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The thymus, a central lymphoid organ in animals, serves as the site for T cell development, differentiation and maturation, vital to adaptive immunity. The thymus is critical for maintaining tissue homeostasis to protect against tumors and tissue damage. An overactive or prolonged immune response can lead to oxidative stress from increased production of reactive oxygen species. Heat stress induces oxidative stress and overwhelms the natural antioxidant defense mechanisms. This study’s objectives were to investigate the protective properties of astaxanthin against heat-induced oxidative stress and apoptosis in the chicken thymus, by comparing the growth performance and gene signaling pathways among three groups: thermal neutral, heat stress, and heat stress with astaxanthin. The thermal neutral temperature was 21–22 °C, and the heat stress temperature was 32–35 °C. Both heat stress groups experienced reduced growth performance, while the astaxanthin-treated group showed a slightly lesser decline. The inflammatory response and antioxidant defense system were activated by the upregulation of the NF-kB, NFE2L2, PPARα, cytoprotective capacity, and apoptotic gene pathways during heat stress compared to the thermal neutral group. However, expression levels showed no significant differences between the thermal neutral and heat stress with antioxidant groups, suggesting that astaxanthin may mitigate inflammation and oxidative stress damage.

With significant advancements in the study of DNA Damage Response (DDR) and Fanconi Anemia (FA) signaling, we previously introduced the term “FA signaling” to encompass “all signaling transductions involving one or more FA proteins.” This network has now evolved into the largest cellular defense network, integrating over 30 key players, including ATM, ATR, BLM, HRR6, RAD18, FANCA, FANCB, FANCC, BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, BRIP1, FANCL, FANCM, PALB2, RAD51C, SLX4, ERCC4, RAD51, BRCA1, UBE2T, XRCC2, MAD2L2, RFWD3, FAAP20, FAAP24, FAAP100, and CENPX. This system responds to both endogenous and exogenous cellular insults. However, the mutational signatures associated with this defense mechanism in non-FA human cancers have not been extensively explored. In this study, we report that different types of human cancers are characterized by distinct somatically mutated genes related to DDR/FA signaling, each accompanied by a unique spectrum of potential driver mutations. For example, in pan-cancer samples, ATM emerges as the most frequently mutated gene (5%) among the 31 genes analyzed, with the highest number of potential driver mutations (1714), followed by BRCA2 (4% with 970 putative driver mutations). However, this pattern is not universal across specific cancer types. For example, FANCT is the most frequently mutated gene in breast (14%) and liver (4%) cancers. In addition, the alteration frequency of DDR/FA signaling due to these mutations exceeds 70% in a subtype of prostate cancer, with each subtype of brain, breast, lung, and prostate cancers displaying distinct patterns of gene alteration frequency. Furthermore, these gene alteration patterns significantly impact patient survival and disease-free periods. Collectively, our findings not only enhance our understanding of cancer development and progression but also have significant implications for cancer patient care and prognosis, particularly in the development of effective therapeutic strategies.

Objectives: The prevalence of respiratory infectious diseases has changed in the post-COVID-19 epidemic era, and mycoplasma pneumoniae (MP) infection in children has attracted wide attention. Methods: Children hospitalized for pneumonia in Wuhan, China, in 2023 were enrolled. Respiratory secretions were obtained for the targeted next-generation sequencing (tNGS) including mutation of MP. Pulmonary inflammation was divided into bronchopneumonia and pulmonary consolidation/atelectasis according to lung computed tomography imaging. Results: Of the 667 pediatric pneumonia, 478 were MP positive (72%). The positive rate of MP detected by tNGS increased from April, and MP had become the primary pathogen of pneumonia in children in 2023. The 23S rRNA mutations were all A2063G, accounting for 85% of detected MP. The clinical symptoms of the mutant and wild-type strains were similar, with half of them experiencing atelectasis and lung consolidation. Early bronchoscopic lavage combined with azithromycin in pediatric pulmonary consolidation was an effective therapy strategy, which could be an alternative selection to MP pneumonia treatment. Conclusions: A2063G mutant strain MP was the primary pathogen of mycoplasma pneumoniae in children recently, which was often complicated by extra-pulmonary symptoms and complications.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new emerging coronavirus that caused coronavirus disease 2019 (COVID-19). Whole-genome tracking of SARS-CoV-2 enhanced our understanding of the mechanism of the disease, control, and prevention of COVID-19. Methods: we analyzed 3368 SARS-CoV-2 protein sequences from Iran and compared them with 15.6 million global sequences in the GISAID database, using the Wuhan-Hu-1 strain as a reference. Results: Our investigation revealed that NSP12-P323L, ORF9c-G50N, NSP14-I42V, membrane-A63T, Q19E, and NSP3-G489S were found to be the most frequent mutations among Iranian SARS-CoV-2 sequences. Furthermore, it was observed that more than 94% of the SARS-CoV-2 genome, including NSP7, NSP8, NSP9, NSP10, NSP11, and ORF8, had no mutations when compared to the Wuhan-Hu-1 strain. Finally, our data indicated that the ORF3a-T24I, NSP3-G489S, NSP5-P132H, NSP14-I42V, envelope-T9I, nucleocapsid-D3L, membrane-Q19E, and membrane-A63T mutations might be responsible factors for the surge in the SARS-CoV-2 Omicron variant wave in Iran. Conclusions: real-time genomic surveillance is crucial for detecting new SARS-CoV-2 variants, updating diagnostic tools, designing vaccines, and understanding adaptation to new environments.

Abstract Background Mutations in one or more genes responsible for encoding subunits within the SWItch/Sucrose Non‐Fermentable (SWI/SNF) chromatin‐remodelling complexes are found in approximately 25% of cancer patients. Bromodomain containing 9 (BRD9) is a more recently identified protein coding gene, which can encode SWI/SNF chromatin‐remodelling complexes subunits. Although initial evaluations of the potential of BRD9‐based targeted therapy have been explored in the clinical application of a small number of cancer types, more detailed study of the diagnostic and prognostic potential, as well as the detailed biological mechanism of BRD9 remains unreported. Methods We used various bioinformatics tools to generate a comprehensive, pan‐cancer analyses of BRD9 expression in multiple disease types described in The Cancer Genome Atlas (TCGA). Experimental validation was conducted in tissue microarrays and cell lines derived from lung and colon cancers. Results Our study revealed that BRD9 exhibited elevated expression in a wide range of tumours. Analysis of survival data and DNA methylation for BRD9 indicated distinct conclusions for multiple tumours. mRNA splicing and molecular binding were involved in the functional mechanism of BRD9. BRD9 may affect cancer progression through different phosphorylation sites or N6‐methyladenosine site modifications. BRD9 could potentially serve as a novel biomarker for diagnosing different cancer types, especially could accurately forecast the prognosis of melanoma patients receiving anti‐programmed cell death 1 immunotherapy. BRD9 has the potential to serve as a therapeutic target, when pairing with etoposide in patients with melanoma. The BRD9/SMARCD1 axis exhibited promising discriminative performance in forecasting the prognosis of patients afflicted with liver hepatocellular carcinoma (LIHC) and mesothelioma. Additionally, this axis appears to potentially influence the immune response in LIHC by regulating the programmed death‐ligand 1 immune checkpoint. For experimental validation, high expression levels of BRD9 were observed in tumour tissue samples from both lung and colon cancer patients. Knocking down BRD9 led to the inhibition of lung and colon cancer development, likely via the Wnt/β‐catenin signalling pathway. Conclusions These pan‐cancer study revealed the diagnostic and prognostic potential, along with the biological mechanism of BRD9 as a novel therapeutic target in human tumours.

The gastrointestinal tract has a pivotal role in nutrient absorption, immune function, and overall homeostasis. The ileum segment of the small intestine plays respective roles in nutrient breakdown and absorption. The purpose of this study was to investigate the impact of heat-induced oxidative stress and the potential mitigating effects of an astaxanthin antioxidant treatment on the ileum of broilers. By comparing the growth performance and gene expression profiles among three groups—thermal neutral, heat stress, and heat stress with astaxanthin—thermal neutral temperature conditions of 21–22 °C and heat stress temperature of 32–35 °C, this research aims to elucidate the role of astaxanthin in supporting homeostasis and cellular protection in the ileum. Results showed both treatments under heat stress experienced reduced growth performance, while the group treated with astaxanthin showed a slightly lesser decline. Results further showed the astaxanthin treatment group significantly upregulated in the cytoprotective gene expression for HSF2, SOD2, GPX3, and TXN, as well as the upregulation of epithelial integrity genes LOX, CLDN1, and MUC2. In conclusion, our experimental findings demonstrate upregulation of cytoprotective and epithelial integrity genes, suggesting astaxanthin may effectively enhance the cellular response to heat stress to mitigate oxidative damage and contribute to cytoprotective capacity.

Small non-coding RNAs are potential diagnostic biomarkers for lung cancer. Mitochondria-derived small RNA (mtRNA) is a novel regulatory small non-coding RNA that only recently has been identified and cataloged. Currently, there are no reports of studies of mtRNA in human lung cancer. Currently, normalization methods are unstable, and they often fail to identify differentially expressed small non-coding RNAs (sncRNAs). In order to identify reliable biomarkers for lung cancer screening, we used a ratio-based method using mtRNAs newly discovered in human peripheral blood mononuclear cells. In the discovery cohort (AUC = 0.981) and independent validation cohort (AUC = 0.916) the prediction model of eight mtRNA ratios distinguished lung cancer patients from controls. The prediction model will provide reliable biomarkers that will allow blood-based screening to become more feasible and will help make lung cancer diagnosis more accurate in clinical practice.

BackgroundAlthough our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complications in COVID-19 infection remains unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequelae of SARS-CoV-2 infection (PASC) with persistent pulmonary symptoms. The dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown.ResultsTo characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing (scRNA-seq) to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from a participant naïve to SARS-CoV-2 (Control) (n=1) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC) (n=2). After integrating scRNA-seq data with a naïve participant from a published dataset, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14+/CD16+monocytes, and dendritic cells) was increased in PPASC (n=2) compared to controls (n=2). MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis-related (VEGF, WNT, and SMAD) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. Further comparison of PPASC with scRNA-seq data with Severe COVID-19 (n=4) data demonstrated enrichment of fibrotic transcriptional signatures. In PPASC, we observed interactive VEGF ligand-receptor pairs among MLCs, and network modules in CD14+ (cluster 4) and CD16+ (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID-19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS-CoV-2 naïve samples.ConclusionAnalysis of a small scRNA-seq dataset demonstrated alterations in the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests a potential role in PPASC development.

Abstract Background At the end of December 2019, a novel strain of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been identified in Wuhan, a central city in China, and then spread to every corner of the globe. As of October 8, 2022, the total number of COVID-19 cases had reached over 621 million worldwide, with more than 6.56 million confirmed deaths. Since SARS-CoV-2 genome sequences change due to mutation and recombination, it is pivotal to surveil emerging variants and monitor changes for improving pandemic management. Methods 10,287,271 SARS-CoV-2 genome sequence samples were downloaded in FASTA format from the GISAID databases from February 24, 2020, to April 2022. Python programming language (version 3.8.0) software was utilized to process FASTA files to identify variants and sequence conservation. The NCBI RefSeq SARS-CoV-2 genome (accession no. NC_045512.2) was considered as the reference sequence. Results Six mutations had more than 50% frequency in global SARS-CoV-2. These mutations include the P323L (99.3%) in NSP12, D614G (97.6) in S, the T492I (70.4) in NSP4, R203M (62.8%) in N, T60A (61.4%) in Orf9b, and P1228L (50.0%) in NSP3. In the SARS-CoV-2 genome, no mutation was observed in more than 90% of nsp11, nsp7, nsp10, nsp9, nsp8, and nsp16 regions. On the other hand, N, nsp3, S, nsp4, nsp12, and M had the maximum rate of mutations. In the S protein, the highest mutation frequency was observed in aa 508–635(0.77%) and aa 381–508 (0.43%). The highest frequency of mutation was observed in aa 66–88 (2.19%), aa 7–14, and aa 164–246 (2.92%) in M, E, and N proteins, respectively. Conclusion Therefore, monitoring SARS-CoV-2 proteomic changes and detecting hot spots mutations and conserved regions could be applied to improve the SARS‐CoV‐2 diagnostic efficiency and design safe and effective vaccines against emerging variants.

Small nucleolar RNAs (snoRNAs) constitute a class of intron-derived non-coding RNAs ranging from 60 to 300 nucleotides. Canonically localized in the nucleolus, snoRNAs play a pivotal role in RNA modifications and pre-ribosomal RNA processing. Based on the types of modifications they involve, such as methylation and pseudouridylation, they are classified into two main families—box C/D and H/ACA snoRNAs. Recent investigations have revealed the unconventional synthesis and biogenesis strategies of snoRNAs, indicating their more profound roles in pathogenesis than previously envisioned. This review consolidates recent discoveries surrounding snoRNAs and provides insights into their mechanistic roles in cancer. It explores the intricate interactions of snoRNAs within signaling pathways and speculates on potential therapeutic solutions emerging from snoRNA research. In addition, it presents recent findings on the long non-coding small nucleolar RNA host gene (lncSNHG), a subset of long non-coding RNAs (lncRNAs), which are the transcripts of parental SNHGs that generate snoRNA. The nucleolus, the functional epicenter of snoRNAs, is also discussed. Through a deconstruction of the pathways driving snoRNA-induced oncogenesis, this review aims to serve as a roadmap to guide future research in the nuanced field of snoRNA–cancer interactions and inspire potential snoRNA-related cancer therapies.

BackgroundThe Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is less likely to cause severe disease in children than the other variants but has become an increasing cause of febrile seizures (FS) among children. In this case-control study, we aimed to examine the risk factors associated with FS in children infected with the COVID-19 Omicron variant and related treatment modalities.MethodsThis retrospective case-control study includes 113 subjects infected with the COVID-19 Omicron variant, grouped into 45 cases (those with FS) and 68 controls (those without FS). Data on clinical features, laboratory parameters, and treatment modalities were collected and analyzed.ResultsApproximately 5.74% of COVID-19 infected children developed COVID-19-associated FS. Children with COVID-19 and high body temperatures [RR 1.474; (95% CI: 1.196–1.818), p

Transfer RNA (tRNA)-derived fragment (tRDF) is a novel small non-coding RNA that presents in different types of cancer. The comprehensive understanding of tRDFs in non-small cell lung cancer remains largely unknown. In this study, 1,550 patient samples of non-small cell lung cancer (NSCLC) were included, and 52 tRDFs with four subtypes were identified. Six tRDFs were picked as diagnostic signatures based on the tRDFs expression patterns, and area under the curve (AUC) in independent validations is up to 0.90. Two signatures were validated successfully in plasma samples, and six signatures confirmed the consistency of distinguished expression in NSCLC cell lines. Ten tRDFs along with independent risk scores can be used to predict survival outcomes by stages; 5a_tRF-Ile-AAT/GAT can be a prognosis biomarker for early stage. Association analysis of tRDFs-signatures-correlated mRNAs and microRNA (miRNA) were targeted to the cell cycle and oocyte meiosis signaling pathways. Five tRDFs were assessed to associate with PD-L1 immune checkpoint and correlated with the genes that target in PD-L1 checkpoint signaling pathway. Our study is the first to provide a comprehensive analysis of tRDFs in lung cancer, including four subtypes of tRDFs, investigating the diagnostic and prognostic values, and demonstrated their biological function and transcriptional role as well as potential immune therapeutic value.

The SARS-CoV-2 pandemic and the COVID-19 disease have affected everyone globally, leading to one of recorded history’s most significant research surges. As our knowledge evolves, our approaches to the virus and treatments must also evolve. The evaluation of future research approaches to SARS-CoV-2 will necessitate reviewing the host immune response and viral antagonism of that response. This review provides an overview of the current knowledge on SARS-CoV-2 by summarizing the virus and human response. The focuses are on the viral genome, replication cycle, host immune activation, response, signaling, and antagonism. To effectively fight the pandemic, efforts must focus on the current state of research to help develop treatments and prepare for future outbreaks.

The study of liquid biopsy with plasma samples is being conducted to identify biomarkers for clinical use. Exosomes, containing nucleic acids and metabolites, have emerged as possible sources for biomarkers. To evaluate the effectiveness of exosomes over plasma, we analyzed the small non-coding RNAs (sncRNAs) and metabolites extracted from exosomes in comparison to those directly extracted from whole plasma under both fasting and non-fasting conditions. We found that sncRNA profiles were not affected by fasting in either exosome or plasma samples. Our results showed that exosomal sncRNAs were found to have more consistent profiles. The plasma miRNA profiles contained high concentrations of cell-derived miRNAs that were likely due to hemolysis. We determined that certain metabolites in whole plasma exhibited noteworthy concentration shifts in relation to fasting status, while others did not. Here, we propose that (1) fasting is not required for a liquid biopsy study that involves both sncRNA and metabolomic profiling, as long as metabolites that are not influenced by fasting status are selected, and (2) the utilization of exosomal RNAs promotes robust and consistent findings in plasma samples, mitigating the impact of batch effects derived from hemolysis. These findings advance the optimization of liquid biopsy methodologies for clinical applications.

Abstract Background Maternal recognition is the crucial step for establishing pregnancy in cattle. This study aims to identify endometrial genes and biological pathways involved in the maternal recognition of pregnancy. Caruncular endometrial tissues were collected from Day 15–17 of gestation (pregnant), non-pregnant (absence of conceptus), and cyclic (non-bred) heifers. Results Total RNAs were isolated from the caruncular endometrial tissues of pregnant, non-pregnant, and cyclic heifers, and were subjected to high-throughput RNA-sequencing. The genes with at least two-fold change and Benjamini and Hochberg p-value ≤ 0.05 were considered differentially expressed genes and further confirmed with quantitative real-time PCR. A total of 107 genes (pregnant vs cyclic) and 98 genes (pregnant vs non-pregnant) were differentially expressed in the pregnant endometrium. The most highly up-regulated genes in the pregnant endometrium were MRS2, CST6, FOS, VLDLR, ISG15, IFI6, MX2, C15H11ORF34, EIF3M, PRSS22, MS4A8, and TINAGL1. Interferon signaling, immune response, nutrient transporter, synthesis, and secretion of proteins are crucial pathways during the maternal recognition of pregnancy. Conclusions The study demonstrated that the presence of conceptus at Day 15–17 of gestation affects the endometrial gene expression related to endometrial remodeling, immune response, nutrients and ion transporters, and relevant signaling pathways in the caruncular region of bovine endometrium during the maternal recognition of pregnancy.

Liver cancer presents divergent clinical behaviors. There remain opportunities for molecular markers to improve liver cancer diagnosis and prognosis, especially since tRNA-derived small RNAs (tsRNA) have rarely been studied. In this study, a random forests (RF) diagnostic model was built based upon tsRNA profiling of paired tumor and adjacent normal samples and validated by independent validation (IV). A LASSO model was used to developed a seven-tsRNA-based risk score signature for liver cancer prognosis. Model performance was evaluated by a receiver operating characteristic curve (ROC curve) and Precision-Recall curve (PR curve). The five-tsRNA-based RF diagnosis model had area under the receiver operating characteristic curve (AUROC) 88% and area under the precision–recall curve (AUPR) 87% in the discovery cohort and 87% and 86% in IV-AUROC and IV-AUPR, respectively. The seven-tsRNA-based prognostic model predicts the overall survival of liver cancer patients (Hazard Ratio 2.02, 95% CI 1.36–3.00, P

The 90 kDa ribosomal S6 kinases (RSKs) are serine threonine kinases comprising four isoforms. The isoforms can have overlapping functions in regulation of migration, invasion, proliferation, survival, and transcription in various cancer types. However, isoform specific differences in RSK1 versus RSK2 functions in gene regulation are not yet defined. Here, we delineate ribosomal S6 kinases isoform-specific transcriptional gene regulation by comparing transcription programs in RSK1 and RSK2 knockout cells using microarray analysis. Microarray analysis revealed significantly different mRNA expression patterns between RSK1 knockout and RSK2 knockout cell lines. Importantly some of these functions have not been previously recognized. Our analysis revealed RSK1 has specific roles in cell adhesion, cell cycle regulation and DNA replication and repair pathways, while RSK2 has specific roles in the immune response and interferon signaling pathways. We further validated that the identified gene sets significantly correlated with mRNA datasets from cancer patients. We examined the functional significance of the identified transcriptional programs using cell assays. In alignment with the microarray analysis, we found that RSK1 modulates the mRNA and protein expression of Fibronectin1, affecting cell adhesion and CDK2, affecting S-phase arrest in the cell cycle, and impairing DNA replication and repair. Under similar conditions, RSK2 showed increased ISG15 transcriptional expression, affecting the immune response pathway and cytokine expression. Collectively, our findings revealed the occurrence of RSK1 and RSK2 specific transcriptional regulation, defining separate functions of these closely related isoforms.

In vitro investigation on human development, disease modeling, and drug discovery has been empowered by human induced pluripotent stem cell (hiPSC) technologies that form the foundation of precision medicine. Race and sex genetic backgrounds have become a major focus of many diseases modeling and drug response evaluation in the pharmaceutical industry. Here, we gathered data from major stem cell repositories to analyze the diversity with respect to ethnicity, sex, and disease types; and we also analyzed public datasets to unravel transcriptomics differences between samples of different ethnicities and sexes. We found a lack of diversity despite the large sample size of human induced pluripotent stem cells. In the ethnic comparison, the White group made up the majority of the banked hiPSCs. Similarly, for the organ/disease type and sex comparisons, the neural and male hiPSCs accounted for the majority of currently available hiPSCs. Bulk RNA-seq and single-cell transcriptomic analysis coupled with Machine Learning and Network Analysis revealed panels of gene features differently expressed in healthy hiPSCs and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of different races and sexes. The data highlights the current ethnic and sex inequality in stem cell research and demonstrates the molecular biological diversity of hiPSCs and cardiomyocytes from different races and genders. We postulate that future efforts in stem cell biology, regenerative and precision medicine should be guided towards an inclusive, diverse repository reflecting the prevalence of diseases across racial and ethnic groups and the sexes, important for both common and rare disease modeling, drug screening, and cell therapeutics.

Abstract Background Cytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify types of cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and cross-validated resource for epigenetics research from the FDA’s Epigenomics Quality Control Group. Results Each sample is processed in multiple replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), enzymatic deamination method (EMSeq), targeted methylation sequencing (Illumina Methyl Capture EPIC), single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies, and 850k Illumina methylation arrays. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, bwa-meth, and BitMapperBS), we find overall high concordance between assays, but also differences in efficiency of read mapping, CpG capture, coverage, and platform performance, and variable performance across 26 microarray normalization algorithms. Conclusions The data provided herein can guide the use of these DNA reference materials in epigenomics research, as well as provide best practices for experimental design in future studies. By leveraging seven human cell lines that are designated as publicly available reference materials, these data can be used as a baseline to advance epigenomics research.

Summary: The MetaSUB Consortium, founded in 2015, is a global consortium with an interdisciplinary team of clinicians, scientists, bioinformaticians, engineers, and designers, with members from more than 100 countries across the globe. This network has continually collected samples from urban and rural sites including subways and transit systems, sewage systems, hospitals, and other environmental sampling. These collections have been ongoing since 2015 and have continued when possible, even throughout the COVID-19 pandemic. The consortium has optimized their workflow for the collection, isolation, and sequencing of DNA and RNA collected from these various sites and processing them for metagenomics analysis, including the identification of SARS-CoV-2 and its variants. Here, the Consortium describes its foundations, and its ongoing work to expand on this network and to focus its scope on the mapping, annotation, and prediction of emerging pathogens, mapping microbial evolution and antibiotic resistance, and the discovery of novel organisms and biosynthetic gene clusters.

Abstract Background The mechanism of egg formation in the oviduct of laying hens is tightly controlled; each segment of the oviduct contributes a unique component of the egg. Several genes/proteins are involved in the synthesis of a completely healthy egg. This implies a time- and tissue-specific expression of genes and proteins in the different oviductal segments. We used hens at different physiological stages and time points to understand the transcriptional regulation of egg-white (albumen) synthesis and secretion onto the eggs in the magnum of laying hens. This study used Next-Generation Sequencing and quantitative real-time PCR (qPCR) to detect the novel genes and the cognate biological pathways that regulate the major events during the albumen formation. Results Magnum tissues collected from laying (n = 5 each at 3 h post-ovulation, p.o. and 15–20 h p.o.), non-laying (n = 4), and molting (n = 5) hens were used for differential gene expression analyses. A total of 540 genes (152 upregulated and 388 down-regulated) were differentially expressed at 3 h p.o. in the magnum of laying hens. Kyoto Encyclopedia of Genes and Genomes pathways analysis of the 152 upregulated genes revealed that glycine, serine, and threonine metabolism was the most-enriched biological pathway. Furthermore, the top two most enriched keywords for the upregulated genes were amino-acid biosynthesis and proteases. Nine candidate genes associated with albumen formation were validated with qPCR to have differential expression in laying, non-laying, and molting hens. Proteases such as TMPRSS9, CAPN2, MMP1, and MMP9 (protein maturation, ECM degradation, and angiogenesis); enzymes such as PSPH, PHGDH, and PSAT1 (amino-acid biosynthesis); RLN3, ACE, and REN (albumen synthesis, secretion and egg transport); and AVD, AvBD11, and GPX3 (antimicrobial and antioxidants) were recognized as essential molecules linked to albumen deposition in the magnum. Conclusions This study revealed some novel genes that participate in the signaling pathways for egg-white synthesis and secretion along with some well-known functional genes. These findings help to understand the mechanisms involved in albumen biosynthesis.

High-risk benign breast tumors are known to develop breast cancer at high rates. However, it is still controversial whether they should be removed during diagnosis or followed up until cancer development becomes evident. Therefore, this study sought to identify circulating microRNAs (miRNAs) that could serve as detection markers of cancers arising from high-risk benign tumors. Small RNA-seq was performed using plasma samples collected from patients with early-stage breast cancer (CA) and high-risk (HB), moderate-risk (MB), and no-risk (Be) benign breast tumors. Proteomic profiling of CA and HB plasma was performed to investigate the underlying functions of the identified miRNAs. Our findings revealed that four miRNAs, hsa-mir-128-3p, hsa-mir-421, hsa-mir-130b-5p, and hsa-mir-28-5p, were differentially expressed in CA vs. HB and had diagnostic power to discriminate CA from HB with AUC scores greater than 0.7. Enriched pathways based on the target genes of these miRNAs indicated their association with IGF-1. Furthermore, the Ingenuity Pathway Analysis performed on the proteomic data revealed that the IGF-1 signaling pathway was significantly enriched in CA vs. HB. In conclusion, these findings suggest that these miRNAs could potentially serve as biomarkers for detecting early-stage breast cancer from high-risk benign tumors by monitoring IGF signaling-induced malignant transformation.

In the United States, besides the US territory Puerto Rico, Hawai‘i is the only state that grows commercial coffee. In Hawai’i, coffee is the second most valuable agricultural commodity. Health benefits associated with moderate coffee consumption, including its antioxidant capacity, have been correlated to its bioactive components. Post-harvest techniques, coffee variety, degree of roasting, and brewing methods significantly impact the metabolites, lipids, minerals, and/or antioxidant capacity of brewed coffees. The goal of our study was to understand the impact of roasting and brewing methods on metabolites, lipids, biogenic amines, minerals, and antioxidant capacity of two Hawai‘i-grown coffee (Coffea arabica) varieties, “Kona Typica” and “Yellow Catuai”. Our results indicated that both roasting and coffee variety significantly modulated several metabolites, lipids, and biogenic amines of the coffee brews. Furthermore, regardless of coffee variety, the antioxidant capacity of roasted coffee brews was higher in cold brews. Similarly, total minerals were higher in “Kona Typica” cold brews followed by “Yellow Catuai” cold brews. Hawai‘i-grown coffees are considered “specialty coffees” since they are grown in unique volcanic soils and tropical microclimates with unique flavors. Our studies indicate that both Hawai‘i-grown coffees contain several health-promoting components. However, future studies are warranted to compare Hawai‘i-grown coffees with other popular brand coffees and their health benefits in vivo.

Abstract Cancer is one of the leading causes of morbidity and mortality in the globe. Microbiological infections account for up to 20% of the total global cancer burden. The human microbiota within each organ system is distinct, and their compositional variation and interactions with the human host have been known to attribute detrimental and beneficial effects on tumor progression. With the advent of next generation sequencing (NGS) technologies, data generated from NGS is being used for pathogen detection in cancer. Numerous bioinformatics computational frameworks have been developed to study viral information from host-sequencing data and can be adapted to bacterial studies. This review highlights existing popular computational frameworks that utilize NGS data as input to decipher microbial composition, which output can predict functional compositional differences with clinically relevant applicability in the development of treatment and prevention strategies.

Abstract Background Evaluating the toxicity of chemical mixture and their possible mechanism of action is still a challenge for humans and other organisms. Microarray classifier analysis has shown promise in the toxicogenomic area by identifying biomarkers to predict unknown samples. Our study focuses on identifying gene markers with better sensitivity and specificity, building predictive models to distinguish metals from non-metal toxicants, and individual metal from one another, and furthermore helping understand underlying toxic mechanisms. Results Based on an independent dataset test, using only 15 gene markers, we were able to distinguish metals from non-metal toxicants with 100% accuracy. Of these, 6 and 9 genes were commonly down- and up-regulated respectively by most of the metals. 8 out of 15 genes belong to membrane protein coding genes. Function well annotated genes in the list include ADORA2B, ARNT, S100G, and DIO3. Also, a 10-gene marker list was identified that can discriminate an individual metal from one another with 100% accuracy. We could find a specific gene marker for each metal in the 10-gene marker list. Function well annotated genes in this list include GSTM2, HSD11B, AREG, and C8B. Conclusions Our findings suggest that using a microarray classifier analysis, not only can we create diagnostic classifiers for predicting an exact metal contaminant from a large scale of contaminant pool with high prediction accuracy, but we can also identify valuable biomarkers to help understand the common and underlying toxic mechanisms induced by metals.

Abstract Background The goal of our study is to investigate whether the methylation levels of AHCY and CBS promoters are related to the risk of cerebral infarction by detecting the methylation level of AHCY and CBS genes. Methods We extracted peripheral venous blood from 152 patients with cerebral infarction and 152 gender- and age-matched healthy controls, and determined methylation levels of AHCY and CBS promoters using quantitative methylation-specific polymerase chain reaction. We used the percentage of methylation reference (PMR) to indicate gene methylation level. Results We compared the promoter methylation levels of two genes (AHCY and CBS) in peripheral blood DNA between the cerebral infarction case group and the control group. Our study showed no significant difference in AHCY promoter methylation between case and control. Subgroup analysis by gender showed that the methylation level of AHCY in males in the case group was lower than that in the control group, but the difference was not statistically significant in females. In a subgroup analysis by age, there was no significant difference in the AHCY methylation level between the case and control in the young group (≤44 years old). However, the level of AHCY gene methylation in the middle-aged group (45–59 years old) was significantly higher and the aged group (≥60 years old) was significantly lower than that in the control groups. However, CBS promoter methylation levels were significantly lower in the case group than in the control group (median PMR: 70.20% vs 104.10%, P = 3.71E-10). In addition, the CBS methylation levels of males and females in the case group were significantly lower than those in the control group (male: 64.33% vs 105%, P = 2.667E-08; female: 78.05% vs 102.8%, P = 0.003). We also found that the CBS levels in the young (23–44), middle-aged (45–59), and older (60–90) groups were significantly lower than those in the control group (young group: 69.97% vs 114.71%; P = 0.015; middle-aged group: 56.04% vs 91.71%; P = 6.744E-06; older group: 81.6% vs 119.35%; P = 2.644E-04). Our ROC curve analysis of CBS hypomethylation showed an area under the curve of 0.713, a sensitivity of 67.4%, and a specificity of 74.0%. Conclusion Our study suggests that hypomethylation of the CBS promoter may be closely related to the risk of cerebral infarction and may be used as a non-invasive diagnostic biomarker for cerebral infarction.

Abstract Background Prostate cancer is a very common and highly fatal in men. Current non-invasive detection methods like serum biomarker are unsatisfactory. Biomarkers with high accuracy for diagnostic of prostate cancer are urgently needed. Many lipid species have been found related to various cancers. The purpose of our study is to explore the diagnostic value of lipids for prostate cancer. Results Using triple quadruple liquid chromatography electrospray ionization tandem mass spectrometry, we performed lipidomics profiling of 367 lipids on a total 114 plasma samples from 30 patients with prostate cancer, 38 patients with benign prostatic hyperplasia (BPH), and 46 male healthy controls to evaluate the lipids as potential biomarkers in the diagnosis of prostate cancer. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database was used to construct the potential mechanism pathway. After statistical analysis, five lipids were identified as a panel of potential biomarkers for the detection of prostate cancer between prostate cancer group and the BPH group; the sensitivity, specificity, and area under curve (AUC) of the combination of these five lipids were 73.3, 81.6%, and 0.800, respectively. We also identified another panel of five lipids in distinguishing between prostate cancer group and the control group with predictive values of sensitivity at 76.7%, specificity at 80.4%, and AUC at 0.836, respectively. The glycerophospholipid metabolism pathway of the selected lipids was considered as the target pathway. Conclusions Our study indicated that the identified plasma lipid biomarkers have potential in the diagnosis of prostate cancer.

Abstract Background Accurate and noninvasive diagnosis and staging of liver fibrosis are essential for effective clinical management of chronic liver disease (CLD). We aimed to identify serum metabolite markers that reliably predict the stage of fibrosis in CLD patients. Methods We quantitatively profiled serum metabolites of participants in 2 independent cohorts. Based on the metabolomics data from cohort 1 (504 HBV associated liver fibrosis patients and 502 normal controls, NC), we selected a panel of 4 predictive metabolite markers. Consequently, we constructed 3 machine learning models with the 4 metabolite markers using random forest (RF), to differentiate CLD patients from normal controls (NC), to differentiate cirrhosis patients from fibrosis patients, and to differentiate advanced fibrosis from early fibrosis, respectively. Results The panel of 4 metabolite markers consisted of taurocholate, tyrosine, valine, and linoelaidic acid. The RF models of the metabolite panel demonstrated the strongest stratification ability in cohort 1 to diagnose CLD patients from NC (area under the receiver operating characteristic curve (AUROC) = 0.997 and the precision-recall curve (AUPR) = 0.994), to differentiate fibrosis from cirrhosis (0.941, 0.870), and to stage liver fibrosis (0.918, 0.892). The diagnostic accuracy of the models was further validated in an independent cohort 2 consisting of 300 CLD patients with chronic HBV infection and 90 NC. The AUCs of the models were consistently higher than APRI, FIB-4, and AST/ALT ratio, with both greater sensitivity and specificity. Conclusions Our study showed that this 4-metabolite panel has potential usefulness in clinical assessments of CLD progression in patients with chronic hepatitis B virus infection.

Identification of microbial composition directly from tumor tissue permits studying the relationship between microbial changes and cancer pathogenesis. We interrogated bacterial presence in tumor and adjacent normal tissue strictly in pairs utilizing human whole exome sequencing to generate microbial profiles. Profiles were generated for 813 cases from stomach, liver, colon, rectal, lung, head & neck, cervical and bladder TCGA cohorts. Core microbiota examination revealed twelve taxa to be common across the nine cancer types at all classification levels. Paired analyses demonstrated significant differences in bacterial shifts between tumor and adjacent normal tissue across stomach, colon, lung squamous cell, and head & neck cohorts, whereas little or no differences were evident in liver, rectal, lung adenocarcinoma, cervical and bladder cancer cohorts in adjusted models. Helicobacter pylori in stomach and Bacteroides vulgatus in colon were found to be significantly higher in adjacent normal compared to tumor tissue after false discovery rate correction. Computational results were validated with tissue from an independent population by species-specific qPCR showing similar patterns of co-occurrence among Fusobacterium nucleatum and Selenomonas sputigena in gastric samples. This study demonstrates the ability to identify bacteria differential composition derived from human tissue whole exome sequences. Taken together our results suggest the microbial profiles shift with advanced disease and that the microbial composition of the adjacent tissue can be indicative of cancer stage disease progression.

Purpose. Septic shock is a severe complication of COVID-19 patients. We aim to identify risk factors associated with septic shock and mortality among COVID-19 patients. Methods. A total of 212 COVID-19 confirmed patients in Wuhan were included in this retrospective study. Clinical outcomes were designated as nonseptic shock and septic shock. Log-rank test was conducted to determine any association with clinical progression. A prediction model was established using random forest. Results. The mortality of septic shock and nonshock patients with COVID-19 was 96.7% (29/30) and 3.8% (7/182). Patients taking hypnotics had a much lower chance to develop septic shock (HR = 0.096, p=0.0014). By univariate logistic regression analysis, 40 risk factors were significantly associated with septic shock. Based on multiple regression analysis, eight risk factors were shown to be independent risk factors and these factors were then selected to build a model to predict septic shock with AUC = 0.956. These eight factors included disease severity (HR = 15, p 65 years (HR = 2.6, p=0.012), temperature > 39.1°C (HR = 2.9, p=0.047), white blood cell count > 10 × 10⁹ (HR = 6.9, p 75 × 10⁹ (HR = 2.4, p=0.022), creatine kinase > 5 U/L (HR = 1.8, p=0.042), glucose > 6.1 mmol/L (HR = 7, p 2 mmol/L (HR = 22, p

Background. Type 2 diabetes (T2D) as a worldwide chronic disease combined with the COVID-19 pandemic prompts the need for improving the management of hospitalized COVID-19 patients with preexisting T2D to reduce complications and the risk of death. This study aimed to identify clinical factors associated with COVID-19 outcomes specifically targeted at T2D patients and build an individualized risk prediction nomogram for risk stratification and early clinical intervention to reduce mortality. Methods. In this retrospective study, the clinical characteristics of 382 confirmed COVID-19 patients, consisting of 108 with and 274 without preexisting T2D, from January 8 to March 7, 2020, in Tianyou Hospital in Wuhan, China, were collected and analyzed. Univariate and multivariate Cox regression models were performed to identify specific clinical factors associated with mortality of COVID-19 patients with T2D. An individualized risk prediction nomogram was developed and evaluated by discrimination and calibration. Results. Nearly 15% (16/108) of hospitalized COVID-19 patients with T2D died. Twelve risk factors predictive of mortality were identified. Older age (HR = 1.076, 95% CI = 1.014–1.143, p=0.016), elevated glucose level (HR = 1.153, 95% CI = 1.038–1.28, p=0.0079), increased serum amyloid A (SAA) (HR = 1.007, 95% CI = 1.001–1.014, p=0.022), diabetes treatment with only oral diabetes medication (HR = 0.152, 95%CI = 0.032–0.73, p=0.0036), and oral medication plus insulin (HR = 0.095, 95%CI = 0.019–0.462, p=0.019) were independent prognostic factors. A nomogram based on these prognostic factors was built for early prediction of 7-day, 14-day, and 21-day survival of diabetes patients. High concordance index (C-index) was achieved, and the calibration curves showed the model had good prediction ability within three weeks of COVID-19 onset. Conclusions. By incorporating specific prognostic factors, this study provided a user-friendly graphical risk prediction tool for clinicians to quickly identify high-risk T2D patients hospitalized for COVID-19.

OverviewProcessed foods make up about 70 percent of the North American diet. Sulfites and other food preservatives are added to these foods largely to limit bacterial contamination. The mouth microbiota and its associated enzymes are the first to encounter food and therefore likely to be the most affected.MethodsEight saliva samples from ten individuals were exposed to two sulfite preservatives, sodium sulfite and sodium bisulfite. One sample set was evaluated for bacteria composition utilizing 16s rRNA sequencing, and the number of viable cells in all sample sets was determined utilizing ATP assays at 10 and 40-minute exposure times. All untreated samples were analyzed for baseline lysozyme activity, and possible correlations between the number of viable cells and lysozyme activity.ResultsSequencing indicated significant increases in alpha diversity with sodium bisulfite exposure and changes in relative abundance of 3 amplicon sequence variants (ASV). Sodium sulfite treated samples showed a significant decrease in the Firmicutes/Bacteroidetes ratio, a marginally significant change in alpha diversity, and a significant change in the relative abundance for Proteobacteria, Firmicutes, Bacteroidetes, and for 6 ASVs. Beta diversity didn't show separation between groups, however, all but one sample set was observed to be moving in the same direction under sodium sulfite treatment. ATP assays indicated a significant and consistent average decrease in activity ranging from 24-46% at both exposure times with both sulfites. Average initial rates of lysozyme activity between all individuals ranged from +/- 76% compared to individual variations of +/- 10-34%. No consistent, significant correlation was found between ATP and lysozyme activity in any sample sets.ConclusionsSulfite preservatives, at concentrations regarded as safe by the FDA, alter the relative abundance and richness of the microbiota found in saliva, and decrease the number of viable cells, within 10 minutes of exposure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious and pathogenic coronavirus that emerged in late 2019 and caused a pandemic of respiratory illness termed as coronavirus disease 2019 (COVID-19). Cancer patients are more susceptible to SARS-CoV-2 infection. The treatment of cancer patients infected with SARS-CoV-2 is more complicated, and the patients are at risk of poor prognosis compared to other populations. Patients infected with SARS-CoV-2 are prone to rapid development of acute respiratory distress syndrome (ARDS) of which pulmonary fibrosis (PF) is considered a sequelae. Both ARDS and PF are factors that contribute to poor prognosis in COVID-19 patients. However, the molecular mechanisms among COVID-19, ARDS and PF in COVID-19 patients with cancer are not well-understood. In this study, the common differentially expressed genes (DEGs) between COVID-19 patients with and without cancer were identified. Based on the common DEGs, a series of analyses were performed, including Gene Ontology (GO) and pathway analysis, protein–protein interaction (PPI) network construction and hub gene extraction, transcription factor (TF)–DEG regulatory network construction, TF–DEG–miRNA coregulatory network construction and drug molecule identification. The candidate drug molecules (e.g., Tamibarotene CTD 00002527) obtained by this study might be helpful for effective therapeutic targets in COVID-19 patients with cancer. In addition, the common DEGs among ARDS, PF and COVID-19 patients with and without cancer are TNFSF10 and IFITM2. These two genes may serve as potential therapeutic targets in the treatment of COVID-19 patients with cancer. Changes in the expression levels of TNFSF10 and IFITM2 in CD14+/CD16+ monocytes may affect the immune response of COVID-19 patients. Specifically, changes in the expression level of TNFSF10 in monocytes can be considered as an immune signature in COVID-19 patients with hematologic cancer. Targeting N6-methyladenosine (m6A) pathways (e.g., METTL3/SERPINA1 axis) to restrict SARS-CoV-2 reproduction has therapeutic potential for COVID-19 patients.

Extrinsic factors such as expression of PD-L1 (programmed dealth-ligand 1) in the tumor microenvironment (TME) have been shown to correlate with responses to checkpoint blockade therapy. More recently two intrinsic factors related to tumor genetics, microsatellite instability (MSI), and tumor mutation burden (TMB), have been linked to high response rates to checkpoint blockade drugs. These response rates led to the first tissue-agnostic approval of any cancer therapy by the FDA for the treatment of metastatic, MSI-H tumors with anti-PD-1 immunotherapy. But there are still very few studies focusing on the association of miRNAs with immune therapy through checkpoint inhibitors. Our team sought to explore the biology of such tumors further and suggest potential companion therapeutics to current checkpoint inhibitors. Analysis by Pearson Correlation revealed 41 total miRNAs correlated with mutation burden, 62 miRNAs correlated with MSI, and 17 miRNAs correlated with PD-L1 expression. Three miRNAs were correlated with all three of these tumor features as well as M1 macrophage polarization. No miRNAs in any group were associated with overall survival. TGF-β was predicted to be influenced by these three miRNAs (p = 0.008). Exploring miRNA targets as companions to treatment by immune checkpoint blockade revealed three potential miRNA targets predicted to impact TGF-β. M1 macrophage polarization state was also associated with tumors predicted to respond to therapy by immune checkpoint blockade.

Colorectal cancer often presents as a highly variable disease with myriad forms that are at times difficult to detect in early screenings with sufficient accuracy, for which novel diagnostic methods are an attractive and valuable area of improvement. To improve colorectal cancer diagnosis and prognosis, new biomarkers that can be assembled into a diagnostic panel must be identified, and tRNA-derived small RNAs (tsRNAs) are a particularly interesting and increasingly visible new class of molecules to examine. In this study, small RNA-seq data were profiled for the expression of 104 human tsRNAs in tumor tissue and adjacent normal tissue samples, and a diagnostic model was built based on four differentially expressed tsRNAs: tRF-22-WB86Q3P92, tRF-22-WE8SPOX52, tRF-22-WE8S68L52, tRF-18-8R1546D2. Furthermore, the diagnostic model was validated by two independent validation datasets (AUC was 0.97 and 0.99), and a LASSO model was applied to develop a seven-tsRNA-based risk score model for colorectal cancer prognosis. Finally, a tsRNA-mRNA interaction network was established according to potential mRNA targets predicted by bioinformatic methods. In conclusion, the results suggest that abnormal expression of tsRNA in colorectal cancer may have a functional effect on tumor action and moreover, that some of the tsRNAs identified in this study with diagnostic and prognostic potential could be of clinical significance.

Abstract This is an editorial report of the supplements to BMC Bioinformatics that includes 6 papers selected from the BIOCOMP’19—The 2019 International Conference on Bioinformatics and Computational Biology. These articles reflect current trend and development in bioinformatics research.

Objective: T cell activation triggers metabolic reprogramming to meet increased demands for energy and metabolites required for cellular proliferation. Ethanolamine phospholipid synthesis has emerged as a regulator of metabolic shifts in stem cells and cancer cells, which led us to investigate its potential role during T cell activation. Methods: As selenoprotein I (SELENOI) is an enzyme participating in two metabolic pathways for the synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, we generated SELENOI-deficient mouse models to determine loss-of-function effects on metabolic reprogramming during T cell activation. Ex vivo and in vivo assays were carried out along with metabolomic, transcriptomic, and protein analyses to determine the role of SELENOI and the ethanolamine phospholipids synthesized by this enzyme in cell signaling and metabolic pathways that promote T cell activation and proliferation. Results: SELENOI knockout (KO) in mouse T cells led to reduced de novo synthesis of PE and plasmenyl PE during activation and impaired proliferation. SELENOI KO did not affect T cell receptor signaling, but reduced activation of the metabolic sensor AMPK. AMPK was inhibited by high [ATP], consistent with results showing SELENOI KO causing ATP accumulation, along with disrupted metabolic pathways and reduced glycosylphosphatidylinositol (GPI) anchor synthesis/attachment Conclusions: T cell activation upregulates SELENOI-dependent PE and plasmenyl PE synthesis as a key component of metabolic reprogramming and proliferation.

Abstract Background Prognostic signatures are vital to precision medicine. However, development of somatic mutation prognostic signatures for cancers remains a challenge. In this study we developed a novel method for discovering somatic mutation based prognostic signatures. Results Somatic mutation and clinical data for lung adenocarcinoma (LUAD) and colorectal adenocarcinoma (COAD) from The Cancer Genome Atlas (TCGA) were randomly divided into training (n = 328 for LUAD and 286 for COAD) and validation (n = 167 for LUAD and 141 for COAD) datasets. A novel method of using the log2 ratio of the tumor mutation frequency to the paired normal mutation frequency is computed for each patient and missense mutation. The missense mutation ratios were mean aggregated into gene-level somatic mutation profiles. The somatic mutations were assessed using univariate Cox analysis on the LUAD and COAD training sets separately. Stepwise multivariate Cox analysis resulted in a final gene prognostic signature for LUAD and COAD. Performance was compared to gene prognostic signatures generated using the same pipeline but with different somatic mutation profile representations based on tumor mutation frequency, binary calls, and gene-gene network normalization. Signature high-risk LUAD and COAD cases had worse overall survival compared to the signature low-risk cases in the validation set (log-rank test p-value = 0.0101 for LUAD and 0.0314 for COAD) using mutation tumor frequency ratio (MFR) profiles, while all other methods, including gene-gene network normalization, have statistically insignificant stratification (log-rank test p-value ≥0.05). Most of the genes in the final gene signatures using MFR profiles are cancer-related based on network and literature analysis. Conclusions We demonstrated the robustness of MFR profiles and its potential to be a powerful prognostic tool in cancer. The results are robust according to validation testing and the selected genes are biologically relevant.

Abstract Background We utilized miRNAs expression and clinical data to develop a prognostic signature for patients with lung adenocarcinoma, with respect to their overall survival, to identify high-risk subjects based on their miRNA genomic profile. Methods MiRNA expressions based on miRNA sequencing and clinical data of lung adenocarcinoma patients (n = 479) from the Cancer Genome Atlas were randomly partitioned into non-overlapping Model (n = 320) and Test (n = 159) sets, respectively, for model estimation and validation. Results Among the ten miRNAs identified using the univariate Cox analysis, six from miR-8, miR-181, miR-326, miR-375, miR-99a, and miR-10, families showed improvement of the overall survival chance, while two miRNAs from miR-582 and miR-584 families showed a worsening of survival chances. The final prognostic signature was developed with five miRNAs—miR-375, miR-582-3p, miR-326, miR-181c-5p, and miR-99a-5p—utilizing a stepwise variable selection procedure. Using the KEGG pathway analysis, we found potential evidence supporting their significance in multiple cancer pathways, including non-small cell lung cancer. We defined two risk groups with a score calculated using the Cox regression coefficients. The five-year survival rates for the low-risk group was approximately 48.76% (95% CI = (36.15, 63.93)); however, it was as low as 7.50% (95% CI = (2.34, 24.01)) for the high-risk group. Furthermore, we demonstrated the effect of the genomic profile using the miRNA signature, quantifying survival rates for hypothetical subjects in different pathological stages of cancer. Conclusions The proposed prognostic signature can be used as a reliable tool for identifying high-risk subjects regarding survival based on their miRNA genomic profile.

Abstract Lung cancer remains a major threat to human health. Low dose CT scan (LDCT) has become the main method of early screening for lung cancer due to the low sensitivity of chest X‐ray. However, LDCT not only has a high false positive rate, but also entails risks of overdiagnosis and cumulative radiation exposure. In addition, cumulative radiation by LDCT screening and subsequent follow‐up can increase the risk of lung cancer. Many studies have shown that long noncoding RNAs (lncRNAs) remain stable in blood, and profiling of blood has the advantages of being noninvasive, readily accessible and inexpensive. Serum or plasma assay of lncRNAs in blood can be used as a novel detection method to assist LDCT while improving the accuracy of early lung cancer screening. LncRNAs can participate in the regulation of various biological processes. A large number of researches have reported that lncRNAs are key regulators involved in the progression of human cancers through multiple action models. Especially, some lncRNAs can affect various hallmarks of lung cancer. In addition to their diagnostic value, lncRNAs also possess promising potential in other clinical applications toward lung cancer. LncRNAs can be used as predictive markers for chemosensitivity, radiosensitivity, and sensitivity to epidermal growth factor receptor (EGFR)‐targeted therapy, and as well markers of prognosis. Different lncRNAs have been implicated to regulate chemosensitivity, radiosensitivity, and sensitivity to EGFR‐targeted therapy through diverse mechanisms. Although many challenges need to be addressed in the future, lncRNAs have bright prospects as an adjunct to radiographic methods in the clinical management of lung cancer.

The association of preterm or low birth weight (LBW) with the risk of metabolic syndrome is still unclear. This study aimed to assess the association between preterm or LBW and metabolic syndrome risk according to study or participants' characteristics. PubMed, Web of Science, and EMBASE were searched for epidemiologic studies on the association published up to April 30, 2020. Pooled odds ratio (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated using the random-effects model. Low birth weight was associated with an increased risk of metabolic syndrome (OR, 1.37; 95% CI, 1.17–1.61). In the subgroup analysis by study design, the pooled ORs for LBW and metabolic syndrome in the cohort and cross-sectional studies were 1.79 and 1.22. In the subgroup analysis by sex, LBW was found to be associated with an increased risk of metabolic syndrome in pooled studies including both men and women or studies including only women. The association between premature birth and risk of metabolic syndrome was significant in cohort studies (OR, 1.72; 95% CI, 1.12–2.65). Also, LBW or preterm was significantly associated with a higher Homeostasis Model Assessment of Insulin Resistance (WMD, 0.28; 95% CI, 0.19–0.36). Low birth weight and preterm might be risk factors for metabolic syndrome.

Abstract Background Lung cancer is a major cause of cancer-related mortality worldwide, and around two-thirds of patients have metastasis at diagnosis. Thus, detecting lung cancer at an early stage could reduce mortality. Aberrant levels of circulating small non-coding RNAs (small ncRNAs) are potential diagnostic or prognostic markers for lung cancer. We aimed to identify plasma small ncRNA pairs that could be used for early screening and detection of lung adenocarcinoma (LAC). Results A panel of seven small ncRNA pair ratios could differentiate patients with LAC or benign lung disease from high-risk controls with an area under the curve (AUC) of 100.0%, a sensitivity of 100.0% and a specificity of 100.0% at the training stage (which included 50 patients with early-stage LAC, 35 patients with benign diseases and 29 high-risk controls) and an AUC of 90.2%, a sensitivity of 91.5% and a specificity of 80.4% at the validation stage (which included 44 patients with early-stage LAC, 32 patients with benign diseases and 51 high-risk controls). The same panel could distinguish LAC from high-risk controls with an AUC of 100.0%, a sensitivity of 100.0% and a specificity of 100.0% at the training stage and an AUC of 89.5%, a sensitivity of 85.4% and a specificity of 83.3% at the validation stage. Another panel of five small ncRNA pair ratios (different from the first) was able to differentiate LAC from benign disease with an AUC of 82.0%, a sensitivity of 81.1% and a specificity of 78.1% in the training cohort and an AUC of 74.2%, a sensitivity of 70.4% and a specificity of 72.7% in the validation cohort. Conclusions Several small ncRNA pair ratios were identified as markers capable of discerning patients with LAC from those with benign lesions or high-risk control individuals.

Among human genetic diseases, Fanconi Anemia (FA) tops all with its largest number of health complications in nearly all human organ systems, suggesting the significant roles played by FA genes in the maintenance of human health. With the accumulated research on FA, the encoded protein products by FA genes have been building up to the biggest cell defense signaling network, composed of not only 22+ FA proteins but also ATM, ATR, and many other non-FA proteins. The FA D2 group protein (FANCD2) and its paralog form the focal point of FA signaling to converge the effects of its upstream players in response to a variety of cellular insults and simultaneously with downstream players to protect humans from contracting diseases, including aging and cancer. In this review, we update and discuss how the FA signaling crucially eases cellular stresses through understanding its focal point.

One in five cancers is attributed to infectious agents, and the extent of the impact on the initiation, progression, and disease outcomes may be underestimated. Infection-associated cancers are commonly attributed to viral, and to a lesser extent, parasitic and bacterial etiologies. There is growing evidence that microbial community variation rather than a single agent can influence cancer development, progression, response to therapy, and outcome. We evaluated microbial sequences from a subset of infection-associated cancers—namely, head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), and stomach adenocarcinoma (STAD) from The Cancer Genome Atlas (TCGA). A total of 470 paired tumor and adjacent normal samples were analyzed. In STAD, concurrent presence of EBV and Selemonas sputigena with a high diversity index were associated with poorer survival (HR: 2.23, 95% CI 1.26–3.94, p = 0.006 and HR: 2.31, 95% CI 1.1–4.9, p = 0.03, respectively). In LIHC, lower microbial diversity was associated with poorer overall survival (HR: 2.57, 95% CI: 1.2, 5.5, p = 0.14). Bacterial within-sample diversity correlates with overall survival in infection-associated cancers in a subset of TCGA cohorts.

Malignant Mesothelioma (MM) is a rare and highly aggressive cancer that develops from mesothelial cells lining the pleura and other internal cavities, and is often associated with asbestos exposure. To date, no effective treatments have been made available for this pathology. Herein, we propose a novel immunotherapeutic approach based on a unique vaccine targeting a series of antigens that we found expressed in different MM tumors, but largely undetectable in normal tissues. This vaccine, that we term p-Tvax, is comprised of a series of immunogenic peptides presented by both MHC-I and -II to generate robust immune responses. The peptides were designed using in silico algorithms that discriminate between highly immunogenic T cell epitopes and other harmful epitopes, such as suppressive regulatory T cell epitopes and autoimmune epitopes. Vaccination of mice with p-Tvax led to antigen-specific immune responses that involved both CD8+ and CD4+ T cells, which exhibited cytolytic activity against MM cells in vitro. In mice carrying MM tumors, p-Tvax increased tumor infiltration of CD4+ T cells. Moreover, combining p-Tvax with an OX40 agonist led to decreased tumor growth and increased survival. Mice treated with this combination immunotherapy displayed higher numbers of tumor-infiltrating CD8+ and CD4+ T cells and reduced T regulatory cells in tumors. Collectively, these data suggest that the combination of p-Tvax with an OX40 agonist could be an effective strategy for MM treatment.