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1.
Scand J Trauma Resusc Emerg Med ; 29(1): 145, 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34602084

RESUMO

BACKGROUND: Sepsis is a life-threatening organ dysfunction and a major healthcare burden worldwide. Although sepsis is a medical emergency that requires immediate management, screening for the occurrence of sepsis is difficult. Herein, we propose a deep learning-based model (DLM) for screening sepsis using electrocardiography (ECG). METHODS: This retrospective cohort study included 46,017 patients who were admitted to two hospitals. A total of 1,548 and 639 patients had sepsis and septic shock, respectively. The DLM was developed using 73,727 ECGs from 18,142 patients, and internal validation was conducted using 7774 ECGs from 7,774 patients. Furthermore, we conducted an external validation with 20,101 ECGs from 20,101 patients from another hospital to verify the applicability of the DLM across centers. RESULTS: During the internal and external validations, the area under the receiver operating characteristic curve (AUC) of the DLM using 12-lead ECG was 0.901 (95% confidence interval, 0.882-0.920) and 0.863 (0.846-0.879), respectively, for screening sepsis and 0.906 (95% confidence interval (CI), 0.877-0.936) and 0.899 (95% CI, 0.872-0.925), respectively, for detecting septic shock. The AUC of the DLM for detecting sepsis using 6-lead and single-lead ECGs was 0.845-0.882. A sensitivity map revealed that the QRS complex and T waves were associated with sepsis. Subgroup analysis was conducted using ECGs from 4,609 patients who were admitted with an infectious disease, and the AUC of the DLM for predicting in-hospital mortality was 0.817 (0.793-0.840). There was a significant difference in the prediction score of DLM using ECG according to the presence of infection in the validation dataset (0.277 vs. 0.574, p < 0.001), including severe acute respiratory syndrome coronavirus 2 (0.260 vs. 0.725, p = 0.018). CONCLUSIONS: The DLM delivered reasonable performance for sepsis screening using 12-, 6-, and single-lead ECGs. The results suggest that sepsis can be screened using not only conventional ECG devices but also diverse life-type ECG machines employing the DLM, thereby preventing irreversible disease progression and mortality.


Assuntos
COVID-19 , Aprendizado Profundo , Sepse , Eletrocardiografia , Humanos , Estudos Retrospectivos , SARS-CoV-2 , Sepse/diagnóstico
2.
J Med Chem ; 64(17): 12525-12536, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34435786

RESUMO

Distinguishing compounds' agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered 6c (Ki = 2.40 nM) as a potent human A3 adenosine receptor (hA3AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA3AR homology models that consider the pharmacological profiles of the ligands. Taken together with molecular dynamics (MD) simulation and three-dimensional (3D) structural network analysis of the receptor-ligand complex, the results indicated that the hydrogen bonding with Thr943.36 and His2727.43 could make a stable interaction between the 3'-amino group with TM3 and TM7, and the corresponding induced-fit effects may play important roles in rendering the agonistic effect. Our results provide a more precise understanding of the compounds' actions at the atomic level and a rationale for the design of new drugs with specific pharmacological profiles.

3.
Theranostics ; 11(16): 8092-8111, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335982

RESUMO

Active c-Src non-receptor tyrosine kinase localizes to the plasma membrane via N-terminal lipid modification. Membranous c-Src causes cancer initiation and progression. Even though transmembrane 4 L six family member 5 (TM4SF5), a tetraspan(in), can be involved in this mechanism, the molecular and structural influence of TM4SF5 on c-Src remains unknown. Methods: Here, we investigated molecular and structural details by which TM4SF5 regulated c-Src devoid of its N-terminus and how cell-penetrating peptides were able to interrupt c-Src activation via interference of c-Src-TM4SF5 interaction in hepatocellular carcinoma models. Results: The TM4SF5 C-terminus efficiently bound the c-Src SH1 kinase domain, efficiently to the inactively-closed form. The complex involved protein tyrosine phosphatase 1B able to dephosphorylate Tyr530. The c-Src SH1 domain alone, even in a closed form, bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation. Homology modeling and molecular dynamics simulation studies predicted the directly interfacing residues, which were further validated by mutational studies. Cell penetration of TM4SF5 C-terminal peptides blocked the interaction of TM4SF5 with c-Src and prevented c-Src-dependent tumor initiation and progression in vivo. Conclusions: Collectively, these data demonstrate that binding of the TM4SF5 C-terminus to the kinase domain of inactive c-Src leads to its activation. Because this binding can be abolished by cell-penetrating peptides containing the TM4SF5 C-terminus, targeting this direct interaction may be an effective strategy for developing therapeutics that block the development and progression of hepatocellular carcinoma.


Assuntos
Proteína Tirosina Quinase CSK/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Membrana/metabolismo , Proteína Tirosina Quinase CSK/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Genes src/genética , Genes src/fisiologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Peptídeos/metabolismo , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Tetraspaninas/genética , Tetraspaninas/metabolismo
4.
J Electrocardiol ; 67: 124-132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34225095

RESUMO

BACKGROUND: Early detection and intervention is the cornerstone for appropriate treatment of arrhythmia and prevention of complications and mortality. Although diverse deep learning models have been developed to detect arrhythmia, they have been criticized due to their unexplainable nature. In this study, we developed an explainable deep learning model (XDM) to classify arrhythmia, and validated its performance using diverse external validation data. METHODS: In this retrospective study, the Sejong dataset comprising 86,802 electrocardiograms (ECGs) was used to develop and internally variate the XDM. The XDM based on a neural network-backed ensemble tree was developed with six feature modules that are able to explain the reasons for its decisions. The model was externally validated using data from 36,961 ECGs from four non-restricted datasets. RESULTS: During internal and external validation of the XDM, the average area under the receiver operating characteristic curves (AUCs) using a 12­lead ECG for arrhythmia classification were 0.976 and 0.966, respectively. The XDM outperformed a previous simple multi-classification deep learning model that used the same method. During internal and external validation, the AUCs of explainability were 0.925-0.991. CONCLUSION: Our XDM successfully classified arrhythmia using diverse formats of ECGs and could effectively describe the reason for the decisions. Therefore, an explainable deep learning methodology could improve accuracy compared to conventional deep learning methods, and that the transparency of XDM can be enhanced for its application in clinical practice.


Assuntos
Aprendizado Profundo , Algoritmos , Arritmias Cardíacas/diagnóstico , Eletrocardiografia , Humanos , Estudos Retrospectivos
5.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199677

RESUMO

The new advances in deep learning methods have influenced many aspects of scientific research, including the study of the protein system. The prediction of proteins' 3D structural components is now heavily dependent on machine learning techniques that interpret how protein sequences and their homology govern the inter-residue contacts and structural organization. Especially, methods employing deep neural networks have had a significant impact on recent CASP13 and CASP14 competition. Here, we explore the recent applications of deep learning methods in the protein structure prediction area. We also look at the potential opportunities for deep learning methods to identify unknown protein structures and functions to be discovered and help guide drug-target interactions. Although significant problems still need to be addressed, we expect these techniques in the near future to play crucial roles in protein structural bioinformatics as well as in drug discovery.


Assuntos
Aprendizado Profundo , Aprendizado de Máquina , Conformação Proteica , Software , Sequência de Aminoácidos , Biologia Computacional , Bases de Dados de Proteínas , Evolução Molecular , Humanos , Redes Neurais de Computação , Alinhamento de Sequência/métodos
6.
Ann Noninvasive Electrocardiol ; 26(3): e12839, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33719135

RESUMO

INTRODUCTION: The detection and monitoring of electrolyte imbalance is essential for appropriate management of many metabolic diseases; however, there is no tool that detects such imbalances reliably and noninvasively. In this study, we developed a deep learning model (DLM) using electrocardiography (ECG) for detecting electrolyte imbalance and validated its performance in a multicenter study. METHODS AND RESULTS: This retrospective cohort study included two hospitals: 92,140 patients who underwent a laboratory electrolyte examination and an ECG within 30 min were included in this study. A DLM was developed using 83,449 ECGs of 48,356 patients; the internal validation included 12,091 ECGs of 12,091 patients. We conducted an external validation with 31,693 ECGs of 31,693 patients from another hospital, and the result was electrolyte imbalance detection. During internal, the area under the receiving operating characteristic curve (AUC) of a DLM using a 12-lead ECG for detecting hyperkalemia, hypokalemia, hypernatremia, hyponatremia, hypercalcemia, and hypocalcemia were 0.945, 0.866, 0.944, 0.885, 0.905, and 0.901, respectively. The values during external validation of the AUC of hyperkalemia, hypokalemia, hypernatremia, hyponatremia, hypercalcemia, and hypocalcemia were 0.873, 0.857, 0.839, 0.856, 0.831, and 0.813 respectively. The DLM helped to visualize the important ECG region for detecting each electrolyte imbalance, and it showed how the P wave, QRS complex, or T wave differs in importance in detecting each electrolyte imbalance. CONCLUSION: The proposed DLM demonstrated high performance in detecting electrolyte imbalance. These results suggest that a DLM can be used for detecting and monitoring electrolyte imbalance using ECG on a daily basis.

7.
J Med Chem ; 64(1): 370-384, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33385210

RESUMO

Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and potent antagonism, whereas 1-oxo-1,2-dihydroisoquinolin-5-yl analogues (e.g., 3) showed full agonism with high potency. Our computational models provide insight into the agonist-antagonist boundary of the analogues suggesting that the Arg557 residue in the S4-S5 linker might be important for sensing the agonist binding and transmitting signals. These results provide structural insights into the TRPV1 and the protein-ligand interactions at a molecular level.


Assuntos
Descoberta de Drogas , Piridonas/química , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/química
8.
Int J Endocrinol ; 2020: 8737912, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178270

RESUMO

Background: Little information is available on the association between parents' metabolic syndrome (MetS) and adolescent offspring's obesity in Korea. The aim of our study is to determine the association between parent's metabolic syndrome and offspring's obesity. Methods: The study data were obtained from the Korean National Health and Nutrition Examination Survey conducted during 2009-2016. In the present study, 3140 adolescents aged 12 to 18 years, their paternal pairs (PP, fathers = 2244), and maternal pairs (MP, mothers = 3022) were analyzed. Of these 3140 adolescents, 2637 had normal weight {age- and sex-specific body mass index (BMI) under the 85th percentile}, whereas 467 were overweight (age- and sex-specific BMI over the 85th percentile). Results: Offspring's overweight and central obesity were associated with all components of the PP's metabolic risk factors, including central obesity (p < 0.001), systolic (p < 0.001) and diastolic blood pressure (p < 0.001), glucose intolerance (p < 0.001), and triglyceride (p < 0.002) and high-density lipoprotein levels (p=0.049). In addition, offspring's overweight and central obesity were also associated with the metabolic risk factors of MP, including central obesity (p < 0.001), systolic (p < 0.001) and diastolic blood pressure (p < 0.001), glucose intolerance (p < 0.001), and triglyceride levels (p < 0.001). In multivariate logistic regression analysis, offspring's overweight was significantly and positively associated with parental central obesity (PP, adjusted odds ratio (OR) = 1.593; 95% confidence interval (CI): 1.192-2.128; MP, adjusted OR = 2.221, 95% CI: 1.755-2.812) and parental metabolic syndrome (PP, adjusted OR = 2.032; 95% CI: 1.451-2.846; MP, adjusted OR = 2.972, 95% CI: 2.239-3.964). As the number of parental metabolic risk factors increased, offspring's risk for overweight and central obesity increased (p for trends < 0.001). Conclusion: Parental metabolic syndrome was associated with obesity in 12- to 18-year-old offspring in Korea.

9.
Mol Biol Cell ; 31(17): 1879-1891, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32520643

RESUMO

The E571K mutation of CRM1 is highly prevalent in some cancers, but its mechanism of tumorigenesis is unclear. Glu571 of CRM1 is located in its nuclear export signal (NES)-binding groove, suggesting that binding of select NESs may be altered. We generated HEK 293 cells with either monoallelic CRM1WT/E571K or biallelic CRM1E571K/E571K using CRISPR/Cas9. We also combined analysis of binding affinities and structures of 27 diverse NESs for wild-type and E571K CRM1 with structure-based bioinformatics. While most NESs bind the two CRM1 similarly, NESs from Mek1, eIF4E-transporter, and RPS2 showed >10-fold affinity differences. These NESs have multiple charged side chains binding close to CRM1 position 571, but this feature alone was not sufficient to predict different binding to CRM1(E571K). Consistent with eIF4E-transporter NES binding weaker to CRM1(E571K), eIF4E-transporter was mislocalized in tumor cells carrying CRM1(E571K). This serves as proof of concept that understanding how CRM1(E571K) affects NES binding provides a platform for identifying cargoes that are mislocalized in cancer upon CRM1 mutation. Finally, we showed that large affinity changes seen with some NES peptides (of Mek1 and RPS2) do not always translate to the full-length cargoes, suggesting limitations with current NES prediction methods. Therefore, comprehensive studies like ours are imperative to identify CRM1 cargoes with real pathogenic potential.


Assuntos
Carioferinas/genética , Sinais de Exportação Nuclear/genética , Receptores Citoplasmáticos e Nucleares/genética , Transporte Ativo do Núcleo Celular , Sequência de Aminoácidos/genética , Núcleo Celular/metabolismo , Cristalografia por Raios X/métodos , Células HEK293 , Humanos , Carioferinas/metabolismo , MAP Quinase Quinase 1/metabolismo , Modelos Moleculares , Mutação/genética , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Ligação Proteica/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Ribossômicas/metabolismo , Proteína ran de Ligação ao GTP/genética , Proteína ran de Ligação ao GTP/metabolismo
10.
Bioinformatics ; 36(3): 961-963, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504173

RESUMO

MOTIVATION: The consensus pattern of Nuclear Export Signal (NES) is a short sequence motif that is commonly identified in protein sequences, whether the motif acts as an NES (true positive) or not (false positive). Finding more plausible NES functioning regions among the vast array of consensus-matching segments would provide an interesting resource for further experimental validation. Better defined NES should also allow meaningful mapping of cancer-related mutation positions, leading to plausible explanations for the relationship between nuclear export and disease. RESULTS: Possible NES candidate regions are extracted from the cancer-related human reference proteome. Extracted NES are scored for reliability by combining sequence-based and structure-based approaches. The confidently identified NES candidate motifs were checked for overlap with cancer-related mutation positions annotated in the COSMIC database. Among the ∼700 cancer-related sequences in the COSMIC Cancer Gene Census, 178 sequences are predicted to have possible NES motifs containing cancer-related mutations at their key positions. These lists are organized into our database (pCRM1exportome), and other protein sequences in the human reference proteome can also be retrieved by their UniProt IDs. AVAILABILITY AND IMPLEMENTATION: The database is freely available at http://prodata.swmed.edu/pCRM1exportome. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Neoplasias , Sinais de Exportação Nuclear , Transporte Ativo do Núcleo Celular , Núcleo Celular , Humanos , Carioferinas , Receptores Citoplasmáticos e Nucleares , Reprodutibilidade dos Testes
11.
Theranostics ; 9(22): 6412-6423, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588226

RESUMO

Targeted delivery of therapeutic agents is of particular interest in the field of cancer treatment. However, there is an urgent need for developing clinically promising targeting approaches that can be readily administered in a green manner. Methods: Five phthalocyanine derivatives bearing different anionic and cationic groups were designed and synthesized. Then, their binding affinity with albumin were studied using gel assays, optical spectra and computational simulation. Finally, in vitro and in vivo fluorescence imaging and photodynamic therapy (PDT) evaluations were carried out. Results: The two positively charged compounds could selectively bind to albumin dimer over albumin monomer, while the three negatively charged phthalocyanines could bind to both albumin monomer and dimer. Following systemic administration, the phthalocyanines show improved tumor accumulation via transport by natural albumin. PDT evaluations indicate that one of the positively charged compounds, ZnPcN4, shows outstanding phototherapeutic efficacy against tumors in preclinical models. Conclusion: Our findings demonstrate that the use of water-soluble phthalocyanines as photosensitizers and in vivo albumin as a natural carrier may provide a green and efficient approach for tumor-targeted imaging and therapy.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Indóis/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Albumina Sérica Humana/metabolismo , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Células HT29 , Humanos , Indóis/administração & dosagem , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Multimerização Proteica , Soroalbumina Bovina/metabolismo , Albumina Sérica Humana/química , Solubilidade , Distribuição Tecidual , Água , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Medicine (Baltimore) ; 98(38): e17184, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567960

RESUMO

Although both multiple sclerosis (MS) and neuromyelitis optica (NMO) are demyelinating diseases, their psychiatric disturbances may differ given differences in the neurological manifestations. We used subjective and objective measurements to compare the psychiatric disturbances in patients with MS and NMO.Psychiatric disturbances were assessed in 24 MS and 35 NMO patients using the Beck Hopelessness Scale, Symptom Checklist-95 and the brief version of World Health Organization Quality of Life. Personality was assessed using the Big Five Inventory-10. Disease-related function was assessed using the Fatigue Severity Scale, Short-Form McGill Pain Questionnaire, and the Global Assessment of Function. Positivity offset (PO) and negativity bias (NB) and heart rate variability (HRV) were measured using a modified implicit affect test and photoplethysmograph, respectively. Data were analyzed using analysis of covariance with age and sex as covariates.MS patients had higher levels of depression, anxiety, panic attacks, obsessive-compulsiveness, aggression, paranoia, interpersonal sensitivity, self-regulation problems, stress vulnerability, and lower psychological quality of life (QOL) compared with NMO patients. The PO and NB and HRV values were not significantly different between groups. However, NMO patients had lower QOL, and higher levels of hopelessness, suicidality, and fatigue than the normal range. Disease duration was associated with hopelessness in NMO patients and with several psychiatric disturbances, but not hopelessness, in MS patients.Subjective psychiatric disturbances were more severe in patients with MS than in those with NMO, whereas PO and NB and HRV in patients with NMO were comparable with those of MS patients. Our findings highlight the need for different clinical approaches to assess and treat psychiatric disturbances in patients with MS and NMO.


Assuntos
Transtornos Mentais/etiologia , Esclerose Múltipla/psicologia , Neuromielite Óptica/psicologia , Adulto , Ansiedade/etiologia , Depressão/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Neuromielite Óptica/complicações , Transtorno Obsessivo-Compulsivo/etiologia , Transtorno de Pânico/etiologia , Transtornos Paranoides/etiologia , Escalas de Graduação Psiquiátrica , Qualidade de Vida/psicologia , Estresse Psicológico/etiologia
13.
Curr Opin Struct Biol ; 55: 147-153, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31102980

RESUMO

Demand for novel GPCR modulators is increasing as the association between the GPCR signaling pathway and numerous diseases such as cancers, psychological and metabolic disorders continues to be established. In silico structure-based drug design (SBDD) offers an outlet where researchers could exploit the accumulating structural information of GPCR to expedite the process of drug discovery. The coupling of structure-based approaches such as virtual screening and molecular docking with molecular dynamics and/or Monte Carlo simulation aids in reflecting the dynamics of proteins in nature into previously static docking studies, thus enhancing the accuracy of rationally designed ligands. This review will highlight recent computational strategies that incorporate protein flexibility into SBDD of GPCR-targeted ligands.


Assuntos
Receptores Acoplados a Proteínas G/química , Sítio Alostérico , Desenho de Fármacos , Descoberta de Drogas , Humanos , Ligantes , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Conformação Proteica
14.
Sci Rep ; 9(1): 6627, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036839

RESUMO

Nuclear export signal (NES) motifs function as essential regulators of the subcellular location of proteins by interacting with the major nuclear exporter protein, CRM1. Prediction of NES is of great interest in many aspects of research including cancer, but currently available methods, which are mostly based on the sequence-based approaches, have been suffered from high false positive rates since the NES consensus patterns are quite commonly observed in protein sequences. Therefore, finding a feature that can distinguish real NES motifs from false positives is desired to improve the prediction power, but it is quite challenging when only using the sequence. Here, we provide a comprehensive table for the validated cargo proteins, containing the location of the NES consensus patterns with the disordered propensity plots, known protein domain information, and the predicted secondary structures. It could be useful for determining the most plausible NES region in the context of the whole protein sequence and suggests possibilities for some non-binders of the annotated regions. In addition, using the currently available crystal structures of CRM1 bound to various classes of NES peptides, we adopted, for the first time, the structure-based prediction of the NES motifs bound to the CRM1's binding groove. Combining sequence-based and structure-based predictions, we suggest a novel and more straight-forward approach to identify CRM1-binding NES sequences by analysis of their structural prerequisites and energetic evaluation of the stability at the CRM1's binding site.


Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Núcleo Celular/metabolismo , Sinais de Exportação Nuclear/fisiologia , Transporte Ativo do Núcleo Celular/genética , Sítios de Ligação , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Sinais de Exportação Nuclear/genética , Ligação Proteica , Estrutura Secundária de Proteína , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo
15.
J Am Chem Soc ; 141(3): 1366-1372, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30565924

RESUMO

Albumin is a promising candidate as a biomarker for potential disease diagnostics and has been extensively used as a drug delivery carrier for decades. In these two directions, many albumin-detecting probes and exogenous albumin-based nanocomposite delivery systems have been developed. However, there are only a few cases demonstrating the specific interactions of exogenous probes with albumin in vivo, and nanocomposite delivery systems usually suffer from tedious fabrication processes and potential toxicity of the complexes. Herein, we demonstrate a facile "one-for-all" switchable nanotheranostic (NanoPcS) for both albumin detection and cancer treatment. In particular, the in vivo specific binding between albumin and PcS, arising from the disassembly of injected NanoPcS, is confirmed using an inducible transgenic mouse system. Fluorescence imaging and antitumor tests on different tumor models suggest that NanoPcS has superior tumor-targeting ability and the potential for time-modulated, activatable photodynamic therapy.


Assuntos
Corantes Fluorescentes/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Albumina Sérica/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/uso terapêutico , Masculino , Camundongos Transgênicos , Nanopartículas/química , Nanopartículas/metabolismo , Neoplasias/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/metabolismo , Gravidez , Ligação Proteica , Nanomedicina Teranóstica/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Psychiatry Investig ; 15(11): 1071-1078, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30380815

RESUMO

OBJECTIVE: We developed easily accessible imagery-based treatment program for patients with post-traumatic stress disorder (PTSD) related to workplace accidents and investigated the effects of the program on various PTSD related symptoms. METHODS: The program was based on an online platform and consisted of eight 15-min sessions that included script-guided imagery and supportive music. Thirty-five patients with workplace-related PTSD participated in this program 4 days per week for 4 weeks. Its effects were examined using self-report questionnaires before and after the take-home online treatment sessions. RESULTS: After completing the 4-week treatment program, patients showed significant improvements in depressed mood (t=3.642, p=0.001) based on the Patient Health Questionnaire-9 (PHQ-9), anxiety (t=3.198, p=0.003) based on the Generalized Anxiety Disorder seven-item (GAD-7) scale, and PTSD symptoms (t=5.363, p<0.001) based on the Posttraumatic Stress Disorder Check List (PCL). In particular, patients with adverse childhood experiences exhibited a greater degree of relief related to anxiety and PTSD symptoms than those without adverse childhood experiences. CONCLUSION: The present. RESULTS: demonstrated that the relatively short online imagery-based treatment program developed for this study had beneficial effects for patients with workplace-related PTSD.

17.
Soc Cogn Affect Neurosci ; 13(12): 1327-1336, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30445473

RESUMO

Does the biased attention toward social threats dwells on or disappears in patients with social anxiety disorder (SAD)? We investigated the neural mechanism of attentional bias in terms of attentional capture and holding in SAD. A total of 31 SAD patients and 30 healthy controls performed a continuous performance task detecting the orientation of a red letter 'T' while angry or neutral face distractors appeared or disappeared at the center of the screen. Behaviorally, typical attentional capture effects were found in response to abruptly appearing distractors in both groups. The patient group showed significant attentional dwelling effects in response to the angry face distractor only. Patients showed increased neural activity in the amygdala, insula/inferior frontal gyrus (IFG) and temporo-parietal junction (TPJ) compared with those of controls for the abruptly appearing angry distractor. Patients also maintained increased activities in brain regions related to attentional reorienting to distractor, namely the TPJ and IFG in line with their behavioral results of attentional holding effects. Our results indicate that patients with SAD showed prolonged attentional bias to task-irrelevant social threats. The underlying mechanism of prolonged attentional bias in SAD was indicated with amygdala hyperactivity and continued activity of the bottom-up attention network including the TPJ and IFG.


Assuntos
Atenção/fisiologia , Fobia Social/fisiopatologia , Adulto , Tonsila do Cerebelo , Ira/fisiologia , Viés de Atenção , Encéfalo/fisiologia , Mapeamento Encefálico , Córtex Cerebral , Face , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Tempo de Reação/fisiologia
18.
Psychiatry Investig ; 15(11): 1087-1093, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30481994

RESUMO

OBJECTIVE: Posttraumatic stress disorder (PTSD) is distinct from anxiety disorders in its etiology and clinical symptomatology, and was reclassified into trauma- and stressor-related disorders in DSM-5. This study aimed to find neurophysiological correlates differentiating PTSD from anxiety disorders using resting-state quantitative electroencephalography (qEEG). METHODS: Thirty-six patients with either PTSD or acute stress disorder and 79 patients with anxiety disorder were included in the analysis. qEEG data of absolute and relative powers and patients' medication status on the day of qEEG examination were obtained. Electrodes were grouped into frontal, central, and posterior regions to analyze for regional differences. General linear models were utilized to test for group differences in absolute and relative powers while controlling for medications. RESULTS: PTSD patients differed from those with anxiety disorders in overall absolute powers [F(5,327)=2.601, p=0.025]. Specifically, overall absolute delta powers [F(1,331)=4.363, p=0.037], and overall relative gamma powers [F(1,331)=3.965, p=0.047] were increased in PTSD group compared to anxiety disorder group. Post hoc analysis regarding brain regions showed that the increase in absolute delta powers were localized to the posterior region [F(1,107)=4.001, p=0.048]. Additionally, frontal absolute gamma powers [F(1,107)=4.138, p=0.044] were increased in PTSD group compared to anxiety disorder group. CONCLUSION: Our study suggests increased overall absolute delta powers and relative gamma powers as potential markers that could differentiate PTSD from anxiety disorders. Moreover, increased frontal absolute gamma and posterior delta powers might pose as novel markers of PTSD, which may reflect its distinct symptomatology.

19.
J Pediatr Endocrinol Metab ; 31(11): 1241-1247, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30325734

RESUMO

Background Thyroid function in children with leukemia during the first year after hematopoietic stem cell transplantation (HSCT) was investigated. Methods The medical records of 186 subjects [111 boys and 75 girls; lymphoid=75, myeloid=111; median age at HSCT was 10.7 (0.8-21.8) years old] were reviewed retrospectively. Results In children with leukemia, T3 decreased at 1 month (p<0.001) and recovered 9 months to the levels before HSCT. TSH decreased at 1 month (p<0.001), recovered at 3 months and increased at 12 months (p<0.001) to the levels before HSCT. The incidence of euthyroid sick syndrome (ESS, 23.2%, 15.5%, 5.9%, 5.2%, 3.9%, p for trend <0.001) decreased and subclinical hypothyroidism (SH, 0%, 3.9%, 14.8%, 22.1%, 21.3%, p for trend <0.001) increased at 1, 3, 6, 9 and 12 months after HSCT. Out of 55 patients developing ESS during 3 months after HSCT, 54 recovered to normal thyroid function within 5 months without medication. Among the total 186 subjects, 21 patients have been treated with levothyroxine. Both height and weight standard deviation scores continued to decrease over 1 year after HSCT. Conclusions In children with leukemia, one-quarter had ESS at 1 month and one-fifth had SH at 12 months and continued growth impairments were observed during 1 year after HSCT. Most of the ESS patients recovered to normal within 5 months without medication. More long-term follow-up of thyroid function and growth in children with leukemia after HSCT is crucial.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipotireoidismo/etiologia , Leucemia/fisiopatologia , Leucemia/cirurgia , Glândula Tireoide/fisiopatologia , Tiroxina/sangue , Tri-Iodotironina/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/fisiopatologia , Lactente , Leucemia/sangue , Masculino , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Adulto Jovem
20.
Medicine (Baltimore) ; 97(38): e12422, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30235717

RESUMO

Numerous studies have provided evidence for the effectiveness of cognitive behavioral therapy (CBT) on panic disorders (PDs). There has also been growing attention on brief CBT with regard to delivering intensive treatment efficiently. This study investigated the essential parts of mindfulness-based brief CBT to optimize treatment benefits.A total of 37 patients were retrospectively enrolled in this study. They were recruited from the anxiety/panic/fear clinic of Seoul National University Hospital. The patients participated in group CBT once a week for a total of 4 sessions over a 4-week period, when they were assessed using the Panic Disorder Severity Scale (PDSS), Anxiety Sensitivity Index-Revised (ASI-R), Albany Panic and Phobia Questionnaire (APPQ), State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Yale-Brown Obsessive Compulsive Scale (Y-BOCS) before and after brief CBT. Twenty-nine patients completed the 1-month follow-up.There were significant reductions in PDSS (P < .001), ASI-R-fear of respiratory symptoms (P = .006), ASI-R-fear of publicly observable anxiety reaction (P = .002), ASI-R-fear of cardiovascular symptoms (P < .001), ASI-R-fear of cognitive dyscontrol (P = .001), ASI-R-Total (P < .001), APPQ-Agoraphobia (P = .003), APPQ-Total (P = .028), STAI-State anxiety (P < .001), STAI-Trait anxiety (P = .002), BAI (P = .003), and BDI (P < .001) scores. We also found significant associations between ASI-R-fear of cardiovascular symptoms, ASI-R-Total, and changes in PDSS scores. A stepwise multiple linear regression analysis indicated that anxiety sensitivity for fear of cardiovascular symptoms predicted an improvement in panic severity (ß = 0.513, P = .004).Our findings suggested that behavioral aspects, especially physiological symptom control, needed to be considered in brief, intensive CBT for PD. The results also suggested that a mindfulness-based brief CBT approach might be particularly helpful for patients with PD who have severe cardiovascular symptoms.


Assuntos
Ansiedade/terapia , Terapia Cognitivo-Comportamental/métodos , Transtorno de Pânico/psicologia , Transtorno de Pânico/terapia , Adulto , Ansiedade/psicologia , Medo/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Transtorno de Pânico/diagnóstico , Inventário de Personalidade/estatística & dados numéricos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , República da Coreia/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença
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