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1.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638817

RESUMO

Local radiotherapy (RT) is important to manage metastatic triple-negative breast cancer (TNBC). Although RT primarily reduces cancer cells locally, this control can be enhanced by triggering the immune system via immunotherapy. RT and immunotherapy may lead to an improved systemic effect, known as the abscopal effect. Here, we analyzed the antitumor effect of combination therapy using RT with an anti-programmed cell death-1 (PD-1) antibody in primary tumors, using poorly immunogenic metastatic mouse mammary carcinoma 4T1 model. Mice were injected subcutaneously into both flanks with 4T1 cells, and treatment was initiated 12 days later. Mice were randomly assigned to three treatment groups: (1) control (no treatment with RT or immune checkpoint inhibitor (ICI)), (2) RT alone, and (3) RT+ICI. The same RT dose was prescribed in both RT-alone and RT+ICI groups as 10Gy/fx in two fractions and delivered to only one of the two tumor burdens injected at both sides of flanks. In the RT+ICI group, 200 µg fixed dose of PD-1 antibody was intraperitoneally administered concurrently with RT. The RT and ICI combination markedly reduced tumor cell growth not only in the irradiated site but also in non-irradiated sites, a typical characteristic of the abscopal effect. This was observed only in radiation-sensitive cancer cells. Lung metastasis development was lower in RT-irradiated groups (RT-only and RT+ICI groups) than in the non-irradiated group, regardless of the radiation sensitivity of tumor cells. However, there was no additive effect of ICI on RT to control lung metastasis, as was already known regarding the abscopal effect. The combination of local RT with anti-PD-1 blockade could be a promising treatment strategy against metastatic TNBC. Further research is required to integrate our results into a clinical setting.

2.
Int J Mol Sci ; 22(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34502547

RESUMO

Cancer stem cells (CSCs) can be induced from differentiated cancer cells in the tumor microenvironment or in response to treatments and exhibit chemo- and radioresistance, leading to tumor recurrence and metastasis. We previously reported that triple negative breast cancer (TNBC) cells with acquired radioresistance exhibited more aggressive features due to an increased CSC population. Therefore, here, we isolated CSCs from radiotherapy-resistant (RT-R)-TNBC cells and investigated the effects of these CSCs on tumor progression and NK cell-mediated cytotoxicity. Compared to MDA-MB-231 and RT-R-MDA-MB-231 cells, CD24-/low/CD44+ cells isolated from RT-R-MDA-MB-231 cells showed increased proliferation, migration and invasion abilities, and induced expression of tumor progression-related molecules. Moreover, similar to MDA-MB-231 cells, CD24-/low/CD44+ cells recruited NK cells but suppressed NK cell cytotoxicity by regulating ligands for NK cell activation. In an in vivo model, CD24-/low/CD44+ cell-injected mice showed enhanced tumor progression and lung metastasis via upregulation of tumor progression-related molecules and altered host immune responses. Specifically, NK cells were recruited into the peritumoral area tumor but lost their cytotoxicity due to the altered expression of activating and inhibitory ligands on tumors. These results suggest that CSCs may cause tumor evasion of immune cells, resulting in tumor progression.

3.
Molecules ; 26(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500557

RESUMO

In this study, we aimed to evaluate the anticancer effect of benzimidazole derivatives on triple-negative breast cancer (TNBC) and investigate its underlying mechanism of action. Several types of cancer and normal breast cells including MDA-MB-231, radiotherapy-resistant (RT-R) MDA-MB-231, and allograft mice were treated with six benzimidazole derivatives including mebendazole (MBZ). Cells were analyzed for viability, colony formation, scratch wound healing, Matrigel invasion, cell cycle, tubulin polymerization, and protein expression by using Western blotting. In mice, liver and kidney toxicity, changes in body weight and tumor volume, and incidence of lung metastasis were analyzed. Our study showed that MBZ significantly induced DNA damage, cell cycle arrest, and downregulation of cancer stem cell markers CD44 and OCT3/4, and cancer progression-related ESM-1 protein expression in TNBC and RT-R-TNBC cells. In conclusion, MBZ has the potential to be an effective anticancer agent that can overcome treatment resistance in TNBC.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Mebendazol/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Pulmonares/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo
4.
Neuroradiology ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34382095

RESUMO

PURPOSE: To validate the use of synthetic magnetic resonance imaging (SyMRI) volumetry by comparing with child-optimized SPM 12 volumetry in 3 T pediatric neuroimaging. METHODS: In total, 106 children aged 4.7-18.7 years who underwent both synthetic and 3D T1-weighted imaging and had no abnormal imaging/neurologic findings were included for the SyMRI vs. SPM T1-only segmentation (SPM T1). Forty of the 106 children who underwent an additional 3D T2-weighted imaging were included for the SyMRI vs. SPM multispectral segmentation (SPM multi). SPM segmentation using an age-appropriate atlas and inverse-transforming template-space intracranial mask was compared with SyMRI segmentation. Volume differences between SyMRI and SPM T1 were plotted against age to evaluate the influence of age on volume difference. RESULTS: Measurements derived from SyMRI and two SPM methods showed excellent agreements and strong correlations except for the CSF volume (CSFV) (intraclass correlation coefficients = 0.87-0.98; r = 0.78-0.96; relative volume difference other than CSFV = 6.8-18.5% [SyMRI vs. SPM T1] and 11.3-22.7% [SyMRI vs. SPM multi]). Dice coefficients of all brain tissues (except CSF) were in the range 0.78-0.91. The Bland-Altman plot and age-related volume difference change suggested that the volume differences between the two methods were influenced by the volume of each brain tissue and subject's age (p < 0.05). CONCLUSION: SyMRI and SPM segmentation results were consistent except for CSFV, which supports routine clinical use of SyMRI-based volumetry in pediatric neuroimaging. However, caution should be taken in the interpretation of the CSF segmentation results.

5.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445501

RESUMO

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Cinamatos/farmacologia , Depsídeos/farmacologia , Glucose/efeitos adversos , Lipoproteínas LDL/efeitos adversos , Macrófagos/citologia , Transportador 1 de Cassete de Ligação de ATP/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Modelos Biológicos , Proteólise/efeitos dos fármacos , Transdução de Sinais , Células THP-1
6.
Arch Oral Biol ; 129: 105214, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34333230

RESUMO

OBJECTIVES: Dysregulated DNA methylation is common in cancers and is considered one of the most important triggers in cancer development and progression. The expression and promoter methylation status of long non-coding RNA (lncRNA) H19 play a key role in several cancers, but its role is unclear in oral cancer. The aim of this study was to evaluate the potential of lncRNA H19 as a prognostic biomarker for oral cancer. DESIGNS: The transcript levels and the methylation status of lncRNA H19 in OSCC cell lines and OSCC patient tissues were investigated by quantitative real-time RT-PCR (qRT-PCR) and methylation-specific PCR (MSP). Methylation ratio (%) were calculated from the intensity of the MSP in the gel image and Kaplan-Meier survival analysis of OSCC patient survival was performed for patients grouped according to the lncRNA H19 promoter methylation ratio. RESULTS: lncRNA H19 was highly expressed and its promoter region was hypomethylated in OSSC cell lines as compared to normal control. Almost all OSCC patients tissues (63 out of 65, 97 %) showed hypomethylation of lncRNA H19 compared to normal oral mucosa tissues. There was a significant correlation between methylation ratio and tumor histopathologic grade. OSCC patients with hypomethylation of lncRNA H19 had a significantly lower 5-year survival rate. CONCLUSIONS: Hypomethylation of lncRNA H19 may serve as a potential prognostic biomarker for oral cancer.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , RNA Longo não Codificante/genética , Biomarcadores , Carcinoma de Células Escamosas/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/genética , Prognóstico , RNA Longo não Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço
7.
Phys Chem Chem Phys ; 23(30): 16289-16295, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34312641

RESUMO

Two-dimensional piezoelectric materials have attracted great attention as they could play a vital role in nano-electromagnetic systems. Herein, we investigate the compelling piezoelectric properties of Janus ZrSeO in monolayer and bulk structures using density functional theory calculations with a van der Waals correction. One of the two independent out-of-plane piezoelectric coefficients (e31) of the bulk ZrSeO is as high as 287.60 pC m-1, which is over five times larger than that of monolayer ZrSeO due to charge changes in the internal structure within each Zr, Se, and O layer. Interestingly, another large negative out-of-plane piezoelectric stress coefficient (e33) of bulk ZrSeO (-467.40 pC m-1) results from the displacement difference between the electronic and ionic center positions, which is at least three times larger than those previously reported for Janus Mo/W/Hf-based transition metal dichalcogenides. The charge transformation between atoms under strain induces negative piezoelectric stress, a process that is clarified using maximally localized Wannier functions (MLWF) and Bader charge analysis. This research also reveals the dependence of piezoelectricity in Janus MXY on the metal (M = Zr, Hf, W, Mo) and chalcogenide (X,Y = S, Se, O) components, which are directly proportional to the electronegativity and the atomic size difference.

8.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073834

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid ß-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Graxos/metabolismo , Lipogênese/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Acetil-CoA Carboxilase/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Peso Corporal , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica , Ácido Graxo Sintases/metabolismo , Insulina/sangue , Resistência à Insulina/fisiologia , Lipase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Obesidade/metabolismo , Receptores Purinérgicos P2Y2/deficiência , Receptores Purinérgicos P2Y2/genética , Estearoil-CoA Dessaturase/metabolismo
9.
Sci Rep ; 11(1): 12992, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155253

RESUMO

Peritumoral edema (PE) of breast cancer at T2-weighted MR images is considered a poor prognostic sign and may represent the microenvironment surrounding the tumor; however, its histopathological mechanism remains unclear. The purpose of the study was to identify and describe detailed histopathological characteristics associated with PE at preoperative breast MRI in breast cancer patients. This retrospective study included breast cancer patients who had undergone preoperative MRI and surgery between January 2011 and December 2012. Two radiologists determined the presence of PE in consensus based on the signal intensity surrounding the tumor at T2-weighted images. The following detailed histopathological characteristics were reviewed by two breast pathologists using four-tiered grades; lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor budding. Tumor necrosis and tumor infiltrating lymphocytes were assessed using a percent scale. Baseline clinicopathological characteristics, including age and histologic grade, were collected. The associations between detailed histopathologic characteristics and PE were examined using multivariable logistic regression with odds ratio (OR) calculation. A total of 136 women (median age, 49 ± 9 years) were assessed; among them 34 (25.0%) had PE. After adjustment of baseline clinicopathological characteristics that were significantly associated with PE (age, T stage, N stage, histologic grade, and subtype, all Ps < 0.05), lymphovascular invasion (P = 0.009), vessel ectasia (P = 0.021), stromal fibrosis (P = 0.024), growth pattern (P = 0.036), and tumor necrosis (P < 0.001) were also associated with PE. In comparison with patients without PE, patients with PE were more likely to have a higher degree of lymphovascular invasion (OR, 2.9), vessel ectasia (OR, 3.3), stromal fibrosis (OR, 2.5), lesser degree of infiltrative growth pattern (OR, 0.4), and higher portion of tumor necrosis (OR, 1.4). PE of breast cancer at MRI is associated with detailed histopathological characteristics of lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor necrosis, suggesting a relevance for tumor microenvironment.

10.
Sci Rep ; 11(1): 11981, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099809

RESUMO

There is an unmet need for new influenza vaccine strategies that compensate for impaired vaccine responses in elderly individuals. Here, we evaluated the effectiveness of a single-stranded RNA (ssRNA) as an adjuvant to enhance the efficacy of inactivated influenza vaccine (IIV) in mouse models. Immunization with the ssRNA along with IIV reduced viral titers as well as pathological and inflammatory scores in the lungs after influenza challenge in aged mice. ssRNA induced balanced Th1/Th2 responses with an increase in IgA titers. Moreover, the ssRNA adjuvant markedly increased the frequency of influenza HA-specific T cells and IFN-γ production along with the expression of genes related to innate and adaptive immune systems that could overcome immunosenescence in aged mice. Our findings indicate that ssRNA is an efficient vaccine adjuvant that boosts cellular and humoral immunity in aged mice, demonstrating its potential as a novel adjuvant for currently available influenza virus vaccines for elderly individuals.

11.
Diagn Interv Radiol ; 27(3): 323-328, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34003120

RESUMO

PURPOSE: Neck ultrasonography (US), computed tomography (CT), and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) are all known to be useful imaging modalities for detecting supraclavicular lymph node (SCN) metastasis in breast cancer. The authors compared the diagnostic values of neck US, CT, and PET/CT in the detection of SCN metastasis in breast cancer. METHODS: SCN metastases identified in neck US, CT, or PET/CT during follow-up visits of patients with breast cancer were pathologically confirmed with the use of US-guided fine-needle aspiration cytology. The clinicopathological factors of the patients were analyzed, and the statistical parameters including sensitivity, specificity, positive and negative predictive values, false-positive and false-negative rates, and accuracy of neck US, CT, and PET/CT were compared. RESULTS: Among 32 cases of suspicious SCNs, 24 were pathologically confirmed as metastasis of breast cancer. The sensitivity of US + CT was 91.7%, which was the same as that of PET/CT, while the sensitivity rates of US alone and CT alone were 87.5% and 83.3%, respectively. Accuracy was 99.8% in PET/CT alone and 98.1% in US + CT. The false-negative rate was 0.1% in US + PET/CT, while it was 0.2% in PET/CT and US + CT, 0.3% in US alone and 0.4% in CT alone. CONCLUSION: PET/CT can be the first choice for detecting SCN metastases in breast cancer. However, if PET/CT is unavailable for any reason, US + CT could be a good second option to avoid false-negative results.


Assuntos
Neoplasias da Mama , Fluordesoxiglucose F18 , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Linfonodos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X , Ultrassonografia
12.
Nat Commun ; 12(1): 2582, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976133

RESUMO

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Proteína Relacionada a TNFR Induzida por Glucocorticoide/agonistas , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral/transplante , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/imunologia , Modelos Animais de Doenças , Feminino , Glioblastoma/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Memória Imunológica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
13.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809701

RESUMO

Evidence suggests that augmented expression of a certain gene can influence the efficacy of targeted and conventional chemotherapies. Here, we tested whether the high expression of enhancer of the rudimentary homolog (ERH), which serves as a prognostic factor in some cancers, can influence the efficacy of anthocyanins isolated from fruits of Vitis coignetiae Pulliat, Meoru in Korea (AIMs) on human gastric cancer cells. The anticancer efficacy of AIMs was augmented in ERH-transfected MKN28 cells (E-MKN28 cells). Molecularly, ERH augmented AIM-induced caspase-dependent apoptosis by activating caspase-3 and -9. The ERH-augmented apoptotic effect was related to mitochondrial depolarization and inhibition of antiapoptotic proteins, XIAP, and Bcl-2. In addition, reactive oxygen species (ROS) generation was augmented in AIMs-treated E-MKN28 cells compared to AIMs-treated naïve MKN28 cells. In conclusion, ERH augmented AIM-induced caspase-dependent mitochondrial-related apoptosis in MKN28 cells. A decrease in expression of Bcl-2 and subsequent excessive ROS generation would be the mechanism for ERH-augmented mitochondrial-related apoptosis in AIMs-treated MKN28 cells. A decrease in expression of XIAP would be another mechanism for ERH-augmented caspase-dependent apoptosis in AIMs-treated MKN28 cells.


Assuntos
Antocianinas/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/metabolismo , Vitis/química , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/patologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
14.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33710256

RESUMO

Landsteiner's definition of human blood groups and the genetic rules that govern blood transfusion represents a milestone in human genetics and a historic event in public health. His research into the specificity of serological reactions, although less well known, has had a critical influence on the development of contemporary views on immune recognition, clonal selection, and immunological self-tolerance.


Assuntos
Especificidade de Anticorpos , Transfusão de Sangue/história , Isoanticorpos/história , Sistema do Grupo Sanguíneo Rh-Hr/história , Linfócitos T/imunologia , Animais , Eritrócitos/imunologia , Hemaglutinação/imunologia , História do Século XX , Humanos , Imunidade Celular , Tolerância a Antígenos Próprios
15.
Medicine (Baltimore) ; 100(10): e24941, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725856

RESUMO

INTRODUCTION: Total knee replacement (TKR) is a surgical procedure that is being increasingly performed as a result of population aging and the increased average human life expectancy in South Korea. Consistent with the growing number of TKR procedures, the number of patients seeking acupuncture for relief from adverse effects, effective pain management, and the enhancement of rehabilitative therapy effects and bodily function after TKR has also been increasing. Thus, an objective examination of the evidence regarding the safety and efficacy of acupuncture treatments is essential. The aim of this study is to verify the hypothesis that the concurrent use of acupuncture treatment and usual care after TKR is more effective, safe, and cost-effective for the relief of TKR symptoms than usual care therapy alone. METHODS/DESIGN: This is an open-label, parallel, assessor-blinded randomized controlled trial that includes 50 patients with TKR. After screening the patients and receiving informed consent, the patients are divided into two groups (usual care + acupuncture group and usual care group); the patients will then undergo TKR surgery and will be hospitalized for 2 weeks. The patients will receive a total of 8 acupuncture treatments over 2 weeks after surgery and will be followed up at 3, 4, and 12 weeks after the end of the intervention. The primary outcome is assessed using the Korean version of the Western Ontario and McMaster Universities Arthritis Index (K-WOMAC), and the secondary outcome is measured using the Numerical Rating Scale (NRS), Risk of Fall, and Range of Motion (ROM). Moreover, the cost per quality-adjusted life years (QALYs) is adopted as a primary economic outcome for economic evaluation, and the cost per NRS is adopted as a secondary economic outcome. ETHICS AND DISSEMINATION: This trial has received complete ethical approval from the Ethics Committee of Catholic Kwandong University International St. Mary's Hospital (IS17ENSS0063). We intend to submit the results to a peer-reviewed journal and/or conferences. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03633097.


Assuntos
Terapia por Acupuntura/efeitos adversos , Artroplastia do Joelho/reabilitação , Osteoartrite do Joelho/cirurgia , Manejo da Dor/métodos , Dor Pós-Operatória/diagnóstico , Terapia por Acupuntura/economia , Idoso , Idoso de 80 Anos ou mais , Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/economia , Terapia Combinada/efeitos adversos , Terapia Combinada/economia , Terapia Combinada/métodos , Análise Custo-Benefício , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/economia , Manejo da Dor/efeitos adversos , Manejo da Dor/economia , Medição da Dor/estatística & dados numéricos , Dor Pós-Operatória/economia , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/reabilitação , Projetos Piloto , Anos de Vida Ajustados por Qualidade de Vida , República da Coreia , Resultado do Tratamento
16.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33573023

RESUMO

c-Jun N-terminal kinase (JNK) is activated by chemotherapeutic reagents including natural plant polyphenols, and cell fate is determined by activated phospho-JNK as survival or death depending on stimuli and cell types. The purpose of this study was to elucidate the role of JNK on the anticancer effects of the Korean plant Artemisia annua L. (pKAL) polyphenols in p53 wild-type HCT116 human colorectal cancer cells. Cell morphology, protein expression levels, apoptosis/necrosis, reactive oxygen species (ROS), acidic vesicles, and granularity/DNA content were analyzed by phase-contrast microscopy; Western blot; and flow cytometry of annexin V/propidium iodide (PI)-, dichlorofluorescein (DCF)-, acridine orange (AO)-, and side scatter pulse height (SSC-H)/DNA content (PI)-stained cells. The results showed that pKAL induced morphological changes and necrosis or late apoptosis, which were associated with loss of plasma membrane/Golgi integrity, increased acidic vesicles and intracellular granularity, and decreased DNA content through downregulation of protein kinase B (Akt)/ß-catenin/cyclophilin A/Golgi matrix protein 130 (GM130) and upregulation of phosphorylation of H2AX at Ser-139 (γ-H2AX)/p53/p21/Bak cleavage/phospho-JNK/p62/microtubule-associated protein 1 light chain 3B (LC3B)-I. Moreover, JNK inhibition by SP600125 enhanced ROS-independently pKAL-induced cell death through downregulation of p62 and upregulation of p53/p21/Bak cleavage despite a reduced state of DNA damage marker γ-H2AX. These findings indicate that phospho-JNK activated by pKAL inhibits p53-dependent cell death signaling and enhances DNA damage signaling, but cell fate is determined by phospho-JNK as survival rather than death in p53 wild-type HCT116 cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Artemisia annua , Neoplasias Colorretais/tratamento farmacológico , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Polifenóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos Fitogênicos/química , Artemisia annua/química , Morte Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Células HCT116 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Polifenóis/química , Inibidores de Proteínas Quinases/química , Espécies Reativas de Oxigênio/metabolismo
17.
Int J Mol Sci ; 22(4)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33562139

RESUMO

Diabetic nephropathy (DN) is a common pathological feature in patients with diabetes and the leading cause of end-stage renal disease. Although several pharmacological agents have been developed, the management of DN remains challenging. Geniposide, a natural compound has been reported for anti-inflammatory and anti-diabetic effects; however, its role in DN remains poorly understood. This study investigated the protective effects of geniposide on DN and its underlying mechanisms. We used a C57BL/6 mouse model of DN in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with geniposide by oral gavage for 5 weeks. Geniposide effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, renal inflammation and interstitial fibrosis. These changes induced by geniposide were associated with an increase of AMPK activity to enhance ULK1-mediated autophagy response and a decrease of AKT activity to block oxidative stress, inflammation and fibrosis in diabetic kidney. In addition, geniposide increased the activities of PKA and GSK3ß, possibly modulating AMPK and AKT pathways, efficiently improving renal dysfunction and ameliorating the progression of DN. Conclusively, geniposide enhances ULK1-mediated autophagy and reduces oxidative stress, inflammation and fibrosis, suggesting geniposide as a promising treatment for DN.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Iridoides/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Fibrose/prevenção & controle , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
18.
Ren Fail ; 43(1): 168-179, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33459127

RESUMO

The two primary mechanisms by which iodinated contrast media (CM) causes contrast-induced acute kidney injury (CIAKI) are the hemodynamic effect causing intrarenal vasoconstriction and the tubular toxic effect causing acute tubular necrosis. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which degrades prostaglandin E2 (PGE2), promotes tissue repair and regeneration in many organs. PGE2 causes intrarenal arterial vasodilation. In this study, we investigated whether a 15-PGDH inhibitor can act as a candidate for blocking these two major mechanisms of CIAKI. We established a CIAKI mouse model by injecting a 10 gram of iodine per body weight (gI/kg) dose of iodixanol into each mouse tail vein. A 15-PGDH inhibitor (SW033291), PGE1, or PGE2 were administered to compare the renal functional parameters, histologic injury, vasoconstriction, and renal blood flow changes. In addition, human renal proximal tubular epithelial cells were cultured in a CM-treated medium. SW033291, PGE1, or PGE2 were added to compare any changes in cell viability and apoptosis rate. CIAKI mice that received SW033291 had lower serum levels of creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1 (p < 0.001); lower histologic injury score and TUNEL positive rates (p < 0.001); and higher medullary arteriolar area (p < 0.05) and renal blood flow (p < 0.001) than CM + vehicle group. In cell culture experiments, Adding SW033291 increased the viability rate (p < 0.05) and decreased the apoptosis rate of the tubular epithelial cells (p < 0.001). This 15-PGDH inhibitor blocks the two primary mechanisms of CIAKI, intrarenal vasoconstriction and tubular cell toxicity, and thus has the potential to be a novel prophylaxis for CIAKI. Abbreviations: 15-PGDH: 15-hydroxyprostaglandin dehydrogenase; AMP: adenosine monophosphate; CIAKI: contrast-induced acute kidney injury; CM: contrast media; EP: prostaglandin E2 receptor; hRPTECs: human-derived renal proximal tubule epithelial cells; KIM-1: kidney injury molecule-1; MTT: 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide; NGAL: neutrophil gelatinase-associated lipocalin; PBS: phosphate-buffered saline; PGE1: prostaglandin E1; PGE2: prostaglandin E2; RBF: renal blood flow; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; α-SMA: α-Smooth muscle actin.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Meios de Contraste/efeitos adversos , Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores , Piridinas/farmacologia , Tiofenos/farmacologia , Animais , Creatinina/sangue , Feminino , Humanos , Rim/fisiopatologia , Lipocalina-2/sangue , Camundongos , Camundongos Endogâmicos C57BL , Prostaglandinas E/farmacologia , Ácidos Tri-Iodobenzoicos/efeitos adversos
19.
Eur Radiol ; 31(4): 2405-2413, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33034748

RESUMO

OBJECTIVES: To develop a radiomics score using ultrasound images to predict thyroid malignancy and to investigate its potential as a complementary tool to improve the performance of risk stratification systems. METHODS: We retrospectively included consecutive patients who underwent fine-needle aspiration (FNA) for thyroid nodules that were cytopathologically diagnosed as benign or malignant. Nodules were randomly assigned to a training and test set (8:2 ratio). A radiomics score was developed from the training set, and cutoff values based on the maximum Youden index (Rad_maxY) and for 5%, 10%, and 20% predicted malignancy risk (Rad_5%, Rad_10%, Rad_20%, respectively) were applied to the test set. The performances of the American College of Radiology (ACR) and the American Thyroid Association (ATA) guidelines were compared with the combined performances of the guidelines and radiomics score with interpretations from expert and nonexpert readers. RESULTS: A total of 1624 thyroid nodules from 1609 patients (mean age, 50.1 years [range, 18-90 years]) were included. The radiomics score yielded an AUC of 0.85 (95% CI: 0.83, 0.87) in the training set and 0.75 (95% CI: 0.69, 0.81) in the test set (Rad_maxY). When the radiomics score was combined with the ACR or ATA guidelines (Rad_5%), all readers showed increased specificity, accuracy, and PPV and decreased unnecessary FNA rates (all p < .05), with no difference in sensitivity (p > .05). CONCLUSION: Radiomics help predict thyroid malignancy and improve specificity, accuracy, PPV, and unnecessary FNA rate while maintaining the sensitivity of the ACR and ATA guidelines for both expert and nonexpert readers. KEY POINTS: • The radiomics score yielded an AUC of 0.85 and 0.75 in the training and test set, respectively. • For all readers, combining a 5% predicted malignancy risk cutoff for the radiomics score with the ACR and ATA guidelines significantly increased specificity, accuracy, and PPV and decreased unnecessary FNA rates, with no decrease in sensitivity. • Radiomics can help predict malignancy in thyroid nodules in combination with risk stratification systems, by improving specificity, accuracy, and PPV and unnecessary FNA rates while maintaining sensitivity for both expert and nonexpert readers.


Assuntos
Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/diagnóstico por imagem , Ultrassonografia , Estados Unidos
20.
J Exp Med ; 218(1)2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33180093

RESUMO

CD8+ T reg cells play an important role in the maintenance of self-tolerance and can inhibit the development of autoimmune disease. In this issue of JEM, Mishra et al. (https://doi.org/10.1084/jem.20200030) reveal that TGF-ß signaling and an Eomes-dependent genetic program contribute to CD8 T reg cell differentiation and function.


Assuntos
Linfócitos T CD8-Positivos , Tolerância Imunológica , Diferenciação Celular , Tolerância a Antígenos Próprios
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