Publications by authors named "Jin Yan"

1,846 Publications

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An Outbreak of Carbapenem-Resistant of K57 Capsular Serotype in an Emergency Intensive Care Unit of a Teaching Hospital in China.

Front Public Health 2021 1;9:724212. Epub 2021 Sep 1.

Clinical Laboratory of Taian City Central Hospital, Tai'an, China.

The emergence of carbapenem-resistant hypervirulent (CR-hvKP) strains has increased the threat posed by . Here, we described an outbreak of 32 CR-hvKP isolates from the emergency intensive care unit (EICU) of a teaching hospital in China. Thirty-two CRKp isolates were collected from six patients and their surrounding environment in EICU. Antimicrobial susceptibility testing was performed using VITEK 2 compact system, E-test or the broth microdilution method. All isolates were serotyped, antimicrobial resistance genes and virulence-associated genes were screened using PCR. Multilocus sequence typing (MLST) and pulse-field gel electrophoresis (PFGE) were employed to characterize the genetic relationships among the CPKP isolates. The virulence capability of 11 CRKp isolates from six patients was evaluated through larva infection assay. PFGE showed that all 32 isolates belonged to one cluster, and MLST revealed that belonged to ST11. All isolates exhibited high resistance to β-lactam antibiotics, quinolones, and aminoglycosides. They were susceptible to ceftazidime/averbatan, tigecycline, and colistin. All 32 isolates harbored , , , , and . The serotype of all 32 isolates was K57. All 32 isolates contained 6 virulence genes, namely, , and . Infection assays demonstrated high mortality in the model. Following measures implemented by the hospital, the outbreak was controlled. The mortality rate was 50.0%. The epidemiology of CR-hvKP should be monitored closely to detect early indications of this emerging public health threat.
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http://dx.doi.org/10.3389/fpubh.2021.724212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441004PMC
September 2021

Structures and hydrogen bonding of 1,7-dioxaspiro[5.5]undecane and its hydrates.

Phys Chem Chem Phys 2021 Sep 15;23(35):19289-19296. Epub 2021 Sep 15.

School of Chemistry and Chemical Engineering, Chongqing University, Daxuecheng South Rd. 55, 401331, Chongqing, China.

The conformations of 1,7DSU and its stepwise solvation by up to 5 water molecules were explored using supersonic-jet Fourier transform microwave spectroscopy with the supplement of theoretical calculations. Experimentally, the rotational spectra of the most stable structures of the monomer, monohydrate and dihydrate were observed and assigned. The characteristics of the stability and intermolecular interaction topologies of the 1,7DSU monomer and its hydrated clusters were obtained by CREST conformational sampling followed by B3LYP-D3(BJ)/def2-TZVP geometrical optimizations and MP2/aug-cc-pVTZ single-point energy calculations. The first water molecule links to the 1,7DSU monomer through an OH⋯O hydrogen bond. The water molecules tend to aggregate with each other and form cyclic structures for the = 2-5 clusters. The interactions between water and the 1,7DSU monomer as well as those between water and water were revealed. The analyses of non-covalent interactions and the natural bond orbital suggest that the OH⋯O, OH⋯O, and CH⋯O hydrogen bonds play a prominent role in structural stability.
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http://dx.doi.org/10.1039/d1cp02964aDOI Listing
September 2021

Escherichia coli infection activates the production of IFN-α and IFN-β via the JAK1/STAT1/2 signaling pathway in lung cells.

Amino Acids 2021 Sep 15. Epub 2021 Sep 15.

Department of Emergency, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, People's Republic of China.

Escherichia coli infections can result in lung injury, which may be closely linked to the induction of interferon secretion. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is one of most important pathways that regulate interferon production. Thus, the present study aimed to dissect whether E. coli infections can regulate interferon production and the underlying mechanisms. For this aim, two lung cell lines, a human bronchial epithelial cell line transformed with Ad12-SV40 2B (BEAS-2b) and a human fetal lung fibroblast (HFL1) cell line, were used. The effects of E. coli infections on interferon production were studied using qRT-PCR, Western blot, and siRNA knockdown assays. E. coli infections remarkably promoted the expression levels of IFN-α, IFN-β, and ISGs. Major components of the JAK/STAT pathway, including JAK1, STAT1, and STAT2, were demonstrated to be regulated by E. coli infections. Importantly, knockdown of JAK1, STAT1, and STAT2 abolished the induction of IFN-α, IFN-β, and ISGs by E. coli. Therefore, experiments in the present study demonstrated that E. coli infections remarkably promoted interferon production in lung cells, which was closely regulated by the JAK/STAT signaling pathway. The findings in the present study are useful for further understanding the pathogenesis of E. coli infections in the lung and finding novel therapies to treat E. coli-induced lung injury.
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http://dx.doi.org/10.1007/s00726-021-03077-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441250PMC
September 2021

Coupling sodium percarbonate (SPC) oxidation and coagulation for membrane fouling mitigation in algae-laden water treatment.

Water Res 2021 Sep 2;204:117622. Epub 2021 Sep 2.

State Key Laboratory of Urban Water Resource and Environment, School of Environment, Harbin Institute of Technology, Harbin 150090, PR China.

To alleviate algal fouling in membrane water treatment processes, conventional technologies such as coagulation with poly aluminum chloride (PACl) has been widely adopted by many drinking water treatment plants. However, coagulation alone exhibited relatively weak removal effect for algal pollutants, and the coagulant residues due to the excess dosage also raised concerns. Thus, a novel process of coupling sodium percarbonate (SPC) oxidation and PACl coagulation was proposed, integrated with membrane filtration for algae-laden water treatment. The dosages of PACl and SPC were optimized, and the SPC dosing strategies were systematically compared. The changes in the characteristics of algal pollutants were investigated, and the results revealed that the resistance of algal foulants to aggregation was decreased, and the particle size of algal foulants became larger. With the synergism of coagulation and oxidation, the degradation of fluorescent organics was strengthened, and macromolecular biopolymers were decomposed into low molecular weight organics. The fouling control efficiency was further explored, and the results indicated that both irreversible and reversible fouling were effectively controlled, among which PACl/SPC (simultaneous treatment) performed best with the irreversible fouling reduced by 90.5%, while the efficiency of SPC-PACl (SPC followed by PACl) was relatively lower (57.3%). The fouling mechanism was altered by slowing the formation of cake filtration, and the reduction of algal cells played a more important role for the fouling alleviation. The interface properties of contaminated membranes (i.e., functional groups, images, and micromorphology) were characterized, and the efficiency of the proposed strategy was further verified. The proposed strategy exhibits great application values for improving membrane performance during algae-laden water treatment.
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http://dx.doi.org/10.1016/j.watres.2021.117622DOI Listing
September 2021

Effects of Door-to-Door Hang-Up Visits on the Use of Long-Lasting Insecticide-Treated Mosquito Nets in the Democratic Republic of the Congo: A Cluster Randomized Controlled Trial.

Int J Environ Res Public Health 2021 Aug 27;18(17). Epub 2021 Aug 27.

Department of Microbiology, Dongguk University College of Medicine, Gyeongju 38067, Korea.

Malaria accounts for 14% of child deaths in the Democratic Republic of the Congo, and one of the key interventions used to prevent malaria is to distribute insecticide-treated bednets (ITNs), especially long-lasting insecticidal nets (LLINs). The global health community and the Roll Back Malaria initiative have been struggling to achieve universal health coverage using ITNs, and recent studies have reported mixed results about the effects of door-to-door visits and mass distribution campaigns. We aimed to compare LLIN use for those provided by door-to-door hang-up visits and by conventional fixed distribution from distribution centers accompanied by a mass distribution campaign. A cluster randomized control trial was conducted in rural areas of Maniema Province, Democratic Republic of the Congo (DR Congo). Cross-sectional surveys were conducted on 2120 and 2156 households, respectively, with at least one child aged less than five in 76 villages. We assessed the effectiveness of door-to-door hang-up visits on the use of LLINs by exploring the interaction between the "intervention group" and "time" using generalized estimating equation models. Increased LLINs use was observed in all age groups in both arms, but usage differences were not significantly different (relative risk (RR) of LLINs use among children < 5 in the intervention group versus the control group after adjusted for clustering: 1.06, 95% CI: 0.85-1.33). We conclude that the door-to-door hang-up visits are not sufficient to persuade individuals (pregnant woman, children < 5, or all study participants) to use LLINs, although it did appear to be effective for the youngest children in the household.
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http://dx.doi.org/10.3390/ijerph18179048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430479PMC
August 2021

Inconsistent Time-Dependent Effects of Tetramethylpyrazine on Primary Neurological Disorders and Psychiatric Comorbidities.

Front Pharmacol 2021 20;12:708517. Epub 2021 Aug 20.

College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, China.

The aim of this study was to investigate the time dependent effects of tetramethylpyrazine (TMP, main activity compound of Hort) on two neurological disorders and their neuropsychiatric comorbidities. 6 Hz corneal rapid kindling was used to induce epileptogenesis and the inflammatory pain was induced by intra-articular Complete Freund's adjuvant (CFA) injection. The mechanical pain thresholds were measured using von Frey hair (D4, D11, D18, D25 after CFA first injection), and the vertical rearings of the mice was observed. To test the neuropsychiatric comorbidities, anxiety-like behaviors of mice were examined by open field and elevated plus maze tests. Two behavioral despair models, tail suspension test and forced swimming test were also used to evaluate the depressive like behaviors. The results showed that TMP administered from the initial day (D1-D35 in kindling model, D0-D14 and D0-D28 in CFA model) of modeling retarded both the developments of 6 Hz corneal rapid kindling epileptogenesis and the CFA induced inflammatory pain. In comparison, late periods administration of TMP (D21-D35 in kindling and D14-D28 in CFA model) showed no effect on the epileptogenesis and the generalized seizures (GS) of kindling, but alleviated maintenance of CFA induced inflammatory pain. Furthermore, we also found all TMP treatments from the initial day of modeling alleviated the co-morbid depressive and anxiety-like behaviors in both models; however, late periods treatments did not, either in kindling or the CFA induced inflammatory pain. BDNF/ERK signaling impairment was also tested by western blot, and the results showed that TMP administered from the initial day of modeling increased the hippocampal BDNF/ERK expression, whereas late period administration showed no effects. Overall, our findings reveal the inconsistent time dependent effects of Tetramethylpyrazine on neurological disorders and their relative neuropsychiatric comorbidities, and provide novel insight into the early application of TMP that might enhance hippocampal BDNF/ERK signaling to alleviate neuropsychiatric comorbidities in neurological diseases.
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http://dx.doi.org/10.3389/fphar.2021.708517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417558PMC
August 2021

Liquiritigenin exerts the anti-cancer role in oral cancer via inducing autophagy-related apoptosis through PI3K/AKT/mTOR pathway inhibition and .

Bioengineered 2021 Dec;12(1):6070-6082

Department of Stomatology, Affiliated Huai'an No.1 People's Hospital, Nanjing Medical University, Jiangsu, China.

Operative treatment on oral cancer greatly damages the chewing and language function of the patient, we aim to find better solution with fewer side effects. The anti-tumor effects of Liquiritigenin (LQ) have been explored in kinds of cancers, but not in oral cancer. In this study, our purpose is to reveal the effects of LQ on oral cancer and the associated mechanism.Cell proliferation was examined through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 5-Ethynyl-2'- deoxyuridine (EDU) staining. Cell apoptosis in cells and tissues were assessed by flow cytometry and terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, respectively. Expressions of AKT and light chain 3 (LC3) were detected through Immunofluorescence. In addition, xenograft model was established by injecting the CAL-27 cells (2 × 10) subcutaneously into the right flanks of mice. Expression of Ki67 and Beclin1 in tissues was valued by Immunohistochemistry (IHC).We found that cell viability of CAL-27 and SCC-9 was effectively inhibited by LQ. Besides, obvious cell apoptosis and cell autophagy were induced by LQ. In addition, PI3K/AKT/mTOR pathway was sharply inactivated by LQ in oral cancer cells. Corresponding experiments demonstrated that tumor growth was largely restricted, cell apoptosis was augmented and autophagy was enhanced by LQ. What is more, phosphorylation of AKT in tumor tissues could also be inhibited by LQ. LQ inhibited the progression of oral cancer through inducing autophagy-associated apoptosis via PI3K/AKT/mTOR pathway inhibition, revealing a new possible scheme for the treatment of oral cancer.
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http://dx.doi.org/10.1080/21655979.2021.1971501DOI Listing
December 2021

Trans-ethnic genome-wide association study of severe COVID-19.

Commun Biol 2021 08 31;4(1):1034. Epub 2021 Aug 31.

College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19.
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http://dx.doi.org/10.1038/s42003-021-02549-5DOI Listing
August 2021

Genome-wide association study of COVID-19 severity among the Chinese population.

Cell Discov 2021 Aug 31;7(1):76. Epub 2021 Aug 31.

State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a broad clinical spectrum of coronavirus disease 2019 (COVID-19). The development of COVID-19 may be the result of a complex interaction between the microbial, environmental, and host genetic components. To reveal genetic determinants of susceptibility to COVID-19 severity in the Chinese population, we performed a genome-wide association study on 885 severe or critical COVID-19 patients (cases) and 546 mild or moderate patients (controls) from two hospitals, Huoshenshan and Union hospitals at Wuhan city in China. We identified two loci on chromosome 11q23.3 and 11q14.2, which are significantly associated with the COVID-19 severity in the meta-analyses of the two cohorts (index rs1712779: odds ratio [OR] = 0.49; 95% confidence interval [CI], 0.38-0.63 for T allele; P = 1.38 × 10; and index rs10831496: OR = 1.66; 95% CI, 1.38-1.98 for A allele; P = 4.04 × 10, respectively). The results for rs1712779 were validated in other two small COVID-19 cohorts in the Asian populations (P = 0.029 and 0.031, respectively). Furthermore, we identified significant eQTL associations for REXO2, C11orf71, NNMT, and CADM1 at 11q23.3, and CTSC at 11q14.2, respectively. In conclusion, our findings highlight two loci at 11q23.3 and 11q14.2 conferring susceptibility to the severity of COVID-19, which might provide novel insights into the pathogenesis and clinical treatment of this disease.
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http://dx.doi.org/10.1038/s41421-021-00318-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408196PMC
August 2021

Evaluation of the Cepheid Xpert C. difficile diagnostic assay: an update meta-analysis.

Braz J Microbiol 2021 Aug 29. Epub 2021 Aug 29.

Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, People's Republic of China.

Background: Accurate and rapid diagnosis of Clostridium difficile infection (CDI) is critical for effective patient management and implementation of infection control measures to prevent transmission.

Objectives: We updated our previous meta-analysis to provide a more reliable evidence base for the clinical diagnosis of Xpert C. difficile (Xpert C. difficile) assay.

Methods: We searched PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and the Chinese Biomedical Literature Database (CBM) databases to identify studies according to predetermined criteria. STATA 13.0 software was used to analyze the tests for sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the summary receiver operating characteristic curves (AUC). QUADAS-2 was used to assess the quality of included studies with RevMan 5.2. Heterogeneity in accuracy measures was tested with Spearman correlation coefficient and chi-square. Meta-regressions and subgroup analyses were performed to figure out the potential sources of heterogeneity. Model diagnostics were used to evaluate the veracity of the data.

Results: A total of 26 studies were included in the meta-analysis. The pooled sensitivity (95% confidence intervals [CI]) for diagnosis was 0.97(0.95-0.98), and specificity was 0.96(0.95-0.97). The AUC was 0.99 (0.98-1.00). Model diagnostics confirmed the robustness of our meta-analysis's results. Significant heterogeneity was still observed when we pooled most of the accuracy measures of selected studies. Meta-regression and subgroup analyses showed that the sample size and type, ethnicity, and disease prevalence might be the conspicuous sources of heterogeneity.

Conclusions: The up-to-date meta-analysis showed the Xpert CD assay had good accuracy for detecting CDI. However, the diagnosis of CDI must combine clinical presentation with diagnostic testing to better answer the question of whether the patient actually has CDI in the future, and inclusion of preanalytical parameters and clinical outcomes in study design would provide a more objective evidence base.
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http://dx.doi.org/10.1007/s42770-021-00563-7DOI Listing
August 2021

Accuracy of Xpert Carba-R Assay for the Diagnosis of Carbapenemase-Producing Organisms from Rectal Swabs and Clinical Isolates: A Meta-Analysis of Diagnostic Studies.

J Mol Diagn 2021 Aug 25. Epub 2021 Aug 25.

Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, PR China. Electronic address:

The Cepheid Xpert Carba-R assay has demonstrated a promising value for the detection of carbapenemase-producing organisms, but its diagnostic performance remains unclear. Studies were retrieved from Cochrane Library, EMBASE, and PubMed databases according to predetermined selection criteria. The specificity, sensitivity, negative likelihood ratio, positive likelihood ratio, and area under the summary receiver operating characteristic curves of Xpert Carba-R were analyzed by STATA version 13.0. The quality of each study was examined by Quality Assessment of Diagnostic Accuracy Studies using RevMan version 5.2. In total, 17 unique studies involving 15,972 samples met the inclusion criteria. Nine studies performed Xpert Carba-R on rectal swabs. The pooled sensitivity, specificity, and area under the curve were as follows: 0.95 (95% CI, 0.91-0.97; I = 90.80%), 0.99 (95% CI, 0.97-0.99; I = 97.17%), and 0.99 (95% CI, 0.98-1.00), respectively. The sensitivity and specificity of Xpert Carba-R in high-risk populations were 0.99 (95% CI, 0.76-1.00; I = 78.51%) and 0.98 (95% CI, 0.97-0.99; I = 84.95%), respectively. The sensitivity and specificity in low-prevalence regions were 0.96 (95% CI, 0.88-0.99; I = 74.58%) and 0.99 (95% CI, 0.98-0.99; I = 77.66%), respectively. Eight studies performed Xpert Carba-R on clinical isolates. The pooled sensitivity and specificity were 1.00 (95% CI, 0.97-1.00; I = 97.43%) and 0.98 (95% CI, 0.97-0.99; I = 55.27%), respectively. This meta-analysis indicates that Xpert Carba-R assay has excellent diagnostic accuracy for diagnosing carbapenemase-producing organisms on rectal swabs and clinical isolates, especially for high-risk populations and low-prevalence regions.
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http://dx.doi.org/10.1016/j.jmoldx.2021.08.006DOI Listing
August 2021

A Bionic Nano-Band-Aid Constructed by the Three-Stage Self-Assembly of Peptides for Rapid Liver Hemostasis.

Nano Lett 2021 09 27;21(17):7166-7174. Epub 2021 Aug 27.

Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.

Critical challenges remain in trauma emergency and surgical procedures involving liver bleeding, particularly in perforating wounds that cannot be pressed and large wounds that cannot be sewn. Self-assembling peptide hydrogels are particularly attractive due to their intrinsic biocompatibility and programmability. Herein, we develop a nano-band-aid (NBA) through a three-stage self-assembly strategy of two functionalized peptides, which were first coassembled into nanofibers and then woven to a meshlike network driven by Ca. Then, catalyzed by blood coagulation factor XIIIa (FXIIIa), NBA underwent a third stage, self-assembly into a densely compacted physical barrier to stop and control the bleeding. As expected, NBA rapidly and efficiently stopped the bleeding in rat liver scratches while effectively reducing the inflammation around the wound and promoting the wound healing. This bionic self-assembly strategy will provide a clinically potential peptide-based treatment for fatal liver bleeding and reinvigorate efforts to develop self-assembling peptide hydrogels as hemostatic agents.
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http://dx.doi.org/10.1021/acs.nanolett.1c01800DOI Listing
September 2021

PTENα functions as an immune suppressor and promotes immune resistance in PTEN-mutant cancer.

Nat Commun 2021 08 26;12(1):5147. Epub 2021 Aug 26.

Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China.

PTEN is frequently mutated in human cancers and PTEN mutants promote tumor progression and metastasis. PTEN mutations have been implicated in immune regulation, however, the underlying mechanism is largely unknown. Here, we report that PTENα, the isoform of PTEN, remains active in cancer bearing stop-gained PTEN mutations. Through counteraction of CD8 T cell-mediated cytotoxicity, PTENα leads to T cell dysfunction and accelerates immune-resistant cancer progression. Clinical analysis further uncovers that PTENα-active mutations suppress host immune responses and result in poor prognosis in cancer as relative to PTENα-inactive mutations. Furthermore, germline deletion of Ptenα in mice increases cell susceptibility to immune attack through augmenting stress granule formation and limiting synthesis of peroxidases, leading to massive oxidative cell death and severe inflammatory damage. We propose that PTENα protects tumor from T cell killing and thus PTENα is a potential target in antitumor immunotherapy.
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http://dx.doi.org/10.1038/s41467-021-25417-6DOI Listing
August 2021

From Green Spaces to Squares: Mapping the Distribution of Taijiquan Organizations in London.

Int J Environ Res Public Health 2021 08 10;18(16). Epub 2021 Aug 10.

School of Wushu, Chengdu Sport University, Chengdu 610041, China.

Contributing to Taijiquan studies, this research uses spatial analysis tools in ArcGIS 10.3 and SPSS 23.0 to map out the spatial distributional pattern of the Taijiquan organizations in London, and then explores factors attributing to the spatial distribution of Taijiquan culture. The result shows that the distribution of Taijiquan organizations in London generally presents a spatial distribution structure of "dense center + sparse periphery"; the spatial distribution is unbalanced, showing a cohesive distribution; the directional distribution tends to be obvious in areas that are proximate to urban traffic arteries and afforestation in London. Through multivariate hierarchical regression analysis, the study explores the influential factors for the spatial distribution of Taijiquan organizations in London. The results show that: population size, economic level, and education level have little influence on the spatial distribution of Taijiquan organizations; however, the population density of people over 65 years old, the accessibility of public service facilities such as green spaces, and public urban traffic has a significant impact on the spatial distribution of Taijiquan organizations.
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http://dx.doi.org/10.3390/ijerph18168452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394250PMC
August 2021

Gli1 Cells Residing in Bone Sutures Respond to Mechanical Force via IPR to Mediate Osteogenesis.

Stem Cells Int 2021 12;2021:8138374. Epub 2021 Aug 12.

State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.

Early orthodontic correction of skeletal malocclusion takes advantage of mechanical force to stimulate unclosed suture remodeling and to promote bone reconstruction; however, the underlying mechanisms remain largely unclear. Gli1 cells in maxillofacial sutures have been shown to participate in maxillofacial bone development and damage repair. Nevertheless, it remains to be investigated whether these cells participate in mechanical force-induced bone remodeling during orthodontic treatment of skeletal malocclusion. In this study, rapid maxillary expansion (RME) mouse models and mechanical stretch loading cell models were established using two types of transgenic mice which are able to label Gli1 cells, and we found that Gli1 cells participated in mechanical force-induced osteogenesis both in vivo and in vitro. Besides, we found mechanical force-induced osteogenesis through inositol 1,4,5-trisphosphate receptor (IPR), and we observed for the first time that inhibition of Gli1 suppressed an increase in mechanical force-induced IP3R overexpression, suggesting that Gli1 cells participate in mechanical force-induced osteogenesis through IPR. Taken together, this study is the first to demonstrate that Gli1 cells in maxillofacial sutures are involved in mechanical force-induced bone formation through IPR during orthodontic treatment of skeletal malocclusion. Furthermore, our results provide novel insights regarding the mechanism of orthodontic treatments of skeletal malocclusion.
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http://dx.doi.org/10.1155/2021/8138374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380501PMC
August 2021

PD-L1 expression in non-small cell lung cancer: heterogeneity by pathologic types, tissue sampling and metastasis.

J Thorac Dis 2021 Jul;13(7):4360-4370

Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Programmed cell death ligand-1 (PD-L1) is a predictive marker of anti-PD-1/PD-L1 therapy response. Intra-tumour heterogeneity of PD-L1 expression has been reported in non-small cell lung cancer (NSCLC), but comprehensive studies regarding the determination of PD-L1 expression in different materials are still lacking. Therefore, we aimed to compare PD-L1 expression in paired tumour samples and in different specimen types.

Methods: A total of 1,002 resected NSCLC specimens, 35 biopsy specimens and 54 endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples were performed PD-L1 immunohistochemistry (IHC) testing using the 22C3 assay. PD-L1 expression was evaluated using the tumour proportion score (TPS) and categorized into three levels: negative (TPS <1%), low expression (TPS 1-49%) and high expression (TPS ≥50%).

Results: A total of 1,002 resected NSCLC specimens, including 852 adenocarcinomas (ADCs) and 150 squamous cell carcinomas (SCCs); 35 paired biopsy and resected samples; 54 paired cell block and biopsy samples; 53 paired blocks from the same resected tissue and 49 paired primary and metastatic lesion samples were included in this study. Interestingly, high PD-L1 expression was significantly more frequent in poorly differentiated subtypes than in well-differentiated subtypes in the ADC subgroup (P<0.001). In the SCC subgroup, high PD-L1 expression was significantly more associated with the nonkeratinizing type than the keratinizing type (P=0.001). PD-L1 expression differed between cell blocks and matched biopsy specimens (discordance rate =11.1%, 6/54) and between biopsy and matched resected specimens (discordance rate =31.4%, 11/35). PD-L1 expression differed between different paraffin blocks from the same resected specimen (discordance rate =35.8%, 19/53), and the discordance rate of PD-L1 expression between primary tumours and matched lymph node metastases was 28.6% (14/49).

Conclusions: Discordant PD-L1 expression is not uncommon in NSCLC and warrants additional studies and serious consideration when interpreting PD-L1 test results. Initial negative test results may lead to repeat PD-L1 testing in additional samples or the use of a different clone if necessary.
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http://dx.doi.org/10.21037/jtd-21-388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339751PMC
July 2021

Long noncoding RNA FAM66C promotes tumor progression and glycolysis in intrahepatic cholangiocarcinoma by regulating hsa-miR-23b-3p/KCND2 axis.

Environ Toxicol 2021 Aug 21. Epub 2021 Aug 21.

Medical School of Chinese PLA, Beijing, China.

Long noncoding RNAs (lncRNAs) are known to be the important regulators in cancer progression. However, the role of lncRNA FAM66C (FAM66C) is yet to be investigated in intrahepatic cholangiocarcinoma (ICC). This study aimed to investigate the effects and related mechanisms of FAM66C in ICC. Human ICC tissues and cell lines were collected. The expression levels of FAM66C, hsa-miR-23b-3p (miR-23b-3p), and KCND2 were detected by qRT-RCR. The transfection experiments were employed to measure the effect of FAM66C on cell viabilities, migration, and invasion in ICC cells by CCK-8, transwell assays. Glycolysis was investigated by glucose consumption, lactate production and ATP levels. The dual-luciferase reporter and RNA pull down assays were conducted as a means of confirming the interactions between FAM66C, miR-23b-3p, and KCND2. Furthermore, the levels of the EMT-associated proteins (KCND2, GLUT1, PKM2, and LDHA) in ICC cells were detected by western blot. FAM66C was increased in ICC tissues and cells, increased cell viability, glycolysis, migration and invasion, and decreased apoptosis were shown in FAM66C overexpressing cells. Mechanistic analyses revealed that FAM66C regulated the downstream target gene KCND2 by sponging miR-23b-3p. FAM66C effect on ICC was further validated in murine xenograft assays. FAM66C knockdown cells gave rise to tumors that were smaller in size, consistent with the role of FAM66C as a promoter of in vivo tumor growth. These data revealed that FAM66C was able to drive ICC tumor progression and glycolytic activity via the miR-23b-3p/KCND2 axis, indicating FAM66C may be a viable target for treating ICC.
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http://dx.doi.org/10.1002/tox.23346DOI Listing
August 2021

Angiogenic Microspheres for the Treatment of a Thin Endometrium.

ACS Biomater Sci Eng 2021 Aug 20. Epub 2021 Aug 20.

Key Laboratory of System Bio-medicine of Jiangxi Province, Jiujiang University, Jiujiang, Jiangxi 332000, P. R. China.

The poor vascular development of an endometrium is the key cause of a thin endometrium due to the vascular endothelial growth factor (VEGF) decreasing in the glandular epithelium. Hence, inducing angiogenesis is an effective strategy for thin endometrium treatment in clinic. Herein, we developed a novel angiogenic hydrogel microsphere based on methacrylated hyaluronic acid (HAMA) loaded with VEGF for the treatment of a thin endometrium by a microfluidic electrospray technique. The generated HAMA microspheres with uniform size, porous structure, and satisfactory biocompatibility increased the drug-loading ability and controlled the drug-release rate by adjusting the hydrogel concentration. Besides, the HAMA microspheres loaded with VEGF showed satisfactory biocompatibility and promoted blood vessel formation in vitro. More importantly, the combination of HA and VEGF promoted new blood vessels and endometrial regeneration of a thin endometrium in vivo. Therefore, the combination of HA and VEGF would be conducive to the development of a drug-delivery microsphere with excellent biocompatibility and therapeutic effect for thin endometrium treatment and other biomedical applications.
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http://dx.doi.org/10.1021/acsbiomaterials.1c00615DOI Listing
August 2021

Revised Korean Society of Infectious Diseases/National Evidence-based Healthcarea Collaborating Agency Guidelines on the Treatment of Patients with COVID-19.

Infect Chemother 2021 Mar;53(1):166-219

Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Despite the global effort to mitigate the spread, coronavirus disease 2019 (COVID-19) has become a pandemic that took more than 2 million lives. There are numerous ongoing clinical studies aiming to find treatment options and many are being published daily. Some effective treatment options, albeit of variable efficacy, have been discovered. Therefore, it is necessary to develop an evidence-based methodology, to continuously check for new evidence, and to update recommendations accordingly. Here we provide guidelines on pharmaceutical treatment for COVID-19 based on the latest evidence.
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http://dx.doi.org/10.3947/ic.2021.0303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032920PMC
March 2021

Comparison of Bosniak Classification of cystic renal masses version 2019 assessed by CT and MRI.

Abdom Radiol (NY) 2021 Aug 14. Epub 2021 Aug 14.

Department of Medical Imaging, The Ottawa Hospital, University of Ottawa, 1053 Carling Avenue, C1, Ottawa, ON, K1Y 4E9, Canada.

Objective: To compare imaging features in cystic masses imaged with both CT and MRI using Bosniak Classification version 2019 (Bosniak.v2019) and original Bosniak Classification (Bosniak.original).

Materials And Methods: This IRB-approved, retrospective, cross-sectional study evaluated sixty-five consecutively identified cystic (≤ 25% enhancing) masses imaged by CT and MRI between 2009 and 2019: 35 with histologic diagnosis and 30 Bosniak.v2019 Class 2 and Class 2F cystic masses verified by an expert radiologist (R1) with minimum 5-year stability. Three radiologists (R2, R3, R4) independently evaluated CT, followed by MRI and assigned Bosniak.original and Bosniak.v2019 class in two sessions separated by ≥ 1 month and assessed the following: septa number, septa/wall thickness, and protrusions. Discrepancies were resolved by consensus with R1.

Results: There was 70.8% agreement (kappa = 0.60, p = 0.0146) in class assigned by CT versus MRI for Bosniak.original and 72.3% agreement (kappa = 0.63, p = 0.006) for Bosniak.v2019. Increased septa number (p < 0.001) and more protrusions (p = 0.034) were identified on MRI, with no differences in septal/wall thickness (p = 0.067, 0.855) or protrusion size (p = 0.467). For both CT and MRI, Bosniak.v2019 improved specificity (79.0% [95% confidence interval 71.0-87.0%] CT, 70% [62.0-77.0%] MRI) compared to Bosniak.original (63.0% [56.0-69.0%] CT, 66.0% [58.0-74.0%] MRI) with maintained sensitivity and higher overall accuracy. Inter-observer agreement was similar-to-slightly higher for Bosniak.v2019 (K = 0.44 CT, 0.39 MRI) versus Bosniak.original (K = 0.35 CT, 0.37 MRI).

Conclusion: Class assignment differs in cystic masses evaluated by CT versus MRI for original and v2019 Bosniak Classification with similar-to-slightly higher agreement and improved specificity and higher overall accuracy on both CT and MRI with Bosniak version 2019.
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http://dx.doi.org/10.1007/s00261-021-03236-zDOI Listing
August 2021

Excavating the pathogenic gene of breast cancer based on high throughput data of tumor and somatic reprogramming.

Cell Cycle 2021 Aug 13:1-15. Epub 2021 Aug 13.

College of Life and Environmental Sciences, Wenzhou University, Chashan University Town, Wenzhou, China.

Breast cancer (BC) is one of the most common malignancies in female, and has a high mortality rate. The mechanisms of tumorigenesis and reprogramming of somatic cells have a certain degree of similarity. Here, we focus on the relationship between gene expression, signaling pathways and functions in BC compared to induced pluripotent stem cells (iPSCs). We first identified differentially expressed genes (DEGs) common to BC and iPSCs in datasets from GEO and TCGA. We found 22 DEGs that were significantly associated with clinicopathological features and prognosis by performing Kaplan-Meier survival analysis and one-way ANOVA. The results of protein mass spectrometry of tumor stem cells (Mcfips) demonstrated that the proteins encoded by 8 of these DEGs were also differentially expressed. The functional enrichment analysis showed that most of the 30 DEGs were related to collagen and chromatin functions. Our results might offer targets for future studies into the mechanisms underlying tumor occurrence and progression, and our studies could provide valuable data for both basic research and clinical applications of BC.
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http://dx.doi.org/10.1080/15384101.2021.1961410DOI Listing
August 2021

The Impact of Multidisciplinary Collaborative Nursing Intervention on Arteriovenous Fistula in Patients Undergoing Hemodialysis.

Clin Nurs Res 2021 Aug 13:10547738211037132. Epub 2021 Aug 13.

Department of Nephrology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

This study was conducted to evaluate the effect of multidisciplinary collaborative nursing intervention on AVF in patients with chronic kidney disease (CKD) undergoing hemodialysis. Patients ( = 84) with CKD who underwent the first autologous AVF were randomly divided into control group and multidisciplinary collaborative nursing intervention (MCNI) group and they received routine nursing procedure and multidisciplinary collaborative nursing intervention procedure, respectively. The natural blood flow and vessel diameter in MCNI group were higher than that in control group at the fourth week after surgery ( < .05). The vessel diameter in MCNI group at 2 and 4 weeks after operation was significantly larger than that in control group ( < .05).In conclusions, the implementation of multidisciplinary collaborative nursing intervention procedure can significantly promote the maturation of AVF, effectively increase the blood flow of AVF and promote the growth of vessel diameter.
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http://dx.doi.org/10.1177/10547738211037132DOI Listing
August 2021

Serum exosomal pregnancy zone protein as a promising biomarker in inflammatory bowel disease.

Cell Mol Biol Lett 2021 Aug 10;26(1):36. Epub 2021 Aug 10.

Department of General Surgery, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, 250031, Shandong, China.

Background: Inflammatory bowel disease (IBD) is a kind of intestinal immune dysfunction disease, and its occurrence and prevalence are on the rise worldwide. As a chronic gastrointestinal disease, its pathogenesis is still unknown. Exosomes are vesicles in various body fluids that carry a variety of substances. They can mediate intercellular communication and long-distance transport of multiple media. In this study, we investigated the protein profile of serum exosomes from healthy people and IBD patients to explore a new serological biomarker for IBD.

Methods: Initially, exosomes were extracted from serum samples, and the proteins within the exosomes were identified by label-free liquid chromatography/mass spectrometry (LC-MS/MS). Western blot and ELISA were used to assess the identified protein. To further analyze the target protein, an acute colitis mouse model was established, and exosomes in colonic tissue and serum were extracted to investigate the protein in them.

Results: Firstly, serum exosomes were extracted from samples, and proteins in exosomes were identified by LC-MS/MS. Through statistical analysis, we identified 633 proteins. Among these proteins, pregnancy zone protein (PZP) showed a marked difference between patients with IBD and healthy people, in that its expression level was much higher in the IBD patients This exosomal protein was associated with immunosuppressive effects. Also, the level of PZP in colon tissue exosomes and serum exosomes of acute colitis mice was significantly higher than that of the control group.

Conclusions: Our findings indicated that serum exosome PZP was present at a high level in the IBD patients. Hence it might be a promising biomarker and enhance auxiliary diagnosis of IBD.
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http://dx.doi.org/10.1186/s11658-021-00280-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353742PMC
August 2021

Development, validation, and application of an LC-MS/MS method for the determination of the AXL/FLT3 inhibitor gilteritinib in mouse plasma.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Aug 30;1179:122882. Epub 2021 Jul 30.

Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. Electronic address:

A simple, fast and precise LC-MS/MS method for the quantitation of the tyrosine kinase inhibitor gilteritinib was developed and validated for micro-volumes of mouse plasma. The assay procedure involved a one-step extraction of gilteritinib and the internal standard [H]-gilteritinib with acetonitrile. An Accucore aQ column was used to separate analytes using a gradient elution delivered at a flow rate of 0.4 mL/min, and a total run time of 2.5 min. Validation studies with quality control samples processed on consecutive days revealed that values for intra-day and inter-day precision were <7.04%, with an accuracy of 101-108%. Linear responses were observed over the entire calibration curve range (up to 500 ng/mL), and the lower limit of quantification was 5 ng/mL. The developed method was successfully used to examine the pharmacokinetics of oral gilteritinib in wild-type mice and mice lacking the organic cation transporters OCT1, OCT2, and MATE1 to further understand mechanisms contributing to drug-drug interactions and causes of inter-individual pharmacokinetic variability.
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http://dx.doi.org/10.1016/j.jchromb.2021.122882DOI Listing
August 2021

Automated tumor proportion score analysis for PD-L1 (22C3) expression in lung squamous cell carcinoma.

Sci Rep 2021 Aug 5;11(1):15907. Epub 2021 Aug 5.

Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.

Programmed cell death ligend-1 (PD-L1) expression by immunohistochemistry (IHC) assays is a predictive marker of anti-PD-1/PD-L1 therapy response. With the popularity of anti-PD-1/PD-L1 inhibitor drugs, quantitative assessment of PD-L1 expression becomes a new labor for pathologists. Manually counting the PD-L1 positive stained tumor cells is an obviously subjective and time-consuming process. In this paper, we developed a new computer aided Automated Tumor Proportion Scoring System (ATPSS) to determine the comparability of image analysis with pathologist scores. A three-stage process was performed using both image processing and deep learning techniques to mimic the actual diagnostic flow of the pathologists. We conducted a multi-reader multi-case study to evaluate the agreement between pathologists and ATPSS. Fifty-one surgically resected lung squamous cell carcinoma were prepared and stained using the Dako PD-L1 (22C3) assay, and six pathologists with different experience levels were involved in this study. The TPS predicted by the proposed model had high and statistically significant correlation with sub-specialty pathologists' scores with Mean Absolute Error (MAE) of 8.65 (95% confidence interval (CI): 6.42-10.90) and Pearson Correlation Coefficient (PCC) of 0.9436 ([Formula: see text]), and the performance on PD-L1 positive cases achieved by our method surpassed that of non-subspecialty and trainee pathologists. Those experimental results indicate that the proposed automated system can be a powerful tool to improve the PD-L1 TPS assessment of pathologists.
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http://dx.doi.org/10.1038/s41598-021-95372-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342621PMC
August 2021

Effect of trypsin concentration on living SMCC-7721 cells studied by atomic force microscopy.

J Microsc 2021 Aug 5. Epub 2021 Aug 5.

International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun, China.

Trypsin is playing an important role in the processes of cancer proliferation, invasion and metastasis which require the precise information of morphology and mechanical properties on the nano-scale for the related research. In this work, living human hepatoma (SMCC-7721) cells were treated with different concentrations of trypsin solution. The morphology and mechanical properties of the cells were measured via atomic force microscope (AFM). Statistical analyses of measurement data indicated that with the increase of trypsin concentration, the average cell height and the surface roughness were both increased, but the cell viability, the cell surface adhesion and the elasticity modulus were decreased significantly. The force required to puncture the cells was also gradually reduced. It indicates that trypsin not only hydrolyses the proteins between the cell and the substrate but also the membrane proteins. The results offer valuable clues for the cancerous process study, pathological analysis and trypsin inhibitor drug development. And this work provides an effective way for overcoming the cell membrane in drug injection for cell-targeted therapy.
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http://dx.doi.org/10.1111/jmi.13053DOI Listing
August 2021

Concerns Regarding Surgeon Special Interest and Years Following Termination of Training.

JAMA Surg 2021 Aug 4. Epub 2021 Aug 4.

Department of Gastrointestinal Surgery, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China (UESTC), Chengdu, China.

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http://dx.doi.org/10.1001/jamasurg.2021.3615DOI Listing
August 2021

Autophagy is required for the promoting effect of angiogenic factor with G patch domain and forkhead-associated domain 1 (AGGF1) in retinal angiogenesis.

Microvasc Res 2021 Nov 31;138:104230. Epub 2021 Jul 31.

Department of Endocrinology, The First Affiliated Hospital of Xi'an Medical University, No.48 West Fenghao Road, Xi'an, 710077, Shaanxi, China.

Objective: To investigate the effect of angiogenic factor with G patch domain and forkhead-associated domain 1 (AGGF1) on retinal angiogenesis in ischemic retinopathy and its association with autophagy.

Methods: RF/6A cells were divided into the control group, hypoxia group and high-glucose group, and the expression of AGGF1 in cells was detected. C57BL/6 J mice were divided into the control group, oxygen-induced retinopathy (OIR) group and diabetic retinopathy (DR) group, and AGGF1 expression in the retina was observed. RF/6A cells were then divided into the control group and different AGGF1 concentration groups, and the expression of autophagy marker, LC3 was detected. Then, RF/6A cells were divided into the control group, AGGF1 group, 3-methyladenine (3-MA, an early autophagy inhibitor) + AGGF1 group and chloroquine (CQ, a late autophagy inhibitor) + AGGF1 group, and the expression of autophagy markers, LC3 and p62, autophagic flux, as well as was key signaling pathway proteins in autophagy, PI3K, AKT, and mTOR was detected. Finally, the cell proliferation, migration and tube formation were detected in the four groups.

Results: AGGF1 expression in RF/6A cells and in the retinas of OIR and DR mouse model was found to be increased in the state of hypoxic and high glucose condition. AGGF1 treatment led to increased expressions of LC3 and decreased p62; therby induced autophagic flux, and the phosphorylation of PI3K, AKT and mTOR was down-regulated in RF/6A cells. When autophagy was inhibited by 3-MA or CQ, confirmed by corresponding changes of these indicators of autophagy, cellular proliferation, migration and tube formation of RF/6A cells were weakened by AGGF1 treatment when compared with that of AGGF1 treatment alone.

Conclusion: This study experimentally revealed that AGGF1 activates autophagy to promote angiogenesis for ischemic retinopathy and inhibition of PI3K/AKT/mTOR pathway may be involved in the activation of autophagy by AGGF1.
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http://dx.doi.org/10.1016/j.mvr.2021.104230DOI Listing
November 2021

Postoperative Radiotherapy for Patients With Resectable Stage III-N2 Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Front Oncol 2021 15;11:680615. Epub 2021 Jul 15.

Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.

Purpose: For resectable cases of stage III-N2 non-small cell lung cancer (NSCLC), the best treatment after surgery is still uncertain. The effect of postoperative radiotherapy (PORT) is controversial. Thus, we performed this updated meta-analysis to reassess the data of PORT in stage III-N2 NSCLC patients, to figure out whether these patients can benefit from PORT.

Methods: We conducted searches of the published literature in EMBASE, PubMed, and the Cochrane Library for relevant randomized control trials (RCTs) comparing PORT group with the non-PORT group in NSCLC patients at stage III-N2. These studies allowed the prior chemotherapy in the treatment. We extracted the data from these articles and used the hazard ratios (HRs) and their 95% confidence intervals (CIs) as summary statistics for estimating the effect of PORT on overall survival (OS), disease-free survival (DFS), local-regional recurrence-free survival (LRFS).

Result: The analyses of seven randomized controlled trials (1,318 participants) show no benefit of PORT on survival (HR, 0.87; 95% CI, 0.71 to 1.07; p = 0.18) but a significantly different effect of PORT on DFS (HR, 0.83; 95% CI, 0.71 to 0.97; p = 0.02) and LRFS (HR, 0.64; 95% CI, 0.50 to 0.81; p = 0.0003). There is not enough evidence of a difference in the effect on survival by the utility of chemotherapy along with PORT though subgroup analysis of no chemotherapy group, concurrent chemoradiotherapy and sequential chemoradiotherapy group. Even in trials with 3D-CRT radiation technique, the pooled analysis shows no benefit of PORT on survival in patients with stage III-N2 NSCLC (data is not shown).

Conclusion: Our findings illustrate that in the postoperative treatment for patients with stage III-N2 NSCLC, PORT contributes to a significantly increased DFS and LR and may not associate with an improved OS, indicating a cautious selection.
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http://dx.doi.org/10.3389/fonc.2021.680615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320322PMC
July 2021

Total Flavones of Ameliorates Podocyte Pyroptosis and Injury in High Glucose Conditions by Targeting METTL3-Dependent mA Modification-Mediated NLRP3-Inflammasome Activation and PTEN/PI3K/Akt Signaling.

Front Pharmacol 2021 15;12:667644. Epub 2021 Jul 15.

Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.

The total flavones of (TFA), a compound that is extracted from , has been widely used in China to reduce podocyte injury in diabetic kidney disease (DKD). However, the mechanisms underlying the therapeutic action of this compound have yet to be elucidated. Podocyte pyroptosis is characterized by activation of the NLRP3 inflammasome and plays an important role in inflammation-mediated diabetic kidneys. Regulation of the PTEN/PI3K/Akt pathway is an effective strategy for improving podocyte damage in DKD. Previous research has also shown that N6-methyladenosine (mA) modification is involved in DKD and that mA-modified PTEN regulates the PI3K/Akt pathway. In this study, we investigated whether TFA alleviates podocyte pyroptosis and injury by targeting mA modification-mediated NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling. We used MPC-5 cells under high glucose (HG) conditions to investigate the key molecules that are involved in podocyte pyroptosis and injury, including activation of the NLRP3 inflammasome and the PTEN/PI3K/Akt pathway. We detected alterations in the levels of three methyltransferases that are involved in mA modification. We also investigated changes in the levels of these key molecules in podocytes with the overexpression or knockdown of methyltransferase-like (METTL)3. Analysis showed that TFA and MCC950 protected podocytes against HG-induced pyroptosis and injury by reducing the protein expression levels of gasdermin D, interleukin-1β, and interleukin-18, and by increasing the protein expression levels of nephrin, ZO-1, WT1 and podocalyxin. TFA and 740Y-P inhibited activation of the NLRP3 inflammasome the PI3K/Akt pathway by inhibiting the protein levels of NIMA-related kinase7, NLRP3, ASC, and caspase-1, and by increasing the protein expression levels of p-PI3K and p-Akt. TFA improved pyroptosis and injury in HG-stimulated podocytes by regulating METTL3-dependent mA modification. Collectively, our data indicated that TFA could ameliorate pyroptosis and injury in podocytes under HG conditions by adjusting METTL3-dependent mA modification and regulating NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling. This study provides a better understanding of how TFA can protect podocytes in DKD.
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http://dx.doi.org/10.3389/fphar.2021.667644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319635PMC
July 2021
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