Publications by authors named "Xinxin Yu"

89 Publications

The protein-protein interaction between connective tissue growth factor and annexin A2 is relevant to pannus formation in rheumatoid arthritis.

Arthritis Res Ther 2021 10 26;23(1):266. Epub 2021 Oct 26.

Department of Anesthesia and Critical Care, School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.

Background: Connective tissue growth factor (CTGF)-induced angiogenesis is a crucial factor in rheumatoid arthritis (RA), but CTGF-interacting protein and related molecular mechanism of their interaction have not been fully elucidated.

Methods: CTGF-interacting proteins were identified through the LC-MS/MS analysis of the Co-IP products from fibroblast-like synoviocyte (FLS) lysates, and the interaction between CTGF and annexin A2 (ANXA2) was further confirmed through Co-IP and BiFC assay. The binding domain, mutant, mechanism, and angiogenesis function were assessed by homology modeling, molecular docking, MTT, cell scratch, tube formation, and chick chorioallantoic membrane (CAM) assays. Additionally, severe combined immunodeficiency (SCID) mouse co-implantation model was constructed to confirm the effect of ANXA2/CTGF-TSP1 in the process of RA in vivo.

Results: ANXA2 was identified and verified as an interaction partner of CTGF for the first time by Co-IP and LC-MS/MS analysis. Co-localization of CTGF and ANXA2 was observed in RA-FLS, and direct interaction of the TSP-1 domain of CTGF and ANXA2 was determined in HEK293T cells. The spatial conformation and stable combination of the ANXA2/CTGF-TSP1 complex were assessed by homology modeling in the biomimetic environment. The function of the ANXA2/CTGF-TSP1 complex was proved on promoting FLS proliferation, migration, and angiogenesis in vitro and deteriorating FLS invasion and joint damage in SCID mice.

Conclusions: TSP-1 is the essential domain in CTGF/ANXA2 interaction and contributes to FLS migration and pannus formation, inducing the process of RA.
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http://dx.doi.org/10.1186/s13075-021-02656-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547044PMC
October 2021

Preoperative CT-Based Deep Learning Model for Predicting Risk Stratification in Patients With Gastrointestinal Stromal Tumors.

Front Oncol 2021 17;11:750875. Epub 2021 Sep 17.

Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.

Objective: To develop and evaluate a deep learning model (DLM) for predicting the risk stratification of gastrointestinal stromal tumors (GISTs).

Methods: Preoperative contrast-enhanced CT images of 733 patients with GISTs were retrospectively obtained from two centers between January 2011 and June 2020. The datasets were split into training (n = 241), testing (n = 104), and external validation cohorts (n = 388). A DLM for predicting the risk stratification of GISTs was developed using a convolutional neural network and evaluated in the testing and external validation cohorts. The performance of the DLM was compared with that of radiomics model by using the area under the receiver operating characteristic curves (AUROCs) and the Obuchowski index. The attention area of the DLM was visualized as a heatmap by gradient-weighted class activation mapping.

Results: In the testing cohort, the DLM had AUROCs of 0.90 (95% confidence interval [CI]: 0.84, 0.96), 0.80 (95% CI: 0.72, 0.88), and 0.89 (95% CI: 0.83, 0.95) for low-malignant, intermediate-malignant, and high-malignant GISTs, respectively. In the external validation cohort, the AUROCs of the DLM were 0.87 (95% CI: 0.83, 0.91), 0.64 (95% CI: 0.60, 0.68), and 0.85 (95% CI: 0.81, 0.89) for low-malignant, intermediate-malignant, and high-malignant GISTs, respectively. The DLM (Obuchowski index: training, 0.84; external validation, 0.79) outperformed the radiomics model (Obuchowski index: training, 0.77; external validation, 0.77) for predicting risk stratification of GISTs. The relevant subregions were successfully highlighted with attention heatmap on the CT images for further clinical review.

Conclusion: The DLM showed good performance for predicting the risk stratification of GISTs using CT images and achieved better performance than that of radiomics model.
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http://dx.doi.org/10.3389/fonc.2021.750875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496403PMC
September 2021

Association Between Carotid Artery Perivascular Fat Density and Intraplaque Hemorrhage.

Front Cardiovasc Med 2021 20;8:735794. Epub 2021 Sep 20.

Shandong Provincial Hospital Affliated to Shandong First Medical University, Jinan, China.

Perivascular adipose tissue plays a key role in atherosclerosis, but its effects on the composition of carotid atherosclerotic plaques are unknown. This study aimed to investigate the association between inflammatory carotid artery and intraplaque hemorrhage (IPH) in the carotid artery. This is a single-center retrospective study. Carotid inflammation was assessed by perivascular fat density (PFD) in 72 participants (mean age, 65.1 years; 56 men) who underwent both computed tomography angiography (CTA) and magnetic resonance imaging (MRI) within 2 weeks. The presence of IPH was assessed with MRI. Carotid stenosis, maximum plaque thickness, calcification, and ulceration were evaluated through CTA. The association between PFD and the occurrence of IPH was studied using generalized estimating equations analysis. Of 156 plaques, 72 plaques (46.2%) had IPH. Plaques with IPH showed higher PFD than those without [-41.4 ± 3.9 vs. -55.8 ± 6.5 Hounsfield unit (HU); < 0.001]. After age, calcification, degree of stenosis, maximum plaque thickness, and ulceration were adjusted for, PFD (OR, 1.96; 95% CI, 1.41-2.73; < 0.001) was found to be strongly associated with the presence of IPH. A higher PFD is associated with the presence of IPH in the carotid artery. These findings may provide a novel marker to identify carotid IPH and risk stratification.
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http://dx.doi.org/10.3389/fcvm.2021.735794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488125PMC
September 2021

Cisplatin Induces Pyroptosis via Activation of MEG3/NLRP3/caspase-1/GSDMD Pathway in Triple-Negative Breast Cancer.

Int J Biol Sci 2021 22;17(10):2606-2621. Epub 2021 Jun 22.

Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.

Cisplatin (DDP) was reported to improve pathological complete response (pCR) rates in triple-negative breast cancer (TNBC) patients, however, the molecular mechanism still remains largely unknown. Emerging evidence suggested that some chemotherapeutic drugs played anti-tumor effects by inducing cell pyroptosis. Nevertheless, whether pyroptosis contributes to the DDP-induced anti-tumor effect in TNBC remains unexploited. In the present study, NLRP3/caspase-1/GSDMD pyroptosis pathway was involved in the DDP-induced anti-tumor effect of TNBC and , providing evidence that DDP might induce pyroptosis in TNBC. Moreover, DDP activated NLRP3/caspase-1/GSDMD pyroptosis pathway by up-regulating the long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3). Furthermore, knockdown of MEG3 not only partly abolished the activation effect of DDP on NLRP3/caspase-1/GSDMD pathway-mediated pyroptosis, but also reversed the suppression of DDP on tumor growth and metastasis ability and further confirming that MEG3 may partially mediate the pyroptotic signaling upon DDP treatment. Thus, our data uncovered a novel mechanism that DDP induced pyroptosis via activation of MEG3/NLRP3/caspase-1/GSDMD pathway in TNBC to exert anti-tumor effects, which may help to develop new strategies for the therapeutic interventions in TNBC.
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http://dx.doi.org/10.7150/ijbs.60292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315016PMC
June 2021

Evaluation of two sexual-stage antigens as bivalent transmission-blocking vaccines in rodent malaria.

Parasit Vectors 2021 May 7;14(1):241. Epub 2021 May 7.

Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, 110122, Liaoning, China.

Background: Transmission-blocking vaccine (TBV) is a promising strategy for malaria elimination. It is hypothesized that mixing or fusing two antigens targeting different stages of sexual development may provide higher transmission-blocking activity than these antigens used individually.

Methods: A chimeric protein composed of fragments of Pbg37 and PSOP25 was designed and expressed the recombinant protein in Escherichia coli Rosetta-gami B (DE3). After immunizing mice with individual recombinant proteins Pbg37 and PSOP25, mixed proteins (Pbg37+PSOP25), or the fusion protein (Pbg37-PSOP25), the antibody titers of individual sera were analyzed by ELISA. IFA and Western blot were performed to test the reactivity of the antisera with the native proteins in the parasite. The transmission-blocking activity of the different immunization schemes was assessed using in vitro and in vivo assays.

Results: When Pbg37 and PSOP25 were co-administered in a mixture or as a fusion protein, they elicited similar antibody responses in mice as single antigens without causing immunological interference with each other. Antibodies against the mixed or fused antigens recognized the target proteins in the gametocyte, gamete, zygote, and ookinete stages. The mixed proteins or the fusion protein induced antibodies with significantly stronger transmission-reducing activities in vitro and in vivo than individual antigens.

Conclusions: There was no immunological interference between Pbg37 and PSOP25. The bivalent vaccines, which expand the portion of the sexual development during which the transmission-blocking antibodies act, produced significantly stronger transmission-reducing activities than single antigens. Altogether, these data provide the theoretical basis for the development of combination TBVs targeting different sexual stages.
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http://dx.doi.org/10.1186/s13071-021-04743-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103607PMC
May 2021

FBS-Derived Exosomes as a Natural Nano-Scale Carrier for Icariin Promote Osteoblast Proliferation.

Front Bioeng Biotechnol 2021 26;9:615920. Epub 2021 Feb 26.

School of Stomatology, Dalian Medical University, Dalian, China.

Icariin is a class IV drug of low solubility, permeability, and poor bioavailability. Synthetic nanomaterials have developed rapidly. However, some literatures point out that synthetic nanomaterials such as liposomes, aptamers, metal nanoparticles, and nanogels have high toxicity and are affected by the reticuloendothelial system or mononuclear phagocyte system. It is known that exosomes could be used as an ideal clinical drug delivery vehicle to avoid the above-mentioned problems to a certain extent. Studies have shown that drugs can be loaded into exosomes by passive and active loading. We used Fetal bovine serum (FBS) exosomes to carry Icariin for the first time in this experiment, FBS exosomes-Icariin (FBS EXO-ICA) more effectively promoted the proliferation of osteoblasts and bone regeneration than Icariin alone. FBS EXO-ICA could become a new nano scale drug formulation for treating diseases associated with bone loss.
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http://dx.doi.org/10.3389/fbioe.2021.615920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952636PMC
February 2021

Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets.

Proc Natl Acad Sci U S A 2021 03;118(9)

Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549;

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-β-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.
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http://dx.doi.org/10.1073/pnas.2022142118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936318PMC
March 2021

Pulmonary mucosa-associated lymphoid tissue lymphoma: CT findings and pathological basis.

J Surg Oncol 2021 Apr 1;123(5):1336-1344. Epub 2021 Feb 1.

Department of Respiratory and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.

Background: Pulmonary mucosa-associated lymphoid tissue lymphoma (MALToma) is the most frequent subset of primary pulmonary lymphoma. This study aimed to identify radiologic characteristics of pulmonary MALToma based on computed tomography (CT) observations and pathologic features, and further investigate its prognosis.

Methods: Sixty-six patients (55.4 ± 10.9 years; 51.5% male) diagnosed as pulmonary MALToma by pathology were retrospectively enrolled. According to distributions and features of lesions shown on CT, patients were divided into three patterns, including single nodular/mass, multiple nodular/mass, and pneumonia-like consolidative.

Results: Variety of the location and extent of the lymphomatous infiltration accounted for different characteristics demonstrated at CT. The pneumonia-like consolidative pattern was the most frequent pattern observed in 42 patients (63.6%), followed by single nodular/mass (21.2%) and multiple nodular/mass (15.2%). CT features included air bronchogram (72.7%), well-marginated halo sign (53.0%), coarse spiculate with different lengths (72.7%), angiogram sign (77.1% of 35 patients), peribronchovascular thickening (48.5%), irregular cavitation (16.7%) and pulmonary cyst (7.6%). The estimated 5-year cumulative overall survival rate of pulmonary MALToma was 100.0%.

Conclusions: Pulmonary MALToma demonstrates several characteristics at CT. Identification of the significant pulmonary abnormalities of this indolent disease entity might be helpful for early diagnosis and optimal treatment.
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http://dx.doi.org/10.1002/jso.26403DOI Listing
April 2021

Comparative multi-omics analyses reveal differential expression of key genes relevant for parasitism between non-encapsulated and encapsulated Trichinella.

Commun Biol 2021 01 29;4(1):134. Epub 2021 Jan 29.

Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.

Genome assemblies provide a powerful basis of comparative multi-omics analyses that offer insight into parasite pathogenicity, host-parasite interactions, and invasion biology. As a unique intracellular nematode, Trichinella consists of two clades, encapsulated and non-encapsulated. Genomic correlation of the distinct differences between the two clades is still unclear. Here, we report an annotated draft reference genome of non-encapsulated Trichinella, T. pseudospiralis, and perform comparative multi-omics analyses with encapsulated T. spiralis. Genome and methylome analyses indicate that, during Trichinella evolution, the two clades of Trichinella exhibit differential expansion and methylation of parasitism-related multi-copy gene families, especially for the DNase II members of the phospholipase D superfamily and Glutathione S-transferases. Further, methylome and transcriptome analyses revealed divergent key excretory/secretory (E/S) genes between the two clades. Among these key E/S genes, TP12446 is significantly more expressed across three life stages in T. pseudospiralis. Overexpression of TP12446 in the mouse C2C12 skeletal muscle cell line could induce inhibition of myotube formation and differentiation, further indicating its key role in parasitism of T. pseudospiralis. This multi-omics study provides a foundation for further elucidation of the mechanism of nurse cell formation and immunoevasion, as well as the identification of pharmacological and diagnostic targets of trichinellosis.
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http://dx.doi.org/10.1038/s42003-021-01650-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846577PMC
January 2021

Tofacitinib restores the balance of γδTreg/γδT17 cells in rheumatoid arthritis by inhibiting the NLRP3 inflammasome.

Theranostics 2021 1;11(3):1446-1457. Epub 2021 Jan 1.

Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.

Tofacitinib (TOF) is a Janus kinase (JAK) inhibitor used in the treatment of rheumatoid arthritis (RA), but the mechanism of its action remains unclear. In this study, we investigated the influence of TOF on gamma delta regulatory T-cell (γδTreg)/γδT17 cell balance in RA and the role of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in this process. We detected levels of inflammatory factors in the serum of RA patients before and after administration of TOF using an enzyme-linked immunosorbent assay (ELISA). A collagen-induced arthritis (CIA) model was constructed to investigate the effect of TOF on arthritis symptoms, γδTreg/γδT17 cell balance and the NLRP3 inflammasome. We used bone marrow-derived macrophages (BMDMs) to study the effect of TOF on NLRP3 inflammasome activation. 3 mice were introduced to assess the influence of NLRP3 on γδT17 cell activation in RA. TOF treatment decreased levels of γδT17 cell-related cytokine interleukin-17 (IL-17) in RA patients. In addition, TOF intervention in the CIA model reduced joint inflammation and damage, rebalanced the γδTreg/γδT17 cell ratio and inhibited excessive NLRP3 inflammasome activation in draining lymph nodes and arthritic joints. BMDM intervention experiments demonstrated that TOF decreased the level of secreted IL-1β via downregulation of NLRP3. Furthermore, experiments using mice verified that the NLRP3 inflammasome mediated the effect of TOF on γδT17 cell activation. Recovery of γδTreg/γδT17 cell balance was a novel mechanism by which TOF alleviated RA. Meanwhile, NLRP3 played a pivotal role in the process of TOF-mediated γδT17 cell activation.
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http://dx.doi.org/10.7150/thno.47860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738886PMC
July 2021

Whole-exome sequencing identifies prognostic mutational signatures in gastric cancer.

Ann Transl Med 2020 Nov;8(22):1484

Department of Gastro-intestine Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.

Background: Gastric cancer (GC) is a heterogeneous disease, and is a leading cause of cancer deaths in Eastern Asia. Genomic analysis, such as whole-exome sequencing (WES), can help identify key genetic alterations leading to the malignancy and diversity of GC, and may help identify new drug targets.

Methods: We identified genomic alterations in a cohort of 38 GC patients, including 26 metastatic and 12 non-metastatic patients. We analyzed the association between novel gene mutations and copy number variations (CNVs) with tumor metastasis and patient survival.

Results: A number of significantly mutated genes in somatic and germline cells were identified. Among them, somatic mutation, a potential biomarker of immunotherapy in stomach cancers, was associated with better patient survival (P=0.0939) and metastasis (P=0.074). germline variation was correlated with shorter overall survival (OS; P=0.0100). Novel CNVs were also identified and can potentially be used as biomarkers. These included 9p24.1 deletion (P=0.0376) and 16p11.2 amplification (P=0.0066), which were both associated with shorter OS. CNVs of several genes including , , and were found to be significantly related to metastasis (P<0.05).

Conclusions: We characterized the mutational landscape of 38 GC patients and discovered several potential new predictive markers of survival and metastasis in GC.
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http://dx.doi.org/10.21037/atm-20-6620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729362PMC
November 2020

Nondestructive monitoring of polyphenols and caffeine during green tea processing using Vis-NIR spectroscopy.

Food Sci Nutr 2020 Nov 15;8(11):5860-5874. Epub 2020 Sep 15.

College of Biosystems Engineering and Food Science Zhejiang University Hangzhou China.

Increasing consumption of green tea is attributed to the beneficial effects of its constituents, especially polyphenols, on human health, which can be varied during leaf processing. Processing technology has the most important effect on green tea quality. This study investigated the system dynamics of eight catechins, gallic acid, and caffeine in the processing of two varieties of tea, from fresh leaves to finished tea. It was found that complex biochemical changes can occur through hydrolysis under different humidity and heating conditions during the tea processing. This process had a significant effect on catechin composition in the finished tea. The potential application of visible and near-infrared (Vis-NIR) spectroscopy for fast monitoring polyphenol and caffeine contents in tea leaves during the processing procedure has been investigated. It was found that a combination of PCA (principal component analysis) and Vis-NIR spectroscopy can successfully classify the two varieties of tea samples and the five tea processing procedures, while quantitative determination of the constituents was realized by combined regression analysis and Vis-NIR spectra. Furthermore, successive projections algorithm (SPA) was proposed to extract and optimize spectral variables that reflected the molecular characteristics of the constituents for the development of determination models. Modeling results showed that the models had good predictability and robustness based on the extracted spectral characteristics. The coefficients of determination for all calibration sets and prediction sets were higher than 0.862 and 0.834, respectively, which indicated high capability of Vis-NIR spectroscopy for the determination of the constituents during the leaf processing. Meanwhile, this analytical method could quickly monitor quality characteristics and provide feedback for real-time controlling of tea processing machines. Furthermore, the study on complex biochemical changes that occurred during the tea processing would provide a theoretical basis for improving the content of quality components and effective controlling processes.
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http://dx.doi.org/10.1002/fsn3.1861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684591PMC
November 2020

T1 Stage Clear Cell Renal Cell Carcinoma: A CT-Based Radiomics Nomogram to Estimate the Risk of Recurrence and Metastasis.

Front Oncol 2020 4;10:579619. Epub 2020 Nov 4.

School of Medicine, Shandong University, Jinan, China.

Objectives: To develop and validate a radiomics nomogram to improve prediction of recurrence and metastasis risk in T1 stage clear cell renal cell carcinoma (ccRCC).

Methods: This retrospective study recruited 168 consecutive patients (mean age, 53.9 years; range, 28-76 years; 43 women) with T1 ccRCC between January 2012 and June 2019, including 50 aggressive ccRCC based on synchronous metastasis or recurrence after surgery. The patients were divided into two cohorts (training and validation) at a 7:3 ratio. Radiomics features were extracted from contrast enhanced CT images. A radiomics signature was developed based on reproducible features by means of the least absolute shrinkage and selection operator method. Demographics, laboratory variables (including sex, age, Fuhrman grade, hemoglobin, platelet, neutrophils, albumin, and calcium) and CT findings were combined to develop clinical factors model. Integrating radiomics signature and independent clinical factors, a radiomics nomogram was developed. Nomogram performance was determined by calibration, discrimination, and clinical usefulness.

Results: Ten features were used to build radiomics signature, which yielded an area under the curve (AUC) of 0.86 in the training cohort and 0.85 in the validation cohort. By incorporating the sex, maximum diameter, neutrophil count, albumin count, and radiomics score, a radiomics nomogram was developed. Radiomics nomogram (AUC: training, 0.91; validation, 0.92) had higher performance than clinical factors model (AUC: training, 0.86; validation, 0.90) or radiomics signature as a means of identifying patients at high risk for recurrence and metastasis. The radiomics nomogram had higher sensitivity than clinical factors mode (McNemar's chi-squared = 4.1667, p = 0.04) and a little lower specificity than clinical factors model (McNemar's chi-squared = 3.2, p = 0.07). The nomogram showed good calibration. Decision curve analysis demonstrated the superiority of the nomogram compared with the clinical factors model in terms of clinical usefulness.

Conclusion: The CT-based radiomics nomogram could help in predicting recurrence and metastasis risk in T1 ccRCC, which might provide assistance for clinicians in tailoring precise therapy.
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http://dx.doi.org/10.3389/fonc.2020.579619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672185PMC
November 2020

Cytochrome P450 2U1 Is a Novel Independent Prognostic Biomarker in Breast Cancer Patients.

Front Oncol 2020 5;10:1379. Epub 2020 Aug 5.

Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China.

The susceptibility of breast cancer is largely affected by the metabolic capacity of breast tissue. This ability depends in part on the expression profile of cytochrome P450 (CYPs). CYPs are a superfamily of enzymes with related catalysis to endogenous and exogenous bioactive substances, including xenobiotic metabolism, drugs, and some endogenous substances metabolism which activate cells and stimulate cell signaling pathways, such as arachidonic acid metabolism, steroid metabolism, fatty acid metabolism. Interestingly, CYP was electively expressed in different tumors, and mediated the metabolic activation of multiple carcinogens and participated in the activation and deactivation of tumor therapeutic drugs. However, the biological action of cytochrome P450 2U1 (CYP2U1) in breast carcinoma is little understood so far. To investigate the biological value of CYP2U1 in breast carcinoma, we performed immunohistochemical (IHC) analysis and survival analysis based on clinico-pathological data of breast cancer. IHC analysis showed that the abundance of CYP2U1 protein was inversely proportional to the state of estrogen receptor(ER) ( < 0.05), and the lower the degree of tumor differentiation, the higher the protein abundance ( < 0.001). Additionally, compared with luminal tumors, the CYP2U1 protein content was more abundant in triple negative breast cancer ( < 0.05). Importantly, survival analysis showed that higher CYP2U1 protein levels predicted poor 5-year overall survival rate ( < 0.01), 5-year disease-free survival rate ( < 0.05), and 5-year metastatic-free survival rate ( < 0.01) for the entire enrolled breast cancer patients. CYP2U1 is generally closely related to the clinicopathological characteristics and is also an adverse prognostic factor for breast carcinoma patients, indicating that CYP2U1 is engaged in the malignant progression of breast carcinoma.
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http://dx.doi.org/10.3389/fonc.2020.01379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419690PMC
August 2020

Interface modification effect on the performance of CsFAPbIBr perovskite solar cells fabricated by evaporation/spray-coating method.

J Chem Phys 2020 Jul;153(1):014706

State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology, Wuhan 430070, People's Republic of China.

In this study, high quality CsFAPbIBr perovskite thin films were successfully fabricated by an evaporation/spray-coating hybrid deposition method. In this method, CsI and PbI were first deposited via thermal evaporation, and then FAI/FABr mixed solution was sprayed on the CsI/PbI substrate to form the CsFAPbIBr film. As confirmed by x-ray diffraction, scanning electron microscopy, and atomic force microscopy, a perovskite film with full surface coverage and small surface roughness was obtained. Then, the effect of interface modification materials on the performance of perovskite solar cells (PSCs) was investigated: the devices with the [6,6]-phenyl-C-butyric acid methyl ester (PCBM) interlayer incorporated via vacuum evaporation deposition between SnO and perovskite showed remarkably higher performance than those with the C interlayer, which was attributed to enhanced charge extraction and reduced recombination at the SnO/PCBM/perovskite interface. As a result, a high power conversion efficiency (PCE) of 18.21% was obtained for the 0.16 cm device. To the best of our knowledge, it is the highest efficiency of CsFAPbIBr based PSCs fabricated by the spray technique. Furthermore, we fabricated mini-modules with the size of 5 × 5 cm and achieved a PCE of 14.7%.
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http://dx.doi.org/10.1063/5.0012803DOI Listing
July 2020

Pollen-derived porous carbon decorated with cobalt/iron sulfide hybrids as cathode catalysts for flexible all-solid-state rechargeable Zn-air batteries.

Nanoscale 2020 Jun;12(21):11746-11758

School of Physics and Materials Science, Anhui University, Hefei, 230601, China. and Key Laboratory of Photoelectric Conversion Energy Materials and Devices of Anhui Province, Key Laboratory of Hybrid Material Structure and Function Regulation, Ministry of Education, Anhui University, Hefei, 230601, China.

The development of flexible all-solid-state rechargeable Zn-air batteries (FS-ZABs) for wearable applications faces challenges from the balance between performance and flexibility of the battery; efficient cathode catalyst and reasonable electrode construction design are key factors. Herein, a low-cost pollen derived N,S co-doped porous carbon decorated with Co9S8/Fe3S4 nanoparticle hybrids ([email protected]) has been synthesized. Owing to the active Co9S8/Fe3S4 nanoparticles, N,S co-doping, and large specific area of the pollen derived porous carbon matrix, the [email protected] composite exhibits an excellent bifunctional catalytic activity with a small potential gap (ΔE = 0.80 V) between the half-wave potential for the ORR (0.80 V) and the potential at 10 mA cm-2 for the OER (1.60 V), and endows a liquid Zn-air battery with a high power density of 138 mW cm-2, a larger specific capacity of 891 mA h g-1 and a stable rechargeability of up to 331 cycles. Based on the [email protected] cathode catalyst, a 2D coplanar FS-ZAB has been fabricated with specially designed parallel narrow strip electrodes alternately arrayed on a polyacrylamide polyacrylic acid copolymer hydrogel solid electrolyte. The presented FS-ZAB exhibits excellent battery performance with high open-circuit-voltage (1.415 V), competitive peak power density (78 mW cm-2), large specific capacity (785 mA h g-1) and stable rechargeability (150 cycles), offers robust flexibility to maintain stable charge/discharge capacity under different bending deformations, and provides convenient coplanar integrability to realize parallel or series connection of multiple cells in a relatively small area.
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http://dx.doi.org/10.1039/d0nr02376kDOI Listing
June 2020

Postnatal Gut Immunity and Microbiota Development Is Minimally Affected by Prenatal Inflammation in Preterm Pigs.

Front Immunol 2020 19;11:420. Epub 2020 Mar 19.

Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Chorioamnionitis (CA), resulting from intra-amniotic inflammation, is a frequent cause of preterm birth and exposes the immature intestine to bacterial toxins and/or inflammatory mediators before birth via fetal swallowing. This may affect intestinal immune development, interacting with the effects of enteral feeding and gut microbiota colonization just after birth. Using preterm pigs as model for preterm infants, we hypothesized that prenatal exposure to gram-negative endotoxin influences postnatal bacterial colonization and gut immune development. Pig fetuses were given intra-amniotic lipopolysaccharide (LPS) 3 days before preterm delivery by cesarean section and were compared with littermate controls (CON) at birth and after 5 days of formula feeding and spontaneous bacterial colonization. Amniotic fluid was collected for analysis of leukocyte counts and cytokines, and the distal small intestine was analyzed for endotoxin level, morphology, and immune cell counts. Intestinal gene expression and microbiota were analyzed by transcriptomics and metagenomics, respectively. At birth, LPS-exposed pigs showed higher intestinal endotoxin, neutrophil/macrophage density, and shorter villi. About 1.0% of intestinal genes were affected at birth, and , a regulator of mucosal immune defense, was identified as the hub gene in the co-expression network. Genes related to innate immune response (), neutrophil chemotaxis (), and antigen processing (MHC II genes and ) were also affected, and expression levels correlated with intestinal neutrophil/macrophage density and amniotic fluid cytokine levels. On day 5, LPS and CON pigs showed similar sensitivity to necrotizing enterocolitis, endotoxin levels, morphology, immune cell counts, gene expressions, and microbiota composition (except for difference in some low-abundant species). Our results show that CA markedly affects intestinal genes at preterm birth, including genes related to immune cell infiltration. However, a few days later, following the physiological adaptations to preterm birth, CA had limited effects on intestinal structure, function, gene expression, bacterial colonization, and necrotizing enterocolitis sensitivity. We conclude that short-term, prenatal intra-amniotic inflammation is unlikely to exert marked effects on intestinal immune development in preterm neonates beyond the immediate neonatal period.
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http://dx.doi.org/10.3389/fimmu.2020.00420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098537PMC
March 2021

Study of Top-down and Bottom-up Approaches by Using Design of Experiment (DoE) to Produce Meloxicam Nanocrystal Capsules.

AAPS PharmSciTech 2020 Jan 23;21(3):79. Epub 2020 Jan 23.

Department of Internal Medicine, Qingdao orthopaedic Hospital, Qingdao, China.

In order to investigate the correlation among energy input-related, drug-related, and stabilizer-related aspects for both top-down and bottom-up nanocrystal production, meloxicam nanosuspensions (NS) were produced by using three different methods (low-energy wet milling, high-pressure homogenization, and precipitation) and each method was optimized by using design of experiment (DoE). Box-Behnken design of 3 factors and 3 levels was applied for the optimization of each method. All the three models were found to be significant and the optimized process parameters were used for production of NS, respectively. Interestingly, by comparison of the top-down and bottom-up approaches, the influence of energy input (homogenization pressure or milling speed) from the instruments seemed not significant for top-down compared with bottom-up for this drug. Different mechanisms of homogenization (relatively high energy zone) and milling (relatively low energy zone) led to obtained various significant correlations for each method. Capsules containing nanocrystals were successfully produced by using a novel method applying NS (after wet bead milling and homogenization processes) as wetting agent for direct capsuling and showed superiority regarding as dissolution rate compared with the traditional two-step method (freeze-dried powder used for capsuling as the first step). Different NS preparation methodologies proved to have a direct influence on the following capsuling process and consequently, in the dissolution rate. This study also proved that residual DMSO in nanosuspension after precipitation process could affect the freeze-drying process, which might further alter the redispersion and influence the downstream processes.
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http://dx.doi.org/10.1208/s12249-020-1621-7DOI Listing
January 2020

Advanced modification of drug nanocrystals by using novel fabrication and downstream approaches for tailor-made drug delivery.

Drug Deliv 2019 Dec;26(1):1092-1103

Institute of Pharmacy, Department of Pharmaceutics, Biopharmaceutics and NutriCosmetics, Freie Universität Berlin, Berlin, Germany.

Drug nanosuspensions/nanocrystals have been recognized as one useful and successful approach for drug delivery. Drug nanocrystals could be further decorated to possess extended functions (such as controlled release) and designed for special in vivo applications (such as drug tracking), which make best use of the advantages of drug nanocrystals. A lot of novel and advanced size reduction methods have been invented recently for special drug deliveries. In addition, some novel downstream processes have been combined with nanosuspensions, which have highly broadened its application areas (such as targeting) besides traditional routes. A large number of recent research publication regarding as nanocrystals focuses on above mentioned aspects, which have widely attracted attention. This review will focus on the recent development of nanocrystals and give an overview of regarding modification of nanocrystal by some new approaches for tailor-made drug delivery.
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http://dx.doi.org/10.1080/10717544.2019.1682721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882472PMC
December 2019

Sequencing of Chinese castor lines reveals genetic signatures of selection and yield-associated loci.

Nat Commun 2019 07 31;10(1):3418. Epub 2019 Jul 31.

Agricultural Genomics Institute, Chinese Academy of Agricultural Sciences, 518120, Shenzhen, Guangdong, China.

Oil produced by castor (Ricinus communis) has broad industrial applications. However, knowledge on the genetic diversity, especially genetic alterations that occurred during domestication and subsequent traits selection, of this oil crop is limited. Here, our population genomics analyses show that the Chinese castors have developed a geographic pattern, classified into the southern-, the middle-, and the northern-China groups. We detect a number of candidate genomic loci that are associated with the selection signals during the geographical differentiation and domestication. Using genome-wide association analysis, we identify candidate genes associated with nine agronomically important traits. One of the candidate genes encoding a glycosyltransferase related to cellulose and lignin biosynthesis is associated with both capsule dehiscence and endocarp thickness. We hypothesize that the abundance of cellulose or lignin in endocarp is an important factor for capsule dehiscence. Our results provide foundation for castor breeding and genetic study.
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http://dx.doi.org/10.1038/s41467-019-11228-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668449PMC
July 2019

Heterogeneity of cough hypersensitivity mediated by TRPV1 and TRPA1 in patients with chronic refractory cough.

Respir Res 2019 Jun 6;20(1):112. Epub 2019 Jun 6.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Rd, Guangzhou, 510120, People's Republic of China.

Background: The differential sensitivity of cough to antitussive therapies implies the existence of heterogeneity in cough hypersensitivity, but how such heterogeneity is expressed across individual patients is poorly understood. We investigated the phenotypes of cough hypersensitivity by examining transient receptor potential ankyrin 1 (TRPA1)- and transient receptor potential vanilloid 1 (TRPV1)-mediated cough sensitivity in patients with chronic refractory cough.

Methods: Using a selective TRPA1 agonist, allyl isothiocyanate (AITC), we established an AITC cough challenge as a measure of TRPA1-mediated cough sensitivity. The AITC cough challenge and the widely used capsaicin (a selective TRPV1 agonist) cough challenge were performed with 250 patients with chronic refractory cough and 56 healthy subjects. The concentration of AITC or capsaicin solution causing at least two (C2) and five coughs (C5) was recorded. Cough sensitivity was expressed as the mean (95% confidence interval) of log C5, and cough hypersensitivity was defined as a log C5 value lower than that of healthy subjects.

Results: A distinct concentration-response effect of inhaled AITC was identified both in patients with chronic refractory cough and in healthy subjects. Cough sensitivity to AITC and capsaicin was significantly higher in patients than in healthy subjects (AITC: 2.42 [2.37-2.48] vs 2.72 [2.66-2.78] mM, p = 0.001; capsaicin: 1.87 [1.75-1.98] vs 2.53 [2.36-2.70] μM, p = 0.001) and was higher in females than in males for both healthy subjects and patients (all p < 0.05). Among the 234 patients who completed both challenges, 25 (10.7%) exhibited hypersensitivity to both AITC and capsaicin, 44 (18.8%) showed hypersensitivity to AITC only, 28 (11.9%) showed hypersensitivity to capsaicin only, and 137 (58.6%) exhibited hypersensitivity to neither. Those with TRPA1- and/or TRPV1-mediated hypersensitivity were predominantly female, while those without TRPA1- and TRPV1-mediated hypersensitivity were mainly male.

Conclusions: Four phenotypes of cough hypersensitivity were identified by the activation of TRPV1 and TRPA1 channels, which supports the existence of heterogeneity in cough pathways and provides a new direction for personalized management of chronic refractory cough.

Trial Registration: ClinicalTrials.gov NCT02591550 .
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http://dx.doi.org/10.1186/s12931-019-1077-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554907PMC
June 2019

A 17 gene panel for non-small-cell lung cancer prognosis identified through integrative epigenomic-transcriptomic analyses of hypoxia-induced epithelial-mesenchymal transition.

Mol Oncol 2019 07 29;13(7):1490-1502. Epub 2019 May 29.

Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.

As a critical feature of the tumor microenvironment, hypoxia is known to be a potent inducer of tumor metastasis, and it has been proposed that the initial steps in metastasis involve epithelial-mesenchymal transition (EMT). The strong correlation among hypoxia, EMT, and metastasis suggests that integrative assessment of gene expression and the DNA modification program of hypoxia-induced EMT via high-throughput sequencing technologies may increase our understanding of the molecular basis of tumor invasion and metastasis. Here, we present the genomewide transcriptional and epigenetic profiles of non-small-cell lung cancer (NSCLC) cells under normoxic and hypoxic conditions. We demonstrate that hypoxia induces EMT along with dynamic alterations of transcriptional expression and epigenetic modifications in both A549 and HCC827 cells. After training using a dataset from patients with invasive and noninvasive lung adenocarcinomas with an artificial neural network algorithm, a characteristic 17-gene panel was identified, consisting of genes involved in EMT, hypoxia response, glycometabolism, and epigenetic modifications. This 17-gene signature clearly stratified NSCLC patients with significant differences in overall survival across three independent datasets. Our study may be suitable as a basis for further selection of gene signatures to potentially guide prognostic stratification in patients with NSCLC.
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http://dx.doi.org/10.1002/1878-0261.12491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599842PMC
July 2019

High drug payload nanoparticles formed from dexamethasone-peptide conjugates for the treatment of endotoxin-induced uveitis in rabbit.

Int J Nanomedicine 2019 14;14:591-603. Epub 2019 Jan 14.

Institute of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, People's Republic of China,

Purpose: To develop and demonstrate the effectiveness of a novel dexamethasone (Dex) nanoformulation for treating uveitis.

Materials And Methods: We designed and screened a dexamethasone-peptide conjugate (Dex-SA-FFFE), formed via a biodegradable ester bond linkage, that could spontaneously form high drug payload nanoparticles in aqueous solution for treating uveitis.

Results: An in vitro release study indicated that Dex and Dex-SA-FFFE sustainably released from Dex-SA-FFFE nanoparticles over a 48 h study period. Meanwhile, the formed Dex-SA-FFFE nanoparticles hardly caused cytotoxicity in human corneal epithelial cell at drug concentrations up to 1 mM after 24 h of incubation but reduced cell viability after 48 h and 72 h of incubation. An in vitro anti-inflammatory efficacy assay showed that the Dex-SA-FFFE nanoparticles exhibited a comparable anti-inflammatory efficacy to that of Dex in lipopolysaccharide (LPS)-activated RAW264.7 macrophages via significant decreases in the secretion of various pro-inflammatory cytokines (e.g., nitric oxide, tumor necrosis factor-α, interleukin-6). Topical instillation of Dex-SA-FFFE nanoparticles showed good ocular tolerance without causing changes in corneal thickness and intraocular pressure during the entire study period. Furthermore, topical instillation of Dex-SA-FFFE nanoparticles displayed a comparable in vivo therapeutic efficacy to that of dexamethasone sodium phosphate (Dexp) aqueous solutions in an endotoxin-induced uveitis (EIU) rabbit model.

Conclusion: Based on these results, it is reasonable to believe that the proposed Dex-SA-FFFE nanoparticles might have great application for the treatment of anterior uveitis.
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http://dx.doi.org/10.2147/IJN.S179118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336024PMC
February 2019

Aquaporin-3 mediates ovarian steroid hormone-induced motility of endometrial epithelial cells.

Hum Reprod 2018 11;33(11):2060-2073

Core Lab Glycobiol & Glycoengn,college of Basic Sciences, Dalian Medical University, Dalian , Liaoning, China.

Study Question: How does aquaporin-3 (AQP3) affect endometrial receptivity?

Summary Answer: AQP3, which is regulated by the combination and estrogen (E2) and progesterone (P4), induces epithelial-mesenchymal transition (EMT) of endometrial epithelial cells.

What Is Known Already: Embryo implantation is an extremely complex process, and endometrial receptivity is essential for successful embryo implantation. Estrogen and progesterone regulate endometrial receptivity. AQP3, which is regulated by estrogen (E2), increases cell migration and invasion ability by regulating the expression of EMT-related factors and influencing the reorganization of the actin cytoskeleton.

Study Design, Size, Duration: This study investigated the pathophysiological significance of AQP3 in human endometrial function during different phases of the menstrual cycle.

Participants/materials, Setting, Methods: AQP3 expression levels during different phases of the menstrual cycle were measured using immunohistochemical assays. In cells of different receptivity (high-receptive RL95-2 cells and low-receptive HEC-1A cells), the expression of AQP3 was measured using western blotting, qRT-PCR and immunofluorescence assays. Activities of AQP3, and its regulation by E2 and P4, were studied through in-vitro experiments using RL95-2 cells.

Main Results And The Role Of Chance: AQP3 expression in the mid- and late-secretory phases of the human endometrium is significantly higher than in other phases. Since AQP3 expression levels were higher in RL95-2 cells than in HEC-1A cells, mechanisms of AQP3 regulation by E2 and P4 were studied using RL95-2 cells. We provided the first report that P4 up-regulates AQP3 by directly targeting the promoter of the AQP3 gene. The up-regulation of AQP3 expression by a combination of E2 and P4 is significantly higher than that caused by either E2 or P4 alone. Together E2 and P4 promote RL95-2 cell migration and invasion by inducing EMT through AQP3. We also found that AQP3 co-localizes with ezrin and affects the formation of filopodia and lamellipodia during the E2 and P4-induced EMT process but has no effect on the expression of ezrin and F-actin.

Large Scale Data: N/A.

Limitations, Reasons For Caution: It is still unclear whether AQP3 is a main regulator of endometrial receptivity or one of several factors influencing the process.

Wider Implications Of The Findings: Further investigation on AQP3 may contribute to a greater understanding of endometrial receptivity.

Study Funding/competing Interest(s): This work was supported by the National Natural Scientific Grants of China (No. 31570798), the Program for Liaoning Excellent Talents in University (LR2017042), the Doctoral Scientific Research Foundation of Liaoning province (201601236), and the Liaoning Provincial Program for Top Discipline of Basic Medical Sciences. There are no conflicts of interest.
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http://dx.doi.org/10.1093/humrep/dey290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195804PMC
November 2018

Osteopontin promotes hepatocellular carcinoma progression via the PI3K/AKT/Twist signaling pathway.

Oncol Lett 2018 Oct 8;16(4):5299-5308. Epub 2018 Aug 8.

Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.

The epithelial-mesenchymal transition (EMT) serves critical roles in the migration, invasion and metastasis of human cancer cells. This process is initiated by regulation of E-cadherin expression by the major inducers of EMT. Previous studies reported that osteopontin (OPN) is essential for hepatocellular carcinoma (HCC) metastasis as it facilitates the EMT in HCC. However, the role and clinical significance of OPN as an EMT regulator in HCC remains unknown. The present study revealed that OPN regulated the expression of Twist by activating RAC serine/threonine-protein kinase (Akt), a critical EMT regulator. Interfering with the phosphoinositide 3-kinase (PI3K)/Akt pathway may suppress the expression of Twist enhanced by OPN. Increased Twist levels in HCC were associated with poor survival and tumor recurrence in patients with HCC following surgery. A significant association was observed between OPN expression and Twist levels in HCC, and a combination of these two parameters was revealed to be a more powerful predictor of poor patient prognosis. The findings of the present study indicate that Twist serves an notable role in OPN-mediated metastasis of HCC through activation of the PI3K/Akt pathway. Twist may be a potential therapeutic target for the prevention of HCC metastasis in patients exhibiting high OPN expression.
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http://dx.doi.org/10.3892/ol.2018.9281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144913PMC
October 2018

Palladium Phosphide as a Stable and Efficient Electrocatalyst for Overall Water Splitting.

Angew Chem Int Ed Engl 2018 Nov 12;57(45):14862-14867. Epub 2018 Oct 12.

Sustainable Energy Laboratory, Faculty of Materials Science and Chemistry, China University of Geosciences Wuhan, 388 Lumo RD, Wuhan, 430074, China.

A palladium phosphide electrocatalyst supported on carbon black (PdP @CB) shows efficient water splitting in both alkaline and neutral electrolytes. Significantly lower overpotentials are required for PdP @CB (27.5 mV in 0.5 m H SO ; 35.4 mV in 1 m KOH; 84.6 mV in 1 m PBS) to achieve a HER electrocatalytic current density of 10 mA cm compared to commercial Pt/CB (30.1 mV in 0.5 m H SO ; 46.6 mV in 1 m KOH; 122.7 mV in 1 m PBS). Moreover, no loss in HER activity is detectable after 5000 potential sweeps. Only 270 mV and 277 mV overpotentials are required to reach a current density of 10 mA cm for PdP @CB to catalyze OER in 1 m KOH and 1 m PBS electrolytes, which is better OER activity than the benchmark IrO electrocatalyst (301 mV and 313 mV to drive a current density of 10 mA cm ). 1.59 V and 1.72 V are needed for PdP @CB to achieve stable water splitting catalytic current density of 10 mA cm in 1 m PBS and 50 mA cm in 1 m KOH for 10 h, respectively.
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http://dx.doi.org/10.1002/anie.201810102DOI Listing
November 2018

Directing the nanoparticle formation by the combination with small molecular assembly and polymeric assembly for topical suppression of ocular inflammation.

Int J Pharm 2018 Nov 10;551(1-2):223-231. Epub 2018 Sep 10.

Institute of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou 325027, PR China. Electronic address:

In this paper, we presented a simple yet versatile strategy to generate a high drug payload nanoparticles by the combination with small molecular assembly and polymeric assembly for topical suppression of ocular inflammation. Upon physical mixing of the succinated triamcinolone acetonide (TA-SA) supramolecular hydrogel with the poly (ethylene glycol)-poly (ɛ-caprolactone)-poly (ethylene glycol) (PECE) aqueous solution at 37 °C, TA-SA/PECE nanoparticles formed spontaneously and characterized thoroughly by transmission electron microscopy (TEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The formed TA-SA/PECE nanoparticles displayed a comparable in vitro anti-inflammatory efficacy to that of native triamcinolone acetonide (TA), through a significant downregulation of various proinflammatory cytokines levels (e.g., NO, TNF-α) in a lipopolysaccharide (LPS) actived RAW264.7 macrophage. Meanwhile, the enhanced transcorneal drug permeability of TA-SA/PECE nanoparticles over that of TA suspension was clearly observed in an isolated rabbit cornea. Intraocular biocompatibility test demonstrated that TA-SA/PECE nanoparticles presented good biocompatibility after topical instillation during entire study period. More importantly, the TA-SA/PECE nanoparticles displayed superior therapeutic efficacy over that of the TA suspension in the endotoxin-induced uveitis (EIU) rabbit model via decreasing neutrophil infiltration in anterior chamber. Overall, the proposed TA-SA/PECE nanoparticles might be a promising candidate for uveitis therapy.
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http://dx.doi.org/10.1016/j.ijpharm.2018.09.015DOI Listing
November 2018

Utilization of Resist Stencil Lithography for Multidimensional Fabrication on a Curved Surface.

ACS Nano 2018 Sep 10;12(9):9626-9632. Epub 2018 Sep 10.

Hefei National Laboratory for Physical Sciences at the Microscale & Synergetic Innovation Center of Quantum Information & Quantum Physics , University of Science and Technology of China , Hefei Anhui 230026 , China.

The limited ability to fabricate nanostructures on nonplanar rugged surfaces has severely hampered the applicability of many emerging technologies. Here we report a resist stencil lithography based approach for in situ fabrication of multidimensional nanostructures on both planar and uneven substrates. By using the resist film as a flexible stencil to form a suspending membrane with predesigned patterns, a variety of nanostructures have been fabricated on curved or uneven substrates of diverse morphologies on demand. The ability to realize 4 in. wafer scale fabrication of nanostructures as well as line width resolution of sub-20 nm is also demonstrated. Its extraordinary capacity is highlighted by the fabrication of three-dimensional wavy nanostructures with diversified cell morphologies on substrates of different curvatures. A robust general scheme is also developed to construct various complex 3D nanostructures. The use of conventional resists and processing ensures the versatility of the method. Such an in situ lithography technique has offered exciting possibilities to construct nanostructures with high dimensionalities that can otherwise not be achieved with existing nanofabrication methods.
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http://dx.doi.org/10.1021/acsnano.8b06534DOI Listing
September 2018

Osteopontin Promotes Bone Destruction in Periapical Periodontitis by Activating the NF-κB Pathway.

Cell Physiol Biochem 2018 5;49(3):884-898. Epub 2018 Sep 5.

College of Basic Medical Sciences, Dalian Medical University, Dalian, China.

Background/aims: Periapical periodontitis is caused by bacterial infection and results in both one destruction and tooth loss. Osteopontin (OPN) is a secreted phosphorylated glycoprotein that participates in bone metabolism.

Methods: Thirty-three patients with chronic periapical periodontitis and 10 patients who had undergone the orthodontic removal of healthy tooth tissue (control) at the periodontal ligament were investigated, and an animal model of mouse periapical periodontitis was established for an in vivo analysis. The relationship between OPN and bone destruction during periapical periodontitis was analyzed. Osteoblasts and osteoclasts were cultured in vitro and treated with lipopolysaccharide. An inhibitor of NF-κB was used to pretreat the transfected cells.

Results: OPN increased osteoclast proliferation and differentiation, but reduced osteoblasts proliferation and differentiation. OPN activated the NF-κB pathway during periapical periodontitis and accelerated the transfer and phosphorylation of P65 from the cytoplasm to the nucleus.

Conclusion: This study demonstrated that OPN played important roles in the progression of periapical periodontitis, and a dual role in bone metabolism during periapical periodontitis, linking osteoclasts and osteoblasts. The underlying mechanism may be related to the NF-κB pathway.
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http://dx.doi.org/10.1159/000493219DOI Listing
October 2018

Osteopontin alters DNA methylation through up-regulating DNMT1 and sensitizes CD133+/CD44+ cancer stem cells to 5 azacytidine in hepatocellular carcinoma.

J Exp Clin Cancer Res 2018 Jul 31;37(1):179. Epub 2018 Jul 31.

Department of General Surgery, Huashan Hospital and Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.

Background: In hepatocellular carcinoma (HCC), CD133+/CD44+ cells are one subgroup with high stemness and responsible for metastatic relapse and resistance to treatment. Our previous studies have demonstrated that osteopontin (OPN) plays critical roles in HCC metastasis. We further investigated the molecular mechanism underlying the role of OPN in regulating the stemness of HCC epigenetically and explored possible targeting strategy.

Methods: CD133+/CD44+ subgroup sorting from HCC cell lines and HCC tissues was used to investigate the effects of OPN knockdown on stemness. iTRAQ and MedIP-sequencing were applied to detect the protein profile and epigenetic modification of CD133+/CD44+ subgroup with or without OPN knockdown. The antitumor effects of 5 Azacytidine were examined in cultured HCC cells and patient derived xenograft (PDX) models.

Results: OPN was accumulated in CD133+/CD44+ subgroup of HCC cells. Knocking down OPN significantly inhibited the sphere formation and stemness-related genes expression, and delayed tumor initiation of CD133+/CD44+ subgroup of HCC cells. Employing MedIP-sequencing, dot blot and iTRAQ analyses of CD133+/CD44+ SCR and CD133+/CD44+ shOPN cells, we found that OPN knockdown leaded to reduction in DNA methylation with particular enrichment in CGI. Meanwhile, DNA (cytosine-5)-methyltransferase 1 (DNMT1), the main methylation maintainer, was downregulated via proteomics analysis, which mediated OPN altering DNA methylation. Furthermore, DNMT1 upregulation could partially rescue the properties of CD133+/CD44+ shOPN cells. Both in vitro and in vivo assays showed that CD133+/CD44+ cells with high OPN levels were more sensitive to DNA methylation inhibitor, 5 Azacytidine (5 Aza). The above findings were validated in HCC primary cells, a more clinically relevant model.

Conclusions: OPN induces methylome reprogramming to enhance the stemness of CD133+/CD44+ subgroup and provides the therapeutic benefits to DNMT1 targeting treatment in HCC.
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http://dx.doi.org/10.1186/s13046-018-0832-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069805PMC
July 2018
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