RESUMO
Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expression in mice. This technique can be used to the visualize neuronal circuit activity elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET allows mapping of neuronal projections in non-human primate brains, demonstrating the applicability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET studies of turnover and self-assembly of proteins tagged with ecDHFR mutants. These results establish opportunities for a broad spectrum of previously unattainable PET analyses of mammalian brain circuits at the molecular level.
Assuntos
Encéfalo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Tetra-Hidrofolato Desidrogenase/genética , Animais , Encéfalo/citologia , Callithrix , Radioisótopos de Carbono/química , Radioisótopos de Flúor/química , Genes Reporter , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Imagem Molecular/métodos , Rede Nervosa/diagnóstico por imagem , Proteínas/análise , Proteínas/metabolismo , Compostos Radiofarmacêuticos/síntese química , Tetra-Hidrofolato Desidrogenase/metabolismo , Trimetoprima/análogos & derivados , Trimetoprima/químicaRESUMO
Cutaneous angiosarcoma (CAS) is an endothelial cell-derived, highly aggressive type of vascular tumour. Although chemoradiotherapy with paclitaxel (PTX) is recognized as a first-line therapy for CAS, second-line therapy for CAS remains controversial, and there is no standard therapy for taxane-resistant CAS. Plasminogen activator inhibitor-1 (PAI-1) is associated with poor clinical outcomes, and elevated levels of PAI-1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancers. Since PAI-1 protects endothelial cells from Fas ligand-mediated apoptosis, PAI-1 inhibition might induce apoptosis of endothelial cell-derived tumours such as CAS. This is a single-arm, open-label, multi-institutional, Phase 2 clinical trial to assess the efficacy and safety of PTX in combination with TM5614 (PAI-1 inhibitor) in patients with PTX-resistant CAS. PTX will be administered for 28 weeks, with oral administration of TM5614. The primary endpoint of this study will be the overall response rate (ORR) at 28 weeks after starting treatment (central image evaluation). The secondary endpoint will include the ORR at 28 weeks after starting treatment (investigator evaluation), ORR at 8 weeks and 16 weeks after initiation of treatment (central and investigator evaluation), progression-free survival, overall survival, disease control rate and safety profiles. Assuming the null hypothesis of a response rate of 13.6% and an alternative hypothesis of 45%, a minimum of 15 patients are required to achieve a two-sided, Type I error of 5% and power of 70% based on the exact binomial distribution. Data quality control will be conducted by a combination of centralized (remote) and on-site monitoring. This study will contribute to the development of novel combination therapy for PTX-resistant CAS patients, which remains an unmet clinical need.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Hemangiossarcoma , Neoplasias Cutâneas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Células Endoteliais , Hemangiossarcoma/tratamento farmacológico , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio , Neoplasias Cutâneas/tratamento farmacológico , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: Extracellular volume fraction (ECV) on magnetic resonance imaging can predict prognosis after aortic valve replacement in patients with aortic stenosis (AS). However, the usefulness of ECV on computed tomography (CT) for patients who have undergone transcatheter aortic valve replacement (TAVR) is unclear, so we investigated whether ECV analysis on CT is associated with clinical outcomes in TAVR candidates.MethodsâandâResults: We analyzed 127 patients with severe AS who underwent preoperative CT for TAVR. We evaluated the utility of ECV analysis on single-energy CT for predicting patient prognosis after TAVR. The primary outcome was a composite of all-cause death and hospitalization due to heart failure (HF) after TAVR. 15 patients (12%) had composite outcomes: 4 deaths and 11 hospitalizations due to HF. In multivariate survival analysis using the Cox proportional hazard model, atrial fibrillation (AF) (hazard ratio (HR), 7.86; 95% confidence interval (CI), 2.57-24.03; P<0.001), history of congestive HF (HR, 4.91; 95% CI, 1.49-16.2; P=0.009) and ECV ≥32.6% on CT (HR, 6.96; 95% CI, 1.92-25.12; P=0.003) were independent predictors of composite outcomes. On Kaplan-Meier analysis, the higher ECV group (≥32.6%) had a significantly greater number of composite outcomes than the lower ECV group (P<0.001). CONCLUSIONS: ECV on CT is an independent predictor of prognosis after TAVR.
Assuntos
Estenose da Valva Aórtica , Substituição da Valva Aórtica Transcateter , Humanos , Substituição da Valva Aórtica Transcateter/métodos , Resultado do Tratamento , Prognóstico , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/complicações , Tomografia Computadorizada por Raios X , Fatores de RiscoRESUMO
Cardiac computed tomography (CT) is useful for the screening of coronary artery stenosis, and extracellular volume fraction (ECV) analysis by CT using new dedicated software is now available. Here, we evaluated the utility of ECV analysis using cardiac CT to predict patient prognosis in cases with dilated cardiomyopathy (DCM). We analyzed 70 cases with DCM and cardiac computed tomography (CT) with available late-phase images. We evaluated the ECV of the left ventricular myocardium (LVM) using commercially available software (Ziostation 2, Ziosoft Inc, Japan). ECV on LVM was 33.96 ± 5.04%. Major adverse cardiac events (MACE) occurred in 21 cases (30%). ECV of the LVM on CT, endo-systolic volume, and rate of significant valvular disease were significantly higher in cases with MACE than in those without (37.16 ± 5.91% vs. 32.59 ± 3.95%, 194 ± 109 vs. 138 ± 78 ml and 57% vs. 20%, all P values < 0.05). LVEF was significantly lower in cases with MACE than in those without (23 ± 8 vs. 31 ± 11%, P = 0.0024). The best cut-off value of ECV on LVM for prediction of MACE was 32.26% based on receiver operating characteristics analysis. Cases with ECV ≥ 32.26% had significantly higher MACE based on Kaplan-Meier analysis (P = 0.0032). Only ECV on LVM was an independent predictor of MACE based on a multivariate Cox proportional hazards model (P = 0.0354). Evaluation of ECV on LVM by CT is useful for predicting MACE in patients with DCM.
Assuntos
Cardiomiopatia Dilatada , Humanos , Cardiomiopatia Dilatada/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodos , Valor Preditivo dos Testes , Miocárdio , Prognóstico , Tomografia Computadorizada por Raios XRESUMO
Fractional flow reserve derived from coronary CT (FFR-CT) is a noninvasive physiological technique that has shown a good correlation with invasive FFR. However, the use of FFR-CT is restricted by strict application standards, and the diagnostic accuracy of FFR-CT analysis may potentially be decreased by severely calcified coronary arteries because of blooming and beam hardening artifacts. The aim of this study was to evaluate the utility of deep learning (DL)-based coronary computed tomography (CT) data analysis in predicting invasive fractional flow reserve (FFR), especially in cases with severely calcified coronary arteries. We analyzed 184 consecutive cases (241 coronary arteries) which underwent coronary CT and invasive coronary angiography, including invasive FFR, within a three-month period. Mean coronary artery calcium scores were 963 ± 1226. We evaluated and compared the vessel-based diagnostic accuracy of our proposed DL model and a visual assessment to evaluate functionally significant coronary artery stenosis (invasive FFR < 0.80). A deep neural network was trained with consecutive short axial images of coronary arteries on coronary CT. Ninety-one coronary arteries of 89 cases (48%) had FFR-positive functionally significant stenosis. On receiver operating characteristics (ROC) analysis to predict FFR-positive stenosis using the trained DL model, average area under the curve (AUC) of the ROC curve was 0.756, which was superior to the AUC of visual assessment of significant (≥ 70%) coronary artery stenosis on CT (0.574, P = 0.011). The sensitivity, specificity, positive and negative predictive value (PPV and NPV), and accuracy of the DL model and visual assessment for detecting FFR-positive stenosis were 82 and 36%, 68 and 78%, 59 and 48%, 87 and 69%, and 73 and 63%, respectively. Sensitivity and NPV for the prediction of FFR-positive stenosis were significantly higher with our DL model than visual assessment (P = 0.0004, and P = 0.024). DL-based coronary CT data analysis has a higher diagnostic accuracy for functionally significant coronary artery stenosis than visual assessment.
Assuntos
Doença da Artéria Coronariana , Estenose Coronária , Aprendizado Profundo , Reserva Fracionada de Fluxo Miocárdico , Humanos , Constrição Patológica , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Estenose Coronária/diagnóstico por imagem , Angiografia Coronária/métodos , Valor Preditivo dos Testes , Angiografia por Tomografia Computadorizada/métodos , Tomografia Computadorizada Multidetectores/métodosRESUMO
Recently, myocardial extracellular volume (ECV) analysis has been measurable on computed tomography (CT) using new software. We evaluated the use of cardiac CT to estimate the myocardial ECV of left ventricular (LV) myocardium (LVM) to predict reverse remodeling (RR) in cases of atrial fibrillation (AF) after catheter ablation (CA). Four hundred and seven patients underwent CA for AF in our institution from April 2014 to Feb 2021. Of these, 33 patients (8%) with an LVEF ≤ 50% and who had undergone CT were included in our study. We estimated the LVM ECV using commercial software to analyze the CT data. RR was defined as an improvement in LVEF to > 50% after CA. LVEF increased to > 50% in 24 patients (73%) after CA. In all 24 patients, LVM ECV, LV end-diastolic and end-systolic volumes (LVEDV and LVESV), and the n-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) were significantly lower than in the other nine patients (P = 0.0037, 0.0273, 0.0443, and < 0.0001). On receiver operating characteristic curve analysis, the best cut-off of ECV, LVEDV, LVESV and NT-proBNP for the prediction of RR were 37.73%, 120 mL, 82 mL, and 1267 pg/mL, respectively. We newly defined the ENL (ECV, NT-proBNP, and LVEDV) score as the summed score for the presence or absence (1 or 0; maximum score = 3) of ECV, NT-proBNP, and LVEDV values less than or equal to each best cut-off value, and found that this score gave the highest area under the curve for the prediction of RR (0.9583, P < 0.0001). The ENL score may be useful for predicting RR in patients with AF undergoing CA.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Humanos , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Volume Sistólico , Peptídeo Natriurético Encefálico , Miocárdio , Fragmentos de Peptídeos , Ablação por Cateter/métodosRESUMO
LL-37, the only member of the cathelicidin family of cationic antimicrobial peptides in humans has been shown to exhibit a wide variety of biological actions in addition to its antimicrobial activity. However, the lymphangiogenic effect of LL-37 has not been elucidated yet. In this study, we examined the effects of LL-37 on lymphangiogenesis and evaluated the underlying molecular mechanisms. LL-37 treatment significantly increased the migration and tube-like formation of human dermal lymphatic microvascular endothelial cells (HDLECs) and promoted the expression of lymphangiogenic factor in HDLECs. Treatment with LL-37 increased phosphorylation of ERK and Akt proteins in HDLECs, and pretreatment with ERK and Akt inhibitors significantly blocked the LL-37-induced HDLEC migration and tube-like formation. Furthermore, to investigate the involvement of formyl peptide receptor-like 1 (FPRL1) signaling in LL-37-induced lymphangiogenesis, HDLECs were treated with an FPRL1 antagonist. Pretreatment with the FPRL1 antagonist inhibited LL-37-induced phosphorylation of ERK and Akt proteins and attenuated LL-37-induced HDLEC migration and tube-like formation. These data indicated that LL-37 induces lymphangiogenesis in lymphatic endothelial cells via FPRL1, and the activation of the ERK and Akt-dependent signaling pathways.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Linfangiogênese/efeitos dos fármacos , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Linfangiogênese/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação , Proteínas Citotóxicas Formadoras de Poros/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Formil Peptídeo/antagonistas & inibidores , Receptores de Lipoxinas/antagonistas & inibidores , CatelicidinasRESUMO
Vascular endothelial cell growth factor-C (VEGF-C) is a member of the VEGF family and plays a role in various biological activities. VEGF-C enhances proliferation and migration of lymphatic endothelial cells and vascular endothelial cells through VEGF receptor 2 (VEGFR2) and/or receptor 3 (VEGFR3), and thereby induces lymphangiogenesis or angiogenesis. However, it remains unclear whether VEGF-C promotes the migration of mesenchymal stem cells (MSCs). Here, we investigated the effects of VEGF-C on the migration of MSCs and evaluated the underlying molecular mechanisms. VEGF-C treatment significantly induced the migration of MSCs, which is accompanied by the promotion of actin cytoskeletal reorganization and focal adhesion assembly. VEGF-C treatment enhanced the phosphorylation of VEGFR2 and VEGFR3 proteins in MSCs, and pretreatment with VEGFR2 and VEGFR3 kinase inhibitors effectively suppressed the VEGF-C-induced MSC migration. In addition, VEGF-C treatment promoted phosphorylation of ERK and FAK proteins in MSCs, and inhibition of VEGFR2 and VEGFR3 signaling pathways abolished the VEGF-C-induced activation of ERK and FAK proteins. Furthermore, treatment with ERK and FAK inhibitors suppressed VEGF-C-induced actin cytoskeletal reorganization and focal adhesion assembly, and then significantly inhibited MSCs migration. These results suggest that VEGF-C-induced MSC migration is mediated via VEGFR2 and VEGFR3, and follows the activation of the ERK and FAK signaling pathway. Thus, VEGF-C may be valuable in tissue regeneration and repair in MSC-based therapy.
Assuntos
Movimento Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/citologiaRESUMO
Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.
Assuntos
Ácidos Carboxílicos/efeitos adversos , Receptores X de Retinoides/efeitos adversos , Teratogênese/efeitos dos fármacos , Animais , Humanos , Peixe-ZebraAssuntos
Anomalias dos Vasos Coronários , Doenças Vasculares , Dissecação da Artéria Vertebral , Gravidez , Feminino , Humanos , Dissecação da Artéria Vertebral/diagnóstico por imagem , Dissecação da Artéria Vertebral/etiologia , Anomalias dos Vasos Coronários/diagnóstico por imagem , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/etiologiaRESUMO
Ras GTPase-activating proteins negatively regulate the Ras/Erk signaling pathway, thereby playing crucial roles in the proliferation, function, and development of various types of cells. In this study, we identified a novel Ras GTPase-activating proteins protein, RASAL3, which is predominantly expressed in cells of hematopoietic lineages, including NKT, B, and T cells. We established systemic RASAL3-deficient mice, and the mice exhibited a severe decrease in NKT cells in the liver at 8 weeks of age. The treatment of RASAL3-deficient mice with α-GalCer, a specific agonist for NKT cells, induced liver damage, but the level was less severe than that in RASAL3-competent mice, and the attenuated liver damage was accompanied by a reduced production of interleukin-4 and interferon-γ from NKT cells. RASAL3-deficient NKT cells treated with α-GalCer in vitro presented augmented Erk phosphorylation, suggesting that there is dysregulated Ras signaling in the NKT cells of RASAL3-deficient mice. Taken together, these results suggest that RASAL3 plays an important role in the expansion and functions of NKT cells in the liver by negatively regulating Ras/Erk signaling, and might be a therapeutic target for NKT-associated diseases.
Assuntos
Células T Matadoras Naturais/imunologia , Proteínas Ativadoras de ras GTPase/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Galactosilceramidas/administração & dosagem , Galactosilceramidas/imunologia , Técnicas de Silenciamento de Genes , Humanos , Interferon gama/biossíntese , Interleucina-4/biossíntese , Células Jurkat , Fígado/imunologia , Fígado/lesões , Fígado/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR/metabolismo , Receptores CXCR6 , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteínas Ativadoras de ras GTPase/deficiência , Proteínas Ativadoras de ras GTPase/genéticaRESUMO
The combination of BRAF kinase inhibitors (BRAFis) and MEK kinase inhibitors (MEKis) is one of the most promising chemotherapy regimens in the treatment of BRAF-mutant melanoma. Although BRAFi plus MEKi combined therapy is widely used for the treatment of BRAFV600-mutated melanoma, the incidence of uveitis caused by BRAFi plus MEKi is limited. In this report, we described five cases (two men and three women) of Vogt-Koyanagi-Harada (VKH) disease-like uveitis in melanoma patients who received BRAFi plus MEKi combined therapy. Of note, all the patients had the HLA-DRB1*04 haplotype, which is frequently detected in VKH-like non-infectious uveitis. On the other hand, among BRAFi plus MEKi-treated patients who did not develop VKH disease-like uveitis, only one of five (20%) patients had the HLA-DRB1*04 haplotype. Collectively, BRAFi/MEKi might induce severe VKH disease-like uveitis in melanoma patients with the HLA-DRB1*04 haplotype.
Assuntos
Cadeias HLA-DRB1 , Melanoma , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Síndrome Uveomeningoencefálica , Humanos , Cadeias HLA-DRB1/genética , Melanoma/tratamento farmacológico , Melanoma/genética , Masculino , Síndrome Uveomeningoencefálica/induzido quimicamente , Síndrome Uveomeningoencefálica/diagnóstico , Síndrome Uveomeningoencefálica/genética , Feminino , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Sulfonamidas/efeitos adversos , Sulfonamidas/administração & dosagem , Vemurafenib/efeitos adversos , Vemurafenib/administração & dosagem , Uveíte/induzido quimicamente , Uveíte/diagnóstico , Uveíte/genética , HaplótiposRESUMO
Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.
Assuntos
Modelos Animais de Doenças , Doença por Corpos de Lewy , Doença de Parkinson , Tomografia por Emissão de Pósitrons , alfa-Sinucleína , Animais , alfa-Sinucleína/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/diagnóstico por imagem , Humanos , Camundongos , Tomografia por Emissão de Pósitrons/métodos , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/diagnóstico por imagem , Callithrix , Masculino , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Feminino , Idoso , Camundongos Endogâmicos C57BLRESUMO
In Alzheimer's disease (AD), network hyperexcitability is frequently observed and associated with subsequent cognitive impairment. Dysfunction of inhibitory interneurons (INs) is thought to be one of the key biological mechanisms of hyperexcitability. However, it is still unknown how INs are functionally affected in tau pathology, which is a major pathology in AD. To clarify this, we evaluated the neuronal activity of cortical INs in 6-month-old rTg4510 mice, a model of tauopathy. Calcium imaging with mDlx enhancer-driven labeling revealed that neuronal activity in INs was decreased in rTg4510 mice. In the patch clamp recording, the firing properties of fast-spiking INs were altered so as to reduce their activity in rTg4510 mice. In parallel with microglial activation, perineuronal nets around parvalbumin-positive INs were partially disrupted in rTg4510 mice. Taken together, our data indicate that the excitability of cortical fast-spiking INs is decreased, possibly because of the disruption of perineuronal nets.
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Objective High-quality images can be obtained with 320-slice computed tomography (CT) with model-based iterative reconstruction (MBIR). We therefore investigated the diagnostic accuracy of 320-slice CT with MBIR for detecting significant coronary artery stenosis. Methods This was a retrospective study of 160 patients who underwent coronary CT and invasive coronary angiography (ICA). The first 100 consecutive patients (Group 1) underwent 320-slice CT without MBIR or small-focus scanning. The next 60 consecutive patients (Group 2) underwent 320-slice CT with both MBIR and small-focus scanning. Patients who underwent coronary artery bypass surgery were excluded. The diagnostic performance of 320-slice CT without MBIR or small-focus scanning and 320-slice CT with both of them, with ICA regarded as a reference standard, was compared to detect significant coronary artery stenosis (≥70% on CT, ≥75% on ICA). Results In a patient-based analysis, the sensitivity, specificity, and overall accuracy of detection of significant stenosis on CT against ICA were 95%, 85%, and 91% in Group 1, and 93%, 83%, and 90% in Group 2, respectively. No significant differences were observed between the two groups in the patient- and segment-based analyses. However, among cases with a severe coronary artery calcium score >400 (31 cases in Group 1 and 28 in Group 2), the specificity and overall accuracy were significantly higher (all p<0.01) in Group 2 than in Group 1 according to the segment-based analysis. Conclusion The diagnostic accuracy of the detection of coronary artery stenosis on CT was improved using 320-slice CT with MBIR.
Assuntos
Estenose Coronária , Vasos Coronários , Humanos , Vasos Coronários/diagnóstico por imagem , Estudos Retrospectivos , Estenose Coronária/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Ponte de Artéria Coronária , Angiografia Coronária/métodos , Sensibilidade e EspecificidadeRESUMO
We treated a female patient known to have a double-chambered right ventricle (DCRV) who presented with symptoms of an acute myocardial infarction (AMI). Emergent coronary artery catheterization revealed acute right coronary artery (RCA) occlusion and proximal left anterior descending (LAD) stenosis. We performed percutaneous coronary intervention (PCI) for the RCA occlusion. Right heart catheterization revealed a pressure gradient across the mid-RV of 58 mmHg. Computed tomography and magnetic resonance imaging revealed no other congenital cardiac abnormalities. She underwent surgical repair of the RV stenosis and coronary artery bypass surgery for LAD stenosis.
Assuntos
Infarto do Miocárdio , Intervenção Coronária Percutânea , Humanos , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/cirurgia , Ventrículos do Coração/patologia , Constrição Patológica , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/cirurgia , CoraçãoRESUMO
Purple sweet potato (Ipomoea batatas L.) leaf extract (PSPLE) is known to exhibit various biological effects. However, the anti-adipogenic effects of PSPLE on mesenchymal stem cells (MSCs) remain unknown. In the present study, we investigated the effect of PSPLE on the adipogenic differentiation of human bone marrow MSCs. PSPLE treatment significantly reduced lipid accumulation and triglyceride levels during adipogenic differentiation. PSPLE suppressed the expression of PPARγ and C/EBPα, which are the master transcription factors orchestrating adipogenesis; moreover, it inhibited the expression of adiponectin, adipocyte protein 2 (aP2), and lipoprotein lipase (LPL), which are downstream target genes involved in adipogenic differentiation. Furthermore, PSPLE treatment suppressed glucose transporter 4 expression and intracellular glucose uptake and significantly inhibited the adipogenic differentiation induced factor-stimulated Akt signaling activation. These results indicate that PSPLE suppresses the differentiation of undifferentiated MSCs into adipocyte lineages and inhibits the terminal differentiation from preadipocytes into mature adipocytes. PRACTICAL APPLICATION: The increase in the prevalence of obesity worldwide is a problem today. Obesity is induced by an excessive accumulation of adipocytes and causes obesity-related diseases, such as diabetes, hypertension, and hyperlipidemia. Natural compounds derived from plants and fruits have a variety of biological activities and are expected to exert therapeutic effects against various diseases. This study shows that purple sweet potato (Ipomoea batatas L.) leaf extract (PSPLE) suppresses adipogenesis of bone marrow-derived mesenchymal stem cells. Thus, PSPLE may be a novel functional food for controlling obesity.
Assuntos
Ipomoea batatas , Células-Tronco Mesenquimais , Adipogenia , Medula Óssea , Humanos , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologiaRESUMO
Introduction: As the movement of water in the brain is known to be involved in neural activity and various brain pathologies, the ability to assess water dynamics in the brain will be important for the understanding of brain function and the diagnosis and treatment of brain diseases. Aquaporin-4 (AQP4) is a membrane channel protein that is highly expressed in brain astrocytes and is important for the movement of water molecules in the brain. Methods: In this study, we investigated the contribution of AQP4 to brain water dynamics by administering deuterium-labeled water (D2O) intraperitoneally to wild-type and AQP4 knockout (AQP4-ko) mice that had undergone surgical occlusion of the middle cerebral artery (MCA). Water dynamics in the infarct region and on either side of the anterior cerebral artery (ACA) was monitored with proton-density-weighted imaging (PDWI) performed on a 7T animal MRI. Results: D2O caused a negative signal change quickly after administration. The AQP4-ko mice showed a delay of the time-to-minimum in both the contralateral and ipsilateral ACA regions compared to wild-type mice. Also, only the AQP4- ko mice showed a delay of the time-to-minimum in the ipsilateral ACA region compared to the contralateral side. In only the wild-type mice, the signal minimum in the ipsilateral ACA region was higher than that in the contralateral ACA region. In the infarct region, the signal attenuation was slower for the AQP4-ko mice in comparison to the wild-type mice. Discussion: These results suggest that AQP4 loss affects water dynamics in the ACA region not only in the infarct region. Dynamic PDWI after D2O administration may be a useful tool for showing the effects of AQP4 in vivo.
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Bexarotene, a retinoid X receptor (RXR) agonist, is used to treat cutaneous T-cell lymphoma, and drug repositioning research has also been reported, despite warnings of teratogenicity. However, fetal transfer of bexarotene and its effect on rat fetal bone formation have not been examined. In this study, we conducted a detailed teratogenicity and fetal transferability assessment of bexarotene in rats. Repeated administration of bexarotene during pregnancy caused marked fetal atrophy and bone dysplasia. Although fetal transfer was not detectable by dynamic imaging of [11C]bexarotene by means of positron emission tomography, transfer to the fetus was confirmed by using a gamma counter. Similar levels were found in mother and fetus. In addition, we found that bexarotene was accumulated in the placenta. These findings will be useful for the toxicity assessment of bexarotene as well as for drug discovery research targeting RXR agonists, which are expected to have therapeutic effects in various diseases.
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A massive increase in the number of mature CD4+ T-cells in peripheral blood (PB) is a defining characteristic of acute type of adult T-cell leukemia (ATL). To date, the site of proliferation of ATL cells in the body has been unclear. In an attempt to address this question, we examined the expression of the proliferation marker, Ki-67, in freshly isolated ATL cells from PB and lymph nodes (LNs) of patients with various types of ATL. Our findings reveal that LN-ATL cells display higher expression of the Ki-67 antigen than PB-ATL cells in acute type patients. The gene expression of T-cell quiescence regulators such as Krüppel-like factor 2/6 and forkhead box protein 1 was substantially high in acute type PB-ATL cells. The expression of human telomerase reverse transcriptase, which is involved in T-cell expansion, was significantly low in PB-ATL cells from acute type patients, similar to that in normal resting T-cells. These findings suggest that ATL cells proliferate in the LNs rather than in PB.