Hyaluronic acid stimulation of stem cells for cardiac repair: a cell-free strategy for myocardial infarct.

BACKGROUND: Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI. RESULTS: HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-ß1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis. CONCLUSIONS: Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart.

Multitemporal analysis of land subsidence induced by open-pit mining activity using improved combined scatterer interferometry with deep learning algorithm optimization.

Mine operational safety is an important aspect of maintaining the operational continuity of a mining area. In this study, we used the InSAR time series to analyze land surface changes using the ICOPS (improved combined scatterers with optimized point scatters) method. This ICOPS method combines persistent scatterers (PS) with distributed scatterers (DS) to increase surface deformation analysis's spatial coverage and quality. One of the improvements of this study is the use of machine learning in postprocessing, based on convolutional neural networks, to increase the reliability of results. This study used data from the Sentinel-1 SAR C-band satellite during the 2016-2022 observation period at the Musan mine, North Korea. In the InSAR surface deformation time analysis, the maximum average rate of land subsidence was approximately > 15.00 cm per year, with total surface deformation of 170 cm and 70 cm for the eastern dumping area and the western dumping area, respectively. Analyzing the mechanism of land surface changes also involved evaluating the geological conditions in the Musan mining area. Our research findings show that combining machine learning and statistical methods has great potential to enhance the understanding of mine surface deformation.

Association between Chronic Atrophic Gastritis and Bone Mineral Density among Women Older than 40 Years of Age in Korea.

Background: Chronic atrophic gastritis causes hypochlorhydria, hypergastrinemia, and malabsorption of nutrients, leading to lower bone mineral density. The few studies that investigated the association between chronic atrophic gastritis and bone mineral density have reported inconsistent findings. As such, the present study assessed the association between chronic atrophic gastritis and bone mineral density among a large sample of women >40 years of age in Korea. Methods: Data from 8,748 women >40 years of age who underwent esophagogastroduodenoscopy and bone densitometry were analyzed. Chronic atrophic gastritis was diagnosed using esophagogastroduodenoscopy. Bone mineral density of the lumbar vertebrae (L), femur neck, and femur total, measured using dual-energy X-ray absorptiometry, were the primary outcome variables. Low bone mineral density, which could be diagnosed as osteoporosis or osteopenia, was defined and analyzed as a secondary outcome. Linear regression was used to calculate adjusted mean values of bone mineral density. The association between low bone mineral density and chronic atrophic gastritis was analyzed using multiple logistic regression. Results: The adjusted mean bone mineral density for L1-L4 was 1.063±0.003, femur neck (0.826±0.002), and femur total (0.890±0.002) were significantly lower in patients with chronic atrophic gastritis than others (1.073±0.002, 0.836±0.001, 0.898±0.002, respectively; all P<0.01). Women with chronic atrophic gastritis exhibited an increased likelihood for osteopenia or osteoporosis, even after adjusting for age and other confounding factors (odds ratio, 1.25; 95% confidence interval, 1.13-1.40; P<0.01). However, subgroup analysis revealed statistical significance only in postmenopausal women (odds ratio, 1.27; P<0.001). Conclusion: Chronic atrophic gastritis was associated with lower bone mineral density and a higher risk for osteopenia or osteoporosis among postmenopausal women.

Effects of a Rice-Farming Simulation Video Game on Nature Relatedness, Nutritional Status, and Psychological State in Urban-Dwelling Adults During the COVID-19 Pandemic: Randomized Waitlist Controlled Trial.

BACKGROUND: During the COVID-19 pandemic, urban inhabitants faced significant challenges in maintaining connections with nature, adhering to nutritional guidelines, and managing mental well-being. OBJECTIVE: Recognizing the urgent need for innovative approaches, this study was designed to explore the potential benefits of a specific digital intervention, the rice-farming simulation game Sakuna: Of Rice and Ruin, for nature relatedness, nutritional behaviors, and psychological well-being. METHODS: A total of 66 adults without any prior major psychiatric disorders residing in an urban area were recruited for the study. They were randomly assigned to 2 groups through block randomization: the immediate intervention group (IIG; 34/66, 52%) and the waitlist group (32/66, 48%). Participants in the IIG were instructed to play the game for at least 4 days per week for 3 weeks, with each session lasting from 30 minutes to 3 hours. Assessments were performed at baseline, week 1, and week 3. The Nature Relatedness Scale (NR) and Nutrition Quotient Scale were used to evaluate nature relatedness and nutritional state, respectively. Furthermore, psychological state was assessed using the World Health Organization Quality of Life-Brief Version (WHOQOL-BREF), Brief Fear of Negative Evaluation Scale, Social Avoidance and Distress Scale, Toronto Alexithymia Scale, State-Trait Anxiety Inventory, Center for Epidemiologic Studies Depression Scale Revised, and Korean Resilience Quotient. RESULTS: This study's results revealed significant time interactions between the IIG and waitlist group for both the total NR score (P=.001) and the score of the self subdomain of NR (P<.001), indicating an impact of the game on nature relatedness. No group×time interactions were found for the total Nutrition Quotient Scale and subdomain scores, although both groups showed increases from baseline. For psychological state, a significant group×time interaction was observed in the total WHOQOL-BREF score (P=.049), suggesting an impact of the game on quality of life. The psychological (P=.01), social (P=.003), and environmental (P=.04) subdomains of the WHOQOL-BREF showed only a significant time effect. Other psychological scales did not display any significant changes (all P>.05). CONCLUSIONS: Our findings suggest that the rice-farming game intervention might have positive effects on nature relatedness, nature-friendly dietary behaviors, quality of life, anxiety, depression, interpersonal relationships, and resilience among urban adults during the COVID-19 pandemic. The impact of pronature games in confined urban environments provides valuable evidence of how digital technologies can be used to enhance urban residents' affinity for nature and psychological well-being. This understanding can be extended in the future to other digital platforms, such as metaverses. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0007657; http://tinyurl.com/yck7zxp7.

Novel molecular mechanism driving neuroprotection after soluble epoxide hydrolase inhibition: Insights for Alzheimer's disease therapeutics.

BACKGROUND: Neuroinflammation is widely recognized as a significant hallmark of Alzheimer's disease (AD). To combat neuroinflammation, the inhibition of the soluble epoxide hydrolase (sEH) enzyme has been demonstrated crucial. Importantly, sEH inhibition could be related to other neuroprotective pathways described in AD. AIMS: The aim of the study was to unveil new molecular pathways driving neuroprotection through sEH, we used an optimized, potent, and selective sEH inhibitor (sEHi, UB-SCG-51). MATERIALS AND METHODS: UB-SCG-51 was tested in neuroblastoma cell line, SH-SY5Y, in primary mouse and human astrocytes cultures challenged with proinflammatory insults and in microglia cultures treated with amyloid oligomers, as well as in mice AD model (5XFAD). RESULTS: UB-SCG-51 (10 and 30 µM) prevented neurotoxic reactive-astrocyte conversion in primary mouse astrocytes challenged with TNF-α, IL-1α, and C1q (T/I/C) combination for 24 h. Moreover, in microglial cultures, sEHi reduced inflammation and glial activity. In addition, UB-SCG-51 rescued 5XFAD cognitive impairment, reducing the number of Amyloid-ß plaques and Tau hyperphosphorylation accompanied by a reduction in neuroinflammation and apoptotic markers. Notably, a transcriptional profile analysis revealed a new pathway modulated by sEHi treatment. Specifically, the eIF2α/CHOP pathway, which promoted the endoplasmic reticulum response, was increased in the 5XFAD-treated group. These findings were confirmed in human primary astrocytes by combining sEHi and eIF2α inhibitor (eIF2αi) treatment. Besides, combining both treatments resulted in increased in C3 gene expression after T/I/C compared with the group treated with sEHi alone in cultures. DISCUSSION: Therefore, sEHi rescued cognitive impairment and neurodegeneration in AD mice model, based on the reduction of inflammation and eIF2α/CHOP signaling pathway. CONCLUSIONS: In whole, our results support the concept that targeting neuroinflammation through sEH inhibition is a promising therapeutic strategy to fight against Alzheimer's disease with additive and/or synergistic activities targeting neuroinflammation and cell stress.

Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. METHODS: We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. FINDINGS: The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study. INTERPRETATION: NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. FUNDING: D&D Pharmatech-Neuraly.

Characteristics of the immune microenvironment associated with RRM2 expression and its application to PD-L1/PD-1 inhibitors in lung adenocarcinoma.

Recent studies have indicated that RRM2 plays a crucial part in the tumor immune microenvironment. According to the expression of RRM2, we evaluated immune cell infiltration, immunotherapy biomarkers, and the expression of immune checkpoint molecules in four lung adenocarcinoma (LUAD) datasets. We employed the Tumor Immune Dysfunction and Exclusion (TIDE) and CIBERSORTx algorithms to examine the patterns of immune cell distribution and evaluate the responses to anti-programmed death protein-1/programmed death ligand-1 (PD-1/PD-L1) therapy in three publicly available LUAD datasets. These findings were corroborated using a validation group comprising patients who received treatment with PD-1/PD-L1 inhibitors. Additionally, we conducted experiments using LUAD cell lines to investigate how RRM2 affects the expression of PD-L1. In comparison to the low RRM2 group, the high RRM2 group exhibited a high interferon gamma signature, high T-cell-inflamed signature, high CD274 expression, high CD8+ T cell levels, low cancer-associated fibroblasts, and low M2 macrophages, according to TIDE analysis in the three LUAD datasets. Analysis of the three LUAD datasets using CIBERSORTx confirmed a positive correlation between RRM2 and CD8+ T cells, and this finding was validated by immunohistochemistry in a separate validation set. In the three LUAD datasets without PD-1/PD-L1 inhibitor treatment, higher RRM2 expression was associated with a poorer prognosis. However, in the LUAD dataset treated with PD-1/PD-L1 inhibitors, higher RRM2 expression was associated with better prognosis. In the three datasets, the high-RRM2 group exhibited higher expression of inhibitory immune checkpoint molecules. In a LUAD cell line study, we discovered that RRM2 regulates PD-L1 expression through the ANXA1/AKT pathway. The expression of RRM2 shows promise as a predictive biomarker for PD-1/PD-L1 inhibitors in LUAD patients, and it may represent a new target to overcome resistance to PD-L1/PD-1 therapies.

Association between serum uric acid level and bone mineral density in men more than 50 years of age.

Background: The results of previous studies on the association between serum uric acid levels and bone mineral density and the risk of osteoporosis are controversial. Fat free mass (FFM) is more strongly associated with bone mineral density (BMD) than it is with body fat mass (BFM). Skeletal muscle mass is assumed to contribute indirectly to the relationship between serum uric acid levels and BMD. Therefore, we aimed to evaluate the association between serum uric acid levels and BMD and abnormal BMD (at least osteopenia) by considering body composition in men aged ≥ 50 years. Methods: This was a retrospective observational cross-sectional study. We used data obtained from 2,991 men aged ≥50 years who completed questionnaires, anthropometric surveys, laboratory tests, and bone mineral density scans. A subgroup analysis of 1,135 men who additionally underwent body composition data analysis using Inbody® was performed. Multiple linear regression analysis was used to explore the relationship between serum uric acid levels and BMD at three sites (L1-L4, Femur neck, Femur total). In addition, multiple logistic regression analysis was performed to determine the association of serum uric acid levels with abnormal BMD (at least osteopenia). Results: Positive correlations between serum uric acid levels and BMD at the three sites (L1-L4, Femur neck, Femur total) were observed in unadjusted and fully adjusted models except the BMD of the femoral neck (P-value=0.054).Furthermore, FFM and skeletal muscle mass index (SMI) showed positive association with serum uric acid level and BMD at three sites, with statistical significance. An increase in serum uric acid level was associated with a lower risk of abnormal BMD after adjusting for confounders including FFM and SMI. Conclusion: Serum uric acid level was positively associated with BMD at three sites and had a protective effect against abnormal BMD after adjusting for multiple confounders, including FFM and SMI, in men aged ≥ 50 years.

The Effects of NLY01, a Novel Glucagon-Like Peptide-1 Receptor Agonist, on Cuprizone-Induced Demyelination and Remyelination: Challenges and Future Perspectives.

Recent evidence suggests that the glucagon-like peptide-1 receptor (GLP-1R) agonists have neuroprotective activities in the CNS in animal models of Parkinson's disease, Alzheimer's disease, and multiple sclerosis (MS). This study aimed to investigate whether a novel long-acting GLP-1R agonist, NLY01, could limit demyelination or improve remyelination as occurs in MS using the cuprizone (CPZ) mouse model. Herein, we assessed the expression of GLP-1R on oligodendrocytes in vitro and found that mature oligodendrocytes (Olig2+PDGFRa-) express GLP-1R. We further confirmed this observation in the brain by immunohistochemistry and found that Olig2+CC1+ cells express GLP-1R. We next administered NLY01 twice per week to C57B6 mice while on CPZ chow diet and found that NLY01 significantly reduced demyelination with greater weight loss than vehicle-treated controls. Because GLP-1R agonists are known to have anorexigenic effect, we then administered CPZ by oral gavage and treated the mice with NLY01 or vehicle to ensure the dose consistency of CPZ ingestion among mice. Using this modified approach, NLY01 was no longer effective in reducing demyelination of the corpus callosum (CC). We next sought to examine the effects of NLY01 treatment on remyelination after CPZ intoxication and during the recovery period using an adoptive transfer-CPZ (AT-CPZ) model. We found no significant differences between the NLY01 and vehicle groups in the amount of myelin or the number of mature oligodendrocytes in the CC. In summary, despite the promising anti-inflammatory and neuroprotective effects of GLP-1R agonists that have been previously described, our experiments provided no evidence to support a beneficial effect of NLY01 on limiting demyelination or enhancing remyelination. This information may be useful in selecting proper outcome measures in clinical trials of this promising class of drugs in MS.

Galactosylated hydroxyl-polyamidoamine dendrimer targets hepatocytes and improves therapeutic outcomes in a severe model of acetaminophen poisoning-induced liver failure.

Toxicity to hepatocytes caused by various insults including drugs is a common cause of chronic liver failure requiring transplantation. Targeting therapeutics specifically to hepatocytes is often a challenge since they are relatively nonendocytosing unlike the highly phagocytic Kupffer cells in the liver. Approaches that enable targeted intracellular delivery of therapeutics to hepatocytes have significant promise in addressing liver disorders. We synthesized a galactose-conjugated hydroxyl polyamidoamine dendrimer (D4-Gal) that targets hepatocytes efficiently through the asialoglycoprotein receptors in healthy mice and in a mouse model of acetaminophen (APAP)-induced liver failure. D4-Gal localized specifically in hepatocytes and showed significantly better targeting when compared with the non-Gal functionalized hydroxyl dendrimer. The therapeutic potential of D4-Gal conjugated to N-acetyl cysteine (NAC) was tested in a mouse model of APAP-induced liver failure. A single intravenous dose of a conjugate of D4-Gal and NAC (Gal-d-NAC) improved survival in APAP mice, decreased cellular oxidative injury and areas of necrosis in the liver, even when administered at the delayed time point of 8 h after APAP exposure. Overdose of APAP is the most common cause of acute hepatic injury and liver transplant need in the United States, and is treated with large doses of NAC administered rapidly within 8 h of overdose leading to systemic side effects and poor tolerance. NAC is not effective when treatment is delayed. Our results suggest that D4-Gal is effective in targeting and delivering therapies to hepatocytes and Gal-D-NAC has the potential to salvage and treat liver injury with a broader therapeutic window.

ONC201/TIC10 plus TLY012 anti-cancer effects via apoptosis inhibitor downregulation, stimulation of integrated stress response and death receptor DR5 in gastric adenocarcinoma.

Gastric adenocarcinoma typically presents with advanced stage when inoperable. Chemotherapy options include non-targeted and toxic agents, leading to poor 5-year patient survival outcomes. Small molecule ONC201/TIC10 (TRAIL-Inducing Compound #10) induces cancer cell death via ClpP-dependent activation of the integrated stress response (ISR) and up-regulation of the TRAIL pathway. We previously found in breast cancer, pancreatic cancer and endometrial cancer that ONC201 primes tumor cells for TRAIL-mediated cell death through ISR-dependent upregulation of ATF4, CHOP and TRAIL death receptor DR5. We investigated the ability of ONC201 to induce apoptosis in gastric adenocarcinoma cells in combination with recombinant human TRAIL (rhTRAIL) or PEGylated trimeric TRAIL (TLY012). AGS (caspase 8-, KRAS-, PIK3CA-mutant, HER2-amplified), SNU-1 (KRAS-, MLH1-mutant, microsatellite unstable), SNU-5 (p53-mutant) and SNU-16 (p53-mutant) gastric adenocarcinoma cells were treated with ONC201 and TRAIL both in cell culture and in vivo. Gastric cancer cells showed synergy following dual therapy with ONC201 and rhTRAIL/TLY012 (combination indices < 0.6 at doses that were non-toxic towards normal fibroblasts). Synergy was observed with increased cells in the sub-G1 phase of the cell cycle with dual ONC201 plus TRAIL therapy. Increased PARP, caspase 8 and caspase 3 cleavage after ONC201 plus TRAIL further documented apoptosis. Increased cell surface expression of DR5 with ONC201 therapy was observed by flow cytometry, and immunoblotting revealed ONC201 upregulation of the ISR, ATF4, and CHOP. We observed downregulation of anti-apoptotic cIAP-1 and XIAP in all cells except AGS, and cFLIP in all cells except SNU-16. We tested the regimen in an organoid model of human gastric cancer, and in murine sub-cutaneous xenografts using AGS and SNU-1 cells. Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

The Primary Process and Key Concepts of Economic Evaluation in Healthcare.

Economic evaluations in the healthcare are used to assess economic efficiency of pharmaceuticals and medical interventions such as diagnoses and medical procedures. This study introduces the main concepts of economic evaluation across its key steps: planning, outcome and cost calculation, modeling, cost-effectiveness results, uncertainty analysis, and decision-making. When planning an economic evaluation, we determine the study population, intervention, comparators, perspectives, time horizon, discount rates, and type of economic evaluation. In healthcare economic evaluations, outcomes include changes in mortality, the survival rate, life years, and quality-adjusted life years, while costs include medical, non-medical, and productivity costs. Model-based economic evaluations, including decision tree and Markov models, are mainly used to calculate the total costs and total effects. In cost-effectiveness or costutility analyses, cost-effectiveness is evaluated using the incremental cost-effectiveness ratio, which is the additional cost per one additional unit of effectiveness gained by an intervention compared with a comparator. All outcomes have uncertainties owing to limited evidence, diverse methodologies, and unexplained variation. Thus, researchers should review these uncertainties and confirm their robustness. We hope to contribute to the establishment and dissemination of economic evaluation methodologies that reflect Korean clinical and research environment and ultimately improve the rationality of healthcare policies.

Design and Methods of a Prospective Smartphone App-Based Study for Digital Phenotyping of Mood and Anxiety Symptoms Mixed With Centralized and Decentralized Research Form: The Search Your Mind (S.Y.M., ) Project.

In this study, the Search Your Mind (S.Y.M., ) project aimed to collect prospective digital phenotypic data centered on mood and anxiety symptoms across psychiatric disorders through a smartphone application (app) platform while using both centralized and decentralized research designs: the centralized research design is a hybrid of a general prospective observational study and a digital platform-based study, and it includes face-to-face research such as informed written consent, clinical evaluation, and blood sampling. It also includes digital phenotypic assessment through an application-based platform using wearable devices. Meanwhile, the decentralized research design is a non-face-to-face study in which anonymous participants agree to electronic informed consent forms on the app. It also exclusively uses an application-based platform to acquire individualized digital phenotypic data. We expect to collect clinical, biological, and digital phenotypic data centered on mood and anxiety symptoms, and we propose a possible model of centralized and decentralized research design.

Mediation Effect of Insomnia Symptoms on Relation Between Stress and Quality of Life.

OBJECTIVE: Among various causes of insomnia, stress is the most common and representative cause. Insomnia is also known to negatively affect the quality of life (QoL). The objective of this study was to explore the effect of stress on QoL and the mediating role of insomnia symptoms in the relationship between stress and QoL. METHODS: In this study, the mediating effect of insomnia symptoms on the relationship between stress and QoL was analyzed by enrolling 3,714 participants from the Ansung and Ansan cohorts of the Korea Association Resource project from 2001 to 2004. These cohort participants were asked about how much they felt stressed during their everyday life. Insomnia symptoms were evaluated by asking participants whether they had trouble sleeping such as difficulty in falling asleep, disrupted sleep, and early morning awakening due to the lack of a validated questionnaire for this cohort. QoL was evaluated using the World Health Organization QoL Scale Brief Version. RESULTS: In total, stress was positively associated with insomnia symptoms, which in turn predicted QoL. The same result could be derived from subgroup analysis according to sex, and it was confirmed that insomnia symptoms acted as a mediating factor more significantly in female than in male. CONCLUSION: In this study, insomnia symptoms were confirmed to act as a significant mediating factor between stress and QoL, suggesting that insomnia symptoms should be actively identified and controlled to alleviate the negative effect of stress on QoL in clinical practice.

On the potential of wearable bioimpedance for longitudinal fluid monitoring in end-stage kidney disease.

Bioimpedance spectroscopy (BIS) has proven to be a promising non-invasive technique for fluid monitoring in haemodialysis (HD) patients. While current BIS-based monitoring of pre- and post-dialysis fluid status utilizes benchtop devices, designed for intramural use, advancements in micro-electronics have enabled the development of wearable bioimpedance systems. Wearable systems meanwhile can offer a similar frequency range for current injection as commercially available benchtop devices. This opens opportunities for unobtrusive longitudinal fluid status monitoring, including transcellular fluid shifts, with the ultimate goal of improving fluid management, thereby lowering mortality and improving quality of life for HD patients. Ultra-miniaturized wearable devices can also offer simultaneous acquisition of multiple other parameters, including haemodynamic parameters. Combination of wearable BIS and additional longitudinal multiparametric data may aid in the prevention of both haemodynamic instability as well as fluid overload. The opportunity to also acquire data during interdialytic periods using wearable devices likely will give novel pathophysiological insights and the development of smart (predicting) algorithms could contribute to personalizing dialysis schemes and ultimately to autonomous (nocturnal) home dialysis. This review provides an overview of current research regarding wearable bioimpedance, with special attention to applications in end-stage kidney disease patients. Furthermore, we present an outlook on the future use of wearable bioimpedance within dialysis practice.

Combination of ONC201 and TLY012 induces selective, synergistic apoptosis in vitro and significantly delays PDAC xenograft growth in vivo.

The five-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained a dismal 9% for approximately 40 years with an urgent need for novel therapeutic interventions. ONC201 is the founding member of the imipridone class, comprised of orally bioavailable small molecules that have shown efficacy in multiple tumor types both in animal models and in Phase I/II clinical trials. ONC201 is a potent inducer of the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. TRAIL is an innate immune mechanism which induces programmed cell death of cancer cells. We observed that PDAC cells upregulated ATF4, CHOP, and DR5 after treatment with ONC201. This occurred in cell lines that are susceptible to ONC201-induced apoptosis and in ones that are not. In response to ONC201, PDAC cells downregulated anti-apoptotic proteins including c-FLIP, BclXL, XIAP, cIAP1, and survivin. We hypothesized that TRAIL receptor agonists might induce selective, synergistic apoptosis in pancreatic cancer cell lines treated with ONC201. We screened 7 pancreatic cancer cell lines and found synergy with ONC201 and rhTRAIL or the novel TRAIL receptor agonist TLY012 in 6 of the 7 cell lines tested. In vivo experiments using BxPC3 and HPAFII xenograft models showed that the combination of ONC201 plus TLY012 significantly delays tumor growth as compared to controls. Immunohistochemical analysis of the tumors after three doses of the combination showed significantly increased cleavage of caspase 3 in vivo as compared to controls. Taken together, the preclinical efficacy of ONC201 and TLY012 represents a novel therapeutic option for further testing in pancreatic cancer patients. This combination showed marked efficacy in tumor cells that are both sensitive and resistant to the pro-apoptotic effects of ONC201, providing rationale to further investigate the combination of ONC201 plus TLY012 in patients with pancreatic cancer.

Myeloid cell modulation by a GLP-1 receptor agonist regulates retinal angiogenesis in ischemic retinopathy.

Ischemic retinopathies including diabetic retinopathy are major causes of blindness. Although neurons and Müller glia are recognized as important regulators of reparative and pathologic angiogenesis, the role of mononuclear phagocytes (MPs) - particularly microglia, the resident retinal immune cells - is unclear. Here, we found MP activation in human diabetic retinopathy, especially in neovessels from human neovascular membranes in proliferative retinopathy, including TNF-α expression. There was similar activation in the mouse oxygen-induced retinopathy (OIR) model of ischemia-induced neovascularization. Glucagon-like peptide-1 receptor (GLP-1R) agonists are in clinical use for glycemic control in diabetes and are also known to modulate microglia. Herein, we investigated the effect of a long-acting GLP-1R agonist, NLY01. Following intravitreal administration, NLY01 selectively localized to MPs in retina with OIR. NLY01 modulated MPs but not retinal endothelial cell viability, apoptosis, and tube formation in vitro. In OIR, NLY01 treatment inhibited MP infiltration and activation, including MP expression of cytokines in vivo. NLY01 significantly suppressed global induction of retinal inflammatory cytokines, promoted reparative angiogenesis, and suppressed pathologic retinal neovascularization. Collectively, these findings indicate the important role of mononuclear phagocytes in regulation of retinal vascularization in ischemia and suggest modulation of MPs as a potentially new treatment strategy for ischemic retinopathies.

A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. The nonreceptor tyrosine kinase c-Abl has shown a potential role in the progression of PD. As such, c-Abl inhibition is a promising candidate for neuroprotection in PD and α-synucleinopathies. Compound 5 is a newly synthesized blood-brain barrier penetrant c-Abl inhibitor with higher efficacy than existing inhibitors. The objective of the current study was to demonstrate the neuroprotective effects of compound 5 on the α-synuclein preformed fibril (α-syn PFF) mouse model of PD. Compound 5 significantly reduced neurotoxicity, activation of c-Abl, and Lewy body pathology caused by α-syn PFF in cortical neurons. Additionally, compound 5 markedly ameliorated the loss of dopaminergic neurons, c-Abl activation, Lewy body pathology, neuroinflammatory responses, and behavioral deficits induced by α-syn PFF injection in vivo. Taken together, these results suggest that compound 5 could be a pharmaceutical agent to prevent the progression of PD and α-synucleinopathies.