Publications by authors named "Shan Zeng"

231 Publications

Analysis and Experimental Validation of Rheumatoid Arthritis Innate Immunity Gene CYFIP2 and Pan-Cancer.

Front Immunol 2022 11;13:954848. Epub 2022 Jul 11.

Department of Orthopaedics, The First Affiliated Hospital, Jinan University, Guangzhou, China.

Rheumatoid arthritis (RA) is a chronic, heterogeneous autoimmune disease. Its high disability rate has a serious impact on society and individuals, but there is still a lack of effective and reliable diagnostic markers and therapeutic targets for RA. In this study, we integrated RA patient information from three GEO databases for differential gene expression analysis. Additionally, we also obtained pan-cancer-related genes from the TCGA and GTEx databases. For RA-related differential genes, we performed functional enrichment analysis and constructed a weighted gene co-expression network (WGCNA). Then, we obtained 490 key genes by intersecting the significant module genes selected by WGCNA and the differential genes. After using the RanddomForest, SVM-REF, and LASSO three algorithms to analyze these key genes and take the intersection, based on the four core genes (BTN3A2, CYFIP2, ST8SIA1, and TYMS) that we found, we constructed an RA diagnosis. The nomogram model showed good reliability and validity after evaluation, and the ROC curves of the four genes showed that these four genes played an important role in the pathogenesis of RA. After further gene correlation analysis, immune infiltration analysis, and mouse gene expression validation, we finally selected CYFIP2 as the cut-in gene for pan-cancer analysis. The results of the pan-cancer analysis showed that CYFIP2 was closely related to the prognosis of patients with various tumors, the degree of immune cell infiltration, as well as TMB, MSI, and other indicators, suggesting that this gene may be a potential intervention target for human diseases including RA and tumors.
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http://dx.doi.org/10.3389/fimmu.2022.954848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311328PMC
July 2022

A Method for Detection of Corn Kernel Mildew Based on Co-Clustering Algorithm with Hyperspectral Image Technology.

Sensors (Basel) 2022 Jul 17;22(14). Epub 2022 Jul 17.

School of Mathematics & Computer Science, Wuhan Polytechnic University, Wuhan 430048, China.

Hyperspectral imaging can simultaneously acquire spectral and spatial information of the samples and is, therefore, widely applied in the non-destructive detection of grain quality. Supervised learning is the mainstream method of hyperspectral imaging for pixel-level detection of mildew in corn kernels, which requires a large number of training samples to establish the prediction or classification models. This paper presents an unsupervised redundant co-clustering algorithm (FCM-SC) based on multi-center fuzzy c-means (FCM) clustering and spectral clustering (SC), which can effectively detect non-uniformly distributed mildew in corn kernels. This algorithm first carries out fuzzy c-means clustering of sample features, extracts redundant cluster centers, merges the cluster centers by spectral clustering, and finally finds the category of corresponding cluster centers for each sample. It effectively solves the problems of the poor ability of the traditional fuzzy c-means clustering algorithm to classify the data with complex structure distribution and the complex calculation of the traditional spectral clustering algorithm. The experimental results demonstrated that the proposed algorithm could describe the complex structure of mildew distribution in corn kernels and exhibits higher stability, better anti-interference ability, generalization ability, and accuracy than the supervised classification model.
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http://dx.doi.org/10.3390/s22145333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315692PMC
July 2022

Activation of VIPR1 suppresses hepatocellular carcinoma progression by regulating arginine and pyrimidine metabolism.

Int J Biol Sci 2022 4;18(11):4341-4356. Epub 2022 Jul 4.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

Vasoactive intestinal polypeptide type-I receptor (VIPR1) overexpression has been reported in numerous types of malignancies and utilized to develop novel target therapeutics and radiolabeled VIP analogue-based tumor imaging technology, but its role in liver carcinogenesis has not been explored. In the current study, we investigated the role of the VIP/VIPR1 signaling in controlling hepatocellular carcinoma (HCC) progression. By analyzing clinical samples, we found the expression level of VIPR1 was downregulated in human HCC tissues, which was correlated with advanced clinical stages, tumor growth, recurrence, and poor outcomes of HCC clinically. and in studies revealed that activation of VIPR1 by VIP markedly inhibited HCC growth and metastasis. Intriguingly, transcriptome sequencing analyses revealed that activation of VIPR1 by VIP regulated arginine biosynthesis. Mechanistical studies in cultured HCC cells demonstrated that VIP treatment partially restored the expression of arginine anabolic key enzyme argininosuccinate synthase (ASS1), and to some extent, inhibited pyrimidine synthetic pathway by downregulating the activation of CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). VIP treatment upregulated ASS1 and subsequently suppressed CAD phosphorylation in an mTOR/p70S6K signaling dependent manner. Clinically, we found human HCC samples were associated with downregulation of ASS1 but upregulation of CAD phosphorylation, and that VIPR1 levels positively correlated with ASS1 levels and serum levels of urea, the end product of the urea cycle and arginine metabolism in HCC. Loss of VIPR1 expression in HCC facilitates CAD phosphorylation and tumor progression, and restoration of VIPR1 and treatment with the VIPR1 agonist may be a promising approach for HCC treatment.
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http://dx.doi.org/10.7150/ijbs.71134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295067PMC
July 2022

Pan-Cancer and Single-Cell Analysis Reveals CENPL as a Cancer Prognosis and Immune Infiltration-Related Biomarker.

Front Immunol 2022 30;13:916594. Epub 2022 Jun 30.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.

Background: Centromere protein L (CENPL) is an important member of the centromere protein (CENP) family. However, the correlation between CENPL expression and cancer development and immune infiltration has rarely been studied. Here, we studied the role of CENPL in pan-cancer and further verified the results in lung adenocarcinoma (LUAD) through experiments.

Methods: The CENPL expression level was studied with TIMER 2.0 and Oncomine databases. The potential value of CENPL as a diagnostic and prognostic biomarker in pan-cancer was evaluated with the TCGA database and GEPIA. The CENPL mutation character was analyzed using the cBioPortal database. The LinkedOmics and CancerSEA databases were used to carry out the function analysis of CENPL. The role of CENPL in immune infiltration was studied using the TIMER and TISIDB websites. Moreover, the expression of CENPL was detected through RT-qPCR and Western blotting. Immunohistochemistry was used to evaluate the infiltration level of CD8 T cells. Cell proliferation was detected by EdU and CCK8. A flow cytometer was used to analyze the influence of CENPL in cell cycle and apoptosis.

Results: CENPL was increased in most of the cancers. The upregulation and mutation of CENPL were associated with a poorer prognosis in many cancers. The results showed a significant positive correlation between CENPL and myeloid-derived suppressor cell (MDSC) infiltration and a negative correlation between CENPL and T-cell NK infiltration in most of the cancers. CENPL regulated cell proliferation and cell cycle, and was negatively correlated with the inflammation level of LUAD. The experiments suggested that CENPL was increased in LUAD tissue and cell lines. There was a negative correlation between CENPL expression and CD8 T-cell infiltration. The knockdown of CENPL significantly suppressed the expression of CDK2 and CCNE2, and induced G0/G1 arrest and apoptosis of LUAD.

Conclusions: CENPL may function as a potential biomarker and oncogene in pan-cancer, especially LUAD. Furthermore, CENPL was associated with immune cell infiltration in pan-cancer, providing a potential immune therapy target for tumor treatment.
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http://dx.doi.org/10.3389/fimmu.2022.916594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279617PMC
June 2022

Effectiveness and Safety of DOACs vs. Warfarin in Patients With Atrial Fibrillation and Frailty: A Systematic Review and Meta-Analysis.

Front Cardiovasc Med 2022 24;9:907197. Epub 2022 Jun 24.

Department of Geriatric, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Patients with atrial fibrillation (AF) and frailty are a considerable group in clinical practice. However, existing studies provide insufficient evidence of anticoagulation strategies for these patients. Therefore, we conducted a meta-analysis to determine the effectiveness and safety outcomes of direct oral anticoagulants (DOACs) for these patients.

Methods: Randomized controlled trials or observational studies reporting the data about the DOACs and warfarin therapy among frail AF patients were included. The search was performed in the PubMed and Embase databases up to March 2022. Frailty was defined using the most widely used claims-based frailty index or the cumulative deficit model-based frailty index.

Results: A total of 4 studies involving 835,520 patients were included. Compared with warfarin, DOACs therapy reduced the risks of stroke or systemic embolism (HR = 0.79, 95%CI: 0.69-0.90), ischemic stroke (HR = 0.79, 95%CI: 0.71-0.87), hemorrhagic stroke (HR = 0.52, 95%CI: 0.35-0.76), and all-cause death (HR = 0.90, 95%CI: 0.84-0.96). In safety outcomes, DOACs was significantly associated with reduced risks of major bleeding (HR = 0.79, 95%CI: 0.64-0.97) and intracranial hemorrhage (HR = 0.58, 95%CI: 0.52-0.65) compared to warfarin, but there were no statistically differences in gastrointestinal bleeding (HR = 0.97, 95%CI: 0.73-1.29).

Conclusions: DOACs exerted superior effectiveness and safety outcome than warfarin in AF patients with frailty.
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http://dx.doi.org/10.3389/fcvm.2022.907197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263568PMC
June 2022

PCBP-1 Regulates the Transcription and Alternative Splicing of Inflammation and Ubiquitination-Related Genes in PC12 Cell.

Front Aging Neurosci 2022 20;14:884837. Epub 2022 Jun 20.

Department of Neurology, People's Hospital of Xinjiang Uygur Autonomous Region, Ürümqi, China.

PCBP-1, a multifunctional RNA binding protein, is expressed in various human cell/tissue types and involved in post-transcriptional gene regulation. PCBP-1 has important roles in cellular Iron homeostasis, mitochondrial stability, and other cellular activities involved in the pathophysiological process of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). However, it remains enigmatic whether PCPB-1 is associated with the pathogenesis of PD. In this study, we cloned and constitutively overexpressed PCBP-1 in rat PC12 cells (PC12 cell is the common cell line studying neurodegenerative disease include PD). RNA-seq was performed to analyze PCBP-1-regulated differentially expressed genes (DEGs) and alternative splicing events (ASEs) between control and PCBP1-overexpressed cells. GO and KEGG pathway analyses were performed to identify functional DEGs and alternatively spliced genes. Consequently, we validated PCBP-1-regulated genes using RT-qPCR. Finally, we downloaded CLIP-seq data from GEO (GSE84700) to analyze the mechanisms of PCBP-1's regulation of gene expression and ASEs by revealing the binding profile of PCBP-1 on its target pre-mRNAs. Overexpression of PCBP-1 partially regulated the ASE and expression of genes enriched in neuroinflammation and protein ubiquitination, which were also associated with PD pathogenesis. Moreover, RT-qPCR assay verified the PCBP-1-modulated expression of neuroinflammatory genes, like , and alternative splicing (AS) of ubiquitination-related gene . Finally, CLIP-seq data analysis indicated that the first UC motif was the critical site for PCBP-1 binding to its targets. In this study, we provided evidence that PCBP-1 could regulate the expression of gene expression associated with neuroinflammation and AS of WWP-2 in relation to protein ubiquitination. These findings thus provided novel insights into the potential application of PCBP-1 as the disease pathophysiological or therapeutic target for neurodegenerative disease.
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http://dx.doi.org/10.3389/fnagi.2022.884837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251440PMC
June 2022

Novel insights into noncanonical open reading frames in cancer.

Biochim Biophys Acta Rev Cancer 2022 07 28;1877(4):188755. Epub 2022 Jun 28.

Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410008, China. Electronic address:

With technological advances, previously neglected noncanonical open reading frames (nORFs) are drawing ever-increasing attention. However, the translation potential of numerous putative nORFs remains elusive, and the functions of noncanonical peptides have not been systemically summarized. Moreover, the relationship between noncanonical peptides and their counterpart protein or RNA products remains elusive and the clinical implementation of noncanonical peptides has not been explored. In this review, we highlight how recent technological advances such as ribosome profiling, bioinformatics approaches and CRISPR/Cas9 facilitate the research of noncanonical peptides. We delineate the features of each nORF category and the evolutionary process underneath the nORFs. Most importantly, we summarize the diversified functions of noncanonical peptides in cancer based on their subcellular location, which reflect their extensive participation in key pathways and essential cellular activities in cancer cells. Meanwhile, the equilibrium between noncanonical peptides and their corresponding transcripts or counterpart products may be dysregulated under pathological states, which is essential for their roles in cancer. Lastly, we explore their underestimated potential in clinical application as diagnostic biomarkers and treatment targets against cancer.
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http://dx.doi.org/10.1016/j.bbcan.2022.188755DOI Listing
July 2022

CLP1 is a Prognosis-Related Biomarker and Correlates With Immune Infiltrates in Rheumatoid Arthritis.

Front Pharmacol 2022 1;13:827215. Epub 2022 Jun 1.

Department of Orthopaedics, The First Affiliated Hospital, Jinan University, Guangzhou, China.

Rheumatoid arthritis (RA) is a chronic, heterogeneous autoimmune disease with a high disability rate that seriously affects society and individuals. However, there is a lack of effective and reliable diagnostic markers and therapeutic targets. In this study, we identified diagnostic markers of RA based on RNA modification and explored its role as well as degree of immune cell infiltration. We used the gene expression profile data of three synovial tissues (GSE55235, GSE55457, GSE77298) from the Gene Expression Omnibus (GEO) database and the gene of 5 RNA modification genes (including m6A, m1A, m5C, APA, A-1), combined with cluster analysis, identified four RNA modifiers closely related to RA (YTHDC1, LRPPRC, NOP2, and CLP1) and five immune cells namely T cell CD8, CD4 memory resting, T cells regulatory (Tregs) Macrophages M0, and Neutrophils. Based on the LASSO regression algorithm, hub genes and immune cell prediction models were established respectively in RA and a nomogram based on the immune cell model was built. Around 4 key RNA modification regulator genes, miRNA-mRNA, mRNA-TF networks have been established, and GSEA-GO, KEGG-GSEA enrichment analysis has been carried out. Finally, CLP1 was established as an effective RA diagnostic marker, and was highly positively correlated with T cells follicular helper (Tfh) infiltration. On the other hand, highly negatively correlated with the expression of mast cells. In short, CLP1 may play a non-negligible role in the onset and development of RA by altering immune cell infiltration, and it is predicted to represent a novel target for RA clinical diagnosis and therapy.
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http://dx.doi.org/10.3389/fphar.2022.827215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201986PMC
June 2022

Transcription factor SNAI2 exerts pro-tumorigenic effects on glioma stem cells via PHLPP2-mediated Akt pathway.

Cell Death Dis 2022 Jun 2;13(6):516. Epub 2022 Jun 2.

Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, PR China.

The current study aimed to investigate the effects associated with SNAI2 on the proliferation of glioma stem cells (GSCs) to elucidate its underlying molecular mechanism in the development of glioma. The expression of Snail family transcriptional repressor 2 (SNAI2) in glioma tissues was initially predicted via bioinformatics analysis and subsequently confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), which revealed that SNAI2 was highly expressed in glioma tissues as well as GSCs, with an inverse correlation with overall glioma patient survival detected. Loss- and gain- of-function assays were performed to determine the roles of SNAI2 and pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) on GSC viability, proliferation and apoptosis. Data were obtained indicating that SNAI2 promoted the proliferation of GSCs, while overexpressed PHLPP2 brought about a contrasting trend. As detected by chromatin immunoprecipitation, RT-qPCR and agarose gel electrophoresis, SNAI2 bound to the promoter region of PHLPP2 and repressed the transcription of PHLPP2 while SNAI2 was found to inhibit PHLPP2 resulting in activation of the Akt pathway. Finally, the roles of SNAI2 and PHLPP2 were verified in glioma growth in nude mice xenografted with tumor. Taken together, the key findings of the present study suggest that SNAI2 may promote the proliferation of GSCs through activation of the Akt pathway by downregulating PHLPP2.
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http://dx.doi.org/10.1038/s41419-021-04481-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9163135PMC
June 2022

AMICA1 is a diagnostic and prognostic biomarker and induces immune cells infiltration by activating cGAS-STING signaling in lung adenocarcinoma.

Cancer Cell Int 2022 Mar 5;22(1):111. Epub 2022 Mar 5.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

Background: Adhesion molecule interacting with CXADR antigen 1 (AMICA1), also known as Junction Adhesion Molecule Like (JAML), a recently identified member of the JAMs family, plays a critical role in mediating cancer development and immune cells transmigration. However, AMICA1 has never been reported to be related to the genesis, development and immunotherapy effect of lung adenocarcinoma (LUAD). In this research, we investigated the role of AMICA1 in LUAD through bioinformatic analysis and in vitro experiments.

Methods: Bioinformatic analysis from TCGA and GEO databases were used to investigate the expression level of AMICA1 and the correlation between AMICA1 and clinical parameters in LUAD patients. The LinkedOmics database was analyzed to investigate the co-expression network of AMICA1. TIMER and TISIDB databases were used to analyze the correlation between AMICA1 expression and immune infiltration level. Except for bioinformatic analysis, the AMICA1 mRNA (26 patients) and protein level (6 patients) were also detected by real-time PCR and western blot. The infiltration level of CD8 T cells (15 patients) and PD1 T cells (13 patients) were detected by immunohistochemistry. The diagnostic value of AMICA1 was revealed by receiver operating characteristic (ROC) curves. The Spearman correlation coefficient was used to analyze the correlation between AMICA1 expression and CD8 T cells and PD1 T cells infiltration level.

Results: Bioinformatic data from public database and our data showed that AMICA1 was significantly downregulated in LUAD. Decreased AMICA1 expression in LUAD was associated with higher T stage, M stage and pathological stage. Kaplan-Meier survival analysis indicated that patients with low AMICA1 expression had a worse prognosis. ROC curves showed that AMICA1 had high diagnostic accuracy for LUAD patients. Multivariate Cox analysis further displayed that AMICA1 expression level was an independent prognostic factor for LUAD patients. Moreover, the expression of AMICA1 was significantly different in the immune cells subtype and was obviously linked to immune cells infiltration. In vitro experiments suggested that AMICA1 significantly suppressed the proliferation of LUAD cells and played an important role in activating cGAS-STING signaling.

Conclusions: Our study suggested that AMICA1 might function as a diagnostic and prognostic biomarker and significantly suppressed the proliferation of LUAD cells. Besides, AMICA1 is positively correlated with immune cells infiltration in LUAD, and cGAS-STING signaling might play an important role in the process.
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http://dx.doi.org/10.1186/s12935-022-02517-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8897931PMC
March 2022

TPFusion: Texture Preserving Fusion of Infrared and Visible Images via Dense Networks.

Entropy (Basel) 2022 Feb 19;24(2). Epub 2022 Feb 19.

School of Mathematics and Computer Science, Wuhan Polytechnic University, Wuhan 430023, China.

In this paper, we design an infrared (IR) and visible (VIS) image fusion via unsupervised dense networks, termed as TPFusion. Activity level measurements and fusion rules are indispensable parts of conventional image fusion methods. However, designing an appropriate fusion process is time-consuming and complicated. In recent years, deep learning-based methods are proposed to handle this problem. However, for multi-modality image fusion, using the same network cannot extract effective feature maps from source images that are obtained by different image sensors. In TPFusion, we can avoid this issue. At first, we extract the textural information of the source images. Then two densely connected networks are trained to fuse textural information and source image, respectively. By this way, we can preserve more textural details in the fused image. Moreover, loss functions we designed to constrain two densely connected convolutional networks are according to the characteristics of textural information and source images. Through our method, the fused image will obtain more textural information of source images. For proving the validity of our method, we implement comparison and ablation experiments from the qualitative and quantitative assessments. The ablation experiments prove the effectiveness of TPFusion. Being compared to existing advanced IR and VIS image fusion methods, our fusion results possess better fusion results in both objective and subjective aspects. To be specific, in qualitative comparisons, our fusion results have better contrast ratio and abundant textural details. In quantitative comparisons, TPFusion outperforms existing representative fusion methods.
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http://dx.doi.org/10.3390/e24020294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870949PMC
February 2022

Extracellular Vesicles Promote the Formation of Pre-Metastasis Niche in Gastric Cancer.

Front Immunol 2022 31;13:813015. Epub 2022 Jan 31.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.

Globally, gastric cancer (GC) ranks fourth in the incidence of malignant tumors. The early clinical manifestations of GC lack specificity. Most patients are already at an advanced stage when they are first diagnosed, and their late progression is mainly due to peritoneal metastasis. A pre-metastatic microenvironment is formed, before the macroscopic tumor metastasis. Extracellular vesicles (EVs) are nanovesicles released by cells into body fluids. Recent studies have shown that EVs can affect the tumor microenvironment by carrying cargos to participate in cell-to-cell communication. EVs derived from GC cells mediate the regulation of the pre-metastasis niche and act as a coordinator between tumor cells and normal stroma, immune cells, inflammatory cells, and tumor fibroblasts to promote tumor growth and metastasis. This review highlights the regulatory role of EVs in the pre-metastatic niche of GC and mulls EVs as a potential biomarker for liquid biopsy.
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http://dx.doi.org/10.3389/fimmu.2022.813015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841609PMC
March 2022

Identification of tumour immune infiltration-associated snoRNAs (TIIsno) for predicting prognosis and immune landscape in patients with colon cancer via a TIIsno score model.

EBioMedicine 2022 Feb 7;76:103866. Epub 2022 Feb 7.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China, 410008; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, China, 410008; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. Electronic address:

Background: Colon cancer (CC) is the leading cause of tumour-related death worldwide. SnoRNA plays a critical role in the tumour microenvironment. The tumour microenvironment can be shaped by tumour-infiltrating immune cells, which control the destiny of immunotherapy efficacy. This study uniquely focused on snoRNAs derived from immune cells to identify new biomarkers for immune landscape.

Methods: A novel computational framework was initiated for identifying tumour immune infiltration-associated snoRNAs (TIIsno) signatures and developed a TIIsno score model from integrative snoRNA profiling analysis of 21 purified immune cell lines, 43 colon cancer cell lines, and three datasets (training, test, real-world validation set).

Findings: Our study found that a high TIIsno score was associated with poor CC prognosis. TIIsno scores were seen to be negatively correlated with (I) the infiltration level of most immune cells, (II) the inhibitory immune checkpoints expression level, and (III) the immune score. These findings, taken together with the observation that TIIsno score is lower in MSI-H patients, suggests that patients with a low TIIsno score may have a better response to immunotherapy.

Interpretation: In conclusion, we successfully identified TIIsno and constructed a TIIsno score model, a new potential biomarker of immunotherapy response, which can effectively predict the prognosis of CC patients as well.

Funding: National Key R & D Program of China, National Natural Science Foundation of China, key projects from the Nature Science Foundation of Hunan Province, projects from Beijing CSCO Clinical Oncology Research Foundation, Fundamental Research Funds for the Central Universities of Central South University.
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http://dx.doi.org/10.1016/j.ebiom.2022.103866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844792PMC
February 2022

tRF3008A suppresses the progression and metastasis of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner.

J Exp Clin Cancer Res 2022 Jan 22;41(1):32. Epub 2022 Jan 22.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

Background: tRNA-derived fragments (tRFs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of tRFs to colorectal cancer (CRC) remain largely unknown.

Methods: tRF3008A (a tRFRNA derived from tRNA) was identified by RNA sequencing and validated by quantitative reverse transcription PCR. The role of tRF3008A in CRC progression was assessed both in vitro and in vivo, and its downstream target genes were identified and validated in CRC cells. RNA pull-down with mass spectrometry and AGO-RIP were used to confirm the interaction of tRF3008A and AGO proteins. The clinical implications of tRF3008A were assessed in CRC tissues and blood samples.

Results: The expression of tRF3008A was reduced in colorectal cancer, and its reduction was significantly correlated with advanced and metastatic disease in CRC. Patients with low tRF3008A expression showed significantly shorter DFS, and multivariate analysis identified tRF3008A as an independent prognostic biomarker in CRC. Functionally, tRF3008A inhibits the proliferation and migration of CRC in vivo and in vitro by repressing endogenous FOXK1, a positive regulator of the Wnt/β-catenin pathway. Mechanistically, tRF3008A binds to AGO proteins as a guide to destabilize oncogenic FOXK1 transcript.

Conclusions: tRF3008A suppresses the metastasis and progression of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner.
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http://dx.doi.org/10.1186/s13046-021-02190-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783529PMC
January 2022

Overexpression of XIAP inhibits cisplatin-induced hair cell loss.

Biochim Biophys Acta Mol Cell Res 2022 04 10;1869(4):119204. Epub 2022 Jan 10.

Department of Otorhinolaryngology-Head & Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai 200092, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200092, China. Electronic address:

Cisplatin is a platinum-containing drug with ototoxicity commonly used clinically and has significant efficacy against a variety of solid tumors. One of the most important mechanisms of ototoxicity is that cisplatin induces apoptosis of hair cells. According to relevant literature, X-linked inhibitor of apoptosis protein (XIAP, anti-apoptotic protein) could inhibit the apoptotic pathway. We hypothesized that this protein might protect cochlear hair cells from cisplatin-induced injury. To figure it out, we treated cochlea of normal mice with various concentrations of cisplatin to observe the response and morphology of hair cells and determine a reasonable concentration. Next, Western Blot and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) experiments were conducted to make an investigation about the expression of XIAP protein and mRNA. In addition, we constructed and identified XIAP overexpressing mice. Finally, we treated cochlear tissues of normal and overexpressing mice with cisplatin to investigate the cyto-protection of XIAP on hair cells, respectively. It was found that 50 μmol/L cisplatin resulted in significant loss and disorganization of hair cells, while simultaneously downregulating the protein and mRNA of XIAP. In XIAP overexpressing mice, the loss and disorganization of hair cells were significantly lessened. These results showed that XIAP can lessen cisplatin-induced hair cell loss and play a role in otoprotection.
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http://dx.doi.org/10.1016/j.bbamcr.2021.119204DOI Listing
April 2022

Is the Trial of Labor after Two Previous Cesarean Sections Contraindicated in China?

Biomed Environ Sci 2021 Dec;34(12):1005-1009

Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, Guangdong, China;Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou 510150, Guangdong, China.

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http://dx.doi.org/10.3967/bes2021.135DOI Listing
December 2021

Efficacy and Safety of Docetaxel and Sodium Cantharidinate Combination Either Agent Alone as Second-Line Treatment for Advanced/Metastatic NSCLC With Wild-Type or Unknown EGFR Status: An Open-Label, Randomized Controlled, Prospective, Multi-Center Phase III Trial (Cando-L1).

Front Oncol 2021 14;11:769037. Epub 2021 Dec 14.

Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China.

Second-line treatment options for advanced/metastatic non-small cell lung cancer (NSCLC) patients are limited. We aimed to evaluate the efficacy and safety of docetaxel/sodium cantharidinate combination . either agent alone as second-line treatment for advanced/metastatic NSCLC patients with wild-type or unknown EGFR status. A randomized, open-label, phase III study was performed at 12 institutions. Patients with failure of first-line platinum regimens were randomized to receive either single-agent sodium cantharidinate (SCA) or single-agent docetaxel (DOX) or docetaxel/sodium cantharidinate combination (CON). The primary endpoints were centrally confirmed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. A total of 148 patients were enrolled in our study between October 2016 and March 2020. After a median follow-up time of 8.02 months, no significant difference was observed among the three groups in ORR (SCA . DOX . CON: 6.00% . 8.33% . 10.00%, respectively; p=0.814) and DCR (74.00% . 52.00% . 62.50%, respectively; p=0.080). In additional, the mOS was significantly higher in the CON group, compared with the single-agent groups (7.27 . 5.03 . 9.83 months, respectively; p=0.035), while no significant differences were observed in terms of PFS (2.7 . 2.9 . 3.1 months, respectively; p=0.740). There was no significant difference in the baseline QoL scores between the three groups (p>0.05); after treatment, life quality in SCA and CON group was significantly better than that in the DOX group (p<0.05). Furthermore, the incidence of adverse events (AEs) in the SCA group was significantly lower (46.00 . 79.17 . 25.00%, respectively; p=0.038) and the incidence of grade ≥3 AEs was also significantly lower in the SCA group compared with the DOX and CON groups (10.00 . 82.00 . 30.00%, respectively; p=0.042). Single-agent SCA and single-agent DOX has similar therapeutic efficacy in the second-line treatment of advanced/metastatic NSCLC with wild-type or unknown EGFR status, but single-agent SCA has fewer AEs and better QoL. Also, SCA plus DOX can significantly improve OS and exerted a significant synergistic effect, with good safety and tolerance profile.
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http://dx.doi.org/10.3389/fonc.2021.769037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8715707PMC
December 2021

The suppression of Brd4 inhibits peripheral plasma cell differentiation and exhibits therapeutic potential for systemic lupus erythematosus.

Int Immunopharmacol 2022 Feb 28;103:108498. Epub 2021 Dec 28.

Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address:

The mechanisms that control B cell terminal differentiation remain undefined. Here, we investigate the role of bromodomain-containing protein 4 (Brd4) in regulating B cell differentiation and its therapeutic potential for B cell-mediated autoimmune diseases including systemic lupus erythematosus (SLE). We showed that Brd4 inhibitor PFI-1 suppressed plasmablast-mediated plasma cell differentiation in healthy human CD19 B cells. PFI-1 reduced IgG and IgM secretion in costimulation-induced human B cells. We also observed a reduced percentage of plasma cells in mice with B cell-specific deletion of the Brd4 gene (Brd4CD19-cre). Mechanistically, using the luciferase reporter assay and the chromatin immunoprecipitation, we explored that Brd4 regulates the expression of B lymphocyte-induced maturation protein 1 (BLIMP1), an important transcript factor that is involved in modulation of plasma cell differentiation. Interestingly, PFI-1 decreased the percentages of plasmablasts and plasma cells from patients with SLE. PFI-1 administration reduced the percentages of plasma cells, hypergammaglobulinemia, and attenuated nephritis in MRL/lpr lupus mice. Pristane-injected Brd4CD19-cre mice exhibited improved nephritis and reduced percentages of plasma cells. These findings suggest an essential factor of Brd4 in regulating plasma cell differentiation. Brd4 inhibition may be a potential strategy for the treatment of B cell-associated autoimmune disorders.
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http://dx.doi.org/10.1016/j.intimp.2021.108498DOI Listing
February 2022

Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients.

Cancer 2022 03 8;128(5):995-1003. Epub 2021 Dec 8.

People's Liberation Army Cancer Centre of Nanjing Bayi Hospital, Nanjing, China.

Background: KEYNOTE-063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second-line therapy in Asian patients with advanced programmed death ligand 1 (PD-L1)-positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer.

Methods: This randomized, open-label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/m of paclitaxel intravenously every week. Primary end points were overall survival (OS) and progression-free survival (PFS). Secondary end points were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and safety.

Results: Between February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE-061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4-10 months) with pembrolizumab versus 8 months (95% CI, 5-11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63-1.54). Median PFS was 2 months (95% CI, 1-3 months) with pembrolizumab versus 4 months (95% CI, 3-6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04-2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any-grade treatment-related adverse events occurred in 28 pembrolizumab-treated patients (60%) and 42 paclitaxel-treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively.

Conclusions: Definitive conclusions about the efficacy of second-line pembrolizumab in Asian patients with advanced PD-L1-positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE-061 trial.
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http://dx.doi.org/10.1002/cncr.34019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299889PMC
March 2022

CXCL13 Is an Indicator of Germinal Center Activity and Alloantibody Formation Following Transplantation.

Transplant Direct 2021 Dec 5;7(12):e785. Epub 2021 Nov 5.

Emory Transplant Center, Atlanta, GA.

Donor-specific antibodies (DSA) are a recognized cause of allograft injury, yet biomarkers that indicate their development posttransplant or guide management are not available. CXCL13 (chemokine [C-X-C motif] ligand 1) is a chemoattractant produced within secondary lymphoid organs necessary for germinal center (GC) and alloantibody formation. Perturbations in serum CXCL13 levels have been associated with humoral immune activity. Therefore, CXCL13 may correlate with the formation of HLA antibodies following transplantation.

Methods: A murine skin graft model was utilized to define the production and kinetics of CXCL13 in response to alloantigen. Human Tfh:B-cell in vitro cocultures were performed to evaluate CXCL13 production by human lymphocytes, and serum from healthy controls and human transplant recipients with and without de novo DSA was tested for CXCL13.

Results: CXCL13 was detectable in the blood of allografted mice and correlated with Tfh and GC B-cell responses. Greater CXCL13 expression was observed in the draining lymph nodes of allografted mice as compared with naïve or syngeneic graft recipients, and serum levels preceded the detection of DSA posttransplant. Similarly, productive human Tfh:B-cell interactions that led to plasmablast differentiation and IgG formation also exhibited CXCL13 expression. CXCL13 levels in human transplant recipients with de novo DSA were greater than in healthy controls and stable transplant patients and also correlated with the development of alloantibodies in a small cohort of serially monitored recipients.

Conclusions: CXCL13 indicates GC alloreactivity and alloantibody formation and correlated with DSA formation in kidney transplant recipients, thereby introducing CXCL13 as a potential biomarker for HLA antibodies.
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http://dx.doi.org/10.1097/TXD.0000000000001247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580198PMC
December 2021

Larotinib in patients with advanced and previously treated esophageal squamous cell carcinoma with epidermal growth factor receptor overexpression or amplification: an open-label, multicenter phase 1b study.

BMC Gastroenterol 2021 Oct 23;21(1):398. Epub 2021 Oct 23.

Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, No. 8 Dongda Avenue, Fengtai District, Beijing, 100071, China.

Background: Larotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This open-label, phase 1b study is aimed to evaluate the efficacy, safety of larotinib in patients with advanced esophageal squamous cell carcinoma (ESCC) with EGFR overexpression or amplification pretreated with one or more system regimens, and to recommend an appropriate dose for its further study.

Methods: Patients received larotinib orally at 3 doses (250, 300, 350 mg), once daily. Clinical response was evaluated every 8 weeks according to RECIST v1.1 criteria by both investigators and independent radiology review (IRC).

Results: 81 patients were enrolled. The investigator-assessed overall response rate (ORR) was 13.7% (10/73), all responses were observed in the 350 mg group of which ORR up to 20.0% (10/50), with 10 of them having EGFR overexpression and 4 having EGFR amplification. Per IRC assessment, ORR for all patients and 350 mg group were 13.9% (10/72) and 16.3% (8/50). In the 350 mg group, median overall survival (OS) and progression-free survival (PFS) were 8.0 (95% CI 4.9-10.2) months and 3.4 (95% CI 2.4-3.7) months, respectively. The most common treatment-related adverse events (TRAEs) were diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome, elevated AST/ALT, vomiting, similarly with other EGFR TKIs.

Conclusions: Larotinib demonstrated promising antitumor activity and manageable safety profiles in patients with pre-treated advanced ESCC with EGFR overexpression or amplification, especially at the dose of 350 mg, which showed better efficacy and acceptable safety. A phase 3 study is underway on 350 mg larotinib in ESCC patients with EGFR overexpression.

Trial Registration: This trial was retrospectively registered on 25/03/2019, NCT03888092. https://clinicaltrials.gov/ct2/show/NCT03888092 .
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http://dx.doi.org/10.1186/s12876-021-01982-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540164PMC
October 2021

The role of the tumor microbe microenvironment in the tumor immune microenvironment: bystander, activator, or inhibitor?

J Exp Clin Cancer Res 2021 Oct 16;40(1):327. Epub 2021 Oct 16.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

The efficacy of cancer immunotherapy largely depends on the tumor microenvironment, especially the tumor immune microenvironment. Emerging studies have claimed that microbes reside within tumor cells and immune cells, suggesting that these microbes can impact the state of the tumor immune microenvironment. For the first time, this review delineates the landscape of intra-tumoral microbes and their products, herein defined as the tumor microbe microenvironment. The role of the tumor microbe microenvironment in the tumor immune microenvironment is multifaceted: either as an immune activator, inhibitor, or bystander. The underlying mechanisms include: (I) the presentation of microbial antigens by cancer cells and immune cells, (II) microbial antigens mimicry shared with tumor antigens, (III) microbe-induced immunogenic cell death, (IV) microbial adjuvanticity mediated by pattern recognition receptors, (V) microbe-derived metabolites, and (VI) microbial stimulation of inhibitory checkpoints. The review further suggests the use of potential modulation strategies of the tumor microbe microenvironment to enhance the efficacy and reduce the adverse effects of checkpoint inhibitors. Lastly, the review highlights some critical questions awaiting to be answered in this field and provides possible solutions. Overall, the tumor microbe microenvironment modulates the tumor immune microenvironment, making it a potential target for improving immunotherapy. It is a novel field facing major challenges and deserves further exploration.
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http://dx.doi.org/10.1186/s13046-021-02128-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520212PMC
October 2021

Intratumor heterogeneity: the hidden barrier to immunotherapy against MSI tumors from the perspective of IFN-γ signaling and tumor-infiltrating lymphocytes.

J Hematol Oncol 2021 10 7;14(1):160. Epub 2021 Oct 7.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.

In this era of precision medicine, with the help of biomarkers, immunotherapy has significantly improved prognosis of many patients with malignant tumor. Deficient mismatch repair (dMMR)/microsatellite instability (MSI) status is used as a biomarker in clinical practice to predict favorable response to immunotherapy and prognosis. MSI is an important characteristic which facilitates mutation and improves the likelihood of a favorable response to immunotherapy. However, many patients with dMMR/MSI still respond poorly to immunotherapies, which partly results from intratumor heterogeneity propelled by dMMR/MSI. In this review, we discuss how dMMR/MSI facilitates mutations in tumor cells and generates intratumor heterogeneity, especially through type II interferon (IFN-γ) signaling and tumor-infiltrating lymphocytes (TILs). We discuss the mechanism of immunotherapy from the perspective of dMMR/MSI, molecular pathways and TILs, and we discuss how intratumor heterogeneity hinders the therapeutic effect of immunotherapy. Finally, we summarize present techniques and strategies to look at the tumor as a whole to design personalized regimes and achieve favorable prognosis.
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http://dx.doi.org/10.1186/s13045-021-01166-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499512PMC
October 2021

Orthotopic Versus Allotopic Implantation: Comparison of Radiological and Pathological Characteristics.

J Magn Reson Imaging 2022 04 5;55(4):1133-1140. Epub 2021 Oct 5.

Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China.

Background: In experimental animal models, implantation location might influence the heterogeneity and overall development of the tumor, leading to an interpretation bias.

Purpose: To investigate the effects of implantation location in experimental tumor model using magnetic resonance imaging (MRI) and pathological findings.

Study Type: Prospective.

Subjects: Forty-five breast cancer-bearing mice underwent orthotopic (N = 15) and heterotopic (intrahepatic [N = 15] and subcutaneous [N = 15]) implantation.

Field Strength/sequence: Sequences including: T1-weighted turbo spin echo sequence, T2-weighted blade sequence, diffusion-weighted imaging, pre- and post-contrast T1 mapping, multi-echo T2 mapping at 3.0 T.

Assessment: MRI was performed at 7, 14, and 21 days after implantation. Native T1, post-contrast T1, T2, and apparent diffusion coefficient (ADC) of tumors, the tumor volume and necrosis volume within tumor were obtained. Lymphocyte cells from H&E staining, Ki67-positive, and CD31-positive cells from immunohistochemistry were determined.

Statistical Tests: One-way analysis of variance and Spearman's rank correlation were performed. P value <0.05 was considered statistically significant.

Results: The tumor volume (intrahepatic vs. orthotopic vs. subcutaneous: 587.50 ± 77.62 mm vs. 814.00 ± 43.85 mm vs. 956.13 ± 119.22 mm ), necrosis volume within tumor (89.10 ± 26.60 mm vs. 292.41 ± 57.92 mm vs. 179.91 ± 31.73 mm , respectively), ADC at day 21 (543.41 ± 42.28 vs. 542.92 ± 99.67 vs. 369.83 ± 42.90, respectively), and post-contrast T1 at all timepoints (day 7: 442.00 ± 11.52 vs. 435.00 ± 22.90 vs. 394.33 ± 29.95; day 14: 459.00 ± 26.11 vs. 436.83 ± 26.01 vs. 377.00 ± 27.83; day 21: 463.50 ± 23.49 vs. 458.00 ± 34.28 vs. 375.00 ± 30.55) were significantly different between three groups. Necrosis volumes of subcutaneous and intrahepatic tumors were significantly lower than those of orthotopic tumors. The CD31-positive rate in the intrahepatic implantation was significantly higher than in orthotopic and subcutaneous groups. Necrosis volume (r = -0.71), ADC (r = -0.85), and post-contrast T1 (r = -0.75) were strongly correlated with vascular invasion index.

Data Conclusion: Orthotopic and heterotopic tumors have their unique growth kinetics, necrosis volume, and vascular invasion. Non-invasive MR quantitative parameters, including ADC and post-contrast T1, may reflect vascular invasion in mice.

Level Of Evidence: 1 TECHNICAL EFFICACY: Stage 3.
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http://dx.doi.org/10.1002/jmri.27940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291575PMC
April 2022

The efficacy of COVID-19 vaccines against the B.1.617.2 (delta) variant.

Mol Ther 2021 10 2;29(10):2890-2892. Epub 2021 Oct 2.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ymthe.2021.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486585PMC
October 2021

Association between long non-coding RNA (lncRNA) GAS5 polymorphism rs145204276 and cancer risk.

J Int Med Res 2021 Sep;49(9):3000605211039798

Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Objective: The long non-coding RNA (lncRNA) growth arrest‑specific transcript 5 (GAS5) plays an important role in various tumors, and an increasing number of studies have explored the association of the GAS5 rs145204276 polymorphism with cancer risk with inconclusive results.

Methods: PubMed, Medline, EMBASE, Cochrane databases, and Web of Science were searched, and nine studies involving 6107 cases and 7909 controls were deemed eligible. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the relationship between rs145204276 and cancer risk in six genetic models.

Results: The pooled results suggest that the variant allele del was not associated with overall cancer risk. However, the subgroup analysis showed that allele del was significantly associated with a 22% decreased risk of gastrointestinal cancer (OR = 0.78, 95% CI: 0.72-0.85). Both sensitivity analyses and trial sequential analyses (TSA) demonstrated that the subgroup results were reliable and robust. Moreover, False-Positive Report Probability (FPRP) analysis indicated that the results had true significant correlations.

Conclusion: These findings provide evidence that the GAS5 rs145204276 polymorphism is associated with the susceptibility to gastrointestinal cancer. Further studies with different ethnicities and larger sample sizes are warranted to confirm these results.
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http://dx.doi.org/10.1177/03000605211039798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447101PMC
September 2021

Efficacy and safety of PD-1/PD-L1 plus CTLA-4 antibodies ± other therapies in lung cancer: a systematic review and meta-analysis.

Eur J Hosp Pharm 2021 Sep 8. Epub 2021 Sep 8.

Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China

Purpose: To investigate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) plus cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies ± other therapies in patients with advanced lung cancer.

Methods: In accordance with the retrieval strategy, we searched electronic databases for randomised controlled trials testing PD-1/PD-L1 plus CTLA-4 antibodies in patients with lung cancer; RR (for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs)) from individual studies were calculated and pooled by using random-effects models or fixed-effects models; heterogeneity and publication bias analyses were also performed, using Review Manager 5.3 and Stata 15.1 for statistical analysis.

Results: We included six studies. Four different immune checkpoint inhibitors (nivolumab, pembrolizumab, durvalumab, tremelimumab) were used. Dual checkpoint inhibitors ± other therapies for advanced lung cancer showed significant improvements in ORR (RR 1.49, 95% CI 1.11 to 1.98; p=0.007), OS (HR 0.72, 95% CI 0.63 to 0.83; p<0.00001), and PFS (HR 0.72, 95% CI 0.63 to 0.82; p<0.00001). The subgroup analyses were consistent with the pooled results. The PD-L1 ≥1% (HR 0.67, 95% CI 0.54 to 0.82; p<0.0001) subgroup differences indicated a statistically significant subgroup effect, but the PD-L1 <1% subgroup (HR 0.88, 95% CI 0.75 to 1.05; p=0.15) was not statistically significant. The incidence of adverse events (grade ≥3) was lower than that of the control group (RR 0.90, 95% CI 0.80 to 1.02; p=0.09), but was not significant.

Conclusions: PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors ± other therapies can improve the ORR, OS and PFS of patients with advanced or metastatic lung cancer, but the incidence of adverse reactions is high although generally tolerable.

Prospero Registration: CRD42020149216.
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http://dx.doi.org/10.1136/ejhpharm-2021-002803DOI Listing
September 2021

Melanoma differentiation-Associated gene 5 protects against NASH in mice.

Hepatology 2022 04 13;75(4):924-938. Epub 2021 Dec 13.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

Background And Aims: NASH is a complicated disease characterized by hepatocyte steatosis, inflammation infiltration, and liver fibrosis. Accumulating evidence suggests that the innate immunity plays a key role in NASH progression. Here, we aimed to reveal the role of melanoma differentiation-associated gene 5 (MDA5, also known as Ifih1), a conventional innate immune regulator following viral infection, in the progression of NASH and investigate its underlying mechanism.

Approach And Results: We first examined the expression of MDA5 and found that MDA5 was markedly down-regulated in the livers with NASH in human individuals and mice models. MDA5 overexpression significantly inhibits the free fatty acid-induced lipid accumulation and inflammation in hepatocyte in vitro, whereas MDA5 knockdown promotes hepatocyte lipotoxicity. Using hepatocyte-specific Mda5 gene knockout and transgenic mice, we found that diet-induced hepatic steatosis, inflammation, and liver fibrosis were markedly exacerbated by Mda5 deficiency but suppressed by Mda5 overexpression. Mechanistically, we found that the activation of apoptosis signal-regulating kinase 1 (ASK1)-mitogen-activated protein kinase pathway was significantly inhibited by MDA5 but enhanced by MDA5 deletion. We further validated that MDA5 directly interacted with ASK1 and suppressed its N-terminal dimerization. Importantly, blockage of ASK1 with adenovirus-expressing dominant negative ASK1 obviously reversed the lipid accumulation and ASK1 pathway activation when Mda5 was knocked out.

Conclusions: These data indicate that MDA5 is an essential suppressor in NASH. The findings support MDA5 as a regulator of ASK1 and a promising therapeutic target for NASH.
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http://dx.doi.org/10.1002/hep.32139DOI Listing
April 2022

Pairwise Elastic Net Representation-Based Classification for Hyperspectral Image Classification.

Entropy (Basel) 2021 Jul 26;23(8). Epub 2021 Jul 26.

School of Mathematics and Computer Science, Wuhan Polytechnic University, Wuhan 430023, China.

The representation-based algorithm has raised a great interest in hyperspectral image (HSI) classification. l1-minimization-based sparse representation (SR) attempts to select a few atoms and cannot fully reflect within-class information, while l2-minimization-based collaborative representation (CR) tries to use all of the atoms leading to mixed-class information. Considering the above problems, we propose the pairwise elastic net representation-based classification (PENRC) method. PENRC combines the l1-norm and l2-norm penalties and introduces a new penalty term, including a similar matrix between dictionary atoms. This similar matrix enables the automatic grouping selection of highly correlated data to estimate more robust weight coefficients for better classification performance. To reduce computation cost and further improve classification accuracy, we use part of the atoms as a local adaptive dictionary rather than the entire training atoms. Furthermore, we consider the neighbor information of each pixel and propose a joint pairwise elastic net representation-based classification (J-PENRC) method. Experimental results on chosen hyperspectral data sets confirm that our proposed algorithms outperform the other state-of-the-art algorithms.
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http://dx.doi.org/10.3390/e23080956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392166PMC
July 2021
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