Publications by authors named "Lulu Sun"

102 Publications

Hexose transporter CsSWEET7a in cucumber mediates phloem unloading in companion cells for fruit development.

Plant Physiol 2021 Feb 5. Epub 2021 Feb 5.

Beijing Key Laboratory of Growth and Developmental Regulation for Protected Vegetable Crops, College of Horticulture, China Agricultural University, Beijing 100193, China.

In the fleshy fruit of cucumbers (Cucumis sativus L.), the phloem flow is unloaded via an apoplasmic pathway, which requires protein carriers to export sugars derived from stachyose and raffinose into the apoplasm. However, transporter(s) involved in this process remain unidentified. Here, we report that a hexose transporter, CsSWEET7a (Sugar Will Eventually be Exported Transporter 7a), was highly expressed in cucumber sink tissues and localized to the plasma membrane in companion cells of the phloem. Its expression level increased gradually during fruit development. Down-regulation of CsSWEET7a by RNA interference (RNAi) resulted in smaller fruit size along with reduced soluble sugar levels and reduced allocation of 14C-labelled carbon to sink tissues. CsSWEET7a overexpression lines showed an opposite phenotype. Interestingly, genes encoding alkaline α-galactosidase (AGA) and sucrose synthase (SUS) were also differentially regulated in CsSWEET7a transgenic lines. Immunohistochemical analysis demonstrated that CsAGA2 co-localized with CsSWEET7a in companion cells, indicating cooperation between AGA and CsSWEET7a in fruit phloem unloading. Our findings indicated that CsSWEET7a is involved in sugar phloem unloading in cucumber fruit by removing hexoses from companion cells to the apoplasmic space to stimulate the raffinose family of oligosaccharides (RFOs) metabolism so that additional sugars can be unloaded to promote fruit growth. This study also provides a possible avenue towards improving fruit production in cucumber.
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http://dx.doi.org/10.1093/plphys/kiab046DOI Listing
February 2021

Surface doping of non-fullerene photoactive layer by soluble polyoxometalate for printable organic solar cells.

Chem Commun (Camb) 2021 Feb 17. Epub 2021 Feb 17.

Wuhan National Laboratory for Optoelectronics, School of Optical and Electronic Information, Huazhong University of Science and Technology, Wuhan 430074, China.

The non-fullerene photoactive layer (PTB7-Th:IEICO-4F) film is first immersed into a PMA solution to induce an effective surface p-type doping. An improved hole-collection and a high PCE of 11.37% was obtained, although the non-fullerene OSCs were without a commonly evaporated MoO3. This surface doping technique is an effective and feasible strategy for the printable electronics technology.
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http://dx.doi.org/10.1039/d1cc00032bDOI Listing
February 2021

The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer.

Nat Rev Gastroenterol Hepatol 2021 Feb 10. Epub 2021 Feb 10.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apc mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
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http://dx.doi.org/10.1038/s41575-020-00404-2DOI Listing
February 2021

Evaluation of exposure risk for healthcare personnel performing the open technique HIPEC procedure using cisplatin.

Gynecol Oncol 2021 Jan 29. Epub 2021 Jan 29.

Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University. No. 10 Tieyi Road, Yangfangdian, Haidian District, Beijing, 100038, China.

Objective: To perform an evaluation of the risk to healthcare personnel of exposure to cisplatin during a Hyperthermic Intraperitoneal Chemotherapy (HIPEC) procedure in an operating room environment.

Methods: Breathing zone air samples were taken from the operating room (OR) before, during and after the procedure of HIPEC filter membrane adsorption and the liquid impact method was applied to collect air samples. The samples of surface wipe from the floor of the OR were taken after the procedure. Inductively coupled plasma mass spectrometry(ICP-MS) was used to detect the content of cisplatin in all the samples.

Results: Thirty-six air samples and three surface wipes were collected from three different locations of healthcare personnel breathing zones. All the breathing zone air samples were negative for cisplatin; however, cisplatin contamination was detected on three surface wipes from the floor, but in a lowconcentration(≤ 2.25 ng).

Conclusion: The results suggest that the risk of inhalation of cisplatin was extremely low for the healthcare personnel during the procedure of HIPEC, but the contamination of the OR floor should be taken into consideration.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.016DOI Listing
January 2021

Ultrasound-Targeted Microbubble Destruction-Mediated Downregulation of EZH2 Inhibits Stemness and Epithelial-Mesenchymal Transition of Liver Cancer Stem Cells.

Onco Targets Ther 2021 11;14:221-237. Epub 2021 Jan 11.

Department of Ultrasound Intervention, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.

Background: Cancer cells could show the characteristics of cancer stem cells (CSCs) through epithelial-mesenchymal transition (EMT). EZH2 was associated with EMT. Ultrasound-targeted microbubble destruction (UTMD) could enhance gene transfection efficiency. Here, we explored the effect of UTMD-mediated shEZH2 on liver CSCs.

Methods: EZH2 expression in liver cancer and the overall survival of liver cancer patients were analyzed by bioinformatics. Liver CSCs (CD133HuH7) were sorted by flow cytometry. After transfection of shEZH2 through UTMD (UTMD-shEZH2) or liposome (LIP-shEZH2), the viability, proliferation, sphere formation, migration, and invasion of CD133HuH7 cells were detected by MTT, colony formation, tumor-sphere formation, wound healing, and transwell assays, respectively. A mice subcutaneous-xenotransplant tumor model was established by injecting CD133HuH7 or CD133HuH7 cells into the limbs of mice. Tumor weight and volume were documented. The expressions of EZH2, EMT-related factors, and STAT3/PI3K/AKT pathway-related factors in CD133HuH7 cells or tumor tissues were detected by RT-qPCR, Western blot, or immunohistochemical.

Results: EZH2 was high-expressed in liver cancer, and the patients with high expression of EZH2 had a poor survival. CD133 HuH7 cells had higher EZH2 expression, higher viability, and stronger sphere-forming and tumor-forming abilities than CD133 HuH7 cells. ShEZH2 inhibited the viability, proliferation, sphere formation, migration, and invasion of CD133 HuH7 cells, decreased the weight and volume of the xenotransplant tumor, inhibited the expressions of EZH2, Vimentin, N-Cadherin, Twist-1, p-STAT3, p-PI3K, and p-AKT, and increased E-Cadherin expression. UTMD-shEZH2 caused a stronger effect on CD133 HuH7 cells than LIP-shEZH2.

Conclusion: UTMD-mediated shEZH2 inhibited the stemness and EMT of liver CSCs in vitro and in vivo through regulating the STAT3/PI3K/AKT pathway.
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http://dx.doi.org/10.2147/OTT.S269589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810681PMC
January 2021

Major educational factors associated with nursing adverse events by nursing students undergoing clinical practice: A descriptive study.

Nurse Educ Today 2021 Mar 26;98:104738. Epub 2020 Dec 26.

Henan University School of Nursing and Health, Longting District, Kaifeng 475004, Henan Province, China. Electronic address:

Background: As the main group of healthcare providers in hospitals, nurses have more frequent contacts than any other clinician and thus are in a better position to improve patient safety. With the purpose of cultivating competent nurses, nursing educators have the responsibility to promote patient safety. A better understanding of educational factors affecting nursing adverse events by nursing students undergoing clinical practice can help nursing educators find appropriate ways to fulfil their duty.

Objective: To examine the status quo of nursing adverse events and to discuss the major educational factors concerned in different regions of China.

Design: A descriptive study design was undertaken in 2018.

Participants And Setting: A convenience sample of 1173 nursing students undergoing clinical practice was recruited from 22 hospitals in different regions of China.

Methods: The Chinese version of the Medical Student Safety Attitudes and Professionalism Survey (MSSAPS) was administered to and demographic and professional data were collected from clinical nursing students after obtaining informed consent.

Results: The incidence of nursing adverse events in clinical student nurses was 17.8%. Approximately 87.01% of nursing adverse events were near miss. The positive response rate of safety attitudes and professionalism by clinical nursing students ranged from 57.5% to 96.9%. Logistic analysis indicated that gender, educational level, hospital regions, safety culture and professional behavior experience dimensions were the major factors influencing nursing adverse events.

Conclusion: Attention should be paid to the situation in which clinical nursing students are prone to nursing adverse events. Cooperation between nursing colleges and hospitals should be strengthened to promote patient safety in clinical nursing students. We suggest that nursing educators implement patient safety education in both theoretical and practical teaching and use multiple forms, especially simulation-based training, to strengthen safe nursing behavior to reduce the incidence of nursing adverse events.
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http://dx.doi.org/10.1016/j.nedt.2020.104738DOI Listing
March 2021

Lipid Peroxidation, GSH Depletion, and Inhibition Are Common Causes of EMT and Ferroptosis in A549 Cells, but Different in Specific Mechanisms.

DNA Cell Biol 2021 Feb 22;40(2):172-183. Epub 2020 Dec 22.

Clinical Medicine Laboratory, Binzhou Medical University Hospital, Binzhou, P.R. China.

Epithelial-mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1) is thought to be involved in the pathogenesis of pulmonary fibrosis. Emerging evidence suggested that there are some common causes between ferroptosis and pulmonary fibrosis. The interaction of EMT and ferroptosis and its mechanism were investigated by detecting the expression levels of α-smooth muscle actin (), E-cadherin, solute carrier family 7 member 11 (), and glutathione peroxidase 4 () and measuring the contents of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH). The cellular morphology and ultrastructure of mitochondria were studied by microscope and transmission electron microscope (TEM), respectively. The results showed that ferroptosis in A549 cells was induced by Erastin, which decreased the expression levels of E-cadherin (), , and , accompanied with ROS and MDA increase, as well as GSH decrease. TGF-β1 promoted ultrastructure variation of mitochondria similar to ferroptosis and mesenchymal changes in morphology during EMT of A549 cells, accompanied with reduced GSH content and expression of , as well as ROS and MDA increase. Ferrostatin-1 (Fer-1) recovered ferroptosis induced by Erastin, but had no effect on the morphological change caused by TGF-β1. Furthermore, Fer-1 reduced ROS and MDA production, and increased expression in the early subsequently increased GSH. However, the effects of Fer-1 on above indicators were different in time. The expression of had no significant change during EMT induced by TGF-β1 and ferroptosis induced by Erastin in A549 cells. It is indicating that Erastin promoted the de-epithelialization of lung epithelial cells, but inhibited the process of myofibroblast differentiation; Fer-1 could partially inhibit EMT induced by TGF-β1, but reverse ferroptosis induced by Erastin. TGF-β1 could delay the ferroptosis, but could not prevent it. Lipid peroxidation, GSH depletion, and inhibition are common causes of EMT and ferroptosis in A549 cells, but different in specific mechanisms. The exact effects of GPX4 involved in EMT and ferroptosis in A549 cells need further study.
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http://dx.doi.org/10.1089/dna.2020.5730DOI Listing
February 2021

Evaluation of remodeling and regeneration of electrospun PCL/fibrin vascular grafts in vivo.

Mater Sci Eng C Mater Biol Appl 2021 Jan 25;118:111441. Epub 2020 Aug 25.

College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China. Electronic address:

The success of artificial vascular graft in the host to obtain functional tissue regeneration and remodeling is a great challenge in the field of small diameter tissue engineering blood vessels. In our previous work, poly(ε-caprolactone) (PCL)/fibrin vascular grafts were fabricated by electrospinning. It was proved that the PCL/fibrin vascular graft was a suitable small diameter tissue engineering vascular scaffold with good biomechanical properties and cell compatibility. Here we mainly examined the performance of PCL/fibrin vascular graft in vivo. The graft showed randomly arranged nanofiber structure, excellent mechanical strength, higher compliance and degradation properties. At 9 months after implantation in the rat abdominal aorta, the graft induced the regeneration of neoarteries, and promoted ECM deposition and rapid endothelialization. More importantly, the PCL/fibrin vascular graft showed more microvessels density and fewer calcification areas at 3 months, which was beneficial to improve cell infiltration and proliferation. Moreover, the ratio of M2/M1macrophage in PCL/fibrin graft had a higher expression level and the secretion amount of pro-inflammatory cytokines started to increase, and then decreased to similar to the native artery. Thus, the electrospun PCL/fibrin tubular vascular graft had great potential to become a new type of artificial blood vessel scaffold that can be implanted in vivo for long term.
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http://dx.doi.org/10.1016/j.msec.2020.111441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445127PMC
January 2021

A soft anti-virulence liposome realizing the explosive release of antibiotics at an infectious site to improve antimicrobial therapy.

J Mater Chem B 2021 01 23;9(1):147-158. Epub 2020 Nov 23.

School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Avenue, Zhengzhou 450001, China.

Pore-forming toxins (PFTs), the most common virulence proteins, are promising therapeutic keys in bacterial infections. CAL02, consisting of sphingomyelin (Sm) and containing a maximum ratio of cholesterol (Ch), has been applied to sequester PFTs. However, Sm, a saturated phospholipid, leads to structural rigidity of the liposome, which does not benefit PFT combination. Therefore, in order to decrease the membrane rigidity and improve the fluidity of liposomes, we have introduced an unsaturated phospholipid, phosphatidylcholine (Pc), to the saturated Sm. In this report, a soft nanoliposome (called CSPL), composed of Ch, Sm and Pc, was artificially prepared. In order to further improve its antibacterial effect, vancomycin (Van) was loaded into the hydrophilic core of CSPL, where Van can be released radically at the infectious site through transmembrane pores formed by the PFTs in CSPL. This soft Van@CSPL nanoliposome with detoxification/drug release was able to inhibit the possibility of antibiotic resistance and could play a better role in treating severe invasive infections in mice.
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http://dx.doi.org/10.1039/d0tb02255aDOI Listing
January 2021

Identification of a novel non-ATP-competitive protein kinase inhibitor of PGK1 from marine nature products.

Biochem Pharmacol 2021 Jan 17;183:114343. Epub 2020 Nov 17.

Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Open Studio for Druggability Research of Marine Natural Products, Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China. Electronic address:

Phosphoglycerate kinase 1 (PGK1) acts as both a glycolytic enzyme and a protein kinase playing critical roles in cancer progression, thereby being regarded as an attractive therapeutic target for cancer treatment. However, no effective inhibitor of PGK1 has been reported. Here, we demonstrate that GQQ-792, a thiodiketopiperazine derivative from marine nature products, is a non-ATP-competitive inhibitor of PGK1 with the disulfide group within the structure of GQQ-792 as a key pharmacophore. The disulfide group of GQQ-792 binds to Cys379 and Cys380 of PGK1, resulting in occlusion of ATP from binding to PGK1. GQQ-792 treatment blocks hypoxic condition- and EGF stimulation-enhanced protein kinase activity of PGK1 that phosphorylates PDHK1 at T338 in glioblastoma cells; this treatment leads to decreased lactate production and glucose uptake, and subsequent apoptosis of glioblastoma cells. Animal studies reveal that GQQ-792 significantly inhibits the growth of tumor derived from glioblastoma cells. These findings underscore the potential of GQQ-792 as a promising anticancer agent and pave an avenue to further optimize the structure of GQQ-792 basing on its target molecule and pharmacophore in future.
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http://dx.doi.org/10.1016/j.bcp.2020.114343DOI Listing
January 2021

Preparation of PU/Fibrin Vascular Scaffold with Good Biomechanical Properties and Evaluation of Its Performance in vitro and in vivo.

Int J Nanomedicine 2020 6;15:8697-8715. Epub 2020 Nov 6.

College of Life Science and Technology, Xinxiang Medical University, Xinxiang, People's Republic of China.

Purpose: The development of tissue-engineered blood vessels provides a new source of donors for coronary artery bypass grafting and peripheral blood vessel transplantation. Fibrin fiber has good biocompatibility and is an ideal tissue engineering vascular scaffold, but its mechanical property needs improvement.

Methods: We mixed polyurethane (PU) and fibrin to prepare the PU/fibrin vascular scaffolds by using electrospinning technology in order to enhance the mechanical properties of fibrin scaffold. We investigated the morphological, mechanical strength, hydrophilicity, degradation, blood and cell compatibility of PU/fibrin (0:100), PU/fibrin (5:95), PU/fibrin (15:85) and PU/fibrin (25:75) vascular scaffolds. Based on the results in vitro, PU/fibrin (15:85) was selected for transplantation in vivo to repair vascular defects, and the extracellular matrix formation, vascular remodeling, and immune response were evaluated.

Results: The results indicated that the fiber diameter of the PU/fibrin (15:85) scaffold was about 712nm. With the increase of PU content, the mechanical strength of the composite scaffolds increased, however, the degradation rate decreased gradually. The PU/fibrin scaffold showed good hydrophilicity and hemocompatibility. PU/fibrin (15:85) vascular scaffold could promote the adhesion and proliferation of mesenchymal stromal cells (MSCs). Quantitative RT-PCR experimental results showed that the expression of collagen, survivin and vimentin genes in PU/fibrin (15:85) was higher than that in PU/fibrin (25:75). The results in vivo indicated the mechanical properties and compliance of PU/fibrin grafts could meet clinical requirements and the proportion of thrombosis or occlusion was significantly lower. The graft showed strong vasomotor response, and the smooth muscle cells, endothelial cells, and ECM deposition of the neoartery were comparable to that of native artery after 3 months. At 3 months, the amount of macrophages in PU/fibrin grafts was significantly lower, and the secretion of pro-inflammatory and anti-inflammatory cytokines decreased.

Conclusion: PU/fibrin (15:85) vascular scaffolds had great potential to be used as small-diameter tissue engineering blood vessels.
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http://dx.doi.org/10.2147/IJN.S274459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656973PMC
December 2020

Clinicopathologic and molecular features of six cases of phosphaturic mesenchymal tumor.

Virchows Arch 2020 Nov 5. Epub 2020 Nov 5.

Department of Pathology and Immunology, Washington University School of Medicine, 425 S. Euclid Ave., Campus Box 8118, St. Louis, MO, 63110, USA.

Phosphaturic mesenchymal tumors (PMT) are rare neoplasms characterized by secretion of FGF23, resulting in renal phosphate wasting and osteomalacia. This tumor-induced osteomalacia (TIO) is cured by complete resection; thus, diagnosis is important, particularly on biopsy. Although PMT have a classic histologic appearance of bland spindled cells with conspicuous vascular network and characteristic smudgy basophilic matrix, there is a broad histologic spectrum and variant histologic patterns can make recognition difficult. Recent studies have demonstrated FN1-FGFR1 and FN1-FGF1 gene fusions in PMT; however, approximately 50% of cases are negative for these fusions. We sought to characterize 6 cases of PMT in-depth, compare fusion detection methods, and determine whether alternative fusions could be uncovered by targeted RNA sequencing. Of the 6 cases of PMT in our institutional archive, 3 were not given diagnoses of PMT at the time of initial pathologic examination. We characterized the immunoprofile (SMA, D2-40, CD56, S100 protein, desmin, SATB2, and ERG) and gene fusion status (FN1 and FGFR1 rearrangements by fluorescent in situ hybridization (FISH) and two targeted RNA sequencing approaches) in these cases. Tumors were consistently positive for SATB2 and negative for desmin, with 5/6 cases expressing ERG and CD56. One specimen was acid-decalcified and failed FISH and RNA sequencing. We found FN1 gene rearrangements by FISH in 2/5 cases, and a FN1-FGFR1 fusion by targeted RNA sequencing. No alternative gene fusions were identified by RNA sequencing. Our findings suggest that IHC and molecular analysis can aid in the diagnosis of PMT, guiding excision of the tumor and resolution of osteomalacia.
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http://dx.doi.org/10.1007/s00428-020-02963-wDOI Listing
November 2020

Long noncoding RNA SNHG4 promotes renal cell carcinoma tumorigenesis and invasion by acting as ceRNA to sponge miR-204-5p and upregulate RUNX2.

Cancer Cell Int 2020 19;20:514. Epub 2020 Oct 19.

Department of Ultrasound Intervention, The First Affiliated Hospital, Zhengzhou University, 1 Jianshe Dong Road, Zhengzhou, 450052 Henan China.

Background: Long noncoding RNAs (lncRNAs) are involved in the tumorigenesis and progression of human cancers, including renal cell carcinoma (RCC). Small nucleolar RNA host gene 4 (SNHG4) is reported to play an essential role in tumor growth and progression. However, the molecular mechanisms and function of SNHG4 in RCC remain undocumented.

Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine expression levels of SNHG4 in RCC tissue samples and cell lines. Cell counting kit-8, western blotting, activities of caspase-3, -8, and -9, wound-healing, and transwell invasion assays were performed to explore cell proliferation, apoptosis, migration, and invasion. The interaction among SNHG4, miR-204-5p, and RUNX2 was verified by bioinformatic analysis, a luciferase gene report, qRT-PCR, western blot analysis, and RNA immunoprecipitation assays. Xenograft mouse models were carried out to examine the role of SNHG4 in RCC in vivo.

Results: SNHG4 was highly expressed in RCC tissue samples and cell lines, and its upregulation was significantly involved in node involvement, distant metastasis, and reduced overall and relapse-free survival of patients with RCC. SNHG4 acted as an oncogenic lncRNA with promoted RCC cell proliferation, migration, invasion, and inhibited apoptosis. SNHG4 boosted tumor growth in xenograft mouse models. Mechanistically, SNHG4 functioned as a competing endogenous RNA (ceRNA) for sponging miR-204-5p, leading to the upregulation of its target RUNX2 to promote RCC cell proliferation and invasion.

Conclusion: SNHG4 and miR-204-5p might be indicated in RCC progression via RUNX2, suggesting the potential use of SNHG4/miR-204-5p/RUNX2 axis in RCC treatment.
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http://dx.doi.org/10.1186/s12935-020-01606-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574175PMC
October 2020

Limiting tumor cells comprehensively at micro and macro levels to improve the therapeutic effect of chemotherapy.

Nanotechnology 2021 Jan;32(1):015301

School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People's Republic of China. Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou, Henan Province 450001, People's Republic of China.

Clinical data shows that antitumor treatments are often ineffective if tumor cells have metastasized. To gain an effective antitumor therapeutic effect, in this report, the tumor cell was limited to the primary site and simultaneously ablated by chemotherapy. Considering the extremely complicated process of cancer metastasis, we seek to comprehensively suppress tumor metastases at both micro and macro levels, which closely link to migration and interact with each other. At the micro level, the motility of the tumor cell was decreased via accelerating mitochondria fusion. At the macro level, the unfavorable hypoxia environment was improved. A liposome-based multifunctional nanomedicine was designed by coloading latrunculin B (LAT-B), an inhibitor of actin polymerization, and doxorubicin (DOX) into the hydrophobic bilayers and aqueous cavity, respectively. Meanwhile, an oxygen reservoir named perfluoropentane (PFP) was encapsulated into the liposome core to fulfill synergistic treatment of metastatic tumors. In this paper, we demonstrated that the metastasis of the tumor cell could be effectively inhibited by LAT-B through promoting mitochondria fusion without affecting its function, making it as an encouraging candidate for effective anti-metastasis therapy. Meanwhile, we found that the combination of LAT-B and DOX shows a synergistic effect against tumors because the combined effect of these two drugs cover the entire cell proliferation process. In a word, this report presents a potential improvement in the treatment of metastatic cancer.
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http://dx.doi.org/10.1088/1361-6528/abb48fDOI Listing
January 2021

Homocysteine promotes hepatic steatosis by activating the adipocyte lipolysis in a HIF1α-ERO1α-dependent oxidative stress manner.

Redox Biol 2020 10 1;37:101742. Epub 2020 Oct 1.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, PR China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, 100191, PR China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, 100191, PR China. Electronic address:

Hyperhomocysteinemia (HHcy) is related to liver diseases, such as nonalcoholic fatty liver (NAFL). Although the precise pathogenesis of NAFL is still largely unknown, the links between organs seem to play a vital role. The current study aimed to explore the role of white adipose tissue in homocysteine (Hcy)-induced NAFL. Blood samples from nonhyperhomocysteinemia or hyperhomocysteinemia individuals were collected to assess correlation between Hcy and triglyceride (TG) or free fatty acids (FFAs) levels. C57BL/6 mice were maintained on a high-methionine diet or administered with Hcy (1.8 g/L) in the drinking water to establish an HHcy mouse model. We demonstrated that Hcy activated adipocyte lipolysis and that this change was accompanied by an increased release of FFAs and glycerol. Excessive FFAs were taken up by hepatocyte, which resulted in lipid accumulation in the liver. Treatment with acipimox (0.08 g kg day ), a potent chemical inhibitor of lipolysis, markedly decreased Hcy-induced NAFL. Mechanistically, hypoxia-inducible factor 1α (HIF1α)-endoplasmic reticulum oxidoreductin 1α (ERO1α) mediated pathway promoted HO accumulation and induced endoplasmic reticulum (ER) overoxidation, ER stress and more closed ER-lipid droplet interactions, which were responsible for activating the lipolytic response. In conclusion, this study reveals that Hcy activates adipocyte lipolysis and suggests the potential utility of targeted ER redox homeostasis for treating Hcy-induced NAFL.
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http://dx.doi.org/10.1016/j.redox.2020.101742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559542PMC
October 2020

SPATS2, negatively regulated by miR-145-5p, promotes hepatocellular carcinoma progression through regulating cell cycle.

Cell Death Dis 2020 10 9;11(10):837. Epub 2020 Oct 9.

Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.

Spermatogenesis associated serine rich 2 (SPATS2) has been reported to contribute to the tumorigenesis of multiple malignancies. The molecular function of SPATS2 in hepatocellular carcinoma (HCC) is still not fully understood. In this study, we aimed to investigate the expression pattern and function roles of SPATS2 in HCC. The regulation of SPATS2 expression was also explored. We found that SPATS2 was highly expressed in HCC tissues in comparison with that in adjacent normal tissues. High expression of SPATS2 was associated with vascular invasion, advanced TNM stages, tumor multiplicity, and poor survival. Functionally, SPATS2 was found to promote the proliferation and metastasis of HCC cells both in vitro and in vivo, while knockdown of SPATS2 enhanced apoptosis and G1 arrest of HCC cells in vitro. Mechanistically, bioinformatics analysis revealed that MiR-145-5p directly targeted SPATS2 and functional rescue experiments verified that MiR-145-5p overexpression could abolish the effect of SPATS2 on the regulation of HCC malignant phenotype. Taken together, our findings suggest that SPATS2 functions as an oncogene in HCC. The MiR-145-5p/SPATS2 axis provides a novel mechanism underlying HCC progression and may serve as a potential therapeutic target for HCC.
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http://dx.doi.org/10.1038/s41419-020-03039-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547105PMC
October 2020

Identification of novel ALK rearrangements in gynecologic clear cell carcinoma.

Int J Cancer 2021 Jan 19;148(2):459-468. Epub 2020 Oct 19.

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

Clear cell carcinomas (CCCs) of the gynecologic tract are aggressive tumors with high resistance rate to conventional platinum-based chemotherapies. Currently, the molecular features of these tumors remain largely unknown and there is no targeted therapy available. The aim of our study was to identify anaplastic lymphoma kinase (ALK) translocations, a potential molecular target for therapy. Ninety-seven patients with gynecologic CCC (62 ovarian, 27 uterine corpus and 8 uterine cervical) were screened for ALK rearrangement and ALK copy number gain using an ALK break-apart fluorescence in situ hybridization probe. The genomic landscape of all cases with ALK rearrangements and 10 random cases with ALK copy number gain was queried using a hybrid capture-based DNA next-generation sequencing assay and an Illumina Fusion RNA assay. Findings were then correlated with ALK immunohistochemistry (clone D5F3) expression. ALK rearrangement was detected in 5% (5/97) and ALK copy number gain in 79% (77/97) of gynecologic CCCs. Next-generation sequencing in ALK-rearranged CCCs identified a novel BABAM2-ALK fusion in one case. ALK translocation partners were not identified in the remaining cases. Our findings show that ALK fusion, which is targetable in other cancers, may be a pathogenetic mechanism in a small number of gynecologic CCCs.
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http://dx.doi.org/10.1002/ijc.33330DOI Listing
January 2021

Deep learning quantification of percent steatosis in donor liver biopsy frozen sections.

EBioMedicine 2020 Oct 24;60:103029. Epub 2020 Sep 24.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States; Lead contact. Electronic address:

Background: Pathologist evaluation of donor liver biopsies provides information for accepting or discarding potential donor livers. Due to the urgent nature of the decision process, this is regularly performed using frozen sectioning at the time of biopsy. The percent steatosis in a donor liver biopsy correlates with transplant outcome, however there is significant inter- and intra-observer variability in quantifying steatosis, compounded by frozen section artifact. We hypothesized that a deep learning model could identify and quantify steatosis in donor liver biopsies.

Methods: We developed a deep learning convolutional neural network that generates a steatosis probability map from an input whole slide image (WSI) of a hematoxylin and eosin-stained frozen section, and subsequently calculates the percent steatosis. Ninety-six WSI of frozen donor liver sections from our transplant pathology service were annotated for steatosis and used to train (n = 30 WSI) and test (n = 66 WSI) the deep learning model.

Findings: The model had good correlation and agreement with the annotation in both the training set (r of 0.88, intraclass correlation coefficient [ICC] of 0.88) and novel input test sets (r = 0.85 and ICC=0.85). These measurements were superior to the estimates of the on-service pathologist at the time of initial evaluation (r = 0.52 and ICC=0.52 for the training set, and r = 0.74 and ICC=0.72 for the test set).

Interpretation: Use of this deep learning algorithm could be incorporated into routine pathology workflows for fast, accurate, and reproducible donor liver evaluation.

Funding: Mid-America Transplant Society.
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http://dx.doi.org/10.1016/j.ebiom.2020.103029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522765PMC
October 2020

Dipeptidyl peptidase-4 inhibitors and risk of venous thromboembolism: data mining of FDA adverse event reporting system.

Int J Clin Pharm 2020 Oct 20;42(5):1364-1368. Epub 2020 Sep 20.

Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.

Background: A recent study is raising concerns that dipeptidyl peptidase 4 inhibitors are associated with increased risk of venous thromboembolism.

Objective: We aimed to assess the association between dipeptidyl peptidase-4 inhibitors and venous thromboembolism using the US Food and Drug Administration Adverse Event Reporting System database.

Methods: We searched the venous thromboembolism cases related to dipeptidyl peptidase-4 inhibitors from 2004 first quarter to 2018 first quarter. We compared dipeptidyl peptidase-4 inhibitors versus three groups: (1) all other glucose-lowering drugs excluding insulins; (2) sulfonylureas and sodium-glucose-cotransporter-2 inhibitors; (3) sodium-glucose-cotransporter-2 inhibitors. In each comparison, we calculated proportional rate ratios and 95% confidence ratios by SAS 9.4.

Results: We obtained 873 dipeptidyl peptidase-4 inhibitors-associated venous thromboembolism events. Compared to all other glucose lowering-drugs excluding insulins, the proportional reporting ratio for overall venous thromboembolism, deep vein thrombosis, pulmonary embolism were 0.92 (0.86, 0.99), 0.91 (0.82,1.01), and 0.82 (0.74,0.90), respectively; the proportional reporting ratio for portal vein thrombosis, splenic vein thrombosis, mesenteric vein thrombosis were 3.94 (2.96, 5.25), 10.80 (6.14, 18.99), and 4.98 (2.76,8.96), respectively.

Conclusion: Our analysis found no association between dipeptidyl peptidase-4 inhibitors and venous thromboembolism risk, while moderate to strong signals of portal vein thrombosis, splenic vein thrombosis, mesenteric vein thrombosis risks were observed.
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http://dx.doi.org/10.1007/s11096-020-01037-wDOI Listing
October 2020

Robust metal ion-chelated polymer interfacial layer for ultraflexible non-fullerene organic solar cells.

Nat Commun 2020 Sep 9;11(1):4508. Epub 2020 Sep 9.

Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, 430074, China.

Achieving high power conversion efficiency and good mechanical robustness is still challenging for the ultraflexible organic solar cells. Interlayers simultaneously having good mechanical robustness and good chemical compatibility with the active layer are highly desirable. In this work, we present an interlayer of Zn-chelated polyethylenimine (denoted as PEI-Zn), which can endure a maximum bending strain over twice as high as that of ZnO and is chemically compatible with the recently emerging efficient nonfullerene active layers. On 1.3 μm polyethylene naphthalate substrates, ultraflexible nonfullerene solar cells with the PEI-Zn interlayer display a power conversion efficiency of 12.3% on PEDOT:PSS electrodes and 15.0% on AgNWs electrodes. Furthermore, the ultraflexible cells show nearly unchanged power conversion efficiency during 100 continuous compression-flat deformation cycles with a compression ratio of 45%. At the end, the ultraflexible cell is demonstrated to be attached onto the finger joint and displays reversible current output during the finger bending-spreading.
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http://dx.doi.org/10.1038/s41467-020-18373-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481191PMC
September 2020

A practical method of using the anatomical space of the vesicouterine ligament for laparoscopic radical hysterectomy: a retrospective cohort study.

J Int Med Res 2020 Jun;48(6):300060520926857

Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Objective: To investigate the practicality of a new method using anatomical spaces for performing standard laparoscopic radical hysterectomy (LRH) without ureteral injury in patients with cervical cancer.

Methods: Clinicopathological characteristics and perioperative complications were retrospectively analysed in 440 patients with stages IB1 to IIB cervical cancer. The patients were assigned to two of the following groups: LRH by our method of using anatomical landmarks (anatomical space group, n = 217) and the traditional method (traditional group, n = 223).

Results: The mean operative duration and time of vesicouterine ligament (VUL) dissection were significantly shorter (173.87 ± 30.39 vs. 210.83 ± 44.55 minutes; 32.75 ± 7.23 vs. 43.48 ± 11.22 minutes), and blood loss was less in the anatomical space group compared with the traditional group. The rate of the intraoperative complication of ureteral injury was also significantly lower in the anatomical space group compared with the traditional group (0 vs. 5).

Conclusions: LRH by the anatomical method, using the axillary space and other potential spaces as anatomical landmarks, results in less blood loss and reduced ureteral injury compared with the traditional method. This method is safe and practical for separating the ureter from the VUL in patients with cervical cancer.
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http://dx.doi.org/10.1177/0300060520926857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328497PMC
June 2020

Visualization of Crystallographic Orientation and Twist Angles in Two-Dimensional Crystals with an Optical Microscope.

Nano Lett 2020 Aug 9;20(8):6059-6066. Epub 2020 Jul 9.

Beijing National Laboratory for Molecular Sciences, Key Laboratory of Organic Solids, Institute of Chemistry, CAS, Beijing 100190, China.

Recently, twisted two-dimensional (2D) bilayers have attracted intense interest due to the emergence of exotic physics in moiré superlattices arising from strong interactions between electrons in the two misaligned lattices. Accurate determination and control of crystallographic orientation is vital to construct twisted 2D bilayers. Here, we demonstrate a very simple method to visualize crystallographic orientation in various 2D crystals by directly imaging -tritriacontane crystallites epitaxially grown on 2D crystals using an ordinary optical microscope. The specific orientation of the molecular assembly allows the lattice orientation of the underlying 2D crystals to be determined with a high precision using an optical microscope. When tested on a 2D bilayer comprising staggered stacked MoS crystals, the twist angle can also be determined accurately. Our findings offer a nondestructive method for determining the lattice structure of 2D crystals and their bilayers and can also be a metrology tool for establishing large-area surface crystalline order.
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http://dx.doi.org/10.1021/acs.nanolett.0c02098DOI Listing
August 2020

MiR-26 regulates ddx3x expression in medaka (Oryzias latipes) gonads.

Comp Biochem Physiol B Biochem Mol Biol 2020 Aug - Sep;246-247:110456. Epub 2020 May 15.

International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China. Electronic address:

MicroRNAs (miRNAs) participate in the reproductive process by regulating the expression of target genes, however, there are few studies on the regulation of mRNA target by miRNAs in medaka (Oryzias latipes). Our previous data showed that miR-202-5p has a sex-biased expression and miR-26 is abundantly expressed in both ovary and testis of medaka. In this study, DEAD-box helicase 3, X-linked (ddx3x) was proposed to be a putative target of miR-26 and miR-202-5p through bioinformatic analysis. Here, medaka ddx3x (Olddx3x) was cloned and sequence alignment analysis indicated that Olddx3x is highly conserved and has more than 90% identity with some other teleosts. Reverse transcription polymerase chain reaction (RT-PCR) showed that Olddx3x was highly expressed in testis and ovary. Meanwhile, chromogenic in situ hybridization manifested that Olddx3x was abundantly expressed in the early oocytes in the ovary and in various stages of spermatogenesis, especially the obvious signal in the testis of spermatocytes and sperm. Dual-luciferase reporter assay and the injection of miR-26 agomir and antagomir demonstrated that the expression of Olddx3x was regulated by miR-26 but not miR-202-5p. The overall results revealed that miR-26 may perform a vital role in medaka reproduction development by regulating the expression of ddx3x.
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http://dx.doi.org/10.1016/j.cbpb.2020.110456DOI Listing
January 2021

Progress in human liver organoids.

Authors:
Lulu Sun Lijian Hui

J Mol Cell Biol 2020 08;12(8):607-617

State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.

Understanding the development, regeneration, and disorders of the liver is the major goal in liver biology. Current mechanistic knowledge of human livers has been largely derived from mouse models and cell lines, which fall short in recapitulating the features of human liver cells or the structures and functions of human livers. Organoids as an in vitro system hold the promise to generate organ-like tissues in a dish. Recent advances in human liver organoids also facilitate the understanding of the biology and diseases in this complex organ. Here we review the progress in human liver organoids, mainly focusing on the methods to generate liver organoids, their applications, and possible future directions.
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http://dx.doi.org/10.1093/jmcb/mjaa013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683012PMC
August 2020

Development and validation of a predictive model for end-stage renal disease risk in patients with diabetic nephropathy confirmed by renal biopsy.

PeerJ 2020 11;8:e8499. Epub 2020 Feb 11.

Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan province, China.

This study was performed to develop and validate a predictive model for the risk of end-stage renal disease (ESRD) inpatients with diabetic nephropathy (DN) confirmed by renal biopsy. We conducted a retrospective study with 968 patients with T2DM who underwentrenal biopsy for the pathological confirmation of DNat the First Affiliated Hospital of Zhengzhou University from February 2012 to January 2015; the patients were followed until December 2018. The outcome was defined as a fatal or nonfatal ESRD event (peritoneal dialysis or hemodialysis for ESRD, renal transplantation, or death due to chronic renal failure or ESRD). The dataset was randomly split into development (75%) and validation (25%) cohorts. We used stepwise multivariablelogistic regression to identify baseline predictors for model development. The model's performance in the two cohorts, including discrimination and calibration, was evaluated by the C-statistic and the value of the Hosmer-Lemeshow test. During the 3-year follow-up period, there were 225 outcome events (47.1%) during follow-up. Outcomes occurred in 187 patients (52.2%) in the derivation cohort and 38 patients (31.7%) in the validation cohort. The variables selected in the final multivariable logistic regression after backward selection were pathological grade, Log Urinary Albumin-to-creatinine ratio (Log ACR), cystatin C, estimated glomerular filtration rate (eGFR) and B-type natriuretic peptide (BNP). 4 prediction models were created in a derivation cohort of 478 patients: a clinical model that included cystatin C, eGFR, BNP, Log ACR; a clinical-pathological model and a clinical-medication model, respectively, also contained pathological grade and renin-angiotensin system blocker (RASB) use; and a full model that also contained the pathological grade, RASB use and age. Compared with the clinical model, the clinical-pathological model and the full model had better C statistics (0.865 and 0.866, respectively, vs. 0.864) in the derivation cohort and better C statistics (0.876 and 0.875, respectively, vs. 0.870) in the validation cohort. Among the four models, the clinical-pathological model had the lowest AIC of 332.53 and the best value of 0.909 of the Hosmer-Lemeshow test. We constructed a nomogram which was a simple calculator to predict the risk ratio of progression to ESRD for patients with DN within 3 years. The clinical-pathological model using routinely available clinical measurements was shown to be accurate and validated method for predicting disease progression in patients with DN. The risk model can be used in clinical practice to improve the quality of risk management and early intervention.
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http://dx.doi.org/10.7717/peerj.8499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020820PMC
February 2020

Flexible All-Solution-Processed Organic Solar Cells with High-Performance Nonfullerene Active Layers.

Adv Mater 2020 Apr 24;32(14):e1907840. Epub 2020 Feb 24.

Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, 430074, China.

All-solution-processed organic solar cells (from the bottom substrate to the top electrode) are highly desirable for low-cost and ubiquitous applications. However, it is still challenging to fabricate efficient all-solution-processed organic solar cells with a high-performance nonfullerene (NF) active layer. Issues of charge extraction and wetting are persistent at the interface between the nonfullerene active layer and the printable top electrode (PEDOT:PSS). In this work, efficient all-solution-processed NF organic solar cells (from the bottom substrate to the top electrode) are reported via the adoption of a layer of hydrogen molybdenum bronze (H MoO ) between the active layer and the PEDOT:PSS. The dual functions of H MoO include: 1) its deep Fermi level of -5.44 eV can effectively extract holes from the active layer; and 2) the wetting issues of the PEDOT:PSS on the hydrophobic surface of the NF active layer can be solved. Importantly, fine control of the H MoO composition during the synthesis is critical in obtaining processing orthogonality between H MoO and the PEDOT:PSS. Flexible all-solution-processed NF organic solar cells with power conversion efficiencies of 11.9% and 10.3% are obtained for solar cells with an area of 0.04 and 1 cm , respectively.
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http://dx.doi.org/10.1002/adma.201907840DOI Listing
April 2020

Exploring the Chemical Interaction between Diiodooctane and PEDOT-PSS Electrode for Metal Electrode-Free Nonfullerene Organic Solar Cells.

ACS Appl Mater Interfaces 2020 Jan 9;12(3):3800-3805. Epub 2020 Jan 9.

Wuhan National Laboratory for Optoelectronics , Huazhong University of Science and Technology , Wuhan 430074 , China.

Metal electrode-free organic solar cells with a printable top electrode are attractive in realizing the low cost of photovoltaics. Interaction between the printable electrode and the active layer is critical to the device performance. In this work, we report the chemical interaction between the printable polymer electrode poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and the typically used additive of 1,8-dioodooctane (DIO) in the active layer. DIO can be converted to hydrogen iodide (HI) under the acidic condition of PEDOT:PSS, and the HI chemically reduces the PEDOT:PSS with the appearance of an absorbance band at 800-1100 nm. The generation of I is verified by the color change of starch. The reaction results in a decrease of its work function that hinders efficient hole collection. A strategy is proposed to circumvent the detrimental interaction by inserting an ultrathin (15 nm) active layer without DIO between the initial active layer and the PEDOT:PSS electrode. A power conversion efficiency of 10.1% is achieved for the metal electrode-free nonfullerene organic solar cells.
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http://dx.doi.org/10.1021/acsami.9b17321DOI Listing
January 2020

Clinical Decision Support for Ovarian Carcinoma Subtype Classification: A Pilot Observer Study With Pathology Trainees.

Arch Pathol Lab Med 2019 Dec 9. Epub 2019 Dec 9.

From the Division of Imaging, Diagnostics, and Software Reliability, Office of Engineering and Science Laboratories (Dr Gavrielides and Ms Miller), and the Office of In Vitro Diagnostics and Radiological Health, Division of Molecular Genetics and Pathology (Dr Seidman), Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland; the Department of Bioengineering, University of Maryland, College Park (Ms Miller); and the Departments of Pathology and Immunology (Drs Hagemann, Abdelal, Alipour, Chen, Salari, Sun, and Zhou) and Obstetrics and Gynecology (Dr Hagemann), Washington University School of Medicine, St Louis, Missouri. Ms Miller is currently with PCTEST Engineering Laboratory, Columbia, Maryland.

Context.—: Clinical decision support (CDS) systems could assist less experienced pathologists with certain diagnostic tasks for which subspecialty training or extensive experience is typically needed. The effect of decision support on pathologist performance for such diagnostic tasks has not been examined.

Objective.—: To examine the impact of a CDS tool for the classification of ovarian carcinoma subtypes by pathology trainees in a pilot observer study using digital pathology.

Design.—: Histologic review on 90 whole slide images from 75 ovarian cancer patients was conducted by 6 pathology residents using: (1) unaided review of whole slide images, and (2) aided review, where in addition to whole slide images observers used a CDS tool that provided information about the presence of 8 histologic features important for subtype classification that were identified previously by an expert in gynecologic pathology. The reference standard of ovarian subtype consisted of majority consensus from a panel of 3 gynecologic pathology experts.

Results.—: Aided review improved pairwise concordance with the reference standard for 5 of 6 observers, by 3.3% to 17.8% (for 2 observers, increase was statistically significant) and mean interobserver agreement by 9.2% (not statistically significant). Observers benefited the most when the CDS tool prompted them to look for missed histologic features that were definitive for a certain subtype. Observer performance varied widely across cases with unanimous and nonunanimous reference classification, supporting the need for balancing data sets in terms of case difficulty.

Conclusions.—: Findings showed the potential of CDS systems to close the knowledge gap between pathologists for complex diagnostic tasks.
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http://dx.doi.org/10.5858/arpa.2019-0390-OADOI Listing
December 2019

Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism.

Cell Metab 2019 11 24;30(5):937-951.e5. Epub 2019 Oct 24.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, PRC; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, PRC. Electronic address:

Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis.
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http://dx.doi.org/10.1016/j.cmet.2019.09.016DOI Listing
November 2019

Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway.

EBioMedicine 2019 Nov 19;49:291-304. Epub 2019 Oct 19.

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Electronic address:

Background: Aortic dissection is a severe inflammatory vascular disease with high mortality and limited therapeutic options. The hallmarks of aortic dissection comprise aortic inflammatory cell infiltration and elastic fiber disruption, highlighting the involvement of macrophage. Here a role for macrophage hypoxia-inducible factor 1-alpha (HIF-1α) in aortic dissection was uncovered.

Methods: Immunochemistry, immunofluorescence, western blot and qPCR were performed to test the change of macrophage HIF-1α in two kinds of aortic dissection models and human tissues. Metabolomics and Seahorse extracellular flux analysis were used to detect the metabolic state of macrophages involved in the development of aortic dissection. Chromatin Immunoprecipitation (ChIP), enzyme-linked immunosorbent assay (ELISA) and cytometric bead array (CBA) were employed for mechanistic studies.

Findings: Macrophages involved underwent distinct metabolic reprogramming, especially fumarate accumulation, thus inducing HIF-1α activation in the development of aortic dissection in human and mouse models. Mechanistic studies revealed that macrophage HIF-1α activation triggered vascular inflammation, extracellular matrix degradation and elastic plate breakage through increased a disintegrin and metallopeptidase domain 17 (ADAM17), identified as a novel target gene of HIF-1α. A HIF-1α specific inhibitor acriflavine elicited protective effects on aortic dissection dependent on macrophage HIF-1α.

Interpretation: This study reveals that macrophage metabolic reprogramming activates HIF-1α and subsequently promotes aortic dissection progression, suggesting that macrophage HIF-1α inhibition might be a potential therapeutic target for treating aortic dissection.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945268PMC
November 2019