Critical reviews in clinical laboratory sciences最新文献

Polycystic ovary syndrome (PCOS) is a complex multifactorial endocrinopathy affecting reproductive aged women globally, whose presentation is strongly influenced by genetic makeup, ethnic, and geographic diversity leaving these affected women substantially predisposed to reproductive and metabolic perturbations. Sophisticated techniques spanning genomics, proteomics, epigenomics, and transcriptomics have been harnessed to comprehensively understand the enigmatic pathophysiology of PCOS, however, conclusive markers for PCOS are still lacking today. Metabolomics represents a paradigm shift in biotechnological advances enabling the simultaneous identification and quantification of metabolites and the use of this approach has added yet another dimension to help unravel the strong metabolic component of PCOS. Reports dissecting the metabolic signature of PCOS have revealed disparate levels of metabolites such as pyruvate, lactate, triglycerides, free fatty acids, carnitines, branched chain and essential amino acids, and steroid intermediates in major biological compartments. These metabolites have been shown to be altered in women with PCOS overall, after phenotypic subgrouping, in animal models of PCOS, and also following therapeutic intervention. This review seeks to supplement previous reviews by highlighting the aforementioned aspects and to provide easy, coherent and elementary access to significant findings and emerging trends. This will in turn help to delineate the metabolic plot in women with PCOS in various biological compartments including plasma, urine, follicular microenvironment, and gut. This may pave the way to design additional studies on the quest of unraveling the etiology of PCOS and delving into novel biomarkers for its diagnosis, prognosis and management.

Pulmonary arterial hypertension (PAH), one subtype of pulmonary hypertension (PH), is a life-threatening condition characterized by pulmonary arterial remodeling, elevated pulmonary vascular resistance, and blood pressure in the pulmonary arteries, leading to right heart failure and increased mortality. The disease is marked by endothelial dysfunction, vasoconstriction, and vascular remodeling. The role of Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors, a class of medications originally developed for diabetes management, is increasingly being explored in the context of cardiovascular diseases, including PAH, due to their potential to modulate these pathophysiological processes. In this review, we systematically examine the burgeoning evidence from both basic and clinical studies that describe the effects of SGLT2 inhibitors on cardiovascular health, with a special emphasis on PAH. By delving into the complex interactions between these drugs and the potential pathobiology that underpins PH, this study seeks to uncover the mechanistic underpinnings that could justify the use of SGLT2 inhibitors as a novel therapeutic approach for PAH. We collate findings that illustrate how SGLT2 inhibitors may influence the normal function of pulmonary arteries, possibly alleviating the pathological hallmarks of PAH such as inflammation, oxidative stress, aberrant cellular proliferation, and so on. Our review thereby outlines a potential paradigm shift in PAH management, suggesting that these inhibitors could play a crucial role in modulating the disease's progression by targeting the potential dysfunctions that drive it. This comprehensive synthesis of existing research underscores the imperative need for further clinical trials to validate the efficacy of SGLT2 inhibitors in PAH and to integrate them into the therapeutic agents used against this challenging disease.

The field of pharmacogenetics, the investigation of the influence of one or more sequence variants on drug response phenotypes, is a special case of pharmacogenomics, a discipline that takes a genome-wide approach. Massively parallel, next generation sequencing (NGS), has allowed pharmacogenetics to be subsumed by pharmacogenomics with respect to the identification of variants associated with responders and non-responders, optimal drug response, and adverse drug reactions. A plethora of rare and common naturally-occurring GPCR variants must be considered in the context of signals from across the genome. Many fundamentals of pharmacogenetics were established for G protein-coupled receptor (GPCR) genes because they are primary targets for a large number of therapeutic drugs. Functional studies, demonstrating likely-pathogenic and pathogenic GPCR variants, have been integral to establishing models used for in silico analysis. Variants in GPCR genes include both coding and non-coding single nucleotide variants and insertion or deletions (indels) that affect cell surface expression (trafficking, dimerization, and desensitization/downregulation), ligand binding and G protein coupling, and variants that result in alternate splicing encoding isoforms/variable expression. As the breadth of data on the GPCR genome increases, we may expect an increase in the use of drug labels that note variants that significantly impact the clinical use of GPCR-targeting agents. We discuss the implications of GPCR pharmacogenomic data derived from the genomes available from individuals who have been well-phenotyped for receptor structure and function and receptor-ligand interactions, and the potential benefits to patients of optimized drug selection. Examples discussed include the renin-angiotensin system in SARS-CoV-2 (COVID-19) infection, the probable role of chemokine receptors in the cytokine storm, and potential protease activating receptor (PAR) interventions. Resources dedicated to GPCRs, including publicly available computational tools, are also discussed.

RNA methylation is a widespread regulatory mechanism that controls gene expression in physiological processes. In recent years, the mechanisms and functions of RNA methylation under diseased conditions have been increasingly unveiled by RNA sequencing technologies with large scale and high resolution. In this review, the fundamental concept of RNA methylation is introduced, and the common types of transcript methylation and their machineries are described. Then, the regulatory roles of RNA methylation, particularly N6-methyladenosine and 5-methylcytosine, in the vascular lesions of ocular and cardiopulmonary diseases are discussed and compared. The ocular diseases include corneal neovascularization, retinopathy of prematurity, diabetic retinopathy, and pathologic myopia; whereas the cardiopulmonary ailments involve atherosclerosis and pulmonary hypertension. This review hopes to shed light on the common regulatory mechanisms underlying the vascular lesions in these ocular and cardiopulmonary diseases, which may be conducive to developing therapeutic strategies in clinical practice.

This scoping review aimed to synthesize the analytical techniques used and methodological limitations encountered when undertaking secondary research using residual neonatal dried blood spot (DBS) samples. Studies that used residual neonatal DBS samples for secondary research (i.e. research not related to newborn screening for inherited genetic and metabolic disorders) were identified from six electronic databases: Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Medline, PubMed and Scopus. Inclusion was restricted to studies published from 1973 and written in or translated into English that reported the storage, extraction and testing of neonatal DBS samples. Sixty-seven studies were eligible for inclusion. Included studies were predominantly methodological in nature and measured various analytes, including nucleic acids, proteins, metabolites, environmental pollutants, markers of prenatal substance use and medications. Neonatal DBS samples were stored over a range of temperatures (ambient temperature, cold storage or frozen) and durations (two weeks to 40.5 years), both of which impacted the recovery of some analytes, particularly amino acids, antibodies and environmental pollutants. The size of DBS sample used and potential contamination were also cited as methodological limitations. Residual neonatal DBS samples retained by newborn screening programs are a promising resource for secondary research purposes, with many studies reporting the successful measurement of analytes even from neonatal DBS samples stored for long periods of time in suboptimal temperatures and conditions.

Parkinson's disease (PD) is a neurodegenerative condition marked by the gradual depletion of dopaminergic neurons in the substantia nigra. Despite substantial strides in comprehending potential causative mechanisms, the validation of biomarkers with unequivocal evidence for routine clinical application remains elusive. Consequently, the diagnosis heavily relies on patients' clinical assessments and medical backgrounds. The imperative need for diagnostic and prognostic biomarkers arises due to the prevailing limitations of treatments, which predominantly address symptoms without modifying the disease course. This comprehensive review aims to elucidate the existing landscape of diagnostic and prognostic biomarkers for PD, drawing insights from contemporary literature.

Transthyretin (TTR), a homotetrameric protein found in plasma, cerebrospinal fluid, and the eye, plays a pivotal role in the onset of several amyloid diseases with high morbidity and mortality. Protein aggregation and fibril formation by wild-type TTR and its natural more amyloidogenic variants are hallmarks of ATTRwt and ATTRv amyloidosis, respectively. The formation of soluble amyloid aggregates and the accumulation of insoluble amyloid fibrils and deposits in multiple tissues can lead to organ dysfunction and cell death. The most frequent manifestations of ATTR are polyneuropathies and cardiomyopathies. However, clinical manifestations such as carpal tunnel syndrome, leptomeningeal, and ocular amyloidosis, among several others may also occur. This review provides an up-to-date listing of all single amino-acid mutations in TTR known to date. Of approximately 220 single-point mutations, 93% are considered pathogenic. Aspartic acid is the residue mutated with the highest frequency, whereas tryptophan is highly conserved. "Hot spot" mutation regions are mainly assigned to β-strands B, C, and D. This manuscript also reviews the protein aggregation models that have been proposed for TTR amyloid fibril formation and the transient conformational states that convert native TTR into aggregation-prone molecular species. Finally, it compiles the various in vitro TTR aggregation protocols currently in use for research and drug development purposes. In short, this article reviews and discusses TTR mutagenesis and amyloidogenesis, and their implications in disease onset.

There is a growing focus on understanding the role of the male microbiome in fertility issues. Although research on the bacterial communities within the male reproductive system is in its initial phases, recent discoveries highlight notable variations in the microbiome's composition and abundance across distinct anatomical regions like the skin, foreskin, urethra, and coronary sulcus. To assess the relationship between male genitourinary microbiome and reproduction, we queried various databases, including MEDLINE (available via PubMed), SCOPUS, and Web of Science to obtain evidence-based data. The literature search was conducted using the following terms "gut/intestines microbiome," "genitourinary system microbiome," "microbiome and female/male infertility," "external genital tract microbiome," "internal genital tract microbiome," and "semen microbiome." Fifty-one relevant papers were analyzed, and eleven were strictly semen quality or male fertility related. The male microbiome, especially in the accessory glands like the prostate, seminal vesicles, and bulbourethral glands, has garnered significant interest because of its potential link to male fertility and reproduction. Studies have also found differences in bacterial diversity present in the testicular tissue of normozoospermic men compared to azoospermic suggesting a possible role of bacterial dysbiosis and reproduction. Correlation between the bacterial taxa in the genital microbiota of sexual partners has also been found, and sexual activity can influence the composition of the urogenital microbiota. Exploring the microbial world within the male reproductive system and its influence on fertility opens doors to developing ways to prevent, diagnose, and treat infertility. The present work emphasizes the importance of using consistent methods, conducting long-term studies, and deepening our understanding of how the reproductive tract microbiome works. This helps make research comparable, pinpoint potential interventions, and smoothly apply microbiome insights to real-world clinical practices.

This article comprehensively elucidates the discovery of Krebs von den Lungen-6 (KL-6), its structural features, functional mechanisms, and the current research status in various respiratory system diseases. Discovered in 1985, KL-6 was initially considered a tumor marker, but its elevated levels in interstitial lung disease (ILD) led to its recognition as a relevant serum marker for ILD. KL-6 is primarily produced by type 2 alveolar epithelial cell regeneration. Over the past 30 years since the discovery of KL-6, the number of related research papers has steadily increased annually. Following the coronavirus disease 2019 (COVID-19) pandemic, there has been a sudden surge in relevant literature. Despite KL-6's potential as a biomarker, its value in the diagnosis, treatment, and prognosis varies across different respiratory diseases, including ILD, idiopathic pulmonary fibrosis (IPF), COVID-19, and lung cancer. Therefore, as an important serum biomarker in respiratory system diseases, the value of KL-6 still requires further investigation.

Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency (PID) characterized by an impaired immunoglobulin production, in association with an increased susceptibility to infections and a diversity of clinical manifestations. This narrative review summarizes immunophenotypic abnormalities in CVID patients and their relevance for diagnosis and disease classification. A comprehensive search across four databases - PubMED, Web of Science, EMBASE and Google Scholar - yielded 170 relevant studies published between 1988 and April 31, 2023. Over the past decades, the role of immunophenotyping in CVID diagnosis has become evident by identifying "hallmark" immunophenotypic aberrancies in patient subsets, with some now integrated in the consensus diagnostic criteria. Furthermore, the role of immunophenotyping in subclassifying CVID in relation to clinical presentation and prognosis has been extensively studied. Certain immunophenotypic patterns consistently correlate with clinical manifestations and/or subsets of CVID, particularly those associated with noninfectious complications (i.e. low switched memory B cells, shifts in follicular helper T cell subsets, low naïve CD4⁺ T cells, low regulatory T cells, and expansion of CD21low B cells, often associated with autoimmunity and/or splenomegaly). Also, efforts to associate subset levels of innate immune cells, such as Natural Killer (NK) cells, invariant (i)NKT cells, innate lymphoid cells (ILCs), and dendritic cells (DCs) to CVID complications are evident albeit in a lesser degree. However, inconsistencies regarding the role of flow cytometry in classification and prognosis persist, reflecting the disease complexity, but probably also cohort variations and methodological differences between published studies. This underscores the need for collaborative efforts to integrate emerging concepts, such as standardized flow cytometry and computational tools, for a more precise CVID classification approach. Additionally, recent studies suggest a potential value of (epi)genetic-based molecular assays to this effort.