mild isolated fetal ventriculomegaly (iFVM) is the most common abnormality of the fetal central nervous system. It is characterized by enlargement of one or both of the lateral ventricles (defined as ventricular width greater than 10 mm, but less than 12 mm). Despite its high prevalence, the pathophysiology of iFVM during fetal brain development and the neurobiological substrate beyond ventricular enlargement remain unexplored. In this work, we aimed to establish the relationships between the structural development of transient fetal brain zones/compartments and increased cerebrospinal fluid volume. For this purpose, we used in vivo structural T2-weighted magnetic resonance imaging of 89 fetuses (48 controls and 41 cases with iFVM). Our results indicate abnormal development of transient zones/compartments belonging to both hemispheres (i.e. on the side with and also on the contralateral side without a dilated ventricle) in fetuses with iFVM. Specifically, compared to controls, we observed enlargement of proliferative zones and overgrowth of the cortical plate in iFVM with associated reduction of volumes of central structures, subplate, and fetal white matter. These results indicate that enlarged lateral ventricles might be linked to the development of transient fetal zones and that global brain development should be taken into consideration when evaluating iFVM.
Assuntos
Hidrocefalia , Imageamento por Ressonância Magnética , Gravidez , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Ultrassonografia Pré-Natal/métodos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/complicações , Hidrocefalia/patologia , Encéfalo/patologia , FetoRESUMO
OBJECTIVE: To address the challenge of assessing sedation status in critically ill patients in the intensive care unit (ICU), we aimed to develop a non-contact automatic classifier of agitation using artificial intelligence and deep learning. METHODS: We collected the video recordings of ICU patients and cut them into 30-second (30-s) and 2-second (2-s) segments. All of the segments were annotated with the status of agitation as "Attention" and "Non-attention". After transforming the video segments into movement quantification, we constructed the models of agitation classifiers with Threshold, Random Forest, and LSTM and evaluated their performances. RESULTS: The video recording segmentation yielded 427 30-s and 6405 2-s segments from 61 patients for model construction. The LSTM model achieved remarkable accuracy (ACC 0.92, AUC 0.91), outperforming other methods. CONCLUSION: Our study proposes an advanced monitoring system combining LSTM and image processing to ensure mild patient sedation in ICU care. LSTM proves to be the optimal choice for accurate monitoring. Future efforts should prioritize expanding data collection and enhancing system integration for practical application.
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Aprendizado Profundo , Agitação Psicomotora , Humanos , Agitação Psicomotora/diagnóstico , Inteligência Artificial , Unidades de Terapia Intensiva , Cuidados CríticosRESUMO
MicroRNAs (miRNAs) can regulate the expression of genes involved in the establishment of the window of implantation (WOI) in the endometrium. Recent studies indicated that cell-free miRNAs in uterine fluid and blood samples could act as alternative and non-invasive sample types for endometrial receptivity analysis. In this study, we attempt to systematically evaluate whether the expression levels of cell-free microRNAs in blood samples could be used as non-invasive biomarkers for assessing endometrial receptivity status. We profiled the miRNA expression levels of 111 blood samples using next-generation sequencing to establish a predictive model for the assessment of endometrial receptivity status. This model was validated with an independent dataset (n = 73). The overall accuracy is 95.9%. Specifically, we achieved accuracies of 95.9%, 95.9%, and 100.0% for the pre-receptive group, the receptive group, and the post-respective group, respectively. Additionally, we identified a set of differentially expressed miRNAs between different endometrial receptivity statuses using the following criteria: p-value < 0.05 and fold change greater than 1.5 or less than -1.5. In conclusion, the expression levels of cell-free miRNAs in blood samples can be utilized in a non-invasive manner to distinguish different endometrial receptivity statuses.
Assuntos
MicroRNA Circulante , MicroRNAs , Feminino , Humanos , Implantação do Embrião/genética , Transferência Embrionária , Endométrio , MicroRNAs/genéticaRESUMO
Spontaneous neurotransmitter release is a fundamental property of synapses in which neurotransmitter filled vesicles release their content independent of presynaptic action potentials (APs). Despite their seemingly random nature, these spontaneous fusion events can be regulated by Ca2+ signaling pathways. Here, we probed the mechanisms that maintain Ca2+ sensitivity of spontaneous release events in synapses formed between hippocampal neurons cultured from rats of both sexes. In this setting, we examined the potential role of vesicle-associated membrane protein 4 (VAMP4), a vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein in spontaneous neurotransmission. Our results show that VAMP4 is required for Ca2+-dependent spontaneous excitatory neurotransmission, with a limited role in spontaneous inhibitory neurotransmission. Key residues in VAMP4 that regulate its retrieval as well as functional clathrin-mediated vesicle trafficking were essential for the maintenance of VAMP4-mediated spontaneous release. Moreover, high-frequency stimulation (HFS) that typically triggers asynchronous release and retrieval of VAMP4 from the plasma membrane also augmentsCa2+-sensitive spontaneous release for up to 30 min in a VAMP4-dependent manner. This VAMP4-mediated link between asynchronous and spontaneous excitatory neurotransmission might serve as a presynaptic substrate for synaptic plasticity coupling distinct forms of release.SIGNIFICANCE STATEMENT Spontaneous neurotransmitter release that occurs independent of presynaptic action potentials (APs) shows significant sensitivity to intracellular Ca2+ levels. In this study, we identify the vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) molecule vesicle-associated membrane protein 4 (VAMP4) as a key component of the machinery that maintains these Ca2+-sensitive fraction of spontaneous release events. Following brief intense activity, VAMP4-dependent synaptic vesicle retrieval supports a pool of vesicles that fuse spontaneously in the long term. We propose that this vesicle trafficking pathway acts to shape spontaneous release and associated signaling based on previous activity history of synapses.
Assuntos
Cálcio/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Proteínas R-SNARE/metabolismo , Vesículas Sinápticas/metabolismo , Potenciais de Ação/fisiologia , Animais , Células Cultivadas , Feminino , Hipocampo/citologia , Masculino , Camundongos , Neurônios/citologia , Técnicas de Patch-Clamp , Proteínas R-SNARE/genética , Ratos , Ratos Sprague-Dawley , Sinapses/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
The strongest evidence of the oncogenicity of Epstein-Barr virus (EBV) in vitro is its ability to immortalize human primary B lymphocytes into lymphoblastoid cell lines (LCLs). Yet the underlying mechanisms explaining how the virus tempers the growth program of the host cells have not been fully elucidated. The mitogen-activated protein kinases (MAPKs) are implicated in many cellular processes and are constitutively activated in LCLs. We questioned the expression and regulation of the dual-specificity phosphatases (DUSPs), the main negative regulator of MAPKs, during EBV infection and immortalization. Thirteen DUSPs, including 10 typical and 3 atypical types of DUSPs, were tested. Most of them were downregulated after EBV infection. Here, a role of viral oncogene latent membrane protein 1 (LMP1) in limiting DUSP6 and DUSP8 expression was identified. Using MAPK inhibitors, we found that LMP1 activates extracellular signal-regulated kinase (ERK) or p38 to repress the expression of DUSP6 and DUSP8, with corresponding substrate specificity. Morphologically, overexpression of DUSP6 and DUSP8 attenuates the ability of EBV-immortalized LCL cells to clump together. Mechanistically, apoptosis induced by restoring DUSP6 and DUSP8 in LCLs indicated a novel mechanism for LMP1 to provide a survival signal during EBV immortalization. Collectively, this report provides the first description of the interplay between EBV genes and DUSPs and contributes considerably to the interpretation of MAPK regulation in EBV immortalization.IMPORTANCE Infections by the ubiquitous Epstein-Barr virus (EBV) are associated with a wide spectrum of lymphomas and carcinomas. It has been well documented that activation levels of MAPKs are found in cancer cells to translate various external or intrinsic stimuli into cellular responses. Physiologically, the dual-specificity phosphates (DUSPs) exhibit great ability in regulating MAPK activities with respect to their capability of dephosphorylating MAPKs. In this study, we found that DUSPs were generally downregulated after EBV infection. EBV oncogenic latent membrane protein 1 (LMP1) suppressed DUSP6 and DUSP8 expression via MAPK pathway. In this way, LMP1-mediated MAPK activation was a continuous process. Furthermore, DUSP downregulation was found to contribute greatly to prevent apoptosis of EBV-infected cells. To sum up, this report sheds light on a novel molecular mechanism explaining how EBV maintains the unlimited proliferation status of the immortalized cells and provides a new link to understand EBV-induced B cell survival.
Assuntos
Fosfatases de Especificidade Dupla/genética , Herpesvirus Humano 4/metabolismo , Proteínas da Matriz Viral/metabolismo , Apoptose/genética , Linfócitos B/virologia , Linhagem Celular Tumoral , Fosfatases de Especificidade Dupla/metabolismo , Infecções por Vírus Epstein-Barr/virologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Genes Virais/genética , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Cultura Primária de Células , Proteínas da Matriz Viral/fisiologia , Proteínas Virais/metabolismo , Latência Viral/genética , Latência Viral/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Sepsis is life-threatening organ dysfunction due to dysregulated systemic inflammatory and immune response to infection, often leading to cognitive impairments. Growing evidence shows that artemisinin, an antimalarial drug, possesses potent anti-inflammatory and immunoregulatory activities. In this study we investigated whether artemisinin exerted protective effect against neurocognitive deficits associated with sepsis and explored the underlying mechanisms. Mice were injected with LPS (750 µg · kg-1 · d-1, ip, for 7 days) to establish an animal model of sepsis. Artemisinin (30 mg · kg-1 · d-1, ip) was administered starting 4 days prior LPS injection and lasting to the end of LPS injection. We showed that artemisinin administration significantly improved LPS-induced cognitive impairments assessed in Morris water maze and Y maze tests, attenuated neuronal damage and microglial activation in the hippocampus. In BV2 microglial cells treated with LPS (100 ng/mL), pre-application of artemisinin (40 µΜ) significantly reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-6) and suppressed microglial migration. Furthermore, we revealed that artemisinin significantly suppressed the nuclear translocation of NF-κB and the expression of proinflammatory cytokines by activating the AMPKα1 pathway; knockdown of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin in BV2 microglial cells. In conclusion, atemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect is probably mediated by activation of the AMPKα1 signaling pathway in microglia.
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Artemisininas/uso terapêutico , Microglia/efeitos dos fármacos , Transtornos Neurocognitivos/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/metabolismo , Neurônios/efeitos dos fármacos , Sepse/induzido quimicamente , Sepse/complicações , Sepse/metabolismoRESUMO
Recent studies demonstrated that FoxO3 circular RNA (circFoxO3) plays an important regulatory role in tumourigenesis and cardiomyopathy. However, the role of circFoxO3 in neurodegenerative diseases remains unknown. The aim of this study was to examine the possible role of circFoxO3 in neurodegenerative diseases and the underlying mechanisms. To model human neurodegenerative conditions, hippocampus-derived neurons were treated with glutamate. Using molecular and cellular biology approaches, we found that circFoxO3 expression was significantly higher in the glutamate treatment group than that in the control group. Furthermore, silencing of circFoxO3 protected HT22 cells from glutamate-induced oxidative injury through the inhibition of the mitochondrial apoptotic pathway. Collectively, our study demonstrates that endogenous circFoxO3 plays a key role in inducing apoptosis and neuronal cell death and may act as a novel therapeutic target for neurodegenerative diseases.
Assuntos
Apoptose/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Hipocampo/metabolismo , Mitocôndrias/metabolismo , RNA Circular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína Forkhead Box O3/genética , Ácido Glutâmico/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Background and Purpose: Oxidative stress is involved in the development of infections. However, whether oxidative stress indicators can be used as markers of stroke-associated infection (SAI) is still unclear. The purpose of this study was to test the predictive values of superoxide dismutase (SOD) and malondialdehyde (MDA) levels for SAI incidence.Methods: A total of 45 consecutive patients with ischemic stroke who were admitted to our hospital were enrolled. A prospective study was carried out to observe the occurrence of SAI during the first 7 days after stroke. Accordingly, the patients were divided into SAI and non-SAI groups. The relationship between SOD and MDA serum levels and SAI was analyzed.Results: The patients in the SAI group had significantly higher serum SOD levels than those in the non-SAI group (41.638 ± 3.428 U/ml vs. 36.542 ± 9.114 U/ml, p = 0.033). However, there were no significant differences in MDA levels between the SAI and non-SAI group (p > 0.05). The discriminating ability of serum SOD level for SAI was measured using an ROC curve. Serum level of SOD >38.16 U/ml was useful in diagnosing SAI with a sensitivity of 88% and a specificity of 61%. Kaplan-Meier curves showed that the group with serum SOD level >38.16 U/ml had higher rates of SAI incidence (χ2 = 9.688, p = 0.002; log rank test). Furthermore, Cox regression analysis indicated that a serum SOD level >38.16 U/ml was an independent risk factor for SAI (hazard ratio = 5.836; 95% CI, 1.298-26.244; p = 0.021).Conclusions: Acute-phase serum SOD level could be a predictor of SAI.
Assuntos
Isquemia Encefálica/sangue , Infecções/sangue , Infecções/diagnóstico , Inflamação/sangue , Estresse Oxidativo , Acidente Vascular Cerebral/sangue , Superóxido Dismutase/sangue , Idoso , Biomarcadores/sangue , Isquemia Encefálica/complicações , Feminino , Humanos , Infecções/etiologia , Inflamação/etiologia , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Estudos Prospectivos , Sensibilidade e Especificidade , Acidente Vascular Cerebral/complicaçõesRESUMO
Early brain development, from the embryonic period to infancy, is characterized by rapid structural and functional changes. These changes can be studied using structural and physiological neuroimaging methods. In order to optimally acquire and accurately interpret this data, concepts from adult neuroimaging cannot be directly transferred. Instead, one must have a basic understanding of fetal and neonatal structural and physiological brain development, and the important modulators of this process. Here, we first review the major developmental milestones of transient cerebral structures and structural connectivity (axonal connectivity) followed by a summary of the contributions from ex vivo and in vivo MRI. Next, we discuss the basic biology of neuronal circuitry development (synaptic connectivity, i.e. ensemble of direct chemical and electrical connections between neurons), physiology of neurovascular coupling, baseline metabolic needs of the fetus and the infant, and functional connectivity (defined as statistical dependence of low-frequency spontaneous fluctuations seen with functional magnetic resonance imaging (fMRI)). The complementary roles of magnetic resonance imaging (MRI), electroencephalography (EEG), magnetoencephalography (MEG), and near-infrared spectroscopy (NIRS) are discussed. We include a section on modulators of brain development where we focus on the placenta and emerging placental MRI approaches. In each section we discuss key technical limitations of the imaging modalities and some of the limitations arising due to the biology of the system. Although neuroimaging approaches have contributed significantly to our understanding of early brain development, there is much yet to be done and a dire need for technical innovations and scientific discoveries to realize the future potential of early fetal and infant interventions to avert long term disease.
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Encéfalo/diagnóstico por imagem , Encéfalo/embriologia , Neuroimagem/métodos , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Mapeamento Encefálico , Feminino , Idade Gestacional , Humanos , Lactente , Vias Neurais/irrigação sanguínea , Vias Neurais/diagnóstico por imagem , Vias Neurais/embriologia , Vias Neurais/fisiologia , Acoplamento Neurovascular , Gravidez , Substância Branca/irrigação sanguínea , Substância Branca/diagnóstico por imagem , Substância Branca/embriologia , Substância Branca/fisiologiaRESUMO
BACKGROUND: Efficient assessment of patients after ischemic stroke has important reference value for doctors to choose appropriate treatment for patients. Our study aimed to develop a new prognostic model for predicting outcomes 3 months after ischemic stroke among Chinese Population. METHODS: A prospective observational cohort study among ischemic stroke patients presenting to Emergency Department in the Second Affiliated Hospital of Guangzhou Medical University was conducted from May 2012 to June 2013. Demographic data of ischemic stroke patients, assessment of NIHSS and laboratory results were collected. Based on 3-month modified Rankin Scale (mRS) ischemic stroke patients were divided into either favorable outcome (mRS: 0-2) or unfavorable outcome groups (mRS: 3-6). The variables closely associated with prognosis of ischemic stroke were selected to develop the new prognostic model (NAAP) consisted of 4 parameters: NIHSS, age, atrial fibrillation, and prealbumin. The prognostic value of the modified prognostic model was then compared with NIHSS alone. RESULTS: A total of 454 patients with suspected stroke were recruited. One hundred eighty-six patients with ischemic stroke were included in the final analysis. A new prognostic model, NAAP was developed. The area under curve (AUC) of NAAP was .861 (95%confidence interval: .803-.907), whilst the AUC of NIHSS was .783 (95%CI: .717-.840), (Pâ¯=â¯.0048). Decision curve analysis showed that NAAP had a higher net benefit for threshold probabilities of 65% for predictive risk of poor outcomes. CONCLUSIONS: The modified prognostic model, NAAP may be a better prognostic tool for predicting 3-month unfavorable outcomes for ischemic stroke than NIHSS alone.
Assuntos
Isquemia Encefálica/diagnóstico , Acidente Vascular Cerebral/diagnóstico , Idoso , Isquemia Encefálica/terapia , China , Técnicas de Apoio para a Decisão , Feminino , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Acidente Vascular Cerebral/terapia , Fatores de TempoRESUMO
Surgical interventions on the alveolar ridges aimed at facilitating orthodontic tooth movement have been extensively reported. However, unexpected events or complications still occur in daily practice. The purpose of this report was to present a novel 3-dimensional (3D) computer-assisted piezocision guide (CAPG) designed to be translucent for increased visibility, rigid for enhanced support during guidance, and porous for profuse irrigation during procedure. Such a design can function to minimize the risk of surgical complications. In this case, we present a novel 3D-printed CAPG to facilitate a minimally invasive periodontal accelerated osteogenic orthodontics (PAOO) procedure with a guide that provides accuracy, adequate visibility, and greater access for the coolant to reach the surgery site. By navigating the cone-beam computed tomography data, we precisely know the cortical bone thickness, root direction, and interrelations between anatomic structures in an individual situation, which allows us to design our cutting slot for the required length and depth according to the operator's knowledge. Finally, 3D printing was applied, transferring our surgical plan to fabricate the CAPG. Moreover, the well designed pores on the CAPG allow effective irrigation during the piezocision procedure. This minimally invasive procedure was uneventful, and no devitalized tooth or alveolar bone was found.
Assuntos
Procedimentos Cirúrgicos Ortognáticos/métodos , Piezocirurgia/métodos , Impressão Tridimensional , Processo Alveolar/cirurgia , Feminino , Humanos , Má Oclusão Classe I de Angle/cirurgia , Pessoa de Meia-Idade , Ortodontia Corretiva/métodosRESUMO
Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and is a significant risk factor for hospitalization and shortened life expectancy. Therefore, developing new serum biomarkers for early diagnosis and prognosis of COPD associated PH is crucial. In the present study, a solid-phase antibody array simultaneously detecting multiple proteins was used to search specific COPD associated PH biomarkers, with COPD patients and healthy subjects as control groups. As a result, compared to the COPD and healthy groups, the levels of MCP-4, SDF-1 alpha, CCL28, Adipsin, IL-28A, CD40 and AgRP were uniquely altered in COPD patient serum with pulmonary hypertension. Among these proteins, CCL28, MCP-4, CD40, AgRP and IL-28A were identified to be differentially expressed in COPD patients with hypertension, indicating that these cytokines may serve as novel biomarkers for the diagnosis and prognosis of COPD associated pulmonary hypertension.
Assuntos
Citocinas/sangue , Hipertensão Pulmonar/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise Serial de Proteínas/métodos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Hong Kong (HK) and Guangzhou (GZ) are cities in China with different healthcare systems. This study aimed to compare 30-day and 6-month mortality and characteristics of patients with suspected cardiac chest pain admitted to two emergency departments (ED) in HK and GZ. METHODS: A prospective observational study enrolled patients with suspected cardiac chest pain presenting to EDs in the Prince of Wales Hospital (PWH), HK and the Second Affiliated Hospital of Guangzhou Medical University (AHGZMU),GZ. The primary outcome was 30-day and 6-month mortality. RESULTS: In total, 996 patients were recruited, 407 cases from GZ and 589 cases from HK.The 30-day and 6-month mortality of chest patients were 3.7% and 4.7% in GZand 0.3% and 1.9% in HK, respectively. Serum creatinine level (Cr) was an independent factor for 30-day mortality whilst Cr and systolic blood pressure (SBP) were independent factors for 6-month mortality. In Cox regression analysis, unadjusted and adjusted hazard ratios for 30-day and 6-month mortality in GZ were significantly increased. CONCLUSION: The 30-day and 6-month mortality of patients with suspected cardiac chest pain in Guangzhou were higher than in Hong Kong due to due to different baseline clinical characteristics of patients and different distributions of diagnoses, which were associated with different healthcare systems. Serum creatinine and SBP were independent factors for 30-day and 6-month mortality.
Assuntos
Angina Pectoris/diagnóstico , Angina Pectoris/mortalidade , Serviço Hospitalar de Cardiologia , Serviço Hospitalar de Emergência , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde , Idoso , Idoso de 80 Anos ou mais , Angina Pectoris/sangue , Angina Pectoris/fisiopatologia , Biomarcadores/sangue , Pressão Sanguínea , Comorbidade , Creatinina/sangue , Feminino , Frequência Cardíaca , Hong Kong/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
OBJECTIVE: The diagnosis of shock in patients presenting to the emergency department (ED) is often challenging. We aimed to compare the accuracy of experienced emergency physician gestalt against Li's pragmatic shock (LiPS) tool for predicting the likelihood of shock in the emergency department, using 30-day mortality as an objective standard. METHOD: In a prospective observational study conducted in an urban, academic ED in Hong Kong, adult patients aged 18years or older admitted to the resuscitation room or high dependency unit were recruited. Eligible patients had a standard ED workup for shock. The emergency physician treating the patient was asked whether he or she considered shock to be probable, and this was compared with LiPS. The proxy 'gold' or reference standard was 30-day mortality. The area under the receiver operating curve (AUROC) was used to predict prognosis. The primary outcome measure was 30-day mortality. RESULTS: A total of 220 patients fulfilled the inclusion criteria and were included in the analysis. The AUROC for LiPS (0.722; sensitivity=0.733, specificity=0.711, P<0.0001) was greater than emergency physician gestalt (0.620, sensitivity=0.467, specificity=0.774, P=0.0137) for diagnosing shock using 30-day mortality as a proxy (difference P=0.0229). LiPS shock patients were 6.750 times (95%CI=2.834-16.076, P<0.0001) more likely to die within 30-days compared with non-shock patients. Patients diagnosed by emergency physicians were 2.991 times (95%CI=1.353-6.615, P=0.007) more likely to die compared with the same reference. CONCLUSIONS: LiPS has a higher diagnostic accuracy than emergency physician gestalt for shock when compared against an outcome of 30-day mortality.