Publications by authors named "M Dwight Chen"

32,084 Publications

Screening of chemical linkers for development of pullulan bioconjugates for intravitreal ocular applications.

Eur J Pharm Sci 2021 Mar 2:105785. Epub 2021 Mar 2.

University of Padova, Department of Pharmaceutical and Pharmacological Sciences, Via F. Marzolo 5, 35131 Padova, Italy. Electronic address:

The treatment of posterior segment disorders of the eye requires therapeutic strategies to achieve drug effects over prolonged times. Innovative colloidal delivery systems can be designed to deliver drugs to the retina and prolong their intravitreal permanence. In order to exploit pullulan (Pull) as polymeric drug carrier for intravitreal drug delivery, derivatives of hydrophobic model molecule rhodamine B (RhB) were conjugated to the pullulan backbone through linkers with different stability, namely ether (Et), hydrazone (Hy) or ester (Es) bond to obtain Pull-Et-RhB, Pull-Hy-RhB and Pull-Es-RhB, respectively. Dynamic light scattering and transmission electron microscopy analyses showed that the polymer conjugates self-assembled into 20-25 nm particles. Pull-Et-RhB was fairly stable at all tested pH values. At the vitreal pH of 7.4, 50% of RhB was released from Pull-Hy-RhB and Pull-Es-RhB in 11 and 6 days, respectively. At endosomal pH (5.5), 50% of RhB was released from Pull-Hy-RhB and Pull-Es-RhB in 4 and 1 days, respectively. Multiple particle tracking analyses in ex vivo porcine eye model showed that the diffusivity of the bioconjugates in the vitreous was about 10 times lower than in water. Flow cytometry and confocal microscopy analyses showed that bioconjugates are remarkably taken up by the retinal RPE cells. In vivo studies showed that after intravitreal injection to mice, the bioconjugates localize in the ganglion cell layer and in the inner and outer plexiform layers. Pull-Hy-RhB particles were detected also inside the retinal blood vessels. These results demonstrate that pullulan with tailored linkers for drug conjugation is a promising vehicle for long-acting intravitreal injectables that are capable to permeate to the retina.
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http://dx.doi.org/10.1016/j.ejps.2021.105785DOI Listing
March 2021

Activation of the δ opioid receptor relieves cerebral ischemic injury in rats via EGFR transactivation.

Life Sci 2021 Mar 2:119292. Epub 2021 Mar 2.

Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China. Electronic address:

Delta opioids are thought to relieve ischemic injury and have tissue-protective properties. However, the detailed mechanisms of delta opioids have not been well identified. Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), have been shown to mediate downstream signals of δ opioid receptor (δOR) activation through the metalloproteinase (MMP)-dependent EGF-like growth factor (HB-EGF) excretion pathway, which is called transactivation. In this study, to investigate the role of EGFR in δOR-induced anti-ischemic effects in the brain, we applied the middle cerebral artery occlusion (MCAO) model followed by reperfusion to mimic ischemic stroke injury in rats. Pre-treatment with the δOR agonist [D-ala, D-leu] enkephalin (DADLE) improved the neurologic deficits and the decreased infarct volume caused by cerebral ischemia/reperfusion injury, which were blocked by the EGFR inhibitor AG1478 and the MMP inhibitor GM6001, respectively. Further results indicated that DADLE activated EGFR, Akt and ERK1/2 and upregulated EGFR expression in the hippocampus in a time-dependent manner, which were inhibited by AG1478 and GM6001. The enzyme-linked immunosorbent assay (ELISA) results showed that δOR activation led to an increase in HB-EGF release, but HB-EGF in tissue was downregulated at the mRNA and protein levels. Moreover, this protective action caused by δOR agonists may involve attenuated hippocampal cellular apoptosis. Overall, these results demonstrate that MMP-mediated transactivation of EGFR is essential for δOR agonist-induced MCAO/reperfusion injury relief. These findings provide a potential molecular mechanism for the neuroprotective property of δOR and may add new insight into mitigating or preventing injury.
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http://dx.doi.org/10.1016/j.lfs.2021.119292DOI Listing
March 2021

Therapeutic IL-6 trans-signalling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease.

Gastroenterology 2021 Mar 2. Epub 2021 Mar 2.

Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. Electronic address:

Background: A large unmet therapeutic need exists in inflammatory bowel diseases (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL-6/IL-6R blockade is limited by profound immunosuppression. Evidence has emerged, that chronic pro-inflammatory activity of IL-6 is mainly mediated by trans-signalling via a complex of IL-6 bound to soluble IL-6R engaging the gp130 receptor without the need of membrane bound IL6R. We have developed a decoy protein, sgp130Fc, which exclusively blocks IL-6 pro-inflammatory trans-signalling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression.

Methods: We present a 12-week, open label, prospective phase IIa trial (FUTURE) in 16 patients with active IBD treated with the trans-signalling inhibitor olamkicept (sgp130Fc) to assess molecular mechanisms, safety and effectiveness of IL-6 trans-signalling blockade in vivo. We performed in-depth molecular profiling at various time points before and after therapy induction to identify the mechanism of action of olamkicept.

Results: Olamkicept was well tolerated and induced clinical response in 44% and clinical remission in 19% of patients. Clinical effectiveness coincided with target inhibition (reduction of phosphorylated STAT3) and marked transcriptional changes in the inflamed mucosa. An olamkicept-specific transcriptional signature, distinguishable from remission signatures of anti-TNF (infliximab) or anti-integrin (vedolizumab) therapies was identified.

Conclusion: Our data suggest that blockade of IL-6 trans-signaling holds large promise for the therapy of IBD and should undergo full clinical development as a new immunoregulatory therapy of IBD.
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http://dx.doi.org/10.1053/j.gastro.2021.02.062DOI Listing
March 2021

Hierarchical Alternate Interaction Network for RGB-D Salient Object Detection.

IEEE Trans Image Process 2021 Mar 5;PP. Epub 2021 Mar 5.

Existing RGB-D Salient Object Detection (SOD) methods take advantage of depth cues to improve the detection accuracy, while pay insufficient attention to the quality of depth information. In practice, a depth map is often with uneven quality and sometimes suffers from distractors, due to various factors in the acquisition procedure. In this paper, to mitigate distractors in depth maps and highlight salient objects in RGB images, we propose a Hierarchical Alternate Interactions Network (HAINet) for RGB-D SOD. Specifically, HAINet consists of three key stages: feature encoding, cross-modal alternate interaction, and saliency reasoning. The main innovation in HAINet is the Hierarchical Alternate Interaction Module (HAIM), which plays a key role in the second stage for cross-modal feature interaction. HAIM first uses RGB features to filter distractors in depth features, and then the purified depth features are exploited to enhance RGB features in turn. The alternate RGB-depth-RGB interaction proceeds in a hierarchical manner, which progressively integrates local and global contexts within a single feature scale. In addition, we adopt a hybrid loss function to facilitate the training of HAINet. Extensive experiments on seven datasets demonstrate that our HAINet not only achieves competitive performance as compared with 19 relevant state-of-the-art methods, but also reaches a real-time processing speed of 43 fps on a single NVIDIA Titan X GPU. The code and results of our method are available at https://github.com/MathLee/HAINet.
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http://dx.doi.org/10.1109/TIP.2021.3062689DOI Listing
March 2021

Limb-bud and Heart (LBH) mediates proliferation, fibroblast-to-myofibroblast transition and EMT-like processes in cardiac fibroblasts.

Mol Cell Biochem 2021 Mar 5. Epub 2021 Mar 5.

Guangdong Provincial Biomedical Engineering Technology Research, Center for Cardiovascular Disease; Sino-Japanese Cooperation Platform for Translational Research in Heart Failure; Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People's Republic of China.

Cardiac fibrosis is an important pathological change after myocardial infarction (MI). Its progression is essential for post-MI infarct healing, during which transforming growth factor beta1 (TGF-β1) plays a critical role. Limb-bud and Heart (LBH), a newly discovered target gene of TGF-β1, was shown to promote normal cardiogenesis. αB-crystallin (CRYAB), an LBH-interacting protein, was demonstrated to be involved in TGF-β1-induced fibrosis. The roles and molecular mechanisms of LBH and CRYAB during cardiac fibrosis remain largely unexplored. In this study, we investigated the alterations of LBH and CRYAB expression in mouse cardiac tissue after MI. LBH and CRYAB were upregulated in activated cardiac fibroblasts (CFs), while in vitro TGF-β1 stimulation induced the upregulation of LBH, CRYAB, and fibrogenic genes in primary CFs of neonatal rats. The results of the ectopic expression of LBH proved that LBH accelerated CF proliferation under hypoxia, mediated the expression of CRYAB and fibrogenic genes, and promoted epithelial-mesenchymal transition (EMT)-like processes in rat CFs, while subsequent CRYAB silencing reversed the effects induced by elevated LBH expression. We also verified the protein-protein interaction (PPI) between LBH and CRYAB in fibroblasts. In summary, our work demonstrated that LBH promotes the proliferation of CFs, mediates TGF-β1-induced fibroblast-to-myofibroblast transition and EMT-like processes through CRYAB upregulation, jointly functioning in post-MI infarct healing. These findings suggest that LBH could be a promising potential target for the study of cardiac repair and cardiac fibrosis.
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http://dx.doi.org/10.1007/s11010-021-04111-7DOI Listing
March 2021

Drug properties and host factors contribute to biochemical presentation of drug-induced liver injury: a prediction model from a machine learning approach.

Arch Toxicol 2021 Mar 5. Epub 2021 Mar 5.

UGC Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga - IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain.

Drug-induced liver injury (DILI) presentation varies biochemically and histologically. Certain drugs present quite consistent injury patterns, i.e., DILI signatures. In contrast, others are manifested as broader types of liver injury. The variety of DILI presentations by a single drug suggests that both drugs and host factors may contribute to the phenotype. However, factors determining the DILI types have not been yet elucidated. Identifying such factors may help to accurately predict the injury types based on drugs and host information and assist the clinical diagnosis of DILI. Using prospective DILI registry datasets, we sought to explore and validate the associations of biochemical injury types at the time of DILI recognition with comprehensive information on drug properties and host factors. Random forest models identified a set of drug properties and host factors that differentiate hepatocellular from cholestatic damage with reasonable accuracy (69-84%). A simplified logistic regression model developed for practical use, consisting of patient's age, drug's lipoaffinity, and hybridization ratio, achieved a fair prediction (68-74%), but suggested potential clinical usability, computing the likelihood of liver injury type based on two properties of drugs taken by a patient and patient's age. In summary, considering both drug and host factors in evaluating DILI risk and phenotypes open an avenue for future DILI research and aid in the refinement of causality assessment.
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http://dx.doi.org/10.1007/s00204-021-03013-3DOI Listing
March 2021

Enhanced Ultrasound Contrast of Renal-Clearable Luminescent Gold Nanoparticles.

Angew Chem Int Ed Engl 2021 Mar 4. Epub 2021 Mar 4.

South China University of Technology, School of Chemistry and Chemical Engineering, 381 Wushan Road Tianhe District, 510641, Guangzhou, CHINA.

Renal-clearable nanoparticles are typically fast eliminated through the free glomerular filtration, which show weak interaction with the renal compartments and negligible ultrasound signals, raising challenges in direct imaging of kidney diseases. Here, we report the ultrasmall renal-clearable luminescent gold nanoparticles (AuNPs) with both pH-induced charge reversal and aggregation properties, and discover that enhanced ultrasound contrast could be facilely acquired through the increased tubular reabsorption and in-situ aggregation of AuNPs in renal tubule cells in injured kidneys. The tuning elimination pathway of the renal-clearable luminescent AuNPs is further demonstrated to provide a synergistical fluorescence and ultrasound imaging strategy for diagnosing early kidney injury with precise anatomical information.
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http://dx.doi.org/10.1002/anie.202017273DOI Listing
March 2021

Combined transcriptome GWAS and TWAS reveal genetic elements leading to male sterility during high temperature stress in cotton.

New Phytol 2021 Mar 4. Epub 2021 Mar 4.

National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, 430070, China.

Global warming has reduced the productivity of many field-grown crops due to effects on male sterility. The genetic regulation of high temperature (HT) response in the major crop cotton is poorly understood. We determined the functionality and transcriptomes of anther of 218 cotton accessions grown under HT stress. By analyzing transcriptome divergence and implementing genome-wide association study (GWAS), we identified three thermal tolerance associated loci which contained 75 protein coding genes and 27 long non-coding RNAs, and provided expression quantitative trait loci (eQTLs) for 13,132 transcripts. A transcriptome-wide association study (TWAS) confirmed six causal elements for the HT response (three genes overlapped with GWAS results), involved in protein kinase activity. The most susceptible gene, GhHRK1 was confirmed as a previously uncharacterized negative regulator of the HT response both in cotton and in Arabidopsis. These functional variants provided new understanding of genetic basis for HT tolerance in male reproduction organs.
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http://dx.doi.org/10.1111/nph.17325DOI Listing
March 2021

Low compositions of human toll-like receptor 7/8-stimulating RNA motifs in the MERS-CoV, SARS-CoV and SARS-CoV-2 genomes imply a substantial ability to evade human innate immunity.

PeerJ 2021 24;9:e11008. Epub 2021 Feb 24.

Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: The innate immune system especially Toll-like receptor (TLR) 7/8 and the interferon pathway, constitutes an important first line of defense against single-stranded RNA viruses. However, large-scale, systematic comparisons of the TLR 7/8-stimulating potential of genomic RNAs of single-stranded RNA viruses are rare. In this study, a computational method to evaluate the human TLR 7/8-stimulating ability of single-stranded RNA virus genomes based on their human TLR 7/8-stimulating trimer compositions was used to analyze 1,002 human coronavirus genomes.

Results: The human TLR 7/8-stimulating potential of coronavirus genomic (positive strand) RNAs followed the order of NL63-CoV > HKU1-CoV >229E-CoV ≅ OC63-CoV > SARS-CoV-2 > MERS-CoV > SARS-CoV. These results suggest that among these coronaviruses, MERS-CoV, SARS-CoV and SARS-CoV-2 may have a higher ability to evade the human TLR 7/8-mediated innate immune response. Analysis with a logistic regression equation derived from human coronavirus data revealed that most of the 1,762 coronavirus genomic (positive strand) RNAs isolated from bats, camels, cats, civets, dogs and birds exhibited weak human TLR 7/8-stimulating potential equivalent to that of the MERS-CoV, SARS-CoV and SARS-CoV-2 genomic RNAs.

Conclusions: Prediction of the human TLR 7/8-stimulating potential of viral genomic RNAs may be useful for surveillance of emerging coronaviruses from nonhuman mammalian hosts.
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http://dx.doi.org/10.7717/peerj.11008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912611PMC
February 2021

KDM6B-mediated histone demethylation of LDHA promotes lung metastasis of osteosarcoma.

Theranostics 2021 6;11(8):3868-3881. Epub 2021 Feb 6.

Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, China.

Osteosarcoma (OS), the most common type of bone tumor, which seriously affects the patients' limb function and life quality. OS has a strong tendency of lung metastasis, and the five-year survival rate of patients with metastatic osteosarcoma is less than 20%. Thus, new treatment targets and strategies are urgently needed. The expression of the histone demethylase KDM6B and H3K27me3 levels in OS specimens were analyzed using quantitative PCR and immunohistochemical assays. The biological functions of KDM6B were determined using transwell, wound healing assays, and an orthotopic injection-induced lung metastasis model. Subsequently, chromatin immunoprecipitation sequencing (ChIP-seq) combined with transcriptomic RNA sequencing (RNA-seq), and subsequent ChIP-qPCR, western blot, and aerobic glycolysis assays were used to explore the mechanism of KDM6B function and validate the candidate target gene of KDM6B. KDM6B expression was significantly upregulated in OS patients, and high KDM6B expression was associated with poorer prognosis in OS patients. Targeting KDM6B significantly inhibited OS cell migration and lung metastasis . RNA-seq and ChIP-seq analysis revealed that KDM6B increases lactate dehydrogenase LDHA expression in OS cells by directly mediating H3K27me3 demethylation. The phenotypes of inhibited cell metastasis in KDM6B-knockdown OS cells was reversed upon overexpression of LDHA. Finally, a small molecule inhibitor targeting KDM6B significantly inhibited OS cell migration and lung metastasis . Collectively, we elucidated that upregulated KDM6B facilitates tumor metastasis in OS via modulating LDHA expression. Our findings deepen the recognition of OS metastasis mechanism and suggest that KDM6B might be a new potential therapeutic target for the treatment of OS (especially highly metastatic OS).
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http://dx.doi.org/10.7150/thno.53347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914357PMC
February 2021

Dual-ligand supramolecular nanofibers inspired by the renin-angiotensin system for the targeting and synergistic therapy of myocardial infarction.

Theranostics 2021 27;11(8):3725-3741. Epub 2021 Jan 27.

Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Department of Cardiology and Laboratory of Heart Center, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.

The compensatory activation of the renin-angiotensin system (RAS) after myocardial infarction (MI) plays a crucial role in the pathogenesis of heart failure. Most existing studies on this subject focus on mono- or dual-therapy of blocking the RAS, which exhibit limited efficacy and often causes serious adverse reactions. Few studies have been conducted on targeted therapy based on the activated RAS post-MI. Thus, the development of multiple-functional nanomedicine with concurrent targeting ability and synergistic therapeutic effect against RAS may show great promise in improving cardiac function post-MI. We utilized a cooperative self-assembly strategy constructing supramolecular nanofibers- telmisartan-doped co-assembly nanofibers ( ) to counter-regulate RAS through targeted delivery and combined therapy. were prepared through serial steps of solvent exchange, heating incubation, gelation, centrifugation, and lyophilization, in which the telmisartan was doped in the self-assembly process of to obtain the co-assembly nanofibers wherein they act as both therapeutic agents and target-guide agents. exhibited the desired binding affinity to the two different receptors, AT1R and MasR. Through the dual ligand-receptor interactions to mediate the coincident downstream pathways, not only displayed favorably targeted properties to hypoxic cardiomyocytes, but also exerted synergistic therapeutic effects in apoptosis reduction, inflammatory response alleviation, and fibrosis inhibition and , significantly protecting cardiac function and mitigating post-MI adverse outcomes. A dual-ligand nanoplatform was successfully developed to achieve targeted and synergistic therapy against cardiac deterioration post-MI. We envision that the integration of multiple therapeutic agents through supramolecular self-assembly would offer new insight for the systematic and targeted treatment of cardiovascular diseases.
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http://dx.doi.org/10.7150/thno.53644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914367PMC
January 2021

Heat shock protein-90alpha (Hsp90α) stabilizes hypoxia-inducible factor-1α (HIF-1α) in support of spermatogenesis and tumorigenesis.

Cancer Gene Ther 2021 Mar 4. Epub 2021 Mar 4.

Department of Dermatology and the Norris Comprehensive Cancer Centre, University of Southern California Keck Medical Center, Los Angeles, CA, USA.

Hypoxia-inducible factor-1 (HIF-1), a master transcriptional factor for protecting cells from hypoxia, plays a critical role in spermatogenesis and tumorigenesis. For the past two decades, numerous small molecule inhibitors that block mRNA synthesis, protein translation, or DNA binding of HIF-1α have entered clinical trials. To date, few have advanced to FDA approval for clinical applications due to limited efficacy at their toxicity-tolerable dosages. New windows for developing effective and safe therapeutics require better understanding of the specific mechanism of action. The finding that a chaperone-defective mutant heat shock protein-90-alpha (Hsp90α) blocks spermatogenesis, a known hypoxia-driven process in mouse testis prompted us to focus on the role of Hsp90α in HIF-1α. Here we demonstrate that Hsp90α gene knockout causes a dramatic reduction of the high steady-state level of HIF-1α in the testis, blocking sperm production and causing infertility of the mice. In HIF-1α-dependent tumor cells, we found that Hsp90α forms protein complexes with hypoxia-elevated HIF-1α and Hsp90α knockout prevents hypoxia-induced HIF-1α accumulation. In contrast, downregulation of Hsp90β had little effect on hypoxia-induced accumulation of HIF-1α. Instead, Hsp90β protects signaling molecules responsible for cellular homeostasis from assault by 17-AAG (17-N-allylamino-17-demethoxygeldanamycin), a general ATPase inhibitor of both Hsp90α and Hsp90β. Since targeting Hsp90β gene is lethal in both cultured cells and in mice, our new finding explains the toxicity of the previous inhibitor trials and identifies the specific binding of Hsp90α to HIF-1α as a new therapeutic window for developing safer and more effective treatment of male infertility and cancer.
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http://dx.doi.org/10.1038/s41417-021-00316-6DOI Listing
March 2021

Regulation of OATP1B1 function by tyrosine kinase-mediated phosphorylation.

Clin Cancer Res 2021 Mar 4. Epub 2021 Mar 4.

University at Buffalo, State University of New York.

Purpose: OATP1B1 (SLCO1B1) is the most abundant and pharmacologically-relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug-drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKIs).

Experimental Design: OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI was measured Tyrosine phosphorylation of OATP1B1 was determined by LC/MS/MS-based proteomics and transport function was measured following exposure to siRNAs targeting 779 different kinases.

Results: 29 of 46 FDA-approved TKIs studied significantly inhibit OATP1B1 function. Inhibition of OATP1B1 by TKIs such as nilotinib is predominantly noncompetitive, can increase systemic concentrations of rosuvastatin , and is associated with reduced phosphorylation of OATP1B1 at tyrosine residue 645. Using genetic screens and functional validation studies, the Src kinase LYN was identified as a potential regulator of OATP1B1 activity that is highly sensitive to inhibition by various TKIs at clinically relevant concentrations.

Conclusions: A novel kinase-dependent post-translational mechanism of OATP1B1 activation was identified and interference with this process by TKIs can influence the elimination of a broad range of xenobiotic substrates.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0023DOI Listing
March 2021

Fine-tuning p53 activity by modulating the interaction between eukaryotic translation initiation factor eIF4E and RNA-binding protein RBM38.

Genes Dev 2021 Mar 4. Epub 2021 Mar 4.

Comparative Oncology Laboratory, School of Veterinary Medicine, School of Medicine, University of California at Davis, Davis, California 95616, USA.

p53 is critical for tumor suppression but also elicits detrimental effects when aberrantly overexpressed. Thus, multiple regulators, including RNA-binding protein RBM38, are found to tightly control p53 expression. Interestingly, RBM38 is unique in that it can either suppress or enhance p53 mRNA translation via altered interaction with eIF4E potentially mediated by serine-195 (S195) in RBM38. Thus, multiple RBM38/eIF4E knock-in (KI) cell lines were generated to investigate the significance of eIF4E-RBM38 interaction in controlling p53 activity. We showed that KI of RBM38-S195D or -Y192C enhances, whereas KI of RBM38-S195K/R/L weakens, the binding of eIF4E to p53 mRNA and subsequently p53 expression. We also showed that KI of eIF4E-D202K weakens the interaction of eIF4E with RBM38 and thereby enhances p53 expression, suggesting that D202 in eIF4E interacts with S195 in RBM38. Moreover, we generated an Rbm38 S193D KI mouse model in which human-equivalent serine-193 is substituted with aspartic acid. We showed that S193D KI enhances p53-dependent cellular senescence and that S193D KI mice have a shortened life span and are prone to spontaneous tumors, chronic inflammation, and liver steatosis. Together, we provide in vivo evidence that the RBM38-eIF4E loop can be explored to fine-tune p53 expression for therapeutic development.
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http://dx.doi.org/10.1101/gad.346148.120DOI Listing
March 2021

[Histone Deacetylase Inhibitors in the in Vitro Expansion of Hematopoietic Stem Cells].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2021 Feb;43(1):109-115

Department of Hematology,PUMC Hospital,CAMS and PUMC,Beijing 100730,China.

The self-renewal and differentiation of hematopoietic stem cells(HSCs)are highly regulated by epigenetic modification,in which histone acetylation can activate or silence gene transcription.Histone deacetylase inhibitors(HDACIs)can inhibit the activity of histone deacetylase in HSCs to increase histone acetylation.A variety of HDACIs,such as trichostatin A and valproic acid,are used to expand HSCs in vitro,especially cord blood HSCs,combined with cytokines in serum-free culture to obtain more long-term repopulating cells.HDACIs promote the transcription of pluripotent genes related to stem cell self-renewal and inhibit the expression of genes related to differentiation,so as to promote the expansion and inhibit differentiation of HSCs.The expansion of cord blood HSCs by small molecular HDACIs in vitro is expected to improve the quantity of cord blood HSCs.The further research will focus on high-throughput screening for the most powerful HDACIs and the highly selective HDACIs,exploring the combination of epigenetic modifiers of different pathways.
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http://dx.doi.org/10.3881/j.issn.1000-503X.12583DOI Listing
February 2021

Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models.

Mol Neurodegener 2021 Mar 4;16(1):14. Epub 2021 Mar 4.

Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China.

Background: Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer's disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear.

Methods: To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, while behavioral studies assessed olfaction and memory function.

Results: LFP measurements demonstrated an increase in gamma oscillations in the OB accompanied by altered olfactory behavior in both APP/PS1 and 3xTg mice at 3-5 months old, i.e. an age before the onset of plaque formation. Fewer olfactory sensory neurons (OSNs) and a reduced EOG contributed to a decrease in the excitatory responses of M/T cells, suggesting a decreased ability of M/T cells to trigger interneuron GABA release indicated by altered paired-pulse ratio (PPR), a presynaptic parameter. Postsynaptically, there was a compensatory increase in levels of GABAR α1 and β3 subunits and subsequent higher amplitude of inhibitory responses. Strikingly, the GABA uptake inhibitor tiagabine (TGB) ameliorated abnormal gamma oscillations and levels of GABAR subunits, suggesting a potential therapeutic strategy for early AD symptoms. These findings reveal increased gamma oscillations in the OB as a core indicator prior to onset of AD and uncover mechanisms underlying aberrant gamma activity in the OB.

Conclusions: This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis: in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.
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http://dx.doi.org/10.1186/s13024-021-00434-7DOI Listing
March 2021

Delirium screening tools in the emergency department: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2021 Feb;100(8):e24779

The First Hospital, Lanzhou University, Lanzhou, China.

Background: Delirium is a common type of acute brain dysfunction among emergency department (ED) patients. The prevalence of delirium in the ED is up to 40%. Although screening instruments used to identify delirium have been developed, it is unclear which tool is the most accurate in the ED. To address this challenging, we systematically examine the accuracy of delirium screening tools used to assess the ED patients.

Methods: This study has been registered at the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY), and the registration number is INPLASY202110041. We will search the PubMed, EMBASE, PsycINFO, and the Cochrane Library. Studies involving patients which compared diagnostic instruments with the criteria in Diagnostic and Statistical Manual of Mental Disorders (DSM) as a reference standard will be included. We will use STATA 15.1 and MetaDiSC to make careful analysis of the results. The quality of included studies will be assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 scale.

Results: In this study, the accuracy of different screening methods among ED patients is assessed by a high-quality synthesis. The number of tools available for screening delirium in the ED, the information of studies including the countries, the study design, the sample size and the characteristic of studies, the quality of the studies and the results of meta-analysis. The systematic review and meta-analysis will be published in a peer-reviewed journal.

Conclusion: According to the conclusion of the systematic review, evidence will be provided to judge which screening method is the best for the ED patients. The results will bring better understanding of screening methods in the ED and highlight gaps for future research.
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http://dx.doi.org/10.1097/MD.0000000000024779DOI Listing
February 2021

Coupling anammox with denitrification in a full-scale combined biological nitrogen removal process for swine wastewater treatment.

Bioresour Technol 2021 Feb 27;329:124906. Epub 2021 Feb 27.

State Key Joint Laboratory of Environmental Simulation and Pollution Control, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China; Laboratory of Water Pollution Control Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.

In order to enhance nitrogen removal through anammox process in the full-scale swine wastewater treatment plant, an innovative regulation strategy of nitrate-based carbon dosage and intermittent aeration was developed to apply the combined biological nitrogen removal process in a full scale anaerobic-anoxic-oxic (A/O) system. TN removal efficiency reached at 65.5 ± 6.0% in Phase 1 with decreasing external carbon dosage in influent due to the reduction of return nitrate concentration, and it increased to 83.5 ± 6.7% when intermittent aeration was adopted in oxic zone and external carbon source was stopped adding into influent in Phase 2. As a result, the energy consumption for the swine wastewater treatment decreased from 1.93 to 0.9 kW h/m and 4.18 to 2.57 kW h/kg N, respectively. Microbial community analysis revealed that the average abundances of Candidatus Brocadia increased from 0.76% to 2.43% and removal of TN through anammox increased from 39% to 77%.
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http://dx.doi.org/10.1016/j.biortech.2021.124906DOI Listing
February 2021

Bioassay- and QSAR-based screening of toxic transformation products and their formation under chlorination treatment on levofloxacin.

J Hazard Mater 2021 Feb 24;414:125495. Epub 2021 Feb 24.

State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.

Levofloxacin (LEV) is a broad-spectrum quinolone antibiotic and widely used for human and veterinary treatment. Overuse of LEV leads to its frequent occurrence in the water environment. In this study, the transformation characteristics of LEV in water during the simulated chlorination disinfection treatment were explored. Fifteen major transformation products (TPs) of LEV were identified, and their plausible formation pathways were proposed. The reaction pathways were strongly dependent on pH condition, and LEV removal was relevant to free available chlorine (FAC) dose. Antibacterial activity of chlorination system was dramatically declined when FAC was more than 3-equivalent (eq) due to the elimination of antibacterial related functional groups. Genotoxicity of chlorination system increased more than 3 times at 0.5-eq of FAC and then decreased with increasing FAC dose, which were in accordance with the relative concentration of toxic TPs estimated by QSAR model. These results implied that the combination of bioassay, QSAR computation and chemical analysis would be an efficient method to screen toxic TPs under chlorination treatment. It is anticipated that the results of this study can provide reference for optimizing operational parameters for water disinfection treatment, and for scientifically evaluating the potential risk of quinolone antibiotics.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125495DOI Listing
February 2021

Discovery of 3,6-disubstutited-imidazo[1,2-a]pyridine derivatives as a new class of CLK1 inhibitors.

Bioorg Med Chem Lett 2021 Mar 1:127881. Epub 2021 Mar 1.

Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China. Electronic address:

Inhibition of cdc2-like kinase1 (CLK1) could efficiently induce autophagy and it has been thought as a potential target for treatment of autophagy-related diseases. Herein we report the discovery of a series of 3,6-disubstutited-imidazo[1,2-a]pyridine derivatives as a new class of CLK1 inhibitors. Among them, compound 9e is the most potent one, which exhibits an IC value of 4 nM against CLK1 kinase. In vitro, this compound reduces the phosphorylation level of the typical downstream substrates of CLK1 and affects their subcellular redistribution. Further study indicates that 9e is efficient to induce autophagy. Overall, this study provides a promising lead compound for drug discovery targeting CLK1 kinase.
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http://dx.doi.org/10.1016/j.bmcl.2021.127881DOI Listing
March 2021

Hepatic COX-2 Expression Protects Mice from an Alcohol-high fat Diet-Induced Metabolic Disorder by Involving Protein Acetylation Related Energy Metabolism.

Alcohol 2021 Mar 1. Epub 2021 Mar 1.

Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States. Electronic address:

Purpose: A diet high in fat and ethanol often results in chronic metabolic disorder, hepatic steatosis, and liver inflammation. Constitutive hepatic cyclooxygenase-2 (COX-2) expression could protect from high fat-induced metabolism disturbance in a murine model. In this study, we explored the influence of hCOX-2 transgenic [TG] to high fat with ethanol-induced metabolic disorder and liver injury using a mouse animal model.

Methods: 12-week-old male hepatic hCOX-2 transgenic (TG) or wild type mice (WT) were fed either a high fat and ethanol liquid diet (HF+Eth) or a regular control diet (RCD) for 5 weeks (four groups: RCD/WT, RCD/TG; HF+Eth/TG, HF+Eth/WT). We assessed metabolic biomarkers, cytokine profiles, histomorphology, and gene expression to study the impact of persistent hepatic COX-2 expression on diet-induced liver injury.

Results: In the HF+Eth diet, constitutively hepatic human COX-2 expression protects mice from body weight gain and white adipose tissue accumulation, accompanied by improved IPGTT response, serum triglyceride/cholesterol levels, and lower levels of serum and liver inflammatory cytokines. Histologically, hCOX-2 mice showed decreased hepatic lipid droplets accumulation, decreased hepatocyte ballooning, and improved steatosis scores. Hepatic hCOX-2 overexpression enhanced AKT insulin signaling and increased fatty acid synthesis in both RCD and HF+Eth diet groups. The anti-lipogenic effect of hCOX-2 TG in the HF+Eth diet animals was mediated by increasing lipid disposal through enhanced β-oxidation via elevations in the expression of PPARα and PPARγ, and increased hepatic autophagy as assessed by the ratio of autophagy markers LC3 II/I in hepatic tissue. Various protein acetylation pathway components, including HAT, HDAC1, SIRT1, and SNAIL1, were modulated in hCOX-2 TG mice in either RCD or HF+Eth diet.

Conclusions: Hepatic human COX-2 expression protected mice from the metabolic disorder and liver injury induced by a high fat and ethanol diet by enhancing hepatic lipid expenditure. Epigenetic reprogramming of diverse metabolic genes might be involved in the anti-lipogenic effect of COX-2.
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http://dx.doi.org/10.1016/j.alcohol.2020.08.007DOI Listing
March 2021

Recent advances of redox-responsive nanoplatforms for tumor theranostics.

J Control Release 2021 Mar 1. Epub 2021 Mar 1.

State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China; Institute of Molecular Sciences and Engineering, Shandong University, Qingdao 266237, People's Republic of China. Electronic address:

Nano-biotechnologies which combine diagnosis with therapy in an integrated nanoplatform provide a promising prospect for cancer theranostics. Currently, the development of personalized medicine requires the exploitation of "smart" theranostic nanoplatforms with specific targeting, precise cargoes release, non-invasive therapeutics for cancers and so on. High levels of hydrogen peroxide (HO) and glutathione (GSH) are prominent features of tumor microenvironment (TME), which are distinctly different from healthy tissues. Accordingly, extensive redox-responsive theranostic nanoplatforms have been exploited by modulating intracellular redox homeostasis. In this review, we first summarized the recent advances of overexpressed HO- and antioxidant GSH-responsive nanoplatforms for tumor diagnose and treatment. Then, the strategies by synergistically boosting reactive oxygen species (ROS) production and GSH depletion for amplifying oxidative stress are highlighted. At last, the prospects and controversies of stimuli-driven nanotheranostics are also discussed for future development.
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http://dx.doi.org/10.1016/j.jconrel.2021.02.030DOI Listing
March 2021

Rab8 attenuates Wnt signaling and is required for mesenchymal differentiation into adipocytes.

J Biol Chem 2021 Mar 1:100488. Epub 2021 Mar 1.

Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA. Electronic address:

Differentiation of mesenchymal stem cells into adipocyte requires coordination of external stimuli and depends upon the functionality of primary cilium. The Rab8 small-GTPases are regulators of intracellular transport of membrane-bound structural and signaling cargo. However, the physiological contribution of the intrinsic trafficking network controlled by Rab8 to mesenchymal tissue differentiation has not been fully defined in vivo and in primary tissue cultures. Here, we show that mouse embryonic fibroblasts (MEFs) lacking Rab8 have severely impaired adipocyte differentiation in vivo and ex vivo. Immunofluorescent localization and biochemical analyses of Rab8a-deficient, Rab8b-deficient, and Rab8a and Rab8b double deficient MEFs revealed that Rab8 controls the Lrp6 vesicular compartment, clearance of basal signalosome, traffic of Frizzled 2 receptor, and thereby a proper attenuation of Wnt signaling in differentiating MEFs. Upon induction of adipogenesis program, Rab8a- and Rab8b-deficient MEFs exhibited severely defective lipid droplet formation and abnormal cilia morphology, despite overall intact cilia growth and ciliary cargo transport. Our results suggest that intracellular Rab8 traffic regulates induction of adipogenesis via proper positioning of Wnt receptors for signaling control in mesenchymal cells.
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http://dx.doi.org/10.1016/j.jbc.2021.100488DOI Listing
March 2021

Beyond protein intake: does dietary fat intake in the year preceding pregnancy and during pregnancy have an impact on gestational diabetes mellitus?

Eur J Nutr 2021 Mar 4. Epub 2021 Mar 4.

Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.

Purpose: Studies regarding the association between dietary fat intake and gestational diabetes mellitus (GDM) are limited and provide conflicting findings. Thus, the study aims to examine the association of dietary fat intake in the year preceding pregnancy and during pregnancy with the risk of GDM, taking the relevance of dietary protein intake on GDM into consideration.

Methods: A prospective study was conducted in 6299 singleton pregnancies, using the data from the Nutrition in Pregnancy and Growth in Southwest China (NPGSC). A validated food frequency questionnaire was used to assess dietary fat intake in the year preceding pregnancy and during the first and second trimesters of pregnancy. Logistic regression analysis was used to assess the prospective associations of dietary fat intake and the type and source of dietary fats in different time windows with GDM risk.

Results: Higher intake of total fat [OR (95% CI): 2.21 (1.19-4.20), P = 0.02] during 12-22 weeks of gestation was associated with higher GDM risk. However, adjustment for animal protein intake greatly attenuated this association [OR (95% CI): 1.81 (0.93, 3.64), P = 0.11]. Total fat intake neither in the year preceding pregnancy nor during the early pregnancy was associated with GDM risk. Moreover, insignificant associations were observed between intakes of vegetable fat, animal fat, cholesterol, saturated fatty acid, monounsaturated fatty acid and polyunsaturated fatty acid one year before pregnancy and during the first and second trimesters and GDM risk.

Conclusion: Our study indicated that dietary fat intake one year before pregnancy and across the two pregnancy trimesters preceding the diagnosis of GDM has no relevance on GDM risk among Chinese women, particularly those with normal BMI, low, or normal calorie intake.
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http://dx.doi.org/10.1007/s00394-021-02525-zDOI Listing
March 2021

Chinese herbal medicine versus antispasmodics in the treatment of irritable bowel syndrome: A network meta-analysis.

Neurogastroenterol Motil 2021 Mar 4:e14107. Epub 2021 Mar 4.

Anorectal Disease Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.

Background: Chinese herbal medicine (CHM) is gaining popularity in treating irritable bowel syndrome (IBS). Although its efficacy was shown in recent randomized controlled trials (RCTs), it is rarely compared with antispasmodics to confirm its effectiveness. We aimed to resolve this uncertainty through a network meta-analysis.

Methods: We searched for RCTs that compared CHM or antispasmodics with placebo or one of them in the treatment of IBS. The primary outcomes were adequate relief of global IBS symptoms and abdominal pain. The data were pooled using a random-effects model. The effect size measure was pooled relative risk (RR), and treatments were ranked according to their P-scores.

Key Results: We included 57 RCTs (n = 8869). After completion of treatment, drotaverine, individual CHM, otilonium, cimetropium, standard CHM, and pinaverium were efficacious in adequate relief of global IBS symptoms, and drotaverine ranked the first (RR, 2.33 [95% CI, 1.31-4.14], P-score =0.91); no difference was found between these treatments. After completion of treatment, drotaverine, standard CHM, pinaverium, and individual CHM were efficacious in abdominal pain, and drotaverine ranked the first (RR, 2.71 [95% CI, 1.69-4.36], P-score =0.91); no difference was found between these treatments. Standard CHM had significantly more adverse events than placebo (RR, 1.82 [95% CI, 1.12-2.94]) and other treatments.

Conclusions: CHM and antispasmodics were efficacious for improvement of global IBS symptoms and abdominal pain. The adverse events of CHM were higher than antispasmodics; however, the heterogeneity of CHM formulas and the very low quality of the evidence warrants further investigation.
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http://dx.doi.org/10.1111/nmo.14107DOI Listing
March 2021

shrub is required for spermatogenesis of Drosophila melanogaster.

Arch Insect Biochem Physiol 2021 Mar 3:e21779. Epub 2021 Mar 3.

Hubei Key Laboratory of Genetic Regulation and Integrative Biology Sciences, School of Life, Central China Normal University, Wuhan, China.

Shrub (CG8055) encodes the vps32/snf7 protein, a filament-forming subunit of the ESCRT (endosomal sorting complexes required for transport)-III complex involved in inward membrane budding. It was reported that shrub was required for abscission in female germline stem cells. In this study, we showed that the expression level of shrub in the testis was significantly higher than that in the ovary of 1-day-old Drosophila melanogaster, suggesting a role in male reproduction. Then we used nosGal4 driver to knockdown shrub specifically in the fly testis and found that this resulted in a significantly lower paternal effect egg hatch rate relative to the control group. Immunofluorescence staining showed that shrub knockdown in fly testes caused an accumulation of early-stage germ cells and lack of spectrin caps. In the late stages (spermiogenesis), the control testis contained multiple compacted spermatid bundles and individualization complexes (ICs) consisting of actin cones, whereas there were scattered spermatid nuclei and only a few ICs with disorganized actin cones in the shrub knockdown testis. Finally, the control seminal vesicle was full of mature sperms with needle-like heads, but in shrub knockdown testis 75% of seminal vesicles had no mature sperms. We also found that knockdown of shrub in fly testes led to upregulated expression of several cytoskeleton-associated genes, and an accumulation of ubiquitylated proteins. These results suggest that knockdown of shrub in fly testes might damage spermatogenesis by affecting transportability.
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http://dx.doi.org/10.1002/arch.21779DOI Listing
March 2021

Long-Term Trends and Predictors of Medical Resource Utilization and Medical Outcomes in Inguinal Hernia Repair: A Nationwide Cohort Study.

World J Surg 2021 Mar 3. Epub 2021 Mar 3.

Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan.

Background: Few studies have comprehensively and systematically analyzed nationwide samples. This study purposed to explore temporal trends and predictors of medical resource utilization and medical outcomes in these patients to obtain data that can be used to improve healthcare policies and to support clinical and administrative decision-making.

Methods: This study used nationwide population data contained in the Longitudinal Health Insurance Database of Taiwan. The 14,970 inguinal hernia repair patients were enrolled in this study (age range, 18-100 years) from 1997 to 2013 in Taiwan. After temporal trends analysis of demographic characteristics, clinical characteristics, and institutional characteristics, predictors of postoperative medical resource utilization and medical outcomes were evaluated through multiple linear regression analysis and Cox regression analysis.

Results: The prevalence of inguinal hernia repair per 100,000 population significantly decreased from 195.38 in 1997 to 39.66 in 2013 (p < 0.05). Demographic characteristics, clinical characteristics, and institutional characteristics were significantly associated with postoperative medical resource utilization and medical outcomes (p < 0.05). Of these characteristics, both surgeon volume and hospital volume had the strongest association.

Conclusions: The inguinal hernia repair prevalence rate gradually decreased during the study period. Demographic characteristics, clinical characteristics, and institutional characteristics had strong associations with postoperative medical resource utilization and medical outcomes. Furthermore, hospital volume and surgeon volume had the strongest associations with postoperative medical resource utilization and medical outcomes. Additionally, providing the education needed to make the most advantageous medical decisions would be a great service not only to patients and their families, but also to the general population.
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http://dx.doi.org/10.1007/s00268-021-06012-8DOI Listing
March 2021

Infectious recombinant Senecavirus A expressing novel reporter proteins.

Appl Microbiol Biotechnol 2021 Mar 3. Epub 2021 Mar 3.

College of Veterinary Medicine, Yangzhou University, 12 Wen-hui East Road, Yangzhou, JS225009, China.

Senecavirus A (SVA) is an emerging picornavirus that has been associated with vesicular disease and neonatal mortality in swine. The construction of SVA virus carrying foreign reporter gene provides a powerful tool in virus research. However, it is often fraught with rescuing a recombinant picornavirus harboring a foreign gene or maintaining the stability of foreign gene in the virus genome. Here, we successfully generated recombinant SVA GD05/2017 viruses (V-GD05-clone) expressing the green fluorescent protein (iLOV), red fluorescent protein (RFP), or NanoLuc luciferase (Nluc). These recombinant viruses have comparable growth kinetics to the parental virus. Genetic stability analysis indicated that V-GD05-iLOV was highly stable in retaining iLOV gene for more than 10 passages, while V-GD05-RFP and V-GD05-Nluc lost the foreign genes in five passages. In addition, high-intensity fluorescent signals were found in the V-GD05-RFP- and V-GD05-iLOV-infected cells by fluorescence observation and flow cytometry analysis, and the luciferase activity assay could quantitatively monitor the replication of V-GD05-Nluc. In order to identify the porcine cell receptor for SVA, anthrax toxin receptor 1 (ANTXR1) was knocked out or overexpressed in the ST-R cells. The ANTXR1 knock-out cells lost the ability for SVA infection, while overexpression of ANTXR1 significantly increased the cell permissivity. These results confirmed that ANTXR1 was the receptor for SVA to invade porcine cells as reported in the human cells. Overall, this study suggests that these SVA reporter viruses will be useful tools in elucidating virus pathogenesis and developing control measures. KEY POINTS: • We successfully generated SVA viruses expressing the iLOV, RFP, or Nluc. • The iLOV was genetically stable in the V-GD05-iLOV genome over ten passages. • ANTXR1 was the receptor for SVA to invade porcine cells.
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http://dx.doi.org/10.1007/s00253-021-11181-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928201PMC
March 2021

A long-term, gridded, subsurface physical oceanography dataset and average annual cycles derived from measurements off the Western Australia coast during 2009-2020.

Data Brief 2021 Apr 29;35:106812. Epub 2021 Jan 29.

CSIRO Oceans and Atmosphere, Indian Ocean Marine Research Centre, Crawley, Western Australia, Australia.

This article reviewed dataset collected from an array of 12 coastal Integrated Marine Observing System (IMOS) moorings off the southwest coast of Western Australia (WA) during 2009-2020, at depths ranging from 47 m to 500 m. The dataset includes temperatures and salinities collected with Seabird SBE37 and SBE39 sensors and Water Quality Monitor (WQM). Velocities were collected by Teledyne RDI Acoustic Doppler Current Profilers (ADCP) and Nortek ADCPs. Here, a daily gridded subsurface temperature, salinity and ocean currents, and their average annual cycles are presented. Monthly data are also included. This integrated dataset provides an overview of data availability and allows users to have a quick access to the mooring data, without the need of manipulating over one thousand files individually. This unique dataset offers an invaluable baseline perspective on physical water column properties and temporal variability in WA coastal waters. The data can be used to characterise subsurface features of extreme events such as marine heat waves, marine cold-spells, and to detect long-term change signals along WA coast, influenced by the Leeuwin Current and the wind-driven Capes Current.
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http://dx.doi.org/10.1016/j.dib.2021.106812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892793PMC
April 2021

Tumor Growth and Spontaneous Metastasis Assays Using A549 Lung Cancer Cells.

Bio Protoc 2020 Apr 5;10(7):e3579. Epub 2020 Apr 5.

Markey Cancer Center, University of Kentucky, Lexington, 40536-0679, USA.

Metastasis accounts for the majority of cancer related deaths. The genetically engineered mouse (GEM) models and cell line-based subcutaneous and orthotopic mouse xenografts have been developed to study the metastatic process. By using lung cancer cell line A549 as an example, we present a modified protocol to establish the cell line-based xenograft. Our protocol ensures sufficient establishment of the mouse xenografts and allows us to monitor tumor growth and spontaneous metastasis. This protocol could be adapted to other types of established cancer cell lines or primary cancer cells to study the mechanism of metastatic process as well as to test the effect of the potential anti-cancer agents on tumor growth and metastatic capacity.
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http://dx.doi.org/10.21769/BioProtoc.3579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842773PMC
April 2020