Optimizing Clinical Trial Eligibility Design Using Natural Language Processing Models and Real-World Data: Algorithm Development and Validation.

Background: Clinical trials are vital for developing new therapies but can also delay drug development. Efficient trial data management, optimized trial protocol, and accurate patient identification are critical for reducing trial timelines. Natural language processing (NLP) has the potential to achieve these objectives.

Divergent landscapes of A-to-I editing in postmortem and living human brain.

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues.

Detecting Ground Glass Opacity Features in Patients With Lung Cancer: Automated Extraction and Longitudinal Analysis via Deep Learning-Based Natural Language Processing.

Background: Ground-glass opacities (GGOs) appearing in computed tomography (CT) scans may indicate potential lung malignancy. Proper management of GGOs based on their features can prevent the development of lung cancer. Electronic health records are rich sources of information on GGO nodules and their granular features, but most of the valuable information is embedded in unstructured clinical notes.

Multiomic foundations of human prefrontal cortex tissue function.

The prefrontal cortex (PFC) is a region of the brain that in humans is involved in the production of higher-order functions such as cognition, emotion, perception, and behavior. Neurotransmission in the PFC produces higher-order functions by integrating information from other areas of the brain. At the foundation of neurotransmission, and by extension at the foundation of higher-order brain functions, are an untold number of coordinated molecular processes involving the DNA sequence variants in the genome, RNA transcripts in the transcriptome, and proteins in the proteome.

Characterizing cell type specific transcriptional differences between the living and postmortem human brain.

Single-nucleus RNA sequencing (snRNA-seq) is often used to define gene expression patterns characteristic of brain cell types as well as to identify cell type specific gene expression signatures of neurological and mental illnesses in postmortem human brains. As methods to obtain brain tissue from living individuals emerge, it is essential to characterize gene expression differences associated with tissue originating from either living or postmortem subjects using snRNA-seq, and to assess whether and how such differences may impact snRNA-seq studies of brain tissue. To address this, human prefrontal cortex single nuclei gene expression was generated and compared between 31 samples from living individuals and 21 postmortem samples.

Transcriptomic landscape of human induced pluripotent stem cell-derived osteogenic differentiation identifies a regulatory role of KLF16.

Osteogenic differentiation is essential for bone development and metabolism, but the underlying gene regulatory networks have not been well investigated. We differentiated mesenchymal stem cells, derived from 20 human induced pluripotent stem cell lines, into preosteoblasts and osteoblasts, and performed systematic RNA-seq analyses of 60 samples for differential gene expression. We noted a highly significant correlation in expression patterns and genomic proximity among transcription factor (TF) and long noncoding RNA (lncRNA) genes.

Anti-correlated feature selection prevents false discovery of subpopulations in scRNAseq.

While sub-clustering cell-populations has become popular in single cell-omics, negative controls for this process are lacking. Popular feature-selection/clustering algorithms fail the null-dataset problem, allowing erroneous subdivisions of homogenous clusters until nearly each cell is called its own cluster. Using real and synthetic datasets, we find that anti-correlated gene selection reduces or eliminates erroneous subdivisions, increases marker-gene selection efficacy, and efficiently scales to millions of cells.

Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV2 Infection.

Background: Acute kidney injury (AKI) is common in hospitalized patients with SARS-CoV2 infection despite vaccination and leads to long-term kidney dysfunction. However, peripheral blood molecular signatures in AKI from COVID-19 and their association with long-term kidney dysfunction are yet unexplored.

Methods: In patients hospitalized with SARS-CoV2, we performed bulk RNA sequencing using peripheral blood mononuclear cells(PBMCs).

Integration of transcriptomes of senescent cell models with multi-tissue patient samples reveals reduced COL6A3 as an inducer of senescence.

Senescent cells are a major contributor to age-dependent cardiovascular tissue dysfunction, but knowledge of their in vivo cell markers and tissue context is lacking. To reveal tissue-relevant senescence biology, we integrate the transcriptomes of 10 experimental senescence cell models with a 224 multi-tissue gene co-expression network based on RNA-seq data of seven tissues biopsies from ∼600 coronary artery disease (CAD) patients. We identify 56 senescence-associated modules, many enriched in CAD GWAS genes and correlated with cardiometabolic traits-which supports universality of senescence gene programs across tissues and in CAD.

Isoform-resolved transcriptome of the human preimplantation embryo.

Human preimplantation development involves extensive remodeling of RNA expression and splicing. However, its transcriptome has been compiled using short-read sequencing data, which fails to capture most full-length mRNAs. Here, we generate an isoform-resolved transcriptome of early human development by performing long- and short-read RNA sequencing on 73 embryos spanning the zygote to blastocyst stages.

Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice.

Background: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer's disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model.

Methods: AAV5-DUSP6 or AAV5-GFP (control) were stereotactically injected into the dorsal hippocampus (dHc) of female and male 5xFAD or wild type mice to overexpress DUSP6 or GFP.

Analysis of real-world data to investigate evolving treatment sequencing patterns in advanced non-small cell lung cancers and their impact on survival.

Background: Although optimal sequencing of systemic therapy in cancer care is critical to achieving maximal clinical benefit, there is a lack of analysis of treatment sequencing in advanced non-small cell lung cancer (aNSCLC) in real-world settings.

Methods: A retrospective cohort study of 13,340 lung cancer patients within the Mount Sinai Health System (MSHS) was performed. Systemic therapy data of aNSCLC in 2,106 patients was the starting point in our analysis to investigate how treatment sequencing has evolved, the impact of sequencing patterns on clinical outcomes, and the effectiveness of 2 line chemotherapy after patients progressed on immune checkpoint inhibitor (ICI)-based therapy as the 1 line of therapy (LOT).

A study of gene expression in the living human brain.

A goal of medical research is to determine the molecular basis of human brain health and illness. One way to achieve this goal is through observational studies of gene expression in human brain tissue. Due to the unavailability of brain tissue from living people, most such studies are performed using tissue from postmortem brain donors.

Proteomic Characterization of Acute Kidney Injury in Patients Hospitalized with SARS-CoV2 Infection.

Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction.

A temporal classifier predicts histopathology state and parses acute-chronic phasing in inflammatory bowel disease patients.

Previous studies have conducted time course characterization of murine colitis models through transcriptional profiling of differential expression. We characterize the transcriptional landscape of acute and chronic models of dextran sodium sulfate (DSS) and adoptive transfer (AT) colitis to derive temporal gene expression and splicing signatures in blood and colonic tissue in order to capture dynamics of colitis remission and relapse. We identify sub networks of patient-derived causal networks that are enriched in these temporal signatures to distinguish acute and chronic disease components within the broader molecular landscape of IBD.

Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females.

Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer's disease converged on (non-acronymic) as a key hub or driver. Within this computational network, we identified the dual-specificity protein phosphatase 4 () [also known as mitogen-activated protein kinase (MAPK) phosphatase 2] as an important node. Importantly, gene expression, like that of , is downregulated in postmortem Alzheimer's disease (AD) brains.

Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae.

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms.