Occurrence of Colorectal cancer (CRC) is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apcmin/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active β-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/β-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-β-catenin axis.

Ferroptosis, an iron-based cell death pathway, has recently attracted great attention owing to its effectiveness in killing cancer cells. Previous investigations focused on the development of iron-based nanomaterials to induce ferroptosis in cancer cells by the upregulation of reactive oxygen species (ROS) generated by the well-known Fenton reaction. Herein, we report a ferroptosis-inducing agent based on arginine-rich manganese silicate nanobubbles (AMSNs) that possess highly efficient glutathione (GSH) depletion ability and thereby induce ferroptosis by the inactivation of glutathione-dependent peroxidases 4 (GPX4). The AMSNs were synthesized via a one-pot reaction with arginine (Arg) as the surface ligand for tumor homing. Subsequently, a significant tumor suppression effect can be achieved by GSH depletion-induced ferroptosis. Moreover, the degradation of AMSNs during the GSH depletion contributed to T1-weighted magnetic resonance imaging (MRI) enhancement as well as on-demand chemotherapeutic drug release for synergistic cancer therapy. We anticipate that the GSH-depletion-induced ferroptosis strategy by using manganese-based nanomaterials would provide insights in designing nanomedicines for tumor-targeted theranostics.

A novel, minimally invasive interventional technique, radiofrequency heat (RFH), has been suggested to improve the efficacy of chemotherapy for solid organ tumors. However, the treatment for prostate cancer has not been completely characterized. The aim of the present study was to investigate the in vitro and in vivo efficiency of chemotherapy in combination with RFH for the treatment of prostate cancer. The following four treatment groups were included: i) No treatment (control); ii) RFH-only; iii) chemotherapy (docetaxel)-only; and iv) combination therapy of docetaxel and RFH in human prostate cancer (HPC) cell lines and mice with HPC xenografts. In the in vitro experiments, a heating guidewire was attached under the bottom of the last chamber of the four-chamber cell culture slide, and was then connected to a radiofrequency (RF) generator. In the in vivo experiments, a tumor model was generated by subcutaneously injecting human prostate cancer cells into 24 male nu/nu mice. RFH was conducted by inserting the 0.022-inch heating-guidewire into the tumor. The follow-up magnetic resonance imaging demonstrated a significant reduction in the average tumor size in animals treated with combination therapy compared with those receiving RFH-only and chemotherapy-only. The number of apoptotic cells and the average apoptotic index of the combination therapy group were significantly higher compared with those of the other three treatment groups. In conclusion, the results of the present study suggested that RFH is able to increase the therapeutic efficiency of docetaxel in prostate cancer, and this study serves as a foundation for the future development of an interventional molecular image-guided local treatment strategy for prostate cancer that integrates RF technology, interventional oncology and direct intratumoral chemotherapy, as a replacement for systemic chemotherapy.

High-resolution imaging is a powerful technique in theranostics and staging of tumors. Dual-modal imaging using lanthanide hybrid nanoparticles as probes has been attracting increasing attention due to their specific and intrinsic physical properties. The present work reports a novel water-soluble micelle of an amphiphilic block copolymer with diketone pendants chelating gadolinium (Gd3+) and europium (Eu3+) cations as a dual probe for magnetic resonance imaging (MRI) and fluorescence imaging for clinical detection. The Gd3+ and Eu3+ hybrid micelles have homogeneous size distribution and hydrodynamic diameters tunable between 80 and 220 nm. The macromolecular diketone ligand enhances the relaxation rate of Gd3+ and sensitizes Eu3+ luminescence efficiently. Further sensitized by the co-doped Gd3+, the Eu3+ complex exhibits a long-lived emission with a large Stokes shift. A strong red light at a wavelength of 614 nm is observed with an excitation in the range of 350 and 405 nm. Cellular uptake experiments reveal excellent biocompatibility and rapid uptake of the nanoparticles by MCF-7 cells. The robust dual-modal probes are promising in applications for early diagnosis of tumors, presurgical planning, and intraoperative fluorescence-guided surgery.

Radiofrequency ablation (RFA) is widely accepted as a first-line interventional oncology approach for hepatocellular carcinoma (HCC) and has the advantages of high treatment efficacy and low complication risk. Local control rates equivalent to hepatic resection can be reached by RFA alone when treating small HCCs (<2 cm) in favorable locations. However, local tumor progression and recurrence rates with RFA monotherapy increase sharply when treating larger lesions (>3 cm). To address this clinical problem, recent efforts have focused on multimodel management of HCC by combining RFA with different techniques, including percutaneous ethanol injection, transarterial chemo-embolization, targeted molecular therapy, nanoparticle-mediated therapy, and immunotherapy. The combination strategy indeed leads to better outcomes in comparison to RFA alone. In this article, we review the current status of RFA-combined multimodal therapies in the management of HCC.

Magnetic resonance (MR) contrast agents focusing on special functions are required to improve cancer diagnosis, particularly in the early stages. Here, we designed multifunctional solid lipid nanoparticles (SLNs) with simultaneous loading of gadolinium (Gd) diethylenetriaminepentaacetic acid (Gd-DTPA) and octadecylamine fluorescein isothiocyanate (FITC) to obtain Gd-FITC-SLNs as a tumor-absorbable nanoparticle contrast agent for the histological confirmation of MR imaging (MRI) findings. Colorectal tumors were evaluated in vitro and in vivo via direct uptake of this contrast agent, which displayed reasonable T1 relaxivity and no significant cytotoxicity at the experimental concentrations in human colon carcinoma cells (HT29) and mouse colon carcinoma cells (CT26). In vitro cell uptake experiments demonstrated that contrast agent absorption by the two types of cancer cells was concentration-dependent in the safe concentration range. During in vivo MRI, transrectal infusion of Gd-FITC-SLNs showed more significant enhancement at the tumor site compared with the infusion of Gd-DTPA in female C57/BL mice with azoxymethane/dextran sulfate sodium-induced colorectal highgrade intraepithelial neoplasia. Subsequent confocal fluorescence microscopy demonstrated Gd-FITC-SLNs as highly concentrated green fluorescent spots distributed from the tumor capsule into the tumor. This study establishes the "proof-of-principle" of a new MRI technique wherein colorectal tumors are enhanced via direct absorption or uptake of the nanoparticle contrast agent.

PurposeTo evaluate the possibility of using a variable flip angle (VFA) T1 mapping technique to diagnose liver fibrosis.Materials and MethodsLiver fibrosis was induced in rabbits by repetitive administration of carbon tetrachloride (CCl4). T1‐weighted magnetic resonance imaging (MRI) was performed in 29 animals (liver fibrosis, n = 18; control, n = 11) using a series of nonenhanced liver acquisition volume acceleration (LAVA) with VFAs at 3.0T. Hepatic T1 relaxation times were measured via regions of interest, which were correlated with subsequent histologic confirmation. The results of T1 mapping in assessment of liver fibrosis were compared with that of apparent diffusion coefficient (ADC) values.ResultsThe mean T1 relaxation time of the control group was the lowest (250.07 ± 88.12 msec), followed by the nonadvanced fibrosis group (387.83 ± 166.58 msec) and the advanced fibrosis group (496.90 ± 291.24 msec). T1 relaxation time measurements differed significantly between the liver fibrosis group and control group (P < 0.05), with a trend of increased mean T1 relaxation times as the fibrotic stage increased. Statistically significant differences were observed between the control group and the nonadvanced fibrosis group (P < 0.05), however with much overlap between the less severe stages. In discriminating between the control group and liver fibrosis group, stage F0‐1 (control and stage F1) and stage F2‐3, stage F0‐2 (control and stage F1‐2) and stage F3, area under the receiver operating characteristic (ROC) curves were 0.803 (cutoff value 273.01 msec), 0.712 (cutoff value 371.54 msec), and 0.696 (cutoff value 276.99 msec), respectively. No difference was found between T1 relaxation times and ADC values in assessment of liver fibrosis in our study.ConclusionVFA T1 mapping may become a noninvasive imaging tool for the diagnosis of liver fibrosis. J. MAGN. RESON. IMAGING 2016;43:698–703.

PurposeTo evaluate the pharmacokinetic parameters of dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) in diagnosing and staging liver fibrosis in rabbits.Materials and MethodsDCE‐MRI with gadodiamide (Gd‐DTPA‐BMA) was performed on a 3.0 Tesla, 60 cm bore MR scanner for rabbits with CCl4‐induced liver fibrosis, and an untreated control group. Fibrosis was staged according to the METAVIR system: control (F0; n = 13), nonadvanced fibrosis (F1–2; n = 15), and advanced fibrosis (F3–4; n = 12). The DCE‐MRI parameters Ktrans, kep, Ve, and vp were measured with a dual‐input extended Tofts model. Receiver operating characteristic analyses were performed to assess the diagnostic performance of Ktrans, Ve, and vp in staging liver fibrosis.ResultsBoth Ktrans and Ve decreased with increasing fibrosis stage. Ktrans of the control group was significantly different from that of the overall fibrosis group, nonadvanced group, and advanced group (P < 0.001 for all). Significant differences were found between Ve of the control group and that of the overall fibrosis and advanced groups (P = 0.019 and P = 0.009, respectively). For Ktrans, the areas under the receiver operating characteristic curve (AUROCs) for discriminating the control group from the overall fibrosis and advanced fibrosis groups were 0.909 (95% confidence interval [CI], 0.809–1.000), and 0.936 (95% CI,0.847–1.000), respectively. For discriminating between the control and nonadvanced fibrosis groups, the AUROC of Ktrans was 0.887 (95% CI, 0.762–1.000). The AUROCs of Ktrans were higher than those of Ve and vp for discriminating between the control and overall fibrosis groups, the control and nonadvanced fibrosis groups, and the control and advanced fibrosis groups. Pharmacokinetic parameters were negatively correlated with fibrosis stage (Ktrans, rho = ‐0.668, P < 0.001; Ve, rho = ‐0.438, P = 0.005; vp, rho = ‐0.360, P = 0.023).ConclusionAmong pharmacokinetic parameters of DCE‐MRI in our study, Ktrans was an excellent predictor for differentiating fibrotic livers from normal livers, and differentiating normal livers from nonadvanced or advanced fibrosis livers. J. Magn. Reson. Imaging 2016;44:98–104.

Breast cancer is the most common malignancy in women worldwide. Recent developments in minimally invasive interventional radiology techniques have significantly improved breast cancer treatment. This study aimed to develop a novel technique for the local management of breast cancers using radiofrequency heat (RFH). We performed both in vitro experiments using human breast cancer cells and in vivo validation in xenograft animal models with magnetic resonance imaging (MRI) and pathological correlation to investigate the feasibility of our approach. Four treatment groups, including (1) no treatment (control), (2) RFH-only, (3) chemo (doxorubicin)-only, and (4) combination therapy with both doxorubicin and RFH, were conducted in each experiment. In vitro combination therapy significantly decreased breast cancer cell proliferation while increased their apoptosis index compared to the other three groups. MRI demonstrated a significant tumor size reduction in animals treated with combination therapy compared to those receiving other treatments in vivo. Such result was further confirmed by pathological examination. In conclusion, our findings suggests that RFH can enhance the therapeutic efficiency of doxorubicin on breast cancers, thus establishing the basis for future development of interventional molecular image-guided local chemotherapy for breast malignancies.