A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice.

Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5TIF) cells. 5TIF cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5TIF4 cells. In asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.

BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α.

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders.

An overview of cyclopropenone derivatives as promising bioactive molecules.

Cyclopropenone is a valuable electrophilic reagent that can react with electrophilic reagents, nucleophilic reagents, free radicals, organic metals, etc. Furthermore, cyclopropenone derivatives have shown significant biological activity in various diseases, such as triple-negative breast cancer (TNBC), melanoma, and alopecia areata (AA). The cyclopropenone analogue diphenylcyclopropenone (DPCP) has been approved for the treatment of AA. Given the potential therapeutic benefits of cyclopropenone derivatives, this review aims to systematically summarize the structures, synthesis routes, and potential pharmacological functions of cyclopropenone analogues in the hope of offering novel insights for further rational design of more drugs based on the cyclopropenone skeleton for the treatment of human diseases.

Establishment and verification of a method for analyzing nasal blackheads images.

BACKGROUND: As people pay more attention to their skin health and the demand of developing skin care products for facial blackheads grows, the value of objective and efficient image recognition methods for blackheads is becoming more evident. Inspired by this current situation, this study attempted to analyze the number of blackheads of different severity automatically on the nose using an object recognition method on photographs of the nasal blackheads of subjects. METHOD: This study collected 350 subjects' facial photos in the laboratory environment, who aged 18-60, with blackhead symptoms in the nasal region. And expert assessment was used as a reference for machine learning to verify the performance of the nasal blackhead image recognition model through consistency and correlation analysis. RESULTS: The study concluded that the algorithm accuracy reached above 0.9, the model itself was effective, and the consistency between the model and the expert assessor assessment results was good, with the number of nasal blackheads, the count of blackheads of different severity, and the intra-group correlation coefficient ICC of blackhead severity all above 0.9, indicating that the deep learning-based assessment model had high overall performance and the evaluation results were comparable to those of the expert assessor. CONCLUSION: The recognition and analyzing model of nasal blackhead images provides a scientifically objective and accurate method for identifying the number and evaluating the severity of nasal blackheads. By using this model, the efficiency of evaluating nasal blackhead images in the cosmetics clinical trial will be improved. The assessment result of nasal blackheads will be objective and stable, and not only rely on the professional knowledge and clinical experience of assessors. The model can try to be applied in cosmetics efficacy testing and continuously optimized.

Association between living alone and all-cause mortality of young and middle-aged patients with acute myocardial infarction: analysis of the China Acute Myocardial Infarction (CAMI) registry.

BACKGROUND: Lack of social support is a known predictor of the prognosis after acute myocardial infarction (AMI). Although as a common factor associated with social support, there are limited data on long-term prognostic impact of living status in young and middle-aged patients with AMI. METHODS: We analyzed data from the China Acute Myocardial Infarction (CAMI) Registry, consecutive AMI young and middle-aged patients admitted at 108 hospitals in China between January 2013 and September 2014 were included. Eligible patients were assigned to living alone and not living alone groups based on their living status. The primary endpoint was 2-year all-cause mortality. The secondary endpoints included in-hospital mortality and 2-year major adverse cardiac and cerebrovascular events (MACCEs; a composite of all-cause mortality, MI, or stroke). Multilevel logistic and multilevel Cox regression models were used to evaluate the effect of living status on short-term and long-term outcomes. RESULTS: A total of 8307 consecutive AMI young and middle-aged patients were included, 192 (2.3%) patients were living alone. Of the analyzed patients, living alone was associated with 2-year all-cause mortality and MACCEs among all analyzed patients after multivariate adjustment (adjusted hazard ratio [HR] = 2.171 [1.210-3.895], P = 0.009; adjusted HR = 2.169 [1.395-3.370], P = 0.001), but not with poorer in-hospital mortality. CONCLUSIONS: The analysis suggested that living alone was associated with both 2-year all-cause mortality and MACCEs in AMI young and middle-aged patients but did not show an extra effect on the in-hospital mortality after covariate adjustment. TRIAL REGISTRATION: Trial registration number: NCT01874691; Registered 31 October 2012.

A Recursive Non-Uniform Sampling Estimator for Asynchronous Nonlinear Systems.

In this paper, we consider the problem of asynchronous estimation in the presence of packet losses for the randomly sampling nonlinear system. Packet losses occur at the control input and at the measurement side. Firstly, the synchronization of the asynchronous sampling system is realized by weighting the state of the adjacent state update points. Secondly, the projection theorem is used to estimate the system state at the sampling time. Due to modeling errors and unmodeled dynamics, obtaining an accurate dynamic model is challenging. Therefore, observation inference based on interpolation techniques is proposed to solve the asynchronous estimation problem. Furthermore, the algorithm is extended to multi-sensor systems to obtain a distributed fusion estimator. Finally, simulation experiments are conducted to validate the effectiveness of the algorithm.

[Intestinal absorption components and absorption characteristics of Wuwei Qingzhuo San by everted intestinal sac models].

This study investigated the absorption profile of Wuwei Qingzhuo San in different intestinal segments and the absorption characteristics of its alkaloids(piperine, piperanine, piperlonguminine, and dihydropiperlonguminine). The everted gut sac model was established, and the chemical components of Wuwei Qingzhuo San in different intestinal segments were detected by UPLC-Q-TOF-MS. The content of piperine, piperanine, piperlonguminine, and dihydropiperlonguminine in intestinal absorption fluid was determined by UPLC-Q-TRAP-MS and the absorption parameters were calculated. The absorption characteristics in different intestinal segments at different time were analyzed. As a result, 27, 27, 8, and 6 absorbent components from Wuwei Qingzhuo San were detected in the intestinal cyst fluid of jejunum, ileum, duodenum, and colon by UPLC-Q-TOF-MS technology, respectively. It was also found that piperine, piperanine, piperlonguminine, and dihydropiperlonguminine from Wuwei Qingzhuo San showed linear absorption in various intestinal segments, with r values exceeding 0.9. In terms of absorption content, the components were ranked as piperine>piperanine>dihydropiperlonguminine>piperlonguminine in various intestinal segments, but the absorption rate and mechanism of each component varied. The results demonstrate that the absorption of the components of Wuwei Qingzhuo San in different intestinal segments is selective and is not a simple semi-permeable membrane permeation process.

[Urinary protein and renal pathological features in children with immunoglobulin A vasculitis with nephritis and hypercoagulability]. / 儿童IgAè¡€ç®¡ç‚Žè‚¾ç‚Žä¼´é«˜å‡çŠ¶æ€çš„å°¿è›‹ç™½å’Œè‚¾è„ç— ç†ç‰¹å¾åˆ†æž.

OBJECTIVES: To study the association of hypercoagulability with urinary protein and renal pathological damage in children with immunoglobulin A vasculitis with nephritis (IgAVN). METHODS: Based on the results of coagulation function, 349 children with IgAVN were divided into a hypercoagulability group consisting of 52 children and a non-hypercoagulability group consisting of 297 children. Urinary protein and renal pathological features were compared between the two groups, and the factors influencing the formation of hypercoagulability in children with IgAVN were analyzed. RESULTS: Compared with the non-hypercoagulability group, the hypercoagulability group had significantly higher levels of urinary erythrocyte count, 24-hour urinary protein, urinary protein/creatinine, urinary immunoglobulin G/creatinine, and urinary N-acetyl-ß-D-glucosaminidase (P<0.05). The hypercoagulability group also had a significantly higher proportion of children with a renal pathological grade of III-IV, diffuse mesangial proliferation, capillary endothelial cell proliferation, or >25% crescent formation (P<0.05). The multivariate logistic regression analysis showed that capillary endothelial cell proliferation and glomerular crescent formation >25% were associated with the formation of hypercoagulability in children with IgAVN (P<0.05). CONCLUSIONS: The renal injury in IgAVN children with hypercoagulability is more severe, with greater than 25% crescent formation and increased proliferation of glomerular endothelial cells being important contributing factors that exacerbate the hypercoagulable state in IgAVN.

Deep Learning for Fully Automated Prediction of Overall Survival in Patients Undergoing Resection for Pancreatic Cancer: A Retrospective Multicenter Study.

OBJECTIVE: To develop an imaging-derived biomarker for prediction of overall survival (OS) of pancreatic cancer by analyzing preoperative multiphase contrast-enhanced computed topography (CECT) using deep learning. BACKGROUND: Exploiting prognostic biomarkers for guiding neoadjuvant and adjuvant treatment decisions may potentially improve outcomes in patients with resectable pancreatic cancer. METHODS: This multicenter, retrospective study included 1516 patients with resected pancreatic ductal adenocarcinoma (PDAC) from 5 centers located in China. The discovery cohort (n=763), which included preoperative multiphase CECT scans and OS data from 2 centers, was used to construct a fully automated imaging-derived prognostic biomarker-DeepCT-PDAC-by training scalable deep segmentation and prognostic models (via self-learning) to comprehensively model the tumor-anatomy spatial relations and their appearance dynamics in multiphase CECT for OS prediction. The marker was independently tested using internal (n=574) and external validation cohorts (n=179, 3 centers) to evaluate its performance, robustness, and clinical usefulness. RESULTS: Preoperatively, DeepCT-PDAC was the strongest predictor of OS in both internal and external validation cohorts [hazard ratio (HR) for high versus low risk 2.03, 95% confidence interval (CI): 1.50-2.75; HR: 2.47, CI: 1.35-4.53] in a multivariable analysis. Postoperatively, DeepCT-PDAC remained significant in both cohorts (HR: 2.49, CI: 1.89-3.28; HR: 2.15, CI: 1.14-4.05) after adjustment for potential confounders. For margin-negative patients, adjuvant chemoradiotherapy was associated with improved OS in the subgroup with DeepCT-PDAC low risk (HR: 0.35, CI: 0.19-0.64), but did not affect OS in the subgroup with high risk. CONCLUSIONS: Deep learning-based CT imaging-derived biomarker enabled the objective and unbiased OS prediction for patients with resectable PDAC. This marker is applicable across hospitals, imaging protocols, and treatments, and has the potential to tailor neoadjuvant and adjuvant treatments at the individual level.

A neoadjuvant therapy compatible prognostic staging for resected pancreatic ductal adenocarcinoma.

OBJECTIVE: To improve prediction, the AJCC staging system was revised to be consistent with upfront surgery (UFS) and neoadjuvant therapy (NAT) for PDAC. BACKGROUND: The AJCC staging system was designed for patients who have had UFS for PDAC, and it has limited predictive power for patients receiving NAT. METHODS: We examined 146 PDAC patients who had resection after NAT and 1771 who had UFS at Changhai Hospital between 2012 and 2021. The clinicopathological factors were identified using Cox proportional regression analysis, and the Neoadjuvant Therapy Compatible Prognostic (NATCP) staging was developed based on these variables. Validation was carried out in the prospective NAT cohort and the SEER database. The staging approach was compared to the AJCC staging system regarding predictive accuracy. RESULTS: The NAT cohort's multivariate analysis showed that tumor differentiation and the number of positive lymph nodes independently predicted OS. The NATCP staging simplified the AJCC stages, added tumor differentiation, and restaged the disease based on the Kaplan-Meier curve survival differences. The median OS for NATCP stages IA, IB, II, and III was 31.7 months, 25.0 months, and 15.8 months in the NAT cohort and 30.1 months, 22.8 months, 18.3 months, and 14.1 months in the UFS cohort. Compared to the AJCC staging method, the NATCP staging system performed better and was verified in the validation cohort. CONCLUSIONS: Regardless of the use of NAT, NATCP staging demonstrated greater predictive abilities than the existing AJCC staging approach for resected PDAC and may facilitate clinical decision-making based on accurate prediction of patients' OS.

Large-cohort humanized NPI mice reconstituted with CD34+ hematopoietic stem cells are feasible for evaluating preclinical cancer immunotherapy.

Cancer immunotherapy has achieved impressive therapeutic effects in many cancers, while only a small subset of patients benefit from it and some patients even have experienced severe toxicity. It is urgent to develop a feasible large-cohort humanized mouse model to evaluate the pre-clinical efficacy and safety of cancer immunotherapy. Furthermore, developing potentially effective combination therapy between cancer immunotherapy and other therapies also needs humanized mouse model to adequately mimic clinical actual setting. Herein, we established a humanized mouse model engrafted with less human CD34+ HSCs than ever before and then evaluated reconstitution efficiency and the profiles of human immune cells in this humanized mouse model. Also, this humanized mouse model was used to evaluate the preclinical efficacy and safety of cancer immunotherapy. For each batch of CD34+ HSCs humanized mouse model, a relatively-large cohort with over 25% human CD45+ cells in peripheral blood was established. This humanized mouse model could efficiently reconstitute human innate and adaptive immune cells. This humanized mouse model supported patient-derived xenograft tumor growth and tumor infiltration of PD-1+ human T cells. Furthermore, therapeutic efficacy, re-activation of tumor-infiltrated T cells, and side effects of checkpoint blockade therapy could be monitored in this humanized mouse model. Human T cells from this humanized mouse model were successfully engineered with CD19-CAR. CD19 CAR-T cells could effectively deplete B cells and suppress tumor growth of acute lymphoblastic leukemia in vivo in this humanized mouse model. This humanized mouse model also could be used to demonstrate the efficacy of bispecific antibodies, such as anti-CD19/CD3. Overall, our work provides a feasible large-cohort humanized mouse model for evaluating a variety of cancer immunotherapy approaches including checkpoint inhibitors, adoptive cell therapy, and bispecific antibody therapy, and demonstrates that human T cells from this humanized mouse model possess anti-tumor activities in vitro and in vivo.

The dysfunction of hormone-sensitive lipase induces lipid deposition and reprogramming of nutrient metabolism in fish.

Hormone-sensitive lipase (HSL) is one of the rate-determining enzymes in the hydrolysis of TAG, playing a crucial role in lipid metabolism. However, the role of HSL-mediated lipolysis in systemic nutrient homoeostasis has not been intensively understood. Therefore, we used CRISPR/Cas9 technique and Hsl inhibitor (HSL-IN-1) to establish hsla-deficient (hsla-/-) and Hsl-inhibited zebrafish models, respectively. As a result, the hsla-/- zebrafish showed retarded growth and reduced oxygen consumption rate, accompanied with higher mRNA expression of the genes related to inflammation and apoptosis in liver and muscle. Furthermore, hsla-/- and HSL-IN-1-treated zebrafish both exhibited severe fat deposition, whereas their expressions of the genes related to lipolysis and fatty acid oxidation were markedly reduced. The TLC results also showed that the dysfunction of Hsl changed the whole-body lipid profile, including increasing the content of TG and decreasing the proportion of phospholipids. In addition, the systemic metabolic pattern was remodelled in hsla-/- and HSL-IN-1-treated zebrafish. The dysfunction of Hsl lowered the glycogen content in liver and muscle and enhanced the utilisation of glucose plus the expressions of glucose transporter and glycolysis genes. Besides, the whole-body protein content had significantly decreased in the hsla-/- and HSL-IN-1-treated zebrafish, accompanied with the lower activation of the mTOR pathway and enhanced protein and amino acid catabolism. Taken together, Hsl plays an essential role in energy homoeostasis, and its dysfunction would cause the disturbance of lipid catabolism but enhanced breakdown of glycogen and protein for energy compensation.

PDK inhibition promotes glucose utilization, reduces hepatic lipid deposition, and improves oxidative stress in largemouth bass (Micropterus salmoides) by increasing pyruvate oxidative phosphorylation.

In omnivorous fish, the pyruvate dehydrogenase kinases (PDKs)-pyruvate dehydrogenase E1α subunit (PDHE1α) axis is essential in the regulation of carbohydrate oxidative catabolism. Among the existing research, the role of the PDKs-PDHE1α axis in carnivorous fish with poor glucose utilization is unclear. In the present study, we determined the effects of PDK inhibition on the liver glycolipid metabolism of largemouth bass (Micropterus salmoides). DCA is a PDK-specific inhibitor that inhibits PDK by binding the allosteric sites. A total of 160 juvenile largemouth bass were randomly divided into two groups, with four replicates of 20 fish each, fed a control diet and a control diet supplemented with dichloroacetate (DCA) for 8 weeks. The present results showed that DCA supplementation significantly decreased the hepatosomatic index, triglycerides in liver and serum, and total liver lipids of largemouth bass compared with the control group. In addition, compared with the control group, DCA treatment significantly down-regulated gene expression associated with lipogenesis. Furthermore, DCA supplementation significantly decreased the mRNA expression of pdk3a and increased PDHE1α activity. In addition, DCA supplementation improved glucose oxidative catabolism and pyruvate oxidative phosphorylation (OXPHOS) in the liver, as evidenced by low pyruvate content in the liver and up-regulated expressions of glycolysis-related and TCA cycle/OXPHOS-related genes. Moreover, DCA consumption decreased hepatic malondialdehyde (MDA) content, enhanced the activities of superoxide dismutase (SOD), and increased transforming growth factor beta (tgf-ß), glutathione S-transferase (gst), and superoxide dismutase 1 (sod1) gene expression compared with the control diet. This study demonstrated that inhibition of PDKs by DCA promoted glucose utilization, reduced hepatic lipid deposition, and improved oxidative stress in largemouth bass by increasing pyruvate OXPHOS. Our findings contribute to the understanding of the underlying mechanism of the PDKs-PDHE1α axis in glucose metabolism and improve the utilization of dietary carbohydrates in farmed carnivorous fish.

Targeting histone deacetylases for heart diseases.

Histone deacetylases (HDACs) are responsible for the deacetylation of lysine residues in histone or non-histone substrates, leading to the regulation of many biological functions, such as gene transcription, translation and remodeling chromatin. Targeting HDACs for drug development is a promising way for human diseases, including cancers and heart diseases. In particular, numerous HDAC inhibitors have revealed potential clinical value for the treatment of cardiac diseases in recent years. In this review, we systematically summarize the therapeutic roles of HDAC inhibitors with different chemotypes on heart diseases. Additionally, we discuss the opportunities and challenges in developing HDAC inhibitors for the treatment of cardiac diseases.

Silencing circ_0080425 alleviates high-glucose-induced endothelial cell dysfunction in diabetic nephropathy by targeting miR-140-3p/FN1 axis.

BACKGROUND: Hsa_circ_0080425 (circ_0080425) is newly identified to correlate with the progression of diabetic nephropathy (DN). However, its role and mechanism in DN process is not very clear. METHODS: Cell counting kit-8 assay, flow cytometry, scratch wound assay, and western blotting were performed to measure endothelial cell dysfunction. Expression of circ_0080425, microRNA (miR)-140-3p and fibronectin 1 (FN1) were determined by quantitative real-time PCR and western blotting. The direct interaction was confirmed by dual-luciferase reporter assay. RESULTS: High-glucose (HG) treatment could induce inhibition of cell proliferation, cell cycle entrance and wound healing rate in human umbilical vein endothelial cells (HRGEC), and enhancement of apoptosis rate. Circ_0080425 expression was upregulated by HG, and exhausting circ_0080425 could attenuate HG-induced above effects in HRGEC. MiR-140-3p was sponged by circ_0080425, and its inhibitor reversed the regulation of circ_0080425 knockdown on HG-induced HRGEC injury. FN1 was targeted by miR-140-3p, and its overexpression also restored the inhibitory effect of miR-140-3p on HC-induced HRGEC injury. CONCLUSION: Circ_0080425 expression might contribute to HG-induced endothelial cell injury, and circ_0080425/miR-140-3p/FN1 axis was a potential therapeutic approach to interfere DN process.

Ginsenoside Rh2 suppresses colon cancer growth by targeting the miR-150-3p/SRCIN1/Wnt axis.

Ginsenoside Rh2, which is extracted from ginseng, exerts antitumor activity. Recent studies suggest that Rh2 may suppress the growth of colon cancer (CC) in vitro. However, the underlying mechanism remains unclear. In this study, we identified the relative levels of miR-150-3p in CC tissues and cells by a comprehensive strategy of data mining, computational biology, and real-time reverse transcription PCR (qRT-PCR) experiments. The regulatory effects of miR-150-3p/SRCIN1 on the proliferative and invasive abilities of CC cells are evaluated by CCK-8, EdU, wound healing, and transwell assays. Cell cycle- and apoptosis-related protein levels are assessed by western blot analysis. An in vivo tumor formation assay was conducted to explore the effects of miR-150-3p on tumor growth. Furthermore, bioinformatics and dual luciferase reporter assays are applied to determine the functional binding of miRNA to mRNA of the target gene. Finally, the relationship between Rh2 and miR-150-3p was further verified in SW620 and HCT-116 cells. miR-150-3p is downregulated in CC tissues and cell lines. Functional assays indicate that the upregulation of miR-150-3p inhibits tumor growth both in vivo and in vitro. In addition, SRCIN1 is upregulated in CC and predicts a poor prognosis, and it is the direct target for miR-150-3p. Moreover, the miR-150-3p mimic decreases Topflash/Fopflash-dependent luciferase activity, resulting in the inhibition of Wnt pathway activity. Rh2 can suppress the growth of CC by increasing miR-150-3p expression. Rh2 alleviates the accelerating effect on Wnt pathway activity, cell proliferation/migration, and colony formation caused by miR-150-3p inhibition. Rh2 inhibits the miR-150-3p/SRCIN1/Wnt axis to suppress colon cancer growth.

MAKO robot-assisted total knee arthroplasty cannot reduce the aggravation of ankle varus incongruence after genu varus correction ≥ 10°: a radiographic assessment.

INTRODUCTION: The objective of this study was to investigate the ankle alignment alterations after the correction of knee varus deformity in MAKO robot-assisted total knee arthroplasty (MA-TKA). METHODS: A retrospective analysis was conducted for 108 patients with TKA from February 2021 to February 2022. Patients were divided into two groups based on MAKO robot involvement during the procedure: the MA-TKA group (n = 36) and the conventional manual total knee arthroplasty (CM-TKA) group (n = 72). The patients were divided into four subgroups according to the degree of surgical correction of the knee varus deformity. Seven radiological measurements were evaluated pre and post-surgery: mechanical tibiofemoral angle (mTFA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), lateral distal tibial angle (LDTA), tibial plafond inclination angle (TPIA), talar inclination angle (TIA), and tibiotalar tilt angle (TTTA). TTTA is a quantitative representation of the extent of ankle incongruence. RESULTS: The number of mTFA, mLDFA, and MPTA outliers in the MA-TKA group was significantly lower compared to the CM-TKA group (P<0.05). Knee varus deformity was properly corrected and the mechanical axis was restored in all patients, regardless of the treatment group. Only for varus corrections ≥ 10° did TTTA change significantly (p < 0.01) and ankle varus incongruence aggravate post-operation. The ΔTTTA correlated negatively with ΔTFA (r=-0.310,P = 0.001) and correlated positively with ΔTPIA (r = 0.490,P = 0.000). When the varus correction was ≥ 7.55°, the probability of ankle varus incongruence exacerbation increased 4.86-fold. CONCLUSION: Compared with CM-TKA, MA-TKA osteotomy showed more precision but was unable to reduce post-operation ankle varus incongruence. When the varus correction ≥ 10°, ankle varus incongruence aggravated, while when the varus correction ≥ 7.55°, the probability of ankle varus incongruence increased 4.86-fold. This may occasion the pathogenesis of ankle pain following TKA.

Combined utility of Ki-67 index and tumor grade to stratify patients with pancreatic ductal adenocarcinoma who underwent upfront surgery.

OBJECTIVE: To investigate the prognostic prediction of a new indicator, combined by tumor grade and Ki-67, in patients with resected pancreatic ductal adenocarcinoma (PDAC). METHODS: Data were retrospectively collected from consecutive patients who underwent primary resection of pancreas from December 2012 to December 2017. Tumor grade and Ki-67 were reviewed from routine pathological reports. G-Ki67 was classified as three categories as I (G1/2 and Ki-67 < 40%), II (G1/2 and Ki-67 ≥ 40%), and III(G3/4 and all Ki-67). RESULTS: Cox regression analyses revealed that tumor stage (II vs. I: hazard ratio (HR), 3.781; 95% confidence index (CI), 2.844-5.025; P < 0.001; III vs. I: HR, 7.476; 95% CI, 5.481-10.20; P < 0.001) and G-Ki67 (II vs. I: HR, 1.299; 95% CI, 1.038-1.624; P = 0.022; III vs. I: HR, 1.942; 95% CI, 1.477-2.554; P < 0.001) were independent prognostic factors in the developing cohort. The result was rectified in the validation cohort. In subgroups analysis, G-Ki67 (II vs. I: HR, 1.866 ; 95% CI, 1.045-3.334; P = 0.035; III vs. I: HR, 2.333 ; 95% CI, 1.156-4.705; P = 0.018) also had a high differentiation for survival prediction. CONCLUSION: Our findings indicate that three-categories of G-Ki67 in resectable PDAC according to the routine pathological descriptions provided additional prognostic information complementary to the TNM staging system.

Ingenious fabrication of bamboo leaf-like ferric vanadate intertwined multi-walled carbon nanotubes nanocomposite as a sensitive sensor for determination of uric acid in fetal bovine serum.

A novel nanocomposite material, ferric vanadate intertwined multi-walled carbon nanotubes (FeV/MWCNTs), has been designed which was drop-coated onto a glassy carbon electrode (GCE). The constructed sensor was used for the sensitive determination of uric acid (UA) in fetal bovine serum (FBS) and human serum (HS). A series of characterization and electrochemical tests showed that the ultrasound-assisted assembly of FeV with MWCNTs not only overcame the disadvantages of low conductivity and easy (unwanted) aggregation, but also avoided the decrease in effective surface area due to the severe aggregation of each individual raw material. The fabricated FeV/MWCNTs nanocomposites exhibited higher conductivity, larger effective surface area, and better electrocatalytic activity. In addition, under optimized conditions, the developed electrochemical sensor FeV/MWCNTs/GCE has a lower limit of detection (LOD, 0.05 µM; Ep = 0.268 V vs. Ag/AgCl) and wider linear range (0.20-100 µM), which can satisfy the criteria of trace UA detection. The results of UA determination in FBS (recovery = 95.5-103%; RSD ≤ 3.1%) and HS (recovery = 95.5-103%; RSD ≤ 4.3%) further validated the feasibility of FeV/MWCNTs-based electrochemical sensors for the determination of UA in biological fluids.

Yersiniabactin-Producing E. coli Induces the Pyroptosis of Intestinal Epithelial Cells via the NLRP3 Pathway and Promotes Gut Inflammation.

The high-pathogenicity island (HPI) was initially identified in Yersinia and can be horizontally transferred to Escherichia coli to produce yersiniabactin (Ybt), which enhances the pathogenicity of E. coli by competing with the host for Fe3+. Pyroptosis is gasdermin-induced necrotic cell death. It involves the permeabilization of the cell membrane and is accompanied by an inflammatory response. It is still unclear whether Ybt HPI can cause intestinal epithelial cells to undergo pyroptosis and contribute to gut inflammation during E. coli infection. In this study, we infected intestinal epithelial cells of mice with E. coli ZB-1 and the Ybt-deficient strain ZB-1Δirp2. Our findings demonstrate that Ybt-producing E. coli is more toxic and exacerbates gut inflammation during systemic infection. Mechanistically, our results suggest the involvement of the NLRP3/caspase-1/GSDMD pathway in E. coli infection. Ybt promotes the assembly and activation of the NLRP3 inflammasome, leading to GSDMD cleavage into GSDMD-N and promoting the pyroptosis of intestinal epithelial cells, ultimately aggravating gut inflammation. Notably, NLRP3 knockdown alleviated these phenomena, and the binding of free Ybt to NLRP3 may be the trigger. Overall, our results show that Ybt HPI enhances the pathogenicity of E. coli and induces pyroptosis via the NLRP3 pathway, which is a new mechanism through which E. coli promotes gut inflammation. Furthermore, we screened drugs targeting NLRP3 from an existing drug library, providing a list of potential drug candidates for the treatment of gut injury caused by E. coli.