Temporal Patterns of Angular Displacement of Endosomes: Insights into Motor Protein Exchange Dynamics.

The material transport system, facilitated by motor proteins, plays a vital role in maintaining a non-equilibrium cellular state. However, understanding the temporal coordination of motor protein activity requires an advanced imaging technique capable of measuring 3D angular displacement in real-time. In this study, a Fourier transform-based plasmonic dark-field microscope has been developed using anisotropic nanoparticles, enabling the prolonged and simultaneous observation of endosomal lateral and rotational motion. A sequence of discontinuous 3D angular displacements has been observed during the pause and run phases of transport. Notably, a serially correlated temporal pattern in the intermittent rotational events has been demonstrated during the tug-of-war mechanism, indicating Markovian switching between the exploitational and explorational modes of motor protein exchange prior to resuming movement. Alterations in transition frequency and the exploitation-to-exploration ratio upon dynein inhibitor treatment highlight the relationship between disrupted motor coordination and reduced endosomal transport efficiency. Collectively, these results suggest the importance of orchestrated temporal motor protein patterns for efficient cellular transport.

Preliminary research on tailored fluid therapy in pigs: comparing customized ionic solutions with Hartmann's solution.

BACKGROUND: Fluid therapy in veterinary medicine is pivotal for treating various conditions in pigs; however, standard solutions, such as Hartmann's solution, may not optimally align with pig physiology. This study explored the development and efficacy of a customized fluid therapy tailored to the ionic concentrations of pig blood, aiming to enhance treatment outcomes and safety in both healthy and diseased pigs. RESULTS: The study involved two experiments: the first to assess the safety and stability of customized fluids in healthy pigs, and the second to evaluate the efficacy in pigs with clinical symptoms of dehydration. In healthy pigs, the administration of customized fluids showed no adverse effects, with slight alterations observed in pO2, hematocrit, and glucose levels in some groups. In symptomatic pigs, the customized fluid group did not show any improvement in clinical symptoms, with no significant changes in blood chemistry or metabolite levels compared to controls. The customized fluid group showed a mild increase in some values after administration, yet within normal physiological ranges. The study reported no significant improvements in clinical or dehydration status, attributing the observed variations in blood test results to the limited sample size and anaesthesia effects rather than fluid characteristics. CONCLUSIONS: Customized fluid therapy, tailored to mimic the ionic concentrations of pig blood, appears to be a safe and potentially more effective alternative to conventional solutions such as Hartmann's solution for treating pigs under various health conditions. Further research with larger sample sizes and controlled conditions is recommended to validate these findings and to explore the full potential of customized fluid therapy in veterinary practice.

Pioneering PGC-1α-boosted secretome: a novel approach to combating liver fibrosis.

Purpose: Liver fibrosis is a critical health issue with limited treatment options. This study investigates the potential of PGC-Sec, a secretome derived from peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-overexpressing adipose-derived stem cells (ASCs), as a novel therapeutic strategy for liver fibrosis. Methods: Upon achieving a cellular confluence of 70%-80%, ASCs were transfected with pcDNA-PGC-1α. PGC-Sec, obtained through concentration of conditioned media using ultrafiltration units with a 3-kDa cutoff, was assessed through in vitro assays and in vitro mouse models. Results: In vitro, PGC-Sec significantly reduced LX2 human hepatic stellate cell proliferation and mitigated mitochondrial oxidative stress compared to the control-secretome. In an in vivo mouse model, PGC-Sec treatment led to notable reductions in hepatic enzyme activity, serum proinflammatory cytokine concentrations, and fibrosis-related marker expression. Histological analysis demonstrated improved liver histology and reduced fibrosis severity in PGC-Sec-treated mice. Immunohistochemical staining confirmed enhanced expression of PGC-1α, optic atrophy 1 (a mitochondrial function marker), and peroxisome proliferator-activated receptor alpha (an antifibrogenic marker) in the PGC-Sec-treated group, along with reduced collagen type 1A expression (a profibrogenic marker). Conclusion: These findings highlight the therapeutic potential of PGC-Sec in combating liver fibrosis by enhancing mitochondrial biogenesis and function, and promoting antifibrotic processes. PGC-Sec holds promise as a novel treatment strategy for liver fibrosis.

Analysis of blood composition by porcine breeding cycle.

BACKGROUND: Pigs for biomedical research are administered commercial fluids made for human consumption when they receive intravenous (IV) fluid therapy. Although pigs and humans have slightly different bodily fluid compositions, the composition shift happens at the same rate as their rapid growth. OBJECTIVE: The study aimed to analyse the composition of porcine blood according to breeding cycle using a portable blood analyser and provides data for developing customized IV fluids for pigs. METHODS: Pigs were sorted 25, 50, 100 and 120 days after birth, and sows were classified into candidate, pregnant and farrowing groups. A blood sample was collected from the external jugular vein and analysed using the EPOC blood analysis system using haematological, biochemical and gas parameters. RESULTS: There was no difference among pig groups by age, but hematocrit and haemoglobin amounts decreased in sows after farrowing, but their concentrations were higher as compared to pigs. Glucose gradually reduced as age increased in pigs and during pregnancy in sows. CONCLUSION: This study provided a comprehensive analysis of porcine blood composition by breeding cycle and highlighted the importance of glucose supplementation for IV fluid therapy in pigs.

Clinical and financial impact of immune checkpoint inhibitors following platinum chemotherapy in patients with advanced or metastatic non-small cell lung cancer: a nationwide population-based study.

Background: Although various studies have demonstrated that the clinical efficacy of immune checkpoint inhibitors (ICIs) improves the prognosis of patients with non-small cell lung cancer (NSCLC), studies on the financial aspects based on large population-based data are needed. This study aimed to analyze the differences in medical expenses and the effect of ICIs on the prognosis of patients with advanced or metastatic NSCLC. Methods: Patients newly diagnosed with stage IIIB or IV NSCLC who received palliative chemotherapy between 2013 and 2020 were selected from the nationwide database of the population covered by the Korean National Health Insurance Service. Interrupted time-series analysis was performed to evaluate the effects of subsequent ICI use after platinum-based cytotoxic chemotherapy (CC) on overall mortality. Progression-free survival and medical expenditure were also assessed. Results: In the final study population, 2,485 and 4,812 patients were included in the ICI and non-ICI groups, respectively. ICI treatment significantly lowered the risk of death [adjusted hazard ratio, 0.79; 95% confidence interval (CI): 0.75-0.84]. And the ICI-treated patients were less likely to experience disease progression (adjusted odds ratios, 0.92; 95% CI: 0.85-0.99). Furthermore, after the introduction of ICIs, both total and cancer-related medical expenses per capita showed an increasing trend [ß: $4.56K, standard error (SE): $0.27K, P<0.0001 and ß: $4.54K, SE: $0.27K, P<0.0001, respectively]. Conclusions: Subsequent ICI use after platinum-based CC improved the overall survival rate of patients with advanced NSCLC. With the increasing burden of individual medical expenses, further research is required to identify patients for whom ICI treatment may be effective.

Comparison of Particulate Steroid Injection vs Nonparticulate Steroid Injection for Lumbar Radicular Pain: A Systematic Review and Meta-analysis.

OBJECTIVE: The objective of this study was to identify the difference on pain intensity and disability between particulate and nonparticulate steroid injections in patients with lumbar radicular pain. Subgroup analysis by study design, type of particulate steroid, and follow-up duration were performed. DATA SOURCES: We performed the literature search in the PubMed, Embase, and Cochrane Library up March, 2023. STUDY SELECTION: Studies, including randomized controlled trials (RCTs) and nonrandomized studies, that compared particulate steroid injection and nonparticulate steroid injection in patients with lumbar radicular pain were independently reviewed by 2 reviewers for eligibility for inclusion. DATA EXTRACTION: Outcomes of interest were pain intensity and disability. Two reviewers independently assessed the quality of included studies using the revised Cochrane Risk of Bias (RoB2.0) tool for RCTs and the Risk of Bias in Nonrandomized Studies of Interventions Tool (ROBINS-I) for nonrandomized studies. Effect sizes were estimated using mean difference (MD) and standardized mean difference (SMD). DATA SYNTHESIS: A total of 10 studies were included in this meta-analysis. The results showed no significant difference in visual analog scale, disability score and the numbers of patients with 50% pain reduction between particulate and nonparticulate steroid injection groups (P>.05). Particulate steroid injections showed significant better effect in pain scale in RCTs (MD=0.62; 95% CI 0.08-1.16, P=.02). In subgroup analysis with steroid types, methylprednisolone showed better effect compared with dexamethasone, while dexamethasone showed better effect compared with betamethasone. CONCLUSIONS: This meta-analysis suggested no significant differences between the particulate and nonparticulate steroid groups in pain or disability score. Therefore, considering the safety profile of nonparticulate steroids, nonparticulate steroid injection may be helpful in patients with lumbar radicular pain.

Reaching New Heights: A Comprehensive Study of Hand Transplantations in Korea after Institutionalization of Hand Transplantation Law.

PURPOSE: With the revision of the Organ and Transplantation Act in 2018, the hand has become legal as an area of transplantable organs in Korea. In January 2021, the first hand allotransplantation since legalization was successfully performed, and we have performed a total of three successful hand transplantation since then. By comparing and incorporating our experiences, this study aimed to provide a comprehensive reconstructive solution for hand amputation in Korea. MATERIALS AND METHODS: Recipients were selected through a structured preoperative evaluation, and hand transplantations were performed at the distal forearm level. Postoperatively, patients were treated with three-drug immunosuppressive regimen, and functional outcomes were monitored. RESULTS: The hand transplantations were performed without intraoperative complications. All patients had partial skin necrosis and underwent additional surgical procedures in 2 months after transplantation. After additional operations, no further severe complications were observed. Also, patients developed acute rejection within 3 months of surgery, but all resolved within 2 weeks after steroid pulse therapy. Motor and sensory function improved dramatically, and patients were very satisfied with the appearance and function of their transplanted hands. CONCLUSION: Hand transplantation is a viable reconstructive option, and patients have shown positive functional and psychological outcomes. Although this study has limitations, such as the small number of patients and short follow-up period, we should focus on continued recovery of hand function, and be careful not to develop side effects from immunosuppressive drugs. Through the present study, we will continue to strive for a bright future regarding hand transplantation in Korea.

Different risks of early-onset and late-onset Parkinson disease in individuals with mental illness.

We aimed to investigate the association of various mental illnesses, including depression, bipolar disorder, schizophrenia, insomnia, and anxiety, with the risk of early-onset Parkinson's disease (EOPD) (age <50 years) and compare it with that of late-onset PD (LOPD) (age ≥50 years). This nationwide cohort study enrolled 9,920,522 people who underwent a national health screening examination in 2009, and followed up until 31 December 2018. There was a significantly increased risk of EOPD and LOPD in individuals with mental illness, and EOPD showed a stronger association than LOPD (EOPD, hazard ratio (HR) = 3.11, 95% CI: 2.61‒3.72; LOPD, HR = 1.70, 95% CI: 1.66‒1.74; p for interaction <0.0001). Our results suggest that people with mental illnesses aged < 50 years are at a higher risk of PD than those aged ≥50 years. Future studies are warranted to elucidate the pathomechanism of EOPD in relation to mental illness.

Improvement of weanling pigs immune status and metabolic condition using ultraweak light.

Weaning stress is the most common issue in swine farms, which increases mortality and morbidity. The use of artificial light is an option for modifying the immune system and metabolic pathways. This study aimed to evaluate the influence of ultraweak light (Photonia) on growth performance, immune system and metabolism of weanling pigs, and the carry-over effect on the growth performance in postweanling growing stages. A total of 30 weaned pigs with an average initial body weight of 7.06 ± 0.11 kg (age: 21 days) were allotted two treatments (Control and Photonia) with 15 replicates. The pelleted form diets were prepared for pigs in three phases including phase 1 (Days 0-14), phase 2 (Days 15-28) and phase 3 (Days 29-48). The gain-to-feed ratio (G:F) of pigs was significantly greater in the Photonia treatment. On Day 28, a higher concentration of immunoglobin A (IgA) (p < 0.01) and IgG (p < 0.01) was observed in the Photonia pigs. On Day 48, the Photonia treatment showed a greater serum IgA (p < 0.01) and IgG (p < 0.05). The concentration of interleukin (IL)-6 was decreased (p < 0.05) in the Photonia treatment. At Day 48, the concentrations of tumour necrotic factor-α, IL-1ß and IL-6 in serum were decreased (p < 0.05) in pigs in the Photonia treatment. Metabolic pathways analysis showed that the Photonia treatment increased the d-glutamine, d-glutamate, alanine, aspartate, glutamate and phenylalanine compared with the control treatment. In conclusion, the use of Photonia for weanling pigs is recommended due to improved G:F, immune status and activation of amino acids metabolic pathways including d-glutamine, d-glutamate, alanine, aspartate, glutamate and phenylalanine.

Depressive Symptoms and the Subsequent Risk of Parkinson's Disease: A Nationwide Cohort Study.

OBJECTIVE: Only a few studies have focused on depressive symptoms and Parkinson's disease (PD) risk. As a time lag exists from the onset of depressive symptoms to the diagnosis of depression, elucidating the association between depressive symptoms and PD development might be helpful for the early prediction of PD. We investigate the association between depressive symptoms and subsequent PD risk using nationwide population-based cohort database. DESIGN AND SETTING: Cohort study using the Korean National Health Insurance Service data between 2007 and 2017, with longitudinal follow-up until 2019. PARTICIPANTS: A total of 98,296 elderly people responded to a self-reported questionnaire from the National Health Screening Program on depressive symptoms. MEASUREMENTS: The association between depressive symptoms such as 1) decreased activity or motivation, 2) worthlessness, and 3) hopelessness and PD risk was analyzed. RESULTS: During median 5.06-year follow-up, 839 PD cases occurred: 230 in individuals with depressive symptoms and 609 in those without symptoms. Results showed an increased risk of PD development in those with depressive symptoms (HR = 1.47, 95% CI, 1.26-1.71), with dose-response association between the number of depressive symptoms and PD risk. Even in those already diagnosed with depression, combined depressive symptoms were linked to a higher risk compared to those without symptoms (with symptoms, HR = 2.71, 95% CI, 2.00-3.68; without symptoms, HR = 1.84, 95% CI, 1.43-2.36). CONCLUSION: Individuals with depressive symptoms were at an increased risk of developing PD, and there was a dose-response association between the number of depressive symptoms and PD risk.

Effects of mesenchymal stem cell on dopaminergic neurons, motor and memory functions in animal models of Parkinson's disease: a systematic review and meta-analysis.

ABSTRACT: Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and although restoring striatal dopamine levels may improve symptoms, no treatment can cure or reverse the disease itself. Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson's disease. Mesenchymal stem cells are considered a promising option due to fewer ethical concerns, a lower risk of immune rejection, and a lower risk of teratogenicity. We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function, memory, and preservation of dopaminergic neurons in a Parkinson's disease animal model. We searched bibliographic databases (PubMed/MEDLINE, Embase, CENTRAL, Scopus, and Web of Science) to identify articles and included only peer-reviewed in vivo interventional animal studies published in any language through June 28, 2023. The study utilized the random-effect model to estimate the 95% confidence intervals (CI) of the standard mean differences (SMD) between the treatment and control groups. We use the systematic review center for laboratory animal experimentation's risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment. A total of 33 studies with data from 840 Parkinson's disease model animals were included in the meta-analysis. Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test. Among the stem cell types, the bone marrow MSCs with neurotrophic factor group showed largest effect size (SMD [95% CI] = -6.21 [-9.50 to -2.93], P = 0.0001, I2 = 0.0 %). The stem cell treatment group had significantly more tyrosine hydroxylase positive dopaminergic neurons in the striatum ([95% CI] = 1.04 [0.59 to 1.49], P = 0.0001, I2 = 65.1 %) and substantia nigra (SMD [95% CI] = 1.38 [0.89 to 1.87], P = 0.0001, I2 = 75.3 %), indicating a protective effect on dopaminergic neurons. Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route (SMD [95% CI] = -2.59 [-3.25 to -1.94], P = 0.0001, I2 = 74.4 %). The memory test showed significant improvement only in the intravenous route (SMD [95% CI] = 4.80 [1.84 to 7.76], P = 0.027, I2 = 79.6 %). Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson's disease. Further research is required to determine the optimal stem cell types, modifications, transplanted cell numbers, and delivery methods for these protocols.

DRG2 in macrophages is crucial for initial inflammatory response and protection against Listeria monocytogenes infection.

Innate immune response is critical for the control of Listeria monocytogenes infection. Here, we identified developmentally regulated GTP-binding protein 2 (DRG2) in macrophages as a major regulator of the innate immune response against L. monocytogenes infection. Both whole-body DRG2 knockout (KO) mice and macrophage-specific DRG2 KO mice had low levels of IL-6 during early infection and increased susceptibility to L. monocytogenes infection. Following an initial impaired inflammatory response of macrophages upon i.p. L. monocytogenes infection, DRG2-/- mice showed delayed recruitment of neutrophils and monocytes into the peritoneal cavity, which led to elevated bacterial burden, inflammatory cytokine production at a late infection time point, and liver micro-abscesses. DRG2 deficiency decreased the transcriptional activity of NF-κB and impaired the inflammatory response of both bone marrow-derived and peritoneal macrophages upon L. monocytogenes stimulation. Our findings reveal that DRG2 in macrophages is critical for the initial inflammatory response and protection against L. monocytogenes infection.

The effect of the introduction of the national lung cancer screening program on short-term mortality in Korea.

BACKGROUND: South Korea introduced the National Lung Cancer Screening Program (NLCSP) in 2019. This study investigated the effect of the NLCSP on one-year mortality in individuals with a history of lung cancer. METHODS: This study used the 2018-2020 National Health Insurance Service claims data. The difference-in-differences approach was used to investigate the effect of participating in the NLCSP between the case and control groups before and after the intervention period. The case group included individuals aged between 54 and 74 years with a smoking history of ≥ 30 pack-years and the control group those aged between 54 and 74 years with a history of smoking of <30 pack-years and non-smokers. The pre-intervention period was from January 2018 to June 2019 and the post-intervention period from July 2019 to December 2020. RESULTS: The introduction of the NLCSP was related to an overall decrease in one-year mortality (-3.21 % points, 95 % Confidence Interval (CI) -4.84 to -1.58). Specifically, this reduction was significant for lung cancer related mortality (lung cancer: -2.69 % points, 95 % CI -4.24 to -1.13). Furthermore, stronger associations were found in individuals of older age, residing in non-metropolitan areas, and who visited healthcare institutions in non-metropolitan areas. CONCLUSION: The findings confirm a relationship between implementation of the NLCSP and one-year mortality in eligible individuals with a history of lung cancer, which is noteworthy considering that Korea is one of the first countries to include lung cancer into the national cancer screening program.

Artificial intelligence-enhanced 12-lead electrocardiography for identifying atrial fibrillation during sinus rhythm (AIAFib) trial: protocol for a multicenter retrospective study.

Introduction: Atrial fibrillation (AF) is the most common arrhythmia, contributing significantly to morbidity and mortality. In a previous study, we developed a deep neural network for predicting paroxysmal atrial fibrillation (PAF) during sinus rhythm (SR) using digital data from standard 12-lead electrocardiography (ECG). The primary aim of this study is to validate an existing artificial intelligence (AI)-enhanced ECG algorithm for predicting PAF in a multicenter tertiary hospital. The secondary objective is to investigate whether the AI-enhanced ECG is associated with AF-related clinical outcomes. Methods and analysis: We will conduct a retrospective cohort study of more than 50,000 12-lead ECGs from November 1, 2012, to December 31, 2021, at 10 Korean University Hospitals. Data will be collected from patient records, including baseline demographics, comorbidities, laboratory findings, echocardiographic findings, hospitalizations, and related procedural outcomes, such as AF ablation and mortality. De-identification of ECG data through data encryption and anonymization will be conducted and the data will be analyzed using the AI algorithm previously developed for AF prediction. An area under the receiver operating characteristic curve will be created to test and validate the datasets and assess the AI-enabled ECGs acquired during the sinus rhythm to determine whether AF is present. Kaplan-Meier survival functions will be used to estimate the time to hospitalization, AF-related procedure outcomes, and mortality, with log-rank tests to compare patients with low and high risk of AF by AI. Multivariate Cox proportional hazards regression will estimate the effect of AI-enhanced ECG multimorbidity on clinical outcomes after stratifying patients by AF probability by AI. Discussion: This study will advance PAF prediction based on AI-enhanced ECGs. This approach is a novel method for risk stratification and emphasizes shared decision-making for early detection and management of patients with newly diagnosed AF. The results may revolutionize PAF management and unveil the wider potential of AI in predicting and managing cardiovascular diseases. Ethics and dissemination: The study findings will be published in peer-reviewed publications and disseminated at national and international conferences and through social media. This study was approved by the institutional review boards of all participating university hospitals. Data extraction, storage, and management were approved by the data review committees of all institutions. Clinical Trial Registration: [cris.nih.go.kr], identifier (KCT0007881).

TGF-ß and SHH Regulate Pluripotent Stem Cell Differentiation into Brain Microvascular Endothelial Cells in Generating an In Vitro Blood-Brain Barrier Model.

Blood-brain barrier (BBB) models are important tools for studying CNS drug delivery, brain development, and brain disease. In vitro BBB models have been obtained from animals and immortalized cell lines; however, brain microvascular endothelial cells (BMECs) derived from them have several limitations. Furthermore, obtaining mature brain microvascular endothelial-like cells (BME-like cells) from human pluripotent stem cells (hPSCs) with desirable properties for establishing BBB models has been challenging. Here, we developed an efficient method for differentiating hPSCs into BMECs that are amenable to the development and application of human BBB models. The established conditions provided an environment similar to that occurring during BBB differentiation in the presence of the co-differentiating neural cell population by the modulation of TGF-ß and SHH signaling. The developed BME-like cells showed well-organized tight junctions, appropriate expression of nutrient transporters, and polarized efflux transporter activity. In addition, BME-like cells responded to astrocytes, acquiring substantial barrier properties as measured by transendothelial electrical resistance. Moreover, the BME-like cells exhibited an immune quiescent property of BBB endothelial cells by decreasing the expression of adhesion molecules. Therefore, our novel cellular platform could be useful for drug screening and the development of brain-permeable pharmaceuticals.

Artificial intelligence-enhanced electrocardiography for early assessment of coronavirus disease 2019 severity.

Despite challenges in severity scoring systems, artificial intelligence-enhanced electrocardiography (AI-ECG) could assist in early coronavirus disease 2019 (COVID-19) severity prediction. Between March 2020 and June 2022, we enrolled 1453 COVID-19 patients (mean age: 59.7 ± 20.1 years; 54.2% male) who underwent ECGs at our emergency department before severity classification. The AI-ECG algorithm was evaluated for severity assessment during admission, compared to the Early Warning Scores (EWSs) using the area under the curve (AUC) of the receiver operating characteristic curve, precision, recall, and F1 score. During the internal and external validation, the AI algorithm demonstrated reasonable outcomes in predicting COVID-19 severity with AUCs of 0.735 (95% CI: 0.662-0.807) and 0.734 (95% CI: 0.688-0.781). Combined with EWSs, it showed reliable performance with an AUC of 0.833 (95% CI: 0.830-0.835), precision of 0.764 (95% CI: 0.757-0.771), recall of 0.747 (95% CI: 0.741-0.753), and F1 score of 0.747 (95% CI: 0.741-0.753). In Cox proportional hazards models, the AI-ECG revealed a significantly higher hazard ratio (HR, 2.019; 95% CI: 1.156-3.525, p = 0.014) for mortality, even after adjusting for relevant parameters. Therefore, application of AI-ECG has the potential to assist in early COVID-19 severity prediction, leading to improved patient management.

The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism.

Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

High- versus Low-dose Steroid Injection for Adhesive Capsulitis (Frozen Shoulder): A Systematic Review and Meta-analysis.

BACKGROUND: Intraarticular steroid injections are a commonly used and proven treatment for frozen shoulder; however, there is no scientific basis for a certified dose. OBJECTIVES: This study aimed to identify the difference between high- and low-dose steroid injections treatments and suggest an appropriate dose. STUDY DESIGN: Systematic review and meta-analysis. METHODS: The MEDLINE, EMBASE, and Cochrane electronic databases were searched through February 15, 2023 for eligible randomized controlled trials. The effects of high- and low-dose steroid injections were calculated as standardized mean differences (SMD) in pain, shoulder range of motion (ROM), and functional improvement. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate evidence quality. RESULTS: Four studies with 274 patients were included in the final analysis. The meta-analysis showed that improvement in pain (SMD, 0.10; 95% CI, -0.12 to 0.32), ROM (SMD, 0.07; 95% CI, -0.05 to 0.19), and functional improvement (SMD, 0.08; 95% CI, -0.10 to 0.26) did not differ significantly between the high- and low-dose steroid injections. Subgroup follow-up analyses also showed no clinically significant differences in SMD for pain, ROM, and functional scale measurement in any subgroups (after 3 weeks, 6 weeks, and one year). One article described that, although there was no significant difference in adverse events frequency between the high- and low-dose groups, flushing tended to occur more frequently in the high-dose group. LIMITATIONS: Limitations are the small number of studies included in the meta-analysis, no disease stage considered, and a short follow-up period. CONCLUSIONS: This meta-analysis suggests there are no significant differences between the high- and low-dose steroid groups in pain, ROM, or functional improvement. Therefore, considering the side effects of high-dose steroids, starting with low-dose steroids is recommended. However, further studies are needed to establish exact protocols according to disease severity. KEY WORDS: Frozen shoulder, adhesive capsulitis, steroids, triamcinolone acetonide, injections, intraarticular, optimal dose, meta-analysis, randomized controlled trial.

Cellular heterogeneity and plasticity during NAFLD progression.

Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.

FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner.

Ferroptosis, a type of cell death induced by lipid peroxidation, has emerged as a novel anti-cancer strategy. Cancer cells frequently acquire resistance to ferroptosis. However, the underlying mechanisms are poorly understood. To address this issue, we conducted a thorough investigation of the genomic and transcriptomic data derived from hundreds of human cancer cell lines and primary tissue samples, with a particular focus on non-small cell lung carcinoma (NSCLC). It was observed that mutations in Kelch-like ECH-associated protein 1 (KEAP1) and subsequent nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) activation are strongly associated with ferroptosis resistance in NSCLC. Additionally, AIFM2 gene, which encodes ferroptosis suppressor protein 1 (FSP1), was identified as the gene most significantly correlated with ferroptosis resistance, followed by multiple NRF2 targets. We found that inhibition of NRF2 alone was not sufficient to reduce FSP1 protein levels and promote ferroptosis, whereas FSP1 inhibition effectively sensitized KEAP1-mutant NSCLC cells to ferroptosis. Furthermore, we found that combined inhibition of FSP1 and NRF2 induced ferroptosis more intensely. Our findings imply that FSP1 is a crucial suppressor of ferroptosis whose expression is partially dependent on NRF2 and that synergistically targeting both FSP1 and NRF2 may be a promising strategy for overcoming ferroptosis resistance in cancer.