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Bioengineering (Basel, Switzerland) Jun 2024Gene pathways and gene-regulatory networks are used to describe the causal relationship between genes, based on biological experiments. However, many genes are still to...
Gene pathways and gene-regulatory networks are used to describe the causal relationship between genes, based on biological experiments. However, many genes are still to be studied to define novel pathways. To address this, a gene-clustering algorithm has been used to group correlated genes together, based on the similarity of their gene expression level. The existing methods cluster genes based on only one type of omics data, which ignores the information from other types. A large sample size is required to achieve an accurate clustering structure for thousands of genes, which can be challenging due to the cost of multi-omics data. Meta-analysis has been used to aggregate the data from multiple studies and improve the analysis results. We propose a computationally efficient meta-analytic gene-clustering algorithm that combines multi-omics datasets from multiple studies, using the fixed effects linear models and a modified weighted correlation network analysis framework. The simulation study shows that the proposed method outperforms existing single omic-based clustering approaches when multi-omics data and/or multiple studies are available. A real data example demonstrates that our meta-analytic method outperforms single-study based methods.
PubMed: 38927823
DOI: 10.3390/bioengineering11060587 -
Bioengineering (Basel, Switzerland) May 2024Six decades ago, Friedenstein and coworkers published a series of seminal papers identifying a cell population in bone marrow with osteogenic potential, now referred to... (Review)
Review
Six decades ago, Friedenstein and coworkers published a series of seminal papers identifying a cell population in bone marrow with osteogenic potential, now referred to as mesenchymal stem cells (MSCs). This work was also instrumental in establishing the identity of hematopoietic stem cell and the identification of skeletal stem/progenitor cell (SSPC) populations in various skeletal compartments. In recognition of the centenary year of Friedenstein's birth, I review key aspects of his work and discuss the evolving concept of the MSC and its various euphemisms indorsed by changing paradigms in the field. I also discuss the recent emphasis on MSC stromal quality attributes and how emerging data demonstrating a mechanistic link between stromal and stem/progenitor functions bring renewed relevance to Friedenstein's contributions and much needed unity to the field.
PubMed: 38927770
DOI: 10.3390/bioengineering11060534 -
Genes Jun 2024Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly affecting premature infants, with limited therapeutic options and increased long-term consequences....
Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly affecting premature infants, with limited therapeutic options and increased long-term consequences. Adrenomedullin (), a proangiogenic peptide hormone, has been found to protect rodents against experimental BPD. This study aims to elucidate the molecular and cellular mechanisms through which influences BPD pathogenesis using a lipopolysaccharide (LPS)-induced model of experimental BPD in mice. Bulk RNA sequencing of -sufficient (wild-type or ) and -haplodeficient () mice lungs, integrated with single-cell RNA sequencing data, revealed distinct gene expression patterns and cell type alterations associated with deficiency and LPS exposure. Notably, computational integration with cell atlas data revealed that -haplodeficient mouse lungs exhibited gene expression signatures characteristic of increased inflammation, natural killer (NK) cell frequency, and decreased endothelial cell and type II pneumocyte frequency. Furthermore, in silico human BPD patient data analysis supported our cell type frequency finding, highlighting elevated NK cells in BPD infants. These results underscore the protective role of in experimental BPD and emphasize that it is a potential therapeutic target for BPD infants with an inflammatory phenotype.
Topics: Adrenomedullin; Bronchopulmonary Dysplasia; Animals; Mice; Humans; Sequence Analysis, RNA; Disease Models, Animal; Lipopolysaccharides; Lung; Killer Cells, Natural; Transcriptome
PubMed: 38927741
DOI: 10.3390/genes15060806 -
Genes May 2024Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and... (Review)
Review
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and prognosis have occurred in SCLC for the past four decades. Recent progress in the treatment of extensive-stage disease (ES-SCLC) has been marked by incorporating immune checkpoint inhibitors (ICIs) into platinum-based chemotherapy, leading to modest improvements. Moreover, few second-line-and-beyond treatment options are currently available. The main limitation for the molecular study of SCLC has been the scarcity of samples, because only very early diseases are treated with surgery and biopsies are not performed when the disease progresses. Despite all these difficulties, in recent years we have come to understand that SCLC is not a homogeneous disease. At the molecular level, in addition to the universal loss of retinoblastoma (RB) and TP53 genes, a recent large molecular study has identified other mutations that could serve as targets for therapy development or patient selection. In recent years, there has also been the identification of new genetic subtypes which have shown us how intertumor heterogeneity exists. Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Immune Checkpoint Inhibitors; Mutation
PubMed: 38927637
DOI: 10.3390/genes15060701 -
Biomedicines Jun 2024The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer...
BACKGROUND
The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox () gene family, has been found involved in various cancers.
METHODS
Immunohistochemical (IHC) analysis was run on lung tissue samples from surgical lung biopsy (SLB) of 19 patients with IPF, retrospectively selected from the IPF database of the University Hospital of Modena. HOXB7 expression was analyzed and compared with that of five patients with no evidence of pulmonary fibrosis as controls.
RESULTS
The semi-quantitative analysis of IHC showed that HOXB7 protein expression was higher in IPF patients compared to controls (difference between means = 6.2 ± 2.37, = 0.0157). Further, HOXB7 expression was higher in IPF patients with a higher extent of fibrosis (50-75%)-measured with high-resolution computer tomography-compared to those with a lower extent (0-25%) (difference between means = 25.74 ± 6.72, = 0.004).
CONCLUSIONS
The expression of HOXB7 is higher in the lung of IPF patients compared to controls, and was represented in different cellular compartments within the lung niche. Further investigations are needed to clarify its role in the pathogenesis and progression of IPF.
PubMed: 38927528
DOI: 10.3390/biomedicines12061321 -
Biomedicines Jun 2024While some long-term effects of COVID-19 are respiratory in nature, a non-respiratory effect gaining attention has been a decline in hemoglobin, potentially mediated by...
While some long-term effects of COVID-19 are respiratory in nature, a non-respiratory effect gaining attention has been a decline in hemoglobin, potentially mediated by inflammatory processes. In this study, we examined the correlations between hemoglobin levels and inflammatory biomarkers and evaluated the association between hemoglobin and fatigue in a cohort of Long-COVID patients. This prospective cohort study in the Netherlands evaluated 95 (mostly hospitalized) patients, aged 40-65 years, 3-6 months post SARS-CoV-2 infection, examining their venous hemoglobin concentration, anemia (hemoglobin < 7.5 mmol/L in women and <8.5 mmol/L in men), inflammatory blood biomarkers, average FSS (Fatigue Severity Score), demographics, and clinical features. Follow-up hemoglobin was compared against hemoglobin during acute infection. Spearman correlation was used for assessing the relationship between hemoglobin concentrations and inflammatory biomarkers, and the association between hemoglobin and fatigue was examined using logistic regression. In total, 11 (16.4%) participants were suffering from anemia 3-6 months after SARS-CoV-2 infection. The mean hemoglobin value increased by 0.3 mmol/L 3-6 months after infection compared to the hemoglobin during the acute phase (-value = 0.003). Whilst logistic regression showed that a 1 mmol/L greater increase in hemoglobin is related to a decrease in experiencing fatigue in Long-COVID patients (adjusted OR 0.38 [95%CI 0.13-1.09]), we observed no correlations between hemoglobin and any of the inflammatory biomarkers examined. Our results indicate that hemoglobin impairment might play a role in developing Long-COVID fatigue. Further investigation is necessary to identify the precise mechanism causing hemoglobin alteration in these patients.
PubMed: 38927441
DOI: 10.3390/biomedicines12061234 -
Biomedicines May 2024Stellate ganglion blocks (SGBs) has been applied in clinics to alleviate pain-related syndromes for almost a century. In recent years, it has been reported that SGB can...
Stellate ganglion blocks (SGBs) has been applied in clinics to alleviate pain-related syndromes for almost a century. In recent years, it has been reported that SGB can attenuate acute lung injury (ALI) in animals. However, the details of these molecular mechanisms remain complex and unclear. In this study, rats were randomly divided into four groups: group C (receiving no treatment), group NS (receiving the intratracheal instillation of normal saline), group L (receiving the intratracheal instillation of LPS) and group LS (receiving SGB after the intratracheal instillation of LPS). The pathological damage of lung tissue, arterial blood gases, the differentiation of alveolar macrophages (AMs) and inflammatory cytokines (IL-1β, IL-6, IL-10) were detected. Furthermore, the oxidative stress indexes (ROS, CYP-D, T-SOD, Mn-SOD and CAT) in serum and the levels of Sirt3 signaling-associated proteins (JAK2/STAT3, NF-κb p65, CIRP and NLRP3) in the lungs were measured. The results revealed that SGB could attenuate lung tissue damage, improve pulmonary oxygenation, promote the differentiation of AMs to the M2 phenotype, decrease the secretion of IL-1β and IL-6, and increase the secretion of IL-10. Meanwhile, SGB was found to inhibit the production of ROS and CYP-D, and enhance the activities of T-SOD, Mn-SOD and CAT. Furthermore, SGB upregulated Sirt3 and downregulated JAK2/STAT3 and NF-κb p65 phosphorylation, CIRP and NLRP3. Our work revealed that SGB could attenuate LPS-induced ALI by activating the Sirt3-mediated regulation of oxidative stress and pulmonary inflammation; this may shed new light upon the protection of SGB and provide a novel prophylactic strategy for LPS-induced ALI.
PubMed: 38927355
DOI: 10.3390/biomedicines12061148 -
Biology Jun 2024Tumor cells display abnormal growth and division, avoiding the natural process of cell death. These cells can be benign (non-cancerous growth) or malignant (cancerous... (Review)
Review
Tumor cells display abnormal growth and division, avoiding the natural process of cell death. These cells can be benign (non-cancerous growth) or malignant (cancerous growth). Over the past few decades, numerous in vitro or in vivo tumor models have been employed to understand the molecular mechanisms associated with tumorigenesis in diverse regards. However, our comprehension of how non-tumor cells transform into tumor cells at molecular and cellular levels remains incomplete. The nematode has emerged as an excellent model organism for exploring various phenomena, including tumorigenesis. Although does not naturally develop cancer, it serves as a valuable platform for identifying oncogenes and the underlying mechanisms within a live organism. In this review, we describe three distinct germline tumor models in , highlighting their associated mechanisms and related regulators: (1) ectopic proliferation due to aberrant activation of GLP-1/Notch signaling, (2) meiotic entry failure resulting from the loss of GLD-1/STAR RNA-binding protein, (3) spermatogenic dedifferentiation caused by the loss of PUF-8/PUF RNA-binding protein. Each model requires the mutations of specific genes (, , and ) and operates through distinct molecular mechanisms. Despite these differences in the origins of tumorigenesis, the internal regulatory networks within each tumor model display shared features. Given the conservation of many of the regulators implicated in tumorigenesis, it is proposed that these unique models hold significant potential for enhancing our comprehension of the broader control mechanisms governing tumorigenesis.
PubMed: 38927305
DOI: 10.3390/biology13060425 -
Biomolecules Jun 2024Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer...
Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer detection and monitoring, utilizing various features of circulating cell-free DNA (cfDNA). In this study, we established two models based on cfDNA coverage patterns at the transcription start sites (TSSs) from 6X whole-genome sequencing: an Early Cancer Screening Model and an mutation status prediction model. The Early Cancer Screening Model showed encouraging prediction ability, especially for early-stage lung cancer. The mutation status prediction model exhibited high accuracy in distinguishing between -positive and wild-type cases. Additionally, cfDNA coverage patterns at TSSs also reflect gene expression patterns at the pathway level in lung cancer patients. These findings demonstrate the potential applications of cfDNA coverage patterns at TSSs in early cancer screening and in cancer subtyping.
Topics: Humans; ErbB Receptors; Lung Neoplasms; Early Detection of Cancer; Mutation; Cell-Free Nucleic Acids; Female; Male; Middle Aged; Aged; Proof of Concept Study; Biomarkers, Tumor; Liquid Biopsy; Whole Genome Sequencing; Transcription Initiation Site; Circulating Tumor DNA
PubMed: 38927119
DOI: 10.3390/biom14060716 -
Biomolecules Jun 2024Selective staining of extracellular vesicles (EVs) is a major challenge for diagnostic and therapeutic applications. Herein, the EV labeling properties of a new class of...
Tetranuclear Polypyridylruthenium(II) Complexes as Selective Nucleic Acid Stains for Flow Cytometric Analysis of Monocytic and Epithelial Lung Carcinoma Large Extracellular Vesicles.
Selective staining of extracellular vesicles (EVs) is a major challenge for diagnostic and therapeutic applications. Herein, the EV labeling properties of a new class of tetranuclear polypyridylruthenium(II) complexes, Rubb-TNL and Rubb-TL, as phosphorescent stains are described. These new stains have many advantages over standard stains to detect and characterize EVs, including: high specificity for EV staining versus cell staining; high phosphorescence yields; photostability; and a lack of leaching from EVs until incorporation with target cells. As an example of their utility, large EVs released from control (basal) or lipopolysaccharide (LPS)-stimulated THP-1 monocytic leukemia cells were studied as a model of immune system EVs released during bacterial infection. Key findings from EV staining combined with flow cytometry were as follows: (i) LPS-stimulated THP-1 cells generated significantly larger and more numerous large EVs, as compared with those from unstimulated cells; (ii) EVs retained native EV physical properties after staining; and (iii) the new stains selectively differentiated intact large EVs from artificial liposomes, which are models of cell membrane fragments or other lipid-containing debris, as well as distinguished two distinct subpopulations of monocytic EVs within the same experiment, as a result of biochemical differences between unstimulated and LPS-stimulated monocytes. Comparatively, the staining patterns of A549 epithelial lung carcinoma-derived EVs closely resembled those of THP-1 cell line-derived EVs, which highlighted similarities in their selective staining despite their distinct cellular origins. This is consistent with the hypothesis that these new phosphorescent stains target RNA within the EVs.
Topics: Humans; Extracellular Vesicles; Flow Cytometry; Monocytes; Lung Neoplasms; Nucleic Acids; Staining and Labeling; THP-1 Cells; Coordination Complexes; Lipopolysaccharides; Cell Line, Tumor; A549 Cells
PubMed: 38927067
DOI: 10.3390/biom14060664