Publications by authors named "Ling Yi"

142 Publications

Maternal periconceptional folic acid supplementation reduced risks of non-syndromic oral clefts in offspring.

Sci Rep 2021 Jun 10;11(1):12316. Epub 2021 Jun 10.

National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, No.17 Section 3 Renminnanlu, Chengdu, 610041, Sichuan, China.

Maternal periconceptional folic acid supplementation (FAS) has been documented to be associated with decreased risk of nonsyndromic oral clefts (NsOC). However, the results remain inconclusive. In this population-based case-control study of 807 singletons affected by NsOC and 8070 healthy neonates who were born between October 2010 and September 2015 in Chengdu, China, we examined the association of maternal FAS with the risk of nonsyndromic cleft lip with or without cleft palate (NsCL/P), and cleft palate (NsCP). Unconditional logistic regression analysis was used to estimate the crude and adjusted odds ratios (ORs) and 95% confidential intervals (CI). Significant associations were found between maternal periconceptional FAS and decreased risk of NsCL/P (aOR = 0.41, 95% CI 0.33-0.51). This protective effect was also detected for NsCL (aOR = 0.42, 95% CI 0.30-0.58) and NsCLP (aOR = 0.41, 95% CI 0.31-0.54). Both maternal FAS started before and after the last menstrual period (LMP) were inversely associated with NsCL/P (before LMP, aOR = 0.43, 95% CI 0.33-0.56; after LMP, aOR = 0.41, 95% CI 0.33-0.51). The association between NsCP and maternal FAS initiating before LMP was also found (aOR = 0.52, 95% CI 0.30-0.90). The findings suggest that maternal periconceptional FAS can reduce the risk of each subtype of NsCL/P in offspring, while the potential effect on NsCP needs further investigations.
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http://dx.doi.org/10.1038/s41598-021-91825-9DOI Listing
June 2021

Association between maternal exposure to gaseous pollutants and atrial septal defect in China: A nationwide population-based study.

Environ Res 2021 Jun 4:111472. Epub 2021 Jun 4.

The Joint Laboratory for Pulmonary Development and Related Diseases, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, 610041, China; National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Med-X Center for Informatics, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address:

Background: The association between maternal exposure to gaseous air pollutants and congenital heart defects (CHD) remains unclear. The concentration-response relationship and the time windows of susceptibility to gaseous pollutants may vary by pollutant species and CHD subtypes.

Objective: We aimed to examine the relationship between maternal exposures to four species of gaseous pollutants (NO, O, SO, and CO) and atrial septal defect (ASD), which is a common subtype of CHD, and to determine the critical time windows of susceptibility for each gaseous pollutant.

Methods: Among 1,253,633 infants born between October 1, 2013 and December 31, 2016 in China, 1937 newborns were diagnosed with isolated ASD, a prevalence of 1.55‰. Maternal exposures to the gaseous pollutants were estimated by matching the geocoded maternal addresses with the gridded ambient concentrations. The adjusted odds ratios (aOR) between exposures and ASD were quantified by using mixed-effects logistic regression models.

Results: We found significantly positive associations between ASD and maternal exposures to NO, O, SO, and CO during entire pregnancy, first-, second-, and third-trimester. However, no statistically significant association was found between maternal exposure to PM, PM and ASD risk (P > 0.05). In the fully adjusted model with respect to average exposure over entire pregnancy, the adjusted odds ratios (aOR) for each 10 μg/m increment of NO, O, SO were 1.33 (95% CI: 1.22-1.45), 1.13 (95% CI: 1.10-1.16), 1.28 (95% CI: 1.20-1.35), respectively; the aOR for each 100 μg/m increment of CO was 1.10 (95% CI: 1.06-1.15). The observed concentration-response relationships varied by exposure periods and pollutants, with the strongest association for NO during the 1st-8th embryology weeks, for O during the third trimester, for SO during the second trimester, and for CO without obvious variation.

Conclusions: The findings suggest an increased risk of ASD in association with maternal exposures to four common gaseous pollutants. From the perspective of birth defects prevention and ASD risk mitigation, it is critical to reduce maternal exposure to gaseous pollutants especially during the most susceptible time windows.
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http://dx.doi.org/10.1016/j.envres.2021.111472DOI Listing
June 2021

Heterogeneity and prognosis of programmed cell death-ligand 1 expression in the circulating tumor cells of non-small cell lung cancer.

Neoplasma 2021 Jun 7. Epub 2021 Jun 7.

Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.

Due to tumor heterogeneity, the consistency of programmed cell death-ligand 1 (PD-L1) expression between circulating tumor cells (CTCs) and tissue is controversial. This study aimed to establish a method for detecting CTC PD-L1 expression and exploring the impact of the same on the prognosis of lung cancer. In 32 patients with non-small cell lung cancer, lung cancer cells in the blood were enriched using CD326 immunomagnetic beads. Goat anti-mouse polyclonal CD326 antibody stained the epithelial lung cancer cells and anti-PD-L1 antibody was used to detect the expression of CTC PD-L1. The DAKO Link 48 automatic staining device detected the expression in lung cancer tissue. The consistency of PD-L1 expression was analyzed in lung cancer tissue and CTCs. The effect of plasma interferon gamma, tumor necrosis factor alpha, and interleukin-2 on PD-L1 expression and prognosis was analyzed. The number of CTCs detected in patients was 1-36, with a median of 2. There was no significant difference in PD-L1 expression fractions between CTCs and paired tumor tissue (p > 0.05). The correlation coefficient was 0.20. Regardless of lung cancer tissue or CTCs, there was no statistically significant difference in the blood cytokine levels between the two groups with positive or negative PD-L1 expression (p > 0.05). There was no correlation between CTCs and PD-L1 in 23 untreated patients. The expression of PD-L1 in CTCs and lung cancer tissue is heterogeneous and unaffected by the peripheral cytokines' levels. PD-L1 expression has no correlation between CTCs and tissues and is not related to prognosis.
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http://dx.doi.org/10.4149/neo_2021_210115N67DOI Listing
June 2021

PAL-mediated SA biosynthesis pathway contributes to nematode resistance in wheat.

Plant J 2021 May 11. Epub 2021 May 11.

Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China.

The pathogen cereal cyst nematode (CCN) is deleterious to Triticeae crops and is a threat to the global crop yield. Accession no. 1 of Aegilops variabilis, a relative of Triticum aestivum (bread wheat), is highly resistant to CCN. Our previous study demonstrated that the expression of the phenylalanine ammonia lyase (PAL) gene AevPAL1 in Ae. variabilis is strongly induced by CCN. PAL, the first enzyme of phenylpropanoid metabolism, is involved in abiotic and biotic stress responses. However, its role in plant-CCN interaction remains unknown. In the present study, we proved that AevPAL1 helps to confer CCN resistance through affecting the synthesis of salicylic acid (SA) and downstream secondary metabolites. The silencing of AevPAL1 increased the incidence of CCN infection in roots and decreased the accumulation of SA and phenylalanine (Phe)-derived specialized metabolites. The exogenous pre-application of SA also improved CCN resistance. Additionally, the functions of PAL in phenylpropanoid metabolism correlated with tryptophan decarboxylase (TDC) functioning in tryptophan metabolism pathways. The silencing of either AevPAL1 or AevTDC1 exhibited a concomitant reduction in the expression of both genes and the contents of metabolites downstream of PAL and TDC. These results suggested that AevPAL1, possibly in coordination with AevTDC1, positively contributes to CCN resistance by altering the downstream secondary metabolites and SA content in Ae. variabilis. Moreover, AevPAL1 overexpression significantly enhanced CCN resistance in bread wheat and did not exhibit significant negative effects on yield-related traits, suggesting that AevPAL1 is valuable for the genetic improvement of CCN resistance in bread wheat.
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http://dx.doi.org/10.1111/tpj.15316DOI Listing
May 2021

Hydrological projections in the upper reaches of the Yangtze River Basin from 2020 to 2050.

Sci Rep 2021 May 6;11(1):9720. Epub 2021 May 6.

State Key Laboratory of Simulation and Regulation of Water Cycle in River Catchment, China Institute of Water Resources and Hydropower Research, Beijing, 100038, China.

Understanding the impact of climate change on runoff is essential for effective water resource management and planning. In this study, the regional climate model (RCM) RegCM4.5 was used to dynamically downscale near-future climate projections from two global climate models to a 50-km horizontal resolution over the upper reaches of the Yangtze River (UYRB). Based on the bias-corrected climate projection results, the impacts of climate change on mid-twenty-first century precipitation and temperature in the UYRB were assessed. Then, through the coupling of a large-scale hydrological model with RegCM4.5, the impacts of climate change on river flows at the outlets of the UYRB were assessed. According to the projections, the eastern UYRB will tend to be warm-dry in the near-future relative to the reference period, whereas the western UYRB will tend to be warm-humid. Precipitation will decreases at a rate of 19.05-19.25 mm/10 a, and the multiyear average annual precipitation will vary between - 0.5 and 0.5 mm/day. Temperature is projected to increases significantly at a rate of 0.38-0.52 °C/10 a, and the projected multiyear average air temperature increase is approximately 1.3-1.5 ℃. The contribution of snowmelt runoff to the annual runoff in the UYBR is only approximately 4%, whereas that to the spring runoff is approximately 9.2%. Affected by climate warming, the annual average snowmelt runoff in the basin will be reduced by 36-39%, whereas the total annual runoff will be reduced by 4.1-5%, and the extreme runoff will be slightly reduced. Areas of projected decreased runoff depth are mainly concentrated in the southeast region of the basin. The decrease in precipitation is driving this decrease in the southeast, whereas the decreased runoff depth in the northwest is mainly driven by the increase in evaporation.
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http://dx.doi.org/10.1038/s41598-021-88135-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102517PMC
May 2021

Low expression of BTN3A3 indicates poor prognosis and promotes cell proliferation, migration and invasion in non-small cell lung cancer.

Ann Transl Med 2021 Mar;9(6):478

No. 2 Department of Thoracic Surgery, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China.

Background: The butyrophilin (BTN) family has many members with diverse functions related to immunomodulation, initiation and progression of tumors. BTN3A3 belongs to the BTN family, and exploring its expression and correlation with the prognosis of non-small cell lung cancer (NSCLC) patients has great clinical significance.

Methods: Clinical specimens were used to detect BTN3A3 expression. Small interfering RNA (siRNA) was used to knock down BTN3A3 and analyze the proliferative, migratory and invading ability of the transfected NSCLC cells. Multiplex immunofluorescence staining was used to detect the expression of BTN3A3 protein in the tumor microenvironment (TME). We analyzed the relationship between the expression of BTN3A3 and the clinicopathological features and prognosis of NSCLC patients.

Results: The expression of BTN3A3 in NSCLC tissues was significantly lower than in adjacent tissues, and patients with low expression of BTN3A3 had late clinical stages and lower degree of tumor differentiation. Knocking down BTN3A3 promoted the proliferation, migration and invasion of NSCLC. In the TME, the density of BTN3A3+ tumor cells positively correlated with the density of CD8+ T cells, and the patients with low expression of BTN3A3 had poor overall survival (OS).

Conclusions: Changes in the BTN3A3 expression level may play a potential key role in the carcinogenesis and development of NSCLC. Patients with low expression of BTN3A3 showed a more aggressive and invasive phenotype and a lower level of CD8+ T-cell infiltration, which may be an important factor affecting the OS of NSCLC patients.
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http://dx.doi.org/10.21037/atm-21-163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039694PMC
March 2021

A randomized controlled trial of brain and heart health manager-led mHealth secondary stroke prevention.

Cardiovasc Diagn Ther 2020 Oct;10(5):1192-1199

Department of Neurology, Chongqing Three Gorges Central Hospital, Chongqing, China.

Background: This study explores the effect of brain and heart health manager (BHHM)-led stroke secondary prevention on blood pressure, and in improving the self-management ability of stroke patients. The BHHM has not been reported.

Methods: A total of 200 stroke patients, who were discharged from our hospital, were randomized into two groups at a 1:1 ratio: intervention group and control group. Patients in the control group were followed up for six months via telephone, while patients in the experimental group were followed up for six months using the BHHM-led mHealth follow-up. The primary outcomes were systolic blood pressure (BP) and self-management ability at 3, 6, 9 and 12 months, while the secondary outcomes included medication adherence, the body mass index (BMI), and blood low-density lipoprotein.

Results: The systolic BP between these two groups at four time points (F =8.734, F =172.075, and F =11.363) was statistically significant (P<0.05). The self-health management ability at four time points during follow-up period (F =115.09, F =1,185.50, and F =108.22) was also significantly different between these two groups. Furthermore, there was a statistically significant difference in compliance with medication at six months (χ=37.616, P=0.000). However, after one year, there were no significant differences in BMI (t=0.214, P=0.644), total cholesterol (t=0.56, P=0.837), and low-density lipoprotein (t=0.042, P=0.455).

Conclusions: The BHHM-led mHealth follow-up is an effective method for managing BP and improving the self-care ability. Furthermore, this approach has no obvious effect on the management of BMI and blood low-density lipoprotein. A potential signal of efficacy with the intervention was observed.
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http://dx.doi.org/10.21037/cdt-20-423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666930PMC
October 2020

Gut Microbiome Signatures Are Biomarkers for Cognitive Impairment in Patients With Ischemic Stroke.

Front Aging Neurosci 2020 23;12:511562. Epub 2020 Oct 23.

Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Post-stroke cognitive impairment (PSCI) is a common neuropsychiatric complication of stroke. Mounting evidence has demonstrated a connection between gut microbiota (GM) and neuropsychiatric disease. Our previous study revealed the changes in the GM in a mouse model of vascular dementia. However, the characteristic GM of PSCI remains unclear. This study aimed to characterize the GM of PSCI and explored the potential of GM as PSCI biomarkers. A total of 93 patients with ischemic stroke were enrolled in this study. The patients were divided into two groups according to their MoCA scores 3 months after stroke onset. Clinical data and biological variables were recorded. GM composition was analyzed using 16S ribosomal RNA sequencing, and the characteristic GM was identified by linear discriminant analysis Effect Size (Lefse). Our results showed that was highly increased in the PSCI group compared with the post-stroke non-cognitive impairment (PSNCI) group, the similar alterations were also observed at the class, order, family, and genus levels of . After age adjustments, the abundance of , and its members, including , , , and , were significantly decreased in the age-matched PSCI group compared with the PSNCI group. Besides, the GM was closely associated with MoCA scores and the risk factors for PSCI, including higher baseline National Institute of Health Stroke Scale score, higher homocysteine (Hcy) level, higher prevalence of stroke recurrence, leukoaraiosis, and brain atrophy. The KEGG results showed the enriched module for folding, sorting and degradation (chaperones and folding catalysts) and the decreased modules related to metabolisms of cofactors and vitamins, amino acid, and lipid in PSCI patients. A significant correlation was observed between PSCI and the abundance of after adjustments ( = 0.035). Moreover, the receiver operating characteristic (ROC) models based on the characteristic GM and could distinguish PSCI patients from PSNCI patients [area under the curve (AUC) = 0.840, 0.629, respectively]. Our findings demonstrated that the characteristic GM, especially , might have the ability to predict PSCI in post-stroke patients, which are expected to be used as clinical biomarkers of PSCI.
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http://dx.doi.org/10.3389/fnagi.2020.511562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645221PMC
October 2020

Perceptions of education quality and influence of language barrier: graduation survey of international medical students at four universities in China.

BMC Med Educ 2020 Nov 7;20(1):410. Epub 2020 Nov 7.

School of International Education, Xuzhou Medical University, No.209 of Tongshan Road, Yunlong District, Xuzhou, Jiangsu, China.

Background: As the number of Asian and African students studying medicine in China increases, it is imperative to evaluate the educational experiences of these international medical students (IMSs). This study was intended to investigate opinions of China-educated IMSs towards the medical curriculum and the impact of Chinese language capability on their clinical studies.

Methods: A self-administered questionnaire was circulated to the final-year IMSs during the graduation time from May 2019 to July 2019 in 4 universities in China. The questionnaire asked IMSs to assess the quality of medical education and provide a self-evaluation of their Chinese language capability. One-way Analysis of Variance (ANOVA) was used to determine whether IMSs' Chinese language capability was associated with their clinical experiences and clinical competence.

Results: Overall, we received 209 valid responses, of which 76.1% were satisfied with the quality of medical education. Genetics, physics, and mathematics were perceived as the least relevant basic courses for medical practice, and 21.5% of student reported that community-oriented medicine was a neglected subject. Notably, 58.9% of students had positive views about discussions on ethical topics during their clerkships, and 71.3% believed they had acquired sufficient clinical skills to begin a residency program. Chinese speaking skills and communication initiatives were found to be critical factors in influencing students' clinical experiences and competence.

Conclusion: This study presents the perceptions of China-educated IMSs towards medical curriculum from various aspects. Results show that language influences the education experiences of IMSs. Collectively, these results indicate that the curriculum for IMSs in China should be more problem-based and community-engaged to improve IMSs' learning experiences and preparation for community deployment. Furthermore, training curriculum for the oral Chinese should be improved to equip IMSs with sufficient language competence to enable them to efficiently carry out clinical clerkship and rotations. Our findings provide evidence for benchmarking medical curricular codifications tailored for Asian and African students.
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http://dx.doi.org/10.1186/s12909-020-02340-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648950PMC
November 2020

Triiodothyronine promotes the osteoblast formation by activating autophagy.

Biophys Chem 2020 12 25;267:106483. Epub 2020 Sep 25.

Department of Pediatrics, Ganzhou People's Hospital, Ganzhou 341000, China. Electronic address:

Based on the osteogenic effect, triiodothyronine (T3) plays an important role in bone growth and development. Autophagy contributes to osteoblast formation and subsequent osteogenesis. Our study aims to explore the relationship among T3, autophagy and osteogenesis. In this study, cranial primary osteoblasts were obtained from 2 to 3 weeks-old Sprague Dawley (SD) rat fetuses. Osteoblasts were treated with T3, and then the autophagic parameters of Osteoblasts (including autophagic proteins, LC3 conversion rate and autophagosome formation) were observed through Western Blotting and Transmission Electron Microscopy. Next, after using autophagic pharmacological inhibitors (3-MA and chloroquine) and silencing vectors of autophagic genes (BECN1, Atg5 and Atg7) to downregulate autophagic activity, osteoblast proliferation and osteoblastic gene expression were detected using cell counting kit-8 (CCK-8) and quantitative real-time PCR (qRT-PCR) assays, respectively. Ultimately, the mice treated with partial thyroidectomy (PTx mice) were used to further observe the effect of T3 on the formation and autophagy of osteoblasts in trabecular bone in vivo. Our results show that T3 enhances osteoblast autophagy. Autophagy suppression with 3-MA, chloroquine or autophagy-genes knockdown reverses T3-promoted osteoblast formation. In vivo assays showed that the formation and autophagy of osteoblasts in bone tissue were reduced in T3-deficient young mice. Overall, T3 can promote osteoblast formation by activation of autophagy.
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http://dx.doi.org/10.1016/j.bpc.2020.106483DOI Listing
December 2020

Characterization of defensive cadinenes and a novel sesquiterpene synthase responsible for their biosynthesis from the invasive Eupatorium adenophorum.

New Phytol 2021 02 14;229(3):1740-1754. Epub 2020 Oct 14.

State Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.

Eupatorium adenophorum is a malignant invasive plant possessing extraordinary defense potency, but its chemical weaponry and formation mechanism have not yet been extensively investigated. We identified six cadinene sesquiterpenes, including two volatiles (amorpha-4,7(11)-diene and (-)-amorph-4-en-7-ol) and four nonvolatiles (9-oxo-10,11-dehydroageraphorone, muurol-4-en-3,8-dione, 9-oxo-ageraphorone and 9β-hydroxy-ageraphorone), as the major constitutive and inducible chemicals of E. adenophorum. All cadinenes showed potent antifeedant activity against a generalist insect Spodoptera exigua, indicating that they have significant defensive roles. We cloned and functionally characterized a sesquiterpene synthase from E. adenophorum (EaTPS1), catalyzing the conversion of farnesyl diphosphate to amorpha-4,7(11)-diene and (-)-amorph-4-en-7-ol, which were purified from engineered Escherichia coli and identified by extensive nuclear magnetic resonance (NMR) spectroscopy. EaTPS1 was highly expressed in the aboveground organs, which was congruent with the dominant distribution of cadinenes, suggesting that EaTPS1 is likely involved in cadinene biosynthesis. Mechanical wounding and methyl jasmonate negatively regulated EaTPS1 expression but caused the release of amorpha-4,7(11)-diene and (-)-amorph-4-en-7-ol. Nicotiana benthamiana transiently expressing EaTPS1 also produced amorpha-4,7(11)-diene and (-)-amorph-4-en-7-ol, and showed enhanced defense function. The findings presented here uncover the role and formation of the chemical defense mechanism of E. adenophorum - which probably contributes to the invasive success of this plant - and provide a tool for manipulating the biosynthesis of biologically active cadinene natural products.
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http://dx.doi.org/10.1111/nph.16925DOI Listing
February 2021

Structural Change of Gut Microbiota in Patients with Post-Stroke Comorbid Cognitive Impairment and Depression and Its Correlation with Clinical Features.

J Alzheimers Dis 2020 ;77(4):1595-1608

Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background: Post-stroke comorbid cognitive impairment and depression (PSCCID) is a severe neuropsychiatric complication after acute stroke. Gut microbiota dysbiosis is associated with many psychiatric disorders. Alterations in the composition of gut microbiota may serve as a critical role in patients with PSCCID.

Objective: We aimed to characterize the microbial profiles of patients with PSCCID.

Method: A total of 175 stroke patients were recruited in the study. The composition of gut bacterial communities of patients was determined by 16S ribosomal RNA Miseq sequencing, and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was used to demonstrate the functional alterations of gut microbiota. We further identified the characteristic gut microbiota of PSCCID using linear discriminant analysis effect size.

Results: Patients with PSCCID exhibited an increased abundance of Proteobacteria, including Gammaproteobacteria, Enterobacteriales, and Enterobacteriaceae, and a decreased abundance of several short-chain fatty acids-producing bacteria compared with non-PSCCID patients. The abundance of Gammaproteobacteria and Enterobacteriaceae showed negative correlations with the MoCA score. Moreover, the Kyoto Encyclopedia of Genes and Genomes results demonstrated the enriched orthologs of glycan biosynthesis and metabolism and decreased orthologs of amino acid metabolism in PSCCID patients. Importantly, the characteristic gut microbiota was identified and achieved an area under the curve of 0.847 between the two groups.

Conclusion: In this study, we characterized the gut microbiota of PSCCID patients, and revealed the correlations of the altered gut microbiota with clinical parameters, which took a further step towards non-invasive diagnostic biomarkers for PSCCID from fecal samples.
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http://dx.doi.org/10.3233/JAD-200315DOI Listing
January 2020

Targeted next generation sequencing for newborn screening of Menkes disease.

Mol Genet Metab Rep 2020 Sep 21;24:100625. Epub 2020 Jul 21.

Parabase Genomics, Inc., Boston, MA, United States of America.

Purpose: Population-based newborn screening (NBS) allows early detection and treatment of inherited disorders. For certain medically-actionable conditions, however, NBS is limited by the absence of reliable biochemical signatures amenable to detection by current platforms. We sought to assess the analytic validity of an targeted next generation DNA sequencing assay as a potential newborn screen for one such disorder, Menkes disease.

Methods: Dried blood spots from control or Menkes disease subjects ( = 22) were blindly analyzed for pathogenic variants in the copper transport gene, The analytical method was optimized to minimize cost and provide rapid turnaround time

Results: The algorithm correctly identified pathogenic variants, including missense, nonsense, small insertions/deletions, and large copy number variants, in 21/22 (95.5%) of subjects, one of whom had inconclusive diagnostic sequencing previously. For one false negative that also had not been detected by commercial molecular laboratories, we identified a deep intronic variant that impaired mRNA splicing.

Conclusions: Our results support proof-of-concept that primary DNA-based NBS would accurately detect Menkes disease, a disorder that fulfills Wilson and Jungner screening criteria and for which biochemical NBS is unavailable. Targeted next generation sequencing for NBS would enable improved Menkes disease clinical outcomes, establish a platform for early identification of other unscreened disorders, and complement current NBS by providing immediate data for molecular confirmation of numerous biochemically screened condition.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378272PMC
September 2020

The association between serum uric acid level and the risk of cognitive impairment after ischemic stroke.

Neurosci Lett 2020 08 30;734:135098. Epub 2020 May 30.

Department of Neurology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, 150 Ximen Street, Linhai, Zhejiang, 317000, China. Electronic address:

Post-stroke cognitive impairment (PSCI) is a severe complication of stroke. Predicting PSCI is difficult because some risk factors for stroke, such as blood glucose level and blood pressure, are affected by many other elements. Although recent studies have shown that high serum uric acid (UA) levels are associated with cognitive dysfunction and may be a risk factor for PSCI, its impact remains unclear. Accordingly, the present study aimed to explore the association between serum UA level and PSCI. In total, 274 patients who experienced acute cerebral infarction, confirmed between January 2016 and December 2018, were enrolled. Baseline data and biological indicators were recorded. According to the Montreal Cognitive Assessment (MoCA) scores, patients were divided into two groups: PSCI and non-PSCI. Logistic regression analysis was used to determine possible risk factors for PSCI. Results demonstrated that serum UA levels were significantly higher in the PSCI group than in the non-PSCI group. Multivariable logistic analysis revealed that age, years of education, and UA level were independent risk factors for PSCI. PSCI patients were subdivided according to serum UA level: high and low. Hypertension history and homocysteine (Hcy) levels differed significantly between the high and low UA level groups. Further analysis revealed that a history of hypertension and Hcy demonstrated a certain correlation (r = 0.163, 0.162; P < 0.05), suggesting that serum UA level was an independent risk factor for PSCI. These findings indicate that serum UA level was correlated with PSCI in post-stroke patients and is anticipated to be used in clinical practice to reduce the incidence of PSCI.
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http://dx.doi.org/10.1016/j.neulet.2020.135098DOI Listing
August 2020

Spatial and temporal variability of soil erosion in the black soil region of Northeast China from 2000 to 2015.

Environ Monit Assess 2020 May 15;192(6):370. Epub 2020 May 15.

Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing, 100101, China.

The black soil region in Northeast China is an important production base of commodity grain. However, soil erosion is a major threat that has caused a decline in arable land area and productivity and a series of environmental problems in recent years. To understand the current situation of soil erosion and its changes in the whole black soil region, including six treatment regions, we used the spatial-temporal analysis of soil erosion from 2000 to 2015 and the overlay analysis with its drivers; additionally, soil erosion was evaluated qualitatively with the integrated evaluation method, and its change was indicated by the soil erosion change index (SECI). We found that soil erosion that caused soil loss occurred in each treatment region mainly at the light level in 2015. Water erosion, the most widely distributed erosion type, affected the largest area, while most serious erosion at intensive or higher levels stemmed from wind erosion. Although the situation of water erosion was improved in 2015 compared to that in 2000, the overall situation of soil erosion was worse due to the deterioration of wind and freeze-thaw erosion. Grassland, woodland, and cultivated land changes, such as the conversion from grassland to cultivated land, from woodland to sparse woodland and from dry land to paddy land, revealed these changes to a great extent.
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http://dx.doi.org/10.1007/s10661-020-08298-yDOI Listing
May 2020

Idiopathic pulmonary arterial hypertension and co-existing lung disease: is this a new phenotype?

Pulm Circ 2020 Jan-Mar;10(1):2045894020914851. Epub 2020 Mar 30.

Royal Brompton Pulmonary Hypertension and Adult Congenital Heart Centre, London, UK.

Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients ( ) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease ( ). Patients with ' ' have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with ' '. We described the outcome of the cohort of patients with ' ' in a previous paper. Here, we have compared incident ' ' patients with ' ' patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001-2009. Compared with ' ' ( = 355), ' ' patients ( = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in ' ' and ' '. However, survival of ' ' was lower than ' ' (one year survival: 72% compared with 93%). This survival was significantly worse in ' ' even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. ' ' patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with ' ' patients. This suggests that ' ' are a separate phenotype and should not be lumped with ' ' in clinical trials of Group 1 pulmonary arterial hypertension.
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http://dx.doi.org/10.1177/2045894020914851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132795PMC
March 2020

Generation of mycobacterial lipoarabinomannan-specific monoclonal antibodies and their ability to identify mycobacterium isolates.

J Microbiol Immunol Infect 2020 Feb 20. Epub 2020 Feb 20.

Department of Central Laboratory, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China. Electronic address:

Background/purpose: The World Health Organization has recommended commercial urine-sourced lipoarabinomannan (LAM) detection as a tool for screening HIV patients with suspected TB, but more sensitive immunodetection assays would help to identify HIV-negative TB patients. Here, we aimed to develop novel rabbit monoclonal antibodies (mAbs) against LAM for immunodetection purposes.

Methods: Rabbits were immunized with cell-wall components from the Mycobacterium tuberculosis (Mtb) H37Rv strain. An immune single-chain fragment variable (scFv) phage display library was generated. The scFv mAbs to LAM were identified through ELISA screening. The light and heavy chain variable region genes from the selected clones were sequenced. Vectors containing the full-length light and heavy chains were constructed and co-expressed in 293 T cells to generate whole IgG antibodies. The performances and binding characteristics of the mAbs against purified LAM from M.tb H37Rv, multiple mycobacteria species (M.tb H37Rv, M. bovis and non-tuberculous mycobacteria (NTM) strains), and mycobacteria clinical isolates (Mtb and NTM isolates) were determined using various immunoassay methods.

Results: We obtained five rabbit mAbs against LAM, four of which had high sensitivities (100 pg/ml) and affinities (1.16-1.73 × 10 M) toward LAM. They reacted with M.tb H37Rv, M. bovis, and slow-growing NTM, but not with rapid-growing NTM. Similar results were obtained with mycobacterium isolates, where 96% of the Mtb isolates and 90% of the M. avium-intracellulare isolates were successfully identified.

Conclusion: The novel rabbit LAM-specific mAbs performed well at recognizing LAM from slow-growing pathogenic mycobacteria, which support their future clinical application.
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http://dx.doi.org/10.1016/j.jmii.2020.02.005DOI Listing
February 2020

Characteristics and Assessment of Toxic Metal Contamination in Surface Water and Sediments Near a Uranium Mining Area.

Int J Environ Res Public Health 2020 01 15;17(2). Epub 2020 Jan 15.

State Key Laboratory of Nuclear Resources and Environment, College of Water Resources and Environmental Engineering, East China University of Technology, Nanchang 330013, China.

Concentrations of potentially toxic metals including Cd, Cu, Pb, Cr, U, Th in surface water and sediment samples collected from a river were analyzed to assess the contaminations, distribution characteristics, and sources of these metals. The contents of the metals were lower than the standard levels set by World Health Organization (WHO) for drinking water. However, U and Th contents were far beyond the background values of surface water. The concentrations of Cd, Cr, and U in sediments were higher than the background values and the Probable Effect Level (PEL) of sediment quality guidelines (SQGs) which may result in high potential harmful biological effects to aquatic ecosystems. Based on the contamination factor (CF), geo-accumulation index (I), and potential ecological risk index (RI), Cd, Cr, and U were considered to be the metals that mainly contribute to the contamination of sediments. The calculation results also indicated that the sites adjacent to the uranium ore field were highly polluted. Results of cluster analysis, principal component analysis, and correlation analysis revealed that Cr, Pb, U, and Th were highly correlated with each other. These metals mainly originated from both anthropogenic sources and natural processes, especially emissions from uranium mining and quarrying, whereas Cd mostly came from anthropogenic sources (agricultural activities) of the upper reaches of the river.
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http://dx.doi.org/10.3390/ijerph17020548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014452PMC
January 2020

Leucosceptroid B from glandular trichomes of Leucosceptrum canum reduces fat accumulation in Caenorhabditis elegans through suppressing unsaturated fatty acid biosynthesis.

Chin J Nat Med 2019 Dec;17(12):892-899

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China. Electronic address:

Obesity that is highly associated with numerous metabolic diseases has become a global health issue nowdays. Plant sesterterpenoids are an important group of natural products with great potential; thus, their bioactivities deserve extensive exploration. RNA-seq analysis indicated that leucosceptroid B, a sesterterpenoid previously discovered from the glandular trichomes of Leucosceptrum canum, significantly regulated the expression of 10 genes involved in lipid metabolism in Caenorhabditis elegans. Furthermore, leucosceptroid B was found to reduce fat storage, and downregulate the expression of two stearoyl-CoA desaturase (SCD) genes fat-6 and fat-7, and a fatty acid elongase gene elo-2 in wild-type C. elegans. In addition, leucosceptroid B significantly decreased fat accumulation in both fat-6 and fat-7 mutant worms but did not affect the fat storage of fat-6; fat-7 double mutant. These findings indicated that leucosceptroid B reduced fat storage depending on the downregulated expression of fat-6, fat-7 and elo-2 and thereby inhibiting the biosynthesis of the corresponding unsaturated fatty acid. These findings provide new insights into the development and utilization of plant sesterterpenoids as potential antilipemic agents.
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http://dx.doi.org/10.1016/S1875-5364(19)30109-8DOI Listing
December 2019

Gallstone Disease is an Independent Predictor for Poststroke Cognitive Impairment in Young Patients with Acute Ischemic Stroke.

Eur Neurol 2019 27;82(1-3):15-22. Epub 2019 Nov 27.

Department of Neurology, Wenzhou People's Hospital, Wenzhou, China,

Background: Poststroke cognitive impairment (PCI) is an important public health issue. Previous studies proved that gallstone disease (GD) was a predictor for cardiovascular and cerebrovascular disease. However, association between PCI and GD remains unclear. We aimed to investigate the predictive value of GD on cognitive impairment after acute ischemic stroke (AIS).

Methods: We recruited 373 AIS patients, and the information on patient demographics and risk factors was collected. Cognitive function would be assessed 3-month after AIS. They would undergo gallbladder ultrasonographic examination and structured assessment during hospitalization. Patients were divided into young group (age <65 years) and elder group (age ≥65 years). Multivariate logistic regression models were used to identify the predictors of PCI.

Results: PCI was identified in 176 (47.18%) AIS patients. Independent predictors of PCI were GD (p = 0.014), the National Institutes of Health Stroke Scale score and age. While carotid plaque (p = 0.058) seemed like a potential risk factor for PCI. In young group, GD (p = 0.027) was associated to PCI, in elder group, carotid plaque (p = 0.006), and age (p = 0.033) were significantly correlated to PCI.

Conclusion: GD was an age-dependent predictor for PCI, particularly in the young AIS patients. Therefore, AIS patients with GD, especially the young, should be systematically evaluated for cognitive function.
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http://dx.doi.org/10.1159/000504343DOI Listing
June 2020

CD137 ligand feedback upregulates PD-L1 expression on lung cancer via T cell production of IFN-γ.

Thorac Cancer 2019 12 17;10(12):2225-2235. Epub 2019 Oct 17.

Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.

Background: The expression of PD-L1 and its regulation in tumors remains unclear. The importance of IFN-γ in upregulating the PD-L1 expression in various tumors, and the effects of other essential cytokines in the tumor microenvironment (TME), need to be further elucidated.

Methods: Constitutive expression of PD-L1 and CD137L in all 13 lung cancer cell lines were tested by flow cytometry. CD137L mRNA of lung cancer cell lines was detected by RT-PCR. PD-L1 expression rates following stimulation with these cytokines (IFN-γ, TNFα and IL2) were measured. After coculture of cells expressing CD137L (lung cancer cells or 293FT cells transfected with CD137L plasmid) with T cells, the PDL1 expression of lung cancer cells and IFN-γ in supernatant was detected.

Results: Our data revealed that adenocarcinoma and squamous cell carcinoma cells had the highest positive expression rate. IFN-γ was the core-inducing factor for enhancing the PD-L1 expression. CD137L was also widely expressed in the lung cancer cell lines at the mRNA level, whereas its expression was generally low at the protein level. However, the low expression of CD137L protein was still enough to induce T cells to produce IFN-γ, which subsequently increased the PD-L1 expression by lung cancer cells. The CD137 signal induces IFN-γ secretion by T cells, which stimulates high-level of PD-L1 expression in cancer cells; this negative immune regulation may represent a mechanism of immune escape regulation.

Conclusions: CD137L mRNA was widely expressed in lung cancer cell lines whereas levels of protein expression were generally low. The low level of CD137L protein was still enough to induce T cells to produce IFN-γ that subsequently increased PD-L1 expression. The CD137L-induced negative immune regulation may represent a mechanism of immune escape.
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http://dx.doi.org/10.1111/1759-7714.13207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885434PMC
December 2019

Therapeutic effects of erythropoietin expressed in mesenchymal stem cells for dilated cardiomyopathy in rat.

Biochem Biophys Res Commun 2019 10 8;517(4):575-580. Epub 2019 Aug 8.

Department of Cardiology, Jinshan Hospital Affiliated to Fudan University, Shanghai, 201508, China. Electronic address:

Dilated cardiomyopathy (DCM) is considered as the final common response of myocardium to diverse genetic and environmental insults and characterized mainly by left ventricular systolic dysfunction. The current therapies for the treatment of DCM are costly high and outcomes are often unsatisfactory. To date, mesenchymal stem cells (MSCs) have been thought to be an ideal stem cell to repair damaged myocardium but was still within relatively small scales and few cases have been conducted in clinical trials. The use of erythropoietin (EPO), a growth factor produced in the kidneys have been found prevent cardiomyocyte apoptosis. This study was aimed to transplant MSCs into DCM rat bone marrow to express EPO in vivo and investigate the regulation of EPO on cell signaling pathways after transfection. The results found that transplantation of MSCs carrying EPO could significantly relief the cardiac dysfunctions of the DCM rat. This underylying mechanism involved with inhibiting p-NF-κB and p-P38, regulateing and promoting the anti-inflammatory balance, thereby alleviating tissue injury in DCM rats and exhibiting a protective role. Meanwhile, the MSCs + EPO treatment in DCM rat also activated the p-Akt pathway and thus protecting the myocardium from apoptosis in DCM rats. The study revealed an potential therapeutic effect of MSCs and EPO in clinical and provided a molecular mechanism of action for treating DCM.
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http://dx.doi.org/10.1016/j.bbrc.2019.07.053DOI Listing
October 2019

Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice.

Transl Psychiatry 2019 08 5;9(1):189. Epub 2019 Aug 5.

Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.

Alzheimer's disease (AD) is the most common dementia in the elderly. Treatment for AD is still a difficult task in clinic. AD is associated with abnormal gut microbiota. However, little is known about the role of fecal microbiota transplantation (FMT) in AD. Here, we evaluated the efficacy of FMT for the treatment of AD. We used an APPswe/PS1dE9 transgenic (Tg) mouse model. Cognitive deficits, brain deposits of amyloid-β (Aβ) and phosphorylation of tau, synaptic plasticity as well as neuroinflammation were assessed. Gut microbiota and its metabolites short-chain fatty acids (SCFAs) were analyzed by 16S rRNA sequencing and H nuclear magnetic resonance (NMR). Our results showed that FMT treatment could improve cognitive deficits and reduce the brain deposition of amyloid-β (Aβ) in APPswe/PS1dE9 transgenic (Tg) mice. These improvements were accompanied by decreased phosphorylation of tau protein and the levels of Aβ40 and Aβ42. We observed an increases in synaptic plasticity in the Tg mice, showing that postsynaptic density protein 95 (PSD-95) and synapsin I expression were increased after FMT. We also observed the decrease of COX-2 and CD11b levels in Tg mice after FMT. We also found that FMT treatment reversed the changes of gut microbiota and SCFAs. Thus, FMT may be a potential therapeutic strategy for AD.
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http://dx.doi.org/10.1038/s41398-019-0525-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683152PMC
August 2019

Epidemiological characteristics of holoprosencephaly in China, 2007-2014: A retrospective study based on the national birth defects surveillance system.

PLoS One 2019 6;14(6):e0217835. Epub 2019 Jun 6.

National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.

Objective: To describe the epidemiology of holoprosencephaly (HPE) in China with special reference to prevalence and associated anomalies.

Methods: Data were abstracted from the Chinese Birth Defects Monitoring Network for the period 2007-2014. Birth prevalence of HPE were assessed by birth year, fetal/infant sex, maternal age, and maternal residential area. Poisson regressions were used to calculate the crude and adjusted prevalence ratios (PR) and their 95% confidence intervals, and linear chi-square test was used to explore time trend for the prevalence of HPE.

Results: A total of 1222 HPE cases were identified in 13,284,142 births, yielding an overall prevalence of 0.92 per 10,000 births. The annual prevalence of HPE presented an upward trend (P<0.001), from 0.54 per 10,000 births in 2007 to 1.21 per 10,000 births in 2014. Higher prevalence was found in older maternal-age groups (30-34 years, adjusted PR: 1.19, 95% CI: 1.02-1.40; ≥35 years, adjusted PR: 1.53, 95% CI: 1.26-1.86) in comparison with the maternal-age group of 25 to 29 years. Higher prevalence was also found in infants born to mothers resided in urban areas (adjusted PR: 1.23, 95% CI: 1.08-1.39) and female infants (adjusted PR: 1.30, 95% CI: 1.15-1.47).

Conclusions: HPE is an important perinatal health issue because of its poor prognosis. This is the first study depicting a picture of epidemiological characteristics of HPE in China, which can provide useful references for future studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217835PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553724PMC
February 2020

Circulating CD137 CD8 T cells accumulate along with increased functional regulatory T cells and thoracic tumour burden in lung cancer patients.

Scand J Immunol 2019 Jun 10;89(6):e12765. Epub 2019 Apr 10.

Department of Medical Oncology, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing, China.

CD137 is a promising target for immunostimulation strategies against cancer. Previous studies showed that CD137 CD8 T cells are enriched in antitumour effector T cells in both preclinical tumour models and cancer patients, but to date, such T cells in the blood of lung cancer patients have not been sufficiently investigated. In this study, circulating antigen-activated CD8 T cell subsets, identified as CD137 CD8 or PD-1 (programmed cell death protein 1) CD8 , and regulatory T cells (Treg), identified as CD4 CD25 CD127 , in 40 untreated lung cancer patients and in 49 age- and sex-matched healthy controls (HCs) were assessed by flow cytometry. Results were evaluated for associations with lung cancer patient clinical characteristics. Correlations between antigen-activated CD8 T cells and effector Treg (CTLA-4 [cytotoxic T-lymphocyte antigen 4] CD4 CD25 CD127 ) were also investigated. Higher percentages of PD-1 , CD137 and PD-1 CD137 amongst CD8 T cells were observed in lung cancer patients compared with HCs. The percentages of CD137 CD8 and PD-1 CD137 CD8 T cell subsets amongst CD8 T cells were positively correlated with thoracic tumour burden and were strongly positively correlated with the percentage of effector Treg subset. Smoking patients harboured higher percentages of the PD-1 CD8 T cell subset compared with non-smoking patients. This study demonstrated that circulating antigen-activated CD8 T cells accumulated in lung cancer patients along with increased effector Treg and thoracic tumour burden. These findings aid a better understanding of immune-host interactions in lung cancer patients using peripheral blood, and further support immunotherapeutic intervention strategies using combination therapy for differential control of Treg and activation of tumour-specific effector T cells.
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http://dx.doi.org/10.1111/sji.12765DOI Listing
June 2019

An artificially engineered "tumor bio-magnet" for collecting blood-circulating nanoparticles and magnetic hyperthermia.

Biomater Sci 2019 Apr;7(5):1815-1824

Institute of Ultrasound Imaging of Chongqing Medical University, Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong Distinct, Chongqing, 400010, P. R. China.

It is a great challenge to directly endow a tumor with specific functions for theranostic treatment. In this study, we report on a novel approach to transform a tumor into a "bio-magnet", to be magnetized on demand, in order to create an intrinsic tumor magnetic field that would collect magnetic nanoparticles (MNPs) circulating in the blood and achieve simultaneous magnetic hyperthermia. This was achieved by the localized intratumoral injection of liquid Nd2Fe14B/Fe3O4-PLGA, followed by solvent exchange that induces a liquid-to-solid transformation. After the magnetism charging process, the solid Nd2Fe14B/Fe3O4-PLGA implant was endowed with permanent magnetic properties and in situ created the magnetic field within the tumor tissue, making the tumor a "bio-magnet". After the creation of the bio-magnet, intravenously injected MNPs accumulated into the tumor tissue due to the tumor magnetic field. Importantly, both the in vitro and ex vivo results demonstrated the high efficiency of the implanted bio-magnet for magnetic hyperthermia. This new approach achieves magnetic targeting by creating a tumor "bio-magnet", which generates a strong magnetic field within the tumor, paving a new way for the development of an efficient targeting strategy for tumor therapy.
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http://dx.doi.org/10.1039/c8bm01658eDOI Listing
April 2019

Characterization of a sesquiterpene cyclase from the glandular trichomes of Leucosceptrum canum for sole production of cedrol in Escherichia coli and Nicotiana benthamiana.

Phytochemistry 2019 Jun 15;162:121-128. Epub 2019 Mar 15.

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, PR China. Electronic address:

Cedrol is an extremely versatile sesquiterpene alcohol that was approved by the Food and Drug Administration of the United States as a flavoring agent or adjuvant and has been commonly used as a flavoring ingredient in cosmetics, foods and medicine. Furthermore, cedrol possesses a wide range of pharmacological properties including sedative, anti-inflammatory and cytotoxic activities. Commercial production of cedrol relies on fractional distillation of cedar wood oils, followed by recrystallization, and little has been reported about its biosynthesis and aspects of synthetic biology. Here, we report the cloning and functional characterization of a cedrol synthase gene (Lc-CedS) from the transcriptome of the glandular trichomes of a woody Lamiaceae plant Leucosceptrum canum. The recombinant Lc-CedS protein catalyzed the in vitro conversion of farnesyl diphosphate into the single product cedrol, suggesting that Lc-CedS is a high-fidelity terpene synthase. Co-expression of Lc-CedS, a farnesyl diphosphate synthase gene and seven genes of the mevalonate (MVA) pathway responsible for converting acetyl-CoA into farnesyl diphosphate in Escherichia coli afforded 363 μg/L cedrol as the sole product under shaking flask conditions. Transient expression of Lc-CedS in Nicotiana benthamiana also resulted in a single product cedrol with a production level of 3.6 μg/g fresh weight. The sole production of cedrol by introducing of Lc-CedS in engineered E. coli and N. benthamiana suggests now alternative production systems using synthetic biology approaches that would better address sufficient supply of cedrol.
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http://dx.doi.org/10.1016/j.phytochem.2019.03.009DOI Listing
June 2019

Isolation of circulating tumor cells and detection of EGFR mutations in patients with non-small-cell lung cancer.

Oncol Lett 2019 Apr 5;17(4):3799-3807. Epub 2019 Feb 5.

Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, P.R. China.

The aim of the present study was to develop a procedure for the isolation of circulating tumor cells (CTCs), and to evaluate its application in the detection of epidermal growth factor receptor (EGFR) mutations, and potential heterogeneity in patients with non-small-cell lung cancer (NSCLC). Peripheral blood samples were collected from 91 patients with lung cancer, 10 patients with benign disease and 10 healthy volunteers. CTCs were enriched by positive immunomagnetic separation, detected by immunocytochemistry, and processed for single-cell capture. Pure CTC DNA was amplified, and the EGFR gene was analyzed using the amplification refractory mutation system (ARMS) and digital polymerase chain reaction (dPCR). The CTC capture rate in patients with lung cancer was 61.5% (56/91), whereas no CTCs were detected in patients with benign lung disease or in healthy volunteers. The CTC-positive detection rates were 69.3% (52/75) and 25.0% (4/16) in patients with TNM stage III and IV disease, respectively. Markedly more CTCs were captured from patients with small-cell lung cancer compared with patients with other types of cancer. In patients who were positive for EGFR mutations, the detection rate of these mutations was low (16.67%, 2/12), at the single CTC level. The sensitivity increased as the number of CTCs per sample increased. A total of four patients displayed consistent detection of EGFR mutations at the 10-cell level, and one patient exhibited a clear, inconsistent and rare mutation (G719×) between CTCs. A simplified technique for isolating CTCs from blood was established, though multiple CTCs were required to sensitively detect mutations in these cells. The detection of EGFR mutations in CTCs and tissue specimens was generally homogeneous, and therefore, the CTC-level mutation analysis may potentially contribute to the discovery of heterogeneous mutations.
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http://dx.doi.org/10.3892/ol.2019.10016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403494PMC
April 2019

Fructooligosaccharides Ameliorating Cognitive Deficits and Neurodegeneration in APP/PS1 Transgenic Mice through Modulating Gut Microbiota.

J Agric Food Chem 2019 Mar 28;67(10):3006-3017. Epub 2019 Feb 28.

Department of Neurology , the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University , Wenzhou , Zhejiang 325027 , China.

Alzheimer's disease (AD) is closely related to gut microbial alteration. Prebiotic fructooligosaccharides (FOS) play major roles by regulating gut microbiota. The present study aimed to explore the effect and mechanism of FOS protection against AD via regulating gut microbiota. Male Apse/PSEN 1dE9 (APP/PS1) transgenic (Tg) mice were administrated with FOS for 6 weeks. Cognitive deficits and amyloid deposition were evaluated. The levels of synaptic plasticity markers including postsynaptic density protein 95 (PSD-95) and synapsin I, as well as phosphorylation of c-Jun N-terminal kinase (JNK), were determined. The intestinal microbial constituent was detected by 16S rRNA sequencing. Moreover, the levels of glucagon-like peptide-1 (GLP-1) in the gut and GLP-1 receptor (GLP-1R) in the brain were measured. The results indicated that FOS treatment ameliorated cognitive deficits and pathological changes in the Tg mice. FOS significantly upregulated the expression levels of synapsin I and PSD-95, as well as decreased phosphorylated level of JNK. The sequencing results showed that FOS reversed the altered microbial composition. Furthermore, FOS increased the level of GLP-1 and decreased the level of GLP-1R in the Tg mice. These findings indicated that FOS exerted beneficial effects against AD via regulating the gut microbiota-GLP-1/GLP-1R pathway.
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http://dx.doi.org/10.1021/acs.jafc.8b07313DOI Listing
March 2019

Study on Drug-Drug Interactions Between Chiglitazar, a Novel PPAR Pan-Agonist, and Metformin Hydrochloride in Healthy Subjects.

Clin Pharmacol Drug Dev 2019 10 27;8(7):934-941. Epub 2019 Feb 27.

Drug Clinical Trials Institution, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, P.R.China.

Chiglitazar (CHI) is a potent and selective peroxisome proliferator-activated receptor potentially for the treatment of patients with type 2 diabetes mellitus (T2DM). An open-label, randomized, 3-period crossover and self-controlled study was conducted to investigate drug-drug interaction potential between CHI and metformin hydrochloride (MET). Eligible subjects received a single oral dose of CHI (48 mg), MET (1000 mg), or a combination in each period, followed by serial blood sampling collected for up to 48 hours postdose, and safety was assessed throughout the trial. The area under the plasma concentration-time curves from time 0 to 48 hours (AUC ) of CHI was similar following administration alone or with MET (AUC , 12 540 ng·h/mL [9811-15 269 ng·h/mL] vs 12 130 ng·h/mL [9304-14 956 ng·h/mL]; 90% confidence interval [CI] of its geometric mean ratio [GMR], 89.7%-103.8%), whereas the maximum concentration (C ) of CHI was reduced during coadministration, as its 90%CI of the GMR was slightly outside the acceptance range for bioequivalence (C , 1620 ng/mL [1418-1822 ng/mL] vs 1420 ng/mL [1049-1791 ng/mL], 90%CI GMR, 77.%-94.1%). However, it was not considered clinically meaningful. The MET exposures remained consistent in the absence or presence of CHI (AUC , 12 570 ng·h/mL [10681-14 459 ng·h/mL] vs 13 190 [10973-15 407 ng·h/mL); 90%CI of GMR: 99.1%-110.5%; C , 1790 ng/mL [1448-2132 ng/mL] vs 1820 ng/mL [1510-2130 ng/mL]; 90%CI of GMR, 94.2%-110.9%). No moderate to severe adverse events were reported. Our study indicated no clinically significant pharmacokinetic drug-drug interaction between CHI and MET and demonstrated good tolerance in subjects. These results support future application of CHI in combination with MET for treatment of T2DM.
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http://dx.doi.org/10.1002/cpdd.668DOI Listing
October 2019