Background Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA and/or DNA damage-response inhibitor (DDRi) therapies. Methods We used a multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies and mechanistic studies to assess SLFN11 as a potential biomarker for stratification of patients treated with several DDA and/or DDRi in the preclinical and clinical setting. Results SLFN11 protein associated with both preclinical and patient treatment response to DDA, but not to non-DDA or DDRi therapies, such as WEE1 inhibitor or olaparib in breast cancer. SLFN11-low/absent cancers were identified across different tumour types tested. Combinations of DDA with DDRi targeting the replication-stress response (ATR, CHK1 and WEE1) could re-sensitise SLFN11-absent/low cancer models to the DDA treatment and were effective in upper gastrointestinal and genitourinary malignancies. Conclusion SLFN11 informs on the standard of care chemotherapy based on DDA and the effect of selected combinations with ATR, WEE1 or CHK1 inhibitor in a wide range of cancer types and models.

Chemical modification of cellulose by phosphorylation enhances its bioactivity and provides new derivatives and materials with specific end uses. In the present study, cellulose derivatized with phosphorous acid was obtained using the reaction of microcrystalline cellulose with phosphorous acid-urea mixture, in molten state, in comparison with others methods that used different solvents and catalysts. Completely water soluble films with a substitution degree close to one were obtained and characterized by analytical and spectral analysis (FT-IR, (31)P NMR), contact angle, metallographic microscopy and atomic force microscopy (AFM). 31P NMR spectra of derivatized cellulose showed a signal at 2.58 ppm (assigned to P-O-C6) while the doublets at 4.99-5.29 and at 7.38 ppm were assigned to P-O-C2 and P-O-C3, respectively; thus, the formation of monosubstituted phosphorous acid esters of cellulose is advocated. Contact angle measurements showed that the work of adhesion is more important in water than in ethylene glycol, for the phosphorous acid derivatized cellulose. The cytocompatibility of this hydrosoluble derivatized cellulose was tested by direct contact and also by indirect assays on normal human dermal fibroblasts and on osteoblast-like cells (human osteosarcoma). Cell growth on phosphorylated cellulose pellicle and the results from viability assays had shown a good cytocompatibility and lack of toxicity. Phosphorous acid derivatized cellulose would offer a promising biomaterial, useful as scaffolds for new biopolymer composites, and subject for further development as an ionic crosslinker.

Trace elements represent a group of essential metals or metaloids necessary for life, present in minute amounts. Analgesic adjuvants can enhance the effect of other pain drugs or be used for pain control themselves. Previous studies on the effects of trace elements on nociception and their potential use as analgesic adjuvants have yielded conflicting results. In this study, we tested the hypothesis that three vital trace elements (Zn²⁺, Mg²⁺, Cu²⁺) have direct antinociceptive effects. Groups of eight Swiss mice were intraperitoneally (i.p) injected with incremental concentrations of Zn²⁺ sulfate (0.5, 2.0 mg/kg), Zn²⁺ citrate (0.125, 0.5 mg/kg), Mg²⁺ chloride (37.5, 75, 150 mg/kg), Cu²⁺ chloride (0.5, 1.0, 2.0 mg/kg), and Cu²⁺ sulfate (0.5, 1.0 mg/kg) or saline (control). Evaluations were made by hot plate (HP) and tail flick (TF) tests for central antinociceptive effect, writhing test (WT) for visceral antinociceptive effect, and activity cage (AC) test for spontaneous behavior. Zn²⁺ induced pain inhibition in HP/TF tests (up to 17%) and WT (up to 25%), with no significant differences among the salts used. Mg²⁺ salts induced pain inhibition for all performed tests (up to 85% in WT). Cu²⁺ salts showed antinociceptive effects for HP/TF (up to 28.6%) and WT (57.28%). Only Mg²⁺ and Cu²⁺ salts have displayed significant effects in AC (Mg²⁺ anxiolytic/depressant effect; Cu²⁺ anxiolytic effect). We interpret these data to mean that all tested trace elements induced antinociceptive effects in central and visceral pain tests. Our data indicate the potential use of these cheap adjuvants in pain therapy.

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