Temporal Trends in Survival Outcomes for Patients with Esophageal Cancer Following Neoadjuvant Chemoradiotherapy: A 14-Year Analysis.

BACKGROUND: The prognosis for patients with esophageal cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery has shown improvement in recent years. We sought to identify the critical factors contributing to enhanced survival outcomes. PATIENTS AND METHODS: We retrospectively examined 427 patients with esophageal cancer treated with nCRT and esophagectomy across two periods: P1 (from 1 January 2004 to 31 December 2011) and P2 (from 1 January 2012 to 31 December 2017). The introduction of the CROSS regimen and total meso-esophagectomy in P2 prompted an evaluation of their effects on perioperative outcomes and overall survival (OS). RESULTS: During P2, the occurrence of recurrent laryngeal nerve palsy increased significantly from 3.9 to 16.8% (p < 0.001), while pneumonia and in-hospital mortality rates remained unchanged. The median OS improved from 19.2 to 29.2 months (p < 0.001) between P1 and P2. Multivariable analysis identified higher nodal yields and the achievement of major response as favorable prognostic factors. Conversely, an involved circumferential resection margin (CRM), an advanced ypN stage, and pneumonia were independently associated with poor outcomes. Patients treated during P2 had a lower prevalence of involved CRM (10% vs. 25.1%, p < 0.001), a higher rate of major response (52.7% vs. 34.8%, p < 0.01), and a greater nodal yield (27.8 vs. 10.9, p < 0.001). CONCLUSIONS: The clinical outcomes following nCRT and surgery have improved significantly over time. This progress can be attributed to multiple factors, with the primary drivers being the refinement of nCRT protocols and the application of radical surgery.

Utilizing a Dual Human Transporter MDCKII-MDR1-BCRP Cell Line to Assess Efflux at the Blood Brain Barrier.

To facilitate the design of drugs readily able to cross the blood brain barrier (BBB), a Madin-Darby canine kidney (MDCK) cell line was established that over expresses both P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), the main human efflux transporters of the BBB. Proteomics analyses indicate BCRP is expressed at a higher level than Pgp in this cell line. This cell line shows good activity for both transporters [BCRP substrate dantrolene efflux ratio (ER) 16.3 ± 0.9, Pgp substrate quinidine ER 27.5 ± 1.2], and use of selective transporter inhibitors enables an assessment of the relative contributions to overall ERs. The MDCKII-MDR1-BCRP ER negatively correlates with rat unbound brain/unbound plasma ratio, Kpuu Highly brain penetrant compounds with rat Kpuu ≥ 0.3 show ERs ≤ 2 in the MDCKII-MDR1-BCRP assay while compounds predominantly excluded from the brain, Kpuu ≤ 0.05, demonstrate ERs ≥ 20. A subset of compounds with MDCKII-MDR1-BCRP ER < 2 and rat Kpuu < 0.3 were shown to be substrates of rat Pgp using a rat transfected cell line, MDCKII-rMdr1a. These compounds also showed ERs > 2 in the human National Institutes of Health (NIH) MDCKI-MDR1 (high Pgp expression) cell line, which suggests that they are weak human Pgp substrates. Characterization of 37 drugs targeting the central nervous system in the MDCKII-MDR1-BCRP efflux assay show 36 have ERs < 2. In drug discovery, use of the MDCKII-MDR1-BCRP in parallel with the NIH MDCKI-MDR1 cell line is useful for identification of compounds with high brain penetration. SIGNIFICANCE STATEMENT: A single cell line that includes both the major human efflux transporters of the blood brain barrier (MDCKII-MDR1-BCRP) has been established facilitating the rapid identification of efflux substrates and enabling the design of brain penetrant molecules. Efflux ratios using this cell line demonstrate a clear relationship with brain penetration as defined by rat brain Kpuu.

Multi-terminal memtransistors from polycrystalline monolayer molybdenum disulfide.

Memristors are two-terminal passive circuit elements that have been developed for use in non-volatile resistive random-access memory and may also be useful in neuromorphic computing. Memristors have higher endurance and faster read/write times than flash memory and can provide multi-bit data storage. However, although two-terminal memristors have demonstrated capacity for basic neural functions, synapses in the human brain outnumber neurons by more than a thousandfold, which implies that multi-terminal memristors are needed to perform complex functions such as heterosynaptic plasticity. Previous attempts to move beyond two-terminal memristors, such as the three-terminal Widrow-Hoff memristor and field-effect transistors with nanoionic gates or floating gates, did not achieve memristive switching in the transistor. Here we report the experimental realization of a multi-terminal hybrid memristor and transistor (that is, a memtransistor) using polycrystalline monolayer molybdenum disulfide (MoS2) in a scalable fabrication process. The two-dimensional MoS2 memtransistors show gate tunability in individual resistance states by four orders of magnitude, as well as large switching ratios, high cycling endurance and long-term retention of states. In addition to conventional neural learning behaviour of long-term potentiation/depression, six-terminal MoS2 memtransistors have gate-tunable heterosynaptic functionality, which is not achievable using two-terminal memristors. For example, the conductance between a pair of floating electrodes (pre- and post-synaptic neurons) is varied by a factor of about ten by applying voltage pulses to modulatory terminals. In situ scanning probe microscopy, cryogenic charge transport measurements and device modelling reveal that the bias-induced motion of MoS2 defects drives resistive switching by dynamically varying Schottky barrier heights. Overall, the seamless integration of a memristor and transistor into one multi-terminal device could enable complex neuromorphic learning and the study of the physics of defect kinetics in two-dimensional materials.

Using unsupervised learning to classify inlet water for more stable design of water reuse in industrial parks.

The water reuse facilities of industrial parks face the challenge of managing a growing variety of wastewater sources as their inlet water. Typically, this clustering outcome is designed by engineers with extensive expertise. This paper presents an innovative application of unsupervised learning methods to classify inlet water in Chinese water reuse stations, aiming to reduce reliance on engineer experience. The concept of 'water quality distance' was incorporated into three unsupervised learning clustering algorithms (K-means, DBSCAN, and AGNES), which were validated through six case studies. Of the six cases, three were employed to illustrate the feasibility of the unsupervised learning clustering algorithm. The results indicated that the clustering algorithm exhibited greater stability and excellence compared to both artificial clustering and ChatGPT-based clustering. The remaining three cases were utilized to showcase the reliability of the three clustering algorithms. The findings revealed that the AGNES algorithm demonstrated superior potential application ability. The average purity in six cases of K-means, DBSCAN, and AGNES were 0.947, 0.852, and 0.955, respectively.

Preclinical and clinical activity of DZD1516, a full blood-brain barrier-penetrant, highly selective HER2 inhibitor.

BACKGROUND: Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable. METHODS: The design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care. RESULTS: DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease. CONCLUSIONS: DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID. CLINICALTRIALS: gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.

Colorectal Sessile Serrated Lesion Detection Using Linked Color Imaging: A Multicenter, Parallel Randomized Controlled Trial.

BACKGROUND & AIMS: Linked color imaging (LCI) is a novel technology that improves the color differences between colorectal lesions and the surrounding mucosa. The present study aims to compare the detection of colorectal sessile serrated lesions (SSL) using LCI with white light imaging (WLI). METHOD: A large-scale, multicenter, parallel prospective randomized controlled trial was conducted in 4 hospitals in China. The participants were randomly assigned to the LCI group and WLI group. The primary endpoint was the SSL detection rate (SDR). RESULTS: A total of 884 patients were involved in the intention-to-treat analysis, with 441 patients in the LCI group and 443 patients in the WLI group. The total polyp detection rate, adenoma detection rate, and SDR were 51.8%, 35.7%, and 8.6%, respectively. The SDR was significantly higher in the LCI group than in the WLI group (11.3% vs 5.9%, P = .004). Furthermore, LCI significantly increased the number of polyps and adenomas detected per patient, when compared with WLI (P < .05). In addition, there was higher detection rate of diminutive and flat lesions in the LCI group (P < .05). Multivariate analysis revealed that LCI is an independent factor associated with SDR (hazard ratio, 1.990; 95% confidence interval, 1.203-3.293; P = .007), along with withdrawal time (hazard ratio, 1.157; 95% confidence interval, 1.060-1.263; P = .001) and operator experience (hazard ratio, 1.850; 95% confidence interval, 1.045-3.273; P = .035). CONCLUSIONS: LCI is significantly superior to WLI for SSL detection, and may improve polyp and adenoma detection. LCI can be recommended as an appropriate method for routine inspection during colonoscopy (http://www.chictr.org.cn number, ChiCTR2000035705).

Colorectal sessile serrated lesion detection using linked-color imaging versus narrow-band imaging: a parallel randomized controlled trial.

BACKGROUND: Previous studies have reported the effectiveness of narrow-band imaging (NBI) and linked-color imaging (LCI) in improving the detection of colorectal neoplasms. There has however been no direct comparison between LCI and NBI in the detection of colorectal sessile serrated lesions (SSLs). The present study aimed to compare the effectiveness of LCI and NBI in detecting colorectal SSLs. METHODS: A prospective, parallel, randomized controlled trial was conducted. The participants were randomly assigned to the LCI or NBI arms. The primary end point was the SSL detection rate (SDR). RESULTS: 406 patients were involved; 204 in the LCI arm and 202 in the NBI arm. The total polyp detection rate, adenoma detection rate, and SDR were 54.2 %, 38.7 %, and 10.8%, respectively. The SDR was not significantly different between the LCI and NBI arms (12.3 % vs. 9.4 %; P = 0.36). The differences in the detection rate and the per-patient number of polyps, adenomas, diminutive lesions, and flat lesions between LCI and NBI also were not statistically significant. Multivariate analysis showed that LCI and NBI were not independent factors associated with SDR, whereas Boston Bowel Preparation Scale score (odds ratio [OR] 1.35, 95 %CI 1.03-1.76; P = 0.03), withdrawal time (OR 1.13, 95 %CI 1.00-1.26; P = 0.04), and operator experience (OR 3.73, 95 %CI 1.67-8.32; P = 0.001) were independent factors associated with SDR. CONCLUSIONS: LCI and NBI are comparable for SSL detection, as well as for the detection of polyps and adenomas.

Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study.

INTRODUCTION: Blood-brain barrier (BBB) remains to be the major obstacle to conquer in treating patients with malignant brain tumors. Radiation therapy (RT), despite being the mainstay adjuvant modality regardless of BBB, the effect of radiation induced cell death is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown not only to open BBB but also potentially increased regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). METHODS: We aimed to provide preclinical evidence of RT-FUS combination in GBM animal model, and to report an interim analysis of an ongoing single arm, prospective, pilot study (NCT01628406) of combining RT-FUS for recurrent malignant high grade glioma patients, of whom re-RT was considered for disease control. In both preclinical and clinical studies, FUS-BBB opening was conducted within 2 h before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression free survival, and overall survival, and adverse events (AE) in clinical study. Survival analysis was performed in preclinical study and descriptive analysis was performed in clinical study. RESULTS: In mouse GBM model, the survival analysis showed RT-FUS (2 Gy) group was significantly longer than RT (2 Gy) group and control, but not RT (5 Gy) group. In the pilot clinical trial, an interim analysis of six recurrent malignant high grade glioma patients underwent a total of 24 RT-FUS treatments was presented. Three patients had rapid disease progression at a mean of 33 days after RT-FUS, while another three patients had at least stable disease (mean 323 days) after RT-FUS with or without salvage chemotherapy or target therapy. One patient had partial response after RT-FUS, making the ORR of 16.7%. There was no FUS-related AEs, but one (16.7%) re-RT-related grade three radiation necrosis. CONCLUSION: Reirradiation is becoming an option after disease recurrence for both primary and secondary malignant brain tumors since systemic therapy significantly prolongs survival in cancer patients. The mechanism behind the synergistic effect of RT-FUS in preclinical model needs further study. The clinical evidence from the interim analysis of an ongoing clinical trial (NCT01628406) showed a combination of RT-FUS was safe (no FUS-related adverse effect). A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.

The effect and safety of probiotics on depression: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: With the escalating social pressures, there has been a continuous rise in the prevalence of depression among the population, leading to substantial healthcare burdens. Moreover, conventional pharmacological interventions still exhibit certain limitations. Therefore, the primary objective of this study is to systematically evaluate the clinical efficacy of probiotics in the treatment of depression. METHODS: Randomized controlled trials of probiotics in treating depressive symptoms were retrieved from Pubmed, Cochrane Library, Web of Science, Wan Fang database, and CNKI between the establishment of the database and March 2022. The primary outcome was Beck's depression rating scale (BDI) scores, while the secondary outcomes were depression scores on the DASS-21 scale, biochemical indicators (IL-6, NO, and TNF-α levels), and adverse events. In addition, Revman 5.3 was used for Meta-analysis and quality evaluation, and Stata 17 was used for the Egger test and Begg's test. A total of 776 patients, including 397 and 379 patients in the experimental and control groups, respectively, were included. RESULTS: The total BDI score of the experimental group was lower than that of the control group (MD = - 1.98, 95%CI - 3.14 to - 0.82), and the score of DASS (MD = 0.90, 95%CI - 1.17 to 2.98), the IL-6 level (SMD = - 0.55, 95%CI - 0.88 to - 0.23), the NO level (MD = 5.27, 95% CI 2.51 to 8.03), and the TNF-α level (SMD = 0.19, 95% CI - 0.25 to 0.63). CONCLUSION: The findings substantiate the therapeutic potential of probiotics in mitigating depressive symptoms by significantly reducing Beck's Depression Inventory (BDI) scores and alleviating the overall manifestation of depression.

A Comparative Study of Oncolytic Vaccinia Viruses Harboring Different Marine Lectins in Breast Cancer Cells.

Our previous studies demonstrated that arming vaccinia viruses with marine lectins enhanced the antitumor efficacy in several cancer cells. This study aims to compare the efficacy of oncolytic vaccinia viruses harboring Tachypleus tridentatus lectin (oncoVV-TTL), Aphrocallistes vastus lectin (oncoVV-AVL), white-spotted charr lectin (oncoVV-WCL), and Asterina pectinifera lectin (oncoVV-APL) in breast cancer cells (BC). These results indicated that oncoVV-AVL elicited the highest anti-tumor effect, followed by oncoVV-APL, while oncoVV-TTL and oncoVV-WCL had lower effects in BC. Further studies showed that apoptosis and replication may work together to enhance the cytotoxicity of oncoVV-lectins in a cell-type dependent manner. TTL/AVL/APL/WCL may mediate multiple pathways, including ERK, JNK, Hippo, and PI3K pathways, to promote oncoVV replication in MDA-MB-231 cells. In contrast, these pathways did not affect oncoVV-TTL/AVL/APL/WCL replication in MCF-7 cells, suggesting that the mechanisms of recombinant viruses in MCF-7 (ER+, PR+) and MDA-MB-231 (TNBC) cells were significantly different. Based on this study, we hypothesized that ER or PR may be responsible for the differences in promoting viral replication and inducing apoptosis between MCF-7 and MDA-MB-231 cells, but the specific mechanism needs to be further explored. In addition, small-molecule drugs targeting key cellular signaling pathways, including MAPK, PI3K/Akt, and Hippo, could be conjunction with oncoVV-AVL to promote breast cancer therapy, and key pathway factors in the JNK and PI3K pathways may be related to the efficacy of oncoVV-APL/TTL/WCL. This study provides a basis for applying oncolytic vaccinia virus in breast carcinoma.

A Classification Method of Point Clouds of Transmission Line Corridor Based on Improved Random Forest and Multi-Scale Features.

Classification of airborne laser scanning (ALS) point clouds of power lines is of great importance to their reconstruction. However, it is still a difficult task to efficiently and accurately classify the ground, vegetation, power lines and power pylons from ALS point clouds. Therefore, in this paper, a method is proposed to improve the accuracy and efficiency of the classification of point clouds of transmission lines, which is based on improved Random Forest and multi-scale features. The point clouds are filtered by the optimized progressive TIN densification filtering algorithm, then the elevations of the filtered point cloud are normalized. The features of the point cloud at different scales are calculated according to the basic features of the point cloud and the characteristics of transmission lines. The Relief F and Sequential Backward Selection algorithm are used to select the best subset of features to estimate the parameters of the learning model, then an Improved Random Forest classification model is built to classify the point clouds. The proposed method is verified by using three different samples from the study area and the results show that, compared with the methods based on Support Vector Machines, AdaBoost or Random Forest, our method can reduce feature redundancy and has higher classification accuracy and efficiency.

Effects of Oncolytic Vaccinia Viruses Harboring Different Marine Lectins on Hepatocellular Carcinoma Cells.

Oncolytic viruses are being developed as novel strategies for cancer therapy. Our previous studies have shown that vaccinia viruses armed with marine lectins improved the antitumor efficacy in diverse cancer types. The objective of this study was to assess the cytotoxic effects of oncoVV harboring Tachypleus tridentatus lectin (oncoVV-TTL), Aphrocallistes vastus lectin (oncoVV-AVL), white-spotted charr lectin (oncoVV-WCL), and Asterina pectinifera lectin (oncoVV-APL) on HCC. Our data revealed that the effects of recombinant viruses on Hep-3B cells were oncoVV-AVL > oncoVV-APL > oncoVV-TTL > oncoVV-WCL; oncoVV-AVL showed stronger cytotoxicity than oncoVV-APL, while oncoVV-TTL/WCL had no effect on cell killing in Huh7 cells, and PLC/PRF/5 cells exhibited sensitivity to oncoVV-AVL/TTL but not to oncoVV-APL/WCL. The cytotoxicity of oncoVV-lectins could be enhanced by apoptosis and replication in a cell-type-dependent manner. Further research revealed that AVL may mediate various pathways, including MAPK, Hippo, PI3K, lipid metabolism, and androgen pathways through AMPK crosstalk, to promote oncoVV replication in HCC in a cell-dependent manner. OncoVV-APL replication could be affected by AMPK/Hippo/lipid metabolism pathways in Hep-3B cells, AMPK/Hippo/PI3K/androgen pathways in Huh7 cells, and AMPK/Hippo pathways in PLC/PRF/5 cells. OncoVV-WCL replication was also multi-mechanistic, which could be affected by AMPK/JNK/lipid metabolism pathways in Hep-3B cells, AMPK/Hippo/androgen pathways in Huh7 cells, and AMPK/JNK/Hippo pathways in PLC/PRF/5 cells. In addition, AMPK and lipid metabolism pathways may play critical roles in oncoVV-TTL replication in Hep-3B cells, and oncoVV-TTL replication in Huh7 cells may depend on AMPK/PI3K/androgen pathways. This study provides evidence for the application of oncolytic vaccinia viruses in hepatocellular carcinoma.

Circ_0000854 regulates the progression of hepatocellular carcinoma through miR-1294 /IRGQ axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer disease with the second highest mortality. Circular RNAs (circRNAs) have been shown to play key roles in many tumors, including HCC. However, the function of circ_0000854 in the progression of HCC has not been clarified. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of circ_0000854, microRNA-1294 (miR-1294) and immunity related GTPase Q (IRGQ) in HCC cells and tissues. Western blot was used for protein expression analysis. Cell processes were detected by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium Bromide (MTT) assay, thymidine analog 5-ethynyl-2'-deoxyuridine (EdU) assay, transwell assay, flow cytometry, and wound healing assay. Mechanically, the interaction of miR-1294 with circ_0000854 or IRGQ was notarized by dual-luciferase reporter assay and RNA pull-down assay. The xenotransplantation model was established to study the role of circ_0000854 in vivo. RESULTS: Circ_0000854 and IRGQ were highly expressed in HCC tissues and cells, while miR-1294 was downregulated. Silencing circ_0000854 suppressed HCC cell malignant behaviors, including proliferation, cell cycle progression, migration and invasion. Circ_0000854 exhibited sponge effect on miR-1294 and miR-1294 inhibition reversed function of circ_0000854 knockdown. In addition, miR-1294 targeted IRGQ and circ_0000854 sponged miR-1294 to upregulate IRGQ. Overexpression of IRGQ restored miR-1294-induced anti-tumor regulation in HCC cells. Animal experiments confirmed that silencing circ_0000854 inhibited tumor growth and metastasis of HCC via mediating miR-1294 and IRGQ levels in vivo. CONCLUSION: Circ_0000854 accelerated HCC progression via the miR-1294/IRGQ axis, providing a novel regulatory mechanism for HCC pathogenesis.

Dephosphorylation of the RNA sensors RIG-I and MDA5 by the phosphatase PP1 is essential for innate immune signaling.

RIG-I and MDA5 have emerged as key cytosolic sensors for the detection of RNA viruses and lead to antiviral interferon (IFN) production. Recent studies have highlighted the importance of posttranslational modifications for controlling RIG-I antiviral activity. However, the regulation of MDA5 signal-transducing ability remains unclear. Here, we show that MDA5 signaling activity is regulated by a dynamic balance between phosphorylation and dephosphorylation of its caspase recruitment domains (CARDs). Employing a phosphatome RNAi screen, we identified PP1α and PP1γ as the primary phosphatases that are responsible for MDA5 and RIG-I dephosphorylation and that lead to their activation. Silencing of PP1α and PP1γ enhanced RIG-I and MDA5 CARD phosphorylation and reduced antiviral IFN-ß production. PP1α- and PP1γ-depleted cells were impaired in their ability to induce IFN-stimulated gene expression, which resulted in enhanced RNA virus replication. This work identifies PP1α and PP1γ as regulators of antiviral innate immune responses to various RNA viruses, including influenza virus, paramyxovirus, dengue virus, and picornavirus.

Cordycepin Protects against Hepatic Ischemia/Reperfusion Injury via Inhibiting MAPK/NF-κB Pathway.

Hepatic ischemia/reperfusion injury (HIRI) is a common complication of liver surgery requiring hepatic disconnection, such as hepatectomy and liver transplantation. The aim of this study was to investigate the effects of cordycepin on HIRI and to elucidate the underlying mechanisms. Balb/c mice were randomly divided into six groups: a normal control group, sham group, H-cordycepin group, HIRI group, L-cordycepin (25 mg/kg) + HIRI group, and H-cordycepin (50 mg/kg) + HIRI group. Mice were subjected to I/R, and cordycepin was intragastrically administered for seven consecutive days before surgery. Orbital blood and liver specimens were collected at 6 and 24 h after HIRI. Serum levels of ALT and AST were decreased in the cordycepin pretreatment groups. Notably, cordycepin attenuated the inflammatory response and the production of proapoptosis proteins, while increasing expression of antiapoptosis proteins and decreasing expression of autophagy-linked proteins. Furthermore, cordycepin inhibited activation of the MAPK/NF-κB signaling pathway. Collectively, these results indicate that cordycepin pretreatment ameliorated hepatocyte injury caused by HIRI. As compared with the HIRI group, cordycepin pretreatment mitigated the inflammatory response and inhibited apoptosis and autophagy via regulation of the MAPK/NF-κB signaling pathway.

Inosine monophosphate dehydrogenase type1 sustains tumor growth in hepatocellular carcinoma.

BACKGROUND: Inosine monophosphate dehydrogenase (IMPDH) is the key enzyme in the biosynthesis of purine nucleotides. IMPDH1 and IMPDH2 are the two isoforms of IMPDH and they share 84% amino acid similarity and virtually indistinguishable catalytic activity. Although high expression of IMPDH2 has been reported in various cancers, the roles of IMPDH1 in hepatocellular carcinoma (HCC) are largely unknown. METHODS: The expression and the clinical relevance of IMPDH1 in 154 HCC patients were detected by immunohistochemistry analysis. The stable IMPDH1 knockdown HuH7 cells were established by lentiviral RNAi approach. The single cell proliferation was detected by colony-forming unit assay. The tumor initiation and growth ability were measured by using xenograft tumor model in immunodeficient mice. The effect of IMPDH1 on cellular signaling pathways was analyzed by genome-wide transcriptomic profiling. RESULTS: The expression of IMPDH1 is upregulated in tumor tissue compared with adjacent liver tissue, and higher expression of IMPDH1 is associated with better patient cumulative survival. In experimental models, loss of IMPDH1 in HCC cells inhibits the ability of single cell colony formation in vitro, and reduces the efficiency of tumor initiation and growth in immunodeficient mice. Consistently, loss of IMPDH1 results in distinct alterations of signaling pathways revealed by genome-wide transcriptomic profiling. CONCLUSION: IMPDH1 sustains HCC growth and progression.

Oncolytic Vaccinia Virus Harboring Aphrocallistes vastus Lectin Inhibits the Growth of Hepatocellular Carcinoma Cells.

Oncolytic vaccinia virus has been developed as a novel cancer therapeutic drug in recent years. Our previous studies demonstrated that the antitumor effect of oncolytic vaccina virus harboring Aphrocallistes vastus lectin (oncoVV-AVL) was significantly enhanced in several cancer cells. In the present study, we investigated the underlying mechanisms of AVL that affect virus replication and promote the antitumor efficacy of oncolytic virus in hepatocellular carcinoma (HCC). Our results showed that oncoVV-AVL markedly exhibited antitumor effects in both hepatocellular carcinoma cell lines and a xenograft mouse model. Further investigation illustrated that oncoVV-AVL could activate tumor immunity by upregulating the expression of type I interferons and enhance virus replication by inhibiting ISRE mediated viral defense response. In addition, we inferred that AVL promoted the ability of virus replication by regulating the PI3K/Akt, MAPK/ERK, and Hippo/MST pathways through cross-talk Raf-1, as well as metabolism-related pathways. These findings provide a novel perspective for the exploitation of marine lectins in oncolytic therapy.

Oncolytic Vaccinia Virus Carrying Aphrocallistes vastus Lectin (oncoVV-AVL) Enhances Inflammatory Response in Hepatocellular Carcinoma Cells.

Aphrocallistes vastus lectin (AVL) is a C-type marine lectin derived from sponges. Our previous study demonstrated that oncolytic vaccinia virus carrying AVL (oncoVV-AVL) significantly enhanced the cytotoxicity of oncoVV in cervical cancer, colorectal cancer and hepatocellular carcinoma through the activation of Ras/ERK, MAPK/ERK and PI3K/Akt signaling pathways. In this study, the inflammatory response induced by oncoVV-AVL in a hepatocellular carcinoma cell (HCC) model was investigated. The results showed that oncoVV-AVL increased the levels of inflammatory cytokines including IL-6, IL-8 and TNF-α through activating the AP-1 signaling pathway in HCC. This study provides novel insights into the utilization of lectin AVL in the field of cancer therapy.

Amelioration of Hepatic Steatosis by the Androgen Receptor Inhibitor EPI-001 in Mice and Human Hepatic Cells Is Associated with the Inhibition of CYP2E1.

Nonalcoholic fatty liver disease (NAFLD) is recognized as a metabolic disease characterized by hepatic steatosis. Despite the growing burden of NAFLD, approved pharmacological treatment is lacking. As an inhibitor of androgen receptor (AR), EPI-001 is being explored for the treatment of prostate cancer. This study aimed to investigate the potential of EPI-001 for treating NAFLD in free fatty acids (FFAs)-induced human hepatic cells and high-fat-high-sugar (HFHS)-feeding mice. Our results showed that EPI-001 reduced lipid accumulation in hepatic cells and ameliorated hepatic steatosis in mouse livers. Further exploration suggested that the effect of EPI-001 was associated with CYP2E1-mediated reduction of reactive oxygen species (ROS). This provides encouraging evidence for further studies on EPI-001 therapy for NAFLD.

Effect of lgals3a on embryo development of zebrafish.

Our study was aimed to investigate the effects of lgals3a (Gal-3 encoding gene) on the development of zebrafish embryo and its underlying mechanisms. Morpholino (MO) technology was used to inhibit the expression of zebrafish lgals3a, and the effect of lgals3a gene knockdown on zebrafish embryo development and the number of monocyte macrophages was observed. Effect of lgals3a-e3i3-MO on apoptosis of zebrafish was detected by acridine orange staining. In addition, the mRNA expression levels of Wnt/ß-catenin signaling pathway-related genes were detected by RT-qPCR. Compared with control-MO group, the zebrafish embryos injected with lgals3a-e3i3-MO had obvious defects in the head, eyes, and tail, and pericardial edema. Lgals3a-e3i3-MO significantly reduced the number of mononuclear macrophages in zebrafish embryos compared with the control-MO group. The results of acridine orange staining showed that compared with the control-MO group, lgals3a-e3i3-MO promoted cardiomyocyte apoptosis in zebrafish. Furthermore, lgals3a-e3i3-MO significantly up-regulated the expression of dkk1b, wnt9a, lrp5, fzd7a, ß-catenin, Gsk-3ß, mycn, myca in the Wnt/ß-catenin pathway, and decreased the expression of lef1. These results indicate that lgals3a-e3i3-MO inhibits zebrafish embryo development, reduces the number of mononuclear macrophages, activates Wnt/ß-catenin signaling pathway and promotes cardiomyocyte apoptosis.