Publications by authors named "Rong Zhang"

2,510 Publications

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Cathepsin B/HSP70 complex induced by Ilexsaponin I suppresses NLRP3 inflammasome activation in myocardial ischemia/reperfusion injury.

Phytomedicine 2022 Jul 25;105:154358. Epub 2022 Jul 25.

Shunde Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan, Guangdong, 528333, PR China; Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou Univ Chinese Med, Guangzhou, Guangdong, 510006, PR China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou Univ Chinese Med, Guangzhou, Guangdong, 510006, PR China. Electronic address:

Background: Myocardial ischemia/reperfusion injury (MI/RI) is a clinical issue in MI therapy that requires effective intervention. Cathepsin B (CTSB) plays an essential role in regulating cell death, inflammatory response and angiogenesis. Ilexsaponin I (ISI), a triterpenoid saponin obtained from Ilex pubescens Hook. et Arn, has anti-inflammatory and cardioprotective effects. However, the effect of ISI on MI/RI is unclear.

Purpose: The study aims to disclose the mechanism of ISI as a potent therapeutic agent for MI/RI.

Methods: Left anterior descending (LAD) coronary artery ligation and oxygen-glucose deprivation and reperfusion (OGD/R) were used to establish MI/RI model in vivo and in vitro. ELISA, western blot and immunofluorescence were carried out to detect CTSB activity and NLRP3 inflammasome activation. Coimmunoprecipitation (Co-IP), molecular docking and surface plasmon resonance (SPR) analysis were used to detect the interaction of CTSB/HSP70 complex. Infarct area determination, echocardiography and hematoxylin and eosin (HE) staining were performed to assess the cardioprotection of ISI in vivo.

Results: Plasma CTSB was elevated in patients after percutaneous coronary intervention (PCI), and was positively correlated with the level of cTnI in plasma, which was also found in MI/RI rat model. ISI significantly suppressed the overexpression and activity of CTSB after MI/RI or OGD/R. ISI remarkably suppressed CTSB triggered-NLRP3 inflammasome activation and reduced the maturation of IL-1β and IL-18. Importantly, we firstly found that ISI promoted CTSB/HSP70 complex formation to disrupt CTSB/NLRP3 complex, leading to NLRP3 inflammasome inactivation. ISI could also limit infarct size, improve cardiac function and reduce inflammatory infiltrates in vivo and protected H9c2 cells against OGD/R insult in vitro. Interrupting the HSP70 and CTSB interaction with HSP70 siRNA blocked the effect of ISI on CTSB, NLRP3 inflammasome activation and the cardioprotective effect.

Conclusion: ISI probably exerts cardioprotective effect against MI/RI by modulating HSP70 competitively bind to CTSB to suppress the activation of the NLRP3 inflammasome.
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http://dx.doi.org/10.1016/j.phymed.2022.154358DOI Listing
July 2022

False-negative and false-positive outcomes of computer aided detection on brain metastasis: secondary analysis of a multicenter, multireader study.

Neuro Oncol 2022 Aug 9. Epub 2022 Aug 9.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center, for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: Errors have seldom been evaluated in computer-aided detection on brain metastases. This study aimed to analyze false negatives (FNs) and false positives (FPs) generated by a brain metastasis detection system (BMDS) and by readers.

Methods: A deep learning-based BMDS was developed and prospectively validated in a multicenter, multireader study. Ad hoc secondary analysis was restricted to the prospective participants (148 with 1,066 brain metastases and 152 normal controls). Three trainees and three experienced radiologists read the MRI images without and with the BMDS. The number of FNs and FPs per patient, jackknife alternative free-response receiver operating characteristic figure of merit (FOM), and lesion features associated with FNs were analyzed for the BMDS and readers using binary logistic regression.

Results: The FNs, FPs, and the FOM of the stand-alone BMDS were 0.49, 0.38, and 0.97, respectively. Compared with independent reading, BMDS-assisted reading generated 79% fewer FNs (1.98 vs. 0.42, P <0.001); 41% more FPs (0.17 vs. 0.24, P <0.001) but 125% more FPs for trainees (P <0.001); and higher FOM (0.87 vs. 0.98, P <0.001). Lesions with small size, greater number, irregular shape, lower signal intensity, and located on non-brain surface were associated with FNs for readers. Small, irregular, and necrotic lesions were more frequently found in FNs for BMDS. The FPs mainly resulted from small blood vessels for the BMDS and the readers.

Conclusions: Despite the improvement detection performance, attention should be paid to FPs and small lesions with lower enhancement for radiologists, especially for less-experienced radiologists.
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http://dx.doi.org/10.1093/neuonc/noac192DOI Listing
August 2022

Huangjia Ruangan Granule Inhibits Inflammation in a Rat Model with Liver Fibrosis by Regulating TNF/MAPK and NF-B Signaling Pathways.

Evid Based Complement Alternat Med 2022 30;2022:8105306. Epub 2022 Jul 30.

School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510000, China.

The Huangjia Ruangan granule (HJRG) is a clinically effective Kampo formula, which has a significant effect on liver fibrosis and early liver cirrhosis. However, the mechanism underlying HJRG in treating liver fibrosis remains unclear. In this study, carbon tetrachloride (CCl) was used to induce liver fibrosis in rats to clarify the effect of HJRG on liver fibrosis and its mechanism. Using network pharmacology, the potential mechanism of HJRG was initially explored, and a variety of analyses were performed to verify this mechanism. In the liver fibrosis model, treatment with HJRG can maintain the liver morphology, lower the levels of AST and ALT in the serum, and ameliorate pathological damage. Histopathological examinations revealed that the liver structure was significantly improved and fibrotic changes were alleviated. It can effectively inhibit collagen deposition and the expression of -SMA, reduce the levels of the rat serum (HA, LN, PC III, and Col IV), and inhibit the expression of desmin, vimentin, and HYP content in the liver. Analyzing the results of network pharmacology, the oxidative stress, inflammation, and the related pathways (primarily the TNF signaling pathway) were identified as the potential mechanism of HJRG against liver fibrosis. Experiments confirmed that HJRG can significantly increase the content of superoxide dismutase and glutathione and reduce the levels of malondialdehyde and myeloperoxidase in the rat liver; in addition, HJRG significantly inhibited the content of proinflammatory cytokines (TNF-, IL-1, and IL-6) and reduced the expression of inflammatory regulators (Cox2 and iNOS). Meanwhile, treatment with HJRG inhibited the phosphorylation of NF-B P65, IB, ERK, JNK, and MAPK P38. Moreover, HJRG treatment reversed the increased expression of TNFR1. The Huangjia Ruangan granule can effectively inhibit liver fibrosis through antioxidation, suppressing liver inflammation by regulating the TNF/MAPK and NF-B signaling pathways, thereby preventing the effect of liver fibrosis.
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http://dx.doi.org/10.1155/2022/8105306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356785PMC
July 2022

Involvement of galectin-9 from koi carp (Cyprinus carpio) in the immune response against Aeromonas veronii infection.

Fish Shellfish Immunol 2022 Aug 5. Epub 2022 Aug 5.

Beijing Key Laboratory of Fishery Biotechnology&Fisheries Research Institute, Beijing Academy of Agriculture and Forestry Sciences, Beijing, PR China; National Freshwater Fisheries Engineering Technology Research Center, Beijing, PR China. Electronic address:

Galectins are β-galactoside sugar binding proteins which function as important pattern recognition receptors (PRRs) in innate immunity. Here, we identified a galectin-9 gene from koi carp (Cyprinus carpio), named kGal-9. The ORF of kGal-9 is 963 bp in length, which encodes a polypeptide of 320 amino acids without either signal peptide. The predicted molecular weight is 36.25 kDa, and the isoelectric point is 8.3. Multiple sequence alignment showed that the putative kGal-9 contains two carbohydrate recognition domains (CRD), which are conserved in Galectin-9s. The phylogenetic tree showed that kGal-9 clustered to Galectin-9s from other teleosts, and shared the highest identity of 87.5% with Qihe crucian (Carassius auratus). kGal-9 mRNA was abundant in head kidney, gills, and gut, but low in liver and muscle. Further, the expression level of kGal-9 in the head kidney and liver increased significantly after Aeromonas veronii (abbreviated A.v) infection. Unexpectedly, kGal-9 showed a remarkable downregulation in the spleen at various time points post A.v infection. Intramuscular injection of pckGal-9 not merely reduced the bacterial load of spleen tissue, but also improved the survival rate of koi carp post A.v challenge. Besides, administration of pckGal-9 stimulated the expression of several immuno-related genes including proinflammatory cytokines (IL-1β, IL-6), anti-inflammatory cytokine (IL-10), complement components (C4, C9), with fluctuation in spleen and head kidney. Taken together, the obtained results suggest that kGal-9 occupies an important role in innate immunity and defense against bacterial infection in koi carp.
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http://dx.doi.org/10.1016/j.fsi.2022.08.006DOI Listing
August 2022

Latent Autoimmune Diabetes in Adults (LADA): From Immunopathogenesis to Immunotherapy.

Front Endocrinol (Lausanne) 2022 21;13:917169. Epub 2022 Jul 21.

National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China.

Latent autoimmune diabetes in adults (LADA) is a type of diabetes characterized by slow autoimmune damage of pancreatic β cells without insulin treatment in the early clinical stage. There are differences between LADA and classical type 1 diabetes (T1D) and type 2 diabetes (T2D) in genetic background, autoimmune response, rate of islet function decline, clinical metabolic characteristics, and so on. The disease progression and drug response of patients with LADA are closely related to the level of islet autoimmunity, thus exploring the pathogenesis of LADA is of great significance for its prevention and treatment. Previous studies reported that adaptive immunity and innate immunity play a critical role in the etiology of LADA. Recent studies have shown that the intestinal microbiota which impacts host immunity hugely, participates in the pathogenesis of LADA. In addition, the progression of autoimmune pancreatic β cell destruction in LADA is slower than in classical T1D, providing a wider window of opportunities for intervention. Therefore, therapies including antidiabetic drugs with immune-regulation effects and immunomodulators could contribute to promising interventions for LADA. We also shed light on potential interventions targeting the gut microbiota and gut-associated immunity, which may be envisaged to halt or delay the process of autoimmunity in LADA.
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http://dx.doi.org/10.3389/fendo.2022.917169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9350734PMC
August 2022

An Analysis of Injury Trends and Disease Burden From Three Surveillance Hospitals in Urumqi From 2006 to 2018.

Front Public Health 2022 22;10:915637. Epub 2022 Jul 22.

Post-doctoral Mobile Research Station of Public Health and Preventive Medicine, School of Public Health, Xinjiang Medical University, Urumqi, China.

Objective: To investigate injury trends, injury distribution, and disease burden from three surveillance hospitals in Urumqi from 2006 to 2018.

Method: Injury data from the National Injury Surveillance System (NISS) from three hospitals in Urumqi (2006 to 2018) were collected to analyze changes in the characteristics of outpatient injury cases. Years of potential life lost (YPLL) were calculated to determine the disease burden of the injury cases.

Results: A total of 161,400 injury cases were recorded over 13 years, and the average age of the patient seeking medical attention was 32.4 years old. Male patients outnumbered female patients with a ratio of 1.6:1, but the proportion of female patients was greater after 45 years of age. The highest number of cases occurred in patients 15-29 years of age, accounting for 26.8% of all injury cases. Injury in females occurred most frequently in the home. A total of 41.4% of injury cases occurred while doing housework. The top three causes of injury were falls (49.7%), blunt force of an object, (13.7%), and motor vehicle accidents (MVA) (13.5%). Years of potential life lost from injury accounted for 7.39% of the total YPLL in the three hospitals.

Conclusion: Males should be targeted for injury prevention and intervention in Urumqi. The prevention of falls, blunt force of objects, and MVA should be made a priority. Injury prevention strategies and targeted projects should be developed to reduce the disease burden of injury.
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http://dx.doi.org/10.3389/fpubh.2022.915637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354953PMC
August 2022

Testing a Family Supportive End of Life Care Intervention in a Chinese Neonatal Intensive Care Unit: A Quasi-experimental Study With a Non-randomized Controlled Trial Design.

Front Pediatr 2022 22;10:870382. Epub 2022 Jul 22.

Department of Nursing, Hunan Children's Hospital, Changsha, China.

Background: Neonatal death often occurs in tertiary Neonatal Intensive Care Units (NICUs). In China, end-of-life-care (EOLC) does not always involve parents.

Aim: The aim of this study is to evaluate a parent support intervention to integrate parents at the end of life of their infant in the NICU.

Methods: A quasi-experimental study using a non-randomized clinical trial design was conducted between May 2020 and September 2021. Participants were infants in an EOLC pathway in the NICU and their parents. Parents were allocated into a family supportive EOLC intervention group or a standard EOLC group based on their wishes. The primary outcomes depression (Edinburgh Postnatal Depression Scale for mothers; Hamilton Depression rating scale for fathers) and Satisfaction with Care were measured 1 week after infants' death. Student -test for continuous variables and the Chi-square test categorical variables were used in the statistical analysis.

Results: In the study period, 62 infants died and 45 infants and 90 parents were enrolled; intervention group 20 infants, standard EOLC group 25 infants. The most common causes of death in both groups were congenital abnormalities ( = 20, 44%). Mean gestational age of infants between the family supportive EOLC group and standard EOLC group was 31.45 vs. 33.8 weeks ( = 0.234). Parents between both groups did not differ in terms of age, delivery of infant, and economic status. In the family support group, higher education levels were observed among mother ( = 0.026) and fathers ( = 0.020). Both mothers and fathers in the family supportive EOLC group had less depression compared to the standard EOLC groups; mothers (mean 6.90 vs. 7.56; = 0.017) and fathers (mean 20.7 vs. 23.1; < 0.001). Parents reported higher satisfaction in the family supportive EOLC group (mean 88.9 vs. 86.6; < 0.001).

Conclusions: Supporting parents in EOLC in Chinese NICUs might decreased their depression and increase satisfaction after the death of their infant. Future research needs to focus on long-term effects and expand on larger populations with different cultural backgrounds.

Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT05270915.
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http://dx.doi.org/10.3389/fped.2022.870382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354658PMC
July 2022

The role of PP2A /NLRP3 signaling pathway in ambient particulate matter 2.5 induced lung injury.

Chemosphere 2022 Aug 1;307(Pt 2):135794. Epub 2022 Aug 1.

Department of Toxicology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China; Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address:

Ambient particulate matter 2.5 (PM) exposure has been linked to pulmonary fibrosis. However, the key signaling pathways remained unclear. In the present study, we applied a mouse model with myeloid-specific deletion of Ppp2r1a gene (encoding protein phosphatase 2 A (PP2A) A subunit) to identify the key signaling pathways involved in PM-induced pulmonary fibrosis. PP2A Aα homozygote mice and matched wild-type (WT) littermates were exposed to filtered air (FA), unfiltered air (UA), and concentrated PM (CA) in a real-ambient PM exposure system for 8 weeks and 16 weeks, respectively. The mice exposed to PM displayed a progressive inflammation and pulmonary fibrosis. Moreover, the expressions of NLRP3, pro-caspase-1, caspase-1, ASC and IL-1β were increased in mice lung following PM exposure, indicating PM exposure caused pulmonary inflammation by the NLRP3 pathways activation. Furthermore, the effects of PM exposure on pulmonary inflammation, pulmonary fibrosis, oxidative stress, and pulmonary function damage were significantly enhanced in PP2A mice compared to WT mice, indicating the role of PP2A in the regulation of pulmonary injury induced by PM exposure. In vitro study confirmed that PP2A was involved in the PM-induced inflammation response and NLRP3 inflammasome activation. Importantly, we identified PP2A regulated the activation of NLRP3 pathways by direct dephosphorylating IRE1α in response to PM exposure. Taken together, our results demonstrated that PP2A-IRE1α-NLRP3 signaling pathway played a crucial role in regulating the inflammation response, triggering the lung fibrogenesis upon PM exposure. Our findings provide new insights into regulatory role of PP2A in human diseases upon the PM exposure.
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http://dx.doi.org/10.1016/j.chemosphere.2022.135794DOI Listing
August 2022

The foam cell formation associated with imbalanced cholesterol homeostasis due to airborne magnetite nanoparticles exposure.

Toxicol Sci 2022 Aug 1. Epub 2022 Aug 1.

Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, 266071, China.

Fine particulate matter (PM) is a leading environmental cause for the increased morbidity and mortality of atherosclerosis (AS) worldwide, but little is known about the toxic component and disturbance of PM exposure on foam cell formation, a crucial pathological process in AS. Airborne magnetite nanoparticles (NPs) have been reported to be detected in human serum, which inevitably encounter with macrophages in atherosclerotic plaques, thus throwing potential disturbance on the formation of macrophage-derived foam cells. Here we comprehensively unveiled that the environmental concentrations of PM exposure triggered and potentiated the formation of macrophage-derived foam cells using both real-ambient PM exposed mice and atherosclerosis mice models, including high-fat diet (HFD)-fed mice and apolipoprotein E (ApoE)-deficient mice. The in vitro model further defined the dose-dependent response of PM treatment on foam cell formation. Interestingly, airborne magnetite NPs rather than non-magnetic NPs at the same concentration were demonstrated to be the key toxic component of PM in the promoted foam cell formation. Furthermore, magnetite NPs exposure led to abnormal cholesterol accumulation in macrophages, which was attributed to the attenuation of cholesterol efflux and enhancement of lipoprotein uptake, but independent of cholesterol esterification. The in-depth data revealed that magnetite NPs accelerated the protein ubiquitination and subsequent degradation of SR-B1, a crucial transporter of cholesterol efflux. Collectively, these findings for the first time identified magnetite NPs as one key toxic component of PM-promoted foam cell formation, and provided new insight of abnormal cholesterol metabolism into the pathogenesis of PM-induced atherosclerosis.
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http://dx.doi.org/10.1093/toxsci/kfac079DOI Listing
August 2022

Patients with infectious diseases undergoing mechanical ventilation in the intensive care unit have better prognosis after receiving metagenomic next-generation sequencing assay.

Int J Infect Dis 2022 Jul 28. Epub 2022 Jul 28.

State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Department of Pulmonary and Critical Care Medicine, 151 Yanjiang Road, Guangzhou, 510120, China.. Electronic address:

Objectives: To evaluate the relation between mNGS and the prognosis of patients with infectious diseases undergoing mechanical ventilation in the intensive care unit (ICU).

Design: This is a single-center observational study, comparing non-randomly assigned diagnostic approaches. We analyzed the medical records of 228 patients with suspected infectious diseases undergoing mechanical ventilation in the ICU from March 2018 to May 2020. The concordance of pathogen results was also assessed for the results of mNGS, culture and PCR assays.

Results: The 28-day mortality of the patients in the mNGS group was lower after the baseline difference correction (19.23% (20/104) vs. 29.03% (36/124) , p=0.039). Subgroup analysis showed that mNGS assay associates with improved 28-day mortality of non-immunosuppressive patients (14.06% vs. 29.82%, p=0.018) . Not performing mNGS assay, higher APACHE II score and hypertension are independent risk factors for 28-day mortality. The mNGS assay presented advantage in pathogen positivity (69.8% double positive and 25.0% mNGS positive only), and the concordance between thest two assays were 79.0%.

Conclusions: mNGS survey may be associated with a better prognosis as the reduction of 28-day mortality of patients with infectious diseases on mechanical ventilation in ICU. This technique presented advantage in pathogen positivity than traditional methods.
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http://dx.doi.org/10.1016/j.ijid.2022.07.062DOI Listing
July 2022

Water-soluble near-infrared fluorescent heptamethine dye for lymphatic mapping applications.

Bioorg Med Chem Lett 2022 Jul 27;73:128910. Epub 2022 Jul 27.

Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address:

The identification of sentinel lymph node (SLN) is an important method for prognostic evaluation and minimally invasive staging of metastatic tumors. Here, we report a series of near-infrared fluorescent heptamethylamine dyes (series A, B and C) with central cycloalkene ring modified by tyrosine or N-Boc tyrosine via ether linkage. N-Boc tyrosine/tyrosine modification provided enhanced absorption coefficient and fluorescence quantum yield in DMSO, however with slight hypsochromic shift compared to the mother dyes in DMSO. In PBS, series A and B were found to be more fluorescent than ICG and showed brighter images. Compound A1 was found to exhibit the most favorable imaging performance among all the dyes investigated and was selected for in vivo sentinel lymph node mapping experiments in mice. A1 showed faster response and stronger fluorescence emission than FDA-approved ICG. The lymph node tracing with A1 could be assisted by MB staining. Ex vivo imaging of harvested organs indicated that similar metabolic characteristics of A1 and ICG. Overall, A1 is advantageous over ICG and is very promising for non-invasive lymph node imaging.
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http://dx.doi.org/10.1016/j.bmcl.2022.128910DOI Listing
July 2022

Carriage of the mcr-9 and mcr-10 genes in clinical strains of the Enterobacter cloacae complex in China: a prevalence and molecular epidemiology study.

Int J Antimicrob Agents 2022 Jul 27:106645. Epub 2022 Jul 27.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China. Electronic address:

Objectives: Enterobacter cloacae complex (ECC) is among the most common carbapenem-resistant Enterobacteriaceae in China. The emergence of the mcr renders CRE strains resistant to the last-line antibiotic colistin. We investigated the prevalence of mcr-9 and mcr-10 in carbapenem-resistant ECC (CRECC) and carbapenem-susceptible ECC (CSECC) in China.

Methods: We collected CRECC and CSECC strains from different regions of China. The antimicrobial susceptibility tests, conjugation experiments, whole genome sequencing, bioinformatic analysis, and quantitative RT-PCR were performed to understand the mechanisms of resistance and transmission of mcr in ECC.

Results: A total of 534 ECC were collected, among which 57 (10.7%) and 23 (4.3%) were positive for mcr-9 and mcr-10, respectively. The prevalence of mcr-9 in CRECC was significantly higher than that in CSECC (31.8% vs 3.7%, p < 0.001), while the prevalence of mcr-10 in CRECC was significantly lower (0.8% vs 5.5%, p < 0.05). Most mcr-9-positive strains (n=45, 78.9%) exhibited multidrug-resistant phenotype, and four (17.4%) of the mcr-10-positive strains exhibited multi-drug resistance. Coexistence of mcr and carbapenemase genes was commonly observed, including 41 (71.9%) mcr-9-positive strains and one (4.3%) mcr-10-positive strain, and the possibility of co-transfer was confirmed by conjugation experiments. The mcr-positive ECC were highly diverse, while most mcr genes were plasmid-encoded indicating the important role of plasmids on the transmission of mcr in ECC. Furthermore, the expression of mcr-9 was increased after induction by colistin.

Conclusions: The widespread of mcr genes, as well as its co-transfer with carbapenemase genes among ECC strains, posed an urgent threat to public health.
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http://dx.doi.org/10.1016/j.ijantimicag.2022.106645DOI Listing
July 2022

Associations between night-time sleep duration and fasting glucose and ratio of triglyceride to high-density lipoprotein cholesterol among adults free of type 2 diabetes or without diagnosed type 2 diabetes: a multicentre, cross-sectional study in China.

BMJ Open 2022 07 29;12(7):e062239. Epub 2022 Jul 29.

School of Medicine, Nankai University, Tianjin, China

Objectives: We aimed to assess the associations between night-time sleep duration and fasting glucose (FG), triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio and body mass index (BMI) among adults free of type 2 diabetes (T2D) or without diagnosed T2D.

Design: Cross-sectional study.

Setting: Medical examination centres at six hospitals in Beijing-Tianjin-Hebei region, China.

Participants: Participants were recruited via multistage, stratified cluster sampling. We included adults free of T2D or without diagnosed T2D who attended for physical examination and completed the validated questionnaire. 32 497 participants were included in the study, of whom 52.50% were men.

Primary And Secondary Outcome Measures: FG, TG, HDL-C, height and weight were measured.

Results: Overall, 12.80% and 9.67% reported night sleep duration <7 hours and ≥9 hours, respectively; 6.91% had elevated FG and 3.57% had undiagnosed T2D. Sleep duration had an independent, U-shaped associated with FG (β (linear term)=-0.111, p=0.047; β (quadratic term)=0.008, p=0.026) with 6.9 hours of sleep associated with the lowest FG and a negative association with BMI (β=-0.154, p<0.001). BMI mediated a U-shaped association of sleep duration with TG/HDL-C (β=-0.040, p=0.017; β=0.003, p=0.023).

Conclusions: Both short and long night-time sleep was associated with elevated FG, and short sleep duration was associated with increased BMI. BMI mediated a U-shaped association between sleep duration and TG/HDL-C.
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http://dx.doi.org/10.1136/bmjopen-2022-062239DOI Listing
July 2022

Edaravone Modulates Neuronal GPX4/ACSL4/5-LOX to Promote Recovery After Spinal Cord Injury.

Front Cell Dev Biol 2022 18;10:849854. Epub 2022 May 18.

Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin, China.

The FDA-approved drug edaravone has a neuroprotective effect on spinal cord injury (SCI) and many other central nervous system diseases. However, its molecular mechanism remains unclear. Since edaravone is a lipid peroxidation scavenger, we hypothesize that edaravone exerts its neuroprotective effect by inhibiting ferroptosis in SCI. Edaravone treatment after SCI upregulates glutathione peroxidase 4 (GPX4) and system Xc-light chain (xCT), which are anti-ferroptosis proteins. It downregulates pro-ferroptosis proteins Acyl-CoA synthetase long-chain family member 4 (ACSL4) and 5-lipoxygenase (5-LOX). The most significant changes in edaravone treatment occur in the acute phase, two days post injury. Edaravone modulates neuronal GPX4/ACSL4/5-LOX in the spinal segment below the lesion, which is critical for maintaining locomotion. Moreover, the GPX4/ACSL4/5-LOX in motor neuron is also modulated by edaravone in the spinal cord. Therefore, secondary injury below the lesion site is reversed by edaravone ferroptosis inhibition. The cytokine array revealed that edaravone upregulated some anti-inflammatory cytokines such as IL-10, IL-13, and adiponectin. Edaravone reduced microgliosis and astrogliosis, indicating reduced neuroinflammation. Edaravone has a long-term effect on neuronal survival, spinal cord tissue sparing, and motor function recovery. In summary, we revealed a novel mechanism of edaravone in inhibiting neuronal ferroptosis in SCI. This mechanism may be generalizable to other neurological diseases.
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http://dx.doi.org/10.3389/fcell.2022.849854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318422PMC
May 2022

Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy.

Biochem Pharmacol 2022 Jul 25:115185. Epub 2022 Jul 25.

School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China. Electronic address:

Dependence of pharmacokinetics and drug effects (efficacy and toxicity) on dosing time has long been recognized. However, significant progress has only recently been made in our understanding of circadian rhythms and their regulation on drug pharmacokinetics, efficacy and toxicity. This review will cover the relevant literature and a series of publications from our work summarizing the effects of circadian rhythms on drug pharmacokinetics, and propose that the influence of circadian rhythms on pharmacokinetics are ultimately translated into therapeutic effects and side effects of drugs. Evidence suggests that daily rhythmicity in expression of drug-metabolizing enzymes and transporters necessary for drug ADME (absorption, distribution, metabolism and excretion) are key factors determining circadian pharmacokinetics. Newly discovered mechanisms for circadian control of the enzymes and transporters are covered. We also discuss how the rhythms of drug-processing proteins are translated into circadian pharmacokinetics and drug chronoefficacy/chronotoxicity, which has direct implications for chronotherapy. More importantly, we will present perspectives on the challenges that are still needed for a breakthrough in translational research. In addition, knowledge of the circadian influence on drug disposition has provided new possibilities for novel pharmacological strategies. Careful application of pharmacokinetics-based chronotherapy strategies can improve efficacy and reduce toxicity. Circadian rhythm-mediated metabolic and transport strategies can also be implemented to design drugs.
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http://dx.doi.org/10.1016/j.bcp.2022.115185DOI Listing
July 2022

Identification and Suppression of Majority Surface States in the Dry-Etched β-GaO.

J Phys Chem Lett 2022 Aug 28;13(30):7094-7099. Epub 2022 Jul 28.

School of Electronic Science and Engineering, Nanjing University, Nanjing 210023, China.

Surface treatment after dry etching is vital to enhance the surface quality of the material and thus improve device performance. In this Letter, we identified the majority surface states induced by the dry etching of β-GaO and optimized surface treatments to suppress these electrically active defects with the improved performance of Schottky barrier diodes. Transient spectroscopies suggested that the majority traps (-0.75 eV) related to divacancies (V-V) were enhanced in the concentration of 3.37 × 10 cm by dry etching and reduced to 0.90 × 10 cm by the combined means of oxygen annealing and piranha solution treatment. The trap evolution is supported by the suppressed donor-acceptor pair radiative recombination related to oxygen vacancies, the improved carrier transport (negligible hysteresis current-voltage and unity ideality factor), and the reduced surface band bending. These findings provide a straightforward strategy to improve surface quality for the further performance improvement of GaO power diodes.
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http://dx.doi.org/10.1021/acs.jpclett.2c02167DOI Listing
August 2022

A Novel Therapeutic Tumor Vaccine Targeting MUC1 in Combination with PD-L1 Elicits Specific Anti-Tumor Immunity in Mice.

Vaccines (Basel) 2022 Jul 8;10(7). Epub 2022 Jul 8.

School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Medical University, Guangzhou 510182, China.

Dendritic cells (DCs), as professional antigen-presenting cells (APCs), play a key role in the initiation and regulation of humoral and cellular immunity. DC vaccines loaded with different tumor-associated antigens (TAAs) have been widely used to study their therapeutic effects on cancer. A number of clinical trials have shown that DCs are safe as an antitumor vaccine and can activate certain anti-tumor immune responses; however, the overall clinical efficacy of DC vaccine is not satisfactory, so its efficacy needs to be enhanced. MUC1 is a TAA with great potential, and the immune checkpoint PD-L1 also has great potential for tumor treatment. Both of them are highly expressed on the surface of various tumors. In this study, we generated a novel therapeutic MUC1-Vax tumor vaccine based on the method of PD-L1-Vax vaccine we recently developed; this novel PD-L1-containing MUC1-Vax vaccine demonstrated an elevated persistent anti-PD-L1 antibody production and elicited a much stronger protective cytotoxic T lymphocyte (CTL) response in immunized mice. Furthermore, the MUC1-Vax vaccine exhibited a significant therapeutic anti-tumor effect, which significantly inhibited tumor growth by expressing a high MUC1 and PD-L1 level of LLC and Panc02 tumor cells, and prolonged the survival of cancer-bearing animals. Taken together, our study provides a new immunotherapy strategy for improving the cross-presentation ability of therapeutic vaccine, which may be applicable to pancreatic cancer, lung cancer and for targeting other types of solid tumors that highly express MUC1 and PD-L1.
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http://dx.doi.org/10.3390/vaccines10071092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9325010PMC
July 2022

AlGaN Quantum Disk Nanorods with Efficient UV-B Emission Grown on Si(111) Using Molecular Beam Epitaxy.

Nanomaterials (Basel) 2022 Jul 21;12(14). Epub 2022 Jul 21.

Key Laboratory of Advanced Photonic and Electronic Materials, School of Electronic Science and Engineering, Nanjing University, Nanjing 210023, China.

AlGaN nanorods have attracted increasing amounts of attention for use in ultraviolet (UV) optoelectronic devices. Here, self-assembled AlGaN nanorods with embedding quantum disks (Qdisks) were grown on Si(111) using plasma-assisted molecular beam epitaxy (PA-MBE). The morphology and quantum construction of the nanorods were investigated and well-oriented and nearly defect-free nanorods were shown to have a high density of about 2 × 10 cm. By controlling the substrate temperature and Al/Ga ratio, the emission wavelengths of the nanorods could be adjusted from 276 nm to 330 nm. By optimizing the structures and growth parameters of the Qdisks, a high internal quantum efficiency (IQE) of the AlGaN Qdisk nanorods of up to 77% was obtained at 305 nm, which also exhibited a shift in the small emission wavelength peak with respect to the increasing temperatures during the PL measurements.
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http://dx.doi.org/10.3390/nano12142508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319290PMC
July 2022

Evaluation on Temperature-Dependent Transient Instability in p-GaN Gate HEMTs under Negative Gate Stress by Fast Sweeping Characterization.

Micromachines (Basel) 2022 Jul 12;13(7). Epub 2022 Jul 12.

Jiangsu Provincial Key Laboratory of Advanced Photonic and Electronic Materials, School of Electronic Science and Engineering, Nanjing University, Nanjing 210093, China.

In this work, temperature-dependent transient threshold voltage () instability behaviors in p-GaN/AlGaN/GaN HEMTs, with both Schottky gate (SG) and Ohmic gate (OG), were investigated systematically, under negative gate bias stress, by a fast voltage sweeping method. For SG devices, a concave-shaped evolution gradually occurs with the increase in temperature, and the concave peak appears faster with increasing reverse bias stress, followed by a corresponding convex-shaped recovery process. In contrast, the concave-shaped evolution for OG devices that occurred at room temperature gradually disappears in the opposite shifting direction with the increasing temperature, but the corresponding convex-shaped recovery process is not observed, substituted, instead, with a quick and monotonic recovery process to the initial state. To explain these interesting and different phenomena, we proposed physical mechanisms of time and temperature-dependent hole trapping, releasing, and transport, in terms of the discrepancies in barrier height and space charge region, at the metal/p-GaN junction between SG and OG HEMTs.
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http://dx.doi.org/10.3390/mi13071096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319980PMC
July 2022

Diversity of Species Causing Apple Bitter Rot and Glomerella Leaf Spot in China.

J Fungi (Basel) 2022 Jul 18;8(7). Epub 2022 Jul 18.

State Key Laboratory of Crop Stress Biology in Arid Areas and College of Plant Protection, Northwest A&F University, Yangling, Xianyang 712100, China.

Bitter rot and Glomerella leaf spot (GLS) of apples, caused by species, are major diseases of apples around the world. A total of 98 isolates were obtained from apple fruits with bitter rot, and 53 isolates were obtained from leaves with leaf spot in the primary apple production regions in China. These isolates were characterized morphologically, and five gene regions (, , , -1 and 2) were sequenced for each isolate. A phylogenetic analysis, combined with a comparison of the morphological, cultural and pathogenic characters, sorted bitter rot isolates into six species: , , sensu stricto, , and one new species, Dandan Fu & G.Y. Sun. Among these, was the predominant pathogen associated with bitter rot. Isolates from leaf spot were identified as two species, and . This is the first report of as an apple bitter rot pathogen worldwide, and the results provide important insights into the diversity of species in China.
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http://dx.doi.org/10.3390/jof8070740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322356PMC
July 2022

Feasibility of EEG Phase-Amplitude Coupling to Stratify Encephalopathy Severity in Neonatal HIE Using Short Time Window.

Brain Sci 2022 Jun 29;12(7). Epub 2022 Jun 29.

Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75220, USA.

Goal: It is challenging to clinically discern the severity of neonatal hypoxic ischemic encephalopathy (HIE) within hours after birth in time for therapeutic decision-making for hypothermia. The goal of this study was to determine the shortest duration of the EEG based PAC index to provide real-time guidance for clinical decision-making for neonates with HIE.

Methods: Neonates were recruited from a single-center Level III NICU between 2017 and 2019. A time-dependent, PAC-frequency-averaged index, tPAC, was calculated to characterize intrinsic coupling between the amplitudes of 12-30 Hz and the phases of 1-2 Hz oscillation from 6-h EEG data at electrode P3 during the first day of life, using different sizes of moving windows including 10 s, 20 s, 1 min, 2 min, 5 min, 10 min, 20 min, 30 min, 60 min, and 120 min. Time-dependent receiver operating characteristic (ROC) curves were generated to examine the performance of the accurate window tPAC as a neurophysiologic biomarker.

Results: A total of 33 neonates (mild-HIE, = 15 and moderate/severe HIE, = 18) were enrolled. Mixed effects models demonstrated that tPAC between the two groups was significantly different with window time segments of 3-120 min. By observing the estimates of group differences in tPAC across different window sizes, we found 20 min was the shortest window size to optimally distinguish the two groups ( < 0.001). Time-varying ROC showed significant average area-under-the-curve of 0.82.

Conclusions: We demonstrated the feasibility of using tPAC with a 20 min EEG time window to differentiate the severity of HIE and facilitate earlier diagnosis and treatment initiation.
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http://dx.doi.org/10.3390/brainsci12070854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313332PMC
June 2022

An Open-Source AI Framework for the Analysis of Single Cells in Whole-Slide Images with a Note on CD276 in Glioblastoma.

Cancers (Basel) 2022 Jul 15;14(14). Epub 2022 Jul 15.

Ken Parker Brain Tumour Research Laboratories, Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia.

Routine examination of entire histological slides at cellular resolution poses a significant if not insurmountable challenge to human observers. However, high-resolution data such as the cellular distribution of proteins in tissues, e.g., those obtained following immunochemical staining, are highly desirable. Our present study extends the applicability of the PathoFusion framework to the cellular level. We illustrate our approach using the detection of CD276 immunoreactive cells in glioblastoma as an example. Following automatic identification by means of PathoFusion's bifocal convolutional neural network (BCNN) model, individual cells are automatically profiled and counted. Only discriminable cells selected through data filtering and thresholding were segmented for cell-level analysis. Subsequently, we converted the detection signals into the corresponding heatmaps visualizing the distribution of the detected cells in entire whole-slide images of adjacent H&E-stained sections using the Discrete Wavelet Transform (DWT). Our results demonstrate that PathoFusion is capable of autonomously detecting and counting individual immunochemically labelled cells with a high prediction performance of 0.992 AUC and 97.7% accuracy. The data can be used for whole-slide cross-modality analyses, e.g., relationships between immunochemical signals and anaplastic histological features. PathoFusion has the potential to be applied to additional problems that seek to correlate heterogeneous data streams and to serve as a clinically applicable, weakly supervised system for histological image analyses in (neuro)pathology.
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http://dx.doi.org/10.3390/cancers14143441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316952PMC
July 2022

Curcumin Alleviates D-Galactose-Induced Cardiomyocyte Senescence by Promoting Autophagy via the SIRT1/AMPK/mTOR Pathway.

Evid Based Complement Alternat Med 2022 16;2022:2990843. Epub 2022 Jul 16.

Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China.

Oxidative stress and impaired autophagy are the hallmarks of cardiac aging. However, there are no specific drugs available to prevent cardiac aging. Curcumin is a natural polyphenolic drug with antioxidant, antiaging, and autophagy-promoting effects. Here, we describe the preventive role of Curcumin in cardiac aging through the induction of autophagy and the restoration of autophagy via the SIRT1/AMPK/mTOR pathway. The number of cells positive for senescence-associated -galactosidase, P53, P16, and intracellular ROS increased significantly in senescent cardiomyocytes, stimulated using D-galactose. Curcumin reversed this effect in a dose-dependent manner. Curcumin-induced autophagy increased the expression of SIRT1and phosphorylated AMPK and decreased phosphorylated mTOR in a dose-dependent manner. SIRT1-siRNA-mediated knockdown inhibited the antioxidation, antiaging, the promotion of autophagy, and the SIRT1/AMPK/mTOR pathway activation effect of curcumin. Therefore, curcumin could be an effective anticardiac aging drug.
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http://dx.doi.org/10.1155/2022/2990843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308546PMC
July 2022

Clonal Dissemination of With Binary Carriage of -Bearing Plasmids in a Chinese Hospital.

Front Microbiol 2022 8;13:918561. Epub 2022 Jul 8.

Clinical Microbiology Laboratory, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.

Dissemination of the carbapenemase (KPC)-encoding gene among Enterobacterales is common but relatively rare in spp. In this study, we characterized two KPC-2-producing strains (Ah2101 and Ah2111), each isolated from a patient in different intensive care units (ICUs) of a Chinese hospital. Whole-genome sequencing (WGS) revealed simultaneous carriage of the and genes, both of which encode high-level carbapenem resistance in these two isolates. The two isolates were shown to be clonally related and each isolate harbored two distinguishable -bearing plasmids, only one of which was transferrable to , but not EC600 conjugation. The genetic element that contains in these two plasmids, namely IS-Δ - -IS, was structurally identical, commonly detected in Enterobacterales, and associated with Tn-based transposons. In addition, more than sixty putative genes that encode various virulence factors were identified in these two isolates. This is the first study that reports clonal dissemination of carbapenem-resistant strains carrying structurally different -bearing plasmids. Further investigation is warranted to monitor the future transmission of -bearing plasmids in in clinical settings.
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http://dx.doi.org/10.3389/fmicb.2022.918561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304888PMC
July 2022

High Power Figure-of-Merit, 10.6-kV AlGaN/GaN Lateral Schottky Barrier Diode with Single Channel and Sub-100-µm Anode-to-Cathode Spacing.

Small 2022 Jul 22:e2107301. Epub 2022 Jul 22.

The Key Laboratory of Advanced Photonic and Electronic Materials, School of Electronic Science and Engineering, Nanjing University, Nanjing, 210033, P. R. China.

GaN-based lateral Schottky barrier diodes (SBDs) have attracted great attention for high-power applications due to its combined high electron mobility and large critical breakdown field. However, the breakdown voltage (BV) of the SBDs are far from exploiting the material advantages of GaN at present, limiting the desire to use GaN for ultra-high voltage (UHV) applications. Then, a golden question is whether the excellent properties of GaN-based materials can be practically used in the UHV field? Here, UHV AlGaN/GaN SBDs are demonstrated on sapphire with a BV of 10.6 kV, a specific on-resistance (R ) of 25.8 mΩ cm , yielding a power figure-of-merit (P-FOM = BV /R ) of 4.35 GW cm . These devices are designed with single channel and 85-µm anode-to-cathode spacing, without other additional electric field management, demonstrating its great potential for the UHV application in power electronics.
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http://dx.doi.org/10.1002/smll.202107301DOI Listing
July 2022

Expandable carboxymethyl chitosan/cellulose nanofiber composite sponge for traumatic hemostasis.

Carbohydr Polym 2022 Oct 2;294:119805. Epub 2022 Jul 2.

Department of Pharmacy, The Second Affiliated Hospital, Army Medical University, 183 Xinqiao Road, Chongqing 400000, China. Electronic address:

Uncontrolled hemorrhage poses a severe life-threatening situation. However, traditional hemostats still have various limitations. It is urgent to develop a material with excellent biocompatibility and hemostatic ability. Evidence has shown that carboxymethyl chitosan (CMCS) has hemostatic properties and good compatibility. Herein, we develop an expandable hemostatic sponge by modifying CMCS with cellulose nanofibrils (CNFs) through the CO-NH cross-linking method. We verified its potential as a hemostatic agent both in vivo and in vitro. The results demonstrated that the prepared carboxymethyl chitosan/cellulose nanofiber composite (CNF-CMCS) sponges could absorb blood, quickly expand to exert pressure in the wound, and exhibit an excellent coagulation ability. The CNF-CMCS sponges significantly decreased the bleeding time and blood loss in several hemorrhage models and possessed a significant advantage in treating the deep penetrating injury hemorrhage. Therefore, the sponges provide a unique application prospect and potential as a penetrating trauma hemostatic agent.
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http://dx.doi.org/10.1016/j.carbpol.2022.119805DOI Listing
October 2022

Tolerance and efficacy of HIFU ablation for uterine fibroids NPVR ≥ 90%: a nested case-control study.

Int J Hyperthermia 2022 ;39(1):946-951

State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China.

Objective: To investigate the tolerance and efficacy of HIFU ablation for uterine fibroids with a non-perfused volume ratio (NPVR) ≥ 90%.

Methods: A prospective cohort study of 2411 patients from 20 clinical centers was available. Contrast-enhanced MRI was used to assess the non-perfused volume ratio (NPVR). The International Society of Interventional Radiotherapy (SIR) complication grading system was used as the tolerance index. Uterine Fibroids-related Symptoms-Quality of Life (UFS-QoL) was used to evaluate the efficacy.

Results: A total of 1352 patients underwent USgHIFU ablation treatment enrolled, NPVR was median 91.9% (IQR, 81.4%,100.0%). There was 761 case (56.3%) in the NPVR ≥ 90% group in which 17.5% case experienced SIR-B abdominal pain, 591 cases (43.7%) in NPVR < 90% group in which 9.3% case had SIR-B abdominal pain. There were statistically differences in the improvement degree of UFS at 12 months among the four subgroups (NPVR < 70%, 70%-80%, 80%-90%, 90%-100%) (all  < 0.05).

Conclusions: Patients with NPVR ≥ 90% had a higher incidence of SIR-B lower abdominal pain. NPVR was positively correlated with the degree of symptom relief at 12 months, and NPVR ≥ 90% was more likely to obtain better clinical symptom relief.
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http://dx.doi.org/10.1080/02656736.2022.2093414DOI Listing
July 2022

Population pharmacokinetic analysis of etrolizumab in patients with moderately-to-severely active ulcerative colitis.

CPT Pharmacometrics Syst Pharmacol 2022 Jul 19. Epub 2022 Jul 19.

Genentech, Inc., South San Francisco, California, USA.

Etrolizumab is an IgG1-humanized monoclonal antibody that specifically targets the β7 subunit of α4β7 and α4Eβ7 integrins, and it has been evaluated for the treatment of moderately-to-severely active ulcerative colitis (UC). Population pharmacokinetic (PK) analysis was performed to characterize etrolizumab PK properties in patients with moderately-to-severely active UC and evaluate covariate impacts on exposure. The population PK model was developed based on etrolizumab serum concentrations from patients with moderately-to-severely active UC enrolled in six studies (one phase I, one phase II, and four phase III) and validated using another phase III clinical trial. Stepwise covariate modeling was used to evaluate the impact of 23 prespecified covariates. Etrolizumab PK was best described by a two-compartment model with first-order absorption, with clearance decreasing over time. Population typical values were 0.260 L/day for clearance (CL) during the first dosing internal, 2.61 L for central volume, 71.2% for bioavailability, and 0.193/day for absorption rate. CL reduced over the study duration, the typical maximum reduction was 26% with an onset half-life of 4.8 weeks. Consequently, the predicted mean terminal half-life was shorter after a single dose (13.0 days) compared to that at steady-state (17.1 days). Baseline body weight and albumin were the most impactful covariates for etrolizumab exposure. Final population PK model well characterized the PK properties of etrolizumab in patients with moderately-to-severely active UC and identified influential covariate effects.
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http://dx.doi.org/10.1002/psp4.12846DOI Listing
July 2022

Single-cell transcriptomes identifies characteristic features of mouse macrophages in liver Mallory-Denk bodies formation.

Exp Mol Pathol 2022 Jul 16;127:104811. Epub 2022 Jul 16.

School of Basic Medical Sciences, Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou, China; The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China. Electronic address:

Mallory-Denk bodies (MDBs) consist of intracellular aggregates of misfolded proteins in ballooned hepatocytes and serve as important markers of progression in certain liver diseases. Resident hepatic macrophage-mediated inflammation influences the development of chronic liver diseases and cancer. Here, the first systematic study of macrophages heterogeneity in mice was conducted to illustrate the pathogenesis of MDB formation using single-nucleus RNA sequencing (snRNA-seq). Furthermore, we provided transcriptional profiles of macrophages obtained from the fractionation of mouse liver tissues following chronic injury. We equally identified seven discrete macrophage subpopulations, each involved in specific cellular activated pathways such as basal metabolism, immune regulation, angiogenesis, and cell cycle regulation. Among these, a specific macrophage cluster (Cluster4), a subpopulation specifically expressing genes that regulate cell division and the cell cycle, was identified. Interestingly, we found that CCR2 was significantly induced in Cluster2, thereby inducing monocytes to migrate to macrophages to promote MDB pathogenesis. Thus, our study is the first to demonstrate the heterogeneity of macrophages associated with liver MDB formation in mice through single-cell resolution. This serves as the basis for further insights into the pathogenesis of liver MDB formation and molecular mechanisms of chronic liver disease progression.
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http://dx.doi.org/10.1016/j.yexmp.2022.104811DOI Listing
July 2022

Effect of Baricitinib on the epithelial-mesenchymal transition of alveolar epithelial cells induced by IL-6.

Int Immunopharmacol 2022 Jul 15;110:109044. Epub 2022 Jul 15.

Department of Rheumatology, The First Affiliated Hospital of China Medical University, China. Electronic address:

Objective: Interstitial lung disease (ILD) is one of the common complications of Connective tissue disease (CTD). Epithelial-mesenchymal transition (EMT) is one of the main pathological mechanisms of ILD. IL-6 may induce ILD through the JAK/STAT pathway. Therefore, exploring the mechanism of IL-6 on the EMT of alveolar epithelial cells and inhibition JAK/STAT pathway with Baricitinib on the EMT of alveolar epithelial cells is helpful in revealing the pathogenesis of CTD-ILD and guiding treatment.

Methods: Electrochemiluminescence was applied to detect the changes in serum IL-6 levels before and after treatment in 37 patients with anti-synthetase syndrome-associated ILD; A549 cells (a human AEC cell line) were incubated with IL-6, Baricitinib, or both IL-6 and Baricitinib, and changes in EMT-related markers levels were measured using real-time PCR, western blotting and fluorescence microscopy. The related proteins in the JAK/STAT signaling pathways were examined by western blot. The level of Connective tissue growth factor (CTGF) and Hydroxyproline (Hyp) in cell supernatants was measured by ELISA.

Results: Serum IL-6 level in patients with anti-synthetase syndrome-associated ILD was significantly higher than that in health (6.78(4.19, 16.14)pg/ml vs. 2.10(1.43, 5.18)pg/ml, p < 0.01). The level of IL-6 in the improvement group of ASS-ILD was considerably decreased than that before treatment(before(7.48(4.54, 22.76) pg/mL vs. 5.00(3.46, 11.32)pg/mL, p < 0.01), p < 0.01), and the level of IL-6 in the progressive group of ASS-ILD was significantly higher than that before treatment(before(7.49(6.77, 35.80) pg/mL vs. 30.02(8.01, 82.98) pg/mL, p < 0.05). IL-6 increased the expression of epithelial phenotypic marker E-cadherin and inhibited mesenchymal phenotypic markers, including vimentin and N-cadherin in A549 cells. Moreover, IL-6-induced EMT was attenuated by Baricitinib. Furthermore, we found that IL-6 activated the phosphorylation of JAK1/2, STAT3, and Baricitinib, partially inhibiting these changes in this process. Baricitinib reduced the secretion of CTGF and Hyp in A549 cells.

Conclusion: The significant higher level of IL-6 in patients with anti-synthase syndrome-associated ILD may be related to disease activity and recurrence. Our results suggest that Baricitinib attenuates epithelial-mesenchymal transition in alveolar epithelial cells in the presence of IL-6 through the JAK/STAT signaling pathway.
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http://dx.doi.org/10.1016/j.intimp.2022.109044DOI Listing
July 2022
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