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1.
Mol Cell ; 76(3): 500-515.e8, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31422874

RESUMO

Diet-induced obesity can be caused by impaired thermogenesis of beige adipocytes, the brown-like adipocytes in white adipose tissue (WAT). Promoting brown-like features in WAT has been an attractive therapeutic approach for obesity. However, the mechanism underlying beige adipocyte formation is largely unknown. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and overexpression of human Naa10p is linked to cancer development. Here, we report that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, and beige adipocyte differentiation. Mechanistically, Naa10p acetylates the N terminus of Pgc1α, which prevents Pgc1α from interacting with Pparγ to activate key genes, such as Ucp1, involved in beige adipocyte function. Consistently, fat tissues of obese human individuals show higher NAA10 expression. Thus, Naa10p-mediated N-terminal acetylation of Pgc1α downregulates thermogenic gene expression, making inhibition of Naa10p enzymatic activity a potential strategy for treating obesity.


Assuntos
Adipócitos Bege/enzimologia , Tecido Adiposo Bege/enzimologia , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/metabolismo , Obesidade/enzimologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Processamento de Proteína Pós-Traducional , Termogênese , Acetilação , Tecido Adiposo Bege/fisiopatologia , Adiposidade , Adolescente , Adulto , Idoso , Animais , Estudos de Casos e Controles , Dieta Hiperlipídica , Modelos Animais de Doenças , Metabolismo Energético , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Acetiltransferase N-Terminal A/deficiência , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/deficiência , Acetiltransferase N-Terminal E/genética , Células NIH 3T3 , Obesidade/genética , Obesidade/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fenótipo , Transdução de Sinais , Adulto Jovem
2.
Mol Cell ; 68(1): 89-103.e7, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28943313

RESUMO

Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), but the underlying mechanism remains largely unclear. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorders, and maternal effect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses further revealed global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-knockout embryos and embryonic stem cells. Mechanistically, Naa10p facilitates binding of DNA methyltransferase 1 (Dnmt1) to DNA substrates, including the ICRs of the imprinted allele during S phase. Moreover, the lethal Ogden syndrome-associated mutation of human Naa10p disrupts its binding to the ICR of H19 and Dnmt1 recruitment. Our study thus links Naa10p mutation-associated Ogden syndrome to defective DNA methylation and genomic imprinting.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Deficiências do Desenvolvimento/genética , Epigênese Genética , Impressão Genômica , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , RNA Longo não Codificante/genética , Animais , DNA/genética , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Deleção de Genes , Genes Letais , Estudo de Associação Genômica Ampla , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/patologia , Acetiltransferase N-Terminal A/deficiência , Acetiltransferase N-Terminal E/deficiência , Ligação Proteica , RNA Longo não Codificante/metabolismo , Fase S/genética
3.
Ann Surg Oncol ; 31(5): 3495-3501, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38300401

RESUMO

BACKGROUND: Previous literatures showed wide range of prevalence of BRAF V600E in papillary thyroid carcinoma (PTC). The correlation of BRAF V600E mutation with aggressive tumor characteristics and poor prognosis is controversial. The present study was designed to evaluate the association between BRAF V600E mutation with clinicopathological factors and tumor recurrence. PATIENTS AND METHODS: We performed a retrospective chart review of 672 patients who underwent thyroid surgery for PTC during 2013 and 2018. The prevalence of the BRAF V600E mutation was studied. Its correlation with clinicopathologic characteristics and aggressive features, including macroscopic extrathyroidal extension, lymph node metastasis, and distant metastasis, were analyzed with Fisher's exact test. RESULTS: A total of 672 patients who underwent surgical treatment for PTC were included in this study with a mean age of 49.7 (± 13.2) years; 76.8% of the patients were detected with BRAF V600E mutation. Mean tumor size was 1.30 (± 1.07) cm. A significant association was demonstrated between negative BRAF V600E and larger primary tumor size, distant metastasis, and advanced staging (p < 0.05), whereas there was no significant association with age, sex, lymph node metastasis, extrathyroidal extension, and multicentricity. Kaplan-Meier curve showed similar disease-free survival rate between the two groups. CONCLUSIONS: Negative BRAF V600E tumors show more aggressive behavior with a higher risk of developing distant metastasis in patients with PTC. The usefulness of BRAF in predicting the prognosis of PTC remains questionable. Further molecular analysis should be conducted for contribution to aggressive tumor phenotype.


Assuntos
Proteínas Proto-Oncogênicas B-raf , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Pessoa de Meia-Idade , Metástase Linfática , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Masculino , Feminino , Adulto
4.
Stem Cells ; 41(5): 453-467, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-36866456

RESUMO

During development, the hypothalamus emerges from the ventral diencephalon and is regionalized into several distinct functional domains. Each domain is characterized by a different combination of transcription factors, including Nkx2.1, Nkx2.2, Pax6, and Rx, which are expressed in the presumptive hypothalamus and its surrounding regions, and play critical roles in defining each area. Here, we recapitulated the molecular networks formed by the gradient of Sonic Hedgehog (Shh) and the aforementioned transcription factors. Using combinatorial experimental systems of directed neural differentiation of mouse embryonic stem (ES) cells, as well as a reporter mouse line and gene overexpression in chick embryos, we deciphered the regulation of transcription factors by different Shh signal intensities. We then used CRISPR/Cas9 mutagenesis to demonstrate the mutual repression between Nkx2.1 and Nkx2.2 in a cell-autonomous manner; however, they induce each other in a non-cell-autonomous manner. Moreover, Rx resides upstream of all these transcription factors and determines the location of the hypothalamic region. Our findings suggest that Shh signaling and its downstream transcription network are required for hypothalamic regionalization and establishment.


Assuntos
Proteínas Hedgehog , Fatores de Transcrição , Animais , Embrião de Galinha , Camundongos , Fatores de Transcrição/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Hipotálamo , Regulação da Expressão Gênica no Desenvolvimento
5.
Hepatol Res ; 54(9): 838-850, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38451566

RESUMO

AIM: We aimed to investigate the prognostic factors for salvage liver transplant in patients with early hepatocellular carcinoma recurrence after hepatectomy. METHODS: This retrospective analysis included 53 patients who underwent salvage living-donor liver transplantation between January 2007 and January 2018. There were 24 and 29 patients in the early (recurrence ≤24 months after primary liver resection) and the late recurrence groups, respectively. RESULTS: In the multivariate Cox regression model, pre-liver transplant downstaging therapy, early recurrence (ER) after primary liver resection , and recurrence-to-liver-transplant ≥12 months were independent risks to predict recurrent hepatocellular carcinoma recurrence after salvage living-donor liver transplantation. Compared with the late recurrence group, the ER group showed lower disease-free survival rates (p < 0.001); however, the overall survival rates did not differ between the two groups (p = 0.355). The 1-, 3-, and 5-year disease-free survival rates were 83.3%, 70.6%, and 66.2%, and 96.0%, 91.6%, and 91.6% in the early and late recurrence groups, respectively. When stratified by recurrence-to-liver transplant time and pre-liver transplant downstaging therapy in the ER group, disease-free survival and overall survival rates were significantly different. CONCLUSION: ER after primary liver resection with advanced tumor status and a longer period of recurrence-to-liver-transplant (≥12 months) have a negative impact on salvage liver transplant. Our findings provide novel recommendations for treatment strategies and eligibility for salvage liver transplant candidates.

6.
Dig Dis Sci ; 69(8): 3069-3078, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38824258

RESUMO

BACKGROUND: In many Asian hepatocellular carcinoma (HCC) guidelines, resection is an option for multiple HCCs. It is difficult to compare small but multiple tumors vs. fewer large tumors in terms of the traditional tumor burden definition. We aimed to evaluate the role of liver resection for multiple HCCs and determine factors associated with survival benefits. METHODS: We reviewed 160 patients with multiple HCCs who underwent liver resection between July 2003 and December 2018. The risk factors for tumor recurrence were assessed using Cox proportional hazards modeling, and survival was analyzed using the Kaplan-Meier method. RESULTS: In all 160 patients, 133 (83.1%) exceeded the Milan criteria. Total tumor volume (TTV) > 275 cm3 and serum alpha-fetoprotein (AFP) level > 20 ng/mL were associated with disease-free survival. Patients beyond the Milan criteria were grouped into three risk categories: no risk (TTV ≤ 275 cm3 and AFP ≤ 20 ng/mL, n = 39), one risk (either TTV > 275 cm3 or AFP > 20 ng/mL, n = 76), and two risks (TTV > 275 cm3 and AFP > 20 ng/mL, n = 18). No-risk group had comparable disease-free survival (p = 0.269) and overall survival (p = 0.215) to patients who met the Milan criteria. CONCLUSION: Patients with TTV ≤ 275 cm3 and AFP ≤ 20 ng/mL can have good outcomes even exceed the Milan criteria.


Assuntos
Carcinoma Hepatocelular , Hepatectomia , Neoplasias Hepáticas , Carga Tumoral , Humanos , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Hepatectomia/métodos , Idoso , Estudos Retrospectivos , alfa-Fetoproteínas/metabolismo , alfa-Fetoproteínas/análise , Fatores de Risco , Recidiva Local de Neoplasia/epidemiologia , Intervalo Livre de Doença , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/sangue , Neoplasias Primárias Múltiplas/mortalidade , Adulto
7.
Biol Pharm Bull ; 47(4): 827-839, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38599826

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disease with progressive loss of dopaminergic neurons in substantia nigra and the presence of α-synuclein-immunoreactive inclusions. Gaucher's disease is caused by homozygous mutations in ß-glucocerebrosidase gene (GBA). GBA mutation carriers have an increased risk of PD. Coptis chinensis (C. chinensis) rhizome extract is a major herb widely used to treat human diseases. This study examined the association of GBA L444P mutation with Taiwanese PD in 1016 cases and 539 controls. In addition, the protective effects of C. chinensis rhizome extract and its active constituents (berberine, coptisine, and palmatine) against PD were assayed using GBA reporter cells, LC3 reporter cells, and cells expressing mutated (A53T) α-synuclein. Case-control study revealed that GBA L444P carriers had a 3.93-fold increased risk of PD (95% confidence interval (CI): 1.37-11.24, p = 0.006) compared to normal controls. Both C. chinensis rhizome extract and its constituents exhibited chemical chaperone activity to reduce α-synuclein aggregation. Promoter reporter and endogenous GBA protein analyses revealed that C. chinensis rhizome extract and its constituents upregulated GBA expression in 293 cells. In addition, C. chinensis rhizome extract and its constituents induced autophagy in DsRed-LC3-expressing 293 cells. In SH-SY5Y cells expressing A53T α-synuclein, C. chinensis rhizome extract and its constituents reduced α-synuclein aggregation and associated neurotoxicity by upregulating GBA expression and activating autophagy. The results of reducing α-synuclein aggregation, enhancing GBA expression and autophagy, and protecting against α-synuclein neurotoxicity open up the therapeutic potentials of C. chinensis rhizome extract and constituents for PD.


Assuntos
Berberina , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Berberina/análogos & derivados , Estudos de Casos e Controles , Coptis chinensis , Neurônios Dopaminérgicos/metabolismo , Mutação , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Rizoma
8.
Int J Med Sci ; 21(1): 8-18, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38164354

RESUMO

Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.


Assuntos
Transtornos da Impressão Genômica , Síndrome de Silver-Russell , Recém-Nascido , Feminino , Gravidez , Humanos , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/patologia , Metilação de DNA/genética , Fenótipo , Dissomia Uniparental/genética
9.
BMC Med Imaging ; 24(1): 75, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38549082

RESUMO

BACKGROUND: Based on a longitudinal cohort design, the aim of this study was to investigate whether individual-based 18F fluorodeoxyglucose positron emission tomography (18F-FDG-PET) regional signals can predict dementia conversion in patients with mild cognitive impairment (MCI). METHODS: We included 44 MCI converters (MCI-C), 38 non-converters (MCI-NC), 42 patients with Alzheimer's disease with dementia, and 40 cognitively normal controls. Data from annual cognitive measurements, 3D T1 magnetic resonance imaging (MRI) scans, and 18F-FDG-PET scans were used for outcome analysis. An individual-based FDG-PET approach was applied using seven volumes of interest (VOIs), Z transformed using a normal FDG-PET template. Hypometabolism was defined as a Z score < -2 of regional standard uptake value ratio. For the longitudinal cognitive test scores, generalized estimating equations were used. A linear mixed-effects model was used to compare the temporal impact of cortical hypometabolism and cortical thickness degeneration. RESULTS: The clinical follow-up period was 6.6 ± 3.8 years (range 3.1 to 16.0 years). The trend of cognitive decline could differentiate MCI-C from MCI-NC after 3 years of follow-up. In the baseline 18F-FDG-PET scan of the patients with MCI, medial temporal lobe (MTL; 94.7% sensitivity, 80.5% specificity) and posterior cingulate cortex (PCC; 89.5% sensitivity, 73.1% specificity) hypometabolism predicted conversion with high accuracy. 18F-FDG-PET hypometabolism preceded dementia conversion at an interval of 3.70 ± 1.68 years and was earlier than volumetric changes, with the exception of the MTL. CONCLUSIONS: Our finding supports the use of individual-based 18F-FDG-PET analysis to predict MCI conversion to dementia. Reduced FDG-PET metabolism in the MTL and PCC were strongly associated with future cognitive decline in the MCI-C group. Changes in 18F-FDG-PET occurred 1 to 8 years prior to conversion to dementia. Progressive hypometabolism in the PCC, precuneus and lateral temporal lobe, but not MTL, preceded MRI findings at the MCI stage.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Fluordesoxiglucose F18 , Progressão da Doença , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/metabolismo
10.
Am J Emerg Med ; 76: 63-69, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37995525

RESUMO

INTRODUCTION: Ludwig's angina (LA) is a life-threatening infection that can affect the floor of the mouth and neck, potentially causing serious airway obstruction. In such cases, rescue airway management and oxygenation can be challenging due to swelling of the mouth floor, trismus, and limited mouth opening. The aim of this study was to assess the efficacy of the Trachway video-stylet (VS) and Pentax AWS hyperangulated videolaryngoscope with channel (HAVL-C) compared to the standard geometric video-laryngoscope (SGVL, Macintosh 3, Trachway) in simulating Ludwig's angina with cadavers. METHODS: Three fresh frozen cadavers were prepared with varying degrees of difficulty to simulate the airway conditions of patients with LA, including mouth floor swelling, restricted mouth opening, and trismus. Fifty-five second-year resident physicians from various specialties participated in the study and received training in airway management using SGVL, VS, and HAVL-C devices. Participants were randomly assigned to intubate simulated LA with cadavers using the three devices in a random order, and intubation times and success rates were recorded. Participants also rated the difficulty of intubation using a visual analogue scale (VAS) score. The primary outcome assessed the first-pass intubation success or failure, while the secondary outcomes measured the intubation time and subjective difficulty using a visual analogue scale with different laryngoscopes. RESULTS: The success rates for intubation within 90 s were 40% for SGVL, 82% for VS, and 76% for HAVL-C. VS and HAVL-C had significantly higher success rates than SGVL, with hazard ratios of 3.4 and 2.7, and 95% confidence intervals (CI) of 2.0-5.7 and 1.6-4.6, p < 0.001, respectively. The odds ratios of successful intubation for VS and HAVL-C were 8.1 and 6.3, respectively, with a 95% CI of 3.7-17.8 and 2.4-16.7, p < 0.001, compared to SGVL. The VAS score was significantly correlated with intubation success rate and time. CONCLUSIONS: In cases of LA, the use of VS and HAVL-C is preferable over SGVL. These findings suggest that using VS and HAVL-C can improve intubation success rates and reduce intubation time in patients with LA.


Assuntos
Laringoscópios , Angina de Ludwig , Humanos , Intubação Intratraqueal , Trismo , Cadáver , Gravação em Vídeo , Laringoscopia
11.
BMC Med Educ ; 24(1): 533, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745156

RESUMO

BACKGROUND: Appropriate communication with dental patients enhances treatment outcomes and patient satisfaction. Implementing simulated patient interviews courses can improve patient-centered care and reduce conflict during clerkship training. Therefore, this study explored the relationship among student participation in a situational simulation course (SSC), academic performance, clerkship performance, and objective structured clinical examination (OSCE) performance. METHODS: This study was conducted with a sample of fifth-year dental students undergoing clerkship training. After implementing a situational simulation course to investigate the relationship among participation in SSC, academic performance, clerkship performance, and OSCE performance, a path analysis model was developed and tested. RESULTS: Eighty-seven fifth-year dental students were eligible for the SSC, and most (n = 70, 80.46%) volunteered to participate. The path analysis model revealed that academic performance had a direct effect on OSCE performance (ß = 0.281, P = 0.003) and clerkship performance (ß = 0.441, P < 0.001). In addition, SSC teaching had a direct effect on OSCE performance (ß = 0.356, P < 0.001). CONCLUSIONS: SSCs can enhance dental students' non-operational clinical competency and OSCE performance effectively. Simulated patient encounters with feedback, incorporated into the dental curricula, have led to improved communication. Based on our findings, we suggest implementing SSC teaching before the OSCE to improve communication and cognitive skills.


Assuntos
Competência Clínica , Educação em Odontologia , Avaliação Educacional , Estudantes de Odontologia , Humanos , Educação em Odontologia/métodos , Educação em Odontologia/normas , Feminino , Masculino , Estágio Clínico , Treinamento por Simulação , Simulação de Paciente , Desempenho Acadêmico
12.
Int J Mol Sci ; 25(19)2024 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-39409036

RESUMO

Polyglutamine (polyQ)-mediated spinocerebellar ataxia (SCA), including SCA1, 2, 3, 6, 7, and 17, are caused by mutant genes with expanded CAG repeats, leading to the intracellular accumulation of aggregated proteins, the production of reactive oxygen species, and cell death. Among SCA, SCA3 is caused by a mutation in the ATXN3 (ataxin-3) gene. In a circumstance of polyQ aggregation, the autophagic pathway is induced to degrade the aggregated proteins, thereby suppressing downstream deleterious effects and promoting neuronal survival. In this study, we tested the effects of synthetic indole (NC009-1, -2, -3, -6) and coumarin (LM-022, -031) derivatives as chemical chaperones to assist mutant ATXN3-Q75 folding, as well as autophagy inducers to clear aggregated protein. Among the tested compounds, NC009-1, -2, and -6 and LM-031 interfered with Escherichia coli-derived ATXN3-Q75 aggregation in thioflavin T binding and filter trap assays. In SH-SY5Y cells expressing GFP-fused ATXN3-Q75, these compounds displayed aggregation-inhibitory and neurite growth-promoting potentials compared to untreated cells. Furthermore, these compounds activated autophagy by increasing the phosphatidylethanolamine-conjugated LC3 (microtubule associated protein 1 light chain 3)-II:cytosolic LC3-I ratio in these cells. A biochemical co-immunoprecipitation assay by using a mixture of HEK 293T cell lysates containing recombinant ATXN3-Q75-Venus-C-terminus (VC) or Venus-N-terminus (VN)-LC3 protein indicated that NC009-1 and -2 and LM-031 served as an autophagosome-tethering compound (ATTEC) to interact with ATXN3-Q75 and LC3, and the interaction was further confirmed by bimolecular fluorescence complementation analysis in cells co-expressing both ATXN3-Q75-VC and VN-LC3 proteins. The study results suggest the potential of NC009-1 and -2 and LM-031 as an ATTEC in treating SCA3 and, probably, other polyQ diseases.


Assuntos
Ataxina-3 , Autofagia , Proteínas Associadas aos Microtúbulos , Peptídeos , Ataxina-3/metabolismo , Ataxina-3/genética , Humanos , Peptídeos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Ligação Proteica , Mutação , Linhagem Celular Tumoral , Indóis/farmacologia , Indóis/metabolismo , Proteínas Repressoras
13.
BMC Oral Health ; 24(1): 120, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38254042

RESUMO

BACKGROUND: A phase-III interdisciplinary quality improvement program, the preanesthetic oral examination (PAOE), was implemented as a new program in an academic medical center to prevent perioperative dental injuries. This study was aimed at surveying the perceived service quality and satisfaction of patients who had undergone PAOE based on the SERVQUAL model. METHODS: This cross-sectional survey was conducted at the Kaohsiung Medical University Hospital using convenience sampling. Patients referred for PAOE (PAOE group) and those who had voluntarily availed dental services (control group) were recruited. A modified SERVQUAL questionnaire was used to assess the perceived service quality and patient satisfaction with dental services. Cronbach's alpha for SERVQUAL was 0.861. RESULTS: We enrolled 286 (68.8%) and 130 (31.2%) participants in the PAOE and control groups, respectively. The path analysis revealed that the PAOE group scored lower in dimensions of reliability (ß = -0.074, P = 0.003), responsiveness (ß = -0.148, P = 0.006), and empathy (ß = -0.140, P = 0.011). Furthermore, reliability (ß = 0.655, P < 0.001) and responsiveness (ß = 0.147, P = 0.008) showed a direct effect on patient satisfaction. Overall, participants were highly satisfied with the dental services. CONCLUSIONS: The PAOE group showed lower satisfaction and perceived quality of dental services compared to the control group. Although implementing an interdisciplinary program reduces the perceived service quality, its influence is limited. Employing an interdisciplinary teamwork is a win-win strategy encouraged to improve patient safety and reduce malpractice claims. Future suggestions should focus on establishing waiting times that are considered reasonable by patients. Patient-centered education related to the risk of perioperative dental injuries should be provided, and awareness of oral conditions for patient safety should be improved. Moreover, interprofessional education in continuous and undergraduate programs is necessary to improve professional quality.


Assuntos
Projetos de Pesquisa , Traumatismos Dentários , Humanos , Estudos Transversais , Reprodutibilidade dos Testes , Percepção
14.
Br J Cancer ; 128(8): 1491-1502, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36759727

RESUMO

BACKGROUND: Chaperon-mediated autophagy (CMA) has taken on a new emphasis in cancer biology. However, the roles of CMA in hypoxic tumours are poorly understood. We investigated the anti-tumour effects of the natural product ManA through the activation of CMA in tumour progression under hypoxia. METHODS: The effect of ManA on CMA activation was assessed in mouse xenograft models and cells. The gene expressions of HIF-1α, HSP90AA1, and transcription factor EB (TFEB) were analysed using The Cancer Genome Atlas (TCGA) datasets to assess the clinical relevance of CMA. RESULTS: ManA activates photoswitchable CMA reporter activity and inhibits Hsp90 chaperone function by disrupting the Hsp90/F1F0-ATP synthase complex. Hsp90 inhibition enhances the interaction between CMA substrates and LAMP-2A and TFEB nuclear localisation, suggesting CMA activation by ManA. ManA-activated CMA retards tumour growth and displays cooperative anti-tumour activity with anti-PD-1 antibody. TCGA datasets show that a combined expression of HSP90AA1High/HIF1AHigh or TFEBLow/HIF1AHigh is strongly correlated with poor prognosis in patients with lung cancer. CONCLUSIONS: ManA-induced CMA activation by modulating Hsp90 under hypoxia induces HIF-1α degradation and reduces tumour growth. Thus, inducing CMA activity by targeting Hsp90 may be a promising therapeutic strategy against hypoxic tumours.


Assuntos
Autofagia Mediada por Chaperonas , Neoplasias Pulmonares , Camundongos , Animais , Humanos , Hipóxia , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares , Autofagia/genética
15.
Cell Tissue Res ; 391(2): 323-337, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36447073

RESUMO

Systemic sclerosis associated with lung interstitial lung disease (SSc-ILD) is the most common cause of death among patients with SSc. Mesenchymal stem cell (MSCs) transplantations had been treated by SSc patients that showed in the previous case report. The therapeutic mechanisms and effects of MSCs on SSc-ILD are still obscure. In this study, we investigated the therapeutic effects and mechanisms of treatment of BM-MSC derived from C57BL/6 on the topoisomerase I (TOPO I) induced SSc-ILD-like mice model. The mice were immunized with a mixture of recombinant human TOPO I in PBS solution (500 U/mL) and completed Freund's adjuvant [CFA; 1:1 (volume/volume)] twice per week for 9 weeks. On week 10, the mice were sacrificed to analyze the related pathological parameters. Lung and skin pathologies were analyzed using histochemical staining. CD4 T-helper (TH) cell differentiation in lung and skin-draining lymph nodes was detected using flow cytometry. Our results revealed that allogeneic and syngeneic MSCs exhibited similar repressive effects on TOPO I-induced IgG1 and IgG2a in the SSc group. After intravascular (IV) treatment with syngeneic or allogeneic MSCs, the dermal thickness and fibrosis dramatically condensed and significantly reduced airway hyperresponsiveness. These findings showed that both allogeneic and syngeneic MSCs have therapeutic potential for SSc-ILD.


Assuntos
Doenças Pulmonares Intersticiais , Células-Tronco Mesenquimais , Pneumonia , Escleroderma Sistêmico , Humanos , Animais , Camundongos , DNA Topoisomerases Tipo I , Camundongos Endogâmicos C57BL , Fibrose , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/terapia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Pneumonia/patologia
16.
Anesth Analg ; 136(2): 355-364, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36135341

RESUMO

BACKGROUND: Perioperative cerebral desaturation events (CDEs) and delayed neurocognitive recovery are common among patients undergoing beach chair position (BCP) shoulder surgery and may be caused by cerebral hypoperfusion. This study tested the hypothesis that the application of goal-directed hemodynamic therapy (GDHT) would attenuate these conditions. METHODS: We randomly assigned 70 adult patients undergoing BCP shoulder surgery to GDHT group or control at a 1:1 ratio. Cerebral oxygenation was monitored using near-infrared spectroscopy, and GDHT was administered using the ClearSight pulse wave analysis system. The primary outcome was CDE duration, whereas the secondary outcomes were CDE occurrence, delayed neurocognitive recovery occurrence, and Taiwanese version of the Quick Mild Cognitive Impairment (Qmci-TW) test score on the first postoperative day (T 2 ) adjusted for the baseline score (on the day before surgery; T 1 ). RESULTS: CDE duration was significantly shorter in the GDHT group (0 [0-0] vs 15 [0-75] min; median difference [95% confidence interval], -8 [-15 to 0] min; P = .007). Compared with the control group, fewer patients in the GDHT group experienced CDEs (23% vs 51%; relative risk [95% confidence interval], 0.44 [0.22-0.89]; P = .025) and mild delayed neurocognitive recovery (17% vs 40%; relative risk [95% confidence interval], 0.60 [0.39-0.93]; P = .034). The Qmci-TW scores at T 2 adjusted for the baseline scores at T 1 were significantly higher in the GDHT group (difference in means: 4 [0-8]; P = .033). CONCLUSIONS: Implementing GDHT using a noninvasive finger-cuff monitoring device stabilizes intraoperative cerebral oxygenation and is associated with improved early postoperative cognitive scores in patients undergoing BCP shoulder surgery.


Assuntos
Oxigênio , Ombro , Adulto , Humanos , Ombro/cirurgia , Objetivos , Posicionamento do Paciente/métodos , Estudos Prospectivos , Hemodinâmica
17.
BMC Health Serv Res ; 23(1): 1279, 2023 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-37986078

RESUMO

BACKGROUND: Communication fosters trust and understanding between patients and physicians, and specific communication steps help to build relationships. Communication in the emergency department may be different from that in other departments due to differences in medical purposes and treatments. However, the characteristics of communication in the clinical settings of various departments have not been explored nor compared. OBJECTIVES: This study aimed to construct the steps in patient-physician communication based on the Roter Communication Model and compare communication performance between the emergency department and three other clinical settings-internal medicine, surgery, and family medicine departments. METHODS: Both qualitative and quantitative approaches were adopted. First, in-depth interviews were used to analyze clinical communication steps and meanings. Then, a quantitative questionnaire was designed based on the interview results to investigate differences in communication between the emergency department and the other three departments. Qualitative and quantitative data were analyzed from 20 interviews and 98 valid questionnaires. RESULTS: Patient-physician communication consists of four steps and ten factors. The four steps-greeting and data gathering, patient education and counseling, facilitation and patient activation, and building a relationship-had significant progressive effects. Patient education and counseling had an additional significant effect on building a relationship. The emergency department performed less well in the facilitation and patient activation, building a relationship step and the evaluation method, enhancement method, and attitude factors than the other departments. CONCLUSIONS: To improve the quality of patient-physician communication in the emergency department, physicians should strengthen the steps of facilitation and patient activation to encourage patients' active engagement in their health care.


Assuntos
Comunicação , Médicos , Humanos , Taiwan , Hospitais , Serviço Hospitalar de Emergência
18.
Int J Technol Assess Health Care ; 39(1): e11, 2023 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-36779272

RESUMO

OBJECTIVES: To report the processes used to design and implement an assessment tool to inform funding decisions for competing health innovations in a tertiary hospital. METHODS: We designed an assessment tool for health innovation proposals with three components: "value to the institution," "novelty," and "potential for adoption and scaling." The "value to the institution" component consisted of twelve weighted value attributes identified from the host institution's annual report; weights were allocated based on a survey of the hospital's leaders. The second and third components consisted of open-ended questions on "novelty" and "barriers to implementation" to support further dialogue. Purposive literature review was performed independently by two researchers for each assessment. The assessment tool was piloted during an institutional health innovation funding cycle. RESULTS: We used 17 days to evaluate ten proposals. The completed assessments were shared with an independent group of panellists, who selected five projects for funding. Proposals with the lowest scores for "value to the institution" had less perceived impact on the patient-related value attributes of "access," "patient centeredness," "health outcomes," "prevention," and "safety." Similar innovations were reported in literature in seven proposals; potential barriers to implementation were identified in six proposals. We included a worked example to illustrate the assessment process. CONCLUSIONS: We developed an assessment tool that is aligned with local institutional priorities. Our tool can augment the decision-making process when funding health innovation projects. The tool can be adapted by others facing similar challenges of trying to choose the best health innovations to fund.


Assuntos
Centros Médicos Acadêmicos , Humanos , Inquéritos e Questionários
19.
Health Commun ; : 1-11, 2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-37161370

RESUMO

Effective physician-patient communication builds robust physician-patient relationships and reduces medical disputes. However, much is unknown about the differences that exist in the communication behaviors of physicians in different departments. Using a mixed-methods research approach, the researchers used Roter Interaction Analysis System to uncover the communication behaviors of internists, surgeons, family physicians, and emergency physicians at a regional hospital in Taiwan. Semi-structured interviews were conducted to collect the communication experiences of 20 physicians from the internal medicine, surgery, family medicine, and emergency departments. The characteristics were presented through descriptive statistics, bar charts, and dendrograms. Physician-patient communications consisted of four dimensions, 10 factors, and 31 behaviors. The characteristics are as follows: (1) Internists need to improve their overall performance in terms of physician-patient communication behaviors; (2) Surgeons performed well in building relationships through non-verbal methods; (3) Family physicians excelled in facilitation and patient activation. (4) Emergency physicians performed well in patient education and counseling. The characteristics of the aforementioned communication behaviors among internists, surgeons, family physicians, and emergency physicians can be used to construct indicators of physician-patient communication in each department and to develop patient-centered healthcare services in the future.

20.
Int J Mol Sci ; 24(22)2023 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-38003425

RESUMO

The treatment and surgical repair of torn Achilles tendons seldom return the wounded tendon to its original elasticity and stiffness. This study explored the in vitro and in vivo simultaneous release of indomethacin and bupivacaine from electrospun polylactide-polyglycolide composite membranes for their capacity to repair torn Achilles tendons. These membranes were fabricated by mixing polylactide-polyglycolide/indomethacin, polylactide-polyglycolide/collagen, and polylactide-polyglycolide/bupivacaine with 1,1,1,3,3,3-hexafluoro-2-propanol into sandwich-structured composites. Subsequently, the in vitro pharmaceutic release rates over 30 days were determined, and the in vivo release behavior and effectiveness of the loaded drugs were assessed using an animal surgical model. High concentrations of indomethacin and bupivacaine were released for over four weeks. The released pharmaceutics resulted in complete recovery of rat tendons, and the nanofibrous composite membranes exhibited exceptional mechanical strength. Additionally, the anti-adhesion capacity of the developed membrane was confirmed. Using the electrospinning technique developed in this study, we plan on manufacturing degradable composite membranes for tendon healing, which can deliver sustained pharmaceutical release and provide a collagenous habitat.


Assuntos
Nanofibras , Traumatismos dos Tendões , Ratos , Animais , Indometacina , Bupivacaína , Adesivos , Traumatismos dos Tendões/tratamento farmacológico , Traumatismos dos Tendões/cirurgia , Ácido Poliglicólico , Tendões
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