SMIFormer: Learning Spatial Feature Representation for 3D Object Detection from 4D Imaging Radar via Multi-View Interactive Transformers.

4D millimeter wave (mmWave) imaging radar is a new type of vehicle sensor technology that is critical to autonomous driving systems due to its lower cost and robustness in complex weather. However, the sparseness and noise of point clouds are still the main problems restricting the practical application of 4D imaging radar. In this paper, we introduce SMIFormer, a multi-view feature fusion network framework based on 4D radar single-modal input. SMIFormer decouples the 3D point cloud scene into 3 independent but interrelated perspectives, including bird's-eye view (BEV), front view (FV), and side view (SV), thereby better modeling the entire 3D scene and overcoming the shortcomings of insufficient feature representation capabilities under single-view built from extremely sparse point clouds. For multi-view features, we proposed multi-view feature interaction (MVI) to exploit the inner relationship between different views by integrating features from intra-view interaction and cross-view interaction. We evaluated the proposed SMIFormer on the View-of-Delft (VoD) dataset. The mAP of our method reached 48.77 and 71.13 in the fully annotated area and the driving corridor area, respectively. This shows that 4D radar has great development potential in the field of 3D object detection.

Effects of Danhong injection, a traditional Chinese medicine, on nine cytochrome P450 isoforms in vitro.

Danhong injection (DHI) is made from Salvia miltiorrhiza Bunge. and Carthamus tinctorius L. extract and is widely used in the clinical treatment of cardiovascular and cerebrovascular diseases. This study aimed to evaluate the effect of DHI on cytochrome P450 (CYP450) enzymes in vitro to predict drug-drug interactions based on CYP450 as combination therapy. To assess the inhibitory effect of DHI on CYP450, we detected the IC50 value of DHI on CYP450 in vitro by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Simultaneously, the induction effect of DHI on CYP450s was also evaluated. The relative induction ratios of DHI on CYP1A2, CYP2B6 and CYP3A4 activity were calculated by LC-MS/MS. The expression level of CYP3A4 mRNA was determined by reverse transcription PCR (RT-PCR). The LC-MS/MS data showed DHI intensively inhibit CYP2A6 activity and the intensity of inhibition was followed by CYP2C8, CYP3A4, CYP2C19, CYP2B6, CYP2D6, CYP1A2, CYP2E1 and CYP2C9 in vitro. The results of RT-PCR showed that there is a certain induction of DHI on CYP3A4 mRNA in human primary hepatocytes in vitro. The study suggested that drug-drug interactions might occur in clinical co-administration of drugs owing to the CYP2A6 inhibition and CYP3A4 induction.

Preclinical evaluation of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys.

The mono-PEGylated recombinant human interleukin-11 (rhIL-11) was evaluated for its pharmacology and toxicology profile in non-human primates. This PEGylated IL-11 (PEG-IL11) showed a much prolonged circulating half-life of 67h in cynomolgus monkeys as compared to its un-PEGylated counterpart (~3h) through subcutaneous administration, implicating that a single injection of the recommended dose will effectively enhance thrombopoiesis in humans for a much longer period of time compared to rhIL-11 in humans (t1/2=6.9h). The toxicokinetics study of single dose and multiple doses showed that systemic exposure was positively correlated with the dosing level, implying that efficacy and toxicity were mechanism-based. A single high dose at 6.25mg/kg through subcutaneous route revealed tolerable and transient toxicity. Multiple-dose in monkeys receiving 0.3mg/kg weekly of the drug developed only mild to moderate toxicity. Major adverse events and immunogenicity in monkeys were only observed in the overdose groups. Bones were positively impacted; while reversible toxicities in heart, liver, kidney and lung observed were likely to be consequences of fluid retention. In summary, the PEG moiety on rhIL-11 did not elicit additional toxicities, and the drug under investigation was found to be well tolerated in monkeys after receiving a single effective dose of 0.1-0.3mg/kg through subcutaneous delivery, which may be allometrically scaled to a future clinical dose at 30-100µg/kg, creating a potential long acting, safer, and more convenient treatment approach based on rhIL-11.

Effects of diosmetin on nine cytochrome P450 isoforms, UGTs and three drug transporters in vitro.

Diosmetin (3', 5, 7-trihydroxy-4'-methoxyflavone), a natural flavonoid from traditional Chinese herbs, has been used in various medicinal products because of its anticancer, antimicrobial, antioxidant, estrogenic and anti-inflammatory activity. However, flavonoids could affect the metabolic enzymes and cause drug-drug interactions (DDI), reducing the efficacy of co-administered drugs and potentially resulting in serious adverse reactions. To evaluate its potential to interact with co-administered drugs, the IC50 value of phase I cytochrome P450 enzymes (CYPs), phase II UDP-glucuronyltransferases (UGTs) and hepatic uptake transporters (organic cation transporters (OCTs), organic anion transporter polypeptides (OATPs) and Na+-taurocholate cotransporting polypeptides (NTCPs)) were examined in vitro by LC-MS/MS. Diosmetin showed strong inhibition of CYP1A2 in a concentration-dependent manner. The intensity of the inhibitory effect was followed by CYP2C8, CYP2C9, CYP2C19 and CYP2E1. For CYP2A6, CYP2B6, CYP2D6 and CYP3A4, diosmetin was found to have no significant inhibitory effects, and the induction effect on CYPs was not significant. For UGTs, diosmetin had a minimal inhibitory effect. In addition, the inhibitory effects of diosmetin on OATP and OCT1 were weak, and it had little effect on NTCP. This finding indicated that drug-drug interactions induced by diosmetin may occur through co-administration of drugs metabolized by CYP1A2.

Detoxification of benzo[a]pyrene primarily depends on cytochrome P450, while bioactivation involves additional oxidoreductases including 5-lipoxygenase, cyclooxygenase, and aldo-keto reductase in the liver.

Cytochrome P450s are involved in detoxification and activation of benzo[a]pyrene (BaP) with unclear balance and unknown contribution of other oxidoreductases. Here, we investigated the BaP and BaP-induced mutagenicity in hepatic and extra-hepatic tissues using hepatic P450 reductase null (HRN) gpt mice. After 2-week treatment (50 mg/kg, i.p. 4 days), BaP in the liver and lung of HRN-gpt mice were increased. BaP promoted gpt mutant frequency (MF) in HRN-gpt mice liver. MF of gpt in the lung and Pig-a in hematopoietic cells induced by BaP in HRN-gpt mice were increased than in gpt mice. BaP-7,8-diol-9,10-epoxide (BPDE)-DNA adducts in vitro was analyzed for enzymes detection in BaP bioactivation. Specific inhibitors of 5-lipoxygenase, cyclooxygenase-1&2, and aldo-keto reductase resulted in more than 80% inhibition rate in the DNA adduct formation, further confirmed by Macaca fascicularis hepatic S9 system. Our results suggested the detoxification of BaP primarily depends on cytochrome P450, while the bioactivation involves additional oxidoreductases.

An improved substrate cocktail for assessing direct inhibition and time-dependent inhibition of multiple cytochrome P450s.

AIM: The substrate cocktail is frequently used to evaluate cytochrome P450 (CYP) enzyme-mediated drug interactions and potential interactions among the probe substrates. Here, we re-optimized the substrate cocktail method to increase the reliability and accuracy of screening for candidate compounds and expanded the method from a direct CYP inhibition assay to a time-dependent inhibition (TDI) assay. METHODS: In the reaction mixtures containing human liver microsome (0.1 mg/mL), both the concentrations of a substrate cocktail (phenacetin for 1A2, coumarin for 2A6, bupropion for 2B6, diclofenac for 2C9, dextromethorphan for 2D6, and testosterone for 3A4) and the incubation time were optimized. Metabolites of the substrate probes were simultaneously analyzed by multiple-reaction monitoring (MRM) using a routine LC/MS/MS. Direct CYP inhibition was validated using 7 inhibitors (α-naphthoflavone, tranylcypromine, ticlopidine, fluconazole, quinidine, ketoconazole and 1-ABT). The time-dependent inhibition was partially validated with 5 inhibitors (ketoconazole, verapamil, quinidine, paroxetine and 1-ABT). RESULTS: The inhibition curve profiles and IC50 values of 7 CYP inhibitors were approximate when a single substrate and the substrate cocktail were tested, and were consistent with the previously reported values. Similar results were obtained in the IC50 shifts of 5 inhibitors when a single substrate and the substrate cocktail were tested in the TDI assay. CONCLUSION: The 6-in-1 substrate cocktail (for 1A2, 2A6, 2B6, 2C9, 2D6 and 3A) is reliable for assessing CYP inhibition and time-dependent inhibition of drug candidates.

Early gastric cancer detection and lesion segmentation based on deep learning and gastroscopic images.

Gastric cancer is a highly prevalent disease that poses a serious threat to public health. In clinical practice, gastroscopy is frequently used by medical practitioners to screen for gastric cancer. However, the symptoms of gastric cancer at different stages of advancement vary significantly, particularly in the case of early gastric cancer (EGC). The manifestations of EGC are often indistinct, leading to a detection rate of less than 10%. In recent years, researchers have focused on leveraging deep learning algorithms to assist medical professionals in detecting EGC and thereby improve detection rates. To enhance the ability of deep learning to detect EGC and segment lesions in gastroscopic images, an Improved Mask R-CNN (IMR-CNN) model was proposed. This model incorporates a "Bi-directional feature extraction and fusion module" and a "Purification module for feature channel and space" based on the Mask R-CNN (MR-CNN). Our study includes a dataset of 1120 images of EGC for training and validation of the models. The experimental results indicate that the IMR-CNN model outperforms the original MR-CNN model, with Precision, Recall, Accuracy, Specificity and F1-Score values of 92.9%, 95.3%, 93.9%, 92.5% and 94.1%, respectively. Therefore, our proposed IMR-CNN model has superior detection and lesion segmentation capabilities and can effectively aid doctors in diagnosing EGC from gastroscopic images.

Matrix stiffness-mediated effects on macrophages polarization and their LOXL2 expression.

Previously, we reported that the secreted lysyl oxidase like 2 (LOXL2) from hepatocellular carcinoma (HCC) cells under higher stiffness stimulation contributed to the formation of lung premetastatic niche. To further clarify whether matrix stiffness also alters LOXL2 expression in other cells within tumor microenvironment, we developed a gel-based culture system combined with a model of macrophage polarization to evaluate the effects of matrix stiffness on the polarization of M2 macrophages and their LOXL2 expression. THP-1 cells cultured on 6KPa, 10KPa, and 16KPa stiffness substrates were first incubated with 100nM phorbol 12-myristate 13-acetate (PMA) for 24 hours and subsequently treated with 20nM interleukin-4 (IL-4) and 20nM interleukin-13 (IL-13) for 48 hours. The polarization states of M2 macrophages under different stiffness stimulation were comparatively analyzed, and their LOXL2 expressions as well as the underlying molecular mechanism were further explored. Our results demonstrated that increased matrix stiffness remarkably strengthened M2 macrophage polarization and promoted their LOXL2 expression. Activation of integrin ß5-FAK-MEK1/2-ERK1/2 pathway participated in matrix stiffness-mediated HIF-1α upregulation, and HIF-1α upregulation resulted in a significant improvement in LOXL2 expression. Additionally, M2 macrophage polarization state and LOXL2 expression in HCC tissues with COL1High /LOXHigh were consistent with the results in vitro, further confirming the regulation roles of matrix stiffness in macrophage polarization and LOXL2 expression. The findings about LOXL2 upregulation in the polarized macrophages under higher stiffness stimulation will be helpful to better understand the underlying mechanism of matrix stiffness-induced premetastatic niche formation in HCC.

The pathological significance of LOXL2 in pre-metastatic niche formation of HCC and its related molecular mechanism.

OBJECTIVE: The mechanisms underlying the contribution of primary tumour to pre-metastatic niche formation remains largely unknown in hepatocellular carcinoma (HCC). We previously reported that the released LOXL2 from HCC cells under higher stiffness stimulation facilitated the formation of lung pre-metastatic niche. Here, we further clarified the pathological role of LOXL2 in promoting lung pre-metastatic niche formation and lung metastasis occurrence in HCC and its relevant molecular mechanism. METHODS: Using two different animal models and an in vitro system of mechanically tuneable gel mirroring lung tissue stiffness, we explored the underlying mechanism of LOXL2 in pre-metastatic niche formation. RESULTS: We applied tail vein injection of CM-LV-LOXL2-OEsimulating tumour-released soluble factors to induce lung pre-metastatic niche formation and found that the injected LOXL2 remarkably enhanced CD11b+/CD45+ bone marrow-derived cells (BMDCs) recruitment and fibronectin expression in lung. Subsequently, LOXL2-overexpressed xenograft HCC models validated that tumour-secreted LOXL2 significantly promoted the occurrence of pulmonary metastasis. In vitro, LOXL2 and LOXL2-caused matrix stiffening not only obviously upregulated the expressions of MMP9 and fibronectin in lung fibroblasts, but also evidently increased the number of adherent HCC cells and the expression of chemokine CXCL12. The activation of PI3K-AKT pathway mediated LOXL2-upregulated fibronectin. HCC patients in High-LOXL2 group had higher ratio of tumour recurrence than HCC patients in Low-LOXL2 group, supporting a significance of LOXL2 in HCC progression and unfavourable outcome. CONCLUSION: Primary tumour-released LOXL2 promotes lung pre-metastatic niche formation and lung metastasis occurrence. LOXL2-caused matrix stiffening synergistically regulates lung pre-metastatic niche formation. Targeting LOXL2-induced lung pre-metastatic niche may be a novel intervention approach against HCC metastasis.

Association of ABCB1 C3435T Polymorphism with Echocardiographic Index Among Patients with Atherosclerotic Ischemic Stroke and Transient Ischemic Attack.

Emerging evidence has suggested that patients with ischemic stroke (IS) and/or transient ischemic attack (TIA) are more likely to exhibit myocardial disorders, which can be reflected by transthoracic echocardiography (TTE). ATP binding cassette transporter 1 (ABCB1) plays an important role in the development and progression of atherosclerotic pathology. The objective of the current study was to investigate the associations of ABCB1 C3435T polymorphism with echocardiographic performances among patients with acute ischemic stroke. Patients with IS or TIA, who were hospitalized and received TTE between October 2016 to March 2019, were enrolled in this study. Demographic data and echocardiographic parameters of each participant were recorded. We included 122 patients, with the respective distribution of 12.30%, 48.36%, and 39.34% in CC, CT, and TT genotypes. There were significant differences among the three ABCB1 types, with respect to RV (P = 0.036). The presence of the TT genotype was associated with increased MVE (OR = 0.13, P = 0.02) but correlated with decreased RV (OR = -1.46, P = 0.02). Our study indicated that ABCB1 C3435T polymorphism is associated with echocardiographic parameters among patients with acute ischemic stroke. The presence of the TT genotype is associated with diastolic function and cardiac hypertrophy.

Immunogenicity and toxicokinetics assessment of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys.

AIM: Protein therapeutics have potential to elicit immune responses resulting in undesirable anti-drug antibodies (ADA) that might affect product efficacy and patient safety, and should be assessed in animals before applying the treatment to humans. In this paper, we aim to assess the immunogenicity and toxicokinetics of the mono-PEGylated recombinant human interleukin-11 (rhIL-11), a novel protein therapeutic for the treatment of chemotherapy-induced thrombocytopenia, in repeated administration to cynomolgus monkeys. MAIN METHODS: Enzyme-linked immunosorbent assay (ELISA) methods were developed to measure ADA responses and plasma PEGylated IL-11 (PEG-IL11) concentration in monkeys. Assay parameters of immunogenicity and toxicokinetics methods were evaluated during validation in accordance with regulatory guidelines. We also employed cell-based assays to test the neutralizing activity of ADA provoked in monkeys. KEY FINDINGS: The results showed that weak immunogenicity occurred in some monkeys after receiving repeated dose of 0.1-0.3 mg/kg by subcutaneous administration and disappeared after the recovery period. More pronounced immunogenicity occurred at high dose of 0.9 mg/kg, with a higher positive rate and titer, and some ADAs had neutralizing activity, but it can be greatly reduced after recovery. Such ADAs generated in monkeys may be accounted for the plasma toxicokinetics changes of PEG-IL11 and a minor reduction in systemic exposure. SIGNIFICANCE: These methods have been successfully applied to immunogenicity and toxicokinetic studies of PEG-IL11 in repeated dose toxicity following subcutaneous administration to monkeys, and could be successfully used in clinical trials after some modifications.

Senescent hepatocyte secretion of matrix metalloproteinases is regulated by nuclear factor-κB signaling.

AIMS: Cellular senescence and matrix metalloproteinases (MMPs) play an important role in liver diseases. The source and regulating factors of MMPs in senescent hepatocytes are not known. We investigated whether senescent hepatocytes secreted MMPs and if this was regulated by nuclear factor (NF)-κB. MATERIALS AND METHODS: The TGF-α transgenic mouse hepatocyte line AML12 was treated with H2O2 to induce senescence. NF-κB signaling was examined by Western blotting and luciferase reporter assays. Quantitative reverse transcription polymerase chain reaction was used to evaluated expression of MMP-2, -9 and -13. KEY FINDINGS: AML12 cells treated with H2O2 showed the characteristic morphology of senescence. The activity of NF-κB and expression of MMP-2, -9 and -13 were increased in senescent AML12 cells. The NF-κB inhibitor BAY 11-7082 decreased the levels of MMPs. SIGNIFICANCE: These results suggest that senescent hepatocytes are involved in the pathology of liver diseases through remodeling the extracellular matrix.

Colony-Stimulating Factor 1 Receptor Blockade Inhibits Tumor Growth by Altering the Polarization of Tumor-Associated Macrophages in Hepatocellular Carcinoma.

Colony-stimulating factor-1 (CSF-1) and its receptor, CSF-1R, regulate the differentiation and function of macrophages and play an important role in macrophage infiltration in the context of hepatocellular carcinoma. The therapeutic effects of CSF-1R blockade in hepatocellular carcinoma remain unclear. In this study, we found that CSF-1R blockade by PLX3397, a competitive inhibitor with high specificity for CSF-1R tyrosine kinase, significantly delayed tumor growth in mouse models. PLX3397 inhibited the proliferation of macrophages in vitro, but intratumoral macrophage infiltration was not decreased by PLX3397 in vivo Gene expression profiling of tumor-associated macrophages (TAM) showed that TAMs from the PLX3397-treated tumors were polarized toward an M1-like phenotype compared with those from vehicle-treated tumors. In addition, PLX3397 treatment increased CD8+ T-cell infiltration, whereas CD4+ T-cell infiltration was decreased. Further study revealed that tumor cell-derived CSF-2 protected TAMs from being depleted by PLX3397. In conclusion, CSF-1R blockade delayed tumor growth by shifting the polarization rather than the depletion of TAMs. CSF-1R blockade warrants further investigation in the treatment of hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1544-54. ©2017 AACR.

Overexpression of platelet-derived growth factor receptor alpha in endothelial cells of hepatocellular carcinoma associated with high metastatic potential.

PURPOSE: Little information is available on the heterogeneity of the vascular endothelium in hepatocellular carcinoma. The aim of this study was to identify the differentially expressed genes in tumor endothelial cells from highly metastatic hepatocellular carcinoma. EXPERIMENTAL DESIGN: Magnetic beads conjugated with anti-CD31 antibody were used to isolate vascular endothelial cells from hepatocellular carcinoma xenografts with different metastatic potentials in nude mice. Gene expression profiles for different endothelial cells were compared by use of cDNA microarray. The up-regulated gene was confirmed by reverse transcription-PCR, real-time PCR, and immunohistochemistry. RESULTS: cDNA microarray analysis revealed differential expression patterns in seven genes consistently presented in endothelial cells isolated from hepatocellular carcinoma with different metastatic potentials. Overexpression of platelet-derived growth factor receptor alpha was found only in the endothelium of highly metastatic hepatocellular carcinoma, which was confirmed by reverse transcription-PCR, real-time PCR, and immunohistochemistry. Oral administration of STI571 (imatinib mesylate or Glivec), a protein tyrosine kinase inhibitor of platelet-derived growth factor receptor, combined with s.c. injection of IFN-alpha not only effectively reduced tumor weight (by 81.8%) and microvessel density (by 70.2%) but also inhibited lung metastasis (by 100%). Furthermore, immunohistochemical analysis of platelet-derived growth factor receptor alpha in human hepatocellular carcinoma tissues revealed its correlation with postoperative recurrence, especially in patients without microvessel invasion. CONCLUSIONS: The gene expression of hepatocellular carcinoma vascular endothelium is different between tumors with different metastatic potential. Platelet-derived growth factor receptor alpha, which is overexpressed in endothelium of highly metastatic hepatocellular carcinoma, may serve as a biomarker for predicting metastasis and a therapeutic target for highly metastatic hepatocellular carcinoma.

[SNP767A/T of FUS2 gene and lung cancer risk in Chinese population].

BACKGROUND: FUS2 gene locating at 3p21.3 is considered a promising candidate tumor suppressor gene. The aim of this study is to examine the difference in FUS2-767A/T polymorphism site between lung cancer patients and normal controls in Chinese population. METHODS: The genotype FUS2-767A/T was detected in 146 lung cancer patients and 113 normal controls by PCR-SSCP method. The relationship between lung cancer risk and difference in genotypes of FUS2 gene was analysed. RESULTS: FUS2-767A/T was significantly related to histological type (P=0.044), age of the patients with lung cancer (P=0.011) and vessel cancer embolus (P=0.031) in lung cancer group. There was no significant difference in distribution of FUS2 genotypes between lung cancer patients and normal controls (P=0.945). CONCLUSIONS: The results suggest that the FUS2-767A/T polymorphism may be a susceptibility factor for lung cancer among Chinese population.

Development and validation of a LC-MS/MS method for quantification of hetrombopag for pharmacokinetics study.

Hetrombopag as the derivative of ethylidene hydrazine carboxamide was recently developed into a novel patented non-peptide thrombopoietin mimetic and thrombopoietin receptor agonist to treat idiopathic thrombocytopenic purpura. To study the pharmacokinetics of hetrombopag, a highly sensitive, rapid and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for determination of hetrombopag in rat plasma. After protein precipitation extraction, the chromatography separation of analyte and internal standard named eltrombopag as an marketed analog of hetrombopag was performed on an Synergi Polar-RP column at the flow rate of 0.5 mL/min, and the determination was conducted on an API4000 triple quadrupole mass spectrometry in the multiple reaction monitoring mode using the respective [M+H](+) ions m/z 459.2 â†’ 200.9 for hetrombopag and m/z 443.2 â†’ 229.0 for IS. The lower limit of quantification was established to be 1 ng/mL, and the linear scope of standard curve was 1-1000 ng/mL. Both the precision (RSD%) and accuracy (RE%) were within the acceptable criterion of below 15 %. The validated method was successfully applied to quantify hetrombopag in the rat plasma and investigate the pharmacokinetics.

A sputtered CdS buffer layer for co-electrodeposited Cu2ZnSnS4 solar cells with 6.6% efficiency.

Cu2ZnSnS4 thin films with thicknesses ranging from 0.35 to 1.85 µm and micron-sized grains (0.5-1.5 µm) were synthesized using co-electrodeposited Cu-Zn-Sn-S precursors with different deposition times. Here we have introduced a sputtered CdS buffer layer for the development of CZTS solar cells for the first time, which enables breakthrough efficiencies up to 6.6%.

The herbal compound Songyou Yin (SYY) inhibits hepatocellular carcinoma growth and improves survival in models of chronic fibrosis via paracrine inhibition of activated hepatic stellate cells.

Chronic fibrosis is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathological progression of hepatic fibrosis has been linked to cellular processes that promote tumor growth and metastasis. Several recent studies have highlighted the cross-talk between tumor cells and activated hepatic stellate cells (aHSCs) in HCC. The herbal compound Songyou Yin (SYY) is known to attenuate hepatoma cell invasion and metastasis via down-regulation of cytokine secretion by aHSCs. However the underlying mechanism of SYY treatment in reversal of hepatic fibrosis and metastasis of liver cancers is not known. In the current study, a nude mouse model with liver fibrosis bearing orthotopic xenograft was established and we found that SYY could reduce associated fibrosis, inhibit tumor growth and improve survival. In the subcutaneous tumor model with fibrosis, we found that SYY could inhibit liver cancer. In vitro, hepatoma cells incubated with conditioned media (CM) from SYY treated aHSCs showed reduced proliferation, decrease in colony formation and invasive potential. SYY treated group showed altered gene expression, with 1205 genes up-regulated and 1323 genes down-regulated. Gene cluster analysis indicated that phosphatidylinositol-3-kinase (PI3K) was one of the key genes altered in the expression profiles. PI3K related markers were all significantly down-regulated. ELISA also indicated decreased secretion of cytokines which were regulated by PI3K/AKT signaling after SYY treatment in the hepatic stellate cell line, LX2. These data clearly demonstrate that SYY therapy inhibits HCC invasive and metastatic potential and improves survival in nude mice models with chronic fibrosis background via inhibition of cytokine secretion by activated hepatic stellate cells.

Arsenic trioxide induces differentiation of CD133+ hepatocellular carcinoma cells and prolongs posthepatectomy survival by targeting GLI1 expression in a mouse model.

BACKGROUND: Cancer stem cells (CSCs) play a key role in the posthepatectomy recurrence of hepatocellular carcinoma (HCC). CD133+ HCC cells exhibit liver CSC-like properties, and CSC differentiation-inducing therapy may lead these cells to lose their self-renewal ability and may induce terminal differentiation, which may in turn allow their malignant potential to be controlled. Because arsenic trioxide (As2O3) increases remission rates and prolongs survival among patients with acute promyelocytic leukemia by inducing differentiation and apoptosis of leukemic cells, we hypothesized that As2O3 might also inhibit HCC recurrence and prolong survival time after hepatectomy by inducing differentiation of HCC CSCs. METHODS: We evaluated the As2O3 induced differentiation of human HCC CSCs and its mechanism in vitro, and we investigated the effects of treatment with As2O3 on recurrence rates and median survival in a mouse xenograft model. RESULTS: We found that As2O3 induced HCC CSC differentiation by down-regulating the expression of CD133 and some stemness genes, thus inhibiting the cells' self-renewal ability and tumorigenic capacity without inhibiting their proliferation in vitro. In vivo experiments indicated that As2O3 decreased recurrence rates after radical resection and prolonged survival in a mouse model. As2O3, which shows no apparent toxicity, may induce HCC CSC differentiation by down-regulating the expression of GLI1. CONCLUSIONS: We found that As2O3 induced HCC CSC differentiation, inhibited recurrence, and prolonged survival after hepatectomy by targeting GLI1expression. Our results suggest that the clinical safety and utility of As2O3 should be further evaluated.