Publications by authors named "Jun Qin"

621 Publications

Current status survey of the extramural hospital management of venous thromboembolism after total hip and knee arthroplasty in China.

BMC Musculoskelet Disord 2021 Sep 13;22(1):787. Epub 2021 Sep 13.

Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan City, Hubei Province, 430071, PR China.

Background: Venous thromboembolism (VTE) is a potentially fatal complication after arthroplasty. Numerous prophylactic strategies and studies to reduce VTEs have focused on the duration of the hospital stay and on few extramural hospitals. This study aimed to investigate extramural hospital management of VTE after total hip/knee arthroplasty (THA/TKA) in China with a novel survey tool.

Methods: A total of 180 patients undergoing arthroplasty, including 68 THA patients and 112 TKA patients, were enrolled in this study. All patients received anticoagulant treatment management. A survey querying VTE management and adherence, such as therapy information, understanding of anticoagulation, satisfaction with the ability of medical staff, and satisfaction with health care costs, was administered by a questionnaire (TKA/THA Patients' Experience with Anticoagulation in the Post-discharge Period) for quality improvement.

Results: The average age of the patients was 65.27 ± 13.62 years. All patients knew their follow-up times. 85 % of them were suggested that re-examine at the next 14 days, and the others at the next 28 days. All patients continued to visit the orthopaedic clinic after discharge without choosing other types of outpatient services, such as an anticoagulant clinic or home visit with a nurse/pharmacist or remote evaluation by telephone. A total of 96.6 % of all patients used new oral anticoagulants, and the most common treatment duration was 2-4 weeks (93.3 %). 48 % informed their physicians that they were taking anticoagulation medications when they visited ophthalmology, dentistry, dermatology, and other departments. The overall rate of satisfaction with anticoagulation management was 81.67 %, and 6.67 % of patients were not unsatisfied with their medical expenses. Patient compliance decreased with increasing follow-up time. Continuous follow-ups after discharge significantly improved patient compliance.

Conclusions: These results elucidate how we can improve the quality of anticoagulation. Continuous follow-up appointments for 30 days after discharge, especially for individuals over 65 years old, significantly improved patient satisfaction and reduced the incidence of VTE and medical costs.
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http://dx.doi.org/10.1186/s12891-021-04663-1DOI Listing
September 2021

Mesenchymal stem cell-conditioned medium alleviates high fat-induced hyperglucagonemia via miR-181a-5p and its target PTEN/AKT signaling.

Mol Cell Endocrinol 2021 Aug 28;537:111445. Epub 2021 Aug 28.

Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China. Electronic address:

Background: α-cell dysregulation gives rise to fasting and postprandial hyperglycemia in type 2 diabetes mellitus(T2DM). Administration of Mesenchymal stem cells (MSCs) or their conditioned medium can improve islet function and enhance insulin secretion. However, studies showing the direct effect of MSCs on islet α-cell dysfunction are limited.

Methods: In this study, we used high-fat diet (HFD)-induced mice and α-cell line exposure to palmitate (PA) to determine the effects of bone marrow-derived MSC-conditioned medium (bmMSC-CM) on glucagon secretion. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay(ELISA). To investigate the potential signaling pathways, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), AKT and phosphorylated AKT(p-AKT) were assessed by Western blotting.

Results: In vivo, bmMSC-CM infusion improved the glucose and insulin tolerance and protected against HFD-induced hyperglycemia and hyperglucagonemia. Meanwhile, bmMSC-CM infusion ameliorated HFD-induced islet hypertrophy and decreased α- and β-cell area. Consistently, in vitro, glucagon secretion from α-cells or primary islets was inhibited by bmMSC-CM, accompanied by reduction of intracellular PTEN expression and restoration of AKT signaling. Previous studies and the TargetScan database indicate that miR-181a and its target PTEN play vital roles in ameliorating α-cell dysfunction. We observed that miR-181a-5p was highly expressed in BM-MSCs but prominently lower in αTC1-6 cells. Overexpression or downregulation of miR-181a-5p respectively alleviated or aggravated glucagon secretion in αTC1-6 cells via the PTEN/AKT signaling pathway.

Conclusions: Our observations suggest that MSC-derived miR-181a-5p mitigates glucagon secretion of α-cells by regulating PTEN/AKT signaling, which provides novel evidence demonstrating the potential for MSCs in treating T2DM.
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http://dx.doi.org/10.1016/j.mce.2021.111445DOI Listing
August 2021

Roles of the Immune/Methylation/Autophagy Landscape on Single-Cell Genotypes and Stroke Risk in Breast Cancer Microenvironment.

Oxid Med Cell Longev 2021 19;2021:5633514. Epub 2021 Aug 19.

Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 200080, China.

This study sought to perform integrative analysis of the immune/methylation/autophagy landscape on breast cancer prognosis and single-cell genotypes. Breast Cancer Recurrence Risk Score (BCRRS) and Breast Cancer Prognostic Risk Score (BCPRS) were determined based on 6 prognostic IMAAGs obtained from the TCGA-BRCA cohort. BCRRS and BCPRS, respectively, were used to construct a risk prediction model of overall survival and progression-free survival. Predictive capacity of the model was evaluated using clinical data. Analysis showed that BCRRS is associated with a high risk of stroke. In addition, PPI and drug-ceRNA networks based on differences in BCPRS were constructed. Single cells were genotyped through integrated scRNA-seq of the TNBC samples based on clustering results of BCPRS-related genes. The findings of this study show the potential regulatory effects of IMAAGs on breast cancer tumor microenvironment. High AUCs of 0.856 and 0.842 were obtained for the OS and PFS prognostic models, respectively. scRNA-seq analysis showed high expression levels of adipocytes and adipose tissue macrophages (ATMs) in high BCPRS clusters. Moreover, analysis of ligand-receptor interactions and potential regulatory mechanisms were performed. The LINC00276&MALAT1/miR-206/FZD4-Wnt7b pathway was also identified which may be useful in future research on targets against breast cancer metastasis and recurrence. Neural network-based deep learning models using BCPRS-related genes showed that these genes can be used to map the tumor microenvironment. In summary, analysis of IMAAGs, BCPRS, and BCRRS provides information on the breast cancer microenvironment at both the macro- and microlevels and provides a basis for development of personalized treatment therapy.
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http://dx.doi.org/10.1155/2021/5633514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397558PMC
September 2021

Induced phase separation of mutant NF2 imprisons the cGAS-STING machinery to abrogate antitumor immunity.

Mol Cell 2021 Aug 24. Epub 2021 Aug 24.

MOE Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center (HIC-ZJU), Hangzhou 310058, China; Cancer Center, Zhejiang University, Hangzhou 310058, China. Electronic address:

Missense mutations of the tumor suppressor Neurofibromin 2 (NF2/Merlin/schwannomin) result in sporadic to frequent occurrences of tumorigenesis in multiple organs. However, the underlying pathogenicity of NF2-related tumorigenesis remains mostly unknown. Here we found that NF2 facilitated innate immunity by regulating YAP/TAZ-mediated TBK1 inhibition. Unexpectedly, patient-derived individual mutations in the FERM domain of NF2 (NF2m) converted NF2 into a potent suppressor of cGAS-STING signaling. Mechanistically, NF2m gained extreme associations with IRF3 and TBK1 and, upon innate nucleic acid sensing, was directly induced by the activated IRF3 to form cellular condensates, which contained the PP2A complex, to eliminate TBK1 activation. Accordingly, NF2m robustly suppressed STING-initiated antitumor immunity in cancer cell-autonomous and -nonautonomous murine models, and NF2m-IRF3 condensates were evident in human vestibular schwannomas. Our study reports phase separation-mediated quiescence of cGAS-STING signaling by a mutant tumor suppressor and reveals gain-of-function pathogenesis for NF2-related tumors by regulating antitumor immunity.
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http://dx.doi.org/10.1016/j.molcel.2021.07.040DOI Listing
August 2021

Quantifying the phase separation property of chromatin-associated proteins under physiological conditions using an anti-1,6-hexanediol index.

Genome Biol 2021 08 17;22(1):229. Epub 2021 Aug 17.

Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Background: Liquid-liquid phase separation (LLPS) is an important organizing principle for biomolecular condensation and chromosome compartmentalization. However, while many proteins have been reported to undergo LLPS, quantitative and global analysis of chromatin LLPS property remains absent.

Results: Here, by combining chromatin-associated protein pull-down, quantitative proteomics and 1,6-hexanediol (1,6-HD) treatment, we develop Hi-MS and define an anti-1,6-HD index of chromatin-associated proteins (AICAP) to quantify 1,6-HD sensitivity of chromatin-associated proteins under physiological conditions. Compared with known physicochemical properties involved in phase separation, we find that proteins with lower AICAP are associated with higher content of disordered regions, higher hydrophobic residue preference, higher mobility and higher predicted LLPS potential. We also construct BL-Hi-C libraries following 1,6-HD treatment to study the sensitivity of chromatin conformation to 1,6-HD treatment. We find that the active chromatin and high-order structures, as well as the proteins enriched in corresponding regions, are more sensitive to 1,6-HD treatment.

Conclusions: Our work provides a global quantitative measurement of LLPS properties of chromatin-associated proteins and higher-order chromatin structure. Hi-MS and AICAP data provide an experimental tool and quantitative resources valuable for future studies of biomolecular condensates.
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http://dx.doi.org/10.1186/s13059-021-02456-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369651PMC
August 2021

Genome-wide association study and genomic selection for yield and related traits in soybean.

PLoS One 2021 13;16(8):e0255761. Epub 2021 Aug 13.

The Key Laboratory of Crop Genetics and Breeding of Hebei Province, National Soybean Improvement Center Shijiazhuang Sub-Center, North China Key Laboratory of Biology and Genetic Improvement of Soybean, Ministry of Agriculture, Laboratory of Crop Genetics and Breeding of Hebei Cereal & Oil Crop Institute, Hebei Academy of Agricultural and Forestry Sciences, Shijiazhuang, Hebei, China.

Soybean [Glycine max (L.) Merr.] is a crop of great interest worldwide. Exploring molecular approaches to increase yield genetic gain has been one of the main challenges for soybean breeders and geneticists. Agronomic traits such as maturity, plant height, and seed weight have been found to contribute to yield. In this study, a total of 250 soybean accessions were genotyped with 10,259 high-quality SNPs postulated from genotyping by sequencing (GBS) and evaluated for grain yield, maturity, plant height, and seed weight over three years. A genome-wide association study (GWAS) was performed using a Bayesian Information and Linkage Disequilibrium Iteratively Nested Keyway (BLINK) model. Genomic selection (GS) was evaluated using a ridge regression best linear unbiased predictor (rrBLUP) model. The results revealed that 20, 31, 37, and 23 SNPs were significantly associated with maturity, plant height, seed weight, and yield, respectively; Many SNPs were mapped to previously described maturity and plant height loci (E2, E4, and Dt1) and a new plant height locus was mapped to chromosome 20. Candidate genes were found in the vicinity of the two SNPs with the highest significant levels associated with yield, maturity, plant height, seed weight, respectively. A 11.5-Mb region of chromosome 10 was associated with both yield and seed weight. Overall, the accuracy of GS was dependent on the trait, year, and population structure, and high accuracy indicates that these agronomic traits can be selected in molecular breeding through GS. The SNP markers identified in this study can be used to improve yield and agronomic traits through the marker-assisted selection and GS in breeding programs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255761PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362977PMC
August 2021

D-methionine immediate and continued rescue after noise exposure does not prevent temporary threshold shift but alters cochlear and serum antioxidant levels.

Int J Audiol 2021 Aug 8:1-9. Epub 2021 Aug 8.

Department of Clinical Research, Springfield Clinic, Springfield, IL, USA.

Objective: Determine if D-methionine (D-met) rescue prevents temporary threshold shift (TTS) from steady-state or impulse noise and determine D-met's impact on serum and cochlear antioxidant levels.

Design: D-met at 50, 100 or 200 mg/kg/doses were administered 0, 6 and 18 hours-post noise. ABRs at baseline and 24 hours post-noise measured TTS. Serum (SOD, CAT, GR, GPx) and cochlear (GSH, GSSG) antioxidant levels measured physiological influence. Three control groups, with impulse or steady-state or without noise, were saline-injected.

Study Sample: Ten /group.

Results: D-met rescue did not significantly reduce TTS or impact serum CAT, SOD, GPx or GR levels vs. noise-exposed control groups, but TTS was greater in all groups relative to no-noise controls. D-met significantly elevated CAT at 50 mg/kg vs. steady-state controls and SOD at 200 mg/kg vs. impulse noise controls. D-met significantly reduced cochlear GSH/GSSG ratios in the 100 mg/kg D-met group vs. impulse noise controls.

Conclusions: While D-met rescue has reduced permanent threshold shift in previous studies, it did not reduce TTS in this study. However, D-met rescue did alter selective serum and cochlear oxidative state changes 24 hours post-noise relative to controls. Results demonstrate TTS studies do not always predict PTS protection in otoprotectant experimental designs.
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http://dx.doi.org/10.1080/14992027.2021.1959659DOI Listing
August 2021

Proteome-Wide Profiling of Readers for DNA Modification.

Adv Sci (Weinh) 2021 Aug 5:e2101426. Epub 2021 Aug 5.

State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.

DNA modifications, represented by 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), play important roles in epigenetic regulation of biological processes. The specific recognition of DNA modifications by the transcriptional protein machinery is thought to be a potential mechanism for epigenetic-driven gene regulation, and many modified DNA-specific binding proteins have been uncovered. However, the panoramic view of the roles of DNA modification readers at the proteome level remains largely unclear. Here, a recently developed concatenated tandem array of consensus transcription factor (TF) response elements (catTFREs) approach is employed to profile the binding activity of TFs at DNA modifications. Modified DNA-binding activity is quantified for 1039 TFs, representing 70% of the TFs in the human genome. Additionally, the modified DNA-binding activity of 600 TFs is monitored during the mouse brain development from the embryo to the adult stages. Readers of these DNA modifications are predicted, and the hierarchical networks between the transcriptional protein machinery and modified DNA are described. It is further demonstrated that ZNF24 and ZSCAN21 are potential readers of 5fC-modified DNA. This study provides a landscape of TF-DNA modification interactions that can be used to elucidate the epigenetic-related transcriptional regulation mechanisms under physiological conditions.
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http://dx.doi.org/10.1002/advs.202101426DOI Listing
August 2021

MTA2 sensitizes gastric cancer cells to PARP inhibition by induction of DNA replication stress.

Transl Oncol 2021 Oct 17;14(10):101167. Epub 2021 Jul 17.

State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address:

Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib selectively kills cancer cells with BRCA-deficiency and is approved for BRCA-mutated breast, ovarian and pancreatic cancers by FDA. However, phase III study of olaparib failed to show a significant improvement in overall survival in patients with gastric cancer (GC). To discover an effective biomarker for GC patient-selection in olaparib treatment, we analyzed proteomic profiling of 12 GC cell lines. MTA2 was identified to confer sensitivity to olaparib by aggravating olaparib-induced replication stress in cancer cells. Mechanistically, we applied Cleavage Under Targets and Tagmentation assay to find that MTA2 proteins preferentially bind regions of replication origin-associated DNA sequences, which could be enhanced by olaparib treatment. Furthermore, MTA2 was validated here to render cancer cells susceptible to combination of olaparib with ATR inhibitor AZD6738. In general, our study identified MTA2 as a potential biomarker for olaparib sensitivity by aggravating olaparib-induced replication stress.
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http://dx.doi.org/10.1016/j.tranon.2021.101167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313750PMC
October 2021

Proteomics provides individualized options of precision medicine for patients with gastric cancer.

Sci China Life Sci 2021 Aug 9;64(8):1199-1211. Epub 2021 Jul 9.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.

While precision medicine driven by genome sequencing has revolutionized cancer care, such as lung cancer, its impact on gastric cancer (GC) has been minimal. GC patients are routinely treated with chemotherapy, but only a fraction of them receive the clinical benefit. There is an urgent need to develop biomarkers or algorithms to select chemo-sensitive patients or apply targeted therapy. Here, we carried out retrospective analyses of 1,020 formalin-fixed, paraffin-embedded GC surgical resection samples from 5 hospitals and developed a mass spectrometry-based workflow for proteomic subtyping of GC. We identified two proteomic subtypes: the chemo-sensitive group (CSG) and the chemo-insensitive group (CIG) in the discovery set. The 5-year overall survival of CSG was significantly improved in patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (64.2% vs. 49.6%; Cox P-value=0.002), whereas no such improvement was observed in CIG (50.0% vs. 58.6%; Cox P-value=0.495). We validated these results in an independent validation set. Further, differential proteome analysis uncovered 9 FDA-approved drugs that may be applicable for targeted therapy of GC. A prospective study is warranted to test these findings for future GC patient care.
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http://dx.doi.org/10.1007/s11427-021-1966-4DOI Listing
August 2021

Regulation of humoral immune response by HIF-1α-dependent metabolic reprogramming of the germinal center reaction.

Cell Immunol 2021 Sep 1;367:104409. Epub 2021 Jul 1.

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Hypoxia-inducible factor-1α (HIF-1α) has been implicated in the regulation of many genes responsible for aerobic glycolysis; however, the role of HIF-1α in B-cell metabolism has not been well defined. Here, we analyzed patterns of gene expression and oxygen consumption rates in B-cell subpopulations from humans and mice and described a model of HIF-1α-mediated B-cell metabolic reprogramming during the germinal center (GC) reaction. Importantly, we found that HIF-1α was highly expressed in GC B-cells, and HIF-1α deficiency in B-cells impaired a functional GC reaction, resulting in defective class-switch recombination and generation of high-affinity plasma cells. These results identified an important role of HIF-1α in regulating humoral immunity through metabolic reprogramming during the GC response. This newly discovered metabolic character of GC B-cells will advance our understanding of GC biology and B-cell lymphomagenesis.
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http://dx.doi.org/10.1016/j.cellimm.2021.104409DOI Listing
September 2021

MS1 is essential for male fertility by regulating the microsporocyte cell plate expansion in soybean.

Sci China Life Sci 2021 Sep 2;64(9):1533-1545. Epub 2021 Jul 2.

Innovative Center of Molecular Genetics and Evolution, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China.

Male sterility is an essential trait in hybrid seed production, especially for monoclinous and autogamous food crops. Soybean male-sterile ms1 mutant has been known for more than 50 years and could be instrumental in making hybrid seeds. However, the gene responsible for the male-sterile phenotype has remained unknown. Here, we report the map-based cloning and characterization of the MS1 gene in soybean. MS1 encodes a kinesin protein and localizes to the nucleus, where it is required for the male meiotic cytokinesis after telophase II. We further substantiated that MS1 colocalizes with microtubules and is essential for cell plate formation in soybean male gametogenesis through immunostaining. Both ms1 and CRISPR/Cas9 knockout mutants show complete male sterility but are otherwise phenotypically normal, making them perfect tools for producing hybrid seeds. The identification of MS1 has the practical potential for assembling the sterility system and speeding up hybrid soybean breeding.
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http://dx.doi.org/10.1007/s11427-021-1973-0DOI Listing
September 2021

Relationship between childhood secondhand smoke exposure and the occurrence of hyperlipidaemia and coronary heart disease among Chinese non-smoking women: a cross-sectional study.

BMJ Open 2021 07 5;11(7):e048590. Epub 2021 Jul 5.

Department of Endocrinology, Shandong University Qilu Hospital, Jinan, Shandong, China

Objective: The objective of this study was to evaluate the influence of secondhand smoke (SHS) exposure during childhood on type 2 diabetes mellitus, hypertension, hyperlipidaemia and coronary heart disease among Chinese non-smoking women.

Methods: In this cross-sectional study, the SHS exposure data in childhood were obtained using a questionnaire survey. Self-reported childhood SHS exposure was defined as the presence of at least one parent who smoked during childhood.

Results: Of the 6522 eligible participants, 2120 Chinese women who had never smoked were assessed. The prevalence of SHS exposure in the entire population was 28.1% (596). SHS exposure during childhood was not significant for the standard risk factors of type 2 diabetes mellitus (p=0.628) and hypertension (p=0.691). However, SHS was positively associated with hyperlipidaemia (p=0.037) after adjusting for age, obesity, education status, physical activity, alcohol consumption, current SHS exposure status, diabetes mellitus and hypertension. In addition, childhood SHS increased the occurrence of coronary heart disease (p=0.045) among non-smokers after further adjusting for hyperlipidaemia.

Conclusion: SHS exposure during childhood is associated with prevalent hyperlipidaemia and coronary heart disease in adulthood among non-smoking Chinese women.
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http://dx.doi.org/10.1136/bmjopen-2020-048590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258554PMC
July 2021

Transcription factor PAX4 facilitates gastric cancer progression through interacting with miR-27b-3p/Grb2 axis.

Aging (Albany NY) 2021 06 23;13(12):16786-16803. Epub 2021 Jun 23.

Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China.

Gastric cancer (GC) is one of the most common aggressive cancers. The discovery of an effective biomarker is necessary for GC diagnosis. In this study, we confirmed that Paired box gene 4 (PAX4) is up-regulated in GC tissues and cells via quantitative real time polymerase chain reaction (qRT-PCR), western blot and immunohistochemical staining. It was also identified that PAX4 contributed to GC cell proliferation, migration and invasion through Cell Counting Kit-8, BrdU, flow cytometry assay, colony formation assay, transwell assays, and wound healing assay. miR-27b-3p was confirmed with the binding site with PAX4 using ChIP assay and served as a tumor suppressor that inhibiting GC cell growth and metastasis, and reversed the effect of PAX4. Bioinformatics prediction and dual luciferase assay results demonstrated that miR-27b-3p targeted Grb2, which could alter the function of miR-27b-3p. Furthermore, the transcriptional control of PAX4-regulated miR-27b-3p activated the Ras-ERK pathway. Taken together, the PAX4/miR-27b-3p/Grb2 loop is known to be involved in GC cell promotion, and can be seen as a promising target for GC therapy.
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http://dx.doi.org/10.18632/aging.203214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266315PMC
June 2021

Detecting Periprosthetic Joint Infection by Using Mass Spectrometry.

J Bone Joint Surg Am 2021 Jun 7. Epub 2021 Jun 7.

Department of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China.

Background: Novel methods for diagnosing periprosthetic joint infection (PJI) are currently being explored. Mass spectrometry (MS) is an approach that can detect whole-protein changes in synovial fluid and may represent a promising method.

Methods: Between March 2017 and July 2018, we successively collected synovial fluid samples from patients who were undergoing diagnostic hip or knee aspiration because PJI was suspected. A PJI diagnosis was based on the modified Musculoskeletal Infection Society (MSIS) criteria. Cluster analysis and receiver operating characteristic (ROC) curves were used to evaluate the results, which were quantitatively confirmed with parallel reaction monitoring in another patient group who underwent aspiration between August 2018 and January 2019.

Results: A total of 117 synovial samples, including 51 PJI and 66 non-PJI samples, were analyzed with liquid chromatography-tandem MS (LC-MS/MS). The cluster analysis sensitivity and specificity based on differentially expressed proteins were 0.961 (95% confidence interval [CI], 0.854 to 0.993) and 0.924 (95% CI, 0.825 to 0.972), respectively. Myeloid nuclear differentiation antigen (MNDA) and polymorphonuclear leukocyte serine protease 3 (PRTN3) were the 2 most important markers for detecting PJI. The areas under the curves (AUCs) of MNDA and PRTN3 were 0.969 (95% CI, 0.936 to 1.000) and 0.900 (95% CI, 0.844 to 0.956), respectively. When MNDA and PRTN3 were combined as variables of a predictive model to diagnose PJI, the AUC reached 0.975 (95% CI, 0.943 to 1.000). Our parallel reaction monitoring-based quantitative analysis of another 40 synovial samples confirmed this result.

Conclusions: MS could be a powerful tool for diagnosing PJI using proteome information or 2 specific markers, MNDA and PRTN3. The parallel reaction monitoring strategy simplified the PJI detection process and provided quantitative results with similar conclusions.

Clinical Relevance: The clinical application of MS adds a new powerful tool for the diagnosis of PJI, and the parallel reaction monitoring strategy lays a foundation for the clinical application of MS.

Level Of Evidence: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.20.01944DOI Listing
June 2021

Selective dispersion of neutral nanoplates and the interfacial structure of copolymers based on coarse-grained molecular dynamics simulations.

Soft Matter 2021 Jun 28;17(24):5950-5959. Epub 2021 May 28.

College of Materials and Metallurgy, Guizhou University, Guiyang 550025, China. and National Engineering Research Center for Compounding and Modification of Polymer Materials, Guiyang 550058, China.

The selective dispersion of neutral nanoplates (NNP) and the control of the interfacial structure of copolymers are challenging. In this work, we employ coarse-grained molecular dynamics (CGMD) to investigate the dispersion of NNP and the interfacial structure. The introduction of NNP significantly changes the interfacial structure and formation mechanism of diblock copolymers (DBCP), which is related to the matrix phase, distribution, composition, and length of two different chain segments (A and B) in AB-DBCP. The phase-weak groups that have a poor interaction with NNP will stack easily, whereas the stacking degree for the phase-rich groups that have a strong interaction with NNP decreases due to the addition of NNP. The interaction between two phases will be enhanced, which is favorable for the formation of a random network structure. Due to the strong interaction of the phase-rich groups with NNP, the NNP change the accumulation types of phase-weak groups and enhances the combination of two chain segments in favor of the formation of a cylindrical micelle-like structure. The transmission electron microscopy (TEM) images show that layered double hydroxide (LDH) orientationally distributes in the acrylic acid chain segments in ethylene acrylic acid (EAA) random copolymers, which is in agreement with the theoretical simulation results. This proves that the selective dispersion of LDH in copolymers affects their interfacial structure.
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http://dx.doi.org/10.1039/d1sm00352fDOI Listing
June 2021

Lymphadenectomy Around Inferior Mesenteric Artery in Low-Tie vs High-Tie Laparoscopic Anterior Resection: Short- and Long-Term Outcome of a Cohort of 614 Rectal Cancers.

Cancer Manag Res 2021 14;13:3963-3971. Epub 2021 May 14.

Department of Gastrointestinal Surgery, Renji Hospital, Jiao Tong University School of Medicine, Shanghai, 200127, People's Republic of China.

Background: Preservation of the left colic artery in low-tie (LT) of inferior mesenteric artery remains controversial compared to high-tie (HT) in the colon and rectal cancers, for lymph node dissection, anastomotic leakage, and oncological outcome. This cohort study aims to analyze short- and long-term outcomes of laparoscopic anterior resections in LT vs HT for rectal cancers.

Methods: We analyzed a cohort of laparoscopic AR for RC from 2013 to 2016 at Renji Hospital, Shanghai, China. Short- and long-term outcome in LT vs HT group were compared for clinico-demographic characteristics, operative-time, lymph node dissection, short-term 30-day outcome, and long-term 3- and 5-year overall survival as well as disease-free survival. The x, -test, and logistic regressions analysis were used and p<0.05 was considered significant.

Results: The cohort consisted of 614 laparoscopic AR with LT (236) and HT (378). The clinicodemographic characteristics were comparable among the groups. The surgery took longer in LT. The yield of LND was similar. Leakage occurred in 12.21% (n=75). Leakage was fewer in LT than HT, 8.89% vs 14.28%, p=0.047. The postoperative severe complications were higher in HT. The 30-day mortality was nil. The long-term 3- and 5-year overall survival and disease-free survival were similar in LT and HT.

Conclusion: The LT with preservation of left colic artery had similar lymph node yield, but lower leakage and complications than HT in laparoscopic anterior resections for rectal cancers. The long-term 3- and 5-year overall and disease-free survival were similar in the two groups.
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http://dx.doi.org/10.2147/CMAR.S282986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131009PMC
May 2021

Endoplasmic reticulum stress regulates the intestinal stem cell state through CtBP2.

Sci Rep 2021 May 10;11(1):9892. Epub 2021 May 10.

Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, Amsterdam, The Netherlands.

Enforcing differentiation of cancer stem cells is considered as a potential strategy to sensitize colorectal cancer cells to irradiation and chemotherapy. Activation of the unfolded protein response, due to endoplasmic reticulum (ER) stress, causes rapid stem cell differentiation in normal intestinal and colon cancer cells. We previously found that stem cell differentiation was mediated by a Protein kinase R-like ER kinase (PERK) dependent arrest of mRNA translation, resulting in rapid protein depletion of WNT-dependent transcription factor c-MYC. We hypothesize that ER stress dependent stem cell differentiation may rely on the depletion of additional transcriptional regulators with a short protein half-life that are rapidly depleted due to a PERK-dependent translational pause. Using a novel screening method, we identify novel transcription factors that regulate the intestinal stem cell fate upon ER stress. ER stress was induced in LS174T cells with thapsigargin or subtilase cytotoxin (SubAB) and immediate alterations in nuclear transcription factor activity were assessed by the CatTFRE assay in which transcription factors present in nuclear lysate are bound to plasmid DNA, co-extracted and quantified using mass-spectrometry. The role of altered activity of transcription factor CtBP2 was further examined by modification of its expression levels using CAG-rtTA3-CtBP2 overexpression in small intestinal organoids, shCtBP2 knockdown in LS174T cells, and familial adenomatous polyposis patient-derived organoids. CtBP2 overexpression organoids were challenged by ER stress and ionizing irradiation. We identified a unique set of transcription factors with altered activation upon ER stress. Gene ontology analysis showed that transcription factors with diminished binding were involved in cellular differentiation processes. ER stress decreased CtBP2 protein expression in mouse small intestine. ER stress induced loss of CtBP2 expression which was rescued by inhibition of PERK signaling. CtBP2 was overexpressed in mouse and human colorectal adenomas. Inducible CtBP2 overexpression in organoids conferred higher clonogenic potential, resilience to irradiation-induced damage and a partial rescue of ER stress-induced loss of stemness. Using an unbiased proteomics approach, we identified a unique set of transcription factors for which DNA-binding activity is lost directly upon ER stress. We continued investigating the function of co-regulator CtBP2, and show that CtBP2 mediates ER stress-induced loss of stemness which supports the intestinal stem cell state in homeostatic stem cells and colorectal cancer cells.
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http://dx.doi.org/10.1038/s41598-021-89326-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111031PMC
May 2021

The Establishment of New Thresholds for PLND-Validated Clinical Nomograms to Predict Non-Regional Lymph Node Metastases: Using Ga-PSMA PET/CT as References.

Front Oncol 2021 15;11:658669. Epub 2021 Apr 15.

Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Purpose: PLND (pelvic lymph node dissection)-validated nomograms are widely accepted clinical tools to determine the necessity of PLND by predicting the metastasis of lymph nodes (LNMs) in pelvic region. However, these nomograms are in lacking of a threshold to predict the metastasis of extrareolar lymph nodes beyond pelvic region, which is not suitable for PLND. The aim of this study is to evaluate a threshold can be set for current clinical PLND-validated nomograms to predict extrareolar LN metastases beyond pelvic region in high-risk prostate cancer patients, by using Ga-PSMA PET/CT as a reference to determine LN metastases (LNMs).

Experimental Design: We performed a retrospective analysis of 57 high-risk treatment-naïve PC patients in a large tertiary care hospital in China who underwent Ga-PSMA-617 PET/CT imaging. LNMs was detected by Ga-PSMA-617 PET/CT and further determined by imaging follow-up after anti-androgen therapy. The pattern of LN metastatic spread of PC patients were evaluated and analyzed. The impact of Ga-PSMA PET/CT on clinical decisions based on three clinical PLND-validated nomograms (Briganti, Memorial Sloan Kettering Cancer Center, Winter) were evaluated by a multidisciplinary prostate cancer therapy team. The diagnostic performance and the threshold of these nomograms in predicting extrareolar LNMs metastasis were evaluated receiver operating characteristic (ROC) curve analysis.

Results: LNMs were observed in 49.1% of the patients by Ga-PSMA PET/CT, among which 65.5% of LNMs were pelvic-regional and 34.5% of LNMs were observed in extrareolar sites (52.1% of these were located above the diaphragm). The Briganti, MSKCC and Winter nomograms showed that 70.2%-71.9% of the patients in this study need to receive ePLND according to the EAU and NCCN guidelines. The LN staging information obtained from Ga-PSMA PET/CT would have led to changes of planned management in 70.2% of these patients, including therapy modality changes in 21.1% of the patients, which were mainly due to newly detected non-regional LNMs. The thresholds of nomograms to predict non-regional LNMs were between 64% and 75%. The PC patients with a score >64% in Briganti nomogram, a score >75% in MSKCC nomogram and a score >67% in Winter nomogram were more likely to have non-regional LNMs. The AUCs (Area under curves) of the clinical nomograms (Briganti, MSKCC and Winter) in predicting non-regional LNMs were 0.816, 0.830 and 0.793, respectively.

Conclusions: By using Ga-PSMA PET/CT as reference of LNM, the PLND-validated clinical nomograms can not only predict regional LNMs, but also predict non-regional LNMs. The additional information from Ga-PSMA PET/CT may provide added benefit to nomograms-based clinical decision-making in more than two-thirds of patients for reducing unnecessary PLND. We focused on that a threshold can be set for current clinical PLND-validated nomograms to predict extrareolar LN metastases with an AUC accuracy of about 80% after optimizing the simple nomograms which may help to improve the efficiency for PC therapy significantly in clinical practice.
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http://dx.doi.org/10.3389/fonc.2021.658669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082014PMC
April 2021

The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability.

Mol Cell 2021 07 30;81(13):2736-2751.e8. Epub 2021 Apr 30.

CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China. Electronic address:

Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5 intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.
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http://dx.doi.org/10.1016/j.molcel.2021.04.009DOI Listing
July 2021

Phosphorylation of Kindlins and the Control of Integrin Function.

Cells 2021 Apr 7;10(4). Epub 2021 Apr 7.

Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Integrins serve as conduits for the transmission of information between cells and their extracellular environment. Signaling across integrins is bidirectional, transducing both inside-out and outside-signaling. Integrin activation, a transition from a low affinity/avidity state to a high affinity/avidity state for cognate ligands, is an outcome of inside-signaling. Such activation is particularly important for the recognition of soluble ligands by blood cells but also influences cell-cell and cell-matrix interactions. Integrin activation depends on a complex series of interactions, which both accelerate and inhibit their interconversion from the low to the high affinity/avidity state. There are three components regarded as being most proximately involved in integrin activation: the integrin cytoplasmic tails, talins and kindlins. The participation of each of these molecules in integrin activation is highly regulated by post-translation modifications. The importance of targeted phosphorylation of integrin cytoplasmic tails and talins in integrin activation is well-established, but much less is known about the role of post-translational modification of kindlins. The kindlins, a three-member family of 4.1-ezrin-radixin-moesin (FERM)-domain proteins in mammals, bind directly to the cytoplasmic tails of integrin beta subunits. This commentary provides a synopsis of the emerging evidence for the role of kindlin phosphorylation in integrin regulation.
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http://dx.doi.org/10.3390/cells10040825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067640PMC
April 2021

Self-reported snoring is associated with chronic kidney disease in obese but not in normal-weight Chinese adults.

Ren Fail 2021 Dec;43(1):709-717

Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Background: The relationship between sleeping disorders and chronic kidney disease (CKD) has already been reported. Snoring, a common clinical manifestation of obstructive sleep apnea-hypopnea syndrome, is of clinical value in assessing sleeping disorder severity. However, investigations of the connection between snoring and CKD are limited, especially in normal-weight populations. This study assessed the relationship between snoring frequency and CKD in obese and normal-weight people in China.

Methods: A community-based retrospective cross-sectional study of 3250 participants was performed. Study participants were divided into three groups - the regularly snoring group, occasionally snoring group, and never snoring group - based on their self-reported snoring frequency. CKD was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m. Multiple logistic regression analysis was used to explore the relevance between snoring frequency and CKD prevalence.

Results: The CKD prevalence in obese participants was higher than that in normal-weight participants. Frequent snorers had a higher prevalence of CKD than those who were not frequent snorers in the obese group. Snoring frequency was correlated with CKD prevalence in obese participants independent of age, sex, smoking and drinking status, systolic blood pressure, triglyceride level, high-density lipoprotein, and homeostasis model assessment of insulin resistance (odds ratio: 2.66; 95% CI: 1.36-5.19; =.004), while the same relationships did not exist in normal-weight participants (odds ratio: 0.79; 95% CI: 0.32-1.98; =.614).

Conclusions: Snoring appears to be independently associated with CKD in obese but not in normal-weight Chinese adults.
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http://dx.doi.org/10.1080/0886022X.2021.1915332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079005PMC
December 2021

Molecular basis for Ras suppressor-1 binding to PINCH-1 in focal adhesion assembly.

J Biol Chem 2021 Jan-Jun;296:100685. Epub 2021 Apr 21.

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Ohio, USA; Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA. Electronic address:

Ras suppressor-1 (Rsu-1) is a leucine-rich repeat (LRR)-containing protein that is crucial for regulating cell adhesion and is involved in such physiological and pathological processes as focal adhesion assembly and tumor metastasis. Rsu-1 interacts with zinc-finger type multi-LIM domain-containing adaptor protein PINCH-1, known to be involved in the integrin-mediated consensus adhesome, but not with its highly homologous family member PINCH-2. However, the structural basis for and regulatory mechanisms of this specific interaction remain unclear. Here, we determined the crystal structures of Rsu-1 and its complex with the PINCH-1 LIM4-5 domains. Rsu-1 displays an arc-shaped solenoid architecture, with eight LRRs shielded by N- and C-terminal capping modules. We showed that the conserved concave surface of the Rsu-1 LRR domain binds and stabilizes the PINCH-1 LIM5 domain via salt bridge and hydrophobic interactions, while the C-terminal non-LIM region of PINCH-2 sterically disfavors Rsu-1 binding. We also showed that Rsu-1 can be assembled, via PINCH-1-binding, into a heteropentamer complex comprising Rsu-1, PINCH-1, ILK, Parvin, and Kindlin-2, which constitute a major consensus integrin adhesome crucial for focal adhesion assembly. Our mutagenesis and cell biological data emphasize the significance of the Rsu-1/PINCH-1 interaction in focal adhesion assembly and cell spreading, providing crucial molecular insights into Rsu-1-mediated cell adhesion with implications for disease development.
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http://dx.doi.org/10.1016/j.jbc.2021.100685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141872PMC
August 2021

Safety and Effectiveness of Orthopaedic Medical Staff in Providing Support in Combating the COVID-19 Pandemic: A Retrospective Investigation from Wuhan, China.

Orthop Surg 2021 May 8;13(3):778-785. Epub 2021 Mar 8.

Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.

Objective: To evaluate whether it is safe and effective for orthopaedic medical staff to provide support to the work against COVID-19.

Methods: One hundred and twenty-two orthopaedic medical staff from the orthopaedic center of Zhongnan Hospital of Wuhan University were included in this retrospective investigation. A total of 43 surgeons and 69 nurses provided medical support in the treatment of COVID-19 patients from 1 January 2020 to 8 April 2020 in four different hospitals in Wuhan. We collected data on the age, gender, and body temperature of orthopaedic medical staff, as well as the results for their chest CT scans, SARS-CoV-2 RNA, SARS-CoV-2 IgM and SARS-CoV-2 IgG tests, and training and examinations on COVID-19 knowledge. We also collected data on the time span of work, the number of infected staff during the support period, the number of COVID-19 patients the surgeons treated and the cure rate, the performance of the surgeons as assessed by the specialists and patients, and the number of infected staff during the pandemic.

Results: Among the 49 surgeons and 73 nurses, 43 surgeons and 69 nurses provided support against COVID-19. A total of 12 surgeons and 11 nurses provided support in the fields of respiration, intensive care, and emergency. A total of 34 surgeons and 58 nurses worked in the designated wards restructured for COVID-19 in the orthopaedic building. The average time span of work for the surgeons and nurses was 14.78 ± 3.64 days and 24.77 ± 7.58 days, respectively. No staff were infected during the support period. Over 1000 patients were received in the fever clinic by orthopaedic surgeons. The overall number of the treated hospitalized patients was 622. Among these patients, 226 cases were mild, 318 were mild to moderate, and 58 were severe or critical. The cure rate was 96.01%, 99.37%, and 52.00% respectively. The performance of the surgeons was scored 87.02 ± 3.17 and 90.69 ± 3.58 by the specialists and the patients, respectively. During the whole pandemic, 3 surgeons and 3 nurses who did not participate in the support work were infected in the early stages. The morbidity of all the orthopaedic staff was 4.92% during the whole pandemic, while no one was infected during the support work.

Conclusion: Our investigation indicated that although they worked outside their specialty, it was safe and effective for the orthopaedic staff to provide medical support in the work against COVID-19 with adequate precautions and proper training.
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http://dx.doi.org/10.1111/os.12898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126947PMC
May 2021

The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration.

PLoS Biol 2021 02 25;19(2):e3001122. Epub 2021 Feb 25.

MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.

The Hippo-YAP pathway responds to diverse environmental cues to manage tissue homeostasis, organ regeneration, tumorigenesis, and immunity. However, how phosphatase(s) directly target Yes-associated protein (YAP) and determine its physiological activity are still inconclusive. Here, we utilized an unbiased phosphatome screening and identified protein phosphatase magnesium-dependent 1A (PPM1A/PP2Cα) as the bona fide and physiological YAP phosphatase. We found that PPM1A was associated with YAP/TAZ in both the cytoplasm and the nucleus to directly eliminate phospho-S127 on YAP, which conferring YAP the nuclear distribution and transcription potency. Accordingly, genetic ablation or depletion of PPM1A in cells, organoids, and mice elicited an enhanced YAP/TAZ cytoplasmic retention and resulted in the diminished cell proliferation, severe gut regeneration defects in colitis, and impeded liver regeneration upon injury. These regeneration defects in murine model were largely rescued via a genetic large tumor suppressor kinase 1 (LATS1) deficiency or the pharmacological inhibition of Hippo-YAP signaling. Therefore, we identify a physiological phosphatase of YAP/TAZ, describe its critical effects in YAP/TAZ cellular distribution, and demonstrate its physiological roles in mammalian organ regeneration.
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http://dx.doi.org/10.1371/journal.pbio.3001122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978383PMC
February 2021

YEATS4 is associated with poor prognosis and promotes epithelial-to-mesenchymal transition and metastasis by regulating ZEB1 expression in breast cancer.

Am J Cancer Res 2021 1;11(2):416-440. Epub 2021 Feb 1.

Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200080, China.

YEATS domain-containing protein 4 (YEATS4) is implicated in several oncogenic signaling pathways, and its expression is involved in various types of cancer; regardless, the pathophysiologic effects of YEATS4 on breast cancer remain unclear. This study finds that YEATS4 is increasingly expressed with breast cancer progression, and its expression is related to poor outcome and distant metastasis. YEATS4 overexpression in breast cancer cells strengthens their malignant characteristics and , particularly inducing epithelial-to-mesenchymal transition (EMT) and consequently, metastatic capability in breast cancer cells. By contrast, deleting YEATS4 in breast cancer cells with high-grade malignancy reduced these characteristics. With regard to the molecular mechanism, YEATS4 mediates histone H3K27ac at specific sites of the ZEB1 promoter to regulate its expression at the transcription level. Depleting ZEB1 blocks YEATS4-induced EMT, migration, invasion, and metastasis. YEATS4 expression is also positively correlated with ZEB1 expression in patients with breast cancer. Co-expression of YEATS4 and ZEB1 correlates with the shortest distant metastasis-free period. Taken together, our data reveal the critical role of YEATS4 in the progression and metastasis of breast cancer, as well as support YEATS4 as a potential therapeutic target and prognostic biomarker for breast cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868763PMC
February 2021

Author Correction: ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions.

Nat Cell Biol 2021 Mar;23(3):293

MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.

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http://dx.doi.org/10.1038/s41556-021-00638-5DOI Listing
March 2021

Tumor-associated antigen Prame targets tumor suppressor p14/ARF for degradation as the  receptor protein of CRL2 complex.

Cell Death Differ 2021 Jun 27;28(6):1926-1940. Epub 2021 Jan 27.

Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.

Protein Preferentially Expressed Antigen in Melanoma (Prame), a tumor-associated antigen, has been found to frequently overexpress in various cancers, which indicates advanced cancer stages and poor clinical prognosis. Moreover, previous reports noted that Prame functions as a substrate recognizing receptor protein of Cullin RING E3 ligases (CRLs) to mediate potential substrates degradation through Ubiquitin Proteasome System (UPS). However, none of the Prame specific substrate has been identified so far. In this study, proteomic analysis of RBX1-interacting proteins revealed p14/ARF, a well-known tumor suppressor, as a novel ubiquitin target of RBX1. Subsequently, immunoprecipitation and in vivo ubiquitination assay determined Cullin2-RBX1-Transcription Elongation Factor B Subunit 2 (EloB) assembled CRL2 E3 ligase complex to regulate the ubiquitination and subsequent degradation of p14/ARF. Finally, through siRNA screening, Prame was identified as the specific receptor protein responsible for recognizing p14/ARF to be degraded. Additionally, via bioinformatics analysis of TCGA database and clinical samples, Prame was determined to overexpress in tumor tissues vs. paired adjacent tissues and associated with poor prognosis of cancer patients. As such, downregulation of Prame expression significantly restrained cancer cell growth by inducing G2/M phase cell cycle arrest, which could be rescued by simultaneously knocking down of p14/ARF. Altogether, targeting overexpressed Prame in cancer cells inactivated RBX1-Cullin2-EloB-Prame E3 ligase (CRL2) and halted p14/ARF degradation to restrain tumor growth by inducing G2/M phase cell cycle arrest.
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http://dx.doi.org/10.1038/s41418-020-00724-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184998PMC
June 2021

Knockdown of circPUM1 impedes cell growth, metastasis and glycolysis of papillary thyroid cancer via enhancing MAPK1 expression by serving as the sponge of miR-21-5p.

Genes Genomics 2021 02 22;43(2):141-150. Epub 2021 Jan 22.

Department of General Surgery, Heping Hospital Affiliated to Changzhi Medical College, No. 110, Yan'an South Road, Changzhi, 046000, Shanxi Province, China.

Background: Circular RNAs (circRNAs) are a crucial class of regulatory RNAs in cancer procession, including papillary thyroid cancer (PTC). Circ-Pumilio 1 (circPUM1) is a novel circRNA with the oncogenic function in ovarian cancer and lung cancer. However, the role of circPUM1 in PTC is undiscovered.

Objective: This study was performed to investigate the biological function and molecular mechanism of circPUM1 in PTC.

Methods: CircPUM1 and microRNA-21-5p (miR-21-5p) levels were analyzed via quantitative real-time polymerase chain reaction (qRT-PCR). Cellular viability and metastasis were measured using Cell Counting Kit 8 (CCK-8) and transwell migration/invasion assay. Glycolysis was evaluated by glucose uptake and lactate production. Associated proteins were examined applying with western blot. Dual-luciferase reporter assay and RNA pull-down assay were used to analyze the interaction between circPUM1 or mitogen-activated protein kinase 1 (MAPK1) and miR-21-5p. Moreover, the role of circPUM1 in vivo was explored by xenograft tumor experiment.

Results: Significantly, circPUM1 was upregulated in PTC tissue samples and cells. Cell growth, metastasis and glycolytic process of PTC cells were all inhibited after downregulation of circPUM1. Besides, circPUM1 could sponge miR-21-5p and MAPK1 was a target gene of miR-21-5p. Furthermore, we found that the anti-cancer effect of circPUM1 knockdown on PTC was partly ascribed to MAPK1 downregulation by upregulating miR-21-5p. Silencing circPUM1 also impeded tumorigenesis of PTC in vivo via miR-21-5p/MAPK1 axis.

Conclusion: These findings suggested that circPUM1 knockdown inhibited MAPK1 expression by targeting miR-21-5p, consequently leading to the repressive effect on PTC progression. CircPUM1 might be a promising target to improve the diagnosis and treatment of PTC.
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http://dx.doi.org/10.1007/s13258-020-01023-6DOI Listing
February 2021

Changes in the Microbiome in the Soil of an American Ginseng Continuous Plantation.

Front Plant Sci 2020 7;11:572199. Epub 2020 Dec 7.

State Key Laboratory of Crop Stress Biology in Arid Areas and College of Plant Protection, Northwest A&F University, Yangling, China.

American ginseng is an important herbal medicinal crop in China. In recent years, there has been an increasing market demand for ginseng, but the production area has been shrinking due to problems associated with continuous monocropping. We analyzed the microbiome in bulk soils to assess whether and, if so, what changes in the bulk soil microbiome are associated with continuous American ginseng cropping. The alpha diversity of fungi and bacteria was significantly lower in the soils planted with American ginseng than the virgin (non-planted) land. The relative abundance of spp. and spp., known plant root pathogens, was much higher in the soils cropped with American ginseng than the non-planted. On the other hand, a number of bacteria with biodegradation function, such as spp., spp., spp., and spp., had lower abundance in the soils cropped with American ginseng than the non-cropped. In addition, soil pH was lower in the field planted with American ginseng than the non-planted. Accumulation of fungal root pathogens and reduction of soil pH may, therefore, have contributed to the problems associated with continuous monocropping of American ginseng.
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http://dx.doi.org/10.3389/fpls.2020.572199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750500PMC
December 2020
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