Publications by authors named "Yan Nie"

113 Publications

Generation of 2.5D lung bud organoid from human induced pluripotent stem cell.

Clin Hemorheol Microcirc 2021 Sep 3. Epub 2021 Sep 3.

Institute of Active Polymers and Berlin-Brandenburg Centre for Regenerative Therapies, Helmholtz-Zentrum Hereon, Teltow, Germany.

Human induced pluripotent stem cells (hiPSCs) are a promising cell source to generate the patient-specific lung organoid given their superior differentiation potential. However, the current 3D cell culture approach is tedious and time-consuming with a low success rate and high batch-to-batch variability. Here, we explored the establishment of lung bud organoids by systematically adjusting the initial confluence levels and homogeneity of cell distribution. The efficiency of single cell seeding and clump seeding was compared. Instead of the traditional 3D culture, we established a 2.5D organoid culture to enable the direct monitoring of the internal structure via microscopy. It was found that the cell confluence and distribution prior to induction were two key parameters, which strongly affected hiPSC differentiation trajectories. Lung bud organoids with positive expression of NKX 2.1, in a single-cell seeding group with homogeneously distributed hiPSCs at 70%confluence (SC_70%_hom) or a clump seeding group with heterogeneously distributed cells at 90%confluence (CL_90%_het), can be observed as early as 9 days post induction. These results suggest that a successful lung bud organoid formation with single-cell seeding of hiPSCs requires a moderate confluence and homogeneous distribution of cells, while high confluence would be a prominent factor to promote the lung organoid formation when seeding hiPSCs as clumps. 2.5D organoids generated with defined culture conditions could become a simple, efficient, and valuable tool facilitating drug screening, disease modeling and personalized medicine.
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http://dx.doi.org/10.3233/CH-219111DOI Listing
September 2021

Localized quenching sites in MAPbI investigated by fluorescence and photothermal microscopy.

Rev Sci Instrum 2021 Aug;92(8):083701

Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210023, China.

In this work, we developed a fluorescence and photothermal microscope with extremely large scanning range and high spatial resolution. We demonstrated the capability of this instrument by simultaneously measuring the photoluminescence and photothermal signals of the CHNHPbI (MAPbI) film. After scanning the MAPbI film on the scale of centimeters, we can obtain information of both emissive and nonemissive processes with a resolution of 200 nm at any location of the large area. We can clearly see the localized photothermal signal while the photoluminescence signal is uniform. These results directly prove that the emissive recombination happens all over the materials, but the nonemissive recombination happens only at certain localized quenching sites. The fluorescence and photothermal microscope with both large scanning range and high spatial resolution can provide information of all the relaxation channels of the excitons, showing potential applications for investigation of photophysical mechanisms in photoelectric materials.
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http://dx.doi.org/10.1063/5.0048239DOI Listing
August 2021

5-Aminosalicylic Acid Prevents Disease Behavior Progression and Intestinal Resection in Colonic and Ileocolonic Crohn's Disease Patients: A Retrospective Study.

Can J Gastroenterol Hepatol 2021 9;2021:1412663. Epub 2021 Aug 9.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China.

Background And Aims: The efficacy of 5-aminosalicylic acid (5-ASA) in the long-term outcome of Crohn's disease (CD) patients was uncertain. This study aimed to evaluate the efficacy of the 5-ASA in preventing disease behavior progression and intestinal resection in CD patients.

Methods: CD patients were prospectively enrolled from January 2008 to September 2019 in Xijing Hospital. Disease behavior progression was defined as the development of stricturing (B2) or penetrating disease (B3) in patients with nonstricturing/nonpenetrating disease (B1) at diagnosis. Cox regression analyses were used to investigate the associations between disease location progression, disease behavior progression, and intestinal resection and multiple covariates.

Results: In total, 122 CD patients were followed up for 4.3 years. At the time of diagnosis, disease location was ileal in 19.7% (24/122), colonic in 41.0% (50/122), and ileocolonic in 39.3% (48/122). A total of 87 (71.3%) patients had B1 at diagnosis. The disease behavior progression and intestinal resection rates were 42.5% (37/87) and 29.5% (36/122). The use of 5-ASA reduced the risk of disease behavior progression (HR 0.30, 95% CI 0.14-0.61,  = 0.001) and intestinal resection (HR 0.33, 95% CI 0.17-0.90,  = 0.027) in colonic and ileocolonic CD patients. Patients who presented with ileal disease at diagnosis did not have the same protective effects when taking 5-ASA ( > 0.05).

Conclusions: The use of 5-ASA could improve the long-term outcome of CD patients with colon involvement. The result emphasized the importance of early use of 5-ASA in the daily management of colonic involved CD.
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http://dx.doi.org/10.1155/2021/1412663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371663PMC
August 2021

Neoadjuvant everolimus plus letrozole versus fluorouracil, epirubicin and cyclophosphamide for ER-positive, HER2-negative breast cancer: a randomized pilot trial.

BMC Cancer 2021 Jul 27;21(1):862. Epub 2021 Jul 27.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yanjiang West Road 107#, Guangzhou, China.

Background: Here we evaluated the feasibility, efficacy, tolerability, and treatment-mediated immune modulation of neoadjuvant everolimus plus letrozole versus chemotherapy in treating postmenopausal patients with ER-positive, HER2-negative breast cancer.

Methods: Postmenopausal women with ER-positive, HER2-negative breast cancer who had a primary tumor > 2 cm or positive axillary lymph node(s) proofed by biopsy were randomly (1,1) enrolled to receive neoadjuvant everolimus plus letrozole for 18 weeks or fluorouracil, epirubicin plus cyclophosphamide (FEC) for 6 cycles before surgery. Primary outcome was feasibility of the trial. Secondary outcome included ultrasound response rate, pathological complete response rate, breast-conserving surgery rate, toxicities, treatment-mediated immune modulation and biomarkers.

Results: Forty patients were randomized. Completion rate was 90.0% in the neoadjuvant endocrine therapy (NET) arm but 70.0% in the neoadjuvant chemotherapy (NAC) arm. The ultrasound response rate was 65.0% in NET arm and 40.0% in FEC arm, respectively. In terms of the adverse events, clearly favored NET arm. Everolimus plus letrozole increased the ratio of peripheral Tregs to CD4 T cells and tumor PD-L1 expression, and decreased Ki67 index and tumor-infiltrating Tregs, and patients with a greater increase of tumor-specific CTLs showed more sensitive to NET.

Conclusion: This pilot trial showed that neoadjuvant everolimus plus letrozole might achieve a favorable ultrasound response rate with low toxicities in treating postmenopausal ER-positive, HER2-negative breast cancer patients. Everolimus plus letrozole might have positive antitumoral immunity effects. Further large randomized controlled trials are needed to confirm our findings.

Trail Registration: A Trial of Neoadjuvant Everolimus Plus Letrozole Versus FEC in Women With ER-positive, HER2-negative Breast Cancer, registered on 07/04/2016 and first posted on 18/04/2016, NCT02742051 .
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http://dx.doi.org/10.1186/s12885-021-08612-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317384PMC
July 2021

Periodic thermomechanical modulation of toll-like receptor expression and distribution in mesenchymal stromal cells.

MRS Commun 2021 Jul 8:1-7. Epub 2021 Jul 8.

Institute of Active Polymers and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Hereon, 14513 Teltow, Germany.

Abstract: Toll-like receptor (TLR) can trigger an immune response against virus including SARS-CoV-2. TLR expression/distribution is varying in mesenchymal stromal cells (MSCs) depending on their culture environments. Here, to explore the effect of periodic thermomechanical cues on TLRs, thermally controlled shape-memory polymer sheets with programmable actuation capacity were created. The proportion of MSCs expressing SARS-CoV-2-associated TLRs was increased upon stimulation. The TLR4/7 colocalization was promoted and retained in the endoplasmic reticula. The TLR redistribution was driven by myosin-mediated F-actin assembly. These results highlight the potential of boosting the immunity for combating COVID-19 via thermomechanical preconditioning of MSCs.

Graphic Abstract: Periodic thermal and synchronous mechanical stimuli provided by polymer sheet actuators selectively promoted the expression of SARS-CoV-2-associated TLRs 4 and 7 in adipose-derived MSCs and recruited TLR4 to Endoplasmic reticulum region where TLR7 was located via controlling myosin-mediated F-actin cytoskeleton assembly.
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http://dx.doi.org/10.1557/s43579-021-00049-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265727PMC
July 2021

Enhanced electrochemical properties of Ni-rich layered cathode materials via Mg and Tico-doping for lithium-ion batteries.

J Colloid Interface Sci 2021 Nov 29;601:853-862. Epub 2021 May 29.

College of Chemistry and Environmental Engineering, Yangtze University, Jingzhou 434023, PR China. Electronic address:

To optimize the electrochemical performance of Ni-rich cathode materials, the 0.005 mol of Mg and 0.005 mol of Tico-doping LiNiCoMnO composite powders, labeled as NCM-11, are successfully prepared by being calcinated at 750 °C for 15 h following by an appropriate post-treatment, which are confirmed by XRD, EDS and XPS. The results suggest that NCM-11 presents a well-ordered layered structure with a low Li/Ni mixing degree of 1.46% and Mg and Ti ions are uniformly distributed across the lattice. The cell assembled with NCM-11 can deliver an initial discharge specific capacity of 194.2 mAh g and retain a discharge specific capacity of 163.0 mAh g after 100cycles at 2.0C at 25 °C. Furthermore, it still maintains a discharge specific capacity of 166.7 mAh g after 100cycles at 2.0C at 60 °C. More importantly, it also exhibits a higher discharge specific capacity of about 150.7 mAh g even at 5.0C. Those superior electrochemical performance can be mainly ascribed to the synergistic effect of Mg and Tico-doping, in which Mg ions can occupy the Li layer to act as pillar ions and Ti ions can occupy the transition metal ions layer to enlarge the interplane spacing. Thus, the heterovalent cations co-doping strategy can be considered as a simple and practical method to improve the electrochemical performance of Ni-rich layered cathode materials for lithium-ion batteries.
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http://dx.doi.org/10.1016/j.jcis.2021.05.167DOI Listing
November 2021

A Study on Internal Defects of PREP Metallic Powders by Using X-ray Computed Tomography.

Materials (Basel) 2021 Mar 3;14(5). Epub 2021 Mar 3.

State Key Lab for Powder Metallurgy, Central South University, Changsha 410083, China.

In this study, the distribution, proportion and characteristics of internal defects in three kinds of powders of Ti-6Al-4V, 316-steel and Co-29Cr-6Mo alloys, produced by the plasma rotating electrode process (PREP) at various rotation speeds, are characterized by using both scanning electron microscopy (SEM) and synchrotron X-ray computed tomography (CT). The results show that in the powder of a given alloy, internal pores are formed more easily in coarse particles than in fine powder during PREP. The proportion of powder with pores can be reduced by appropriately increasing the rotation speed. In addition, the composition of an alloy has a great influence on the defect formation.
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http://dx.doi.org/10.3390/ma14051177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958947PMC
March 2021

Cerium oxide nanoparticle-loaded polyvinyl alcohol nanogels delivery for wound healing care systems on surgery.

Drug Deliv 2021 Dec;28(1):390-399

Emergency Department, Dongying People's Hospital, Dongying, China.

This study was designed to establish the composition of wound bandages based on Cerium nanoparticle (CeNP)-loaded polyvinyl alcohol (PVA) nanogels. The CeNP nanogel (Ce-nGel) was fabricated by the fructose-mediated reduction of Cerium oxide solutions within the PVA matrix. The influences of different experimental limitations on PVA nanogel formations were examined. The nanogel particle sizes were evaluated by transmission electron microscopy and determined to range from ∼10 to 50 nm. Additionally, glycerol was added to the Ce-nGels, and the resulting compositions (Ce-nGel-Glu) were coated on cotton fabrics to generate the wound bandaging composite. The cumulative drug release profile of the Cerium from the bandage was found to be ∼38% of the total loading after two days. Additionally, antibacterial efficacy was developed for Gam positive and negative microorganisms. Moreover, we examined healing of skin wounds formed in mouse models over 24 days. In contrast to the untreated wounds, rapid healing was perceived in the Ce-nGel-Glu-treated wound with less damage. These findings indicate that Ce-nGel-Glu-based bandaging materials could be a potential candidate for wound healing applications in the future.
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http://dx.doi.org/10.1080/10717544.2020.1858998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894430PMC
December 2021

Biofunction of Polydopamine Coating in Stem Cell Culture.

ACS Appl Mater Interfaces 2021 Mar 17;13(9):10748-10759. Epub 2021 Feb 17.

Institute of Active Polymers and Berlin-Brandenburg Centre for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, 14513 Teltow, Germany.

High levels of reactive oxygen species (ROS) during stem cell expansion often lead to replicative senescence. Here, a polydopamine (PDA)-coated substrate was used to scavenge extracellular ROS for mesenchymal stem cell (MSC) expansion. The PDA-coated substrate could reduce the oxidative stress and mitochondrial damage in replicative senescent MSCs. The expression of senescence-associated β-galactosidase of MSCs from three human donors (both bone marrow- and adipose tissue-derived) was suppressed on PDA. The MSCs on the PDA-coated substrate showed a lower level of interleukin 6 (IL-6), one of the senescence-associated inflammatory components. Cellular senescence-specific genes, such as p53 and p21, were downregulated on the PDA-coated substrate, while the stemness-related gene, OCT4, was upregulated. The PDA-coated substrate strongly promoted the proliferation rate of MSCs, while the stem cell character and differentiation potential were retained. Large-scale expansion of stem cells would greatly benefit from the PDA-coated substrate.
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http://dx.doi.org/10.1021/acsami.0c22565DOI Listing
March 2021

Development of a Broadly Applicable Cas12a-Linked Beam Unlocking Reaction for Sensitive and Specific Detection of Respiratory Pathogens Including SARS-CoV-2.

ACS Chem Biol 2021 03 15;16(3):491-500. Epub 2021 Feb 15.

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.

The outbreak of novel coronavirus SARS-CoV-2 has caused a worldwide threat to public health. COVID-19 patients with SARS-CoV-2 infection can develop clinical symptoms that are often confused with the infections of other respiratory pathogens. Sensitive and specific detection of SARS-CoV-2 with the ability to discriminate from other viruses is urgently needed for COVID-19 diagnosis. Herein, we streamlined a highly efficient CRISPR-Cas12a-based nucleic acid detection platform, termed s12a-nked eam nlocking eactio (CALIBURN). We show that CALIBURN could detect SARS-CoV-2 and other coronaviruses and influenza viruses with little cross-reactivity. Importantly, CALIBURN allowed accurate diagnosis of clinical samples with extremely low viral loads, which is a major obstacle for the clinical applications of existing CRISPR diagnostic platforms. When tested on the specimens from SARS-CoV-2-positive and negative donors, CALIBURN exhibited 73.0% positive and 19.0% presumptive positive rates and 100% specificity. Moreover, unlike existing CRISPR detection methods that were mainly restricted to respiratory specimens, CALIBURN displayed consistent performance across both respiratory and nonrespiratory specimens, suggesting its broad specimen compatibility. Finally, using a mouse model of SARS-CoV-2 infection, we demonstrated that CALIBURN allowed detection of coexisting pathogens without cross-reactivity from a single tissue specimen. Our results suggest that CALIBURN can serve as a versatile platform for the diagnosis of COVID-19 and other respiratory infectious diseases.
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http://dx.doi.org/10.1021/acschembio.0c00840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901234PMC
March 2021

Mediator structure and conformation change.

Mol Cell 2021 04 10;81(8):1781-1788.e4. Epub 2021 Feb 10.

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210 Shanghai, China; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Mediator is a universal adaptor for transcription control. It serves as an interface between gene-specific activator or repressor proteins and the general RNA polymerase II (pol II) transcription machinery. Previous structural studies revealed a relatively small part of Mediator and none of the gene activator-binding regions. We have determined the cryo-EM structure of the Mediator at near-atomic resolution. The structure reveals almost all amino acid residues in ordered regions, including the major targets of activator proteins, the Tail module, and the Med1 subunit of the Middle module. Comparison of Mediator structures with and without pol II reveals conformational changes that propagate across the entire Mediator, from Head to Tail, coupling activator- and pol II-interacting regions.
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http://dx.doi.org/10.1016/j.molcel.2021.01.022DOI Listing
April 2021

Effect of surface deformation on biocompatibility of biomedical alloys.

Mater Sci Eng C Mater Biol Appl 2021 Feb 17;119:111636. Epub 2020 Oct 17.

State Key Lab for Powder Metallurgy, Central South University, Changsha 410083, China. Electronic address:

In this study, biocompatibility of Co-29Cr-5Mo (CCM), 316L steel (316L) and Ti-6Al-4V (TC4) alloys after surface plastic deformation under the condition comparable to the human ankle activities were investigated in details. Biocompatibility of all alloys decreases after surface deformation, while it is most significantly observed in CCM alloy. The different responses of biocompatibility are related to the corresponding microstructure evolution during surface deformation: martensitic phase transformation, dislocation slipping and mechanical twinning in CCM alloy result in the extremely localized microstructure, giving rise to the obviously decreased corrosion resistance or biocompatibility; quite homogenous microstructure after surface deformation leads to the slightly decreased corrosion resistance or biocompatibility in both 316L and TC4 alloys, since the surface deformation is dominated by slipping in 316L and by both slipping and a few mechanical twinning in TC4.
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http://dx.doi.org/10.1016/j.msec.2020.111636DOI Listing
February 2021

Spheroid formation of human keratinocyte: Balancing between cell-substrate and cell-cell interaction.

Clin Hemorheol Microcirc 2020 ;76(2):329-340

Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany.

Background: The formation of spheroids is tightly regulated by intrinsic cell-cell and cell-substrate interactions.

Objective: The chitosan (CS)-coating was applied to investigate the driven force directed the spheroid formation.

Methods: The effects of CS on cell functions were studied. Atomic force microscopy was employed to measure the cell- biomaterial interplay at single cell level.

Results: HaCaT cells shifted from their flattened sheet to a compact 3D spheroidal morphology when increasing CS-coating concentration. The proliferative capacity of HaCaT was preserved in the spheroid. The expression and activation of integrin β1 (ITGB1) were enhanced on CS modified surfaces, while the active to total ratio of ITGB1 was decreased. The adhesive force of a single HaCaT cell to the tissue culture plate (TCP) was 4.84±0.72 nN. It decreased on CS-coated surfaces as CS concentration increased, from 2.16±0.26 nN to 0.96±0.17 nN. The adhesive force between the single HaCaT cell to its neighbor cell increased as CS concentration increased, from 1.15±0.09 nN to 2.60±0.51 nN.

Conclusions: Conclusively, the decreased cell- substrate adhesion was the main driven force in the spheroid formation. This finding might serve as a design criterion for biomaterials facilitating the formation of epithelial spheroids.
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http://dx.doi.org/10.3233/CH-209217DOI Listing
December 2020

The effects of oscillatory temperature on HaCaT keratinocyte behaviors.

Clin Hemorheol Microcirc 2020 ;76(2):317-327

Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany.

Background: Keratinocytes are exposed to a thermal gradient throughout epidermal layers in human skin depending on environmental temperatures.

Objective: Here, the effect of cyclic temperature changes (ΔT) on HaCaT cell behaviors was explored.

Methods: HaCaT cells were cultured at constant temperature (37 °C or 25 °C) or under ΔT conditions. The morphology, mechanics, cell cycle progression, proliferation, and lipid synthesis of HaCaT cells were determined.

Results: ΔT conditions led to the inhomogeneous arrangement of the cytoskeleton in HaCaT cells, which resulted in enlarged size, rounder shape, and increased stiffness. Accumulation in the G2/M phase in the cell cycle, a decreased proliferation rate, and a delayed lipogenesis were detected in HaCaT cells cultured under ΔT conditions.

Conclusions: ΔT conditions resulted in the re-arrangement of the cytoskeleton in HaCaT cells, which showed similarity to the temperature-induced disassemble and re-assemble of cytoskeletons in keratinocyte in vivo. The altered cytoskeleton arrangement resulted in the cell enlargement and stiffening, which reflected the changes in cellular functions. The application of oscillatory temperature in the in vitro culture of keratinocytes provides a way to gain more insights into the role of skin in response to environmental stimuli and maintaining its homeostasis in vivo.
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http://dx.doi.org/10.3233/CH-209208DOI Listing
December 2020

GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer.

Nat Commun 2020 08 21;11(1):4205. Epub 2020 Aug 21.

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data suggests that the functionality of the E2F pathway may reflect to some extent OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) strongly correlate with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.
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http://dx.doi.org/10.1038/s41467-020-18020-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442809PMC
August 2020

Protective effect of hypothermia and vitamin E on spermatogenic function after reduction of testicular torsion in rats.

Exp Ther Med 2020 Aug 27;20(2):796-801. Epub 2020 May 27.

Department of Dermatology, Dongying People's Hospital, Dongying, Shandong 257091, P.R. China.

This study was designed to investigate the protective effect of hypothermia and vitamin E on spermatogenic function after reduction of testicular torsion in rats. Ninety-six pure inbred male SD rats were divided into group A, B, C and D according to the principle of body weight and birth similarity, with 24 rats in each group. Four groups of rats were respectively twisted on the left testis to establish unilateral testicular torsion rats. Rats in groups A, B, C, D were respectively given normal saline, hypothermia therapy, vitamin E therapy, and hypothermia and vitamin E therapy. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) content of the four groups were detected, and the correlation levels of inflammatory factors IL-1β, hs-CRP and related sex hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T) were detected by ELISA. Apoptosis of spermatogenic cells of testis in the four groups was detected by flow cytometry. SOD activity and MDA content in groups B, C and D were significantly higher than those in group A, MDA content was significantly lower than that in group A (P<0.05), SOD activity in group D was higher than that in groups B and C, while MDA content was lower than that in groups B and C (P<0.05). The levels of IL-1β and hs-CRP in group A were much higher than those in groups B, C and D (P<0.05). LH and FSH levels in group A were significantly higher than those in groups B, C and D (P<0.05), and in group D were significantly lower than those in groups B and C (P<0.05). Apoptosis rate of spermatogenic cells in group A was significantly higher than that in groups B, C and D (P<0.05). Hypothermia combined with vitamin E can reverse testicular injury in rats and reduce the apoptosis rate of spermatogenic cells.
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http://dx.doi.org/10.3892/etm.2020.8800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388547PMC
August 2020

A nitric oxide-releasing hydrogel for enhancing the therapeutic effects of mesenchymal stem cell therapy for hindlimb ischemia.

Acta Biomater 2020 09 11;113:289-304. Epub 2020 Jul 11.

Nankai University School of Medicine, 94 Weijin Road, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Sciences, 94 Weijin Road, Tianjin 300071, China; State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China; Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China. Electronic address:

Therapeutic angiogenesis with mesenchymal stem cells (MSCs) is promising for the clinical treatment of peripheral artery disease (PAD). However, the heterogeneous proangiogenic nature of MSCs is a key challenge in developing more effective treatments with MSCs for therapeutic angiogenesis purposes. Here, we propose to enhance the therapeutic function of human placenta-derived MSCs (hP-MSCs) in hindlimb ischemia therapy by using nitric oxide (NO)-releasing chitosan hydrogel (CS-NO). Our data showed that the co-transplantation of CS-NO hydrogel with hP-MSCs remarkably improved the grafting of hP-MSCs and ameliorated the functional recovery of ischemic hindlimbs. Moreover, we found that the neovascularization of damaged hindlimbs was significantly increased after co-transplanting CS-NO hydrogel and hP-MSCs, as confirmed by bioluminescence imaging (BLI). Further analysis revealed an endothelial-like status transformation of hP-MSCs in the presence of NO, which was identified as a potential mechanism contributing to the enhanced endothelium-protective and proangiogenic capacities of hP-MSCs that promote angiogenesis in mouse models of hindlimb ischemia. In conclusion, this study provides a promising approach for using NO hydrogel to improve the proangiogenic potency of MSCs in ischemic diseases, and the strategy used here facilitates the development of controlled-release scaffolds for enhancing the therapeutic efficiency of MSCs in angiogenic therapy. STATEMENT OF SIGNIFICANCE: The heterogeneous proangiogenic nature of mesenchymal stem cells (MSCs) is a key challenge in developing more effective treatments with MSCs for therapeutic angiogenesis purposes. In this study, we investigated whether nitric oxide (NO)-releasing chitosan hydrogel (CS-NO) could improve the proangiogenic potency of MSCs in ischemic diseases. Our results revealed an endothelial-like status transformation of human placenta-derived MSCs (hP-MSCs) in the presence of NO, which was identified as a potential mechanism contributing to the enhanced endothelium-protective and proangiogenic capacities of hP-MSCs that promote angiogenesis in mouse models of hindlimb ischemia. The strategy for enhancing the pro-angiogenic activity of MSCs with biomaterials provides a practical idea for overcoming the challenges associated with the clinical application of MSCs in therapeutic angiogenesis.
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http://dx.doi.org/10.1016/j.actbio.2020.07.011DOI Listing
September 2020

Comparison of the effect of two internal fixation methods for proximal clavicle fractures.

Rev Assoc Med Bras (1992) 2020 May 3;66(5):654-658. Epub 2020 Jul 3.

Department of Orthopaedics, Dongying People's Hospital, Dongying, Shandong, China.

OBJECTIVE To compare the effect of two internal fixation methods in the treatment of proximal clavicle fractures. METHODS Fifty patients with proximal clavicle fractures received surgical treatment. They were divided into a clavicular T-plate group and a double mini-plates group. The duration of the operation, blood loss during the operation, fracture healing time, and incision infection were evaluated between the two groups. RESULTS Operation time (t=2.063, P=0.058), intraoperative bleeding (t=1.979, P=0.062), and fracture healing time (t=1.082, P=0.066) were not statistically significant in the two groups. The patients were followed up for 12-18 months; one patient in the T-plate group had early removal of nails, but no clinical symptoms. At the 2-month follow-up, the ASES score in the double mini-plates group was significantly better than in the T-plate group (P<0.001); but at the 6-month follow-up, 1-week before removal of internal fixation and the final follow-up, the two groups had no significant differences (P>0.05). CONCLUSIONS Both internal fixations have similar clinical results in the duration of operation, blood loss during the operation, and fracture healing time. The double mini-plates fixation presents advantages by reducing complications and speeding fracture healing; thus it is a more effective method to treat proximal clavicle fractures.
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http://dx.doi.org/10.1590/1806-9282.66.5.654DOI Listing
May 2020

Nomogram for Predicting the Overall Survival of Patients With Breast Cancer With Pathologic Nodal Status N3.

Clin Breast Cancer 2020 12 7;20(6):e778-e785. Epub 2020 Jun 7.

Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address:

Background: Patients with breast cancer with pathologic N3 (pN3) lymph node status have been proven to have a poor prognosis. This study aimed to establish a nomogram to predict overall survival (OS) in patients with pN3 breast cancer.

Materials And Methods: The eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database were randomly divided into training and validation cohorts. χ tests and survival curves were performed to define the consistency between these 2 cohorts. Univariate and multivariate logistic regressions were carried out to identify the independent clinicopathologic factors of patients with pN3 breast cancer. A nomogram was developed and validated internally and externally by a calibration curve and compared with the seventh edition American Joint Committee on Cancer TNM staging classification in discrimination ability.

Results: Race, age at diagnosis, marital status, grade, T stage, N stage, breast cancer subtype, surgery, radiotherapy, and chemotherapy were independent predictive factors of OS in pN3 breast cancer. We developed a nomogram to predict 1-, 3-, and 5-year OS and further validated it in both cohorts, demonstrating better prediction capacity in OS than that of the seventh edition American Joint Committee on Cancer TNM staging classification (area under the curve in the receiver operating characteristic curve, 0.745 and 0.611 in the training cohort and 0.768 and 0.624 in the validation cohort, respectively).

Conclusion: We have developed and validated the first nomogram for predicting the survival of pN3 breast cancer. This nomogram accurately and reliably predicted the OS of patients with pN3 breast cancer. However, more prognostic factors need to be further explored to improve the nomogram.
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http://dx.doi.org/10.1016/j.clbc.2020.06.002DOI Listing
December 2020

Intellectual disability-associated gene ftsj1 is responsible for 2'-O-methylation of specific tRNAs.

EMBO Rep 2020 08 18;21(8):e50095. Epub 2020 Jun 18.

School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

tRNA modifications at the anti-codon loop are critical for accurate decoding. FTSJ1 was hypothesized to be a human tRNA 2'-O-methyltransferase. tRNA (GAA) from intellectual disability patients with mutations in ftsj1 lacks 2'-O-methylation at C32 and G34 (Cm32 and Gm34). However, the catalytic activity, RNA substrates, and pathogenic mechanism of FTSJ1 remain unknown, owing, in part, to the difficulty in reconstituting enzymatic activity in vitro. Here, we identify an interacting protein of FTSJ1, WDR6. For the first time, we reconstitute the 2'-O-methylation activity of the FTSJ1-WDR6 complex in vitro, which occurs at position 34 of specific tRNAs with m G37 as a prerequisite. We find that modifications at positions 32, 34, and 37 are interdependent and occur in a hierarchical order in vivo. We also show that the translation efficiency of the UUU codon, but not the UUC codon decoded by tRNA (GAA), is reduced in ftsj1 knockout cells. Bioinformatics analysis reveals that almost 40% of the high TTT-biased genes are related to brain/nervous functions. Our data potentially enhance our understanding of the relationship between FTSJ1 and nervous system development.
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http://dx.doi.org/10.15252/embr.202050095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403668PMC
August 2020

Solute Carrier Family 37 Member 2 (SLC37A2) Negatively Regulates Murine Macrophage Inflammation by Controlling Glycolysis.

iScience 2020 May 4;23(5):101125. Epub 2020 May 4.

Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Electronic address:

Increased flux of glucose through glycolysis is a hallmark of inflammatory macrophages and is essential for optimal effector functions. Solute carrier (SLC) 37A2 is an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter that is highly expressed in macrophages and neutrophils. We demonstrate that SLC37A2 plays a pivotal role in murine macrophage inflammatory activation and cellular metabolic rewiring. Toll-like receptor (TLR) 4 stimulation by lipopolysaccharide (LPS) rapidly increases macrophage SLC37A2 protein expression. SLC37A2 deletion reprograms macrophages to a hyper-glycolytic process and accelerates LPS-induced inflammatory cytokine production, which partially depends on nicotinamide adenine dinucleotide (NAD) biosynthesis. Blockade of glycolysis normalizes the differential expression of pro-inflammatory cytokines between control and SLC37A2 deficient macrophages. Conversely, overexpression of SLC37A2 lowers macrophage glycolysis and significantly reduces LPS-induced pro-inflammatory cytokine expression. In conclusion, our study suggests that SLC37A2 dampens murine macrophage inflammation by down-regulating glycolytic reprogramming as a part of macrophage negative feedback system to curtail acute innate activation.
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http://dx.doi.org/10.1016/j.isci.2020.101125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232099PMC
May 2020

Re-excision or "wait and watch"-a prediction model in breast phyllodes tumors after surgery.

Ann Transl Med 2020 Mar;8(6):371

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.

Background: The prognosis of breast phyllodes tumors (PTs) largely depending on the pathological grading, which lacks objectivity. This study aimed to develop a nomogram based on clinicopathological features to evaluate the recurrence probability of PTs following surgery.

Methods: Data from 334 patients with breast PTs, who underwent surgical treatment at Sun Yat-sen Memorial Hospital from January 2005 to December 2014, were used to develop a prediction model. Additionally, data of 36 patients from Peking University Shenzhen Hospital (cohort 1) and data of 140 patients from Sun Yat-sen University Cancer Center (cohort 2) during the same period were used to validate the model. The medical records and tumor slides were retrospectively reviewed. The log-rank and Cox regression tests were used to develop a clinical prediction model of breast PTs. All statistical analyses were performed using R and STATA.

Results: Of all 334 patients included in the primary cohort, 224 had benign, 91 had borderline, and 19 had malignant tumors. The 1-, 3-, and 5-year recurrence-free survival was 98.5%, 97.9%, and 96.8%, respectively. Ultrasound-guided vacuum-assisted biopsy (UGVAB) is a non-inferior treatment application in benign PTs compared with open surgery [hazard ratio (HR), 2.38; 95% confidence interval (CI), 0.59-9.58]. Width of surgical margin, mitoses, and tumor border were identified as independent risk factors for breast PTs. A nomogram was developed based on these three variables. The C-index of internal and external validation was 0.71, 0.67 (cohort 1) and 0.73 (cohort 2), respectively.

Conclusions: The study model presented more concise and objective variables to evaluate the recurrence-free survival of patients after surgery, which can help deciding whether to do a re-excision or "wait and watch".
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http://dx.doi.org/10.21037/atm.2020.02.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186749PMC
March 2020

FANCD2 is required for the repression of germline transposable elements.

Reproduction 2020 06;159(6):659-668

Division of Experimental Hematology and Cancer Biology, Cincinnati, Ohio, USA.

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http://dx.doi.org/10.1530/REP-19-0436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193181PMC
June 2020

Flexible 3D carbon cloth as a high-performing electrode for energy storage and conversion.

Nanoscale 2020 Mar 24;12(9):5261-5285. Epub 2020 Feb 24.

Center for Research on Leading Technology of Special Equipment, School of Mechanical and Electric Engineering, Guangzhou University, Guangzhou 510006, People's Republic of China.

High-performance energy storage and conversion devices with high energy density, power density and long-term cycling life are of great importance in current consumer electronics, portable electronics and electric vehicles. Carbon materials have been widely investigated and utilized in various energy storage and conversion devices due to their excellent conductivity, mechanical and chemical stability, and low cost. Abundant excellent reviews have summarized the most recent progress and future outlooks for most of the current prime carbon materials used in energy storage and conversion devices, such as carbon nanotubes, fullerene, graphene, porous carbon and carbon fibers. However, the significance of three-dimensional (3D) commercial carbon cloth (CC), one of the key carbon materials with outstanding mechanical stability, high conductivity and flexibility, in the energy storage and conversion field, especially in wearable electronics and flexible devices, has not been systematically summarized yet. In this review article, we present a careful investigation of flexible CC in the energy storage and conversion field. We first give a general introduction to the common properties of CC and the roles it has played in energy storage and conversion systems. Then, we meticulously investigate the crucial role of CC in typical electrochemical energy storage systems, including lithium-ion batteries, sodium-ion batteries, lithium-sulfur batteries and supercapacitors. Following a description of the wide application potential of CC in electrocatalytic hydrogen evolution, oxygen evolution/reduction, full-water splitting, etc., we will give a brief introduction to the application of CC in the areas of photocatalytically and photoelectrochemically induced solar energy conversion and storage. The review will end with a brief summary of the typical superiorities that CC has in current energy conversion and storage systems, as well as providing some perspectives and outlooks on its future applications in the field. Our main interest will be focused on CC-based flexible devices due to the inherent superiority of CC and the increasing demand for flexible and wearable electronics.
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http://dx.doi.org/10.1039/c9nr09785fDOI Listing
March 2020

Myeloid atg5 deletion impairs n-3 PUFA-mediated atheroprotection.

Atherosclerosis 2020 02 12;295:8-17. Epub 2020 Jan 12.

Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA; Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. Electronic address:

Background And Aims: Dietary long-chain (≥20 carbons) n-3 polyunsaturated fatty acids (PUFAs) reduce atherosclerosis and enhance macrophage autophagy activation. How macrophage autophagy impacts atherosclerotic progression, particularly when comparing dietary n-3 PUFA supplementation vs. saturated fat feeding, is unknown.

Methods: We generated myeloid-specific autophagy-deficient and control mice in the Ldlr background by transplanting bone marrow from myeloid-specific autophagy-related (atg) 5 knockout mice and wild type controls into irradiated Ldlr recipients. After 7 weeks for recovery from radiation, mice were fed an atherogenic diet containing 0.2% cholesterol and 20% calories as palm oil (PO diet), or 10% calories as PO plus 10% calories as fish oil (FO diet) for 16 weeks.

Results: Compared to PO, FO significantly reduced plasma cholesterol, triglyceride, hepatic neutral lipid, and aortic caspase-1 cleavage, but increased aortic efferocytosis, leading to attenuated atherosclerosis in Ldlr mice receiving wild type bone marrow. Myeloid atg5 deletion had little impact on plasma lipid concentrations and hepatic neutral lipid content, regardless of diet. Myeloid atg5 deletion increased aortic caspase-1 cleavage, decreased aortic efferocytosis and worsened atherosclerosis only in the FO-fed Ldlr mice.

Conclusions: Deficient myeloid autophagy significantly attenuated FO-induced atheroprotection, suggesting that dietary n-3 PUFAs reduce atherosclerosis, in part, by activation of macrophage autophagy.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034781PMC
February 2020

Redox-responsive polyprodrug nanoparticles for targeted siRNA delivery and synergistic liver cancer therapy.

Biomaterials 2020 03 6;234:119760. Epub 2020 Jan 6.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China. Electronic address:

Combination therapy has been developed as an innovative modality for effective cancer therapy. However, the administration of combinatorial therapeutics is limited by the varying pharmacokinetics of different drugs. Although numerous nanoparticles (NPs) can synchronize the delivery of combinatorial therapeutics to tumor cells, their clinical translation is still challenged, which is partly due to the complexity to precisely control the loading of combinatorial therapeutics to maximize therapeutic efficacy and suboptimal NP properties. Herein, a new redox-responsive polyprodrug nanoplatform was developed for targeted siRNA delivery and synergistic cancer therapy. This NP platform is made with redox-responsive 10-hydroxycamptothecin (HCPT)-based polyprodrug (polyHCPT) as the inner core, amphiphilic lipid-poly (ethylene glycol) (lipid-PEG) as the outer shell, and lactobionic acid (LA) decoration on the surface. After siRNA loading and subsequent systemic administration, the resulting NP platform could accumulate in tumor tissues and target hepatoma cells via specific recognition between LA and asialoglycoprotein (ASGP) receptors. With the high concentration of glutathione (GSH) in the cytoplasm to break the disulfide bonds in the polyHCPT, intact HCPT molecules and encapsulated B-cell lymphoma 2 (Bcl-2) siRNA (siBcl-2) could be rapidly released, leading to the synergistic inhibition of tumor growth via the induction of apoptosis by HCPT and the concurrent silencing of the anti-apoptotic gene by siBcl-2.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119760DOI Listing
March 2020

Chimeric antigen receptor T cells in solid tumors: a war against the tumor microenvironment.

Sci China Life Sci 2020 Feb 23;63(2):180-205. Epub 2019 Dec 23.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.

Chimeric antigen receptor (CAR) T cell is a novel approach, which utilizes anti-tumor immunity for cancer treatment. As compared to the traditional cell-mediated immunity, CAR-T possesses the improved specificity of tumor antigens and independent cytotoxicity from major histocompatibility complex molecules through a monoclonal antibody in addition to the T-cell receptor. CAR-T cell has proven its effectiveness, primarily in hematological malignancies, specifically where the CD 19 CAR-T cells were used to treat B-cell acute lymphoblastic leukemia and B-cell lymphomas. Nevertheless, there is little progress in the treatment of solid tumors despite the fact that many CAR agents have been created to target tumor antigens such as CEA, EGFR/EGFRvIII, GD2, HER2, MSLN, MUC1, and other antigens. The main obstruction against the progress of research in solid tumors is the tumor microenvironment, in which several elements, such as poor locating ability, immunosuppressive cells, cytokines, chemokines, immunosuppressive checkpoints, inhibitory metabolic factors, tumor antigen loss, and antigen heterogeneity, could affect the potency of CAR-T cells. To overcome these hurdles, researchers have reconstructed the CAR-T cells in various ways. The purpose of this review is to summarize the current research in this field, analyze the mechanisms of the major barriers mentioned above, outline the main solutions, and discuss the outlook of this novel immunotherapeutic modality.
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http://dx.doi.org/10.1007/s11427-019-9665-8DOI Listing
February 2020

Observation of immediate and mid-term effects of partial spleen embolization in reducing hepatic venous pressure gradient.

Medicine (Baltimore) 2019 Nov;98(47):e17900

Department of Gastroenterology, Hainan Hospital of PLA General Hospital, Haitang District, Sanya, Hainan.

Objective: To observe the immediate and mid-term effects of partial spleen embolization (PSE) in reducing hepatic venous pressure gradient (HVPG) in patients with cirrhotic esophagogastric varices.

Methods: Patients diagnosed with cirrhosis and esophagogastric varices in our hospital between July 2016 and March 2018 were consecutively selected. Forty-three patients were selected based on the eligibility criteria to undergo PSE. The change in HVPG 5 minutes before and after embolization, was used to determine the immediate effect of PSE on HVPG reduction. HVPG was retested after 6 months to observe the change in the antihypertensive effect along with time.

Results: Forty-three patients successfully underwent PSE and HVPG measurements. The HVPG was 17.7 ± 3.9 mmHg and 13.9 ± 3.1 mmHg before and after PSE, respectively, showing a significant decrease (21.5%, P < .05). Among them, 18 cases were retested for HVPG at 6 months after PSE, and the results showed significant differences in the HVPG levels before, immediately and 6 months after PSE. Compared with preoperative PSE, HVPG was decreased by 22.9% and 17.7% (P < 0.05) immediately and at 6 months after operation, respectively. There was no significant change at 6 months after PSE when compared with immediate postoperative PSE. No serious complications were observed in patients during their postoperative hospital stay.

Conclusion: PSE immediately reduced the portal pressure, and HVPG remained stable at 6 months after surgery. PSE is considered as a safe and easy to implement method, and is expected to be one of the treatments for reducing the portal pressure.
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http://dx.doi.org/10.1097/MD.0000000000017900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882594PMC
November 2019

TAOK3, a Regulator of LCK-SHP-1 Crosstalk during TCR Signaling.

Crit Rev Immunol 2019 ;39(1):59-81

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; Microbiome and Disease Tolerance Centre, and Department of Microbiology and Immunology, McGill University, Montréal, Quebec.

Signaling from the T cell receptor for antigen turns on the physiological response of a T cell. The canonical TCR signaling pathway relies on early activation of the Src kinase LCK. This step initiates a cascade of events that lead not only to the phenotypic changes that characterize effector T cells but also to the activation of negative regulatory mechanisms that stop early TCR signaling. These mechanisms ensure qualitative and quantitative fine-tuning of T cell activation. The tyrosine phosphatase SHP-1 is a key player in the downregulation of LCK activation. In this review, we focus on the crosstalk between LCK and SHP-1 and, based on recent data, we introduce the putative kinase TAOK3 as an important regulator of this crosstalk. Given the widespread expression of TAOK3 and SHP-1, we propose that the function of TAOK3 extends beyond T cells and may be fundamental in the regulation of early signaling from receptors that utilize Src kinases.
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http://dx.doi.org/10.1615/CritRevImmunol.2019030480DOI Listing
June 2020

Microscale roughness regulates laminin-5 secretion of bone marrow mesenchymal stem cells.

Clin Hemorheol Microcirc 2019 ;73(1):237-247

Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany.

Laminin-5 (Ln-5), an important extracellular matrix (ECM) protein, plays a critical role in regulating the growth and differentiation of mesodermal tissues, including bone. Ln-5 can be secreted by the mesenchymal stem cells (MSCs), and Ln-5 promotes MSCs osteogenic differentiation. It has been demonstrated that a substrate's surface topography could regulate MSC secretion and differentiation. A better understanding of the mechanism of how Ln-5 and surface roughness regulate MSC osteogenic differentiation would guide the design of surface topography and coatings of orthopedic implants and cell culture substrates. However, few studies have investigated the relationship between surface roughness and the secretion of Ln-5 in MSC osteogenic differentiation. Whether substrate surface topography regulates MSC differentiation via regulating Ln-5 secretion and how surface topography contributes to the secretion of Ln-5 are still not known. In this study, the influence of microscale roughness at different levels (R0, R1 and R2) on the secretion of Ln-5 of human bone marrow MSCs (hBMSCs) and subsequent osteogenic differentiation were examined. hBMSCs spreading, distribution and morphology were greatly affected by different roughness levels. A significantly higher level of Ln-5 secretion was detected on R2, which correlated to the local cell density regulated by the rough surface. Ln-5 binding integrins (α2 and α3) were strongly activated on R2. In addition, the results from hBMSCs on R0 inserts with different cell densities further confirmed that local cell density regulated Ln-5 secretion and cell surface integrin activation. In addition, the mineralization level of MSCs on R2 was remarkably higher than that on R0 and R1. These results suggest that hBMSC osteogenic differentiation level on R2 roughness was enhanced via increased Ln-5 secretion that was attributed to rough surface regulated local cell density. Thus, the microroughness could serve as effective topographical stimulus in cell culture devices and bone implant materials.
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http://dx.doi.org/10.3233/CH-199205DOI Listing
February 2020
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