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Respiratory Care Jul 2023COPD is a heterogeneous condition, the onset and trajectory of which is influenced not only by tobacco exposure but also an individual's genetics and the exposures they... (Review)
Review
COPD is a heterogeneous condition, the onset and trajectory of which is influenced not only by tobacco exposure but also an individual's genetics and the exposures they accumulate over their life course. In such a complex chronic disease, phenotyping individuals based on similar clinical or molecular characteristics can aid in guiding appropriate therapeutic management. Treatable traits, characteristics for which evidence exists for a specific favorable treatment response, are increasingly incorporated into COPD clinical guidelines. But the COPD phenotyping literature is evolving. Innovations in lung imaging and physiologic metrics, as well as omics technologies and biomarker science, are contributing to a better understanding of COPD heterogeneity. This review summarizes the evolution of COPD phenotyping, the current use of phenotyping to direct clinical care, and how innovations in clinical and molecular approaches to unraveling disease heterogeneity are refining our understanding of COPD phenotypes.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Lung; Biomarkers; Phenotype
PubMed: 37353326
DOI: 10.4187/respcare.11035 -
American Journal of Respiratory and... Nov 2023Chronic obstructive pulmonary disease is a major health problem with a high prevalence, a rising incidence, and substantial morbidity and mortality. Its course is... (Review)
Review
Chronic obstructive pulmonary disease is a major health problem with a high prevalence, a rising incidence, and substantial morbidity and mortality. Its course is punctuated by acute episodes of increased respiratory symptoms, termed exacerbations of chronic obstructive pulmonary disease (ECOPD). ECOPD are important events in the natural history of the disease, as they are associated with lung function decline and prolonged negative effects on quality of life. The present-day therapy for ECOPD with short courses of antibiotics and steroids and escalation of bronchodilators has resulted in only modest improvements in outcomes. Recent data indicate that ECOPD are heterogeneous, raising the need to identify distinct etioendophenotypes, incorporating traits of the acute event and of patients who experience recurrent events, to develop novel and targeted therapies. These characterizations can provide a complete clinical picture, the severity of which will dictate acute pharmacological treatment, and may also indicate whether a change in maintenance therapy is needed to reduce the risk of future exacerbations. In this review we discuss the latest knowledge of ECOPD types on the basis of clinical presentation, etiology, natural history, frequency, severity, and biomarkers in an attempt to characterize these events.
Topics: Humans; Quality of Life; Disease Progression; Pulmonary Disease, Chronic Obstructive; Anti-Bacterial Agents; Phenotype
PubMed: 37560988
DOI: 10.1164/rccm.202209-1748SO -
Drugs Jul 2023Chronic neuropathic pain after a spinal cord injury (SCI) continues to be a complex condition that is difficult to manage due to multiple underlying pathophysiological... (Review)
Review
Chronic neuropathic pain after a spinal cord injury (SCI) continues to be a complex condition that is difficult to manage due to multiple underlying pathophysiological mechanisms and the association with psychosocial factors. Determining the individual contribution of each of these factors is currently not a realistic goal; however, focusing on the primary mechanisms may be more feasible. One approach used to uncover underlying mechanisms includes phenotyping using pain symptoms and somatosensory function. However, this approach does not consider cognitive and psychosocial mechanisms that may also significantly contribute to the pain experience and impact treatment outcomes. Indeed, clinical experience supports that a combination of self-management, non-pharmacological, and pharmacological approaches is needed to optimally manage pain in this population. This article will provide a broad updated summary integrating the clinical aspects of SCI-related neuropathic pain, potential pain mechanisms, evidence-based treatment recommendations, neuropathic pain phenotypes and brain biomarkers, psychosocial factors, and progress regarding how defining neuropathic pain phenotypes and other surrogate measures in the neuropathic pain field may lead to targeted treatments for neuropathic pain after SCI.
Topics: Humans; Neuralgia; Biomarkers; Phenotype; Pain Management; Spinal Cord Injuries
PubMed: 37326804
DOI: 10.1007/s40265-023-01903-7 -
European Journal of Heart Failure Sep 2023Heart failure (HF) is a heterogeneous syndrome affecting more than 60 million individuals globally. Despite recent advancements in understanding of the pathophysiology... (Review)
Review
Heart failure (HF) is a heterogeneous syndrome affecting more than 60 million individuals globally. Despite recent advancements in understanding of the pathophysiology of HF, many issues remain including residual risk despite therapy, understanding the pathophysiology and phenotypes of patients with HF and preserved ejection fraction, and the challenges related to integrating a large amount of disparate information available for risk stratification and management of these patients. Risk prediction algorithms based on artificial intelligence (AI) may have superior predictive ability compared to traditional methods in certain instances. AI algorithms can play a pivotal role in the evolution of HF care by facilitating clinical decision making to overcome various challenges such as allocation of treatment to patients who are at highest risk or are more likely to benefit from therapies, prediction of adverse outcomes, and early identification of patients with subclinical disease or worsening HF. With the ability to integrate and synthesize large amounts of data with multidimensional interactions, AI algorithms can supply information with which physicians can improve their ability to make timely and better decisions. In this review, we provide an overview of the AI algorithms that have been developed for establishing early diagnosis of HF, phenotyping HF with preserved ejection fraction, and stratifying HF disease severity. This review also discusses the challenges in clinical deployment of AI algorithms in HF, and the potential path forward for developing future novel learning-based algorithms to improve HF care.
Topics: Humans; Artificial Intelligence; Heart Failure; Algorithms; Clinical Decision-Making; Phenotype
PubMed: 37560778
DOI: 10.1002/ejhf.2994 -
Redox Biology Aug 2023Cardiovascular diseases caused by atherosclerosis (AS) seriously endanger human health, which is closely related to vascular smooth muscle cell (VSMC) phenotypes. VSMC... (Review)
Review
Cardiovascular diseases caused by atherosclerosis (AS) seriously endanger human health, which is closely related to vascular smooth muscle cell (VSMC) phenotypes. VSMC phenotypic transformation is marked by the alteration of phenotypic marker expression and cellular behaviour. Intriguingly, the mitochondrial metabolism and dynamics altered during VSMC phenotypic transformation. Firstly, this review combs VSMC mitochondrial metabolism in three aspects: mitochondrial ROS generation, mutated mitochondrial DNA (mtDNA) and calcium metabolism respectively. Secondly, we summarized the role of mitochondrial dynamics in regulating VSMC phenotypes. We further emphasized the association between mitochondria and cytoskelton via presenting cytoskeletal support during mitochondrial dynamics process, and discussed its impact on their respective dynamics. Finally, considering that both mitochondria and cytoskeleton are mechano-sensitive organelles, we demonstrated their direct and indirect interaction under extracellular mechanical stimuli through several mechano-sensitive signaling pathways. We additionally discussed related researches in other cell types in order to inspire deeper thinking and reasonable speculation of potential regulatory mechanism in VSMC phenotypic transformation.
Topics: Humans; Muscle, Smooth, Vascular; Cardiovascular Diseases; Cytoskeleton; Mitochondria; Phenotype; Myocytes, Smooth Muscle; Cells, Cultured; Cell Proliferation
PubMed: 37321061
DOI: 10.1016/j.redox.2023.102778 -
Cell Reports. Medicine Nov 2023The post-acute sequelae of COVID-19 (PASC), also known as long COVID, is often associated with debilitating symptoms and adverse multisystem consequences. We obtain...
The post-acute sequelae of COVID-19 (PASC), also known as long COVID, is often associated with debilitating symptoms and adverse multisystem consequences. We obtain plasma samples from 117 individuals during and 6 months following their acute phase of infection to comprehensively profile and assess changes in cytokines, proteome, and metabolome. Network analysis reveals sustained inflammatory response, platelet degranulation, and cellular activation during convalescence accompanied by dysregulation in arginine biosynthesis, methionine metabolism, taurine metabolism, and tricarboxylic acid (TCA) cycle processes. Furthermore, we develop a prognostic model composed of 20 molecules involved in regulating T cell exhaustion and energy metabolism that can reliably predict adverse clinical outcomes following discharge from acute infection with 83% accuracy and an area under the curve (AUC) of 0.96. Our study reveals pertinent biological processes during convalescence that differ from acute infection, and it supports the development of specific therapies and biomarkers for patients suffering from long COVID.
Topics: Humans; Post-Acute COVID-19 Syndrome; Convalescence; Multiomics; COVID-19; Biomarkers; Phenotype
PubMed: 37890487
DOI: 10.1016/j.xcrm.2023.101254 -
Genes Sep 2023The astounding number of genetic variants revealed in the 15 years of genome-wide association studies of asthma has not kept pace with the goals of translational... (Review)
Review
The astounding number of genetic variants revealed in the 15 years of genome-wide association studies of asthma has not kept pace with the goals of translational genomics. Moving asthma diagnosis from a nonspecific umbrella term to specific phenotypes/endotypes and related traits may provide insights into features that may be prevented or alleviated by therapeutical intervention. This review provides an overview of the different asthma endotypes and phenotypes and the genomic findings from asthma studies using patient stratification strategies and asthma-related traits. Asthma genomic research for treatable traits has uncovered novel and previously reported asthma loci, primarily through studies in Europeans. Novel genomic findings for asthma phenotypes and related traits may arise from multi-trait and specific phenotyping strategies in diverse populations.
Topics: Humans; Genome-Wide Association Study; Genomics; Asthma; Phenotype
PubMed: 37761964
DOI: 10.3390/genes14091824 -
Molecular Cell Aug 2023To maintain genome integrity, cells must accurately duplicate their genome and repair DNA lesions when they occur. To uncover genes that suppress DNA damage in human...
To maintain genome integrity, cells must accurately duplicate their genome and repair DNA lesions when they occur. To uncover genes that suppress DNA damage in human cells, we undertook flow-cytometry-based CRISPR-Cas9 screens that monitored DNA damage. We identified 160 genes whose mutation caused spontaneous DNA damage, a list enriched in essential genes, highlighting the importance of genomic integrity for cellular fitness. We also identified 227 genes whose mutation caused DNA damage in replication-perturbed cells. Among the genes characterized, we discovered that deoxyribose-phosphate aldolase DERA suppresses DNA damage caused by cytarabine (Ara-C) and that GNB1L, a gene implicated in 22q11.2 syndrome, promotes biogenesis of ATR and related phosphatidylinositol 3-kinase-related kinases (PIKKs). These results implicate defective PIKK biogenesis as a cause of some phenotypes associated with 22q11.2 syndrome. The phenotypic mapping of genes that suppress DNA damage therefore provides a rich resource to probe the cellular pathways that influence genome maintenance.
Topics: Humans; CRISPR-Cas Systems; DNA Damage; Mutation; DNA Repair; Phenotype
PubMed: 37478847
DOI: 10.1016/j.molcel.2023.06.025 -
Annual Review of Genetics Nov 2023Assigning functions to genes and learning how to control their expression are part of the foundation of cell biology and therapeutic development. An efficient and... (Review)
Review
Assigning functions to genes and learning how to control their expression are part of the foundation of cell biology and therapeutic development. An efficient and unbiased method to accomplish this is genetic screening, which historically required laborious clone generation and phenotyping and is still limited by scale today. The rapid technological progress on modulating gene function with CRISPR-Cas and measuring it in individual cells has now relaxed the major experimental constraints and enabled pooled screening with complex readouts from single cells. Here, we review the principles and practical considerations for pooled single-cell CRISPR screening. We discuss perturbation strategies, experimental model systems, matching the perturbation to the individual cells, reading out cell phenotypes, and data analysis. Our focus is on single-cell RNA sequencing and cell sorting-based readouts, including image-enabled cell sorting. We expect this transformative approach to fuel biomedical research for the next several decades.
Topics: CRISPR-Cas Systems; Genome; Genetic Testing; Phenotype
PubMed: 37562410
DOI: 10.1146/annurev-genet-072920-013842 -
RMD Open Aug 2023The VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset systemic autoinflammatory condition that is caused by an acquired...
The VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset systemic autoinflammatory condition that is caused by an acquired deficiency of the UBA1 gene in hematopoietic progenitor cells. The clinical spectrum of the VEXAS syndrome currently comprises a broad range of phenotypes such as vasculitis, relapsing polychondritis and Sweet's syndrome. In the past, VEXAS patients have left clinicians puzzled and the true nature of this disease has not been captured until late 2020. This viewpoint describes the relevant clinical features of the VEXAS syndrome and reviews different approaches to establish the diagnosis. Finally, future directions within the field of systemic inflammatory diseases caused by somatic mutations are being discussed.
Topics: Humans; Myelodysplastic Syndromes; Phenotype
PubMed: 37532466
DOI: 10.1136/rmdopen-2023-003332