Identification of a Complex Karyotype Signature with Clinical Implications in AML and MDS-EB Using Gene Expression Profiling.

Complex karyotype (CK) is associated with a poor prognosis in both acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB). Transcriptomic analyses have improved our understanding of the disease and risk stratification of myeloid neoplasms; however, CK-specific gene expression signatures have been rarely investigated. In this study, we developed and validated a CK-specific gene expression signature. Differential gene expression analysis between the CK and non-CK groups using data from 348 patients with AML and MDS-EB from four cohorts revealed enrichment of the downregulated genes localized on chromosome 5q or 7q, suggesting that haploinsufficiency due to the deletion of these chromosomes possibly underlies CK pathogenesis. We built a robust transcriptional model for CK prediction using LASSO regression for gene subset selection and validated it using the leave-one-out cross-validation method for fitting the logistic regression model. We established a 10-gene CK signature (CKS) predictive of CK with high predictive accuracy (accuracy 94.22%; AUC 0.977). CKS was significantly associated with shorter overall survival in three independent cohorts, and was comparable to that of previously established risk stratification models for AML. Furthermore, we explored of therapeutic targets among the genes comprising CKS and identified the dysregulated expression of superoxide dismutase 1 (SOD1) gene, which is potentially amenable to SOD1 inhibitors.

Stress Granules Inhibit Coxsackievirus B3-Mediated Cell Death via Reduction of Mitochondrial Reactive Oxygen Species and Viral Extracellular Release.

Stress granules (SGs) are cytoplasmic aggregates of RNA-protein complexes that form in response to various cellular stresses and are known to restrict viral access to host translational machinery. However, the underlying molecular mechanisms of SGs during viral infections require further exploration. In this study, we evaluated the effect of SG formation on cellular responses to coxsackievirus B3 (CVB3) infection. Sodium arsenite (AS)-mediated SG formation suppressed cell death induced by tumor necrosis factor-alpha (TNF-a)/cycloheximide (CHX) treatment in HeLa cells, during which G3BP1, an essential SG component, contributed to the modulation of apoptosis pathways. SG formation in response to AS treatment blocked CVB3-mediated cell death, possibly via the reduction of mitochondrial reactive oxygen species. Furthermore, we examined whether AS treatment would affect small extracellular vesicle (sEV) formation and secretion during CVB3 infection and modulate human monocytic cell (THP-1) response. CVB3-enriched sEVs isolated from HeLa cells were able to infect and replicate THP-1 cells without causing cytotoxicity. Interestingly, sEVs from AS-treated HeLa cells inhibited CVB3 replication in THP-1 cells. These findings suggest that SG formation during CVB3 infection modulates cellular response by inhibiting the release of CVB3-enriched sEVs.

Asterias pectinifera-Derived Collagen Peptides Mixed with Halocynthia roretzi Extracts Exhibit Anti-Photoaging Activities during Exposure to UV Irradiation, and Antibacterial Properties.

Asterias pectinifera, a species of starfish and cause of concern in the aquaculture industry, was recently identified as a source of non-toxic and highly water-soluble collagen peptides. In this study, we investigated the antioxidant and anti-photoaging functions of compounds formulated using collagen peptides from extracts of Asterias pectinifera and Halocynthia roretzi (AH). Our results showed that AH compounds have various skin protective functions, including antioxidant effects, determined by measuring the scavenging activity of 2,2-diphenyl-1-picrylhydrazyl radicals, as well as anti-melanogenic effects, determined by measuring tyrosinase inhibition activity. To determine whether ethosome-encapsulated AH compounds (E(AH)) exert ultraviolet (UV)-protective effects, human dermal fibroblasts or keratinocytes were incubated with E(AH) before and after exposure to UVA or UVB. E(AH) treatment led to inhibition of photoaging-induced secretion of matrix metalloproteinase-1 and interleukin-6 and -8, which are associated with inflammatory responses during UV irradiation. Finally, the antibacterial effects of AH and E(AH) were confirmed against both gram-negative and gram-positive bacteria. Our results indicate that E(AH) has the potential for use in the development of cosmetics with a range of skin protective functions.

Unique characteristics of lung-resident neutrophils are maintained by PGE2/PKA/Tgm2-mediated signaling.

Lung-resident neutrophils need to be tightly regulated to avoid degranulation- and cytokine-associated damage to fragile alveolar structures that can lead to fatal outcomes. Here we show that lung neutrophils (LNs) express distinct surface proteins and genes that distinguish LNs from bone marrow and blood neutrophils. Functionally, LNs show impaired migratory activity toward chemoattractants and produce high levels of interleukin-6 (IL-6) at steady state and low levels of tumor necrosis factor-α in response to lipopolysaccharide (LPS) challenge. Treating bone marrow neutrophils with bronchoalveolar lavage fluid or prostaglandin E2 induces LN-associated characteristics, including the expression of transglutaminase 2 (Tgm2) and reduced production of inflammatory cytokines upon LPS challenge. Neutrophils from Tgm2-/- mice release high levels of inflammatory cytokines in response to LPS. Lung damage is significantly exacerbated in Tgm2-/- mice in an LPS-induced acute respiratory distress syndrome model. Collectively, we demonstrate that prostaglandin E2 is a key factor for the generation of LNs with unique immune suppressive characteristics, acting through protein kinase A and Tgm2, and LNs play essential roles in protection of the lungs against pathogenic inflammation.

2-Undecanone derived from Pseudomonas aeruginosa modulates the neutrophil activity.

Pseudomonas aeruginosa (P. aeruginosa) is a well-known Gramnegative opportunistic pathogen. Neutrophils play key roles in mediating host defense against P. aeruginosa infection. In this study, we identified a metabolite derived from P. aeruginosa that regulates neutrophil activities. Using gas chromatography-mass spectrometry, a markedly increased level of 2-undecanone was identified in the peritoneal fluid of P. aeruginosa-infected mice. 2-Undecanone elicited the activation of neutrophils in a Gαi-phospholipase C pathway. However, 2-undecanone strongly inhibited responses to lipopolysaccharide and bactericidal activity of neutrophils against P. aeruginosa by inducing apoptosis. Our results demonstrate that 2-undecanone from P. aeruginosa limits the innate defense activity of neutrophils, suggesting that the production of inhibitory metabolites is a strategy of P. aeruginosa for escaping the host immune system. [BMB Reports 2022; 55(8): 395-400].

Insight into the bovine milk peptide LPcin-YK3 selection in the proteolytic system of Lactobacillus species.

Antimicrobial peptides are class of small, positively charged peptides known for their broad-spectrum antimicrobial activity. Antimicrobial activities for most antimicrobial peptides have largely remained elusive, particularly in the lactic acid bacteria. However, recently our investigation using LPcin-YK3, an antimicrobial peptide from bovine milk, suggests that in vitro antimicrobial activity was reduced over 100-fold compared with pathogenic bacteria. Additionally, for the structural study of how antimicrobial peptide undergoes its reaction at the proteolytic pathway of lactic acid bacteria based on degradation assay and propidium iodide staining, we performed molecular docking for interaction between oligopeptide-binding protein A and LPcin-YK3 peptide. Given that degradation related to the LPcin-YK3 peptide in lactic acid bacteria proteolytic system, the inhibitory inactivity of LPcin-YK3 against beneficial lactic acid bacteria strains may be one of the primary pharmacological properties of recombinant peptide discovered in bovine milk. These results provide structural and functional insights into the proteolytic mechanism and possibility as a putative substrate of oligopeptide-binding protein A in respect of LPcin-YK3 peptide.

Pulmonary Nodular Lymphoid Hyperplasia in a 33-Year-Old Woman.

Pulmonary nodular lymphoid hyperplasia is a reactive lymphoproliferative disease. It is very rare, which means that many aspects of the disease are unknown or have not been proven. Pulmonary nodular lymphoid hyperplasia can be symptomatic or asymptomatic, progressive or not, and solitary or multiple, and a surgical approach is the current treatment of choice. We present a case of pulmonary nodular lymphoid hyperplasia that was visualized as multiple ground glass opacities on a computed tomography (CT) scan, and observed for 1 year because the patient was pregnant. Over this period, the number and extent of the opacities progressed, but no symptoms were reported. A surgical biopsy was done and some remaining lesions regressed on follow-up CT scans, while others progressed, without any appearance of symptoms.

Vanishing Venous Coronary Artery Bypass Grafts after Sepsis.

The dehiscence of saphenous vein grafts (SVGs) is a rare, often fatal, complication of coronary artery bypass grafting (CABG). We present the case of a 57-year-old man who underwent hemiarch graft interposition and CABG for a Stanford type A aortic dissection. Five months after discharge, the patient developed streptococcal sepsis caused by a hemodialysis catheter. Complete rupture of the proximal anastomoses of the saphenous veins and containment by the obliterated pericardial cavity was observed 25 months after the initial operation. The patient was successfully treated surgically. This report describes a patient who developed potentially fatal dehiscence of SVGs secondary to infection and outlines preventive and management strategies for this complication.

Clinical Manifestations of Spontaneous Pneumomediastinum.

BACKGROUND: Spontaneous pneumomediastinum (SPM) is an uncommon disorder with only a few reported clinical studies. The goals of this study were to investigate the clinical manifestations and the natural course of SPM, as well as examine the current available treatment options for SPM. METHODS: We retrospectively reviewed 91 patients diagnosed with SPM between January 2008 and June 2015. RESULTS: The mean age of the patients was 22.7±13.2 years, and 67 (73.6%) were male. Chest pain (58, 37.2%) was the predominant symptom. The most frequent precipitating factor before developing SPM was a cough (15.4%), but the majority of patients (51, 56.0%) had no precipitating factors. Chest X-ray was diagnostic in 44 patients (48.4%), and chest computed tomography (CT) showed mediastinal air in all cases. Esophagography (10, 11.0%), esophagoduodenoscopy (1, 1.1%), and bronchoscopy (5, 5.5%) were performed selectively due to clinical suspicion, but no abnormal findings that implicated organ injury were documented. Twelve patients (13.2%) were discharged after a visit to the emergency room, and the others were admitted and received conservative treatment. The mean length of hospital stay was 3.0±1.6 days. There were no complications related to SPM except for recurrence in 2 patients (2.2%). CONCLUSION: SPM responds well to conservative treatment and follows a benign natural course. Hospitalization and aggressive treatment can be performed in selective cases.