The Role of Long Noncoding RNAs in Gene Expression Regulation

Accumulating evidence highlights that noncoding RNAs, especially the long noncoding RNAs (lncRNAs), are critical regulators of gene expression in development, differentiation, and human diseases, such as cancers and heart diseases. The regulatory mechanisms of lncRNAs have been categorized into four major archetypes: signals, decoys, scaffolds, and guides. Increasing evidence points that lncRNAs are able to regulate almost every cellular process by their binding to proteins, mRNAs, miRNA, and/or DNAs. In this review, we present the recent research advances about the regulatory mechanisms of lncRNA in gene expression at various levels, including pretranscription, transcription regulation, and posttranscription regulation. We also introduce the interaction between lncRNA and DNA, RNA and protein, and the bioinformatics applications on lncRNA research

Phenotype-Genotype analysis of caucasian patients with high risk of osteoarthritis.

Background: Osteoarthritis (OA) is a common cause of disability and pain around the world. Epidemiologic studies of family history have revealed evidence of genetic influence on OA. Although many efforts have been devoted to exploring genetic biomarkers, the mechanism behind this complex disease remains unclear. The identified genetic risk variants only explain a small proportion of the disease phenotype. Traditional genome-wide association study (GWAS) focuses on radiographic evidence of OA and excludes sex chromosome information in the analysis. However, gender differences in OA are multifactorial, with a higher frequency in women, indicating that the chromosome X plays an essential role in OA pathology. Furthermore, the prevalence of comorbidities among patients with OA is high, indicating multiple diseases share a similar genetic susceptibility to OA. Methods: In this study, we performed GWAS of OA and OA-associated key comorbidities on 3366 OA patient data obtained from the Osteoarthritis Initiative (OAI). We performed Mendelian randomization to identify the possible causal relationship between OA and OA-related clinical features. Results: One significant OA-associated locus rs2305570 was identified through sex-specific genome-wide association. By calculating the LD score, we found OA is positively correlated with heart disease and stroke. A strong genetic correlation was observed between knee OA and inflammatory disease, including eczema, multiple sclerosis, and Crohn\u27s disease. Our study also found that knee alignment is one of the major risk factors in OA development, and we surprisingly found knee pain is not a causative factor of OA, although it was the most common symptom of OA. Conclusion: We investigated several significant positive/negative genetic correlations between OA and common chronic diseases, suggesting substantial genetic overlaps between OA and these traits. The sex-specific association analysis supports the critical role of chromosome X in OA development in females

Revealing chronic disease progression patterns using Gaussian process for stage inference.

OBJECTIVE: The early stages of chronic disease typically progress slowly, so symptoms are usually only noticed until the disease is advanced. Slow progression and heterogeneous manifestations make it challenging to model the transition from normal to disease status. As patient conditions are only observed at discrete timestamps with varying intervals, an incomplete understanding of disease progression and heterogeneity affects clinical practice and drug development. MATERIALS AND METHODS: We developed the Gaussian Process for Stage Inference (GPSI) approach to uncover chronic disease progression patterns and assess the dynamic contribution of clinical features. We tested the ability of the GPSI to reliably stratify synthetic and real-world data for osteoarthritis (OA) in the Osteoarthritis Initiative (OAI), bipolar disorder (BP) in the Adolescent Brain Cognitive Development Study (ABCD), and hepatocellular carcinoma (HCC) in the UTHealth and The Cancer Genome Atlas (TCGA). RESULTS: First, GPSI identified two subgroups of OA based on image features, where these subgroups corresponded to different genotypes, indicating the bone-remodeling and overweight-related pathways. Second, GPSI differentiated BP into two distinct developmental patterns and defined the contribution of specific brain region atrophy from early to advanced disease stages, demonstrating the ability of the GPSI to identify diagnostic subgroups. Third, HCC progression patterns were well reproduced in the two independent UTHealth and TCGA datasets. CONCLUSION: Our study demonstrated that an unsupervised approach can disentangle temporal and phenotypic heterogeneity and identify population subgroups with common patterns of disease progression. Based on the differences in these features across stages, physicians can better tailor treatment plans and medications to individual patients

COVIDanno, COVID-19 Annotation in Human

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 19 (COVID-19), has caused a global health crisis. Despite ongoing efforts to treat patients, there is no universal prevention or cure available. One of the feasible approaches will be identifying the key genes from SARS-CoV-2-infected cells. SARS-CoV-2-infected in vitro model, allows easy control of the experimental conditions, obtaining reproducible results, and monitoring of infection progression. Currently, accumulating RNA-seq data from SARS-CoV-2 in vitro models urgently needs systematic translation and interpretation. To fill this gap, we built COVIDanno, COVID-19 annotation in humans, available at http://biomedbdc.wchscu.cn/COVIDanno/. The aim of this resource is to provide a reference resource of intensive functional annotations of differentially expressed genes (DEGs) among different time points of COVID-19 infection in human in vitro models. To do this, we performed differential expression analysis for 136 individual datasets across 13 tissue types. In total, we identified 4,935 DEGs. We performed multiple bioinformatics/computational biology studies for these DEGs. Furthermore, we developed a novel tool to help users predict the status of SARS-CoV-2 infection for a given sample. COVIDanno will be a valuable resource for identifying SARS-CoV-2-related genes and understanding their potential functional roles in different time points and multiple tissue types

Revealing Chronic Disease Progression Patterns Using Gaussian Process for Stage Inference

OBJECTIVE: The early stages of chronic disease typically progress slowly, so symptoms are usually only noticed until the disease is advanced. Slow progression and heterogeneous manifestations make it challenging to model the transition from normal to disease status. As patient conditions are only observed at discrete timestamps with varying intervals, an incomplete understanding of disease progression and heterogeneity affects clinical practice and drug development. MATERIALS AND METHODS: We developed the Gaussian Process for Stage Inference (GPSI) approach to uncover chronic disease progression patterns and assess the dynamic contribution of clinical features. We tested the ability of the GPSI to reliably stratify synthetic and real-world data for osteoarthritis (OA) in the Osteoarthritis Initiative (OAI), bipolar disorder (BP) in the Adolescent Brain Cognitive Development Study (ABCD), and hepatocellular carcinoma (HCC) in the UTHealth and The Cancer Genome Atlas (TCGA). RESULTS: First, GPSI identified two subgroups of OA based on image features, where these subgroups corresponded to different genotypes, indicating the bone-remodeling and overweight-related pathways. Second, GPSI differentiated BP into two distinct developmental patterns and defined the contribution of specific brain region atrophy from early to advanced disease stages, demonstrating the ability of the GPSI to identify diagnostic subgroups. Third, HCC progression patterns were well reproduced in the two independent UTHealth and TCGA datasets. CONCLUSION: Our study demonstrated that an unsupervised approach can disentangle temporal and phenotypic heterogeneity and identify population subgroups with common patterns of disease progression. Based on the differences in these features across stages, physicians can better tailor treatment plans and medications to individual patients

A Novel Integrated Approach to Predicting Cancer Immunotherapy Efficacy

Immunotherapies have revolutionized cancer treatment modalities; however, predicting clinical response accurately and reliably remains challenging. Neoantigen load is considered as a fundamental genetic determinant of therapeutic response. However, only a few predicted neoantigens are highly immunogenic, with little focus on intratumor heterogeneity (ITH) in the neoantigen landscape and its link with different features in the tumor microenvironment. To address this issue, we comprehensively characterized neoantigens arising from nonsynonymous mutations and gene fusions in lung cancer and melanoma. We developed a composite NEO2IS to characterize interplays between cancer and CD8+ T-cell populations. NEO2IS improved prediction accuracy of patient responses to immune-checkpoint blockades (ICBs). We found that TCR repertoire diversity was consistent with the neoantigen heterogeneity under evolutionary selections. Our defined neoantigen ITH score (NEOITHS) reflected infiltration degree of CD8+ T lymphocytes with different differentiation states and manifested the impact of negative selection pressure on CD8+ T-cell lineage heterogeneity or tumor ecosystem plasticity. We classified tumors into distinct immune subtypes and examined how neoantigen-T cells interactions affected disease progression and treatment response. Overall, our integrated framework helps profile neoantigen patterns that elicit T-cell immunoreactivity, enhance the understanding of evolving tumor-immune interplays and improve prediction of ICBs efficacy

Causal Discovery in Radiographic Markers of Knee Osteoarthritis and Prediction for Knee Osteoarthritis Severity With Attention-Long Short-Term Memory.

The goal of this study is to build a prognostic model to predict the severity of radiographic knee osteoarthritis (KOA) and to identify long-term disease progression risk factors for early intervention and treatment. We designed a long short-term memory (LSTM) model with an attention mechanism to predict Kellgren/Lawrence (KL) grade for knee osteoarthritis patients. The attention scores reveal a time-associated impact of different variables on KL grades. We also employed a fast causal inference (FCI) algorithm to estimate the causal relation of key variables, which will aid in clinical interpretability. Based on the clinical information of current visits, we accurately predicted the KL grade of the patient\u27s next visits with 90% accuracy. We found that joint space narrowing was a major contributor to KOA progression. Furthermore, our causal structure model indicated that knee alignments may lead to joint space narrowing, while symptoms (swelling, grinding, catching, and limited mobility) have little impact on KOA progression. This study evaluated a broad spectrum of potential risk factors from clinical data, questionnaires, and radiographic markers that are rarely considered in previous studies. Using our statistical model, providers are able to predict the risk of the future progression of KOA, which will provide a basis for selecting proper interventions, such as proceeding to joint arthroplasty for patients. Our causal model suggests that knee alignment should be considered in the primary treatment and KOA progression was independent of clinical symptoms

Radiogenomics-Based Risk Prediction of Glioblastoma Multiforme with Clinical Relevance

Glioblastoma multiforme (GBM)is the most common and aggressive primary brain tumor. Although temozolomide (TMZ)-based radiochemotherapy improves overall GBM patients\u27 survival, it also increases the frequency of false positive post-treatment magnetic resonance imaging (MRI) assessments for tumor progression. Pseudo-progression (PsP) is a treatment-related reaction with an increased contrast-enhancing lesion size at the tumor site or resection margins miming tumor recurrence on MRI. The accurate and reliable prognostication of GBM progression is urgently needed in the clinical management of GBM patients. Clinical data analysis indicates that the patients with PsP had superior overall and progression-free survival rates. In this study, we aimed to develop a prognostic model to evaluate the tumor progression potential of GBM patients following standard therapies. We applied a dictionary learning scheme to obtain imaging features of GBM patients with PsP or true tumor progression (TTP) from the Wake dataset. Based on these radiographic features, we conducted a radiogenomics analysis to identify the significantly associated genes. These significantly associated genes were used as features to construct a 2YS (2-year survival rate) logistic regression model. GBM patients were classified into low- and high-survival risk groups based on the individual 2YS scores derived from this model. We tested our model using an independent The Cancer Genome Atlas Program (TCGA) dataset and found that 2YS scores were significantly associated with the patient\u27s overall survival. We used two cohorts of the TCGA data to train and test our model. Our results show that the 2YS scores-based classification results from the training and testing TCGA datasets were significantly associated with the overall survival of patients. We also analyzed the survival prediction ability of other clinical factors (gender, age, KPS (Karnofsky performance status), normal cell ratio) and found that these factors were unrelated or weakly correlated with patients\u27 survival. Overall, our studies have demonstrated the effectiveness and robustness of the 2YS model in predicting the clinical outcomes of GBM patients after standard therapies