Publications by authors named "Min Shen"

603 Publications

Ocular manifestations in Chinese adult patients with NLRP3-associated autoinflammatory disease.

Sci Rep 2021 Jun 7;11(1):11904. Epub 2021 Jun 7.

Department of Ophthalmology, Key Laboratory of Ocular Fundus Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.

NLRP3-associated autoinflammatory disease (NLRP3-AID) is a rare autosomal dominant disorder involving multiple systems. We aim to assess the ocular manifestations of Chinese adult patients with NLRP3-AID. Twelve adult patients (> 18 years old) were diagnosed as NLRP3-AID at the Department of Rheumatology, Peking Union Medical College Hospital. All patients underwent ophthalmologic evaluation by an ophthalmologist. Clinical and genetic features of these patients were collected and compared with those from Caucasian population. A total of 7 NLRP3-AID patients (58%) 14 eyes had ocular manifestations. Five NLRP3 variants were identified, and 3 patients (43%) with severe ocular damages were all found to have the NLRP3 T348M variant. The incidences of papilledema and optic atrophy in the Chinese adult NLRP3-AID patients of moderate type were similar to those in the Caucasian NLRP3-AID patients of severe type. This is the first cohort of Chinese adult NLRP3-AID patients with ocular involvement. Ocular manifestations were diverse and even severe in NLRP3-AID, particularly in patients with the moderate phenotype, and may have relationship with genotypes. Awareness of these manifestations by rheumatologists and ophthalmologists could help to avoid the irreversible ocular damages.
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http://dx.doi.org/10.1038/s41598-021-91315-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184759PMC
June 2021

Genome-Wide Detection of Copy Number Variations and Their Association With Distinct Phenotypes in the World's Sheep.

Front Genet 2021 20;12:670582. Epub 2021 May 20.

College of Animal Science and Technology, China Agricultural University, Beijing, China.

Copy number variations (CNVs) are a major source of structural variation in mammalian genomes. Here, we characterized the genome-wide CNV in 2059 sheep from 67 populations all over the world using the Ovine Infinium HD (600K) SNP BeadChip. We tested their associations with distinct phenotypic traits by conducting multiple independent genome-wide tests. In total, we detected 7547 unique CNVs and 18,152 CNV events in 1217 non-redundant CNV regions (CNVRs), covering 245 Mb (∼10%) of the whole sheep genome. We identified seven CNVRs with frequencies correlating to geographical origins and 107 CNVRs overlapping 53 known quantitative trait loci (QTLs). Gene ontology and pathway enrichment analyses of CNV-overlapping genes revealed their common involvement in energy metabolism, endocrine regulation, nervous system development, cell proliferation, immune, and reproduction. For the phenotypic traits, we detected significantly associated (adjusted < 0.05) CNVRs harboring functional candidate genes, such as for polycerate; and for tail weight; for supernumerary nipple; , , , and for ear size; and and in Wadi sheep; , , and in Hu sheep; , , and in Icelandic; in Finnsheep; in Romanov; and in Texel sheep for litter size. These CNVs and associated genes are important markers for molecular breeding of sheep and other livestock species.
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http://dx.doi.org/10.3389/fgene.2021.670582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175073PMC
May 2021

Case Report: A Rare Case of Autoinflammatory Phospholipase Cγ2 (PLCγ2)-Associated Antibody Deficiency and Immune Dysregulation Complicated With Gangrenous Pyoderma and Literature Review.

Front Immunol 2021 19;12:667430. Epub 2021 May 19.

Department of General Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.

Background: Autoinflammatory phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) is a rare autoinflammatory disease caused by gain-of-function mutations in the gene. Here we report a rare case of APLAID patient carrying a novel heterozygous missense I169V mutation with gangrenous pyoderma and concomitant high serum immunoglobulin (Ig) E level.

Methods: The patient was diagnosed as APLAID and has been treated in our department. His phenotype and genotype were carefully documented and studied. We also conducted a comprehensive literature review on APLAID.

Results: A 23-year-old Chinese Han man presented with recurrent fever for 18 years and vesiculopustular rashes for 9 years, along with chronic bronchitis, leukocytosis, increased C-reactive protein, immunodeficiency and high serum IgE. Skin biopsy showed chronic inflammatory cells infiltration. A paternal heterozygous missense variant in exon 6 of the gene p. I169V was identified. His vesiculopustular and IgE level responded to medium dose corticosteroids. After withdrawal of steroids, he developed severe arthritis and a large deteriorating ulceration resembling pyoderma gangrenosum on the left knee. Large dose corticosteroids were suboptimal. Then he received adalimumab with satisfactory response for arthritis and skin lesion. But he got an immunodeficiency-associated lymphoproliferative disorder 2 months later. Through literature review, there were a total of 10 APLAID patients reported by six English-language publications. Vesiculopustular rashes, sinopulmonary infection and immunodeficiency were the most frequent symptoms of APLAID patients. Glucocorticoids, intravenous immunoglobulin and biologics were clinically used to treat APLAID but none of these patients had a complete recovery.

Conclusions: The rarity and diversity of APLAID make it difficult to be diagnosed. Our study reported the first case of APLAID with gangrenous pyoderma and concomitant high IgE carrying a novel mutation, which may expand the clinical phenotype and genotype of APLAID.
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http://dx.doi.org/10.3389/fimmu.2021.667430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170136PMC
May 2021

Differences in Maturation Status and Immune Phenotypes of Circulating Helios and Helios Tregs and Their Disrupted Correlations With Monocyte Subsets in Autoantibody-Positive T1D Individuals.

Front Immunol 2021 12;12:628504. Epub 2021 May 12.

Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

CD4 Tregs are involved in the regulation of various autoimmune diseases but believed to be highly heterogeneous. Studies have indicated that Helios controls a distinct subset of functional Tregs. However, the immunological changes in circulating Helios and Helios Tregs are not fully explored in type 1 diabetes (T1D). Here, we elucidated the differences in maturation status and immune regulatory phenotypes of Helios and Helios Tregs and their correlations with monocyte subsets in T1D individuals. As CD25 FOXP3 Tregs also represent a subset of functional Tregs, we defined Tregs as FOXP3CD127 and examined circulating Helios and Helios Treg subpopulations in 68 autoantibody-positive T1D individuals and 68 age-matched healthy controls. We found that expression of both FOXP3 and CTLA4 diminished in Helios Tregs, while the proportion of CD25 Tregs increased in Helios Tregs of T1D individuals. Although the frequencies of neither Helios nor Helios Tregs were affected by investigated T1D genetic risk loci, Helios Tregs correlated with age at T1D diagnosis negatively and disease duration positively. Moreover, the negative correlation between central and effector memory proportions of Helios Tregs in healthy controls was disrupted in T1D individuals. Finally, regulatory non-classical and intermediate monocytes also decreased in T1D individuals, and positive correlations between these regulatory monocytes and Helios/Helios Treg subsets in healthy controls disappeared in T1D individuals. In conclusion, we demonstrated the alternations in maturation status and immune phenotypes in Helios and Helios Treg subsets and revealed the missing association between these Treg subsets and monocyte subsets in T1D individuals, which might point out another option for elucidating T1D mechanisms.
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http://dx.doi.org/10.3389/fimmu.2021.628504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149963PMC
May 2021

[email protected] Octahedral Nanocrystals: Enhancing Their Activity and Durability toward Oxygen Reduction with an Intermetallic Core and an Ultrathin Shell.

J Am Chem Soc 2021 Jun 27;143(22):8509-8518. Epub 2021 May 27.

School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.

Despite extensive efforts devoted to the synthesis of Pt-Co bimetallic nanocrystals for fuel cell and related applications, it remains a challenge to simultaneously control atomic arrangements in the bulk and on the surface. Here we report a synthesis of [email protected] octahedral nanocrystals that feature an intermetallic, face-centered tetragonal Pt-Co core and an ultrathin Pt shell, together with the dominance of {111} facets on the surface. When evaluated as a catalyst toward the oxygen reduction reaction (ORR), the nanocrystals delivered a mass activity of 2.82 A mg and a specific activity of 9.16 mA cm, which were enhanced by 13.4 and 29.5 times, respectively, relative to the values of a commercial Pt/C catalyst. More significantly, the mass activity of the nanocrystals only dropped 21% after undergoing 30 000 cycles of accelerated durability test, promising an outstanding catalyst with optimal performance for ORR and related reactions.
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http://dx.doi.org/10.1021/jacs.1c04160DOI Listing
June 2021

Journals on legal and forensic medicine in Web of Science Core Collection: focus on Forensic Sciences Research.

Forensic Sci Res 2021 Mar 5;6(1):92-94. Epub 2021 Mar 5.

Shanghai Key Lab of Forensic Medicine, Key Lab of Forensic Science, Ministry of Justice, Shanghai Forensic Service Platform, Academy of Forensic Science, Shanghai, China.

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http://dx.doi.org/10.1080/20961790.2021.1879718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110180PMC
March 2021

Acute Ischemic Stroke in a Pediatric Patient due to Osteosarcoma Embolism.

Pediatr Neurol 2021 Jul 23;120:36-37. Epub 2021 Apr 23.

Department of Neurology, Columbia University Irving Medical Center, New York, New York; New York-Presbyterian Hospital, New York, New York.

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http://dx.doi.org/10.1016/j.pediatrneurol.2021.04.009DOI Listing
July 2021

Circulating microRNA‑135a‑3p in serum extracellular vesicles as a potential biological marker of non‑alcoholic fatty liver disease.

Mol Med Rep 2021 Jul 6;24(1). Epub 2021 May 6.

Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.

Non‑alcoholic fatty liver disease (NAFLD) is a widespread threat to human health. However, the present screening methods for NAFLD are time‑consuming or invasive. The present study aimed to assess the potential of microRNAs (miRNAs/miRs) in serum extracellular vesicles (EVs) as a biomarker of NAFLD. C57BL/6J mice were fed either a 12‑week high‑fat diet (HFD) or standard chow to establish NAFLD and control groups, respectively. Serum samples were obtained from the mouse model of NAFLD, as well as 50 patients with NAFLD and 50 healthy individuals, and EVs were extracted and verified. Using reverse transcription‑quantitative PCR, the mRNA expression level of selected miRNAs in the serum and EVs was analyzed. In order to determine the diagnostic value, receiver operating characteristic (ROC) curves were used. The mice treated with HFD showed notable hepatic steatosis and higher concentrations of serum alanine aminotransferase (ALT). There was also a significant decrease in the expression levels of miR‑135a‑3p, miR‑129b‑5p and miR‑504‑3p, and an increase in miR‑122‑5p expression levels in circulating EVs in mice treated with HFD and patients with NAFLD. There were also similar miR‑135a‑3p and miR‑122‑5p expression patterns in the serum. ROC analysis demonstrated that miR‑135a‑3p in circulating EVs was highly accurate in diagnosing NAFLD, with the area under the curve value being 0.849 (95% CI, 0.777‑0.921; P<0.0001). Bioinformatics analysis indicated that dysregulated miR‑135a‑3p was associated with 'platelet‑derived growth factor receptor signaling pathway' and 'AMP‑activated protein kinase signaling pathway'. In summary, circulating miR‑135a‑3p in EVs may serve as a potential non‑invasive biomarker to diagnose NAFLD. This miRNA was a more sensitive and specific biological marker for NAFLD compared with ALT.
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http://dx.doi.org/10.3892/mmr.2021.12137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127071PMC
July 2021

Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor.

EMBO J 2021 Jun 1;40(11):e107226. Epub 2021 May 1.

Malaria Biochemistry Laboratory, The Francis Crick Institute, London, UK.

Malaria parasite egress from host erythrocytes (RBCs) is regulated by discharge of a parasite serine protease called SUB1 into the parasitophorous vacuole (PV). There, SUB1 activates a PV-resident cysteine protease called SERA6, enabling host RBC rupture through SERA6-mediated degradation of the RBC cytoskeleton protein β-spectrin. Here, we show that the activation of Plasmodium falciparum SERA6 involves a second, autocatalytic step that is triggered by SUB1 cleavage. Unexpectedly, autoproteolytic maturation of SERA6 requires interaction in multimolecular complexes with a distinct PV-located protein cofactor, MSA180, that is itself a SUB1 substrate. Genetic ablation of MSA180 mimics SERA6 disruption, producing a fatal block in β-spectrin cleavage and RBC rupture. Drug-like inhibitors of SERA6 autoprocessing similarly prevent β-spectrin cleavage and egress in both P. falciparum and the emerging zoonotic pathogen P. knowlesi. Our results elucidate the egress pathway and identify SERA6 as a target for a new class of antimalarial drugs designed to prevent disease progression.
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http://dx.doi.org/10.15252/embj.2020107226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167364PMC
June 2021

COVID-19 pandemic and systemic autoinflammatory diseases management: a cross-sectional survey.

Rheumatol Int 2021 Apr 12. Epub 2021 Apr 12.

Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.

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http://dx.doi.org/10.1007/s00296-021-04846-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040754PMC
April 2021

Identification of SARS-CoV-2 viral entry inhibitors using machine learning and cell-based pseudotyped particle assay.

Bioorg Med Chem 2021 05 26;38:116119. Epub 2021 Mar 26.

National Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Dr., Rockville, MD 20850, USA. Electronic address:

In response to the pandemic caused by SARS-CoV-2, we constructed a hybrid support vector machine (SVM) classification model using a set of publicly posted SARS-CoV-2 pseudotyped particle (PP) entry assay repurposing screen data to identify novel potent compounds as a starting point for drug development to treat COVID-19 patients. Two different molecular descriptor systems, atom typing descriptors and 3D fingerprints (FPs), were employed to construct the SVM classification models. Both models achieved reasonable performance, with the area under the curve of receiver operating characteristic (AUC-ROC) of 0.84 and 0.82, respectively. The consensus prediction outperformed the two individual models with significantly improved AUC-ROC of 0.91, where the compounds with inconsistent classifications were excluded. The consensus model was then used to screen the 173,898 compounds in the NCATS annotated and diverse chemical libraries. Of the 255 compounds selected for experimental confirmation, 116 compounds exhibited inhibitory activities in the SARS-CoV-2 PP entry assay with IC values ranged between 0.17 µM and 62.2 µM, representing an enrichment factor of 3.2. These 116 active compounds with diverse and novel structures could potentially serve as starting points for chemistry optimization for COVID-19 drug discovery.
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http://dx.doi.org/10.1016/j.bmc.2021.116119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997310PMC
May 2021

Discovery and Optimization of 2-1λ-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer.

J Med Chem 2021 04 6;64(8):4913-4946. Epub 2021 Apr 6.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2-1λ-quinoline-2,5(6)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (-, ). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
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http://dx.doi.org/10.1021/acs.jmedchem.1c00019DOI Listing
April 2021

Temporal metabolic and transcriptomic characteristics crossing islets and liver reveal dynamic pathophysiology in diet-induced diabetes.

iScience 2021 Apr 5;24(4):102265. Epub 2021 Mar 5.

Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.

To investigate the molecular mechanisms underlying islet dysfunction and insulin resistance in diet-induced diabetes, we conducted temporal RNA sequencing of tissues responsible for insulin secretion (islets) and action (liver) every 4 weeks in mice on high-fat (HFD) or chow diet for 24 weeks, linking to longitudinal profile of metabolic characteristics. The diverse responses of α, β, and δ cells to glucose and palmitate indicated HFD-induced dynamic deterioration of islet function from dysregulation to failure. Insulin resistance developed with variable time course in different tissues. Weighted gene co-expression network analysis and Ingenuity Pathway Analysis implicated islets and liver jointly programmed β-cell compensatory adaption via cell proliferation at early phase and irreversible islet dysfunction by inappropriate immune response at later stage, and identified interconnected molecules including growth differentiation factor 15. Frequencies of T cell subpopulation showed an early decrement in Tregs followed by increases in Th1 and Th17 cells during progression to diabetes.
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http://dx.doi.org/10.1016/j.isci.2021.102265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008187PMC
April 2021

The Effects of Tai Chi Exercise Among Adults With Chronic Heart Failure: An Overview of Systematic Review and Meta-Analysis.

Front Cardiovasc Med 2021 18;8:589267. Epub 2021 Mar 18.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.

Tai chi (TC) is a popular form of exercise among adults with chronic heart failure (CHF), yet services are greatly underutilized. The aim of the current study was to identify and summarize the existing evidence and to systematically determine the clinical effectiveness of Tai Chi in the management of CHF using a systematic overview. Both English and Chinese databases were searched for systematic reviews (SRs)/meta-analyses (MAs) on TC for CHF from their inception to June 2020. The methodological quality, reporting quality, and risk of bias of SRs/MAs were assessed using Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2), the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, and Risk of Bias in Systematic reviews (ROBIS), respectively. The evidence quality of outcome measures was assessed by the Grades of Recommendations, Assessment, Development and Evaluation (GRADE). Six SRs/MAs using a quantitative synthesis to assess various outcomes of TC in CHF were included in this overview. The methodological quality, reporting quality and risk of bias of the SRs/MAs and the evidence quality of the outcome measures are generally unsatisfactory. The limitations of the past SRs/MAs included the lack of either the protocol or registration, the list of excluded studies, and the computational details of meta-analysis were inadequately reported. The critical problems were that qualitative data synthesis relied on trials with small sample sizes and critical low quality. TC may be a promising complementary treatment for CHF. However, further rigorous and comprehensive SRs/MAs and RCTs are required to provide robust evidence for definitive conclusions.
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http://dx.doi.org/10.3389/fcvm.2021.589267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012482PMC
March 2021

Development and Validation of a Nomogram for Predicting Bronchopulmonary Dysplasia in Very-Low-Birth-Weight Infants.

Front Pediatr 2021 19;9:648828. Epub 2021 Mar 19.

Neonatal Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Bronchopulmonary dysplasia is a common pulmonary disease in newborns and is one of the main causes of death. The aim of this study was to build a new simple-to-use nomogram to screen high-risk populations. In this single-center retrospective study performed from January 2017 to December 2020, we reviewed data on very-low-birth-weight infants whose gestational ages were below 32 weeks. LASSO regression was used to select variables for the risk model. Then, we used multivariable logistic regression to build the prediction model incorporating these selected features. Discrimination was assessed by the C-index, and and calibration of the model was assessed by and calibration curve and the Hosmer-Lemeshow test. The LASSO regression identified gestational age, duration of ventilation and serum NT-proBNP in the 1st week as significant predictors of BPD. The nomogram-illustrated model showed good discrimination and calibration. The C-index was 0.853 (95% CI: 0.851-0.854) in the training set and 0.855 (95% CI: 0.77-0.94) in the validation set. The calibration curve and Hosmer-Lemeshow test results showed good calibration between the predictions of the nomogram and the actual observations. We demonstrated a simple-to-use nomogram for predicting BPD in the early stage. It may help clinicians recognize high-risk populations.
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http://dx.doi.org/10.3389/fped.2021.648828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017311PMC
March 2021

A Critical Overview of Systematic Reviews of Shenfu Injection for Heart Failure.

Cardiovasc Ther 2021 6;2021:8816590. Epub 2021 Mar 6.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong Province 510515, China.

Objectives: Shenfu Injection (SFI) was widely used in the treatment of heart failure (HF) in China. A plethora of systematic reviews/meta-analyses (SRs/MAs) has been conducted in this research area, although with scattered results. The purpose of this overview was to conduct a comprehensive review to summarize and critically evaluate the existing evidence.

Methods: Digital databases were searched for SRs/MAs up to January 28, 2021. Two authors independently screened the reviews and assessed the methodological quality of included SRs/MAs using Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2). Quality of evidence for outcomes evaluated within the reviews was appraised with the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE).

Results: Thirteen SRs/MAs met the inclusion criteria. Based on AMSTAR-2, the quality of all SRs/MAs was critically low, because all of them have more than one critical domains that were unmet. Based on GRADE, the evidence quality of 24 outcome measures was low or very low, 27 outcome measures was moderate, and none outcome measure was high. Descriptive analysis showed that SFI was an effective and safe method for HF.

Conclusions: The use of SFI for the treatment of HF may be clinically effective and safe. However, this conclusion must be interpreted cautiously due to the generally low methodological quality and low evidence quality of the included SRs/MAs. More rigorously designed SRs/MAs and RCTs with high methodological quality are necessary for further proof.
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http://dx.doi.org/10.1155/2021/8816590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960068PMC
June 2021

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2.

Front Pharmacol 2020 25;11:592737. Epub 2021 Jan 25.

National Center for Advancing Translational Sciences, Rockville, MD, United States.

Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drugs and 49 investigational drugs. The anti-SARS-CoV-2 activities of 230 of these confirmed compounds, of which 38 are approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA-approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set is a useful resource for drug repurposing efforts, including design of new drug combinations for clinical trials for SARS-CoV-2.
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http://dx.doi.org/10.3389/fphar.2020.592737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942396PMC
January 2021

Development and Validation of a Dynamic Nomogram to Predict the Risk of Neonatal White Matter Damage.

Front Hum Neurosci 2020 23;14:584236. Epub 2021 Feb 23.

Neonatal Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Purpose: White matter damage (WMD) was defined as the appearance of rough and uneven echo enhancement in the white matter around the ventricle. The aim of this study was to develop and validate a risk prediction model for neonatal WMD.

Materials And Methods: We collected data for 1,733 infants hospitalized at the Department of Neonatology at The First Affiliated Hospital of Zhengzhou University from 2017 to 2020. Infants were randomly assigned to training ( = 1,216) or validation ( = 517) cohorts at a ratio of 7:3. Multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to establish a risk prediction model and web-based risk calculator based on the training cohort data. The predictive accuracy of the model was verified in the validation cohort.

Results: We identified four variables as independent risk factors for brain WMD in neonates by multivariate logistic regression and LASSO analysis, including gestational age, fetal distress, prelabor rupture of membranes, and use of corticosteroids. These were used to establish a risk prediction nomogram and web-based calculator (https://caowenjun.shinyapps.io/dynnomapp/). The C-index of the training and validation sets was 0.898 (95% confidence interval: 0.8745-0.9215) and 0.887 (95% confidence interval: 0.8478-0.9262), respectively. Decision tree analysis showed that the model was highly effective in the threshold range of 1-61%. The sensitivity and specificity of the model were 82.5 and 81.7%, respectively, and the cutoff value was 0.099.

Conclusion: This is the first study describing the use of a nomogram and web-based calculator to predict the risk of WMD in neonates. The web-based calculator increases the applicability of the predictive model and is a convenient tool for doctors at primary hospitals and outpatient clinics, family doctors, and even parents to identify high-risk births early on and implementing appropriate interventions while avoiding excessive treatment of low-risk patients.
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http://dx.doi.org/10.3389/fnhum.2020.584236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940363PMC
February 2021

Application of niclosamide and analogs as small molecule inhibitors of Zika virus and SARS-CoV-2 infection.

Bioorg Med Chem Lett 2021 05 6;40:127906. Epub 2021 Mar 6.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3370, USA. Electronic address:

Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Here, we conducted SAR studies focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2'-OMe and 2'-H substitutions were also advantageous. We found that the 4'-NO substituent can be replaced with a 4'-CN or 4'-CF substituents. Together, these modifications provide a basis for optimizing the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika and other viral infections. Indeed, key analogs were also able to rescue cells from the cytopathic effect of SARS-CoV-2 infection, indicating relevance for therapeutic strategies targeting the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.bmcl.2021.127906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936759PMC
May 2021

Adult-onset deficiency of adenosine deaminase 2-a case report and literature review.

Clin Rheumatol 2021 Feb 26. Epub 2021 Feb 26.

McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease caused by ADA2 gene mutation that is characterized by three phenotype domains: vasculopathy and inflammation, hematological abnormality, and immunodeficiency. Most patients are pediatric patients; adult-onset patients are only occasionally reported. To describe a Chinese case of adult-onset DADA2 in a Chinese patient and explore the genotype and phenotype characteristics of adult-onset DADA2. We examined the clinical, serological, and genetic features of a Chinese adult-onset DADA2 patient. English literature on DADA2 was reviewed. The clinical and genetic characteristics of different age and mutation subgroups were compared. A Chinese Han male presented with recurrent fever, rash, immunodeficiency, and significant vascular events since the age of 25 years. Serum ADA2 activity was diminished, and genotyping revealed a unique compound heterozygous mutation of exon2-10del/exon7del in the ADA2 gene leading to complete exon 7 deletion. Treatment with a TNFα inhibitor achieved disease control. A total of 269 cases carrying 102 mutations were analyzed through a literature review. Adult-onset patients had few symptoms in all three clinical domains; vasculopathy and inflammation were the major symptoms. Patients with null mutations had early disease onset and more frequent hematological abnormalities and immunodeficiency. Patients in all subgroups responded well to TNFα inhibitors. We reported the first Chinese adult-onset DADA2 patient, with a unique mutation. Screening for and differentiation of DADA2 are recommended for patients of all ages, as they might become symptomatic later in life and treatment strategies differ from those of traditional vasculitis. Key Points • We report a novel compound heterozygous deletion mutations of exons 2-10 and exon 7, leading to complete loss of exon 7 in the ADA2 gene. • Adult-onset DADA2 patients had high similarity to systemic vasculitis. • Null mutations contribute to earlier disease onset and more aggressive disease. • We suggest screening for DADA2 in patients with significant central vasculitis, hematological abnormality and immunodeficiency.
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http://dx.doi.org/10.1007/s10067-021-05587-wDOI Listing
February 2021

Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management.

Endocr Pract 2021 Feb 16;27(2):165-169. Epub 2020 Dec 16.

Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address:

Objective: Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 or programmed death 1 and its ligand (programmed death ligand 1) have been approved for the treatment of a variety of cancers. However, ICI therapy is associated with a risk of immune-related adverse events. In this study, we reviewed reported cases of adrenalitis and primary adrenal insufficiency (PAI)-rare but lethal endocrine immune-related adverse events-in patients who underwent ICI therapy.

Methods: We searched multiple databases (PubMed, Web of Science, Cochrane, and Scopus) up to February 2020 for case reports on adrenalitis and PAI caused by ICIs.

Results: We identified 15 case reports on ICI-induced adrenalitis and PAI and reviewed their clinical presentation, characteristics, immunologic and imaging features, and treatment. We also developed a screening strategy for PAI in patients treated with ICIs.

Conclusion: Given the morbidity and mortality associated with acute adrenal crisis, physicians-especially endocrinologists and oncologists-should be aware of this particular risk. PAI caused by autoimmune adrenalitis predominantly occurs in patients treated with programmed death 1 inhibitor monotherapy. PAI often coexists with other endocrinopathies and requires mineralocorticoid as well as glucocorticoid replacement. Even after withdrawal of ICIs, PAI can persist and requires lifelong replacement therapy.
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http://dx.doi.org/10.1016/j.eprac.2020.09.016DOI Listing
February 2021

Personalized Monitoring Model for Electrocardiogram Signals: Diagnostic Accuracy Study.

JMIR Biomed Eng 2020 Jan-Dec;5(1):e24388. Epub 2020 Dec 29.

Trendalyze Inc Newark, NJ United States.

Background: Due to the COVID-19 pandemic, the demand for remote electrocardiogram (ECG) monitoring has increased drastically in an attempt to prevent the spread of the virus and keep vulnerable individuals with less severe cases out of hospitals. Enabling clinicians to set up remote patient ECG monitoring easily and determining how to classify the ECG signals accurately so relevant alerts are sent in a timely fashion is an urgent problem to be addressed for remote patient monitoring (RPM) to be adopted widely. Hence, a new technique is required to enable routine and widespread use of RPM, as is needed due to COVID-19.

Objective: The primary aim of this research is to create a robust and easy-to-use solution for personalized ECG monitoring in real-world settings that is precise, easily configurable, and understandable by clinicians.

Methods: In this paper, we propose a Personalized Monitoring Model (PMM) for ECG data based on motif discovery. Motif discovery finds meaningful or frequently recurring patterns in patient ECG readings. The main strategy is to use motif discovery to extract a small sample of personalized motifs for each individual patient and then use these motifs to predict abnormalities in real-time readings of that patient using an artificial logical network configured by a physician.

Results: Our approach was tested on 30 minutes of ECG readings from 32 patients. The average diagnostic accuracy of the PMM was always above 90% and reached 100% for some parameters, compared to 80% accuracy for the Generalized Monitoring Models (GMM). Regardless of parameter settings, PMM training models were generated within 3-4 minutes, compared to 1 hour (or longer, with increasing amounts of training data) for the GMM.

Conclusions: Our proposed PMM almost eliminates many of the training and small sample issues associated with GMMs. It also addresses accuracy and computational cost issues of the GMM, caused by the uniqueness of heartbeats and training issues. In addition, it addresses the fact that doctors and nurses typically do not have data science training and the skills needed to configure, understand, and even trust existing black box machine learning models.
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http://dx.doi.org/10.2196/24388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814508PMC
December 2020

Correlation Between Symptom Clusters and Quality of Life in Children With Acute Leukemia During Chemotherapy.

Cancer Nurs 2021 Jan 20. Epub 2021 Jan 20.

Author Affiliations: Department of Hematology (Mss Li and Yang), Department of Nursing (Mss Yao, Shen, Wang, and Wen), and Discipline Supervision Office (Ms Chan), Children's Hospital Affiliated to Soochow University, Suzhou, China.

Background: Children with acute leukemia experience various distressing symptoms due to the disease and its treatment during chemotherapy. These symptoms cluster together and have negative impacts on patient outcomes.

Objective: The aim of this study was to examine symptom clusters that children with acute leukemia undergoing chemotherapy are experiencing and the impact of these symptom clusters on their quality of life.

Methods: A cross-sectional study design was used, and 184 Chinese children with acute leukemia who were undergoing chemotherapy were invited to participate in the study. Memorial Symptom Assessment Scale 10-18 and Pediatric Quality of Life Inventory General Core Module version 4.0 were applied. Exploratory factor analysis and multiple regression were used to identify symptom clusters and their influence on the quality of life.

Results: Six symptom clusters were identified as gastrointestinal, emotional, neurological, skin mucosal, self-image disorder, and somatic cluster. The severity of each symptom cluster was negatively correlated with quality of life. Among them, gastrointestinal, emotional, and somatic clusters were significant predictors of quality of life.

Conclusions: There are multiple symptom clusters in children with acute leukemia, which seriously affect children's quality of life. To relieve symptom burden and improve quality of life, nursing and medical staff should pay attention to the symptom management and control in a symptom cluster perspective.

Implications For Practice: The results of this study will provide suggestions for the healthcare provider to plan for these symptoms and manage any concurrent symptoms for the successful promotion of children's quality of life.
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http://dx.doi.org/10.1097/NCC.0000000000000920DOI Listing
January 2021

Identification of Antifungal Compounds against Multidrug-Resistant Candida auris Utilizing a High-Throughput Drug-Repurposing Screen.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

is an emerging fatal fungal infection that has resulted in several outbreaks in hospitals and care facilities. Current treatment options are limited by the development of drug resistance. Identification of new pharmaceuticals to combat these drug-resistant infections will thus be required to overcome this unmet medical need. We have established a bioluminescent ATP-based assay to identify new compounds and potential drug combinations showing effective growth inhibition against multiple strains of multidrug-resistant The assay is robust and suitable for assessing large compound collections by high-throughput screening (HTS). Utilizing this assay, we conducted a screen of 4,314 approved drugs and pharmacologically active compounds that yielded 25 compounds, including 6 novel anti- compounds and 13 sets of potential two-drug combinations. Among the drug combinations, the serine palmitoyltransferase inhibitor myriocin demonstrated a combinational effect with flucytosine against all tested isolates during screening. This combinational effect was confirmed in 13 clinical isolates of .
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http://dx.doi.org/10.1128/AAC.01305-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097445PMC
March 2021

Sexual function in Chinese women from pregnancy to postpartum: a multicenter longitudinal prospective study.

BMC Pregnancy Childbirth 2021 Jan 19;21(1):65. Epub 2021 Jan 19.

Department of Nursing, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, 210008, Jiangsu, China.

Background: The aims of our research were as follows: First, to estimate the prevalence of female sexual dysfunction in early, middle, late stages of pregnancy, and postpartum 6 months after delivery. Second, to discuss relevant factors associated with female sexual dysfunction among women in 6 months after delivery in Nanjing, Yangzhou and Huaian Main, China.

Methods: Our multicenter longitudinal study was carried out from September 2017 to March 2019, with participants recruited from Southeast China: Nanjing, Yangzhou and Huaian. Participants were recruited when they built their Record of Prenatal Care in community hospitals. The online questionnaires included a set of validated tools, sociodemographic information as wells as medical history data. In the meantime, qualitative interviews were conducted during different periods of pregnancy (from the first trimester to the third trimester of pregnancy and following up to six-month postpartum) respectively. All participants have obtained written informed consent.

Results: By qualitative interview, the vast majority of the participants were inactive in having sex from pregnancy to postpartum. There were negative aspects of sexual experiences, emotional responses closely related to self-attitudes toward sexual behavior during this period. Through quantitative analysis, pre pregnancy BMI (OR = 1.15, P = 0.012), postpartum weight gain (OR = 1.057, P = 0.033) and partnership quality (OR = 1.181, P = 0.04) were associated with postpartum sexual dysfunction 6 months after delivery.

Conclusions: Women are at the risk of significantly different FSD with regard to pre-pregnancy BMI, postpartum weight gain and partnership quality. The impaired sexual function from pregnancy to postpartum period indicated the requirement for further survey as well as extensive investigation.
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http://dx.doi.org/10.1186/s12884-021-03546-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816506PMC
January 2021

Pharmacokinetic study of midazolam and α-hydroxymidazolam in guinea pig blood and hair roots after a single dose of midazolam.

J Pharm Biomed Anal 2021 Feb 4;195:113890. Epub 2021 Jan 4.

Department of Forensic Toxicology, Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Academy of Forensic Science, Shanghai, China. Electronic address:

The appearance of midazolam (M) and its metabolites into the hair root following a single administration was examined by following the time course of M and α-hydroxymidazolam (αHM) in hair roots and blood from guinea pigs. The back hair of guinea pigs was shaved before drug administration and before each sampling, and hair roots (3-5 mm) were plucked at 5, 15, and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120, 144 h, and 7, 14, 21, and 28 days. The kinetic parameters of M and αHM in guinea pig blood and hair roots were determined for three doses (5, 10, and 25 mg/kg). Comparisons of drug time course between hair roots and blood indicated an association between drug concentrations in the hair root and the blood. M and αHM entered the hair root within 5 min after a single exposure. The detection windows were also longer for the hair root than for the blood. Consequently, the hair root can be a valuable specimen in acute poisonings or drug-facilitated crime (DFC) cases, if other matrices are unavailable, or if blood and urine results are negative. Hair shafts (with hair roots) were plucked at 28 days and segmented. The concentrations of M and αHM were lower in the hair shafts than in the hair roots. The concentrations of the metabolite αHM in hair shafts were barely detectable. The concentrations of M and αHM in the hair root showed a moderate correlation with dose. Comparison of drug levels in hair roots between the washed group and the unwashed group indicated a generally stable percentage between the washed and unwashed groups of 40-60 % during the entire time course. This indicates that drugs are likely to be immobilized in the hair root at the beginning of the incorporation process.
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http://dx.doi.org/10.1016/j.jpba.2021.113890DOI Listing
February 2021

Acute Ischemic Stroke in a Pediatric Patient With Known Exposure to COVID-19 and Positive Serology.

Pediatr Neurol 2021 03 15;116:39-40. Epub 2020 Dec 15.

Department of Neurology, Columbia University Irving Medical Center, New York, New York; New York-Presbyterian Hospital, New York, New York.

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http://dx.doi.org/10.1016/j.pediatrneurol.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737529PMC
March 2021

GATA2 mutation with recurrent hemophagocytic lymphohistiocytosis and panniculitis: a case report.

Rheumatology (Oxford) 2021 Jan 7. Epub 2021 Jan 7.

McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1093/rheumatology/keaa913DOI Listing
January 2021

Non-covalent TMPRSS2 inhibitors identified from virtual screening.

bioRxiv 2020 Dec 29. Epub 2020 Dec 29.

The SARS-CoV-2 pandemic has prompted researchers to pivot their efforts to finding anti-viral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 (TMPRSS2), which plays an important role in the viral life cycle by cleaving the spike protein to initiate membrane fusion. TMPRSS2 is an attractive target and has received significant attention for the development of drugs against SARS and MERS. Starting with comparative structural modeling and binding model analysis, we developed an efficient pharmacophore-based approach and applied in a large-scale database screening for small molecule inhibitors against TMPRSS2. A number of novel inhibitors were identified, providing starting points for further development of drug candidates for the treatment of COVID-19.
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http://dx.doi.org/10.1101/2020.12.28.424413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781311PMC
December 2020

Virus load and virus shedding of SARS-CoV-2 and their impact on patient outcomes.

World J Clin Cases 2020 Dec;8(24):6252-6263

Expert Panel of Shenzhen 2019-nCoV Pneumonia, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, Guangdong Province, China.

Background: Understanding a virus shedding patterns in body fluids/secretions is important to determine the samples to be used for diagnosis and to formulate infection control measures.

Aim: To investigate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding patterns and its risk factors.

Methods: All laboratory-confirmed coronavirus disease 2019 patients with complete medical records admitted to the Shenzhen Third People's Hospital from January 28, 2020 to March 8, 2020 were included. Among 145 patients (54.5% males; median age, 46.1 years), three (2.1%) died. The bronco-alveolar lavage fluid (BALF) had the highest virus load compared with the other samples. The viral load peaked at admission (3.3 × 10 copies) and sharply decreased 10 d after admission.

Results: The viral load was associated with prolonged intensive care unit (ICU) duration. Patients in the ICU had significantly longer shedding time compared to those in the wards ( < 0.0001). Age > 60 years [hazard ratio (HR) = 0.6; 95% confidence interval (CI): 0.4-0.9] was an independent risk factor for SARS-CoV-2 shedding, while chloroquine (HR = 22.8; 95%CI: 2.3-224.6) was a protective factor.

Conclusion: BALF had the highest SARS-CoV-2 load. Elderly patients had higher virus loads, which was associated with a prolonged ICU stay. Chloroquine was associated with shorter shedding duration and increased the chance of viral negativity.
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http://dx.doi.org/10.12998/wjcc.v8.i24.6252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760445PMC
December 2020