Knockdown of NFIL3 modulates the AMPK pathway to suppress excessive cell proliferation, inflammation, and migration in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is one autoimmune disease that badly influences the lives of humans. Nuclear factor interleukin 3 (NFIL3) has been elucidated to join into the progression of diversiform diseases. According to a recent report, NFIL3 expression levels are increased in the peripheral blood and synovial tissues of individuals with RA. However, the detailed regulatory impacts of NFIL3 and associated pathways in RA progression need more investigations. METHODS: The mRNA and protein expressions were tested through RT-qPCR and western blot. The cell proliferation was evaluated through CCK-8 and EdU assay. The cell apoptosis was measured through flow cytometry. The levels of TNF-α, IL-6, and IL-8 were assessed through ELISA. The cell migration and invasion were tested through Transwell assay. RESULTS: In this study, NFIL3 exhibited higher expression in RA fibroblast-like synoviocytes (interleukin-1ß [IL-1ß]-triggered MH7A cell model). In addition, knockdown of NFIL3 repressed the growth of IL-1ß-mediated MH7A cells. It was also demonstrated that suppressing NFIL3 resulted in reduced inflammatory reactions in IL-1ß-mediated MH7A cells. Suppression of NFIL3 alleviated cell migration and invasion in the RA cell model. Ultimately, it was demonstrated that NFIL3 retarded the AMPK/mTOR pathway. CONCLUSION: This study demonstrated that the inhibition of NFIL3 effectively controlled the AMPK/mTOR pathway, thereby suppressing the overactive proliferation, inflammation, and migration of fibroblast-like synoviocytes in human RA. This discovery implied that NFIL3 can be a serviceable biomarker for RA therapy.

Nontargeted metabolomic profiling analysis of patients with type 2 diabetes mellitus undergoing corn silk treatment.

To explore the corn silk's effect and possible mechanism on patients with type 2 diabetes mellitus (T2DM) by untargeted metabolomics. Newly diagnosed patients with T2DM admitted to the endocrinology department of the author's hospital from March 2020 to September 2021 were chosen and then allocated to either the intervention or the control group (NC) randomly. Patients in the intervention group were administered corn silk in the same way as the patients in the NC were given a placebo. A hypoglycemic effect was observed, and an untargeted metabolomics study was done on patients of both groups. Compared with the NC, the glycosylated hemoglobin and fasting blood glucose of patients in the intervention group significantly decreased after 3 months of treatment (P < .05), identified using tandem mass spectrometry, and analyzed by orthogonal partial least squares-discriminant analysis. A total of 73 differential metabolites were screened under the conditions of variable important in projection value >1.0 and P < .05. Differential metabolites are mainly enriched in signaling pathways such as oxidative phosphorylation, purine metabolism, and endocrine resistance. Through untargeted metabolomic analysis, it is found that corn silk water extract may reduce blood glucose in patients with T2DM through multiple pathways, including oxidative phosphorylation and purine metabolism.

Necrostatin-1 protects corneal epithelial cells by inhibiting the RIPK1/RIPK3/MLKL cascade in a benzalkonium chloride-induced model of necroptosis.

PURPOSE: Benzalkonium chloride (BAC) is commonly used as a preservative in ophthalmic medications, despite its potential to induce chemical injury. Extensive research has demonstrated that BAC can lead to adverse effects, including injuries to the ocular surface. Our study aimed to elucidate the underlying mechanism of necroptosis induced by BAC. METHODS: Human corneal epithelial (HCE) cells and mouse corneas were subjected to chemical injury, and the necrostatin-1 (Nec1) group was compared to the dimethylsulfoxide (DMSO) group. The extent of damage to HCE cells was assessed using CCK-8 and flow cytometry. Hematoxylin and eosin staining, as well as fluorescein sodium staining, were used to detect and characterize corneal injury. The activation of inflammatory cytokines and necroptosis-related proteins and genes was evaluated using Western blotting, immunofluorescence staining, and quantitative RT‒PCR. RESULTS: In our study, the induction of necroptosis by a hypertonic solution was not observed. However, necroptosis was observed in HCE cells exposed to NaOH and BAC, which activated the receptor-interacting protein kinase 1 (RIPK1) - receptor-interacting protein kinase 3 (RIPK3) - mixed lineage kinase domain-like protein (MLKL) signaling pathway. In mouse corneal tissues, BAC could induce necroptosis and inflammation. The administration of Nec1 mitigated the inflammatory response and ocular surface damage caused by BAC-induced necroptosis in our experimental models. Furthermore, our in vivo experiments revealed that the severity of necroptosis was greater in the 3-day group than in the 7-day group. CONCLUSIONS: Necroptosis plays a role in the pathological development of ocular surface injury caused by exposure to BAC. Furthermore, our study demonstrated that the administration of Nec1 could mitigate the pathological effects of necroptosis induced by BAC in clinical settings.

Increased Activity of Epithelial Cdc42 Rho GTPase and Tight Junction Permeability in the Cftr Knockout Intestine.

Increased intestinal permeability is a manifestation of cystic fibrosis (CF) in people with CF (pwCF) and in CF mouse models. CF transmembrane conductance regulator knockout (Cftr KO) mouse intestine exhibits increased proliferation and Wnt/ß-catenin signaling relative to wild-type mice (WT). Since the Rho GTPase Cdc42 plays a central role in intestinal epithelial proliferation and tight junction remodeling, we hypothesized that Cdc42 may be altered in the Cftr KO crypts. Immunofluorescence showed distinct tight junction localization of Cdc42 in Cftr KO fresh crypts and enteroids, the latter indicating an epithelial-autonomous feature. Quantitative PCR and immunoblots revealed similar expression of Cdc42 in the Cftr KO crypts/enteroids relative to WT, whereas pull-down assays showed increased GTP-bound (active) Cdc42 in proportion to total Cdc42 in Cftr KO enteroids. Cdc42 activity in the Cftr KO and WT enteroids could be reduced by inhibition of the Wnt transducer Disheveled 2. Using a dye permeability assay, Cftr KO enteroids exhibited increased paracellular permeability to 3kD dextran relative to WT. In Cftr KO relative to WT enteroids, leak permeability and Cdc42 tight junction localization were reduced to a greater extent by inhibition of Wnt/ß-catenin signaling with Endo-IWR1. Increased proliferation or inhibition of Cdc42 activity with ML141 had no effect on WT enteroid permeability. In contrast, inhibition of Cdc42 with ML141 increased permeability to both 3kD dextran and tight-junction impermeant 500 kD dextran in Cftr KO enteroids. These data suggest that increased constitutive Cdc42 activity may alter the stability of paracellular permeability in Cftr KO crypt epithelium.

Sulfhydryl functionalized two-dimensional Ti3C2Tx MXene for efficient removal of Hg2+ in water samples.

This study describes an adsorption method for the removal of Hg2+ from aquatic environments using sulfhydryl-functionalized Ti3C2Tx (SH-Ti3C2Tx). SH-Ti3C2Tx materials were synthesized through covalent interactions between dithiothreitol and two-dimensional Ti3C2Tx. The insertion of -SH groups increased the interlayer spacing of Ti3C2Tx, resulting in a 3-fold increase in the specific surface area of SH-Ti3C2Tx compared with the original Ti3C2Tx. The maximum Hg2+ adsorption capacity of SH-Ti3C2Tx was 3042 mg/g, which was 2.3-fold greater than that of Ti3C2Tx. After Hg2+ adsorption, SH-Ti3C2Tx was regenerated for repeated used by rinsing with HCl-thiourea. Next, SH-Ti3C2Tx was loaded onto a melamine sponge to construct SH-Ti3C2Tx adsorption columns suitable for continuous flow Hg2+ removal with extremely low flow resistance. Hg2+ removal rates exceeded 95 % when treating both high and low-concentration solutions (20 mg/L Hg2+ and 10 µg/L Hg2+). This study demonstrates the excellent adsorption-regeneration performance of SH-Ti3C2Tx, which has broad application prospects for the in-situ treatment of water contaminated with Hg2+.

Bioinformatics analysis of signature genes related to cell death in keratoconus.

Keratoconus is corneal disease in which the progression of conical dilation of cornea leads to reduced visual acuity and even corneal perforation. However, the etiology mechanism of keratoconus is still unclear. This study aims to identify the signature genes related to cell death in keratoconus and examine the function of these genes. A dataset of keratoconus from the GEO database was analysed to identify the differentially expressed genes (DEGs). A total of 3558 DEGs were screened from GSE151631. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that they mainly involved in response to hypoxia, cell-cell adhesion, and IL-17 signaling pathway. Then, the cell death-related genes datasets were intersected with the above 3558 DEGs to obtain 70 ferroptosis-related DEGs (FDEGs), 32 autophagy-related DEGs (ADEGs), six pyroptosis-related DEGs (PDEGs), four disulfidptosis-related DEGs (DDEGs), and one cuproptosis-related DEGs (CDEGs). After using Least absolute shrinkage and selection operator (LASSO), Random Forest analysis, and receiver operating characteristic (ROC) curve analysis, one ferroptosis-related gene (TNFAIP3) and five autophagy-related genes (CDKN1A, HSPA5, MAPK8IP1, PPP1R15A, and VEGFA) were screened out. The expressions of the above six genes were significantly decreased in keratoconus and the area under the curve (AUC) values of these genes was 0.944, 0.893, 0.797, 0.726, 0.882 and 0.779 respectively. GSEA analysis showed that the above six genes mainly play an important role in allograft rejection, asthma, and circadian rhythm etc. In conclusion, the results of this study suggested that focusing on these genes and autoimmune diseases will be a beneficial perspective for the keratoconus etiology research.

Chemerin attracts neutrophil reverse migration by interacting with C-C motif chemokine receptor-like 2.

Neutrophil reverse migration (rM) is a recently identified phenomenon in which neutrophils migrate away from the inflammatory site back into the vasculature following initial infiltration, which involved in the resolution of loci inflammatory response or dissemination of inflammation. Present study was aimed to explore the mechanisms in neutrophil rM. By scRNA-seq on the white blood cells in acute lung injury model, we found rM-ed neutrophils exhibited increased gene expression of C-C motif chemokine receptor-like 2 (Ccrl2), an atypical chemokine receptor. Furthermore, an air pouch model was established to directly track rM-ed neutrophils in vivo. Air pouches were generated by 3 ml filtered sterile air injected subcutaneously for 3 days, and then LPS (2 mg/kg) was injected into the pouches to mimic the inflammatory state. For the rM-ed neutrophil tracking system, cell tracker CMFDA were injected into the air pouch to stain the inflammatory loci cells, and after 6 h, stained cells in blood were regarded as the rM-ed neutrophil. Based on this tracking system, we confirmed that rM-ed neutrophils showed increased CCRL2. We also found that the concentrations of the CCRL2 ligand chemerin in plasma was increased in the late stage. Neutralizing chemerin decreased the rM-ed neutrophil ratio in the blood. These results suggest that circulating chemerin attracts neutrophils to leave inflammatory sites by interacting with CCRL2, which might involve in the dissemination of inflammation.

Comparison of intravascular lithotripsy versus rotational atherectomy for the treatment of severe coronary artery calcification.

BACKGROUND: Calcified lesions are one of the most challenging cases for PCI, where optimal angiographic results and satisfying outcomes are hard to achieve. METHODS: We evaluated the baseline clinical, procedures characteristics and outcomes of patients with severe coronary artery calcification (CAC) who underwent coronary intravascular lithotripsy (IVL) and rotational atherectomy (RA). RESULTS: Respectively 152 and 238 patients who underwent IVL and RA are enrolled from January 2023 to November 2023. Regarding demographic characteristics, the gender proportion, medical history of PCI and smoke history among groups reach statistical significance. Left anterior descending and right coronary artery were the main vessels treated in both groups. The 2.5 and 3.0 mm IVL balloons and 1.5 mm burr were the most commonly used. 99.3% cases were successfully implanted drug-eluting stents after IVL balloon pre-treatment, which was higher than in the group treated with RA. During hospitalization, there were no serious adverse events in the IVL group, but there were two adverse events in the RA group. Procedural complications were higher in the RA group than the IVL group (5.5% vs. 0.7%, P = 0.027). CONCLUSIONS: IVL appears to be safe and effective for the treatment of severe CAC lesions compared to RA.

Efficacy and safety of drug-coated balloons in chronic total coronary occlusion recanalization: a systematic review and meta-analysis.

BACKGROUND: With advancements in chronic total coronary occlusion (CTO) recanalization techniques and concepts, the success rate of recanalization has been steadily increasing. However, the current data are too limited to draw any reliable conclusions about the efficacy and safety of drug-coated balloons (DCBs) in CTO percutaneous coronary intervention (PCI). Herein, we conducted a meta-analysis to confirm the efficacy of DCB in CTO PCI. METHODS: We systematically searched PubMed, Web of Science and Embase from inception to July 25, 2023. The primary outcome was major advent cardiovascular events (MACE), including cardiac death, nonfatal myocardial infarction (MI), target lesion revascularization (TLR), and target vessel revascularization (TVR). The follow-up angiographic endpoints were late lumen enlargement (LLE), reocclusion and restenosis. RESULTS: Five studies with a total of 511 patients were included in the meta-analysis. Across studies, patients were predominantly male (72.9-85.7%) and over fifty years old. The summary estimate rate of MACE was 13.0% (95% CI 10.1%-15.9%, I2 = 0%, p = 0.428). The summary estimate rates of cardiac death and MI were 2.2% (95% CI 0.7%-3.7%, I2 = 0%, p = 0.873) and 1.2% (95% CI -0.2-2.6%, I2 = 13.7%, p = 0.314), respectively. Finally, the pooled incidences of TLR and TVR were 10.1% (95% CI 5.7%-14.5%, I2 = 51.7%, p = 0.082) and 7.1% (95% CI 3.0%-11.2%, I2 = 57.6%, p = 0.070), respectively. Finally, the summary estimate rates of LLE, reocclusion and restenosis were 59.4% (95% CI 53.5-65.3%, I2 = 0%, p = 0.742), 3.3% (95% CI 1.1-5.4%, I2 = 0%, p = 0.865) and 17.5% (95% CI 12.9-22.0%, I2 = 0%, p = 0.623), respectively. CONCLUSION: Accordingly, DCB has the potential to be used as a treatment for CTO in suitable patients.

Machine learning predictions of the adverse events of different treatments in patients with ischemic left ventricular systolic dysfunction.

This study aimed to develop several new machine learning models based on hibernating myocardium to predict the major adverse cardiac events(MACE) of ischemic left ventricular systolic dysfunction(LVSD) patients receiving either percutaneous coronary intervention(PCI) or optimal medical therapy(OMT). This study included 329 LVSD patients, who were randomly assigned to the training or validation cohort. Least absolute shrinkage and selection operator(LASSO) regression was used to identify variables associated with MACE. Subsequently, various machine learning models were established. Model performance was compared using receiver operating characteristic(ROC) curves, the Brier score(BS), and the concordance index(C-index). A total of 329 LVSD patients were retrospectively enrolled between January 2016 and December 2021. Utilizing LASSO regression analysis, five factors were selected. Based on these factors, RSF, GBM, XGBoost, Cox, and DeepSurv models were constructed. In the development and validation cohorts, the C-indices were 0.888 vs. 0.955 (RSF). The RSF model (0.991 vs. 0.982 vs. 0.980) had the highest area under the ROC curve (AUC) compared with the other models. The BS (0.077 vs. 0.095vs. 0.077) of RSF model were less than 0.25 at 12, 18, and 24 months. This study developed a novel predictive model based on RSF to predict MACE in LVSD patients who underwent either PCI or OMT.

Mesenchymal Stem Cell-Derived Exosomes as Drug Carriers for Delivering miRNA-29b to Ameliorate Inflammation in Corneal Injury Via Activating Autophagy.

Purpose: Corneal injury (CI) resulting in corneal opacity remains a clinical challenge. Exosomes (Exos) derived from bone marrow mesenchymal stem cells (BMSCs) have been proven effective in repairing various tissue injuries and are also considered excellent drug carriers due to their biological properties. Recently, microRNA-29b (miR-29b) was found to play an important role in the autophagy regulation which correlates with cell inflammation and fibrosis. However, the effects of miR-29b and autophagy on CI remain unclear. To find better treatments for CI, we used Exos to carry miR-29b and investigated its effects in the treatment of CI. Methods: BMSCs were transfected with miR-29b-3p agomir/antagomir and negative controls (NCs) to obtain Exos-29b-ago, Exos-29b-anta, and Exos-NC. C57BL/6J mice that underwent CI surgeries were treated with Exos-29b-ago, Exos-29b-anta, Exos-NC, or PBS. The autophagy, inflammation, and fibrosis of the cornea were estimated by slit-lamp, hematoxylin and eosin (H&E) staining, immunofluorescence, RT‒qPCR, and Western blot. The effects of miR-29b-3p on autophagy and inflammation in immortalized human corneal epithelial cells (iHCECs) were also investigated. Results: Compared to PBS, Exos-29b-ago, Exos-29b-anta, and Exos-NC all could ameliorate corneal inflammation and fibrosis. However, Exos-29b-ago, which accumulated a large amount of miR-29b-3p, exerted excellent potency via autophagy activation by inhibiting the PI3K/AKT/mTOR pathway and further inhibited corneal inflammation via the mTOR/NF-κB/IL-1ß pathway. After Exos-29b-ago treatment, the expressions of collagen type III, α-smooth muscle actin, fibronectin, and vimentin were significantly decreased than in other groups. In addition, overexpression of miR-29b-3p prevented iHCECs from autophagy impairment and inflammatory injury. Conclusions: Exos from BMSCs carrying miR-29b-3p can significantly improve the therapeutic effect on CI via activating autophagy and further inhibiting corneal inflammation and fibrosis.

Development of a Novel Nomogram to Predict Major Adverse Cardiac Events in Patients with Chronic Total Occlusion.

Objectives: To create a nomogram using single photon emission computed tomography (SPECT) myocardial perfusion imaging and 18F-FDG positron emissions tomography (PET) gated myocardial metabolism imaging to forecast major adverse cardiovascular events (MACE) in chronic total occlusion (CTO) patients treated with optimal medical therapy (OMT). Methods: A total of 257 patients who received OMT between January 2016 and December 2021 were included in this retrospective study. Patients were randomly divided into development (n=179) and validation (n=78) cohorts. A thorough evaluation was conducted, encompassing clinical features and imaging analysis, which involved assessing myocardial perfusion and metabolism. Independent risk factors were identified using least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses. Calibration curves and decision curve analysis (DCA) were used to evaluate the clinical usefulness. Results: In the development cohort, 53 patients (29.6%) experienced MACE out of 179 patients, while in the validation cohort, MACE occurred in 23 (29.5%) patients out of 78. The PET-left ventricular end-systolic volume (P-ESV) (HR 1.01; 95% CI 1.003-1.017; p=0.003), hibernating myocardium / total perfusion defect (HM/TPD) (HR 1.053; 95% CI 1.038-1.069; p<0.001), PET-left ventricular ejection fraction (P-LVEF) (HR 0.862; 95% CI 0.788-0.943; p=0.001), and left anterior descending branch (LAD) (HR 2.303; 95% CI 1.086-4.884; p=0.03) were significantly associated with MACE and were used to develop the nomogram. The nomogram demonstrated excellent discrimination with C-indexes of 0.931 and 0.911 in the development and validation cohorts. DCA determined that the model exhibited a considerably superior net advantage in predicting MACE. Conclusion: A new nomogram integrating clinical factors and imaging features was created to predict the risk of MACE in patients with CTO.

Biolimus-coated versus paclitaxel-coated balloons for coronary in-stent restenosis (BIO ASCEND ISR): a randomised, non-inferiority trial.

BACKGROUND: The treatment of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation remains challenging in current clinical practice. AIMS: The study was conducted to investigate a novel biolimus-coated balloon (BCB) for the treatment of coronary DES-ISR compared with the best-investigated paclitaxel-coated balloon (PCB). METHODS: This was a prospective, multicentre, randomised, non-inferiority trial comparing a novel BCB with a clinically proven PCB for coronary DES-ISR. The primary endpoint was in-segment late lumen loss (LLL) at 9 months assessed by an independent core laboratory. Baseline and follow-up optical coherence tomography were performed in a prespecified subgroup of patients. RESULTS: A total of 280 patients at 17 centres were randomised to treatment with a BCB (n=140) versus a PCB (n=140). At 9 months, LLL in the BCB group was 0.23±0.37 mm compared to 0.25±0.35 mm in the PCB group; the mean difference between the groups was -0.02 (95% confidence interval [CI]: -0.12 to 0.07) mm; p-value for non-inferiority<0.0001. Similar clinical outcomes were also observed for both groups at 12 months. In the optical coherence tomography substudy, the neointimal area at 9 months was 2.32±1.04 mm2 in the BCB group compared to 2.37±0.93 mm2 in the PCB group; the mean difference between the groups was -0.09 (95% CI: -0.94 to 0.76) mm2; p=non-significant. CONCLUSIONS: This head-to-head comparison of a novel BCB shows similar angiographic outcomes in the treatment of coronary DES-ISR compared with a clinically proven PCB. (ClinicalTrials.gov: NCT04733443).

Current advances and future trends of hormesis in disease.

Hormesis, an adaptive response, occurs when exposure to low doses of a stressor potentially induces a stimulatory effect, while higher doses may inhibit it. This phenomenon is widely observed across various organisms and stressors, significantly advancing our understanding and inspiring further exploration of the beneficial effects of toxins at doses both below and beyond traditional thresholds. This has profound implications for promoting biological regulation at the cellular level and enhancing adaptability throughout the biosphere. Therefore, conducting bibliometric analysis in this field is crucial for accurately analyzing and summarizing its current research status. The results of the bibliometric analysis reveal a steady increase in the number of publications in this field over the years. The United States emerges as the leading country in both publication and citation numbers, with the journal Dose-Response publishing the highest number of papers in this area. Calabrese E.J. is a prominent person with significant contributions and influence among authors. Through keyword co-occurrence and trend analysis, current hotspots in this field are identified, primarily focusing on the relationship between hormesis, oxidative stress, and aging. Analysis of highly cited references predicts that future research trends may center around the relationship between hormesis and stress at different doses, as well as exploring the mechanisms and applications of hormesis. In conclusion, this review aims to visually represent hormesis-related research through bibliometric methods, uncovering emerging patterns and areas of focus within the field. It provides a summary of the current research status and forecasts trends in hormesis-related research.

Efficacy of revascularization in CTO patients based on hibernating myocardium therapy.

BACKGROUND: The effectiveness of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is still uncertain, especially for patients with ischemic left ventricular dysfunction. This study aimed to assess hibernating myocardium (HM), as determined by single-photon emission computed tomography (SPECT) and 18F-FDG positron emission tomography (PET), and to compare the benefits of PCI and optimal medical therapy (OMT). METHODS: A retrospective study collected data from 332 patients with CTO and ischemic left ventricular dysfunction. The study compared patients who underwent PCI or OMT via propensity score matching (PSM) analysis which was performed with a 1:2 matching protocol using the nearest neighbour matching algorithm. The primary endpoint of the study was the occurrence of major adverse cardiac events (MACE), defined as a composite of cardiac death, readmission for worsening heart failure (WHF), revascularization and myocardial infarction (MI). RESULTS: After PSM, there were a total of 246 individuals in the PCI and OMT groups. Following Cox regression, hibernating myocardium/total perfusion defect (HM/TPD) was identified as an independent risk factor (hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.008-1.052, p = .007). The cut-off value of HM/TPD was 38%. The results of the subgroup analysis suggest that for patients with HM/TPD >38%, the OMT group had a greater risk of MACE (p = .035). A sensitivity analysis restricting patients with single-vessel CTO lesions, HM/TPD remained an independent predictor (HR 1.025, 95% CI 1.008-1.043, p = .005). CONCLUSION: HM/TPD is an independent predictor of MACE, and for patients with HM/TPD > 38%, CTO-PCI had a lower risk of MACE compared with OMT. However, further validation is still needed through large-scale studies.

Oligonucleotide therapies for nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver disease (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It is characterized by a series of substantial liver damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage of NASH, in some cases, may result in cirrhosis and hepatocellular carcinoma (HCC). Nowadays a large number of investigations are actively under way to test various therapeutic strategies, including emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor RNA, and small activating RNA) that have shown high potential in treating this fatal liver disease. This article systematically reviews the pathogenesis of NASH/NAFLD, the promising druggable targets proven by current studies in chemical compounds or biological drug development, and the feasibility and limitations of oligonucleotide-based therapeutic approaches under clinical or pre-clinical studies.

Ultrasound and clinical factors predicting central lymph node metastases in patients with unilateral multifocal papillary thyroid carcinoma.

OBJECTIVE: This retrospective study involving a large dataset of unilateral multifocal papillary thyroid carcinoma (UM-PTC) sought to identify factors that predict central lymph node metastases (CLNM) in patients. METHODS: We identified a cohort of 158 patients who underwent cervical ultrasonography followed by UM-PTC diagnosis based on postoperative pathology. The relationship between CLNM and UM-PTC clinical ultrasound features was evaluated using univariate and multivariate analyses. Receiver operating characteristic (ROC) curve analysis was used to determine the ability of total tumor diameter (TTD) to predict CLNM. RESULTS: Among the 158 UM-PTC patients, the incidence of CLNM was 29.7% (47/158). Univariate and multivariate analyses revealed that a number of similarity of sonographic features (NSSF) ≥4 (odds ratio [OR] = 11.335, 95% confidence interval [CI]: 3.95-32.50, p = 0.000), microcalcifications (OR = 3.54, 95% CI: 1.30-9.70, p = 0.014), a TTD of ≥2 cm (OR = 4.48, 95% CI: 1.62-12.34, p = 0.004), number of nodules ≥3 (OR = 13.17, 95% CI: 3.24-53.52, p = 0.000), and Lateral cervical lymph node metastasis (LLNM) (OR = 5.57, 95% CI: 1.59-19.48, p = 0.007) were independently associated with CLNM in UM-PTC. ROC curve analysis revealed that the TTD cut-off of 1.795 cm had a sensitivity of 0.723 and a specificity of 0.676 for predicting CLNM. CONCLUSIONS: Patients with UM-PTC are at high risk of CLNM. NSSF ≥4, microcalcifications, TTD of ≥2 cm, LLNM, and a number of nodules ≥3 were independently associated with CLNM. Our data show that ultrasound may guide surgical decisions in the treatment of UM-PTC.

Development and validation of a predicting nomogram for in-hospital mortality of COVID-19 Omicron variant: A cohort study of 1324 cases in Beijing Anzhen Hospital.

Coronavirus disease 2019 (COVID-19) is continuously posing high global public health concerns due to its high morbidity and mortality. This study aimed to construct a convenient risk model for predicting in-hospital mortality of COVID-19 Omicron variant. A total of 1324 hospitalized patients with Omicron variant were enrolled from Beijing Anzhen Hospital. During hospitalization, the Omicron variant mortality rate was found to be 24.4%. Using the datasets of clinical demographics and laboratory tests, three machine learning algorithms, including best subset selection, stepwise selection, and least absolute shrinkage and selection operator regression analyses were employed to identify the potential predictors of in-hospital mortality. The results found that a panel of twenty-four clinical variables (including age, hyperlipemia, stroke, tumor, and several cardiovascular markers) identified by stepwise selection model exhibited significant performances in predicting the in-hospital mortality of COVID-19. The resultant nomogram showed good discrimination, highlighted by the areas under the curve values of 0.88 for 10 days, 0.81 for 20 days, and 0.82 for 30 days, respectively. Furthermore, decision curve analysis showed a significant reliability and precision for the established stepwise selection model. Collectively, this study developed an accurate and convenience risk model for predicting the in-hospital mortality of COVID-19 Omicron.

Mea6/cTAGE5 cooperates with TRAPPC12 to regulate PTN secretion and white matter development.

Mutations of TRAPPC12 are associated with progressive childhood encephalopathy including abnormal white matter. However, the underlying pathogenesis is still unclear. Here, we found that Trappc12 deficiency in CG4 and oligodendrocyte progenitor cells (OPCs) affects their differentiation and maturation. In addition, TRAPPC12 interacts with Mea6/cTAGE5, and Mea6/cTAGE5 ablation in OPCs affects their proliferation and differentiation, leading to marked hypomyelination, compromised synaptic functionality, and aberrant behaviors in mice. We reveal that TRAPPC12 is associated with COPII components at ER exit site, and Mea6/cTAGE5 cKO disrupts the trafficking pathway by affecting the distribution and/or expression of TRAPPC12, SEC13, SEC31A, and SAR1. Moreover, we observed marked disturbances in the secretion of pleiotrophin (PTN) in Mea6-deficient OPCs. Notably, exogenous PTN supplementation ameliorated the differentiation deficits of these OPCs. Collectively, our findings indicate that the association between TRAPPC12 and MEA6 is important for cargo trafficking and white matter development.