Publications by authors named "Jun Zhu"

2,209 Publications

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Maternal Trichloroethylene Exposure and Metabolic Gene Polymorphisms May Interact during Fetal Cardiovascular Malformation.

Reprod Toxicol 2021 Sep 20. Epub 2021 Sep 20.

Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China; Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Sec. No.17, South RenMin Road, Chengdu, Sichuan, China. Electronic address:

This study aimed to analyze the potential association between trichloroethylene (TCE) exposure and congenital heart disease (CHD) and to explore the effect of metabolic enzyme gene polymorphisms on heart development. A multicenter case-control study was conducted. The trichloroethylene concentrations were measured by UPLC-MSMS in urine. Fourteen SNPs in the GSTA1, GSTP1, MPO, NAT1, NAT2, CYP1A1, CYP1A2, CYP2E1 and EPHX1 genes were genotyped using an improved multiplex ligation detection reaction (iMLDR) technique. A total of 283 cases and 331 controls with maternal urine and/or venous blood were included in the present study. The median NAcDCVC was 7.65 ng/mL in the case group and 7.43 ng/mL in the control group. There was no significant difference in the NAcDCVC concentration between the CHD subtypes and controls (P > 0.05). The GA/AA of GSTA1 rs3957357 could increase the risk of CHDs under the dominant model (aOR = 2.26, 95% CI: 1.31, 3.90), but other SNPs were not associated with CHDs (P > 0.05). GA or AA genotypes of GSTA1 rs3957357 with lower levels of TCE exposure were 3.53 times at risk relative to mothers carrying the wild type genotype. In conclusion, maternal exposure to trichloroethylene alone is not associated with the occurrence of fetal CHD and CHD subtypes. Maternal GSTA1 rs3957357 may increase the risk of CHD in offspring. TCE exposure and metabolic gene polymorphisms probably interact with each other to induce fetal cardiovascular malformation, but larger sample size studies are needed to confirm this hypothesis.
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http://dx.doi.org/10.1016/j.reprotox.2021.09.010DOI Listing
September 2021

Releasing Antiaromaticity in Metal-Bridgehead Naphthalene.

J Am Chem Soc 2021 Sep 17. Epub 2021 Sep 17.

Shenzhen Grubbs Institute, Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, P. R. China.

As a fundamental chemical property, aromaticity guides the synthesis of novel structures and materials. Replacing the carbon moieties of aromatic hydrocarbons with transition metal fragments is a promising strategy to synthesize intriguing organometallic counterparts with a similar aromaticity to their organic parents. However, since antiaromaticity will endow compound instability, it is a great challenge to obtain an antiaromatic organometallic counterpart based on such transition metal replacement in aromatic hydrocarbons. Here, we report an efficient aromaticity transformation on aromatic naphthalene through the bridgehead replacement of an osmium fragment, leading to the unprecedented synthesis of metal-bridgehead naphthalene featuring a highly twisted structure as confirmed by X-ray crystallography characterization. Such a twisted conformation works together with its phosphonium substituents to release the antiaromaticity in the planar conformation of the metal-bridgehead naphthalene. Our findings prove the bridgehead involvement of transition metals in unexpected aromaticity modifications and open an avenue for novel metal-bridgehead complexes.
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http://dx.doi.org/10.1021/jacs.1c08106DOI Listing
September 2021

and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis.

Food Funct 2021 Sep 17. Epub 2021 Sep 17.

Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.

Dietary interventions, including dietary ingredients, nutrients and probiotics, exert anti-inflammatory effects in ulcerative colitis (UC). Our previous study showed that (), a promising probiotic, could protect against colitis the regulation of the immune response. However, whether it can restore aberrant tryptophan (Trp) metabolism during colitis remains unclear. In this study, untargeted serum metabolomics of patients with UC and colitis mice showed that Trp metabolism was activated, which was confirmed by quantification of Trp metabolites from a validation cohort and animal study. Integrative analysis of faecal metagenomes and serum metabolomes revealed significant associations between and three Trp metabolites. Live , pasteurised and Amuc_1100 failed to restore the reduction in Trp metabolites involved in the serotonin pathway in colitis mice. However, live , pasteurised and Amuc_1100 increased kynurenine (Kyn) but decreased 2-picolinic acid (PIC) levels and the PIC/Kyn ratio without regulating any of the genes involved in Trp metabolism, suggesting that they could suppress the Kyn pathway (KP) independent of colon tissue. In addition, they could significantly restore the enrichment of Trp metabolism mediated by faecal microbiota. Specifically, live , pasteurised and Amuc_1100 could significantly offset the reduction in indoleacetic acid (IAA) levels. Pasteurised significantly elevated the serum levels of indole acrylic acid (IA). In addition, live , pasteurised and Amuc_1100 could upregulate aryl hydrocarbon receptor (AhR) targeted genes, including , and , suggesting that could activate AhR signaling by regulating Trp metabolism, thereby attenuating colonic inflammation.
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http://dx.doi.org/10.1039/d1fo02172aDOI Listing
September 2021

A narrative review of tumor heterogeneity and challenges to tumor drug therapy.

Ann Transl Med 2021 Aug;9(16):1351

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Objective: To accurately evaluate tumor heterogeneity, make multidimensional diagnosis according to the causes and phenotypes of tumor heterogeneity, and assist in the individualized treatment of tumors.

Background: Tumor heterogeneity is one of the most essential characteristics of malignant tumors. In tumor recurrence, development, and evolution, tumor heterogeneity can lead to the formation of different cell groups with other molecular characteristics. Tumor heterogeneity can be characterized by the uneven distribution of tumor cell subsets of other genes between and within the disease site (spatial heterogeneity) or the time change of cancer cell molecular composition (temporal heterogeneity). The discovery of tumor targeting drugs has dramatically promoted tumor therapy. However, the existence of heterogeneity seriously affects the effect of tumor treatment and the prognosis of patients.

Methods: The literature discussing tumor heterogeneity and its resistance to tumor therapy was broadly searched to analyze tumor heterogeneity as well as the challenges and solutions for gene detection and tumor drug therapy.

Conclusions: Tumor heterogeneity is affected by many factors consist of internal cell factors and cell microenvironment. Tumor heterogeneity greatly hinders effective and individualized tumor treatment. Understanding the fickle of tumors in multiple dimensions and flexibly using a variety of detection methods to capture the changes of tumors can help to improve the design of diagnosis and treatment plans for cancer and benefit millions of patients.
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http://dx.doi.org/10.21037/atm-21-1948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422119PMC
August 2021

Clinical Features of Spontaneous Regression of Retinopathy of Prematurity in China: A 5-Year Retrospective Case Series.

Front Med (Lausanne) 2021 31;8:731421. Epub 2021 Aug 31.

Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

The aim of this study is to explore the clinical features of spontaneous regression of retinopathy of prematurity (ROP) in China, including fundus appearance, time course, and affecting factors. Data of pediatric patients in whom ROP spontaneously regressed without treatment were collected, including general demographics, medical history, zones and stages of ROP, and changes of fundus appearance. The fundus manifestations of spontaneous regression in ROP were systematically summarized. Meanwhile, the time course of spontaneous regression in ROP was further analyzed, including the onset time, completion time, and duration of regression, which were all compared across different ROP zones and stages. The associated factors were analyzed by survival analysis for their correlation with delayed regression for the first time. Two hundred thirty-seven eyes of 237 pediatric patients were included. The fundus manifestations of regression differed across stages. Lesions gradually subsided, and the retinal vessels gradually vascularized completely. However, despite ROP regression, some abnormalities remained. We observed avascular retina in the temporal periphery (19.0%), increased vascular branching (6.8%), retinal pigmentary changes (6.8%), and smaller angle between the upper and lower temporal retinal vessel trunks (3.0%). Acute ROP started to regress at a median 40 weeks of postmenstrual age (PMA) and completely regressed by median 49.0 weeks of PMA. The median duration for regression was 8.5 weeks. The zone II ROP and stage 3 ROP had a later time for onset and completion of regression, and longer duration. Anemia and retinal hemorrhage (RH) were identified as independent risk factors for delayed regression by survival analysis. During spontaneous regression, the fundus appearance is diverse, and the retinal vessels gradually vascularized completely. The time course of regression differs depending on the ROP zone and stage. Anemia and RH are independent risk factors for delayed regression. Further research of the natural course of the regression of ROP is needed to help design effective screening and follow-up plans.
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http://dx.doi.org/10.3389/fmed.2021.731421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439357PMC
August 2021

Triple-Memory Networks: A Brain-Inspired Method for Continual Learning.

IEEE Trans Neural Netw Learn Syst 2021 Sep 16;PP. Epub 2021 Sep 16.

Continual acquisition of novel experience without interfering with previously learned knowledge, i.e., continual learning, is critical for artificial neural networks, while limited by catastrophic forgetting. A neural network adjusts its parameters when learning a new task but then fails to conduct the old tasks well. By contrast, the biological brain can effectively address catastrophic forgetting through consolidating memories as more specific or more generalized forms to complement each other, which is achieved in the interplay of the hippocampus and neocortex, mediated by the prefrontal cortex. Inspired by such a brain strategy, we propose a novel approach named triple-memory networks (TMNs) for continual learning. TMNs model the interplay of the three brain regions as a triple-network architecture of generative adversarial networks (GANs). The input information is encoded as specific representations of data distributions in a generator, or generalized knowledge of solving tasks in a discriminator and a classifier, with implementing appropriate brain-inspired algorithms to alleviate catastrophic forgetting in each module. Particularly, the generator replays generated data of the learned tasks to the discriminator and the classifier, both of which are implemented with a weight consolidation regularizer to complement the lost information in the generation process. TMNs achieve the state-of-the-art performance of generative memory replay on a variety of class-incremental learning benchmarks on MNIST, SVHN, CIFAR-10, and ImageNet-50.
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http://dx.doi.org/10.1109/TNNLS.2021.3111019DOI Listing
September 2021

Process optimization to enhance utilization efficiency of precipitants for chloride removal from flue gas desulfurization wastewater via Friedel's salt precipitation.

J Environ Manage 2021 Sep 8;299:113682. Epub 2021 Sep 8.

College of Environmental and Chemical Engineering, Shanghai University of Electric Power, Shanghai, 200090, China; Shanghai Institute of Pollution Control and Ecological Security, Shanghai, 200092, China. Electronic address:

The treatment cost for Cl removal by Friedel's salt precipitation depended significantly on utilization rate of the precipitant aluminate. In this study, effects of Ca/Al molar ratio, reaction time, temperature and Al/Cl molar ratio were investigated to maximize Al utilization rate for Cl removal from flue gas desulfurization wastewater. Batch results showed that the maximum Al utilization rate of 55.8-60.3% was obtained at Ca/Al ratio of 3.00, reaction time of 90 min, temperature of 35 °C and Al/Cl ratio of 0.50 regardless of the initial Cl concentration. The precipitate obtained at the highest Al utilization rate had the highest interlayer spacing, the best crystal integrity, and the strongest binding energy of the Al-OH bond. The optimized condition made ion exchange between Cl and OH easier, and obtained more stable Friedel's salt structure to adsorb Cl. Pilot-scale results showed that maximizing Al utilization rate with low dosages of precipitants had insignificant effects on the removal of Mg, Ca and sulfate compared to the strategy to maximize Cl, but enhanced Al utilization rate from 38.2% to 56.4%. Economic analysis showed that enhancing Al utilization rate greatly reduced treatment cost of the Friedel's salt precipitation method by 30.5%, and made the two-stage desalination process more feasible and worth popularizing.
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http://dx.doi.org/10.1016/j.jenvman.2021.113682DOI Listing
September 2021

Knowledge domain and emerging trends in visual hallucination research: A scientometric analysis.

World J Psychiatry 2021 Aug 19;11(8):491-506. Epub 2021 Aug 19.

Department of Geriatric Neurology, Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.

Background: Visual hallucination (VH) refers to a spontaneous visual perception without corresponding external stimuli and often occurs in ophthalmological and neuropsychiatric disorders. It is associated with poor quality of life, and increased patient hospitalization and nursing home admission. To date, a scientometric analysis of research on VH is lacking.

Aim: To objectively summarize the features of VH research and gain insights into the emerging trends in research on VH.

Methods: CiteSpace V was used in this article. Publication outputs, document types, geographic distributions, co-authorship status, research hotspots, and co-citation status were analyzed. A total of 2176 original articles and 465 reviews were included in the database downloaded from the Web of Science Core Collection. We selected the top 50 most cited or occurring articles or items to create a visualized network with a 1-year interval. In the document co-citation analysis stage, we performed clustering analysis on co-cited references, and log likelihood tests were used to name the clusters.

Results: The results showed that most publications can be classified into neurology, sports, and ophthalmology studies. In addition, North America, Europe, Asia and Australia published the most documents. Some well-known authors have always had a leading role in this field; meanwhile, new authors keep emerging. A relatively stable cooperation has been formed among many authors. Furthermore, neuropsychiatric symptom and functional connectivity are the top hotspots. Research on VH in dementia with Lewy bodies and Parkinson's disease (PD) have received much attention. Studies on VH in PD are likely to be the new emerging trends in the future, especially the mechanisms of VH.

Conclusion: Research on VH has formed a complete system. More large-scale clinical and in-depth basic research are required to better understand the mechanisms underlying VH, which will contribute to our understanding of the pathophysiology and therapeutic options for VH.
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http://dx.doi.org/10.5498/wjp.v11.i8.491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394690PMC
August 2021

miR-328a-3p stimulates endothelial cell migration and tubulogenesis.

Exp Ther Med 2021 Oct 2;22(4):1104. Epub 2021 Aug 2.

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, P.R. China.

Endothelial cells have important biological roles after peripheral nerve injury by forming blood vessels within the nerve gap and guiding Schwann cell migration. MicroRNAs (miRNAs/miRs) affect cellular behavior and regulate a wide variety of physiological and pathological activities, including peripheral nerve regeneration. Emerging studies have identified the essential roles of miRNAs in the phenotype modulation of Schwann cells, while the effects of miRNAs on endothelial cells have remained to be thoroughly investigated. miR-328a-3p was differentially expressed in peripheral nerve stumps after nerve injury. In the present study, the effects of miR-328a-3p on biological functions of endothelial cells were determined by transfecting cultured human umbilical vein endothelial cells (HUVECs) with miR-328a-3p mimics or inhibitor. Transfection with miR-328a-3p mimics led to slightly decreased HUVEC proliferation and robustly increased HUVEC migration and tubulogenesis, while transfection with miR-328a-3p inhibitor led to opposite results. Using bioinformatics analysis, potential regulators and effectors of miR-328a-3p were further discovered and a miR-328a-3p-centered competing endogenous RNA network was constructed. Collectively, the present study demonstrated that dysregulated miR-328a-3p after peripheral nerve injury may affect the migration and angiogenesis of endothelial cells and contribute to peripheral nerve regeneration.
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http://dx.doi.org/10.3892/etm.2021.10538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383776PMC
October 2021

The Synergistic Anti-Tumor Activity of EZH2 Inhibitor SHR2554 and HDAC Inhibitor Chidamide through ORC1 Reduction of DNA Replication Process in Diffuse Large B Cell Lymphoma.

Cancers (Basel) 2021 Aug 24;13(17). Epub 2021 Aug 24.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China.

Background: Upregulation of H3K27me3 induced by EZH2 overexpression or somatic heterozygous mutations were implicated in lymphomagenesis. It has been demonstrated that several EZH2-target agents have notable therapeutic effects in EZH2-mutant B-cell lymphoma patients. Here we present a novel highly selective EZH2 inhibitor SHR2554 and possible combination strategy in diffuse large B-cell lymphoma (DLBCL).

Methods: Cell proliferation, cell cycle and apoptosis were analyzed by CellTiter-Glo Luminescent Cell Viability Assay and flow cytometry. Western Blot was used to detect the expression of related proteins. The gene expression profiling post combination treatment was analyzed by RNA-Seq. Finally, CDX and PDX models were used to evaluate the synergistic anti-tumor effects of the combination treatment in vivo.

Results: The novel EZH2 inhibitor SHR2554 inhibited proliferation and induced G1 phase arrest in EZH2-mutant DLBCL cell lines. The combination of EZH2 inhibitor SHR2554 with histone deacetylase (HDAC) inhibitor chidamide (hereafter referred to as HBI8000) exerted synergistic anti-proliferative activity in vitro and in vivo. Gene expression profile analysis revealed dramatic inhibition of the DNA replication process in combined treatment.

Conclusions: SHR2554, a potent, highly selective small molecule inhibitor of EZH2, inhibited EZH2-mutant DLBCL more significantly in vitro and in vivo. The combination of HDAC inhibitor HBI8000 with EZH2 inhibitor SHR2554 exhibited dramatic anti-tumor activity in both mutant and wild-type DLBCL, which may become a potential therapeutic modality for the treatment of DLBCL patients.
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http://dx.doi.org/10.3390/cancers13174249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428225PMC
August 2021

Molecular characterization of limited ulcerative colitis reveals novel biology and predictors of disease extension.

Gastroenterology 2021 Sep 1. Epub 2021 Sep 1.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension, is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension.

Methods: We performed RNA sequence analysis of biopsies from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsies were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments.

Results: Differentially expressed genes were identified in the endoscopically inflamed biopsies taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsies transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation and homeodomain pathways. A subset of these genes in inflamed biopsies was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and PARP14 was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsies of limited UC patients that subsequently extended.

Conclusion: Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.
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http://dx.doi.org/10.1053/j.gastro.2021.08.053DOI Listing
September 2021

Tunable 2D Group-III Metal Alloys.

Adv Mater 2021 Sep 4:e2104265. Epub 2021 Sep 4.

Center for 2-Dimensional and Layered Materials, The Pennsylvania State University, University Park, Berkeley, PA, 16802, USA.

Chemically stable quantum-confined 2D metals are of interest in next-generation nanoscale quantum devices. Bottom-up design and synthesis of such metals could enable the creation of materials with tailored, on-demand, electronic and optical properties for applications that utilize tunable plasmonic coupling, optical nonlinearity, epsilon-near-zero behavior, or wavelength-specific light trapping. In this work, it is demonstrated that the electronic, superconducting, and optical properties of air-stable 2D metals can be controllably tuned by the formation of alloys. Environmentally robust large-area 2D-In Ga alloys are synthesized byConfinement Heteroepitaxy (CHet). Near-complete solid solubility is achieved with no evidence of phase segregation, and the composition is tunable over the full range of x by changing the relative elemental composition of the precursor. The optical and electronic properties directly correlate with alloy composition, wherein the dielectric function, band structure, superconductivity, and charge transfer from the metal to graphene are all controlled by the indium/gallium ratio in the 2D metal layer.
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http://dx.doi.org/10.1002/adma.202104265DOI Listing
September 2021

[Comprehensive analysis of components in Chinese medicines derived from Apocynum venetum and Poacynum pictum in Xinjiang based on HPLC fingerprint and chemometrics].

Zhongguo Zhong Yao Za Zhi 2021 Aug;46(15):3886-3892

Altay Gebao Tea Co., Ltd. Altay 836300, China.

This study established high-performance liquid chromatography(HPLC) fingerprints of Chinese medicines derived from Apocynum venetum and Poacynum pictum in Xinjiang and explored their composition differences with the combination of content determination, similarity analysis, cluster analysis and principal component analysis. The HPLC conditions included Phenomenex Kinetex C_(18) column(4.6 mm ×100 mm, 2.6 μm), acetonitrile-0.01% trifluoroacetic acid aqueous solution as mobile phase, gradient elution, flow rate of 0.6 mL·min~(-1), detection wavelength of 281 nm and column temperature of 25 ℃. The content of chlorogenic acid, quercetin-3-O-sophoroside, rutin, hyperin, isoquercitrin, trifolin and astragalin was determined in 31 batches of medicinal materials, and fingerprint research and chemometric analysis were performed with Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine(Version 2004 A) and SPSS 21.0. In the Chinese Pharmacopoeia 2020, the quality of Apocyni Veneti Folium is controlled by character identification, microscopic identification, thin layer chromatography identification and quantitative determination of hyperin. There were 21 common peaks of A. venetum and P. pictum in the HPLC fingerprints, 5 of which were identified as chlorogenic acid, hyperin, isoquercitrin, trifolin and astragalin, with their content also determined. Except for 3 batches of medicinal materials, the similarity of other 28 batches was higher than 0.83, indicating good similarity. Two categories were formed in the cluster analysis based on content determination, which showed that some differences existed in similarities between different regions of Xinjiang. The medicinal materials were ranked by quality with principal component analysis, and the results indicated that the top 15 all came from northern Xinjiang. The quality difference of A. venetum and P. pictum had a correlation with the place of origin. This study provides a reference for the analysis and evaluation of A. venetum and P. pictum from different habitats and the selection of introduction and cultivation areas.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20210422.304DOI Listing
August 2021

Conditional Survival and Annual Hazard Estimates of Classical Hodgkin Lymphoma.

Cancer Manag Res 2021 26;13:6731-6741. Epub 2021 Aug 26.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China.

Background: In the present study, we have tried to understand how the level of risk and survival probability changes over time for patients with classical Hodgkin's lymphoma by employing conditional survival and annual hazard as dynamic estimates of prognosis and survival.

Methods: This retrospective study reviewed the clinical data of patients with newly diagnosed classical Hodgkin's lymphoma admitted to Peking University Cancer Hospital between January 1, 2008, and December 31, 2017. Conditional survival and annual hazard rate were defined as the survival probability and yearly event rate, respectively, assuming that patients have survived for a defined time.

Results: A total of 384 patients were included (median age, 32 years; range, 6-77 years), of which 218 (56.8%) patients had early-stage disease. The median follow-up time was 41.3 months. The 5-year conditional overall survival (COS) rates remained favorable and showed an increase from 89% at treatment to 94% at year 5, while the 5-year conditional failure-free survival (CFFS) rate increased from 70% at treatment to 96% at year 5. The annual hazard of failure decreased from over 15% at diagnosis to less than 5% after 3 years. Early-stage patients had constantly lower annual estimates for hazard of death (range, 0-3.0%) and failure (range, 0-14.3%). However, the hazard of failure in advanced-stage patients decreased from 24.2% at diagnosis to below 8% after 3 years, whereas the hazard of death was always at relatively low levels. Patients with a high IPS risk score (≥3) had significantly lower COS and CFFS during the first 4 years. Patients who received the BEACOPP regimen had better 5-year COS and 5-year CFFS than those who received the ABVD regimen.

Conclusion: The survival probability increased and hazard of failure decreased over time.
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http://dx.doi.org/10.2147/CMAR.S324543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405168PMC
August 2021

Protocol of a prospective and multicentre China Teratology Birth Cohort (CTBC): association of maternal drug exposure during pregnancy with adverse pregnancy outcomes.

BMC Pregnancy Childbirth 2021 Sep 1;21(1):593. Epub 2021 Sep 1.

Key Laboratory of Birth Defects And Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China.

Background: As reported, 27-93 % of pregnant women take at least one drug during pregnancy. However, drug exposure during pregnancy still lacks sufficient foetal safety evidence of human origin. It is urgent to fill the knowledge gap about medication safety during pregnancy for optimization of maternal disease treatment and pregnancy drug consultation.

Methods And Analysis: The China Teratology Birth Cohort (CTBC) was established in 2019 and is a hospital-based open-ended prospective cohort study with the aim of assessing drug safety during pregnancy. Pregnant women who set up the pregnancy health records in the first trimester or who seek drug consultation regardless of gestational age in the member hospitals are recruited. Enrolled pregnant women need to be investigated four times, namely, 6-14 and 24-28 weeks of gestational age, before discharge after hospital delivery, and 28-42 days after birth. Maternal medication exposure during pregnancy is the focus of the CTBC. For drugs, information on the type, name, and route of medication; start and end time of medication; single dose; frequency of medication; dosage form; manufacturer; and reason for medication is collected. The adverse pregnancy outcomes collected in the study include birth defects, stillbirth, spontaneous abortion, preterm birth, post-term birth, low birth weight, macrosomia, small for gestational age, large for gestational age and low Apgar score. CTBC uses an electronic questionnaire for data collection and a cloud system for data management. Biological samples are collected if informed consents are obtained. Multi-level logistic regression, mixed-effect negative binomial distribution regression and spline function regression are used to explore the effect of drugs on the occurrence of birth defects.

Discussion: The findings of the study will assist in further understanding the risk of birth defects and other adverse pregnancy outcomes associated with maternal drug exposure and developing the optimal treatment plans and drug counselling for pregnant women.

Trial Registration: This study was approved by the Research Ethics Committee of the West China Second Hospital of Sichuan University and registered at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx , registration number ChiCTR1900022569 ).
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http://dx.doi.org/10.1186/s12884-021-04073-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411516PMC
September 2021

Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis.

Lancet 2021 Aug 27. Epub 2021 Aug 27.

Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada. Electronic address:

Background: In randomised controlled trials, fixed-dose combination treatments (or polypills) have been shown to reduce a composite of cardiovascular disease outcomes in primary prevention. However, whether or not aspirin should be included, effects on specific outcomes, and effects in key subgroups are unknown.

Methods: We did an individual participant data meta-analysis of large randomised controlled trials (each with ≥1000 participants and ≥2 years of follow-up) of a fixed-dose combination treatment strategy versus control in a primary cardiovascular disease prevention population. We included trials that evaluated a fixed-dose combination strategy of at least two blood pressure lowering agents plus a statin (with or without aspirin), compared with a control strategy (either placebo or usual care). The primary outcome was time to first occurrence of a composite of cardiovascular death, myocardial infarction, stroke, or arterial revascularisation. Additional outcomes included individual cardiovascular outcomes and death from any cause. Outcomes were also evaluated in groups stratified by the inclusion of aspirin in the fixed-dose treatment strategy, and effect sizes were estimated in prespecified subgroups based on risk factors. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to compare strategies.

Findings: Three large randomised trials were included in the analysis (TIPS-3, HOPE-3, and PolyIran), with a total of 18 162 participants. Mean age was 63·0 years (SD 7·1), and 9038 (49·8%) participants were female. Estimated 10-year cardiovascular disease risk for the population was 17·7% (8·7). During a median follow-up of 5 years, the primary outcome occurred in 276 (3·0%) participants in the fixed-dose combination strategy group compared with 445 (4·9%) in the control group (hazard ratio 0·62, 95% CI 0·53-0·73, p<0·0001). Reductions were also observed for the separate components of the primary outcome: myocardial infarction (0·52, 0·38-0·70), revascularisation (0·54, 0·36-0·80), stroke (0·59, 0·45-0·78), and cardiovascular death (0·65, 0·52-0·81). Significant reductions in the primary outcome and its components were observed in the analyses of fixed-dose combination strategies with and without aspirin, with greater reductions for strategies including aspirin. Treatment effects were similar at different lipid and blood pressure levels, and in the presence or absence of diabetes, smoking, or obesity. Gastrointestinal bleeding was uncommon but slightly more frequent in the fixed-dose combination strategy with aspirin group versus control (19 [0·4%] vs 11 [0·2%], p=0·15). The frequencies of haemorrhagic stroke (10 [0·2%] vs 15 [0·3%]), fatal bleeding (two [<0·1%] vs four [0·1%]), and peptic ulcer disease (32 [0·7%] vs 34 [0·8%]) were low and did not differ significantly between groups. Dizziness was more common with fixed-dose combination treatment (1060 [11·7%] vs 834 [9·2%], p<0·0001).

Interpretation: Fixed-dose combination treatment strategies substantially reduce cardiovascular disease, myocardial infarction, stroke, revascularisation, and cardiovascular death in primary cardiovascular disease prevention. These benefits are consistent irrespective of cardiometabolic risk factors.

Funding: Population Health Research Institute.
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http://dx.doi.org/10.1016/S0140-6736(21)01827-4DOI Listing
August 2021

Non-cell Autonomous Cell Wall Transition Defects Mediate Thermo/photoperiod-sensitive Genic Male Sterility.

Mol Plant 2021 Aug 28. Epub 2021 Aug 28.

Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai 200234, China; Development Center of Plant Germplasm Resources, College of Life Sciences, Shanghai Normal University, Shanghai 200234, China.

During anther development, the process from microspore to mature pollen is under the protection from tetrad wall to pollen wall. Mutations of the genes involved in this wall transition often lead to microspore rupture and male sterility, some of which are thermo/photoperiod-sensitive genic male sterile (P/TGMS) lines, such as the reversible male sterile (rvms) mutant. Previous investigation shows slow development is a general mechanism of P/TGMS fertility restoration. We identified a restorer of rvms-2 (res2), which is an allele of the polygalacturonase QUARTET 3 (QRT3) with a delayed degradation of the tetrad pectin wall. MS188, a tapetum-specific transcription factor essential for pollen wall formation, was demonstrated to activate QUARTET 3 (QRT3) expression for pectin wall degradation, revealing a non-cell-autonomous pathway regulating the cell wall transition. Further assay shows that a delay in degradation of the tetrad pectin wall is responsible for fertility restoration of rvms and other P/TGMS lines, while early expression of QRT3 eliminates low temperature restoration of rvms-2 fertility. We propose that slow development during the cell wall transition reduces the requirement of wall protection which supports P/TGMS microspores to develop into functional pollen and restore their fertilities.
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http://dx.doi.org/10.1016/j.molp.2021.08.019DOI Listing
August 2021

Efficacy and safety of GLS-010 (zimberelimab) in patients with relapsed or refractory classical Hodgkin lymphoma: A multicenter, single-arm, phase II study.

Eur J Cancer 2021 Aug 27. Epub 2021 Aug 27.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), The Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China. Electronic address:

Background: GLS-010 (zimberelimab) is a novel, fully human, anti-programmed death-1 monoclonal antibody that shows promising efficacy and safety in advanced solid tumors. This trial aimed to evaluate the efficacy and safety of GLS-010 (zimberelimab) in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r-cHL).

Methods: This phase II, single-arm, open-label, multicenter clinical trial was conducted at 24 centers in China and enrolled patients with r/r-cHL after two or more lines of therapy. The patients were administered intravenous GLS-010 (zimberelimab) (240 mg, once every 2 weeks) until progression, death, unacceptable toxicity, or consent withdrawal. The primary end-point was the objective response rate assessed by an independent radiology review committee (IRC). This study was registered (NCT03655483).

Results: Eighty-five patients were enrolled between August 2018 and August 2019. The median follow-up was 15.8 months. Seventy-seven patients (90.6%; 95% confidence interval [CI] 82.3-95.9) had an IRC-assessed objective response. The complete response rate was 32.9% (n = 28). The 12-month progression-free survival and overall survival rates were 78% (95% CI 67.5-85.6) and 99% (95% CI 91.9-99.8), respectively. Treatment-related adverse events (TRAEs) were observed in 92.9% of participants. Grade III or IV TRAEs occurred in 24 (28.2%) of the 85 participants. The most common grade III or IV TRAEs were abnormal hepatic function (5.9%), hyperuricemia (4.7%), decreased neutrophil count (3.5%), and increased weight (3.5%). Only one grade V AE, gastrointestinal infection, occurred.

Conclusions: GLS-010 (zimberelimab) appears to be effective and safe for the treatment of Chinese patients with r/r-cHL. Long-term follow-up is required to confirm these clinical benefits.
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http://dx.doi.org/10.1016/j.ejca.2021.07.021DOI Listing
August 2021

Facile Synthesis of a Fully Fused, Three-Dimensional π-Conjugated Archimedean Cage with Magnetically Shielded Cavity.

J Am Chem Soc 2021 Sep 29;143(35):14314-14321. Epub 2021 Aug 29.

Department of Chemistry, National University of Singapore, Singapore 117543.

The synthesis of molecular cages consisting of fully fused, π-conjugated rings is rare due to synthetic challenges including preorganization, large strain, and poor solubility. Herein, we report such an example in which a tris-2-aminobenzophenone precursor undergoes acid-mediated self-condensation to form a truncated tetrahedron, one of the 13 Archimedean solids. Formation of eight-membered [1,5]diazocine rings provides preorganization and releases the strain while still maintains weak π-conjugation of the backbone. Thorough characterizations were performed by X-ray, NMR, and UV-vis analysis, assisted by theoretical calculations. The cage exhibits a rigid backbone structure with a well-defined cavity that confines a magnetically shielded environment. The solvent molecule, -dichlorobenzene, is precisely encapsulated in the cavity at a 1:1 ratio with multiple π···π, C-H···π, and halogen···π interactions with the cage skeleton, implying its template effect for the cage closing reaction. Our synthetic strategy opens the opportunity to access more complex, fully fused, three-dimensional π-conjugated cages.
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http://dx.doi.org/10.1021/jacs.1c06490DOI Listing
September 2021

Quantitative analysis of FQs antibiotics content in FMF using THz spectral and imaging technology.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Aug 17;264:120284. Epub 2021 Aug 17.

Beijing Research Center of Intelligent Equipment for Agriculture, Beijing 100097, China.

Rapid and accurate detection of fluoroquinolones (FQs) antibiotics residues in food substrate are of great significance to food safety. In this study, terahertz spectroscopy was employed to conduct the spectral and imaging analysis to explore its feasibility for detection concentrations of FQs in fish meal feeds (FMF). Four methods (frequency of maximum difference in frequency-domain, characteristic absorption peak, successive projections algorithm and stepwise regression) were used to selected characteristic frequencies of sample. Terahertz imaging was formed at selected characteristic frequency and back propagation neural network was used to establish quantitative evaluation models to select optimal characteristic imaging frequency. Finally, relationship between concentrations of FQs and their gray values was revealed, and each data had a small range of error bar. The results showed that terahertz spectral and imaging technique can visualize norfloxacin and enrofloxacin concentrations in FMF precisely. This study explored a brand-new visualization method for quantitative detection of FQs in FMF based on terahertz spectral and imaging technology.
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http://dx.doi.org/10.1016/j.saa.2021.120284DOI Listing
August 2021

Risk-score model to predict prognosis of malignant airway obstruction after interventional bronchoscopy.

Transl Lung Cancer Res 2021 Jul;10(7):3173-3190

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Background: Interventional bronchoscopy exhibits substantial effects for patients with malignant airway obstruction (MAO), while little information is available regarding the potential prognostic factors for these patients.

Methods: Between October 31, 2016, and July 31, 2019, a total of 150 patients undergoing interventional bronchoscopy and histologically-confirmed MAO were collected, in which 112 eligible participants formed the cohort for survival study. External validation cohort from another independent institution comprised 33 MAO patients with therapeutic bronchoscopy. The least absolute shrinkage and selection operator regression (LASSO) was applied to the model development dataset for selecting features correlated with MAO survival for inclusion in the Cox regression from which we elaborated the risk score system. A nomogram algorithm was also utilized.

Results: In our study, we observed a significant decline of stenosis rate after interventional bronchoscopy from 71.7%±2.1% to 36.6%±2.7% (P<0.001) and interventional bronchoscopy dilated airway effectively. Patients in our study undergoing interventional bronchoscopy had a median survival time of 614.000 days (95% CI: 269.876-958.124). Patients receiving distinct therapeutic methods of interventional bronchoscopy had different prognosis (P=0.022), and patients receiving treatment of electrocoagulation in combination with stenting and electrosurgical snare had worse survival than those receiving other options. Multivariate Cox analysis revealed that nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, as independent predictive factors for better overall survival (OS) of MAO patients. Then, the nomogram based on Cox regression and risk score system based on results from LASSO regression were elaborated respectively. Importantly, this risk score system was proved to have better performance than the nomogram and other single biomarkers such as traditional staging system (area under the curve 0.855 0.392-0.739). Survival curves showed that patients with the higher risk-score had poorer prognosis than those with lower risk-score (third quantile of OS: 126.000 days, 95% CI: 73.588-178.412 532.000 days, 95% CI: 0.000-1,110.372; P<0.001).

Conclusions: Nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, were independent predictive factors for better OS of MAO patients. We proposed a nomogram and risk score system for survival prediction of MAO patients undergoing interventional bronchoscopy with good performance.
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http://dx.doi.org/10.21037/tlcr-21-301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350098PMC
July 2021

Intraarticular bone grafting in atlantoaxial facet joints via a posterior approach: nonstructural or structural-a minimum 24-month follow-up.

J Orthop Surg Res 2021 Aug 23;16(1):524. Epub 2021 Aug 23.

Division of Spine Surgery, Department of Orthopedics, Daping Hospital of Army Medical University, Chongqing, 400042, China.

Objective: To investigate the necessity of nonstructural or structural intraarticular bone grafting in atlantoaxial facet joints via a posterior approach and the influence by the presence of basilar invagination (BI).

Methods: From November 2016 to October 2018, patients who underwent posterior atlantoaxial or occipitocervical arthrodesis surgery at one institute were retrospectively reviewed. Operation records, preoperative and postoperative clinical status, and radiological films were analyzed.

Results: Thirty-three patients (19 without BI, 14 with BI) underwent posterior facet joint release followed by intraarticular bone grafting were enrolled finally. Twenty-four nonstructural (15 without BI, 9 with BI) and 9 structural (4 without BI, 5 with BI) grafting were performed. The average follow-up was 32.15±6.73 months (24-47 months). Among them, 1 (3.03%) implant failure occurred, and 32 (96.97%) achieved satisfactory neurological outcomes, including 28 (84.85%) complete and 4 (12.12%) acceptable reductions with complete fusion within 6 months. For patients without BI, structural and nonstructural grafting showed no significant difference in terms of reduction maintenance (100% vs 73.33%, p = 0.530), while for those with BI, structural grafting significantly increased the postoperative height of the joint space (5.67±1.22 mm vs 3.43±1.78 mm, p = 0.002) and maintained it much better than nonstructural grafting (88.89% vs 20.00%, p = 0.023), contributing notably to BI correction.

Conclusion: Intraarticular structural bone grafting in atlantoaxial facet joints has the advantage of maintaining anterior column height in the case of lateral mass collapse or when BI correction is needed; otherwise, nonstructural bone grafting is enough.
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http://dx.doi.org/10.1186/s13018-021-02630-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381565PMC
August 2021

Ethyl ferulate protects against lipopolysaccharide-induced acute lung injury by activating AMPK/Nrf2 signaling pathway.

Acta Pharmacol Sin 2021 Aug 20. Epub 2021 Aug 20.

Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China.

Ethyl ferulate (EF) is abundant in Rhizoma Chuanxiong and grains (e.g., rice and maize) and possesses antioxidative, antiapoptotic, antirheumatic, and anti-inflammatory properties. However, its effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is still unknown. In the present study, we found that EF significantly alleviated LPS-induced pathological damage and neutrophil infiltration and inhibited the gene expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in murine lung tissues. Moreover, EF reduced the gene expression of TNF-α, IL-1β, IL-6, and iNOS and decreased the production of NO in LPS-stimulated RAW264.7 cells and BMDMs. Mechanistic experiments revealed that EF prominently activated the AMPK/Nrf2 pathway and promoted Nrf2 nuclear translocation. AMPK inhibition (Compound C) and Nrf2 inhibition (ML385) abolished the beneficial effect of EF on the inflammatory response. Furthermore, the protective effect of EF on LPS-induced ALI was not observed in Nrf2 knockout mice. Taken together, the results of our study suggest that EF ameliorates LPS-induced ALI in an AMPK/Nrf2-dependent manner. These findings provide a foundation for developing EF as a new anti-inflammatory agent for LPS-induced ALI/ARDS therapy.
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http://dx.doi.org/10.1038/s41401-021-00742-0DOI Listing
August 2021

Preterm births in China between 2012 and 2018: an observational study of more than 9 million women.

Lancet Glob Health 2021 09;9(9):e1226-e1241

Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China; Med-X Center for Informatics, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; Key Laboratory of Chronobiology (Sichuan University), National Health Commission of China, Chengdu, China.

Background: Preterm birth rates have increased significantly worldwide over the past decade. Few epidemiological studies on the incidence of preterm birth and temporal trends are available in China. This study used national monitoring data from China's National Maternal Near Miss Surveillance System (NMNMSS) to estimate the rate of preterm birth and trends between 2012 and 2018 in China and to assess risk factors associated with preterm birth.

Methods: In this observational study, data were sourced from the NMNMSS between Jan 1, 2012, and Dec 31, 2018. Pregnancies with at least one livebirth, with the baby born at 28 weeks of gestation or more or 1000 g or more birthweight were included. We estimated the rates of overall preterm, very preterm (born between 28 and 31 weeks' gestation), moderate preterm (born between 32 and 33 weeks' gestation), and late preterm (born between 34 and 36 weeks' gestation) births in singleton and multiple pregnancies and assessed their trends over time. We used logistic regression analysis to examine the associations between preterm birth and sociodemographic characteristics and obstetric complications, considering the sampling strategy and clustering of births within hospitals. Interrupted time series analysis was used to assess the changes in preterm birth rates during the period of the universal two child policy intervention.

Findings: From Jan 1, 2012, to Dec 31, 2018, 9 645 646 women gave birth to at least one live baby, of whom 665 244 (6·1%) were born preterm. In all pregnancies, the overall preterm birth rate increased from 5·9% in 2012 to 6·4% in 2018 (8·8% increase; annual rate of increase [ARI] 1·3 [95% CI 0·6 to 2·1]). Late preterm births (8·8%; ARI 1·5% [0·9 to 2·2]) and very preterm births (13·3%; ARI 1·8% [0·5 to 3·0]) significantly increased from 2012 to 2018, whereas moderate preterm births did not (3·8%; ARI 0·3% [95% CI -0·9 to 1·5]). In singleton pregnancies, the overall preterm birth rate showed a small but significant 6·4% increase (ARI 1·0% [0·4 to 1·7]) over the 7 year period. In multiple pregnancies, the overall preterm birth rate significantly increased from 46·8% in 2012 to 52·7% in 2018 (12·4% increase; ARI 1·9% [1·2 to 2·6]). Compared with women who gave birth in 2012, those who gave birth in 2018 were more likely to be older (aged ≥35 years; 7·4% in 2012 vs 15·9% in 2018), have multiples (1·6% vs 1·9%), have seven or more antenatal visits (50·2% vs 70·7%), and have antepartum complications and medical disease (17·9% vs 35·1%), but they were less likely to deliver via caesarean section (47·5% vs 45·0%). Compared with the baseline period (January, 2012 to June, 2016), a higher increase in preterm birth was observed after the universal two child policy came into effect in July, 2016 (β=0·034; p=0·03).

Interpretation: An increase in preterm births was noted for both singleton and multiple pregnancies between 2012 and 2018 in China. China's strategic investment in maternal and neonatal health has been crucial for the prevention of preterm birth. Due to rapid changes in sociodemographic and obstetric factors related to preterm birth-particularly within the context of the universal two child policy-such as advanced maternal age at delivery, maternal complications, and multiple pregnancies, greater efforts to reduce the burden of preterm birth are urgently needed.

Funding: National Key R&D Program of China, National Health Commission of the People's Republic of China, China Medical Board, WHO, and UNICEF.
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http://dx.doi.org/10.1016/S2214-109X(21)00298-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386289PMC
September 2021

Germline SUCLG2 Variants in Patients with Pheochromocytoma and Paraganglioma.

J Natl Cancer Inst 2021 08 20. Epub 2021 Aug 20.

Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Background: Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors with frequent mutations in genes linked to the tricarboxylic acid cycle. However, no pathogenic variant has been found to date in succinyl-CoA ligase (SUCL), an enzyme that provides substrate for succinate dehydrogenase (SDH; mitochondrial complex II; CII), a known tumor suppressor in PPGL.

Methods: A cohort of 352 subjects with apparently sporadic PPGL underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health, including the SUCLG2 subunit of SUCL. Gene deletion, succinate levels, and protein levels were assessed in tumors where possible. To confirm the possible mechanism, we used a progenitor cell line, hPheo1, derived from a human pheochromocytoma, and ablated and re-expressed SUCLG2.

Results: We describe eight germline variants in the GTP-binding domain of SUCLG2 in 15 patients (15 of 352, 4.3%) with apparently sporadic PPGL. Analysis of SUCLG2-mutated tumors and SUCLG2-deficient hPheo1 cells revealed absence of SUCLG2 protein, decrease in the level of the SDHB subunit of CII and faulty assembly of the complex, resulting in aberrant respiration and elevated succinate accumulation.

Conclusions: Our study suggests SUCLG2 as a novel candidate gene in the genetic landscape of PPGL. Large-scale sequencing may uncover additional cases harboring SUCLG2 variants and provide more detailed information about their prevalence and penetrance.
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http://dx.doi.org/10.1093/jnci/djab158DOI Listing
August 2021

Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs.

Bone Res 2021 Aug 16;9(1):37. Epub 2021 Aug 16.

Department of Spine Surgery, Center of Orthopedics, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

A comprehensive understanding of the cellular heterogeneity and molecular mechanisms underlying the development, homeostasis, and disease of human intervertebral disks (IVDs) remains challenging. Here, the transcriptomic landscape of 108 108 IVD cells was mapped using single-cell RNA sequencing of three main compartments from young and adult healthy IVDs, including the nucleus pulposus (NP), annulus fibrosus, and cartilage endplate (CEP). The chondrocyte subclusters were classified based on their potential regulatory, homeostatic, and effector functions in extracellular matrix (ECM) homeostasis. Notably, in the NP, a PROCR resident progenitor population showed enriched colony-forming unit-fibroblast (CFU-F) activity and trilineage differentiation capacity. Finally, intercellular crosstalk based on signaling network analysis uncovered that the PDGF and TGF-β cascades are important cues in the NP microenvironment. In conclusion, a single-cell transcriptomic atlas that resolves spatially regulated cellular heterogeneity together with the critical signaling that underlies homeostasis will help to establish new therapeutic strategies for IVD degeneration in the clinic.
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http://dx.doi.org/10.1038/s41413-021-00163-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368097PMC
August 2021

Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs.

Cancer Cell Int 2021 Aug 16;21(1):432. Epub 2021 Aug 16.

Xijing Hospital, Airforce Medical University, Xi'an, 710032, China.

Background: Gastric cancer (GC) is a globally prevalent cancer, ranking fifth for incidence and fourth for mortality worldwide. The N6-methyladenosine (mA) related long noncoding RNAs (lncRNAs) were widely investigated in recent studies. Nevertheless, the underlying prognostic implication and tumor immune mechanism of mA-related lncRNA in GC remain unknown.

Methods: We systematically assessed the mA modification expression of 407 GC clinical samples based on 23 mA regulators and comprehensively associated these genes with lncRNAs. Then, we constructed a mA-related lncRNA prognostic signature (mA-LPS) to evaluate both status and prognosis of the disease. Immune-related mechanisms were explored via dissecting tumor-infiltrating cells as well as applying tumor immune dysfunction and the exclusion algorithm. Furthermore, we validated the latent regulative mechanism of mA-related lncRNA in GC cell lines.

Results: The mA-LPS containing nine hub lncRNAs was built, which possessed a superior capability to predict the outcomes of GC patients. Meanwhile, we found an intimate correlation between the mA-LPS and tumor infiltrating cells, and that the low-risk group had a higher expression of immune checkpoints and responsed more to immunotherapy than the high-risk group. Clinically, these crucial lncRNAs expression levels were verified in ten pairs of GC samples. In in vitro experiments, the abilities of migration and proliferation were significantly enhanced via downregulating the lncRNA AC026691.1. Both migrative and proliferative capabilities of tumor cells were significantly enhanced via downregulating the lncRNA AC026691.1. in vitro.

Conclusions: Collectively, the mA-LPS could provide a novel prediction insight into the prognosis of GC patients and serve as an independent clinical factor for GC. These mA-related lncRNAs might remodel the tumor microenvironment and affect the anti-cancer ability of immune checkpoint blockers. Importantly, lncRNA AC026691.1 could inhibit both migration and proliferation of GC by means of FTO regulation.
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http://dx.doi.org/10.1186/s12935-021-02146-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365962PMC
August 2021

Examining heterogeneity of stromal cells in tumor microenvironment based on pan-cancer single-cell RNA sequencing data.

Cancer Biol Med 2021 Aug 17. Epub 2021 Aug 17.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Tumor tissues contain both tumor and non-tumor cells, which include infiltrated immune cells and stromal cells, collectively called the tumor microenvironment (TME). Single-cell RNA sequencing (scRNAseq) enables the examination of heterogeneity of tumor cells and TME. In this review, we examined scRNAseq datasets for multiple cancer types and evaluated the heterogeneity of major cell type composition in different cancer types. We further showed that endothelial cells and fibroblasts/myofibroblasts in different cancer types can be classified into common subtypes, and the subtype composition is clearly associated with cancer characteristic and therapy response.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0762DOI Listing
August 2021

Restoration of the ATG5-dependent autophagy sensitizes DU145 prostate cancer cells to chemotherapeutic drugs.

Oncol Lett 2021 Sep 6;22(3):638. Epub 2021 Jul 6.

Department of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.

Autophagy serves an important role in cancer cell survival and drug resistance. In the present study, the prostate cancer DU145 cell line was used, which lacks autophagy related 5 (ATG5) expression and is defective in induction of ATG5-dependent autophagy. The aim of the study was to examine the effects of the restoration of autophagy on cell proliferation and migration, and to assess the cytotoxicity caused by chemotherapeutic drugs, using microscopic, wound-healing, western blot and apoptotic assays. The restoration of the autophagic activity in DU145 cells by the overexpression of ATG5 enhanced the cell proliferation and migration rates. Notably, restoration of the ATG5-dependent autophagy in DU145 cells significantly increased the cytotoxic effects of the chemotherapeutic drugs, docetaxel and valproic acid, and the endoplasmic reticulum stress inducers, brefeldin A, tunicamycin and thapsigargin. The present study provides a novel perspective on the role of ATG5-dependent autophagy in drug resistance and chemotherapy.
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http://dx.doi.org/10.3892/ol.2021.12899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298997PMC
September 2021

Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

Nat Commun 2021 08 11;12(1):4854. Epub 2021 Aug 11.

Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56CD57 natural killer (NK) cells and exhausted CD8 T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8 T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.
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http://dx.doi.org/10.1038/s41467-021-24981-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357784PMC
August 2021
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