Sodium-glucose co-transporter-2 inhibitors and the risk of venous thromboembolism: A nationwide population-based study and meta-analysis.

AIMS: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have off-target effects on haemoconcentration and anti-inflammation. The impact of SGLT-2i on the risk of venous thromboembolism (VTE) in patients with diabetes mellitus (DM) remains unclear. This study aimed to evaluate the risk of newly diagnosed VTE in patients with DM using SGLT-2i in comparison to dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1RA). MATERIALS AND METHODS: In this nationwide retrospective cohort study, we used data from Taiwan's National Health Insurance Research Database. Patients with diabetes aged 20 years or older who received SGLT-2i, DPP-4i, or GLP-1RA between 1 May 2016, and 31 December 2020, were included. The risks of VTE in SGLT-2i users were compared with those of DPP-4i and GLP-1RA users. A Cox regression model with stabilised inverse probability of treatment weighting was used to calculate hazard ratio (HR) for VTE risk. Additionally, a meta-analysis of relevant articles published before 23 May 2023, was conducted. RESULTS: Data from 136,530 SGLT-2i, 598,280 DPP-4i, and 5760 GLP-1RA users were analysed. SGLT-2i use was associated with a lower risk of VTE than DPP-4i (HR, 0.70; 95% CI, 0.59-0.84; p < 0·001), but not with GLP-1RA (HR, 1.39; 95% CI, 0.32-5.94; p = 0.66). Our meta-analysis further supported these findings (SGLT-2i vs. DPP-4i: HR, 0.71; 95% CI, 0.62-0.82; p < 0·001; SGLT-2i vs. GLP-1RA: HR, 0.91; 95% CI, 0.73-1.15; p = 0.43), suggesting the robustness of our retrospective analysis. CONCLUSIONS: In patients with DM, SGLT-2i was associated with a lower risk of VTE compared to DPP-4i, but not GLP-1RA.

Current status and development trends in CKD with frailty research from 2000 to 2021: a bibliometric analysis.

INTRODUCTION: The prevalence of chronic kidney disease (CKD) is gradually increasing in the elderly population. At the same time, frailty has become one of the research hotspots in the field of geriatrics. Bibliometric analyses help to understand the direction of a field. Therefore, this study aimed to analyze the status and emerging trends of frailty in CKD patients. DATA AND METHODS: The Web of Science Core Collection (WoSCC) database was screened for relevant literature published between 1 January 2000 and 31 December 2021. Next, publications were analyzed for information including authors, journals, cited references, citing journals, institutions, countries and regions, high-frequency keywords and co-citations using VOSviewer, Microsoft Excel, and R software. RESULTS: A total of 2223 articles were obtained, from which 613 relevant articles were selected based on title and abstract screening. There was an upward trend in the number of annual publications and Johansen KL was considered the most contributing author in the field. The Clinical Journal of the American Society of Nephrology was the most productive research journal. Johns Hopkins University is the most published organization. The United States is the global leader in the field and contributes the most to research. Research hotspots focus on epidemiological studies of frailty and frailty intervention. CONCLUSIONS: This study presents a comprehensive bibliometric analysis of CKD and frailty research. Key findings highlight the current focus on early screening and assessment of frailty in CKD patients, as well as physical function interventions in frail patients.

Ultra-processed food consumption and the risk of incident chronic kidney disease: a systematic review and meta-analysis of cohort studies.

BACKGROUND: Recent individual studies have indicated that ultra-processed food (UPF) consumption may be associated with the incidence of chronic kidney disease (CKD). We conducted a systematic review and meta-analysis based on those longitudinal studies evaluating the relationship between UPF consumption and the risk of incident CKD, and synthesizing the results. METHOD: PubMed, Embase, The Cochrane Library, Web of Science, and Scopus were searched from inception through 22 March 2023. Any longitudinal studies evaluating the relationship between UPF consumption and the risk of incident CKD were included. Two researchers independently conducted the literature screening and data extraction. RR and its 95% CI were regarded as the effect size. The Newcastle-Ottawa Scale (NOS) was applied to assess the quality of the studies included, and the effect of UPF consumption on the risk of incident CKD was analyzed with STATA version 15.1. This study's protocol was registered in PROSPERO (CRD42023411951). RESULTS: Four cohort studies with a total of 219,132 participants were included after screening. The results of the meta-analysis suggested that the highest UPF intake was associated with an increased risk of incident CKD (RR = 1.25; 95% CI: 1.18-1.33). CONCLUSIONS: High-dose UPF intake was associated with an increased risk of incident CKD. However, the underlying mechanisms remain unknown. Thus, more standardized clinical studies and further exploration of the mechanisms are needed in the future.

Evaluation of Differentially Expressed Genes in Leaves vs. Roots Subjected to Drought Stress in Flax (Linum usitatissimum L.).

Drought stress is a common environmental challenge that plants face, severely constraining plant growth and reducing crop yield and quality. Several studies have highlighted distinct responses between monocotyledonous and dicotyledonous plants. However, the mechanisms underlying flax tolerance to abiotic stress, such as drought, remain unclear. In this study, we investigated the morphological, physiological, and biochemical characteristics and the genome-wide gene expression of oil flax and fiber flax in response to drought stress. The results revealed that drought stress caused significant wilting of flax leaves. Within the first 24 h of stress, various physiological and biochemical characteristics exhibited rapid responses. These included fresh weight, relative water content (RWC), proline, soluble protein, soluble sugar, superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) in the leaves or roots of flax. Additionally, drought stress led to a significant rise in lignin content in fiber flax. In addition, the transcriptome analysis demonstrated genome-wide variations in gene expression induced by drought stress. Specifically, genes associated with photosynthesis, proline biosynthesis, and phytohormone metabolism exhibited significant differences in expression levels under stress conditions in flax. These findings highlight the rapid response of flax to drought stress within a short-term period. Our experiment also revealed that, although there were variations in the levels of small compound content or gene expression between Longya10 and Fany under drought stress, most stress-resistance responses were similar. Furthermore, the results provide additional evidence supporting the existence of mechanisms underlying the response to drought stress in plants.

[Artificial intelligence in wearable electrocardiogram monitoring].

Electrocardiogram (ECG) monitoring owns important clinical value in diagnosis, prevention and rehabilitation of cardiovascular disease (CVD). With the rapid development of Internet of Things (IoT), big data, cloud computing, artificial intelligence (AI) and other advanced technologies, wearable ECG is playing an increasingly important role. With the aging process of the population, it is more and more urgent to upgrade the diagnostic mode of CVD. Using AI technology to assist the clinical analysis of long-term ECGs, and thus to improve the ability of early detection and prediction of CVD has become an important direction. Intelligent wearable ECG monitoring needs the collaboration between edge and cloud computing. Meanwhile, the clarity of medical scene is conducive for the precise implementation of wearable ECG monitoring. This paper first summarized the progress of AI-related ECG studies and the current technical orientation. Then three cases were depicted to illustrate how the AI in wearable ECG cooperate with the clinic. Finally, we demonstrated the two core issues-the reliability and worth of AI-related ECG technology and prospected the future opportunities and challenges.

Effects of different exercise types on outdoor thermal comfort in a severe cold city.

The promotion of China's National Fitness Program has caused an upsurge in the construction of outdoor sports venues and sparked an interest in research on the thermal comfort of people exercising outside. The design of exercise facilities and parks is usually function-oriented, and the spatial layout and arrangement of exercise paths are based on the exercise type. However, few studies compared the thermal comfort of different exercise types. This study investigated seasonal differences in thermal sensation, thermal comfort, and other influencing factors among people who engaged in various types of exercise in a severe cold city in China. The results showed significant differences in thermal comfort among the different exercise types. The acceptable thermal range of exercising people is greater than that of the resting ones. In the cold season, the thermal comfort of different exercise types had a significant correlation with thermal sensation, but not with humidity and wind sensations. On the other hand, the thermal comfort of jogging respondents was more affected by humidity, wind, and sun sensations during the hot season. The modified UTCI range of thermal stress category was proposed as a design reference for the thermal environment of outdoor exercise venues. Overall, this study can help enrich and guide outdoor thermal comfort research in severe cold regions and aid the design of urban exercise spaces.

Alkaline Stress Induces Different Physiological, Hormonal and Gene Expression Responses in Diploid and Autotetraploid Rice.

Saline-alkaline stress is a critical abiotic stress that negatively affects plants' growth and development. Considerably higher enhancements in plant tolerance to saline-alkaline stress have often been observed in polyploid plants compared to their diploid relatives, the underlying mechanism of which remains elusive. In this study, we explored the variations in morphological and physiological characteristics, phytohormones, and genome-wide gene expression between an autotetraploid rice and its diploid relative in response to alkaline stress. It was observed that the polyploidization in the autotetraploid rice imparted a higher level of alkaline tolerance than in its diploid relative. An eclectic array of physiological parameters commonly used for abiotic stress, such as proline, soluble sugars, and malondialdehyde, together with the activities of some selected antioxidant enzymes, was analyzed at five time points in the first 24 h following the alkaline stress treatment between the diploid and autotetraploid rice. Phytohormones, such as abscisic acid and indole-3-acetic acid were also comparatively evaluated between the two types of rice with different ploidy levels under alkaline stress. Transcriptomic analysis revealed that gene expression patterns were altered in accordance with the variations in the cellular levels of phytohormones between diploid and autotetraploid plants upon alkaline stress. In particular, the expression of genes related to peroxide and transcription factors was substantially upregulated in autotetraploid plants compared to diploid plants in response to the alkaline stress treatment. In essence, diploid and autotetraploid rice plants exhibited differential gene expression patterns in response to the alkaline stress, which may shed more light on the mechanism underpinning the ameliorated plant tolerance to alkaline stress following genome duplication.

ATB0,+-targeted delivery of triptolide prodrugs for safer and more effective pancreatic cancer therapy.

Triptolide (TP) is a diterpene epoxide component extracted from Tripterygium wilfordii and has been shown to possess an impressive anticancer effect. However, TP has not yet entered any clinic trials due to the severe adverse effects that resulted from the off-target absorption and distribution found in animal studies. In this study, we designed and synthesized three amino acids (tryptophan, valine, and lysine) based TP prodrugs to target ATB0,+ which are highly expressed in pancreatic cancer cells for more effective pancreatic cancer therapy. The stability, uptake profiles, uptake mechanism, and cancer-killing ability were studied in vitro. All three prodrugs showed increased uptake and enhanced cytotoxicity in pancreatic cancer cells, but not in normal pancreatic cells. The difference in killing effect on normal and cancer cells was attributed to pancreatic cancer over-expressed ATB0,+-mediated uptake. Specifically, tryptophan-conjugated TP prodrug (TP-Trp) showed the highest uptake and the best cancer cell killing effect, considered as the best candidate. The present study provided the proof-of-concept of exploiting TP prodrug to target ATB0,+ for pancreatic cancer-selective delivery and treatment.

Investigation of transfusion associated hepatitis C virus infection in Taiwan, 2015-2018.

Continuous strengthening of the safety of blood products to reduce the risk of transfusion-transmitted HCV in recipients is an important issue of Taiwanese government concern. Since 2013, highly sensitivity serology and NAT assays were simultaneously used for blood donation screening to shorten the window period of HIV, HBV and HCV infections. 15 cases of suspected transfusion-transmitted HCV infection were analyzed in 2015-2018. No HCV nucleic acid was detected among a total 91 bags of donated blood. Eleven cases among the 15 suspected recipients were positive for HCV nucleic acid, and 9 recipients had genotype results. Of these 9 recipients, five for genotype 1b (5/9, 55.6%), three for genotype 2a (3/9, 33.3%) and one for genotype 2b (1/9, 11.1%). We will continuously monitor the blood safety of recipients. There have been no confirmed cases of acute hepatitis C (AHC) infection due to transfusions of HCV contaminated blood product in 2015-2018 in Taiwan.

Associations of the PTPN22 and CTLA-4 genetic polymorphisms with Taiwanese ankylosing spondylitis.

Ankylosing spondylitis (AS) is an autoimmune disease, and the imbalance of peripheral tolerance is involved in its pathogenesis. Importantly, the negative signal of activated T cells plays a crucial role in the balance of peripheral tolerance. It has been postulated that human protein tyrosine phosphatase nonreceptor 22 (PTPN22) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) genes encode proteins that are actively involved in regulating T-cell activation. Therefore, we evaluated the effects of PTPN22 and CTLA-4 genotypes on the occurrence of AS. Genetic polymorphisms of PTPN22 -1123G/C and CTLA-4 +49A/G were identified by polymerase chain reaction for 391 AS patients and 391 healthy controls. Subjects with PTPN22 CC and GC genotypes had a greater risk of AS occurrence than those with PTPN22 GG genotype [relative risk = 1.39, 95 % confidence interval (95 % CI) 1.03-1.88]. Further, subjects with PTPN22 CC/CTLA-4 AA or PTPN22 GC/CTLA-4 AA genotypes had 1.90-fold (95 % CI 1.02-3.49) greater risk of AS development than those with other combinations of PTPN22 and CTLA-4 genotypes. Our findings indicated that PTPN22 -1123G/C and CTLA-4 +49A/G genetic polymorphisms have a combined effect on the development of AS.

Atractylenolide II regulates the proliferation, ferroptosis, and immune escape of hepatocellular carcinoma cells by inactivating the TRAF6/NF-κB pathway.

Hepatocellular carcinoma (HCC) is a common and lethal tumor worldwide. Atractylenolide II (AT-II) is a natural sesquiterpenoid monomer, with anti-tumor effect. To address the effect and mechanisms of AT-II on HCC. The role and mechanisms of AT-II were assessed through cell counting kit-8, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescence, and western blot experiments in Hep3B and Huh7 cells. In vivo experiments were conducted in BALB/c nude mice using immunohistochemistry and western blot assays. AT-II decreased the cell viability of Hep3B and Huh7 cells with a IC50 of 96.43 µM and 118.38 µM, respectively. AT-II increased relative Fe2+ level, which was further promoted with the incubation of erastin and declined with the ferrostatin-1 in Hep3B and Huh7 cells. AT-II enhanced the level of ROS and MDA, but reduced the GSH level, and the expression of xCT and GPX4. AT-II elevated the percent of CD8+ T cells and the IFN-γ contents, and declined the IL-10 concentrations and the expression of PD-L1 in Hep3B and Huh7 cells. AT-II downregulated the relative protein level of TRAF6, p-p65/p-65, and p-IkBα/IkBα, which was rescued with overexpression of TRAF6. Upregulation of TRAF6 also reversed the effect of AT-II on proliferation, ferroptosis, and immune escape in Hep3B cells. In vivo, AT-II reduced tumor volume and weight, the level of GPX4, xCT, and PD-L1, and the expression of TRAF6, p-p65/p-65, and p-IkBα/IkBα, with the increased expression of CD8. AT-II modulated the proliferation, ferroptosis, and immune escape of HCC cells by downregulating the TRAF6/NF-κB pathway.

Association of cardiovascular health using Life's Essential 8 with depression: Findings from NHANES 2007-2018.

OBJECTIVE: Few studies have explored the correlation between cardiovascular health (CVH) and depression. We aimed to investigate the relationship between CVH using Life's Essential 8 (LE8) and depression among US adults. METHODS: 16,362 individuals from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018 were included. The patient Health Questionnaire (PHQ-9) was utilized to recognized depression (PHQ-9 ≥ 10). LE8 was scored by four health behaviors (sleep, tobacco/nicotine exposure, physical activity and diet) and four health factors (body mass index, non-high-density lipoprotein cholesterol, blood glucose and blood pressure) and classified into low, moderate and high CVH groups. Weighted logistic regressions, restricted cubic splines and sensitivity analyses were utilized to investigate the correlation between LE8 and depression. RESULTS: 1306 subjects had depression (7.98% of the participants), of which 860 (7.42%), 305 (17.24%) and 141 (3.01%) had low, moderate and high CVH, separately. In the fully adjusted model, LE8 was negatively correlated with depression (OR: 5.50, 95% CI 3.92-7.71, P < 0.001). Furthermore, there were inversely dose-response relationships between LE8 and depression (overall P < 0.001). CONCLUSIONS: Adhering to a high CVH, estimated by the LE8 score, was correlated with lower odds of depression.

Relationship of the Neutrophil-Lymphocyte Ratio with All-Cause and Cardiovascular Mortality in Patients with Diabetic Kidney Disease: A Prospective Cohort Study of NHANES Study.

Background: To investigate the association between the NLR and the risk of all-cause and cardiovascular mortality in US adults with diabetic kidney disease (DKD). Methods: The data utilized for this analysis were sourced from ten National Health and Nutrition Examination Survey cycles (1999-2018) with mortality data (up to 31 December 2019) via linkage to the National Death Index. The optimum NLR threshold for predicting survival outcomes was determined through the maximally selected rank statistics. Restricted cubic spline (RCS), weighted Cox proportional hazard regression, stratified analyses, and time-dependent receiver-operating characteristic curve (ROC) were employed to delineate the prospective correlations of the NLR with both all-cause and cardiovascular mortality. Results: In this investigation, a cohort comprising 2581 patients diagnosed with DKD was examined, encompassing 624 individuals with a higher NLR (≥3.07) and 1957 subjects with a lower NLR (<3.07). Over a median follow-up of 79 months (interquartile range, 44-128 months), 1103 deaths occurred, including 397 from cardiovascular causes and 706 from non-cardiovascular causes. The RCS analysis elucidated the positive linear correlation (both nonlinear P > 0.05). In the multivariable analyses, each one-unit increase in the NLR value was correlated with a 51% increased risk of all-cause mortality (1.51(1.28, 1.77)) and a 71% increased risk of cardiovascular mortality (1.71(1.32, 2.21)). The results were largely consistent across stratified analyses encompassing variables such as age, sex, race/ethnicity, marital status, family income, education levels, BMI, drinking status, smoking status, hypertension, CVD, and anti-infective drugs (P for interaction >0.05 for all). Time-dependent ROC analyses underscored the NLR's credible predictive efficacy for both short-term and extended durations in forecasting both all-cause and cardiovascular mortality. Conclusion: The findings emphasize the promising use of the NLR in stratifying and prognosticating the risk of mortality in DKD in clinical practice.

MACE and Hyperthyroidism Treated With Medication, Radioactive Iodine, or Thyroidectomy.

Importance: Excessive thyroid hormones from hyperthyroidism increase cardiovascular risks. Among 3 available treatments for hyperthyroidism, comparisons of long-term outcomes associated with antithyroid drugs (ATDs), radioactive iodine (RAI), and surgery to treat newly diagnosed hyperthyroidism are lacking. Objective: To compare risks of major adverse cardiovascular events (MACE) and all-cause mortality among patients with hyperthyroidism treated with ATDs, RAI, or surgery. Design, Setting, and Participants: This nationwide cohort study used the Taiwan National Health Insurance Research Database. Patients aged 20 years or older with newly diagnosed hyperthyroidism between 2011 and 2020 were enrolled. Treatment groups were determined within 18 months from diagnosis, with follow-up until the development of MACE, death, or the end date of the database, whichever came first. Data were analyzed from October 2022 through December 2023. Exposures: The ATD group received ATDs only. RAI and surgery groups could receive ATDs before treatment. Anyone who underwent thyroid surgery without RAI was classified into the surgery group and vice versa. Main Outcomes and Measures: The primary outcomes included MACE (a composite outcome of acute myocardial infarction, stroke, heart failure, and cardiovascular mortality) and all-cause mortality. Results: Among 114 062 patients with newly diagnosed hyperthyroidism (mean [SD] age, 44.1 [13.6] years; 83 505 female [73.2%]), 107 052 patients (93.9%) received ATDs alone, 1238 patients (1.1%) received RAI, and 5772 patients (5.1%) underwent surgery during a mean (SD) follow-up of 4.4 (2.5) years. Patients undergoing surgery had a significantly lower risk of MACE (hazard ratio [HR] = 0.76; 95% CI, 0.59-0.98; P = .04), all-cause mortality (HR = 0.53; 95% CI, 0.41-0.68; P < .001), heart failure (HR = 0.33; 95% CI, 0.18-0.59; P < .001), and cardiovascular mortality (HR = 0.45; 95% CI, 0.26-0.79; P = .005) compared with patients receiving ATDs. Compared with ATDs, RAI was associated with lower MACE risk (HR = 0.45; 95% CI, 0.22-0.93; P = .03). Risks for acute myocardial infarction and stroke did not significantly differ between treatment groups. Conclusions and Relevance: In this study, surgery was associated with lower long-term risks of MACE and all-cause mortality, while RAI was associated with a lower MACE risk compared with ATDs.

GSDMD in regulated cell death: A novel therapeutic target for sepsis.

Sepsis is a life-threatening multi-organ dysfunction syndrome caused by an abnormal host response to infection. Regulated cell death is essential for maintaining tissue homeostasis and eliminating damaged, infected, or aging cells in multicellular organisms. Gasdermin D, as a member of the gasdermin family, plays a crucial role in the formation of cytoplasmic membrane pores. Research has found that GSDMD plays important roles in various forms of regulated cell death such as pyroptosis, NETosis, and necroptosis. Therefore, through mediating regulated cell death, GSDMD regulates different stages of disease pathophysiology. This article mainly summarizes the concept of GSDMD, its role in regulated cell death, its involvement in organ damage associated with sepsis-related injuries mediated by regulated cell death via GSDMD activation and introduces potential drugs targeting GSDMD that may provide more effective treatment options for sepsis patients through drug modification.

Recent research on material-based methods for isolation of extracellular vesicles.

Extracellular vesicles (EVs) are nanoparticles secreted by cells with a closed phospholipid bilayer structure, which can participate in various physiological and pathological processes and have significant clinical value in disease diagnosis, targeted therapy and prognosis assessment. EV isolation methods currently include differential ultracentrifugation, ultrafiltration, size exclusion chromatography, immunoaffinity, polymer co-precipitation and microfluidics. In addition, material-based biochemical or biophysical approaches relying on intrinsic properties of the material or its surface-modified functionalized monomers, demonstrated unique advantages in the efficient isolation of EVs. In order to provide new ideas for the subsequent development of material-based EV isolation methods, this review will focus on the principle, research status and application prospects of material-based EV isolation methods based on different material carriers and functional monomers.

A Chinese patent medicine's long-term efficacy on non-dialysis patients with CKD stages 3-5: a retrospective cohort study.

Background: Chinese patent medicine is commonly used in China as an important treatment mechanism to thwart the progression of chronic kidney disease (CKD) stages 3-5, among which Niaoduqing granules are a representative Chinese patent medicine; however, its long-term efficacy on CKD prognosis remains unclear. Methods: Patients were grouped according to Niaoduqing granule prescription duration (non-Niaoduqing granule (non-NDQ) group vs Niaoduqing granule (NDQ) group). Serum creatinine (SCr) variation was compared using a generalized linear mixed model (GLMM). Multivariate Cox regression models were constructed, adjusting for confounding factors, to explore the risk of composite outcomes (receiving renal replacement therapy (RRT) or having an estimated glomerular filtration rate (eGFR)<5 mL/min/1.73 m2, ≥50% decline in the eGFR from the baseline, and doubling of SCr) in individuals consuming Niaoduqing granules. Results: A total of 1,271 patients were included, with a median follow-up duration of 29.71 (12.10, 56.07) months. The mean SCr Z-scores for the non-NDQ group and NDQ group were -0.175 and 0.153, respectively, at baseline (p = 0.015). The coefficients of the NDQ group from visit 1 to visit 5 were -0.207 (95% CI: -0.346, -0.068, p = 0.004), -0.214 (95% CI: 0.389, -0.039, p = 0.017), -0.324 (95% CI: 0.538, -0.109, p = 0.003), -0.502 (95% CI: 0.761, -0.243, p = 0.000), and -0.252 (95% CI: 0.569, 0.065, p = 0.119), respectively. The survival probability was significantly higher in the NDQ group (p = 0.0039). Taking Niaoduqing granules was a significant protective factor for thwarting disease progression (model 1: HR 0.654 (95% CI 0.489-0.875, p = 0.004); model 2: HR 0.646 (95% CI 0.476, 0.877, p = 0.005); and model 3: HR 0.602 (95% CI 0.442, 0.820, p = 0.001)). Conclusion: The long-term use of Niaoduqing granules improved SCr variation and lowered the risk of CKD progression by 39.8%.

Use of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients With Type 2 Diabetes and the Incidence of Retinal Vein Occlusion in Taiwan.

Purpose: The purpose of this study was to evaluate the risk of newly diagnosed retinal vein occlusion (RVO) in patients with type 2 diabetes (T2D) using sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared to dipeptidyl peptidase-4 inhibitors (DPP-4i). Methods: Claims data from the National Health Insurance Research Database of Taiwan were used in this nationwide retrospective cohort study. A target trial emulation framework was applied. Patients with T2D with no prior diagnosis of RVO who had newly commenced treatment with SGLT-2i or DPP-4i between May 1, 2016, and December 31, 2020, were included. Potential systematic differences in baseline characteristics between the paired groups were controlled using stabilized inverse probability of treatment weighting. The outcome of interest was incident RVO. The hazard ratio (HR) for SGLT-2i compared with that of DPP-4i was estimated using a Cox regression model. Results: Data from 123,567 and 578,665 patients receiving SGLT-2i and DPP-4i, respectively, were analyzed. The incidence of RVO was lower in patients newly receiving SGLT-2i (0.59 events per 1000 person-years) compared to those receiving DPP-4i (0.77 events per 1000 person-years) over a mean follow-up of 1.61 years. SGLT-2i users had a significantly lower risk of developing RVO compared with DPP-4i users (HR = 0.76, 95% confidence interval [CI] = 0.59-0.98). In the individual outcome analysis, SGLT-2i use was significantly associated with a lower risk of branch RVO (HR = 0.71, 95% CI = 0.52-0.96), but not central RVO (HR = 0.84, 95% CI = 0.57-1.24). Conclusions: The risk of developing RVO was lower in patients with T2D receiving SGLT-2i compared with that in those receiving DPP-4i.

Targeting the KAT8/YEATS4 Axis Represses Tumor Growth and Increases Cisplatin Sensitivity in Bladder Cancer.

Bladder cancer (BC) is one of the most common tumors characterized by a high rate of relapse and a lack of targeted therapy. Here, YEATS domain-containing protein 4 (YEATS4) is an essential gene for BC cell viability using CRISPR-Cas9 library screening is reported, and that HUWE1 is an E3 ligase responsible for YEATS4 ubiquitination and proteasomal degradation by the Protein Stability Regulators Screening Assay. KAT8-mediated acetylation of YEATS4 impaired its interaction with HUWE1 and consequently prevented its ubiquitination and degradation. The protein levels of YEATS4 and KAT8 are positively correlated and high levels of these two proteins are associated with poor overall survival in BC patients. Importantly, suppression of YEATS4 acetylation with the KAT8 inhibitor MG149 decreased YEATS4 acetylation, reduced cell viability, and sensitized BC cells to cisplatin treatment. The findings reveal a critical role of the KAT8/YEATS4 axis in both tumor growth and cisplatin sensitivity in BC cells, potentially generating a novel therapeutic strategy for BC patients.

The Transplantation of 3-Dimensional Spheroids of Adipose-Derived Stem Cells Promotes Achilles Tendon Healing in Rabbits by Enhancing the Proliferation of Tenocytes and Suppressing M1 Macrophages.

BACKGROUND: Tendons have limited regenerative potential, so healing of ruptured tendon tissue requires a prolonged period, and the prognosis is suboptimal. Although stem cell transplantation-based approaches show promise for accelerating tendon repair, the resultant therapeutic efficacy remains unsatisfactory. HYPOTHESIS: The transplantation of stem cells preassembled as 3-dimensional spheroids achieves a superior therapeutic outcome compared with the transplantation of single-cell suspensions. STUDY DESIGN: Controlled laboratory study. METHODS: Adipose-derived stem cells (ADSCs) were assembled as spheroids using a methylcellulose hydrogel system. The secretome of ADSC suspensions or spheroids was collected and utilized to treat tenocytes and macrophages to evaluate their therapeutic potential and investigate the mechanisms underlying their effects. RNA sequencing was performed to investigate the global difference in gene expression between ADSC suspensions and spheroids in an in vitro inflammatory microenvironment. For the in vivo experiment, rabbits that underwent Achilles tendon transection, followed by stump suturing, were randomly assigned to 1 of 3 groups: intratendinous injection of saline, rabbit ADSCs as conventional single-cell suspensions, or preassembled ADSC spheroids. The tendons were harvested for biomechanical testing and histological analysis at 4 weeks postoperatively. RESULTS: Our in vitro results demonstrated that the secretome of ADSCs assembled as spheroids exhibited enhanced modulatory activity in (1) tenocyte proliferation (P = .015) and migration (P = .001) by activating extracellular signal-regulated kinase (ERK) signaling and (2) the suppression of the secretion of interleukin-6 (P = .005) and interleukin-1α (P = .042) by M1 macrophages via the COX-2/PGE2/EP4 signaling axis. Gene expression profiling of cells exposed to an inflammatory milieu revealed significantly enriched terms that were associated with the immune response, cytokines, and tissue remodeling in preassembled ADSC spheroids. Ex vivo fluorescence imaging revealed that the engraftment efficiency of ADSCs in the form of spheroids was higher than that of ADSCs in single-cell suspensions (P = .003). Furthermore, the transplantation of ADSC spheroids showed superior therapeutic effects in promoting the healing of sutured stumps, as evidenced by improvements in the tensile strength (P = .019) and fiber alignment (P < .001) of the repaired tendons. CONCLUSION: The assembly of ADSCs as spheroids significantly advanced their potential to harness tenocytes and macrophages. As a proof of concept, this study clearly demonstrates the effectiveness of using ADSC spheroids to promote tendon regeneration. CLINICAL RELEVANCE: The present study lays a foundation for future clinical applications of stem cell spheroid-based therapy for the management of tendon injuries.