Publications by authors named "Mengjie Chen"

92 Publications

A mAvalue predictive of prostate cancer stemness, tumor immune landscape and immunotherapy response.

NAR Cancer 2022 Mar 25;4(1):zcac010. Epub 2022 Mar 25.

School of Biomedical Sciences, Hunan University, Changsha 410082, China.

The molecular mechanisms underpinning prostate cancer (PCa) progression are incompletely understood, and precise stratification of aggressive primary PCa (pri-PCa) from indolent ones poses a major clinical challenge. Here, we comprehensively dissect, genomically and transcriptomically, the mA ( -methyladenosine) pathway as a whole in PCa. Expression, but not the genomic alteration, repertoire of the full set of 24 mA regulators at the population level successfully stratifies pri-PCa into three mA clusters with distinct molecular and clinical features. These three mA modification patterns closely correlate with androgen receptor signaling, stemness, proliferation and tumor immunogenicity of cancer cells, and stroma activity and immune landscape of tumor microenvironment (TME). We observe a discrepancy between a potentially higher neoantigen production and a deficiency in antigen presentation processes in aggressive PCa, offering insights into the failure of immunotherapy. Identification of PCa-specific mA phenotype-associated genes provides a basis for construction of mAvalue to measure mA methylation patterns in individual patients. Tumors with lower mAvalue are relatively indolent with abundant immune cell infiltration and stroma activity. Interestingly, mAvalue separates PCa TME into fibrotic and nonfibrotic phenotypes (instead of previously reported immune-proficient or -desert phenotypes in other cancer types). Significantly, mAvalue can be used to predict drug response and clinical immunotherapy efficacy in both castration-resistant PCa and other cancer types. Therefore, our study establishes mA methylation modification pattern as a determinant in PCa progression via impacting cancer cell aggressiveness and TME remodeling.
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http://dx.doi.org/10.1093/narcan/zcac010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953419PMC
March 2022

mA RNA modifications are measured at single-base resolution across the mammalian transcriptome.

Nat Biotechnol 2022 Mar 14. Epub 2022 Mar 14.

Department of Chemistry, The University of Chicago, Chicago, IL, USA.

Functional studies of the RNA N-methyladenosine (mA) modification have been limited by an inability to map individual mA-modified sites in whole transcriptomes. To enable such studies, here, we introduce mA-selective allyl chemical labeling and sequencing (mA-SAC-seq), a method for quantitative, whole-transcriptome mapping of mA at single-nucleotide resolution. The method requires only ~30 ng of poly(A) or rRNA-depleted RNA. We mapped mA modification stoichiometries in RNA from cell lines and during in vitro monocytopoiesis from human hematopoietic stem and progenitor cells (HSPCs). We identified numerous cell-state-specific mA sites whose methylation status was highly dynamic during cell differentiation. We observed changes of mA stoichiometry as well as expression levels of transcripts encoding or regulated by key transcriptional factors (TFs) critical for HSPC differentiation. mA-SAC-seq is a quantitative method to dissect the dynamics and functional roles of mA sites in diverse biological processes using limited input RNA.
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http://dx.doi.org/10.1038/s41587-022-01243-zDOI Listing
March 2022

Establishment of pediatric developmental dysplasia of the hip biobank: Shanghai children's hospital experience.

Cell Tissue Bank 2022 Feb 25. Epub 2022 Feb 25.

Department of Orthopedics, Shanghai Children's Hospital, Shanghai Jiao Tong University, 355 Lane Luding Rd, Putuo District, Shanghai, 200062, People's Republic of China.

Developmental dysplasia of the hip (DDH) is a debilitating condition that affects 1-7% of newborns. Children with DDH, not treated early and effectively, will easily lead to disability. A better understanding of the biology of DDH is critical to the development of prognostic biomarkers and novel therapies. The purpose of this study was to establish a biobank of DDH genetic resources, to facilitate clinical and basic scientific research. The biological specimen and clinical data of DDH were collected in Shanghai Children's Hospital from 2014 to 2021. The collection of blood samples was performed at definitive diagnosis and review, tissue specimens were performed at definitive surgery. The clinical data was collected at the whole stage of DDH patients at diagnosis, treatment and follow-up. A total of 528 patients with DDH were enrolled in this study, 90 were men and 438 were women, with the mean age of 4.67 years. The numbers of tissue and blood specimens reached 2172 and 1490, respectively. The quality test results showed that the DNA concentration decreased slightly with the extension of storage time, but the DNA purity did not change. Meanwhile, the extension of storage time slightly affected the stability of protein of tissue samples but did not affect the expression of the housekeeping gene. The DDH biobank built has the potential of monitoring disease pathogenesis and progress, which could provide specimens to the researchers improving the biological understanding and provide guidance of clinical treatment of this disease to clinicians.
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http://dx.doi.org/10.1007/s10561-022-09995-3DOI Listing
February 2022

KAS-seq: genome-wide sequencing of single-stranded DNA by N-kethoxal-assisted labeling.

Nat Protoc 2022 02 10;17(2):402-420. Epub 2022 Jan 10.

Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA.

Transcription and its dynamics are crucial for gene expression regulation. However, very few methods can directly read out transcriptional activity with low-input material and high temporal resolution. This protocol describes KAS-seq, a robust and sensitive approach for capturing genome-wide single-stranded DNA (ssDNA) profiles using N-kethoxal-assisted labeling. We developed N-kethoxal, an azido derivative of kethoxal that reacts with deoxyguanosine bases of ssDNA in live cells within 5-10 min at 37 °C, allowing the capture of dynamic changes. Downstream biotinylation of labeled DNA occurs via copper-free click chemistry. Altogether, the KAS-seq procedure involves N-kethoxal labeling, DNA isolation, biotinylation, fragmentation, affinity pull-down, library preparation, sequencing and bioinformatics analysis. The pre-library construction labeling and enrichment can be completed in as little as 3-4 h and is applicable to both animal tissue and as few as 1,000 cultured cells. Our recent study shows that ssDNA signals measured by KAS-seq simultaneously reveal the dynamics of transcriptionally engaged RNA polymerase (Pol) II, transcribing enhancers, RNA Pol I and Pol III activities and potentially non-canonical DNA structures with high analytical sensitivity. In addition to the experimental protocol, we also introduce here KAS-pipe, a user-friendly integrative data analysis pipeline for KAS-seq.
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http://dx.doi.org/10.1038/s41596-021-00647-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923001PMC
February 2022

Research and Progress on the Mechanism of Iron Transfer and Accumulation in Rice Grains.

Plants (Basel) 2021 Nov 28;10(12). Epub 2021 Nov 28.

MOA Key Laboratory of Crop Ecophysiology and Farming System in the Middle Reaches of the Yangtze River, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.

Iron (Fe) is one of the most important micronutrients for organisms. Currently, Fe deficiency is a growing nutritional problem and is becoming a serious threat to human health worldwide. A method that could help alleviate this "hidden hunger" is increasing the bioavailable Fe concentrations in edible tissues of major food crops. Therefore, understanding the molecular mechanisms of Fe accumulation in different crop tissues will help to develop crops with higher Fe nutritional values. Biofortification significantly increases the concentration of Fe in crops. This paper considers the important food crop of rice ( L.) as an example and highlights recent research advances on the molecular mechanisms of Fe uptake and allogeneic uptake in different tissues of rice. In addition, different approaches to the biofortification of Fe nutrition in rice and their outcomes are described and discussed. To address the problems that occur during the development and application of improving nutritional Fe in rice, technical strategies and long-term solutions are also proposed as a reference for the future improvement of staple food nutrition with micronutrients.
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http://dx.doi.org/10.3390/plants10122610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708893PMC
November 2021

Cell type-aware analysis of RNA-seq data.

Nat Comput Sci 2021 Apr 15;1(4):253-261. Epub 2021 Apr 15.

Department of Biostatistics, University of North Carolina at Chapel Hill.

Most tissue samples are composed of different cell types. Differential expression analysis without accounting for cell type composition cannot separate the changes due to cell type composition or cell type-specific expression. We propose a computational framework to address these limitations: ell Type ware analysis of NA- (CARseq). CARseq employs a negative binomial distribution that appropriately models the count data from RNA-seq experiments. Simulation studies show that CARseq has substantially higher power than a linear model-based approach and it also provides more accurate estimate of the rankings of differentially expressed genes. We have applied CARseq to compare gene expression of schizophrenia/autism subjects versus controls, and identified the cell types underlying the difference and similarities of these two neuron-developmental diseases. Our results are consistent with the results from differential expression analysis using single cell RNA-seq data.
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http://dx.doi.org/10.1038/s43588-021-00055-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8697413PMC
April 2021

Resilience as a Mediator of the Association between Spirituality and Self-Management among Older People with Chronic Obstructive Pulmonary Disease.

Healthcare (Basel) 2021 Nov 25;9(12). Epub 2021 Nov 25.

Research Office of Chronic Disease Management and Rehabilitation, Wuxi School of Medicine, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, China.

This study examined the mediating effect of resilience in the relationship between spirituality and self-management among older people with chronic obstructive pulmonary disease (COPD). The participants were 151 older people with COPD in four general hospitals in Jiangsu Province, China. Data were collected from September 2020 to May 2021 using a questionnaire developed by the investigator, the Function Assessment of Chronic Illness Therapy-Spiritual Scale (FACIT-SP-12), 10-item Connor-Davidson Resilience Scale (CD-RISC-10), and COPD Self-Management Scale (CSMS). One-way ANOVA and -test were used to compare the level of self-management in patients with different sociodemographic and clinical characteristics. Partial correlation analysis was used to explore the correlation between spirituality, resilience, and self-management. Hierarchical multiple regression analyses were performed to examine the contribution of spirituality and resilience to the prediction of self-management. A bootstrapping test was implemented using the SPSS PROCESS macro to test the statistical significance of the mediating effect. There was a pairwise positive correlation between spirituality, resilience, and self-management. Resilience mediated the relationship between spirituality and self-management. These findings suggested that resilience interventions could be incorporated into future COPD self-management interventions to better improve self-management and health outcomes. Moreover, resilience should be an important component of healthy aging initiatives.
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http://dx.doi.org/10.3390/healthcare9121631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700824PMC
November 2021

Effective and scalable single-cell data alignment with non-linear canonical correlation analysis.

Nucleic Acids Res 2022 02;50(4):e21

Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.

Data alignment is one of the first key steps in single cell analysis for integrating multiple datasets and performing joint analysis across studies. Data alignment is challenging in extremely large datasets, however, as the major of the current single cell data alignment methods are not computationally efficient. Here, we present VIPCCA, a computational framework based on non-linear canonical correlation analysis for effective and scalable single cell data alignment. VIPCCA leverages both deep learning for effective single cell data modeling and variational inference for scalable computation, thus enabling powerful data alignment across multiple samples, multiple data platforms, and multiple data types. VIPCCA is accurate for a range of alignment tasks including alignment between single cell RNAseq and ATACseq datasets and can easily accommodate millions of cells, thereby providing researchers unique opportunities to tackle challenges emerging from large-scale single-cell atlas.
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http://dx.doi.org/10.1093/nar/gkab1147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887421PMC
February 2022

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes.

Nat Commun 2021 11 26;12(1):6946. Epub 2021 Nov 26.

Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.

Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.
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http://dx.doi.org/10.1038/s41467-021-27079-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626467PMC
November 2021

Neoadjuvant Chemotherapy Induces Genomic and Transcriptomic Changes in Ovarian Cancer.

Cancer Res 2022 01 4;82(1):169-176. Epub 2021 Nov 4.

Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.

The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA sequencing and panel DNA sequencing of 596 cancer-related genes was performed on paired formalin-fixed paraffin-embedded specimens collected before and after chemotherapy, and differentially expressed genes (DEG) and copy-number variations (CNV) in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy-resistant specimens. AP-1 transcription factor family genes (, , ) were particularly upregulated in chemotherapy-resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses . , combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and copy-number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance. SIGNIFICANCE: Genomic and transcriptomic analyses identify increased AP-1 activity and copy-number amplifications in resistant ovarian cancer following neoadjuvant chemotherapy, uncovering synergistic effects of AP-1 and SIK2 inhibitors with chemotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936832PMC
January 2022

Integrins regulate stemness in solid tumor: an emerging therapeutic target.

J Hematol Oncol 2021 10 29;14(1):177. Epub 2021 Oct 29.

School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.

Integrins are the adhesion molecules and transmembrane receptors that consist of α and β subunits. After binding to extracellular matrix components, integrins trigger intracellular signaling and regulate a wide spectrum of cellular functions, including cell survival, proliferation, differentiation and migration. Since the pattern of integrins expression is a key determinant of cell behavior in response to microenvironmental cues, deregulation of integrins caused by various mechanisms has been causally linked to cancer development and progression in several solid tumor types. In this review, we discuss the integrin signalosome with a highlight of a few key pro-oncogenic pathways elicited by integrins, and uncover the mutational and transcriptomic landscape of integrin-encoding genes across human cancers. In addition, we focus on the integrin-mediated control of cancer stem cell and tumor stemness in general, such as tumor initiation, epithelial plasticity, organotropic metastasis and drug resistance. With insights into how integrins contribute to the stem-like functions, we now gain better understanding of the integrin signalosome, which will greatly assist novel therapeutic development and more precise clinical decisions.
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http://dx.doi.org/10.1186/s13045-021-01192-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555177PMC
October 2021

P2Y2 promotes fibroblasts activation and skeletal muscle fibrosis through AKT, ERK, and PKC.

BMC Musculoskelet Disord 2021 Aug 11;22(1):680. Epub 2021 Aug 11.

Department of Otorhinolaryngology, The First Affiliate Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.

Background: Skeletal muscle atrophy and fibrosis are pathological conditions that contribute to morbidity in numerous conditions including aging, cachexia, and denervation. Muscle atrophy is characterized as reduction of muscle fiber size and loss of muscle mass while muscle fibrosis is due to fibroblasts activation and excessive production of extracellular matrix. Purinergic receptor P2Y2 has been implicated in fibrosis. This study aims to elucidate the roles of P2Y2 in sleketal muscle atrophy and fibrosis.

Methods: Primary muscle fibroblasts were isolated from wild type and P2Y2 knockout (KO) mice and their proliferating and migrating abilities were assessed by CCK-8 and Transwell migration assays respectively. Fibroblasts were activated with TGF-β1 and assessed by western blot of myofibroblast markers including α-SMA, CTGF, and collagen I. Muscle atrophy and fibrosis were induced by transection of distal sciatic nerve and assessed using Masson staining.

Results: P2Y2 KO fibroblasts proliferated and migrated significantly slower than WT fibroblasts with or without TGF-β1.The proliferation and ECM production were enhanced by P2Y2 agonist PSB-1114 and inhibited by antagonist AR-C118925. TGF-β1 induced fibrotic activation was abolished by P2Y2 ablation and inhibited by AKT, ERK, and PKC inhibitors. Ablation of P2Y2 reduced denervation induced muscle atrophy and fibrosis.

Conclusions: P2Y2 is a promoter of skeletal muscle atrophy and activation of fibroblasts after muscle injury, which signaling through AKT, ERK and PKC. P2Y2 could be a potential intervention target after muscle injury.
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http://dx.doi.org/10.1186/s12891-021-04569-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359595PMC
August 2021

Immune infiltration and a ferroptosis-associated gene signature for predicting the prognosis of patients with endometrial cancer.

Aging (Albany NY) 2021 06 24;13(12):16713-16732. Epub 2021 Jun 24.

Department of Gynecologic Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region 530021, PR China.

Ferroptosis, a form of programmed cell death induced by excess iron-dependent lipid peroxidation product accumulation, plays a critical role in cancer. However, there are few reports about ferroptosis in endometrial cancer (EC). This article explores the relationship between ferroptosis-related gene (FRG) expression and prognosis in EC patients. One hundred thirty-five FRGs were obtained by mining the literature, retrieving GeneCards and analyzing 552 malignant uterine corpus endometrial carcinoma (UCEC) samples, which were randomly assigned to training and testing groups (1:1 ratio), and 23 normal samples from The Cancer Genome Atlas (TCGA). We established a signature using eight screened FRGs ( and ) related to overall survival using LASSO regression analysis. The samples were divided into low- and high-risk subgroups according to the median risk score. Kaplan-Meier survival curves showed that the low-risk group had better OS. ROC curves showed that this signature performed well in predicting OS (1-, 2-, 3-, and 5-year AUCs of 0.676, 0.775, 0.797, and 0.826, respectively). We systematically analyzed the immune infiltrating profile in UCEC samples from TCGA. Overall, our study identified a novel prognostic signature of 8 FRGs that can potentially predict the prognosis of EC.
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http://dx.doi.org/10.18632/aging.203190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266342PMC
June 2021

Family interaction among young Chinese breast cancer survivors.

BMC Fam Pract 2021 06 21;22(1):122. Epub 2021 Jun 21.

School of Nursing, Shanghai Jiao Tong University, 227 South Chongqing road, Huangpu, Shanghai, 200025, China.

Background: Family interaction is an important factor contributing to the quality of survivorship among breast cancer survivors. The dearth of studies involving young females with breast cancer has limited the understanding of family interaction in this increasingly large population.

Methods: The aim of this study was to explore family interaction patterns among young Chinese breast cancer survivors. We conducted in-depth interviews with seventeen young breast cancer survivors (YBCSs) in China between May 2019 and December 2019. A content analysis was performed to identify the characteristics of family interaction in this population. Conceptualizations of feminism and social support were used to guide the data analysis.

Results: Family interaction patterns were categorized into 5 domains from the perceptions of Chinese YBCSs: (1) adjustment of parenthood (changes in child-rearing approaches, perception of children's care) (2) ambivalence towards intimacy (desire for intimate relationships, perceived relationship insecurity); (3) concerns regarding fertility; (4) return to work (coping with gratitude and guilt by working, readapting to family and society by working); (5) activation of the support system in a large family (instrumental support from core family members, instrumental, informational, and appraisal support from relatives).

Conclusions: The study provides a deeper understanding of the interactions between young breast cancer survivors and their family members in China. These findings can support health professionals in developing female-sensitive, culturally specific interventions to assist Chinese YBCSs and their families in increasing positive interactions and family resilience as well as quality of life. In addition, the findings are highly applicable to other female cancer survivors and their vulnerable families exposed to similar social and cultural contexts.
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http://dx.doi.org/10.1186/s12875-021-01476-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218435PMC
June 2021

Tracking the Electrocatalytic Activity of a Single Palladium Nanoparticle for the Hydrogen Evolution Reaction.

Chemistry 2021 Aug 5;27(46):11799-11803. Epub 2021 Jul 5.

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China.

The nanoparticle-based electrocatalysts' performance is directly related to their working conditions. In general, a number of nanoparticles are uncontrollably fixed on a millimetre-sized electrode for electrochemical measurements. However, it is hard to reveal the maximum electrocatalytic activity owing to the aggregation and detachment of nanoparticles on the electrode surface. To solve this problem, here, we take the hydrogen evolution reaction (HER) catalyzed by palladium nanoparticles (Pd NPs) as a model system to track the electrocatalytic activity of single Pd NPs by stochastic collision electrochemistry and ensemble electrochemistry, respectively. Compared with the nanoparticle fixed working condition, Pd NPs in the nanoparticle diffused working condition results in a 2-5 orders magnitude enhancement of electrocatalytic activity for HER at various bias potential. Stochastic collision electrochemistry with high temporal resolution gives further insights into the accurate study of NPs' electrocatalytic performance, enabling to dramatically enhance electrocatalytic efficiency.
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http://dx.doi.org/10.1002/chem.202101263DOI Listing
August 2021

Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of and .

Science 2021 06;372(6546):1085-1091

Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.

Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting and from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.
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http://dx.doi.org/10.1126/science.abf1008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386003PMC
June 2021

Circular RNA circMYBPC1 promotes skeletal muscle differentiation by targeting MyHC.

Mol Ther Nucleic Acids 2021 Jun 16;24:352-368. Epub 2021 Mar 16.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning 530004, China.

Skeletal muscle development is a complex and highly orchestrated biological process mediated by a series of myogenesis regulatory factors. Numerous studies have demonstrated that circular RNAs (circRNAs) are involved in muscle differentiation, but the exact molecular mechanisms involved remain unclear. Here, we analyzed the expression of circRNAs at the adult and embryo development stages of cattle . A stringent set of 1,318 circRNAs candidates were identified, and we found that 495 circRNAs were differentially expressed between embryonic and adult tissue libraries. We subsequently focused on one of the most downregulated circRNAs (using the adult stage expression as control), and this was named muscle differentiation-associated circular RNA (circMYBPC1). With RNA binding protein immunoprecipitation (RIP) and RNA pull-down assays, circMYBPC1 was identified to promote myoblast differentiation by directly binding miR-23a to relieve its inhibition on myosin heavy chain (). In addition, RIP assays demonstrated that circMYBPC1 could directly bind MyHC protein. observations also suggested that circMYBPC1 may stimulate skeletal muscle regeneration after muscle damage. These results revealed that the novel non-coding circRNA circMYBPC1 promotes differentiation of myoblasts and may promote skeletal muscle regeneration. Our results provided a basis for in-depth analysis of the role of circRNA in myogenesis and muscle diseases.
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http://dx.doi.org/10.1016/j.omtn.2021.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027698PMC
June 2021

Promoting Atomically Dispersed MnN Sites Sulfur Doping for Oxygen Reduction: Unveiling Intrinsic Activity and Degradation in Fuel Cells.

ACS Nano 2021 Apr 31;15(4):6886-6899. Epub 2021 Mar 31.

Giner Inc., Newton, Massachusetts 02466, United States.

Carbon supported and nitrogen coordinated single Mn site (Mn-N-C) catalysts are the most desirable platinum group metal (PGM)-free cathode catalysts for proton-exchange membrane fuel cells (PEMFCs) due to their insignificant Fenton reactions ( Fe), earth abundances ( Co), and encouraging activity and stability. However, current Mn-N-C catalysts suffer from high overpotential due to low intrinsic activity and less dense MnN sites. Herein, we present a sulfur-doped Mn-N-C catalyst (Mn-N-C-S) synthesized through an effective adsorption-pyrolysis process. Using electron microscopy and X-ray absorption spectroscopy (XAS) techniques, we verify the uniform dispersion of MnN sites and confirm the effect of S doping on the Mn-N coordination. The Mn-N-C-S catalyst exhibits a favorable oxygen reduction reaction (ORR) activity in acidic media relative to the S-free Mn-N-C catalyst. The corresponding membrane electrode assembly (MEA) generates enhanced performance with a peak power density of 500 mW cm under a realistic H/air environment. The constant voltage tests of fuel cells confirm the much-enhanced stability of the Mn-N-C-S catalyst compared to the Fe-N-C and Fe-N-C-S catalysts. The electron microscopy and Fourier transform XAS analyses provide insights into catalyst degradation associated with Mn oxidation and agglomeration. The theoretical calculation elucidates that the promoted ORR activity is mainly attributed to the spatial effect stemmed from the repulsive interaction between the ORR intermediates and adjacent S dopants.
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http://dx.doi.org/10.1021/acsnano.0c10637DOI Listing
April 2021

Alignment of single-cell RNA-seq samples without overcorrection using kernel density matching.

Genome Res 2021 04 19;31(4):698-712. Epub 2021 Mar 19.

Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.

Single-cell RNA sequencing (scRNA-seq) technology is poised to replace bulk cell RNA sequencing for many biological and medical applications as it allows users to measure gene expression levels in a cell type-specific manner. However, data produced by scRNA-seq often exhibit batch effects that can be specific to a cell type, to a sample, or to an experiment, which prevent integration or comparisons across multiple experiments. Here, we present Dmatch, a method that leverages an external expression atlas of human primary cells and kernel density matching to align multiple scRNA-seq experiments for downstream biological analysis. Dmatch facilitates alignment of scRNA-seq data sets with cell types that may overlap only partially and thus allows integration of multiple distinct scRNA-seq experiments to extract biological insights. In simulation, Dmatch compares favorably to other alignment methods, both in terms of reducing sample-specific clustering and in terms of avoiding overcorrection. When applied to scRNA-seq data collected from clinical samples in a healthy individual and five autoimmune disease patients, Dmatch enabled cell type-specific differential gene expression comparisons across biopsy sites and disease conditions and uncovered a shared population of pro-inflammatory monocytes across biopsy sites in RA patients. We further show that Dmatch increases the number of eQTLs mapped from population scRNA-seq data. Dmatch is fast, scalable, and improves the utility of scRNA-seq for several important applications. Dmatch is freely available online.
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http://dx.doi.org/10.1101/gr.261115.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015859PMC
April 2021

Evaluation of correlation between sagittal balance and plantar pressure distributions in adolescent idiopathic scoliosis: A pilot study.

Clin Biomech (Bristol, Avon) 2021 03 26;83:105308. Epub 2021 Feb 26.

Department of Orthopedics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, PR China. Electronic address:

Background: To evaluate the correlation between baropodometric parameters and sagittal parameters for adolescent idiopathic scoliosis.

Methods: 44 volunteers (7 males and 37 females) were recruited. All participants were diagnosed as adolescent idiopathic scoliosis by X-ray before baropodometric study. Sagittal parameters included thoracic kyphosis, lumbar lordosis, sagittal vertical axis, pelvic tilt, sacral slope and pelvic incidence. A static baropodometry was performed for each patient. The foot area was divided into four quadrants. The contact surface and weight percentage were measured.

Findings: Lumbar lordosis was positively correlated to pelvic incidence, sacral slope and (P < 0.001, P < 0.001, respectively). On the major curve side, pelvic tilt showed a positive correlation with all baropodometric parameters (P < 0.05) except forefoot weight percentage. Thoracic kyphosis showed negative correlations with contact surface and weight percentage of the forefoot (P = 0.04, 0.02 respectively) but no correlation with any rearfoot feature. Lumbar lordosis, sagittal vertical axis, pelvic incidence and sacral slope were not in correlation with plantar pressure. On the opposite side, sagittal profile showed no obvious correlation with any baropodometric parameter.

Interpretation: In scoliosis, sagittal balance is closely correlated to plantar pressure distributions. Baropodometry is a feasible method to assess sagittal balance.
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http://dx.doi.org/10.1016/j.clinbiomech.2021.105308DOI Listing
March 2021

Development of GPC3 and EGFR-dual-targeting chimeric antigen receptor-T cells for adoptive T cell therapy.

Am J Transl Res 2021 15;13(1):156-167. Epub 2021 Jan 15.

Department of Hematology and Oncology, Hwa Mei Hospital, University of Chinese Academy of Sciences Ningbo 315000, Zhejiang, China.

Adoptive transfer of T cells expressing specific anti-glypican-3 (GPC3) chimeric antigen receptors (CARs) has demonstrated therapeutic potential against hepatocellular carcinoma (HCC). However, normal tissues with low expression of neoplasm-associated antigens often show on-target, off-tumor toxicity. Previous studies have revealed that the development of HCC xenografts in mice could be inhibited effectively by GPC3-targeting CAR-T cells. However, these studies did not provide information regarding on-target, off-tumor toxicity. We hypothesized that on-target, off-tumor toxicity may decrease in dual-targeting CAR-T cells that co-express GPC3 with epidermal growth factor receptor (EGFR)-targeted CARs characterized by CD3ζ and 28BB expression. Our research confirmed that dual-targeting CAR-T (CARgpc3-egfr) cells exhibited similar proliferative ability and cytotoxicity to CARgpc3 T cells against GPC3+EGFR+ HCC . However, EGFR-targeting CAR-T (CARegfr) cells showed poor proliferation activity and cytotoxicity against GPC3+EGFR+ HCC cells, similar to mock CAR-T cells. CARgpc3 and CARgpc3-egfr T cells showed enhanced cytokine secretion compared to CARegfr and mock CAR-T cells . , tumor growth suppression was better for CARgpc3-egfr T cells than for CARgpc3 T cells in GPC3+EGFR+ HCC, while it was not observed for CARegfr or mock CAR-T cells. Taken together, our data indicated that dual-targeting CAR-T cells with two CARs against GPC3 and EGFR may maintain relatively effective anti-neoplasm functions in GPC3+EGFR+ HCC and , a strategy that may reduce off-tumor toxicity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847509PMC
January 2021

Circular RNA Profiling Reveals an Abundant circEch1 That Promotes Myogenesis and Differentiation of Bovine Skeletal Muscle.

J Agric Food Chem 2021 Jan 21;69(1):592-601. Epub 2020 Dec 21.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning 530004, China.

Beef is considered to be a good quality meat product because it contains linoleic acid and specific proteins, which can bring significant benefits to health. Circular RNAs (circRNAs) have been reported to regulate skeletal myogenesis. RNA-seq was used to investigate the circRNA molecular regulatory mechanisms with respect to differences in muscle quality between buffalo and cattle. A total of 10,449 circRNA candidates were detected, and 1128 of these were found to be differentially expressed between cattle and buffalo muscle tissue libraries. Differentially expressed 23 circRNAs were verified by qPCR. CircEch1, one of the most up-regulated circRNAs during muscle development, was subsequently characterized. CCK-8 (65.05 ± 2.33%, < 0.0001), EdU (72.99 ± 0.04%, < 0.001), and Western blotting assays showed that overexpression of circEch1 inhibited the proliferation of bovine myoblasts but promoted differentiation. studies suggested that circEch1 stimulates skeletal muscle regeneration. These results demonstrate that the novel regulator circEch1 induces myoblast differentiation and skeletal muscle regeneration. They also provide new insights into the mechanisms of circRNA regulation of beef quality.
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http://dx.doi.org/10.1021/acs.jafc.0c06400DOI Listing
January 2021

Development and validation of a risk prediction model and scoring system for post-endoscopic retrograde cholangiopancreatography pancreatitis.

Ann Transl Med 2020 Oct;8(20):1299

Department of Artificial intelligence, Ewell Technology Enterprise Institute, Hangzhou, China.

Background: A few models have been proposed for the prediction of the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), but many include factors that are not assessed routinely. Herein, we intend to develop and validate a predictive model for the occurrence of PEP.

Methods: Data of patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) from January 01, 2016 to May 16, 2019 (training set and internal test set) and from May 17, 2019 to December 25, 2019 (external test set) were retrospectively collected. The performance of the model was validated in the two validation cohorts.

Results: A total of 342 patients were included for the external test set, and 47 (13.7%) developed PEP. The variables included in the scoring system were gastrectomy history, high direct bilirubin (DBIL), high albumin (ALB), villous type of papillary orifice, nodular type of papillary orifice, pancreatic guidewire passages, precut sphincterotomy, and high operator experience. A total score >5 indicated high risk. In the external test set, the area under the curve (AUC) was 0.718, the sensitivity was 0.723, and the specificity was 0.676. In the external test set, the probability of PEP was 6.1%, 17.0%, and 37.5% in patients with low (<0), moderate (0-5), and high (>5) risk scores, respectively.

Conclusions: This study established a scoring system for predicting the risk of PEP using routinely measured clinical variables. Its application in routine work warrants further investigation.
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http://dx.doi.org/10.21037/atm-20-5769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661903PMC
October 2020

Aberrant regulation of RNA methylation during spermatogenesis.

Reprod Domest Anim 2021 Jan 1;56(1):3-11. Epub 2020 Dec 1.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning, China.

Natural modifications of cellular RNA include various chemical modifications, such as N6-methyladenosine (m A), which enable the orderly metabolism and function of RNA structural diversity, thereby affecting gene expression. Spermatogenesis is a complex differentiating developmental process, which includes the proliferation of spermatogonial stem cells, spermatocyte meiosis and sperm maturation. Emerging evidence has shown that RNA methylation can influence RNA splicing, exportation and translation, which are controlled in the male germline in order to ensure coordinated gene expression. In this review, we summarize the typical characteristics of different types of RNA methylation during the process of spermatogenesis. In particular, we emphasize the functions of the RNA methylation effectors during the male germ cell development.
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http://dx.doi.org/10.1111/rda.13856DOI Listing
January 2021

A G-quadruplex nanoswitch in the SGK1 promoter regulates isoform expression by K/Na balance and resveratrol binding.

Biochim Biophys Acta Gen Subj 2021 02 2;1865(2):129778. Epub 2020 Nov 2.

Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China. Electronic address:

Background: High sodium intake can up-regulate the level of renal serum- and glucocorticoid-inducible kinase-1 (SGK1), which plays a pivotal role in controlling blood pressure via activation of the epithelial sodium channel (ENaC), which can lead to salt-sensitive hypertension. Increased potassium intake, or a vegetarian diet, counteracts salt-sensitive hypertension, but the underlying mechanisms are not fully understood.

Methods: Bioinformatics and molecular modeling were used to identify G-quadruplex (G4) and their conformations in the SGK1 promoter. CD spectra and UV melting dynamics were measured to study the stability of G4 as influenced by potassium/sodium balance and resveratrol. RT-PCR and Western blot were employed to study the effects of potassium and resveratrol on the SGK1 isoform expression.

Results: The SGK1 gene encodes a G4 structure in the proximal upstream of promoter-2; the G4 structure is stabilized by potassium or resveratrol, but destabilized by sodium. Super-physiological levels of sodium stimulate the transcription of all SGK1 isoforms, whereas resveratrol or potassium supplementation inhibits the transcription of iso-2 and iso-3, but not iso-1.

Conclusions: Stabilizing the G4 by potassium or resveratrol induces alternative promoter usage and/or pre-mRNA splicing in the transcription of SGK1.

General Significance: Potassium/sodium ion balance or resveratrol binding can act to regulate G4 molecular switches for controlling SGK1 gene expression, thereby presenting a new avenue for drug development.
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http://dx.doi.org/10.1016/j.bbagen.2020.129778DOI Listing
February 2021

Establishment of multifactor predictive models for the occurrence and progression of cervical intraepithelial neoplasia.

BMC Cancer 2020 Sep 29;20(1):926. Epub 2020 Sep 29.

Guangxi Medical University affiliated Cancer Hospital, NO.71 Hedi Road Qingxiu Square, Nanning City, Guangxi Province, China.

Background: To study the risk factors involved in the occurrence and progression of cervical intraepithelial neoplasia (CIN) and to establish predictive models.

Methods: Genemania was used to build a gene network. Then, the core gene-related pathways associated with the occurrence and progression of CIN were screened in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) experiments were performed to verify the differential expression of the identified genes in different tissues. R language was used for predictive model establishment.

Results: A total of 10 genes were investigated in this study. A total of 30 cases of cervical squamous cell cancer (SCC), 52 cases of CIN and 38 cases of normal cervix were enrolled. Compared to CIN cases, the age of patients in the SCC group was older, the number of parities was greater, and the percentage of patients diagnosed with CINII+ by TCT was higher. The expression of TGFBR2, CSKN1A1, PRKCI and CTBP2 was significantly higher in the SCC groups. Compared to patients with normal cervix tissue, the percentage of patients who were HPV positive and were diagnosed with CINII+ by TCT was significantly higher. FOXO1 expression was significantly higher in CIN tissue, but TGFBR2 and CTBP2 expression was significantly lower in CIN tissue. The significantly different genes and clinical factors were included in the models.

Conclusions: Combination of clinical and significant genes to establish the random forest models can provide references to predict the occurrence and progression of CIN.
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http://dx.doi.org/10.1186/s12885-020-07265-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523359PMC
September 2020

Prevalence and Clinical Significance of Occult Fractures in the Extremities in Children.

Front Pediatr 2020 4;8:393. Epub 2020 Aug 4.

Department of Orthopedics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.

Diagnosis of occult fractures by initial plain radiographs remains challenging in children in the emergency room. This study was to assess the prevalence and distribution of occult fracture in children with acute extremities injuries (AEI) and clinical suspicion of fracture. We conducted a retrospective study to review the medical records of all pediatric patients with AEI in the orthopedic emergency room from January 1, 2017, to December 31, 2019. For patients with concerning history and physical examination but negative initial radiographs, we conducted the following three diagnostic strategies according to the choic of children's parents: immediate MRI scanning, [2] immediate CT scanning, or [3] empiric cast immobilization with orthopedic follow-up radiographs at 2 weeks post-injury (late radiographs). Prevalence and distribution of occult fracture were recorded. A total of 43,560 pediatric patients meet the inclusion criteria. A total of 4,916 fractures of the extremities were confirmed by initial plain radiographs, and 550 occult fractures were confirmed by immediate MRI, immediate CT, or late radiographs. The prevalence of occult fracture in the extremities was 10.1% (550/5,466). Supracondylar fractures were the most prevalent (2,325/5,466, 42.5%) but had the lowest rate of occult fractures (117/2,325, 5.0%). The highest rate of occult fracture was distal epiphyseal fracture of the tibia and fibula (49/145, 33.8%), but these had a relatively lower prevalence of fractures (145/5,466, 2.65%). We should be aware of the relative high prevalence of occult fractures in the extremities in children, especially when the injured site is in the high incidence area of occult fracture such as ankle.
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http://dx.doi.org/10.3389/fped.2020.00393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438767PMC
August 2020

Demystifying "drop-outs" in single-cell UMI data.

Genome Biol 2020 08 6;21(1):196. Epub 2020 Aug 6.

Department of Human Genetics and Department of Medicine, University of Chicago, Chicago, USA.

Many existing pipelines for scRNA-seq data apply pre-processing steps such as normalization or imputation to account for excessive zeros or "drop-outs." Here, we extensively analyze diverse UMI data sets to show that clustering should be the foremost step of the workflow. We observe that most drop-outs disappear once cell-type heterogeneity is resolved, while imputing or normalizing heterogeneous data can introduce unwanted noise. We propose a novel framework HIPPO (Heterogeneity-Inspired Pre-Processing tOol) that leverages zero proportions to explain cellular heterogeneity and integrates feature selection with iterative clustering. HIPPO leads to downstream analysis with greater flexibility and interpretability compared to alternatives.
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http://dx.doi.org/10.1186/s13059-020-02096-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412673PMC
August 2020

Allele-specific open chromatin in human iPSC neurons elucidates functional disease variants.

Science 2020 07;369(6503):561-565

Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.

Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, we reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. Using human induced pluripotent stem cell (iPSC)-derived neurons that model developing brains, we identified thousands of genetic variants exhibiting allele-specific open chromatin (ASoC). These neuronal ASoCs were partially driven by altered transcription factor binding, overrepresented in brain gene enhancers and expression quantitative trait loci, and frequently associated with distal genes through chromatin contacts. ASoCs were enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. This study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.
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http://dx.doi.org/10.1126/science.aay3983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773145PMC
July 2020

Clinical analysis of HPV58-positive cervical cancer.

Infect Agent Cancer 2020 5;15:38. Epub 2020 Jun 5.

Guangxi Medical University affiliated Cancer Hospital, NO.71 Hedi Road Qingxiu Square, Nanning City, Guangxi Province China.

Objective: To study the clinical features of HPV58-positive cervical cancer.

Methods: A retrospective analysis of 347 patients with HPV58- or HPV16 positive cervical cancer from the Department of Gynecology Tumor of Guangxi Medical University Affiliated Cancer Hospital was performed. Molecular hybridization was used to detect HPV genotypes. The clinical features, including age, pathology, and invasion, were compared between the HPV58 positive and HPV16 positive cervical cancer groups.

Results: A total of 347 patients were eligible for this study, and the proportion of patients who were with poorly differentiated cancer ( = 0.015) was significantly higher in the HPV58 positive group. HPV58 positivity was an independent risk factor for poorly differentiated cancer [HR 2.156, 95% confidence interval: 1.167-3.984,  = 0.014]. The percentage of uterus corps invasion is significantly lower in HPV58 ( = 0.041), but HPV58 positivity is the independent risk factor for uterus corps invasion [HR = 3.985, 95% confidence interval: 1.066-14.893,  = 0.040]. The overall survival of HPV58-positive cervical cancer patients with uterine corpus invasion was significantly lower ( = 0.000). The age of patients in the HPV58-positive cervical cancer at advanced stage was significantly older ( = 0.045).

Conclusions: HPV58-positive cervical cancer patients are at higher risk of poorly differentiated cancer and uterus corps invasion. The patients with HPV58 positive cervical cancer with uterus corps invasion may result a worse prognosis.
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http://dx.doi.org/10.1186/s13027-020-00303-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275583PMC
June 2020
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