The FHP01 DDX3X helicase inhibitor exerts potent anti-tumor activity in vivo in breast cancer pre-clinical models

Inhibition of DDX3X expression or activity reduces proliferation in cells from various tumor tissues, in particular in breast cancer, and its expression often correlates to tumor aggressiveness. This makes DDX3X a prominent candidate for the design of drugs for novel personalized therapeutic strategies. Starting from an in silico drug discovery approach, a group of molecules has been selected by molecular docking at the RNA binding site of DDX3X. Here, the most promising among them, FHP01, was evaluated in breast cancer preclinical models. Specifically, FHP01 exhibited very effective antiproliferative and killing activity against different breast cancer cell types, among which those from triple-negative breast cancer (TNBC). Interestingly, FHP01 also inhibited WNT signaling, a key tumorigenic pathway already correlated to DDX3X functions in breast cancer model cell lines. Ultimately, FHP01 also caused a significant reduction, in vivo, in the growth of MDA MB 231- derived TNBC xenograft models. Importantly, FHP01 showed good bioavailability and no toxicity on normal peripheral blood mononuclear cells in vitro and on several mouse tissues in vivo. Overall, our data suggest that the use of FHP01 and its related compounds may represent a novel therapeutic approach with high potential against breast cancer, including the triple-negative subtype usually correlated to the most unfavorable outcomes because of the lack of available targeted therapies

An Analysis of Reinsurance and Firm Performance: Evidence from the Taiwan Property-Liability Insurance Industry

[[abstract]]This study investigates the relationship between reinsurance and firm performance by sourcing panel data from the 1999 to 2009 period of the property-liability insurance industry in Taiwan. The results of this investigation offer some insight that firm performance and reinsurance are interdependent. We find that insurers with higher return on assets (ROA) tend to purchase less reinsurance and insurers with higher reinsurance dependence tend to have a lower level of firm performance. Therefore, managers have to strike a balance between decreasing insolvency risk and reducing potential profitability. Other empirical results show that ROA, underwriting risks, liquidity ratio, business line concentration, return on investment (ROI) and financial holding dummy have a significant correlation with reinsurance. In addition, firm size, financial leverage, reinsurance, underwriting risks, liquidity ratio and ROI have a significant influence on firm performance. Our results have practical implications for the property-liability insurance industry and competent authorities in Taiwan.[[incitationindex]]SSCI[[booktype]]紙

Quality of life and disability assessment in neuropathy: a multicenter study

BACKGROUND: pain is a common symptom of peripheral neuropathies that may severely affect patients' Quality of Life. Pain questionnaires, based on verbal descriptors, are a useful way to investigate it. METHODS: we performed a multicentre study through validated measures to characterize pain in a sample of consecutive patients affected by immune-mediated neuropathies. RESULTS: ninety-three patients were enrolled in 16 Italian centres. Based on the numeric rating scale, almost half of the patients complained of moderate pain and one-third of the patients severe pain. Overall, up to 50% of our patients with immune-mediated neuropathies complained of neuropathic pain. The most common neuropathic symptoms were paraesthesia/dysesthesia and superficial spontaneous pain. Surprisingly, also patients with neuropathies commonly thought to be painless (such as multifocal motor neuropathy) reported discomfort and painful symptoms. CONCLUSIONS: pain questionnaires should be considered in the clinical evaluation of immune-mediated neuropathies, also when evaluating therapy efficacy, because they may provide clinicians with useful information on painful symptoms and patients' quality of life

Identification of new pyrrolo[2,3-d]pyrimidines as Src tyrosine kinase inhibitors in vitro active against Glioblastoma

In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3-d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AblT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3-d]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC50 value of 7.1 \u3bcM