Publications by authors named "Xiaobo Yang"

330 Publications

Dysregulated APP expression and α-secretase processing of APP is involved in manganese-induced cognitive impairment.

Ecotoxicol Environ Saf 2021 May 28;220:112365. Epub 2021 May 28.

Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, Guangxi, China. Electronic address:

Excessive exposure to manganese (Mn) can cause cognitive impairment, a common feature of Alzheimer's disease (AD), but the mechanisms remain unclear. Amyloid precursor protein (APP) is key to AD pathogenesis, and whether APP and its secretase processing are involved in Mn-induced cognitive impairment remains unknown. In the present study, we established a model of Mn-induced neurotoxicity in vivo (male C57BL/6, 0-100 mg/kg Mn, 90 days, gastric gavage) and in vitro (Neuro-2a (N2a) cells, 0-800 μM Mn for 24 h; APP overexpression and APP shRNA N2a cells, 0 and 800 μM Mn for 24 h). We found impaired cognition of Mn-treated mice. Both in vivo and in vitro results consistently showed that Mn exposure inhibited the expression of APP, α-secretase, soluble APP alpha protein (sAPPα), and synapse proteins as well as the activity of α-secretase. However, Mn exposure showed no effect on the protein levels of β-secretase, Aβ40, and Aβ42 or the activity of β-secretase. Collectively, these findings demonstrate key roles of APP and its α-secretase processing in the regulation of Mn-induced cognitive impairment, which may act as a target for ameliorating Mn-induced neurotoxicity.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112365DOI Listing
May 2021

Influence of manganese exposure on cognitive function, plasma APP and Aβ levels in older men.

J Trace Elem Med Biol 2021 Sep 14;67:126788. Epub 2021 May 14.

Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, Guangxi, China. Electronic address:

Background: Elevated manganese (Mn) exposure impairs cognition in adults and children, but the association between Mn and cognitive function in elderly people is unclear. Previous studies have linked Mn neurotoxicity in AD to Aβ-dependent mechanisms. However, the association between Mn and plasma APP and Aβ in the general elderly population remains unknown. This study aimed to investigate the association between Mn exposure and cognitive function, plasma APP and plasma Aβ in older adults.

Methods: Cognitive abilities in 375 men aged 60 and older in Guangxi, China were assessed using the Mini-Mental State Examination (MMSE) and cognitive impairment were identified using education-stratified cut-off points of MMSE scores. Urinary Mn levels and plasma APP, and Aβ levels were measured using ICP-MS and ELISA, respectively.

Results: A total of 109 (29.07 %) older men were identified as having cognitive impairment. The median urinary Mn level was 0.22 μg/g creatinine. Urinary Mn levels were negatively correlated with MMSE scores (β = -1.35, 95 % CI: -2.65 to -0.06; p = 0.041). In addition, higher concentrations of urinary manganese were associated with a greater risk of cognitive impairment (OR = 2.03, 95 % CI: 1.14-3.59; comparing the highest and lowest manganese; p = 0.025). Moreover, plasma APP levels were inversely associated with urinary Mn levels (r = -0.123, p = 0.020), and positively associated with MMSE scores (r = 0.158, p = 0.002). Surprisingly, no correlations were observed between plasma Aβ42, Aβ40, Aβ40/Aβ42, or Aβ42/Aβ40 and urinary Mn levels and MMSE scores.

Conclusion: These results suggested that Mn exposure is negatively associated with older men's cognition and plasma APP levels, but not plasma Aβ levels.
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http://dx.doi.org/10.1016/j.jtemb.2021.126788DOI Listing
September 2021

Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers.

J Immunother Cancer 2021 May;9(5)

Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Background: This study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.

Methods: Three cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel.

Results: Based on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05).

Conclusions: The CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.
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http://dx.doi.org/10.1136/jitc-2020-001942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112417PMC
May 2021

Tiaochang Xiaoliu Decoction Granules prevent the recurrence of colorectal adenoma: a study protocol for a randomized controlled trial.

Ann Palliat Med 2021 Apr;10(4):4897-4905

Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China.

Background: With the changes in lifestyle and diet, the incidence and mortality of colorectal cancer (CRC) is increasing in China. CRC mainly develops from colorectal adenomas (CRAs). There is a lack of chemopreventative drugs with definite efficacy for CRAs. Tiaochang Xiaoliu Decoction (TXD) was developed by Professor Yunjian Luo and has been used clinically over the last ten years for the prevention of CRA recurrence. To facilitate its clinical use, TXD was further standardized and produced as "Tiaochang Xiaoliu Decoction Granules (TXDG)". A study was designed to investigate the preventive effects of TXDG on the recurrence of CRA.

Methods: A randomized, double-blinded, controlled, and multi-center experiment is proposed to assess the effectiveness and safety of TXDG. Patients with CRAs (after complete polypectomy under colonoscopy) will be randomly divided into two groups, one will be treated with TXDG (the TXDG group) and the other will be treated with a TXDG mimetic agent (the TXDG mimetic group). The patients will be treated for 6 months and followed up for 3 years. Follow-up colonoscopy is expected to be carried out within 1 to 3 years after the baseline examinations. The primary outcome measure is adenoma detection rate within 1 to 3 years. The secondary outcome measures are the number, location, and pathology of the adenomas, and the polyp detection rate.

Discussion: Reliable objective evidence will be provided to evaluate the efficacy and safety of TXDG as an accessorial therapy for CRA occurrence in post-polypectomy patients.

Trial Registration: ChiCTR2000035257.
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http://dx.doi.org/10.21037/apm-21-650DOI Listing
April 2021

Single-cell transcriptomes reveal characteristic features of cell types within the human adrenal microenvironment.

J Cell Physiol 2021 May 2. Epub 2021 May 2.

Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang, China.

Various cells within the adrenal microenvironment are important in maintaining the body homeostasis. However, our understanding of adrenal disease pathogenesis is limited by an incomplete molecular characterization of the cell types responsible for the organ's multiple homeostatic functions. We report a cellular landscape of the human adrenal gland using single-cell RNA sequencing. We reveal characteristic features of cell types within the human adrenal microenvironment and found immune activation of nonimmune cells in the adrenal endothelial cells. We also reveal that abundant immune cells occupied a lot of space in adrenal gland. Additionally, Sex-related diversity in the adrenocortical cells and different gene expression profiles between the left and right adrenal gland are also observed at single-cell resolution. Together, at single-cell resolution, the transcriptomic map presents a comprehensive view of the human adrenal gland, which serves as a fundamental baseline description of this organ and paves a way for the further studies of adrenal diseases.
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http://dx.doi.org/10.1002/jcp.30398DOI Listing
May 2021

The Efficacy and Safety of Apatinib Plus Camrelizumab in Patients With Previously Treated Advanced Biliary Tract Cancer: A Prospective Clinical Study.

Front Oncol 2021 12;11:646979. Epub 2021 Apr 12.

Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: PD-1/L1 inhibitor-based immunotherapy is currently under investigation in biliary tract cancer (BTC). Apatinib combined with camrelizumab has achieved promising results in various tumor types. The aim of this study was to assess the safety and efficacy of apatinib plus camrelizumab for advanced biliary tract cancer patients who have received previously treatments.

Methods: This prospective, non-randomized, open-label trial was conducted at Peking Union Medical College Hospital (PUMCH). All included patients received apatinib orally at 250 mg per a day and camrelizumab intravenously at 200 mg every three weeks until disease progression or intolerable toxicity occurred. Efficacy was evaluated based on the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1). Adverse events (AEs) were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0).

Results: A total of 22 patients were consecutively enrolled from 1st December, 2018 until 1st August, 2020. Among 21 patients for whom we could conduct efficacy evaluations, no patients achieved a complete response (CR), 4 patients (19%) achieved partial response (PR), and 11 patients had stable disease with a disease control rate of 71.4%. The median overall survival was 13.1 months (95% CI, 8.1-18.2), and the median progression-free survival was 4.4 months (95% CI, 2.4-6.3). All patients experienced treatment related AEs, and grade 3 or 4 AEs occurred in 14 (63.6%) of 22 patients. No treatment related deaths were observed.

Conclusions: This is the first report focusing on the efficacy and safety of camrelizumab plus apatinib in pretreated biliary tract cancer patients. The finding suggests this regimen has favorable therapeutic effects with relatively manageable toxicity. Further trials with a control arm are required to investigate.

Clinical Trial Registration: identifier NCT04642664.
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http://dx.doi.org/10.3389/fonc.2021.646979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071846PMC
April 2021

Bioinformatic analysis identifies potential biomarkers and therapeutic targets of septic-shock-associated acute kidney injury.

Hereditas 2021 Apr 16;158(1):13. Epub 2021 Apr 16.

Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Jiefang Avenue, Wuhan, 430022, China.

Background: Sepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI).

Methods: Two gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI.

Results: We identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future.

Conclusions: Septic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.
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http://dx.doi.org/10.1186/s41065-021-00176-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052759PMC
April 2021

Relationship of gene variations with NAFLD risk in Chinese men.

Open Life Sci 2020 30;15(1):860-867. Epub 2020 Nov 30.

Department of chemotherapy, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.

Background: Fat mass and obesity-associated () gene is an obesity susceptibility gene and its relationship with the nonalcoholic fatty liver disease (NAFLD) remains unclear. This study aims to investigate the relationships of gene variations with NAFLD risk in a Chinese male population.

Methods: A 1:2 matched case-control study was performed on 275 cases of NAFLD and 550 controls matched for age. Nine of the gene single nucleotide polymorphisms (SNPs) were genotyped.

Results: Logistic regression analysis found that rs1477196 was significantly associated with the susceptibility to NAFLD in recessive genetic models [unadjusted odds ratio (OR) = 2.52, 95% confidence interval (CI): 1.22-5.19, = 0.012] and the relativity weakened after further adjustment for body mass index (BMI), uric acid, metabolic syndrome, smoking, and drinking (adjusted OR = 2.18, 95% CI: 0.96-4.99, = 0.06). In the obese group, the AA + AG genotypes of rs1121980 and rs9940128 were associated with a decreased risk of NAFLD, when compared with the GG genotype, respectively (rs1121980: adjusted OR = 0.62, 95% CI = 0.39-0.99, = 0.044; rs9940128: adjusted OR = 0.61, 95% CI = 0.38-0.97, = 0.038). Furthermore, rs1477196 was associated with the severity of NAFLD (OR = 2.95, 95% CI = 1.09-7.94, = 0.034).

Conclusions: Our results demonstrated that the gene was related to the presence and severity of NAFLD in a Chinese male population, and the relationships of the tested SNPs with NAFLD are most probably mediated by BMI.
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http://dx.doi.org/10.1515/biol-2020-0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874577PMC
November 2020

Therapeutic Efficacy and Safety of Safflower Injection in the Treatment of Acute Coronary Syndrome.

Evid Based Complement Alternat Med 2021 16;2021:6617772. Epub 2021 Mar 16.

The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.

Background: Safflower injection (SFI), a popular Chinese patent drug, is commonly used to treat acute coronary syndromes (ACSs) in China. The research seeks to scientifically estimate the clinical efficacy of SFI for ACS patients.

Methods: Eight electronic databases were retrieved for eligible research from the founding date to September 8, 2020. Odds ratio (OR) was adopted to assess the total effective rate, ECG improvement, and adverse reaction, and mean difference (MD) was used for assessing the hemorheology indexes as well as the LVEF.

Results: Sixteen randomized controlled trials involving 1620 sufferers with ACS were incorporated. The outcomes showed that, in comparison to conventional medication alone, SFI combined with conventional treatment remarkably enhanced the total effective rate (OR = 3.66, 95% CI [2.73, 4.90], < 0.00001), ECG improvement (OR = 2.85, 95% CI [2.04, 3.99], < 0.00001), and LVEF (MD = 5.13, 95% CI [3.73, 6.53], < 0.00001). Moreover, SFI combined with conventional treatment significantly decreased hemorheology indexes including BV (MD = -0.95, 95% CI [-1.76, -0.13], =0.02), HCT (MD = -2.37, 95% CI [-3.25, -1.50], < 0.00001), FIB (MD = -0.44, 95% CI [-0.60, -0.29], < 0.00001), and PAR (OR = -7.65, 95% CI [-10.16, -5.14], < 0.00001). However, no notable contrast was observed to link the experimental and the control team for PV (MD = -0.42, 95% CI [-0.83, 0.00], =0.05) and adverse reactions (OR = 0.59, 95% CI [0.13, 2.74], =0.50).

Conclusion: Despite the limitations that existed in this meta-analysis, the outcomes demonstrated that SFI and conventional combined medication is an effective and relatively safe therapy for ACS sufferers.
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http://dx.doi.org/10.1155/2021/6617772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994092PMC
March 2021

Covalent Organic Frameworks toward Diverse Photocatalytic Aerobic Oxidations.

Chemistry 2021 May 30;27(28):7738-7744. Epub 2021 Apr 30.

Institute of Catalysis for Energy and Environment, College of Chemistry and Chemical Engineering, Shenyang Normal University, 110034, Shenyang, P. R. China.

Photoactive two-dimensional covalent organic frameworks (2D-COFs) have become promising heterogenous photocatalysts in visible-light-driven organic transformations. Herein, a visible-light-driven selective aerobic oxidation of various small organic molecules by using 2D-COFs as the photocatalyst was developed. In this protocol, due to the remarkable photocatalytic capability of hydrazone-based 2D-COF-1 on molecular oxygen activation, a wide range of amides, quinolones, heterocyclic compounds, and sulfoxides were obtained with high efficiency and excellent functional group tolerance under very mild reaction conditions. Furthermore, benefiting from the inherent advantage of heterogenous photocatalysis, prominent sustainability and easy photocatalyst recyclability, a drug molecule (modafinil) and an oxidized mustard gas simulant (2-chloroethyl ethyl sulfoxide) were selectively and easily obtained in scale-up reactions. Mechanistic investigations were conducted using radical quenching experiments and in situ ESR spectroscopy, all corroborating the proposed role of 2D-COF-1 in photocatalytic cycle.
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http://dx.doi.org/10.1002/chem.202100398DOI Listing
May 2021

PI3K/Akt Signaling Pathway Ameliorates Oxidative Stress-Induced Apoptosis upon Manganese Exposure in PC12 Cells.

Biol Trace Elem Res 2021 Mar 27. Epub 2021 Mar 27.

Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Manganese (Mn)-induced neurotoxicity has aroused public concerns for many years, but its precise mechanism is still poorly understood. Herein, we report the impacts of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway in mediating neurological effects induced by manganese sulfate (MnSO) exposure in PC12 cells. In this study, cells were treated with MnSO for 24 h in the absence or presence of LY294002 (a special inhibitor of PI3K). We investigated cell viability and apoptosis signals, as well as levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA). The mRNA levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and Caspase-3 were also quantified through real-time quantitative PCR (RT-qPCR); protein levels of serine/threonine protein kinase (Akt) and forkhead box O3A (Foxo3a) were determined by western blot. Increasing of MnSO doses led to decreased SOD, GSH-Px, and CAT activities, while the level of MDA was upregulated. Moreover, cell apoptosis was significantly increased, as the mRNA of Bcl-2 and Caspase-3 was significantly decreased, while Bax mRNA was increased. Phosphorylated Akt (p-Akt) and Foxo3a (p-Foxo3a) were upregulated in a dose-dependent manner. In addition, LY294002 pretreatment reduced the activity of SOD, GSH-Px, and CAT but elevated MDA levels. Meanwhile, LY294002 pretreatment also increased cell apoptosis given the upregulated Bax and Caspase-3 mRNAs and decreased Bcl-2 mRNA. In summary, the PI3K/Akt signaling pathway can be activated by MnSO exposure and mediate MnSO-induced neurotoxicity.
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http://dx.doi.org/10.1007/s12011-021-02687-1DOI Listing
March 2021

Mutational spectrum and precision oncology for biliary tract carcinoma.

Theranostics 2021 4;11(10):4585-4598. Epub 2021 Mar 4.

Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Beijing 100730, China.

The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included (53%), (26%), (18%), (14%) and (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. and mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.
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http://dx.doi.org/10.7150/thno.56539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978308PMC
March 2021

Mediated relationships between multiple metals exposure and fasting blood glucose by reproductive hormones in Chinese men.

Environ Pollut 2021 Jun 19;278:116791. Epub 2021 Feb 19.

Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China; Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Key Laboratory for Genomic and Personalized Medicine, Nanning, Guangxi, China; Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi, China; Department of Public Health, School of Medicine, Guangxi University of Science and Technology, Liuzhou, Guangxi, China. Electronic address:

Previous studies have reported metals exposure contribute to the change of fasting blood glucose (FBG) level. However, the roles of reproductive hormones in their associations have not been fully elucidated. The aim of the study is to investigate the associations of multiple serum metals with reproductive hormones, and to further explore potential roles of reproductive hormones in relationships between metals exposure and FBG level. A total of 1911 Chinese Han men were analyzed by a cross-sectional study. We measured serum levels of 22 metals by inductively coupled plasma mass spectrometer (ICP-MS). FBG, total testosterone (TT), estradiol (E2), follicle stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) levels were determined. Least absolute shrinkage and selection operator (LASSO) regression models were conducted to select important metals, and restricted cubic spline models were then used to estimate dose-response relationships between selected metals and reproductive hormones. We also conducted mediation analyses to evaluate whether reproductive hormones played mediating roles in the associations between metals and FBG. We found significant inverse dose-dependent trends of copper, tin and zinc with E2; zinc with SHBG; copper and nickel with TT, while significant positive dose-dependent trend of iron with E2, respectively. Moreover, approximately inverted U-shaped associations existed between lead and SHBG, iron and TT. In addition, E2, SHBG and TT were negatively associated with FBG level. In mediation analyses, the association of copper with FBG was mediated by E2 and TT, with a mediation ratio of 10.4% and 22.1%, respectively. Furthermore, E2 and SHBG mediated the relationship of zinc with FBG, with a mediation ratio of 7.8% and 14.5%, respectively. E2 mediated 11.5% of positive relationship between tin with FBG. Our study suggested that the associations of metals exposure with FBG may be mediated by reproductive hormones.
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http://dx.doi.org/10.1016/j.envpol.2021.116791DOI Listing
June 2021

NIR-laser-triggered gadolinium-doped carbon dots for magnetic resonance imaging, drug delivery and combined photothermal chemotherapy for triple negative breast cancer.

J Nanobiotechnology 2021 Mar 2;19(1):64. Epub 2021 Mar 2.

State Key Laboratory of Non-Food Biomass and Enzyme Technology, Guangxi Academy of Sciences, Nanning, 530007, China.

Background: Owing to high genetic diversities of tumor cells and low response rate of standard chemotherapy, patients with triple negative breast cancer (TNBC) have short progression-free survivals and poor outcomes, which need to explore an effective approach to improve therapeutic efficacy.

Methods: Novel gadolinium doped carbon dots ([email protected]) have been designed and prepared through hydrothermal method with 3,4-dihydroxyhydrocinnamic acid, 2,2'-(ethylenedioxy)bis(ethylamine) and gadolinium chloride. The synthesized nanostructures were characterized. Taking advantage of good biocompatibility of [email protected], a nanoplatform based on [email protected] has been developed to co-deliver chemotherapy drug doxorubicin hydrochloride (Dox) and a near-infrared (NIR) photothermal agent, IR825 for magnetic resonance imaging (MRI) guided photothermal chemotherapy for TNBC.

Results: The as-synthesized [email protected]@[email protected] displayed favorable MRI ability in vivo. Upon NIR laser irradiation, [email protected]@[email protected] could convert the NIR light to heat and efficiently inhibit tumor growth through photothermal chemotherapy in vitro and in vivo. Additionally, the impact of photothermal chemotherapy on the murine motor coordination was assessed by rotarod test. [email protected]@[email protected] presented low toxicity and high photothermal chemotherapy efficiency.

Conclusion: A noble theranostic nanoplatform ([email protected]@[email protected]) was developed that could be tailored to achieve loading of Dox and IR825, intracellular delivery, favorable MRI, excellent combination therapy with photothermal therapy and chemotherapy to enhance therapeutic effect against TNBC cells. This study will provide a promising strategy for the development of Gd-based nanomaterials for MRI and combinational therapy for TNBC.
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http://dx.doi.org/10.1186/s12951-021-00811-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923633PMC
March 2021

Rs41291957 polymorphism in the promoter region of microRNA‑143 serves as a prognostic biomarker for patients with intracranial hemorrhage.

Mol Med Rep 2021 Apr 2;23(4). Epub 2021 Mar 2.

Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.

The present study aimed to investigate the function of the single nucleotide polymorphism (SNP) rs41291957 in the prognosis of intracerebral hemorrhage (ICH). In addition, the molecular mechanisms underlying the role of microRNA (miR)‑143, Toll‑like receptor 2 (TLR2) and interleukin‑16 (IL‑16) were studied in patients with ICH that carried different alleles in the locus of the rs41291957 SNP. Kaplan‑Meier survival curves were calculated for 182 patients with ICH, genotyped as CC, presenting a cytosine in both chromosome, CT, presenting both variants, and TT, presents a thymine in both chromosomes. In addition, the possible regulatory relationships between miR‑143 and TLR2/IL‑16 were studied using computational analysis, luciferase assays and western blot assay. In addition, the inflammatory profiles of cerebrospinal fluid (CSF) and serum samples collected from the subjects were compared. The patients genotyped as TT presented the lowest survival rate, while patients genotyped as CC presented the highest survival rate. TLR2 mRNA was identified as a potential target of miR‑143, while IL‑16 showed no direct interaction with miR‑143. The above regulatory relationships were further investigated using cells transfected with miR‑143 precursor or TLR2 small interfering RNA. In addition, the expression levels of inflammatory factors, such as tumor necrosis factor α, interferon, IL‑6, IL‑10 and NF‑L‑6, were highest in the CSF/serum samples collected from patients genotyped as TT and lowest in patients genotyped as CC. By contrast, the expression levels of miR‑143 showed an opposite trend in the expression of the above inflammatory factors. The rs41291957 SNP, located in the promoter region of miR‑143, reduced the expression of miR‑143 and upregulated the expression of the pro‑inflammatory factor TLR2, eventually leading to a poorer prognosis in patients with ICH.
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http://dx.doi.org/10.3892/mmr.2021.11928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930929PMC
April 2021

The peak levels of highly sensitive troponin I predicts in-hospital mortality in COVID-19 patients with cardiac injury: a retrospective study.

Eur Heart J Acute Cardiovasc Care 2021 Mar;10(1):6-15

Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave, Wuhan, 430022 Hubei, China.

Aims: To investigate the association between levels of highly sensitive troponin I (hs-troponin I) and mortality in novel coronavirus disease 2019 (COVID-19) patients with cardiac injury.

Methods And Results: We retrospectively reviewed the medical records of all COVID-19 patients with increased levels of hs-troponin I from two hospitals in Wuhan, China. Demographic information, laboratory test results, cardiac ultrasonographic findings, and electrocardiograms were collected, and their predictive value on in-hospital mortality was explored using multivariable logistic regression. Of 1500 patients screened, 242 COVID-19 patients were enrolled in our study. Their median age was 68 years, and (48.8%) had underlying cardiovascular diseases. One hundred and seventy-six (72.7%) patients died during hospitalization. Multivariable logistic regression showed that C-reactive protein (>75.5 mg/L), D-dimer (>1.5 μg/mL), and acute respiratory distress syndrome were risk factors of mortality, and the peak hs-troponin I levels (>259.4 pg/mL) instead of the hs-troponin I levels at admission was predictor of death. The area under the receiver operating characteristic curve of the peak levels of hs-troponin I for predicting in-hospital mortality was 0.79 (95% confidence interval, 0.73-0.86; sensitivity, 0.80; specificity, 0.72; P < 0.0001).

Conclusion: Our results demonstrated that the risk of in-hospital death among COVID-19 patients with cardiac injury can be predicted by the peak levels of hs-troponin I during hospitalization and was significantly associated with oxygen supply-demand mismatch, inflammation, and coagulation.
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http://dx.doi.org/10.1093/ehjacc/zuaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665398PMC
March 2021

Matrix stiffness promotes glioma cell stemness by activating BCL9L/Wnt/β-catenin signaling.

Aging (Albany NY) 2021 02 1;13(4):5284-5296. Epub 2021 Feb 1.

Sichuan Clinic Research Center for Neurosurgery, Luzhou, China.

Matrix stiffness is a key physical characteristic of the tumor microenvironment and correlates tightly with tumor progression. Here, we explored the association between matrix stiffness and glioma development. Using atomic force microscopy, we observed higher matrix stiffness in highly malignant glioma tissues than in low-grade/innocent tissues. and analyses revealed that culturing glioma cells on stiff polyacrylamide hydrogels enhanced their proliferation, tumorigenesis and CD133 expression. Greater matrix stiffness could obviously up-regulated the expression of BCL9L, thereby promoting the activation of Wnt/β-catenin signaling and ultimately increasing the stemness of glioma cells. Inhibiting Wnt/β-catenin signaling using gigantol consistently improved the anticancer effects of chemotherapy and radiotherapy in mice with subcutaneous glioma tumors. These findings demonstrate that a stiffer matrix increases the stemness of glioma cells by activating BCL9L/Wnt/β-catenin signaling. Moreover, we have provided a potential strategy for clinical glioma treatment by demonstrating that gigantol can improve the effectiveness of traditional chemotherapy/radiotherapy by suppressing Wnt/β-catenin signaling.
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http://dx.doi.org/10.18632/aging.202449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950305PMC
February 2021

Apatinib as non-first-line treatment in patients with Intrahepatic Cholangiocarcinoma.

J Cancer 2021 10;12(5):1555-1562. Epub 2021 Jan 10.

Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Peking Union Medical College Hospital, Beijing, China.

There is limited standard treatment for patients with advanced cholangiocarcinoma after refractory of chemotherapy. Apatinib is a tyrosine kinase inhibitor targeting VEGFR-2, which exhibited broad-spectrum antitumor activities in previous studies. We aim to evaluate the efficacy and safety of apatinib as non-first-line treatment in patients with advanced cholangiocarcinoma. This was a prospective open-label phase II trial (NCT03251443). Patients with pathology-confirmed cholangiocarcinoma after prior systemic therapy were enrolled. Participants were treated with apatinib 500 mg orally once daily. The primary end point was overall response rate (ORR). Between August 8, 2017 and November 13, 2018, 30 patients participated in this study, and 26 patients received apatinib treatment except 4 patients withdrew consent before the first dosage. For full analysis set, the ORR was 11.5% and the disease control rate was 50.0%. 3 patients (11.5%) achieved partial response and no patients achieved complete response. The median progression free time was 2.0 (95% CI: 0.7-3.3) months and median overall survival was 9. 0 (95% CI: 4.6-13.4) months. The most common adverse events of any grade were fatigue (80.8%), hypertension (73.1%) and decreased appetite (38.5%). Grade 3 adverse events occurred in 23.1% patients and no grade 4 adverse events occurred. The most common grade 3 adverse events were hypertension (23.1%) and elevated transaminase (11.5%). Apatinib as non-first-line monotherapy has potential therapeutic efficacy in patients with advanced cholangiocarcinoma.
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http://dx.doi.org/10.7150/jca.53482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847639PMC
January 2021

Extracorporeal Membrane Oxygenation for SARS-CoV-2 Acute Respiratory Distress Syndrome: A Retrospective Study From Hubei, China.

Front Med (Lausanne) 2020 12;7:611460. Epub 2021 Jan 12.

Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The data on long-term outcomes of patients infected by SARS-CoV-2 and treated with extracorporeal membrane oxygenation (ECMO) in China are merely available. A retrospective study included 73 patients infected by SARS-CoV-2 and treated with ECMO in 21 intensive care units in Hubei, China. Data on demographic information, clinical features, laboratory tests, ECMO durations, complications, and living status were collected. The 73 ECMO-treated patients had a median age of 62 (range 33-78) years and 42 (63.6%) were males. Before ECMO initiation, patients had severe respiratory failure on mechanical ventilation with a median PO/FiO of 71.9 [interquartile range (IQR), 58.6-87.0] mmHg and a median PCO of 62 [IQR, 43-84] mmHg on arterial blood analyses. The median duration from symptom onset to invasive mechanical ventilation, and to ECMO initiation was19 [IQR, 15-25] days, and 23 [IQR, 19-31] days. Before and after ECMO initiation, the proportions of patients receiving prone position ventilation were 58.9 and 69.9%, respectively. The median duration of ECMO support was 18.5 [IQR 12-30] days. During the treatments with ECMO, major hemorrhages occurred in 31 (42.5%) patients, and oxygenators were replaced in 21 (28.8%) patients. Since ECMO initiation, the 30-day mortality and 60-day mortality were 63.0 and 80.8%, respectively. In Hubei, China, the ECMO-treated patients infected by SARS-CoV-2 were of a broad age range and with severe hypoxemia. The durations of ECMO support, accompanied with increased complications, were relatively long. The long-term mortality in these patients was considerably high.
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http://dx.doi.org/10.3389/fmed.2020.611460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835137PMC
January 2021

Regulation of Toll-like receptor-mediated inflammatory response by microRNA-152-3p-mediated demethylation of MyD88 in systemic lupus erythematosus.

Inflamm Res 2021 Mar 28;70(3):285-296. Epub 2021 Jan 28.

Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China.

Objective: microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE.

Methods: We determined the miR-152-3p expression profiles in CD4 T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4 T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88).

Results: The obtained findings revealed that miR-152-3p was highly-expressed in CD4 T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4 T cells and but also to restrain their cellular inflammation, which were also validated in vivo.

Conclusion: Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4 T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.
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http://dx.doi.org/10.1007/s00011-020-01433-yDOI Listing
March 2021

Selective Separation of HNO and HCl by Extraction: The Investigation on the Noncovalent Interaction between Extractants and Acids by Density Functional Theory.

J Phys Chem B 2021 02 26;125(4):1214-1226. Epub 2021 Jan 26.

Engineering Research Center of Resources Process Engineering, Ministry of Education, East China University of Science and Technology, Shanghai 200237, China.

There is a huge demand for the highly selective separation of HNO and HCl in many industries, and solvent extraction is considered a feasible method. In this article, DFT calculations were performed to investigate the interactions between acids and extractants including alcohols, ketones, phosphorus, and amines. One of the significant findings to emerge from this study is that amines bind to acids through ion association. Nevertheless, the interaction between acids and alcohols, ketones, and phosphorus with a (RO)P═O structure is mainly dominated by hydrogen bonds. The change of Gibbs free energy in the extraction process shows that the phosphorus ((RO)P═O) is superior to other types of extractants in the selective separation of HNO and HCl. Furthermore, after the alkoxyl group (RO-) in phosphorus ((RO)P═O) is replaced by RN- or R- with less electronegativity, the interaction between HCl and the substituted extractants transitions from a hydrogen bond to ion association, but there are still strong hydrogen bonds between them and HNO. That will lead to a decrease in the selectivity of phosphorus due to the change in interaction types. This new understanding should help the design and screening of efficient extractants for the separation of mineral acids.
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http://dx.doi.org/10.1021/acs.jpcb.0c09562DOI Listing
February 2021

Apoptotic activities of brusatol in human non-small cell lung cancer cells: Involvement of ROS-mediated mitochondrial-dependent pathway and inhibition of Nrf2-mediated antioxidant response.

Toxicology 2021 03 16;451:152680. Epub 2021 Jan 16.

Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, P.R. China; The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, P.R. China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, P.R. China.

Brusatol occurs as a characteristic bioactive principle of Brucea javanica (L.) Merr., a traditional medicinal herb frequently employed to tackle cancer in China. This work endeavored to unravel the potential anti-cancer activity and action mechanism of brusatol against non-small cell lung cancer (NSCLC) cell lines. The findings indicated that brusatol remarkably inhibited the growth of wild-type NSCLC cell lines (A549 and H1650) and epidermal growth factor receptor-mutant cell lines (PC9 and HCC827) in a dose- and time-related fashion, and profoundly inhibited the clonogenic capability and migratory capacity of PC9 cells. Treatment with brusatol resulted in significant apoptosis in PC9 cells, as evidenced by Hoechst 33342 staining and flow cytometric analysis. The apoptotic effect was closely related to induction of G0-G1 cell cycle arrest, stimulation of reactive oxygen species (ROS) and malondialdehyde, decrease of glutathione levels and disruption of mitochondrial membrane potential. Furthermore, pretreatment with N-acetylcysteine, a typical ROS scavenger, markedly ameliorated the brusatol-induced inhibition of PC9 cells. Western blotting assay indicated that brusatol pronouncedly suppressed the expression levels of mitochondrial apoptotic pathway-associated proteins Bcl-2 and Bcl-xl, accentuated the expression of Bax and Bak, and upregulated the protein expression of XIAP, cleaved caspase-3/pro caspase-3, cleaved caspase-8/pro caspase-8, and cleaved PARP/total PARP. In addition, brusatol significantly suppressed the expression of Nrf2 and HO-1, and abrogated tBHQ-induced Nrf2 activation. Combinational administration of brusatol with four chemotherapeutic agents exhibited marked synergetic effect on PC9 cells. Together, the inhibition of PC9 cells proliferation by brusatol might be intimately associated with the modulation of ROS-mediated mitochondrial-dependent pathway and inhibition of Nrf2-mediated antioxidant response. This novel insight might provide further evidence to buttress the antineoplastic efficacy of B. javanica, and support a role for brusatol as a promising anti-cancer candidate or adjuvant to current chemotherapeutic medication in the therapy of EGFR-mutant NSCLC.
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http://dx.doi.org/10.1016/j.tox.2021.152680DOI Listing
March 2021

Tracheostomy in 80 COVID-19 Patients: A Multicenter, Retrospective, Observational Study.

Front Med (Lausanne) 2020 17;7:615845. Epub 2020 Dec 17.

Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.

The outbreak of coronavirus disease 2019 (COVID-19) has led to a large and increasing number of patients requiring prolonged mechanical ventilation and tracheostomy. The indication and optimal timing of tracheostomy in COVID-19 patients are still unclear, and the outcomes about tracheostomy have not been extensively reported. We aimed to describe the clinical characteristics and outcomes of patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who underwent elective tracheostomies. The multi-center, retrospective, observational study investigated all the COVID-19 patients who underwent elective tracheostomies in intensive care units (ICUs) of 23 hospitals in Hubei province, China, from January 8, 2020 to March 25, 2020. Demographic information, clinical characteristics, treatment, details of the tracheostomy procedure, successful weaning after tracheostomy, and living status were collected and analyzed. Data were compared between early tracheostomy patients (tracheostomy performed within 14 days of intubation) and late tracheostomy patients (tracheostomy performed after 14 days). A total of 80 patients were included. The median duration from endotracheal intubation to tracheostomy was 17.5 [IQR 11.3-27.0] days. Most tracheotomies were performed by ICU physician [62 (77.5%)], and using percutaneous techniques [63 (78.8%)] at the ICU bedside [76 (95.0%)]. The most common complication was tracheostoma bleeding [14 (17.5%)], and major bleeding occurred in 4 (5.0%) patients. At 60 days after intubation, 31 (38.8%) patients experienced successful weaning from ventilator, 17 (21.2%) patients discharged from ICU, and 43 (53.8%) patients had died. Higher 60 day mortality [22 (73.3%) vs. 21 (42.0%)] were identified in patients who underwent early tracheostomy. In patients with SARS-CoV-2 pneumonia, tracheostomies were feasible to conduct by ICU physician at bedside with few major complications. Compared with tracheostomies conducted after 14 days of intubation, tracheostomies within 14 days were associated with an increased mortality rate.
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http://dx.doi.org/10.3389/fmed.2020.615845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793766PMC
December 2020

A Novel Risk-Stratification Models of the High-Flow Nasal Cannula Therapy in COVID-19 Patients With Hypoxemic Respiratory Failure.

Front Med (Lausanne) 2020 8;7:607821. Epub 2020 Dec 8.

Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

High-flow nasal cannula (HFNC) has been recommended as a suitable choice for the management of coronavirus disease 2019 (COVID-19) patients with acute hypoxemic respiratory failure before mechanical ventilation (MV); however, delaying MV with HFNC therapy is still a dilemma between the technique and clinical management during the ongoing pandemic. Retrospective analysis of COVID-19 patients treated with HFNC therapy from four hospitals of Wuhan, China. Demographic information and clinical variables before, at, and shortly after HFNC initiation were collected and analyzed. A risk-stratification model of HFNC failure (the need for MV) was developed with the 324 patients of Jin Yin-tan Hospital and validated its accuracy with 69 patients of other hospitals. Among the training cohort, the median duration of HFNC therapy was 6 (range, 3-11), and 147 experienced HFNC failure within 7 days of HFNC initiation. Early predictors of HFNC failure on the basis of a multivariate regression analysis included age older than 60 years [odds ratio (OR), 1.93; 95% confidence interval (CI), 1.08-3.44; = 0.027; 2 points], respiratory rate-oxygenation index (ROX) <5.31 (OR, 5.22; 95% CI, 2.96-9.20; < 0.001; 5 points) within the first 4 h of HFNC initiation, platelets < 125 × 10/L (OR, 3.04; 95% CI, 1.46-6.35; = 0.003; 3 points), and interleukin 6 (IL-6) >7.0 pg/mL (OR, 3.34; 95% CI, 1.79-6.23; < 0.001; 3 points) at HFNC initiation. A weighted risk-stratification model of these predictors showed sensitivity of 80.3%, specificity of 71.2% and a better predictive ability than ROX index alone [area under the curve (AUC) = 0.807 vs. 0.779, < 0.001]. Six points were used as a cutoff value for the risk of HFNC failure stratification. The HFNC success probability of patients in low-risk group (84.2%) was 9.84 times that in the high-risk group (34.8%). In the subsequent validation cohort, the AUC of the model was 0.815 (0.71-0.92). Aged patients with lower ROX index, thrombocytopenia, and elevated IL-6 values are at increased risk of HFNC failure. The risk-stratification models accurately predicted the HFNC failure and early stratified COVID-19 patients with HFNC therapy into relevant risk categories.
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http://dx.doi.org/10.3389/fmed.2020.607821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793962PMC
December 2020

Imaging Mass Cytometric Analysis of Postmortem Tissues Reveals Dysregulated Immune Cell and Cytokine Responses in Multiple Organs of COVID-19 Patients.

Front Microbiol 2020 23;11:600989. Epub 2020 Dec 23.

Department of Critical Care Medicine, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.

SARS-coronavirus-2-induced immune dysregulation and inflammatory responses are involved in the pathogenesis of coronavirus disease-2019 (COVID-19). However, very little is known about immune cell and cytokine alterations in specific organs of COVID-19 patients. Here, we evaluated immune cells and cytokines in postmortem tissues, i.e., lungs, intestine, liver, kidneys, and spleen of three patients with COVID-19. Imaging mass cytometry revealed monocyte, macrophage, and dendritic cell (DC) infiltration in the lung, intestine, kidney, and liver tissues. Moreover, in patients with COVID-19, natural killer T cells infiltrated the liver, lungs, and intestine, whereas B cells infiltrated the kidneys, lungs, and intestine. CD11b macrophages and CD11c DCs also infiltrated the lungs and intestine, a phenomenon that was accompanied by overproduction of the immunosuppressive cytokine interleukin (IL)-10. However, CD11b macrophages and CD11c DCs in the lungs or intestine of COVID-19 patients did not express human leukocyte antigen DR isotype. In contrast, tumor necrosis factor (TNF)-α expression was higher in the lungs, intestine, liver, and kidneys, but not in the spleen, of all COVID-19 patients (compared to levels in controls). Collectively, these findings suggested that IL-10 and TNF-α as immunosuppressive and pro-inflammatory agents, respectively,-might be prognostic and could serve as therapeutic targets for COVID-19.
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http://dx.doi.org/10.3389/fmicb.2020.600989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785801PMC
December 2020

T lymphocytes in hepatocellular carcinoma immune microenvironment: insights into human immunology and immunotherapy.

Am J Cancer Res 2020 1;10(12):4585-4606. Epub 2020 Dec 1.

Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC) Beijing, China.

Hepatocellular carcinoma (HCC) is characterized by poor outcome and shows limited drug-response in clinical trials. Tumor immune microenvironment (TIME) exerts a strong selection pressure on HCC, leading to HCC evolvement and recurrence after multiple therapies. T cell-mediated immunoreaction during cancer surveillance and clearance is central in cancer immunity. Heterogenous T cell subsets play multiple roles in HCC development and progression. The re-educated T cells in TIME usually lead to deteriorated T cell response and tumor progression. Investigation into immune system dysregulation during HCC development will shed light on how to turn immune suppressive state to immune activation and induce more efficient immune response. Emerging T cell-based treatment such as cancer vaccines, CAR-T cell therapy, adoptive cell therapy, and immune checkpoint inhibitors (ICIs), have been proved to cause tumor regression in some clinical and preclinical trials. In this review, we focused on recent studies that explored T cells involved in HCC and how they affect the course of disease. We also briefly outlined current T cell-based immunotherapies in HCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783774PMC
December 2020

Remodeling cancer stemness by collagen/fibronectin the AKT and CDC42 signaling pathway crosstalk in glioma.

Theranostics 2021 1;11(4):1991-2005. Epub 2021 Jan 1.

Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, Luzhou China.

Cancer development is a complex set of proliferative progression, which arises in most cases via multistep pathways associated with various factors, including the tumor microenvironment and extracellular matrix. However, the underlying mechanisms of cancer development remain unclear and this study aimed to explore the role of extracellular matrix in glioma progression. The expression of type I collagen and fibronectin in tumor tissues from glioma patients was examined by immunofluorescence staining. The correlations between collagen/fibronectin and glioma progression were then analyzed. A 3D collagen/fibronectin cultured system was established for tumor cells culture . Quantitative, real-time PCR and western blot were used to detect PI3K/ATK and CDC42 signals associated proteins expression in glioma. We used Cell Counting Kit-8, colony formation, and tumorigenesis assays to investigate the function of PI3K/AKT and CDC42 signals associated proteins. A xenograft glioma mice model was also used to study the anticancer effects of integrin inhibitor . Our study demonstrated that type I collagen and fibronectin collaborate to regulate glioma cell stemness and tumor growth. In a 3D collagen/fibronectin culture model, glioma cells acquired tumorigenic potential and revealed strengthened proliferative characteristics. More significantly, collagen/fibronectin could facilitate the activation of PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways integrin αvβ3, eliciting sustained tumor growth and cancer relapse. Combination of the integrin signaling pathway inhibitor and the chemotherapeutic agent efficiently suppressed glioma cell proliferation and tumorigenic ability. We demonstrated that type I collagen and fibronectin could collaborate to promote glioma progression through PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways. Blockade of the upstream molecular integrin αvβ3 revealed improved outcome in glioma therapy, which provide new insights for eradicating tumors and reducing glioma cancer relapse.
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http://dx.doi.org/10.7150/thno.50613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778591PMC
January 2021

Sex-specific associations of plasma metals and metal mixtures with glucose metabolism: An occupational population-based study in China.

Sci Total Environ 2021 Mar 3;760:143906. Epub 2020 Dec 3.

Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China; Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, Guangxi, China; Department of Public Health, School of Medicine, Guangxi University of Science and Technology, Liuzhou 545006, Guangxi, China. Electronic address:

Studies with multi-pollutant approach on the relationships between multiple metals and fasting plasma glucose (FPG) are limited. Few studies are available on the potential sex-specific associations between metal exposures and glucose metabolism. We explored the associations between 22 plasma metals and FPG level among the 769 participants from the manganese-exposed workers healthy cohort in China. We applied a sparse partial least squares (sPLS) regression followed by ordinary least-squares regression to evaluate multi-pollutant association. Bayesian kernel machine regression (BKMR) model was used to deal with metal mixtures and evaluate their joint effects on FPG level. In the sPLS model, negative associations on FPG levels were observed for plasma iron (belta = -0.066), cobalt (belta = -0.075), barium (belta = -0.109), and positive associations for strontium (belta = 0.082), and selenium (belta = 0.057) in men, which overlapped with the results among the overall participants. Among women, plasma copper (belta = 0.112) and antimony (belta = 0.137) were positively associated with elevated FPG level. Plasma magnesium was negatively associated with FPG level in both sexes (belta = -0.071 in men and belta = -0.144 in women). The results of overlapped for plasma magnesium was selected as the significant contributor to decreasing FPG level in the multi-pollutant, single-metal, and multi-metal models. BKMR model showed a significantly negative over-all effect of six metal mixtures (magnesium, iron, cobalt, selenium, strontium and barium) on FPG level among the overall participants from all the metals fixed at 50th percentile. In summary, our findings underline the probable role of metals in glucose homeostasis with potential sex-dependent heterogeneities, and suggest more researches are needed to explore the sex-specific associations of metal exposures with risk of diabetes.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143906DOI Listing
March 2021

The associations of multiple metals mixture with accelerated DNA methylation aging.

Environ Pollut 2021 Jan 5;269:116230. Epub 2020 Dec 5.

Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China; Department of Public Health, School of Medicine, Guangxi University of Science and Technology, Liuzhou, Guangxi, China. Electronic address:

Aging is a leading cause of mortality for the elderly and DNA methylation age is reported to be predictive of biological aging. However, few studies have investigated the associations between multiple metals exposure and accelerated aging in the elderly. We performed a pilot study of 288 elderly participants aged 50-115 years and measured genome-wide DNA methylation and 22 blood metals concentrations. Measures of DNA methylation age were estimated using CpGs from Illumina HumanMethylation EPIC BeadChip. Linear mixed regression and Bayesian kernel machine regression (BKMR) models were used to estimate the individual and overall associations between multiple metals and accelerated methylation aging. Single metal models revealed that each 1-standard deviance (SD) increase in log-transformed vanadium, cobalt, nickel, zinc, arsenic, and barium was associated with a -2.256, -1.318, 1.004, -1.926, 1.910 and -1.356 changes in ΔAge, respectively; meanwhile, for aging rate, the change was -0.019, -0.013, 0.010, -0.018, 0.023, and -0.012, respectively (all P < 0.05). The BKMR models showed reverse U-shaped associations of the overall metals mixture with ΔAge and aging rate. Downward trends of ΔAge and aging rate were observed for increasing quantiles of essential metals mixture, but upward trends were observed for non-essential metals mixture. Further individual analysis of the BKMR revealed that the 95% confidence interval of ΔAge and aging rate associated with vanadium, zinc, and arsenic did not cross 0, when other metals concentrations set at 25th, 50th, and 75th percentile. Our findings suggest reverse U-shaped associations of the overall metals mixture with accelerated methylation aging for the first time, and vanadium, zinc, and arsenic may be major contributors driving the associations.
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http://dx.doi.org/10.1016/j.envpol.2020.116230DOI Listing
January 2021

The Efficacy and Safety of Compound Danshen Dripping Pill Combined with Percutaneous Coronary Intervention for Coronary Heart Disease.

Evid Based Complement Alternat Med 2020 17;2020:5067137. Epub 2020 Nov 17.

State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.

Objective: Compound Danshen dripping pill (CDDP) is a well-known Chinese patent medicine, which is commonly used for the treatment of coronary heart disease (CHD) in China. This study is aimed at systematically assessing the clinical efficacy of CDDP for CHD patients.

Methods: Eight databases were retrieved for eligible research studies from the founding date to April 20, 2020. Risk ratio (RR) was used to assess major adverse cardiac events (MACE) and adverse reactions, and mean difference (MD) was adopted to evaluate the hemorheology and blood lipid indexes, vascular endothelial function, cardiac function, and inflammation.

Result: Twenty randomized controlled trials involving 2574 participants with CHD were included. The results indicated that, compared with percutaneous coronary intervention (PCI) alone, the combination of CDDP with PCI treatment remarkably reduced MACE (RR = 0.53, 95% confidence interval (CI) (0.44, 0.65), < 0.00001). Moreover, hemorheology and blood lipid parameters and inflammatory mediators of CHD patients were also dramatically mitigated after the combined therapy ( < 0.01). In addition, vascular endothelial function and cardiac function were prominently improved by this combination ( < 0.001). However, there was no significant difference in adverse reactions between the two groups ( > 0.05).

Conclusion: Evidence from the meta-analysis demonstrated that CDDP combined with PCI treatment prominently reduced the incidence of MACE, improved cardiovascular functions, and inhibited inflammation in CHD patients. Therefore, CDDP combined with PCI treatment could be an effective and safe therapeutic method for CHD patients.
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http://dx.doi.org/10.1155/2020/5067137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685822PMC
November 2020