Functional metabolomics characterizes the contribution of farnesoid X receptor in pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.

Consumption of herbal products containing pyrrolizidine alkaloids (PAs) is one of the major causes for hepatic sinusoidal obstruction syndrome (HSOS), a deadly liver disease. However, the crucial metabolic variation and biomarkers which can reflect these changes remain amphibious and thus to result in a lack of effective prevention, diagnosis and treatments against this disease. The aim of the study was to determine the impact of HSOS caused by PA exposure, and to translate metabolomics-derived biomarkers to the mechanism. In present study, cholic acid species (namely, cholic acid, taurine conjugated-cholic acid, and glycine conjugated-cholic acid) were identified as the candidate biomarkers (area under the ROC curve 0.968 [95% CI 0.908-0.994], sensitivity 83.87%, specificity 96.55%) for PA-HSOS using two independent cohorts of patients with PA-HSOS. The increased primary bile acid biosynthesis and decreased liver expression of farnesoid X receptor (FXR, which is known to inhibit bile acid biosynthesis in hepatocytes) were highlighted in PA-HSOS patients. Furtherly, a murine PA-HSOS model induced by senecionine (50 mg/kg, p.o.), a hepatotoxic PA, showed increased biosynthesis of cholic acid species via inhibition of hepatic FXR-SHP singling and treatment with the FXR agonist obeticholic acid restored the cholic acid species to the normal levels and protected mice from senecionine-induced HSOS. This work elucidates that increased levels of cholic acid species can serve as diagnostic biomarkers in PA-HSOS and targeting FXR may represent a therapeutic strategy for treating PA-HSOS in clinics.

Metabolomics Study Revealing Purines as Potential Diagnostic Biomarkers of Acute Respiratory Distress Syndrome in Patients with Community─Acquired Pneumonia.

Community-acquired pneumonia (CAP) is a significant threat to human health and the leading cause of acute respiratory distress syndrome (ARDS). We aimed to reveal the metabolic profiling whether can be used for assessing CAP with or without ARDS (nARDS) and therapeutic effects on CAP patients after treatment. Urine samples were collected at the onset and recovery periods, and metabolomics was employed to identify robust biomarkers. 19 metabolites were significantly changed in the ARDS relative to nARDS, mainly involving purines and fatty acids. After treatment, 7 metabolites in the nARDS and 14 in the ARDS were found to be significantly dysregulated, including fatty acids and amino acids. In the validation cohort, we observed that the biomarker panel consisted of N2,N2-dimethylguanosine, 1-methyladenosine, 3-methylguanine, 1-methyladenosine, and uric acid exhibited better AUCs of 0.900 than pneumonia severity index and acute physiology and chronic health evaluation II (APACHE II) scores between the ARDS and nARDS. Combining L-phenylalanine, phytosphingosine, and N-acetylaspartylglutamate as biomarkers for discriminating the nARDS and ARDS patients after treatment exhibited good AUCs of 0.811 and 0.821, respectively. The metabolic pathway and defined biomarkers may serve as crucial indicators for predicting the development of ARDS in CAP patients and for assessing therapeutic effects.

Pararespiratory and paradigestive lymph node metastases in esophageal squamous cell carcinoma: predicting survival and refining the N staging system.

BACKGROUND: The site of lymph node metastasis (LNM) may affect the prognosis of patients with esophageal squamous cell carcinoma (ESCC). To investigate the prognoses of pararespiratory and paradigestive LNM and to propose a novel N (nN) staging system that integrates both the LNM site and count. METHODS: This study was a multicenter, large-sample, retrospective cohort study that included ESCC patients with LNM between January 2014 and December 2019 from three Chinese institutes. Patients were set into training (two institutes) and external validation (one institute) cohorts. The primary outcomes were survival differences in LNM site and the development of novel nodal staging system. The overall survival (OS) of patients with pararespiratory LNM only (Group A), paradigestive LNM only (Group B), and both sites (Group C) was evaluated by Kaplan-Meier. Cox proportional hazards models were used to identify the independent prognostic factors. An nN staging system considering both the LNM site and count was developed and evaluated by the area under the receiver operating characteristic curve (AUC). RESULTS: In total, 1313 patients were included and split into training (n = 1033) and external validation (n = 280) cohorts. There were 342 (26.0%), 568 (43.3%) and 403 (30.7%) patients in groups A, B and C, respectively. The OS of patients with pararespiratory and patients with paradigestive LNM presented significant differences in the training and validation cohorts (P < 0.050). In the training cohort, LNM site was an independent prognostic factor (hazard ratio: 1.58, 95% confidence intervals: 1.41-1.77, P < 0.001). The nN staging definition: nN1 (1-2 positive pararespiratory/paradigestive LNs), nN2 (3-6 pararespiratory LNs or 1 pararespiratory with 1paradigestive LN), nN3 (3-6 LNs with ≥ 1 paradigestive LN), nN4 (≥ 7 LNs). Subsets of patients with different nN stages showed significant differences in OS (P < 0.050). The prognostic model of the nN staging system presented higher performance in the training and validation cohorts at 3-year OS (AUC, 0.725 and 0.751, respectively) and 5-year OS (AUC, 0.740 and 0.793, respectively) than the current N staging systems. CONCLUSIONS: Compared to pararespiratory LNM, the presence of paradigestive LNM is associated with worse OS. The nN staging system revealed superior prognostic ability than current N staging systems.

A TMT-based shotgun proteomics uncovers overexpression of thrombospondin 1 as a contributor in pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.

Hepatic sinusoidal obstruction disease (HSOS) is a rare but life-threatening vascular liver disease. However, its underlying mechanism and molecular changes in HSOS are largely unknown, thus greatly hindering the development of its effective treatment. Hepatic sinusoidal endothelial cells (HSECs) are the primary and essential target for HSOS. A tandem mass tag-based shotgun proteomics study was performed using primary cultured HSECs from mice with HSOS induced by senecionine, a representative toxic pyrrolizidine alkaloid (PA). Dynamic changes in proteome were found at the initial period of damage and the essential role of thrombospondin 1 (TSP1) was highlighted in PA-induced HSOS. TSP1 over-expression was further confirmed in human HSECs and liver samples from patients with PA-induced HSOS. LSKL peptide, a known TSP1 inhibitor, protected mice from senecionine-induced HSOS. In addition, TSP1 was found to be covalently modified by dehydropyrrolizidine alkaloids in human HSECs and mouse livers upon senecionine treatment, thus to form the pyrrole-protein adduct. These findings provide useful information on early changes in HSECs upon PA treatment and uncover TSP1 overexpression as a contributor in PA-induced HSOS.

Cerebral ischemia-reperfusion is modulated by macrophage-stimulating 1 through the MAPK-ERK signaling pathway.

Cerebral ischemia-reperfusion (IR) injury is associated with mitochondrial damage. Macrophage-stimulating 1 (MST1) reportedly stimulates mitochondrial apoptosis by suppressing BCL-2. We investigated whether MST1 promotes the progression of cerebral IR injury by inducing mitochondrial dysfunction in vivo and in vitro. Western blot analysis, quantitative polymerase chain reaction, immunofluorescence, and mitochondrial function assays were conducted in cells from wild-type and Mst1-knockout mice subjected to cerebral IR injury. MST1 expression in wild-type glial cells increased following cerebral IR injury. Cerebral IR injury reduced the mitochondrial membrane potential and mitochondrial metabolism in glial cells, while it enhanced mitochondrial reactive oxygen species generation and mitochondrial calcium levels in these cells. The deletion of Mst1 attenuated cerebral IR injury by improving mitochondrial function and reducing mitochondrial damage. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway was suppressed in wild-type glial cell upon cerebral IR injury but was reactivated in Mst1-knockout glial cell. Accordingly, blocking the MAPK/ERK pathway abolished the beneficial effects of Mst1 deletion during cerebral IR injury by inducing mitochondrial damage in glial cells. Our results suggest that cerebral IR injury is associated with MST1 upregulation in the brain, while the genetic ablation of Mst1 can attenuate mitochondrial damage and sustain brain function following cerebral IR injury.

Depth of Invasion into the Circular and Longitudinal Muscle Layers in T2 Esophageal Squamous Cell Carcinoma Does Not Affect Prognosis or Lymph Node Metastasis: A Multicenter Retrospective Study.

BACKGROUND: Although a greater depth of tumor invasion is correlated with a poorer prognosis in esophageal squamous cell carcinoma (ESCC), it remains controversial whether T2 ESCC should be subclassified by circular and longitudinal muscle invasion. We conducted a multicenter retrospective study to evaluate the relationship between the depth of invasion and long-term outcome and to identify the clinical significance of subclassifying T2 ESCC. METHODS: Patients with T2 ESCC who underwent esophagectomy at two different institutes between January 2009 and December 2017 were analyzed retrospectively. ESCC with circular and longitudinal muscle invasion was defined as T2 circular and T2 longitudinal ESCC, respectively. Survival outcomes and risk factors for lymph node metastasis (LNM) were evaluated by univariate and multivariate analyses. In addition, data from stage T1b ESCC cases during the same period were retrieved for use as a comparison cohort to evaluate the prognostic significance of the T2 substage. RESULTS: A total of 536 T2 ESCC patients were eligible, and 192 (36%) patients developed LNM. No significant difference was found in general characteristics between the T2 circular and T2 longitudinal ESCC groups (n = 219 and n = 317, P > 0.05), except for tumor location (P = 0.02). The T2 substage was not significantly correlated with survival on univariate or multivariate analysis (P = 0.30 and P = 0.34, respectively). Multivariate analysis also indicated that the T2 substage was not an independent risk factor for LNM (P = 0.15). When patients with stage T1b ESCC were considered, their survival time was significantly different from that of patients with T2 circular and T2 longitudinal disease (P = 0.01). CONCLUSIONS: The depth of tumor invasion into the circular and longitudinal muscle layers in T2 ESCC does not affect the prognosis or risk of LNM.

Seneciphylline, a main pyrrolizidine alkaloid in Gynura japonica, induces hepatotoxicity in mice and primary hepatocytes via activating mitochondria-mediated apoptosis.

Herbal drug-induced liver injury has been reported worldwide and gained global attention. Thousands of hepatic sinusoidal obstruction syndrome (HSOS) cases have been reported after consumption of herbal medicines and preparations containing pyrrolizidine alkaloids (PAs), which are natural phytotoxins globally distributed. And herbal medicines, such as Gynura japonica, are the current leading cause of PA-induced HSOS. The present study aimed to reveal the mechanism underlying the hepatotoxicity of seneciphylline (Seph), a main PA in G. japonica. Results showed that Seph induced severe liver injury through apoptosis in mice (70 mg/kg Seph, orally) and primary mouse and human hepatocytes (5-50 µM Seph). Further research uncovered that Seph induced apoptosis by disrupting mitochondrial homeostasis, inducing mitochondrial depolarization, mitochondrial membrane potential (MMP) loss, and cytochrome c (Cyt c) release and activating c-Jun N-terminal kinase (JNK). The Seph-induced apoptosis in hepatocytes could be alleviated by Mdivi-1 (50 µM, a dynamin-related protein 1 inhibitor), as well as SP600125 (25 µM, a specific JNK inhibitor) and ZVAD-fmk (50 µM, a general caspase inhibitor). Moreover, the Seph-induced MMP loss in hepatocytes was also rescued by Mdivi-1. In conclusion, Seph induced liver toxicity via activating mitochondrial-mediated apoptosis in mice and primary hepatocytes. Our results provide further information on Seph detoxification and herbal medicines containing Seph such as G. japonica.

A Novel LiDAR Data Classification Algorithm Combined CapsNet with ResNet.

LiDAR data contain feature information such as the height and shape of the ground target and play an important role for land classification. The effect of convolutional neural network (CNN) for feature extraction on LiDAR data is very significant, however CNN cannot resolve the spatial relationship of features adequately. The capsule network (CapsNet) can identify the spatial variations of features and is widely used in supervised learning. In this article, the CapsNet is combined with the residual network (ResNet) to design a deep network-ResCapNet for improving the accuracy of LiDAR classification. The capsule network represents the features by vectors, which can account for the direction of the features and the relative position between the features. Therefore, more detailed feature information can be extracted. ResNet protects the integrity of information by passing input information to the output directly, which can solve the problem of network degradation caused by information loss in the traditional CNN propagation process to a certain extent. Two different LiDAR data sets and several classic machine learning algorithms are used for comparative experiments. The experimental results show that ResCapNet proposed in this article `improve the performance of LiDAR classification.

[Quantification of hepatotoxic pyrrolizidine alkaloid adonifoline in traditional Chinese medicine preparations containing Senecionis Scandentis Herba].

Pyrrolizidine alkaloids(PAs) are a kind of natural toxins, which can cause severe hepatotoxicity, pulmonary toxicity, genotoxicity, neurotoxicity, embryotoxicity and even death. Therefore, international organizations and countries such as World Health Organization have paid great attention to herbal medicines and preparations containing PAs. PAs are widely distributed in Chinese herb medicines and contained in hundreds of traditional Chinese medicine preparations. The content of adonifoline, the main PAs in Senecionis Scandentis Herba, shall be less than 0.004% in herbal medicines as described in Chinese pharmacopeia. However, there is no guidance in preparations which contain Senecionis Scandentis Herba. In this study, 14 preparations were analyzed by an UPLC-MS method. Among them, 8 preparations were found to contain adonifoline much higher than the content limits of such countries as Germany, Netherlands and New Zealand. And the highest contents of adonifoline were found in Qianbai Biyan Tablets and Qianbai Biyan Capsules, which are officially recorded in Chinese Pharmacopeia. The contents of adonifoline varied in different batches of the same preparations. The highest content was 156.10 µg·g~(-1) Qianbai Biyan Tablets, whose daily intake of adonifoline was up to 1 030.26 µg according to the recommended dosage of the preparation. Our results showed the potential risk of these preparations, and the content limit of adonifoline shall be inspected Chinese medicine preparations containing Senecionis Scandentis Herba.

A Dual Neural Architecture Combined SqueezeNet with OctConv for LiDAR Data Classification.

Light detection and ranging (LiDAR) is a frequently used technique of data acquisition and it is widely used in diverse practical applications. In recent years, deep convolutional neural networks (CNNs) have shown their effectiveness for LiDAR-derived rasterized digital surface models (LiDAR-DSM) data classification. However, many excellent CNNs have too many parameters due to depth and complexity. Meanwhile, traditional CNNs have spatial redundancy because different convolution kernels scan and store information independently. SqueezeNet replaces a part of 3 × 3 convolution kernels in CNNs with 1 × 1 convolution kernels, decomposes the original one convolution layer into two layers, and encapsulates them into a Fire module. This structure can reduce the parameters of network. Octave Convolution (OctConv) pools some feature maps firstly and stores them separately from the feature maps with the original size. It can reduce spatial redundancy by sharing information between the two groups. In this article, in order to improve the accuracy and efficiency of the network simultaneously, Fire modules of SqueezeNet are used to replace the traditional convolution layers in OctConv to form a new dual neural architecture: OctSqueezeNet. Our experiments, conducted using two well-known LiDAR datasets and several classical state-of-the-art classification methods, revealed that our proposed classification approach based on OctSqueezeNet is able to provide competitive advantages in terms of both classification accuracy and computational amount.

Learn from orientation prior for radiograph super-resolution: Orientation operator transformer.

BACKGROUND AND OBJECTIVE: High-resolution radiographic images play a pivotal role in the early diagnosis and treatment of skeletal muscle-related diseases. It is promising to enhance image quality by introducing single-image super-resolution (SISR) model into the radiology image field. However, the conventional image pipeline, which can learn a mixed mapping between SR and denoising from the color space and inter-pixel patterns, poses a particular challenge for radiographic images with limited pattern features. To address this issue, this paper introduces a novel approach: Orientation Operator Transformer - O2former. METHODS: We incorporate an orientation operator in the encoder to enhance sensitivity to denoising mapping and to integrate orientation prior. Furthermore, we propose a multi-scale feature fusion strategy to amalgamate features captured by different receptive fields with the directional prior, thereby providing a more effective latent representation for the decoder. Based on these innovative components, we propose a transformer-based SISR model, i.e., O2former, specifically designed for radiographic images. RESULTS: The experimental results demonstrate that our method achieves the best or second-best performance in the objective metrics compared with the competitors at ×4 upsampling factor. For qualitative, more objective details are observed to be recovered. CONCLUSIONS: In this study, we propose a novel framework called O2former for radiological image super-resolution tasks, which improves the reconstruction model's performance by introducing an orientation operator and multi-scale feature fusion strategy. Our approach is promising to further promote the radiographic image enhancement field.

Radiotherapy and chemoradiotherapy for postoperative recurrence in patients with esophageal squamous cell carcinoma.

BACKGROUND: The optimal treatment for esophageal squamous cell carcinoma (ESCC) patients with postoperative recurrence remains controversial. We aimed to evaluate the effects of radiotherapy (RT) and chemoradiotherapy (CRT) on postoperative recurrence in ESCC patients. METHODS: Recurrence ESCC patients who received salvage RT and CRT from January 2015 to January 2019 were retrospectively reviewed. Post-recurrence survival (PRS) and prognostic factors were evaluated by Kaplan-Meier and Cox proportional hazards models, respectively. Subgroup analyses were performed based on pathological lymph node (LN) status (negative/positive) to evaluate the differences in salvage treatments and toxic reaction. RESULTS: A total of 170 patients were enrolled, with a median age of 60 years (range 43-77). No significant difference was found in the median PRS between the salvage RT and CRT groups (p > 0.05). Multivariate analysis revealed that TNM stage III and IV, macroscopic medullary type, and distant metastasis recurrence pattern were independent prognostic factors (all p < 0.05) for PRS. Salvage treatment was not associated with PRS (p = 0.897). However, in patients with negative LN, CRT was associated with prolonged survival (p = 0.043) and had no significant differences in toxic reactions compared to RT (p = 0.924). In addition, RT showed better prognoses (p = 0.020) and lower toxic reactions (p = 0.030) than CRT in patients with positive LNs. CONCLUSIONS: Based on prognosis and toxic reactions, ESCC recurrence patients with negative LNs could benefit from CRT, but RT should be recommended for patients with positive LNs.

Prognostic factors for patients with pathologic T1-T2N+ esophageal squamous cell carcinoma: A retrospective study with external validation.

BACKGROUND: Lymph node metastasis is significantly associated with a worse prognosis in patients with localized early-stage esophageal squamous cell carcinoma. This study aimed to explore the prognostic factors and develop a nomogram for predicting survival in patients with pathologic T1-2N+ esophageal squamous cell carcinoma. METHODS: Between 2014 and 2022, patients with pT1-2N+ esophageal squamous cell carcinoma who underwent esophagectomy with lymphadenectomy at 2 institutes were reviewed and assigned to training and external validation cohorts. Independent prognostic factors were identified via univariate and multivariate Cox regression analyses. The nomogram model was developed and evaluated by the area under the receiver operating characteristic curve and calibration curve. RESULTS: In total, 268 patients with a median age of 65 years (range, 40-82) were included and assigned to training (n = 190) and external validation (n = 78) cohorts. The Cox proportional hazards model demonstrated that body mass index (P = .031), surgical approach (P < .001), T stage (P = .015), and Clavien-Dindo classification (P < .001) were independent prognostic factors in the training cohort. The nomogram showed good discrimination, with an area under the receiver operating characteristic curve for 1-year, 3-year, and 5-year of 0.810, 0.789, and 0.809 in the training cohort and 0.782, 0.679, and 0.698 in the validation cohort. The calibration curve showed that the predicted survival probability was in good agreement with the actual survival probability. CONCLUSION: Lower body mass index, left surgical approach, T2 stage, and Clavien-Dindo classification grade III to V were related to worse prognosis in patients with pT1-T2N+ esophageal squamous cell carcinoma. The developed nomogram may predict individual survival accurately.

Prognostic prediction model for patients with pathological T1N0 stage esophageal squamous cell carcinoma undergone esophagectomy.

Background: There is a shortage of reliable predictive models to provide valuable prognostic information for early esophageal squamous cell carcinoma (ESCC) without lymph node metastasis (LNM). We aimed to develop and validate a nomogram using the prognostic factors in T1N0 ESCC patients. Methods: Patients with pathological T1N0 ESCC who underwent esophagectomy between 2014 and 2021 at three institutes were reviewed. The prognostic factors were evaluated by Cox proportional hazards model and a nomogram was developed. Patients were divided into high- and low-risk groups based on cut-off value of total points in the nomogram. Overall survival (OS) was estimated by the Kaplan-Meier method and compared using the log-rank test. Results: A total of 275 patients were included and split into training (n=180) and external validation (n=95) cohorts. In the training cohort, multivariable analysis showed that the surgical approach, T1 substage, and carcinoembryonic antigen (CEA) level were independent prognostic factors. The developed nomogram had relatively high performance, with the area under the receiver operating characteristic (ROC) curve (AUC) of 0.783, 0.711 and 0.612 for 1-, 3-, and 5-year OS, respectively. The calibration curves showed that the predicted probability was in good agreement with the actual probability. Forty-seven was determined as cut-off value of total points. High-risk group (n=148) showed a significant poor OS than low-risk group (n=127) (P<0.001). Conclusions: Left surgical approach, stage T1b, and higher CEA were associated with poorer prognosis in T1N0 ESCC patients. The nomogram demonstrated a good performance to predict the individual survival.

Mechanism of triterpenoids from Alismatis Rhizoma against liver fibrosis based on an integrated approach using network pharmacology, molecular docking, and luciferase assay.

Protostane-type triterpenoids are antifibrotic nature components with unique structures in Alismatis Rhizoma. However, the underlying mechanisms of them against liver fibrosis are not well illustrated. The present study aims to study the targets and mechanisms of Alismatis Rhizoma triterpenes responsible for their antifibrotic effects by network pharmacology, molecular docking, and luciferase assay. As a result, six molecular targets responsible for the antifibrotic effects of alisols against liver fibrosis were uncovered by network pharmacology, among which the activation of farnesoid X receptor (FXR/NR1H4) was highlighted and further confirmed by molecular docking and luciferase assay. Our present study provides a scientific basis for treating liver fibrosis by using Alismatis Rhizoma, especially via the FXR activation effects of alisols.

3D printed elastomeric biomaterial mitigates compaction during in vitro vasculogenesis.

A key parameter for the success of most cellular implants is the formation of a complete and comprehensive intra-implant vessel network. Pre-vascularization, the generation of vessel structures in vitro prior to transplantation, provides accelerated implant perfusion via anastomosis, but scalability and ease of integration hinder clinical translation. For fibrin-based vasculogenesis approaches, the remodeling and degradation of the fragile, hydrogel matrix during the formation of vessel-like structures results in rapid, cell-mediated construct compaction leading to dense, capillary-like structures with ineffective network coverage. To resolve these challenges, vasculogenic hydrogels were embedded within a highly porous, biostable three-dimensional (3D) polydimethylsiloxane (PDMS) scaffold. Using reverse-casting of 3D-printed molds, scaffolds exhibited highly interconnected and reproducible pore structures. Pore size was optimized via in vivo screening of intra-device angiogenesis. The inclusion of the PDMS frame with vasculogenic hydrogels significantly reduced fibrin compaction in vitro, resulting in easily manipulated constructs with predictable dimensionality and increased surface area compared to fibrin hydrogel alone. Globally, vascular morphogenesis was altered by the PDMS frame, with significantly larger and less dense network structures. Vasculogenic proteomic evaluation showed a temporal impact of the addition of the PDMS frame, indicating altered cellular proliferation and migration signaling. This work establishes a platform for improving the generation of translational pre-vascularized networks for greater flexibility to meet the needs of clinically scaled, engineered tissues. STATEMENT OF SIGNIFICANCE: Competent intra-implant vascularization is a significant issue hindering the success of engineered tissues. Pre-vascularization approaches, whereby a vascular network is formed in vitro and subsequently implanted into the host to anastomose, is a promising approach but it is limited by the compacted, dense, and poorly functional microcapillary structures typically formed using soft hydrogels. Herein, we have uniquely addressed this challenge by adding a 3D printed PDMS-based open framework structure that serves to prevent hydrogel compaction. Globally, we observed distinct differences in overall construct geometry, vascular network density, compaction, and morphogenesis, indicating that this PDMS framework lead to elevated maturity of this in vitro network while retaining its global dimensions. Overall, this novel approach elevates the translational potential of pre-vascularized constructs.

Intermittent fasting alleviates type 1 diabetes-induced cognitive dysfunction by improving the frontal cortical metabolic disorder.

Intermittent fasting (IF) is an ecological strategy to control various metabolic disorder symptoms, but its protective effect on type 1 diabetes (T1D)-induced cognitive dysfunction and the underlying mechanisms remain poorly defined. Herein, we examined the efficacy of IF in altering the behaviors and brain metabolome in T1D mice and investigated the potential molecular mechanisms. We demonstrated that IF remarkably improved frontal cortical-dependent memory in T1D mice and reduced the loss of neuronal cells. Metabolomics and targeted mass spectrometry assays showed that IF reprogrammed the composition of the frontal cortical metabolome in T1D mice, including activating the aspartate and glutamate pathway and reversing glycerophospholipid and sphingolipid depositions. Mechanistically, IF attenuated the levels of oxidative stress proteins, like NOX2, NOX4, 8-OHdG, and 4-HNE, and inhibited the levels of pro-apoptotic factors Bax and cleaved Caspase-3, ultimately improving the memory ability of T1D mice. In vitro studies confirmed the protective effect of the supplemented N-acetylaspartate, a pivotal metabolite involved in IF-regulated T1D-induced cognitive dysfunction, in high glucose-stimulated SH-SY5Y cells by eliminating toxic lipids accumulation, oxidative stress, and apoptosis. To conclude, the frontal cortical metabolites mediated the protective effects of IF against T1D-induced cognitive dysfunction by attenuating oxidative stress and apoptotic signaling. Thus, IF can be a potential therapeutic strategy for T1D-induced cognitive dysfunction.

The application of radiomics in esophageal cancer: Predicting the response after neoadjuvant therapy.

Esophageal cancer (EC) is one of the fatal malignant neoplasms worldwide. Neoadjuvant therapy (NAT) combined with surgery has become the standard treatment for locally advanced EC. However, the treatment efficacy for patients with EC who received NAT varies from patient to patient. Currently, the evaluation of efficacy after NAT for EC lacks accurate and uniform criteria. Radiomics is a multi-parameter quantitative approach for developing medical imaging in the era of precision medicine and has provided a novel view of medical images. As a non-invasive image analysis method, radiomics is an inevitable trend in NAT efficacy prediction and prognosis classification of EC by analyzing the high-throughput imaging features of lesions extracted from medical images. In this literature review, we discuss the definition and workflow of radiomics, the advances in efficacy prediction after NAT, and the current application of radiomics for predicting efficacy after NAT.

Bear bile powder attenuates senecionine-induced hepatic sinusoidal obstruction syndrome in mice.

Hepatic sinusoidal obstruction syndrome (HSOS) via exposure to pyrrolizidine alkaloids (PAs) is with high mortality and there is no effective treatment in clinics. Bear bile powder (BBP) is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis, inflammation, and fibrosis. Here, we aim to evaluate the protective effect of BBP against HSOS induced by senecionine, a highly hepatotoxic PA compound. Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently, which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells, alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells, as well as decreased conventional serum liver function indicators. In addition, BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts, two well-known markers positively associated with the severity of PA-induced HSOS. Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules. BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines, in which tauroursodeoxycholic acid played an important role. What's more, BBP treatment also decreased the accumulation of hydrophobic bile acids, such as cholic acid, taurocholic acid, glycocholic acid, as well. We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis, preventing liver fibrosis, and alleviating liver inflammation. Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.

The minimum number of examined lymph nodes for accurate nodal staging and optimal survival of stage T1-2 esophageal squamous cell carcinoma: A retrospective multicenter cohort with SEER database validation.

BACKGROUND: The extent of lymphadenectomy during esophagectomy remains controversial for patients with T1-2 ESCC. The aim of this study was to identify the minimum number of examined lymph node (ELN) for accurate nodal staging and overall survival (OS) of patients with T1-2 esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Patients with T1-2 ESCC from three institutes between January 2011 and December 2020 were retrospectively reviewed. The associations of ELN count with nodal migration and OS were evaluated using multivariable models, and visualized by using locally weighted scatterplot smoothing (LOWESS). Chow test was used to determine the structural breakpoints of ELN count. External validation in the SEER database was performed. RESULTS: In total, 1537 patients were included. Increased ELNs was associated with an increased likelihood of having positive nodal disease and incremental OS. The minimum numbers of ELNs for accurate nodal staging and optimal survival were 14 and 18 with validation in the SEER database (n = 519), respectively. The prognostic prediction ability of N stage was improved in the group with ≥14 ELNs compared with those with fewer ELNs (iAUC, 0.70 (95%CI 0.66-0.74) versus 0.61(95%CI 0.57-0.65)). The higher prognostic value was found for patients with ≥18 ELNs than those with <18 ELNs (iAUC, 0.78 (95%CI 0.74-0.82) versus 0.73 (95%CI 0.7-0.77)). CONCLUSION: The minimum numbers of ELNs for accurate nodal staging and optimal survival of stage T1-2 ESCC patients were 14 and 18, respectively.