Metastatic chondrosarcoma is a bone malignancy not responsive to conventional therapies; new approaches and therapies are urgently needed. We have previously reported that mTORC1 inhibitor, antitumorigenic cytostatic proline rich polypeptide 1 (PRP-1), galarmin caused a significant upregulation of tumor suppressors including TET1/2 and SOCS3 (known to be involved in inflammatory processes), downregulation of oncoproteins and embryonic stem cell marker miR-302C and its targets Nanog, c-Myc and Bmi-1 in human chondrosarcoma. To understand better the mechanism of PRP-1 action it was very important to identify the receptor it binds to. Nuclear pathway receptor and GPCR assays indicated that PRP-1 receptors are not G protein coupled, neither do they belong to family of nuclear or orphan receptors. In the present study, we have demonstrated that PRP-1 binding interacting partners belong to innate immunity pattern recognition toll like receptors TLR1/2 and TLR6 and gel forming secreted mucin MUC5B. MUC5B was identified as PRP-1 receptor in human chondrosarcoma JJ012 cell line using Ligand-receptor capture technology. Toll like receptors TLR1/2 and TLR6 were identified as binding interaction partners with PRP-1 by western blot analysis in human chondrosarcoma JJ012 cell line lysates. Immunocytochemistry experiments confirmed the finding and indicated the localization of PRP-1 receptors in the tumor nucleus predominantly. TLR1/2, TLR6 and MUC5B were downregulated in human chondrosarcoma and upregulated in dose-response manner upon PRP-1 treatment. Experimental data indicated that in this cellular context the mentioned receptors had tumor suppressive function.
Hepatocellular carcinoma (HCC) has a recurrence rate of up to 70% in 5 years after resection, detrimentally lowering survival. The role of adjuvant therapy remains controversial; therefore, the aim of this study was to evaluate the disease‐free and overall survival of patients with HCC, not candidates for transplantation, undergoing resection and adjuvant hepatic artery infusion therapy vs resection alone. Our meta‐analysis showed that adjuvant HAIC improves overall and disease‐free survival after resection, especially in tumors ≥7 cm.
Chondrosarcomas are malignant bone tumors refractory to chemotherapy and radiation treatment; thus, novel therapeutic strategies are required. Proline-rich polypeptide 1 (PRP-1) has previously demonstrated antitumor properties in chondrosarcoma. To further investigate the role of PRP-1 in chondrosarcoma cells, its effects on cancer stem cell (CSC) populations were determined by analyzing aldehyde dehydrogenase (ALDH) activity, an established marker of CSCs, in association with regulation of the Wnt/β-catenin signaling. A significant decrease in ALDH high CSCs was observed following treatment of chondrosarcoma JJ012 cells with PRP-1. For RT 2 profiler PCR array analysis of Wnt/β-catenin signaling genes, cells were sorted into: i) Bulk JJ012 cells; ii) ALDH high cells sorted from untreated JJ012 cells (ALDH high-untreated ); and iii) ALDH low cells sorted from PRP-1-treated JJ012 cells (ALDH low-PRP-1 ). The expression levels of Wnt/β-catenin signaling genes were determined to be downregulated in the ALDH high-untreated cells and upregulated in ALDH low-PRP-1 cells when compared to the bulk JJ012 cells. Additionally, two important oncogenes involved in this pathway, MMP7 and CCND2, were found to be downregulated in the ALDH low-PRP-1 cells. Immunocytochemistry demonstrated the localization of β-catenin in the nuclei of the PRP-1-treated cells. Western blotting indicated increased β-catenin expression in the ALDH low-PRP-1 cells compared with the bulk JJ012 cells. Analysis of the cytoplasmic and nuclear fractions of cells treated with increasing concentrations of PRP-1 and β-catenin nuclear translocation inhibitor CGP57380, suggested the nuclear translocation of β-catenin following PRP-1 treatment. In addition, treatment of JJ012 cells with a specific ALDH inhibitor, diethylaminobenzaldehyde, and PRP-1 resulted in a significant decrease in cytoplasmic β-catenin protein expression. This indicated that ALDH inactivation may be associated with the nuclear translocation of β-catenin. Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway has been previously documented. The findings of the present study support the notion that Wnt/β-catenin activation may serve a differential role in sarcomas, limiting tumor progression in association with decreased CSC activity.
A 61-year-old female with pernicious anemia presented with a 20-year history of walking-induced, erythematous, macular rash on her lower extremities. The rash was usually provoked by prolonged walking, especially in hot weather, although walking for as little as 30 minutes could trigger it as well. The eruption usually started at her shin (Panel A) and could extend all the way to her lower abdomen. She was treated with cortisone cream, vitamin E, and holistic approaches without significant improvement. Previous extensive workup for autoimmune diseases was non-revealing.Golfer's vasculitis, also known as exercise-induced vasculitis (EIV), is a specific form of benign cutaneous vasculitis affecting healthy individuals. 1,2 It is underappreciated, and mostly misdiagnosed as erythematous rash, or a purpuric itchy eruption. Unlike other idiopathic cutaneous vasculitides, golfer's vasculitis constitutes a stereotyped clinical entity, occurring after prolonged exercise such as a long walk or golf session. Other activities, such as dancing, cycling, or intensive cleaning are also reported as rare triggers. 1 A hot climate is considered a prerequisite; however, milder eruptions may occur in some patients in cooler seasons. Sun exposure does not appear as a contributory factor. Skin manifestations of golfer's vasculitis can vary among patients, including isolated erythematous rash, isolated purpura, erythematous rash and purpura, pseudo-urticaria, and/or lower extremity edema.The etiology of golfer's vasculitis is unknown. It is likely multifactorial and related to excessive heat production during prolonged exercise, leading to muscular hyperthermia and tissue damage, exercise-related immune system alteration, venous stasis, and alterations in skin blood flow. [1][2][3] Histological features on skin biopsy range from urticarial vasculitis with eosinophils to typical leukocytoclastic vasculitis. 1,2 Complement components C3 and C1q, immunoglobulin IgM, fibrinoid necrosis deposition, and erythrocyte extravasation can be present as well. 1,3 In most cases, cutaneous lesions resolve within a few days, but relapses are very frequent.Treatment of golfer's vasculitis is not standardized or mandatory given its self-resolving nature. Topical corticosteroids are reported to be beneficial at the acute phase, although no clinical trials have evaluated their efficacy. Properly fitting compression stockings decrease recurrence in about one-half of cases but can sometimes increase the symptoms. 1 Antihistamines have been used in some cases but have not been shown to be effective. 1
Annexin V analysis demonstrated that PRP-1 induced CSC cell death, and that this was not attributed to apoptosis or necrosis. Western blot analysis confirmed the expression of mesenchymal markers, and the spheroid self-renewal assay confirmed the presence of self-renewing CSCs. The results of the present study demonstrate that PrP-1 eliminates anchorage independent cSc growth and spheroid formation, indicating that PrP-1 likely inhibits tumor formation in a murine model. additionally, a decrease in non-cSc bulk tumor cells indicates an advantageous decline in tumor stromal cells. These findings confirm that PRP-1 inhibits CSC proliferation in a 3D tumor model which mimics the behavior of chondrosarcoma in vivo.
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