Publications by authors named "Hai Zhu"

196 Publications

Integrative Network Analysis Revealed Genetic Impact of Pyruvate Kinase L/R on Hepatocyte Proliferation and Graft Survival after Liver Transplantation.

Oxid Med Cell Longev 2021 2;2021:7182914. Epub 2021 Sep 2.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.

Background: Pyruvate kinase L/R (PKLR) has been suggested to affect the proliferation of hepatocytes via regulation of the cell cycle and lipid metabolism. However, its impact on the global metabolome and its clinical implications remain unclear.

Aims: We aimed to clarify the genetic impact of PKLR on the metabolomic profiles of hepatoma cells and its potential effects on grafts for liver transplantation (LT).

Methods: Nontargeted and targeted metabolomic assays were performed in human hepatoma cells transfected with lentiviral vectors causing PKLR overexpression and silencing, respectively. We then constructed a molecular network based on integrative analysis of transcriptomic and metabolomic data. We also assessed the biological functions of PKLR in the global metabolome in LT grafts in patients via a weighted correlation network model.

Results: Multiomic analysis revealed that PKLR perturbations significantly affected the pyruvate, citrate, and glycerophospholipid metabolism pathways, as crucial steps in de novo lipogenesis (DNL). We also confirmed the importance of phosphatidylcholines (PC) and its derivative lyso-PC supply on improved survival of LT grafts in patients. Coexpression analysis revealed beneficial effects of PKLR overexpression on posttransplant prognosis by alleviating arachidonic acid metabolism of the grafts, independent of operational risk factors.

Conclusion: This systems-level analysis indicated that PKLR affected hepatoma cell viability via impacts on the whole process of DNL, from glycolysis to final PC synthesis. PKLR also improved prognosis after LT, possibly via its impact on the increased genesis of beneficial glycerophospholipids.
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http://dx.doi.org/10.1155/2021/7182914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429008PMC
September 2021

Therapeutic effects of bone marrow mesenchymal stem cells-derived exosomes on osteoarthritis.

J Cell Mol Med 2021 Aug 27. Epub 2021 Aug 27.

Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, China.

Mesenchymal stem cells (MSCs) have shown chondroprotective effects in clinical models of osteoarthritis (OA). However, effects of MSC-derived exosomes on OA remain unclear. The study aimed to investigate the therapeutic potential of exosomes from human bone marrow MSCs (BM-MSCs) in alleviating OA. The anterior cruciate ligament transection (ACLT) and destabilization of the medial meniscus (DMM) surgery were performed on the knee joints of a rat OA model, followed by intra-articular injection of BM-MSCs or their exosomes. In addition, BM-MSC-derived exosomes were administrated to primary human chondrocytes to observe the functional and molecular alterations. Both of BM-MSCs and BM-MSC-derived exosomes alleviated cartilage destruction and subchondral bone remodelling in OA rat model. Administration of BM-MSCs and exosomes could reduce joint damage and restore the trabecular bone volume fraction, trabecular number and connectivity density of OA rats. In addition, in vitro assays showed that BM-MSCs-exosomes could maintain the chondrocyte phenotype by increasing collagen type II synthesis and inhibiting IL-1β-induced senescence and apoptosis. Furthermore, exosomal lncRNA MEG-3 also reduced the senescence and apoptosis of chondrocytes induced by IL-1β, indicating that lncRNA MEG-3 might partially account the anti-OA effects of BM-MSC exosomes. The exosomes from BM-MSCs exerted beneficial therapeutic effects on OA by reducing the senescence and apoptosis of chondrocytes, suggesting that MSC-derived exosomes might provide a candidate therapy for OA treatment.
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http://dx.doi.org/10.1111/jcmm.16860DOI Listing
August 2021

Phytophthora infection signals-induced translocation of NAC089 is required for endoplasmic reticulum stress response-mediated plant immunity.

Plant J 2021 Aug 10. Epub 2021 Aug 10.

The Key Laboratory of Plant Immunity, College of Plant Protection, Nanjing Agricultural University, Nanjing, 210095, China.

Plants deploy various immune receptors to recognize pathogen-derived extracellular signals and subsequently activate the downstream defense response. Recently, increasing evidence indicates that the endoplasmic reticulum (ER) plays a part in the plant defense response, known as ER stress-mediated immunity (ERSI), that halts pathogen infection. However, the mechanism for the ER stress response to signals of pathogen infection remains unclear. Here, we characterized the ER stress response regulator NAC089, which was previously reported to positively regulate programed cell death (PCD), functioning as an ERSI regulator. NAC089 translocated from the ER to the nucleus via the Golgi in response to Phytophthora capsici culture filtrate (CF), which is a mixture of pathogen-associated molecular patterns (PAMPs). Plasma membrane localized co-receptor BRASSINOSTEROID INSENSITIVE 1-associated receptor kinase 1 (BAK1) was required for the CF-mediated translocation of NAC089. The nuclear localization of NAC089, determined by the NAC domain, was essential for immune activation and PCD. Furthermore, NAC089 positively contributed to host resistance against the oomycete pathogen P. capsici and the bacteria pathogen Pseudomonas syringae pv. tomato (Pst) DC3000. We also proved that NAC089-mediated immunity is conserved in Nicotiana benthamiana. Together, we found that PAMP signaling induces the activation of ER stress in plants, and that NAC089 is required for ERSI and plant resistance against pathogens.
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http://dx.doi.org/10.1111/tpj.15425DOI Listing
August 2021

Matching sensor ontologies through siamese neural networks without using reference alignment.

PeerJ Comput Sci 2021 18;7:e602. Epub 2021 Jun 18.

Intelligent Information Processing Research Center, Fujian University of Technology, Fuzhou, Fujian, China.

Sensors have been growingly used in a variety of applications. The lack of semantic information of obtained sensor data will bring about the heterogeneity problem of sensor data in semantic, schema, and syntax levels. To solve the heterogeneity problem of sensor data, it is necessary to carry out the sensor ontology matching process to determine correspondences among heterogeneous sensor concepts. In this paper, we propose a Siamese Neural Network based Ontology Matching technique (SNN-OM) to align the sensor ontologies, which does not require the utilization of reference alignment to train the network model. In particular, a representative concepts extraction method is presented to enhance the model's performance and reduce the time of the training process, and an alignment refining method is proposed to enhance the alignments' quality by removing the logically conflict correspondences. The experimental results show that SNN-OM is capable of efficiently determining high-quality sensor ontology alignments.
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http://dx.doi.org/10.7717/peerj-cs.602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237319PMC
June 2021

Mitochondria-acting carrier-free nanoplatform self-assembled by α-tocopheryl succinate carrying cisplatin for combinational tumor therapy.

Regen Biomater 2021 Aug 30;8(4):rbab029. Epub 2021 Jun 30.

National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.

Unsatisfactory drug loading capability, potential toxicity of the inert carrier and the limited therapeutic effect of a single chemotherapy drug are all vital inhibitory factors of carrier-assisted drug delivery systems for chemotherapy. To address the above obstacles, a series of carrier-free nanoplatforms self-assembled by dual-drug conjugates was constructed to reinforce chemotherapy against tumors by simultaneously disrupting intratumoral DNA activity and inhibiting mitochondria function. In this nanoplatform, the mitochondria-targeting small-molecular drug, α-tocopheryl succinate (TOS), firstly self-assembled into nanoparticles, which then were used as the carrier to conjugate cisplatin (CDDP). Systematic characterization results showed that this nanoplatform exhibited suitable particle size and a negative surface charge with good stability in physicochemical environments, as well as pH-sensitive drug release and efficient cellular uptake. Due to the combined effects of reactive oxygen species (ROS) generation by TOS and DNA damage by CDDP, the developed nanoplatform could induce mitochondrial dysfunction and elevated cell apoptosis, resulting in highly efficient anti-tumor outcomes . Collectively, the combined design principles adopted for carrier-free nanodrugs construction in this study aimed at targeting different intracellular organelles for facilitating ROS production and DNA disruption can be extended to other carrier-free nanodrugs-dependent therapeutic systems.
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http://dx.doi.org/10.1093/rb/rbab029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242230PMC
August 2021

Targeting peripheral immune organs with self-assembling prodrug nanoparticles ameliorates allogeneic heart transplant rejection.

Am J Transplant 2021 Jul 1. Epub 2021 Jul 1.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Organ transplantation has become a mainstay of therapy for patients with end-stage organ diseases. However, long-term administration of immunosuppressive agents, a scheme for improving the survival of transplant recipients, has been compromised by severe side effects and posttransplant complications. Therapeutic delivery targeting immune organs has the potential to address these unmet medical issues. Here, through screening of a small panel of mammalian target of rapamycin complex kinase inhibitor (TORKinib) compounds, a TORKinib PP242 is identified to be able to inhibit T cell function. Further chemical derivatization of PP242 using polyunsaturated fatty acids (i.e., docosahexaenoic acid) transforms this water-insoluble hydrophobic agent into a self-assembling nanoparticle (DHA-PP242 nanoparticle [DPNP]). Surface PEGylation of DPNP with amphiphilic copolymers renders the nanoparticles aqueously soluble for preclinical studies. Systemically administered DPNP shows tropism for macrophages within peripheral immune organs. Furthermore, DPNP regulates differentiation of adoptively transferred T cells in a macrophage-dependent manner in Rag1-/- mouse model. In an experimental model of heart transplantation, DPNP significantly extends the survival of grafts through inducing immune suppression, thus reducing the inflammatory response of the recipients. These findings suggest that targeted delivery of TORKinibs exploiting prodrug-assembled nanoparticle scaffolds may provide a therapeutic option against organ rejection.
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http://dx.doi.org/10.1111/ajt.16748DOI Listing
July 2021

Inflammatory Markers and Duration of Symptoms Have a Close Connection With Diagnosis and Staging of Acute Appendicitis in Children.

Front Pediatr 2021 4;9:583719. Epub 2021 Jun 4.

Department of Pediatric General Surgery and Liver Transplantation, Children's Hospital, Chongqing Medical University, Chongqing, China.

For children with acute appendicitis (AA), a clear diagnosis is a challenge. The purpose of this study is to explore whether inflammatory markers in the blood combined with symptom duration are helpful in the diagnosis of acute appendicitis and in predicting the severity of acute appendicitis. All the selected patients underwent appendectomy between November 10, 2011 and November 15, 2019, in whom preoperative WBCC, CRP, and NE% had been measured in a short time. All patients were divided into two groups: uncomplicated AA and complicated AA, postoperatively. For our standards, 813 patients were selected, 442 of them had complicated AA. The mean [standard deviation (SD)] age for the uncomplicated AA group was 9.78 ± 2.02 years and for the complicated AA group was 9.69 ± 2.16 years ( = 0.55). Elevated WBCC, CRP, and NE% had a higher relatively sensitivity in complicated AA than uncomplicated AA especially when WBCC, CRP, and NE% were at normal levels, which had a sensitivity of 100% in uncomplicated AA, but this only applied to nine patients. CRP values were significantly different in three time groups, whether uncomplicated or complicated AA. The combination of WBCC, CRP, and NE% values is very sensitive for the diagnosis of acute appendicitis, and when we predict complicated AA using the CRP value, we also need to consider the time of symptom onset.
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http://dx.doi.org/10.3389/fped.2021.583719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212955PMC
June 2021

Low expression of developing brain homeobox 2 (Dbx2) may serve as a biomarker to predict poor prognosis in endometrial cancer.

Am J Transl Res 2021 15;13(5):4738-4748. Epub 2021 May 15.

Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou University Zhengzhou 450000, Henan, P. R. China.

Objective: For investigating Dbx2's expression in endometrial cancer (EC) and its effect on prognosis of patients with EC.

Methods: A comparison was performed in the Cancer Genome Atlas (TCGA) database in terms of the expression profiling of EC and the survival data. To obtain differential expression genes (DEGs), Volcano plot and Venn analysis were adopted. DEGs function was performed by carrying out the GO annotation analysis (GO) and gene set enrichment analysis (GSEA). In clinical EC samples, PCR was applied to the verification of Dbx2's expression.

Results: Dbx2 was a downregulated expression in tumor tissues. Dbx2 can have a poor prognosis role in EC by regulating the apoptotic signaling pathway and the immune pathway. Lower expression of Dbx2 was related to lymph node metastasis and FIGO stage.

Conclusion: Dbx2 is downregulated in endometrial cancer, which serves as a biomarker to predict poor prognosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205784PMC
May 2021

The stabilization of yes-associated protein by TGFβ-activated kinase 1 regulates the self-renewal and oncogenesis of gastric cancer stem cells.

J Cell Mol Med 2021 Jul 1;25(14):6584-6601. Epub 2021 Jun 1.

Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China.

Gastric cancer (GC) is the most frequent digestive system malignant tumour and the second most common cause of cancer death globally. Cancer stem cell (CSC) is a small percentage of cancer cells in solid tumours that have differentiation, self-renewal and tumorigenic capabilities. They have an active participation in the initiation, development, metastasis, recurrence and resistance of tumours to chemotherapy and radiotherapy. Gastric cancer stem cells (GCSCs) have been shown to be correlated with GC initiation and metastasis. In this study, we found that TAK1 expression level in GC tissues was significantly increased compared to the adjacent non-cancerous tissues by RT-qPCR, Western blot and immunohistochemistry. TAK1 has been identified as a critical molecule that promoted a variety of malignant GC phenotypes both in vivo and in vitro and promoted the self-renewal of GCSCs. Mechanistically, TAK1 was up-regulated by IL-6 and prevented the degradation of yes-associated protein (YAP) in the cytoplasm by binding to YAP. Thus, TAK1 promoted the SOX2 and SOX9 transcription and the self-renewal and oncogenesis of GCSCs. Our findings provide insights into the mechanism of self-renewal and tumorigenesis of TAK1 in GCSCs and have broad implications for clinical therapies.
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http://dx.doi.org/10.1111/jcmm.16660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278074PMC
July 2021

[Comparison of Available Nitrogen and Phosphorus Characteristics in the Land-Water Transition Zone of Different Watersheds and Their Environmental Significance].

Huan Jing Ke Xue 2021 Jun;42(6):2787-2795

College of Environment, Hohai University, Nanjing 210098, China.

In order to explore the characteristics and environmental significance of available nitrogen and phosphorus in different land-water transition zones, soil and sediment samples from three study areas, including the upstream watershed of Minjiang River (MJU), western watershed of Hongze Lake (HZW), and western watershed of Taihu Lake (THW), were collected and analyzed. The results showed that the contents of total nitrogen and phosphorus in THW were higher than those of other two study areas. The contents of nitrogen and phosphorus in sediments were higher than those in soils of HZW. The distribution trend of available nitrogen and available phosphorus was generally consistent with the distribution trend of total nitrogen and phosphorus. The proportions of available nitrogen and phosphorus in THW and HZW were much higher than those in MJU, and the proportions of available nitrogen and phosphorus in sediments were higher than those in soils. The physiochemical properties such as pH value, organic matter, and iron and aluminum oxides were related to the available nitrogen and phosphorus in the soil and sediment, but correlations between them were complex. The distribution patterns of available nitrogen and phosphorus in the soil and sediments of the land-water transition zone reflect the impacts of the natural environment and human activities, particularly those of the latter.
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http://dx.doi.org/10.13227/j.hjkx.202009183DOI Listing
June 2021

MTFR2, A Potential Biomarker for Prognosis and Immune Infiltrates, Promotes Progression of Gastric Cancer Based on Bioinformatics Analysis and Experiments.

J Cancer 2021 26;12(12):3611-3625. Epub 2021 Apr 26.

Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230001, People's Republic of China.

Mitochondrial fission regulator 2 (MTFR2) which can promote mitochondrial fission, has recently been reported to be involved in tumorigenesis. However, little is known about its expression levels and function in gastric cancer (GC). This study aims to clarify the role of MTFR2 in GC. We firstly determined the expression level and prognostic value of MTFR2 in GC by integrated bioinformatics (Oncomine, GEPIA, Kaplan-Meier Plotter database) and experimental approaches (RT-qPCR, western blot, immunohistochemistry). After constructing stable down-regulated GC cells, the biological functions of MTFR2 and were studied through cell clone formation, wound healing, transwell and tumor formation experiments.To understand the reason for the high expression of MTFR2 in GC, copy number alternation, promoter methylation and mutation of MTFR2 were detected by UALCAN and cBioPortal. TargetScanHuman and PROMO databases were also used to explore the miRNAs and transcription factors of MTFR2, and the regulatory network was visualized by Cytoscape. LinkedOmics was used to detect the co-expression profile, and then these co-expressed genes were used for gene oncology function and pathway enrichment analysis to deepen the understanding of MTFR2 mechanism. The protein interaction network of MTFR2 was constructed by the GeneMANIA platform. Docking study of the binding mode was conducted by H DOCK webserver, and PYMOL is used for visualization, and analysis. TIMER database was used to explore the correlation between MTFR2 expression level and immune cells infiltration and gene markers of tumor infiltrating immune cells. We demonstrated that MTFR2 was up-regulated in GC, and its overexpression led to poorer prognosis. MTFR2 downregulation inhibited the proliferation, migration, and invasion of GC cells and . By bioinformatics analysis, we identified the possible factors in MTFR2 overexpression. Moreover, function and pathway enrichment analyses found that MTFR2 was involved in chromosome segregation, catalytic activity, cell cycle, and ribonucleic acid transport. A MTFR2-protein interaction network revealed a potential direct protein interaction between MTFR2 and protein kinase adenosine-monophosphate-activated catalytic subunit alpha 1 (PRKAA1), and their potential binding site was predicted in a molecular docking model. In addition, we also found that MTFR2 may be correlated with immune infiltration in GC. Our study has effectively revealed the expression, prognostic value, potential functional networks, protein interactions and immune infiltration of MTFR2 in GC. Altogether, our data identify the possible underlying mechanisms of MTFR2 and suggest that MTFR2 may be a prognostic biomarker and therapeutic target in GC.
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http://dx.doi.org/10.7150/jca.58158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120185PMC
April 2021

Long non-coding RNA SNHG17 enhances the aggressiveness of C4-2 human prostate cancer cells in association with β-catenin signaling.

Oncol Lett 2021 Jun 13;21(6):472. Epub 2021 Apr 13.

Department of Urology, Qingdao Municipal Hospital Affiliated to Qingdao Medical College of Qingdao University, Qingdao, Shandong 266071, P.R. China.

Long non-coding (lnc) RNAs have emerged as important regulators of cancer development and progression. Several lncRNAs have been reported to be associated with prostate cancer (PCa); however, the involvement of lncRNA SNHG17 in PCa remains unclear. In the present study, the mRNA expression level of SNHG17 in 58 pairs of PCa tumor samples and adjacent non-tumor tissues, as well as in PCa tumor cell lines was analyzed. The regulatory effect of SNHG17 on the oncogenic phenotypes of the C4-2 tumor cell line was also investigated. The clinicopathological analysis revealed that SNHG17 mRNA expression level was increased in the PCa tumor samples, and its high expression levels were associated with poor patient outcomes, indicating that SNHG17 may act as a biomarker for the prognosis of PCa. SNHG17 mRNA expression level was also increased in different PCa tumor cell lines. Functionally, SNHG17 increased C4-2 tumor cell growth and aggressiveness by stimulating tumor cell proliferation, survival, invasion and resistance to chemotherapy. Furthermore, SNHG17 promoted tumor growth in a xenograft mouse model. Notably, the SNHG17-induced and oncogenic effects were associated with activation of the β-catenin pathway. The results from the present study revealed that lncRNA SNHG17 could be an important regulator in the oncogenic properties of human PCa and may; therefore, represent a potential PCa therapeutic target.
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http://dx.doi.org/10.3892/ol.2021.12733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063240PMC
June 2021

An isothermal recombinase polymerase amplification and lateral flow strip combined method for rapid on-site detection of Vibrio vulnificus in raw seafood.

Food Microbiol 2021 Sep 15;98:103664. Epub 2020 Oct 15.

School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China. Electronic address:

Vibrio vulnificus is an important foodborne pathogenic bacterium that mainly contaminates seafood. Rapid and accurate technologies that suitable for on-site detection are critical for effective control of its spreading. Conventional detection methods and polymerase chain reaction (PCR)-based and qPCR-based approaches have application limitations in on-site scenarios. Application of loop-mediated isothermal amplification (LAMP) technology was a good step towards the on-site detection. In this study, a recombinase polymerase amplification (RPA)-based detection method for V. vulnificus was developed combining with lateral flow strip (LFS) for visualized signal. The method targeted the conservative empV gene encoding the extracellular metalloproteinase, and finished detection in 35 min at a conveniently low temperature of 37 °C. It showed good specificity and an excellent sensitivity of 2 copies of the genome or 10 colony forming unit (CFU) per reaction, or 1 CFU/10 g in spiked food samples with enrichment. The method tolerated unpurified templates directly from sample boiling, which added the convenience of the overall procedure. Application of the RPA-LFS method for clinical samples showed accurate and consistent detection results compared to bioassay and quantitative PCR. This RPA-LFS combined method is well suited for on-site detection of V. vulnificus.
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http://dx.doi.org/10.1016/j.fm.2020.103664DOI Listing
September 2021

The type 2 diabetes mellitus susceptibility gene CDKAL1 polymorphism is associated with depressive symptom in first-episode drug-naive schizophrenic patients.

Hum Psychopharmacol 2021 Sep 15;36(5):e2790. Epub 2021 Apr 15.

Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China.

Background: Patients with schizophrenia have an increased prevalence of type 2 diabetes mellitus that has shown a significant association with the rs7754840 polymorphism in the gene encoding the cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1).

Objective: To examine whether this polymorphism was involved in the susceptibility in first-episode drug-naive schizophrenic patients (FDSP), and further influenced their clinical symptoms.

Methods: This polymorphism was genotyped in 239 FDSP and 368 healthy controls. The clinical symptoms in FDSP were assessed using the Positive and Negative Syndrome Scale (PANSS) five-factor models.

Results: There was no significant difference in the allelic and genotypic frequencies of this polymorphism between two groups (both p > 0.05) after adjusting for covariates. However, the PANSS depressive score significantly differed by genotype in FDSP after adjusting for covariates (F = 5.25, p = 0.006). This significant difference also persisted after Bonferroni correction (p < 0.05). FDSP with C/C genotype had significantly higher PANSS depressive score than those with C/G genotype (p = 0.007) and those with G/G genotype (p = 0.005). Moreover, further stepwise multivariate regression analysis showed the significant association between the rs7754840 polymorphism and PANSS depressive score in FDSP (β = -1.07, t = -2.75, p = 0.007).

Conclusions: Our findings demonstrated that although the CDKAL1 rs7754840 polymorphism did not contribute to the susceptibility to FDSP, it might be implicated in depressive symptoms in this patient group.
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http://dx.doi.org/10.1002/hup.2790DOI Listing
September 2021

Nanoparticle formulation of mycophenolate mofetil achieves enhanced efficacy against hepatocellular carcinoma by targeting tumour-associated fibroblast.

J Cell Mol Med 2021 04 13;25(7):3511-3523. Epub 2021 Mar 13.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Hepatocellular carcinoma (HCC) is one of the most aggressive tumours with marked fibrosis. Mycophenolate mofetil (MMF) was well-established to have antitumour and anti-fibrotic properties. To overcome the poor bioavailability of MMF, this study constructed two MMF nanosystems, [email protected] and [email protected], by covalently conjugating linoleic acid (LA) to MMF and then loading the conjugate into polymer materials, PEG -PLA and DSPE- PEG , respectively. Hepatocellular carcinoma cell lines and C57BL/6 xenograft model were used to examine the anti-HCC efficacy of nanoparticles (NPs), whereas NIH-3T3 fibroblasts and highly-fibrotic HCC models were used to explore the anti-fibrotic efficacy. Administration of NPs dramatically inhibited the proliferation of HCC cells and fibroblasts in vitro. Animal experiments revealed that [email protected] achieved significantly higher anti-HCC efficacy than free MMF and [email protected] both in C57BL/6 HCC model and highly-fibrotic HCC models. Immunohistochemistry further confirmed that [email protected] dramatically reduced cancer-associated fibroblast (CAF) density in tumours, as the expression levels of alpha-smooth muscle actin (α-SMA), fibroblast activation protein (FAP) and collagen IV were significantly downregulated. In addition, we found the presence of CAF strongly correlated with increased HCC recurrence risk after liver transplantation. [email protected] might act as a rational therapeutic strategy in treating HCC and preventing post-transplant HCC recurrence.
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http://dx.doi.org/10.1111/jcmm.16434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034467PMC
April 2021

ITGA5 is a prognostic biomarker and correlated with immune infiltration in gastrointestinal tumors.

BMC Cancer 2021 Mar 12;21(1):269. Epub 2021 Mar 12.

Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, People's Republic of China.

Background: Integrin Subunit Alpha 5 (ITGA5), belongs to the integrin alpha chain family, is vital for promoting cancer cell invasion, metastasis. However, the correlation between ITGA5 expression and immune infiltration in gastrointestinal tumors remain unclear.

Methods: The expression level of ITGA5 was detected by Oncomine and Tumor Immune Estimation Resource (TIMER). The association between ITGA5 and prognosis of patients was identified by Kaplan-Meier plotter, Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and PrognoScan. We evaluated the correlation between ITGA5 expression and immune infiltrating level via TIMER. Besides, TIMER, immunohistochemistry (IHC) staining and western blot were used to explore correlations between ITGA5 expression and markers of immune infiltrates cells. Furthermore, we constructed protein-protein interaction (PPI) network and performed functional enrichment by GeneMANIA and Metascape.

Results: ITGA5 was generally overexpressed and correlated with worse prognosis in multiple types of gastrointestinal tumors. In addition, ITGA5 expression level was significantly associated with tumor purity and immune infiltration levels of different immune cells in gastrointestinal tumors. Interestingly, immune markers for monocytes, tumor - associated macrophages (TAMs), macrophages 2 (M2) cells and T-helper 2 (Th2) cells were found to be significantly and positively correlated with ITGA5 expression levels in colon and gastric cancer. Results from IHC staining and western blot further proved that markers of Th2 and M2 cell were significantly increased in gastric cancer patients with high ITGA5 expression levels. Lastly, interaction network and function enrichment analysis revealed ITGA5 was mainly involved in "integrin mediated signaling pathway", "leukocyte migration", "cell-substrate adhesion".

Conclutions: Our study demonstrated that ITGA5 may act as an essential regulator of tumor immune cell infiltration and a valuable prognostic biomarker in gastrointestinal tumors. Additional work is needed to fully elucidate the underlying mechanisms behind these observations.
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http://dx.doi.org/10.1186/s12885-021-07996-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953822PMC
March 2021

A Phytophthora sojae CRN effector mediates phosphorylation and degradation of plant aquaporin proteins to suppress host immune signaling.

PLoS Pathog 2021 03 12;17(3):e1009388. Epub 2021 Mar 12.

Key Laboratory of Plant Immunity, Academy for Advanced Interdisciplinary Studies, College of Plant Protection, Nanjing Agricultural University, Nanjing, China.

Phytophthora genomes encode a myriad of Crinkler (CRN) effectors, some of which contain putative kinase domains. Little is known about the host targets of these kinase-domain-containing CRNs and their infection-promoting mechanisms. Here, we report the host target and functional mechanism of a conserved kinase CRN effector named CRN78 in a notorious oomycete pathogen, Phytophthora sojae. CRN78 promotes Phytophthora capsici infection in Nicotiana benthamiana and enhances P. sojae virulence on the host plant Glycine max by inhibiting plant H2O2 accumulation and immunity-related gene expression. Further investigation reveals that CRN78 interacts with PIP2-family aquaporin proteins including NbPIP2;2 from N. benthamiana and GmPIP2-13 from soybean on the plant plasma membrane, and membrane localization is necessary for virulence of CRN78. Next, CRN78 promotes phosphorylation of NbPIP2;2 or GmPIP2-13 using its kinase domain in vivo, leading to their subsequent protein degradation in a 26S-dependent pathway. Our data also demonstrates that NbPIP2;2 acts as a H2O2 transporter to positively regulate plant immunity and reactive oxygen species (ROS) accumulation. Phylogenetic analysis suggests that the phosphorylation sites of PIP2 proteins and the kinase domains of CRN78 homologs are highly conserved among higher plants and oomycete pathogens, respectively. Therefore, this study elucidates a conserved and novel pathway used by effector proteins to inhibit host cellular defenses by targeting and hijacking phosphorylation of plant aquaporin proteins.
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http://dx.doi.org/10.1371/journal.ppat.1009388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990189PMC
March 2021

In vitro genotoxicity study of silver nanoparticles and titanium dioxide nanoparticles.

Yi Chuan 2020 Dec;42(12):1192-1200

School of Chemistry and Chemical Engineer, Shanghai University of Engineering Science, Shanghai 201620, China.

Nanoparticles are widely used in cosmetic, pharmaceutical, and food industries, but their safety and genetic toxicity are still unclear. In this study, the genotoxicity of silver nanoparticles (AgNPs) and titanium dioxide nanoparticles (titanium dioxide nanoparticles) were evaluated by in vitro comet assay and PIG-A assay in TK6 cells. We exposed TK6 cells to two types of nanoparticles at the highest concentration of 200 μmol/L for 4 h and conducted the in vitro comet assay. We examined the mutation results of PIG-A gene in vitro after 4 h, 24 ho and 10 days of exposure, respectively. We also examined the endocytosis of nanoparticles in TK6 cells exposed to nanoparticles for 24 h. In the endocytosis assay, with the increase of nano-material concentration, the side scatter (SSC) of TK6 cells in flow cytometry showed a concentration-dependent and time-dependent increase, indicating that TK6 cells could uptake both types of nanoparticles. In the comet assay, AgNPs could induce a concentration-dependent increase in DNA tail intensity. However, titanium dioxide NPs could not induce the concentration-dependent increase of DNA fluorescence intensity of comet tail. In the PIG-A assay, both AgNPs and TiONPs did not induce PIG-A gene mutation frequency in TK6 cells. The results showed that AgNPs could induce DNA damage in TK6 cells, but could not induce increase of PIG-A gene mutation frequency. TiONPs neither induce DNA damage in TK6 cells nor increase PIG-A mutation frequency. Further tests are needed to determine whether TiONPs are genotoxic.
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http://dx.doi.org/10.16288/j.yczz.20-161DOI Listing
December 2020

Identification of MicroRNA-92a-3p as an Essential Regulator of Tubular Epithelial Cell Pyroptosis by Targeting Nrf1 via HO-1.

Front Genet 2020 11;11:616947. Epub 2021 Jan 11.

Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.

Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and has no effective treatment. Exploring the molecular mechanisms of renal IRI is critical for the prevention of AKI and its evolution to chronic kidney disease and end-stage renal disease. The aim of the present study was to determine the biological function and molecular mechanism of action of miR-92a-3p in tubular epithelial cell (TEC) pyroptosis. We investigated the relationship between nuclear factor-erythroid 2-related factor 1 (Nrf1) and TEC pyroptosis induced by ischemia-reperfusion and oxygen-glucose deprivation/reoxygenation (OGD/R) . MicroRNAs (miRNAs) are regulators of gene expression and play a role in the progression of renal IRI. Nrf1 was confirmed as a potential target for miRNA miR-92a-3p. In addition, the inhibition of miR-92a-3p alleviated oxidative stress and decreased the expression levels of NLRP3, caspase-1, GSDMD-N, IL-1β, and IL-18 and . Moreover, Zn-protoporphyrin-IX, an inhibitor of heme oxygenase-1, reduced the protective effect of Nrf1 overexpression on OGD/R-induced TEC oxidative stress and pyroptosis. The results of this study suggest that the inhibition of miR-92a-3p can alleviate TEC oxidative stress and pyroptosis by targeting Nrf1 in renal IRI.
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http://dx.doi.org/10.3389/fgene.2020.616947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831883PMC
January 2021

Icaritin inhibits PD-L1 expression by Targeting Protein IκB Kinase α.

Eur J Immunol 2021 04 9;51(4):978-988. Epub 2021 Feb 9.

Beijing Shenogen Pharma Group. Ltd, Beijing, P. R. China.

Icaritin, a small molecule currently being investigated in phase III clinical trials in China (NCT03236636 and NCT03236649) for treatment of advanced hepatocellular carcinoma (HCC), is a prenylflavonoid derivative obtained from the Epimedium genus. Previously, it was found that Icaritin decreased the expression of PD-L1, but its direct molecular targets and the underlying mechanisms have not been identified. In this study, we report the identification of IKK-α as the protein target of Icaritin by biotin-based affinity binding assay. The further mutagenesis assay has provided evidence that C46 and C178 in IKK-α were essential amino acids for Icaritin binding to IKK-α, revealing the binding sites of Icaritin to IKK-α for the first time. Functionally, Icaritin inhibited the NF-κB signalling pathway by blocking IKK complex formation, which led to decreased nuclear translocation of NF-κB p65, and subsequent downregulation of PD-L1 expression in a dose-dependent manner. More importantly, PD-L1-positive patients exhibited longer overall survival upon Icaritin therapy. Finally, Icaritin in combination with checkpoints antibodies, such as α-PD-1, has demonstrated much better efficacy than any single therapy in animal models. This is the first report that anticancer effects of Icaritin are mediated, at least in part, by impairing functions of IKK-α.
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http://dx.doi.org/10.1002/eji.202048905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248075PMC
April 2021

Chronic trichlorfon stress induces differential transcriptome expression and interferes with multifunctional pathways in the brain of .

J Environ Sci Health B 2021 8;56(1):1-9. Epub 2020 Oct 8.

College of Life Science, Shaanxi Normal University, Xi'an, China.

Trichlorfon is widely used to control pest insects and various parasitic infestations in agriculture, aquaculture and human medicine. However, the long-term widespread use and overuse of trichlorfon poses risks to public and environmental health. Thus, the aim of this study was to evaluate the interference of trichlorfon on gene transcription patterns in the brain of with 4 weeks treatment under control conditions and 0.1 mg/L exposure. In total, 102,013 unigenes were obtained from the brain tissue of , and 874 differentially expressed genes (DEGs) were identified. Functional annotation indicated that out of 118,643 unigenes, 45,600 (44.7%) were annotated in the Nr, Nt, the Swiss-Prot, KEGG, COG, and GO databases. The differential expression patterns of 4 genes associated with neural activity were selected and validated by quantitative polymerase chain reaction (qPCR). The results revealed that except for the canonical cholinesterase-based mechanism, trichlorfon could act on other receptors and alter certain types of neuronal ion channels as the major target sites. All of these effects ultimately cause disorders of multifunctional pathways and other neurotransmitter pathways in the host. The results further our understanding of the mechanisms underlying nontarget effects of organophosphate insecticides (OPs) through multitargets studies.
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http://dx.doi.org/10.1080/03601234.2020.1830666DOI Listing
March 2021

Metabonomic Profile of Macrosteatotic Allografts for Orthotopic Liver Transplantation in Patients With Initial Poor Function: Mechanistic Investigation and Prognostic Prediction.

Front Cell Dev Biol 2020 28;8:826. Epub 2020 Aug 28.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Background: Our previous study revealled amplified hazardous effects of macrosteatosis (MaS) on graft failure (GF) in recipients with severe liver damage in short post-operative days, with vague mechanism inside.

Aim: We aimed to uncover the molecular mechanism of donor MaS on GF, and construct the predictive model to monitor post-transplant prognosis based on "omics" perspective.

Methods: Ultra-performance liquid chromatography coupled to mass spectrometry metabolomic analysis was performed in allograft tissues from 82 patients with initial poor function (IPF) from multi-liver transplant (LT) centers. Pathway analysis was performed by on-line toolkit Metaboanalyst (v 3.0). Predictive model was constructed based on combinative metabonomic and clinical data extracted by stepwised cox proportional analysis.

Results: Principle component analysis (PCA) analysis revealled stratification on metabolic feature in organs classified by MaS status. Differential metabolits both associated with MaS and GF were significantly enriched on pathway of glycerophospholipid metabolism ( < 0.05). Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) involved in glycerophospholipid metabolism was significantly decreased in cases with MaS donors and GF ( < 0.05). Better prediction was observed on graft survival by combinative model (area under the curve = 0.91) and confirmed by internal validation.

Conclusion: Metabonomic features of allografts can be clearly distinguished by MaS status in patients with IPF. Dysfunction on glycerophospholipid metabolism was culprit to link donor MaS and final GF. Decrement on PC and PE exerted the fatal effects of MaS on organ failure. Metabonomic data might help for monitoring long-term graft survival after LT.
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http://dx.doi.org/10.3389/fcell.2020.00826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484052PMC
August 2020

Tisp40 Induces Tubular Epithelial Cell GSDMD-Mediated Pyroptosis in Renal Ischemia-Reperfusion Injury via NF-κB Signaling.

Front Physiol 2020 13;11:906. Epub 2020 Aug 13.

Department of Traditional Chinese Medicine, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.

Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). As a transcription factor, the Transcript induced in spermiogenesis 40 (Tisp40) has been found to be involved in renal IRI. However, the role of Tisp40 in tubular epithelial cell (TEC) pyroptosis of renal IRI remains unknown. In this study, we investigated effects of Tisp40 on Gasdermin D (GSDMD)-mediated TEC pyroptosis in renal IRI and underlying molecular mechanisms in I/R-induced kidney by hematoxylin and eosin (HE) staining, Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay,immunohistochemistry (IHC), reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis and oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated TCMK-1 cells by lactate dehydrogenase (LDH) release assay, CCK-8 assay,enzyme-linked immunosorbent assay (ELISA), flow cytometric analysis, immunofluorescence staining,RT-qPCRand western blot analysis . We found that the levels of Tisp40 and GSDMD-N expression increased gradually, and peaked at 30 min ischemia/24 h reperfusion and 24 h OGD/R/6 h reoxygenation , simultaneously, the levels of TEC pyroptosis and renal injury were correspondingly increased. The data of Pearson's correlation analysis showed that the expression of Tisp40 and GSDMD-N was positively correlated. Furthermore, Tisp40 overexpression aggravated TEC pyroptosis rate and increased the expressions of related proteins, including GSDMD-N, NLRP3, caspase-1, IL-1β, and IL-18 in the OGD/R-stimulated TCMK-1 cell line, whereas the opposite occurred in cells treated with small interfeing RNA (siRNA) targeting Tisp40. Tisp40-deficient mice showed attenuated renal IRI and pyroptosis compared with wild-type mice. In addition, Tisp40 knockout remarkably decreased the levels of GSDMD-N, IL-1β, IL-18, NLRP3, and caspase-1 expression, and alleviated renal pyroptosis induced by I/R. Importantly, Tisp40 overexpression significantly increased TECs pyroptosis via p-p65 activation, however, the effects of Tisp40 overexpression were partially blocked by parthenolide (PTL). Collectively, our findings provide insight into the mechanism of how Tisp40 regulated GSDMD-mediated pyroptosis in renal IRI.
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http://dx.doi.org/10.3389/fphys.2020.00906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438479PMC
August 2020

Target-oriented delivery of self-assembled immunosuppressant cocktails prolongs allogeneic orthotopic liver transplant survival.

J Control Release 2020 12 28;328:237-250. Epub 2020 Aug 28.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, NHC Key Laboratory of Combined Multi-Organ Transplantation; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China. Electronic address:

Organ transplantation remains the gold standard therapeutic option for patients with end-stage organ failure. However, there have been few improvements in the management of post-transplant immunosuppression. As the long-term use of immunosuppressive agents (ISAs) may result in off-target systemic toxicity and complications, minimizing the ISA dosage while preserving the pharmacological efficacy could be a promising solution to address these challenges. Here, we present the design and application of self-assembled prodrug nanoparticles based on chemically derived mycophenolate mofetil, which further provide a hydrophobic core to noncovalently encapsulate additional ISAs such as tacrolimus. The resulting immunosuppressant cocktail nanoparticles are further refined by PEGylation with amphiphilic polymers to form colloidally stable self-assembled immunosuppressant cocktails (SAICs) that are suitable for preclinical studies. In a rat model of allogeneic orthotopic liver transplantation (OLT), administration of SAICs markedly extends graft/recipient survival, retards weight loss and attenuates allograft damage. Furthermore, SAICs significantly abolish intragraft inflammatory cell infiltration and proinflammatory cytokine profiles as well as improve liver graft function. This study demonstrates the superiority of SAICs over traditional ISAs in the treatment of allograft rejection and may support the emerging application of the SAIC platform in clinical settings.
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http://dx.doi.org/10.1016/j.jconrel.2020.08.043DOI Listing
December 2020

Spatial Distribution and Environmental Significance of Phosphorus Fractions in River Sediments and Its Influencing Factor from Hongze and Tiaoxi Watersheds, Eastern China.

Int J Environ Res Public Health 2020 08 10;17(16). Epub 2020 Aug 10.

Key Laboratory of Integrated Regulation and Resources Development of Shallow Lakes of Ministry of Education, College of Environment, Hohai University, Nanjing 210098, China.

This study explored the spatial distribution of phosphorus fractions in river sediments and analyzed the relationship between different phosphorus fractions and their environmental influence on the sediments within different watersheds in Eastern China. River sediments from two inflow watersheds (Hongze and Tiaoxi) to Hongze and Taihu Lake in Eastern China were analyzed by the sequential extraction procedure. Five fractions of sedimentary phosphorus, including freely sorbed phosphorus (NHCl-P), redox-sensitive phosphorus (BD-P), bound phosphorus metal oxide (NaOH-P), bound phosphorus calcium (HCl-P), and residual phosphorus (Res-P) were all analyzed. The orders of rankings for the P fractions of the rivers Anhe and Suihe were HCl-P > NaOH-P > BD-P > NHCl-P and HCl-P > BD-P > NaOH-P > NHCl-P, respectively. For the rank order of the Hongze watershed, HCl-P was higher while the NHCl-P contents were significantly lower. The rank order for the Dongtiaoxi River was NaOH-P > HCl-P > BD-P > NHCl-P, and that of Xitiaoxi River was NaOH-P > BD-P > HCl-P > NHCl-P. Compared with the phosphorus forms of the Tiaoxi watershed, NaOH-P contents were significantly higher compared to HCl-P, which was significantly higher in the Hongze watershed. In comparison, NHCl-P contents were significantly lower in both. Variations may be attributed to differential discharge of the P form in the watershed due to land-use changes and urban river ambient conditions.
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http://dx.doi.org/10.3390/ijerph17165787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459694PMC
August 2020

Spatial variations in and environmental significance of nitrogen forms in river sediments from two different watersheds in eastern China.

Environ Monit Assess 2020 May 9;192(6):351. Epub 2020 May 9.

College of Environment, Key Laboratory of Integrated Regulation and Resources Development on Shallow Lakes, Ministry of Education, Hohai University, Nanjing, 210098, China.

Nitrogen is considered an essential nutrient element limiting water productivity, and its distribution in sediments directly affects its release potential. This study aimed to analyse the spatial characteristics, distribution, and influence of nitrogen forms in two different river catchments situated in eastern China. Using sequential extraction methods, the study divided sediment nitrogen into four forms, namely, an ion-exchangeable form (IEF-N), weak acid-extractable form (WAEF-N), strong alkali-extractable form (SAEF-N), and strong oxidant-extractable form (SOEF-N). The results for the two catchments showed significant differences in the physicochemical properties as well as variations in space. The mean proportion of total transferable nitrogen (TTN) in the Anhe, Suihe, Dongtiaoxi, and Xitiaoxi rivers accounted for 50.64%, 32.87%, 34.63%, and 40.45%, respectively. The results also revealed a higher total TTN in the Hongze watershed than in the Tiaoxi watershed. The order of mean TTN in sediments from the Hongze watershed was SOEF-N > SAEF-N > IEF-N > WAEF-N, whereas that for the Tiaoxi watershed was SOEF-N > SAEF-N > WAEF-N > IEF-N. The distribution of nitrogen forms in the sediments was significantly impacted by the sediment composition and environmental factors, as shown by correlation and redundancy analysis (RDA).
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http://dx.doi.org/10.1007/s10661-020-08283-5DOI Listing
May 2020

Unplanned surgical reoperations as a quality indicator in pediatric tertiary general surgical specialties: Associated risk factors and hospitalization, a retrospective case-control analysis.

Medicine (Baltimore) 2020 May;99(19):e19982

Class 2, Department 1 of Clinical Medicine, 2016.

Unplanned reoperations have not been studied extensively in pediatric patients, especially concerning risk factors. We aim to estimate the rate of unplanned reoperations and to determine the associated factors in pediatric general surgical specialties.This analysis included a retrospective case-control study of unplanned reoperations from July 1, 2010 to June 30, 2017 in the general surgical specialties. For each case, we identified approximately 2 randomly selected controls who underwent the same type of operation. The factors involved in the unplanned reoperations were investigated using univariate and multivariate analysis.Of the 3263 patients who underwent surgery, unplanned reoperations were performed in 139 patients (4.3%). The main indications for unplanned reoperations were wound complications (n = 52, 42.6%), followed by postoperative ileus (n = 12, 9.8%), postoperative bleeding (n = 8, 6.6%), and intraabdominal infection (n = 13, 10.7%). Following multivariate analysis, 2 factors remained significantly associated with unplanned reoperation: higher initial surgery-related risk level (P = .007, risk ratio (RR) = 0.48; 95% confidence interval (CI) = 0.27-0.82) and operation performed outside working hours (P = .031, RR = 0.52; 95% CI = 0.30-0.89).Various patient- and procedure-related factors were associated with unplanned reoperations. This information might be helpful for the optimization of treatment planning and resource allocation.
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http://dx.doi.org/10.1097/MD.0000000000019982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220400PMC
May 2020

Vasopressor treatment and mortality following nontraumatic subarachnoid hemorrhage: a nationwide electronic health record analysis.

Neurosurg Focus 2020 05;48(5):E4

2School of Public Health, and.

Objective: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular condition, not only due to the effect of initial hemorrhage, but also due to the complication of delayed cerebral ischemia (DCI). While hypertension facilitated by vasopressors is often initiated to prevent DCI, which vasopressor is most effective in improving outcomes is not known. The objective of this study was to determine associations between initial vasopressor choice and mortality in patients with nontraumatic SAH.

Methods: The authors conducted a retrospective cohort study using a large, national electronic medical record data set from 2000-2014 to identify patients with a new diagnosis of nontraumatic SAH (based on ICD-9 codes) who were treated with the vasopressors dopamine, phenylephrine, or norepinephrine. The relationship between the initial choice of vasopressor therapy and the primary outcome, which was defined as in-hospital death or discharge to hospice care, was examined.

Results: In total, 2634 patients were identified with nontraumatic SAH who were treated with a vasopressor. In this cohort, the average age was 56.5 years, 63.9% were female, and 36.5% of patients developed the primary outcome. The incidence of the primary outcome was higher in those initially treated with either norepinephrine (47.6%) or dopamine (50.6%) than with phenylephrine (24.5%). After adjusting for possible confounders using propensity score methods, the adjusted OR of the primary outcome was higher with dopamine (OR 2.19, 95% CI 1.70-2.81) and norepinephrine (OR 2.24, 95% CI 1.80-2.80) compared with phenylephrine. Sensitivity analyses using different variable selection procedures, causal inference models, and machine-learning methods confirmed the main findings.

Conclusions: In patients with nontraumatic SAH, phenylephrine was significantly associated with reduced mortality in SAH patients compared to dopamine or norepinephrine. Prospective randomized clinical studies are warranted to confirm this finding.
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http://dx.doi.org/10.3171/2020.2.FOCUS191002DOI Listing
May 2020

pSTAT3 Y705 is a prognostic biomarker identified from time-series gene expression profiles of a chemically induced mouse model of hepatocellular carcinoma.

Am J Transl Res 2020 15;12(4):1443-1458. Epub 2020 Apr 15.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University Hangzhou, China.

Development of hepatocellular carcinoma (HCC) is a dynamic process that includes a spectrum ranging from precancerous exposure to carcinogenesis and metastasis stages. In this process, numerous dysregulated genes resulted in aberrant activation or inhibition of signaling pathways. Herein, time-series gene expression profiles of dimethylnitrosamine (DEN)-induced mice with HCC covering different stages are provided. Gene expression patterns of liver tissues were detected at different time intervals [0 (negative control; NC), 15, 28, 30, and 42 weeks]. A comparison of gene expression between DEN-treated groups and NC yielded a total of 726 differentially expressed genes (DEGs), 76 of which were enriched in 10 statistically significant Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways (adjusted value <0.05). After assessing regulation among these cascades, we found that Stat3 was a crucial transcription factor. Additionally, it was a connector in the PPI network constituting the 76 DEGs. Western blotting and immunohistochemistry suggested that the phosphorylation of Stat3 at tyrosine 705 (pStat3 Y705) was down-regulated in early stage HCC. Following, survival analysis revealed that patients with down-regulated pSTAT3 Y705 exhibited reduced overall survival rates in both the early stage and well-differentiated groups (p=0.00022 and p=0.0026, respectively). This is the first study evaluating dynamic gene expression profiles in a time-series DEN-induced mouse HCC model. Stat3 was identified as a crucial node during HCC progression, and pSTAT3 Y705 serves as a prognostic biomarker for early-stage HCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191170PMC
April 2020

Enantioseparation of racemic amlodipine using immobilized ionic liquid by solid-phase extraction.

Chirality 2020 08 27;32(8):1062-1071. Epub 2020 Apr 27.

School of Chemical and Process Engineering, University of Leeds, Leeds, UK.

In this paper, a novel l-glutamate based immobilized chiral ionic liquid (SBA-IL (Glu)) was prepared by chemical bonding method and applied as a solid sorbent for chiral separation of amlodipine. The performance of SBA-IL (Glu) was investigated for the absorption of (S)-amlodipine and separation of amlodipine enantiomer. The static experiment showed that equilibrium adsorption was achieved within 80 minutes, and the saturation adsorptions capacity was 12 mg/g. The complex was then packed in a glass chromatographic column for the separation of amlodipine and the enantiomeric excess (%ee) of (S)-amlodipine reached 24.67%. The immobilized ionic liquids exhibit good reusability, and the separation efficiency remains 18.24% after reused five times, which allows potential scale-up for the chiral separation of amlodipine.
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http://dx.doi.org/10.1002/chir.23231DOI Listing
August 2020
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