bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction of a Novel Prognostic Signature in Lung Adenocarcinoma Based on Necroptosis-Related lncRNAs
Authors: Diao Xiayao , Guo Chao , Li Shanqing
Published: July 2022

Background: Long non-coding RNAs (lncRNAs) are drawing increasing attention as promising predictors of prognosis for lung adenocarcinoma (LUAD) patients. Necroptosis, a novel regulated mechanism of necrotic cell death, plays an important role in the biological process of cancer. The aim of this study was to identify the necroptosis-related lncRNAs (NRLRs) in a LUAD cohort and establish a necroptosis-related lncRNA signature (NRLSig) to stratify LUAD patients.

Methods: NRLRs were identified in LUAD patients from The Cancer Genome Atlas (TCGA) database using Pearson correlation analysis between necroptosis-related genes and lncRNAs. Then the NRLSig was identified using univariate Cox regression analysis and LASSO regression analysis. Assessments of the signature were performed based on survival analysis, receiver operating characteristic (ROC) curve analysis and clustering analysis. Next, a nomogram containing the NRLSig and clinical information was developed through univariate and multivariate Cox regression analysis. Further, functional enrichment analysis of the selected lncRNAs in NRLSig and the association between NRLSig and the immune infiltration were also evaluated.

Results: A 4-lncRNA signature, incorporating LINC00941, AP001453.2, AC026368.1, and AC236972.3, was identified to predict overall survival (OS) and stratify LUAD patients into different groups. Survival analysis, ROC curve analysis and clustering analysis showed good performance in the prognostic prediction of the lncRNA signature. Then, a nomogram containing the NRLSig was developed and showed satisfactory predictive accuracy, calibration and clinical usefulness. The co-expressed genes of selected NRLRs were enriched in several biological functions and signaling pathways. Finally, differences in the abundance of immune cells were investigated among the high-risk group and low-risk group divided by the NRLSig.

Conclusion: The proposed NRLSig may provide promising therapeutic targets or prognostic predictors for LUAD patients.
PRECISION.array: An R Package for Benchmarking microRNA Array Data Normalization in the Context of Sample Classification
Authors: Huang Huei-Chung , Wu Yilin , Yang Qihang , Qin Li-Xuan
Published: July 2022

We present a new R package PRECISION.array for assessing the performance of data normalization methods in connection with methods for sample classification. It includes two microRNA microarray datasets for the same set of tumor samples: a re-sampling-based algorithm for simulating additional paired datasets under various designs of sample-to-array assignment and levels of signal-to-noise ratios and a collection of numerical and graphical tools for method performance assessment. The package allows users to specify their own methods for normalization and classification, in addition to implementing three methods for training data normalization, seven methods for test data normalization, seven methods for classifier training, and two methods for classifier validation. It enables an objective and systemic evaluation of the operating characteristics of normalization and classification methods in microRNA microarrays. To our knowledge, this is the first such tool available. The R package can be downloaded freely at https://github.com/LXQin/PRECISION.array.
N6-methyladenosine RNA methylation regulator-related alternative splicing gene signature as prognostic predictor and in immune microenvironment characterization of patients with low-grade glioma
Authors: Maimaiti Aierpati , Tuersunniyazi Abudireheman , Meng Xianghong , Pei Yinan , Ji Wenyu , Feng Zhaohai , Jiang Lei , Wang Zengliang , Kasimu Maimaitijiang , Wang Yongxin , Shi Xin
Published: July 2022

Background: N6-methyladenosine (m6A) RNA methylation is an important epigenetic modification affecting alternative splicing (AS) patterns of genes to regulate gene expression. AS drives protein diversity and its imbalance may be an important factor in tumorigenesis. However, the clinical significance of m6A RNA methylation regulator-related AS in the tumor microenvironment has not been investigated in low-grade glioma (LGG).

Methods: We used 12 m6A methylation modulatory genes (WTAP, FTO, HNRNPC, YTHDF2, YTHDF1, YTHDC2, ALKBH5, YTHDC1, ZC3H13, RBM15, METTL14, and METTL3) from The Cancer Genome Atlas (TCGA) database as well as the TCGA-LGG (n = 502) dataset of AS events and transcriptome data. These data were downloaded and subjected to machine learning, bioinformatics, and statistical analyses, including gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Univariate Cox, the Least Absolute Shrinkage and Selection Operator (LASSO), and multivariable Cox regression were used to develop prognostic characteristics. Prognostic values were validated using Kaplan-Maier survival analysis, proportional risk models, ROC curves, and nomograms. The ESTIMATE package, TIMER database, CIBERSORT method, and ssGSEA algorithm in the R package were utilized to explore the role of the immune microenvironment in LGG. Lastly, an AS-splicing factor (SF) regulatory network was examined in the case of considering the role of SFs in regulating AS events.

Results: An aggregate of 3,272 m6A regulator-related AS events in patients with LGG were screened using six machine learning algorithms. We developed eight AS prognostic characteristics based on splice subtypes, which showed an excellent prognostic prediction performance. Furthermore, quantitative prognostic nomograms were developed and showed strong validity in prognostic prediction. In addition, prognostic signatures were substantially associated with tumor immune microenvironment diversity, ICB-related genes, and infiltration status of immune cell subtypes. Specifically, UGP2 has better promise as a prognostic factor for LGG. Finally, splicing regulatory networks revealed the potential functions of SFs.

Conclusion: The present research offers a novel perspective on the role of AS in m6A methylation. We reveal that m6A methylation regulator-related AS events can mediate tumor progression through the immune-microenvironment, which could serve as a viable biological marker for clinical stratification of patients with LGG so as to optimize treatment regimens.
Precise, Genotype-First Breast Cancer Prevention: Experience With Transferring Monogenic Findings From a Population Biobank to the Clinical Setting
Authors: Jürgens Hannes , Roht Laura , Leitsalu Liis , Nõukas Margit , Palover Marili , Nikopensius Tiit , Reigo Anu , Kals Mart , Kallak Kersti , Kütner Riina , Budrikas Kai , Kuusk Saskia , Valvere Vahur , Laidre Piret , Toome Kadri , Rekker Kadri , Tooming Mikk , Ülle Murumets  , Kahre Tiina , Kruuv-Käo Krista , Õunap Katrin , Padrik Peeter , Metspalu Andres , Esko Tõnu , Fischer Krista , Tõnisson Neeme
Published: July 2022

Although hereditary breast cancer screening and management are well accepted and established in clinical settings, these efforts result in the detection of only a fraction of genetic predisposition at the population level. Here, we describe our experience from a national pilot study (2018–2021) in which 180 female participants of Estonian biobank (of >150,000 participants in total) were re-contacted to discuss personalized clinical prevention measures based on their genetic predisposition defined by 11 breast cancer–related genes. Our results show that genetic risk variants are relatively common in the average-risk Estonian population. Seventy-five percent of breast cancer cases in at-risk subjects occurred before the age of 50 years. Only one-third of subjects would have been eligible for clinical screening according to the current criteria. The participants perceived the receipt of genetic risk information as valuable. Fluent cooperation of project teams supported by state-of-art data management, quality control, and secure transfer can enable the integration of research results to everyday medical practice in a highly efficient, timely, and well-accepted manner. The positive experience in this genotype-first breast cancer study confirms the value of using existing basic genomic data from population biobanks for precise prevention.
Association Between the Individual and Combined Effects of the GSTM1 and GSTT1 Polymorphisms and Risk of Leukemia: A Meta-Analysis
Authors: Hu Ting , Zhou Guozhong , Li Wenjin
Published: July 2022

Background: Fourteen meta-analyses reported the individual effects of the GSTM1 and GSTT1 polymorphisms on leukemia risk. However, over 40 studies were not included in previously published meta-analyses. Moreover, one key aspect was that previous meta-analyses did not conduct the false-positive test on the aforementioned issues. Furthermore, previous meta-analyses did not observe the combined effects of GSTM1 present/null and GSTT1 present/null polymorphism with leukemia risk. Therefore, we conducted the current study to further analyze these associations.

Objectives: This study aimed to investigate the association between the individual and combined effects of the GSTM1 present/null and GSTT1 present/null polymorphisms and the risk of leukemia.

Methods: A meta-analysis was performed applying Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Moreover, false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP) were applied to investigate the false-positive results.

Results: The individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes were associated with a significantly increased leukemia risk in overall and several subgroup analyses, such as Asians, Caucasians, and so on. Then, further analysis was conducted using FPRP and BFDP. Significant associations were considered as “positive” results on the GSTM1 null genotype with leukemia risk in overall populations (FPRP < 0.001 and BFDP = 0.006), Asians (FPRP < 0.001 and BFDP < 0.001), and East Asian population (FPRP < 0.001 and BFDP = 0.002). For the GSTT1 null genotype, significant associations were regarded “positive” results in overall populations, acute myeloid leukemia (AML), Asians, and East Asian population. For the combined effects of the GSTM1 and GSTT1 polymorphisms, significant associations were also considered “positive” results in the overall analysis of Asians, Indians, and East Asian population.

Conclusion: This study strongly indicates that the individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes are associated with increased leukemia risk in Asians, especially in the East Asian population; the GSTT1 null genotype is associated with increased AML risk; the combined effects of the two genes are associated with increased leukemia risk in Indians.
Association of SLC11A1 Polymorphisms With Tuberculosis Susceptibility in the Chinese Han Population
Authors: Hu Baoping , Wang Yuhe , Wang Zhongtao , He Xue , Wang Li , Yuan Dongya , He Yongjun , Jin Tianbo , He Shumei
Published: July 2022

Tuberculosis (TB) is an important health issue in the world. Although the relation of SLC11A1 polymorphisms with TB risk has been extensively studied, it has not been reported in the northwest Chinese Han population. Therefore, this study aimed to investigate the relationships between five polymorphisms in or near the SLC11A1 gene and susceptibility to TB. The Agena MassARRAY platform was conducted for genotyping from 510 TB patients and 508 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were analyzed through logistic regression adjustment age and gender to assess the relationships between polymorphisms and TB risk. Our results identified that rs7608307 was related to increased TB risk in males (CT vs. CC: OR = 1.69, 95%CI: 1.12–2.56, p = 0.013; CT-TT vs. CC: OR = 1.61, 95%CI: 1.08–2.41, p = 0.020) and age ≤41 group (CT vs. CC: OR = 1.66, 95%CI: 1.04–2.65, p = 0.035), respectively. The SNP rs13062 was associated with the TB risk both in males (p = 0.012) and age >41 group (p = 0.021). In addition, we observed that the CC genotype of rs4674301 was correlated with increased TB risk in females (p = 0.043). Our results demonstrated the relationships between polymorphisms (rs7608307, rs4674301, and rs13062) in or near the SLC11A1 gene and age- and sex-specific TB risk in the northwest Chinese Han population.
MLEE: A method for extracting object-level medical knowledge graph entities from Chinese clinical records
Authors: Zhao Genghong , Gu Wenjian , Cai Wei , Zhao Zhiying , Zhang Xia , Liu Jiren
Published: July 2022

As a typical knowledge-intensive industry, the medical field uses knowledge graph technology to construct causal inference calculations, such as “symptom-disease”, “laboratory examination/imaging examination-disease”, and “disease-treatment method”. The continuous expansion of large electronic clinical records provides an opportunity to learn medical knowledge by machine learning. In this process, how to extract entities with a medical logic structure and how to make entity extraction more consistent with the logic of the text content in electronic clinical records are two issues that have become key in building a high-quality, medical knowledge graph. In this work, we describe a method for extracting medical entities using real Chinese clinical electronic clinical records. We define a computational architecture named MLEE to extract object-level entities with “object-attribute” dependencies. We conducted experiments based on randomly selected electronic clinical records of 1,000 patients from Shengjing Hospital of China Medical University to verify the effectiveness of the method.
Ferroptosis-Related Hub Genes in Hepatocellular Carcinoma: Prognostic Signature, Immune-Related, and Drug Resistance Analysis
Authors: Wang Wei , Pan Fan , Lin Xinrong , Yuan Jiakai , Tao Chunyu , Wang Rui
Published: July 2022

Background: Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer with a high fatality rate and dismal prognosis because of frequent recurrence and lack of efficient therapies. Ferroptosis is a recently recognized iron-dependent cell death distinct from necroptosis and apoptosis. The relationship between ferroptosis-related hub gene expression and prognosis in HCC remains to be further elucidated.

Methods: Ferroptosis-related genes from the FerrDb database and the mRNA sequencing data and clinical information of HCC patients were obtained from The Cancer Genome Atlas (TCGA) database. The least absolute shrinkage and selection operator (LASSO) Cox regression was applied to identify a prognostic signature consisting of five ferroptosis-related hub genes in the TCGA cohort. The International Cancer Genome Consortium (ICGC) database was utilized to validate the reliability of the signature. Functional enrichment and immune-related analysis, including single-sample gene set enrichment analysis (ssGSEA), immune checkpoints, TIP-related genes, tumor stemness, and m6A-related genes, were performed to analyze the underlying mechanism. Additionally, the correlations between ferroptosis and drug resistance were evaluated using the NCI-60 database.

Results: A 5–hub-gene signature associated with ferroptosis was constructed by multivariate Cox regression analysis to stratify patients into two risk groups. Patients with high risk had worse prognosis than those with low risk. Multivariate Cox regression analysis uncovered that the risk score was an independent prognostic indicator. We also proved the signature’s predictive capacity using the Kaplan–Meier method and receiver operating characteristic (ROC) curve analysis. Functional analysis showed that nuclear division and the cell cycle were enriched. Immune-related analysis revealed that the signature was enriched in immune-related pathways. Moreover, the risk signature was significantly associated with immune cell infiltration, immune checkpoints, TIP-related genes, tumor stem cells, as well as m6A-related genes. Furthermore, these genes were crucial regulators of drug resistance.

Conclusion: We identified and validated a novel hub gene signature that is closely associated with ferroptosis as a new and efficient biomarker with favorable potential for predicting the prognosis of HCC patients. In addition, it also offers new insights into the molecular mechanisms of HCC and provides an effective approach for the treatment of HCC. Further studies are necessary to validate the results of our study.
Identification of Immune-Related Hub Genes in Parkinson’s Disease
Authors: Chen Lin , Wang Yong , Huang Juan , Hu Binbin , Huang Wei
Published: July 2022

Background: Parkinson’s disease (PD) is a common, age-related, and progressive neurodegenerative disease. Growing evidence indicates that immune dysfunction plays an essential role in the pathogenic process of PD. The objective of this study was to explore potential immune-related hub genes and immune infiltration patterns of PD.

Method: The microarray expression data of human postmortem substantia nigra samples were downloaded from GSE7621, GSE20141, and GSE49036. Key module genes were screened via weighted gene coexpression network analysis, and immune-related genes were intersected to obtain immune-key genes. Functional enrichment analysis was performed on immune-key genes of PD. In addition to, immune infiltration analysis was applied by a single-sample gene set enrichment analysis algorithm to detect differential immune cell types in the substantia nigra between PD samples and control samples. Least absolute shrinkage and selection operator analysis was performed to further identify immune-related hub genes for PD. Receiver operating characteristic curve analysis of the immune-related hub genes was used to differentiate PD patients from healthy controls. Correlations between immune-related hub genes and differential immune cell types were assessed.

Result: Our findings identified four hub genes (SLC18A2, L1CAM, S100A12, and CXCR4) and seven immune cell types (neutrophils, T follicular helper cells, myeloid-derived suppressor cells, type 1 helper cells, immature B cells, immature dendritic cells, and CD56 bright natural killer cells). The area under the curve (AUC) value of the four-gene-combined model was 0.92. The AUC values of each immune-related hub gene (SLC18A2, L1CAM, S100A12, and CXCR4) were 0.81, 0.78, 0.78, and 0.76, respectively.

Conclusion: In conclusion, SLC18A2, L1CAM, S100A12, and CXCR4 were identified as being associated with the pathogenesis of PD and should be further researched.
Putative Candidate Drug Targets for Sarcopenia-Related Traits Identified Through Mendelian Randomization Analysis of the Blood Proteome
Authors: Chen Bin-Bin , Wang Jia-Qi , Meng Xiang-He , Luo Zhe , Liu Xiao-Wen , Shen Hui , Xiao Hong-Mei , Deng Hong-Wen
Published: July 2022

Purpose: The increasing prevalence of sarcopenia remains an ongoing challenge to health care systems worldwide. The lack of treatments encouraged the discovery of human proteomes to find potential therapeutic targets. As one of the major components of the human proteome, plasma proteins are functionally connected with various organs of the body to regulate biological processes and mediate overall homeostasis, which makes it crucial in various complex processes such as aging and chronic diseases. By performing a systematic causal analysis of the plasma proteome, we attempt to reveal the etiological mechanism and discover drug targets for sarcopenia.

Methods: By using data from four genome-wide association studies for blood proteins and the UK Biobank data for sarcopenia-related traits, we applied two-sample Mendelian randomization (MR) analysis to evaluate 310 plasma proteins as possible causal mediators of sarcopenia-related traits: appendicular lean mass (ALM) and handgrip strength (right and left). Then we performed a two-sample bidirectional Mendelian randomization analysis for the identified putatively causal proteins to assess potential reverse causality that the trait values may influence protein levels. Finally, we performed phenome-wide MR analysis of the identified putatively causal proteins for 784 diseases to test the possible side effects of these proteins on other diseases.

Results: Five plasma proteins were identified as putatively causal mediators of sarcopenia-related traits. Specifically, leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), asporin (ASPN), and contactin-2 (CNTN2) had potential causal effects on appendicular lean mass, and ecto-ADP-ribosyltransferase 4 (ART4) and superoxide dismutase 2 (SOD2) had putative causal effects on the handgrip strength, respectively. None of the five putatively causal proteins had a reverse causality relationship with sarcopenia-related traits, and no side effects on other diseases were identified.

Conclusion: We identified five plasma proteins that may serve as putatively potential novel drug targets for sarcopenia. Our study attested to the value of two-sample MR analysis in identifying and prioritizing putatively potential therapeutic targets for complex diseases.
Pyroptosis-Related Signature as Potential Biomarkers for Predicting Prognosis and Therapy Response in Colorectal Cancer Patients
Authors: Li Zhiyong , Liu Yang , Lin Baiqiang , Yan Wei , Yi Huijie , Wang Haoran , Wei Yunwei
Published: July 2022

Background: Abnormal mucosal inflammation is a critical risk factor for pathogenesis and progression of colorectal cancer (CRC). As a type of proinflammatory death, pyroptosis can recast a suitable microenvironment to promote tumor growth. However, the potential role of pyroptosis in CRC remains unclear.

Methods: A total of 38 pyroptosis-related gene (PRG) expression profiles and clinical information were collected from multiple public datasets. Bioinformatics methods were used to analyze the clinical significance, functional status, immune infiltration, genomic alteration, and drug sensitivity in different subgroups. Whole-genome microarray analysis was performed to analyze the regulation of gut microbiota on the expression of PRGs.

Results: Two distinct molecular subtypes were identified and suggested that multilayer PRG alterations were associated with patient clinicopathological features, prognosis, and tumor microenvironment (TME) infiltrating characteristics. Furthermore, we obtained eight PRG signatures by applying differential expression analysis and univariate Cox and Lasso regression analyses. A risk prognosis model was constructed for predicting overall survival (OS) and recurrence-free survival (RFS) based on the PRG signature. There were significant differences in clinical characteristics, 22 immune cells, and immune functions between the high- and low-risk groups. In addition, the PRG signature was significantly associated with the microsatellite instability (MSI), tumor mutation burden (TMB), cancer stem cell (CSC) index, immunotherapeutic characteristics, and chemotherapeutic drug sensitivity. Moreover, the in vitro experiments had shown that Fusobacterium nucleatum (F.n) could affect the CASP6 expression, which was associated with the chemoresistance to 5-fluorouracil (5-Fu) in CRC.

Conclusion: Our findings provided a foundation for future research targeting pyroptosis and a new insight into the prognosis and immune cell infiltration of CRC, and they suggested that F.n might influence CRC progression through pyroptosis.
A Pan-Cancer Analysis Reveals the Prognostic and Immunotherapeutic Value of Stanniocalcin-2 (STC2)
Authors: Jiang Zhong-Hui , Shen Xianfeng , Wei Yanhong , Chen Yongji , Chai Hongbo , Xia Lingyun , Leng Weidong
Published: July 2022

Background: Stanniocalcin-2 (STC2) is a secreted glycoprotein which plays an important role in regulating the homeostasis of calcium, glucose homeostasis, and phosphorus metastasis. Accumulating evidence suggests that STC2 is implicated in cancer mechanisms. However, the effects of STC2 on cancer development and progression across pan-cancer are not yet completely known.

Methods: Data were downloaded from The Cancer Genome Atlas database to obtain differentially expressed genes significantly associated with prognosis (key genes). A gene was selected for subsequent correlation studies by integrating the significance of prognosis and the time-dependent ROC curve. Gene expression of different tumor types was analyzed based on the UCSC XENA website. Furthermore, our study investigated the correlation of STC2 expression between prognosis, immune cell infiltration, immune checkpoint genes (ICGs), mismatch repair genes (MMRs), tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity in various malignant tumors. Gene set enrichment analysis (GSEA) was conducted for correlated genes of STC2 to explore potential mechanisms.

Results: A total of 3,429 differentially expressed genes and 397 prognosis-related genes were identified from the TCGA database. Twenty-six key genes were found by crossing the former and the latter, and the highest risk gene, STC2, was selected for subsequent correlation studies. STC2 had good diagnostic performance for HNSCC, and was closely related to the survival status and clinicopathological stage of HNSCC patients. In pan-cancer analysis, STC2 was upregulated in 20 cancers and downregulated in seven cancers. STC2 overexpression was overall negatively correlated with overall survival, disease-free survival, disease-specific survival, and progress-free survival. STC2 was profoundly correlated with the tumor immune microenvironment, including immune cell infiltration, ICGs, MMRs, TMB, and MSI. Moreover, STC2 was significantly negatively correlated with the sensitivity or resistance of multiple drugs.

Conclusion: STC2 was a potential prognostic biomarker for pan-cancer and a new immunotherapy target.
Unraveling Origin, History, Genetics, and Strategies for Accelerated Domestication and Diversification of Food Legumes
Authors: Ambika  , Aski Muraleedhar S. , Gayacharan  , Hamwieh Aladdin , Talukdar Akshay , Kumar Gupta Santosh , Sharma Brij Bihari , Joshi Rekha , Upadhyaya H. D. , Singh Kuldeep , Kumar Rajendra
Published: July 2022

Domestication is a dynamic and ongoing process of transforming wild species into cultivated species by selecting desirable agricultural plant features to meet human needs such as taste, yield, storage, and cultivation practices. Human plant domestication began in the Fertile Crescent around 12,000 years ago and spread throughout the world, including China, Mesoamerica, the Andes and Near Oceania, Sub-Saharan Africa, and eastern North America. Indus valley civilizations have played a great role in the domestication of grain legumes. Crops, such as pigeon pea, black gram, green gram, lablab bean, moth bean, and horse gram, originated in the Indian subcontinent, and Neolithic archaeological records indicate that these crops were first domesticated by early civilizations in the region. The domestication and evolution of wild ancestors into today’s elite cultivars are important contributors to global food supply and agricultural crop improvement. In addition, food legumes contribute to food security by protecting human health and minimize climate change impacts. During the domestication process, legume crop species have undergone a severe genetic diversity loss, and only a very narrow range of variability is retained in the cultivars. Further reduction in genetic diversity occurred during seed dispersal and movement across the continents. In general, only a few traits, such as shattering resistance, seed dormancy loss, stem growth behavior, flowering–maturity period, and yield traits, have prominence in the domestication process across the species. Thus, identification and knowledge of domestication responsive loci were often useful in accelerating new species’ domestication. The genes and metabolic pathways responsible for the significant alterations that occurred as an outcome of domestication might aid in the quick domestication of novel crops. Further, recent advances in “omics” sciences, gene-editing technologies, and functional analysis will accelerate the domestication and crop improvement of new crop species without losing much genetic diversity. In this review, we have discussed about the origin, center of diversity, and seed movement of major food legumes, which will be useful in the exploration and utilization of genetic diversity in crop improvement. Further, we have discussed about the major genes/QTLs associated with the domestication syndrome in pulse crops and the future strategies to improve the food legume crops.
Evaluating the Prognostic and Therapeutic Potentials of the Proteasome 26S Subunit, ATPase (PSMC) Family of Genes in Lung Adenocarcinoma: A Database Mining Approach
Authors: Ullah Md. Asad , Islam Nafisa Nawal , Moin Abu Tayab , Park Su Hyun , Kim Bonglee
Published: July 2022

This study explored the prognostic and therapeutic potentials of multiple Proteasome 26S Subunit, ATPase (PSMC) family of genes (PSMC1-5) in lung adenocarcinoma (LUAD) diagnosis and treatment. All the PSMCs were found to be differentially expressed (upregulated) at the mRNA and protein levels in LUAD tissues. The promoter and multiple coding regions of PSMCs were reported to be differentially and distinctly methylated, which may serve in the methylation-sensitive diagnosis of LUAD patients. Multiple somatic mutations (alteration frequency: 0.6–2%) were observed along the PSMC coding regions in LUAD tissues that could assist in the high-throughput screening of LUAD patients. A significant association between the PSMC overexpression and LUAD patients’ poor overall and relapse-free survival (p < 0.05; HR: >1.3) and individual cancer stages (p < 0.001) was discovered, which justifies PSMCs as the ideal targets for LUAD diagnosis. Multiple immune cells and modulators (i.e., CD274 and IDO1) were found to be associated with the expression levels of PSMCs in LUAD tissues that could aid in formulating PSMC-based diagnostic measures and therapeutic interventions for LUAD. Functional enrichment analysis of neighbor genes of PSMCs in LUAD tissues revealed different genes (i.e., SLIRP, PSMA2, and NUDSF3) previously known to be involved in oncogenic processes and metastasis are co-expressed with PSMCs, which could also be investigated further. Overall, this study recommends that PSMCs and their transcriptional and translational products are potential candidates for LUAD diagnostic and therapeutic measure discovery.
The association of MTHFR (rs1801133) with hypertension in an indigenous south African population
Authors: Mabhida Sihle E. , Sharma Jyoti R. , Apalata Teke , Masilela Charity , Nomatshila Sibusiso , Mabasa Lawrence , Fokkens Hannah , Benjeddou Mongi , Muhamed Babu , Shabalala Samukelisiwe , Johnson Rabia
Published: July 2022

Aims: The current study sought to investigate the association between the methylenetetrahydrofolate reductase (MTHFR) variant (rs1801133) and the risk of developing hypertension (HTN) in an indigenous South African population.

Methods: A total of 442 participants (hypertensive, n = 279 and non-hypertensive, n = 163) from the indigenous tribe residing in Mthatha, Eastern Cape (South Africa) were recruited. HTN was defined as a systolic (SBP) and diastolic blood pressure (DBP) of ≥130/80 mmHg following American Heart Association guidelines. The genotyping of MTHFR (rs1801133) was assessed using MassARRAY® System. Thereafter, the association between rs1801133 in various genetic models and HTN was determined by logistic regression model analysis. Furthermore, the interaction between rs1801133 and selected risk factors on HTN was performed using the open-source multifactor dimensionality reduction (MDR).

Results: The low frequency of the T allele (5%) was also observed when compared with the C allele (95%) in both cases and controls. After adjusting for confounding factors (gender, smoking status, BMI, and blood glucose levels), there were no significant associations were observed between rs1801133 and the risk of HTN in all genetic models: genotypic (OR 0.75, 95% CI 0.29–1.95, p = 0.56), dominant (OR 0.86, 95% CI 0.35–2.16, p = 0.75), co-dominant (OR 1.33, 95% CI 0.51–3.48, p = 0.55) and allelic (OR 0.80, 95% CI 0.49–1.62, p = 0.70) in logistic regression analysis. However, a significant interaction was reported among rs1801133, age, and gender (p < 0.0001) with the risk of HTN.

Conclusion: The present study reports on the lack of association between MTHFR (rs1801133) and the risk of HTN in an indigenous South African tribe. However, an interaction between gender, age, and rs1801133 was observed. Thus, future studies with a large sample size are required to further validate these findings.
Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness
Authors: Tian Xinyuan , Zhang Chuan , Zhou Bingbo , Chen Xue , Feng Xuan , Zheng Lei , Wang Yupei , Hao Shengju , Hui Ling
Published: July 2022

Dominant variants in the gap junction beta-2 (GJB2) gene may lead to various degrees of syndromic hearing loss (SHL) which is manifest as sensorineural hearing impairment and hyperproliferative epidermal disorders, including palmoplantar keratoderma with deafness (PPKDFN). So far, only a few GJB2 dominant variants causing PPKDFN have been discovered. Through the whole-exome sequencing (WES), a Chinese female patient with severe palmoplantar hyperkeratosis and delayed-onset hearing loss has been identified. She had a novel heterozygous variant, c.224G>C (p.R75P), in the GJB2 gene, which was unreported previously. The proband’s mother who had a mild phenotype was suggested the possibility of mosaicism by WES (∼120×), and the ultra-deep targeted sequencing (∼20,000×) was used for detecting low-level mosaic variants which provided accurate recurrence-risk estimates and genetic counseling. In addition, the analysis of protein structure indicated that the structural stability and permeability of the connexin 26 (Cx26) gap junction channel may be disrupted by the p.R75P variant. Through retrospective analysis, it is detected that the junction of extracellular region-1 (EC1) and transmembrane region-2 (TM2) is a variant hotspot for PPKDFN, such as p.R75. Our report reflects the important and effective diagnostic role of WES in PPKDFN and low-level mosaicism, expands the spectrum of the GJB2 variant, and furthermore provides strong proof about the relevance between the p.R75P variant in GJB2 and PPKDFN.
Case Report: Immune Microenvironment and Mutation Features in a Patient With Epstein–Barr Virus Positive Large B-Cell Lymphoma Secondary to Angioimmunoblastic T-Cell Lymphoma
Authors: Zhang Fen , Li Wenyu , Cui Qian , Chen Yu , Liu Yanhui
Published: July 2022

On rare occasions, secondary Epstein–Barr virus (EBV)-associated B-cell lymphoma can develop in patients with angioimmunoblastic T-cell lymphoma (AITL). Here, we describe the tumor microenvironment and mutation features of a patient with EBV + large B-cell lymphoma (LBCL) secondary to AITL. He was admitted to hospital due to a 1-year history of fever and enlarged right inguinal lymph nodes. A biopsy of the right inguinal lymph node demonstrated that numerous diffuse medium-sized atypical lymphocytes proliferated, together with increased extrafollicular follicular dendritic cell meshwork, and the lymphocytes expressed CD3, CD4, BCL6, CD10, PD-1, CXCL13, and Ki-67 (75%). Thus, a diagnosis of AITL was made. However, the disease progressed following treatment by CHOP regimen (cyclophosphamide, adriamycin, vincristine, and prednisone). Biopsy showed that most of the cells were positive for CD20 staining and IgH rearrangement. Analysis of 22 kinds of immune cells showed that the numbers of activated NK cells and activated memory T cells increased, while the T-follicular helper population decreased in the transformed sample. In addition, compared with the primary sample, RHOA (G17V) mutation was not detected, while JAK2 and TRIP12 gene mutations were detected in the transformed sample. Overall, we described the immune microenvironment and mutation features of a patient with EBV + LBCL secondary to AITL. This study will help us to understand the mechanisms by which AITL transforms to B-cell lymphoma.
CDH6 as a prognostic indicator and marker for chemotherapy in gliomas
Authors: Meng Ming , Zhou Hongshu , He Ye , Chen Lu , Wang Wanpeng , Yang Liting , Wang Zeyu , Zhang Liyang , Wang Sha
Published: July 2022

Glioma is the most malignant cancer of the central nervous system. There are various therapies for treating gliomas, but their outcomes are not satisfactory. Therefore, new targets for glioma treatment are needed. This study examined the cadherin-6 (CDH6) expression in gliomas using The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets. CDH6 expression positively correlated with the World Health Organization (WHO) tumor grade and negatively correlated with patient prognosis. A significant decrease in CDH6 promoter methylation was identified with an increase in the WHO grade severity. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that CDH6 might be involved in cell–cell interactions and immune processes in the glioma microenvironment. Weighted gene co-expression network analysis revealed a correlation between CDH6 and cell adhesion molecules, focal adhesions, phosphatidylinositol 3-kinase-protein kinase B signaling pathways, nuclear division, chromosome segregation, mitotic nuclear division, and immune-related pathways. CDH6 strongly correlated with immunosuppressive cells, including regulatory T cells, monocytes, macrophages, tumor-associated macrophages, and myeloid-derived suppressor cells. It also showed correlations with immune-active cells such as B cells, CD8+ T cells, and dendritic cells. Single-cell analysis showed that CDH6 was expressed mainly in astrocyte (AC)-like malignant cells. Differentially expressed genes of AC-like malignant cells were found to be associated with stress response, membranous processes, viral infections, and several types of cancers. Potential drugs associated with high CDH6 expression were also predicted, including AMG-22, rutin, CCT128930, deforolimus, bis(maltolato)oxovanadium, anagrelide, vemurafenib, CHIR-98014, and AZD5582. Thus, this study showed that CDH6 correlates with glioma immune infiltration, it is expressed mainly in AC-like malignant cells, and it may act as a new target for glioma therapy.
Research Progress for RNA Modifications in Physiological and Pathological Angiogenesis
Authors: Chen Hui-Ming , Li Hang , Lin Meng-Xian , Fan Wei-Jie , Zhang Yi , Lin Yan-Ting , Wu Shu-Xiang
Published: July 2022

As a critical layer of epigenetics, RNA modifications demonstrate various molecular functions and participate in numerous biological processes. RNA modifications have been shown to be essential for embryogenesis and stem cell fate. As high-throughput sequencing and antibody technologies advanced by leaps and bounds, the association of RNA modifications with multiple human diseases sparked research enthusiasm; in addition, aberrant RNA modification leads to tumor angiogenesis by regulating angiogenesis-related factors. This review collected recent cutting-edge studies focused on RNA modifications (N6-methyladenosine (m6A), N5-methylcytosine (m5C), N7-methylguanosine (m7G), N1-methyladenosine (m1A), and pseudopuridine (Ψ)), and their related regulators in tumor angiogenesis to emphasize the role and impact of RNA modifications.
N7-methylguanosine-related lncRNAs: Predicting the prognosis and diagnosis of colorectal cancer in the cold and hot tumors
Authors: Wu Jing-Yu , Song Qing-Yu , Huang Chang-Zhi , Shao Yu , Wang Zhen-Ling , Zhang Hong-Qiang , Fu Zan
Published: July 2022

Background: 7-Methylguanosine(m7G) contributes greatly to its pathogenesis and progression in colorectal cancer. We proposed building a prognostic model of m7G-related LncRNAs. Our prognostic model was used to identify differences between hot and cold tumors.

Methods: The study included 647 colorectal cancer patients (51 cancer-free patients and 647 cancer patients) from The Cancer Genome Atlas (TCGA). We identified m7G-related prognostic lncRNAs by employing the univariate Cox regression method. Assessments were conducted using univariate Cox regression, multivariate Cox regression, receiver operating characteristics (ROC), nomogram, calibration curves, and Kaplan-Meier analysis. All of these procedures were used with the aim of confirming the validity and stability of the model. Besides these two analyses, we also conducted half-maximal inhibitory concentration (IC50), immune analysis, principal component analysis (PCA), and gene set enrichment analysis (GSEA). The entire set of m7G-related (lncRNAs) with respect to cold and hot tumors has been divided into two clusters for further discussion of immunotherapy.

Results: The risk model was constructed with 17 m7G-related lncRNAs. A good correlation was found between the calibration plots and the prognosis prediction in the model. By assessing IC50 in a significant way across risk groups, systemic treatment can be guided. By using clusters, it may be possible to distinguish hot and cold tumors effectively and to aid in specific therapeutic interventions. Cluster 1 was identified as having the highest response to immunotherapy drugs and thus was identified as the hot tumor.

Conclusion: This study shows that 17 m7G-related lncRNA can be used in clinical settings to predict prognosis and use them to determine whether a tumor is cold or hot in colorectal cancer and improve the individualization of treatment.
The interaction between the soluble programmed death ligand-1 (sPD-L1) and PD-1+ regulator B cells mediates immunosuppression in triple-negative breast cancer
Authors: Li Xuejiao , Du Huan , Zhan Shenghua , Liu Wenting , Wang Zhangyu , Lan Jing , PuYang Longxiang , Wan Yuqiu , Qu Qiuxia , Wang Sining , Yang Yang , Wang Qin , Xie Fang
Published: July 2022

Accumulating evidence suggests that regulatory B cells (Bregs) play important roles in inhibiting the immune response in tumors. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important molecules that maintain the balance of the immune response and immune tolerance. This study aims to evaluate the soluble form of PD-L1 and its function in inducing the differentiation of B lymphocytes, investigate the relationship between soluble PD-L1 (sPD-L1) and B-cell subsets, and explore the antitumor activity of T lymphocytes after PD-L1 blockade in coculture systems. In an effort to explore the role of sPD-L1 in human breast cancer etiology, we examined the levels of sPD-L1 and interleukin-10 (IL-10) in the serum of breast tumor patients and the proportions of B cells, PD-1+ B cells, Bregs, and PD-1+ Bregs in the peripheral blood of patients with breast tumors and assessed their relationship among sPD-L1, IL-10, and B-cell subsets. The levels of sPD-L1 and IL-10 in serum were found to be significantly higher in invasive breast cancer (IBCa) patients than in breast fibroadenoma (FIBma) patients. Meanwhile, the proportions and absolute numbers of Bregs and PD-1+ Bregs in the peripheral blood of IBCa patients were significantly higher than those of FIBma patients. Notably, they were the highest in triple-negative breast cancer (TNBC) among other subtypes of IBCa. Positive correlations of sPD-L1 and IL-10, IL-10 and PD-1+ Bregs, and also sPD-L1 and PD-1+ Bregs were observed in IBCa. We further demonstrated that sPD-L1 could induce Breg differentiation, IL-10 secretion, and IL-10 mRNA expression in a dose-dependent manner in vitro. Finally, the induction of regulatory T cells (Tregs) by Bregs was further shown to suppress the antitumor response and that PD-L1 blockade therapies could promote the apoptosis of tumor cells. Together, these results indicated that sPD-L1 could mediate the differentiation of Bregs, expand CD4+ Tregs and weaken the antitumor activity of CD4+ T cells. PD-L1/PD-1 blockade therapies might be a powerful therapeutic strategy for IBCa patients, particularly for TNBC patients with high level of PD-1+ Bregs.
Local and Systemic Immunity Are Impaired in End-Stage-Renal-Disease Patients Treated With Hemodialysis, Peritoneal Dialysis and Kidney Transplant Recipients Immunized With BNT162b2 Pfizer-BioNTech SARS-CoV-2 Vaccine
Authors: Piotrowska Magdalena , Zieliński Maciej , Tylicki Leszek , Biedunkiewicz Bogdan , Kubanek Alicja , Ślizień Zuzanna , Polewska Karolina , Tylicki Piotr , Muchlado Marta , Sakowska Justyna , Renke Marcin , Sudoł Adam , Dąbrowska Małgorzata , Lichodziejewska-Niemierko Monika , Smiatacz Tomasz , Dębska-Ślizień Alicja , Trzonkowski Piotr
Published: July 2022

Vaccination against COVID-19 in patients with end-stage renal disease (ESRD) on replacement therapy and kidney transplant recipients (KTRs) is particularly important due to the high mortality rate. Here, we tested the local and systemic immunity to the novel Pfizer BioNTech (BNT162b2) messenger RNA (mRNA) in ESRD, KTR patients, and healthy individuals (150 subjects). The ESRD group was divided into: hemodialysis (HD) and peritoneal dialysis (PD). We investigated the local and systemic immunity based on anti-N (nucleoprotein) and anti-S (spike1/2) Immunoglobulin A (IgA) and Immunoglobulin G (IgG) antibodies, respectively. Additionally, we performed an Interferon gamma (IFN-γ) release test Interferon-gamma release assay (IGRA) to monitor the cellular component of vaccine response. The control group had the highest level of anti-S IgG antibodies (153/2,080 binding antibody units (BAU)/ml) among all analyzed patients after the 1st and 2nd dose, respectively. The HD group (48/926 BAU/ml) had a diminished antibody level compared to PD (93/1,607 BAU/ml). Moreover, the seroconversion rate after the 1st dose was lower in HD than PD (56% vs. 86%). KTRs had extremely low seroconversion (33%). IgA-mediated immunity was the most effective in the control group, while other patients had diminished IgA production. We observed a lower percentage of vaccine responders based on the IFN-γ level in all research participants (100% vs. 85% in control, 100% vs. 80% in PD, 97% vs. 64% in HD). 63% of seropositive KTRs had a positive IGRA, while 28% of seronegative patients produced IFN-γ. Collectively, PD patients had the strongest response among ESRD patients. Two doses of the Pfizer vaccine are ineffective, especially in HD and KTRs. A closer investigation of ESRD and KTRs is required to set the COVID-19 vaccine clinical guidance.

Clinical Trial Registration Number

www.ClinicalTrials.gov, identifier: NCT04 905 862
Gene-Based Variant Analysis of Whole-Exome Sequencing in Relation to Eosinophil Count
Authors: Höglund Julia , Hadizadeh Fatemeh , Ek Weronica E. , Karlsson Torgny , Johansson Åsa
Published: July 2022

Eosinophils play important roles in the release of cytokine mediators in response to inflammation. Many associations between common genetic variants and eosinophils have already been reported, using single nucleotide polymorphism (SNP) array data. Here, we have analyzed 200,000 whole-exome sequences (WES) from the UK Biobank cohort and performed gene-based analyses of eosinophil count. We defined five different variant weighting schemes to incorporate information on both deleteriousness and frequency. A total of 220 genes in 55 distinct (>10 Mb apart) genomic regions were found to be associated with eosinophil count, of which seven genes (ALOX15, CSF2RB, IL17RA, IL33, JAK2, S1PR4, and SH2B3) are driven by rare variants, independent of common variants identified in genome-wide association studies. Two additional genes, NPAT and RMI1, have not been associated with eosinophil count before and are considered novel eosinophil loci. These results increase our knowledge about the effect of rare variants on eosinophil count, which can be of great value for further identification of therapeutic targets.