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1.
Clin Immunol ; 227: 108753, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33945871

RESUMO

Neutrophils are conspicuous components of gastric cancer (GC) tumors, increasing with tumor progression and poor patient survival. However, the phenotype, regulation and clinical relevance of neutrophils in human GC are presently unknown. Most intratumoral neutrophils showed an activated CD54+ phenotype and expressed high level B7-H3. Tumor tissue culture supernatants from GC patients induced the expression of CD54 and B7-H3 on neutrophils in time-dependent and dose-dependent manners. Locally enriched CD54+ neutrophils and B7-H3+ neutrophils positively correlated with increased granulocyte-macrophage colony stimulating factor (GM-CSF) detection ex vivo; and in vitro GM-CSF induced the expression of CD54 and B7-H3 on neutrophils in both time-dependent and dose-dependent manners. Furthermore, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H3 expression via JAK-STAT3 signaling pathway activation. Finally, intratumoral B7-H3+ neutrophils increased with tumor progression and independently predicted reduced overall survival. Collectively, these results suggest B7-H3+ neutrophils to be potential biomarkers in GC.

2.
Ann Palliat Med ; 10(3): 3105-3114, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33752428

RESUMO

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are associated with recurrent episodes of optic neuritis and transverse myelitis, often resulting in high attack-related disability. Therapeutic apheresis has been recommended as a second-line treatment for steroid-refractory NMOSD. To assess the efficacy and safety of two apheresis techniques, lymphoplasmapheresis (LPE) and therapeutic plasma exchange (TPE), in refractory NMOSD and to provide a new treatment option for patients with refractory NMOSD. METHODS: This retrospective study examined NMOSD patients who had undergone either LPE or TPE treatment between January 2015 and January 2018. The patients were monitored for improvements in disabilities, incidences of adverse reactions, and safety of the procedure over a one-year follow-up period. The primary outcome measures included changes in the visual outcome scale (VOS) score, the expanded disability status scale (EDSS), and the annualized relapse rate (ARR). RESULTS: Neurological function and objective response rates were significantly improved in 76.5% of patients treated with LPE and 83.3% of patients treated with TPE. There were no significant differences in the two treatment groups (P=0.392). Similarly, there were no differences in the reduction in the relative relapse rate between the two groups (P=0.494). Adverse reactions, mostly of mild or moderate intensity, were recorded in 9.3% of procedures in 38% of patients. The most commonly observed adverse events (AEs) were similar between the two treatment cohorts. CONCLUSIONS: Patients treated with LPE showed improved neurological function comparable to that reported with TPE treatment. No superiority was shown for either of the apheresis techniques.

3.
Mol Cancer Res ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771880

RESUMO

Actin cytoskeleton dynamic rearrangement is required for tumor cell metastasis and is a key characteristic of Helicobacter pylori (H. pylori)-infected host cells. Actin cytoskeleton modulation is coordinated by multiple actin-binding proteins (ABP). Through Kyoto encyclopedia of gene and genomes database, GEPIA website, and real-time PCR data, we found that H. pylori infection significantly induced L-plastin, a key ABP, in gastric cancer cells. We further explored the regulation and function of L-plastin in H. pylori-associated gastric cancer and found that, mechanistically, H. pylori infection induced gastric cancer cells to express L-plastin via cagA-activated ERK signaling pathway to mediate SP1 binding to L-plastin promoter. Moreover, this increased L-plastin promoted gastric cancer cell proliferation and migration in vitro and facilitated the growth and metastasis of gastric cancer in vivo. Finally, we detected the expression pattern of L-plastin in gastric cancer tissues, and found that L-plastin was increased in gastric cancer tissues and that this increase of L-plastin positively correlated with cagA + H. pylori infection status. Overall, our results elucidate a novel mechanism of L-plastin expression induced by H. pylori, and a new function of L-plastin-facilitated growth and metastasis of gastric cancer, and thereby implicating L-plastin as a potential therapeutic target against gastric cancer. IMPLICATIONS: Our results elucidate a novel mechanism of L-plastin expression induced by H. pylori in gastric cancer, and a new function of L-plastin-facilitated gastric cancer growth and metastasis, implicating L-plastin as a potential therapeutic target against gastric cancer.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33676046

RESUMO

BACKGROUND & AIMS: Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori (H. pylori) infection are presently unknown. METHODS: Rev-erbα was examined in gastric samples from H. pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H. pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα-/- and wild-type (littermate control) mice or these mice adoptively transferred with CD4+ T cells from IFN-γ-/- and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45+CD11c-Ly6G-CD11b+CD68- myeloid cells and CD4+ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays. RESULTS: Rev-erbα was increased in gastric mucosa of H. pylori-infected patients and mice. H. pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and ß-defensin-1 expression, which resulted in impaired bactericidal effects against H. pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45+CD11c-Ly6G-CD11b+CD68- myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H. pylori-specific Th1 cell response. CONCLUSIONS: Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H. pylori.

5.
J Immunol Res ; 2021: 6613247, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763491

RESUMO

Neutrophils are prominent components of gastric cancer (GC) tumors and exhibit distinct phenotypes in GC environment. However, the phenotype, regulation, and clinical relevance of neutrophils in human GC are presently unknown. Here, immunohistochemistry, real-time PCR, and flow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 41 patients with GC, and also isolated, stimulated, and/or cultured neutrophils for in vitro regulation assays. Finally, we performed Kaplan-Meier plots for overall survival by using the log-rank test to evaluate the clinical relevance of neutrophils and their subsets. In our study, neutrophils in tumor tissues were significantly higher than those in nontumor tissues and were positively associated with tumor progression but negatively correlated with GC patient survival. Most intratumoral neutrophils showed an activated CD54+ phenotype and expressed high-level immunosuppressive molecule B7-H4. Tumor tissue culture supernatants from GC patients induced neutrophils to express CD54 and B7-H4 in both time-dependent and dose-dependent manners. Locally enriched CD54+ neutrophils and B7-H4+ neutrophils positively correlated with increased granulocyte-macrophage colony-stimulating factor (GM-CSF) detection ex vivo, and in vitro GM-CSF induced the expression of CD54 and B7-H4 on neutrophils in a time-dependent and dose-dependent manner. Moreover, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H4 expression via Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway activation. Furthermore, higher intratumoral B7-H4+ neutrophil percentage/number was found in GC patients with advanced tumor node metastasis stage and reduced overall survival following surgery. Our results illuminate a novel regulating mechanism of B7-H4 expression on tumor-activated neutrophils in GC, suggesting that functional inhibition of these novel GM-CSF-B7-H4 pathways may be a suitable therapeutic strategy to treat the immune tolerance feature of GC.

6.
Environ Pollut ; 267: 115456, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33254715

RESUMO

On-road remote sensing (RS) is a rapid, non-intrusive and economical tool to monitor and control the emissions of in-use vehicles, and currently is gaining popularity globally. However, a majority of studies used a single RS technique, which may bias the measurements since RS only captures a snapshot of vehicle emissions. This study aimed to use a unique dual RS technique to assess the characteristics of on-road vehicle emissions. The results show that instantaneous vehicle emissions are highly dynamic under real-world driving conditions. The two emission factors measured by the dual RS technique show little correlation, even under the same driving condition. This indicates that using the single RS technique may be insufficient to accurately represent the emission level of a vehicle based on one measurement. To increase the accuracy of identifying high-emitting vehicles, using the dual RS technique is essential. Despite little correlation, the dual RS technique measures the same average emission factors as the single RS technique does when a large number of measurements are available. Statistical analysis shows that both RS systems demonstrate the same Gamma distribution with ≥200 measurements, leading to converged mean emission factors for a given vehicle group. These findings point to the need for a minimum sample size of 200 RS measurements in order to generate reliable emission factors for on-road vehicles. In summary, this study suggests that using the single or dual RS technique will depend on the purpose of applications. Both techniques have the same accuracy in calculating average emission factors when sufficient measurements are available, while the dual RS technique is more accurate in identifying high-emitters based on one measurement only.

7.
Water Res ; 190: 116660, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33279743

RESUMO

Particulate manganese oxide (MnOx) deposition in drinking water distribution systems (DWDS) gives rise to the risk of water discoloration at the consumers' tap; however, its role in the fate and transport of trace organic pollutants in DWDS is not clear. Perfluorooctanoic acid (PFOA), a persistent organic pollutant frequently detected in natural water, was selected to investigate the potential effect of MnOx on its transportation behavior under DWDS conditions through laboratory batch experiments. The results show that PFOA can be greatly combined with MnOx formed in-situ through a Mn(II) oxidation process by free chlorine. However, the accumulation of PFOA by preformed MnOx was negligible. It was found that 1 mg/L Mn captured over 50% of PFOA with an initial concentration of 50 ng/L during oxidation. The water compositions of actual water could contribute to the effect of PFOA accumulation to a certain extent. Characterization of the solid products revealed that PFOA is homogenously embedded into MnOx. The combination of PFOA with MnOx occurs through a bridging effect of Mn(II) between the surface hydroxyls of MnOx and the -COOH group of PFOA. The resulting MnOx-PFOA particles were more inclined to agglomerate, enabling possibly easy deposition onto the pipe wall than ordinary MnOx particles. This study provides insights into the co-occurrence of metal deposits with PFOA and the potential risks posed by PFOA accumulation to consumers through the water distribution process.

8.
Water Res ; 189: 116632, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33227611

RESUMO

In drinking water distribution system (DWDS), disinfection byproducts (DBPs) have a large possibility of participating in iron oxidation by dissolved oxygen (DO), which may induce particle structure transformations and increase unknown risks. In this work, the influence of trichloroacetic acid (TCAA, one of the most typical DBPs) on iron oxidation processes was studied, and the potential effects of the resulting α-FeOOH particles were evaluated through two aspects: (i) influence on the bacterial community and (ii) toxicity to human cells. TCAA promoted iron oxidation process through an Fe-O-C linkage, which led to a sharper surface of the particles (TCAA-mediated Fe oxide particles, TFOP) than that without TCAA (Fe oxide particles, FOP). Interestingly, the influence of particles on the richness of bacterial community of drinking water was different under anaerobic and aerobic conditions: under anaerobic conditions, the richness of bacterial community increased with the addition of particles, while under aerobic conditions, the richness of bacterial community decreased. The higher affinity of TFOP for electron-accepting DO than FOP indicated the role of DO on TFOP under aerobic conditions. TFOP exhibited the strongest cytotoxicity among FOP and the actual deposits. DFT calculations confirmed that TCAA in iron particles promoted the adsorption and dissociation of H2O2 to generate more •OH with an obvious decrease in the energy barrier from 1.51 to 0.80 eV. This study indicates the high potential of adverse effects of DBPs on loose deposits in DWDS and gives implications for the control of DBPs and deposits in drinking water.

9.
Inorg Chem ; 59(23): 17650-17658, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33206500

RESUMO

The low utilization efficiency in the visible region of the sunlight spectrum and the rapid recombination of photogenerated charge carriers are two crucial drawbacks that suppress the practical usage of metal oxide semiconductors as photocatalysts. In this article, we report a rational design of In2O3-In2S3 heterojunctions encapsulated by N-doped carbon with a hollow dodecahedral structure (In2O3-In2S3/N-C HDS), which can effectively handle the two drawbacks of metal oxide semiconductors and behave active for organic transformation under the irradiation of visible light even with long wavelengths. As exemplified by the selective oxidative coupling reaction of amine to imine, the obtained In2O3-In2S3/N-C HDS as the photocatalyst has exhibited excellent activity and stability. Experimental and density functional theory studies have verified that the excellent performance of In2O3-In2S3/N-C HDS can be attributed to the synergistic effect of In2O3-In2S3 heterojunctions, the coating of N-doped carbon, and the hollow porous structure with nanosheets as subunits.

10.
J Exp Clin Cancer Res ; 39(1): 264, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33246486

RESUMO

BACKGROUND: It is known that the transcription factor zinc finger protein 703 (ZNF703) plays an important role in physiological functions and the occurrence and development of various tumors. However, the role and mechanism of ZNF703 in ovarian cancer are unclear. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expression of ZNF703 in ovarian cancer patients and to assess the effect of ZNF703 expression on the survival and prognosis of ovarian cancer patients. ZNF703 overexpression and suppression expression experiments were used to evaluate the effect of ZNF703 on malignant biological behavior of ovarian cancer cells in vitro. Detecting the interaction between HE4 and ZNF703 by immunofluorescence colocalization and coprecipitation, and nuclear translocation. Chromatin immunoprecipitation-sequencing (ChIP-Seq), dual luciferase reporter assay, ChIP-PCR, in vivo model were applied to study the molecular mechanism of ZNF703 affecting the development of ovarian cancer. RESULTS: ZNF703 was highly expressed in ovarian cancer tissues, and its expression level is related to the prognosis of ovarian cancer patients. In vivo and in vitro experiments confirmed that ZNF703 overexpression/inhibition expression will promoted/inhibited the malignant biological behavior of ovarian cancer. Mechanically, ZNF703 interacted with HE4, and HE4 promoted nuclear translocation of ZNF703. ChIP-Seq identified multiple regulatory targets of ZNF703, of which ZNF703 directly binds to the enhancer region of PEA15 to promote the transcription of PEA15 and thereby promoted the proliferation of cancer cells. CONCLUSION: The results showed that ZNF703 as an oncogene played an important role in the epigenetic modification of ovarian cancer proliferation, and suggested that ZNF703 as a transcription factor may become a prognostic factor and a potential therapeutic target for ovarian cancer.

11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1726-1732, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067981

RESUMO

OBJECTIVE: To analyze the affecting factors of hemoglobin changes in apheresis red blood cells (RBCs), and to establish a predictive model for the evaluation of apheresis. METHODS: The clinical data of 130 patients undergoing selective surgery for apheresis autologous RBCs from January 2017 to December 2018 were collected. The change of hemoglobin and its affecting factors before and after apheresis were analyzed. The predictive model of the hemoglobin change was established by machine learning algorithm and compared with the theoretical predictive model. RESULTS: The average Hb level in the 300 ml autologous RBC group decreased by 22.61±8.85 g/L, and the average Hb in 400 ml group decreased by 29.08±7.25 g/L. The change of Hb was mainly affected by Hb level before apheresis and peripheral circulation blood volume (P<0.05). Sex, age, and the interval time between blood collection and operation not significantly influenced Hb change (P>0.05). The initially established predictive model by the machine learning (MAE 6.27) is superior to the theoretical predictive model (MAE 8.11). CONCLUSION: The predictive model established by the machine learning can provide a reference for more accurate evaluation of apheresis autologous red blood cells.


Assuntos
Remoção de Componentes Sanguíneos , Hemoglobinas , Contagem de Eritrócitos , Eritrócitos , Hemoglobinas/análise , Humanos
12.
Proc Natl Acad Sci U S A ; 117(45): 28212-28220, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33106431

RESUMO

Somatic mutations are major genetic contributors to cancers and many other age-related diseases. Many disease-causing somatic mutations can initiate clonal growth prior to the appearance of any disease symptoms, yet experimental models that can be used to examine clonal abnormalities are limited. We describe a mosaic analysis system with Cre or Tomato (MASCOT) for tracking mutant cells and demonstrate its utility for modeling clonal hematopoiesis. MASCOT can be induced to constitutively express either Cre-GFP or Tomato for lineage tracing of a mutant and a reference group of cells simultaneously. We conducted mosaic analysis to assess functions of the Id3 and/or Tet2 gene in hematopoietic cell development and clonal hematopoiesis. Using Tomato-positive cells as a reference population, we demonstrated the high sensitivity of this system for detecting cell-intrinsic phenotypes during short-term or long-term tracking of hematopoietic cells. Long-term tracking of Tet2 mutant or Tet2/Id3 double-mutant cells in our MASCOT model revealed a dynamic shift from myeloid expansion to lymphoid expansion and subsequent development of lymphoma. This work demonstrates the utility of the MASCOT method in mosaic analysis of single or combined mutations, making the system suitable for modeling somatic mutations identified in humans.

13.
Physiol Rep ; 8(18): e14492, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32975899

RESUMO

Claudins are a family of tight junction proteins that are expressed during mouse kidney development. They regulate paracellular transport of solutes along the nephron and contribute to the final composition of the urinary filtrate. To understand their roles during development, we used a protein reagent, a truncated version of the Clostridium perfringens enterotoxin (C-CPE), to specifically remove a subset of claudin family members from mouse embryonic kidney explants at embryonic day 12. We observed that treatment with C-CPE decreased the number and the complexity of ureteric bud tips that formed: there were more single and less bifid ureteric bud tips when compared to control-treated explants. In addition, C-CPE-treated explants exhibited ureteric bud tips with larger lumens when compared to control explants (p < .05). Immunofluorescent analysis revealed decreased expression and localization of Claudin-3, -4, -6, and -8 to tight junctions of ureteric bud tips following treatment with C-CPE. Interestingly, Claudin-7 showed higher expression in the basolateral membrane of the ureteric bud lineage and poor localization to the tight junctions of the ureteric bud lineage both in controls and in C-CPE-treated explants. Taken together, it appears that claudin proteins may play a role in ureteric bud branching morphogenesis through changes in lumen formation that may affect the efficiency by which ureteric buds emerge and branch.

14.
Sci Rep ; 10(1): 15039, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929165

RESUMO

Gas-insulated switchgear (GIS) is widely used across multiple electric stages and different power grid levels. However, the threat from several inevitable faults in the GIS system surrounds us for the safety of electricity use. In order to improve the evaluation ability of GIS system safety, we propose an efficient strategy by using machine learning to conduct SF6 decomposed components analysis (DCA) for further diagnosing discharge fault types in GIS. Note that the empirical probability function of different faults fitted by the Arrhenius chemical reaction model has been investigated into the robust feature engineering for machine learning based GIS diagnosing model. Six machine learning algorithms were used to establish models for the severity of discharge fault and main insulation defects, where identification algorithms were trained by learning the collection dataset composing the concentration of the different gas types (SO2, SOF2, SO2F2, CF4, and CO2, etc.) in the system and their ratios. Notably, multiple discharge fault types coexisting in GIS can be effectively identified based on a probability model. This work would provide a great insight into the development of evaluation and optimization on solving discharge fault in GIS.

15.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 750-754, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958132

RESUMO

Integrins are transmembrane glycoproteins expressed on the surface of various cells. They can conduct bidirectional signal transduction across cell membranes, exchange information between extracellular matrix proteins and intracellular molecules, and regulate cell adhesion and activation. During cancer development, integrins mediate crucial regulatory functions in anti-tumor response including tumor antigen uptake, activation of tumor-specific T cells, leukocyte trafficking into the tumor site and tumor cell killing. We provided a comprehensive overview of the structure of integrins, immune regulation, effects of integrins on tumor immunity and covered in vivo and in vitro studies of tissue culture, animal models of human diseases and gene knockout animals as well as the progress in clinical diagnosis and therapy of tumors.


Assuntos
Integrinas , Neoplasias , Animais , Adesão Celular , Movimento Celular , Humanos , Integrinas/química , Integrinas/genética , Integrinas/imunologia , Neoplasias/diagnóstico , Neoplasias/imunologia , Neoplasias/terapia , Pesquisa/tendências , Transdução de Sinais , Linfócitos T
16.
Artigo em Inglês | MEDLINE | ID: mdl-32935629

RESUMO

The particulate size distributions of aerosol pollutants (particulates and Hg(p)) at a mixed site were measured and their seasonal variations identified. Atmospheric particulates and the Hg(p) mass median diameter (m.m.d.) were obtained. Hg(p) concentrations increased by approximately 20% during the peak demand period for all particle sizes (18, 10, 2.5, 1 and 0.3 µm). The mean percentage concentration of Hg(p) was highest in summer and followed the order summer > spring > winter > autumn for all particle sizes. Hg(p) concentration exhibited increased from 2004 to 2019.

17.
Ther Adv Neurol Disord ; 13: 1756286420947977, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32913445

RESUMO

Background: Plasma exchange (PE) is often considered as an effective treatment for neuromyelitis optica spectrum disorder (NMOSD) and several inflammatory demyelinating disorders of the central nervous system. This study aimed to evaluate the visual outcomes of Chinese patients with severe acute isolated optic neuritis (ON) who received PE therapy after high-dose intravenous methylprednisolone (IVMP) treatment. Methods: Thirty-seven acute isolated ON patients experiencing their first attack of severe visual impairment without neurological disability were recruited. All subjects received five cycles of double-filtration plasmapheresis. Visual acuity (VA) was documented at onset, 1 day before PE treatment, at each cycle of PE therapy and at the 1-month follow-up visit. Results: This study included 26 female (70.3%) and 11 male (29.7%) subjects, and 18 subjects (48.6%) had bilateral involvement. The time window between onset and PE treatment was 27.3 ± 12.7 days (range: 6-53 days). Mean VA (logMAR) of the studied eyes at onset, 1-day before PE treatment/after IVMP and after the fifth PE treatment were 3.41 ± 1.50, 2.61 ± 1.64 and 1.66 ± 1.52, respectively (p < 0.001). Nineteen eyes (51.4%) showed no light perception at the onset, and 17 eyes (45.9%) improved to Snellen VA >20/800 after IVMP and PE treatments, among which five eyes (13.5%) recovered to Snellen VA 20/20 (p < 0.001). Predictors of good visual outcome included body mass index [odds ratio (OR) = 0.734, p = 0.044], serum AQP4 antibody-positive status (OR = 0.004, p = 0.001), bilaterality (OR = 0.042, p = 0.008) and time window from onset to PE therapy per 1 day (OR = 0.79, p = 0.002). Conclusion: This study revealed that PE treatment effectively improves the visual outcomes of patients experiencing their first attack of severe acute isolated ON after high-dose IVMP treatment. Better visual outcomes can be achieved with early PE treatment.

18.
Am J Physiol Gastrointest Liver Physiol ; 319(6): G703-G717, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32878470

RESUMO

Pancreatic cancer (PC) is a malignant tumor that is difficult to diagnose and treat. Circular RNAs (circRNAs) are biomarkers that may be used to diagnose certain cancers or act as targets for cancer treatment. We aimed to explore the functions of human circular RNA 001587 (hsa_circRNA_001587) on the progression of PC and the underlying mechanism. The expression pattern of hsa_circRNA_001587 and microRNA-223 (miR-223) in PC tissues and cells was determined by RT-qPCR. Dual-luciferase reporter gene assay, RNA-pulldown, Argonaute 2 (AGO2) immunoprecipitation assay, and Northern blot analysis were applied to verify the binding relationships among hsa_circRNA_001587, miR-223 and solute carrier family 4 member 4 (SLC4A4). Further analysis of their roles was performed in PC cell line PANC-1. Moreover, we either downregulated or upregulated the expression of hsa_circRNA_001587, miR-223, and SLC4A4 by transfection in vitro. A mouse xenograft model of PC cells was established to evaluate tumor growth in vivo. hsa_circRNA_001587 was poorly expressed, but miR-223 was highly expressed in PC tissues and cell lines. Upregulation of hsa_circRNA_001587 downregulated the expression of matrix metalloproteinase-2 and-9, minichromosome maintenance 2, and vascular endothelial growth factor, and decreased the proliferation, migration, invasion, angiogenic and tumorigenic abilities of PC cells. MiR-223, which can bind with hsa_circRNA_001587, reversed the effects of hsa_circRNA_001587 on PC cells. In addition, SLC4A4 was identified as a target of miR-223, and its knockdown could counteract the regulatory effects of overexpressed hsa_circRNA_001587 or inhibited miR-223 expression on PC cells. Therefore, hsa_circRNA_001587 inhibits PC cell migration, invasion, angiogenesis and tumorigenesis by impairing miR-223-mediated SLC4A4 inhibition.NEW & NOTEWORTHY Human circular (hsa_circ)RNA_001587 and solute carrier family 4 member 4 (SLC4A4) are poorly expressed but microRNA (miR)R-223 is overexpressed in pancreatic cancer (PC) cells. hsa_circRNA_001587 binds to miR-223. Overexpression of hsa_circRNA_001587 inhibits PC progression. Overexpression of miR-223 downregulates the expression of SLC4A4 and promotes PC cell growth. hsa_circRNA_001587 may be a potential target for PC treatment.

19.
J Immunother Cancer ; 8(2)2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32753468

RESUMO

BACKGROUND: Overexpression of programmed cell death protein 1 (PD-1) is linked to CD8+ T cell dysfunction and contributes to tumor immune escape. However, the prevalence and functional regulations of PD-1 expression on CD8+ T cells in human gastric cancer (GC) remain largely unknown. METHODS: Flow cytometry was performed to analyze the level, phenotype, functional and clinical relevance of PD-1+CD8+ T cells in GC patients. Peripheral blood CD8+ T cells were purified and subsequently exposed to culture supernatants from digested primary GC tumor tissues (TSN) in vitro for PD-1 expression and functional assays. Tumor responses to adoptively transferred TSN-stimulated CD8+ T cells or to the TSN-stimulated CD8+ T cell transfer combined with an anti-PD-1 antibody injection were measured in an in vivo xenograft mouse model. RESULTS: GC patients' tumors showed a significantly increased PD-1+CD8+ T cell infiltration. However, these GC-infiltrating PD-1+CD8+ T cells showed equivalent function to their PD-1-CD8+ counterparts and they did not predict tumor progression. High level of transforming growth factor-ß1 (TGF-ß1) in tumors was positively correlated with PD-1+CD8+ T cell infiltration, and in vitro GC-derived TGF-ß1 induced PD-1 expression on CD8+ T cells via Smad3 signaling, whereas Smad2 signaling was involved in GC-derived TGF-ß1-mediated CD8+ T cell dysfunction. Furthermore, GC-derived TGF-ß1-mediated CD8+ T cell dysfunction contributed to tumor growth in vivo that could not be attenuated by PD-1 blockade. CONCLUSIONS: Our data highlight that GC-derived TGF-ß1 promotes PD-1 independent CD8+ T cell dysfunction. Therefore, restoring CD8+ T cell function by a combinational PD-1 and TGF-ß1 blockade might benefit future GC immunotherapy.

20.
Adv Mater ; : e1907452, 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32743868

RESUMO

Magnetic skyrmions are attracting interest as efficient information-storage devices with low energy consumption, and have been experimentally and theoretically investigated in multilayers including ferromagnets, ferrimagnets, and antiferromagnets. The 3D spin texture of skyrmions demonstrated in ferromagnetic multilayers provides a powerful pathway for understanding the stabilization of ferromagnetic skyrmions. However, the manipulation mechanism of skyrmions in antiferromagnets is still lacking. A Hall balance with a ferromagnet/insulating spacer/ferromagnet structure is considered to be a promising candidate to study skyrmions in synthetic antiferromagnets. Here, high-density Néel-type skyrmions are experimentally observed at zero field and room temperature by Lorentz transmission electron microscopy in a Hall balance (core structure [Co/Pt]n /NiO/[Co/Pt]n ) with interfacial canted magnetizations because of interlayer ferromagnetic/antiferromagnetic coupling between top and bottom [Co/Pt]n multilayers, where the Co layers in [Co/Pt]n are always ferromagnetically coupled. Micromagnetic simulations show that the generation and density of skyrmions are strongly dependent on interlayer exchange coupling (IEC) and easy-axis orientation. Direct experimental evidence of skyrmions in synthetic antiferromagnets is provided, suggesting that the proposed approach offers a promising alternative mechanism for room-temperature spintronics.

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