LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis.

Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.

A distinct subset of urothelial cells with enhanced EMT features promotes chemotherapy resistance and cancer recurrence by increasing COL4A1-ITGB1 mediated angiogenesis.

Drug resistance and tumor recurrence remain clinical challenges in the treatment of urothelial carcinoma (UC). However, the underlying mechanism is not fully understood. Here, we performed single-cell RNA sequencing and identified a subset of urothelial cells with epithelial-mesenchymal transition (EMT) features (EMT-UC), which is significantly correlated with chemotherapy resistance and cancer recurrence. To validate the clinical significance of EMT-UC, we constructed EMT-UC like cells by introducing overexpression of two markers, Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and Desmin (DES), and examined their histological distribution characteristics and malignant phenotypes. EMT-UC like cells were mainly enriched in UC tissues from patients with adverse prognosis and exhibited significantly elevated EMT, migration and gemcitabine tolerance in vitro. However, EMT-UC was not specifically identified from tumorous tissues, certain proportion of them were also identified in adjacent normal tissues. Tumorous EMT-UC highly expressed genes involved in malignant behaviors and exhibited adverse prognosis. Additionally, tumorous EMT-UC was associated with remodeled tumor microenvironment (TME), which exhibited high angiogenic and immunosuppressive potentials compared with the normal counterparts. Furthermore, a specific interaction of COL4A1 and ITGB1 was identified to be highly enriched in tumorous EMT-UC, and in the endothelial component. Targeting the interaction of COL4A1 and ITGB1 with specific antibodies significantly suppressed tumorous angiogenesis and alleviated gemcitabine resistance of UC. Overall, our findings demonstrated that the driven force of chemotherapy resistance and recurrence of UC was EMT-UC mediated COL4A1-ITGB1 interaction, providing a potential target for future UC treatment.

Characterization of Acid-Responsive-Release Matrine/ZIF-8@Sodium Alginate Microcapsules Prepared by Electrostatic Spray and Their Application in the Control of Soybean Cyst Nematode.

Matrine (MT) is a kind of alkaloid extracted from Sophora and is a promising substitute for chemical nematicides and botanical pesticides. The present study utilized sodium alginate (SA), zeolite imidazole salt skeleton (ZIF), and MT as raw materials to prepare a pH-response-release nematicide through the electrostatic spray technique. Zinc metal-organic framework (ZIF-8) was initially synthesized, followed by the successful loading of MT. Subsequently, the electrostatic spray process was employed to encapsulate it in SA, resulting in the formation of MT/ZIF-8@SA microcapsules. The efficiency of encapsulation and drug loadings can reach 79.93 and 26.83%, respectively. Soybean cyst nematode (SCN) is one of the important pests that harm crops; acetic acid produced by plant roots and CO2 produced by root respiration causing a decrease in the pH of the surrounding environment, which is most attractive to the SCN when the pH is between 4.5 and 5.4. MT/ZIF-8@SA releases the loaded MT in response to acetic acid produced by roots and acidic oxides produced by root respiration. The rate of release was 37.67% higher at pH 5.25 compared with pH 8.60. The control efficiency can reach 89.08% under greenhouse conditions. The above results demonstrate that the prepared MT/ZIF-8@SA not only exhibited excellent efficacy but also demonstrated a pH-responsive release of the nematicide.

Modified Approach for Extraperitoneal Colostomy Creation in Laparoscopic Abdominoperineal Resection.

BACKGROUND: Parastomal hernia is a major long-term complication after abdominoperineal resection. Extraperitoneal colostomy has been proposed as an effective step for parastomal hernia prevention, but it has not been widely used as it is technically demanding and time-consuming. We proposed a modified approach for extraperitoneal colostomy creation by entering the extraperitoneal space through the arcuate line of the posterior rectus sheath. OBJECTIVE: To evaluate the safety, difficulty, and efficacy of long-term parastomal hernia prevention of the modified approach for extraperitoneal colostomy creation compared with the conventional transperitoneal colostomy approach. DESIGN: This was a retrospective evaluation of a surgical and video database. SETTINGS: This was a single-institution retrospective study. PATIENTS: Clinical data of 74 patients who underwent laparoscopic abdominoperineal resection surgery from January 2019 to January 2020 in the Department of General Surgery, Qilu Hospital of Shandong University, were retrospectively reviewed. MAIN OUTCOME MEASURES: Baseline characteristics, time required for colostomy creation (from skin incision to colostomy maturation), perioperative complications, and long-term colostomy-related complications were compared. RESULTS: Baseline characteristics did not differ between the 2 approaches. The BMI level ranged from 19.5 to 29.4 for patients undergoing extraperitoneal approach. Time required for colostomy creation median [interquartile range], (22 [21-25] minutes for extraperitoneal vs 23 [21-25] minutes for transperitoneal, p = 0.861) were comparable between the 2 approaches. The cumulative incidence of parastomal hernia was significantly greater with transperitoneal colostomy than extraperitoneal colostomy at 2 and 3 years postoperatively (16.2% vs 0%, p = 0.025, and 21.6% vs 0%, p = 0.005). The remaining perioperative complications and long-term colostomy-related complications did not differ between the 2 approaches. LIMITATIONS: This study is limited by its retrospective design and small sample size. CONCLUSIONS: The modified approach for extraperitoneal colostomy creation is safe, technically simple, and effective for long-term parastomal hernia prevention in patients with a BMI of 19.5 to 29.4.

Is cryoablation still suitable for advanced non-small cell lung cancer after failure of first-line chemotherapy? A multicenter, prospective, randomized-controlled trial of eighty-seven patients.

The aim of this study was to investigate the therapeutic effect of cryoablation treatment in advanced NSCLC patients who had failed first-line chemotherapy. Eighty-seven patients from ten hospitals in China were enrolled into the study, forty-four patients received cryoablation treatment plus basic treatment (experimental group), and forty-three patients had basic treatment alone (control group). Follow-up was performed once every three months until the end of the study or the death of the patient. The primary endpoints were overall and post-intervention survival; secondary endpoints included tumor markers, solid tumor efficacy, and symptom changes before and after treatment. There was no significant difference in median OS between the two groups of patients (9.0 months vs 11.2 months, P = 0.583). The disease control rate (DCR) and living quality of the experimental group was higher than that of the control group. In terms of OS, indiscriminate use of cryoablation for such patients was not beneficial, though it could improve symptoms of patients. Cryoablation had a significant effect on selected advanced NSCLC patients after the failure of first-line chemotherapy.

Discovery of Novel Marine-Derived Phidiandine/Lipoic Acid Hybrid as a Potential Anti-Atherosclerosis Agent: Design, Synthesis and in Vitro/in Vivo Evaluation.

In the present study, a novel derivative, IOP-LA, was prepared by hybridizing antioxidant lipoic acid (LA) and our recently reported antioxidative marine phidianidine B-inspired indole/1,2,4-oxadiazole derivative. Our results demonstrated that IOP-LA could protect vascular endothelial cells (VECs) from oxidized low-density lipoprotein (oxLDL)-induced oxidative stress by activating the Nrf2 pathway, inhibit the production of atherosclerotic plaque, and promote the stability of atherosclerotic plaque in apoE-/- mice. Moreover, the protective effect of IOP-LA was superior to LA at the same concentration. Mechanistic studies revealed that IOP-LA significantly inhibited the increase of reactive oxygen species (ROS) levels and the translocation of nuclear factor kappa-B (NF-κB) nuclear induced by oxLDL through the nuclear factor erythroid2-related factor 2 (Nrf2) pathway. In summary, the data demonstrate that IOP-LA, as a new antioxidant, protects VECs from oxLDL-induced oxidative stress by activating the Nrf2 pathway. It is worth noting that this study provides a promising lead compound for the prevention and treatment of atherosclerosis.

Mechanism of Action of Dihydroquercetin in the Prevention and Therapy of Experimental Liver Injury.

Liver disease is a global health problem that affects the well-being of tens of thousands of people. Dihydroquercetin (DHQ) is a flavonoid compound derived from various plants. Furthermore, DHQ has shown excellent activity in the prevention and treatment of liver injury, such as the inhibition of hepatocellular carcinoma cell proliferation after administration, the normalization of oxidative indices (like SOD, GSH) in this tissue, and the down-regulation of pro-inflammatory molecules (such as IL-6 and TNF-α). DHQ also exerts its therapeutic effects by affecting molecular pathways such as NF-κB and Nrf2. This paper discusses the latest research progress of DHQ in the treatment of various liver diseases (including viral liver injury, drug liver injury, alcoholic liver injury, non-alcoholic liver injury, fatty liver injury, and immune liver injury). It explores how to optimize the application of DHQ to improve its effectiveness in treating liver diseases, which is valuable for preparing potential therapeutic drugs for human liver diseases in conjunction with DHQ.

Discovery of marine phidianidine-based Nrf2 activators and their potential against oxLDL- and HG-induced injury in HUVECs.

One effective strategy for treating atherosclerosis is to inhibit the injury of vascular endothelial cells (VECs) induced by oxidized low-density lipoprotein (oxLDL) and high glucose (HG). This study synthesized and evaluated a series of novel Nrf2 activators derived from the marine natural product phidianidine for their ability to protect human umbilical VECs against oxLDL- and HG-induced injury. The results of in vitro bioassays demonstrated that compound D-36 was the most promising Nrf2 activator, effectively inhibiting the apoptosis of HUVECs induced by oxLDL and HG. Furthermore, Nrf2 knockdown experiments confirmed that compound D-36 protected against oxLDL- and HG-induced apoptosis in HUVECs by activating the Nrf2 pathway. These findings provide important insights into a new chemotype of marine-derived Nrf2 activators that could potentially be optimized to develop effective anti-atherosclerosis agents.

CT-based radiomics signature to predict CD8+ tumor infiltrating lymphocytes in non-small-cell lung cancer.

BACKGROUND: An abundance of CD8+ tumor infiltrating lymphocytes (TILs) in the center of solid tumors is a reliable predictive biomarker for patients eligible for immunotherapy. PURPOSE: To develop a computed tomography (CT)-based radiomics signature for a preoperative prediction of an abundance of CD8+ TILs in non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: In this retrospective study, 117 consecutive patients with pathologically confirmed NSCLC were included and randomly divided into training (n = 77) and test sets (n = 40). A total of 107 radiomics features were extracted from the three-dimensional volumes of interest of each patient. Least absolute shrinkage and selection operator (LASSO) regression was used to select the strongest features for abundance of CD8+ TILs in NSCLC, and the radiomics score was constructed through a linear combination of these selected features. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive performance of the radiomics score. RESULTS: The radiomics score was associated with an abundance of CD8+ TILs in NSCLC, which achieved an area under the curve (AUC) of 0.83 (95% CI=0.73-0.92) and 0.68 (95% CI=0.54-0.87) in the training and test sets, respectively. The difference was not statistically significant (P = 0.20). The tumors with high CD8+ TILs tended to have heterogeneous dependences (high value of Dependence Non-Uniformity Normalized) and complicated texture (high value of Informational Measure of Correlation 1). CONCLUSION: CT-based radiomics features have the ability to predict CD8+ TILs expression levels of an abundance of CD8+ TILs in NSCLC, which was shown to be a potential imaging biomarker for stratifying patients who may benefit from immunotherapy.

Complications of preventive loop ileostomy versus colostomy: a meta-analysis, trial sequential analysis, and systematic review.

BACKGROUND: Preventive colostomy is required for colorectal surgery, and the incidence of complications associated with ileostomy and colostomy remains controversial. This study aimed to compare the incidence of postoperative complications between ileostomy and colostomy procedures. METHODS: Data analysis was conducted on 30 studies, and meta-analysis and trial sequential analysis (TSA) were performed on five studies. The basic indicators, such as stoma prolapse, leak, wound infection, ileus, and a series of other indicators, were compared. RESULTS: No statistically significant differences were observed with complications other than stoma prolapse. Meta-analysis and TSA showed that the incidence of ileostomy prolapse was lower than that of colostomy prolapse, and the difference was statistically significant. Apart from the four complications listed above, the general data analysis showed differences in incidence between the two groups. The incidence of skin irritation, parastomal hernia, dehydration, pneumonia, and urinary tract infections was higher with ileostomy than with colostomy. In contrast, the incidence of parastomal fistula, stenosis, hemorrhage, and enterocutaneous fistula was higher with colostomy than with ileostomy. CONCLUSIONS: There were differences in the incidence of ileostomy and colostomy complications in the selected studies, with a low incidence of ileostomy prolapse. PROSPERO REGISTRATION NUMBER: CRD42022303133.

GPR41 Regulates the Proliferation of BRECs via the PIK3-AKT-mTOR Pathway.

Short-chain fatty acids (SCFAs) play a pivotal role in regulating the proliferation and development of bovine rumen epithelial cells (BRECs). G protein-coupled receptor 41 (GPR41) is involved in the signal transduction in BRECs as a receptor for SCFAs. Nevertheless, the impact of GPR41 on the proliferation of BRECs has not been reported. The results of this research showed that the knockdown of GPR41 (GRP41KD) decreased BRECs proliferation compared with the wild-type BRECs (WT) (p < 0.001). The RNA sequencing (RNA-seq) analysis showed that the gene expression profiles differed between WT and GPR41KD BRECs, with the major differential genes enriched in phosphatidylinositol 3-kinase (PIK3) signaling, cell cycle, and amino acid transport pathways (p < 0.05). The transcriptome data were further validated by Western blot and qRT-PCR. It was evident that the GPR41KD BRECs downregulated the level of the PIK3-Protein kinase B (AKT)-mammalian target of the rapamycin (mTOR) signaling pathway core genes, such as PIK3, AKT, eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and mTOR contrasted with the WT cells (p < 0.01). Furthermore, the GPR41KD BRECs downregulated the level of Cyclin D2 p < 0.001) and Cyclin E2 (p < 0.05) compared with the WT cells. Therefore, it was proposed that GPR41 may affect the proliferation of BRECs by mediating the PIK3-AKT-mTOR signaling pathway.

Preparation of Azoxystrobin-Zinc Metal-Organic Framework/Biomass Charcoal Composite Materials and Application in the Prevention and Control of Gray Mold in Tomato.

In order to reduce the use of fungicide and ensure food safety, it is necessary to develop fungicide with low toxicity and high efficiency to reduce residues. Azoxystrobin (AZOX), which is derived from mushrooms, is an excellent choice. However, conventional AZOX release is difficult to regulate. In this paper, a pH-responsive fungicide delivery system for the preparation of AZOX by impregnation method was reported. The Zinc metal-organic framework/Biomass charcoal (ZIF-8/BC) support was first prepared, and subsequently, the AZOX-ZIF-8/BC nano fungicide was prepared by adsorption of AZOX onto ZIF-8/BC by dipping. Gray mold, caused by Botrytis cinerea, is one of the most important crop diseases worldwide. AZOX-ZIF-8/BC could respond to oxalic acid produced by Botrytis cinerea to release loaded AZOX. When pH = 4.8, it was 48.42% faster than when pH = 8.2. The loading of AZOX on ZIF-8/BC was 19.83%. In vitro and pot experiments showed that AZOX-ZIF-8/BC had significant fungicidal activity, and 300 mg/L concentration of AZOX-ZIF-8-BC could be considered as a safe and effective control of Botrytis cinerea. The above results indicated that the prepared AZOX-ZIF-8/BC not only exhibited good drug efficacy but also demonstrated pH-responsive fungicide release.

Real-world outcomes of regorafenib combined with immune checkpoint inhibitors in patients with advanced or metastatic microsatellite stable colorectal cancer: A multicenter study.

BACKGROUND: Treatment strategies are limited for patients with chemotherapy refractory microsatellite stable (MSS) colorectal cancer. We aim to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with regorafenib in this population in routine clinical practice. METHODS: We retrospectively analyzed patients with advanced or metastatic colorectal cancer who received at least one dose of ICIs combined with regorafenib in 14 Chinese medical centers. The primary outcome was objective response rate (ORR). This study was registered at ClinicalTrials.gov on February 2020 (NCT04771715). RESULTS: Eighty-four patients received ICIs combined with regorafenib from January 2019 to January 2021. Most patients (91%) received two or more systemic treatment lines before the study treatment. Seventy-six patients (90%) had confirmed MSS status. At a median follow-up of 5.5 months, four patients achieved partial response (5%) and 37 patients achieved stable disease (45%) as the best response. The median progression-free survival (PFS) was 3.1 months, and the median overall survival was 17.3 months. Eleven patients (13%) remained progression-free for more than 6 months. Baseline liver metastasis (HR 1.98, 95%CI 1.07-3.69, P = 0.03) and neutrophil-lymphocyte ratio (NLR) of ≥ 1.5 (HR 2.83, 95%CI 1.00-7.98, P = 0.05) were associated with shorter PFS in multivariate analysis. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 16 patients (19%). CONCLUSION: The combination of ICIs with regorafenib can be a valuable treatment option for a proportion of patients with chemotherapy refractory MSS colorectal cancer. Patients with no liver metastasis and a low NLR at baseline may derive most benefit from this strategy.

Activity Measurement of Iodine Fission Products in 2LiF-BeF2 Salt and Its Application in Redox Potential Surveillance for a Thorium Molten Salt Reactor.

The activities of 131I, 132I, 133I, and 135I produced by neutron-induced fission of 235U in 2LiF-BeF2 (FLiBe) eutectic salt and their dependence on the redox potential were studied. The dependence observed experimentally suggested that the activity ratio for 131I to 132I could be used as an indicator of the redox potential for FLiBe salt. Relying on the selective adsorption of iodine ions on the activated silver probe by ion exchange, a novel method for activity distribution measurement of the iodine isotopes in FLiBe salt was founded. The method is simple, fast, and easy to operate and would be suitable particularly to in situ monitor the redox potential of a thorium molten salt reactor, where the redox potential should keep at a high level to avoid possible safety risk induced by 233Pa deposition in the reactor.

Aronia melanocarpa polysaccharide ameliorates liver fibrosis through TGF-ß1-mediated the activation of PI3K/AKT pathway and modulating gut microbiota.

The purpose of this experiment was to investigate the anti-hepatic fibrosis effect of Aronia melanocarpa polysaccharide (AMP) on TAA-induced liver fibrosis mice and its mechanism, as well as the changes in intestinal flora in vivo. This was established with a dose of 200 mg/kg TAA (i.p) once every three days, lasting for eight weeks. Colchicine with 0.4 mg/kg, and AMP (200 and 400 mg/kg) were given by intragastric administration (i.g) after 28 days of intraperitoneal injection of TAA. AMP treatment significantly inhibited the activities of liver injury markers ALT and AST in serum. Histopathological staining demonstrated that AMP significantly reversed TAA-induced hepatocyte necrosis and collagen deposition. In addition, AMP treatment block TGF- ß1/Smads pathway inhibited the production of ECM and alleviates liver fibrosis. Furthermore, AMP treatment enhanced the phosphorylation of PI3K/AKT and decreased the expression of its downstream apoptosis-related proteins in liver, thus effectively alleviating TAA-induced liver fibrosis. In addition, 16S rDNA gene sequencing analysis showed that AMP treatment helped restore the imbalanced ecosystem of gut microbes, increased the proportion of Bacteroidetes and Proteobacteria, and increased species richness. Above findings clearly show that AMP is an effective method for treating liver fibrosis, possibly by improving the gut microbiota.

Design, synthesis and biological evaluation of marine phidianidine-inspired derivatives against oxidized ldl-induced endothelial injury by activating Nrf2 anti-oxidation pathway.

Inhibition of oxidized low-density lipoprotein (oxLDL)-induced vascular endothelial cell (VEC) injury is one of the effective strategies for treating atherosclerosis. In the present study, a series of novel marine phidianidine-inspired indole-1,2,4-oxadiazoles was designed, synthesized, and evaluated for their effects against oxLDL-induced injury in VECs. Among them, compound D-6, displaying the most effective protective activity, was found to inhibit oxLDL-induced apoptosis and the expression of ICAM-1 and VCAM-1 in VECs. Mechanistic studies showed that D-6 could trigger Nrf2 nuclear translocation, subsequently resulting in increased expression of Nrf2 target gene HO-1. Meanwhile, D-6 suppressed the increase of ROS level and nuclear translocation of NF-κB induced by oxLDL. Importantly, Nrf2 knockdown attenuated the inhibition effects of D-6 on oxLDL-induced apoptosis, ROS production and NF-κB nuclear translocation. Collectively, our studies demonstrated that compound D-6 protected against oxLDL-induced endothelial injury by activating Nrf2/HO-1 anti-oxidation pathway.

State-selective exciton-plasmon interplay in a hybrid WSe2/CuFeS2 nanosystem.

The integration of confined exciton and localized surface plasmon in a hybrid nanostructure has recently stimulated extensive interests. The mechanistic insights into the elusive exciton-plasmon interplay at the nanoscale are of both fundamental and applicable values. Herein, by taking a hybrid WSe2/CuFeS2 system as a prototype, in which the excitonic semiconductor WSe2 nanosheets are interfaced with the plasmonic semiconductor CuFeS2 nanocrystals to form a heterostructure, we design and perform an ultrafast dynamics study to glean information in this regard. Specifically, the band-alignment relationship between the two components enables the contrasting case studies in which the excitonic excited states of WSe2 are pre-selected to be on-/off-resonant with the plasmon band of CuFeS2. As revealed by the joint observations from steady-state absorption and photoexcitation-dependent/temperature-dependent femtosecond time-resolved transient absorption (fs-TA) spectroscopy, an effective energy transfer process occurs in this exciton-plasmon system where the energy donor (acceptor) is the excitonic WSe2 (plasmonic CuFeS2) and its efficiency is modulated by the exciton-plasmon coupling strength. Furthermore, as inferred from the temperature-dependent fs-TA analysis, the opening of such an energy-transfer channel turns out to take place during the early phase of plasmon decay (∼1 ps). In addition, the activation energy of energy transfer for a specific exciton-state-selected case is estimated (∼200 meV). This work provides a dynamics perspective to the plasmon semiconductor-involved exciton-plasmon interplay that features excited-state selectivity of exciton band and, hence, would be of guiding value for rational design and optimization of relevant applications based on exciton-plasmon manipulation.

Central GLP-1 contributes to improved cognitive function and brain glucose uptake after duodenum-jejunum bypass on obese and diabetic rats.

The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB), and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (Glp-1r) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including glucose transporter 1 (GLUT-1), GLUT-4, phospho-Akt substrate of 160kDa (pAS160), AS160, Rab10, Myosin-Va as well as the c-fos marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups whereas the Exe-9 and Glp-1r KD were opposite. Known to activate insulin-signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.NEW & NOTEWORTHY The improvement of cognitive function following bariatric surgery has been highlighted while its mechanisms remain elusive. The brain glucose uptake of patients was improved after RYGB, and the DJB and sham surgery performed on obese and diabetic Wistar rats revealed that the elevated central GLP-1 contributes to the dramatic improvement of cognitive function, brain glucose uptake, transport, glucose sensing, and neuronal activation.

Deep learning-based six-type classifier for lung cancer and mimics from histopathological whole slide images: a retrospective study.

BACKGROUND: Targeted therapy and immunotherapy put forward higher demands for accurate lung cancer classification, as well as benign versus malignant disease discrimination. Digital whole slide images (WSIs) witnessed the transition from traditional histopathology to computational approaches, arousing a hype of deep learning methods for histopathological analysis. We aimed at exploring the potential of deep learning models in the identification of lung cancer subtypes and cancer mimics from WSIs. METHODS: We initially obtained 741 WSIs from the First Affiliated Hospital of Sun Yat-sen University (SYSUFH) for the deep learning model development, optimization, and verification. Additional 318 WSIs from SYSUFH, 212 from Shenzhen People's Hospital, and 422 from The Cancer Genome Atlas were further collected for multi-centre verification. EfficientNet-B5- and ResNet-50-based deep learning methods were developed and compared using the metrics of recall, precision, F1-score, and areas under the curve (AUCs). A threshold-based tumour-first aggregation approach was proposed and implemented for the label inferencing of WSIs with complex tissue components. Four pathologists of different levels from SYSUFH reviewed all the testing slides blindly, and the diagnosing results were used for quantitative comparisons with the best performing deep learning model. RESULTS: We developed the first deep learning-based six-type classifier for histopathological WSI classification of lung adenocarcinoma, lung squamous cell carcinoma, small cell lung carcinoma, pulmonary tuberculosis, organizing pneumonia, and normal lung. The EfficientNet-B5-based model outperformed ResNet-50 and was selected as the backbone in the classifier. Tested on 1067 slides from four cohorts of different medical centres, AUCs of 0.970, 0.918, 0.963, and 0.978 were achieved, respectively. The classifier achieved high consistence to the ground truth and attending pathologists with high intraclass correlation coefficients over 0.873. CONCLUSIONS: Multi-cohort testing demonstrated our six-type classifier achieved consistent and comparable performance to experienced pathologists and gained advantages over other existing computational methods. The visualization of prediction heatmap improved the model interpretability intuitively. The classifier with the threshold-based tumour-first label inferencing method exhibited excellent accuracy and feasibility in classifying lung cancers and confused nonneoplastic tissues, indicating that deep learning can resolve complex multi-class tissue classification that conforms to real-world histopathological scenarios.

Inhibition of ELF3 confers synthetic lethality of PARP inhibitor in non-small cell lung cancer.

BACKGROUND: E74 Like ETS Transcription Factor 3 (ELF3) functions as a transcriptional factor to regulate non-small cell lung cancer (NSCLC) differentiation and progression. Poly(ADP-ribose) polymerase (PARP) inhibitors demonstrate anti-tumor effect in NSCLC. This study aimed to investigate whether ELF3 confers synthetic lethal with PARP inhibitor in NSCLC. MATERIALS AND METHODS: The sensitivity of PARP inhibitor, Olaparib, to different NSCLC cell lines was determined by half maximal inhibitory concentration (IC50). Expression of ELF3 in NSCLC cell lines was evaluated by western blot. The effects of ELF3 on cytotoxicity of Olaparib to NSCLC were investigated by MTT (3-(4,5- di methyl thiazol -2-yl)-2,5-di phenyl tetrazolium bromide) and colony formation assays. The underlying mechanism involved in synthetic lethality with ELF3 and PARP inhibitors in NSCLC were detected by immunofluorescence and Western blot. RESULTS: ELF3 was up-regulated in NSCLC cell lines exhibiting resistance to PARP inhibitor, Olaparib. Knock down of ELF3 decreased the sensitivity and enhanced cytotoxicity of Olaparib to NSCLC cells. Moreover, knock down of ELF3 increased S139 phosphorylated histone H2AX (γH2AX), and inhibited homologous recombination activity via down-regulation of DNA repair protein RAD51 homolog 1 (RAD51), thus showing deficiency in DNA damage repair. Over-expression of ELF3 could up-regulate phosphorylation of AKT (Protein kinase B), while knock down of ELF3 regulated homologous recombination-mediated DNA repair via down-regulation of phosphorylation of AKT. CONCLUSION: Knock down of ELF3 revealed homologous recombination deficiency via AKT signaling pathway, and synthetic lethality with ELF3 inhibition and PARP inhibitor indicated the clinical significance of PARP inhibitor in ELF3-deficient NSCLC.