Publications by authors named "Min Huang"

1,191 Publications

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Randomized Trial of Different initial IVIG Regimens in Kawasaki Disease.

Pediatr Int 2021 Feb 18. Epub 2021 Feb 18.

Pediatric Heart Center, Children's Hospital of Fudan University, Shanghai, China.

Background: We aimed to assess the efficacy of different initial intravenous immunoglobulin (IVIG) regimens in Kawasaki disease (KD) patients to find more cost-effective therapy options.

Methods: A multicentre, open-label, blind-endpoint randomized controlled trial was conducted from January 2014 to December 2015. KD Patients within 10 days of illness were randomly assigned to receive different IVIG regimens (Group A, 2 g/kg once; Group B, 1 g/kg for 2 consecutive days; Group C, 1 g/kg once) and aspirin 30mg/kg/d. Primary outcomes included hours to defervescence and development of coronary artery lesions (CAL) during the study period. Major secondary outcomes included total fever days, total dose of IVIG, changes of laboratory data, length of stay, and hospitalization expenses. (ClinicalTrials.gov: NCT02439996).

Results: A total of 404 patients underwent randomization. No difference was found in the outcomes of defervescence among three groups at 6, 12, 24, and 36 hours after completion of initial IVIG infusion. There were no differences in the incidence of CAL during the study period (at week 2, month 1, month 3, and month 6 of illness), changes of laboratory data, total fever days and length of stay. Group C patients had the lowest total dose of IVIG (mean: 1.2 vs 2.2 vs 2.1 g/kg; P<0.001) and hospitalization expenses (mean: 8443.8 vs 10798.4 vs 11011.4 RMB; P<0.001) than other two groups.

Conclusions: A single dose of 1g/kg IVIG is a low-cost treatment with the same efficacy as 2 g/kg IVIG and can be an option for the initial therapy of KD patients.
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http://dx.doi.org/10.1111/ped.14656DOI Listing
February 2021

PATZ1 (MAZR) Co-occupies Genomic Sites With p53 and Inhibits Liver Cancer Cell Proliferation via Regulating p27.

Front Cell Dev Biol 2021 1;9:586150. Epub 2021 Feb 1.

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1/MAZR) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial largely due to lack of genome-wide studies. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma cells. Our PATZ1 ChIP-seq and gene expression microarray analyses revealed that PATZ1 is strongly related to cancer signatures and cellular proliferation. We further discovered that PATZ1 depletion led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Importantly, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, we found that PATZ1 binds to the genomic loci flanking the transcriptional start site of and positively regulates its transcription. Notably, we demonstrated that PATZ1 is a p53 partner and p53 is essential for CDKN1B regulation. In conclusion, our study provides novel mechanistic insights into the inhibitory role of PATZ1 in liver cancer progression, thereby yielding a promising therapeutic intervention to alleviate tumor burden.
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http://dx.doi.org/10.3389/fcell.2021.586150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882738PMC
February 2021

Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes.

Proc Natl Acad Sci U S A 2021 Feb;118(8)

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

In this study, we utilized a panel of human immunoglobulin (Ig) IgA monoclonal antibodies isolated from the plasmablasts of eight donors after 2014/2015 influenza virus vaccination (Fluarix) to study the binding and functional specificities of this isotype. In this cohort, isolated IgA monoclonal antibodies were primarily elicited against the hemagglutinin protein of the H1N1 component of the vaccine. To compare effector functionalities, an H1-specific subset of antibodies targeting distinct epitopes were expressed as monomeric, dimeric, or secretory IgA, as well as in an IgG1 backbone. When expressed with an IgG Fc domain, all antibodies elicited Fc-effector activity in a primary polymorphonuclear cell-based assay which differs from previous observations that found only stalk-specific antibodies activate the low-affinity FcγRIIIa. However, when expressed with IgA Fc domains, only antibodies targeting the stalk domain showed Fc-effector activity in line with these previous findings. To identify the cause of this discrepancy, we then confirmed that IgG signaling through the high-affinity FcγI receptor was not restricted to stalk epitopes. Since no corresponding high-affinity Fcα receptor exists, the IgA repertoire may therefore be limited to stalk-specific epitopes in the context of Fc receptor signaling.
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http://dx.doi.org/10.1073/pnas.2018102118DOI Listing
February 2021

Discovery of Novel Pyrrolo[2,3-]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors.

J Med Chem 2021 Feb 15. Epub 2021 Feb 15.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.

It remains a big challenge to develop HDAC inhibitors effective for solid tumors. Previous studies have suggested that the feedback activation of JAK-STAT3 pathway represents a key mechanism leading to resistance to HDAC inhibitors in breast cancer, suggesting the therapeutic promise of JAK/HDAC dual inhibitors. In this work, we discovered a series of pyrrolo[2,3-]pyrimidine-based derivatives as potent JAK and HDAC dual inhibitors. Especially, compounds and potently inhibited JAK1/2/3 and HDAC1/6 and displayed antiproliferative and proapoptotic activities in triple-negative breast cancer cell lines. Besides, compounds and also diminished the activation of LIFR-JAK-STAT signaling triggered by tumor-associated fibroblasts, which suggests that these compounds could potentially overcome the drug resistance caused by the tumor microenvironment. More importantly, compound effectively inhibited the tumor growth in MDA-MB-231 xenograft tumor model. Overall, this work provides valuable leads and novel antitumor mechanisms for the treatment of the SAHA-resistant triple-negative breast cancers.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02111DOI Listing
February 2021

Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation.

Front Cell Neurosci 2020 11;14:540669. Epub 2021 Jan 11.

Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Ischemic cerebral infarction represents a significant cause of disability and death worldwide. Caspase-1 is activated by the NLRP3/ASC pathway and inflammasomes, thus triggering pyroptosis, a programmed cell death. In particular, this death is mediated by gasdermin D (GSDMD), which induces secretion of interleukin (IL)-1β and IL-18. Accordingly, inhibition of caspase-1 prevents the development and worsening of multiple neurodegenerative diseases. However, it is not clear whether inhibition of caspase-1 can preserve blood-brain barrier (BBB) integrity following cerebral infarction. This study therefore aimed at understanding the effect of caspase-1 on BBB dysfunction and its underlying mechanisms in permanent middle cerebral artery occlusion (MCAO). Our findings in rat models revealed that expression of caspase-1 was upregulated following MCAO-induced injury in rats. Consequently, pharmacologic inhibition of caspase-1 using vx-765 ameliorated ischemia-induced infarction, neurological deficits, and neuronal injury. Furthermore, inhibition of caspase-1 enhanced the encapsulation rate of pericytes at the ischemic edge, decreased leakage of both Evans Blue (EB) and matrix metalloproteinase (MMP) proteins, and upregulated the levels of tight junctions (TJs) and tissue inhibitors of metalloproteinases (TIMPs) in MCAO-injured rats. This in turn improved the permeability of the BBB. Meanwhile, vx-765 blocked the activation of ischemia-induced pyroptosis and reduced the expression level of inflammatory factors such as caspase-1, NLRP3, ASC, GSDMD, IL-1β, and IL-18. Similarly, vx-765 treatment significantly reduced the expression levels of inflammation-related receptor for advanced glycation end products (RAGE), high-mobility family box 1 (HMGB1), mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB). Evidently, inhibition of caspase-1 significantly improves ischemia-associated BBB permeability and integrity by suppressing pyroptosis activation and the RAGE/MAPK pathway.
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http://dx.doi.org/10.3389/fncel.2020.540669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874210PMC
January 2021

A chlorophyll a oxygenase 1 gene ZmCAO1 contributes to grain yield and waterlogging tolerance in maize.

J Exp Bot 2021 Feb 11. Epub 2021 Feb 11.

College of life science, Yangtze University, Jingzhou, Hubei, P.R.China.

Chlorophylls function in photosynthesis, and are critical to plant developmental processes and responses to environmental stimuli. Chlorophyll b is synthesized from chlorophyll a by chlorophyll a oxygenase (CAO). Here, we characterize a yellow-green leaf (ygl) mutant and identify the causal gene which encodes a chlorophyll a oxygenase in maize (ZmCAO1). A 51-bp Popin transposon inserts in ZmCAO1, and strongly disrupts its transcription. Low enzyme activity of ZmCAO1 leads to the reduction of contents of chlorophylls a and b and total chlorophylls, resulting in the yellow-green leaf phenotype of the ygl mutant. The net photosynthetic rate, stomatal conductance, and transpiration rate are decreased in the ygl mutant, while contents of δ-aminolevulinic acid (ALA), porphobilinogen (PBG) and protochlorophyllide (Pchlide) are increased. In addition, the zmcao1 mutation results in down-regulation of key photosynthetic genes, limits photosynthetic assimilation and reduces plant height, ear size, kernel weight and grain yield. Furthermore, zmcao1 enhances reactive oxygen species production leading to sensitivity to waterlogging. These results demonstrate the pleiotropy of ZmCAO1 in photosynthesis, grain yield and waterlogging tolerance in maize.
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http://dx.doi.org/10.1093/jxb/erab059DOI Listing
February 2021

Microglial TLR4-induced TAK1 phosphorylation and NLRP3 activation mediates neuroinflammation and contributes to chronic morphine-induced antinociceptive tolerance.

Pharmacol Res 2021 Feb 5:105482. Epub 2021 Feb 5.

Department of Anesthesiology, Tongzhou People's Hospital, Nantong 226300, China; Department of Anesthesiology and Pain Clinic, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai 200233, China. Electronic address:

Background And Purpose: The aim of this work was to investigate the role and signal transduction of toll-like receptor 4 (TLR4), TGF-β-activated kinase 1 (TAK1) and nod-like receptor protein 3 (NLRP3) in microglial in the development of morphine-induced antinociceptive tolerance.

Methods: TLR4 and NLRP3 knockout mice and 5Z-7-oxozeaeno (a selective inhibitor against TAK1 activity) were used to observe their effect on the development of morphine tolerance. Intrathecal injections of morphine (0.75 mg/kg once daily for 7 days) were used to establish anti-nociceptive tolerance, which was measured by the tail-flick test. Spinal TLR4, TAK1, and NLRP3 expression levels and phosphorylation of TAK1 were evaluated by Western blotting and immunofluorescence.

Results: Repeated treatment with morphine increased total expression of spinal TLR4, TAK1, and NLRP3 and phosphorylation of TAK1 in wild-type mice. TLR4 knockout attenuated morphine-induced tolerance and inhibited the chronic morphine-induced increase in NLRP3 and phosphorylation of TAK1. Compared with controls, mice that received 5Z-7-oxozeaenol showed decreased development of morphine tolerance and inhibition on repeated morphine-induced increase of NLRP3 but not TLR4. NLRP3 knockout mice showed resistance to morphine-induced analgesic tolerance with no effect on chronic morphine-induced expression of TLR4 and TAK1. TLR4, TAK1, and NLRP3 were collectively co-localized together and with the microglia marker Iba1.

Conclusions: Microglial TLR4 regulates TAK1 expression and phosphorylation and results in NLRP3 activation contributes to the development of morphine tolerance through regulating neuroinflammation. Targeting TLR4-TAK1-NLRP3 signaling to regulate neuro-inflammation will be alternative therapeutics and strategies for chronic morphine-induced antinociceptive tolerance.
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http://dx.doi.org/10.1016/j.phrs.2021.105482DOI Listing
February 2021

[A cross-sectional survey of attention and knowledge level among dental students in Jiangxi province during the epidemic period of COVID-19].

Shanghai Kou Qiang Yi Xue 2020 Oct;29(5):544-549

Affiliated Stomatological Hospital of Nanchang University, Jiangxi Province Key Laboratory of Oral Biology Medicine. Nanchang 330006, China.

Purpose: To investigate the level of attention and knowledge level of dental students in Jiangxi province during the epidemic period of COVID-19, and provide data support for optimizing the training program of dental professionals in the future.

Methods: Two thousand and sixty-five valid questionnaires were collected from stomatological colleges in Jiangxi province through internet. SPSS 20.0 software was used for statistical analysis, Chi-square test and binary logistic regression were used for single factor and multi factor analysis.

Results: According to the survey, 74.72% of dental students expressed their concern about the epidemic situation, and 75.93% expressed that they checked the number of confirmed cases in China once or more every day. Students with higher education background, licensed doctor certificate and better family status paid more attention to the epidemic period and frequently checked the information(P<0.05). The categories of information most concerned by all respondents was data such as the number of newly diagnosed patients and the number of cured cases, followed by the diagnosis and treatment of patients with COVID-19.The average score of knowledge about epidemic situation was 5.60±1.88. Analysis of influencing factors showed that the knowledge level of women was higher than that of men(OR=1.371,95%CI:1.143-1.644).Medical students from Hubei province had a good level of knowledge, high education, party members, and students with medical qualifications had a high level of knowledge about epidemic situation of COVID-19(P<0.05).

Conclusions: The epidemic period of COVID-19 is a high concern among dental students in Jiangxi province , and the awareness rate of related knowledge is low. In order to improve the quality of dental personnel training, the medical colleges or school should strengthen the training of students' operations in the hospital, and add relevant courses of public health emergency in the training program.
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October 2020

SIRT6 as a key event linking P53 and NRF2 counteracts APAP-induced hepatotoxicity through inhibiting oxidative stress and promoting hepatocyte proliferation.

Acta Pharm Sin B 2021 Jan 4;11(1):89-99. Epub 2020 Jul 4.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration. Sirtuin 6 (SIRT6) has been reported to protect against oxidative stress-associated DNA damage. But whether SIRT6 regulates APAP-induced hepatotoxicity remains unclear. In this study, the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment, respectively. knockdown in AML12 cells aggravated APAP-induced hepatocyte death and oxidative stress, inhibited cell viability and proliferation, and downregulated CCNA1, CCND1 and CKD4 protein levels. knockdown significantly prevented APAP-induced NRF2 activation, reduced the transcriptional activities of and and the mRNA levels of , , and . Furthermore, SIRT6 showed potential protein interaction with NRF2 as evidenced by co-immunoprecipitation (Co-IP) assay. Additionally, the protective effect of P53 against APAP-induced hepatocytes injury was -dependent. The mRNA was significantly down-regulated in mice. activated the transcriptional activity of and exerted interaction with SIRT6. Our results demonstrate that SIRT6 protects against APAP hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation, and provide new insights in the function of SIRT6 as a crucial docking molecule linking P53 and NRF2.
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http://dx.doi.org/10.1016/j.apsb.2020.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838028PMC
January 2021

Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome.

Genet Med 2021 Feb 2. Epub 2021 Feb 2.

Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Purpose: Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS.

Methods: Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants.

Results: We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants.

Conclusion: IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.
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http://dx.doi.org/10.1038/s41436-021-01106-zDOI Listing
February 2021

Water loss and status in sponge cake: Impact of Eucheuma as a flour replacement.

J Food Sci 2021 Feb 2. Epub 2021 Feb 2.

Department of Food Science & Technology, National University of Singapore, Singapore, 117542, Singapore.

The impact of Eucheuma on water loss and status in sponge cakes was measured and analyzed in this study. Eucheuma was used to replace 0%, 10%, and 20% of wheat flour to make sponge cakes, coded as the control, EP10, and EP20, respectively. The initial water content of batters showed no significant differences (around 57.0%, dry basis), whereas the final EP10 and EP20 products had higher water content. Three stages were found during baking in control sample and these three stages were fitted by linear, linear, and exponential models with root mean squared error (RMSE) of 0.016, 0.018, and 0.133, respectively. Eucheuma addition decreased the water loss rate and changed the water loss stages, which were fitted by linear, linear, and linear models in EP20 sample (RMSE = 0.027, 0.047, and 0.108, respectively). The crust formation and crumb structure analysis showed that the formation of cracks and the disappearance of pore structures hindered the water evaporation. The low-field proton nuclear magnetic resonance and magnetic resonance imaging results showed that the water status in the final EP20 products was not as tightly as that in the control samples. A proposed schematic diagram was developed based on the qualitative analysis of the transfer mechanisms to explain the total effect of Eucheuma on the water loss rate and status. These results aid our understanding of the water loss process of sponge cakes and promote the potential application of Eucheuma in bakery products. PRACTICAL APPLICATION: Eucheuma as a flour replacement can improve the contents of dietary fiber and minerals like potassium of sponge cake. The impact of Eucheuma on water loss and status in sponge cake was measured and analyzed in this study. The results can promote the potential application of Eucheuma in bakery products and predict the quality attributes of baking products.
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http://dx.doi.org/10.1111/1750-3841.15609DOI Listing
February 2021

Association of leptin and adiponectin levels with endometriosis: a systematic review and meta-analysis.

Gynecol Endocrinol 2021 Jan 27:1-9. Epub 2021 Jan 27.

Department of General Practice, Suzhou Municipal Hospital, Suzhou, China.

Background: We aimed to summarize the available data regarding the levels of leptin and adiponectin and the key modulators of endometriosis compared to the controls.

Methods: The electronic databases such as MEDLINE, Embase, Scopus, Cochrane Library, and Web of Science were searched up to October 2020. The circulating and peritoneal levels of leptin and circulating levels of adiponectin were included. We used the Cochrane's Q test and the statistic in this study. These tests' weighted mean difference (WMD) and 95% CIs were considered as the summary effect size. They were then pooled using a random-effects model with the DerSimonian-Laird method.

Results: Twenty eligible articles (or 25 studies) with 2645 participants (1362 women with endometriosis and 1283 controls) were included. Pooled results showed that women with endometriosis had significantly higher leptin levels (WMD = 4.45 mg/ml, 95%CI = 2.42-6.49,  < .01) and leptin/BMI ratio (WMD = 0.32 mg/ml, 95%CI = 0.23-0.42,  < .001) than the controls, whereas adiponectin levels (WMD = -0.24 mg/ml, 95%CI = -4.27 to -0.01,  = .038) were significantly lower. The pooled results also indicated significantly lower leptin levels in women with advanced-stage endometriosis (WMD = -8.07 mg/ml, 95%CI = -14.22 to -1.92,  = .01) than in the early stage. It was found, however, that there were no significant differences in adiponectin levels of women with advanced-stage endometriosis (WMD = -0.16 mg/ml, 95%CI = -0.64 to 0.32,  = .512) and the early-stage ones.

Conclusion: We showed that leptin levels and leptin/BMI ratio were significantly higher in women with endometriosis than the controls. Nonetheless, patients with endometriosis had significantly lower levels of adiponectin than the controls.
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http://dx.doi.org/10.1080/09513590.2021.1878139DOI Listing
January 2021

An Adaptive Localized Decision Variable Analysis Approach to Large-Scale Multiobjective and Many-Objective Optimization.

IEEE Trans Cybern 2021 Jan 21;PP. Epub 2021 Jan 21.

This article proposes an adaptive localized decision variable analysis approach under the decomposition-based framework to solve the large-scale multiobjective and many-objective optimization problems (MaOPs). Its main idea is to incorporate the guidance of reference vectors into the control variable analysis and optimize the decision variables using an adaptive strategy. Especially, in the control variable analysis, for each search direction, the convergence relevance degree of each decision variable is measured by a projection-based detection method. In the decision variable optimization, the grouped decision variables are optimized with an adaptive scalarization strategy, which is able to adaptively balance the convergence and diversity of the solutions in the objective space. The proposed algorithm is evaluated with a suite of test problems with 2-10 objectives and 200-1000 variables. Experimental results validate the effectiveness and efficiency of the proposed algorithm on the large-scale multiobjective and MaOPs.
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http://dx.doi.org/10.1109/TCYB.2020.3041212DOI Listing
January 2021

Application of a new drainage plug for large mandibular cysts after fenestration decompression.

Ann Palliat Med 2021 Jan 18;10(1):590-596. Epub 2021 Jan 18.

Department of Prosthodontics, The Affiliated Stomatological Hospital of Nanchang University, Nanchang, China; The Key Laboratory of Oral Biomedicine, Nanchang, China. Email:

Background: In order to improve the postoperative decompression and drainage of large mandibular cysts after fenestration decompression, a new drainage plug was designed and its feasibility for clinical application was explored.

Methods: A total of 74 patients with large mandibular cysts requiring fenestration decompression were included and randomly divided into the control group (n=34) and model group (n=40). Patients in the control group were given a conventional plug, while patients in the model group were given the new silicone drainage plug. The drainage plug mold was printed using 3D printing technology. Subsequently, the mold was filled with silicone material and the drainage tube was placed into the mold to make a drainage plug. The clinical effect of the new drainage plug was assessed, and the postoperative recovery time was compared between the 2 groups.

Results: In the model group, the average wear time of the new drainage plug was approximately 13 months. Compared with the control group, the course of treatment in the model group was shortened by approximately 5 months, with a better fit, less food debris, and easier installation and removal.

Conclusions: The new drainage plug provides more convenience and better prognosis for patients after fenestration decompression, and holds great promise for clinical application.
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http://dx.doi.org/10.21037/apm-20-2464DOI Listing
January 2021

SARS-CoV-2 Infection Severity Is Linked to Superior Humoral Immunity against the Spike.

mBio 2021 01 19;12(1). Epub 2021 Jan 19.

Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, Illinois, USA

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity of the antibody response mounted against this novel virus is not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and nonstructural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection exhibit a greater overall antibody response to the spike and nucleocapsid protein and a larger memory B cell response against the spike. With the ongoing pandemic, it is critical to understand how natural immunity against SARS-CoV-2 and COVID-19 develops. We have identified that subjects with more severe COVID-19 disease mount a more robust and neutralizing antibody response against SARS-CoV-2 spike protein. Subjects who mounted a larger response against the spike also mounted antibody responses against other viral antigens, including the nucleocapsid protein and ORF8. Additionally, this study reveals that subjects with more severe disease mount a larger memory B cell response against the spike. These data suggest that subjects with more severe COVID-19 disease are likely better protected from reinfection with SARS-CoV-2.
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http://dx.doi.org/10.1128/mBio.02940-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845638PMC
January 2021

Paraquat-activated BV-2 microglia induces neuroinflammatory responses in the neuron model through NF-κB signaling pathway.

Toxicol In Vitro 2021 Apr 4;72:105076. Epub 2021 Jan 4.

Department of Occupational and Environmental Health, School of Public Health and Management, Ningxia Medical University, Yin Chuan, China. Electronic address:

Paraquat (PQ), a non-selective contact herbicide, has been generally accepted as one of the environmental neurotoxicants. Despite the direct evidence that PQ could induce inflammation responses in microglia, little is known about the effects of the inflammatory microglia on neurons. Thus in the present study, mouse primary cortical neurons and PC12 cells, widely-used in vitro neuron models for neurotoxicity research were applied to investigate the neuroinflammatory effects of PQ-activated microglia on neurons. We observed that the secretion levels of TNF-α and IL-6 in PC12 cells were markedly increased upon treatment with the supernatants of inflammatory BV2 microglia, and NF-κB p65 protein expression was also elevated. Specific inhibition of NF-κB by PDTC dramatically attenuated the increase of TNF-α and IL-6 release. These results suggested that PQ-induced inflammatory microglia exerts secondary inflammatory effects on neurons through activation of NF-κB pathway.
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http://dx.doi.org/10.1016/j.tiv.2021.105076DOI Listing
April 2021

Selective exosome exclusion of miR-375 by glioma cells promotes glioma progression by activating the CTGF-EGFR pathway.

J Exp Clin Cancer Res 2021 Jan 6;40(1):16. Epub 2021 Jan 6.

The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.

Background: Exosomes are membrane-bound extracellular vesicles of 40-150 nm in size, that are produced by many cell types, and play an important role in the maintenance of cellular homeostasis. Exosome secretion allows for the selective removal of harmful substances from cells. However, it remains unclear whether this process also takes place in glioma cells.

Methods: Herein, the role of the tumour-suppressor miR-375 was explored in human glioma cells. Immunoblotting and qRT-PCR experiments demonstrated a functional link between miR-375 and its target, connective tissue growth factor (CTGF), which led to the identification of the underlying molecular pathways. The exosomes secreted by glioma cells were extracted by ultracentrifugation and examined by transmission electron microscopy. Exosomal expression of miR-375 was then analysed by qRT-PCR; while the exosome secretion inhibitor, GW4869, was used to examine the biological significance of miR-375 release. Moreover, the dynamics of miR-375 release by glioma cells was investigated using fluorescently labelled exosomes. Finally, exosomal miR-375 release was examined in an orthotopic xenograft model in nude mice.

Results: MiR-375 expression was downregulated in gliomas. MiR-375 suppressed glioma proliferation, migration, and invasion by inhibiting the CTGF-epidermal growth factor receptor (EGFR) signalling pathway. MiR-375-containing exosomes were also identified in human peripheral blood samples from glioma patients, and their level correlated with disease progression status. Exosomal miR-375 secretion impacted the CTGF-EGFR pathway activity. Once secreted, exosomal miR-375 was not taken back up by glioma cells.

Conclusions: Exosomal miR-375 secretion allowed for sustained activation of the CTGF-EGFR oncogenic pathway, promoting the proliferation and invasion of glioma cells. These findings enhance our understanding of exosome biology and may inspire development of new glioma therapies.
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http://dx.doi.org/10.1186/s13046-020-01810-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789663PMC
January 2021

Natural Products in Cancer Therapy: Past, Present and Future.

Nat Prod Bioprospect 2021 Jan 3. Epub 2021 Jan 3.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Natural products, with remarkable chemical diversity, have been extensively investigated for their anticancer potential for more than a half-century. The collective efforts of the community have achieved the tremendous advancements, bringing natural products to clinical use and discovering new therapeutic opportunities, yet the challenges remain ahead. With remarkable changes in the landscape of cancer therapy and growing role of cutting-edge technologies, we may have come to a crossroads to revisit the strategies to understand nature products and to explore their therapeutic utility. This review summarizes the key advancements in nature product-centered cancer research and calls for the implementation of systematic approaches, new pharmacological models, and exploration of emerging directions to revitalize natural products search in cancer therapy.
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http://dx.doi.org/10.1007/s13659-020-00293-7DOI Listing
January 2021

Lipidomic profiling reveals triacylglycerol accumulation in the liver during pregnane X receptor activation-induced hepatomegaly.

J Pharm Biomed Anal 2021 Feb 17;195:113851. Epub 2020 Dec 17.

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China. Electronic address:

Pregnane X receptor (PXR) is highly expressed in the liver and plays an integral role in the control of xenobiotic and endobiotic metabolism to maintain homeostasis. We previously reported that activation of PXR significantly induced liver enlargement. But the lipid profiling during PXR-induced hepatomegaly remains unclear. This study aimed to characterize the effect of PXR activation on hepatic lipid homeostasis by lipidomics analysis. Mice were intraperitoneally administered with the typical mPXR agonist, pregnenolone 16α-carbonitrile (PCN, 100 mg/kg/d), for 5 days. Liver and serum were collected for further analysis. The results confirmed that PXR activation can significantly induce liver enlargement. An obvious hepatic lipid accumulation was observed in PCN-treated mice, as determined by H&E and Oil Red O staining. Ultra-high performance liquid chromatography-Q Exactive Orbitrap high-resolution mass spectrometer (UHPLC-Q Exactive Orbitrap HRMS)-based lipidomics was performed to characterize the change in lipid species. A total of 20 potential lipid biomarkers were significantly perturbed. The most significant change was found in the triacylglycerol (TG), which constituted with the lower number of carbon atoms and double bonds. Moreover, the mRNA expression levels showed that PCN-induced PXR activation significantly regulated the expression of genes involved in the uptake, synthesis and metabolism of TG, which was consistent with increased TG levels. Collectively, these findings demonstrated that lipids such as TG were significantly accumulated during PXR-induced hepatomegaly.
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http://dx.doi.org/10.1016/j.jpba.2020.113851DOI Listing
February 2021

Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients.

J Cancer Res Clin Oncol 2021 Mar 2;147(3):725-737. Epub 2021 Jan 2.

Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China.

Purpose: Crizotinib is the first-line small molecule tyrosine kinase inhibitor for ALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity in ALK-positive NSCLC patients.

Methods: The variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing of HGFR (c-Met) genes was carried out on the Ion Torrent Proton.

Results: In total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKT pathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406-32.24, P = 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219-24.81, P = 0.027) for STAT1 rs10208033 CC genotype to develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib.

Conclusion: Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.
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http://dx.doi.org/10.1007/s00432-020-03476-4DOI Listing
March 2021

Prediction for Intravenous Immunoglobulin Resistance Combining Genetic Risk Loci Identified From Next Generation Sequencing and Laboratory Data in Kawasaki Disease.

Front Pediatr 2020 4;8:462367. Epub 2020 Dec 4.

Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.

Kawasaki disease (KD) is the most common cause of acquired heart disease. A proportion of patients were resistant to intravenous immunoglobulin (IVIG), the primary treatment of KD, and the mechanism of IVIG resistance remains unclear. The accuracy of current models predictive of IVIG resistance is insufficient and doesn't meet the clinical expectations. To develop a scoring model predicting IVIG resistance of patients with KD. We recruited 330 KD patients (50 IVIG non-responders, 280 IVIG responders) and 105 healthy children to explore the susceptibility loci of IVIG resistance in Kawasaki disease. A next generation sequencing technology that focused on 4 immune-related pathways and 472 single nucleotide polymorphisms (SNPs) was performed. An R package SNPassoc was used to identify the risk loci, and student's -test was used to identify risk factors associated with IVIG resistance. A random forest-based scoring model of IVIG resistance was built based on the identified specific SNP loci with the laboratory data. A total of 544 significant risk loci were found associated with IVIG resistance, including 27 previous published SNPs. Laboratory test variables, including erythrocyte sedimentation rate (ESR), platelet (PLT), and C reactive protein, were found significantly different between IVIG responders and non-responders. A scoring model was built using the top 9 SNPs and clinical features achieving an area under the ROC curve of 0.974. It is the first study that focused on immune system in KD using high-throughput sequencing technology. Our findings provided a prediction of the IVIG resistance by integrating the genotype and clinical variables. It also suggested a new perspective on the pathogenesis of IVIG resistance.
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http://dx.doi.org/10.3389/fped.2020.462367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746618PMC
December 2020

Five new species of the leafhopper genus Limassolla Dlabola (Hemiptera: Cicadellidae: Typhlocybinae).

Zootaxa 2020 Nov 16;4878(3):zootaxa.4878.3.7. Epub 2020 Nov 16.

Key Laboratory of Plant Protection Resources and Pest Management of Ministry of Education, Entomological Museum, Northwest AF University, Yangling, Shaanxi Province, 712100, China.

Five new species of the leafhopper genus Limassolla Dlabola, Limassolla bicruralis, L. kunyica, L. uncata, L. nigropunctata, L. spinulata spp. nov., are described and illustrated and a key to separate males of those species is provided.
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http://dx.doi.org/10.11646/zootaxa.4878.3.7DOI Listing
November 2020

Clinical features and risk factors in patients with acute myocardial infarction in different age groups.

Panminerva Med 2020 Dec 14. Epub 2020 Dec 14.

Department of Cardiovascular Medicine, Gongan County People's Hospital, Jingzhou, China -

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http://dx.doi.org/10.23736/S0031-0808.20.04181-6DOI Listing
December 2020

Comparison Between SonoVue and Sonazoid Contrast-Enhanced Ultrasound in Characterization of Focal Nodular Hyperplasia Smaller Than 3 cm.

J Ultrasound Med 2020 Dec 11. Epub 2020 Dec 11.

Department of Ultrasound, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Objectives: This study aimed to compare the diagnostic efficacy of contrast-enhanced ultrasound (CEUS), including SonoVue (SV; sulfur hexafluoride; Bracco SpA, Milan, Italy) and Sonazoid (SZ; perflubutane; GE Healthcare, Oslo, Norway), and explore the differences between them in the characterization of CEUS features in focal nodular hyperplasia (FNH) smaller than 3 cm.

Methods: This retrospective study included 31 lesions smaller than 3 cm diagnosed as FNH by CEUS between April 2019 and November 2019. Nine patients underwent SZ CEUS examinations, and 22 patients underwent SV CEUS examinations; all of them were confirmed by pathologic examinations or 2 other kinds of CEUS methods. We compared the CEUS features between SZ and SV in different phases, including arterial, portal venous, delayed, and Kupffer (SZ) phases.

Results: Twenty-eight lesions were eventually diagnosed as FNH; 3 were misdiagnosed as FNH by SV CEUS. The overall diagnostic accuracy of CEUS including SZ and SV was 90.3% (28 of 31). No significant difference was found (P > .05) for the positive predictive value. Likewise, no significant difference in depicting centrifugal filling (9 of 9 versus 19 of 19), spoke wheel artery (6 of 9 versus 8 of 19), or feeding artery (2 of 9 versus 10 of 19) features was found between the contrast agents; However, SZ was significantly better at depicting the presence of a central scar than SV (5 of 9 versus 3 of 19; P = .030). Misdiagnosed cases are discussed in detail.

Conclusions: Contrast-enhanced ultrasound enables an accurate diagnosis in FNH smaller than 3 cm. Sonazoid CEUS and SV CEUS were comparable in diagnosing small FNH, and both agents were highly capable of depicting the centrifugal filling dynamic process of FNH smaller than 3 cm. Sonazoid CEUS might be better than SV CEUS at depicting a central scar.
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http://dx.doi.org/10.1002/jum.15589DOI Listing
December 2020

Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans.

Sci Transl Med 2020 12;12(573)

Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.

Humans are repeatedly exposed to variants of influenza virus throughout their lifetime. As a result, preexisting influenza-specific memory B cells can dominate the response after infection or vaccination. Memory B cells recalled by adulthood exposure are largely reactive to conserved viral epitopes present in childhood strains, posing unclear consequences on the ability of B cells to adapt to and neutralize newly emerged strains. We sought to investigate the impact of preexisting immunity on generation of protective antibody responses to conserved viral epitopes upon influenza virus infection and vaccination in humans. We accomplished this by characterizing monoclonal antibodies (mAbs) from plasmablasts, which are predominantly derived from preexisting memory B cells. We found that, whereas some influenza infection-induced mAbs bound conserved and neutralizing epitopes on the hemagglutinin (HA) stalk domain or neuraminidase, most of the mAbs elicited by infection targeted non-neutralizing epitopes on nucleoprotein and other unknown antigens. Furthermore, most infection-induced mAbs had equal or stronger affinity to childhood strains, indicating recall of memory B cells from childhood exposures. Vaccination-induced mAbs were similarly induced from past exposures and exhibited substantial breadth of viral binding, although, in contrast to infection-induced mAbs, they targeted neutralizing HA head epitopes. Last, cocktails of infection-induced mAbs displayed reduced protective ability in mice compared to vaccination-induced mAbs. These findings reveal that both preexisting immunity and exposure type shape protective antibody responses to conserved influenza virus epitopes in humans. Natural infection largely recalls cross-reactive memory B cells against non-neutralizing epitopes, whereas vaccination harnesses preexisting immunity to target protective HA epitopes.
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http://dx.doi.org/10.1126/scitranslmed.abd3601DOI Listing
December 2020

A Gaussian-Distributed Quantum Random Number Generator Using Vacuum Shot Noise.

Entropy (Basel) 2020 Jun 2;22(6). Epub 2020 Jun 2.

Department of Electronics, and Center for Quantum Information Technology, State Key Laboratory of Advanced Optical Communication Systems and Networks, Peking University, Beijing 100871, China.

Among all the methods of extracting randomness, quantum random number generators are promising for their genuine randomness. However, existing quantum random number generator schemes aim at generating sequences with a uniform distribution, which may not meet the requirements of specific applications such as a continuous-variable quantum key distribution system. In this paper, we demonstrate a practical quantum random number generation scheme directly generating Gaussian distributed random sequences based on measuring vacuum shot noise. Particularly, the impact of the sampling device in the practical system is analyzed. Furthermore, a related post-processing method, which maintains the fine distribution and autocorrelation properties of raw data, is exploited to extend the precision of generated Gaussian distributed random numbers to over 20 bits, making the sequences possible to be utilized by the following system with requiring high precision numbers. Finally, the results of normality and randomness tests prove that the generated sequences satisfy Gaussian distribution and can pass the randomness testing well.
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http://dx.doi.org/10.3390/e22060618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517154PMC
June 2020

CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells.

Signal Transduct Target Ther 2020 12 4;5(1):283. Epub 2020 Dec 4.

National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China.

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.
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http://dx.doi.org/10.1038/s41392-020-00426-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714896PMC
December 2020

Early triple-negative breast cancer in women aged ≥65: retrospective study of outcomes, resource use and costs, 2010-2016.

Future Oncol 2021 Mar 2;17(9):1039-1054. Epub 2020 Dec 2.

MRL, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

To examine real-world treatment patterns and outcomes in neoadjuvant and adjuvant settings for early-stage triple-negative breast cancer (TNBC). Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients (≥65 years) with newly diagnosed stage II/III TNBC in 2010-2015 who had surgery plus neoadjuvant and/or adjuvant (systemic and/or radiation) therapy. Treatment, survival, healthcare resource use and costs were assessed through 2016. Of 1569 patients (>99% women), 6%/74%/20% received neoadjuvant-only/adjuvant-only/both (neo + adj) therapies, respectively. Median overall survival was 23 months/not reached (NR)/78 months, with longer survival at stage II (NR/NR/78 months) than stage III (22/43/38 months). Mean per patient per month costs were $10,620 and $17,872 in neoadjuvant and adjuvant periods. These findings provide insights into clinical and economic outcomes for early-stage TNBC in 2010-2016.
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http://dx.doi.org/10.2217/fon-2020-0996DOI Listing
March 2021

A spatio-temporal noise map completion method based on crowd-sensing.

Environ Pollut 2021 Apr 19;274:115703. Epub 2020 Oct 19.

School of Software Engineering, South China University of Technology, Guangzhou, China.

The construction of noise maps is of great significance for the development of urban sustainability and the protection of residents' physical and mental health. The traditional noise map construction method is difficult to be widely used because of its low update frequency and high drawing cost. Based on the crowd-sensing technology and Latent Factor Model (LFM), this paper proposes a new noise map completion method called Spatial-Temporally Related LFM (STR-LFM) for solving the problem of data sparseness. First, the geographic information features including Point of Interest (POI), road network and building outline are fully excavated, and then combine the correlation of the samples in the time dimension to construct the similarity matrixes. After that, use the k-nearest neighbor algorithm to find out the similar samples of missing positions, and finally regard their weighted fusion as the predicted values. Experimental results show that the recovery error is lower than other commonly used methods, and the proposed method has better stability when faced with data sparseness problems at different levels.
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http://dx.doi.org/10.1016/j.envpol.2020.115703DOI Listing
April 2021