IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis.

Rationale: Nab-paclitaxel (Abx) is widely employed in malignant tumor therapy. In tumor cells and pro-tumoral M2-type macrophages, the IL4 receptor (IL4R) is upregulated. This study aimed to elucidate the selective delivery of Abx to M2-type macrophages by targeting IL4R and reprogramming them into an anti-tumoral M1-type. Methods: Abx was conjugated with the IL4R-binding IL4RPep-1 peptide using click chemistry (IL4R-Abx). Cellular internalization, macrophage reprogramming and signal pathways, and tumor growth and metastasis by IL4R-Abx were examined. Results: IL4R-Abx was internalized into M2 macrophages more efficiently compared to the unmodified Abx and control peptide-conjugated Abx (Ctrl-Abx), which was primarily inhibited using an anti-IL4R antibody and a receptor-mediated endocytosis inhibitor compared with a macropinocytosis inhibitor. IL4R-Abx reprogrammed the M2-type macrophages into M1-like phenotype and increased reactive oxygen species (ROS) levels and extracellular release of high mobility group box 1 (HMGB1) in M2 macrophages at higher levels than Abx and Ctrl-Abx. The conditioned medium of IL4R-Abx-treated M2 macrophages skewed M2 macrophages into the M1-like phenotype, in which an anti-HMGB1 antibody and a toll-like receptor 4 (TLR4) inhibitor induced a blockade. IL4R-Abx accumulated at tumors, heightened immune-stimulatory cells while reducing immune-suppressing cells, and hampered tumor growth and metastasis in mice more efficiently than Abx and Ctrl-Abx. Conclusions: These results indicate that IL4R-targeting allows enhancement of M2-macrophage shaping into M1-like phenotype by Abx through the ROS-HMGB1-TLR4 axis, improvement of antitumor immunity, and thereby inhibition of tumor growth and metastasis, presenting a new approach to cancer immunotherapy.

Tribody: robust self-assembled trimeric targeting ligands with high stability and significantly improved target-binding strength.

The C-terminal coiled-coil region of mouse and human cartilage matrix protein (CMP) self-assembles into a parallel trimeric complex. Here, we report a general strategy for the development of highly stable trimeric targeting ligands (tribodies), against epidermal growth factor receptor (EGFR) and prostate-specific membrane antigen (PSMA) as examples, by fusing a specific target-binding moiety with a trimerization domain derived from CMP. The resulting fusion proteins can efficiently self-assemble into a well-defined parallel homotrimer with high stability. Surface plasmon resonance (SPR) analysis of the trimeric targeting ligands demonstrated significantly enhanced target-binding strength compared with the corresponding monomers. Cellular-binding studies confirmed that the trimeric targeting ligands have superior binding strength toward their respective receptors. Significantly, the EGFR-binding tribody was considerably accumulated in the tumor of mice bearing xenografted EGFR-positive tumors, indicating its effective cancer-targeting feature under in vivo conditions. Our results demonstrate that CMP-based self-assembly of tribodies can be a general strategy for the facile and robust generation of trivalent targeting ligands for a wide variety of in vitro and in vivo applications.

[Occurrence of diabetic ketoacidosis and autoimmune thyroiditis in a patient treated with pegylated interferon-alpha 2b and ribavirin for chronic hepatitis C].

Combined pegylated interferon and ribavirin therapy for chronic hepatitis C infection cause a wide range of side effects, including flu-like syndrome, hematological abnormalities, cardiovascular symptoms, gastrointestinal symptoms, pulmonary dysfunction, depression, and retinopathy. Interferon-alpha has been shown to be related to the development of various autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroid disease, and type 1 diabetes mellitus (DM). Type 1 DM and thyroid disease respectively develop in 0.08-2.61% and 10-15% of patients treated with combined interferon-alpha and ribavirin for chronic hepatitis C. The coexistence of type 1 DM and autoimmune thyroiditis was rarely reported. We report a case of a 33-year-old female patient with chronic hepatitis C who simultaneously developed diabetic ketoacidosis and autoimmune thyroiditis after treatment with pegylated interferon-alpha 2b and ribavirin.

Multidetector row computed tomographic gastrography findings after endoscopic submucosal dissection for early gastric cancer: emphasis on time evolution and factors for predicting residual tumor.

PURPOSE: To retrospectively investigate multidetector row computed tomographic (CT) gastrography (CTG) findings after endoscopic submucosal dissection (ESD) of the stomach and to analyze the time evolution and factors for predicting residual tumor. MATERIALS AND METHODS: During an 18-month period, ESD was performed for 92 early gastric cancers (EGCs) in 86 patients. All patients were followed up with CTG, and 6 patients underwent CTG 2times. A total of 98 CTGs were analyzed by 2 radiologists for the presence of mucosal break, overlying enhancing layer and the attenuation of the lesion on 2-dimensional (2D) images, and malignant-looking fold convergence on 3D volume-rendered images. Multidetector row computed tomographic gastrography findings were categorized into 5 types: deep benign ulcer (BU), deformed BU, shallow depressed ulcer, EGC, and advanced gastric cancer (AGC). To analyze the time evolution of CTG findings, the mean time interval between the procedure and CT was calculated and compared among the 5 types using the Kruskal-Wallis test. The chi test or Fisher exact test was used to determine significant CT findings for predicting residual tumor after ESD. RESULTS: Tumor involvement was found at the resection margin in 7 lesions (6 radial and 1 deep). Of 98 lesions, 5 (5.1%) were not visualized on either 2D or 3D images. Most lesions had mucosal break (82/93) and showed intermediate low attenuation (67/93) on 2D images. Prominent enhancement of overlying layer above ESD site was seen in 23 lesions. Malignant-looking fold convergence was observed in 11 lesions. Sixty-five lesions appeared as shallow depressed ulcers, 13 as deformed BUs, 8 as EGCs, 4 AGCs, and 3 deep BUs. Among them, deep BUs appeared first (average, 0.2 month after ESD; P < 0.05), followed by deformed BUs (5.3 months), then AGCs (6.0 months), EGCs (7.3 months), and shallow depressed ulcers (7.7 months). However, the only significant time interval difference was between the deep BUs and the other types (P < 0.05). There was no correlation between the presence of marginal tumor involvement and any CT findings. CONCLUSIONS: Immediately after ESD, lesions appear as deep BUs then evolve over time into shallow depressed ulcers. The presence of malignant-looking fold convergence and enhancing layer above the mucosal break on CT do not indicate tumor involvement at the ESD margin.

[Long-term results of endoscopic histoacryl (N-butyl-2-cyanoacrylate) injection for treatment of gastric varices--a 10-year experience].

BACKGROUND/AIMS: Gastric variceal bleeding is an infrequent but serious complication of portal hypertension. Endoscopic injection of Histoacryl (N-butyl-2-cyanoacrylate) has been approved as an effective treatment for gastric variceal bleeding. The aim of this study was to evaluate the long-term efficacy and safety of the endoscopic injection of Histoacryl for the treatment of gastric varices. METHODS: Between January 1994 and January 2005, eighty-five patients with gastric varices received endoscopic injections of Histoacryl. Among these 85 patients, 65 received the procedure within 1 week after gastric variceal bleeding, and 13 received as a prophylactic procedure. According to the Sarin classification, 32 patients were GOV1 and 53 were GOV2. Most of the varices were large (F2 or F3, 75 patients). The average volume of Histoacryl per each session was 1.43 ml. Among 85 patients, 72 patients were followed-up and the median duration was 24.5 months. RESULTS: The rate of initial hemostasis was 98.6% and recurrent bleeding occurred in 29.2% (21 of 72). When rebleeding occurred, 76.2% was within 1 year after the initial injection. Treatment failure-related mortality rate was 1.4% (1 of 85). Twenty-seven patients died, mostly due to hepatocelluar carcinoma or liver failure. Two patients experienced pulmonary embolism and one experienced splenic infarction. They recovered without specific treatment. Rebleeding rate had a tendency to increase in patients with hepatocelluar carcinoma (p=0.051) and GOV2 (p=0.061). CONCLUSIONS: Histoacryl injection therapy is a effective treatment method for gastric varices with high initial hemostasis rate and low major complications.