LncRNA FOXD1-AS1 regulates pancreatic cancer stem cell properties and 5-FU resistance by regulating the miR-570-3p/SPP1 axis as a ceRNA.

Cancer stem cells (CSCs) play a pivotal role in the pathogenesis of human cancers. Previous studies have highlighted the role of long non-coding RNA (lncRNA) in modulating the stemness of CSCs. In our investigation, we identified an upregulation of lncRNA FOXD1-AS1 in CSCs. The enforced expression of lncRNA FOXD1-AS1 promotes tumorigenesis and self-renewal in pancreatic cancer CSCs. Conversely, the knockdown of lncRNA FOXD1-AS1 inhibits tumorigenesis and self-renewal in pancreatic cancer CSCs. Furthermore, our findings reveal that lncRNA FOXD1-AS1 enhances self-renewal and tumorigenesis in pancreatic cancer CSCs by up-regulating osteopontin/secreted phosphoprotein 1(SPP1) and acting as a ceRNA to sponge miR-570-3p in pancreatic cancer (PC) CSCs. Additionally, lncRNA FOXD1-AS1 depleted pancreatic cancer cells exhibit heightened sensitivity to 5-FU-indued cell growth inhibition and apoptosis. Analysis of patient-derived xenografts (PDX) indicates that a low level of lncRNA FOXD1-AS1 may serve as a predictor of 5-FU benefits in PC patients. Moreover, the introduction of SPP1 can reverse the sensitivity of lncRNA FOXD1-AS1-knockdown PC cells to 5-FU-induced cell apoptosis. Importantly, molecular studies have indicated that the elevated levels of lncRNAFOXD1-AS1 in PC are facilitated through METTL3 and YTHDF1-dependent m6A methylation. In summary, our results underscore the critical functions of lncRNA FOXD1-AS1 in the self-renewal and tumorigenesis of pancreatic cancer CSCs, positioning lncRNA FOXD1-AS1 as a promising therapeutic target for PC.

Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency in Vascular Smooth Muscle Cells Exacerbates Arterial Calcification.

BACKGROUND: IDO1 (indoleamine 2,3-dioxygenase 1) is the rate-limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMCs) with an osteogenic phenotype promote calcification and features of plaque instability. However, it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes VSMCs osteogenic reprogramming and calcification. METHODS: We generated global Apoe (apolipoprotein E) and Ido1 double knockout mice, and Apoe knockout mice with specific deletion of IDO1 in VSMCs or macrophages. Arterial intimal calcification was evaluated by a Western diet-induced atherosclerotic calcification model. RESULTS: Global deficiency of IDO1 boosted calcific lesion formation without sex bias in vivo. Conditional IDO1 loss of function in VSMCs rather than macrophages promoted calcific lesion development and the abundance of RUNX2 (runt-related transcription factor 2). In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression in both Apoe-/- and Apoe-/-Ido1-/- mice. We found that IDO1 deletion restrained RUNX2 from proteasomal degradation, which resulted in enhanced osteogenic reprogramming of VSMCs. Kynurenine administration downregulated RUNX2 in an aryl hydrocarbon receptor-dependent manner. Kynurenine acted as the endogenous ligand of aryl hydrocarbon receptor, controlled resultant interactions between cullin 4B and aryl hydrocarbon receptor to form an E3 ubiquitin ligase that bound with RUNX2, and subsequently promoted ubiquitin-mediated instability of RUNX2 in VSMCs. Serum samples from patients with coronary artery calcification had impaired IDO1 activity and decreased kynurenine catabolites compared with those without calcification. CONCLUSIONS: Kynurenine, an IDO1-mediated tryptophan metabolism main product, promotes RUNX2 ubiquitination and subsequently leads to its proteasomal degradation via an aryl hydrocarbon receptor-dependent nongenomic pathway. Insufficient kynurenine exerts the deleterious role of IDO1 ablation in promoting RUNX2-mediated VSMCs osteogenic reprogramming and calcification in vivo.

Nomogram for predicting rebleeding after initial endoscopic epinephrine injection monotherapy hemostasis in patients with peptic ulcer bleeding: a retrospective cohort study.

BACKGROUND: Although the current guidelines recommend endoscopic combination therapy, endoscopic epinephrine injection (EI) monotherapy is still a simple, common and effective modality for treating peptic ulcer bleeding (PUB). However, the rebleeding risk after EI monotherapy is still high, and identifying rebleeding patients after EI monotherapy is unclear, which is highly important in clinical practice. This study aimed to identify risk factors and constructed a predictive nomogram related to rebleeding after EI monotherapy. METHODS: We consecutively and retrospectively analyzed 360 PUB patients who underwent EI monotherapy between March 2014 and July 2021 in our center. Then we identified independent risk factors associated with rebleeding after initial endoscopic EI monotherapy by multivariate logistic regression. A predictive nomogram was developed and validated based on the above predictors. RESULTS: Among all PUB patients enrolled, 51 (14.2%) had recurrent hemorrhage within 30 days after endoscopic EI monotherapy. After multivariate logistic regression, shock [odds ratio (OR) = 12.691, 95% confidence interval (CI) 5.129-31.399, p < 0.001], Rockall score (OR = 1.877, 95% CI 1.250-2.820, p = 0.002), tachycardia (heart rate > 100 beats/min) (OR = 2.610, 95% CI 1.098-6.203, p = 0.030), prolonged prothrombin time (PT > 13 s) (OR = 2.387, 95% CI 1.019-5.588, p = 0.045) and gastric ulcer (OR = 2.258, 95% CI 1.003-5.084, p = 0.049) were associated with an increased risk of rebleeding after an initial EI monotherapy treatment. A nomogram incorporating these independent high-risk factors showed good discrimination, with an area under the receiver operating characteristic curve (AUROC) of 0.876 (95% CI 0.817-0.934) (p < 0.001). CONCLUSIONS: We developed a predictive nomogram of rebleeding after EI monotherapy, which had excellent prediction accuracy. This predictive nomogram can be conveniently used to identify low-risk rebleeding patients after EI monotherapy, allowing for decision-making in a clinical setting.

The anterior talofibular ligament: A thin-slice three-dimensional magnetic resonance imaging study.

PURPOSE: The aim of this study was to provide an accurate and improved understanding of anterior talofibular ligament (ATFL) anatomy, and to determine the exact positioning and diameter of the bony tunnel during ATFL repair and/or reconstruction surgery. METHOD: A total of 58 healthy asymptomatic volunteers were examined, wherein 38 underwent bilateral ankle 3D MRI, and 20 underwent unilateral ankle 3D MRI (10 left and 10 right ankles). Data from a total of 96 MRI datasets were collected. The MRI data from these cases were exported into Mimics to enable reconstruction of 3D ATFL models. The resulting image quality was evaluated using a 5-point subjective scoring system. In addition, the length, width, thickness, and positioning of each ATFL and the area of the ATFL footprints were identified within the 3D model using Mimics and SolidWorks. RESULTS: The image quality score was 4.48 ± 0.50. The ATFL formed one (65.6%), two (31.3%), or three (3.1%) bundles forms. The footprint area was 31.25 ± 6.29 mm2 on the fibular side, and 17.48 ± 4.49 mm2 on the talar side. CONCLUSION: Thin-slice 3D MRI aids in the reconstruction of the 3D ATFL model, and it provides reference for the accurate anatomy of the area and location of the ATFL. This technology will facilitate diagnosis of ATFL injuries and choice of surgical methods. LEVEL OF EVIDENCE: level IV.

Epidemiological, Clinical, Radiological Characteristics and Outcomes of Medical Staff with COVID-19 in Wuhan, China: Analysis of 101 Cases.

Objectives: As of 11 Feb 2020, a total of 1,716 medical staff infected with laboratory-confirmed the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) in China had been reported. The predominant cause of the infection among medical staff remains unclear. We sought to explore the epidemiological, clinical characteristics and prognosis of infected medical staff. Methods: Medical staff who infected with SARS-Cov-2 and admitted to Union Hospital, Wuhan between 16 Jan to 25 Feb, 2020 were included in this single-centered, retrospective study. Data were compared by occupation and analyzed with the Kaplan-Meier and Cox regression methods. Results: A total of 101 medical staff (32 males and 69 females; median age: 33) were included in this study and 74.3% were nurses. A small proportion of the cohort had contact with specimens (3%) as well as patients infected with SARS-Cov-2 in fever clinics (15%) and isolation wards (3%). 80% of medical staff showed abnormal IL-6 levels and 33% had lymphocytopenia. Chest CT mainly manifested as bilateral (62%), septal/subpleural (77%) and groundglass opacities (48%). The major differences between doctors and nurses manifested in laboratory indicators. As of the last observed date, no patient was transferred to intensive care unit or died. Fever (HR=0.57; 95% CI 0.36-0.90) and IL-6 levels greater than 2.9 pg/ml (HR=0.50; 95% CI 0.30-0.86) were unfavorable factors for discharge. Conclusions: Our findings suggested that the infection of medical staff mainly occurred at the early stages of SARS-CoV-2 epidemic in Wuhan, and only a small proportion of infection had an exact mode. Meanwhile, medical staff infected with COVID-19 have relatively milder symptoms and favorable clinical course than ordinary patients, which may be partly due to their medical expertise, younger age and less underlying diseases. The potential risk factors of fever and IL-6 levels greater than 2.9 pg/ml could help to identify medical staff with poor prognosis at an early stage.

Chest CT Imaging Features of Typical Covert COVID-19 Cases.

Purpose: To analyze the chest CT imaging findings of patients with initial negative RT-PCR and to compare with the CT findings of the same sets of patients when the RT-PCR turned positive for SARS-CoV-2 a few days later. Materials and methods: A total of 32 patients (8 males and 24 females; 52.9±7years old) with COVID-19 from 27 January and 26 February 2020 were enrolled in this retrospective study. Clinical and radiological characteristics were analyzed. Results: The median period (25%, 75%) between initial symptoms and the first chest CT, the initial negative RT-PCR, the second CT and the positive RT-PCR were 7(4.25,11.75), 7(5,10.75), 15(11,23) and 14(10,22) days, respectively. Ground glass opacities was the most frequent CT findings at both the first and second CTs. Consolidation was more frequently observed on lower lobes, and more frequently detected during the second CT (64.0%) with positive RT-PCR than the first CT with initial negative RT-PCR (53.1%). The median of total lung severity score and the number of lobes affected had significant difference between twice chest CT (P=0.007 and P=0.011, respectively). Conclusion: In the first week of disease course, CT was sensitive to the COVID-19 with initial negative RT-PCR. Throat swab test turned positive while chest CT mostly demonstrated progression.

Evaluation of 3-Dimensional Magnetic Resonance Imaging (3D MRI) in Diagnosing Anterior Talofibular Ligament Injury.

BACKGROUND It is challenging to entirely show the anterior talofibular ligament (ATFL) and accurately diagnose ATFL injury with traditional 2-dimensional (2D) magnetic resonance imaging (MRI). With the introduction of 3.0T MRI, a 3-dimensional (3D) MRI sequence can achieve images with high spatial resolution. This study aimed to evaluate the accuracy of 3D MRI and compare it with 2D MRI in diagnosing ATFL injury. MATERIAL AND METHODS This was a prospective study in which 45 patients with clinically suspected ATFL injury underwent 2D MRI, 3D MRI, and 3D model reconstruction followed by arthroscopic surgery between February 2018 and April 2019. Two radiologists who had over 11 and 13 years of musculoskeletal experience assessed the injury of ATFL in consensus without any clinical clues. Arthroscopic surgery results were the standard reference of MRI accuracy. RESULTS The 3D MRI results of ATFL injury showed the sensitivity of diagnosis of complete tears of 83% and specificity of 82%. The partial tears diagnosis sensitivity was 78%, and specificity was 100%. The sensitivity of diagnosis of sprains was 100%, and the specificity was 97%. The 3D MRI accuracy of diagnosis was 98% for no injury, 98% for sprain, 91% for partial tear, and 82% for complete tear. The difference in the diagnosis of sprain and partial tears by 3D MRI and 2D MRI was statistically significant (P<0.05). A 3D reconstruction model was successfully created for all patients. CONCLUSIONS 3D MRI may be a reliable and accurate method to detect ATFL injury. The 3D reconstruction model using 3D MRI sequences has excellent prospects in application.

A Multimodality Machine Learning Approach to Differentiate Severe and Nonsevere COVID-19: Model Development and Validation.

BACKGROUND: Effectively and efficiently diagnosing patients who have COVID-19 with the accurate clinical type of the disease is essential to achieve optimal outcomes for the patients as well as to reduce the risk of overloading the health care system. Currently, severe and nonsevere COVID-19 types are differentiated by only a few features, which do not comprehensively characterize the complicated pathological, physiological, and immunological responses to SARS-CoV-2 infection in the different disease types. In addition, these type-defining features may not be readily testable at the time of diagnosis. OBJECTIVE: In this study, we aimed to use a machine learning approach to understand COVID-19 more comprehensively, accurately differentiate severe and nonsevere COVID-19 clinical types based on multiple medical features, and provide reliable predictions of the clinical type of the disease. METHODS: For this study, we recruited 214 confirmed patients with nonsevere COVID-19 and 148 patients with severe COVID-19. The clinical characteristics (26 features) and laboratory test results (26 features) upon admission were acquired as two input modalities. Exploratory analyses demonstrated that these features differed substantially between two clinical types. Machine learning random forest models based on all the features in each modality as well as on the top 5 features in each modality combined were developed and validated to differentiate COVID-19 clinical types. RESULTS: Using clinical and laboratory results independently as input, the random forest models achieved >90% and >95% predictive accuracy, respectively. The importance scores of the input features were further evaluated, and the top 5 features from each modality were identified (age, hypertension, cardiovascular disease, gender, and diabetes for the clinical features modality, and dimerized plasmin fragment D, high sensitivity troponin I, absolute neutrophil count, interleukin 6, and lactate dehydrogenase for the laboratory testing modality, in descending order). Using these top 10 multimodal features as the only input instead of all 52 features combined, the random forest model was able to achieve 97% predictive accuracy. CONCLUSIONS: Our findings shed light on how the human body reacts to SARS-CoV-2 infection as a unit and provide insights on effectively evaluating the disease severity of patients with COVID-19 based on more common medical features when gold standard features are not available. We suggest that clinical information can be used as an initial screening tool for self-evaluation and triage, while laboratory test results should be applied when accuracy is the priority.

Accurately Differentiating Between Patients With COVID-19, Patients With Other Viral Infections, and Healthy Individuals: Multimodal Late Fusion Learning Approach.

BACKGROUND: Effectively identifying patients with COVID-19 using nonpolymerase chain reaction biomedical data is critical for achieving optimal clinical outcomes. Currently, there is a lack of comprehensive understanding in various biomedical features and appropriate analytical approaches for enabling the early detection and effective diagnosis of patients with COVID-19. OBJECTIVE: We aimed to combine low-dimensional clinical and lab testing data, as well as high-dimensional computed tomography (CT) imaging data, to accurately differentiate between healthy individuals, patients with COVID-19, and patients with non-COVID viral pneumonia, especially at the early stage of infection. METHODS: In this study, we recruited 214 patients with nonsevere COVID-19, 148 patients with severe COVID-19, 198 noninfected healthy participants, and 129 patients with non-COVID viral pneumonia. The participants' clinical information (ie, 23 features), lab testing results (ie, 10 features), and CT scans upon admission were acquired and used as 3 input feature modalities. To enable the late fusion of multimodal features, we constructed a deep learning model to extract a 10-feature high-level representation of CT scans. We then developed 3 machine learning models (ie, k-nearest neighbor, random forest, and support vector machine models) based on the combined 43 features from all 3 modalities to differentiate between the following 4 classes: nonsevere, severe, healthy, and viral pneumonia. RESULTS: Multimodal features provided substantial performance gain from the use of any single feature modality. All 3 machine learning models had high overall prediction accuracy (95.4%-97.7%) and high class-specific prediction accuracy (90.6%-99.9%). CONCLUSIONS: Compared to the existing binary classification benchmarks that are often focused on single-feature modality, this study's hybrid deep learning-machine learning framework provided a novel and effective breakthrough for clinical applications. Our findings, which come from a relatively large sample size, and analytical workflow will supplement and assist with clinical decision support for current COVID-19 diagnostic methods and other clinical applications with high-dimensional multimodal biomedical features.

Inhibition of exosomal miR-24-3p in diabetes restores angiogenesis and facilitates wound repair via targeting PIK3R3.

Diabetic foot ulcer (DFU) is one of the common ailments of elderly people suffering from diabetes. Exosomes containing various active regulators have been found to play a significant role in apoptosis, cell proliferation and other biological processes. However, the effect and the underlying mechanism of action of diabetes patients derived from circulating exosomes (Dia-Exos) on DFU remain unclear. Herein, we aim to explore the potential regulatory role of Dia-Exos. First, we attempted to demonstrate the harmful effect of Dia-Exos both in vivo and in vitro. miRNA-24-3p (miR-24-3p) was found enriched with Dia-Exos. Hence, inhibition of this miRNA could partially reverse the negative effect of Dia-Exos, thus, in ture, accelerates wound repair. Luciferase assay further verified the binding of miR-24-3p to the 3'-UTR of phosphatidylinositol 3-kinase regulatory subunit gamma (PIK3R3) mRNA and the PIK3R3 expression enhanced human umbilical vein endothelial cells functionality in vitro. Hence, the findings of this study reveal the regulatory role of Dia-Exos in the process of wound healing and provide experimental evidence for the therapeutic effects of knocking down miR-24-3p in DFU treatment.

Therapeutic effect of omega-3 fatty acids on T cell-mediated autoimmune diseases.

The present study was to demonstrate that the G protein coupled receptors serve as targets for the treatment of autoimmune disease such as rheumatoid arthritis and multiple sclerosis. Rats received pristane at the base of the tail. Affected joints were counted daily. The T cell mediated autoimmune diseases such as pristine-induced arthritis (PIA) and autoimmune encephalomyelitis (EAE) in a rat model were profoundly ameliorated by treatment with the specific G protein couple receptors 120 (GPR120) stimuli omega-3 fatty acids (ω-3 FAs). Our study further revealed that the activation of GPR120 by ω-3 FAs can result in a decrease of phosphorylated transforming growth factor-ß activated kinase 1 (TAK1), and further inhibit the downstream IKKß/I-κB pathway and the terminal NF-κB activation which serves as a mediator of T cell activation. ω-3 Fatty acids exhibited an inhibitory effect on TAK1 by enhancing the association of ß-arrestin2 and TAK1 binding protein 1 (TAB1), thus the disassociation of TAB1 from the TAB1/TAK1 complex renders a limited effect on ß-arrestin2 signaling as an innate immunity regulation. GPR120 is a functional receptor of ω-3 fatty acids in T cell-mediated autoimmune disease compared with its effect on innate immunity.

Suture Anchor Versus Allogenic Tendon Suture in Treatment of Haglund Syndrome.

BACKGROUND Haglund's deformity is an abnormal bony enlargement on the back of the heel. It can cause the impact of the posterior calcaneal bursa and Achilles tendon insertion, and finally result in pain. This syndrome is called Haglund syndrome. The purpose of this study was to explore the effect of the suture anchor and allogeneic tendon suture in the treatment of Haglund syndrome. MATERIAL AND METHODS We retrospectively studied 20 patients with Haglund syndrome treated from January 2015 to December 2016. The patients were randomly divided into Group 1 (the suture anchor group) and Group 2 (the allogeneic tendon group), with 10 patients in each group and an average follow-up of 32 months after surgery. The AOFAS, VAS, and Arner-Lindholm scales were used to summarize the patient follow-up results and complications. RESULTS In the 2 groups of patients, the postoperative AOFAS, VAS scores, and the Arner-Lindholm scale showed good results. However, the postoperative AOFAS score and VAS of the suture anchor group were better than those of the allogeneic tendon group, with shorter operation times. No Achilles tendon rupture or wound infection occurred during the entire postoperative period in either group. These results show the superiority of suture anchors. CONCLUSIONS The higher AOFAS and VAS score and shorter operation time in the suture anchor group suggest it is the better alternative for treatment of Haglund syndrome.

Roles of platelet-derived growth factor in vascular calcification.

Vascular calcification (VC) is prevalent in aging, and patients with hypertension, chronic kidney disease (CKD), or diabetes. VC is regarded as an active and complex process that involves multiple mechanisms responsible for calcium deposition in vessel wall. In light of the complicated pathogenesis of VC, effective therapy for ameliorating VC is limited. Thus, it is urgent to explore the potential mechanisms and find new targets for the therapy of VC. Platelet-derived growth factor (PDGF), a potent mitogen, and chemoattractant have been found to disturb the vascular homeostasis by inducing inflammation, oxidative stress, and phenotype transition, all of which accelerate the process of VC. The aim of current review is to present a review about the roles of PDGF in affecting VC and to establish a potential target for treating VC.

Investigation of the Relationship Between Flatfoot and Patellar Subluxation in Adolescents.

Patellar subluxation is common in adolescents, and a variety of factors are related to this condition, with valgus of the knee joint an important factor. The results of many studies suggest that flatfoot can cause an abnormality of the lower limb power line. Structural abnormalities of the foot caused by the high stresses exerted by body weight can lead to structural deformity of the knee and can also cause knee valgus. Screening for foot problems can help determine the risk of patellar subluxation, and early intervention can lessen the incidence of this condition. The purpose of the present study was to investigate the effects of flatfoot on the structure and function of the knees and, especially, the risk of patellar subluxation. A total of 72 participants were recruited for this cross-sectional study. The mean age at examination was 15.4 ± 4.0 (range 9 to 22) years. The measured parameters were heel valgus angle, arch index, and quadriceps angle (Q-angle). Overall, the mean values of the heel valgus angle, arch index, and Q-angle were 5.9° ± 2.4° (range 1° to 11°), 0.33 ± 0.07 (range 0.23 to 0.46), and 19.1° ± 3.5° (range 9° to 26°), respectively. The Q-angle was directly associated with the heel valgus angle (r = 0.818, p < .001) and arch index (r = 0.655, p < .001). We found that flatfoot can affect the morphology of the knee joint and increase the risk of patellar subluxation.

Pumilio RNA binding family member 1 deficiency activates anti-tumor immunity in hepatocellular carcinoma via restraining M2 macrophage polarization.

Pumilio RNA-binding family member 1 (PUM1) has been implicated in both the progression of colorectal cancer and the regulation of inflammation. The role of PUM1 in the polarization of tumor-associated macrophages (TAMs) into the M2 phenotype has not yet been reported in hepatocellular carcinoma. Using the PUM1-knockout mice model, flow cytometry, and IHC, we validated the role of PUM1 in hepatocellular carcinoma (HCC) TAMs. One-way analysis of variance (ANOVA) or student's t-tests was used to compare the experimental groups. We found that PUM1 inhibited anti-tumor immunity in HCC through TAM-mediated inhibition of CD8+ T cells. We also showed that PUM1 promotes the transformation of TAMs into pro-tumorigenic M2-like phenotypes by activating cAMP signaling pathway. This study emphasized the potential of PUM1 as a target for immunotherapy in HCC through TAMs. The present study revealed the molecular mechanism underlying the pro-tumor role of PUM1 in HCC.

Identification of a novel intronic mutation of MAGED2 gene in a Chinese family with antenatal Bartter syndrome.

BACKGROUND: Antenatal Bartter syndrome is a life-threatening disease caused by a mutation in the MAGED2 gene located on chromosome Xp11. It is characterized by severe polyhydramnios and extreme prematurity. While most reported mutations are located in the exon region, variations in the intron region are rarely reported. METHODS: In our study, we employed whole exome sequencing and Sanger sequencing to genotype members of this family. Additionally, a minigene assay was conducted to evaluate the impact of genetic variants on splicing. RESULTS: Our findings reveal a novel intronic variant (NM_177433.3:c.1271 + 4_1271 + 7delAGTA) in intron 10 of the MAGED2 gene. Further analysis using the minigene assay demonstrated that this variant activated an intronic cryptic splice site, resulting in a 96 bp insertion in mature mRNA. CONCLUSIONS: Our results indicate that the novel intronic variant (c.1271 + 4_1271 + 7delAGTA) in intron 10 of the MAGED2 gene is pathogenic. This expands the mutation spectrum of MAGED2 and highlights the significance of intronic sequence analysis.

Early oral feeding versus nasojejunal early enteral nutrition in patients following pancreaticoduodenectomy: a propensity score-weighted analysis of 428 consecutive patients.

BACKGROUND: Notwithstanding that significant medical progress has been achieved in recent years, the optimal nutritional support method following pancreaticoduodenectomy (PD) remains uncertain. This study compared the safety and feasibility of early oral feeding (EOF) with nasojejunal early enteral nutrition (NJEEN) after PD. METHODS: A retrospective cohort study was conducted on 428 consecutive patients who underwent PD between August 2018 and December 2020. During the first study phase, the routine postoperative feeding strategy was NJEEN, later replaced by EOF during the second study phase. The primary outcome was the incidence of delayed gastric emptying (DGE) following PD. Propensity score weighting was used to control for confounding factors. RESULTS: Four hundred forty patients underwent PD during the overall study period, with 438 patients aged 18 years and older. Ten patients experienced accidental tube dislodgement or migration and were excluded from the study based on the exclusion criteria. Finally, 211 patients and 217 patients underwent EOF and NJEEN, respectively. After propensity score weighting, it was observed that patients who underwent postoperative EOF experienced a significantly lower DGE (B/C) rate compared to those who underwent postoperative NJEEN [7.38% (31/424) vs. 14.97% (62/413), P =0.0005]. Subgroup analyses according to the presence of soft pancreatic texture yielded consistent results. The EOF group exhibited lower DGE grade, DGE (B/C) rate [5.90% (11/194) vs. 22.07% (43/193), P <0.0001], postoperative gastrointestinal endoscopic intervention rate, and Clavien-Dindo Grade III or higher rate. CONCLUSIONS: EOF is superior to NJEEN in reducing the incidence of grade B/C DGE after PD. The EOF procedure is safe and feasible and should be recommended as the optimal postoperative feeding method following PD.

Continuous age- and sex-specific reference ranges of liver enzymes in Chinese children and application in pediatric non-alcoholic fatty liver disease.

BACKGROUND: Alanine aminotransferase (ALT) is widely used to screen patients with hepatic diseases. However, the current reference ranges (< 50 U/L) were developed by laboratories and have not been validated in populations with a large number of healthy individuals. METHODS: This study collected venous blood and anthropometric data from a total of 13,287 healthy children aged 3 months to 18 years who underwent routine physical examinations in the Department of Pediatric Healthcare. We applied the least mean square algorithm to establish age- and sex-related reference percentiles of serum levels of transaminases. For validation, we recruited 4276 children and adolescents with obesity/overweight who underwent evaluation and metabolic tests in the hospital. Using receiver operating characteristic curves, we determined age- and sex-specific upper limit percentiles of liver enzymes for fatty liver diseases. RESULTS: This study revealed a significant correlation between serum transaminase levels and age and sex (P < 0.01). These transaminase levels exhibited age- and sex-specific patterns. Among individuals in the non-alcoholic fatty liver disease (NAFLD) cohort, elevated ALT levels displayed a positive association with clinical markers of disease severity, including homeostatic model assessment of insulin resistance, waist-hip ratio, and serum uric acid levels (P < 0.01). According to the receiver operating characteristic curves, ALT levels at the 92.58th percentile for boys and the 92.07th percentile for girls yielded the highest accuracy and specificity. CONCLUSIONS: This study provides age- and sex-specific reference ranges for ALT, aspartate aminotransferase, and γ-glutamyltransferase in Chinese children and adolescents, making it the largest population study to date. Furthermore, the study establishes a precise upper limit for ALT levels, facilitating their use in NAFLD screening. Video Abstract.

Nicotine exacerbates atherosclerosis and plaque instability via NLRP3 inflammasome activation in vascular smooth muscle cells.

Rationale: Nicotine has been reported to be a strong risk factor for atherosclerosis. However, the underlying mechanism by which nicotine controls atherosclerotic plaque stability remain largely unknown. Objective: The aim of this study was to evaluate the impact of lysosomal dysfunction mediated NLRP3 inflammasome activation in vascular smooth muscle cell (VSMC) on atherosclerotic plaque formation and stability in advanced atherosclerosis at the brachiocephalic arteries (BA). Methods and Results: Features of atherosclerotic plaque stability and the markers for NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome were monitored in the BA from nicotine or vehicle-treated apolipoprotein E deficient (Apoe-/-) mice fed with Western-type diet (WD). Nicotine treatment for 6 weeks accelerated atherosclerotic plaque formation and enhanced the hallmarks of plaque instability in BA of Apoe-/- mice. Moreover, nicotine elevated interleukin 1 beta (IL-1ß) in serum and aorta and was preferred to activate NLRP3 inflammasome in aortic vascular smooth muscle cells (VSMC). Importantly, pharmacological inhibition of Caspase1, a key downstream target of NLRP3 inflammasome complex, and genetic inactivation of NLRP3 significantly restrained nicotine-elevated IL-1ß in serum and aorta, as well as nicotine-stimulated atherosclerotic plaque formation and plaque destabilization in BA. We further confirmed the role of VSMC-derived NLRP3 inflammasome in nicotine-induced plaque instability by using VSMC specific TXNIP (upstream regulator of NLRP3 inflammasome) deletion mice. Mechanistic study further showed that nicotine induced lysosomal dysfunction resulted in cathepsin B cytoplasmic release. Inhibition or knockdown of cathepsin B blocked nicotine-dependent inflammasome activation. Conclusions: Nicotine promotes atherosclerotic plaque instability by lysosomal dysfunction-mediated NLRP3 inflammasome activation in vascular smooth muscle cells.

Increased m6A modification of lncRNA DBH-AS1 suppresses pancreatic cancer growth and gemcitabine resistance via the miR-3163/USP44 axis.

Background: Gemcitabine is among the most commonly utilized chemotherapeutic agents for treating pancreatic cancer (PC), yet patients ultimately develop chemoresistance and thus exhibit a poor prognosis. Long noncoding RNAs (lncRNAs) can function as key regulators of PC progression and may serve as prognostic biomarkers in individuals with gemcitabine-resistant PC. This study sought to explore the role of the lncRNA DBH-AS1 in this oncogenic setting. Methods: Based on public databases and qRT-PCR analyses the expression of lncRNA DBH-AS1 in PC tissues and cell lines. The effects of lncRNA DBH-AS1 on proliferation and gemcitabine resistance were determined by in vitro and in vivo experiments. Luciferase reporter assay and RNA immunoprecipitation (RIP) were carried out to reveal the interaction between lncRNA DBH-AS1, miR-3163 and USP44. Results: We found that PC tissues exhibited DBH-AS1 downregulation that was particularly pronounced in gemcitabine-resistant PC tissues and cells. This DBH-AS1 downregulation was negatively correlated with the malignancy of PC tumors and with patient survival outcomes. Additionally, decreased DBH-AS1 expression in PC was found to be linked to the METTL3-dependent m6A methylation of the lncRNA, with functional analyses revealing that DBH-AS1 was able to suppress the growth of PC cells. Mechanistically, DBH-AS1 was able to increase PC cell sensitivity to gemcitabine by sequestering miR-3163 and thus upregulating USP44 in these tumor cells. Clinically, patient-derived PC tumor xenografts exhibiting high levels of DBH-AS1 expression were found to be responsive to gemcitabine treatment. Conclusions: Overall, these data underscore a key role for DBH-AS1 as a regulator of PC tumor growth and a promising therapeutic target capable of predicting PC patient responsiveness to gemcitabine treatment.