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1.
Proc Natl Acad Sci U S A ; 116(33): 16314-16319, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31363054

RESUMO

Critical for diverse biological processes, proteases represent one of the largest families of pharmaceutical targets. To inhibit pathogenic proteases with desired selectivity, monoclonal antibodies (mAbs) hold great promise as research tools and therapeutic agents. However, identification of mAbs with inhibitory functions is challenging because current antibody discovery methods rely on binding rather than inhibition. This study developed a highly efficient selection method for protease inhibitory mAbs by coexpressing 3 recombinant proteins in the periplasmic space of Escherichia coli-an antibody clone, a protease of interest, and a ß-lactamase modified by insertion of a protease cleavable peptide sequence. During functional selection, inhibitory antibodies prevent the protease from cleaving the modified ß-lactamase, thereby allowing the cell to survive in the presence of ampicillin. Using this method to select from synthetic human antibody libraries, we isolated panels of mAbs inhibiting 5 targets of 4 main protease classes: matrix metalloproteinases (MMP-14, a predominant target in metastasis; MMP-9, in neuropathic pain), ß-secretase 1 (BACE-1, an aspartic protease in Alzheimer's disease), cathepsin B (a cysteine protease in cancer), and Alp2 (a serine protease in aspergillosis). Notably, 37 of 41 identified binders were inhibitory. Isolated mAb inhibitors exhibited nanomolar potency, exclusive selectivity, excellent proteolytic stability, and desired biological functions. Particularly, anti-Alp2 Fab A4A1 had a binding affinity of 11 nM and inhibition potency of 14 nM, anti-BACE1 IgG B2B2 reduced amyloid beta (Aß40) production by 80% in cellular assays, and IgG L13 inhibited MMP-9 but not MMP-2/-12/-14 and significantly relieved neuropathic pain development in mice.

2.
Nanotechnology ; 30(38): 385205, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31239427

RESUMO

A blue organic light-emitting diode (OLED) with silica-coated silver nanocubes (Ag@SiO2 NCs) inserted at the hole transporting layer/emission layer interface is reported. The localized surface plasmon resonance (LSPR) properties of the Ag@SiO2 NCs were characterized by the measured absorption spectra, stable-stated and transient photoluminescence, and calculated dipole radiation power. The results suggest that the Ag NCs significantly improved the radiation intensity of the nearby excitons due to their sharp corners and edges, but had less impact on the radiation rate of the excitons. The exciton recombination zone in the blue OLED was confirmed by a group of devices with an ultra-thin yellow emission layer located at different places, which helped to figure out the distribution of the excitons around the Ag@SiO2 NCs and deeply understand the coupling between the excitons and the Ag@SiO2 NCs. In our blue OLED, an appropriate distance between the Ag NCs and the excitons was realized by the SiO2 coating layer and the exciton distribution, which greatly improved the energy transfer between the excitons and the Ag NCs. In addition, the LSPR enhanced electric field around the Ag@SiO2 NCs improved the carrier injection at the hole transporting layer/emission layer interface and increased the current density of the blue OLED. Finally, the blue OLED with a simple triple layer structure achieved a high current efficiency of 51.1 cd A-1.

3.
Toxicol Appl Pharmacol ; 378: 114603, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152816

RESUMO

Hexavalent chromium [Cr(VI)] is a known occupational and environmental contaminant and carcinogen, but new mechanisms of Cr(VI)-induced carcinogenesis remain to be elucidated. In this study, we found that expression of miR-143 is decreased, whereas that of Interleukin 6 (IL-6) is increased in blood samples of Cr(VI)-exposing workers compared with corresponding unexposed workers. In addition, IL-6 was increased in human bronchial epithelial cells (BEAS-Cr) exposed to Cr(VI) compared with unexposed BEAS-2B cells. To further investigate the mechanisms by which Cr(VI) promotes these changes, we assessed the effects of miR-143 on gene expression and found that miR-143 suppressed expression of IL-6, HIF-1α and NF-κB p65, and that inhibiting miR-143 promoted expression of IL-6, HIF-1α and NF-κB p65. Interestingly, IL-6 regulated expression of HIF-1α, and HIF-1α transcriptionally regulated expression of IL-6. Experiments in animals showed that miR-143 inhibited tumor growth and angiogenesis by regulating IL-6/HIF-1α and downstream signaling pathways in vivo. These outcomes support the hypothesis that the miR-143/IL-6/HIF-1α pathway functions to regulate Cr(VI)-induced carcinogenesis.

4.
Toxicol Appl Pharmacol ; 378: 114606, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170415

RESUMO

Inorganic arsenic is an environmental carcinogen that poses a major global public health risk. A high percentage of drinking water from wells in the U.S. contains higher-than-normal levels of arsenic, suggesting an increased risk of arsenic-induced deleterious effects. In addition to primary preventive measures, therapeutic strategies need to effectively address and integrate multiple molecular mechanisms underlying arsenic-induced carcinogenesis. We previously showed that the loss of miR-199a-5p in arsenic-transformed cells is pivotal to promote arsenic-induced angiogenesis and tumor growth in lung epithelial cells. In this study, we further showed that subacute or chronic exposure to arsenic diminished miR-199a-5p levels largely due to DNA methylation, which was achieved by increased DNA methyltransferase-1 (DNMT1) activity, mediated by the formation of specific protein 1 (Sp1)/DNMT1 complex. In addition to the DNA hypermethylation, arsenic exposure also repressed miR-199a transcription through a transcriptional repressor Sp1. We further identified an association between miR-199a-5p repression and the arsenic-mediated energy metabolic shift, as reflected by mitochondria defects and a switch to glycolysis, in which a glycolytic enzyme pyruvate kinase 2 (PKM2) was a functional target of miR-199a-5p. Taken together, the repression of miR-199a-5p through both Sp1-dependent DNA methylation and Sp1 transcriptional repression promotes an arsenic-mediated metabolic shift from mitochondria respiration to aerobic glycolysis via PKM2.

5.
J Cell Physiol ; 234(12): 23409-23420, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31141164

RESUMO

The resistance against tamoxifen therapy has become one of the major obstacles in the clinical treatment of breast cancer. Nicotinamide phosphoribosyltransferase (NAMPT) is an essential enzyme catalyzing nicotinamide adenine dinucleotide biosynthesis and is important for tumor metabolism. The study here sought to explore the effect of NAMPT on breast cancer survival with tamoxifen conditioning. We found that NAMPT was highly expressed in breast cancer cells compared with normal mammary epithelial cells. Inhibition of NAMPT by FK866 inhibited cell viability and aggravated apoptosis in cancer cells treated with 4-hydroxytamoxifen. NAMPT overexpression upregulated 14-3-3ζ expression. Knockdown of 14-3-3ζ reduced cell survival and promoted apoptosis. Activation of Akt signaling, rather than ERK1/2 pathway, is responsible for 14-3-3ζ regulation by NAMPT overexpression. Furthermore, NAMPT overexpression led to PKM2 accumulation in the cell nucleus and could be dampened by 14-3-3ζ inhibition. In addition, NAMPT overexpression promoted xenografted tumor growth and apoptosis in nude mice, while 14-3-3ζ inhibition attenuated its effect. Collectively, our data demonstrate that NAMPT contributes to tamoxifen resistance through regulation of 14-3-3ζ expression and PKM2 translocation.

6.
J Biophotonics ; 12(9): e201900073, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31100192

RESUMO

Imaging nuclei of keratinocytes in the stratified squamous epithelium has been a subject of intense research since nucleus associated cellular atypia is the key criteria for the screening and diagnosis of epithelial cancers and their precursors. However, keratinocyte nuclei have been reported to be either low scattering or high scattering, so that these inconsistent reports might have led to misinterpretations of optical images, and more importantly, hindered the establishment of optical diagnostic criteria. We disclose that they are generally low scattering in the core using Micro-optical coherence tomography (µOCT) of 1.28-µm axial resolution in vivo; those previously reported "high scattering" or "bright" signals from nuclei are likely from the nucleocytoplasmic boundary, and the low-scattering nuclear cores were missed possibly due to insufficient axial resolutions (~4µm). It is further demonstrated that the high scattering signals may be associated with flattening of nuclei and cytoplasmic glycogen accumulation, which are valuable cytologic hallmarks of cell maturation.

7.
Scand J Gastroenterol ; 54(4): 480-484, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31017491

RESUMO

Objective: To investigate the risk factors affecting the survival of patients with gastrointestinal stromal tumors (GISTs) in different age groups. Methods: Information on 6089 GIST patients was screened from the Surveillance, Epidemiology, and End Results (SEER) database. Risk factor analysis was performed using a chi-square test (univariate analysis). Survival analysis was performed using the Kaplan-Meier method (log-rank test) and the COX proportional hazard model. p Value < .05 was considered statistically significant. Results: Analyzed statistically to reveal that in addition to tumor size, mitotic index, and primary location, age, gender, race, and surgical treatment also were independent risk factors for GISTs. Gender, race, and location of disease influenced the survival rate of patients, which was higher in the young group (≤60 years old) than the elderly group (>60 years). Risk factors such as primary location, tumor diameter, and mitotic index varied significantly between the different age groups. Conclusions: Age, gender, race, and surgical treatment are independent risk factors that influence the prognosis in patients with GISTs. Some risk factors affecting prognosis are age dependent.

8.
J Sep Sci ; 42(13): 2231-2238, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31021051

RESUMO

This study proposed a new ballpoint connector-protected salt-oil-salt liquid phase microextraction for extraction and enrichment of trace rhein and chrysophanol in rhubarb prior to determination of the analytes by high performance liquid chromatography. In this study, a handy ballpoint connector (between ballpoint tip and ink chamber) was used as extraction device, in which its cavity was filled with n-octanol, and the bare n-octanol in its two opening ends was covered with a thin layer of sodium chloride film. The design subtly assembled salt film onto ballpoint connector for extraction and enrichment, which greatly improved the enrichment factors of the target analytes. Moreover, the novel procedure and its extraction mechanism were described and analyzed, and several crucial parameters reflecting the extraction effect were investigated and optimized. Under optimum conditions, high enrichment factors (247 and 127), good linearities with r ≥ 0.9998, limits of detection (0.6-1.1 ng/mL), relative standard deviations of intra- and interday (2.2-8.8% and 4.3-8.9%), and average recoveries (97.6-98.1%), were obtained, respectively. The proposed method can not only eliminate the negative effects from viscosity and ion strength at high salt concentration of sample phase, but also make salting-out effect be focused on small area so as to maximize the extraction effect.

9.
Tissue Eng Part A ; 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30929614

RESUMO

Low back pain caused by degenerative disc disease affects many people worldwide and brings huge economical burden. Thus, attentions have focused on annulus fibrosus (AF) tissue engineering for treatment of intervertebral disc degeneration. To engineer a functional replacement for the AF, it is important to fabricate scaffolds which mimic the structural and mechanical properties of native tissue. AF-derived stem cells are promising seed cells for AF tissue engineering due to their tissue specificity. In the present study, Decellularized annulus fibrosus matrix (DAFM)/chitosan hybrid hydrogels were fabricated using genipin as a crosslinker. AF stem cells were cultured on hydrogel scaffolds with or without basic fibroblast growth factor (bFGF), and cell proliferation, morphology, gene expression, and AF tissue synthesis were examined. Overall, more collagen-I, collagen-II, and aggrecan were secreted by AF stem cells grown on hydrogels with bFGF compared to those without. These results support the application of DAFM/chitosan hybrid hydrogels as an appropriate candidate for AF tissue engineering. Furthermore, incorporation of bFGF into hydrogels promoted AF-related tissue synthesis.

10.
BMC Cancer ; 19(1): 381, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023247

RESUMO

BACKGROUND: Salinomycin is a monocarboxylic polyether antibiotic and is a potential chemotherapy drug. Our previous studies showed that salinomycin inhibited cell growth and targeted CSCs in prostate cancer. However, the precise target of salinomycin action is unclear. METHODS: In this work, we analyzed and identified differentially expressed genes (DEGs) after treatment with or without salinomycin using a gene expression microarray in vitro (PC-3 cells) and in vivo (NOD/SCID mice xenograft model generated from implanted PC-3 cells). Western blotting and immunohistochemical staining were used to analyze the expression of ATP2A3 and endoplasmic reticulum (ER) stress biomarkers. Flow cytometry was used to analyze the cell cycle, apoptosis and intracellular Ca2+ concentration. RESULTS: A significantly upregulated gene, ATPase sarcoplasmatic/endoplasmatic reticulum Ca2+ transporting 3 (ATP2A3), was successfully identified. In subsequent studies, we found that ATP2A3 overexpression could trigger ER stress and exert anti-cancer effects in PC-3 and DU145 cells. ATP2A3 was slightly expressed, but the ER stress biomarkers showed strong staining in prostate cancer tissues. We also found that salinomycin could trigger ER stress, which might be related to ATP2A3-mediated Ca2+ release in PC-3 cells. Furthermore, we found that salinomycin-triggered ER stress could promote apoptosis and thus exert anti-cancer effects in prostate cancer cells. CONCLUSION: This study demonstrates that ATP2A3 might be one of the potential targets for salinomycin, which can inhibit Ca2+ release and trigger ER stress to exert anti-cancer effects.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Piranos/administração & dosagem , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Technol Cancer Res Treat ; 18: 1533033819837261, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30871415

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer death. Platelet-related indictors, including platelet count, plateletcrit, mean platelet volume, and platelet distribution width, not only associate with morphology and functions of platelet but also correlate with tumor development and metastasis. In the present study, we investigated the values of platelet-related indictors in the prognosis evaluation of resectable lung cancers. METHODS: In total, 101 patients with resectable lung cancer were recruited in this study. Patients were divided into 2 groups according to the median pretreatment values. To evaluate the individual value changes after treatment, we introduced the concept of post-/pretreatment ratio (≤1 indicated value was not increased after treatment, while >1 suggested increased value). RESULTS: The high pretreatment platelet count level was correlated with larger tumor size. High pretreatment plateletcrit level was associated with more lymph nodes metastasis. Patients with high pretreatment plateletcrit level had worse overall survival, whereas pretreatment platelet count, mean platelet volume, and platelet distribution width levels were not correlated with outcomes. Surgery had no impact on the values of platelet count, plateletcrit, mean platelet volume, or platelet distribution width. Adjuvant chemotherapy significantly decreased the values of platelet count and plateletcrit, whereas it had no effect on the values of mean platelet volume or platelet distribution width. Whole course of treatment (surgery combined with adjuvant chemotherapy) significantly decreased the values of platelet count and platelet distribution width, whereas it had no effect on the values of plateletcrit or mean platelet volume. Post-/pretreatment platelet count, plateletcrit, mean platelet volume, and platelet distribution width ratios were not correlated with outcomes. Univariate analyses demonstrated that American Joint Committee on Cancer stage and pretreatment plateletcrit level were significant risk factors for prognosis. Cox regression analysis revealed that no factor independently associated with worse survival. CONCLUSION: Pretreatment plateletcrit level could be a potential prognostic factor in resectable lung cancers.


Assuntos
Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/secundário , Plaquetas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Metástase Linfática , Masculino , Volume Plaquetário Médio , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/cirurgia , Taxa de Sobrevida
12.
Biochemistry ; 58(14): 1861-1868, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30839197

RESUMO

Direct biocatalytic conversion of CO2 to formic acid is an attractive means of reversibly storing energy in chemical bonds. Formate dehydrogenases (FDHs) are a heterogeneous group of enzymes that catalyze the oxidation of formic acid to carbon dioxide, generating two protons and two electrons. Several FDHs have recently been reported to catalyze the reverse reaction, i.e., the reduction of carbon dioxide to formic acid, under appropriate conditions. The main challenges with these enzymes are relatively low rates of CO2 reduction and high oxygen sensitivity. Our earlier studies (Yu et al. (2017) J. Biol. Chem. 292, 16872-16879) have shown that the FdsABG formate dehydrogenase from Cupriavidus necator is able to effectively catalyze the reduction of CO2, using NADH as a source of reducing equivalents, with a good oxygen tolerance. On the basis of this result, we have developed a highly thermodynamically efficient and cost-effective biocatalytic process for the transformation of CO2 to formic acid using FdsABG. We have  cloned the full-length soluble formate dehydrogenase (FdsABG) from C. necator and expressed it in Escherichia coli with a His-tag fused to the N terminus of the FdsG subunit; this overexpression system has greatly simplified the FdsABG purification process. Importantly, we have also combined this recombinant C. necator FdsABG with another enzyme, glucose dehydrogenase, for continuous regeneration of NADH for CO2 reduction and demonstrated that the combined system is highly effective in reducing CO2 to formate. The results indicate that this system shows significant promise for the future development of an enzyme-based system for the industrial reduction of CO2.

13.
J Coll Physicians Surg Pak ; 29(2): 189-190, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30700365

RESUMO

The aim of this study was to investigate the clinical diagnostic value of combined detection of serum C-reactive protein (CRP) and procalcitonin (PCT) for bacterial infectious diseases in children. It was a case control study carried out from October 2016 to March 2018. A total of 150 children with bacterial infectious disease were assigned to the observation group, and 150 healthy children without infectious diseases were assigned to the control group. The research showed that CRP and PCT levels, positive rates of CRP and PCT detection in observation group were higher than those in control group (p<0.001); sensitivity and diagnostic coincidence rate, detection specificity of CRP combined with PCT were higher than those in single PCT or CRP (p<0.001, <0.001 and 0.013, respectively). CRP combined with PCT detection enjoys good clinical application value in diagnosis of bacterial infectious diseases in children.


Assuntos
Infecções Bacterianas/diagnóstico , Proteína C-Reativa/análise , Pró-Calcitonina/sangue , Infecções Bacterianas/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença
14.
Exp Cell Res ; 376(2): 133-148, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30763583

RESUMO

Activating transcription factor 2 (ATF2), a member of the alkaline-leucine zipper family, is widely expressed in various tissues, and reportedly involved in inflammatory responses to various irritates, but its role in the central nervous system (CNS) remains unclear. This study aimed to investigate the expression and biological function of ATF2 in CNS inflammation. Utilizing the LPS-induced neuroinflammation model on mice, we first found ATF2 up-regulation and its co-localization with microglia in inflamed mice brain. In vitro, we revealed an increased expression, phosphorylation, and nuclear accumulation of ATF2 in LPS-treated BV2 microglia cells. Inhibiting ATF2 significantly decreased the expression of pro-inflammatory factors in LPS-treated microglia, and alleviated neuronal apoptosis induced by the conditioned medium of activated microglia. Knocking down TRAF6, an important adaptor of the TLR4/MAPK/NF-κB signaling pathway, suppressed the LPS-induced ATF2 expression and phosphorylation, accompanied by the decreased p38/JNK phosphorylation, in microglia. Blocking p38 or JNK signaling pathway by the specific inhibitors reversed the TRAF6-overexpression mediated ATF2 activation. Taken together, our data first proved the pro-inflammatory function of ATF2 in microglia, and suggested that the TRAF6-JNK/p38-ATF2 axis might promote microglial inflammatory activation and thus aggravate neuronal injury in brain, which might become a potential therapeutic target for CNS diseases.

15.
Int Immunopharmacol ; 70: 187-200, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30807932

RESUMO

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a member of the scavenger receptor family, recognizes multiple ligands and participates in several inflammatory responses, but its function within the central nervous system (CNS) remains unclear. In this study, we discovered an increased LOX-1 expression in activated microglia in vivo and in vitro. Employing the specific inhibitors, we found that conditioned medium of necrotic neurons (Necrotic-CM) induced microglial LOX-1 expression through the MAPKs/NF-κB pathway. Silencing LOX-1 inhibited MAPK phosphorylation, NF-κB-p65 nuclear transportation, and pro-inflammatory factor production in microglia exposed to Necrotic-CM. Furthermore, utilizing the conditioned medium of activated microglia (MG-CM), we discovered microglial LOX-1 aggravated the neuroinflammation-induced neuronal apoptosis. Collectively, a LOX-1/MPAKs/NF-κB positive loop might promote microglia activation and drive the vicious cycle of neuroinflammation and neuronal injury.


Assuntos
Sistema Nervoso Central/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Microglia/fisiologia , NF-kappa B/metabolismo , Inflamação Neurogênica/metabolismo , Neurônios/patologia , Receptores Depuradores Classe E/metabolismo , Animais , Apoptose , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose , RNA Interferente Pequeno/genética , Receptores Depuradores Classe E/genética , Transdução de Sinais , Regulação para Cima
16.
Mol Med Rep ; 19(3): 2330-2340, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664202

RESUMO

The count and classification of white blood cells (WBCs) may be used as prognostic markers in certain types of cancer. The present study investigated the prognostic potential of the counts of WBCs, including lymphocytes (LYs), monocytes (MOs), neutrophils (NEs), eosinophils (EOs) and basophils (BAs), in the prognosis of resectable colorectal cancer. The present study recruited 153 resectable colorectal cancer cases retrospectively, which were pathologically confirmed. All patients were divided into two groups, according to the median value of LY (low LY, ≤1.632x109/l or high LY, >1.632x109/l), MO (low MO, ≤0.330x109/l or high MO, >0.330x109/l), NE (low NE, ≤3.600x109/l or high NE, >3.600x109/l), EO (low EO, ≤0.085x109/l or high EO, >0.085x109/l), BA (low BA, ≤0.010x109/l or high BA, >0.010x109/l), or WBC (low WBC, ≤5.780x109/l or high WBC, >5.780x109/l). To evaluate the alterations in WBC counts following surgery and adjuvant chemotherapy; all samples received oxiplatin and capecitabine (XELOX) for 6­8 cycles or 5­fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) for 10­12 cycles. XELOX included oxaliplatin administered intravenously at a dose of 130 mg/m2 on day 1 and 850­1,250 mg/m2 capecitabine twice daily for days 1­14, repeated every 3 weeks. mFOLFOX6 included oxaliplatin administered intravenously at a dose of 85 mg/m2, 400 mg/m2 leucovorin and 400 mg/m2 5­FU on day 1 followed by 1,200 mg/m2/days continuous infusion for 2 days (in total, 2,400 mg/m2 over 46­48 h), repeated every 2 weeks. The present study investigated the post/pre­treatment of LY, MO, NE, EO, BA and WBC ratios (≤1 indicated that LY, MO, NE, EO, BA and WBC counts were not increased following therapy; whereas, >1 suggested increased counts). Kaplan­Meier curves were constructed to demonstrate overall survival (OS). A multivariate and univariate logistic regression analyses model was employed to identify the independent risk factors. Low pre­treatment BA counts were associated with larger tumor size (>5 cm); pre­treatment BA levels were positively associated with OS. Surgery significantly decreased the count of BAs and increased the count of EOs; whereas, no effect was observed on LYs, MOs, NEs or WBCs. Adjuvant chemotherapy markedly decreased the counts of LY, NE and WBC; whereas, no notable effects on MOs, EOs or BAs were observed. Whole course treatment (surgery combined with adjuvant chemotherapy) significantly decreased the values of LY, NE and WBC; however, increased the value of EO; no effects on the MO or BA counts were observed. An increased post­/pre­treatment NE ratio suggested poorer prognosis. Multivariate Cox regression analysis revealed that sex, tumor size, pre­treatment BA count and the post­/pre­treatment NE ratio were independent prognostic factors affecting OS. The results of the present study suggested that the pre­treatment BA count and post­/pre­treatment NE ratio may be potential prognostic factors for resectable colorectal cancer.


Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Contagem de Leucócitos , Prognóstico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Basófilos/efeitos dos fármacos , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Eosinófilos/efeitos dos fármacos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Leucovorina/administração & dosagem , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Compostos Organoplatínicos/administração & dosagem
17.
J Magn Reson Imaging ; 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659687

RESUMO

BACKGROUND: Microstructural changes of lupus nephritis (LN) kidney such as inflammatory cell infiltration or fibrosis could influence water molecular movement or diffusion, which indicates that diffusion-weighted imaging (DWI) may become a valuable tool in evaluation of this disease. PURPOSE: To explore whether multiparameter diffusion-weighted imaging (mDWI) could contribute to characterize pathological patterns in LN patients. STUDY TYPE: Retrospective. POPULATION: Twenty-two patients with LN. FIELD STRENGTH/SEQUENCE: Multi-b value DWI was performed with a 3.0 T scanner. ASSESSMENT: Apparent diffusion coefficient (ADC)m , perfusion-related diffusion coefficient (Df ), molecular diffusion coefficient (Ds ), perfusion fraction (f), ADCs , α, ADCk , and mean kurtosis (MK) were calculated by monoexponential, biexponential, stretched-exponential, and kurtosis models fits, respectively. STATISTICAL TESTS: Independent sample t-test, Pearson analysis and receiver operating characteristic (ROC). RESULTS: In the whole group, the activity index (AI) correlated significantly with alpha values in the medulla (rho = -0.54, P = 0.03). The chronicity index (CI) correlated significantly with Ds values in the medulla (rho = -0.61, P = 0.02). No significant association was found between any other diffusion parameter and histologic grade with all P > 0.05. For differentiating proliferative LN (Class III or IV) from Class V, the area under the ROC curve (AUC) of alpha in the medulla was 0.833 (P = 0.023). DATA CONCLUSION: mDWI might be used for the characterization of pathological patterns in LN patients. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019.

18.
Opt Express ; 27(2): 1298-1309, 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30696198

RESUMO

Current optical coherence tomography (OCT) technology, which is used for imaging the eye's anterior segment, has been established as a clinical gold standard for the diagnosis of corneal diseases. However, the cellular resolution level information that is critical for many clinical applications is still not available. The major technical challenges toward cellular resolution OCT imaging are the limited ranging depth and depth of focus (DOF). In this work, we present a novel ultrahigh resolution OCT system that achieves an isotropic spatial resolution of <2 µm in tissue. The proposed system could approximately double the ranging depth and extend the DOF using the dual-spectrometer design and the forward-model based digital refocusing method, respectively. We demonstrate that the novel system is capable of visualizing the full thickness of the pig cornea over the ranging depth of 3.5 mm and the border of the corneal endothelial cells 8 times Rayleigh range away from the focal plane. This technology has the potential to realize cellular resolution corneal imaging in vivo.


Assuntos
Córnea/anatomia & histologia , Processamento de Imagem Assistida por Computador , Animais , Endotélio/anatomia & histologia , Suínos , Tomografia de Coerência Óptica
19.
Dev Cell ; 48(3): 345-360.e7, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30595535

RESUMO

NANOG is an essential transcriptional factor for the maintenance of embryonic stem cells (ESCs) and cancer stem cells (CSCs) in prostate cancer (PCa). However, the regulation mechanism of NANOG protein stability in cancer progression is still elusive. Here, we report that NANOG is degraded by SPOP, a frequently mutated tumor suppressor of PCa. Cancer-associated mutations of SPOP or the mutation of NANOG at S68Y abrogates the SPOP-mediated NANOG degradation, leading to elevated PCa cancer stemness and poor prognosis. In addition, SPOP-mediated NANOG degradation is controlled by the AMPK-BRAF signal axis through the phosphorylation of NANOG at Ser68, which blocked the interaction between SPOP and NANOG. Thus, our study provides a regulation mechanism of PCa stemness controlled by phosphorylation-mediated NANOG stability, which helps to identify novel drug targets and improve therapeutic strategy for PCa.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteína Homeobox Nanog/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Repressoras/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas Culina/metabolismo , Genes Supressores de Tumor , Humanos , Masculino , Camundongos Nus , Mutação/genética , Neoplasias da Próstata/genética , Fatores de Transcrição/metabolismo , Ubiquitinação/fisiologia
20.
Acta Pharmacol Sin ; 40(8): 1095-1105, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30643208

RESUMO

ß-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). ß-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the ß-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects. In the present study, we evaluated agonist bias for compounds developed along a drug discovery project of ß2-adrenoceptor agonists. About 150 compounds, including derivatives of fenoterol, 2-amino-1-phenylethanol and 2-amino-2-phenylethanol, were obtained or synthesized, and initially screened for their ß-adrenoceptor-mediated activities in the guinea pig tracheal smooth muscle relaxation assay or the cardiomyocyte contractility assay. Nineteen bioactive compounds were further assessed using both the HTRF cAMP assay and the PathHunter ß-arrestin assay. Their concentration-response data in stimulating cAMP synthesis and ß-arrestin recruitment were applied to the Black-Leff operational model for ligand bias quantitation. As a result, three compounds (L-2, L-4, and L-12) with the core structure of 5-(1-amino-2-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one were identified as a new series of ß-arrestin-biased ß2-adrenoceptor agonists, whereas salmeterol was found to be Gs-biased. These findings would facilitate the development of novel drugs for the treatment of both heart failure and asthma.

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