Important cellular processes such as inflammation, apoptosis, differentiation, and proliferation confer critical roles in the pathogenesis of human diseases. In the past decade, an emerging process ...named “autophagy” has generated intense interest in both biomedical research and clinical medicine. Autophagy is a regulated cellular pathway for the turnover of organelles and proteins by lysosomal-dependent processing. Although autophagy was once considered a bulk degradation event, research shows that autophagy selectively degrades specific proteins, organelles, and invading bacteria, a process termed “selective autophagy.” It is increasingly clear that autophagy is directly relevant to clinical disease, including pulmonary disease. This review outlines the principal components of the autophagic process and discusses the importance of autophagy and autophagic proteins in pulmonary diseases from COPD, α1 -antitrypsin deficiency, pulmonary hypertension, acute lung injury, and cystic fibrosis to respiratory infection and sepsis. Finally, we examine the dual nature of autophagy in the lung, which has both protective and deleterious effects resulting from adaptive and maladaptive responses, and the challenge this duality poses for designing autophagy-based diagnostic and therapeutic targets in lung disease.
Design of the RAON accelerator systems Jeon, D.; Hong, I. S.; Kim, H. J. ...
Journal of the Korean Physical Society,
10/2014, Letnik:
65, Številka:
7
Journal Article
Recenzirano
The RAON is the name of the heavy ion accelerator facility under construction in Korea that includes the In-flight Fragment (IF) and Isotope Separation On-Line (ISOL) facilities to support ...cutting-edge research in various science fields. The superconducting linac is the driver for the IF facility that can accelerate beams from proton to uranium with 200 MeV/u, 400 kW (for uranium beam). A 70-MeV, 1-mA H
−
cyclotron is the driver for the ISOL facility and is followed by a post-accelerator consisting of s superconducting linac that can accelerate rare-isotope (RI) beams and deliver them to experimental halls. These facilities provide high-intensity stable ion and rare isotope (RI) beams for domestic and international users. In this paper, design and prototyping efforts for the RAON accelerator systems are presented.
Once regarded as a smoker's disease, small-cell lung cancer (SCLC) has been occasionally detected in never-smokers as smoking rates decrease worldwide. We investigated the clinical and genetic ...characteristics of SCLC in never-smokers.
Patients diagnosed with SCLC were grouped into smokers and never-smokers. The clinical outcomes of the two groups were compared. For SCLC in never-smokers, somatic mutation profiling was carried out using the AmpliSeq™ Cancer Hotspot Panel v2 and semiconductor sequencing technology. Epidermal growth factor receptor (EGFR) mutation was confirmed by PNAClamp™.
In total, 391 SCLC patients treated over a 5-year period were analyzed. Fifty patients (13%) were never-smokers. The median overall survival was 18.2 months in never-smokers and 13.1 months in smokers (P = 0.054). Never-smoking history was independently a good prognostic factor hazard ratio = 0.645, 95% confidence interval (CI) 0.456–0.914, as were limited disease (HR = 0.372, 95% CI 0.294–0.471), and lower age (HR = 0.709, 95% CI 0.566–0.888). The objective response rates to first-line etoposide/cisplatin therapy were similar between never-smokers and smokers (75% versus 81%). Of 28 genetically evaluable never-smokers, EGFR mutations were detected in four cases (two L858R, one deletion in exon 19, and one G719A). Other mutations were in TP53 (n = 26), RB1 (n = 7), PTEN (n = 5), MET (n = 4), and SMAD4 (n = 3).
Never-smokers with SCLC are increasingly prevalent and have a better prognosis than smokers with SCLC in Korea. Our study warrants further investigation in this group.
The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially ...reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1Liv-/- mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and bilirubin levels, despite the lack of exogenous liver injury. Inflammation was further studied using cytokine arrays, unveiling elevated levels of CCL2, TIMP1, CXCL10, and IL1-Rn in Cdk1Liv-/- liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1Liv-/- mice reversed most of these phenotypes. Overall, our data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype. It suggests that the decrease in hepatocyte division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue.
Summary
Background
Recent studies suggest that Staphylococcus aureus enterotoxin sensitization is a risk factor for asthma. However, there is a paucity of epidemiologic evidence on adult‐onset asthma ...in community‐based populations.
Objective
We sought to evaluate the epidemiology and the clinical significance of staphylococcal enterotoxin sensitization in community‐based adult populations.
Methods
The present analyses were performed using the baseline data set of Korean adult population surveys, consisting of 1080 adults (mean age = 60.2 years) recruited from an urban and a rural community. Questionnaires, methacholine challenge tests, and allergen skin tests were performed for defining clinical phenotypes. Sera were analysed for total IgE and enterotoxin‐specific IgE using ImmunoCAP.
Results
Staphylococcal enterotoxin sensitization (≥ 0.35 kU/L) had a prevalence of 27.0%. Risk factors were identified as male sex, current smoking, advanced age (≥ 61 years), and inhalant allergen sensitization. Current asthma was mostly adult onset (≥ 18 years old) and showed independent associations with high enterotoxin‐specific IgE levels in multivariate logistic regression tests. In multivariate linear regressions, staphylococcal enterotoxin‐specific IgE level was identified as the major determinant factor for total IgE level.
Conclusions and Clinical Relevance
Staphylococcal enterotoxin sensitization was independently associated with adult‐onset asthma in adult community populations. Strong correlations between the enterotoxin‐specific IgE and total IgE levels support the clinical significance. The present findings warrant further studies for the precise roles of staphylococcal enterotoxin sensitization in the asthma pathogenesis.
Mitochondria in health, disease, and aging Harrington, John S; Ryter, Stefan W; Plataki, Maria ...
Physiological reviews,
10/2023, Letnik:
103, Številka:
4
Journal Article
Recenzirano
Mitochondria are well known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. Although oxidative phosphorylation may be their most important ...function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
Aging is associated with metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease, cancer, and neurodegeneration. Aging contributes to common processes including metabolic ...dysfunction, DNA damage, and reactive oxygen species generation. Although glycolysis has been linked to cell growth and proliferation, the mechanisms by which the activation of glycolysis by aging regulates fibrogenesis in the lung remain unclear. The objective of this study was to determine if glucose transporter 1 (GLUT1)-induced glycolysis regulates age-dependent fibrogenesis of the lung. Mouse and human lung tissues were analyzed for GLUT1 and glycolytic markers using immunoblotting. Glycolytic function was measured using a Seahorse apparatus. To study the effect of GLUT1, genetic inhibition of GLUT1 was performed by short hairpin RNA transduction, and phloretin was used for pharmacologic inhibition of GLUT1. GLUT1-dependent glycolysis is activated in aged lung. Genetic and pharmacologic inhibition of GLUT1 suppressed the protein expression of α-smooth muscle actin, a key cytoskeletal component of activated fibroblasts, in mouse primary lung fibroblast cells. Moreover, we demonstrated that the activation of AMP-activated protein kinase, which is regulated by GLUT1-dependent glycolysis, represents a critical metabolic pathway for fibroblast activation. Furthermore, we demonstrated that phloretin, a potent inhibitor of GLUT1, significantly inhibited bleomycin-induced lung fibrosis in vivo. These results suggest that GLUT1-dependent glycolysis regulates fibrogenesis in aged lung and that inhibition of GLUT1 provides a potential target of therapy of age-related lung fibrosis.
Rapid prototyping (RP) is a relatively new technology that produces physical models by selectively solidifying UV-sensitive liquid resin using a laser beam. The technology has gained a great amount ...of attentin, particularly in oral and maxillofacial surgery. An important issue in RP applications in this field is how to obtain RP models of the required accuracy. We investigated errors generated during the production of medical RP models, and identified the factors that caused dimensional errors in each production phase. The errors were mainly due to the volume-averaging effect, threshold value, and difficulty in the exact replication of landmark locations. We made 16 linear measurements on a dry skull, a replicated three-dimensional (3-D) visual (STL) model, and an RP model. The results showed that the absolute mean deviation between the original dry skull and the RP model over the 16 linear measurements was 0.62±0.35mm (0.56±0.39%), which is smaller than values reported in previous studies. A major emphasis is placed on the dumb-bell effect. Classifying measurements as internal and external measurements, we observed that the effect of an inadequate threshold value differs with the type of measurement.
Autophagy is a highly conserved process by which cells can recycle organelles and proteins by degrading them in the lysosomes. Although autophagy is considered a dynamic system responsible for ...cellular renovation and homeostasis under physiological conditions, it is increasingly clear that autophagy is directly relevant to clinical disease. During disease progression, autophagy not only serves as a cellular protective mechanism but also can represent a harmful event under certain conditions. In addition, although autophagy can act as a nonselective bulk degradation process, recent research shows that autophagy can selectively degrade specific proteins, organelles, and invading bacteria, in processes termed "selective autophagy." Selective autophagy has drawn the attention of researchers because of its potential importance in clinical diseases. In this article, we outline the most recent studies implicating autophagy and selective autophagy in human lung diseases, including chronic obstructive pulmonary disease, pulmonary hypertension, idiopathic pulmonary fibrosis, and sepsis. We also discuss the relationship between autophagy and other molecular mechanisms related to disease progression, including programmed necrosis (necroptosis) and the inflammasome, an inflammatory signaling platform that regulates the secretion of IL-1β and IL-18. Finally, we examine the dual nature of autophagy and selective autophagy in the lung, which have both protective and injurious effects for human lung disease.
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