Search

Ming Zhang,1,* Feng Chen,2,* Shaoguang Feng,3,* Xu Liu,4 Zhen Wang,5 Nan Shen,6 Lingjian Meng,7 Dongsheng Zhu,1 Zhitao Zhu8 1Department of Pediatric Surgery, The First People’s Hospital of Lianyungang, Lianyungang, People’s Republic of China; 2Department of Pediatric, Luodian Hospital, Shanghai, People’s Republic of China; 3Department of Pediatric Surgery, The Children’s Hospital of Hangzhou, Hangzhou, People’s Republic of China; 4Department of Pediatric Surgery, The Children’s Hospital of Xuzhou, Xuzhou, People’s Republic of China; 5Department of Pediatric, the Maternal and Child Health Hospital of Zibo, Zibo, People’s Republic of China; 6Department of Pediatrics, Suqian Hospital Affiliated to Xuzhou Medical University, Suqian, People’s Republic of China; 7Department of Pediatrics, Hospital Affiliated to Xuzhou Medical University, Xuzhou, People’s Republic of China; 8Department of Radiology, The Second People’s Hospital of Lianyungang, Lianyungang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhitao Zhu; Dongsheng Zhu, Email zhuzhitao621@126.com; zhudongsheng@tmu.edu.cnObjective: To investigate the role of FBLN5in renal clear cell carcinoma (KIRC), in particular on the tumor’s immune microenvironment, including children and young adults.Methods: FBLN5 expression in tumor and normal samples was explored using SangerBox, TIMER2.0, GEPIA, UALCAN, HPA databases. The Linkedomics database was used to obtain FBLN5 co-expressed genes in KIRC tissue. SangerBox was also used to estimate immune infiltration of FBLN5 in KIRC. The Kaplan-Meier plotter was used to investigate the survival effects of FBLN5 expression in the presence of immune infiltration. We then collected 48 cases from 7 hospitals over a-20 year period to calculate the impact of FBLN5 on the prognosis of children and young adults with KIRC.Results: FBLN5 expression was significantly reduced in KIRC tissue compared to normal adjacent tissue. FBLN5 was potentially involved in the immune-related biological processes. In addition, FBLN5 expression has been linked to a number of immune checkpoints, cytokines, chemokines and chemokine receptors in KIRC. At the same time, the expression of FBLN5 affected the survival rates differently in KIRC patients with high or low levels of immune infiltration. High expression of FBLN5 in children and young adults with KIRC was associated with a favorable prognosis.Conclusion: This study shed light on the potential of FBLN5 as a prognostic marker in children and young adults with KIRC and as an immune-related target for clinical treatment.Keywords: FBLN5, immune microenvironment, prognostic biomarker, kidney cancer, children

Ziyu Guo,1 Yanxiang Gao,2 Enmin Xie,3 Zixiang Ye,1 Yike Li,3 Xuecheng Zhao,2 Nan Shen,1 Jingang Zheng1– 3 1Department of Cardiology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, People’s Republic of China; 2Department of Cardiology, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3Graduate School of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Jingang Zheng, Department of Cardiology, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China, Tel +86 18810966781, Email mdjingangzheng@yeah.netPurpose: The pandemic of coronavirus disease 2019 (COVID-19) has highlighted the intricate relationship between underlying conditions and death. We designed this study to determine whether metformin therapy for type 2 diabetes mellitus (T2D) is associated with low in-hospital mortality in patients hospitalized for COVID-19.Materials and Methods: This was a retrospective study including patients with COVID-19 and T2D in Wuhan, from February 4th to April 11th, 2020. Patients were divided into two groups according to metformin exposure. The hazard ratio (HR) of COVID-19-related mortality and invasive mechanical ventilation was estimated using Cox regression.Results: There were 571 T2D patients among the 4330 confirmed COVID-19 patients. Of those patients, 241 received metformin therapy. The in-hospital mortality and invasive mechanical ventilation of metformin group was lower than non-metformin group. In the multivariate model, metformin use was linked to a decreased in-hospital mortality and invasive mechanical ventilation when compared with that of the control group (HR: 0.376 [95% CI 0.154– 0.922]; P = 0.033).Conclusion: Our study indicated that metformin therapy was associated with decreased death risk in COVID-19 patients with T2D.Keywords: COVID-19, diabetes mellitus, metformin, mortality

Jian Wang, Ningning Shen, Huiliang Shen Department of Dermatology, Zhejiang Provincial Institute for Dermatoses Prevention and Cure, Huzhou City, Zhejiang Province, 313200, People’s Republic of ChinaCorrespondence: Huiliang Shen, Department of Dermatology, Zhejiang Provincial Institute for Dermatoses Prevention and Cure, No. 61, Wuyuan Street, Wukang Town, Deqing County, Huzhou City, Zhejiang Province, 313200, People’s Republic of China, Email shl.1168@163.comAbstract: Local hyperthermia treatment, a common immunoadjuvant therapy, has been used in treating various human papillomavirus (HPV) infections. For multiple warts, it can clear off all warts of the body through targeted irradiation on one wart. We reported a case of a 22-year-old patient with multiple plantar warts combined with periungual warts, in which previous treatments were ineffective. Therefore, we utilized local hyperthermia treatment at 44°C using the largest fused-wart plaque on the right plantar as the treatment target for 30-minute irradiation each time. The hyperthermia induction therapy was performed on day 1, 2, 3, 12 and 13, followed by weekly maintenance therapy for 6 times. After 2 months of treatment, both irradiated and non-irradiated lesions disappeared, and no recurrence occurred during the follow-up period. This case indicates that local hyperthermia treatment may be a safe and effective approach for patients with multiple, recalcitrant, and site-specific viral warts due to the ineffectiveness of conventional treatment.Keywords: local hyperthermia treatment, multiple, plantar warts, periungual warts

Ping Yang,1,2 Chao Liu,3 Zhenchao Wu,2 Jiajia Zheng,4 Juan Yi,1 Nan Wu,2 Zhangli Wu,1,2 Ming Lu,2,3 Liyan Cui,4,&ast; Ning Shen1– 3,&ast; 1Institute of Medical Technology, Peking University Health Science Center, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 3Department of Infectious Diseases, Peking University Third Hospital, Beijing, People’s Republic of China; 4Department of Laboratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liyan Cui; Ning Shen, Email cliyan@163.com; shenningputh@163.comPurpose: This study aimed to identify the clinical outcomes, microbiological features and risk factors for difficult-to-treat resistance (DTR) Klebsiella pneumoniae (Kp) infection.Materials and Methods: A retrospective study was conducted at Peking University Third Hospital from January 2020 to March 2021. DTR was defined as resistance to ≥ 1 carbapenem, ≥ 1 extended-spectrum cephalosporin, and ≥ 1 fluoroquinolone. Hypervirulent Kp (HvKp) was defined as peg-344-, iroB-, iucA-, rmpA-, or rmpA2-positive. Clinical data were collected. Antimicrobial susceptibility testing and string tests were performed to determine resistance and hypermucoviscosity phenotype. Whole genome sequencing was performed to analyze the sequence type (ST), capsular serotypes, resistance and virulence genes. Risk factors for 30-day mortality were analyzed.Results: Fifty DTR-Kp (50.0%) strains were identified among 100 patients. Compared to non-DTR-Kp group, a significant number of patients with DTR-Kp infection experienced ICU admission (44.0% versus 10.0%, P< 0.001) and mechanical ventilation after Kp detection (26.0% versus 10.0%, P=0.037). Notably, the percentage of hvKp among the DTR-Kp isolates increased consistently over the 15 months evaluated. Most DTR-Kp strains belonged to ST11 (82.0%), followed by ST15 (12.0%), ST86 (2.0%), ST996 (2.0%), and ST3157 (2.0%). DTR-Kp isolates possessed various resistance genes, such as blaKPC-2, blaTEM-1D and fosA3 (90.0%, 80.0% and 72.0%, respectively). Importantly, the yersiniabactin genes were significantly clustered in DTR group (48/50, 96.0%). The 30-day mortality was significantly higher in patients with DTR-Kp infection than non-DTR-Kp group (38.0% versus 8.2%, P=0.001). DTR-Kp infection (odds ratio [OR] = 4.196) was an independent risk factor for the 30-day mortality of Kp-infected patients. Additionally, cerebrovascular disease (OR = 2.780) and Charlson comorbidity index (OR= 1.584) were independent risk factors for DTR-Kp infections.Conclusion: DTR-hvKp is rapidly emerging. The DTR-Kp strains harbored various resistance genes and high rates of yersiniabactin siderophore genes. DTR-Kp infection was an independent risk factor for mortality, suggesting that enhanced awareness essential.Keywords: Klebsiella pneumoniae, difficult-to-treat resistance, mortality, risk factor

Yuanjie Qiu, Yan Wang, Nirui Shen, Qingting Wang, Limin Chai, Jin Liu, Yuqian Chen, Manxiang Li Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaCorrespondence: Manxiang Li, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277, West Yanta Road, Xi’an, 710061, People’s Republic of China, Tel/Fax +86-029-85323850, Email manxiangli@hotmail.comPurpose: High levels of red blood cell distribution width (RDW) and hypoalbuminemia are markers of poor prognosis in chronic obstructive pulmonary disease (COPD) patients. However, few studies have shown that the red blood cell distribution width–albumin ratio (RAR) is related to the mortality of COPD. This study aimed to explore the relationship between RAR and hospital mortality in COPD patients admitted to the intensive care unit (ICU).Patients and Methods: Patients were retrospectively incorporated from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and divided into two groups by a cutoff value of RAR. Propensity score matching (PSM) was performed to adjust for the imbalance of covariates. Logistic regression models and subgroup analyses were carried out to investigate the relationship between RAR and hospital mortality. The receiver operating characteristic (ROC) curve was used to evaluate the predictive performance of RAR and decision curve analysis (DCA) to assess the clinical utility.Results: In total, 1174 patients were finally identified from the MIMIC-IV database. The cutoff value for RAR was 5.315%/g/dL. After PSM at a 1:1 ratio, 638 patients were included in the matched cohort. In the original and matched cohorts, the high RAR group had higher hospital mortality and longer hospital stays. Logistic regression analysis suggested that RAR was an independent risk factor for hospital mortality. The areas under the ROC curve in the original and matched cohorts were 0.706 and 0.611, respectively, which were larger than applying RDW alone (the original cohort: 0.600, the matched cohort: 0.514). The DCA indicated that RAR had a clinical utility.Conclusion: A higher RAR (> 5.315%/g/dL) was associated with hospital mortality in COPD patients admitted to ICU. As an easily available peripheral blood marker, RAR can predict hospital mortality in critically ill patients with COPD independently.Graphical Abstract: Keywords: chronic obstructive pulmonary disease, red blood cell distribution width, albumin, hospital mortality, MIMIC-IV

To improve crowd evacuation efficiency in large building spaces during fires, a spatial layout optimization method using PyroSim and Pathfinder software was proposed. Disaster-causing factors that hinder safe evacuation - such as smoke spread, fire scene temperature, CO concentration, and visibility - were compared. The arrival time of danger in fire environments was analysed, the time required for crowd evacuation was calculated, structural characteristics of building space affecting evacuation efficiency were identified, and evacuation bottlenecks in large-scale buildings were revealed. Taking the super-large building of Silk Clothing City in Jiangsu Province, China as an example, a spatial layout optimization scheme focused on evacuation efficiency was proposed and its effectiveness was verified. Results show that before spatial layout optimization, the available safe evacuation time is 145 seconds, which is shorter than the required safe evacuation time of 197.8 seconds, indicating high safety risks during evacuation in a fire. After optimizing the layout of smoke exhaust equipment, the available safe evacuation time is increased to 205 seconds, substantially enhancing crowd evacuation safety. [ABSTRACT FROM AUTHOR]

Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid-binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and interleukin (IL)-6 in the sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and signal transducer and activator of transcription factor 3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15INK4B tumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15INK4B expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia.

Yue Wang,1 Qun Lin,1 Zhongju Chen,1 Hongyan Hou,1 Na Shen,1 Zhen Wang,2 Feng Wang,1 Ziyong Sun1 1Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China; 2Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of ChinaCorrespondence: Ziyong SunDepartment of Laboratory Medicine, Tongji Hospital, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, 430030, People’s Republic of ChinaEmail zysun@tjh.tjmu.edu.cnBackground: To establish a risk prediction model for carbapenem-resistant Enterobacteriaceae (CRE) bloodstream infection (BSI) in intestinal carriers.Methods: CRE screenings were performed every two weeks in hematology department and intensive care unit (ICU). Patients with positive CRE rectal swab screening were identified using electronic medical records from 15 May 2018 to 31 December 2019. Intestinal carriers who developed CRE BSI were compared with those who did not develop CRE infection. A 1:1 matched case-control study was conducted. The control group was selected by stratified random sampling based on the department to ensure that all the departments were represented. Univariate logistic analysis, multivariate logistic analysis and stepwise regression analysis were carried on a variety of patient factors and microbial factors.Results: A total of 42 cases were included. Multivariate analysis showed that gastrointestinal injury (OR 86.819, 95% CI 2.584– 2916.592, P=0.013), tigecycline exposure (OR 14.991, 95% CI 1.816– 123.737, P=0.012) and carbapenem resistance score (OR 11.236, 95% CI 1.811– 69.700, P=0.009) were independent risk factors for CRE BSI in intestinal carriers (P< 0.050). They were included in the Logistic regression model to predict BSI. According to receiver operating characteristic (ROC) curve analysis, the cut-off value of the model was 0.722, and the sensitivity, specificity and area under the curve (AUC) were 90.5%, 85.7% and 0.921, respectively.Conclusion: The risk prediction model based on gastrointestinal injury, tigecycline exposure and carbapenem resistance score of colonizing strain can effectively predict CRE BSI in patients with CRE colonization. Early CRE screening and detection for inpatients in key departments may promote early warning and reduce the risk of nosocomial infection of CRE.Keywords: carbapenem-resistant Enterobacteriaceae, colonization, bloodstream infection, risk factor, risk prediction model

Chenxia Guo, Xiaoyan Sun, Wenqi Diao, Ning Shen,* Bei He* Department of Respiratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bei HePeking University Third Hospital, Beijing, People’s Republic of ChinaTel +86 13910125933Email puh3_hb@bjmu.edu.cnNing ShenPeking University Third Hospital, People’s Republic of ChinaTel +86 13693638871Email shenning1972@126.comAbstract: Short-term exposure to major air pollutants can increase the risk of acute exacerbation in chronic obstructive pulmonary disease (COPD) patients. However, evidence on the mechanism of acute exacerbation of COPD (AECOPD) caused by air pollutants is still limited. A total of 78 patients with stable COPD and 58 healthy controls were recruited in Peking University Third Hospital in China from December 2014 to January 2015. The correlation and lag effect over 7 days (lag1– 7) of 6 air pollutants with clinical symptoms and inflammatory markers in induced sputum were analyzed. PM2.5, NO2 and CO were positively correlated with the COPD assessment test (CAT) score at lag 5, PM10 was positively correlated with the CAT score at lag 3, MMP-9 and IL-8 were positively correlated with PM2.5, PM10 and NO2 at lag 2, and CO was positively correlated with each other marker at lag 4. Short-term exposure to PM2.5, PM10, NO2, and CO can cause a neutrophil-mediated airway inflammatory response, followed by increased clinical symptoms. If the PM2.5, PM10, NO2 and CO exposure levels increase during air pollution monitoring, the early usage of medication or reduction of exposure to pollutants can effectively reduce the clinical symptoms of patients.Keywords: chronic obstructive pulmonary disease, air pollution, matrix metalloproteinase 9, interleukin 8, induced sputum

The mechanisms by which AML1/ETO (A/E) fusion protein induces leukemogenesis in acute myeloid leukemia (AML) without mutagenic events remain elusive. Here we show that interactions between A/E and hypoxia-inducible factor 1α (HIF1α) are sufficient to prime leukemia cells for subsequent aggressive growth. In agreement with this, HIF1α is highly expressed in A/E-positive AML patients and strongly predicts inferior outcomes, regardless of gene mutations. Co-expression of A/E and HIF1α in leukemia cells causes a higher cell proliferation rate in vitro and more serious leukemic status in mice. Mechanistically, A/E and HIF1α form a positive regulatory circuit and cooperate to transactivate DNMT3a gene leading to DNA hypermethylation. Pharmacological or genetic interventions in the A/E-HIF1α loop results in DNA hypomethylation, a re-expression of hypermethylated tumor-suppressor p15(INK4b) and the blockage of leukemia growth. Thus high HIF1α expression serves as a reliable marker, which identifies patients with a poor prognosis in an otherwise prognostically favorable AML group and represents an innovative therapeutic target in high-risk A/E-driven leukemia.

Wenqi Diao1, Wassim W Labaki2, MeiLan K Han2, Larisa Yeomans3, Yihan Sun4, Zyad Smiley4, Jae Hyun Kim3, Cora McHugh4, Pingchao Xiang5, Ning Shen6, Xiaoyan Sun6, Chenxia Guo6, Ming Lu6, Theodore J Standiford2, Bei He*,7, Kathleen A Stringer*,2,4 1Department of Respiratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, MI, USA; 3Biochemical Nuclear Magnetic Resonance Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; 4NMR Metabolomics Laboratory, Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; 5Department of Respiratory and Critical Care Medicine, Shou-Gang Hospital Affiliated to Peking University, Beijing, People’s Republic of China; 6Department of Respiratory Medicine, Peking University Third Hospital, Beijing 100191, People’s Republic of China; 7Department of Respiratory Medicine, Peking University Health Sciences Center, Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kathleen A StringerCollege of Pharmacy, University of Michigan, Ann Arbor, MI 48104, USATel +1 734 647 4775Email stringek@umich.eduBackground: Chronic obstructive pulmonary disease (COPD) is a systemic condition that is too complex to be assessed by lung function alone. Metabolomics has the potential to help understand the mechanistic underpinnings that contribute to COPD pathogenesis. Since blood metabolomics may be affected by sex and body mass index (BMI), the aim of this study was to determine the metabolomic variability in male smokers with and without COPD who have a narrow BMI range.Methods: We compared the quantitative proton nuclear magnetic resonance acquired serum metabolomics of a male Chinese Han population of non-smokers without COPD, and smokers with and without COPD. We also assessed the impact of smoking status on metabolite concentrations and the associations between metabolite concentrations and inflammatory markers such as serum interleukin-6 and histamine, and blood cell differential (%). Metabolomics data were log-transformed and auto-scaled for parametric statistical analysis. Mean normalized metabolite concentration values and continuous demographic variables were compared by Student’s t-test with Welch correction or ANOVA with post-hoc Tukey’s test, as applicable; t-test p-values for metabolomics data were corrected for false discovery rate (FDR). A Pearson association matrix was built to evaluate the relationship between metabolite concentrations, clinical parameters and markers of inflammation.Results: Twenty-eight metabolites were identified and quantified. Creatine, glycine, histidine, and threonine concentrations were reduced in COPD patients compared to non-COPD smokers (FDR ≤15%). Concentrations of these metabolites were inversely correlated with interleukin-6 levels. COPD patients had overall dampening of metabolite concentrations including energy-related metabolic pathways such as creatine metabolism. They also had higher histamine levels and percent basophils compared to smokers without COPD.Conclusion: COPD is associated with alterations in the serum metabolome, including a disruption in the histidine-histamine and creatine metabolic pathways. These findings support the use of metabolomics to understand the pathogenic mechanisms involved in COPD.Trial registration www.clinicaltrials.gov, NCT03310177.Keywords: China, metabolomics, histidine, energy homeostasis, inflammation, chronic obstructive pulmonary disease

Wenqi Diao,1,* Ning Shen,1,* Yipeng Du,1,* John R Erb-Downward,2 Xiaoyan Sun,1 Chenxia Guo,1 Qian Ke,1 Gary B Huffnagle,2,3 Margaret R Gyetko,2 Bei He1 1Department of Respiratory Medicine, Peking University Third Hospital, Beijing 100191, China; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; 3Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA *These authors contributed equally to this work Background: The role of airway microbiota in COPD is highly debated. Symptomology assessment is vital for the management of clinically stable COPD patients; however, the link between symp­toms and the airway microbiome is currently unknown. Purpose: The present study aimed to evaluate the relationship among stable COPD patients. Patients and methods: We conducted pyrosequencing of bacterial 16S rRNA using induced sputum samples in a Han Chinese cohort that included 40 clinically stable COPD patients and 19 healthy controls. Results: Alterations in community composition and core bacte­rial taxa (Neisseria subflava, etc.) were observed in patients with severe symptoms compared with controls. The co-occurrence network indicated that the key microbiota enriched in COPD patients showed higher expression in patients with severe symptoms. The association pattern of symptoms with the sputum microbiome was obviously different from that of lung function in COPD patients. Conclusion: These findings broaden our insights into the relationship between the sputum microbiota and the symptom severity in COPD patients, emphasizing the role of symptoms in the airway microbiome, independent of lung function. Keywords: chronic obstructive pulmonary disease, symptom, sputum, microbiome

We consider the evolution of a spatially periodic, perturbed vortex sheet for small times after the formation of a curvature singularity at time t = tc as demonstrated by Moore (Proc. R. Soc. Lond. A, vol. 365, issue 1720, 1979, pp. 105-119). The Moore analysis is extended to provide the small-amplitude, full-sheet structure at t = tc for a general single-mode initial condition in terms of polylogarithmic functions, from which its asymptotic form near the singular point is determined. This defines an intermediate evolution problem for which the leading-order, and most singular, approximation is solved as a Taylor-series expansion in τ = t - tc, where coefficients are calculated by repeated differentiation of the defining Birkhoff-Rott (BR) equation. The first few terms are in good agreement with numerical calculation based on the full-sheet solution. The series is summed, providing an analytic continuation which shows sheet rupture at circulation r = 0+, τ > 0+, but with non-physical features owing to the absence of end-tip sheet roll up. This is corrected by constructing an inner solution with r < τ, as a perturbed similarity form with small parameter τ1/2. Numerical solutions of both the inner, nonlinear zeroth-order and first-order linear BR equations are obtained whose outer limits match the intermediate solution. The composite solution shows sheet tearing at τ = 0+ into two separate, rolled up algebraic spirals near the central singular point. Branch separation distance scales as T with a non-local, τ3/2 correction. Properties of the intermediate and inner solutions are discussed. [ABSTRACT FROM AUTHOR]

Lei Yin,* Zheng Fang,* Ning-jia Shen, Ying-he Qiu, Ai-jun Li, Yong-jie Zhang The Second Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China *These authors contributed equally to this work Abstract: Hepatocellular carcinoma (HCC) is a highly fatal disease mandating development of novel, effective therapeutic strategy. Interferon-gamma (IFN-γ) is a pleiotropic cytokine with immunomodulatory, antiviral, and antitumor effects. Although IFN-γ is a promising antitumor agent, its application is limited by resistance in tumor cells. A20 is a zinc-finger protein that was initially identified as a gene product induced by tumor necrosis factor α in human umbilical vein endothelial cells. In this study, we found that silencing of A20 combined with IFN-γ significantly represses cell viability, and induces apoptosis and cell-cycle arrest in HCC cells. By investigating mechanisms implicated in A20 and IFN-γ-mediated signaling pathways, we revealed that the phosphoinositide 3-kinase/Akt signaling pathway and antiapoptotic B-cell lymphoma 2 proteins were repressed. Moreover, we also found that phosphorylation of STAT1 and STAT3 was significantly enhanced after the downregulation of A20 in combination with treatment of IFN-γ. Inhibitor of STAT1 but not STAT3 could block the antitumor effect of IFN-γ. Therefore, targeting A20 enhances the cytotoxicity of IFN-γ against HCC cells and may present a promising therapeutic strategy for HCC. Keywords: IFN-γ, A20, hepatocellular carcinoma, PI3K/Akt, STAT1, STAT3

Wenqi Diao,* Ning Shen,* Yipeng Du, Ke Qian, Bei He Department of Respiratory Medicine, Peking University Third Hospital, Beijing, China *These authors contributed equally to this work Abstract: The study aimed to determine the relationship between throat microbiome and COPD. Sixty-five Chinese males (n=20, smokers without COPD; n=45 smokers with COPD) were included. Nonmetric multidimensional scaling indicated differences of microbiome between COPD and controls, but no difference was observed between COPD patients with differing degrees of lung function or disease severity. Rarefaction analyses suggested that operational taxonomic units (OTUs, species-level) richness decreased in COPD. The dominant taxa between COPD and controls were similar, but the proportions of taxonomic distribution were different. The dominant phyla were Bacteroidetes, Proteobacteria, Firmicutes and Fusobacteria. The dominant genera were Haemophilus, Leptotrichia, Porphyromonas, Fusobacterium, Veillonella, Streptococcus, Neisseria and Prevotella. Two dominant OTUs, otu3 (Veillonella_dispar) and otu4 (Streptococcus_unclassified), were identified. Otu3 and its father-level taxa, which were negatively correlated with predicted percent of forced expiratory volume in a second (FEV1%pred), were increased in COPD. By contrast, otu4 and its father-level taxa, which were positively correlated with FEV1%pred, were decreased in COPD. Otu4 also showed a slight potential as a COPD biomarker. To conclude, the throat microbiome was different between smokers with or without COPD, which is similar to findings from the lower respiratory tract. This study may strengthen our understanding of the relationship between microbiomes of different airway sites and COPD. Keywords: microbiome, throat, chronic obstructive pulmonary disease

Wenqi Diao,1 Ning Shen,1 Yipeng Du,1 Xiaoyan Sun,1 Beibei Liu,1 Ming Xu,2,3 Bei He1 1Department of Respiratory Medicine, 2Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, 3Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, People’s Republic of China Abstract: Biomarkers for the management of chronic obstructive pulmonary disease (COPD) are limited. The aim of this study was to explore new plasma biomarkers in patients with COPD. Thyroxine-binding globulin (THBG) was initially identified by proteomics in a discovery panel and subsequently verified by enzyme-linked immunosorbent assay in another verification panel with a 1-year follow-up. THBG levels were elevated in patients with COPD (9.2±2.3 µg/mL) compared to those of the controls (6.6±2.0 µg/mL). Receiver operating characteristic curves suggested that THBG was able to slightly differentiate between patients with COPD and controls (area under the curve [AUC]: 0.814) and performed better if combined with fibrinogen (AUC: 0.858). THBG was more capable of distinguishing Global Initiative for Obstructive Lung Disease stages I–III and IV (AUC: 0.851) compared with fibrinogen (AUC 0.582). THBG levels were negatively associated with predicted percentage forced expiratory volume in 1 s and positively related to predicted percentage residual volume, RV/percentage total lung capacity, and percentage low-attenuation area. COPD patients with higher baseline THBG levels had a greater risk of acute exacerbation (AE) than those with lower THBG levels (P=0.014, by Kaplan–Meier curve; hazard ratio: 4.229, by Cox proportional hazards model). In summary, THBG is a potential plasma biomarker of COPD and can assist in the management of stable stage and AEs in COPD patients. Keywords: thyroxine-binding globulin, biomarker, chronic obstructive pulmonary disease, proteomics

Shear instabilities at the interface of two fluids, such as classical Kelvin-Helmholtz instability (KHI), is the precursor of interface destabilization, leading to fluid fragmentation critical in a wide range of applications. While many insights into such instabilities are derived for steady background forcing flow, unsteady impulse flows are ubiquitous in environmental and physiological processes. Yet, little is understood on how unsteadiness shapes the initial interface amplification necessary for the onset of its topological change enabling subsequent fragmentation. In this combined theoretical, numerical and experimental study, we focus on an air-on-liquid interface exposed to canonical unsteady shear flow profiles. Evolution of the perturbed interface is formulated theoretically as an impulse-driven initial value problem using both linearized potential flow and nonlinear boundary integral methods. We show that the unsteady airflow forcing can amplify the interface's inherent gravity-capillary wave, up to wave-breaking transition, even if the configuration is classically KH stable. For impulses much shorter than the gravity-capillary wave period, it is the cumulative action, akin to total energy, that determines amplification, independent of the details of the impulse profile. However, for longer impulses, the details of the impulse profile become important. In this limit, akin to a resonance, it is the entangled history of the interaction of the forcing, i.e. the impulse, that changes rapidly in amplitude, and the response of the oscillating interface that matters. The insights gained are discussed and experimentally illustrated in the context of interface distortion and destabilization relevant for upper respiratory mucosalivary fluid fragmentation in violent exhalations. [ABSTRACT FROM AUTHOR]

Blood vessel formation is an important initial step for bone formation during development as well as during remodelling and repair in the adult skeleton. This results in a heavily vascularized tissue where endothelial cells and skeletal cells are constantly in crosstalk to facilitate homeostasis, a process that is mediated by numerous environmental signals, including mechanical loading. Breakdown in this communication can lead to disease and/or poor fracture repair. Therefore, this study aimed to determine the role of mature bone cells in regulating angiogenesis, how this is influenced by a dynamic mechanical environment, and understand the mechanism by which this could occur. Herein, we demonstrate that both osteoblasts and osteocytes coordinate endothelial cell proliferation, migration, and blood vessel formation via a mechanically dependent paracrine mechanism. Moreover, we identified that this process is mediated via the secretion of extracellular vesicles (EVs), as isolated EVs from mechanically stimulated bone cells elicited the same response as seen with the full secretome, while the EV-depleted secretome did not elicit any effect. Despite mechanically activated bone cell-derived EVs (MA-EVs) driving a similar response to VEGF treatment, MA-EVs contain minimal quantities of this angiogenic factor. Lastly, a miRNA screen identified mechanoresponsive miRNAs packaged within MA-EVs which are linked with angiogenesis. Taken together, this study has highlighted an important mechanism in osteogenic-angiogenic coupling in bone and has identified the mechanically activated bone cell-derived EVs as a therapeutic to promote angiogenesis and potentially bone repair. [ABSTRACT FROM AUTHOR]