Publications by authors named "Cheng Zhang"

2,486 Publications

  • Page 1 of 1

Global proteome response to Pb(II) toxicity in poplar using SWATH-MS-based quantitative proteomics investigation.

Ecotoxicol Environ Saf 2021 Jun 11;220:112410. Epub 2021 Jun 11.

Co-Innovation Center for Sustainable Forestry in Southern China, College of Biology and the Environment, Nanjing Forestry University, Nanjing, China; International Cultivar Registration Center for Osmanthus, College of Biology and the Environment, Nanjing Forestry University, Nanjing 210037, China. Electronic address:

Lead (Pb) toxicity is a growing serious environmental pollution that threatens human health and crop productivity. Poplar, as an important economic and ecological forest species, has the characteristics of fasting growth and accumulating heavy metals, which is a powerful model plant for phytoremediation. Here, a novel label-free quantitative proteomic platform of SWATH-MS was applied to detect proteome changes in poplar seedling roots following Pb treatment. In total 4388 unique proteins were identified and quantified, among which 542 proteins showed significant abundance changes upon Pb(II) exposure. Functional categorizations revealed that differentially expressed proteins (DEPs) primarily distributed in specialized biological processes. Particularly, lignin and flavonoid biosynthesis pathway were strongly activated upon Pb exposure, implicating their potential roles for Pb detoxification in poplar. Furthermore, hemicellulose and pectin related cell wall proteins exhibited increased abundances, where may function as a sequestration reservoir to reduce Pb toxicity in cytoplasm. Simultaneously, up-regulation of glutathione metabolism may serve as a protective role for Pb-induced oxidative damages in poplar. Further correlation investigation revealed an extra layer of post-transcriptional regulation during Pb response in poplar. Overall, our work represents multiply potential regulators in mediating Pb tolerance in poplar, providing molecular targets and strategies for phytoremediation.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112410DOI Listing
June 2021

Dysregulated KRAS gene-signaling axis and abnormal chromatin remodeling drive therapeutic resistance in heterogeneous-sized circulating tumor cells in gastric cancer patients.

Cancer Lett 2021 Jun 11. Epub 2021 Jun 11.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. Electronic address:

The mechanism by which heterogeneous-sized circulating tumor cells (CTCs) in gastric cancer (GC) patients are resistant to the targeted therapy and/or chemotherapy remains unclear. This study investigated prognostic value and genomic variations of size-heterogenous CTCs, in an attempt to unravel the molecular mechanisms underlying the therapeutic resistance, which is relevant to poor prognosis in GC. Aneuploid CTCs, detected in 111 advanced GC patients, were categorized into small (≤white blood cell [WBC], 25.54%) and large (>WBC, 74.46%) cells. Pre-treatment patients possessing ≥3 baseline small CTCs with trisomy 8 (CTCs) or ≥6 large multiploid CTCs (CTCs) showed an inferior median progression-free survival. Moreover, the cut-off value of ≥6 CTCs was also an effective prognosticator for poor median overall survival. Single cell-based DNA sequencing of 50 targeted CTCs indicated that CTCs and CTCs harbored distinct gene variations respectively. Mutations in the KRAS and Rap1 pathway were remarkably abundant in CTCs, whereas several unique mutations in the MET/PI3K/AKT pathway and SMARCB1 gene were identified in CTCs. Obtained results suggested that CTCs and CTCs exhibited different mechanisms to therapy resistance and correlated with patients' poor outcome.
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http://dx.doi.org/10.1016/j.canlet.2021.06.002DOI Listing
June 2021

Total Structure of Bimetallic Coreshell [Au42Cd40(SR)52]2- Nanocluster and Its Implications.

Angew Chem Int Ed Engl 2021 Jun 14. Epub 2021 Jun 14.

Qingdao University of Science and Technology, Chem, CHINA.

Bimetallic coreshell nanostructures hold great promise in elucidating the bimetallic synergism. However, it remains a challenge to construct atomically precise core-shell with high-valence active metals on the gold surface. In this work, we report the total structure of a [Au42Cd40(SR)52]2- coreshell nanocluster and multiple implications. Single crystal X-ray diffraction (SCXRD) reveals that the structure possesses a two-shelled [email protected] core and a closed cadmium shell of Cd40, and the coreshell structure is then protected by 52 thiolate (-SR) ligands. The composition of the nanocluster is further confirmed by electrospray ionization mass spectrometry (ESI-MS). A catalytic test for styrene oxidation and a comparison with relevant nanoclusters reveal the surface effect on the catalytic activity and selectivity.
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http://dx.doi.org/10.1002/anie.202106804DOI Listing
June 2021

Editorial: Application of Systems Biology in Molecular Characterization and Diagnosis of Cancer.

Front Mol Biosci 2021 28;8:668146. Epub 2021 May 28.

Department of Surgery, School of Medicine, University of Maryland, College Park, MD, United States.

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http://dx.doi.org/10.3389/fmolb.2021.668146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193925PMC
May 2021

Discovery and Characterization of Benzimidazole Derivative XY123 as a Potent, Selective, and Orally Available RORγ Inverse Agonist.

J Med Chem 2021 Jun 14. Epub 2021 Jun 14.

Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China.

Receptor-related orphan receptor γ (RORγ) has emerged as an attractive therapeutic target for the treatment of cancer and inflammatory diseases. Herein, we report our effort on the discovery, optimization, and evaluation of benzothiazole and benzimidazole derivatives as novel inverse agonists of RORγ. The representative compound (designated as XY123) potently inhibited the RORγ transcription activity with a half-maximal inhibitory concentration (IC) value of 64 nM and showed excellent selectivity against other nuclear receptors. also potently suppressed cell proliferation, colony formation, and the expression of androgen receptor (AR)-regulated genes in AR-positive prostate cancer cell lines. In addition, demonstrated good metabolic stability and a pharmacokinetic property with reasonable oral bioavailability (32.41%) and moderate half-life ( = 4.98 h). Significantly, oral administration of compound achieved complete and long-lasting tumor regression in the 22Rv1 xenograft tumor model in mice. Compound may serve as a new valuable lead compound for further development of drugs for the treatment of prostate cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00763DOI Listing
June 2021

ITGA2 Overexpression Promotes Esophageal Squamous Cell Carcinoma Aggression via FAK/AKT Signaling Pathway.

Onco Targets Ther 2021 3;14:3583-3596. Epub 2021 Jun 3.

Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.

Background: Integrin alpha 2 (ITGA2) is highly expressed in various cancers. ITGA2 up regulation promotes tumor proliferation, invasion, migration, and angiogenesis and ITGA2 is a poor prognostic factor in many tumors. However, the mechanism underlying its role in esophageal squamous cell carcinoma (ESCC) is unknown.

Methods: The expression profile of ITGA2 in ESCC was analyzed using the Gene expression profiling interactive analysis (GEPIA). ESCC tissues were analyzed by real time PCR (RT-qPCR) and immunohistochemistry to verify ITGA2 expression. The impact of ITGA2 on the clinicopathological characteristics was explored using a chi-square test. Apoptosis, Transwell, colony formation, and wound healing assays were conducted to characterize the roles of ITGA2 in ESCC. Its impact on tumorigenesis was further examined using a tumor xenograft model. The expression of proteins associated with the epithelial-mesenchymal Transition (EMT) and focal adhesion kinase (FAK)/AKT pathway and regulated by ITGA2 was evaluated with Western blot analysis. The Akt inhibitor MK-2206 was used to explore the interaction of ITGA2 with the FAK/Akt pathway.

Results: ITGA2 was upregulated in ESCC tissues and related to lymph node metastasis as well as TNM stage. In vitro experimental models revealed that ITGA2 promotes proliferation, invasion, and migration, and inhibits apoptosis. In vivo experiments show that ITGA2 promotes ESCC proliferation. Additionally, Western blot analysis revealed that ITGA2 silencing inhibits FAK/AKT signaling and suppresses EMT, while its overexpression activates FAK/AKT signaling and promotes EMT. Moreover, treatment with the AKT inhibitor MK-2206 successfully repressed the progression of ESCC caused by ITGA2 overexpression.

Conclusion: Our findings indicated that in ESCC, ITGA2 promotes proliferation, invasion and migration, while inhibiting apoptosis and promoting EMT in ESCC, possibly via FAK/AKT phosphorylation. These findings highlight the therapeutic value of ITGA2 in ESCC.
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http://dx.doi.org/10.2147/OTT.S302028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185252PMC
June 2021

The Impact of Aortic Angulation on Contemporary Transcatheter Aortic Valve Replacement Outcomes.

JACC Cardiovasc Interv 2021 Jun;14(11):1209-1215

Section of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC, USA. Electronic address:

Objectives: The aim of this study was to investigate whether the degree of aortic angulation (AA) affects outcomes after transcatheter aortic valve replacement (TAVR) using newer-generation transcatheter heart valves (THVs).

Background: AA ≥48° has been reported to adversely influence accurate THV deployment, procedural success, fluoroscopy time, and paravalvular leak (PVL) in patients undergoing TAVR with early generation self-expanding (SE) THVs.

Methods: A retrospective observational study was conducted among 841 patients across all risk strata who underwent transfemoral TAVR using the balloon-expandable (BE) SAPIEN 3 or the SE CoreValve Evolut PRO from 2015 to 2020. The previously published cutoff of 48° was used to analyze procedural success and in-hospital outcomes according to THV type. Receiver-operating characteristic analysis was performed to investigate the impact of AA on an in-hospital composite outcome (need for >1 THV, more than mild PVL, new permanent pacemaker implantation, stroke, and death).

Results: AA ≥48° did not influence outcomes in patients with BE THVs. Additionally, AA ≥48° did not influence procedural success (99.1% vs. 99.1%; p = 0.980), number of THVs used (1.02 vs. 1.04; p = 0.484), rates of more than mild PVL (0.4% vs. 0%; p = 0.486), new permanent pacemaker implantation (11.8% vs. 17.1%; p = 0.178), in-hospital stroke (3.9% vs. 1.8%; p = 0.298), or in-hospital death (0.4% vs. 0.9%; p = 0.980) in patients with SE THVs. Receiver-operating characteristic analysis demonstrated similar outcomes irrespective of AA, with areas under the curve of 0.5525 for SE THVs and 0.5115 for BE THVs.

Conclusions: AA no longer plays a role with new-generation BE or SE THVs in contemporary TAVR practice. AA ≥48° did not affect procedural success or in-hospital outcomes and should no longer be a consideration when determining THV selection.
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http://dx.doi.org/10.1016/j.jcin.2021.03.027DOI Listing
June 2021

Strong Anisotropy and Bipolar Conduction-Dominated Thermoelectric Transport Properties in the Polycrystalline Topological Phase of ZrTe.

Inorg Chem 2021 Jun 10. Epub 2021 Jun 10.

State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China.

ZrTe has unique features of a temperature-dependent topological electronic structure and anisotropic crystal structure and has obtained intensive attention from the thermoelectric community. This work revealed that the sintered polycrystalline bulk ZrTe possesses both (020) and (041) preferred orientations. The transport properties of polycrystalline bulk p-type ZrTe exhibits an obvious anisotropic characteristic, that is, the room-temperature resistivity and thermal conductivity, possessing anisotropy ratios of 0.71 and 1.49 perpendicular and parallel to the pressing direction, respectively. The polycrystalline ZrTe obtained higher values in the direction perpendicular to the pressing direction, as compared to that in the other direction. The highest value of 0.11 is achieved at 350 K. Depending on the temperature-dependent topological electronic structure, the electronic transport of p-type ZrTe is dominated by high-mobility electrons from linear bands and low-mobility holes from the valence band, which, however, are merely influenced by valence band holes at around room temperature. Furthermore, external magnetic fields are detrimental to thermoelectric properties of our ZrTe, mainly arising from the more prominent negative effects of electrons under fields. This research is instructive to understand the transport features of ZrTe and paves the way for further optimizing their s.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00781DOI Listing
June 2021

Large Low-Field Magnetoresistance (LFMR) Effect in Free-Standing LaSrMnO Films.

ACS Appl Mater Interfaces 2021 Jun 9. Epub 2021 Jun 9.

Beijing National Laboratory of Condensed Matter Physics & Institute of Physics, Chinese Academy of Sciences, Beijing 100190, People's Republic of China.

The realization of a large low-field magnetoresistance (LFMR) effect in free-standing magnetic oxide films is a crucial goal toward promoting the development of flexible, low power consumption, and nonvolatile memory devices for information storage. LaSrMnO (LSMO) is an ideal material for spintronic devices due to its excellent magnetic and electronic properties. However, it is difficult to achieve both a large LFMR effect and high flexibility in LSMO films due to the lack of research on LFMR-related mechanisms and the strict LSMO growth conditions, which require rigid substrates. Here, we induced a large LFMR effect in an LSMO/mica heterostructure by utilizing a disorder-related spin-polarized tunneling effect and developed a simple transfer method to obtain free-standing LSMO films for the first time. Electrical and magnetic characterizations of these free-standing LSMO films revealed that all of the principal properties of LSMO were sustained under compressive and tensile conditions. Notably, the magnetoresistance of the processed LSMO film reached up to 16% under an ultrasmall magnetic field (0.1 T), which is 80 times that of a traditional LSMO film. As a demonstration, a stable nonvolatile multivalue storage function in flexible LSMO films was successfully achieved. Our work may pave the way for future wearable resistive memory device applications.
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http://dx.doi.org/10.1021/acsami.1c03753DOI Listing
June 2021

High electrochemical performance of Ni-foam supported TiCTMXene/rGO nanocomposite.

Nanotechnology 2021 Jun 8. Epub 2021 Jun 8.

Minjiang University, Xiyuangong Road 200 , Shangjie Town, Minhou County, Fuzhou City, PR China, Fuzhou, 350108, CHINA.

Two-dimensional (2D) materials have attracted extensive attention owing to their unique electronic/physiochemical properties, and wide application potential in energy storage and conversion. However, 2D materials are often tendency to aggregate due to the strong van der Waals interactions, leading to gradually decrease of an efficient mass transfer pathway and accessible surface area for the electrolyte. Here, we demonstrate an efficient approach for large-scale production of a hybrid nanostructures (TiCT/rGO) based on ultrathin MXene nanosheets anchored on layered reduced graphene (rGO) supported by porous Ni-foam via a plain chemical dipping-method followed by high temperature annealing process. TiCT/rGO electrode exhibits a porous structure, excellent ionic and electrical conductivities, and remarkable specific capacitance. Furthermore, it shows ultra-high cycle stability, for example, 88.70% of its specific capacity can be maintained through 3000 cycles. This kind of porous nanostructure and integrated design idea is significant to design other energy storage modules.
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http://dx.doi.org/10.1088/1361-6528/ac0934DOI Listing
June 2021

Tanshinones inhibit NLRP3 inflammasome activation by alleviating mitochondrial damage to protect against septic and gouty inflammation.

Int Immunopharmacol 2021 Jun 3;97:107819. Epub 2021 Jun 3.

The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, PR China. Electronic address:

Tanshinones, the active ingredients derived from the roots of Salvia miltiorrhiza, have been widely used as traditional medicinal herbs for treating human diseases. Although tanshinones showed anti-inflammatory effects in many studies, large knowledge gaps remain regarding their underlying mechanisms. Here, we identified 15 tanshinones that suppressed the activation of NLRP3 inflammasome and studied their structure-activity relationships. Three tanshinones (tanshinone IIA, isocryptotanshinone, and dihydrotanshinone I) reduced mitochondrial reactive-oxygen species production in lipopolysaccharide (LPS)/nigericin-stimulated macrophages and correlated with altered mitochondrial membrane potentials, mitochondria complexes activities, and adenosine triphosphate and protonated-nicotinamide adenine dinucleotide production. The tanshinones may confer mitochondrial protection by promoting autophagy and the AMP-activated protein kinase pathway. Importantly, our findings demonstrate that dihydrotanshinone I improved the survival of mice with LPS shock and ameliorated inflammatory responses in septic and gouty animals. Our results suggest a potential pharmacological mechanism whereby tanshinones can effectively treat inflammatory diseases, such as septic and gouty inflammation.
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http://dx.doi.org/10.1016/j.intimp.2021.107819DOI Listing
June 2021

Childhood Clear Cell Sarcoma of Kidney: Incidence and Survival.

Front Pediatr 2021 20;9:675373. Epub 2021 May 20.

Anhui Provincial Cancer Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

This study is to describe current incidence of childhood clear cell sarcoma of kidney (CCSK) and to investigate the present survival of this cancer. Surveillance, Epidemiology, and End Result (SEER) data was used to identify children with CCSK and Wilms tumor (WT) aged 0-19 years in the US. Age-adjusted incidences were estimated over the decades. Age- and sex-specific epidemiology was also presented. Propensity score matching was used to balance features of CCSK and WT cases. Log rank test was used to compare survivals and Cox regression was used to evaluate independent effects of factors. The present age-adjusted incidence of childhood CCSK was 0.205 per million, which remained stable for years and ranked third in all pediatric renal tumors. The incidence rate ratios for boy and age under 4 were 3 and 21, respectively. The current 5-year overall survival (OS) rate for CCSK was 87%, which is not evidently inferior to that for WT (90%); however the outcome of CCSK was significantly poorer if both groups were well-balanced (OS rate was 86 vs. 95%). Early year of diagnosis and distant metastasis were independent survival factors. In conclusion, occurrence of CCSK remains stable over the years, with an age-adjusted incidence of 0.205 per million. Boy and age under 4 are risk factors for tumor development. CCSK currently has a favorable outcome but its nature may be more aggressive than common kidney tumor, which in turn proves efficacy of modern treatment.
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http://dx.doi.org/10.3389/fped.2021.675373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173214PMC
May 2021

LINC00467 Promotes Prostate Cancer Progression M2 Macrophage Polarization and the miR-494-3p/STAT3 Axis.

Front Oncol 2021 19;11:661431. Epub 2021 May 19.

Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Background: The long non-coding RNA LINC00467 plays a vital role in many malignancies. Nevertheless, the role of LINC00467 in prostate carcinoma (PC) is unknown. Herein, we aimed to explore the mechanism by which LINC00467 regulates PC progression.

Methods: We used bioinformatics analyses and RT-qPCR to investigate the expression of LINC00467 in PC tissues and cells. The function of LINC00467 in the progression of PC was confirmed by loss-of-function experiments. PC cell proliferation was assessed by CCK-8 and EdU assays. The cell cycle progression of PC cells was examined by flow cytometry. Moreover, Transwell assays were used to investigate the migration and invasion of PC cells. Western blot assays were used to detect the expression of factors associated with epithelial-mesenchymal transition. The interactions of LINC00467 with prostate cancer progression and M2 macrophage polarization were confirmed by RT-qPCR. The subcellular localization of LINC00467 was investigated the fractionation of nuclear and cytoplasmic RNA. Bioinformatics data analysis was used to predict the correlation of LINC00467 expression with miR-494-3p expression. LINC00467/miR-494-3p/STAT3 interactions were identified by using a dual-luciferase reporter system. Finally, the influence of LINC00467 expression on PC progression was investigated with an nude mouse model of tumorigenesis.

Results: We established that LINC00467 expression was upregulated in PC tissues and cells. Downregulated LINC00467 expression inhibited PC cell growth, cell cycle progression, migration, and invasion. Downregulated LINC00467 expression similarly inhibited PC cell migration M2 macrophage polarization. Western blot analysis showed that LINC00467 could regulate the STAT3 pathway. We established that LINC00467 is mainly localized to the cytoplasm. Bioinformatics analysis and rescue experiments indicated that LINC00467 promotes PC progression the miR-494-3p/STAT3 axis. Downregulated LINC00467 expression was also able to suppress PC tumor growth .

Conclusions: Our study reveals that LINC00467 promotes prostate cancer progression M2 macrophage polarization and the miR-494-3p/STAT3 axis.
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http://dx.doi.org/10.3389/fonc.2021.661431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170392PMC
May 2021

Deep-red fluorescence from isolated dimers: a highly bright excimer and imaging .

Chem Sci 2020 May 25;11(23):6020-6025. Epub 2020 May 25.

School of Engineering, HuZhou University, Huzhou Cent Hosp 759 Erhuan Rd Huzhou Zhejiang P. R. China

Restricted by the energy-gap law, the development of bright near-infrared (near-IR) fluorescent luminophors in the solid state remains a challenge. Herein, we report a new design strategy for realizing high brightness and deep-red/near-IR-emissive organic molecules based on the incorporation of a hybridized local and charge-transfer (HLCT) state and separated dimeric stacks into one aggregate. Experimental and theoretical analyses show that this combination not only contributes to high photoluminescent quantum yields (PLQYs) but also significantly lessens the energy gap. The fluorophore exhibits excellent fluorescence performance, achieving a PLQY of 54.8% for the fluorescence peak at 690 nm, which is among the highest reported for near-IR fluorescent excimers. In addition, because of its bioimaging performance, the designed luminophor has potential for use as a deep-red fluorescent probe for biomedical applications. This research opens the door for developing deep-red/near-IR emissive materials with high PLQYs.
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http://dx.doi.org/10.1039/d0sc01873bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159302PMC
May 2020

Machine learning reveals hidden stability code in protein native fluorescence.

Comput Struct Biotechnol J 2021 28;19:2750-2760. Epub 2021 Apr 28.

Department of Biochemical Engineering, UCL, London WC1E 6BT, UK.

Conformational stability of a protein is usually obtained by spectroscopically measuring the unfolding melting temperature. However, optical spectra under native conditions are considered to contain too little resolution to probe protein stability. Here, we have built and trained a neural network model to take the temperature-dependence of intrinsic fluorescence emission under native-only conditions as inputs, and then predict the spectra at the unfolding transition and denatured state. Application to a therapeutic antibody fragment demonstrates that thermal transitions obtained from the predicted spectra correlate highly with those measured experimentally. Crucially, this work reveals that the temperature-dependence of native fluorescence spectra contains a high-degree of previously hidden information relating native ensemble features to stability. This could lead to rapid screening of therapeutic protein variants and formulations based on spectroscopic measurements under non-denaturing temperatures only.
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http://dx.doi.org/10.1016/j.csbj.2021.04.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131987PMC
April 2021

Comparison of the pH- and thermally-induced fluctuations of a therapeutic antibody Fab fragment by molecular dynamics simulation.

Comput Struct Biotechnol J 2021 4;19:2726-2741. Epub 2021 May 4.

Department of Biochemical Engineering, University College London, Gordon Street, London WC1E 7JE, United Kingdom.

Successful development of protein therapeutics depends critically on achieving stability under a range of conditions. A deeper understanding of the drivers of instability across different stress conditions, will enable the engineering of more robust protein scaffolds. We compared the impacts of low pH and high temperature stresses on the structure of a humanized antibody fragment (Fab) A33, using atomistic molecular dynamics simulations, using a recent 2.5 Å crystal structure. This revealed that low-pH induced the loss of native contacts in the domain C. By contrast, thermal stress led to 5-7% loss of native contacts in all four domains, and simultaneous loss of >30% of native contacts in the V-V and C-C interfaces. This revealed divergent destabilising pathways under the two different stresses. The underlying cause of instability was probed using FoldX and Rosetta mutation analysis, and packing density calculations. These agreed that mutations in the C domain, and C-C1 interface have the greatest potential for stabilisation of Fab A33. Several key salt bridge losses underpinned the conformational change in C at low pH, whereas at high temperature, salt bridges became more dynamic, thus contributing to an overall destabilization. Lastly, the unfolding events at the two stress conditions exposed different predicted aggregation-prone regions (APR) to solvent, which would potentially lead to different aggregation mechanisms. Overall, our results identified the early stages of unfolding and stability-limiting regions of Fab A33, and the V and C domains as interesting future targets for engineering stability to both pH- and thermal-stresses simultaneously.
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http://dx.doi.org/10.1016/j.csbj.2021.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131956PMC
May 2021

Safety and Efficacy of a Phage, kpssk3, in an Model of Carbapenem-Resistant Hypermucoviscous Bacteremia.

Front Microbiol 2021 20;12:613356. Epub 2021 May 20.

State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Antimicrobial resistance (AMR) is one of the most significant threats to global public health. As antibiotic failure is increasing, phages are gradually becoming important agents in the post-antibiotic era. In this study, the therapeutic effects and safety of kpssk3, a previously isolated phage infecting carbapenem-resistant hypermucoviscous (CR-HMKP), were evaluated in a mouse model of systemic CR-HMKP infection. The therapeutic efficacy experiment showed that intraperitoneal injection with a single dose of phage kpssk3 (1 × 10 PFU/mouse) 3 h post infection protected 100% of BALB/c mice against bacteremia induced by intraperitoneal challenge with a 2 × LD dose of NY03, a CR-HMKP clinical isolate. In addition, mice were treated with antibiotics from three classes (polymyxin B, tigecycline, and ceftazidime/avibactam plus aztreonam), and the 7 days survival rates of the treated mice were 20, 20, and 90%, respectively. The safety test consisted of 2 parts: determining the cytotoxicity of kpssk3 and evaluating the short- and long-term impacts of phage therapy on the mouse gut microbiota. Phage kpssk3 was shown to not be cytotoxic to mammalian cells or . Fecal samples were collected from the phage-treated mice at 3 time points before (0 day) and after (3 and 10 days) phage therapy to study the change in the gut microbiome via high-throughput 16S rDNA sequence analysis, which revealed no notable alterations in the gut microbiota except for decreases in the Chao1 and ACE indexes.
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http://dx.doi.org/10.3389/fmicb.2021.613356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175031PMC
May 2021

Diagnostic value of oncofetal miRNAs in cancers: A comprehensive analysis of circulating miRNAs in pan-cancers and UCB.

Cancer Biomark 2021 May 28. Epub 2021 May 28.

Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Background: Circulating miRNAs are promising biomarkers for detection of various cancers. As a "developmental" disorder, cancer showed great similarities with embryos.

Objective: A comprehensive analysis of circulating miRNAs in umbilical cord blood (UCB) and pan-cancers was conducted to identify circulating miRNAs with potential for cancer detection.

Methods: A total of 3831 cancer samples (2050 serum samples from 15 types of cancers and 1781 plasma samples from 13 types of cancers) and 248 UCB samples (120 serum and 128 plasma samples) with corresponding NCs from Chinese populations were analyzed via consistent experiment workflow with Exiqon panel followed by multiple-stage validation with qRT-PCR.

Results: Thirty-four serum and 32 plasma miRNAs were dysregulated in at least one type of cancer. Eighteen serum and 16 plasma miRNAs were related with embryos. Among them, 9 serum and 8 plasma miRNAs with consistent expression patterns between pan-cancers and UCB were identified as circulating oncofetal miRNAs. Retrospective analysis confirmed the diagnostic ability of circulating oncofetal miRNAs for specific cancers. And the oncofetal miRNAs were mainly up-regulated in tissues of pan-cancers.

Conclusions: Our study might serve as bases for the potential application of the non-invasive biomarkers in the future clinical.
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http://dx.doi.org/10.3233/CBM-203085DOI Listing
May 2021

Feasibility and Safety of High-Risk Percutaneous Coronary Intervention Without Mechanical Circulatory Support.

Circ Cardiovasc Interv 2021 Jun 7;14(6):e009960. Epub 2021 Jun 7.

Section of Interventional Cardiology, MedStar Washington Hospital Center, DC (N.K., T.R., C.Z., C.S., E.S., Y.C., A.M., J.P.W., B.C., H.H., I.B.-D., N.L.B., L.S., R.W.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009960DOI Listing
June 2021

Novel compound heterozygous CPLANE1 variants identified in a Chinese family with Joubert syndrome.

Int J Dev Neurosci 2021 Jun 5. Epub 2021 Jun 5.

Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, China.

Joubert syndrome (JS) and JS-related disorders (JSRD) are a group of neurodevelopmental diseases that share the "molar tooth sign" on axial brain magnetic resonance imaging (MRI), accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. To identify variants responsible for the clinical symptoms of a Chinese family with JS and to explore the genotype-phenotype associations, we conducted a series of clinical examinations, including blood tests, brain MRI scans, ultrasound imaging, and ophthalmologic examination. Genomic DNA was extracted from the peripheral blood of the six-person family, and the pathogenic variants were detected by whole-exome sequencing (WES) and verified by Sanger sequencing. WES revealed two novel compound heterozygous variants in CPLANE1: c.1270C>T (p.Arg424*) in exon 10 and c.8901C>A (p.Tyr2967*) in exon 48 of one child, inherited from each parent. Both variants were absent in ethnically matched Chinese control individuals and were either absent or present at very low frequencies in public databases, suggesting that these variants could be the pathogenic triggers of the JS phenotype. Notably, these CPLANE1 sequence variants were related to the pathogenesis of autosomal recessive JS in this study. The newly discovered variants expand the mutation spectrum of CPLANE1, which assists in understanding the molecular mechanism underlying JS and improving the recognition of genetic counseling, particularly for families with a history of autosomal recessive JS.
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http://dx.doi.org/10.1002/jdn.10135DOI Listing
June 2021

A patient-level, pooled analysis of mortality rates with the Passeo-18 Lux paclitaxel drug-coated balloon in peripheral arterial disease.

Cardiovasc Revasc Med 2021 Apr 15. Epub 2021 Apr 15.

Section of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC, United States of America. Electronic address:

Background: Recent meta-analyses have raised concerns about mortality with paclitaxel drug-coated balloons (DCB). This pooled, patient-level analysis of the BIOLUX P-I, P-II, and P-III studies was performed to evaluate the safety and efficacy of Passeo-18 Lux DCB.

Materials And Methods: Individual patient-level demographic, clinical, diagnostic, and procedural data from the BIOLUX P-I, BIOLUX P-II, and BIOLUX P-III studies were pooled in a common database. Clinical safety (all-cause mortality and cardiovascular mortality) and efficacy (any amputation, target lesion/vessel revascularization) were extracted. Cox proportional modeling was used to assess the effect of critical limb ischemia at the time of enrollment and the occurrence of new amputation as a time-dependent variable on mortality.

Results: A total of 1009 patients were included in the analysis. Sixty-six patients were treated with percutaneous transluminal angioplasty (PTA) and 943 underwent DCB angioplasty. The cumulative incidence of all-cause mortality did not differ between the groups (PTA 6.7%, DCB 6.7%, p = 0.65). The composite efficacy endpoint of freedom from any amputation and target lesion/vessel revascularization was superior in the DCB arm compared to PTA [PTA 28.8%, DCB 16.7%, p = 0.02]. Both in unadjusted and adjusted Cox proportional models (adjusted for critical limb ischemia and amputation), the use of DCB was not associated with any mortality at 1 year.

Conclusions: Our patient-level analysis shows that overall the use of the Passeo-18 Lux paclitaxel DCB in infrainguinal arteries was not associated with increased mortality at 1 year and reinforces the efficacy of DCB angioplasty in preventing amputation or the need for reintervention.
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http://dx.doi.org/10.1016/j.carrev.2021.04.010DOI Listing
April 2021

The impact of COVID-19 patients with troponin elevation on renal impairment and clinical outcome.

Cardiovasc Revasc Med 2021 May 8. Epub 2021 May 8.

Section of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC, United States of America. Electronic address:

Background: Cardiac involvement in coronavirus disease 2019 (COVID-19) is known, manifested by troponin elevation, and these patients have a worse prognosis than patients without myocardial injury.

Methods: We analyzed COVID-19-positive patients who presented to the MedStar Health system (11 hospitals in Washington, DC, and Maryland) during the pandemic (March 1-September 30, 2020). We compared renal function and subsequent in-hospital clinical outcomes based on the presence or absence of troponin elevation. The primary outcome was the incidence of acute kidney injury in COVID-19 patients with troponin elevation. We also evaluated in-hospital mortality, overall and based on the presence and absence of both troponin elevation and renal dysfunction.

Results: The cohort included 3386 COVID-19-positive admitted patients for whom troponin was drawn. Of these patients, 195 had troponin elevation (defined as ≥1.0 ng/mL), mean age was 61 ± 16 years, and 51% were men. In-hospital mortality was significantly higher (53.8%) in COVID-19-positive patients with concomitant troponin elevation than in those without troponin elevation (14.5%; p < 0.001). COVID-19-positive patients with troponin elevation had a higher prevalence of renal dysfunction (58.5%) than those without troponin elevation (23.4%; p < 0.001). Further analysis demonstrated that having both troponin elevation and renal dysfunction carried the worst in-hospital prognosis (in-hospital mortality 57.9%; intensive-care-unit admission 76.8%; ventilation requirement 63.2%), as compared to the absence or presence of either.

Conclusion: COVID-19 patients with troponin elevation are at higher risk for worsening renal function, and these patients subsequently have worse in-hospital clinical outcomes. Efforts should focus on early recognition, evaluation, and intensifying care of these patients.
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http://dx.doi.org/10.1016/j.carrev.2021.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106189PMC
May 2021

Mapping typical salt-marsh species in the Yellow River Delta wetland supported by temporal-spatial-spectral multidimensional features.

Sci Total Environ 2021 Aug 12;783:147061. Epub 2021 Apr 12.

College of Resources, Environment and Tourism, Capital Normal University, Beijing 100048, China; Key Laboratory of 3D Information Acquisition and Application of Ministry, Beijing 100048, China; Beijing Key Laboratory of Resources Environment and GIS, Beijing 100048, China; Beijing Laboratory of Water Resources Security, Beijing 10048, China.

The native salt marsh plants of the Yellow River Delta wetland such as Suaeda salsa and Phragmites australis, providing significant habitats for rare waterfowl, are the key to conserve biodiversity and enhance habitats of this critical wetland. These plants are undergoing severe degradation due to rapid invasion of Spartina alterniflora, which has been a major growing threat to the livelihood of waterfowl and the sustainability of the Yellow River Delta wetland. Monitoring the spatial pattern of salt marsh species is fundamental to the conservation and restoration of the ecological functions in the Yellow River Delta wetland. The development of remote sensing technologies is making a leap forward, particularly the high resolution synthetic aperture radar (SAR), which holds the potential to map heterogeneous wetland regardless of weather. In this study, we developed an innovative framework to map the distribution of salt marsh species with the integration of optical (Sentinel-2) and SAR (Sentinel-1) images. Within this framework, a comprehensive set of features including spectral, spatial and temporal features were considered, and the best feature combination was selected and applied in a random forest classification model to obtain the final map. The results show that the temporal-spectral features combined with the spatial-temporal features of the SAR data can effectively improve the separability of Suaeda salsa, Phragmites australis, and Spartina alterniflora. Compared with using optical or SAR data alone, the combination of optical and SAR data improved the kappa coefficient and the overall classification accuracy by 0.10-0.19 and 6.04-11.61%, respectively. The spatial distribution of the two main native plants and the invasive plant can facilitate ecological restoration of the Yellow River Delta wetland. The framework developed by this study can be efficiently replicated and transferred by similar studies. Our approach lays a solid foundation for intelligent monitoring and management of coastal wetland.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147061DOI Listing
August 2021

The Inhibition of B7H3 by 2-HG Accumulation Is Associated With Downregulation of VEGFA in IDH Mutated Gliomas.

Front Cell Dev Biol 2021 17;9:670145. Epub 2021 May 17.

Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.

B7H3 (also known as CD276) is a co-stimulator checkpoint protein of the cell surface B7 superfamily. Recently, the function beyond immune regulation of B7H3 has been widely studied. However, the expression preference and the regulation mechanism underlying B7H3 in different subtypes of gliomas is rarely understood. We show here that B7H3 expression is significantly decreased in IDH-mutated gliomas and in cultured IDH1-R132H glioma cells. Accumulation of 2-HG leads to a remarkable downregulation of B7H3 protein and the activity of IDH1-R132H mutant is responsible for B7H3 reduction in glioma cells. Inhibition of autophagy by inhibitors like leupeptin, chloroquine (CQ), and Bafilomycin A1 (Baf-A1) blocks the degradation of B7H3 in glioma cells. In the meantime, the autophagy flux is more active with higher LC3B-II and lower p62 in IDH1-R132H glioma cells than in IDH1-WT cells. Furthermore, sequence alignment analysis reveals potential LC3-interacting region (LIR) motifs "F-V-S/N-I/V" in B7H3. Moreover, B7H3 interacts with p62 and CQ treatment significantly enhances this interaction. Additionally, we find that is positively correlated with and by bioinformatics analysis in gliomas. B7H3 and VEGFA are decreased in IDH-mutated gliomas and further reduced in 2-HG gliomas compared to 2-HG glioma sections by IHC staining. Our study demonstrates that B7H3 is preferentially overexpressed in IDH wild-type gliomas and could serve as a potential theranostic target for the precise treatment of glioma patients with wild-type IDH.
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http://dx.doi.org/10.3389/fcell.2021.670145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165280PMC
May 2021

Transvesical Retzius-Sparing Versus Standard Robot-Assisted Radical Prostatectomy: A Retrospective Propensity Score-Adjusted Analysis.

Front Oncol 2021 17;11:687010. Epub 2021 May 17.

Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang City, China.

Objectives: To estimate the safety and efficiency of transvesical Retzius-sparing robot-assisted radical prostatectomy (T-RARP) compared with standard robot-assisted radical prostatectomy (S-RARP) for localized prostate cancer (PCa).

Materials And Methods: 174 patients bearing localized PCa and undergoing T-RARP or S-RARP between October 2017 and January 2020 were retrospectively enrolled in our analysis. All potential baseline confounders were strictly restrained with propensity-score matching (PM) method (1: 1). Within the matched setting, the perioperative and functional outcomes were compared between the T-RARP and S-RARP groups, while the oncological results and functional recovery of the two arms were presented with Kaplan-Meier curves.

Results: Finally, 114 and 60 eligible patients harbouring localized PCa were identified in the S-RARP and T-RARP group, respectively. No significant differences between the two groups were found in all baseline characteristics after PM. Within the matched cohort, no case was converted to open surgery in either group. The T-RARP group was significantly related to a higher mean operative time ( = 0.001) and shorter median hospital stay length ( < 0.001). There were not significant differences in the median estimated blood loss and specimen Gleason score between the two arms. The proportions of transfusion, pT3a disease, postoperative complication, and positive surgical margin in the T-RARP group were also comparable to that in the S-RARP group. The mean prostate-specific antigen and median erectile functional scores did not differ significantly between the two groups at postoperative 3 months and last follow-up. T-RARP vs. S-RARP had significantly improved urinary continence (UC) rates at the removal of catheter ( < 0.001) and postoperative 3 months ( < 0.001), but the significant difference between the two groups in UC recovery disappeared at last follow-up ( = 0.119). No significant difference in biochemical recurrence-free survival was observed following the two surgeries ( = 0.727).

Conclusions: T-RARP by experienced hands was feasible for selected patients with clinically localized PCa, yielding significantly improved early return to UC and similar erectile functional preservation without compromising oncological control when compared with the standard approach.
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http://dx.doi.org/10.3389/fonc.2021.687010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165391PMC
May 2021

Balloon-expandable valve geometry after transcatheter aortic valve replacement in low-risk patients with bicuspid versus tricuspid aortic stenosis.

Cardiovasc Revasc Med 2021 Apr 6. Epub 2021 Apr 6.

Section of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC, United States of America. Electronic address:

Background: Prospective bicuspid low-risk transcatheter aortic valve replacement (TAVR) registries' data demonstrated encouraging short-term results. Detailed data on transcatheter heart valve (THV) geometry after deployment using contemporary devices are lacking. This study sought to examine valve geometry after TAVR in patients with bicuspid aortic stenosis (AS).

Methods: The study population was patients from the LRT (Low Risk TAVR) trial who underwent TAVR using the SAPIEN 3 THV for bicuspid and tricuspid AS. THV geometry measured on 30-day computed tomography (CT) included valve height, angle, depth, and eccentricity. Additionally, THV hemodynamics and outcomes post-TAVR were compared among patients with bicuspid and tricuspid AS.

Results: A total of 107 patients from the LRT trial using the SAPIEN 3 THV were included in our analysis. On 30-day CT, the valve height ratio (1.07 vs. 1.07; p = 0.348), depths (right [5.6 mm vs. 6.2 mm; p = 0.223], left [5.3 mm vs. 4.4 mm; p = 0.082] and non [4.8 mm vs. 4.5 mm; p = 0.589] coronary cusps), eccentricities (1.08 vs. 1.07; p = 0.9550), and angles (except the right [3.9 degrees vs. 6.3 degrees; p = 0.003] and left [3.6 degrees vs. 6.0 degrees; p = 0.007]) were similar between bicuspid and tricuspid patients. Hemodynamics, stroke, and mortality were similar at 1 year.

Conclusion: Despite challenging bicuspid anatomy of the aortic valve, our comprehensive CT analysis supports similar THV geometry between patients with bicuspid and tricuspid AS undergoing TAVR using the SAPIEN 3 THV in low-risk patients. This translated to excellent short-term clinical outcomes and THV hemodynamics in both aortic valve morphologies.

Trial Registry: NCT02628899, https://clinicaltrials.gov/ct2/show/NCT02628899.
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http://dx.doi.org/10.1016/j.carrev.2021.03.027DOI Listing
April 2021

Risk factors of lymphovascular invasion in hypopharyngeal squamous cell carcinoma and its influence on prognosis.

Eur Arch Otorhinolaryngol 2021 Jun 2. Epub 2021 Jun 2.

Department of Otorhinolaryngology Head and Neck Surgery, Shanghai General Hospital of Nanjing Medical University, Shanghai, 200080, China.

Purpose: Lymphatic vascular invasion (LVI) is a poor prognostic factor for hypopharyngeal squamous cell carcinoma (HPSCC), but the risk factors of LVI and its relationship with clinicopathological of HPSCC remain unclear. This study aims to explore these issues.

Methods: We retrospectively analyzed the clinicopathological data of 170 patients with HPSCC from January 2011 to December 2015. The relationship between LVI and clinicopathologic was analyzed by Chi-square test or Fisher's exact test. The risk factors of LVI were examined using a logistic regression model, while risk factors of survival rate were carried out using the Cox regression model.

Results: LVI occurred in 59 cases (34.7%). In multivariate analysis, T3-4 stage (HR = 2.877; 95% CI: 1.379-6.004; p = 0.005), N2-3 stage (HR = 2.325; 95% CI: 1.120-4.824; p = 0.024), and poor differentiation (HR = 2.983; 95% CI: 1.229-7.242; p = 0.016) were independent risk factors for LVI; positive LVI was an independent risk factor for local recurrence (HR = 2.488; 95% CI: 1.150-5.383; p = 0.021), poor 5-year OS (HR = 0.375; 95% CI: 0.232-0.606; p < 0.000), DSS (HR = 0.374; 95% CI: 0.235-0.595; p < 0.000), and DFS (HR = 0.454; 95% CI:0.254-0.813; p = 0.008).

Conclusion: T3-4 stage, N2-3 stage and poor differentiation are independent risk factors for LVI of HPSCC; LVI increases the local recurrence and regional recurrence rate, and decreases 5-year OS, DFS and DSS of HPSCC.
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http://dx.doi.org/10.1007/s00405-021-06906-2DOI Listing
June 2021

Low dietary choline intake is associated with the risk of osteoporosis in elderly individuals: a population-based study.

Food Funct 2021 Jun 1. Epub 2021 Jun 1.

Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China. and Multidisciplinary Team (MDT) for Geriatric Hip Fracture Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China and School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China and Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, Jiangsu, P.R. China and Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, P.R. China.

Currently, little is known regarding the association between dietary choline intake and osteoporosis in elderly individuals, as well as if such intakes affect bone health and result in fractures. This study was aimed to examine associations between daily dietary choline intake and osteoporosis in elderly individuals. A total of 31 034 participants from the National Health and Nutritional Examination Survey (NHANES) during 2005-2010 were enrolled, and 3179 participants with complete data and aged 65 years and older were identified. Baseline characteristics and dietary intake data were obtained through method of in-home administered questionnaires. Of 3179 individuals with a mean age of 73.7 ± 5.6 years, female (P < 0.001) and non-hispanic white (P < 0.001) occupied a higher proportion in the osteoporosis group. The logistic regression analysis indicated that the prevalence of osteoporosis in three tertile categories with gradually enhanced dietary choline intake was decreased progressively (P for trend <0.001). The restricted cubic spline (RCS) showed that the risk of osteoporosis generally decreased with increasing daily dietary choline intake (P < 0.001), while this trend was not apparent in relation between the daily dietary choline intake and risk of hip fracture (P = 0.592). The receiver operating characteristic (ROC) analysis identified a daily dietary choline intake of 232.1 mg as the optimal cutoff value for predicting osteoporosis. Our nationwide data suggested that a lower level of daily dietary choline intake was positively associated with the increased risk of osteoporosis in the US elderly population.
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http://dx.doi.org/10.1039/d1fo00825kDOI Listing
June 2021

Band-pass filter-assisted ratiometric fluorescent nanoprobe composed of N-(2-aminoethyl-1,8-naphthalimide)-functionalized gold nanoclusters for the determination of alkaline phosphatase using digital image analysis.

Mikrochim Acta 2021 Jun 1;188(6):218. Epub 2021 Jun 1.

School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, 243032, Anhui, China.

A smartphone-based dual-wavelength digital imaging platform containing red (539-695 nm) and blue (389-511 nm) band-pass filters was developed for point-of-care (POC) testing of alkaline phosphatase (ALP) activity. The platform was based on dual-emitting fluorescent nanohybrids ([email protected]), the ratiometric probe, which had a fluorescence "on-off-on-off" response. The probe comprised red-emitting gold nanoclusters (AuNCs) acting as the signal report units and blue-emitting N-(2-aminoethyl-1,8-naphthalimide) (NAN) acting as an internal reference. The different responses of the ratiometric probes resulted in a continuous color-multiplexing change from pink-red to dark-purple upon exposure to ALP. The dual-wavelength digital imaging platform was employed to acquire images of AuNC or NAN fluorescence signals without the influence of background light. Unlike the classical one-time digital imaging mode, the accurate red (R) and blue (B) channel values of the generated images can help to directly judge or eliminate the disturbance from unavoidable interfering factors. The R/B values were successfully employed for determining the ALP activity at a range 2.0 to 35.0 mU·mL with the detection limit of 1.04 mU·mL. Such sensing imaging platform is also successful in determining ALP activity in human serum with 94.9-105% recoveries and relative standard deviation in the range 4.2-5.6%. A novel dual-wavelength smartphone-based digital imaging platform was proposed for simultaneous readout of the reporting and internal reference signals from dual-emitting ratiometric fluorescence probes, which allowed us to the accurate, reliable, and highly sensitive assay of ALP activity in complex samples.
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http://dx.doi.org/10.1007/s00604-021-04870-6DOI Listing
June 2021

The Role of Interleukin-1-Receptor-Antagonist in Bladder Cancer Cell Migration and Invasion.

Int J Mol Sci 2021 May 30;22(11). Epub 2021 May 30.

Department of Urology, Ulm University Hospital, 89081 Ulm, Germany.

Background: The interleukin-1-receptor antagonist IL1RA (encoded by the gene) is a potent competitive antagonist to interleukin-1 (IL1) and thereby is mainly involved in the regulation of inflammation. Previous data indicated a role of IL1RA in muscle-invasive urothelial carcinoma of the bladder (UCB) as well as an IL1-dependent decrease in tissue barrier function, potentially contributing to cancer cell invasion.

Objective: Based on these observations, here we investigated the potential roles of IL1RA, IL1A, and IL1B in bladder cancer cell invasion in vitro.

Methods: Cell culture, real-time impedance sensing, invasion assays (Boyden chamber, pig bladder model), qPCR, Western blot, ELISA, gene overexpression.

Results: We observed a loss of IL1RA expression in invasive, high-grade bladder cancer cell lines T24, UMUC-3, and HT1197 while IL1RA expression was readily detectable in the immortalized UROtsa cells, the non-invasive bladder cancer cell line RT4, and in benign patient urothelium. Thus, we modified the invasive human bladder cancer cell line T24 to ectopically express IL1RA, and measured changes in cell migration/invasion using the xCELLigence Real-Time-Cell-Analysis (RTCA) system and the Boyden chamber assay. The real-time observation data showed a significant decrease of cell migration and invasion in T24 cells overexpressing IL1RA (T24-IL1RA), compared to cells harboring an empty vector (T24-EV). Concurrently, tumor cytokines, e.g., IL1B, attenuated the vascular endothelial barrier, which resulted in a reduction of the Cell Index (CI), an impedance-based dimensionless unit. This reduction could be reverted by the simultaneous incubation with IL1RA. Moreover, we used an ex vivo porcine organ culture system to evaluate cell invasion capacity and showed that T24-IL1RA cells showed significantly less invasive capacity compared to parental T24 cells or T24-EV.

Conclusions: Taken together, our results indicate an inverse correlation between IL1RA expression and tumor cell invasive capacity and migration, suggesting that IL1RA plays a role in bladder carcinogenesis, while the exact mechanisms by which IL1RA influences tumor cells migration/invasion remain to be clarified in future studies. Furthermore, we confirmed that real-time impedance sensing and the porcine ex vivo organ culture methods are powerful tools to discover differences in cancer cell migration and invasion.
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http://dx.doi.org/10.3390/ijms22115875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198563PMC
May 2021