Ultrastable Copper Iodide Hybrid with Intrinsic Greenish White-Light Emission by Incorporating an Anionic Inorganic Functional Unit into an Extended Structure.

Incorporating a functional unit into the multidimensional coordination polymer skeleton is an efficient way to improve the stability of materials and expand their application. In this paper, anionic copper iodide inorganic functional modules are incorporated into one-dimensional extended chains by using a unique bidentate cationic organic ligand. Benefiting from the ionic extended structure, the resulting hybrid possesses a remarkable stability with a decomposition temperature as high as 300 °C. Meanwhile, the hybrid material exhibits intrinsic greenish white-light emission with a high photoluminescent quantum yield of 70%. The emission was investigated by temperature-dependent emission spectra, which proved to be the result of the synergistic effect of two energy states. The novel synthetic strategy provides an efficient route for the development of functional organic metal halides.

The early change in pH values after out-of-hospital cardiac arrest is not associated with neurological outcome at hospital discharge.

Background: The association between pH values and outcome for patients after out-of-hospital cardiac arrest (OHCA) was not fully elucidated; besides, the relationship of change in pH values and neurological outcome was unknown. The aim was to explore the association of pH values as well as change in pH values and neurological outcome for OHCA cardiac patients. Methods: The adult patients with non-traumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, and at least two arterial blood gases analysis recorded after admission were included. The change in pH values is calculated as the difference between the second and first pH value, and divided by time interval got the rate of change in pH values. The primary outcome was modified Rankin Score (mRS), dichotomized to good (mRS 0-3) and poor (mRS 4-6) outcomes at hospital discharge. The independent relationship of the first pH value, second pH value, and changes in pH values with neurological outcome was investigated with multivariable logistic regression models, respectively. Results: A total of 1388 adult patients were included for analysis, of which 514 (37%) had good neurological outcome. The median first pH value and second pH value after admission were 7.21 (interquartile range [IQR] 7.09-7.29) and 7.28 (IQR 7.20-7.36), respectively. The median absolute, relative change, and rate of changes in pH values were 0.08 (IQR 0.01-0.16), 1.10% (IQR 0.11-2.22%), and 0.02 (IQR 0-0.06) per hour, respectively. After adjusting for confounders, the higher first pH value (odds ratio [OR] 3.81, confidence interval [CI] 1.60-9.24, P = 0.003) and higher second pH value (OR 9.54, CI 3.45-26.87, P < 0.001) after admission were associated with good neurological outcome, respectively. The absolute (OR 1.58, CI 0.58-4.30, P = 0.368) and relative (OR 1.03, CI 0.96-1.11, P = 0.399) change as well as the rate of change (OR 0.98, CI 0.33-2.71, P = 974) in pH values were not associated with neurological outcome. Conclusions: For OHCA patients, abnormality in pH values was very common, with a more acidic pH value indicating poor neurological outcome. However, the change in pH values was not associated with outcomes.

Overexpression of Fgf18 in cranial neural crest cells recapitulates Pierre Robin sequence in mice.

The pivotal role of FGF18 in the regulation of craniofacial and skeletal development has been well established. Previous studies have demonstrated that mice with deficiency in Fgf18 exhibit severe craniofacial dysplasia. Recent clinical reports have revealed that the duplication of chromosome 5q32-35.3, which encompasses the Fgf18 gene, can lead to cranial bone dysplasia and congenital craniosynostosis, implicating the consequence of possible overdosed FGF18 signaling. This study aimed to test the effects of augmented FGF18 signaling by specifically overexpressing the Fgf18 gene in cranial neural crest cells using the Wnt1-Cre;pMes-Fgf18 mouse model. The results showed that overexpression of Fgf18 leads to craniofacial abnormalities in mice similar to the Pierre Robin sequence in humans, including abnormal tongue morphology, micrognathia, and cleft palate. Further examination revealed that elevated levels of Fgf18 activated the Akt and Erk signaling pathways, leading to an increase in the proliferation level of tongue tendon cells and alterations in the contraction pattern of the genioglossus muscle. Additionally, we observed that excessive FGF18 signaling contributed to the reduction in the length of Meckel's cartilage and disrupted the development of condylar cartilage, ultimately resulting in mandibular defects. These anomalies involve changes in several downstream signals, including Runx2, p21, Akt, Erk, p38, Wnt, and Ihh. This study highlights the crucial role of maintaining the balance of endogenous FGF18 signaling for proper craniofacial development and offers insights into potential formation mechanisms of the Pierre Robin sequence.

Perioperative remedial antiviral therapy in hepatitis B virus-related hepatocellular carcinoma resection: How to achieve a better outcome.

BACKGROUND: Although the benefits of antiviral therapy for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) have been proven, researchers have not confirmed the differences in patient outcomes between patients who received preoperative antiviral therapy for a period of time (at least 24 wk) and patients who received remedial antiviral therapy just before radical resection for HBV-related HCC. AIM: To investigate the efficacy of perioperative remedial antiviral therapy in patients with HBV-related HCC. METHODS: A retrospective study of patients who underwent radical resection for HBV-related HCC at the First Affiliated Hospital of Xi'an Jiaotong University from January 2016 to June 2019 was conducted. Considering the history of antiviral therapy, patients were assigned to remedial antiviral therapy and preoperative antiviral therapy groups. RESULTS: Kaplan-Meier analysis revealed significant differences in overall survival (P < 0.0001) and disease-free survival (P = 0.035) between the two groups. Multivariate analysis demonstrated that a history of preoperative antiviral treatment was independently related to improved survival (hazard ratio = 0.27; 95% confidence interval: 0.08-0.88; P = 0.030). CONCLUSION: In patients with HBV-related HCC, it is ideal to receive preoperative long-term antiviral therapy, which helps patients tolerate more extensive hepatectomy; however, remedial antiviral therapy, which reduces preoperative HBV-DNA levels to less than 4 Log10 copies DNA/mL, can also result in improved outcomes.

Efficacy, safety, and advantages of magnetic anchor-guided endoscopic submucosal dissection vs conventional endoscopic submucosal dissection: A retrospective paired cohort study.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been recommended as the first-line treatment for early gastric cancer (EGC). However, poor visualization of the operative field increases both the procedure time and the risk of complications, especially for large and difficult lesions. We introduced a novel technique, magnetic anchor-guided ESD (MAG-ESD) and compared it with conventional ESD (C-ESD) for the treatment of large EGCs in terms of efficacy, safety, and advantages. METHODS: Patients with large EGCs who underwent MAG-ESD or C-ESD at the First Affiliated Hospital of Xi'an Jiaotong University from March 2020 to March 2022 were retrospectively enrolled in this study. The patients in the MAG-ESD cohort were matched to those in the C-ESD cohort using propensity score-based matching. The operation time, submucosal dissection time, complete resection status, magnetic anchor, adverse event rate, and tumor recurrence rate were evaluated. RESULTS: Twenty-two patients who underwent MAG-ESD were ultimately matched to those who underwent C-ESD. The median operation time of MAG-ESD and C-ESD was 43 minutes (IQR, 35.2-49.5) and 50.5 minutes (IQR, 42.0-76.0), respectively, among which the submucosal dissection time was 7.6 minutes (IQR, 5.2-10.4) and 14.8 minutes (IQR, 10.8-19.6), respectively. The operation time of MAG-ESD was shorter than that of C-ESD, especially the submucosal dissection time (P < .05). There was a lower incidence of adverse events associated with MAG-ESD (P < .05) when magnetic anchors were successfully placed and retrieved. CONCLUSION: MAG-ESD is feasible, effective, safe, and simple for the treatment of large EGCs at different sites and has a high anchor success rate, which could shorten the operation time and reduce the adverse event rate.

Near-Infrared Catalytic Chemiluminescence System based on Zinc Gallate Nanoprobe for Hydrazine Sensing.

To the deep tissue penetration and ultra-low background, developing near-infrared (NIR) chemiluminescence probes for human health and environmental safety has attracted more and more attention, but it remains a huge challenge. Herein, a novel NIR chemiluminescence (CL) system was rationally designed and developed, utilizing Cr3+-activated ZnGa2O4 (ZGC) nanoparticles as a catalytic luminophore via hypochlorite (NaClO) activation for poisonous target (hydrazine, N2H4) detection. With superior optical performance and unique catalytic structure of ZGC nanoparticles, the fabricated ZGC-NaClO-N2H4 CL system successfully demonstrated excellent NIR emission centered at 700 nm, fast response, and high sensibility (limit of detection down to 0.0126 µM). Further experimental studies and theoretical calculations found the cooperative catalytic chemiluminescence resonance energy transfer mechanism in the ZGC-NaClO-N2H4 system. Remarkably, the ZGC-based NIR CL system was further employed for N2H4 detection in a complicated matrix involving bioimaging and real water samples, thereby opening a new way as a highly reliable and accurate tool in biomedical and environmental monitoring applications.

Centric Sc(HPO3)(H2PO3)(H2O) and Acentric Sc(H2PO3)3: Two Ultraviolet Scandium Phosphite Optical Crystals.

Exploring ultraviolet (UV) nonlinear-optical (NLO) materials is significant for the conversion of a high-frequency laser. Two scandium phosphites, Sc(HPO3)(H2PO3)(H2O) and Sc(H2PO3)3, were successfully synthesized. Centric Sc(HPO3)(H2PO3)(H2O) exhibits a short UV cutoff edge (<200 nm) and a unique double-layer structure of [Sc2(HPO3)2(H2PO3)2(H2O)2]∞. The acentric Sc(H2PO3)3 exhibits a three-dimensional [Sc(H2PO3)3]∞ structure with a large band gap of 4.05 eV, and it demonstrates a moderately phase-matchable second-harmonic-generation response [0.60 × KDP (KH2PO4)] at 1064 nm. The crystal structures, optical properties, and theoretical calculations of the two compounds are discussed. This work will promote the exploration of new NLO phosphite materials.

Extracellular CIRP co-stimulated T cells through IL6R/STAT3 in pediatric IgA vasculitis.

Immunoglobulin A vasculitis (IgAV) is the most common vasculitis of childhood. Disordered immune responses play important roles in its pathogenesis, but the comprehensive immune profile of the disease and the underlying mechanisms are still largely unknown. Here we found a potential disease biomarker cold inducible RNA binding protein (CIRP) in our pediatric IgAV cohort. Serum CIRP level in these patients were elevated and positively correlated with the increased early memory (CD45RA+CD62L+CD95+) T cells revealed using multicolor flow cytometry. Immune phenotyping of the patients showed they had more activated T cells with higher IL6Ra expression. T cell culture experiment showed CIRP further activated both human CD4+ and CD8+ T cells as indicated by increased perforin secretion and phosphorylation of STAT3. Blockade of IL6Rα attenuated CIRP-induced T cell toxicity in vitro. RNA-sequencing data further supported CIRP stimulation promoted human T cell activation and migration, fueled inflammation through the JAK-STAT signaling pathway. Therefore, IL6Ra-mediated T cell activation by extracellular CIRP may contribute to pathogenesis of IgAV in children, both CIRP and IL6Ra could be new therapeutic targets for IgAV.

Persistent Luminescence Lifetime-Based Near-Infrared Nanoplatform via Deep Learning for High-Fidelity Biosensing of Hypochlorite.

In light of deep tissue penetration and ultralow background, near-infrared (NIR) persistent luminescence (PersL) bioprobes have become powerful tools for bioapplications. However, the inhomogeneous signal attenuation may significantly limit its application for precise biosensing owing to tissue absorption and scattering. In this work, a PersL lifetime-based nanoplatform via deep learning was proposed for high-fidelity bioimaging and biosensing in vivo. The persistent luminescence imaging network (PLI-Net), which consisted of a 3D-deep convolutional neural network (3D-CNN) and the PersL imaging system, was logically constructed to accurately extract the lifetime feature from the profile of PersL intensity-based decay images. Significantly, the NIR PersL nanomaterials represented by Zn1+xGa2-2xSnxO4: 0.4 % Cr (ZGSO) were precisely adjusted over their lifetime, enabling the PersL lifetime-based imaging with high-contrast signals. Inspired by the adjustable and reliable PersL lifetime imaging of ZGSO NPs, a proof-of-concept PersL nanoplatform was further developed and showed exceptional analytical performance for hypochlorite detection via a luminescence resonance energy transfer process. Remarkably, on the merits of the dependable and anti-interference PersL lifetimes, this PersL lifetime-based nanoprobe provided highly sensitive and accurate imaging of both endogenous and exogenous hypochlorite. This breakthrough opened up a new way for the development of high-fidelity biosensing in complex matrix systems.

Accurate and robust segmentation of cerebral vasculature on four-dimensional arterial spin labeling magnetic resonance angiography using machine-learning approach.

Segmentation of cerebral vasculature on MR vascular images is of great significance for clinical application and research. However, the existing cerebrovascular segmentation approaches are limited due to insufficient image contrast and complicated algorithms. This study aims to explore the potential of the emerging four-dimensional arterial spin labeling magnetic resonance angiography (4D ASL-MRA) technique for fast and accurate cerebrovascular segmentation with a simple machine-learning approach. Nine temporal features were extracted from the intensity-time signal of each voxel, and eight spatial features from the neighboring voxels. Then, the unsupervised outlier detection algorithm, i.e. Isolation Forest, is used for segmentation of the vascular voxels based on the extracted features. The total length of the centerlines of the intracranial arterial vasculature, the dice similarity coefficient (DSC), and the average Hausdorff Distance (AVGHD) on the cross-sections of small- to large-sized vessels were calculated to evaluate the performance of the segmentation approach on 4D ASL-MRA of 18 subjects. Experiments show that the temporal information on 4D ASL-MRA can largely improve the segmentation performance. In addition, the proposed segmentation approach outperforms the traditional methods that were performed on the 3D image (i.e. the temporal average intensity projection of 4D ASL-MRA) and the previously proposed frame-wise approach. In conclusion, this study demonstrates that accurate and robust segmentation of cerebral vasculature is achievable on 4D ASL-MRA by using a simple machine-learning approach with appropriate features.

Development of a new Cox model for predicting long-term survival in hepatitis cirrhosis patients underwent transjugular intrahepatic portosystemic shunts.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) placement is a procedure that can effectively treat complications of portal hypertension, such as variceal bleeding and refractory ascites. However, there have been no specific studies on predicting long-term survival after TIPS placement. AIM: To establish a model to predict long-term survival in patients with hepatitis cirrhosis after TIPS. METHODS: A retrospective analysis was conducted on a cohort of 224 patients who underwent TIPS implantation. Through univariate and multivariate Cox regression analyses, various factors were examined for their ability to predict survival at 6 years after TIPS. Consequently, a composite score was formulated, encompassing the indication, shunt reasonability, portal venous pressure gradient (PPG) after TIPS, percentage decrease in portal venous pressure (PVP), indocyanine green retention rate at 15 min (ICGR15) and total bilirubin (Tbil) level. Furthermore, the performance of the newly developed Cox (NDC) model was evaluated in an internal validation cohort and compared with that of a series of existing models. RESULTS: The indication (variceal bleeding or ascites), shunt reasonability (reasonable or unreasonable), ICGR15, postoperative PPG, percentage of PVP decrease and Tbil were found to be independent factors affecting long-term survival after TIPS placement. The NDC model incorporated these parameters and successfully identified patients at high risk, exhibiting a notably elevated mortality rate following the TIPS procedure, as observed in both the training and validation cohorts. Additionally, in terms of predicting the long-term survival rate, the performance of the NDC model was significantly better than that of the other four models [Child-Pugh, model for end-stage liver disease (MELD), MELD-sodium and the Freiburg index of post-TIPS survival]. CONCLUSION: The NDC model can accurately predict long-term survival after the TIPS procedure in patients with hepatitis cirrhosis, help identify high-risk patients and guide follow-up management after TIPS implantation.

Hg16O12(NO3)6F2(H2O): A Mercury-Rich Nitrate Oxyfluoride with Diverse Triple-Coordinated Mercury-Based Units That Exhibits an Unparalleled [(Hg16O12F2(H2O))6+]∞ Cationic Framework and a Large Birefringence.

Designing new compounds based on anion regulation has been widely favored due to the production of diverse crystal structures and excellent optical properties. Here, a new nitrate oxyfluoride, Hg16O12(NO3)6F2(H2O), has been obtained through a hydrothermal reaction. It crystallizes in the centric Ibca space group and shows a novel three-dimensional [(Hg16O12F2(H2O))6+]∞ cationic framework composed of interconnected HgO2F, HgO3, and HgO2(H2O) units, with isolated NO3- groups as balanced anions to build the whole structure. Notably, the HgO2F and HgO2(H2O) units are first presented here among mercury (Hg)-based compounds. Additionally, Hg16O12(NO3)6F2(H2O) exhibits a large birefringence of 0.17 at 546 nm. This work enriches the multiformity of Hg-based compounds and provides a route for developing promising birefringent materials.

Abnormal phosphorylation / dephosphorylation and Ca2+ dysfunction in heart failure.

Heart failure (HF) can be caused by a variety of causes characterized by abnormal myocardial systole and diastole. Ca2+ current through the L-type calcium channel (LTCC) on the membrane is the initial trigger signal for a cardiac cycle. Declined systole and diastole in HF are associated with dysfunction of myocardial Ca2+ function. This disorder can be correlated with unbalanced levels of phosphorylation / dephosphorylation of LTCC, endoplasmic reticulum (ER), and myofilament. Kinase and phosphatase activity changes along with HF progress, resulting in phased changes in the degree of phosphorylation / dephosphorylation. It is important to realize the phosphorylation / dephosphorylation differences between a normal and a failing heart. This review focuses on phosphorylation / dephosphorylation changes in the progression of HF and summarizes the effects of phosphorylation / dephosphorylation of LTCC, ER function, and myofilament function in normal conditions and HF based on previous experiments and clinical research. Also, we summarize current therapeutic methods based on abnormal phosphorylation / dephosphorylation and clarify potential therapeutic directions.

MFG-E8 induces epithelial-mesenchymal transition and anoikis resistance to promote the metastasis of pancreatic cancer cells.

Pancreatic cancer is an extremely malignant tumor, and only a few clinical treatment options exist. MFG-E8 and kindlin-2 all play an important role in cancer progression. However, the specific mechanism occurring between MFG-E8, kindlin-2 and the migration and invasion of pancreatic cancer cells remains unelucidated. To unravel the specific mechanism, this study assessed the potential association between MFG-E8 and kindlin-2 as well as the involvement of MFG-E8 in pancreatic cancer using two pancreatic cancer cell lines (MiaPaCa-2 and PANC-1). Pancreatic cancer cells were treated with 0, 250, and 500 ng/ml MFG-E8, and the effects of MFG-E8 on the migration, invasion, and anoikis of pancreatic cancer cells were observed. To investigate the role of kindlin-2 in pancreatic cancer, kindlin-2-shRNAi was transfected to knock down its expression level in the two pancreatic cancer cell lines. Furthermore, cilengitide, a receptor blocker of MFG-E8, was used to explore the relationship between MFG-E8, kindlin-2, and pancreatic cancer progression. Our findings demonstrated that MFG-E8 promotes the migration and invasion of pancreatic cancer cells and induces cell anoikis resistance in a dose-dependent manner, which was effectively counteracted by cilengitide, a receptor blocker. Additionally, the knockdown of kindlin-2 expression nullified the effect of MFG-E8 on the migration and invasion of pancreatic cancer cells. Consequently, this study provides insights into the specific mechanism underlying the interplay between MFG-E8 and kindlin-2 in the progression of pancreatic cancer cells.

Wind-driven hydrodynamic characteristics of Lake Taihu, a large shallow lake in China.

As an essential drinking water source and one of the largest eutrophic shallow lakes in China, the management of Lake Taihu requires an adequate understanding of its hydrodynamic characteristics. Studying the hydrodynamic characteristics of Lake Taihu based on field observations is limited owing to its large area and the lack of flow field stability. Previous studies using hydrodynamic models experienced challenges, such as dimensionality and lack of dynamic response analysis between flow field and realistic wind; therefore, the results were still inconclusive. In this study, a 3D model of Lake Taihu, calibrated and validated based on field observations, was used to simulate and compare three scenarios: windless, steady wind, and realistic wind. The hydrodynamic characteristics of Lake Taihu were analyzed as close to the actual conditions as possible. The results showed that wind-driven currents dominated the flow field in Lake Taihu, and the horizontal velocity driven by wind was more than 6 times that without wind. Observing a stable flow field in Lake Taihu was difficult because of the variability of realistic wind. The hydrodynamic characteristics of Lake Taihu were defined as "strongly affected by wind," "higher on the surface and smaller at the bottom," and "difference between the surface and the bottom." Vertical turbulent kinetic energy can be used to characterize the variable flow field of a wind-driven lake and has a positive correlation with wind speed. Therefore, it could be used as a key component to predict water blooms with practical implications.

Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model.

Background: Since boosting stem cell resilience in stressful environments is critical for the therapeutic efficacy of stem cell-based transplantations in liver disease, this study aimed to establish the efficacy of a transient plasmid-based preconditioning strategy for boosting the capability of mesenchymal stromal cells (MSCs) for anti-inflammation/antioxidant defenses and paracrine actions in recipient hepatocytes. Methods: Human adipose mesenchymal stem cells (hADMSCs) were subjected to transfer, either with or without the nuclear factor erythroid 2-related factor 2 (Nrf2)/Dickkopf1 (DKK1) genes, followed by exposure to TNF-α/H2O2. Mouse models were subjected to acute chronic liver failure (ACLF) and subsequently injected with either transfected or untransfected MSCs. These hADMSCs and ACLF mouse models were used to investigate the interaction between Nrf2/DKK1 and the hepatocyte receptor cytoskeleton-associated protein 4 (CKAP4). Results: Activation of Nrf2 and DKK1 enhanced the anti-stress capacity of MSCs in vitro. In a murine model of ACLF, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy, and promoted recipient liver regeneration due to a shift from the activation of the anti-regenerative IFN-γ/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Importantly, the therapeutic benefits of MSC transplantation were nullified when the receptor CKAP4, which interacts with DKK1, was specifically removed from recipient hepatocytes. However, the removal of the another receptor low-density lipoprotein receptor-related protein 6 (LRP6) had no impact on the effectiveness of MSC transplantation. Moreover, in long-term observations, no tumorigenicity was detected in mice following transplantation of transiently preconditioned MSCs. Conclusions: Co-stimulation with Nrf2/DKK1 safely improved the efficacy of human MSC-based therapies in murine models of ACLF through CKAP4-dependent paracrine mechanisms.

Chelatococcus albus sp. nov., a bacterium isolated from hot spring microbial mat.

A Gram-stain-negative, non-endospore-forming, motile, short rod-shaped strain, designated SYSU G07232T, was isolated from a hot spring microbial mat, sampled from Rehai National Park, Tengchong, Yunnan Province, south-western China. Strain SYSU G07232T grew at 25-50 °C (optimum, 37 °C), at pH 5.5-9.0 (optimum, pH 6.0) and tolerated NaCl concentrations up to 1.0 % (w/v). Phylogenetic analysis based on the 16S rRNA gene sequences revealed that strain SYSU G07232T showed closest genetic affinity with Chelatococcus daeguensis K106T. The genomic features and taxonomic status of this strain were determined through whole-genome sequencing and a polyphasic approach. The predominant quinone of this strain was Q-10. Major cellular fatty acids comprised C19 : 0 cyclo ω8c and summed feature 8. The whole-genome length of strain SYSU G07232T was 4.02 Mbp, and the DNA G+C content was 69.26 mol%. The average nucleotide identity (ANIm ≤84.85 % and ANIb ≤76.08  %) and digital DNA-DNA hybridization (≤ 21.9 %) values between strain SYSU G07232T and the reference species were lower than the threshold values recommended for distinguishing novel prokaryotic species. Thus, based on the provided phenotypic, phylogenetic, and genetic data, it is proposed that strain SYSU G07232T (=KCTC 8141T=GDMCC 1.4178T) be designated as representing a novel species within the genus Chelatococcus, named Chelatococcus albus sp. nov.

Milk fat globule epidermal growth factor 8 alleviates liver injury in severe acute pancreatitis by restoring autophagy flux and inhibiting ferroptosis in hepatocytes.

BACKGROUND: Liver injury is common in severe acute pancreatitis (SAP). Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes, which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis. Our previous study found that milk fat globule epidermal growth factor 8 (MFG-E8) alleviates acinar cell damage during SAP via binding to αvß3/5 integrins. MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy. AIM: To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux. METHODS: SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50 µg/kg cerulein plus lipopolysaccharide. mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAP-induced liver injury. Cilengitide, a specific αvß3/5 integrin inhibitor, was used to investigate the possible mechanism of MFG-E8. RESULTS: The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice, enhanced autophagy flux in hepatocyte, and worsened the degree of ferroptosis. Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner. Mechanistically, MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells. Cilengitide abolished MFG-E8's beneficial effects in SAP-induced liver injury. CONCLUSION: MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury. MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrin αVß3/5.

Uncommon de novo EGFRT790M-Mutant NSCLC characterized with unique genetic Features: Clinical response and acquired resistance to the third-generation EGFR-TKIs treatment.

INTRODUCTION: The literature on de novo EGFRT790M-mutant patients diagnosed with lung cancer is limited, and there is currently no consensus concerning the most effective treatment protocols. This study aimed to investigate the genomic characteristics of de novoEGFRT790M-mutant non-small cell lung cancer (NSCLC) and provide insights into its clinical response and resistance mechanism to third-generation EGFR-TKIs. METHODS: Next-generation sequencing was utilized to screen a substantial cohort of 4,228 treatment-naïve patients from the Mygene genomic database to identifythe de novo EGFR-T790M mutation. Meanwhile, we recruited 83 individuals diagnosed with lung cancer who harbored de novo EGFRT790M mutation in the real world. In addition, 166 patients who acquired EGFR-T790M mutation after becoming resistant to first- or second-generation EGFR-TKIs were included as a comparison cohort. RESULTS: De novo EGFRT790M mutation identified by next-generation sequencing is rare (∼1.3 %) in Chinese lung cancer patients. The relative variant allele frequency (VAF) of de novo EGFRT790M mutation was either comparable to or significantly lower than those of EGFR-activating mutations. Patients with de novo-T790M mutations exhibited less favorable clinical outcomes when administered third-generation EGFR-TKIs as first-line therapy thanthose with 19del mutationsdue to a high overlap rate in EGFR p.L858R mutation. In patients with a de novo EGFRT790M mutation, no correlation was observed between T790M clonality and treatment outcomes with third-generation EGFR-TKIs. In contrast, the sub-clonality of the T790M mutation detrimentally affected the third-generation EGFR-TKI treatment efficacy in patients with acquired T790M mutation. Potential resistance mechanisms of third-generation EGFR TKIs in NSCLC patients with de novo or acquired EGFRT790M mutations included EGFR p.C797S in cis or EGFR p.E709X mutation, as well as activation of bypass pathways. CONCLUSIONS: The present study characterized the uncommon but unique de novo EGFRT790M-mutant NSCLC and laid a foundation for designing future clinical trials in the setting of uncommon EGFR mutation.