Publications by authors named "Ling Xie"

179 Publications

Impact of early protein provision on the mortality of acute critically ill stroke patients.

Nutr Clin Pract 2021 Sep 28. Epub 2021 Sep 28.

Neurology Department, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Background: Stroke is the leading cause of death in China, and dysphagia is a common symptom of stroke. For acute critically ill stroke patients, whether the protein provision overwhelming calorie provision impacts the outcome still requires investigation.

Materials And Methods: We conducted a retrospectively observational study. Acute stroke patients admitted to our neurocritical care unit between January 2013 and January 2017 were enrolled. Primary end points were short-term (30-day) and long-term (6-month) mortality, as well as long-term poor outcome with a modified Rankin scale score ≥4.

Results: Of 208 eligible patients, 127 (61.1%) patients were diagnosed with acute ischemic stroke and 81 (38.9%) with intracranial hemorrhage. In multivariate logistic regression analysis, the increased protein provision was significantly associated with reduced 30-day and 6-month mortality (P = .041 and P = .020, respectively) but not 6-month functional outcome (P = .365), whereas calorie provision had no independent association with either mortality or functional outcome. When the protein provision ≤1.74 g/kg/day, there was a 9.37% decrease in short-term mortality and a 9.21% decrease in long-term mortality with each 0.1 g/kg/day increase in protein delivery. The patients were further divided into five subgroups based on the amount of protein provision, and Linear-by-Linear Association tests showed there was a negative linear relationship between the protein provision and 30-day and 6-month mortality (P = .048 and P = .017, respectively).

Conclusions: Early protein provision during the first week is an independent predictor of short-term and long-term mortality in acute critically ill stroke patients.
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http://dx.doi.org/10.1002/ncp.10768DOI Listing
September 2021

Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders.

Nat Cancer 2021 Apr 1;2(4):429-443. Epub 2021 Mar 1.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York NY.

CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.
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http://dx.doi.org/10.1038/s43018-021-00174-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462800PMC
April 2021

Suppression of GOLM1 by EGCG through HGF/HGFR/AKT/GSK-3β/β-catenin/c-Myc signaling pathway inhibits cell migration of MDA-MB-231.

Food Chem Toxicol 2021 Sep 16;157:112574. Epub 2021 Sep 16.

State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, 200237, China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCICBT), Shanghai, 200237, China. Electronic address:

Golgi Membrane Protein 1 (GOLM1) has been identified as a prime target for cancer therapy because it overexpresses in many solid tumors, increases tumor growth and metastasis and leads to unfavorable survival. Though various approaches including siRNA interference and antibody targeting have been attempted, GOLM1 has remained an un-targetable molecule because of its mainly intracellular location and the lack of domains that could possibly be interfered with by small molecules. Numerous natural anti-tumoral plant substances have been identified, while their possible function on GOLM1 has never been revealed. This is the first report to study the relationship between GOLM1 downregulation and natural anti-tumoral plant substances and the possible mechanism. Among three tested possible migration-inhibiting natural substances (Epigallocatechin gallate (EGCG), Betulinic acid (BA) and Lupeol), EGCG showed the most potent inhibition effect on GOLM1 expression and MDA-MB-231 cell migration. Knocking down GOLM1 expression further increased the EGCG treatment effect. Molecular docking prediction and following experiments suggested that EGCG may inhibit GOLM1 expression and MDA-MB-231 cells migration through HGF/HGFR/AKT/GSK-3/β-catenin/c-Myc signaling pathway. In all, EGCG is the first identified GOLM1 downregulation natural product. Silencing GOLM1 may be a novel mechanism of potentiated anti-cancer migration effects and cytotoxic effect of EGCG. In addition, this study shed a new way for cancer therapy by combination of GOLM1 silencing and EGCG treatment in the future.
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http://dx.doi.org/10.1016/j.fct.2021.112574DOI Listing
September 2021

Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation.

J Am Chem Soc 2021 Sep 14;143(37):15073-15083. Epub 2021 Sep 14.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.
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http://dx.doi.org/10.1021/jacs.1c04841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480205PMC
September 2021

Functional role of miR‑155 in physiological and pathological processes of liver injury (Review).

Mol Med Rep 2021 10 13;24(4). Epub 2021 Aug 13.

Department of Emergency Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China.

There are several types of liver injury, including alcohol‑induced liver injury, drug‑induced liver injury, infectious liver injury, cirrhosis, liver ischemia/reperfusion injury and liver failure. In recent years, accumulated data have demonstrated that microRNAs (miRNAs/miRs) may be involved in the occurrence and development of a variety of systemic diseases, such as immune diseases, tumors and nervous system diseases. miR‑155 is a key miRNA, which has been studied extensively and has been shown to target different genes. In the present review, the potential effects and mechanisms of miR‑155 on the physiological and pathological processes of liver injury were reviewed from the perspective of cell stress, inflammation and activation of fibrosis. In addition, the potential benefits of miR‑155 as a therapeutic target and predictor of liver injury were summarized.
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http://dx.doi.org/10.3892/mmr.2021.12353DOI Listing
October 2021

The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism.

Front Physiol 2021 26;12:659211. Epub 2021 Jul 26.

Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China.

The orphan G protein-coupled receptor G2A has been linked to atherosclerosis development. However, available data from mouse models are controversial. Rat G2A receptor bears more similarities with its human homolog. We proposed that the atherosclerosis model established from rat, which has been reported to share more similar phenotypes with the human disease, may help to further understand this lipid receptor. G2A deletion was found markedly aggravated in the lipid disorder in the rat model, which has not been reported in mouse studies. Examination of aortas revealed exacerbated atherosclerotic plaques in G2A deficient rats, together with increased oxidative stress and macrophage accumulation. In addition, consistently promoted migration and apoptosis were noticed in G2A deficient macrophages, even in macrophages from G2A single knockout rats. Further analysis found significantly declined phosphorylation of PI3 kinase (PI3K) and AKT, together with reduced downstream genes Bcl2 and Bcl-xl, suggesting possible involvement of PI3K/AKT pathway in G2A regulation to macrophage apoptosis. These data indicate that G2A modulates atherosclerosis by regulating lipid metabolism and macrophage migration and apoptosis. Our study provides a new understanding of the role of G2A in atherosclerosis, supporting it as a potential therapeutic target.
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http://dx.doi.org/10.3389/fphys.2021.659211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351205PMC
July 2021

[The Clinical Characteristics and Influencing Factors of Patients with Severe COVID-19].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2021 Aug;29(4):1295-1300

Health Care Department, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan 430060, Hubei Province, China,E-mail:

Objective: To investigate the clinical characteristic of coagulation, possible causes and countermeasures of patients with severe corona virus disease 2019 (COVID-19).

Methods: The clinical data of the 142 patients diagnosed as COVID-19 at Wuhan Third Hospital in Wuhan, China, from February 10 to February 16, 2020 were collected and analyzed retrospective. Among the patients, 17 cases of dead patients were divided into observe group, and 125 cases of cured patients were divided into control group. The clinical characteristics, laboratory tests, influencing factors, anticoagulant therapy, embolization and bleeding events of the two groups were observed.

Results: The average hospital stay time in 142 patients was 22 d. For the 17 dead patients in the observe group, the average hospital stay time was 9.9 d, and the D-dimer, prothrombin time, WBC count and Padua score of the patients in the observe group were significantly higher as compared with the patients in the control group. PT(OR=1.064, 95%CI 1.012-1.119) and D-D(OR=1.045, 95%CI 1.027-1.064) were the independent risk factors that causing the death of COVID-19 patients. Among the patients, 36(25.4%) patients received low-molecular-weight heparin for anticoagulant therapy, with the average course of 9.6 d. The cumulative incidence of the embolism of the patients in the observe group was 7(41.2%), while 2(11.8%) patients developed to deep vein thrombosis (DVT) and pulmonary embolism (PE), 3 (17.6%) patients occurred acute cerebral infarction and 2 (11.8%) patients occurred acute myocardial infarction. 3 (17.6%) dead patients revealed dominant disseminated intravascular coagulation (DIC).

Conclusion: Most patients with severe COVID-19 shows a variety of risk factors for thrombus, and those with coagulation dysfunction shows a high dead rate and rapid disease progression. Therefore, coagulation indicators should be dynamically monitored, and mechanical and drug prevention should be actively carried out.
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http://dx.doi.org/10.19746/j.cnki.issn.1009-2137.2021.04.044DOI Listing
August 2021

Prediction of BRCA Gene Mutation in Breast Cancer Based on Deep Learning and Histopathology Images.

Front Genet 2021 20;12:661109. Epub 2021 Jul 20.

Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.

Background: Breast cancer is one of the most common cancers and the leading cause of death from cancer among women worldwide. The genetic predisposition to breast cancer may be associated with a mutation in particular genes such as gene BRCA1/2. Patients who carry a germline pathogenic mutation in BRCA1/2 genes have a significantly increased risk of developing breast cancer and might benefit from targeted therapy. However, genetic testing is time consuming and costly. This study aims to predict the risk of gBRCA mutation by using the whole-slide pathology features of breast cancer H&E stains and the patients' gBRCA mutation status.

Methods: In this study, we trained a deep convolutional neural network (CNN) of ResNet on whole-slide images (WSIs) to predict the gBRCA mutation in breast cancer. Since the dimensions are too large for slide-based training, we divided WSI into smaller tiles with the original resolution. The tile-based classification was then combined by adding the positive classification result to generate the combined slide-based accuracy. Models were trained based on the annotated tumor location and gBRCA mutation status labeled by a designated breast cancer pathologist. Four models were trained on tiles cropped at 5×, 10×, 20×, and 40× magnification, assuming that low magnification and high magnification may provide different levels of information for classification.

Results: A trained model was validated through an external dataset that contains 17 mutants and 47 wilds. In the external validation dataset, AUCs (95% CI) of DL models that used 40×, 20×, 10×, and 5× magnification tiles among all cases were 0.766 (0.763-0.769), 0.763 (0.758-0.769), 0.750 (0.738-0.761), and 0.551 (0.526-0.575), respectively, while the corresponding magnification slides among all cases were 0.774 (0.642-0.905), 0.804 (0.676-0.931), 0.828 (0.691-0.966), and 0.635 (0.471-0.798), respectively. The study also identified the influence of histological grade to the accuracy of the prediction.

Conclusion: In this paper, the combination of pathology and molecular omics was used to establish the gBRCA mutation risk prediction model, revealing the correlation between the whole-slide histopathological images and gRCA mutation risk. The results indicated that the prediction accuracy is likely to improve as the training data expand. The findings demonstrated that deep CNNs could be used to assist pathologists in the detection of gene mutation in breast cancer.
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http://dx.doi.org/10.3389/fgene.2021.661109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329536PMC
July 2021

Spatial-temporal heterogeneity and meteorological factors of hand-foot-and-mouth disease in Xinjiang, China from 2008 to 2016.

PLoS One 2021 2;16(8):e0255222. Epub 2021 Aug 2.

Faculty of Geographical Science, Beijing Normal University, Beijing, China.

The study aims to depict the temporal and spatial distributions of hand-foot-and-mouth disease (HFMD) in Xinjiang, China and reveal the relationships between the incidence of HFMD and meteorological factors in Xinjiang. With the national surveillance data of HFMD in Xinjiang and meteorological parameters in the study area from 2008 to 2016, in GeoDetector Model, we examined the effects of meteorological factors on the incidence of HFMD in Xinjiang, China, tested the spatial-temporal heterogeneity of HFMD risk, and explored the temporal-spatial patterns of HFMD through the spatial autocorrelation analysis. From 2008 to 2016, the HFMD distribution showed a distinct seasonal pattern and HFMD cases typically occurred from May to July and peaked in June in Xinjiang. Relative humidity, precipitation, barometric pressure and temperature had the more significant influences on the incidence of HFMD than other meteorological factors with the explanatory power of 0.30, 0.29, 0.29 and 0.21 (P<0.000). The interaction between any two meteorological factors had a nonlinear enhancement effect on the risk of HFMD. The relative risk in Northern Xinjiang was higher than that in Southern Xinjiang. Global spatial autocorrelation analysis results indicated a fluctuating trend over these years: the positive spatial dependency on the incidence of HFMD in 2008, 2010, 2012, 2014 and 2015, the negative spatial autocorrelation in 2009 and a random distribution pattern in 2011, 2013 and 2016. Our findings revealed the correlation between meteorological factors and the incidence of HFMD in Xinjiang. The correlation showed obvious spatiotemporal heterogeneity. The study provides the basis for the government to control HFMD based on meteorological information. The risk of HFMD can be predicted with appropriate meteorological factors for HFMD prevention and control.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255222PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328314PMC
August 2021

AKT degradation selectively inhibits the growth of PI3K/PTEN pathway mutant cancers with wild-type KRAS and BRAF by destabilizing Aurora kinase B.

Cancer Discov 2021 Jul 23. Epub 2021 Jul 23.

Oncological Sciences, Icahn School of Medicine at Mount Sinai

Using a panel of cancer cell lines, we characterized a novel degrader of AKT, MS21. In mutant PI3K/PTEN pathway lines, AKT degradation was superior to AKT kinase inhibition for reducing cell growth and sustaining lower signaling over many days. AKT degradation but not kinase inhibition profoundly lowered Aurora kinase B (AURKB) protein, which is known to be essential for cell division, and induced G2/M arrest and hyperploidy. PI3K activated AKT phosphorylation of AURKB on threonine 73, which protected it from proteasome degradation. A mutant of AURKB (T73E) that mimics phosphorylation and blocks degradation rescued cells from growth inhibition. Degrader resistant lines were associated with low AKT phosphorylation, wild type PI3K/PTEN status, and mutation of KRAS/BRAF. Pan-cancer analysis identified that 19% of cases have PI3K/PTEN pathway mutation without RAS pathway mutation, suggesting that these cancer patients could benefit from AKT degrader therapy that leads to loss of AURKB.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0815DOI Listing
July 2021

Relation of red cell distribution width with HAS-BLED score in patients with non-valvular atrial fibrillation.

J Thorac Dis 2021 May;13(5):3070-3075

The Affiliated Hospital 2 of Nantong University, Nantong, China.

Background: Numerous researchers have shown that there is a close correlation between red cell distribution width (RDW) and cardiovascular disease such as heart failure, coronary heart disease, and atrial fibrillation. This study was designated to investigate the correlation between RDW and the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol (HAS-BLED) score.

Methods: The HAS-BLED scores of 251 hospitalized patients with non-valvular atrial fibrillation were calculated and the receiver operating characteristics were used to evaluate the predictive value of RDW on high HAS-BLED score (≥3 scores). Multiple logistic regression analysis was used to analyze the independent predictor of high HAS-BLED scores.

Results: Correlation analysis between RDW and HAS-BLED scores showed the RDW was positively correlated with HAS-BLED score, with r=0.393 (P<0.0001). The RDW of the high HAS-BLED score group was higher than that of the no-high HAS-BLED score group. The area under the receiver operating characteristic curve of RDW was 0.796 (0.740-0.844, P<0.0001) to predict a high HAS-BLED score, and multiple logistic regression analysis showed that a high RDW value could be used as an independent predictor of high HAS-BLED.

Conclusions: RDW value is associated with HAS-BLED value, and can be used as the independent predictive factor of high HAS-BLED scores.
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http://dx.doi.org/10.21037/jtd-21-567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182543PMC
May 2021

Methyltransferase-like 3 contributes to inflammatory pain by targeting TET1 in YTHDF2-dependent manner.

Pain 2021 07;162(7):1960-1976

Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.

Abstract: The methyltransferase-like 3 (Mettl3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m6A) modification, which plays an important role in gene post-transcription modulation. Although RNA m6A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m6A level and m6A writer Mettl3 in the spinal cord. Mimicking this decease by knocking down or conditionally deleting spinal Mettl3 elevated the levels of m6A in ten-eleven translocation methylcytosine dioxygenases 1 (Tet1) mRNA and TET1 protein in the spinal cord, leading to production of pain hypersensitivity. By contrast, overexpressing Mettl3 reversed a loss of m6A in Tet1 mRNA and blocked the CFA-induced increase of TET1 in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m6A reader, stabilized upregulation of spinal TET1 because of the reduction of Tet1 mRNA decay by the binding to m6A in Tet1 mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.
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http://dx.doi.org/10.1097/j.pain.0000000000002218DOI Listing
July 2021

TF-PROTACs Enable Targeted Degradation of Transcription Factors.

J Am Chem Soc 2021 Jun 8;143(23):8902-8910. Epub 2021 Jun 8.

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.

Transcription factors (TFs) represent a major class of therapeutic targets for the treatment of human diseases including cancer. Although the biological functions and even crystal structures of many TFs have been clearly elucidated, there is still no viable approach to target the majority of TFs, thus rendering them undruggable for decades. PROTACs (proteolysis targeting chimeras) emerge as a powerful class of therapeutic modalities, which rely on induced protein-protein interactions between the proteins of interest (POIs) and E3 ubiquitin ligases to aid the degradation of POIs by the ubiquitin-proteasome system (UPS). Here, we report the development of a platform termed TF-PROTAC, which links an DNA oligonucleotide to an E3 ligase ligand via a click reaction, to selectively degrade the TF of interest. The selectivity of these TF-PROTACs depends on the DNA oligonucleotides utilized that can be specific to the TFs of interest. We have developed two series of VHL-based TF-PROTACs, NF-κB-PROTAC (dNF-κB) and E2F-PROTAC (dE2F), which effectively degrade endogenous p65 and E2F1 proteins in cells, respectively, and subsequently display superior antiproliferative effects in cells. Collectively, our results suggest that TF-PROTACs provide a generalizable platform to achieve selective degradation of TFs and a universal strategy for targeting most "undruggable" TFs.
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http://dx.doi.org/10.1021/jacs.1c03852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225582PMC
June 2021

The predictive value of soluble osteoclast-associated receptor for the prognosis of acute coronary syndrome.

Sci Rep 2021 06 1;11(1):11412. Epub 2021 Jun 1.

The Department of General Practice, Affiliated Hospital 2 of Nantong University, No. 6, Hai'er Xiang North Road, Chongchuan District, Nantong, 226001, China.

At present, prognostic biomarkers of acute coronary syndrome (ACS) are fewer. The aim of this study was to explore the predictive value of soluble osteoclast-associated receptor (sOSCAR) level for the major adverse cardiovascular events (MACE) occurring within 30 days after ACS. From January to August 2020, a total of 108 patients with ACS who were admitted to our hospital, were enrolled in this study. Of the 108 patients, 79 were men and 29 women. Patient-related data, including age, sex, body mass index, history of type 2 diabetes, history of hyperlipidemia and serum sOSCAR level, were collected. All patients were followed up for 30 days. Based on MACE occurrence, the 108 patients were divided into MACE group (n = 17) and non-MACE group (n = 91). The baseline data were compared between the two groups, MACE-independent risk factors were identified by multivariate regression analysis, and the predictive value of sOSCAR for MACE occurring within 30 days after CAS was analyzed using receiver operating characteristic (ROC) curve. At the same time, according to the type of ACS, the 108 patients with ACS were divided into unstable angina (UA) group (n = 29), non ST-segment elevation myocardial infarction (USTEMI) group (n = 45) and ST-segment elevation myocardial infarction (STEMI) group (n = 34), and then the sOSCAR level and MACE incidence were observed in each group. The serum sOSCAR level was significantly lower in the MACE group [130(100,183)] than in the non-MACE group [301(220,370)] (P = 0.000). The area under ROC curve of sOSCAR level for MACE occurring within 30 days after CAS was 0.860 with 95%CI 0.782-0.919, P < 0.001. Multivariate regression analysis indicated that the sOSCAR level was an independent risk factor for the MACE occurring within 30 days after CAS (OR 0.26, 95%CI 0.087-0.777, P = 0.04). The MACE incidence (0%) was the lowest but the sOSCAR level was the highest in the UA group, while in the STEMI group, the MACE incidence (23.53%) was the higest but the sOSCAR level was the lowest among the UA, STEMI and NSTEMI groups. Serum sOSCAR level may be used as a predictor of MACE occurring within the short-term after ACS. The higher the sOSCAR level, the lower the MACE incidence.
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http://dx.doi.org/10.1038/s41598-021-91054-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169834PMC
June 2021

Pretreatment Inflammatory-Nutritional Biomarkers Predict Responses to Neoadjuvant Chemoradiotherapy and Survival in Locally Advanced Rectal Cancer.

Front Oncol 2021 17;11:639909. Epub 2021 Mar 17.

Department of Radiation Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.

Background: To evaluate the value of pretreatment inflammatory-nutritional biomarkers in predicting responses to neoadjuvant chemoradiotherapy (nCRT) and survival in patients with locally advanced rectal cancer (LARC).

Methods: Patients with LARC who underwent nCRT and subsequent surgery between October 2012 and December 2019 were considered for inclusion. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and prognostic nutritional index (PNI) were calculated from according to routine laboratory data within 1 week prior to nCRT. The correlations between baseline inflammatory-nutritional biomarkers and responses were analyzed using Chi-square test or Fisher's exact test, and multivariate logistic regression analysis was performed to identify the independent predictors of pathological responses to nCRT. Univariate and multivariate Cox proportional hazard models were used to assess the correlations of predictors with disease-free survival (DFS) and overall survival (OS).

Results: A total of 273 patients with LARC were enrolled in this study. Higher LMR and PNI were observed in the good-response group, meanwhile higher NLR and PLR were observed in the poor-response group. Multivariate logistic regression analysis results revealed that PLR and PNI independently predicted responses to nCRT. Multivariable Cox regression analysis determined that PNI was an independent predictor of DFS and OS in patients with LARC. The value of pretreatment PNI in predicting responses and survival was continuously superior to those of NLR, PLR, and LMR. The optimal cutoff value of the PNI was approximate 45. Subgroup analyses indicated that the pathological responses and survival in the high PNI group (≥ 45) were significantly better than those in the low PNI group (< 45), especially in patients with clinical stage III rectal cancer.

Conclusion: The pretreatment PNI can serve as a promising predictor of response to nCRT and survival in patients with LACR, which is superior to NLR, PLR, and LMR, and the patients with clinical stage III rectal cancer who have a higher PNI are more likely to benefit from nCRT.
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http://dx.doi.org/10.3389/fonc.2021.639909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010250PMC
March 2021

Astragaloside II Ameliorated Podocyte Injury and Mitochondrial Dysfunction in Streptozotocin-Induced Diabetic Rats.

Front Pharmacol 2021 16;12:638422. Epub 2021 Mar 16.

Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Astragaloside II (AS II), a novel saponin purified from Astragalus membranes, has been reported to modulate the immune response, repair tissue injury, and prevent inflammatory response. However, the protective effects of AS II on podocyte injury in diabetic nephropathy (DN) have not been investigated yet. In this study, we aimed to investigate the beneficial effects of AS II on podocyte injury and mitochondrial dysfunction in DN. Diabetes was induced with streptozotocin (STZ) by intraperitoneal injection at 55 mg/kg in rats. Diabetic rats were randomly divided into four groups, namely, diabetic rats and diabetic rats treated with losartan (10 mg·kg·d) or AS II (3.2 and 6.4 mg·kg·d) for 9 weeks. Normal Sprague-Dawley rats were chosen as nondiabetic control group. Urinary albumin/creatinine ratio (ACR), biochemical parameters, renal histopathology and podocyte apoptosis, and morphological changes were evaluated. Expressions of mitochondrial dynamics-related and autophagy-related proteins, such as Mfn2, Fis1, P62, and LC3, as well as Nrf2, Keap1, PINK1, and Parkin, were examined by immunohistochemistry, western blot, and real-time PCR, respectively. Our results indicated that AS II ameliorated albuminuria, renal histopathology, and podocyte foot process effacement and podocyte apoptosis in diabetic rats. AS II also partially restored the renal expression of mitochondrial dynamics-related and autophagy-related proteins, including Mfn2, Fis1, P62, and LC3. AS II also increased the expression of PINK1 and Parkin associated with mitophagy in diabetic rats. Moreover, AS II facilitated antioxidative stress ability via increasing Nrf2 expression and decreasing Keap1 protein level. These results suggested that AS II ameliorated podocyte injury and mitochondrial dysfunction in diabetic rats partly through regulation of Nrf2 and PINK1 pathway. These important findings might provide an innovative therapeutic strategy for the treatment of DN.
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http://dx.doi.org/10.3389/fphar.2021.638422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008105PMC
March 2021

9,10-Anhydrodehydroartemisinin Attenuates Experimental Autoimmune Encephalomyelitis by Inhibiting Th1 and Th17 Cell Differentiation.

Inflammation 2021 Oct 31;44(5):1793-1802. Epub 2021 Mar 31.

Putuo People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Human inflammatory disease, multiple sclerosis (MS), is a demyelinating disease of central nervous system (CNS). The experimental autoimmune encephalomyelitis (EAE) is the most commonly used as experimental model because of its key pathological features' approximation of MS. The interaction between complex elements in immune system and in the CNS determines the MS pathogenesis. However, there is no cure for MS and the treatment for MS still encounters great challenges. Thus, finding a more effective disease-modifying treatment is imminent. In the present study, we investigated whether 9,10-Anhydrodehydroartemisin (ADART), a compound derived from artemisinin, could decrease demyelination in EAE and the underlying mechanisms. In established EAE mice, 100 mg/kg 9,10-Anhydrodehydroartemisinin (ADART) effectively reduced CNS and peripheral immune system infiltration inflammatory cells including CD4 IFN-γ Th1 cells and CD4 IL-17A Th17 cells. Correspondingly, the serum level of IFN-γ and IL-17A was also reduced. In vitro, ADART almost completely inhibited Th17 differentiation, and partially inhibited Th1 differentiation in 10 μM. This research revealed that ADART could be a great promising avenue among current therapies for MS.
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http://dx.doi.org/10.1007/s10753-021-01456-5DOI Listing
October 2021

Correlation between serum cartilage oligomeric matrix protein and major adverse cardiovascular events within 30 days in patients with acute coronary syndrome.

Ann Transl Med 2021 Feb;9(4):353

Department of Cardiology, The Second Affiliated Hospital of Nantong University, Nantong, China.

Background: We studied the correlation between cartilage oligomeric matrix protein (COMP) and major adverse cardiovascular events in patients with acute coronary syndrome (ACS) within 30 days.

Methods: This study included 170 ACS patients who were hospitalized in the Second Affiliated Hospital of Nantong University from August 2017 to April 2019. Serum COMP level was measured at baseline. The enrolled patients were followed up for 30 days and grouped according to the occurrence of major adverse cardiovascular events (MACE) during follow-up. Among the 170 patients, 23 patients had MACE during hospitalization (MACE group), and 147 patients had no MACE (no MACE group).

Results: The serum COMP levels in the MACE group were significantly higher than those of the non-MACE group [84.85 (51.55, 141.75) . 20.65 (9.11, 46.31) ng/mL, respectively, P<0.05]. The area under the receiver operating characteristic (ROC) curve for COMP in predicting the occurrence of MACE within 30 days was 0.839, with a cutoff level of 39.9 ng/mL [95% confidence interval (CI): 0.774-0.890], 86.96% sensitivity, and 72.79% specificity (P<0.0001). Multivariate logistic regression analysis showed that serum COMP could be used as an independent predictor of MACE within 30 days in ACS patients [odds ratio (OR): 1.024, 95% CI: 1.0133-1.0349, P=0.0001].

Conclusions: Serum COMP is associated with the short-term prognosis of ACS patients. High serum COMP levels can be used as a predictor of MACE within 30 days in ACS patients.
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http://dx.doi.org/10.21037/atm-21-333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944313PMC
February 2021

Spatial and Temporal Characteristics of Hand-Foot-and-Mouth Disease and Its Response to Climate Factors in the Ili River Valley Region of China.

Int J Environ Res Public Health 2021 02 17;18(4). Epub 2021 Feb 17.

College of Resources and Environmental Sciences, Xinjiang University, Urumqi 830046, China.

Background: As the global climate changes, the number of cases of hand-foot-and-mouth disease (HFMD) is increasing year by year. This study comprehensively considers the association of time and space by analyzing the temporal and spatial distribution changes of HFMD in the Ili River Valley in terms of what climate factors could affect HFMD and in what way.

Methods: HFMD cases were obtained from the National Public Health Science Data Center from 2013 to 2018. Monthly climate data, including average temperature (MAT), average relative humidity (MARH), average wind speed (MAWS), cumulative precipitation (MCP), and average air pressure (MAAP), were obtained from the National Meteorological Information Center. The temporal and spatial distribution characteristics of HFMD from 2013 to 2018 were obtained using kernel density estimation (KDE) and spatiotemporal scan statistics. A regression model of the incidence of HFMD and climate factors was established based on a geographically and temporally weighted regression (GTWR) model and a generalized additive model (GAM).

Results: The KDE results show that the highest density was from north to south of the central region, gradually spreading to the whole region throughout the study period. Spatiotemporal cluster analysis revealed that clusters were distributed along the Ili and Gongnaisi river basins. The fitted curves of MAT and MARH were an inverted V-shape from February to August, and the fitted curves of MAAP and MAWS showed a U-shaped change and negative correlation from February to May. Among the individual climate factors, MCP coefficient values varied the most while MAWS values varied less from place to place. There was a partial similarity in the spatial distribution of coefficients for MARH and MAT, as evidenced by a significant degree of fit performance in the whole region. MCP showed a significant positive correlation in the range of 15-35 mm, and MAAP showed a positive correlation in the range of 925-945 hPa. HFMD incidence increased with MAT in the range of 15-23 °C, and the effective value of MAWS was in the range of 1.3-1.7 m/s, which was positively correlated with incidences of HFMD.

Conclusions: HFMD incidence and climate factors were found to be spatiotemporally associated, and climate factors are mostly non-linearly associated with HFMD incidence.
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http://dx.doi.org/10.3390/ijerph18041954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923010PMC
February 2021

Protocol for proteogenomic dissection of intronic splicing enhancer interactome for prediction of individualized cancer prognosis.

STAR Protoc 2021 Mar 11;2(1):100338. Epub 2021 Feb 11.

Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Inter- or intra-patient tumor heterogeneity hinders the discovery of biomarkers for predicting individualized prognosis. Here, we present a protocol for an alternative splicing activity-based proteogenomic approach for identification of candidate prognostic markers in cancer cell lines and human breast cancer specimens. The pull-down of protein complexes with intronic splicing enhancer (ISE) probes is followed by tandem mass spectrometry (MS/MS) peptide sequencing. The proteogenomic analysis of data from these ISE-MS/MS assays identifies new prognostic markers that can be utilized to stratify patients with poor prognosis. For complete details on the use and execution of this protocol, please refer to Wang et al. (2018).
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http://dx.doi.org/10.1016/j.xpro.2021.100338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887646PMC
March 2021

AIM2 in regulatory T cells restrains autoimmune diseases.

Nature 2021 03 27;591(7849):300-305. Epub 2021 Jan 27.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells. It consists of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1β and IL-18 in myeloid cells. Here we show that the DNA-binding inflammasome receptor AIM2 has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (T) cells. AIM2 is highly expressed by both human and mouse T cells, is induced by TGFβ, and its promoter is occupied by transcription factors that are associated with T cells such as RUNX1, ETS1, BCL11B and CREB. RNA sequencing, biochemical and metabolic analyses demonstrated that AIM2 attenuates AKT phosphorylation, mTOR and MYC signalling, and glycolysis, but promotes oxidative phosphorylation of lipids in T cells. Mechanistically, AIM2 interacts with the RACK1-PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of T cells during inflammation. Although AIM2 is generally accepted as an inflammasome effector in myeloid cells, our results demonstrate a T cell-intrinsic role of AIM2 in restraining autoimmunity by reducing AKT-mTOR signalling and altering immune metabolism to enhance the stability of T cells.
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http://dx.doi.org/10.1038/s41586-021-03231-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080937PMC
March 2021

Acidic fibroblast growth factor attenuates type 2 diabetes-induced demyelination via suppressing oxidative stress damage.

Cell Death Dis 2021 01 21;12(1):107. Epub 2021 Jan 21.

Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000, Wenzhou, Zhejiang, China.

Prolonged type 2 diabetes mellitus (T2DM) produces a common complication, peripheral neuropathy, which is accompanied by nerve fiber disorder, axon atrophy, and demyelination. Growing evidence has characterized the beneficial effects of acidic fibroblast growth factor (aFGF) and shown that it relieves hyperglycemia, increases insulin sensitivity, and ameliorates neuropathic impairment. However, there is scarce evidence on the role of aFGF on remodeling of aberrant myelin under hyperglycemia condition. Presently, we observed that the expression of aFGF was rapidly decreased in a db/db T2DM mouse model. Administration of exogenous aFGF was sufficient to block acute demyelination and nerve fiber disorganization. Furthermore, this strong anti-demyelinating effect was most likely dominated by an aFGF-mediated increase of Schwann cell (SC) proliferation and migration as well as suppression of its apoptosis. Mechanistically, the beneficial biological effects of aFGF on SC behavior and abnormal myelin morphology were likely due to the inhibition of hyperglycemia-induced oxidative stress activation, which was most likely activated by kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-derived-like 2 (Nrf2) signaling. Thus, this evidence indicates that aFGF is a promising protective agent for relieving myelin pathology through countering oxidative stress signaling cascades under diabetic conditions.
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http://dx.doi.org/10.1038/s41419-021-03407-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819983PMC
January 2021

LINC00324 facilitates cell proliferation through competing for miR‑214‑5p in immature ovarian teratocarcinoma.

Int J Mol Med 2021 01 25;47(1):397-407. Epub 2020 Nov 25.

Department of Obstetrics and Gynecology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430013, P.R. China.

Immature ovarian teratocarcinoma (IOT) is a rare and malignant type of ovarian teratoma, and the molecular mechanisms underlying the pathogenesis and malignant phenotype of IOT remain uncharacterized. The present study examined a long non‑coding RNA (lncRNA), long‑chain intergenic non‑coding RNA324 (LINC00324), which may serve a crucial role in pathogenesis of IOT. According to the results, LINC00324 was upregulated in IOT tissues and cells, as determined by reverse transcription‑quantitative PCR, and its depletion impaired cell proliferation ability and improved cell apoptosis ability in IOT. Furthermore, LINC00324 acted as a miR‑214‑5p sponge to derepress cyclin dependent kinase 6 (CDK6), cyclin D1 (CCND1), murine double minute homolog 2 (MDM2), and mouse double minute 4 (MDM4) expression, thus increasing IOT cell proliferation and repressing apoptosis. Taken together, these results demonstrated that LINC00324 could serve as a competing endogenous RNA to facilitate IOT cell proliferation by regulation of miR‑214‑5p‑CDK6/CCND1/MDM2/MDM4 network, which possibly provide a novel therapeutic target for IOT.
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http://dx.doi.org/10.3892/ijmm.2020.4800DOI Listing
January 2021

CRL4 E3 ubiquitin ligase controls ribosome biogenesis, cell proliferation, and development.

Sci Adv 2020 Dec 18;6(51). Epub 2020 Dec 18.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Evolutionarily conserved DCAF1 is a major substrate receptor for the DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4) and controls cell proliferation and development. The molecular basis for these functions is unclear. We show here that loss in multiple tissues and organs selectively eliminates proliferating cells and causes perinatal lethality, thymic atrophy, and bone marrow defect. Inducible loss eliminates proliferating, but not quiescent, T cells and MEFs. We identify the ribosome assembly factor PWP1 as a substrate of the CRL4 ligase. loss results in PWP1 accumulation, impairing rRNA processing and ribosome biogenesis. Knockdown or overexpression of PWP1 can rescue defects or cause similar defects as loss, respectively, in ribosome biogenesis. loss increases free RPL11, resulting in L11-MDM2 association and p53 activation. Cumulatively, these results reveal a critical function for DCAF1 in ribosome biogenesis and define a molecular basis of DCAF1 function in cell proliferation and development.
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http://dx.doi.org/10.1126/sciadv.abd6078DOI Listing
December 2020

Potent and Selective Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) Heterobifunctional Small-molecule Degraders.

J Med Chem 2020 12 7;63(24):15883-15905. Epub 2020 Dec 7.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Previously, we reported a first-in-class von Hippel-Lindau (VHL)-recruiting mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) degrader, MS432. To date, only two MEK1/2 degrader papers have been published and very limited structure-activity relationships (SAR) have been reported. Here, we describe our extensive SAR studies exploring both von Hippel-Lindau (VHL) and cereblon (CRBN) E3 ligase ligands and a variety of linkers, which resulted in two novel, improved VHL-recruiting MEK1/2 degraders, (MS928) and (MS934), and the first CRBN-recruiting MEK1/2 degrader (MS910). These compounds potently and selectively degraded MEK1/2 by hijacking the ubiquitin-proteasome system, inhibited downstream signaling, and suppressed cancer cell proliferation. Furthermore, concurrent inhibition of BRAF or PI3K significantly potentiated the antitumor activity of degrader , suggesting that the combination of MEK1/2 degradation with BRAF or PI3K inhibition may provide potential therapeutic benefits. Finally, besides being more potent, degrader displayed improved plasma exposure levels in mice, representing the best MEK1/2 degrader to date for in vivo studies.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770057PMC
December 2020

Novel gene-specific translation mechanism of dysregulated, chronic inflammation reveals promising, multifaceted COVID-19 therapeutics.

bioRxiv 2020 Nov 16. Epub 2020 Nov 16.

Hyperinflammation and lymphopenia provoked by SARS-CoV-2-activated macrophages contribute to the high mortality of Coronavirus Disease 2019 (COVID-19) patients. Thus, defining host pathways aberrantly activated in patient macrophages is critical for developing effective therapeutics. We discovered that G9a, a histone methyltransferase that is overexpressed in COVID-19 patients with high viral load, activates translation of specific genes that induce hyperinflammation and impairment of T cell function or lymphopenia. This noncanonical, pro-translation activity of G9a contrasts with its canonical epigenetic function. In endotoxin-tolerant (ET) macrophages that mimic conditions which render patients with pre-existing chronic inflammatory diseases vulnerable to severe symptoms, our chemoproteomic approach with a biotinylated inhibitor of G9a identified multiple G9a-associated translation regulatory pathways that were upregulated by SARS-CoV-2 infection. Further, quantitative translatome analysis of ET macrophages treated progressively with the G9a inhibitor profiled G9a-translated proteins that unite the networks associated with viral replication and the SARS-CoV-2-induced host response in severe patients. Accordingly, inhibition of G9a-associated pathways produced multifaceted, systematic effects, namely, restoration of T cell function, mitigation of hyperinflammation, and suppression of viral replication. Importantly, as a host-directed mechanism, this G9a-targeted, combined therapeutics is refractory to emerging antiviral-resistant mutants of SARS-CoV-2, or any virus, that hijacks host responses.
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http://dx.doi.org/10.1101/2020.11.14.382416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685324PMC
November 2020

The novel small-molecule TPN10456 inhibits Th17 cell differentiation and protects against experimental autoimmune encephalomyelitis.

Cell Mol Immunol 2020 12 27;17(12):1290-1293. Epub 2020 Oct 27.

Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

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http://dx.doi.org/10.1038/s41423-020-00566-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784672PMC
December 2020

Highly Sensitive and Rapid Identification of Based on Multiple Cross Displacement Amplification Coupled With Lateral Flow Biosensor Assay.

Front Microbiol 2020 28;11:1926. Epub 2020 Aug 28.

Department of Respiratory and Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, China.

() is an important neonatal pathogen that is associated with mortality and morbidity. Therefore, we developed a rapid, accurate, and sensitive method based on multiple cross displacement amplification (MCDA) for the detection of the target pathogen. Four sets of MCDA primers were designed for targeting the -specific gene, and one set of MCDA primers with the optimum amplification efficiency was screened for establishing the -MCDA assay. As a result, the newly-developed assay could be conducted at a fixed temperature (61°C) for only 30 min, eliminating the use of complex instruments. A portable and user-friendly nanoparticle-based lateral flow biosensor (LFB) assay was employed for reporting MCDA results within 2 min. Our results suggested that the detection limit of the -MCDA-LFB assay is 300 fg per reaction, and no cross-reaction occurred with non- strains. For 260 vaginal and rectal swabs, the detection rate of the MCDA-LFB assay was 7.7%, which was in accordance with the reference method of enrichment/qPCR, and higher by 4.6% than the CHROMagar culture. Moreover, the total procedure time of the MCDA-LFB assay was around 50 min, including sample collection, template preparation, MCDA reaction, and result reporting. Therefore, the MCDA-LFB assay is superior to enrichment/qPCR and CHROMagar culture and has great promise for point-of-care testing of from vaginal and rectal swabs of pregnant women in resource-limited settings.
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http://dx.doi.org/10.3389/fmicb.2020.01926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485445PMC
August 2020

Sensitivity and polymorphism of Bethesda panel markers in Chinese population.

Bull Cancer 2020 Nov 23;107(11):1091-1097. Epub 2020 Sep 23.

Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine), Department of Pathology, No.155 Hanzhong Road, 210029 Nanjing, China. Electronic address:

Purpose: This study aims to analyze sensitivities and polymorphisms of the Bethesda panel markers (BAT25, BAT26, D2S123, D5S346 and D17S250) for microsatellite instability testing in Chinese from Jiangsu Province and their clinical implication.

Methods: MSI, sensitivity and polymorphism analysis in 541 colorectal cancer (CRC) patients were detected by fragment analysis.

Results: Five hundred and twenty-five tissue samples and 541 blood samples of the 541 sample pairs were successfully amplified. Thirty-four (6.5%) cases were MSI-high (MSI-H) while 33 (6.3%) and 458 (87.2%) were MSI-low (MSI-L) and microsatellite stable (MSS), respectively. BAT26 (85.3%) exhibited the highest instability followed by BAT25 (82.4%), D2S123 (67.6%), D17S250 (64.7%) and D5S346 (50.0%) in MSI-H cases. The median ages of CRC patients with LS, MSI-H, MSI-L and MSS status were 38-43, 48, 60 and 63, respectively. 75.0%, 44.1%, 12.1% and 7.0% CRC cases were mucinous carcinomas in LS, MSI-H, MSI-L and MSS group, respectively. For D2S123, D17S250 and D5S346, heterozygosity was 80.8%, 74.1% and 57.7% and sizes of polymorphic variation range (PVR) were 207bp to 234bp, 140bp to 169bp and 109bp to 137bp, respectively. For D2S123 and D5S346, there was a bimodal distribution distinguishing the D17S250 from an indistinct trimodal or tetramodal distribution.

Conclusion: MSI-H cases showed earlier onset and higher proportion of mucinous carcinomas. Mononucleotide BAT26 and BAT25 exhibited higher sensitivity than dinucleotides D2S123, D17S250 and D5S346 in the Chinese population. The dinucleotide markers were highly polymorphic with high percent of heterozygosity, great variation in repeat length and non-normal distribution in Chinese population from Jiangsu Province.
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http://dx.doi.org/10.1016/j.bulcan.2020.08.001DOI Listing
November 2020
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