DDX56 promotes EMT and cancer stemness via MELK-FOXM1 axis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major global cause of death, with epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties contributing to its metastasis. DEAD box helicase 56 (DDX56) is involved in carcinogenesis, but its role in EMT induction and stem phenotype maintenance is unclear. This study assessed the impact of DDX56 absence on HCC cell stemness and EMT. DDX56 was found to be overexpressed in HCC tissues, correlating with disease stage and prognosis. In vitro, DDX56 stimulated tumor cell proliferation, migration, invasion, EMT, and stemness. It also enhanced maternal embryonic leucine-zipper kinase (MELK)-mediated forkhead box protein M1 (FOXM1) expression, regulating cancer stemness and malignant traits. In vivo, DDX56 knockdown in tumor-bearing mice reduced tumorigenicity and lung metastasis by modulating the MELK-FOXM1 signaling pathway. Collectively, DDX56 initiates stem cell-like traits in HCC and promotes EMT via MELK-FOXM1 activation, shedding light on HCC pathogenesis and suggesting a potential anti-cancer therapeutic target.

Pinecone derived hierarchical carbon nanostructure as a transducer in a solid-state ion-selective electrode for in vivo analysis of calcium ion.

Monitoring extracellular calcium ion (Ca2+) chemical signals in neurons is crucial for tracking physiological and pathological changes associated with brain diseases in live animals. Potentiometry based solid-state ion-selective electrodes (ISEs) with the assist of functional carbon nanomaterials as ideal solid-contact layer could realize the potential response for in vitro and in vivo analysis. Herein, we employ a kind of biomass derived porous carbon as a transducing layer to prompt efficient ion to electron transduction while stabilizes the potential drift. The eco-friendly porous carbon after activation (APB) displays a high specific area with inherit macropores, micropores, and large specific capacitance. When employed as transducer in ISEs, a stable potential response, minimized potential drift can be obtained. Benefiting from these excellent properties, a solid-state Ca2+ selective carbon fiber electrodes (CFEs) with a sandwich structure is constructed and employed for real time sensing of Ca2+ under electrical stimulation. This study presents a new approach to develop sustainable and versatile transducers in solid-state ISEs, a crucial way for in vivo sensing.

lncRNA-056298 Regulates GAP43 and Promotes Cardiac Intrinsic Autonomic Nerve Remodelling in a Canine Model of Atrial Fibrillation Induction after Ganglionated Plexus Ablation.

BACKGROUND: Cardiac intrinsic autonomic nerve remodelling has been reported to play an important role in the recurrence of atrial fibrillation after radiofrequency ablation, which significantly affects the long-term efficacy of this procedure. lncRNAs have been shown to interact in the pathological processes underlying heart diseases. However, the roles and mechanisms of lncRNAs in cardiac intrinsic autonomic nerve remodelling during atrial fibrillation reduction after ganglionated plexus ablation remain unknown. OBJECTIVES: The aim of this study was to investigate the mechanism by which lncRNA- 056298 modulates GAP43 to affect cardiac intrinsic autonomic nerve remodelling and facilitate the induction of atrial fibrillation after ganglionated plexus ablation. METHODS: A canine model of right atrial ganglionated plexus ablation was established. The atrial electrophysiological characteristics and neural markers were detected before and after 6 months of ganglionated plexus ablation. High-throughput sequencing was used to screen differentially expressed lncRNAs in target atrial tissues, and lncRNA- 056298 was selected to further explore its effects and mechanisms on cardiac intrinsic autonomic nerve remodelling. RESULTS: The induction rate of atrial fibrillation increased in dogs after ganglionated plexus ablation. Overexpression of lncRNA-056298 by lentivirus can shorten the atrial effective refractory period and increase the induction of atrial fibrillation. lncRNA- 056298 promoted cardiac intrinsic autonomic nerve remodelling via endogenous competition with cfa-miR-185 to induce transcription of its target gene GAP43, thereby affecting the induction of atrial fibrillation. CONCLUSIONS: lncRNA-056298 regulates GAP43 by sponging miR-185, which affects cardiac intrinsic autonomic nerve remodelling and mediates atrial fibrillation induction after ganglionated plexus ablation.

Metabolic subtypes and immune landscapes in esophageal squamous cell carcinoma: prognostic implications and potential for personalized therapies.

BACKGROUND: This study aimed to identify metabolic subtypes in ESCA, explore their relationship with immune landscapes, and establish a metabolic index for accurate prognosis assessment. METHODS: Clinical, SNP, and RNA-seq data were collected from 80 ESCA patients from the TCGA database and RNA-seq data from the GSE19417 dataset. Metabolic genes associated with overall survival (OS) and progression-free survival (PFS) were selected, and k-means clustering was performed. Immune-related pathways, immune infiltration, and response to immunotherapy were predicted using bioinformatic algorithms. Weighted gene co-expression network analysis (WGCNA) was conducted to identify metabolic genes associated with co-expression modules. Lastly, cell culture and functional analysis were performed using patient tissue samples and ESCA cell lines to verify the identified genes and their roles. RESULTS: Molecular subtypes were identified based on the expression profiles of metabolic genes, and univariate survival analysis revealed 163 metabolic genes associated with ESCA prognosis. Consensus clustering analysis classified ESCA samples into three distinct subtypes, with MC1 showing the poorest prognosis and MC3 having the best prognosis. The subtypes also exhibited significant differences in immune cell infiltration, with MC3 showing the highest scores. Additionally, the MC3 subtype demonstrated the poorest response to immunotherapy, while the MC1 subtype was the most sensitive. WGCNA analysis identified gene modules associated with the metabolic index, with SLC5A1, NT5DC4, and MTHFD2 emerging as prognostic markers. Gene and protein expression analysis validated the upregulation of MTHFD2 in ESCA. MTHFD2 promotes the progression of ESCA and may be a potential therapeutic target for ESCA. CONCLUSION: The established metabolic index and identified metabolic genes offer potential for prognostic assessment and personalized therapeutic interventions for ESCA, underscoring the importance of targeting metabolism-immune interactions in ESCA. MTHFD2 promotes the progression of ESCA and may be a potential therapeutic target for ESCA.

High-fat stimulation induces atrial neural remodeling by reducing NO production via the CRIF1/eNOS/P21 axi.

BACKGROUND: Autonomic remodeling of the atria plays a pivotal role in the development of atrial fibrillation (AF) and exerts a substantial influence on the progression of this condition. Hyperlipidemia is a predisposing factor for AF, but its effect on atrial nerve remodeling is unclear. The primary goal of this study was to explore the possible mechanisms through which the consumption of a high-fat diet (HFD) induces remodeling of atrial nerves, and to identify novel targets for clinical intervention. METHODS: Cell models were created in vitro by subjecting cells to palmitic acid (PA), while rat models were established by feeding them a high-fat diet. To investigate the interplay between cardiomyocytes and nerve cells in a co-culture system, we utilized Transwell cell culture plates featuring a pore size of 0.4 µm. The CCK-8 assay was employed to determine cell viability, fluorescent probe DCFH-DA and flow cytometry were utilized for measuring ROS levels, JC-1 was used to assess the mitochondrial membrane potential, the Griess method was employed to measure the nitric oxide (NO) level in the supernatant, a fluorescence-based method was used to measure ATP levels, and MitoTracker was utilized for assessing mitochondrial morphology. The expression of pertinent proteins was evaluated using western blotting (WB) and immunohistochemistry techniques. SNAP was used to treat nerve cells in order to replicate a high-NO atmosphere, and the level of nitroso was assessed using the iodoTMT reagent labeling method. RESULTS: The study found that cardiomyocytes' mitochondrial morphology and function were impaired under high-fat stimulation, affecting nitric oxide (NO) production through the CRIF1/SIRT1/eNOS axis. In a coculture model, overexpression of eNOS in cardiomyocytes increased NO expression. Moreover, the increased Keap1 nitrosylation within neuronal cells facilitated the entry of Nrf2 into the nucleus, resulting in an augmentation of P21 transcription and a suppression of proliferation. Atrial neural remodeling occurred in the HFD rat model and was ameliorated by increasing myocardial tissue eNOS protein expression with trimetazidine (TMZ). CONCLUSIONS: Neural remodeling is triggered by high-fat stimulation, which decreases the production of NO through the CRIF1/eNOS/P21 axis. Additionally, TMZ prevents neural remodeling and reduces the occurrence of AF by enhancing eNOS expression.

Clinical Research of Lupus Retinopathy: Quantitative Analysis of Retinal Vessels by Optical Coherence Tomography Angiography in Patients with Systemic Lupus Erythematosus.

BACKGROUND: Lupus retinopathy, an ocular manifestation of systemic lupus erythematosus (SLE), is the major pathology attributed to retinal vasculopathy. Our study is to analyze the changes in retinal vessels in patients with SLE by optical coherence tomography angiography. METHODS: A total of 61 SLE patients without obvious retinal manifestation and 71 healthy people were included. The SLE patients were further divided into a lupus nephritis (LN) group and a non-LN group. The changes in central macular thickness (CMT) and the retinal vessel densities were compared between the two groups, and the correlation between retinal vascular changes and disease activity was analyzed. RESULTS: Compared with healthy control, the CMT and the retinal vascular densities in both superficial and deep retina were decreased significantly in SLE patients. There was no significant difference in retinal vascular densities between LN groups and non-LN groups. CONCLUSION: The CMT and retinal vessel densities were decreased in SLE patients without clinical manifestations, which might serve as a sensitive biomarker for early changes of lupus retinopathy in SLE patients.

Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis.

Radiotherapy resistance is a challenge for colorectal cancer (CRC) treatment. Circular RNAs (circRNAs) play vital roles in the occurrence and development of CRC. This study aimed to investigate the role of circ_0005615 in regulating the radiosensitivity of CRC. The levels of circ_0005615, microRNA-665 (miR-665), and notch receptor 1 (NOTCH1) were detected by quantitative real-time PCR or western blot. The radiosensitivity of CRC cells was assessed by colony formation assay. Cell viability, apoptosis, and colony formation were assessed by Cell Counting Kit-8 assay, flow cytometry, and colony formation assay. Cell migration and invasion were confirmed by transwell assay and scratch assay. The binding relationship between miR-665 and circ_0005615 or NOTCH1 was verified by dual-luciferase reporter assay. Xenograft assay was used to test the effect of circ_0005615 on radiosensitivity in vivo. circ_0005615 and NOTCH1 were up-regulated, and miR-665 was down-regulated in CRC tissues and cells. Radiation decreased circ_0005615 and NOTCH1 levels and increased miR-665 level. Knockdown of circ_0005615 enhanced radiosensitivity of CRC cells. Moreover, circ_0005615 sponged miR-665 to regulate the radioresistance of CRC cells. Besides, miR-665 targeted NOTCH1 to mediate the radiosensitivity of CRC cells. Furthermore, circ_0005615 depletion increased CRC radiosensitivity in vivo. circ_0005615 silencing elevated radiosensitivity of CRC by regulating miR-665/NOTCH1 axis.

IL-33 Downregulates Hepatic Carboxylesterase 1 in Acute Liver Injury via Macrophage-derived Exosomal miR-27b-3p.

Background and Aims: We previously reported that carboxylesterase 1 (CES1) expression was suppressed following liver injury. The study aimed to explore the role of interleukin (IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1. Methods: IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide (LPS)-, acetaminophen (APAP)-treated mice. We constructed IL-33 and ST2 knockout (KO) mice. ST2-enriched immune cells in livers were screened to identify the responsible cells. Macrophage-derived exosome (MDE) activity was tested by adding exosome inhibitors. Micro-RNAs (miRs) were extracted from control and IL-33-stimulated MDEs (IL-33-MDEs) and subjected miR sequencing (miR-Seq). Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays. Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p. Results: Patient liver IL-33 and CES1 expression levels were inversely correlated. CES1 downregulation in liver injury was rescued in both IL-33-deficient and ST2 KO mice. Macrophages were shown to be responsible for IL-33 effects. IL-33-MDEs reduced CES1 levels in hepatocytes. Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs; miR-27b-3p was implicated in Nrf2 targeting. IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent. Conclusions: IL-33-ST2-GATA3 pathway signaling increases miR-27b-3p content in MDEs, which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2. The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury.

Reconsideration of interferon treatment for viral diseases: Lessons from SARS, MERS, and COVID-19.

Periodic pandemics of coronavirus (CoV)-related pneumonia have been a major challenging issue since the outbreak of severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012. The ongoing pandemic of CoV disease (COVID-19) poses a substantial threat to public health. As for the treatment options, only limited antiviral agents have been approved hitherto, and clinicians mainly focus on currently available drugs including the conventional antiviral interferons (IFNs). In clinical practice, IFNs, when used either alone or in combination with ribavirin and/or lopinavir/ritonavir, have shown promising outcomes, to some extent, in SARS-CoV or MERS-CoV treatment. Although the efficacy and safety of IFNs in COVID-19 treatment remain unclear, their possible use merits further evaluation. We present a review that summarizes current evidence of IFN treatment for COVID-19 and elaborates on other challenges in terms of the timing of IFN treatment initiation, treatment duration, and IFN type to be used. The review findings suggested that IFN acts by directly inhibiting viral replication and activating immune cell subsets. However, there is a lack of well-designed and controlled clinical trials providing firm evidence for the efficacy or safety of IFN therapy for CoVs. Additionally, critically ill patients with multiple immunosuppression-associated comorbidities may not benefit from IFN therapy, necessitating screening of those patients who would most benefit from IFN treatment.

Analysis of risk factors of hepatocellular carcinoma and establishment of a clinical prognosis model.

Liver cancer is a common malignancy of the digestive system. Hepatocellular carcinoma (HCC) accounts for the most majority of these tumors and it has brought a heavy medical burden to underdeveloped countries and regions. Many factors affect the prognosis of HCC patients, however, there is no specific statistical model to predict the survival time of clinical patients. This study derived a risk factor signature of HCC and reliable clinical prediction model by statistically analyzing The Surveillance, Epidemiology, and End Results (SEER) database patient information using an open source package in the python environment.

Inhibition of sepsis-induced acute kidney injury via the circITCH-miR-579-3p-ZEB2 axis.

Circular RNAs (circRNAs) are linked to the regulation of sepsis-induced acute kidney injury (AKI). However, the function of circITCH in the development of sepsis-induced AKI is still unclear. The levels of circITCH, miR-579-3p and ZEB2 were examined by real-time PCR and immunoblotting. Then, the roles of circITCH in cell viability, apoptosis, and inflammation in lipopolysaccharide (LPS)-treated HK-2 cells were evaluated. The further mechanism was investigated using rescue assays. CircITCH was downregulated in septic AKI patients and LPS-triggered HK-2 cells. CircITCH overexpression restored cell viability in LPS-treated HK-2 cells and restrained apoptosis and inflammatory cytokine production. CircITCH negatively regulated miR-579-3p, thereby upregulating ZEB2 expression. Taken together, circITCH alleviates LPS-induced HK-2 cell injury by regulating miR-579-3p/ZEB2 signal axis, which provides a theoretical basis for AKI therapy.

Establishment of a CaCC-based Cell Model and Method for High-throughput Screening of M3 Receptor Drugs.

Muscarinic acetylcholine receptor subtype 3 (M3 receptor) is a G Protein-Coupled Receptor (GPCR) that mediates many important physiological functions. Currently, most M3 receptor drugs also have high affinity for other subtypes of muscarinic acetylcholine receptors (mAChRs) and produce the risk of side effects. Therefore, in order to find M3 receptor drugs with high specificity, high activity and low side effects, we established a cell model and method for efficient and sensitive screening of M3 receptor based on calcium-activated chloride channels (CaCCs), and this method is also suitable for the screening of other GPCR drugs. This screening model consists of Fischer rat thyroid follicular epithelial (FRT) cells that endogenously express M3 receptors, CaCCs, and the indicator YFP-H148Q/I152L. We verified that the model can sensitively detect changes in intracellular Ca2+ concentration using fluorescence quenching kinetics experiments, confirmed the screening function of the model by applying available M3 receptor drugs, and also evaluated the good performance of the model in high-throughput screening.

Synergy of Losartan and chemotherapy for patients with cholangiocarcinoma: A propensity score-matched analysis.

Background: Cholangiocarcinoma (CCA) is a malignant tumor originating from bile duct epithelial cells that no obvious clinical symptoms and specific clinical manifestations are shown in the early stage of CCA. Methods: Propensity score matching (PSM) is a quasi-experimental method in which this study used. Patients were enrolled from Department of General surgery, First Affiliated Hospital of Jinzhou Medical University from March 1, 2010, to December 30, 2019. Totally 170 patients with CCA were enrolled in this study. Results: We performed a 1:2 PSM study and found that patients with losartan group showed both comparable median OS (overall survival) and TTR (time to recurrence) to those in the patients without losartan group before PSM. However, after matching, patients with losartan group showed favorable median OS and TTR than those in the patients without losartan group. Then we performed Cox proportional hazards models and found that patients with losartan was an independent factor after multivariable analysis for patients with CCA. Furtherly, we sequenced serial cfDNA were performed in 10 patients with losartan and 9 patients without losartan who received adjuvant chemotherapy after tumor resection. These results showed that the treatment of losartan was related with tumor microenvironment and could be potentially useful to combine the immunotherapy for patients with CCA. Conclusion: In conclusion, this study demonstrated that the treatment of losartan could increase the efficacy of adjuvant chemotherapy and identified as an independent survival predictor for patients with CCA. Moreover, losartan could be potentially useful to combine the immunotherapy for patients with CCA.

Association between high-dose methotrexate-induced toxicity and polymorphisms within methotrexate pathway genes in acute lymphoblastic leukemia.

Methotrexate (MTX) is a folic acid antagonist, the mechanism of action is to inhibit DNA synthesis, repair and cell proliferation by decreasing the activities of several folate-dependent enzymes. It is widely used as a chemotherapy drug for children and adults with malignant tumors. High-dose methotrexate (HD-MTX) is an effective treatment for extramedullary infiltration and systemic consolidation in children with acute lymphoblastic leukemia (ALL). However, significant toxicity results in most patients treated with HD-MTX, which limits its use. HD-MTX-induced toxicity is heterogeneous, and this heterogeneity may be related to gene polymorphisms in related enzymes of the MTX intracellular metabolic pathway. To gain a deeper understanding of the differences in toxicity induced by HD-MTX in individuals, the present review examines the correlation between HD-MTX-induced toxicity and the gene polymorphisms of related enzymes in the MTX metabolic pathway in ALL. In this review, we conclude that only the association of SLCO1B1 and ARID5B gene polymorphisms with plasma levels of MTX and MTX-related toxicity is clearly described. These results suggest that SLCO1B1 and ARID5B gene polymorphisms should be evaluated before HD-MTX treatment. In addition, considering factors such as age and race, the other exact predictor of MTX induced toxicity in ALL needs to be further determined.

Attention and Intervention of Oncologists on Oxaliplatin-induced Adverse Reactions in Mainland China: A Cross-sectional Internet-based Survey.

OBJECTIVE: This cross-sectional study aimed to investigate the current attention and intervention of oncologists on oxaliplatin (OXA)-induced adverse reactions (ADRs). METHODS: In 31 provinces or administrative regions across China, 401 oncologists were surveyed through a self-designed questionnaire. The survey queried the basic information of respondents, clinical use of OXA, OXA-induced ADRs, and relative interventions. Chi-square tests and multiple logistic regression were used to explore the sociodemographic factors influencing the safety perception of OXA and the relevant interventions. RESULTS: The survey showed that the age of respondents was mainly distributed between 30 and 40 years and the working period for most oncologists was no more than 5 years. Oncologists with long working years were more willing to conduct patient education and inquire about ADRs than those with short working years. The rate of ADRs reported by oncologists with intermediate professional titles was significantly higher than that reported by oncologists with junior and senior professional titles. CONCLUSION: Our findings indicate that oncologists in mainland China are concerned about OXA-induced ADRs, but the reporting of ADRs still needs to be strengthened. Therefore, training and educational programs are urgently needed to improve the risk management of OXA-induced ADRs among oncologists.

Measurement and analysis of instantaneous microwave frequency based on an optical frequency comb.

A microwave photonics instantaneous frequency measurement scheme with 14 channels based on an optical frequency comb (OFC) is proposed. In this scheme, a 14-line flat OFC is generated by cascading a dual-parallel Mach-Zehnder modulator (DPMZM) with a Mach-Zehnder modulator (MZM). The intercepted microwave signal with multiple-frequency components can be measured by using DPMZM, Fabry-Perot filter (FPF), wavelength division multiplexer (WDM), and optical power detector array. This scheme can measure and analyze the frequency of microwave signals in the ranges of 0.5-13.5 GHz, 13.5-26.5 GHz, and 26.5-39.5 GHz with the measurement accuracy of ±0.5GHz. The reconfigurability of the system can be realized by adjusting the comb-line spacing of the OFC and the free spectral range (FSR) of the FPF.

Serum microRNAs as non-invasive diagnostic biomarkers for intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis of pregnancy (IHCP) causes itching, preterm birth, and stillbirth. However, there is no accurate diagnostic method for IHCP. Currently, circulating microRNAs (miRNAs) have become candidate biomarkers for the diagnosis of multiple diseases. Here, we investigated the diagnostic value of miRNAs in IHCP and aimed to predict the molecular mechanism of IHCP pathogenesis. METHODS: We analyzed differentially expressed miRNAs in both women with IHCP and normal pregnant women. The selected candidate miRNAs were validated in 46 IHCP cases and 46 normal pregnant subjects, and we constructed receiver operator characteristic curves of miRNAs. Pearson correlations between levels of total bile acid (TBA) and differentially expressed miRNAs were also calculated. In addition, we clustered functionally significant biological pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. RESULTS: The expression levels of 13 miRNAs were remarkably upregulated while the other 35 miRNAs were significantly downregulated, in women with IHCP (P≤0.05) when compared with healthy pregnant women. The areas under the curves of miRNA-7706, miRNA-877-3p, and miRNA-128-3p were higher than 0.90, indicating more reliable diagnosis of IHCP. The Pearson analysis showed that the levels of these miRNAs were positively correlated to TBA level. Additionally, the results of bioinformatics analysis revealed that the differentially expressed miRNAs mainly influenced fatty acid biosynthesis, the endoplasmic reticulum ubiquitin ligase complex, and the p53, and mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways. CONCLUSION: The panel of three-miRNAs (miRNA-7706, miRNA-877-3p, and miRNA-128-3p) may be a useful noninvasive diagnostic biomarker of IHCP.

Ginsenosides Restore Lipid and Redox Homeostasis in Mice with Intrahepatic Cholestasis through SIRT1/AMPK Pathways.

Intrahepatic cholestasis (IC) occurs when the liver and systemic circulation accumulate bile components, which can then lead to lipid metabolism disorders and oxidative damage. Ginsenosides (GS) are pharmacologically active plant products derived from ginseng that possesses lipid-regulation and antioxidation activities. The purpose of this study was to evaluate the possible protective effects of ginsenosides (GS) on lipid homeostasis disorder and oxidative stress in mice with alpha-naphthylisothiocyanate (ANIT)-induced IC and to investigate the underlying mechanisms. A comprehensive strategy via incorporating pharmacodynamics and molecular biology technology was adopted to investigate the therapeutic mechanisms of GS in ANIT-induced mice liver injury. The effects of GS on cholestasis were studied in mice that had been exposed to ANIT-induced cholestasis. The human HepG2 cell line was then used in vitro to investigate the molecular mechanisms by which GS might improve IC. The gene silencing experiment and liver-specific sirtuin-1 (SIRT1) knockout (SIRT1LKO) mice were used to further elucidate the mechanisms. The general physical indicators were assessed, and biological samples were collected for serum biochemical indexes, lipid metabolism, and oxidative stress-related indicators. Quantitative PCR and H&E staining were used for molecular and pathological analysis. The altered expression levels of key pathway proteins (Sirt1, p-AMPK, Nrf2) were validated by Western blotting. By modulating the AMPK protein expression, GS decreased hepatic lipogenesis, and increased fatty acid ß-oxidation and lipoprotein lipolysis, thereby improving lipid homeostasis in IC mice. Furthermore, GS reduced ANIT-triggered oxidative damage by enhancing Nrf2 and its downstream target levels. Notably, the protective results of GS were eliminated by SIRT1 shRNA in vitro and SIRT1LKO mice in vivo. GS can restore the balance of the lipid metabolism and redox in the livers of ANIT-induced IC models via the SIRT1/AMPK signaling pathway, thus exerting a protective effect against ANIT-induced cholestatic liver injury.

Model establishment and microarray analysis of mice with oxaliplatin­induced hepatic sinusoidal obstruction syndrome.

Hepatic sinusoidal obstruction syndrome (HSOS) is a serious side effect of oxaliplatin (OXA) treatment. The present study aimed to establish a reproducible mouse model of OXA­induced HSOS and to preliminarily explore the underlying molecular mechanisms using mRNA microarray analysis. A total of 45 C57BL/6 male mice were randomly divided into five groups: Control, 5 mg/kg OXA, 10 mg/kg OXA, 15 mg/kg OXA and 20 mg/kg OXA. The mice were respectively injected intraperitoneally with 5% glucose solution, or 5, 10, 15 or 20 mg/kg OXA solution once a week for 6 consecutive weeks. The body weight of the mice was recorded every day. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Hematoxylin and eosin staining, Sirius red staining and scanning electron microscopy were used to identify pathological changes. mRNA microarray was used to analyze changes in the gene expression profiles mainly from the functional aspects of Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. The oxidation mechanism was verified by measuring oxidative stress­related markers and reactive oxygen species with dihydroethidium probe technology, according to the microarray results. Among all of the OXA groups, 10 mg/kg OXA resulted in an acceptable survival rate of 78%. The mice showed obvious splenomegaly, increases in serum levels of ALT and AST, aggravation of liver pathological injuries and hepatic sinusoidal injuries. The microarray results suggested that mRNA expression changes after OXA treatment were associated with 'oxidative stress', 'coagulation function', 'steroid anabolism' and 'pro­inflammatory responses'. The results confirmed that OXA aggravated oxidative damage in the livers of the mice. The present study successfully established a mouse model of OXA­induced HSOS and preliminarily analyzed the underlying molecular mechanisms involved, thus laying a foundation for a subsequent in­depth study.

Transformers Improve Breast Cancer Diagnosis from Unregistered Multi-View Mammograms.

Deep convolutional neural networks (CNNs) have been widely used in various medical imaging tasks. However, due to the intrinsic locality of convolution operations, CNNs generally cannot model long-range dependencies well, which are important for accurately identifying or mapping corresponding breast lesion features computed from unregistered multiple mammograms. This motivated us to leverage the architecture of Multi-view Vision Transformers to capture long-range relationships of multiple mammograms from the same patient in one examination. For this purpose, we employed local transformer blocks to separately learn patch relationships within four mammograms acquired from two-view (CC/MLO) of two-side (right/left) breasts. The outputs from different views and sides were concatenated and fed into global transformer blocks, to jointly learn patch relationships between four images representing two different views of the left and right breasts. To evaluate the proposed model, we retrospectively assembled a dataset involving 949 sets of mammograms, which included 470 malignant cases and 479 normal or benign cases. We trained and evaluated the model using a five-fold cross-validation method. Without any arduous preprocessing steps (e.g., optimal window cropping, chest wall or pectoral muscle removal, two-view image registration, etc.), our four-image (two-view-two-side) transformer-based model achieves case classification performance with an area under ROC curve (AUC = 0.818 ± 0.039), which significantly outperforms AUC = 0.784 ± 0.016 achieved by the state-of-the-art multi-view CNNs (p = 0.009). It also outperforms two one-view-two-side models that achieve AUC of 0.724 ± 0.013 (CC view) and 0.769 ± 0.036 (MLO view), respectively. The study demonstrates the potential of using transformers to develop high-performing computer-aided diagnosis schemes that combine four mammograms.