bluuebunny/crossref_metadata_2025 huggingface dataset:
A disease-related essential protein prediction model based on the transfer neural network
Authors: Chen Sisi , Huang Chiguo , Wang Lei , Zhou Shunxian
Published: January 2023

Essential proteins play important roles in the development and survival of organisms whose mutations are proven to be the drivers of common internal diseases having higher prevalence rates. Due to high costs of traditional biological experiments, an improved Transfer Neural Network (TNN) was designed to extract raw features from multiple biological information of proteins first, and then, based on the newly-constructed Transfer Neural Network, a novel computational model called TNNM was designed to infer essential proteins in this paper. Different from traditional Markov chain, since Transfer Neural Network adopted the gradient descent algorithm to automatically obtain the transition probability matrix, the prediction accuracy of TNNM was greatly improved. Moreover, additional antecedent memory coefficient and bias term were introduced in Transfer Neural Network, which further enhanced both the robustness and the non-linear expression ability of TNNM as well. Finally, in order to evaluate the identification performance of TNNM, intensive experiments have been executed based on two well-known public databases separately, and experimental results show that TNNM can achieve better performance than representative state-of-the-art prediction models in terms of both predictive accuracies and decline rate of accuracies. Therefore, TNNM may play an important role in key protein prediction in the future.
Machine learning in the development of targeting microRNAs in human disease
Authors: Luo Yuxun , Peng Li , Shan Wenyu , Sun Mengyue , Luo Lingyun , Liang Wei
Published: January 2023

A microRNA is a small, single-stranded, non-coding ribonucleic acid that plays a crucial role in RNA silencing and can regulate gene expression. With the in-depth study of miRNA in development and disease, miRNA has become an attractive target for novel therapeutic strategies. Exploring miRNA targeting therapy only through experiments is expensive and laborious, so it is essential to develop novel and efficient computational methods to narrow down the search. Recent advances in machine learning applied in biomedical informatics provide opportunities to explore miRNA-targeting drugs, thus promoting miRNA therapeutics. This review provides an overview of recent advancements in miRNA targeting therapeutic using machine learning. First, we mainly describe the basics of predicting miRNA targeting drugs, including pharmacogenomic data resources and data preprocessing. Then we present primary machine learning algorithms and elaborate their application in discovering relationships among miRNAs, drugs, and diseases. Along with the progress of miRNA targeting therapeutics, we finally analyze and discuss the current challenges and opportunities that machine learning confronts.
Identification of a tissue resident memory CD8 T cell-related risk score signature for colorectal cancer, the association with TME landscapes and therapeutic responses
Authors: Li Jiazheng , Yang Chao , Zheng Yongbin
Published: January 2023

Backgrounds: The tissue resident memory CD8 T cell (Trm) constitutes an important component of the local immunity. In the context of malignant tumors, mounting evidence also supports the potential anti-tumor property of this cell subset. Therefore, identification of Trm marker genes and exploration of the causative effect of Trm in shaping tumor microenvironment (TME) heterogeneity might provide novel insights for the comprehensive management of cancer patients.

Methods: By dissecting a single T cell transcriptome dataset, we acquired marker genes for Trm, which were latter applied to bulk RNA sequencing profiles of two large colorectal cancer (CRC) patient cohorts downloaded from TCGA and GEO databases. First, colorectal cancer patients were divided into different Trm clusters using consensus clustering algorithm. Then, we established a Trm-related gene (TRMRG) risk score signature and tested its efficacy in predicting prognosis for colorectal cancer patients. Moreover, a sequence of rigorous and robust analyses were also carried out to investigate the potential role of Trm-related gene risk score in tumor microenvironment remodeling and therapeutic utility of it in colorectal cancer treatment.

Results: A total of 49 Trm marker genes were identified by analyzing single cell RNA sequencing profiles. First, colorectal cancer patients were successfully classified into two Trm clusters with significant heterogeneity in functional enrichment patterns and tumor microenvironment landscapes. Then, we developed a Trm-related gene risk score signature and divided patients into different risk levels. High risk patients were characterized by attenuated immunogenicity, weakened sensitivity to immunotherapy, as well as adverse clinical outcomes. While low risk patients with advantages in survival exhibited increased immunogenicity, stronger metabolic activity and improved immunotherapeutic responses.

Conclusion: Through combinatorial analysis of single cell and bulk RNA sequencing data, the present study identified Trm to play a non-negligible role in regulating the complexity and heterogeneity of tumor microenvironment for colorectal cancer. Moreover, the Trm-related gene risk score signature developed currently was corroborated to be tightly correlated with prognosis and therapeutic responses of colorectal cancer patients, thus exhibiting potential application value for clinical practice.
Mapping of a QTL associated with sucrose content in peanut kernels using BSA-seq
Authors: Guo Junjia , Qi Feiyan , Qin Li , Zhang Maoning , Sun Ziqi , Li Hongyan , Cui Mengjie , Zhang Mengyuan , Li Chenyu , Li Xiaona , Zhao Qi , Luo Dandan , Tian Mengdi , Liu Hua , Xu Jing , Miao Lijuan , Huang Bingyan , Dong Wenzhao , Han Suoyi , Zhang Xinyou
Published: January 2023

As an important factor affecting the edible quality of peanut kernels, sucrose content is a complex quantitative trait regulated by multiple factors. In this study, an F2 segregating population and a recombinant inbred line (RIL) population, derived from a cross between the high sucrose content variety Jihuatian 1 and the low sucrose content line PI478819, were used as materials to map a quantitative trait locus (QTL) associated with sucrose content in peanut kernels. Four QTLs were initially located on chromosomes A03 and A06 based on BSA-seq technology, and multiple kompetitive allele-specific PCR markers were developed based on single-nucleotide polymorphisms (SNPs) in the intervals. The markers were genotyped in the RIL population and finely mapped to a stable QTL, qSUCA06, located on chromosome A06 within a 0.29-Mb physical genomic interval (112367085–112662675 bp), which accounted for 31.95%–41.05% of the phenotypic variance explained. SNP and insertion/deletion annotations were performed on genes in the candidate interval, and having screened out those genes with mutations in exons, candidate genes were verified by qRT-PCR. The results revealed that Arahy.Y2LWD9 may be the main gene regulating sucrose content. The QTL identified in this study will not only contribute to marker-assisted breeding for improvement of peanut sucrose content but also paves the way for identifying gene function.
Case report: A third variant in the 5′ UTR of TWIST1 creates a novel upstream translation initiation site in a child with Saethre-Chotzen syndrome
Authors: Diaz-Gonzalez Francisca , Sacedo-Gutiérrez Javier M. , Twigg Stephen R. F. , Calpena Eduardo , Carceller-Benito Fernando E. , Parrón-Pajares Manuel , Santos-Simarro Fernando , Heath Karen E.
Published: January 2023

Introduction: Saethre-Chotzen syndrome, a craniosynostosis syndrome characterized by the premature closure of the coronal sutures, dysmorphic facial features and limb anomalies, is caused by haploinsufficiency of TWIST1. Although the majority of variants localize in the coding region of the gene, two variants in the 5′ UTR have been recently reported to generate novel upstream initiation codons.

Methods: Skeletal dysplasia Next-generation sequencing (NGS) panel was used for genetic analysis in a patient with bicoronal synostosis, facial dysmorphisms and limb anomalies. The variant pathogenicity was assessed by a luciferase reporter promoter assay.

Results: Here, we describe the identification of a third ATG-creating de novo variant, c.-18C>T, in the 5′ UTR of TWIST1 in the patient with a clinical diagnosis of Saethre-Chotzen syndrome. It was predicted to create an out-of-frame new upstream translation initiation codon resulting in a 40 amino acid larger functionally inactive protein. We performed luciferase reporter promoter assays to demonstrate that the variant does indeed reduce translation from the main open reading frame.

Conclusion: This is the third variant identified in this region and confirms the introduction of upstream ATGs in the 5′ UTR of TWIST1 as a pathogenic mechanism in Saethre-Chotzen syndrome. This case report shows the necessity for performing functional characterization of variants of unknown significance within national health services.
Relationship between the image characteristics of artificial intelligence and EGFR gene mutation in lung adenocarcinoma
Authors: Zhou Guoping , Xu Shuhua , Liu Xiaoli , Ge Jingjun , He Qiyu , Cao Weikang , Ding Junning , Kai Xinghua
Published: January 2023

Lung Adenocarcinoma (LUAD) is a kind of Lung Cancer (LCA) with high incidence rate, which is very harmful to human body. It is hidden in the human body and is not easy to be discovered, so it brings great inconvenience to the treatment of LUAD. Artificial Intelligence (AI) technology provides technical support for the diagnosis and treatment of LUAD and has great application space in intelligent medicine. In this paper, 164 patients with primary LUAD who underwent surgery in Hospital A from January 2020 to December 2021 were selected as the study subjects, and the correlation between the imaging characteristics of LUAD and Epidermal Growth Factor Receptor (EGFR) gene mutation was analyzed. Finally, the conclusion was drawn. In terms of the study on the correlation between EGFR mutation of LUAD and the imaging characteristics of Computed Tomography (CT), it was concluded that there were significant differences between the patient’s sex, smoking history, pulmonary nodule morphology and the EGFR gene, and there was no significant difference between the patient’s tumor size and EGFR gene; in the study of the relationship between EGFR gene mutation and CT signs of LUAD lesions, it was found that there were significant differences between the symptoms of cavity sign, hair prick sign and chest depression sign and EGFR gene, but there was no significant difference between the symptoms of lobulation sign and EGFR gene; in the study of pathological subtype and EGFR gene mutation status of LUAD patients, it was concluded that the pathological subtype was mainly micropapillary. The mutation rate was 44.44%, which was the highest; in terms of CT manifestations of adjacent structures of lung cancer and the study of EGFR gene mutation status, it was found that there was a statistical difference between the tumor with vascular convergence sign and EGFR gene mutation, and pleural effusion, pericardial effusion, pleural thickening and other signs in tumor imaging were not significantly associated with EGFR gene mutation; in terms of the study of CT manifestations of adjacent structures of LCA and EGFR gene mutation status, it was concluded that pleural effusion, pericardial effusion, pleural thickening and other signs in tumor images were not significantly associated with EGFR gene mutation; in terms of analysis and cure of LUAD, it was concluded that the cure rate of patients was relatively high, and only a few people died of ineffective treatment. This paper provided a reference for the field of intelligent medicine and physical health.
A classification method of gastric cancer subtype based on residual graph convolution network
Authors: Liu Can , Duan Yuchen , Zhou Qingqing , Wang Yongkang , Gao Yong , Kan Hongxing , Hu Jili
Published: January 2023

Background: Clinical diagnosis and treatment of tumors are greatly complicated by their heterogeneity, and the subtype classification of cancer frequently plays a significant role in the subsequent treatment of tumors. Presently, the majority of studies rely far too heavily on gene expression data, omitting the enormous power of multi-omics fusion data and the potential for patient similarities.

Method: In this study, we created a gastric cancer subtype classification model called RRGCN based on residual graph convolutional network (GCN) using multi-omics fusion data and patient similarity network. Given the multi-omics data’s high dimensionality, we built an artificial neural network Autoencoder (AE) to reduce the dimensionality of the data and extract hidden layer features. The model is then built using the feature data. In addition, we computed the correlation between patients using the Pearson correlation coefficient, and this relationship between patients forms the edge of the graph structure. Four graph convolutional network layers and two residual networks with skip connections make up RRGCN, which reduces the amount of information lost during transmission between layers and prevents model degradation.

Results: The results show that RRGCN significantly outperforms other classification methods with an accuracy as high as 0.87 when compared to four other traditional machine learning methods and deep learning models.

Conclusion: In terms of subtype classification, RRGCN excels in all areas and has the potential to offer fresh perspectives on disease mechanisms and disease progression. It has the potential to be used for a broader range of disorders and to aid in clinical diagnosis.
Immune-related gene signature associates with immune landscape and predicts prognosis accurately in patients with skin cutaneous melanoma
Authors: Shen Xin , Shang Lifeng , Han Junwei , Zhang Yi , Niu Wenkai , Liu Haiwang , Shi Hai
Published: January 2023

Skin cutaneous melanoma (SKCM) is the skin cancer that causes the highest number of deaths worldwide. There is growing evidence that the tumour immune microenvironment is associated with cancer prognosis, however, there is little research on the role of immune status in melanoma prognosis. In this study, data on patients with Skin cutaneous melanoma were downloaded from the GEO, TCGA, and GTEx databases. Genes associated with the immune pathway were screened from published papers and lncRNAs associated with them were identified. We performed immune microenvironment and functional enrichment analyses. The analysis was followed by applying univariate/multivariate Cox regression algorithms to finally identify three lncRNAs associated with the immune pathway for the construction of prognostic prediction models (CXCL10, RXRG, and SCG2). This stepwise downscaling method, which finally screens out prognostic factors and key genes and then uses them to build a risk model, has excellent predictive power. According to analyses of the model’s reliability, it was able to differentiate the prognostic value and continued existence of Skin cutaneous melanoma patient populations more effectively. This study is an analysis of the immune pathway that leads lncRNAs in Skin cutaneous melanoma in an effort to open up new treatment avenues for Skin cutaneous melanoma.
Single-cell omics: A new direction for functional genetic research in human diseases and animal models
Authors: Kong Siyuan , Li Rongrong , Tian Yunhan , Zhang Yaqiu , Lu Yuhui , Ou Qiaoer , Gao Peiwen , Li Kui , Zhang Yubo
Published: January 2023

Over the past decade, with the development of high-throughput single-cell sequencing technology, single-cell omics has been emerged as a powerful tool to understand the molecular basis of cellular mechanisms and refine our knowledge of diverse cell states. They can reveal the heterogeneity at different genetic layers and elucidate their associations by multiple omics analysis, providing a more comprehensive genetic map of biological regulatory networks. In the post-GWAS era, the molecular biological mechanisms influencing human diseases will be further elucidated by single-cell omics. This review mainly summarizes the development and trend of single-cell omics. This involves single-cell omics technologies, single-cell multi-omics technologies, multiple omics data integration methods, applications in various human organs and diseases, classic laboratory cell lines, and animal disease models. The review will reveal some perspectives for elucidating human diseases and constructing animal models.
RNA Pol III promoters—key players in precisely targeted plant genome editing
Authors: Kor Sakshi Dharmendra , Chowdhury Naimisha , Keot Ajay Kumar , Yogendra Kalenahalli , Chikkaputtaiah Channakeshavaiah , Sudhakar Reddy Palakolanu
Published: January 2023

The clustered regularly interspaced short palindrome repeat (CRISPR)/CRISPR-associated protein Cas) system is a powerful and highly precise gene-editing tool in basic and applied research for crop improvement programs. CRISPR/Cas tool is being extensively used in plants to improve crop yield, quality, and nutritional value and make them tolerant to environmental stresses. CRISPR/Cas system consists of a Cas protein with DNA endonuclease activity and one CRISPR RNA transcript that is processed to form one or several short guide RNAs that direct Cas9 to the target DNA sequence. The expression levels of Cas proteins and gRNAs significantly influence the editing efficiency of CRISPR/Cas-mediated genome editing. This review focuses on insights into RNA Pol III promoters and their types that govern the expression levels of sgRNA in the CRISPR/Cas system. We discussed Pol III promoters structural and functional characteristics and their comparison with Pol II promoters. Further, the use of synthetic promoters to increase the targeting efficiency and overcome the structural, functional, and expressional limitations of RNA Pol III promoters has been discussed. Our review reports various studies that illustrate the use of endogenous U6/U3 promoters for improving editing efficiency in plants and the applicative approach of species-specific RNA pol III promoters for genome editing in model crops like Arabidopsis and tobacco, cereals, legumes, oilseed, and horticultural crops. We further highlight the significance of optimizing these species-specific promoters’ systematic identification and validation for crop improvement and biotic and abiotic stress tolerance through CRISPR/Cas mediated genome editing.
SDHB exon 1 deletion: A recurrent germline mutation in Colombian patients with pheochromocytomas and paragangliomas
Authors: Manotas María Carolina , Rivera Ana Lucía , Gómez Ana Milena , Abisambra Patricia , Guevara Gonzalo , Medina Vilma , Tapiero Sandra , Huertas Antonio , Riaño-Moreno Julián , Mejía Juan Carlos , Gonzalez-Clavijo Angélica María , Tapiero-García Mireya , Cuéllar-Cuéllar Andrés Arturo , Fierro-Maya Luis Felipe , Sanabria-Salas María Carolina
Published: January 2023

Pheochromocytomas (PCCs) and paragangliomas (PGLs) (known as PPGL in combination) are rare neuroendocrine tumors of the adrenal medulla and extra-adrenal ganglia. About 40% of the patients with PPGL have a hereditary predisposition. Here we present a case-series of 19 unrelated Colombian patients with a clinical diagnosis of PPGL tumors that underwent germline genetic testing as part of the Hereditary Cancer Program developed at the Instituto Nacional de Cancerología, Colombia (INC-C), the largest reference cancer center in the country. Ten of 19 patients (52.63%) were identified as carriers of a pathogenic/likely pathogenic (P/LP) germline variant in a known susceptibility gene. The majority of the P/LP variants were in the SDHB gene (9/10): one corresponded to a nonsense variant c.268C>T (p.Arg90*) and eight cases were found to be carriers of a recurrent CNV consisting of a large deletion of one copy of exon 1, explaining 42% (8/19) of all the affected cases. Only one additional case was found to be a carrier of a missense mutation in the VHL gene: c.355T>C (p.Phe119Leu). Our study highlights the major role of SDHB in Colombian patients with a clinical diagnosis of PGL/PCC tumors and supports the recommendation of including the analysis of large deletions/duplications of the SDHB gene as part of the genetic counselling to improve the detection rate of hereditary cases and their clinical care.
Case report: Amphiphysin-IgG autoimmunity: a paraneoplastic presentation of appendiceal goblet cell carcinoma
Authors: Lin Jingfang , Yu Tianping , Wang Minjin , Wang Jierui , Li Jinmei
Published: January 2023

Background

Appendiceal goblet cell carcinoma (aGCC) is a rare neoplasm with mixed endocrine and exocrine features. No paraneoplastic neurological syndromes or autoantibodies have been identified in cases of aGCC or even appendiceal tumors. Amphiphysin-immunoglobulin G (IgG) autoimmunity was first described in stiff-person syndrome with breast cancer. We firstly described the clinical course and pathological findings of a patient with aGCC-associated amphiphysin-IgG autoimmunity.

Case presentation

A 54-year-old man who developed aGCC was admitted for acute disturbance of consciousness, psychiatric symptoms, cognitive impairment, seizure and hypotension. Amphiphysin-IgG was detected in the patient’s serum and CSF by immunoblotting and tissue-based indirect immunofluorescence assay confirming the diagnosis of definite paraneoplastic amphiphysin-IgG-positive encephalitis. Histopathology revealed amphiphysin protein expression and accompanying immune cell infiltration (predominantly CD20+ B cells, CD3+ and CD8+ T cells) within the tumor tissue, suggesting a possible paraneoplastic origin of amphiphysin-associated paraneoplastic neurological syndromes (PNSs) in this case. Although the patient’s symptoms resolved after high-dose corticosteroid therapy, he experienced recurrence 6 months later, manifesting as paraneoplastic cerebellar dysfunction. Despite treatment with IV cyclophosphamide and oral mycophenolate mofetil, no improvement was noted.

Conclusions

This case suggests that aGCC may trigger amphiphysin-IgG autoimmunity.
Single-cell transcriptome analysis reveals heterogeneity and convergence of the tumor microenvironment in colorectal cancer
Authors: Xie Siyuan , Cai Yangke , Chen Delong , Xiang Yu , Cai Wen , Mao Jianshan , Ye Jun
Published: January 2023

Introduction

Colorectal cancer (CRC) ranks second for mortality and third for morbidity among the most commonly diagnosed cancers worldwide. We aimed to investigate the heterogeneity and convergence of tumor microenvironment (TME) in CRC.

Methods

We analyzed the single-cell RNA sequencing data obtained from the Gene Expression Omnibus (GEO) database and identified 8 major cell types and 25 subgroups derived from tumor, para-tumor and peripheral blood.

Results

In this study, we found that there were significant differences in metabolic patterns, immunophenotypes and transcription factor (TF) regulatory patterns among different subgroups of each major cell type. However, subgroups manifested similar lipid metabolic patterns, immunosuppressive functions and TFs module at the end of the differentiation trajectory in CD8+ T cells, myeloid cells and Fibroblasts. Meanwhile, TFs regulated lipid metabolism and immunosuppressive ligand-receptor pairs were detected by tracing the differentiation trajectory. Based on the cell subgroup fractions calculated by CIBERSORTx and bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA), we constructed an immune risk model and clinical risk model of CRC which presented excellent prognostic value.

Conclusion

This study identified that the differentiation was accompanied by remodeling of lipid metabolism and suppression of immune function, which suggest that lipid remodeling may be an important trigger of immunosuppression. More importantly, our work provides a new perspective for understanding the heterogeneity and convergence of the TME and will aid the development of prognosis and immunotherapies of CRC patients.
Functional status and spatial interaction of T cell subsets driven by specific tumor microenvironment correlate with recurrence of non-small cell lung cancer
Authors: Yang Liying , Zhang Wei , Sun Jujie , Yang Guanqun , Cai Siqi , Sun Fenghao , Xing Ligang , Sun Xiaorong
Published: January 2023

Background

The anti-tumoral or pro-tumoral roles of CD4+ and CD8+ T cells typify the complexity of T cell subsets function in cancer. In the non-small cell lung cancer (NSCLC), the density and topology of distinct T cell phenotypes at the tumor center (TC) versus the invasive margin (IM) are largely unknown. Here, we investigated T cell subsets density and distribution within TC and IM regions in NSCLC and its impact on the prognosis.

Methods

We performed multiplex immunofluorescence using a tissue microarray of samples from 99 patients with locally advanced NSCLC to elucidate the distributions of tumor cell, T cell subpopulations (CD4/conventional CD4/regulatory CD4/CD8/cytotoxic CD8/pre-dysfunctional CD8/dysfunctional CD8), microvessel density (MVD), cancer-associated fibroblasts (CAFs) and hypoxia-inducible factor-1α (HIF-1α) in TC and IM tissues. Cell-to-cell nearest neighbor distances and interactions were analyzed using the phenoptrreports R package. Cox regression was used to evaluate the associations between T cell subsets density and proximity to tumor cells and recurrence-free survival (RFS). Correlations between different cell subsets were examined by Spearman’s or Kruskal-Wallis tests.

Results

In the locally advanced NSCLC, the proportion of tumor cells and CAFs in IM is lower than in the TC, while MVD, CD4+, and CD8+ T lymphocytes were increased, and tumor cells were closer to T lymphocytes and their subsets. The density and proximity of CD4+ and CD8+ T cells in the TC and IM regions were not associated with RFS, but in the IM area, increased density of dysfunctional CD8 and closer regulatory CD4 to tumor cells were independent risk factors for recurrence (HR were 3.536 and 2.884, respectively), and were positively correlated with HIF-1α+CD8 (r = 0.41, P = 0.000) and CAFs (P = 0.017), respectively.s

Conclusions

In locally advanced NSCLC, the functional status of T cells in the IM region is closely related to recurrence. The density of dysfunctional CD8 and the proximity of regulatory CD4 to tumor cells were independent risk factors for recurrence, and are positively correlated with the hypoxia response of CD8+ T cells and CAFs. Targeting hypoxia or CAFs is expected to further sensitize therapy.
Apoptosis in megakaryocytes: Safeguard and threat for thrombopoiesis
Authors: Yang Shuo , Wang Long , Wu Yuesong , Wu Anguo , Huang Feihong , Tang Xiaoqin , Kantawong Fahsai , Anuchapreeda Songyot , Qin Dalian , Mei Qibing , Chen Jianping , Huang Xinwu , Zhang Chunxiang , Wu Jianming
Published: January 2023

Platelets, generated from precursor megakaryocytes (MKs), are central mediators of hemostasis and thrombosis. The process of thrombopoiesis is extremely complex, regulated by multiple factors, and related to many cellular events including apoptosis. However, the role of apoptosis in thrombopoiesis has been controversial for many years. Some researchers believe that apoptosis is an ally of thrombopoiesis and platelets production is apoptosis-dependent, while others have suggested that apoptosis is dispensable for thrombopoiesis, and is even inhibited during this process. In this review, we will focus on this conflict, discuss the relationship between megakaryocytopoiesis, thrombopoiesis and apoptosis. In addition, we also consider why such a vast number of studies draw opposite conclusions of the role of apoptosis in thrombopoiesis, and try to figure out the truth behind the mystery. This review provides more comprehensive insights into the relationship between megakaryocytopoiesis, thrombopoiesis, and apoptosis and finds some clues for the possible pathological mechanisms of platelet disorders caused by abnormal apoptosis.
Deep dive into the immune response against murine mesothelioma permits design of novel anti-mesothelioma therapeutics
Authors: Stern Esther , Caruso Stefano , Meiller Clément , Mishalian Inbal , Hirsch Theo Z. , Bayard Quentin , Tadmor Carmit T. , Wald Hanna , Jean Didier , Wald Ori
Published: January 2023

Given the need to improve the efficacy of standard-of-care immunotherapy (anti-CTLA-4 + anti-PD-1) in human malignant pleural mesothelioma (hMPM), we thoroughly characterized the immunobiology of the AB12 murine mesothelioma (MM) model, aiming to increase its accuracy in predicting the response of hMPM to immunotherapy and in designing novel anti-hMPM treatments. Specifically, we used immunologic, transcriptomic and survival analyses, to synchronize the MM tumor growth phases and immune evolution with the histo-molecular and immunological characteristics of hMPM while also determining the anti-MM efficacy of standard-of-care anti-hMPM immunotherapy as a benchmark that novel therapeutics should meet. We report that early-, intermediate- and advanced- AB12 tumors are characterized by a bell-shaped anti-tumor response that peaks in intermediate tumors and decays in advanced tumors. We further show that intermediate- and advanced- tumors match with immune active (“hot”) and immune inactive (“cold”) hMPM respectively, and that they respond to immunotherapy in a manner that corresponds well with its performance in real-life settings. Finally, we show that in advanced tumors, addition of cisplatin to anti CTLA-4 + anti PD-1 can extend mice survival and invigorate the decaying anti-tumor response. Therefore, we highlight this triple combination as a worthy candidate to improve clinical outcomes in hMPM.
Osteopontin contributes to virus resistance associated with type I IFN expression, activation of downstream ifn-inducible effector genes, and CCR2+CD115+CD206+ macrophage infiltration following ocular HSV-1 infection of mice
Authors: Filiberti Adrian , Gmyrek Grzegorz B. , Berube Amanda N. , Carr Daniel J. J.
Published: January 2023

Ocular pathology is often associated with acute herpes simplex virus (HSV)-1 infection of the cornea in mice. The present study was undertaken to determine the role of early T lymphocyte activation 1 protein or osteopontin (OPN) in corneal inflammation and host resistance to ocular HSV-1 infection. C57BL/6 wild type (WT) and osteopontin deficient (OPN KO) mice infected in the cornea with HSV-1 were evaluated for susceptibility to infection and cornea pathology. OPN KO mice were found to possess significantly more infectious virus in the cornea at day 3 and day 7 post infection compared to infected WT mice. Coupled with these findings, HSV-1-infected OPN KO mouse corneas were found to express less interferon (IFN)-α1, double-stranded RNA-dependent protein kinase, and RNase L compared to infected WT animals early post infection that likely contributed to decreased resistance. Notably, OPN KO mice displayed significantly less corneal opacity and neovascularization compared to WT mice that paralleled a decrease in expression of vascular endothelial growth factor (VEGF) A within 12 hr post infection. The change in corneal pathology of the OPN KO mice aligned with a decrease in total leukocyte infiltration into the cornea and specifically, in neutrophils at day 3 post infection and in macrophage subpopulations including CCR2+CD115+CD206+ and CD115+CD183+CD206+ -expressing cells. The infiltration of CD4+ and CD8+ T cells into the cornea was unaltered comparing infected WT to OPN KO mice. Likewise, there was no difference in the total number of HSV-1-specific CD4+ or CD8+ T cells found in the draining lymph node with both sets functionally competent in response to virus antigen comparing WT to OPN KO mice. Collectively, these results demonstrate OPN deficiency directly influences the host innate immune response to ocular HSV-1 infection reducing some aspects of inflammation but at a cost with an increase in local HSV-1 replication.
The influences of microbial colonisation and germ-free status on the chicken TCRβ repertoire
Authors: Dascalu Stefan , Preston Stephen G. , Dixon Robert J. , Flammer Patrik G. , Fiddaman Steven , Boyd Amy , Sealy Joshua E. , Sadeyen Jean-Remy , Kaspers Bernd , Velge Philippe , Iqbal Munir , Bonsall Michael B. , Smith Adrian L.
Published: January 2023

Microbial colonisation is paramount to the normal development of the immune system, particularly at mucosal sites. However, the relationships between the microbiome and the adaptive immune repertoire have mostly been explored in rodents and humans. Here, we report a high-throughput sequencing analysis of the chicken TCRβ repertoire and the influences of microbial colonisation on tissue-resident TCRβ+ cells. The results reveal that the microbiome is an important driver of TCRβ diversity in both intestinal tissues and the bursa of Fabricius, but not in the spleen. Of note, public TCRβ sequences (shared across individuals) make a substantial contribution to the repertoire. Additionally, different tissues exhibit biases in terms of their V family and J gene usage, and these effects were influenced by the gut-associated microbiome. TCRβ clonal expansions were identified in both colonised and germ-free birds, but differences between the groups were indicative of an influence of the microbiota. Together, these findings provide an insight into the avian adaptive immune system and the influence of the microbiota on the TCRβ repertoire.
Clinical response trajectories and drug persistence in systemic lupus erythematosus patients on belimumab treatment: A real-life, multicentre observational study
Authors: Nikoloudaki Myrto , Nikolopoulos Dionysis , Koutsoviti Sofia , Flouri Irini , Kapsala Noemin , Repa Argyro , Katsimbri Pelagia , Theotikos Evangelos , Pitsigavdaki Sofia , Pateromichelaki Katerina , Bertsias Antonios , Elezoglou Antonia , Sidiropoulos Prodromos , Fanouriakis Antonis , Boumpas Dimitrios , Bertsias George
Published: January 2023

Objective

To obtain real-world data on outcomes of belimumab treatment and respective prognostic factors in patients with systemic lupus erythematosus (SLE).

Methods

Observational study of 188 active SLE patients (median disease duration 6.2 years, two previous immunosuppressive/biological agents) treated with belimumab, who were monitored for SLEDAI-2K, Physician Global Assessment (PGA), LLDAS (lupus low disease activity state), remission (DORIS/Padua definitions), SELENA-SLEDAI Flare Index, SLICC/ACR damage index and treatment discontinuations. Group-based disease activity trajectories were modelled followed by multinomial regression for predictive variables. Drug survival was analysed by Cox-regression.

Results

At 6, 12 and 24 months, LLDAS was attained by 36.2%, 36.7% and 33.5%, DORIS-remission by 12.3%, 11.6% and 17.8%, and Padua-remission by 21.3%, 17.9% and 29.0%, respectively (attrition-corrected). Trajectory analysis of activity indices classified patients into complete (25.5%), partial (42.0%) and non-responder (32.4%) groups, which were predicted by baseline PGA, inflammatory rash, leukopenia and prior use of mycophenolate. During median follow-up of 15 months, efficacy-related discontinuations occurred in 31.4% of the cohort, especially in patients with higher baseline PGA (hazard ratio [HR] 2.78 per 1-unit; 95% CI 1.32-5.85). Conversely, PGA improvement at 3 months predicted longer drug retention (HR 0.57; 95% CI 0.33-0.97). Use of hydroxychloroquine was associated with lower risk for safety-related drug discontinuation (HR 0.33; 95% CI 0.13-0.85). Although severe flares were reduced, flares were not uncommon (58.0%) and contributed to treatment stops (odds ratio [OR] 1.73 per major flare; 95% CI 1.09-2.75) and damage accrual (OR 1.83 per mild/moderate flare; 95% CI 1.15-2.93).

Conclusions

In a real-life setting with predominant long-standing SLE, belimumab was effective in the majority of patients, facilitating the achievement of therapeutic targets. Monitoring PGA helps to identify patients who will likely benefit and stay on the treatment. Vigilance is required for the prevention and management of flares while on belimumab.
Associations of cord blood meta-inflammation and vitamin D with neurodevelopmental delay: A prospective birth cohort study in China
Authors: Wang Peng , Wu Lin , Yin Wan-jun , Tao Rui-xue , Zhang Ying , Li Pei-pei , Jiang Xiao-min , Shao Zi-yu , Zhu Peng
Published: January 2023

Aim

To estimate the associations of cord meta-inflammatory markers with neurodevelopment, including the potential impact of cord blood vitamin D levels.

Method

The prospective cohort study comprised 7198 participants based on the Maternal & Infants Health in Hefei study. Cord blood C-peptide, high-sensitive C-reactive protein (hsCRP), high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, total cholesterol, triglycerides and 25(OH)D levels were measured. The Gesell Developmental Schedules were used to assess neurodevelopmental outcomes in offspring.

Results

After adjusting potential confounders, per quartile increase in cord blood 25(OH)D concentrations was associated with a decreased risk of neurodevelopmental delay [hazard ratios (HR) 0.65 (95% CI 0.57, 0.74)]. Conversely, significant positive associations with cord blood serum C-peptide levels above the 90th percentile [HR 2.38 (95% CI 1.81, 3.13)] and higher levels of cord hsCRP (per quartile increase) [HR 1.18 (95% CI 1.01, 1.37)] with neurodevelopmental delay were observed. These associations could vary by quartiles of cord blood 25(OH)D levels: the adjusted HRs in neurodevelopmental delay comparing children with vs without hyperinsulinemia were 1.28 (95% CI: 1.03, 1.59) for quartiles 1 (lowest), and 1.06 (95% CI: 0.78, 1.44) for quartile 4 (highest).

Conclusions

Immune activation and metabolic abnormalities in fetal circulation were associated with neurodevelopmental delay in offspring, which could be attenuated by higher cord blood 25(OH)D levels in a dose-response manner.
Using two-step cluster analysis to classify inpatients with primary biliary cholangitis based on autoantibodies: A real-world retrospective study of 537 patients in China
Authors: Zhao Dan-Tong , Yan Hui-Ping , Liao Hui-Yu , Liu Yan-Min , Han Ying , Zhang Hai-Ping , Zhang Wei-Ming , Huang Chun-Yang , Liu Xiu-Hong , Lou Jin-Li , Zhao Yan
Published: January 2023

Background

A variety of autoantibodies have been detected in primary biliary cholangitis (PBC), while the presence of autoantibody clusters and their clinical significance have not been fully understood. We aimed at defining autoantibody clusters and to better understand the clinical features and prognosis of PBC patients based on autoantibody clusters under real-world conditions.

Methods

We retrospectively analyzed 788 inpatients with PBC evaluated between October 2008 and July 2019, and included 537 patients. Nineteen autoantibodies which were measured routinely were investigated for cluster analysis. Two-step clustering, Kaplan-Meier survival, and Cox regression analyses were used.

Results

Five clusters were defined. A cluster of antinuclear antibodies (ANA) and anti-gp210 positive patients were identified with a high rate of cirrhosis at baseline and low survival rate; a cluster of ANA, anti-centromere antibodies (ACA) and/or anti-CENP-B female dominant patients with older disease onset, low level of platelet count at baseline, high rate of hepatic decompensation, and low survival rate was also characterized; and another cluster of anti-mitochondrial antibodies (AMA) and/or AMA-M2, anti-Ro52 and a high rate of anti-gp210 positive patients were identified with a high proportion of male patients and low survival rate. A subgroup of patients with anti-SSA and/or anti-SSB coexists with SjS was also identified; patients with only AMA and/or AMA-M2-positive with a benign clinical outcome and relatively high complication of non-alcoholic fatty liver disease (NAFLD) were also identified. Only anti-gp210 was considered as a significant predictor for poor outcomes especially in patients with cirrhosis.

Conclusion

Clustering methods allow the identification of distinct autoantibody profiles of PBC that form clinical subsets and can be useful for personalized approaches to diagnosis, clinical management, and the prediction of clinical outcomes. Anti-gp210 was the strongest predictive factor for poor outcomes especially in PBC patients with cirrhosis under real-world conditions.
Genetic analysis of potential biomarkers and therapeutic targets in ferroptosis from psoriasis
Authors: Wu Man-Ning , Zhou Dong-Mei , Jiang Chun-Yan , Chen Wei-Wen , Chen Jia-Chi , Zou Yue-Min , Han Tao , Zhou Li-Jia-Ming
Published: January 2023

Introduction

Ferroptosis is associated with multiple pathophysiological processes. Inhibition of ferroptosis has received much concern for some diseases. Nonetheless, there is no study comprehensively illustrating functions of ferroptosis-related genes (FRGs) in psoriasis.

Methods

In this study, FRGs together with psoriasis-associated data were obtained in Ferroptosis Database (FerrDb) and gene expression omnibus (GEO) database separately. This work identified altogether 199 psoriasis-associated DE-FRGs, and they were tightly associated with immunity and autophagy modulation. Thereafter, the present study utilized SVM-RFE and LASSO algorithms to identify NR5A2, CISD1, GCLC, PRKAA2, TRIB2, ABCC5, ACSF2, TIMM9, DCAF7, PEBP1, and MDM2 from those 199 DE-FRGs to be marker genes. As revealed by later functional annotation, the marker genes possibly had important effects on psoriasis through being involved in diverse psoriasis pathogenesis-related pathways such as cell cycle, toll-like receptor (TLR), chemokine, and nod-like receptor (NLR) pathways. Moreover, altogether 37 drugs that targeted 11 marker genes were acquired. Besides, based on CIBERSORT analysis, alterations of immune microenvironment in psoriasis cases were possibly associated with PRKAA2, PEBP1, CISD1, and ACSF2.

Discussion

Taken together, this work established the diagnostic potency and shed more lights on psoriasis-related mechanism. More investigations are warranted to validate its value in diagnosing psoriasis before it is applied in clinic.
Postpartum hepatitis and host immunity in pregnant women with chronic HBV infection
Authors: Zhang Lu , Jiang Tingting , Yang Ying , Deng Wen , Lu Huihui , Wang Shiyu , Liu Ruyu , Chang Min , Wu Shuling , Gao Yuanjiao , Hao Hongxiao , Shen Ge , Xu Mengjiao , Chen Xiaoxue , Hu Leiping , Yang Liu , Bi Xiaoyue , Lin Yanjie , Lu Yao , Jiang Yuyong , Li Minghui , Xie Yao
Published: January 2023

In order to develop immune tolerant to the fetal, maternal immune system will have some modification comparing to the time before pregnancy. Immune tolerance starts and develops at the maternal placental interface. In innate immunity, decidual natural killer (dNK) cells, macrophages and dendritic cells play a key role in immue tolerance. In adaptive immunity, a moderate increase of number and immune inhibition function of regulatory T cells (Treg) are essential for immune tolerance. The trophoblast cells and immune cells expressing indoleamine 2,3-dioxygenase (IDO), the trophoblast cells expressing HLA-G, and Th1/Th2 shifting to Th2 dominant and Th17/Treg shifting to Treg domiant are in favor of maternal fetal immune tolerance. Steroids (estrogen and progesterone) and human chorionic gonadotropin (HCG) also participate in immune tolerance by inducing Treg cells or upregulating immunosuppressive cytokines. Most of the patients with chronic HBV infection are in the “HBV immune tolerance period” before pregnancy, and the liver disease is relatively stable during pregnancy. In chronic HBV infection women, after delivery, the relative immunosuppression in vivo is reversed, and Th1 is dominant in Th1/Th2 and Th17 is dominant in Th17/Treg balance. After delivery, the number of Treg decrease and NK cells increase in quantity and cytotoxicity in peripheral blood. Liver NK cells may cause liver inflammation through a non-antigen specific mechanism. After delivery, the number of CD8+ T cells will increase and HBV specific T cell response recovers from the disfunction in pregnancy. Under the background of postpartum inflammation, the rapid decrease of cortisol after delivery, and especially the enhancement of HBV specific T cell response induced by HBV DNA and cytokines, are the main reasons for postpartum hepatitis. HBeAg positive, especially HBeAg<700 S/CO, and HBV DNA>3-5Log10IU/ml are risk factors for postpartum hepatitis. Antiviral treatment in late pregnancy can reduce the incidence of mother to child transmission (MTCT) in chronic HBV infection women. Chronic HBV infection women have hepatitis both during pregnancy and more often in 12 weeks postpartum. It is generally agreed that postpartum hepatitis is mild symptoms and self-limited. Delaying drug withdrawal to 48 weeks can increase the seroconversion rate of HBeAg in delivery women with elevated alanine aminotransferase (ALT) in pregnancy.
Comprehensive analysis of cuproptosis-related lncRNAs for prognostic significance and immune microenvironment characterization in hepatocellular carcinoma
Authors: Li Duguang , Jin Shengxi , Chen Peng , Zhang Yiyin , Li Yirun , Zhong Cheng , Fan Xiaoxiao , Lin Hui
Published: January 2023

Cuproptosis was characterized as a novel type of programmed cell death. Recently, however, the role of cuproptosis-related long noncoding RNAs (CRLs) in tumors has not yet been studied. Identifying a predictive CRL signature in hepatocellular carcinoma (HCC) and investigating its putative molecular function were the goals of this work. Initially, Pearson’s test was used to assess the relationship between lncRNAs and cuproptosis-associated genes obtained from HCC data of The Cancer Genome Atlas (TCGA). By implementing differential expression and univariate Cox analysis, 61 prognostic CRLs were subsequent to the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. A prognostic risk score model was then constructed to evaluate its ability to predict patients’ survival when combined with clinicopathological parameters in HCC. The five-lncRNA prognostic signature categorized the HCC patients into high- and low-risk groups. The low-risk group exhibited more sensitivity to elesclomol than the high-risk one. Surprisingly, distinct mitochondrial metabolism pathways connected to cuproptosis and pivotal immune-related pathways were observed between the two groups via gene set enrichment analysis (GSEA). Meanwhile, there were substantial differences between the high-risk group and the low-risk group in terms of tumor-infiltrating immune cells (TIICs). Furthermore, a positive relationship was shown between the risk score and the expression of immune checkpoints. Additionally, differential expression of the five lncRNAs was confirmed in our own HCC samples and cell lines via RT-qPCR. Finally, in vitro assays confirmed that WARS2-AS1 and MKLN1-AS knockdown could sensitize HCC cells to elesclomol-induced cuproptosis. Overall, our predictive signature may predict the prognosis of HCC patients in an independent manner, give a better understanding of how CRLs work in HCC, and offer therapeutic reference for patients with HCC.