Publications by authors named "Li Su"

1,123 Publications

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Cytosolic-DNA-mediated STING-dependent inflammation contributes to the progression of psoriasis.

J Invest Dermatol 2021 Sep 16. Epub 2021 Sep 16.

School of Medicine, Shanghai University, Shangda Road 99, Shanghai, 200444, China. Electronic address:

Psoriasis is a chronic inflammatory skin disease characterized by an active dynamic interplay between immune cells and keratinocytes. Stimulator of IFN genes (STING) is a universal receptor that recognizes cytosolic DNA and triggers innate immune activation. The aim of current work was to elucidate the role of STING in the inflammation during psoriasis. STING deficiency alleviated psoriatic symptoms and inflammation in mouse models of psoriasis. Stimulation of macrophages with double-stranded DNA (dsDNA) induced STING-dependent release of TNF-α and HOin vitro. Furthermore, incubation of keratinocytes with TNF-α or HO increased oxidative DNA damage, induced nuclear DNA release into cytosol, and inhibited dsDNA-induced degradation of STING protein. More importantly, transfection of keratinocytes with dsDNA synergized with TNF-α or HO to induce STING-dependent activation of NF-κB and subsequent expression of Il1b, Ccl20, and Cxcl10. Finally, exposure to 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a STING agonist) aggravated psoriatic symptoms and inflammation in wild-type mice, but not in STING-deficient mice. Collectively, STING functioned as a self DNA sensor in macrophages and keratinocytes of psoriatic skin. Cytosolic-DNA-induced activation of STING in immune cells and keratinocytes acted synergistically and contributed to the inflammation in psoriasis.
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http://dx.doi.org/10.1016/j.jid.2021.08.430DOI Listing
September 2021

Novel Oral Iron Therapy for Iron Deficiency: How to Value Safety in a New Drug?

Br J Clin Pharmacol 2021 Sep 12. Epub 2021 Sep 12.

Centre for Health Economics and Medicines Evaluation, Bangor University.

Objective: Novel oral iron supplements may be associated with a reduced incidence of adverse drug reactions compared to standard treatments of iron deficiency anaemia. The aim was to establish their value-based price under conditions of uncertainty surrounding their tolerability.

Methods: A discrete-time Markov model was developed to assess the value-based price of oral iron preparations based on their incremental cost per quality-adjusted life year (QALY) gained from the perspective of the NHS in the UK. Primary and secondary care resource use and health state occupancy probabilities were estimated from routine electronic health records; and unit costs and health state utilities were derived from published sources. Patients were pre-menopausal women with iron deficiency anaemia who were prescribed oral iron supplementation between 2000 and 2014.

Results: The model reflecting current use of iron salts yielded a mean total cost to the NHS of £779, and 0.84 QALYs over 12 months. If a new iron preparation were to reduce the risk of adverse drug reactions by 30-40%, then its value-based price, based on a threshold of £20,000 per QALY, would be in the region of £10 to £13 per month, or about 7-9 times the average price of basic iron salts.

Discussion: There are no adequate, direct comparisons of new oral iron supplements to ferrous iron salts, and therefore other approaches are needed to assess their value. Our modelling shows that they are potentially cost-effective at prices that are an order of magnitude higher than existing iron salts.
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http://dx.doi.org/10.1111/bcp.15078DOI Listing
September 2021

Influence of the rs6736 Polymorphism on Ischemic Stroke Susceptibility in Han Chinese Individuals via the Disruption of miR-7-1 Binding to the C14orf119 Gene.

J Mol Neurosci 2021 Sep 11. Epub 2021 Sep 11.

School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.

This study investigates the association between the C14orf119 gene rs6736 polymorphism and ischemic stroke (IS) susceptibility, and explores the influence of the rs6736 polymorphism on the binding between miR-7-1 and the C14orf119 gene. mRNA expression levels were determined in 45 IS patients and 45 matched controls via real-time quantitative PCR. A total of 774 IS patients and 793 matched controls were recruited from a Han Chinese population for genotyping, performed with the Sequenom MassARRAY iPLEX platform. A dual-luciferase reporter assay was used for the analysis of miRNA-mRNA binding. The results showed that the mRNA expression of C14orf119 differed significantly between IS patients and controls (t =  -2.235, P = 0.030). Significant associations were noted between the C14orf119 gene rs6736 polymorphism and IS susceptibility in Han Chinese individuals under the additive model [OR (95% CI) = 0.87 (0.76-1.00) P = 0.048] and dominant model [OR (95% CI) = 0.76 (0.61-0.94), P = 0.014], with adjustment for age and sex. Mutations in the rs6736 polymorphism disrupted the binding of miR-7-1 and the C14orf119 gene. The results of this study show that the rs6736 polymorphism in the 3'-untranslated region of the C14orf119 gene not only is associated with IS but also modifies the binding between miR-7-1 and the C14orf119 gene. The C14orf119 gene may participate in the relationship between IS and miR-7-1.
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http://dx.doi.org/10.1007/s12031-021-01895-7DOI Listing
September 2021

Prognostic Function of Programmed Cell Death-Ligand 1 in Esophageal Squamous Cell Carcinoma Patients Without Preoperative Therapy: A Systematic Review and Meta-Analysis.

Front Oncol 2021 18;11:693886. Epub 2021 Aug 18.

Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China.

Background: Studies investigating the correlation between the expression of programmed cell death-ligand 1 (PD-L1) and prognosis in patients with esophageal squamous cell carcinoma (ESCC) not receiving preoperative therapy have increased significantly, but conclusions remain inconclusive. Therefore, this study aimed to determine the association between clinical outcomes and expression of PD-L1 in ESCC patients without preoperative therapy.

Methods: We conducted a comprehensive literature search using four databases up to May 2020. Quality assessment was carried out according to the Newcastle-Ottawa Quality Assessment Scale (NOS). Hazard ratios (HRs) were used to analyze the association between PD-L1 expression with prognosis. Furthermore, we evaluated the correlation between PD-L1 and clinicopathological characteristics using odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Twenty studies (19 publications) comprising 3,677 patients were included in this meta-analysis. We found that the expression of PD-L1 was not related to overall survival (OS, HR: 1.16, 95% CI: 0.94-1.42, = 0.16) or disease-free survival (DFS, HR: 0.85, 95% CI: 0.66-1.10, = 0.21) in ESCC. Furthermore, although PD-L1 expression was not significantly associated with sex, degree of differentiation, TNM stage, T stage, lymph node status, smoking, or alcohol use, the merged OR demonstrated that the expression of PD-L1 was higher in older patients compared to younger patients (OR: 1.40, 95% CI: 1.07-1.83, = 0.01). No obvious publication bias was observed.

Conclusions: Our present study illustrated that PD-L1 expression was not related to poor prognosis of ESCC patients not receiving preoperative therapy, albeit the association only showed a tendency for statistical significance. Notably, PD-L1 expression showed a significant association with age. This meta-analysis had several limitations; therefore, our results need to be verified through further large-scale and prospective studies.
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http://dx.doi.org/10.3389/fonc.2021.693886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416500PMC
August 2021

CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1.

Cell Death Dis 2021 Aug 30;12(9):820. Epub 2021 Aug 30.

National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Tongji Hospital, Huazhong University of Science and Technology, 430074, Wuhan, China.

Failures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.
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http://dx.doi.org/10.1038/s41419-021-04114-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405615PMC
August 2021

Surfactant protein-A inhibits thymic stromal lymphopoietin-mediated T follicular helper cell differentiation and IgE production in asthma.

Clin Immunol 2021 Aug 13;231:108822. Epub 2021 Aug 13.

Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai 200025, PR China. Electronic address:

Lung surfactant protein A (SP-A) is critical for immunomodulation. Thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) drive T follicular helper (Tfh) cells differentiation in allergic asthma. We employed wild-type (WT) and SP-A mice injected with TSLP and ovalbumin (OVA)-activated DCs and challenged with OVA. Compared with WT mice, we showed that allergic inflammation was dramatically increased in SP-A mice. In parallel, both IL-4-producing CD45RACXCR5PD-1CD4 cells (Tfh2) and IgE were markedly increased in SP-A mice. Further study showed that SP-A prohibited TSLP activated-DCs from expressing OX40L. When we blocked OX40L-OX40 and IL-4R signaling, the differentiation of Tfh2 and IgE responses in SP-A mice was significantly inhibited. In severe asthma patients, SP-A is dysfunctional in modulating the TSLP-DCs-mediated differentiation of Tfh cells. This study suggests that SP-A acts as a modulator of Tfh differentiation and IgE generation in asthma.
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http://dx.doi.org/10.1016/j.clim.2021.108822DOI Listing
August 2021

Alterations of Signaling Pathways in Essential Thrombocythemia with Calreticulin Mutation.

Cancer Manag Res 2021 7;13:6231-6238. Epub 2021 Aug 7.

Department of Hematology, Xuan Wu Hospital, Capital Medical University, Beijing, People's Republic of China.

Purpose: Though mutations of the calreticulin () gene have been identified in essential thrombocythemia patients, the detailed mechanisms for mutations have not been completely clarified. Our study is aimed at characterizing alteration of protein expression in ET patients with mutated and further recognizing possible involvement of signaling pathways associated with mutations.

Patients And Methods: Protein pathway array was performed to analyze the expression levels of proteins involved in various signaling pathways in peripheral blood neutrophils from 18 ET patients with mutated , 20 ET patients with mutation and 20 controls.

Results: We found 20 proteins differentially expressed in ET patients with mutated compared with healthy controls. These proteins were associated with molecular mechanisms of cancer in ingenuity pathways analysis (IPA) network. We identified top ten canonical pathways which including apoptotic pathways and cellular cytokine pathways might participate in pathogenesis of ET with mutated . Additionally, there were 8 proteins found to be dysregulated differently between ET patients with mutated and those with mutation. These proteins might be related to the unique signaling pathways activated by mutation which were different to JAK/STATs pathway by mutation.

Conclusion: Our study demonstrated that numerous alterations of signaling proteins and pathways in ET patients with mutated . These findings could help to gain insights into the pathological mechanisms of ET.
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http://dx.doi.org/10.2147/CMAR.S316919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357313PMC
August 2021

Thymosin β4 increases cardiac cell proliferation, cell engraftment, and the reparative potency of human induced-pluripotent stem cell-derived cardiomyocytes in a porcine model of acute myocardial infarction.

Theranostics 2021 26;11(16):7879-7895. Epub 2021 Jun 26.

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.

Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin β4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks . After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 10 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. : , 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. : Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.
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http://dx.doi.org/10.7150/thno.56757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315077PMC
August 2021

Resting-state brain connectivity in healthy young and middle-aged adults at risk of progressive Alzheimer's disease.

Neurosci Biobehav Rev 2021 10 24;129:142-153. Epub 2021 Jul 24.

Edinburgh Dementia Prevention and Centre for Clinical Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom.

Functional brain connectivity of the resting-state networks has gained recent attention as a possible biomarker of Alzheimer's Disease (AD). In this paper, we review the literature of functional connectivity differences in young adults and middle-aged cognitively intact individuals with non-modifiable risk factors of AD (n = 17). We focus on three main intrinsic resting-state networks: The Default Mode network, Executive network, and the Salience network. Overall, the evidence from the literature indicated early vulnerability of functional connectivity across different at-risk groups, particularly in the Default Mode Network. While there was little consensus on the interpretation on directionality, the topography of the findings showed frequent overlap across studies, especially in regions that are characteristic of AD (i.e., precuneus, posterior cingulate cortex, and medial prefrontal cortex areas). We conclude that while resting-state functional connectivity markers have great potential to identify at-risk individuals, implementing more data-driven approaches, further longitudinal and cross-validation studies, and the analysis of greater sample sizes are likely to be necessary to fully establish the effectivity and utility of resting-state network-based analyses.
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http://dx.doi.org/10.1016/j.neubiorev.2021.07.024DOI Listing
October 2021

Hierarchical Vitalization of Oligotyrosine in Mitigating Islet Amyloid Polypeptide Amyloidogenesis through Multivalent Macromolecules with Conformation-Restrained Nanobody Ligands.

ACS Nano 2021 Jul 23. Epub 2021 Jul 23.

National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.

The development of inhibitors that can effectively mitigate the amyloidogenesis of human islet amyloid polypeptide (hIAPP), which is linked to type II diabetes, remains a great challenge. Oligotyrosines are intriguing candidates in that they can block the hIAPP aggregation through multiplex phenol-hIAPP interactions. However, oligotyrosines containing too many tyrosine units (larger than three) may fail to inhibit amyloidogenesis due to their increased hydrophobicity and strong self-aggregation propensity. In this work, we developed a strategy to hierarchically vitalize oligotyrosines in mitigating hIAPP amyloidogenesis. Tetratyrosine YYYY (4Y) was grafted into the third complementary-determining region (CDR3) of a parent nanobody to construct a sequence-programmed nanobody N4Y, in which the conformation of the grafted 4Y fragment was constrained for a significantly enhanced binding affinity with hIAPP. We next conjugated N4Y to a polymer to approach a secondary vitalization of 4Y through a multivalent effect. The and experiments validated that the resulting PDN4Y could completely inhibit the hIAPP amyloidogenesis at low stoichiometric concentrations and effectively suppress the generation of toxic reactive oxygen species and alleviate amyloidogenesis-mediated damage to INS-1 cells and zebrafish () embryos. The hierarchical vitalization of 4Y via a synergistic conformation restraint and multivalent effect represents a strategic prototype of boosting the efficacy of peptide-based amyloidogenesis inhibitors, especially those with a high hydrophobicity and strong aggregation tendency, which holds great promise for future translational studies.
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http://dx.doi.org/10.1021/acsnano.1c03083DOI Listing
July 2021

LncRNA SERPINB9P1 expression and polymorphisms are associated with ischemic stroke in a Chinese Han population.

Neurol Sci 2021 Jul 17. Epub 2021 Jul 17.

School of Public Health of Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China.

Long noncoding RNAs (lncRNAs) were reported to play important roles in the pathogenesis of ischemic stroke (IS). Our study aimed to investigate the role of lncRNA SERPINB9P1 expression in ischemic stroke and the association between SERPINB9P1 polymorphisms and IS risk, as well as examine the correlation of SERPINB9P1 expression and variants with clinical parameters of IS. The SERPINB9P1 levels in human participants and oxygen-glucose deprivation (OGD)-treated human A172 cells were measured by qRT-PCR. The SERPINB9P1 polymorphisms (rs375556 and rs318429) were genotyped by the MassARRAY platform. We found that the SERPINB9P1 expression was significantly downregulated in patients with IS compared with that in healthy controls. On the 14th day in the hospital, the SERPINB9P1 level in patients with moderate and severe stroke was significantly downregulated compared with the normal group. After stratification by gender, the rs375556 polymorphism was significantly associated with susceptibility to female IS in the recessive model, and the significant association remained after adjusting for age. After adjusting for gender and age, rs318429 was significantly associated with FPG and D-D levels, and rs375556 was significantly associated with INR and PTA levels in IS cases. Besides, the lncRNA SERPINB9P1 expressed downregulated in OGD/reoxygenation-treated human A172 cells. In conclusion, the lncRNA SERPINB9P1 may protect against cerebral ischemia-reperfusion injury and neurological impairment after IS. The SERPINB9P1 rs375556 polymorphism was associated with susceptibility to female IS, and SERPINB9P1 polymorphisms may influence the metabolism of blood glucose and regulation of coagulation function in patients with IS.
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http://dx.doi.org/10.1007/s10072-021-05418-5DOI Listing
July 2021

Real-World Study of Cisplatin, Etoposide, and Bleomycin Chemotherapy Regimen in Gestational Trophoblastic Neoplasia.

Biomed Res Int 2021 24;2021:6661698. Epub 2021 Jun 24.

Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

Objective: Little observational data exist regarding the use of cisplatin, etoposide, and bleomycin (BEP) chemotherapy regimen in patients with gestational trophoblastic neoplasia (GTN).

Methods: This is a retrospective study of 95 patients with GTN in our center from June/2010 to June/2018. All patients received at least 2 cycles of BEP chemotherapy. The primary outcomes were the rate of complete remission (CR) and overall survival (OS). The secondary outcomes were disease-free survival (DFS), pregnancy rates after BEP exposure, drug resistance rate, and other adverse events.

Results: Of the 95 patients included, 66 (69.5%) patients received BEP as primary treatment and 29 (30.5%) were Salvage chemotherapy. The median age at diagnosis was 37 years (range 29.75-46) and 34 years (range 27-40) in two groups, respectively. The median WHO prognostic scores were 6 (range 3.5-8), and 77.32% of patients were FIGO stage III-IV in the primary treatment group. The median WHO prognostic scores were 5 (range 3-9), and 66.55% of patients were FIGO stage III-IV in the salvage treatment group. Median cycles of BEP treatment were 4 (3, 5) and 3 (2, 4) in two groups, respectively. In the primary chemotherapy group, 18.2% received additional hysterectomy, 4.5% received UAE for vaginal bleeding, and 1.52% received whole-brain radiotherapy. In the salvage chemotherapy group, 20.7% received hysterectomy, 6.9% received lobectomy, 3.4% received hysteroscopic lesion resection, and 3.4% received whole-brain radiotherapy. CR rates to initial chemotherapy were 86.4%, including 87.9% in the primary chemotherapy group and 82.8% in the salvage chemotherapy group. No predictive factor of chemotherapy resistance was identified. The rate of 5 year-DFS was 96.52% (95% CI 86.78-99.12) in the primary chemotherapy group and 92.44% (95% CI 73.02-98.06) in the salvage chemotherapy group. The rate of 5 year-OS was 98.31% (95% CI 88.57-99.76) and 95.65% (95% CI 79.93-99.38) in the two groups, respectively. During the treatment, neutropenia, thrombocytopenia, anemia, and liver dysfunction occurred in 80.3%, 6.1%, 25.8%, and 50% primary chemotherapy patients and 82.8%, 31%, 10.3%, and 86.2% salvage chemotherapy patients. In patients with fertility requirements, live birth rates were 100% (10/10) in primary chemotherapy patients and 80% (4/5) in salvage chemotherapy patients.

Conclusions: BEP regimen was effective in the treatment of GTINs. The treatment was well tolerated, with no safety concerns on patients' fertility.
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http://dx.doi.org/10.1155/2021/6661698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249144PMC
June 2021

Clinical efficacy of low-dose emetine for patients with COVID-19: a real-world study.

J BioX Res 2021 Jun 3;4(2):53-59. Epub 2020 Dec 3.

Anhui Feidong County People's Hospital.

Objective: Emetine, an isoquinoline alkaloid that is enriched at high concentrations in the lung, has shown potent in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to better understand the effectiveness of low-dose emetine for patients with coronavirus disease 2019 (COVID-19).

Methods: In this real-world study, 63 patients with mild or common COVID-19 were recruited from Wuhan Fangcang Shelter Hospital and five COVID-19-designated hospitals in Anhui Province, China from February to March 2020. Thirty-nine patients from Wuhan Fangcang Shelter Hospital were assigned to a pragmatic randomized controlled clinical trial, and 24 patients from the 5 COVID-19-designated hospitals in Anhui Province underwent a real-world study. The medication course of emetine was less than 10 days. The main symptoms and adverse reactions of all patients were observed and recorded. The primary outcome measure was the time required for a negative SARS-CoV-2 RNA result or the negative result rate on day 10. Secondary outcomes included axillary temperature, transcutaneous oxygen saturation, and respiratory frequency recovery. The study was approved by the Ethics Committee of The First Affiliated Hospital of Anhui Medical University on February 20, 2019 (approval No. PJ2020-03-19) and was registered with the Chinese Clinical Trial Registry on February 20, 2019 (registration number: ChiCTR2000030022).

Results: The oxygen saturation values were higher in the treatment group than in the control group on the first day after enrollment for patients treated at Fangcang Shelter Hospital. The axillary body temperature, respiratory rate, and oxygen saturation among patients in Fangcang Shelter Hospital were related to the time effect but not to the intervention measures. The respiratory rate and oxygen saturation of patients in the Anhui designated hospitals were related to the intervention measures but not to the time effect. The axillary body temperature of patients in Anhui designated hospitals was related to the time effect but not to the intervention measures.

Conclusion: Our preliminary study shows that low-dose emetine combined with basic conventional antiviral drugs improves clinical symptoms in patients with mild and common COVID-19 without apparent adverse effects, suggesting that moderately increased doses of emetine may have good potential for treatment and prevention of COVID-19.
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http://dx.doi.org/10.1097/JBR.0000000000000076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237841PMC
June 2021

Decomposition and Completion Network for Salient Object Detection.

IEEE Trans Image Process 2021 12;30:6226-6239. Epub 2021 Jul 12.

Recently, fully convolutional networks (FCNs) have made great progress in the task of salient object detection and existing state-of-the-arts methods mainly focus on how to integrate edge information in deep aggregation models. In this paper, we propose a novel Decomposition and Completion Network (DCN), which integrates edge and skeleton as complementary information and models the integrity of salient objects in two stages. In the decomposition network, we propose a cross multi-branch decoder, which iteratively takes advantage of cross-task aggregation and cross-layer aggregation to integrate multi-level multi-task features and predict saliency, edge, and skeleton maps simultaneously. In the completion network, edge and skeleton maps are further utilized to fill flaws and suppress noises in saliency maps via hierarchical structure-aware feature learning and multi-scale feature completion. Through jointly learning with edge and skeleton information for localizing boundaries and interiors of salient objects respectively, the proposed network generates precise saliency maps with uniformly and completely segmented salient objects. Experiments conducted on five benchmark datasets demonstrate that the proposed model outperforms existing networks. Furthermore, we extend the proposed model to the task of RGB-D salient object detection, and it also achieves state-of-the-art performance. The code is available at https://github.com/wuzhe71/DCN.
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http://dx.doi.org/10.1109/TIP.2021.3093380DOI Listing
July 2021

Cordyceps sinensis aqueous extract regulates the adaptive immunity of mice subjected to Co γ irradiation.

Phytother Res 2021 Jul 8. Epub 2021 Jul 8.

School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China.

Cordyceps sinensis (CS) is a traditional Chinese medicine that is known for treating various diseases, and particularly for exerting therapeutic effects in immune disorders. The adaptive immunoregulatory effects of CS aqueous extract (CSAE) on γ-irradiated mice have not been reported previously. The study aimed to evaluate the therapeutic effects of CSAE in mice immunosuppressed by irradiation. We observed that CSAE administration significantly increased body weight and spleen index, as well as the number of white blood cells, lymphocytes, and platelets in peripheral blood, T and B lymphocytes in spleen tissue, and total serum immunoglobulins in irradiated mice, whereas total serum pro-inflammatory cytokine levels were decreased. Collectively, CSAE maintained the structural integrity of spleen tissue and repaired its damage in irradiated mice as shown by hematoxylin and eosin staining, and decreased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive splenocytes. Mechanistically, CSAE upregulated Bcl-2, and downregulated Bax and cleaved caspase-3 in spleen of irradiated mice. However, there were no significant differences in red blood cells and neutrophils in different groups. The results revealed that CSAE had protective effects against irradiation-induced immunosuppression, which was likely associated with an antiapoptotic effect and the regulation of adaptive immunity.
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http://dx.doi.org/10.1002/ptr.7186DOI Listing
July 2021

The Association Between Inflammatory and Oxidative Stress Biomarkers and Plasma Metabolites in a Longitudinal Study of Healthy Male Welders.

J Inflamm Res 2021 29;14:2825-2839. Epub 2021 Jun 29.

Environmental Health, Harvard University T H Chan School of Public Health, Boston, MA, USA.

Introduction: Human metabolism and inflammation are closely related modulators of homeostasis and immunity. Metabolic profiling is a useful tool to understand the association between metabolism and inflammation at a systemic level.

Objective: To investigate the longitudinal associations between the concentration of plasma metabolites and biomarkers related to inflammation and oxidative stress.

Methods: We conducted a repeated cross-sectional analysis consisting of 8 short-term panels that included 88 healthy adult male welders in Massachusetts, USA. In each panel, we collected 1-6 repeated measurements of blood and urine. We used a human vascular injury panel assay and custom cytokine/chemokine assay to quantify inflammatory biomarker plasma levels, liquid chromatography-mass spectrometry to quantify the concentrations of 665 plasma metabolites, and a competitive enzyme-linked immunoassay to quantify urinary 8-OHdG and 8-isoprostane levels. We used linear mixed effects models to estimate the longitudinal association between each inflammatory and oxidative stress biomarker and each metabolite.

Results: At a 5% FDR threshold, we detected ≥1metabolite association for 8 unique inflammatory and oxidative stress biomarkers: urinary 8-isoprostane, plasma C-reactive protein (CRP), serum amyloid A (SAA), intercellular adhesion molecule 1, circulating vascular cell adhesion molecule-1, interleukin 8 (IL-8), interleukin 10 (IL-10) and vascular endothelial growth factor. Specifically, 3 metabolites in the androgenic steroids pathway were negatively associated with SAA; 3 dihydrosphingomyelins metabolites were positively associated with 1 or more of CRP, SAA, IL-8 and IL-10; 4 metabolites in acyl choline metabolism pathways were negatively associated with IL-8; 7 lysophospholipid metabolites were negatively associated with 1 or more of CRP, SAA and IL-8; 4 sphingomyelins were positively associated with CRP and/or SAA; and 10 metabolites in the xanthine pathway were positively associated with urinary 8-isoprostane.

Conclusion: We found that metabolites in phospholipid groups had strong associations with multiple inflammatory biomarkers, especially CRP, SAA and IL-8. The mechanism of these associations warrants further investigation.
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http://dx.doi.org/10.2147/JIR.S316262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254568PMC
June 2021

Functional Characterization of VDACs in Grape and Its Putative Role in Response to Pathogen Stress.

Front Plant Sci 2021 16;12:670505. Epub 2021 Jun 16.

State Key Laboratory of Crop Stress Biology for Arid Areas, College of Horticulture, Northwest A&F University, Yangling, China.

Voltage-dependent anion channels (VDACs) are the most abundant proteins in the mitochondrial outer membranes of all eukaryotic cells. They participate in mitochondrial energy metabolism, mitochondria-mediated apoptosis, and cell growth and reproduction. Here, the chromosomal localizations, gene structure, conserved domains, and phylogenetic relationships were analyzed. The amino acid sequences of VDACs were found to be highly conserved. The tissue-specific transcript analysis from transcriptome data and qRT-PCR demonstrated that grapevine VDACs might play an important role in plant growth and development. It was also speculated that VDAC3 might be a regulator of modulated leaf and berry development as the expression patterns during these developmental stages are up-regulated. Further, we screened the role of all grape ' response to pathogen stress and found that from downy mildew -resistant Chinese wild grapevine species "Liuba-8" had a higher expression than the downy mildew susceptible species cv. "Thompson Seedless" after inoculation with Overexpression of resulted in increased resistance to pathogens, which was found to prevent VpVDAC3 protein accumulation through protein post-transcriptional regulation. Taken together, these data indicate that plays a role in defense and provides the evidence with which to understand the mechanism of grape response to pathogen stress.
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http://dx.doi.org/10.3389/fpls.2021.670505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242593PMC
June 2021

Anxiety and depression status prior to radiotherapy in patients with nasopharyngeal carcinoma and its effect on acute radiation toxicities.

Eur J Cancer Care (Engl) 2021 Jul 5:e13487. Epub 2021 Jul 5.

Department of Radiotherapy, Cancer Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.

Objective: The objective of this work is to explore anxiety and depression status prior to radiotherapy in patients with nasopharyngeal carcinoma (NPC) and its effect on acute radiation toxicities.

Methods: A total of 267 NPC patients were enrolled between August 2013 and September 2016. The anxiety and depression status of the patients prior to radiotherapy was evaluated using the Hospital Anxiety and Depression Scale. Acute radiation toxicities were assessed weekly and recorded according to the Common Terminology Criteria for Adverse Events version 4.0. Logistic regression analysis was used to identify the predictive factors for acute radiation toxicities.

Results: The rates of anxiety and depression status prior to radiotherapy were 35.2% and 25.5%, respectively. Anxiety was a significant predictor of vomiting (P = 0.001, OR = 2.874) and dysphagia (P = 0.029, OR = 2.080). Depression was a significant predictor of dysgeusia (P = 0.030, OR = 2.957). In addition, age was a significant predictor of dysphagia (P = 0.001, OR = 1.131).

Conclusions: Anxiety and depression status prior to radiotherapy aggravate acute radiation toxicities in patients with NPC. Assessment of the anxiety and depression status and appropriate interventions should be an integral part of treatment to relieve radiation injury during intensity-modulated radiotherapy.
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http://dx.doi.org/10.1111/ecc.13487DOI Listing
July 2021

Cord serum elementomics profiling of 56 elements depicts risk of preterm birth: Evidence from a prospective birth cohort in rural Bangladesh.

Environ Int 2021 11 28;156:106731. Epub 2021 Jun 28.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China; China International Cooperation Center for Environment and Human Health, Center of Global Health, Nanjing Medical University, Nanjing 211166, China.

Maternal exposure to some individual rare earth elements and trace elements is associated with preterm birth, but few elements have been studied and little is known about the potential effect of simultaneous exposure to multiple elements. We examined individual and mixture effects of elements on preterm birth among 745 pregnant women in a prospective birth cohort in Bangladesh (2008-2011). We measured 56 elements in umbilical cord blood collected during delivery using inductively coupled plasma-mass spectrometry. Using elastic net (ENET) regularization and multivariate logistic regression, we examined independent associations between element concentrations and preterm birth. Bayesian kernel machine regression identified mixture effects of elements most critical to preterm birth, accounting for correlated exposure and interaction. ENET identified titanium (Ti), arsenic (As), and barium (Ba) as the most important predictors of shortened gestational age and preterm birth. In adjusted models, cord blood Ti (OR = 2.52; 95% CI: 1.08-5.93; P = 0.033), As (odds ratio (OR) = 1.34; 95% CI: 1.04-1.73; P = 0.023), and Ba (OR = 1.18; 95% CI: 1.02-1.38; P = 0.029) were significantly associated with preterm birth. Bayesian kernel machine regression suggested an interaction effect between As and Ba. Further, we constructed an element risk score (ERS) using estimated weights from a multivariate regression model for Ti, As, and Ba and regressed preterm birth by this score (OR = 2.72, 95% CI: 1.57-4.69; P = 3.35 × 10). Additionally, we observed a significant modification effect of child marriage on ERS, which means marriage before the age of 18 (P = 0.0438). This study identified element exposures profiles in cord blood and constructed metal risk score that are jointly associated with the risk of preterm birth. Ti, As, and Ba exposure may adversely affect birth outcomes as well as child marriage may be a modifiable factor potentially affecting environmental element exposure and preterm birth.
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http://dx.doi.org/10.1016/j.envint.2021.106731DOI Listing
November 2021

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia.

Theranostics 2021 25;11(15):7337-7359. Epub 2021 May 25.

Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.

Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O environment. MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.
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http://dx.doi.org/10.7150/thno.57804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210597PMC
July 2021

Application of machine learning in diagnostic value of mRNAs for bipolar disorder.

Nord J Psychiatry 2021 Jun 22:1-8. Epub 2021 Jun 22.

School of Public Health, Guangxi Medical University, Guangxi, China.

Purpose: Bipolar disorder (BD) is a type of severe mental illness with symptoms of mania or depression, it is necessary to find out effective diagnostic biomarkers for BD due to diagnosing BD is based on clinical interviews without objective indicators.

Materials And Methods: The mRNA expression levels of genes included , and in the peripheral blood of 43 patients with bipolar disorder and 47 healthy controls were detected. Machine learning methods included Artificial Neural Networks, Extreme Gradient Boosting, Random Forest, and Support Vector Machine were adopted to fit different gene combinations to evaluate diagnostic value for bipolar disorder.

Results: The combination ' +' in the SVM model showed the best diagnostic value, with AUC, sensitivity, and specificity values of 0.951, 0.928, and 0.937, respectively.

Conclusions: The diagnostic efficiency for bipolar disorder was significantly improved by fitting and through the Support Vector Machine model.
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http://dx.doi.org/10.1080/08039488.2021.1937311DOI Listing
June 2021

Flexible electrocatalysts: interfacial-assembly of iron nanoparticles for nitrate reduction.

Chem Commun (Camb) 2021 Jul 15;57(55):6740-6743. Epub 2021 Jun 15.

State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China.

We report a novel template-assisted epitaxial assembly strategy to assemble carbon-coated iron nanoparticles on a functionalized carbon cloth (CC/[email protected]). This delicate assembled architecture provides a useful guideline for designing flexible iron-based electrocatalysts.
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http://dx.doi.org/10.1039/d1cc02129jDOI Listing
July 2021

Aberrant expression and genetic alteration of c-MYC in anaplastic large cell lymphoma.

J Cancer Res Clin Oncol 2021 Jun 16. Epub 2021 Jun 16.

Department of Pathology, Shanxi Fenyang Hospital, Fenyang, China.

Purpose: c-MYC plays an important role in regulating cellular growth and apoptosis, and it is aberrantly expressed in many human malignancies. Although c-MYC has been extensively investigated in Burkitt lymphoma and diffuse large B cell lymphoma, little has been reported in anaplastic large cell lymphoma (ALCL). The aim of this study was to investigate the expression and genetic alterations of c-MYC in primary systemic ALCL, characterize its clinicopathologic features and immunophenotypes, and discuss their implications in prognosis.

Methods: Tissue microarrays using samples from 85 ALCL patients were used to evaluate expression of c-MYC and anaplastic lymphoma kinase (ALK). c-MYC and ALK genetic alterations were detected using fluorescence in situ hybridization. The Kaplan-Meier and multivariate Cox regression methods were used for survival analysis.

Results: c-MYC was expressed in 24 of 85 samples (28.2%), and ALK was expressed in 54 (63.5%). c-MYC and ALK were co-expressed in 16 samples (18.8%). c-MYC expression and c-MYC and ALK co-expression increased with ALCL clinical stages and the International Prognostic Index (IPI) score (p < 0.05). Fifty of the samples (58.8%) had ALK rearrangement, and 18 (22.1%) had aneuploidy. c-MYC rearrangement was not detected, but aneuploidy was observed in 19 cases (22.4%). c-MYC aneuploidy was significantly different based on c-MYC expression and the IPI score (p < 0.05). c-MYC was a significant independent prognostic factor for progression-free survival and overall survival in patients with ALCL.

Conclusion: c-MYC protein expression and c-MYC aneuploidy could predict worse survival in patients with ALCL.
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http://dx.doi.org/10.1007/s00432-021-03691-7DOI Listing
June 2021

The Value of MR-DWI and T1 Mapping in Indicating Radiation-Induced Soft Tissue Injury.

Front Oncol 2021 27;11:651637. Epub 2021 May 27.

Key Laboratory of Radiation Biology of Fujian Higher Education Institutions, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

Objective: To explore the value of MR-DWI and T1 mapping in predicting radiation-induced soft tissue fibrosis and its correlation with radiation inflammation.

Methods: ① a total of 30 C57BL/6 mice were randomly divided into a control group (Nor group), irradiation group (IR group) and irradiation plus glycyrrhetinic acid group (GA group). The IR group and GA group were treated with 6MV X-rays to irradiate the right hind limbs of mice for 30 Gy in a single shot. MRI examinations were performed before and on the 7th day after irradiation to measure the apparent diffusion coefficient (ADC) value and the longitudinal relaxation time (T1) value of the hind limb muscles of the mice. On the 90th day after irradiation, the hind limb contracture was measured, and the right hind limb muscle was taken for HE staining, masson staining, immunohistochemical staining and Western blot analysis to detect the expression of a-SMA and Fibronectin. ② The other 30 mice were grouped randomly as above. On the 7th day after irradiation, the right hind limbs of the mice were examined by MRI to measure the ADC value and T1 value of the thigh muscles, and then the right hind thigh muscles were immediately sacrificed to detect IL-1β, IL-6, TNF-a and TGF-β1 expression with ELISA.

Results: On the 7th day after irradiation, the ADC values ​​of right hind thigh muscles of mice in Nor group, IR group and GA group were (1.35 ± 0.11)*10mm2/s, (1.48 ± 0.07) *10mm2/s and (1.36 ± 0.13)*10mm2/s, respectively, by which the differences between the IR group and Nor group (=0.008) and that between IR group and GA group (=0.013) were statistically significant; T1 values ​​were (1369.7 ± 62.7)ms, (1483.7 ± 127.7)ms and (1304.1 ± 82.3)ms, respectively, with which the differences in the T1 value between the IR group and Nor group (=0.012) and between IR group and GA group (<0.001) were also statistically significant. On the 90th day after irradiation, the contracture lengths of the right hind limbs of the three groups of mice were (0.00 ± 0.07)cm, (2.08 ± 0.32)cm, and (1.49 ± 0.70) cm, respectively. There were statistically significant differences in the IR group compared with the Nor group (<0.001) and the GA group (=0.030). The ADC value (r=0.379, =0.039) and T1 value (r=0.377, =0.040) of the mice's hindlimbs on Day 7 after irradiation were correlated with the degree of contracture on Day 90 after irradiation; the ADC value (r=0.496, =0.036) and T1 value (r=0.52, =0.027) were positively correlated with the Masson staining results and with the expression of α-SMA and Fibronectin. While the ADC value was positively correlated with IL-6 (r=0.553, =0.002), there was no obvious correlation with IL-1β, TNF-a and TGF-β1; the T1 value was positively correlated with IL-1β (r=0.419, =0.021), IL-6 (r=0.535, =0.002) and TNF-a (r=0.540, =0.002) but not significantly related to TGF-β1 (r=0.155, =0.413).

Conclusion: The MR-DWI and T1 mapping values on the 7th day after irradiation can reflect the early condition of tissue inflammation after the soft tissue is irradiated, and the values have a certain correlation with the degree of radiofibrosis of the soft tissue in the later period and may be used as an index to predict radiofibrosis.
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http://dx.doi.org/10.3389/fonc.2021.651637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190401PMC
May 2021

The psychological status in patients with nasopharyngeal carcinoma during radiotherapy.

Eur Arch Otorhinolaryngol 2021 Jun 10. Epub 2021 Jun 10.

Department of Radiotherapy, Cancer Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.

Purpose: The psychological status of nasopharyngeal carcinoma (NPC) patients cannot be ignored. Few studies have studied the dynamic changes and influencing factors of psychological status in NPC patients during radiotherapy. The purpose of this study was to investigate the changing trends and risk factors of anxiety and depression in NPC patients during radiotherapy.

Methods: Demographic and clinical data of 232 newly treated NPC patients were collected. Before radiotherapy, the fourth week, and the end of radiotherapy were observational timepoints. Anxiety and depression states were evaluated by the hospital anxiety and depression scale.

Results: Scores of anxiety before radiotherapy, in the fourth week and at the end of radiotherapy were 6.32 ± 3.19, 7.87 ± 3.49, and 9.08 ± 3.69, respectively (P < 0.001). Incidence rates of anxiety were 34.0%, 55.1%, and 64.0% (P < 0.001). Depression scores were 5.31 ± 3.19, 7.07 ± 3.63, and 8.32 ± 3.89 (P < 0.001). Incidence rates of depression were 25.0%, 43.9%, and 56.0% (P < 0.001). Gender, age, education level, smoking, and treatment-related toxicity scores (P < 0.05) were independent risk factors for anxiety in patients with NPC during radiotherapy, while age, education level, and treatment-related toxicity scores (P < 0.05) were independent risk factors for depression in these patients.

Conclusion: The incidence and degree of anxiety and depression in NPC patients increased during radiotherapy. Age, education level, and treatment-related side effects influenced anxiety and depression. More psychological nursing should be given to the NPC patients who are more likely to suffer from psychological distress.
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http://dx.doi.org/10.1007/s00405-021-06892-5DOI Listing
June 2021

Genetic variants of , and in the natural killer cell-related pathway are associated with non-small cell lung cancer survival.

Am J Cancer Res 2021 15;11(5):2264-2277. Epub 2021 May 15.

Duke Cancer Institute, Duke University Medical Center Durham, NC 27710, USA.

Although natural killer (NK) cells are a known major player in anti-tumor immunity, the effect of genetic variation in NK-associated genes on survival in patients with non-small cell lung cancer (NSCLC) remains unknown. Here, in 1,185 with NSCLC cases of a discovery dataset, we evaluated associations of 28,219 single nucleotide polymorphisms (SNPs) in 276 NK-associated genes with their survival. These patients were from the reported genome-wide association study (GWAS) from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We further validated the findings in an additional 984 cases from the Harvard Lung Cancer Susceptibility (HLCS) Study. We identified three SNPs (i.e., rs261083 G>C, rs2519996 C>T and rs36215 A>G) to be independently associated with overall survival (OS) in NSCLC cases with adjusted hazards ratios (HRs) of 1.16 (95% confidence interval [CI] = 1.07-1.26, = 3.34×10), 1.28 (1.12-1.47, = 4.57×10) and 0.75 (0.67-0.83, = 1.50×10), respectively. Additional joint assessment of the unfavorable genotypes of the three SNPs showed significant associations with OS and disease-specific survival of NSCLC cases in the PLCO dataset ( <0.0001 and <0.0001, respectively). Moreover, the survival-associated rs261083 C allele had a significant correlation with reduced transcript levels in lung adenocarcinoma (LUAD), while the rs36215 G allele was significantly correlated with reduced transcript levels in lymphoblastoid cell lines in the 1000 Genomes Project. These results revealed that and genetic variants may be prognostic biomarkers of NSCLC survival, likely via transcription regulation of respective genes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167686PMC
May 2021

Evidence of cerebral hemodynamic dysregulation in middle-aged APOE ε4 carriers: The PREVENT-Dementia study.

J Cereb Blood Flow Metab 2021 Jun 2:271678X211020863. Epub 2021 Jun 2.

Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer's disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged apolipoprotein ε4 carriers (APOEε4+) were investigated. Longitudinal 3 T T1-weighted and arterial spin labelling MRI data from 158 participants (40-59 years old) in the PREVENT-Dementia study were analysed (125 two-year follow-up). Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. CBF was corrected for underlying atrophy and individual hematocrit. Hemodynamic measures were the dependent variables in linear regression models, with age, sex, years of education and APOEε4 carriership as predictors. Further analyses were conducted with cognitive outcomes as dependent variables, using the same model as before with additional APOEε4 × hemodynamics interactions. At baseline, APOEε4+ showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEε4 non-carriers) and verbal fluency (for APOEε4 carriers) cognitive tests. These observations are consistent with neurovascular dysregulation in middle-aged APOEε4+.
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http://dx.doi.org/10.1177/0271678X211020863DOI Listing
June 2021

Genetic variants of CHEK1, PRIM2 and CDK6 in the mitotic phase-related pathway are associated with nonsmall cell lung cancer survival.

Int J Cancer 2021 09 10;149(6):1302-1312. Epub 2021 Jun 10.

Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA.

The mitotic phase is a vital step in cell division and may be involved in cancer progression, but it remains unclear whether genetic variants in mitotic phase-related pathways genes impact the survival of these patients. Here, we investigated associations between 31 032 single nucleotide polymorphisms (SNPs) in 368 mitotic phase-related pathway genes and overall survival (OS) of patients with nonsmall cell lung cancer (NSCLC). We assessed the associations in a discovery data set of 1185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another data set of 984 patients from the Harvard Lung Cancer Susceptibility Study. As a result, we identified three independent SNPs (ie, CHEK1 rs76744140 T>C, PRIM2 rs6939623 G>T and CDK6 rs113181986 G>C) to be significantly associated with NSCLC OS with an adjusted hazard ratio of 1.29 (95% confidence interval = 1.11-1.49, P = 8.26 × 10 ), 1.26 (1.12-1.42, 1.10 × 10 ) and 0.73 (0.63-0.86, 1.63 × 10 ), respectively. Moreover, the number of combined unfavorable genotypes of these three SNPs was significantly associated with NSCLC OS and disease-specific survival in the PLCO data set (P  < .0001 and .0003, respectively). Further expression quantitative trait loci analysis showed that the rs76744140C allele predicted CHEK1 mRNA expression levels in normal lung tissues and that rs113181986C allele predicted CDK6 mRNA expression levels in whole blood tissues. Additional analyses indicated CHEK1, PRIM2 and CDK6 may impact NSCLC survival. Taken together, these findings suggested that these genetic variants may be prognostic biomarkers of patients with NSCLC.
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http://dx.doi.org/10.1002/ijc.33702DOI Listing
September 2021

Integrative omics provide biological and clinical insights into acute respiratory distress syndrome.

Intensive Care Med 2021 07 25;47(7):761-771. Epub 2021 May 25.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA.

Purpose: Acute respiratory distress syndrome (ARDS) is accompanied by a dysfunctional immune-inflammatory response following lung injury, including during coronavirus disease 2019 (COVID-19). Limited causal biomarkers exist for ARDS development. We sought to identify novel genetic susceptibility targets for ARDS to focus further investigation on their biological mechanism and therapeutic potential.

Methods: Meta-analyses of ARDS genome-wide association studies were performed with 1250 cases and 1583 controls in Europeans, and 387 cases and 387 controls in African Americans. The functionality of novel loci was determined in silico using multiple omics approaches. The causality of 114 factors potentially involved in ARDS development was assessed using Mendelian Randomization analysis.

Results: There was distinct genetic heterogeneity in ARDS between Europeans and African Americans. rs7967111 at 12p13.2 was functionally associated with ARDS susceptibility in Europeans (odds ratio = 1.38; P = 2.15 × 10). Expression of two genes annotated at this locus, BORCS5 and DUSP16, was dynamic but ultimately decreased during ARDS development, as well as downregulated in immune cells alongside COVID-19 severity. Causal inference implied that comorbidity of inflammatory bowel disease and elevated levels of C-reactive protein and interleukin-10 causally increased ARDS risk, while vitamin D supplementation and vasodilator use ameliorated risk.

Conclusion: Our findings suggest a novel susceptibility locus in ARDS pathophysiology that implicates BORCS5 and DUSP16 as potentially acting in immune-inflammatory processes. This locus warrants further investigation to inform the development of therapeutic targets and clinical care strategies for ARDS, including those induced by COVID-19.
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http://dx.doi.org/10.1007/s00134-021-06410-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144871PMC
July 2021
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