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1.
Phys Rev Lett ; 132(18): 186904, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38759170

RESUMO

We experimentally demonstrate the enhancement of the far-field thermal radiation between two nonabsorbent Si microplates coated with energy-absorbent silicon dioxide (SiO_{2}) nanolayers supporting the propagation of surface phonon polaritons. By measuring the radiative thermal conductance between two coated Si plates, we find that its values are twice those obtained without the SiO_{2} coating. This twofold increase results from the hybridization of polaritons with guided modes inside Si and is well predicted by fluctuational electrodynamics and an analytical model based on a two-dimensional density of polariton states. These findings could be applied to thermal management in microelectronics, silicon photonics, energy conversion, atmospheric sciences, and astrophysics.

2.
Phys Rev Lett ; 128(1): 015901, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-35061463

RESUMO

Understanding and quantifying the fundamental physical property of coherence of thermal excitations is a long-standing and general problem in physics. The conventional theory, i.e., the phonon gas model, fails to describe coherence and its impact on thermal transport. In this Letter, we propose a general heat conduction formalism supported by theoretical arguments and direct atomic simulations, which takes into account both the conventional phonon gas model and the wave nature of thermal phonons. By naturally introducing wave packets in the heat flux from fundamental concepts, we derive an original thermal conductivity expression including coherence times and lifetimes. Our theory and simulations reveal two distinct types of coherence, i.e., intrinsic and mutual, appearing in two different temperature ranges. This contribution establishes a fundamental frame for understanding and quantifying the coherence of thermal phonons, which should have a general impact on the estimation of the thermal properties of solids.

3.
World J Surg Oncol ; 19(1): 4, 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33388058

RESUMO

BACKGROUND: Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported. CASE PRESENTATION: We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels. CONCLUSION: We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.


Assuntos
Infecções por Vírus Epstein-Barr , Perfuração Intestinal , Transtornos Linfoproliferativos , Idoso de 80 Anos ou mais , Feminino , Herpesvirus Humano 4 , Humanos , Perfuração Intestinal/cirurgia , Jejuno/cirurgia , Metotrexato/efeitos adversos , Recidiva Local de Neoplasia , Prognóstico
4.
Sci Technol Adv Mater ; 19(1): 863-870, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30479674

RESUMO

Phononic crystals have been studied for the past decades as a tool to control the propagation of acoustic and mechanical waves. Recently, researchers proposed that nanosized phononic crystals can also control heat conduction and improve the thermoelectric efficiency of silicon by phonon dispersion engineering. In this review, we focus on recent theoretical and experimental advances in phonon and thermal transport engineering using pillar-based phononic crystals. First, we explain the principles of the phonon dispersion engineering and summarize early proof-of-concept experiments. Next, we review recent simulations of thermal transport in pillar-based phononic crystals and seek to uncover the origin of the observed reduction in the thermal conductivity. Finally, we discuss first experimental attempts to observe the predicted thermal conductivity reduction and suggest the directions for future research.

5.
Environ Health Prev Med ; 21(6): 439-445, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27312140

RESUMO

OBJECTIVES: The present study measures heart rate (HR) on a number of professional race-car drivers during actual car races through annual seasons to test hypotheses that faster relative speed and higher cabin temperature would induce higher HR. METHODS: Heart rates in fifteen male drivers (31.2 ± 5.5 years old) were obtained by chest-strap sensors during official-professional 13 races. Average HR was calculated while the driver was racing from the start to the end of each race. RESULTS: The average HR during races was 164.5 ± 15.1 beats min-1 and the average amount of time each driver spent driving per race was 54.2 ± 13.7 min. Average HR significantly and positively correlated with mean speed ratio (P < 0.001), but not with the average cabin temperatures (P = 0.533, range 25.6-41.8 °C) by the multiple linear regression analysis. Both average HR and mean speed ratio were significantly lower under wet, than dry conditions (151.9 ± 16.5 vs. 168.3 ± 12.5 beats min-1, 86.9 ± 4.4 vs. 93.4 ± 1.5 %). CONCLUSIONS: The cardiovascular system of drivers is considerably stressed at extremely high HR. This high average HR positively correlated with mean speed ratio, suggesting that faster driving speed would induce greater cardiovascular stress to professional drivers during actual races. However, contrary to our hypothesis, cabin temperature was not significantly correlated with average HR. It is speculated that direct body cooling systems used in this professional race category work well against increases in HR by thermal stress under the temperature range found herein.


Assuntos
Condução de Veículo , Frequência Cardíaca , Esportes , Adulto , Temperatura Alta , Humanos , Masculino , Veículos Automotores
6.
Nippon Ganka Gakkai Zasshi ; 118(1): 33-9, 2014 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-24505934

RESUMO

BACKGROUND: We compared therapeutic outcomes in two cases of juxtapapillary capillary hemangiomas associated with von Hippel-Lindau disease. CASES: Case 1 was a 47-year-old man whose left eye was blind due to proliferative vitreoretinopathy. Visual acuity of the right eye was 1.2. No exudative change was found, but the juxtapapillary retinal hemangioma was enlarged. Three injections of intravitreal bevacizmab were not effective and laser photocoagulation was performed. Humphry microperimetry revealed a decreased sensitivity corresponding to the papillo-macular bundle damage. Vision was restored with regression of the retinal hemangioma. Case 2 was a 36-year-old woman with bilateral visual acuity of 1.2. The right eye had an inferior juxtapapillary retinal hemangioma at the optic disc surrounded by exudative retinal detachment. Laser photocoagulation, intravitreal injection of bevacizmab, transpapillary thermotherapy, photodynamic therapy, and vitrectomy were performed, but vision decreased to 0.02. CONCLUSIONS: Photocoagulation in the early stage of juxtapapillary hemangioma before development of exudative detachment may preserve visual acuity.


Assuntos
Hemangioma Capilar/cirurgia , Fotocoagulação , Neoplasias do Nervo Óptico/cirurgia , Doença de von Hippel-Lindau/complicações , Adulto , Feminino , Hemangioma Capilar/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias do Nervo Óptico/etiologia
7.
ACS Nano ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38958360

RESUMO

Phonon engineering at the nanoscale holds immense promise for a myriad of applications. However, the design of phononic devices continues to rely on regular shapes chosen according to long-established simple rules. Here, we demonstrate an inverse design approach to create a two-dimensional phononic metasurface exhibiting a highly anisotropic phonon dispersion along the main axes of the Brillouin zone. A partial hypersonic bandgap of approximately 3.5 GHz is present along one axis, with gap closure along the orthogonal axis. Such a level of control is achieved through genetically optimized unit cells, with shapes exceeding conventional intuition. We experimentally validated our theoretical predictions using Brillouin light scattering, confirming the effectiveness of the inverse design method. Our approach unlocks the potential for automated engineering of phononic metasurfaces with on-demand functionalities, thus leading toward innovative phononic devices beyond the limitations of traditional design paradigms.

8.
ACS Nano ; 18(15): 10557-10565, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38575375

RESUMO

Nanostructured semiconductors promise functional thermal management for microelectronics and thermoelectrics through a rich design capability. However, experimental studies on anisotropic in-plane thermal conduction remain limited, despite the demand for directional heat dissipation. Here, inspired by an oriental wave pattern, a periodic network of bent wires, we investigate anisotropic in-plane thermal conduction in nanoscale silicon phononic crystals with the thermally dead volume. We observed the anisotropy reversal of the material thermal conductivity from 1.2 at 300 K to 0.8 at 4 K, with the reversal temperature of 80 K mediated by the transition from a diffusive to a quasi-ballistic regime. Our Monte Carlo simulations revealed that the backflow of the directional phonons induces the anisotropy reversal, showing that the quasi-ballistic phonon transport introduces preferential thermal conduction channels with anomalous temperature dependence. Accordingly, the anisotropy of the effective thermal conductivity varied from 2.7 to 5.0 in the range of 4-300 K, indicating an anisotropic heat manipulation capability. Our findings demonstrate that the design of nanowire networks enables the directional thermal management of electronic devices.

9.
Opt Express ; 21(19): 21961-9, 2013 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-24104089

RESUMO

We investigate a structure consisting of two parallel GaAs thin membranes with an air-slot type photonic crystal (PhC) nanocavity, which is designed to achieve highly efficient optomechanical coupling. The structure shows a large theoretical optomechanical coupling factor of ~990 GHz/nm. We designed, fabricated, and performed optical characterization of a system consisting of a grating coupler, a PhC waveguide, and a PhC nanocavity, which achieves highly efficient vertical emission using the band folding technique. The experimentally obtained overall efficiency is about 0.3% for a microscope objective lens with a moderate numerical aperture of 0.65. This waveguide coupled air-slot PhC nanocavity with efficient vertical light coupling can be useful for on-chip cavity optomechanical systems.


Assuntos
Aumento da Imagem/instrumentação , Lentes , Sistemas Microeletromecânicos/instrumentação , Microscopia/instrumentação , Nanotecnologia/instrumentação , Ressonância de Plasmônio de Superfície/instrumentação , Desenho Assistido por Computador , Desenho de Equipamento , Análise de Falha de Equipamento
10.
Nanomaterials (Basel) ; 13(12)2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37368283

RESUMO

The super-ballistic temperature dependence of thermal conductivity, facilitated by collective phonons, has been widely studied. It has been claimed to be unambiguous evidence for hydrodynamic phonon transport in solids. Alternatively, hydrodynamic thermal conduction is predicted to be as strongly dependent on the width of the structure as is fluid flow, while its direct demonstration remains an unexplored challenge. In this work, we experimentally measured thermal conductivity in several graphite ribbon structures with different widths, from 300 nm to 1.2 µm, and studied its width dependence in a wide temperature range of 10-300 K. We observed enhanced width dependence of the thermal conductivity in the hydrodynamic window of 75 K compared to that in the ballistic limit, which provides indispensable evidence for phonon hydrodynamic transport from the perspective of peculiar width dependence. This will help to find the missing piece to complete the puzzle of phonon hydrodynamics, and guide future attempts at efficient heat dissipation in advanced electronic devices.

11.
J Pestic Sci ; 48(4): 168-174, 2023 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-38090218

RESUMO

Flometoquin, 2-ethyl-3,7-dimethyl-6-[4-(trifluoromethoxy)phenoxy]quinolin-4-yl methyl carbonate, is a novel insecticide with a structurally unique phenoxy-quinoline. It was discovered in 2004 by the collaborative research of Nippon Kayaku and Meiji Seika Kaisha, Ltd. (currently, Mitsui Chemicals Crop & Life Solutions, Inc.). The compound demonstrates strong and quick insecticidal action against a variety of thrips species at the nymphal and adult stages through contact and feeding activity, which could minimize crop damage and economic loss by insect pest species. In addition, flometoquin is safe for tested non-target arthropods, which makes it suitable for controlling the insect pests mentioned above under Integrated Pest Management (IPM) programs. Here, we describe a structure-activity relationship study from lead generation to the discovery of flometoquin and its insecticidal properties, including knockdown activity and effects against non-targeted arthropods.

12.
Sci Adv ; 9(31): eadf9775, 2023 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-37531440

RESUMO

The Starling principle describes exchanges between blood and tissues based on the balance of hydrostatic and osmotic flows. However, the permeation properties of the main constituent of tissues, namely, collagen, in response to the stress exerted by blood pressure remain poorly characterized. Here, we develop an instrument to determine the elasticity and permeability of collagen gels under tensile and compressive stress based on measuring the temporal change in pressure in an air cavity sealed at the outlet of a collagen slab. Data analysis with an analytical model reveals a drop in the permeability and enhanced strain stiffening of native collagen gels under compression versus tension, both effects being essentially lost after chemical cross-linking. Furthermore, we report the control of the permeability of native collagen gels using sinusoidal fluid injection, an effect explained by the asymmetric response in tension and compression. We lastly suggest that blood-associated pulsations could contribute to exchanges within tissues.


Assuntos
Colágeno , Modelos Biológicos , Estresse Mecânico , Força Compressiva/fisiologia , Resistência à Tração , Elasticidade , Permeabilidade , Géis
13.
Nanoscale ; 15(5): 2248-2253, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36628951

RESUMO

The performance of silicon-based thermoelectric energy generators is limited by the high thermal conductivity of silicon. Theoretical works have long proposed reducing the thermal conductivity by resonant phonon modes in nanopillars placed on the surface of silicon films. However, these predictions have never been confirmed due to the difficulty in the nanofabrication and measurements of such nanoscale systems. In this work, we report on the fabrication and measurements of silicon films with nanopillars as small as 12 nm in diameter. Our Brillouin light scattering spectroscopy experiments revealed that nanopillars indeed host resonant phonon modes. Yet, our thermal measurements using the micro time-domain thermoreflectance technique showed only a statistically insignificant difference between the thermal properties of silicon membranes with and without nanopillars. Results of this work contrast with the predictions of a substantial reduction in the thermal conductivity due to nanopillars and suggest refining the simulations to account for realistic experimental conditions.

14.
Nat Commun ; 14(1): 2044, 2023 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-37076484

RESUMO

In recent times, the unique collective transport physics of phonon hydrodynamics motivates theoreticians and experimentalists to explore it in micro- and nanoscale and at elevated temperatures. Graphitic materials have been predicted to facilitate hydrodynamic heat transport with their intrinsically strong normal scattering. However, owing to the experimental difficulties and vague theoretical understanding, the observation of phonon Poiseuille flow in graphitic systems remains challenging. In this study, based on a microscale experimental platform and the pertinent occurrence criterion in anisotropic solids, we demonstrate the existence of the phonon Poiseuille flow in a 5.5 µm-wide, suspended and isotopically purified graphite ribbon up to a temperature of 90 K. Our observation is well supported by our theoretical model based on a kinetic theory with fully first-principles inputs. Thus, this study paves the way for deeper insight into phonon hydrodynamics and cutting-edge heat manipulating applications.

15.
Int J Cancer ; 130(8): 1768-76, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21618516

RESUMO

MUC4 mucin is now known to be expressed in various normal and cancer tissues. We have previously reported that MUC4 expression is a novel prognostic factor in several malignant tumors; however, it has not been investigated in oral squamous cell carcinoma (OSCC). The aim of our study is to evaluate the prognostic significance of MUC4 expression in OSCC. We examined the expression profile of MUC4 in OSCC tissues from 150 patients using immunohistochemistry. Its prognostic significance in OSCC was statistically analyzed. MUC4 was expressed in 61 of the 150 patients with OSCC. MUC4 expression was significantly correlated with higher T classification (p = 0.0004), positive nodal metastasis (p = 0.049), advanced tumor stage (p = 0.002), diffuse invasion of cancer cells (p = 0.004) and patient's death (p = 0.004) in OSCC. Multivariate analysis showed that MUC4 expression (p = 0.011), tumor location (p = 0.032) and diffuse invasion (p = 0.009) were statistically significant risk factors. Backward stepwise multivariate analysis demonstrated MUC4 expression (p = 0.0015) and diffuse invasion (p = 0.018) to be statistically significant independent risk factors of poor survival in OSCC. The disease-free and overall survival of patients with MUC4 expression was significantly worse than those without MUC4 expression (p < 0.0001 and p = 0.0001). In addition, the MUC4 expression was a significant risk factor for local recurrence and subsequent nodal metastasis in OSCC (p = 0.017 and p = 0.0001). We first report MUC4 overexpression is an independent factor for poor prognosis of patients with OSCC; therefore, patients with OSCC showing positive MUC4 expression should be followed up carefully.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Bucais/metabolismo , Mucina-4/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Carcinoma de Células Escamosas/diagnóstico , Epitélio/química , Epitélio/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/química , Mucosa Bucal/patologia , Neoplasias Bucais/diagnóstico , Análise Multivariada , Prognóstico , Sensibilidade e Especificidade
16.
Cancer ; 118(21): 5251-64, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22434549

RESUMO

BACKGROUND: DF3/MUC1 mucin is expressed in various cancer tissues, and many in vitro studies have suggested that it may play a role in the aggressive behavior of malignant tumors. However, to the best of the authors' knowledge, the relation between DF3/MUC1 expression and outcome has not yet been investigated in patients with oral squamous cell carcinoma (OSCC). The objective of the current study was to evaluate the prognostic significance of DF3/MUC1 expression in patients with OSCC. METHODS: The expression profile of DF3/MUC1 in OSCC tissues from 206 patients was examined using immunohistochemistry. Its prognostic significance in OSCC was statistically analyzed on the basis of detailed clinicopathologic factors. RESULTS: DF3/MUC1 expression was found to be significantly correlated with tumor aggressiveness, such as pathologic lymph node metastasis (P = .002), advanced tumor stage (P = .02), diffuse invasion of cancer cells (P = .03), and vascular invasion (P = .01). Respectively, the overall survival (OS)and disease-free survival (DFS) rates were significantly worse for patients with DF3/MUC1 expression compared with those without DF3/MUC1 expression (P = .001 and P = .0003, respectively). Multivariate analysis demonstrated that DF3/MUC1 expression was an independent prognostic factor for both OS and DFS (P = .04 for both). In addition, DF3/MUC1 expression was found to be an independent risk factor for subsequent regional lymph node metastasis (P = .03). CONCLUSIONS: Aberrant expression of DF3/MUC1 is an independent prognostic factor indicating poor prognosis in patients with OSCC. DF3/MUC1 expression is a risk factor for subsequent lymph node metastasis in patients with OSCC and therefore may represent an indication for elective neck dissection. Patients with OSCC demonstrating positive expression of DF3/MUC1 should be followed carefully.


Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/metabolismo , Neoplasias Bucais/metabolismo , Mucina-1/análise , Idoso , Carcinoma de Células Escamosas/patologia , Epitopos/análise , Feminino , Humanos , Metástase Linfática , Masculino , Neoplasias Bucais/patologia , Prognóstico
17.
Cancer ; 118(17): 4298-308, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22252571

RESUMO

BACKGROUND: The early detection of oral squamous cell carcinoma (OSCC) is important, and a screening test with high sensitivity and specificity is urgently needed. Therefore, in this study, the authors investigated the methylation status of tumor-related genes with the objective of establishing a noninvasive method for the detection of OSCC. METHODS: Oral rinse samples were obtained from 34 patients with OSCC and from 24 healthy individuals (controls). The methylation status of 13 genes was determined by using methylation-specific polymerase chain reaction analysis and was quantified using a microchip electrophoresis system. Promoter methylation in each participant was screened by receiver operating characteristic analysis, and the utility of each gene's methylation status, alone and in combination with other genes, was evaluated as a tool for oral cancer detection. RESULTS: Eight of the 13 genes had significantly higher levels of DNA methylation in samples from patients with OSCC than in controls. The genes E-cadherin (ECAD), transmembrane protein with epidermal growth factor-like and 2 follistatin-like domains 2 (TMEFF2), retinoic acid receptor beta (RARß), and O-6 methylguanine DNA methyltransferase (MGMT) had high sensitivity (>75%) and specificity for the detection of oral cancer. OSCC was detected with 100% sensitivity and 87.5% specificity using a combination of ECAD, TMEFF2, RARß, and MGMT and with 97.1% sensitivity and 91.7% specificity using a combination of ECAD, TMEFF2, and MGMT. CONCLUSIONS: The aberrant methylation of a combination of marker genes present in oral rinse samples was used to detect OSCC with >90% sensitivity and specificity. The detection of methylated marker genes from oral rinse samples has great potential for the noninvasive detection of OSCC.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Detecção Precoce de Câncer , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/genética , Oncogenes/genética , Saliva/química , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Sensibilidade e Especificidade
18.
Opt Express ; 20(5): 5204-12, 2012 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-22418326

RESUMO

We theoretically investigate an optomechanical structure consisting of two parallel GaAs membranes with an air-slot type photonic crystal nanocavity. The optical cavity has a quality factor of 4.8 × 106 at 1.52 µm and an extremely small modal volume of 0.015 of a cubic wavelength for the fundamental mode in a vacuum. The localized electric field near the air/dielectric-object boundary provides a large optomechanical coupling factor of ~990 GHz/nm. The fundamental mechanical mode resonance is 95 MHz and a quality factor is 83,800 at room temperature, nearly seven times higher than that for a similar Si-based structure. This high mechanical quality factor of a GaAs-based structure stems from low thermoelastic loss and leads to more effective optical control of nanomechanical oscillators.


Assuntos
Arsenicais/química , Gálio/química , Sistemas Microeletromecânicos/instrumentação , Nanotecnologia/instrumentação , Oscilometria/instrumentação , Ressonância de Plasmônio de Superfície/instrumentação , Ar , Cristalização/métodos , Desenho de Equipamento , Análise de Falha de Equipamento , Fótons
19.
Bioorg Med Chem Lett ; 22(1): 334-8, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22133631

RESUMO

A series of novel cyclic amine-substituted benzoic acid derivatives were synthesized and evaluated for their PPARα agonist activity. Strucure-activity relationship studies led to the identification of (S)-3-[3-[2-(4-chlorophenyl)-4-methylthyazole-5-carboxamido]piperidin-1-yl]benzoic acid (S)-4f (KRP-105) as a potent and high subtype-selective human PPARα agonist. (S)-4f showed excellent PK profile and oral administration of (S)-4f to high-fat diet dogs effectively lowered triglycerides.


Assuntos
PPAR alfa/agonistas , Administração Oral , Aminas/química , Animais , Ácido Benzoico/química , Células CHO , Química Farmacêutica/métodos , Colesterol/metabolismo , Cricetinae , Dieta Hiperlipídica , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Modelos Químicos , PPAR alfa/química , Relação Estrutura-Atividade , Ativação Transcricional , Triglicerídeos/química
20.
Bioorg Med Chem Lett ; 22(2): 1005-8, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22202172

RESUMO

We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3ß inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Nitrilas/química , Quinolizinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolizinas/síntese química , Quinolizinas/química , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
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