Publications by authors named "Yang Chen"

3,491 Publications

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A urine and serum metabolomics study of gastroesophageal reflux disease in TCM syndrome differentiation using UPLC-Q-TOF/MS.

J Pharm Biomed Anal 2021 Sep 15;206:114369. Epub 2021 Sep 15.

Department of Chemistry, Capital Normal University, No. 105, Xisanhuanbeilu, Haidian District, Beijing 100048, PR China. Electronic address:

Gastroesophageal reflux disease (GERD) is a common, chronic and complex upper gastrointestinal disease. In Traditional Chinese medicine (TCM) theory, GERD is classified into two main types: stagnant heat of liver and stomach (SHLS) and deficient cold of spleen and stomach (DCSS). The discovery and evaluation of potential biomarkers for different syndrome types of GERD may contribute to comprehend specific molecular mechanism and identify new targets for diagnosis and appropriate management. In our study, 60 subjects including 40 GERD patients (20 SHLS and 20 DCSS) and 20 healthy controls were recruited, and the serum and urine metabolic profiles from untargeted liquid chromatography coupled to mass spectrometry (LC-MS) metabolomics approach were obtained. Finally 38 biomarkers associated with disease were identified and 9 metabolic pathways were enriched. The most enriched pathways were amino acid metabolism, steroid hormone biosynthesis, glycerophospholipid metabolism, sphingolipid metabolism and TCA cycle. According to the area under curve (AUC) value, we propose a cohort of three metabolites from urine and serum samples as promising biomarkers for TCM syndrome differentiation of GERD, which are prolylhydroxyproline, glycitein-4'-O-glucuronide, capsianoside I in urine and neuAcalpha2-3Galbeta-Cer (d18:1/16:0), sphinganine, arachidonic acid in serum. The cumulative AUC value of merged biomarkers in urine and serum was 0.979 (95%CI 0.927-1) and 0.842 (95%CI 0.704-0.980), respectively. The results indicated that LC-MS based metabolomic profiling method might be an effective and promising tool on further pathogenesis discovering of GERD. The findings provided new strategy for the diagnosis of GERD TCM syndrome differentiation in clinic.
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http://dx.doi.org/10.1016/j.jpba.2021.114369DOI Listing
September 2021

A novel compound heterozygous mutation of the MTO1 gene associated with complex oxidative phosphorylation deficiency type 10.

Clin Chim Acta 2021 Sep 18. Epub 2021 Sep 18.

Department of Laboratory Medicine, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China. Electronic address:

Background: The mitochondrial tRNA translation optimization 1 (MTO1) gene, which is closely related to defective mitochondrial oxidative phosphorylation, is an evolutionarily conserved protein expressed in high energy-demanding tissues and is associated with complex oxidative phosphorylation deficiency type 10 (COXPD10) in humans. Related cases and studies are still scarce and have not been reported in the Chinese region.

Materials And Methods: Detailed clinical assessment was applied to the patient. Based on next-generation sequencing technology, we performed whole-exome sequencing of the patient and the parents. Sanger sequencing was used for validation. Bioinformatics software and protein simulations were used to predict the pathogenicity of the variants.

Results: The patient was diagnosed with a possible association with mitochondrial disease according to the clinical manifestations and physical examination. A novel frameshift mutation c.344delA (p. Asn115Thrfs*11) and a novel point mutation c.1055C>T (p. Thr352Met) in the MTO1 gene were identified. They were found to cause abnormal changes in amino acids and the protein by biochemical tools, indicating it may be pathogenic.

Conclusion: We present two novel and possibly pathogenic variants in the MTO1 gene in a Chinese Han family.
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http://dx.doi.org/10.1016/j.cca.2021.09.014DOI Listing
September 2021

Long-term outcome of stereotactic aspiration, endoscopic evacuation, and open craniotomy for the treatment of spontaneous basal ganglia hemorrhage: a propensity score study of 703 cases.

Ann Transl Med 2021 Aug;9(16):1289

Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China.

Background: To compare the long-term therapeutic effects of stereotactic aspiration (SA), endoscopic evacuation (EE), and open craniotomy (OC) in the surgical treatment of spontaneous basal ganglia hemorrhage and explore the appropriate clinical indications for each technique.

Methods: Multiple-treatment inverse probability of treatment weighting (IPTW)-adjusted logistic regression analysis was performed to evaluate the therapeutic effects of these techniques. The primary and secondary outcomes were 6-month modified Rankin Scale (mRS) and mortality rates, respectively.

Results: A total of 703 patients were ultimately enrolled. For the entire cohort, the 6-month mortality rate was significantly higher (OR 2.396, 95% CI: 1.865-3.080), and the 6-month functional outcome was significantly worse (OR 1.359, 95% CI: 1.091-1.692) for SA than that of EE. The 6-month mortality rate for OC was significantly higher (OR 1.395, 95% CI: 1.059-1.837) than that of EE. Further subgroup analysis was stratified by initial hematoma volume and Glasgow Coma Scale (GCS) score. The mortality rate for SA was significantly higher for patients with hematoma volume of 20-40 mL (OR 6.226, 95% CI: 3.848-10.075), 40-80 mL (OR 2.121, 95% CI: 1.492-3.016), and ≥80 mL (OR 5.544, 95% CI: 3.315-9.269) than in the same subgroups of EE. The functional outcomes for SA were significantly worse than that of EE for hematoma volume subgroups of 40-80 mL (OR 1.424, 95% CI: 1.039-1.951) and ≥80 mL (OR 4.224, 95% CI: 1.655-10.776). The mortality rate for SA was significantly higher than that of EE for the GCS score subgroups of 6-8 (OR 2.082, 95% CI: 1.410-3.076) and 3-5 (OR 2.985, 95% CI: 1.904-4.678). The mortality rate for OC was significantly higher for the GCS score of 3-5 subgroup (OR 1.718, 95% CI: 1.115-2.648), and a tendency for a higher mortality rate of 6-8 subgroup (OR 1.442, 95% CI: 0.965-2.156) than that of EE.

Conclusions: EE can decrease the 6-month mortality rate and improve the 6-month functional outcomes of spontaneous basal ganglia hemorrhage in patients with a hematoma volume ≥40 mL. EE can decrease the 6-month mortality rate of spontaneous basal ganglia hemorrhage in patients with a GCS score of 3-8.
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http://dx.doi.org/10.21037/atm-21-1612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422088PMC
August 2021

Mapping the landscape of synthetic lethal interactions in liver cancer.

Theranostics 2021 26;11(18):9038-9053. Epub 2021 Aug 26.

Department of Clinical Medicine, School of Medicine, Zhejiang University City College, Hangzhou, China.

Almost all the current therapies against liver cancer are based on the "one size fits all" principle and offer only limited survival benefit. Fortunately, synthetic lethality (SL) may provide an alternate route towards individualized therapy in liver cancer. The concept that simultaneous losses of two genes are lethal to a cell while a single loss is non-lethal can be utilized to selectively eliminate tumors with genetic aberrations. To infer liver cancer-specific SL interactions, we propose a computational pipeline termed SiLi (statistical inference-based synthetic lethality identification) that incorporates five inference procedures. Based on large-scale sequencing datasets, SiLi analysis was performed to identify SL interactions in liver cancer. By SiLi analysis, a total of 272 SL pairs were discerned, which included 209 unique target candidates. Among these, polo-like kinase 1 () was considered to have considerable therapeutic potential. Further computational and experimental validation of the SL pair demonstrated that inhibition of PLK1 could be a novel therapeutic strategy specifically targeting those patients with -mutant liver tumors. In this study, we report a comprehensive analysis of synthetic lethal interactions of liver cancer. Our findings may open new possibilities for patient-tailored therapeutic interventions in liver cancer.
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http://dx.doi.org/10.7150/thno.63416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419043PMC
August 2021

Transcatheter Arterial Embolization Containing Donafenib Induces Anti-Angiogenesis and Tumoricidal CD8 T-Cell Infiltration in Rabbit VX2 Liver Tumor.

Cancer Manag Res 2021 7;13:6943-6952. Epub 2021 Sep 7.

Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.

Purpose: To evaluate the effect and immune response of transcatheter arterial embolization (TAE) combined with donafenib in rabbit VX2 liver tumor model.

Materials And Methods: Thirty-six New Zealand white rabbits with VX2 liver tumor were randomly divided into three groups. The LD group was treated with the emulsion of 0.5 mL lipiodol and 4 mg donafenib via hepatic arterial administration. The LE group was treated with the emulsion of 0.5 mL lipiodol and 4 mg epirubicin. The control group was treated with the equal volume of saline. Four rabbits were euthanized in each group on day 1, 3 and 7 after treatment. The tumor growth, histological markers associated with angiogenesis and immune response were assessed by imaging and histopathology. In addition, immune modulatory cytokines included interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and biochemical hepatorenal function were measured.

Results: Compared to other groups, LD group achieved lower tumor growth rate, fewer metastatic lesions, and higher tumor necrosis rate on day 7 after treatment. The percentage of CD31-positive area in the LD group was significantly lower than that in the LE group on day 3 and 7 after treatment. In addition, CD8 lymphocytes infiltration was more pronounced in LD group than in LE group on day 7 after treatment, regardless of in the tumor or adjacent liver tissue. Serum cytokines including IL-6, TNF-α and IFN-γ were strongly upregulated in the LD group on day 1 after treatment. And there was no significant difference in the hepatorenal function between LD group and LE group after treatment.

Conclusion: The combination of TAE and angiogenesis inhibitor donafenib resulted in a potentiated tumoricidal effect, anti-angiogenesis and antitumour T cell response in rabbit VX2 liver tumor model. This may provide a potential basis for exploring the immune-related mechanisms of embolization in liver cancer.
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http://dx.doi.org/10.2147/CMAR.S328294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434853PMC
September 2021

Increased Liquefactive Necrosis Formation After Transarterial Chemoembolization Combined with Molecular Targeted Agents Plus Immune Checkpoint Inhibitors for Hepatocellular Carcinoma.

Cancer Manag Res 2021 7;13:6935-6941. Epub 2021 Sep 7.

Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.

Purpose: In clinical practice, we found some of the patients who received transarterial chemoembolization (TACE) with molecular targeted agents (MTGs) plus immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) had obvious liquefactive necrosis formation within the tumor and some even progressed to a liver abscess, which seems more frequent than patients who received other treatments. Thus, we aim to identify this condition and analyze the potential risk factors.

Patients And Methods: Medical records of 72 consecutive patients with intermediate (BCLC B) and advanced (BCLC C) HCC who received TACE plus MTGs combined with (n=30) or without (n=42) ICIs were reviewed. Liquefactive necrosis formation was defined as the presence of obvious liquefactive necrosis within the tumor that required intervention.

Results: The liquefactive necrosis rate was higher in the TACE+MTGs+ICIs group than in the TACE+MTGs group (30% vs 4.8%, P=0.006). Moreover, 18.2% (2/11) of the patients with liquefactive necrosis within the tumor had a bacterial infection. We then take the binary logistic regression analysis model to identify the predictors of liquefactive necrosis formation, and which showed the tumor size (P=0.006, OR=1.355, 95% CI: 1.090-1.684), alpha-fetoprotein level (P=0.036, OR=6.745, 95% CI: 1.130-40.262) and treatment modality (P=0.015, OR=11.717, 95% CI: 1.617-84.887) were the independent risk factor for liquefactive necrosis formation within the tumor.

Conclusion: Patients with HCC who received TACE combined with MTGs plus ICIs have increased liquefactive necrosis formation, and the larger tumor size and higher alpha-fetoprotein level were associated with more liquefactive necrosis formation within the tumor.
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http://dx.doi.org/10.2147/CMAR.S328812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434848PMC
September 2021

Bi-layered hollow amphoteric composites: Rational construction and ultra-efficient sorption performance for anionic Cr(VI) and cationic Cu(II) ions.

J Colloid Interface Sci 2021 Sep 4;607(Pt 1):556-567. Epub 2021 Sep 4.

Liaoning Key Laboratory of Lignocellulosic Chemistry and Biomaterials, College of Light Industry and Chemical Engineering, Dalian Polytechnic University, Dalian 116034, China.

Here, we have developed a novel bilayer hollow amphiphilic biosorbent (BHAB-3) with large adsorption capacity, rapid adsorption kinetics, and cost-effective for the removal of Cr(VI) and Cu(II) from aqueous solutions. The synthesis was based on the clever use of freeze-drying to fix the structure, secondary modification of the carboxymethyl cellulose microspheres with polyethyleneimine and cross-linking by glutaraldehyde. The consequences of pH, initial concentration, contact time and temperature on adsorption were investigated. The Langmuir model fits showed that the maximum adsorption capacities of the two target heavy metal ions reached 835.91 and 294.79 mg/g, respectively. Moreover, BHAB-3 was characterized by SEM, FT-IR, TGA, and XPS synergistically, showing that it exhibits a strong complexation ability for Cu(II) and a strong electrostatic effect for Cr(VI). Adsorption and desorption experiments showed only a slight decrease in the adsorption capacity of the BHAB-3 for Cr(VI) and Cu(II) ions after 5 and 26 cycles, respectively. Given the excellent properties of this adsorbent, it is a promising candidate for heavy metal ion removal.
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http://dx.doi.org/10.1016/j.jcis.2021.08.197DOI Listing
September 2021

Approaching Nearly 40% External Quantum Efficiency in Organic Light Emitting Diodes Utilizing a Green Thermally Activated Delayed Fluorescence Emitter with an Extended Linear Donor-Acceptor-Donor Structure.

Adv Mater 2021 Sep 13:e2103293. Epub 2021 Sep 13.

Key Lab of Organic Optoelectronics and Molecular Engineering of Ministry of Education, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China.

Thermally activated delayed fluorescence (TADF) emitters featuring preferential horizontal emitting dipole orientation (EDO) are in urgent demand for enhanced optical outcoupling efficiency in organic light-emitting diodes (OLEDs). However, simultaneously manipulating EDO and optoelectronic properties remains a formidable challenge. Here, an extended linear D-A-D structure with both enlarged donor (D) and acceptor (A) π-systems is established, not only elaborately manipulating parallel horizontal molecular orientation and EDO along its long axis by multi-driving-forces for a high horizontal dipole ratio (Θ ), but also delocalizing distribution of frontier energy levels for optimized electronic properties. The proof-of-the-concept emitter simultaneously affords a high Θ of 92%, a high photoluminescence quantum yield of 95%, and a fast reverse intersystem crossing rate of 1.16 × 10 s . The corresponding OLED achieves a champion maximum external quantum efficiency of 39.1% among all green TADF devices without any external light-extraction techniques, together with a maximum power efficiency of 112.0 lm W and alleviated efficiency roll-off. These findings may inspire even better full-color TADF emitters that push the device efficiency toward the theoretical limits.
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http://dx.doi.org/10.1002/adma.202103293DOI Listing
September 2021

LISA2: Learning Complex Single-Cell Trajectory and Expression Trends.

Front Genet 2021 23;12:681206. Epub 2021 Aug 23.

Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, United States.

Single-cell transcriptional and epigenomics profiles have been applied in a variety of tissues and diseases for discovering new cell types, differentiation trajectories, and gene regulatory networks. Many methods such as Monocle 2/3, URD, and STREAM have been developed for tree-based trajectory building. Here, we propose a fast and flexible trajectory learning method, LISA2, for single-cell data analysis. This new method has two distinctive features: (1) LISA2 utilizes specified leaves and root to reduce the complexity for building the developmental trajectory, especially for some special cases such as rare cell populations and adjacent terminal cell states; and (2) LISA2 is applicable for both transcriptomics and epigenomics data. LISA2 visualizes complex trajectories using 3D Landmark ISOmetric feature MAPping (L-ISOMAP). We apply LISA2 to simulation and real datasets in cerebellum, diencephalon, and hematopoietic stem cells including both single-cell transcriptomics data and single-cell assay for transposase-accessible chromatin data. LISA2 is efficient in estimating single-cell trajectory and expression trends for different kinds of molecular state of cells.
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http://dx.doi.org/10.3389/fgene.2021.681206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428276PMC
August 2021

Prognostic Value of Podoplanin in Various Tumors.

Technol Cancer Res Treat 2021 Jan-Dec;20:15330338211038142

Department of Breast and Thyroid Surgery, Yangzhou University Affiliated Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China.

Background: The prognostic significance of podoplanin (PDPN) in tumor cells for cancer patients' survival remains controversial. Therefore, we performed this meta-analysis to clarify the relationship between the podoplanin-positive tumor cells and cancer prognosis.

Method: Eligible studies were identified by searching the Pubmed and EBSCO online databases up to August 2019. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the correlation between podoplanin expression and overall survival (OS) and/or disease-free survival (DFS) and odds ratios (ORs) with 95% CIs severed as the summarized statistics for clinicopathological characteristic.

Results: A total of 2155 patients from 21 eligible studies were included. The results revealed that high expression of podoplanin was associated with a poor survival rate in cancer patients. Further subgroup analysis stratified by tumor type showed that podoplanin-positive tumor cell infiltration had a negative prognostic effect associated with survival in esophageal cancer and oropharyngeal cancer. In addition, high expression of these cells was significantly associated with N stage, T stage, TNM stage and vascular invasion.

Conclusion: Our study suggests the over-expression of podoplanin might be a significant prognostic indicator for patients with esophageal and oropharyngeal cancer.
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http://dx.doi.org/10.1177/15330338211038142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442494PMC
September 2021

Peripheral Delivery of Ganglioside GM1 Exacerbates the Pathogenesis of Alzheimer's Disease in a Mouse Model.

Neurosci Bull 2021 Sep 12. Epub 2021 Sep 12.

Department of Neurology and Clinical Center for Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.

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http://dx.doi.org/10.1007/s12264-021-00768-8DOI Listing
September 2021

Metagenomic Next-Generation Sequencing of Bloodstream Microbial Cell-Free Nucleic Acid in Children With Suspected Sepsis in Pediatric Intensive Care Unit.

Front Cell Infect Microbiol 2021 24;11:665226. Epub 2021 Aug 24.

Paediatric Intensive Care Unit, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.

Bloodstream infection is a life-threatening complication in critically ill patients. Multi-drug resistant bacteria or fungi may increase the risk of invasive infections in hospitalized children and are difficult to treat in intensive care units. The purpose of this study was to use metagenomic next-generation sequencing (mNGS) to understand the bloodstream microbiomes of children with suspected sepsis in a pediatric intensive care unit (PICU). mNGS were performed on microbial cell-free nucleic acid from 34 children admitted to PICU, and potentially pathogenic microbes were identified. The associations of serological inflammation indicators, lymphocyte subpopulations, and other clinical phenotypes were also examined. mNGS of blood samples from children in PICU revealed potential eukaryotic microbial pathogens. The abundance of was positively correlated with a decrease in total white blood cell count and immunodeficiency. Hospital-acquired pneumonia patients showed a significant increase in blood bacterial species richness compared with community-acquired pneumonia children. The abundance of bloodstream bacteria was positively correlated with serum procalcitonin level. Microbial genome sequences from potential pathogens were detected in the bloodstream of children with suspected sepsis in PICU, suggesting the presence of bloodstream infections in these children.
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http://dx.doi.org/10.3389/fcimb.2021.665226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421769PMC
August 2021

Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer's Disease.

Front Aging Neurosci 2021 24;13:717263. Epub 2021 Aug 24.

Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China.

Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer's disease (AD)-type β-amyloid (Aβ) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.
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http://dx.doi.org/10.3389/fnagi.2021.717263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421777PMC
August 2021

Predictive Performance and Optimal Cut-Off Points of Blood Pressure for Identifying Arteriosclerosis among Adults in Eastern China.

Int J Environ Res Public Health 2021 Aug 25;18(17). Epub 2021 Aug 25.

Faculty of Sport Science, Research Academy of Grand Health, Ningbo University, Ningbo 315211, China.

This study aimed to assess the predictive performance and establish optimal cut-off points of blood pressure for identifying arteriosclerosis in eastern Chinese adults. Brachial-ankle pulse wave velocity (baPWV) was utilized to evaluate arteriosclerosis. The predictive performance of blood pressure for arteriosclerosis was determined by the area under the curve (AUC) of receiver operating characteristics; the optimal blood pressure cut-off points were determined by Youden's index. A logistic regression model was used to acquire the odds ratio (OR) of blood pressure for arteriosclerosis. The AUCs of blood pressure for identifying arteriosclerosis were 0.868 (95%CI: 0.860-0.875) for systolic blood pressure (SBP) and 0.835 (95%CI: 0.827-0.843) for diastolic blood pressure (DBP), both < 0.01. The AUCs of women were higher than that of men (0.903 vs. 0.819 for SBP; 0.847 vs. 0.806 for DBP; Z test < 0.05). The AUCs in the 18-39.9-years group were higher than that in the 40-59.9-years and 60-84-years groups (0.894 vs. 0.842 and 0.818 for SBP; 0.889 vs. 0.818 and 0.759 for DBP; Z test 0.05). The total optimal cut-off points of blood pressure for predicting arteriosclerosis were 123.5/73.5 mmHg (SBP/DBP) overall; 123.5/73.5 and 126.5/79.5 mmHg for women and men, respectively; and 120.5/73.5, 123.5/76.5, and 126.5/75.5 mmHg for 18-39.9-years, 40-59.9-years, and 60-84-years groups, respectively. Blood pressure indexes had a high predictive performance for identifying arteriosclerosis with the optimal cut-off point of 123.5/73.5 mmHg (SBP/DBP) in eastern Chinese adults. Women or the younger population have a higher predictive performance and lower cut-off points to identify arteriosclerosis.
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http://dx.doi.org/10.3390/ijerph18178927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430655PMC
August 2021

An automated ASPECTS method with atlas-based segmentation.

Comput Methods Programs Biomed 2021 Aug 31;210:106376. Epub 2021 Aug 31.

Laboratory of Image Science and Technology, Southeast University, Nanjing 210096, China; Key Laboratory of Computer Network and Information Integration (Southeast University), Ministry of Education, Nanjing 210096, China. Electronic address:

Background And Purpose: As a simple and reliable systematic method to evaluate the early ischemic changes in the blood supply region of the middle cerebral artery of patients with ischemic stroke, the Alberta Stroke Program Early CT score (ASPECTS) can be used for rapid semi-quantitative evaluation of ischemic lesions, which is helpful to select potential candidates for intravenous and intra-arterial therapies, determine the thrombolytic effect and long-term prognosis. This method mainly relies on doctors' visual observation. However, due to different levels of doctor's experience, the poor inter-reader agreement may result in errors in the final ASPECTS. The purpose of this work was to propose an automated semi-quantitative method for the diagnosis of acute ischemic stroke based on non-contrast computed tomography (NCCT), to provide a reference for doctors in the diagnosis and evaluation.

Methods: NCCT data from a total of 90 patients were included for auto-ASPECTS training and testing. After preprocessing CT images, the regions of interest (ROI) for ASPECTS were labeled using atlas-based segmentation. The mean difference, mean ratio and brain density shifts (BDS) of the corresponding regions of the contralateral brain were used as the standard for quantitative analysis. The auto-ASPECTS method was developed and validated to predict early ischemic changes whose performance was evaluated by the agreement (accuracy) of predictions and consensus scores of two observers.

Results: A comparison was made among the results on mean difference, mean ratio, BDS and the combination of multiple parameters as the standard. The result of using BDS alone was relatively better than the result of using any other parameter alone or any combination of multiple parameters, and accuracy in the test set was 0.80. In the test set, accuracy with using different BDS thresholds increased by 6.67% compared with using the consistent BDS threshold. After dichotomy of auto-ASPECTS and consensus scores with the threshold of 7, the agreement of them was 83.3% and there was no significant difference between the two distributions (p = 0.344) in McNemar test.

Conclusions: The proposed auto-ASPECTS method for NCCT images can provide useful information for early diagnosis and evaluation of patients with acute ischemic stroke (AIS).
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http://dx.doi.org/10.1016/j.cmpb.2021.106376DOI Listing
August 2021

Evolutionary Overview of Consumer Health Informatics: Bibliometric Study on the Web of Science from 1999 to 2019.

J Med Internet Res 2021 Sep 9;23(9):e21974. Epub 2021 Sep 9.

The Second Xiangya Hospital, Central South University, Changsha, China.

Background: Consumer health informatics (CHI) originated in the 1990s. With the rapid development of computer and information technology for health decision making, an increasing number of consumers have obtained health-related information through the internet, and CHI has also attracted the attention of an increasing number of scholars.

Objective: The aim of this study was to analyze the research themes and evolution characteristics of different study periods and to discuss the dynamic evolution path and research theme rules in a time-series framework from the perspective of a strategy map and a data flow in CHI.

Methods: The Web of Science core collection database of the Institute for Scientific Information was used as the data source to retrieve relevant articles in the field of CHI. SciMAT was used to preprocess the literature data and construct the overlapping map, evolution map, strategic diagram, and cluster network characterized by keywords. Besides, a bibliometric analysis of the general characteristics, the evolutionary characteristics of the theme, and the evolutionary path of the theme was conducted.

Results: A total of 986 articles were obtained after the retrieval, and 931 articles met the document-type requirement. In the past 21 years, the number of articles increased every year, with a remarkable growth after 2015. The research content in 4 different study periods formed the following 38 themes: patient education, medicine, needs, and bibliographic database in the 1999-2003 study period; world wide web, patient education, eHealth, patients, medication, terminology, behavior, technology, and disease in the 2004-2008 study period; websites, information seeking, physicians, attitudes, technology, risk, food labeling, patient, strategies, patient education, and eHealth in the 2009-2014 study period; and electronic medical records, health information seeking, attitudes, health communication, breast cancer, health literacy, technology, natural language processing, user-centered design, pharmacy, academic libraries, costs, internet utilization, and online health information in the 2015-2019 study period. Besides, these themes formed 10 evolution paths in 3 research directions: patient education and intervention, consumer demand attitude and behavior, and internet information technology application.

Conclusions: Averaging 93 publications every year since 2015, CHI research is in a rapid growth period. The research themes mainly focus on patient education, health information needs, health information search behavior, health behavior intervention, health literacy, health information technology, eHealth, and other aspects. Patient education and intervention research, consumer demand, attitude, and behavior research comprise the main theme evolution path, whose evolution process has been relatively stable. This evolution path will continue to become the research hotspot in this field. Research on the internet and information technology application is a secondary theme evolution path with development potential.
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http://dx.doi.org/10.2196/21974DOI Listing
September 2021

Machine learning-based CT radiomics model distinguishes COVID-19 from non-COVID-19 pneumonia.

BMC Infect Dis 2021 Sep 8;21(1):931. Epub 2021 Sep 8.

Department of Radiology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), No. 19, Xiuhua St, Xiuying Dic, Haikou, Hainan, 570311, People's Republic of China.

Background: To develop a machine learning-based CT radiomics model is critical for the accurate diagnosis of the rapid spreading coronavirus disease 2019 (COVID-19).

Methods: In this retrospective study, a total of 326 chest CT exams from 134 patients (63 confirmed COVID-19 patients and 71 non-COVID-19 patients) were collected from January 20 to February 8, 2020. A semi-automatic segmentation procedure was used to delineate the volume of interest (VOI), and radiomic features were extracted. The Support Vector Machine (SVM) model was built on the combination of 4 groups of features, including radiomic features, traditional radiological features, quantifying features, and clinical features. By repeating cross-validation procedure, the performance on the time-independent testing cohort was evaluated by the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity.

Results: For the SVM model built on the combination of 4 groups of features (integrated model), the per-exam AUC was 0.925 (95% CI 0.856 to 0.994) for differentiating COVID-19 on the testing cohort, and the sensitivity and specificity were 0.816 (95% CI 0.651 to 0.917) and 0.923 (95% CI 0.621 to 0.996), respectively. As for the SVM models built on radiomic features, radiological features, quantifying features, and clinical features, individually, the AUC on the testing cohort reached 0.765, 0.818, 0.607, and 0.739, respectively, significantly lower than the integrated model, except for the radiomic model.

Conclusion: The machine learning-based CT radiomics models may accurately classify COVID-19, helping clinicians and radiologists to identify COVID-19 positive cases.
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http://dx.doi.org/10.1186/s12879-021-06614-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424152PMC
September 2021

A Conjugative IncI1 Plasmid Carrying (B) and That Mediates Resistance to Azithromycin and Cephalosporins.

Microbiol Spectr 2021 Sep 8:e0028621. Epub 2021 Sep 8.

Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Konggrid.35030.35, Kowloon, Hong Kong.

In this study, an IncI1 plasmid encoding resistance to both cefotaxime and azithromycin was recovered from a clinical Klebsiella pneumoniae strain. The azithromycin resistance was confirmed to be mediated by the (B) gene. This plasmid could be readily conjugated to strains of Escherichia coli and Salmonella, promoting rapid dissemination of azithromycin- and ceftriaxone-resistance-encoding elements among Gram-negative bacterial pathogens. Transmission of this plasmid in Salmonella is of particular concern, since it could mediate expression of phenotypic resistance to azithromycin and ceftriaxone, which are the current choices for treatment of Salmonella infections. Our findings suggest a need to monitor the efficiency and pattern of transmission of this plasmid among key Gram-negative bacterial pathogens. Since the approval by the FDA of azithromycin for treatment of Salmonella infections, efforts have been made to monitor the development of resistance to azithromycin in these organisms. In this study, we report an IncI1 plasmid from a clinical K. pneumoniae strain that encodes resistance to both cefotaxime and azithromycin. This plasmid could be readily conjugated to strains of Escherichia coli and Salmonella, promoting rapid dissemination of azithromycin- and ceftriaxone-resistance-encoding elements among Gram-negative bacterial pathogens. Furthermore, data from this study confirmed for the first time the role of the (B) gene in mediating resistance to azithromycin in various bacterial species, particularly Salmonella.
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http://dx.doi.org/10.1128/Spectrum.00286-21DOI Listing
September 2021

Changes and Correlations of the Intestinal Flora and Liver Metabolite Profiles in Mice With Gallstones.

Front Physiol 2021 19;12:716654. Epub 2021 Aug 19.

Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

There is increasing appreciation for the roles of the gut-liver axis in liver and gall diseases. Specific gut microbes are associated with susceptibility to gallstone diseases, while the relationship between intestinal flora and liver metabolism in the formation of gallstones remains unclear. In this study, an experimental group of model mice was given a lithogenic diet, and a control group was given a normal diet. Both groups were fed for 8 weeks. Integrating 16S rRNA gene sequencing and non-targeted metabolomics to explore the impact of the lithogenic diet on intestinal flora and liver metabolism, Spearman correlation analysis reveals the network of relationships between the intestine and liver. Our findings showed that the gut microbiome and liver metabolome compositions of the test group were significantly changed compared with those of the normal group. Through our research, biomarkers of gallstones were identified at the phylum (5), class (5), order (5), family (7), and genus levels. We predicted the function of the differential flora. We analyzed the liver metabolism of mice with gallstones paired with their flora, and the results showed that there were 138 different metabolites between the two groups. The metabolic pathways enriched by these differential metabolites are highly consistent with the functions of the disordered flora. We focused on an analysis of the relationship between deoxycholic acid, asymmetric dimethylarginine, glucosamine, tauroursodeoxycholic acid, and the disordered flora. This provides a basis for the establishment of the intestine-liver axis in gallstone disease. This research provides a theoretical basis for the research and development of probiotics and prebiotics.
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http://dx.doi.org/10.3389/fphys.2021.716654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416897PMC
August 2021

Clinical and therapeutic relevance of cancer-associated fibroblasts.

Nat Rev Clin Oncol 2021 Sep 6. Epub 2021 Sep 6.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cancer-associated fibroblasts (CAFs) found in primary and metastatic tumours are highly versatile, plastic and resilient cells that are actively involved in cancer progression through complex interactions with other cell types in the tumour microenvironment. As well as generating extracellular matrix components that contribute to the structure and function of the tumour stroma, CAFs undergo epigenetic changes to produce secreted factors, exosomes and metabolites that influence tumour angiogenesis, immunology and metabolism. Because of their putative pro-oncogenic functions, CAFs have long been considered an attractive therapeutic target; however, clinical trials of treatment strategies targeting CAFs have mostly ended in failure and, in some cases, accelerated cancer progression and resulted in inferior survival outcomes. Importantly, CAFs are heterogeneous cells and their characteristics and interactions with other cell types might change dynamically as cancers evolve. Studies involving single-cell RNA sequencing and novel mouse models have increased our understanding of CAF diversity, although the context-dependent roles of different CAF populations and their interchangeable plasticity remain largely unknown. Comprehensive characterization of the tumour-promoting and tumour-restraining activities of CAF subtypes, including how these complex bimodal functions evolve and are subjugated by neoplastic cells during cancer progression, might facilitate the development of novel diagnostic and therapeutic approaches. In this Review, the clinical relevance of CAFs is summarized with an emphasis on their value as prognosis factors and therapeutic targets.
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http://dx.doi.org/10.1038/s41571-021-00546-5DOI Listing
September 2021

Association between serum phosphate and mortality in critically ill patients: a large retrospective cohort study.

BMJ Open 2021 09 6;11(9):e044473. Epub 2021 Sep 6.

Emergency, Affiliated Hospital of Southwest Jiaotong University / The Third People's Hospital of Chengdu, Chengdu, Sichuan, China

Objectives: This research aims to explore the impact of serum phosphate on the mortality of critically ill patients.

Design: A retrospective large cohort study.

Setting: Our data were extracted from a publicly accessible database named 'Multiparameter Intelligent Monitoring in Intensive Care Database III'.

Participants: 27 131 patients were included by clear definitions of selection and exclusion criteria.

Interventions: We used initial phosphate at admission as a design variable. Patients were divided into six groups with different serum phosphate levels and five groups at different intensive care unit (ICU) departments.

Primary And Secondary Outcomes: 28-day and 90-day mortality were primary outcomes. All-cause mortality and length of stay ICU were secondary outcomes.

Results: Patients with very-high-normal serum phosphate, hypophosphataemia and hyperphosphataemia had worse outcomes. And the relationship between serum phosphate and the probability of 28-day or 90-day mortality had a linear relationship. After adjustment for potential confounders, hypophosphataemia and hyperphosphataemia were not significantly associated with 28-day or 90-day mortality. Nevertheless, at the medical ICU, hyperphosphataemia was associated with increased 28-day or 90-day mortality (HR=0.64, 95% CI 0.48 to 0.84, p=0.0017; HR=0.72, 95% CI 0.57 to 0.91, p=0.0067, respectively), using group 2 (≥2.5 mg/dL and <3.0 mg/dL) as the reference group.

Conclusions: Patients with very-high-normal serum phosphate also had worse outcomes, it might be necessary to re-evaluate the definitions of the normal reference range for serum phosphate. Hypophosphataemia and hyperphosphataemia are not the independent risk factors of 28-day or 90-day ICU mortality, which leads us to consider whether phosphate monitoring is not a necessary measure in critically ill patients. But hyperphosphataemia was associated with increased 28-day or 90-day mortality at the medical ICU, which emphasises the potential importance of early diagnosis and treatment of hyperphosphataemia for the patients who were admitted to the medical ICU.
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http://dx.doi.org/10.1136/bmjopen-2020-044473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422318PMC
September 2021

Prussian blue-based theranostics for ameliorating acute kidney injury.

J Nanobiotechnology 2021 Sep 6;19(1):266. Epub 2021 Sep 6.

Marshall Laboratory of Biomedical Engineering, International Cancer Center, Laboratory of Evolutionary Theranostics (LET), School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China.

Background: Acute kidney injury (AKI) with high mortality rates is associated with an excess of reactive oxygen/nitrogen species (RONS) within kidney tissues. Recently, nanomedicine antioxidant therapy has been used to alleviate AKI. Herein, we synthesized ultrasmall Prussian blue nanozymes (PB NZs, 4.5 nm) as theranostic agents for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided AKI treatment.

Results: PB NZs exhibited multi-enzyme mimetic abilities, promoting the effective elimination of RONS both in vitro and in vivo. Moreover, benefiting from their imaging contrast properties, the rapid renal accumulation of PB NZs was verified by in vivo PA/MR dual-modal imaging. Due to their excellent enrichment in the kidney and unique multi-enzyme mimetic abilities, ultrasmall PB NZs displayed superior AKI treatment efficacy compared with that of amifostine in two clinically relevant types of AKI induced murine models (either by rhabdomyolysis or cisplatin).

Conclusion: Our findings suggested ultrasmall PB NZs, as nanozyme theranostics, have great potential for AKI management.
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http://dx.doi.org/10.1186/s12951-021-01006-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419910PMC
September 2021

Carcinogenic effect of adenylosuccinate lyase (ADSL) in prostate cancer development and progression through the cell cycle pathway.

Cancer Cell Int 2021 Sep 6;21(1):467. Epub 2021 Sep 6.

Center for Genomic and Personalized Medicine, Guangxi key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, No. 22 Shuangyong Road, Guangxi Zhuang Autonomous Region, Nanning, 530021, China.

Background: Prostate cancer (PCa) is still a serious male malignant disease across the world. However, no exact pathogenesis had been explained. Although adenylosuccinate lyase (ADSL) gene was identified to be important in PCa early in 1987, its comprehensive functions for PCa have not been presented.

Methods: The cBioPortal for Cancer Genomics, Oncomine and GEO database were retrieved to investigate the associations between of the ADSL gene and PCa. Then, the PC-3, DU145 and C4-2B cell lines were applied in vitro experiments. RNA sequencing and further western blot (WB) were applied to explore the potential mechanisms of ADSL gene in PCa.

Results: Based on PCa clinical datasets, we firstly found ADSL gene highly expressed in PCa tissues. Moreover, its transcript level increased in the metastatic PCa further. Elevated ADSL gene expression indicated a poor prognosis of PCa. While inhibiting the expression of ADSL with siRNA, the ability of cell proliferation and migration all declined markedly, with increased cell apoptosis inversely. Most of cells were blocked in the G0/G1 phase. Additionally, RNA sequencing also discovered the inactivity of cell cycle pathway after ADSL knockdown, which had also confirmed on the proteins levels.

Conclusions: Our study identified the ADSL as an oncogene of PCa through regulating the cell cycle pathway firstly, with explicit cell and clinical phenotypes. Further mechanisms were needed to confirm its carcinogenic effect.
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http://dx.doi.org/10.1186/s12935-021-02174-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419980PMC
September 2021

Female reproductive abnormalities in mouse adolescent pregnancy.

Reproduction 2021 Sep 1. Epub 2021 Sep 1.

Z Yang, Veterinary Medicine, South China Agricultural University, Guangzhou, China.

There are around 300 million adolescent pregnancies worldwide, accounting for 11% of all births worldwide. Accumulating evidence demonstrates that many adverse perinatal outcomes are associated with adolescent pregnancies. However, how and why these abnormalities occur remain to be defined. In this study, pregnancy at different stages were compared between 25-30 day old and mature female mice. We found the litter size of adolescent pregnancy is significantly decreased from F1 to F3 generations compared to mature pregnancy. On days 8 and 12 of pregnancy, multiple abnormalities in decidual and placental development appear in F3 adolescent pregnancy. On days 5 and 8, uterine endoplasmic reticulum stress is dysregulated in F3 adolescent pregnancy. Embryo implantation and decidualization are also compromised in adolescent pregnancy. Many genes are abnormally expressed in adolescent estrous uteri. The abnormal endocrine environment and abnormal implantation from uterine immaturity may result in multiple pregnancy failures in adolescent pregnancy. This study should shed light on human adolescent pregnancy.
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http://dx.doi.org/10.1530/REP-21-0240DOI Listing
September 2021

A chromosome-level genome of Antechinus flavipes provides a reference for an Australian marsupial genus with male death after mating.

Mol Ecol Resour 2021 Sep 6. Epub 2021 Sep 6.

Integrative Biology Laboratory, College of Life Sciences, Nanjing Normal University, Nanjing, China.

The 15 species of small carnivorous marsupials that comprise the genus Antechinus exhibit semelparity, a rare life-history strategy in mammals where synchronized death occurs after one breeding season. Antechinus males, but not females, age rapidly (demonstrate organismal senescence) during the breeding season and show promise as new animal models of ageing. Some antechinus species are also threatened or endangered. Here, we report a chromosome-level genome of a male yellow-footed antechinus Antechinus flavipes. The genome assembly has a total length of 3.2 Gb with a contig N50 of 51.8 Mb and a scaffold N50 of 636.7 Mb. We anchored and oriented 99.7% of the assembly on seven pseudochromosomes and found that repetitive DNA sequences occupy 51.8% of the genome. Draft genome assemblies of three related species in the subfamily Phascogalinae, two additional antechinus species (Antechinus argentus and A. arktos) and the iteroparous sister species Murexia melanurus, were also generated. Preliminary demographic analysis supports the hypothesis that climate change during the Pleistocene isolated species in Phascogalinae and shaped their population size. A transcriptomic profile across the A. flavipes breeding season allowed us to identify genes associated with aspects of the male die-off. The chromosome-level A. flavipes genome provides a steppingstone to understanding an enigmatic life-history strategy and a resource to assist the conservation of antechinuses.
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http://dx.doi.org/10.1111/1755-0998.13501DOI Listing
September 2021

Prognostic Analysis of Lung Adenocarcinoma Based on DNA Methylation Regulatory Factor Clustering.

J Oncol 2021 26;2021:1557968. Epub 2021 Aug 26.

Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China.

There is a known link between DNA methylation and cancer immunity/immunotherapy; however, the effect of DNA methylation on immunotherapy in lung adenocarcinoma (LUAD) remains to be elucidated. In the current study, we aimed to screen key markers for prognostic analysis of LUAD based on DNA methylation regulatory factor clustering. We classified LUAD using the NMF clustering method, and as a result, we obtained 20 DNA methylation regulatory genes. These 20 regulatory genes were used to determine the pattern of DNA methylation regulation, and patients were grouped for further analysis. The risk score model was analyzed in the TCGA dataset and an external validation set, and the correlation between the risk score and DNA methylation regulatory gene expression was explored. We analyzed the correlation between the prognostic model and immune infiltration and checkpoints. Finally, we analyzed the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functions of the prognosis model and established the nomogram model and decision tree model. The survival analyses of ClusterA and ClusterB were significantly different. Survival analysis showed that patients with a high risk score had a poor prognosis. Survival models (tobacco, T, N, M, stage, sex, age, status, and risk score) were abnormally correlated with T cells and macrophages. The higher the risk score associated with smoking was and the higher the stage was, the more severe the LUAD and the more maladjusted the immune system were. Immune infiltration and abnormal expression of immune checkpoint genes in the prognostic model of LUAD were associated with the risk score. The prognostic models were mainly enriched in the cell cycle and DNA replication. Characterization of DNA methylation regulatory patterns is helpful to improve our understanding of the immune microenvironment in LUAD and to guide the development of a more personalized immunotherapy strategy in the future.
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http://dx.doi.org/10.1155/2021/1557968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413078PMC
August 2021

Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis.

Redox Biol 2021 Oct 31;46:102122. Epub 2021 Aug 31.

Laboratory Medicine Center, Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China. Electronic address:

Hepatocellular carcinoma (HCC) is one of the paramount causes of cancer-related death worldwide. Despite recent advances have been made in clinical treatments of HCC, the general prognosis of patients remains poor. Therefore, it is imperative to develop a less toxic and more effective therapeutic strategy. Currently, series of cellular, molecular, and pharmacological experimental approaches were utilized to address the unrecognized characteristics of disulfiram (DSF), pursuing the goal of repurposing DSF for cancer therapy. We found that DSF/Cu selectively exerted an efficient cytotoxic effect on HCC cell lines, and potently inhibited migration, invasion, and angiogenesis of HCC cells. Importantly, we confirmed that DSF/Cu could intensively impair mitochondrial homeostasis, increase free iron pool, enhance lipid peroxidation, and eventually result in ferroptotic cell death. Of note, a compensatory elevation of NRF2 accompanies the process of ferroptosis, and contributes to the resistance to DSF/Cu. Mechanically, we found that DSF/Cu dramatically activated the phosphorylation of p62, which facilitates competitive binding of Keap1, thus prolonging the half-life of NRF2. Notably, inhibition of NRF2 expression via RNA interference or pharmacological inhibitors significantly facilitated the accumulation of lipid peroxidation, and rendered HCC cells more sensitive to DSF/Cu induced ferroptosis. Conversely, fostering NRF2 expression was capable of ameliorating the cell death activated by DSF/Cu. Additionally, DSF/Cu could strengthen the cytotoxicity of sorafenib, and arrest tumor growth both in vitro and in vivo, by simultaneously inhibiting the signal pathway of NRF2 and MAPK kinase. In summary, these results provide experimental evidence that inhibition of the compensatory NRF2 elevation strengthens HCC cells more vulnerable to DSF/Cu induced ferroptosis, which facilitates the synergistic cytotoxicity of DSF/Cu and sorafenib.
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http://dx.doi.org/10.1016/j.redox.2021.102122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416961PMC
October 2021

Microbial production of riboflavin: Biotechnological advances and perspectives.

Metab Eng 2021 Sep 2;68:46-58. Epub 2021 Sep 2.

Key Laboratory of Industrial Biotechnology of the Ministry of Education, Laboratory of Applied Microorganisms and Metabolic Engineering, School of Biotechnology, Jiangnan University, Wuxi, 214122, China. Electronic address:

Riboflavin is an essential nutrient for humans and animals, and its derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are cofactors in the cells. Therefore, riboflavin and its derivatives are widely used in the food, pharmaceutical, nutraceutical and cosmetic industries. Advances in biotechnology have led to a complete shift in the commercial production of riboflavin from chemical synthesis to microbial fermentation. In this review, we provide a comprehensive review of biotechnologies that enhance riboflavin production in microorganisms, as well as representative examples. Firstly, the synthesis pathways and metabolic regulatory processes of riboflavin in microorganisms; and the current strategies and methods of metabolic engineering for riboflavin production are systematically summarized and compared. Secondly, the using of systematic metabolic engineering strategies to enhance riboflavin production is discussed, including laboratory evolution, histological analysis and high-throughput screening. Finally, the challenges for efficient microbial production of riboflavin and the strategies to overcome these challenges are prospected.
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http://dx.doi.org/10.1016/j.ymben.2021.08.009DOI Listing
September 2021

Gemcitabine synergizes with cisplatin to inhibit nasopharyngeal carcinoma cell proliferation and tumor growth.

FASEB J 2021 Oct;35(10):e21885

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.

In a recently published phase III clinical trial, gemcitabine (GEM) plus cisplatin (DDP) induction chemotherapy significantly improved recurrence-free survival and overall survival and became the standard of care among patients with locoregionally advanced NPC. However, the molecular mechanisms of GEM synergized with DPP in NPC cells remain elucidated. These findings prompt us to explore the effect of the combination between GEM and DDP in NPC cell lines through proliferative phenotype, immunofluorescence, flow cytometry, and western blotting assays. In vitro studies reveal that GEM or DPP treated alone induces cell cycle arrest, promotes cell apoptosis, forces DNA damage response, and GEM synergism with DDP significantly increases the above effects in NPC cells. In vivo studies indicate that GEM or DPP treated alone significantly inhibits the tumor growth and prolongs the survival time of mice injected with SUNE1 cells compared to the control group. Moreover, the mice treated with GEM combined with DDP have smaller tumors and survive longer than those in GEM or DPP treated alone group. In addition, P-gp may be the key molecule that regulates the synergistic effect of gemcitabine and cisplatin. GEM synergizes with DPP to inhibit NPC cell proliferation and tumor growth by inducing cell cycle arrest, cell apoptosis, and DNA damage response, which reveals the mechanisms of combined GEM and DDP induction chemotherapy in improving locoregionally advanced NPC.
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http://dx.doi.org/10.1096/fj.202100076RRDOI Listing
October 2021

Unveiling the full reaction path of the Suzuki-Miyaura cross-coupling in a single-molecule junction.

Nat Nanotechnol 2021 Sep 2. Epub 2021 Sep 2.

Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, P. R. China.

Conventional analytic techniques that measure ensemble averages and static disorder provide essential knowledge of the reaction mechanisms of organic and organometallic reactions. However, single-molecule junctions enable the in situ, label-free and non-destructive sensing of molecular reaction processes at the single-event level with an excellent temporal resolution. Here we deciphered the mechanism of Pd-catalysed Suzuki-Miyaura coupling by means of a high-resolution single-molecule platform. Through molecular engineering, we covalently integrated a single molecule Pd catalyst into nanogapped graphene point electrodes. We detected sequential electrical signals that originated from oxidative addition/ligand exchange, pretransmetallation, transmetallation and reductive elimination in a periodic pattern. Our analysis shows that the transmetallation is the rate-determining step of the catalytic cycle and clarifies the controversial transmetallation mechanism. Furthermore, we determined the kinetic and thermodynamic constants of each elementary step and the overall catalytic timescale of this Suzuki-Miyaura coupling. Our work establishes the single-molecule platform as a detection technology for catalytic organochemistry that can monitor transition-metal-catalysed reactions in real time.
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http://dx.doi.org/10.1038/s41565-021-00959-4DOI Listing
September 2021
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