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1.
Hepatology ; 71(1): 148-163, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31155734

RESUMO

The oncogene c-Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c-Myc is significantly up-regulated by tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/- mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63-linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c-Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c-Myc. Second, the K63-linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c-Myc and promotes c-Myc protein acetylation, which thereby enhances c-Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70-kDa-interacting protein-mediated c-Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c-Myc signaling is also primed in hepatitis B virus-transgenic mice, unveiling a critical role for a mechanism in inflammation-cancer transition. In clinical specimens, TRAF6 positively correlates with c-Myc at both the mRNA and protein levels, and high TRAF6 and c-Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c-Myc to promote human hepatocarcinogenesis. Consistently, curbing c-Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c-Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c-Myc signaling, with potential implications for HCC therapy.

2.
Mol Cancer Ther ; 19(1): 63-74, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31548293

RESUMO

Autotaxin catalyzes the formation of lysophosphatidic acid, which stimulates tumor growth and metastasis and decreases the effectiveness of cancer therapies. In breast cancer, autotaxin is secreted mainly by breast adipocytes, especially when stimulated by inflammatory cytokines produced by tumors. In this work, we studied the effects of an ATX inhibitor, GLPG1690, which is in phase III clinical trials for idiopathic pulmonary fibrosis, on responses to radiotherapy and chemotherapy in a syngeneic orthotopic mouse model of breast cancer. Tumors were treated with fractionated external beam irradiation, which was optimized to decrease tumor weight by approximately 80%. Mice were also dosed twice daily with GLPG1690 or vehicle beginning at 1 day before the radiation until 4 days after radiation was completed. GLPG1690 combined with irradiation did not decrease tumor growth further compared with radiation alone. However, GLPG1690 decreased the uptake of 3'-deoxy-3'-[18F]-fluorothymidine by tumors and the percentage of Ki67-positive cells. This was also associated with increased cleaved caspase-3 and decreased Bcl-2 levels in these tumors. GLPG1690 decreased irradiation-induced C-C motif chemokine ligand-11 in tumors and levels of IL9, IL12p40, macrophage colony-stimulating factor, and IFNγ in adipose tissue adjacent to the tumor. In other experiments, mice were treated with doxorubicin every 2 days after the tumors developed. GLPG1690 acted synergistically with doxorubicin to decrease tumor growth and the percentage of Ki67-positive cells. GLPG1690 also increased 4-hydroxynonenal-protein adducts in these tumors. These results indicate that inhibiting ATX provides a promising adjuvant to improve the outcomes of radiotherapy and chemotherapy for breast cancer.

3.
Cancers (Basel) ; 11(11)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752313

RESUMO

Breast cancer patients are usually treated with multiple fractions of radiotherapy (RT) to the whole breast after lumpectomy. We hypothesized that repeated fractions of RT would progressively activate the autotaxin-lysophosphatidate-inflammatory cycle. To test this, a normal breast fat pad and a fat pad containing a mouse 4T1 tumor were irradiated with X-rays using a small-animal "image-guided" RT platform. A single RT dose of 7.5 Gy and three daily doses of 7.5 Gy increased ATX activity and decreased plasma adiponectin concentrations. The concentrations of IL-6 and TNFα in plasma and of VEGF, G-CSF, CCL11 and CXCL10 in the irradiated fat pad were increased, but only after three fractions of RT. In 4T1 breast tumor-bearing mice, three fractions of 7.5 Gy augmented tumor-induced increases in plasma ATX activity and decreased adiponectin levels in the tumor-associated mammary fat pad. There were also increased expressions of multiple inflammatory mediators in the tumor-associated mammary fat pad and in tumors, which was accompanied by increased infiltration of CD45+ leukocytes into tumor-associated adipose tissue. This work provides novel evidence that increased ATX production is an early response to RT and that repeated fractions of RT activate the autotaxin-lysophosphatidate-inflammatory cycle. This wound healing response to RT-induced damage could decrease the efficacy of further fractions of RT.

4.
J Nutr ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529091

RESUMO

BACKGROUND: Choline, an essential nutrient, is required for cell membranes, lipoprotein secretion, and methyl-group metabolism. Recently, it has been proposed that excess dietary choline consumption is metabolized to trimethylamine (TMA) by the gut microbiota; TMA is then oxidized to trimethylamine N-oxide (TMAO) in the liver. Epidemiological studies have clearly shown a positive correlation between plasma TMAO concentrations and cardiovascular events. Furthermore, some studies have shown an association between excess dietary choline, plasma TMAO concentrations, and atherosclerotic lesion size in apoE knockout (Apoe-/-) mice. OBJECTIVE: The aim of this study was to further investigate the relation between dietary choline and atherosclerosis in 2 atherogenic mouse models, the LDL receptor knockout (Ldlr-/-) and Apoe-/- mice. METHODS: Six feeding trials were performed in Ldlr-/- (40% high-fat diet) and Apoe-/- (unpurified diet) male mice, aged 8-10 wk. Mice randomly received control diet (0.1% choline), or choline- (1% choline), betaine- (0.1% choline and 0.9% betaine), or TMAO- (0.1% choline and 0.12% or 0.2% TMAO) supplemented diet for ≤28 wk. After the dietary intervention, the animals were killed and tissues and blood collected. Aortic atherosclerotic plaque area, plasma lipids, and choline metabolites were quantified. RESULTS: In Ldlr-/- mice, dietary supplementation for 8 wk with choline or TMAO increased plasma TMAO concentrations by 1.6- and 4-fold, respectively. After 16 wk, there was a 2-fold increase in plasma TMAO after dietary TMAO supplementation. In Apoe-/- mice, dietary supplementation with choline, betaine, or TMAO for 12 wk did not increase plasma TMAO concentrations. However, choline and TMAO supplementation for 28 wk significantly increased plasma TMAO concentrations by 1.8- and 1.5-fold, respectively. Contrary to predictions, atherosclerotic lesion size was not altered by any of the dietary interventions, irrespective of mouse model. CONCLUSIONS: In our study, high intakes of dietary choline or TMAO supplementation did not influence atherosclerosis development in Ldlr-/- or Apoe-/- male mice.

5.
Phys Rev Lett ; 122(22): 220401, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31283283

RESUMO

It is well known that the violation of a local uncertainty relation can be used as an indicator for the presence of entanglement. Unfortunately, the practical use of these nonlinear witnesses has been limited to few special cases in the past. However, new methods for computing uncertainty bounds have become available. Here we report on an experimental implementation of uncertainty-based entanglement witnesses, benchmarked in a regime dominated by strong local noise. We combine the new computational method with a local noise tomography in order to design noise-adapted entanglement witnesses. This proof-of-principle experiment shows that quantum noise can be successfully handled by a fully quantum model in order to enhance the ability to detect entanglement.

6.
Front Neurosci ; 13: 701, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354412

RESUMO

Xiaoshuan enteric-coated capsule (XSEC) is a Chinese medicinal compound widely used for treatment of ischemic cerebrovascular diseases. Enriched environment (EE) is an effective rehabilitative protocol designed to enhance sensorimotor, cognitive and social stimulation. This study aimed to apply magnetic resonance imaging (MRI) to non-invasively assess whether EE could augment the therapeutic benefits of XSEC on post-ischemic neurovascular remodeling. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO) and treated with XSEC and EE alone or combination for 30 consecutive days. Beam walking test and Morris water maze (MWM) test were performed to evaluate motor and cognitive function, respectively. Multimodal MRI was applied to examine alterations to brain structures, intracranial vessels, and cerebral perfusion on the 31st day after MCAO. Double-immunofluorescent staining was used to evaluate neurogenesis and angiogenesis. Western blot and RT-PCR were used to detect the expressions of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and the axon guidance molecules. Combination therapy with XSEC and EE significantly reduced cystic volume compared with XSEC and EE monotherapies. In line with this, combination treated rats performed better in the beam walking test and exhibited improved spatial memory in the probe trial of the MWM. Moreover, XSEC and EE combination treatment improved cerebral blood flow (CBF), amplified angiogenesis and upregulated VEGF protein levels. This proangiogenic effect was consistent with the increased progenitor cell proliferation and neuronal differentiation in the peri-infarct cortex and striatum. Specifically, the combined therapy of XSEC and EE markedly increased the Netrin-1 and Robo-1 protein expression levels compared with vehicle group, while no difference was observed between XSEC or EE monotherapy and vehicle group. Together, these findings indicate that the combination of XSEC and EE benefits neurovascular reorganization. This correlates with restoration of CBF, promotion of neurogenesis and angiogenesis, and activation of the intrinsic axonal guidance molecules, thereby facilitating greater physical rehabilitation after ischemic stroke.

7.
Zhongguo Gu Shang ; 32(5): 401-406, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31248232

RESUMO

OBJECTIVE: To explore the clinical effect of acupoint puncture combined with Ilizarov technique in the treatment of knee osteoarthritis in the elderly. METHODS: From March 2015 to February 2016, 76 patients with primary knee osteoarthritis were treated with tibial osteotomy acupoint puncture grouop and Ilizarov technique anatomical puncture group, including 24 males and 52 females, aged 56 to 75 years old with an average of 61.4 years old, and a course of 3 to 17 years with an average of 5.2 years. Among them, 38 cases were treated with external fixation of acupoint puncture needle and 38 cases were treated with external fixation of anatomical puncture needle. Preoperative full-length X-ray of both lower limbs showed tibial varus deformity, narrowing of medial knee joint space and enlargement of lateral knee joint space. The force line of the affected knee and lower limb was moved inward by body surface measurement, and the KSS knee function score was decreased. Symptoms included medial knee pain, flexion and extension, and conservative treatment for more than 2 years. RESULTS: The lower limb force lines of both groups were corrected and the osteotomy ends healed well. No nonunion of osteotomy, inadequate correction of lower limbs or recurrence of deformity were found. Seventy-five patients were followed up for 3, 6, 12 and 24 months after operation. There was no significant difference in knee joint mobility between the two groups before operation and on 6, 12, 24 months after operation(F=1.346, P>0.05). There were significant difference in KSS pain and total score between the two groups at 3 months after operation, acupoint puncture group was better than anatomical puncture group(P<0.05); there was no significant difference in KSS score at 12 months after operation(P>0.05). CONCLUSIONS: The acupoint puncture group formed a potential acupuncture effect in the acupoint area by continuously tightening the steel needle on Ilizarov ring external fixator during the post-operative adjustment. Within three months after wearing external fixator, the knee pain symptoms of knee osteoarthritis were relieved rapidly, continuously and effectively, which was significantly better than that of the anatomical puncture group.


Assuntos
Técnica de Ilizarov , Osteoartrite do Joelho , Pontos de Acupuntura , Idoso , Feminino , Humanos , Articulação do Joelho , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/terapia , Punções , Tíbia , Resultado do Tratamento
8.
Cancer Med ; 8(6): 2840-2857, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016890

RESUMO

BACKGROUND: To evaluate the significance and benefit of radiotherapy (RT) in young early-stage breast cancer patients according to different molecular subtypes. METHODS: We conducted a retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results database with known hormone receptor (HoR) and human epidermal growth factor receptor 2 (HER2) status. Female patients aged 18-45, received RT treatment, and diagnosed with stage T1-3, N0-3, M0 primary breast cancer between 2010 and 2013 were identified. RESULTS: Of all the 23 148 included patients, 14 708 (63.54%), 3385 (14.62%), 1225 (5.29%), and 3830 (16.55%) were diagnosed with luminal-A (HoR + HER2-), luminal-B (HoR + HER2+), HER2-enriched (HoR-HER2+), and triple-negative (HoR-HER2-) breast cancer, respectively. RT was significantly correlated with improved overall survival (OS, HR: 0.295; 95% CI:0.138-0.63, P = 0.002) and breast cancer-specific survival (BCSS, HR: 0.328; 95% CI: 0.153-0.702, P = 0.004) in HER2-enriched patients. In addition, a significantly prolonged OS was also observed when RT was given to luminal-A (HR: 0.696; 95% CI: 0.538-0.902, P = 0.006) and luminal-B (HR: 0.385; 95% CI:0.199-0.744, P = 0.005) breast cancer patients compared to those without RT. Multivariable-adjusted analyses showed that HER2 was a significant favorable factor for RT benefit in breast cancer patients. CONCLUSIONS: RT could offer significant survival benefit in luminal-A, luminal-B, and especially HER2-enriched young early-stage breast cancer female patients. The results enabled clinicians to predict the benefits of RT and improve evidence-based treatment for breast cancer patients.

9.
Sci Total Environ ; 671: 608-616, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-30933817

RESUMO

Heat storage (Q) is an important component of the near-surface energy balance, and has been increasingly considered in recent energy balance studies. Studies have revealed that the hysteresis of heat storage was always been ignored, which leaded to the underestimation of heat storage proportion in energy balance. So, for further understanding the role of hysteresis effect in forestry heat storage, an observation experiment of heat storage in forestry of Pinus sylvestris var. mongolica Litv forestry - a common species in northern China - was conducted. Heat storage in the atmosphere beneath canopy, in the canopy biomass, and in the soil above a soil heat-flow plate were monitored continuously, to determine the distribution of stored heat, and solar radiation was simultaneously monitored to verify the hysteresis of heat storage versus radiation. Seasonal variations were separately analyzed to further clarify phenological effect on hysteresis. Correlation relationship was tested of lag time and underestimated energy versus climatic factors and physiological characteristics, for clarifying the reasons that resulting in hysteresis differences under different experimental day. The main results were as follows: (1) Hysteresis exists in heat storage and the lag time was 3.79 h in our study area; (2) The evaluation of hysteresis is crucial to avoid an underestimation of heat storage. Correction of lag time increases the heat storage proportion in R from 3.78% to 8.48%; (3) Increasing of air temperature and humility daily differences will enhance the underestimated energy. High radiation condition will weak the underestimation on heat storage and short the lag time. Soil moisture and leaf area index were not effect energy hysteresis significantly in sandy vegetation. Climatic factors were the main reason that resulting in the differences of hysteresis. This study helps to improve understanding energy transmitting in canopy and offering a new view in solving surface energy imbalance.


Assuntos
Monitoramento Ambiental/métodos , Agricultura Florestal , Florestas , Temperatura Alta , China , Pinus sylvestris , Solo
10.
Phys Chem Chem Phys ; 21(12): 6643-6650, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30855607

RESUMO

A direct NO-releasing reaction of nitrite catalyzed by [N(afaCy)3Fe(OTf)]+ (afa (azafulvene-amine); OTf (trifluoromethanesulfonate); Cy (cyclohexyl)) was investigated using density functional theory (DFT) with D3 dispersion correction. The complex featured a secondary coordination sphere that facilitated the formation of the iron-oxo product [N(afaCy)3FeO]+ with three (Fe)OH-N hydrogen bonds. As a high-spin iron(ii), the O-binding initial intermediate Fe(O)-nitrito was thermodynamically favorable in the S = 2 state. The cleavage of the (Fe)O-NO bond was performed by a ß-electron shift to produce Fe(iii)-O by electron rearrangement in the S = 5/2 state. The different electron configurations are responsible for the structural properties, the valence of iron in the complexes, and the pathways of the reactions. Moreover, the two different H-bonds, (Fe)OH-N and (Fe)O-HN (by O-protonation), in the product complexes played a role in determining the reaction channels by impacting the N-H bond rotation. Thus, an exothermic sequence of conversions Fe(ii) → Fe(iii)-O → Fe(iii)-OH → Fe(iii)-O was established for the targeted product formation. This process provided a clue to build two key intermediates, iron-oxo and iron-hydroxo, in a variety of biological and synthetic systems. The results of this study are in agreement with experimental observations and describe the roles of H-bonding in nitrite reduction catalyzed by the non-heme iron complex.

11.
J Pediatr Gastroenterol Nutr ; 68(6): 861-867, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889135

RESUMO

OBJECTIVES: In parenteral nutrition-dependent infants and children, intestinal failure (IF)-associated liver disease (IFALD) remains an important problem. A comparative study was undertaken of parenteral mixed lipid (ML), ω-3 predominant fish oil (FO), and ω-6 predominant soybean oil (SO) emulsions in regards to hepatic phytosterol, neutral lipid, fatty acid (FA) content, and the relationship to cholestasis in piglets. METHODS: Neonatal piglets received parenteral nutrition, varying in lipid dose (5 or 10 g·â€Škg ·â€Šday) and formulation: SO5 (n = 5), SO10 (n = 5), FO5 (n = 5), and ML10 (n = 5). On day 14, liver chemistry, bile flow, histology and neutral lipid staining were assessed. Hepatic triglyceride FA content was determined using thin layer and gas chromatography, and phytosterol content was assessed using gas chromatography-mass spectrometry. RESULTS: SO groups had higher prevalence of biochemical cholestasis (P < 0.04) and lower bile flow (P < 0.0001). Hepatic campesterol, stigmasterol, and ß-sitosterol were highest in SO10 (P < 0.0001). Hepatic FA (P < 0.03) and ω-6/ω-3 FA ratio (P < 0.0001) were higher in the SO groups. Neutral lipid accumulation (P = 0.3) and liver histology (P = 0.16) were not different between groups. Univariate predictors of bile flow were: campesterol (r = -0.77, P = 0.001), ß-sitosterol (r = -0.74, P = 0.002), stigmasterol (r = -0.74, P = 0.002), ω-6 FA (r = -0.72, P = 0.002), and ω-3 FA (r = 0.59, P = 0.02). Only campesterol independently predicted bile flow. CONCLUSIONS: ML and FO lipid emulsions reduce cholestasis in association with lowered hepatic phytosterol and lipid content. Lower hepatic phytosterol and ω-6 FA content, and higher ω-3 FA content are hepatoprotective. Multivariate analysis suggests reduced phytosterol accumulation may best explain the hepatoprotective effect of fish oil-containing lipids.

12.
J Hazard Mater ; 369: 601-610, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30825806

RESUMO

Sclerotinia sclerotiorum (S. sclerotiorum) is a soil-borne pathogen with broad host range. Dissolved organic matter (DOM) plays a vital role in regulating microbial activity in soil. Exogenous selenium (Se) inhibits plant pathogen growth and enhances the capacity of plants to resist disease. DOM from rape straw with Se treated in soil (RSDOMSe) was extracted, and the inhibitory effect on S. sclerotiorum growth was investigated. RSDOMSe inhibited S. sclerotiorum growth, which not only caused severe damage to S. sclerotiorum hyphae but also enhanced soluble protein leakage, thereby improving the growth inhibition ratio by 20.9%. As the action in intercellular, RSDOMSe led to a significant increase in oxalic acid and decrease in CWDE (cell wall-degrading enzyme, which helps pathogens to invade plants) activities, downregulation of Bi1 (BAX inhibitor-1, required for S. sclerotiorum virulence), Ggt1 (γ-glutamyl transpeptidase, regulates the ROS antioxidant system), CWDE2 and CWDE10 gene expression levels, compared with non-Se treated RSDOM (RSDOMN). Eight metabolites upregulated in RSDOMSe were identified by GC-TOF-MS, and among these metabolites, fumaric acid, maleic acid, malonic acid, mucic acid, saccharic acid, succunic acid and phenylacetic acid showed significant inhibition on S. sclerotiorum growth. These findings provide valuable insight into a new approach for developing eco-friendly fungicides.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30781695

RESUMO

Since the establishment of blown sand physics, surface roughness has been widely used in current research to indicate the ability of a surface to resist wind erosion and to evaluate the windproof effect of protective measures. However, since the calculation of surface roughness can result in different values and its applicability is poor, there are disadvantages to its use. Therefore, it is proposed that the boundary layer displacement thickness should be used rather than roughness as an indicator to solve such problems. To analyze the new indicator's accuracy and applicability when evaluating the effect of protective measures, a wind tunnel simulation experiment on a typical mechanical protection measure commonly used for sand control in China was conducted. Indicators of roughness and boundary layer displacement thickness were compared in evaluating the windproof performance of a Salix psammophila sand barrier of differing heights, side lengths, and porosities. The wind speed acceleration rate and effective protection area, which can directly reflect the protective effect of a sand barrier, were analyzed as evaluation criteria. The results show that roughness can only reflect the influence of height on the windbreak effect of sand barriers, whereas the boundary layer displacement thickness accurately showed the influence of height, side length, and porosity on the windproof effect of the sand barriers. Compared with roughness, the boundary layer displacement thickness was more strongly correlated with the effective protection area. Therefore, the boundary layer displacement thickness, rather than roughness, should be used as a new indicator when evaluating the windproof effect of protective measures.


Assuntos
Conservação dos Recursos Naturais/métodos , Salix/crescimento & desenvolvimento , Dióxido de Silício/análise , Vento , Movimentos do Ar , China
14.
Front Pharmacol ; 10: 69, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800068

RESUMO

Despite substantial efforts to develop novel therapeutic strategies for treating hepatocellular carcinoma (HCC), the effectiveness and specificity of available drugs still require further improvement. Previous work has shown that exogenous ceramide can play a key role in inducing the apoptotic death of cancer cells, however, the poor water-solubility of this compound has hampered its use for cancer treatment. In the present study, we used polyethylene glycol (PEG) and polyethylenimine (PEI) co-conjugated ultra-small nano-GO (NGO-PEG-PEI) loaded with C6-ceramide (NGO-PEG-PEI/Cer) as a strategy for HCC treatment. We assessed the biological role of NGO-PEG-PEI/Cer, and we assessed its antitumor efficacy against HCC both in vitro and in vivo in combination with the chemotherapeutic drug sorafenib. We found that NGO-PEG-PEI significantly enhanced the cellular uptake of C6-ceramide. By investigating the mechanism of cellular delivery, we determined that the internalization of NGO-PEG-PEI/Cer progressed primarily via a clathrin-mediated mechanism. The combination of NGO-PEG-PEI/Cer and sorafenib exhibited synergy between these two drugs. Further work revealed that NGO-PEG-PEI/Cer may play a role in subverting multidrug resistance (MDR) in HCC cells by inactivating MDR and Akt signaling. NGO-PEG-PEI/Cer also significantly inhibited tumor growth and improved survival times in vivo, and the synergetic effect of NGO-PEG-PEI/Cer combined with sorafenib was also observed in drug-resistant HCC xenografts. In conclusion, our NGO-PEG-PEI nanocomposite is an effective nano-platform for loading C6-ceramide for therapeutic use in treating HCC, exhibiting high cancer cell killing potency in this tumor model. The NGO-PEG-PEI/Cer/sorafenib combination additionally represents a promising potential therapeutic strategy for the treatment of drug-resistant HCC.

15.
J Pathol ; 248(1): 103-115, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30666650

RESUMO

Liver metastasis is the main cause of death in patients with colorectal cancer (CRC). Here, we searched for CRC metastasis-associated circular RNA in a mouse model of liver metastasis of CRC by using RNA (transcriptome)-sequencing. We identified a novel and conserved circular RNA, circ-NSD2, functioning as a promoter of CRC metastasis. Circ-NSD2 expression was elevated in CRC tissues and was markedly increased in advanced stages or metastatic tumours of CRC patients. Gain-of-function and loss-of-function experiments demonstrated that circ-NSD2 promoted migration and metastasis of CRC in vitro and in vivo. Mechanistically, circ-NSD2 acted as a sponge for the tumour suppressor miR-199b-5p and activated DDR1 (discoidin domain receptor tyrosine kinase 1) and JAG1 (Jagged 1) genes, which synergistically helped with cell-matrix interaction, migration and metastasis of CRC cells. Taken together, our findings highlight a novel oncogenic function of circ-NSD2 and uncover a key mechanism for the circ-NSD2/miR-199b-5p/DDR1/JAG1 axis in CRC metastasis, which may serve as a prognostic factor and therapeutic target for antimetastatic therapy in CRC patients. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

16.
Sci Rep ; 9(1): 286, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670771

RESUMO

Invasive micropapillary carcinoma (IMPC) is a rare histopathological variant of breast carcinoma that is usually associated with poor clinical characteristics. Whether IMPC has worse prognosis than invasive ductal carcinoma (IDC) is controversial. This retrospective study examined the prognostic difference between IMPC and IDC. We analysed 327 cases of IMPC patients and 4979 IDC cases who underwent primary resection in our institution between 2008 and 2012. Using propensity score matching, the two groups were matched at 1:1 by age, tumour size, nodal status, hormone status, and HER2 status. Differences in prognosis were assessed by Kaplan-Meier estimates and Cox regression analysis. We established the IMPC group and identified 324 IDC patients by propensity score matching. The survival analysis indicated that IMPC patients had no significant reduced overall survival (p = 0.752) or disease-free survival (p = 0.578) compared with IDC patients. Multivariate Cox regression analysis revealed that IMPC was not an independent prognostic factor for disease-free survival (hazard ratio [HR] = 0.944; 95% confidential interval [CI], 0.601-1.481) or overall survival (HR = 0.727; 95% CI, 0.358-1.478). Survival analysis demonstrated no statistically significant difference between IMPC and IDC, indicating that proactive or radical clinical therapy is unnecessary.

17.
ACS Appl Mater Interfaces ; 11(2): 1782-1789, 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30608644

RESUMO

We have introduced a novel water-soluble two-photon photoinitiator based on the host-guest interaction between 3,6-bis[2-(1-methyl-pyridinium)vinyl]-9-pentyl-carbazole diiodide (BMVPC) and cucurbit[7]uril (CB7) because most of the commercial photoinitiators have poor two-photon initiating efficiency in aqueous solutions. The binding ratio of BMVPC and CB7 was determined as 1:1 by isothermal titration calorimetry and quantum chemical calculation. The formation of the host-guest complex increases the two-photon absorption cross-section about five times, and improves the water solubility required as the photoinitiator for hydrogel fabrication. The BMVPC-CB7 inclusion complex was used as the one-component photoinitiator, and the polyethylene glycol diacrylate with promising biocompatibility was used as the hydrogel monomer to form the aqueous-phase photoresist system applied to two-photon polymerization microfabrication. A relatively low laser threshold of 4.5 mW, a high fabricating resolution of 180 nm, and the true three-dimensional (3D) fabricating capability in the aqueous solution have been obtained by using the as-prepared photoresist system. Finally, 3D engineering hydrogel scaffold microstructures with low toxicity and good biocompatibility have been fabricated and cocultured with living HeLa cells, which demonstrates the potential for further application in tissue engineering.


Assuntos
Materiais Biocompatíveis , Hidrocarbonetos Aromáticos com Pontes/química , Carbazóis/química , Hidrogéis , Imidazóis/química , Lasers , Tecidos Suporte/química , Materiais Biocompatíveis/química , Células HeLa , Humanos , Hidrogéis/síntese química , Hidrogéis/química , Microtecnologia , Polietilenoglicóis/química , Engenharia Tecidual
18.
Endoscopy ; 51(4): 333-341, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30469155

RESUMO

BACKGROUND: We developed a computer-assisted diagnosis model to evaluate the feasibility of automated classification of intrapapillary capillary loops (IPCLs) to improve the detection of esophageal squamous cell carcinoma (ESCC). METHODS: We recruited patients who underwent magnifying endoscopy with narrow-band imaging for evaluation of a suspicious esophageal condition. Case images were evaluated to establish a gold standard IPCL classification according to the endoscopic diagnosis and histological findings. A double-labeling fully convolutional network (FCN) was developed for image segmentation. Diagnostic performance of the model was compared with that of endoscopists grouped according to years of experience (senior > 15 years; mid level 10 - 15 years; junior 5 - 10 years). RESULTS: Of the 1383 lesions in the study, the mean accuracies of IPCL classification were 92.0 %, 82.0 %, and 73.3 %, for the senior, mid level, and junior groups, respectively. The mean diagnostic accuracy of the model was 89.2 % and 93.0 % at the lesion and pixel levels, respectively. The interobserver agreement between the model and the gold standard was substantial (kappa value, 0.719). The accuracy of the model for inflammatory lesions (92.5 %) was superior to that of the mid level (88.1 %) and junior (86.3 %) groups (P < 0.001). For malignant lesions, the accuracy of the model (B1, 87.6 %; B2, 93.9 %) was significantly higher than that of the mid level (B1, 79.1 %; B2, 90.0 %) and junior (B1, 69.2 %; B2, 79.3 %) groups (P < 0.001). CONCLUSIONS: Double-labeling FCN automated IPCL recognition was feasible and could facilitate early detection of ESCC.

19.
FASEB J ; 33(2): 1899-1910, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30192654

RESUMO

Lysophosphatidate (LPA) signaling through 6 receptors is regulated by the balance of LPA production by autotaxin (ATX) vs. LPA degradation by lipid phosphate phosphatases (LPPs). LPA promotes an inflammatory cycle by increasing the synthesis of cyclooxygenase-2 and multiple inflammatory cytokines that stimulate further ATX production. We aimed to determine whether the anti-inflammatory glucocorticoid (GC) dexamethasone (Dex) functions partly by decreasing the ATX-LPA inflammatory cycle in adipose tissue, a major site of ATX secretion. Treatment of human adipose tissue with 10-1000 nM Dex decreased ATX secretion, increased LPP1 expression, and decreased mRNA expressions of IL-6, TNF-α, peroxisome proliferator-activated receptor (PPAR)-γ, and adiponectin. Cotreatment with rosiglitazone (an insulin sensitizer), insulin, or both abolished Dex-induced decreases in ATX and adiponectin secretion, but did not reverse Dex-induced decreases in secretions of 20 inflammatory cytokines and chemokines. Dex-treated mice exhibited lower ATX activity in plasma, brain, and adipose tissue; decreased mRNA levels for LPA and sphingosine 1-phosphate (S1P) receptors in brain; and decreased plasma concentrations of LPA and S1P. Our results establish a novel mechanism for the anti-inflammatory effects of Dex through decreased signaling by the ATX-LPA-inflammatory axis. The GC action in adipose tissue has implications for the pathogenesis of insulin resistance and obesity in metabolic syndrome and breast cancer treatment.-Meng, G., Tang, X., Yang, Z., Zhao, Y., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Dexamethasone decreases the autotaxin-lysophosphatidate-inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer.


Assuntos
Tecido Adiposo/metabolismo , Dexametasona/farmacologia , Lisofosfolipídeos/sangue , Neoplasias Mamárias Experimentais/sangue , Síndrome Metabólica/sangue , Proteínas de Neoplasias/sangue , Diester Fosfórico Hidrolases/sangue , Transdução de Sinais/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Feminino , Humanos , Inflamação , Neoplasias Mamárias Experimentais/patologia , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos BALB C
20.
Cancer Lett ; 440-441: 189-201, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30393159

RESUMO

TMEM126A is a mitochondrial transmembrane protein, and its functions in breast cancer progression remain unclear. In this study, via the iTRAQ assay using primary and metastatic breast cancer cell models, we found that TMEM126A expression decreased in metastatic cells. We further confirmed that low TMEM126A expression correlated with tumor progression and poor prognosis in patients. The downregulation of TMEM126A in breast cancer cell lines significantly enhanced the metastatic properties in vitro and in vivo, whereas its overexpression decreased the metastatic potential of cell lines. Mechanistic studies based on RNA-sequencing indicated that TMEM126A might regulate cell metastasis via ECM-receptor interaction, focal adhesions, and actin cytoskeleton, among other processes. Furthermore, the loss of TMEM126A activated extracellular matrix (ECM) remodeling and promoted epithelial-to-mesenchymal transition (EMT). Moreover, TMEM126A silencing induced reactive oxygen species (ROS) production and mitochondrial membrane potential depolarization. The ROS scavengers reversed ECM remodeling and EMT mediated by TMEM126A. Collectively, our findings show that the loss of TMEM126A induces mitochondrial dysfunction and subsequently metastasis by activating ECM remodeling and EMT. These findings suggest that TMEM126A is a novel suppressor of metastasis and that it can be a potential prognostic indicator for patients with breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Membrana/deficiência , Mitocôndrias/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Animais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Criança , Regulação para Baixo , Transição Epitelial-Mesenquimal , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Humanos , Células MCF-7 , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Mitocôndrias/patologia , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Adulto Jovem
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