Inhibition of P2RX7 contributes to cytotoxicity by suppression of glycolysis and AKT activation in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. HCC occurs people with chronic liver diseases. The purinergic receptor P2X 7 (P2RX7) is involved in tumor proliferation and growth. Also, P2RX7 is associated with tumor invasion and metastatic dissemination. High glucose utilization is important for the survival of various types of tumors. However, the role of P2RX7 in glucose metabolism and cellular survival of HCC remains unclear. Here, our results show that the gene and protein levels of P2RX7 were elevated in tumor cells of patients with HCC. The pharmacological inhibition of P2RX7 by A-804598, a selective P2RX7 antagonist, and genetic inhibition by P2RX7 knockdown suppressed the glycolytic activity by reduction of hexokinase 2 (HK2), a key enzyme of the glycolysis pathway, in human HCC cells. Also, both A-804598 treatment and P2RX7 knockdown induced cytotoxicity via inhibition of AKT activation which is critical for tumor cell survival in human HCC cells. Moreover, A-804598 treatment and P2RX7 knockdown increased cytotoxicity and caspase-3 activation in human HCC cells. These results suggest that inhibition of P2RX7 contributes to cytotoxicity by suppression of glycolysis and AKT activation in human HCC.

Protein phosphatase PP2Cα S-glutathionylation regulates cell migration.

Redox signaling is a fundamental mechanism that controls all major biological processes partly via protein cysteine oxidations, including S-glutathionylation. Despite over 2,000 cysteines identified to form S-glutathionylation in databases, the identification of redox cysteines functionally linked to a biological process of interest remains challenging. Here, we demonstrate a strategy combining glutathionylation proteomic database, bioinformatics, and biological screening, which resulted in the identification of S-glutathionylated proteins, including PP2Cα, as redox players of cell migration. We showed that PP2Cα, a prototypical magnesium-dependent serine/threonine phosphatase, is susceptible to S-glutathionylation selectively at non-conserved C314. PP2Cα glutathionylation causes increased migration and invasion of breast cancer cell lines in oxidative stress or upon hydrogen peroxide production. Mechanistically, PP2Cα glutathionylation modulates its protein-protein interactions, activating c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways to elevate migration and invasion. In addition, PP2Cα glutathionylation occurs in response to epidermal-growth factor, supporting a serine/threonine phosphatase PP2Cα as a new redox player in growth factor signal transduction.

Coronavirus nucleocapsid-based vaccine provides partial protection against hetero-species coronavirus in murine models.

Most coronavirus vaccines focus on the spike (S) antigen, but the frequent mutations in S raise concerns about the vaccine efficacy against new variants. Although additional antigens with conserved sequences are have been tested, the extent to which these vaccines can provide immunity against different coronavirus species remains unclear. In this study, we assessed the potential of nucleocapsid (N) as a coronavirus vaccine antigen. Immunization with MERS-CoV N induced robust immune responses, providing significant protection against MERS-CoV. Notably, MERS-CoV N elicited cross-reactive T cell responses to SARS-CoV-2 N and significantly reduced lung inflammation following a SARS-CoV-2 challenge in the transient hACE2 mouse model. However, in K18-hACE transgenic mice, the vaccine showed limited protection. Collectively, our findings suggest that coronavirus N can be an effective vaccine antigen against homologous viruses, but its efficacy may vary across different coronaviruses, highlighting the need for further research on pan-coronavirus vaccines using conserved antigens.

Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor.

The calcium-sensing receptor (CaSR), abundantly expressed in the parathyroid gland and kidney, plays a central role in calcium homeostasis. In addition, CaSR exerts multimodal roles, including inflammation, muscle contraction, and bone remodeling, in other organs and tissues. The diverse functions of CaSR are mediated by many endogenous and exogenous ligands, including calcium, amino acids, glutathione, cinacalcet, and etelcalcetide, that have distinct binding sites in CaSR. However, strategies to evaluate ligand interactions with CaSR remain limited. Here, we developed a glutathione-based photoaffinity probe, DAZ-G, that analyzes ligand binding to CaSR. We showed that DAZ-G binds to the amino acid binding site in CaSR and acts as a positive allosteric modulator of CaSR. Oxidized and reduced glutathione and phenylalanine effectively compete with DAZ-G conjugation to CaSR, while calcium, cinacalcet, and etelcalcetide have cooperative effects. An unexpected finding was that caffeine effectively competes with DAZ-G's conjugation to CaSR and acts as a positive allosteric modulator of CaSR. The effective concentration of caffeine for CaSR activation (<10 µM) is easily attainable in plasma by ordinary caffeine consumption. Our report demonstrates the utility of a new chemical probe for CaSR and discovers a new protein target of caffeine, suggesting that caffeine consumption can modulate the diverse functions of CaSR.

Magnetic engineering nanoparticles: Versatile tools revolutionizing biomedical applications.

The use of nanoparticles has increased significantly over the past few years in a number of fields, including diagnostics, biomedicine, environmental remediation, and water treatment, generating public interest. Among various types of nanoparticles, magnetic nanoparticles (MNPs) have emerged as an essential tool for biomedical applications due to their distinct physicochemical properties compared to other nanoparticles. This review article focuses on the recent growth of MNPs and comprehensively reviews the advantages, multifunctional approaches, biomedical applications, and latest research on MNPs employed in various biomedical techniques. Biomedical applications of MNPs hold on to their ability to rapidly switch magnetic states under an external field at room temperature. Ideally, these MNPs should be highly susceptible to magnetization when the field is applied and then lose that magnetization just as quickly once the field is removed. This unique property allows MNPs to generate heat when exposed to high-frequency magnetic fields, making them valuable tools in developing treatments for hyperthermia and other heat-related illnesses. This review underscores the role of MNPs as tools that hold immense promise in transforming various aspects of healthcare, from diagnostics and imaging to therapeutic treatments, with discussion on a wide range of peer-reviewed articles published on the subject. At the conclusion of this work, challenges and potential future advances of MNPs in the biomedical field are highlighted.

A homogeneous time-resolved fluorescence screen to identify SIRT2 deacetylase and defatty-acylase inhibitors.

Human sirtuin-2 (SIRT2) has emerged as an attractive drug target for a variety of diseases. The enzyme is a deacylase that can remove chemically different acyl modifications from protein lysine residues. Here, we developed a high-throughput screen based on a homogeneous time-resolved fluorescence (HTRF) binding assay to identify inhibitors of SIRT2's demyristoylase activity, which is uncommon among many ligands that only affect its deacetylase activity. From a test screen of 9600 compounds, we identified a small molecule that inhibited SIRT2's deacetylase activity (IC50 = 7 µM) as well as its demyristoylase activity (IC50 = 37 µM). The inhibitor was composed of two small fragments that independently inhibited SIRT2: a halogenated phenol fragment inhibited its deacetylase activity, and a tricyclic thiazolobenzimidazole fragment inhibited its demyristoylase activity. The high-throughput screen also detected multiple deacetylase-specific SIRT2 inhibitors.

miR-200-mediated inactivation of cancer-associated fibroblasts via targeting of NRP2-VEGFR signaling attenuates lung cancer invasion and metastasis.

Cancer-associated fibroblasts (CAFs) play a substantial role in promoting cancer cell motility, drug resistance, angiogenesis, and metastasis; therefore, extensive research has been conducted to determine their mode of activation. We aimed to identify whether miRNA-200 (miR-200), a widely recognized suppressor of epithelial-mesenchymal transition, prevents CAFs from promoting cancer progression. Overexpression of miR-200 prevented CAFs from promoting lung cancer cell migration, invasion, tumorigenicity, and metastasis. Additionally, miR-200 suppressed the ability of CAFs to recruit and polarize macrophages toward the M2 phenotype, as well as the migration and tube formation of vascular endothelial cells. NRP2, a co-receptor of vascular endothelial growth factor receptor (VEGFR), was confirmed to be a target of miR-200, which mediates the functional activity of miR-200 in CAFs. NRP2-VEGFR signaling facilitates the secretion of VEGF-D and pleiotrophin from CAFs, leading to the activation of cancer cell migration and invasion. These findings suggest that miR-200 remodels CAFs to impede cancer progression and metastasis and that miR-200 and NRP2 are potential therapeutic targets in the treatment of lung cancer.

Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.

Prognostic Implications of N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Non-ST-Elevation Myocardial Infarction.

BACKGROUND: Limited data exist regarding the prognostic implications of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with non-ST-elevation myocardial infarction (NSTEMI) who undergo percutaneous coronary intervention (PCI). METHODS AND RESULTS: Of 13,104 patients in the nationwide Korea Acute Myocardial Infarction Registry-National Institutes of Health, 3,083 patients with NSTEMI who underwent PCI were included in the present study. The primary endpoint was major adverse cardiovascular events (MACE) at 3 years, a composite of all-cause death, recurrent myocardial infarction, unplanned repeat revascularization, and admission for heart failure. NT-proBNP was measured at the time of initial presentation for the management of NSTEMI, and patients were divided into a low (<700 pg/mL; n=1,813) and high (≥700 pg/mL; n=1,270) NT-proBNP group. The high NT-proBNP group had a significantly higher risk of MACE, driven primarily by a higher risk of cardiac death or admission for heart failure. These results were consistent after confounder adjustment by propensity score matching and inverse probability weighting analysis. CONCLUSIONS: In patients with NSTEMI who underwent PCI, an initial elevated NT-proBNP concentration was associated with higher risk of MACE at 3 years, driven primarily by higher risks of cardiac death or admission for heart failure. These results suggest that the initial NT-proBNP concentration may have a clinically significant prognostic value in NSTEMI patients undergoing PCI.

Preventive percutaneous coronary intervention versus optimal medical therapy alone for the treatment of vulnerable atherosclerotic coronary plaques (PREVENT): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Acute coronary syndrome and sudden cardiac death are often caused by rupture and thrombosis of lipid-rich atherosclerotic coronary plaques (known as vulnerable plaques), many of which are non-flow-limiting. The safety and effectiveness of focal preventive therapy with percutaneous coronary intervention of vulnerable plaques in reducing adverse cardiac events are unknown. We aimed to assess whether preventive percutaneous coronary intervention of non-flow-limiting vulnerable plaques improves clinical outcomes compared with optimal medical therapy alone. METHODS: PREVENT was a multicentre, open-label, randomised controlled trial done at 15 research hospitals in four countries (South Korea, Japan, Taiwan, and New Zealand). Patients aged 18 years or older with non-flow-limiting (fractional flow reserve >0·80) vulnerable coronary plaques identified by intracoronary imaging were randomly assigned (1:1) to either percutaneous coronary intervention plus optimal medical therapy or optimal medical therapy alone, in block sizes of 4 or 6, stratified by diabetes status and the performance of percutaneous coronary intervention in a non-study target vessel. Follow-up continued annually in all enrolled patients until the last enrolled patient reached 2 years after randomisation. The primary outcome was a composite of death from cardiac causes, target-vessel myocardial infarction, ischaemia-driven target-vessel revascularisation, or hospitalisation for unstable or progressive angina, assessed in the intention-to-treat population at 2 years. Time-to-first-event estimates were calculated with the Kaplan-Meier method and were compared with the log-rank test. This report is the principal analysis from the trial and includes all long-term analysed data. The trial is registered at ClinicalTrials.gov, NCT02316886, and is complete. FINDINGS: Between Sept 23, 2015, and Sept 29, 2021, 5627 patients were screened for eligibility, 1606 of whom were enrolled and randomly assigned to percutaneous coronary intervention (n=803) or optimal medical therapy alone (n=803). 1177 (73%) patients were men and 429 (27%) were women. 2-year follow-up for the primary outcome assessment was completed in 1556 (97%) patients (percutaneous coronary intervention group n=780; optimal medical therapy group n=776). At 2 years, the primary outcome occurred in three (0·4%) patients in the percutaneous coronary intervention group and in 27 (3·4%) patients in the medical therapy group (absolute difference -3·0 percentage points [95% CI -4·4 to -1·8]; p=0·0003). The effect of preventive percutaneous coronary intervention was directionally consistent for each component of the primary composite outcome. Serious clinical or adverse events did not differ between the percutaneous coronary intervention group and the medical therapy group: at 2 years, four (0·5%) versus ten (1·3%) patients died (absolute difference -0·8 percentage points [95% CI -1·7 to 0·2]) and nine (1·1%) versus 13 (1·7%) patients had myocardial infarction (absolute difference -0·5 percentage points [-1·7 to 0·6]). INTERPRETATION: In patients with non-flow-limiting vulnerable coronary plaques, preventive percutaneous coronary intervention reduced major adverse cardiac events arising from high-risk vulnerable plaques, compared with optimal medical therapy alone. Given that PREVENT is the first large trial to show the potential effect of the focal treatment for vulnerable plaques, these findings support consideration to expand indications for percutaneous coronary intervention to include non-flow-limiting, high-risk vulnerable plaques. FUNDING: The CardioVascular Research Foundation, Abbott, Yuhan Corp, CAH-Cordis, Philips, and Infraredx, a Nipro company.

Intravascular imaging-guided percutaneous coronary intervention in patients with acute myocardial infarction and cardiogenic shock.

INTRODUCTION AND OBJECTIVES: There are no clinical data on the efficacy of intravascular imaging-guided percutaneous coronary intervention (PCI) compared with angiography-guided PCI in patients with acute myocardial infarction (AMI) and cardiogenic shock. The current study sought to evaluate the impact of intravascular imaging-guided PCI in patients with AMI and cardiogenic shock. METHODS: Among a total of 28 732 patients from the nationwide pooled registry of KAMIR-NIH (November, 2011 to December, 2015) and KAMIR-V (January, 2016 to June, 2020), we selected a total of 1833 patients (6.4%) with AMI and cardiogenic shock who underwent PCI of the culprit vessel. The primary endpoint was major adverse cardiovascular events (MACE) at 1 year, a composite of cardiac death, myocardial infarction, repeat revascularization, and definite or probable stent thrombosis. RESULTS: Among the study population, 375 patients (20.5%) underwent intravascular imaging-guided PCI and 1458 patients (79.5%) underwent angiography-guided PCI. Intravascular imaging-guided PCI was associated with a significantly lower risk of 1-year MACE than angiography-guided PCI (19.5% vs 28.2%; HR, 0.59; 95%CI, 0.45-0.77; P<.001), mainly driven by a lower risk of cardiac death (13.7% vs 24.0%; adjusted HR, 0.53; 95%CI, 0.39-0.72; P<.001). These results were consistent in propensity score matching (HR, 0.68; 95%CI, 0.46-0.99), inverse probability weighting (HR, 0.61; 95%CI, 0.45-0.83), and Bayesian analysis (Odds ratio, 0.66, 95% credible interval, 0.49-0.88). CONCLUSIONS: In AMI patients with cardiogenic shock, intravascular imaging-guided PCI was associated with a lower risk of MACE at 1-year than angiography-guided PCI, mainly driven by the lower risk of cardiac death.

Redox Regulation of Phosphatase and Tensin Homolog by Bicarbonate and Hydrogen Peroxide: Implication of Peroxymonocarbonate in Cell Signaling.

Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) signaling pathway. Notably, its active site contains a cysteine residue that is susceptible to oxidation by hydrogen peroxide (H2O2). This oxidation inhibits the phosphatase function of PTEN, critically contributing to the activation of the PI3K/AKT pathway. Upon the stimulation of cell surface receptors, the activity of NADPH oxidase (NOX) generates a transient amount of H2O2, serving as a mediator in this pathway by oxidizing PTEN. The mechanism underlying this oxidation, occurring despite the presence of highly efficient and abundant cellular oxidant-protecting and reducing systems, continues to pose a perplexing conundrum. Here, we demonstrate that the presence of bicarbonate (HCO3-) promoted the rate of H2O2-mediated PTEN oxidation, probably through the formation of peroxymonocarbonate (HCO4-), and consequently potentiated the phosphorylation of AKT. Acetazolamide (ATZ), a carbonic anhydrase (CA) inhibitor, was shown to diminish the oxidation of PTEN. Thus, CA can also be considered as a modulator in this context. In essence, our findings consolidate the crucial role of HCO3- in the redox regulation of PTEN by H2O2, leading to the presumption that HCO4- is a signaling molecule during cellular physiological processes.

Understanding the Interplay between Wellness Motivation, Engagement, Satisfaction, and Destination Loyalty.

Increased awareness of negative psychological symptoms and the negative impact of the pandemic has led to a rising demand for wellness-related travel experiences. There is a need for research on tourists' experiential and reflective engagement in order to maximize positive outcomes such as overall satisfaction, positive WOM, and recommendations. These positive outcomes are crucial for attracting tourists and strengthening destinations' brands. As there are few empirical studies, research on the effects of engagement on satisfaction and behavioral intentions is necessary. This study aimed to examine the relationships between wellness motivation, engagement, satisfaction, and destination loyalty among wellness tourists. It also aimed to examine the mediating effects of two engagement factors, experiential and reflective engagement, between wellness motivation and positive outcomes. A total of 319 respondents were used for the analysis, and structural equation modeling (SEM) was conducted. The results found that wellness motivation is composed of six wellness motivation components, namely physical motivation, transcendence, relaxation, social motivation, self-esteem, and escape, each representing first-order factors. Wellness motivation is positively associated with reflective and experiential engagement. Engagement positively affects satisfaction and destination loyalty. This study provides several implications, theoretically and practically.

Association between body mass index and three-year outcome of acute myocardial infarction.

Body mass index (BMI), as an important risk factor related to metabolic disease. However, in some studies higher BMI was emphasized as a beneficial factor in the clinical course of patients after acute myocardial infarction (AMI) in a concept known as the "BMI paradox." The purpose of this study was to investigate how clinical outcomes of patients treated for AMI differed according to BMI levels. A total of 10,566 patients in the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH) from May 2010 to June 2015 were divided into three BMI groups (group 1: BMI < 22 kg/m2, group 2: ≥ 22 and < 26 kg/m2, and group 3: ≥ 26 kg/m2). The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) at 3 years of follow-up. At 1 year of follow-up, the incidence of MACCE in group 1 was 10.1% of that in group 3, with a hazard ratio (HR) of 2.27, and 6.5% in group 2, with an HR of 1.415. This tendency continued up to 3 years of follow-up. The study demonstrated that lower incidence of MACCE in the high BMI group of Asians during the 3-year follow-up period compared to the low BMI group. The results implied higher BMI could exert a positive effect on the long-term clinical outcomes of patients with AMI undergoing percutaneous coronary intervention (PCI).

Development of a greenhouse gas - air pollution interactions and synergies model for Korea (GAINS-Korea).

This study aimed to create Greenhouse Gas - Air Pollution Interactions and Synergies (GAINS)-Korea, an integrated model for evaluating climate and air quality policies in Korea, modeled after the international GAINS model. GAINS-Korea incorporates specific Korean data and enhances granularity for enabling local government-level analysis. The model includes source-receptor matrices used to simulate pollutant dispersion in Korea, generated through CAMx air quality modeling. GAINS-Korea's performance was evaluated by examining different scenarios for South Korea. The business as usual scenario projected emissions from 2010 to 2030, while the air quality scenario included policies to reduce air pollutants in line with air quality and greenhouse gas control plans. The maximum feasible reduction scenario incorporated more aggressive reduction technologies along with air quality measures. The developed model enabled the assessment of emission reduction effects by both greenhouse gas and air pollutant emission reduction policies across 17 local governments in Korea, including changes in PM2.5 (particulate matter less than 2.5 µm) concentration and associated benefits, such as reduced premature deaths. The model also provides a range of visualization tools for comparative analysis among different scenarios, making it a valuable resource for policy planning and evaluation, and supporting decision-making processes.

The interplay of low H2O2 doses, lytic cyanophage, and Microcystis aeruginosa: Implications for cyanobacterial bloom control and microcystin production/release.

Low H2O2 doses can suppress cyanobacterial blooms without damaging non-target species but enable undesirable regrowth. Besides, the role of cyanophage in preventing regrowth after low H2O2 exposure remains unclear. Applying phages to cyanobacteria pre-exposed to low H2O2 in early growth stages may improve host removal and reduce microcystin (MC) production/release. Lytic cyanophage MDM-1 with a 172 PFU/cell burst size, 2-day short latent period against MCs-producing Microcystis, shows high H2O2 stability. Low H2O2 (1 to 2.5 mg/L) doses significantly (p < 0.05) inhibited Microcystis aeruginosa growth rate, biofilm and MCs concentration reduction in a dose-dependent manner but regrowth occurred at all concentrations. Phage treatment eliminated cells without H2O2 pretreatment within 3 days and reduced MC production. H2O2-pretreated M. aeruginosa cells altered the phage dynamics, affecting adsorption, latency, production, and cell lysis in response to H2O2-induced oxidative stress. At 1.5 mg H2O2/L pretreatment, cells were eliminated with reduced MC production, like untreated cells. H2O2 pretreatment with 2.0 and 2.5 mg/L resulted in an extension of the phage absorption phase and the latent period. This was accompanied by a reduction in lysis efficacy, attributed to the increased ROS production. At 2.5 mg H2O2/L, 17.10 % of phages remain un-adsorbed, with cell lysis rate dropped from 0.89 d-1 to 0.26 d-1 compared to the untreated control. The highest phage titer (70 %) was obtained with 1.5 mg/H2O2 pretreated cells. This study emphasizes that low-dose H2O2 eliminates Microcystis but severely affects phage lysis and MCs release depending on H2O2-induced ROS levels. It is a crucial consideration when using phages to control cyanobacterial blooms with H2O2-induced stress.

The Prospect of Hydrolytic Enzymes from Bacillus Species in the Biological Control of Pests and Diseases in Forest and Fruit Tree Production.

Plant diseases and insect pest damage cause tremendous losses in forestry and fruit tree production. Even though chemical pesticides have been effective in the control of plant diseases and insect pests for several decades, they are increasingly becoming undesirable due to their toxic residues that affect human life, animals, and the environment, as well as the growing challenge of pesticide resistance. In this study, we review the potential of hydrolytic enzymes from Bacillus species such as chitinases, ß-1,3-glucanases, proteases, lipases, amylases, and cellulases in the biological control of phytopathogens and insect pests, which could be a more sustainable alternative to chemical pesticides. This study highlights the application potential of the hydrolytic enzymes from different Bacillus sp. as effective biocontrol alternatives against phytopathogens/insect pests through the degradation of cell wall/insect cuticles, which are mainly composed of structural polysaccharides like chitins, ß-glucans, glycoproteins, and lipids. This study demonstrates the prospects for applying hydrolytic enzymes from Bacillus sp. as effective biopesticides in forest and fruit tree production, their mode of biocidal activity and dual antimicrobial/insecticidal potential, which indicates a great prospect for the simultaneous biocontrol of pests/diseases. Further research should focus on optimizing the production of hydrolytic enzymes, and the antimicrobial/insecticidal synergism of different Bacillus sp. which could facilitate the simultaneous biocontrol of pests and diseases in forest and fruit tree production.

Clinical outcomes of mild to moderate coronavirus disease 2019 patients treated with Regdanvimab in delta-variant outbreak: Retrospective cohort study.

Regdanvimab is a novel neutralizing antibody agent used for the treatment of coronavirus disease 2019 (COVID-19). However, the effectiveness of regdanvimab in delta-variant patients has rarely been investigated. We examined the clinical outcomes and adverse events in COVID 19 patients treated with regdanvimab in the delta-variant era. Data were collected from laboratory-confirmed COVID-19 hospitalized patients who received regdanvimab in 2021 and categorized into pre-delta and delta variant groups. The primary outcome was the need for oxygen therapy. Rescue therapy, clinical improvement, and adverse events were analyzed. Among 101 patients treated with regdanvimab, 31 (30.7%) were delta patients and 49 (48.5) were pre-delta patients. 64.4% were male, the mean age was 60.3 years, and 70 patients (69%) had at least one underlying disease. The median interval from symptom onset to injection was 4 days. Twenty-three patients (23%) needed oxygen therapy, including 9 (29%) in the delta and 8 (16.3%) in the pre-delta group. (P = .176) The risk of early oxygen supplement was higher in the delta group (adjusted hazard ratio (aHR), 6.75; 95% confidence interval(CI), 1.53-29.8). The in-hospital survival rate was 100%, and no patients were admitted to the intensive care unit. Adverse events occurred in 43% of patients:13 (42%) delta patients and 23 (47%) pre-delta patients had any adverse events (P = .661). Patients treated with regdanvimab 4 days after symptom onset showed a favorable prognosis (aHR, 0.26; 95% CI, 0.26-0.91). We found that the high-risk mild to moderate COVID-19 patients treated with regdanvimab showed similar disease progression in delta-variant patients and pre-delta variants; however, we need to be more closely observed delta-variant patients than those in the pre-delta group despite regdanvimab treatment due to rapid disease aggravation.

Noggin contributes to brain metastatic colonization of lung cancer cells.

BACKGROUND: Brain metastasis is a common complication among patients with lung cancer, yet the underlying mechanisms remain unclear. In this study, we aimed to investigate the pathogenesis of brain metastasis in lung cancer. METHODS: We established highly colonizing metastatic lung cancer cells, A549-M2, through multiple implantations of A549 human lung cancer cells in the carotid artery of athymic nude mice. RESULTS: Compared to parental cells (M0), M2 cells demonstrated slower growth in culture plates and soft agar, as well as lower motility and higher adhesion, key characteristics of mesenchymal-epithelial transition (MET). Further analysis revealed that M2 cells exhibited decreased expression of epithelial-mesenchymal transition markers, including ZEB1 and Vimentin. M2 cells also demonstrated reduced invasiveness in co-culture systems. RNA sequencing and gene set enrichment analysis confirmed that M2 cells underwent MET. Intriguingly, depletion of Noggin, a BMP antagonist, was observed in M2 cells, and replenishment of Noggin restored suppressed migration and invasion of M2 cells. In addition, Noggin knockdown in control M0 cells promoted cell attachment and suppressed cell migration, suggesting that Noggin reduction during brain colonization causes inhibition of migration and invasion of metastatic lung cancer cells. CONCLUSIONS: Our results suggest that lung cancer cells undergo MET and lose their motility and invasiveness during brain metastatic colonization, which is dependent on Noggin.

An Unexpected Complication Resulting from Radiofrequency Ablation for Treating Facet Joint Syndrome: A Case Report.

Lumbar facet joints have been identified as a potential source of chronic low back pain (LBP) in 15% to 45% of patients, with the prevalence of such pain varying based on specific populations and settings examined. Lumbar facet joint interventions are useful in the diagnosis as well as the therapeutic management of chronic LBP. Radiofrequency ablation (RFA) of medial branch nerves is recognized as a safe and effective therapy for chronic facet joint pain in the lumbosacral spine, and its efficacy has already been established. The use of RFA is currently widespread in the management of spinal pain, but it is noteworthy that there have been works in the literature reporting complications, albeit at a very low frequency. We present a case of third-degree skin burns following radiofrequency ablation (RFA) for the management of facet joint syndrome. Postoperatively, the patient's skin encircling the needle displayed a pallor and exhibited deterioration in conjunction with the anatomical anomaly. The affected area required approximately 5 months to heal completely. During RFA, heat can induce burns not only at the point of contact with the RF electrode but also along the length of the needle. Vigilant attention is necessary to ensure patient safety and to address any potential complications that may arise during the procedure, including the possibility of minor technical errors.