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Additional file 1. Supplementary information: Systematic review of anti-miRNA therapeutics of human cancer. Fig S1: Dose-escalation phase I treatments according to a 3+3 design and Fibonacci dose-escalation protocol. Table S1: Patients, demography, pathology and stage. Table S2: Previous treatments. Table S3: AE distribution in terms of CTCAE System Organ Class. Table S4: Adverse events. Safety analysis set. Table S5: Analysis of LNA-i-miR-221 in urine, 0.5 mg/kg dose. A) Treatment Day 1, B) Treatment Day 4. Table S6: Mean plasma PK parameters for each LNA-i-miR-211 dose. Access Link to the Clinical Trial Protocol (Version 3.0).

Additional file 2: Supplementary Methods

Additional file 1: Supplementary Figures Figure S1. A Cartoon backbone representation of the superimposed DNA Binding Domains (DBD) of DNA Ligase I (green), III (orange) and IV (blue). B. Surface view of the DBD of ligase III (PDB ID 3L2P) . The positively charged groove targeted in the virtual screening is encircled by the dashed line. C. Surface view of the DBD of ligase I (PDB ID 1X9N). D. Surface view of the DBD of ligase IV (PDB ID 3W5O). Figure S2. A Immunoblot analysis of LIG4 expression in MM cell lines. GAPDH was used as loading control. B Representative FACS traces of Annexin V assay in AMO1 and H929 cells 4 days after RHM treatment (5 μM). C H929 cells were treated with vehicle or RHM (5 μM). 6 hours after either DMSO (NT) or Z-VAD-FMK were added to culture medium, at final concentration of 25 μM. Annexin V staining 4 days after treatment is shown. D Annexin V assay on U266 cells after 4 days of treatment with vehicle or RHM (5 μM). E Colony formation of AMO1 cells treated with vehicle or increasing dose of RHM. Light microscopy after 2 weeks is shown. F H&E stain of AMO1 and KMS26 cells after 5 days of treatment with vehicle or RHM (5 μM). Figure S3. A Cell cycle analysis in H929 cells treated with RHM (5 μM) with or without Caffeine (5 mM) for 48h. B ROS-Glo H2O2 assay performed in AMO1 and KMS26 cells 48h after treatment with vehicle or RHM (5 μM). C Relative percentage of CNV acquisition in AMO1 treated with RHM (2,5 μM) or vehicle, as evaluated by Affymetrix CytoScan HD Array analysis. Figure 4. A Cell viability of AMO1 and ABZB, treated with vehicle or increasing dose of Bortezomib for 48h. B Graphs of correlations between endogenous mRNA expression levels of LIG3 and MYC in MM patients with EFS

Figure S3. A GSEA results according to clueGO grouped by functions dependent on upregulated or downregulated genes. B Genes belonging to NER pathway resulted to be upregulated following trabectedin treatment in U266. Below, western blot to confirm DDB2 upregulation in 2 different cell lines. (PDF 974 kb)

Figure S4. A Western blot showing expression levels of anti-apoptotic proteins BCL-2 and MCL-1 in U266 and MM1S treated with different doses of trabectedin. B Representative dot plot of apoptosis induction and ROS production in U266 and MM1S cells after trabectedin-treatment respect to control, in presence or absence of ascorbic acid. C Western blot reporting protein expression of cell-cycle and DNA-damage regulators (p21, p-Chk2, RAD51 and gH2AX) in OPM2 cell line, after trabectedin treatment. D Representative immunohistochemistry showing gamma-h2ax foci (in brown) in the nuclei of U266 cells growth in matrigel-based spheroids, after 2.5 nM trabectedin treatment. E Surface expression of MICA/B and ULBP1 in U266, OPM2, RPMI8226 and MM1S cells treated with different concentrations of trabectedin for 48 h. All results represent the mean of at least 3 different individual experiments. F Dot plots report CD107a surface expression on NK-92 CI co-cultured with RPMI8226 untreated and exposed to trabectedin for 48 h. In the lowest part, histogram reporting the mean of the CD107a expression on NK92 co-cultured with U266 and OPM2 in 3 different experiments. G Gene expression levels of CRBN, CUL4 and DDB2 genes, all involved in the ubiquitination of IKZF1 protein, extracted from our gene expression profiling performed on U266 after 24 exposure to trabectedin. H Expression of pri-miR-17-92 in U266 and OPM2 in both cell lines after trabectedin treatment (2.5 Nm for U266 and 1 nM for OPM2). I Expression of miR-19b and miR-92a in U266 and OPM2 in absence or presence of trabectedin. These miRNAs do not belong to miR-17 family and were used as control for trabectedin specific activity. J Expression levels of mature miRNAs belonging to miR-17-92 cluster in stably pri-miR-17-92 overexpressing U266. K Representative dot plot of apoptotic activity of trabectedin treatment (2 .5nM) in 17–92-U266 cells respect to EV-U266 cells. *: p

Figure S2. A Dot plots reporting pro-apoptotic activity of trabectedin after 24 h treatment in primary myeloma cells from three different patients. On the right, histogram reporting the % of viable cells. B Western blot images of a panel of 12 MM cell lines representing proteins belonging to NER pathway, which not exhibited a pattern associated with response to trabectedin. C Expression of the genes belonging to the NER pathway obtained by interrogating 2 different publicly available datasets (GSE68379 and GSE6205) including several MM cell lines used in our in vitro experiments. Cell lines segregate, in an unsupervised hierarchical clustering, accordingly to their response to trabectedin. D Dot plots of apoptotic activity of trabectedin in OPM2 and MM1S in presence (right) or absence (left) of monocytes, treated with 1 nM and 0.1 nM of the trabectedin, respectively in 3D model. E Unsupervised hierarchical clustering demonstrating that both duplicates achieved comparable results. In green cluster: trabectedin treated U266; in yellow cluster: control U266. F Shows the first 9 results of the gene set enrichment analysis according to their ranking. Importantly, 5/9 gene-sets affected involves DNA damages. Additionally, GSEA correctly identified that the whole transcriptome modulation may be dependent upon trabectedin treatment. *: p

Figure S1. A Meta-analysis of 4 different GEP datasets of MM comparing the expression levels of genes belonging to different DNA-repair pathways (BER, MMR, HR, c-NHEJ, a-NHEJ, FA) in PCs from MM patients with PCs from healthy donors. B For each panel: on the left, forest plot showing the results of the multivariate COX regression analysis performed on all genes included in the specific DNA repair system. On the right, Kaplan-Meyer curve report results of prognostic system in which patients were divided into “low” and “high” risk group, according to the expression of genes identified by previous multivariate analysis. (PDF 605 kb)

Additional file 3: Table S3. Economic evaluation studies of interventions for diagnosis and treatment of colorectal cancer (2011â 2016).

Additional file 2: Table S2. Conversion of different currencies via PPPs (purchasing power parities) into Euro values.

Additional file 1: Table S1. Search strategy.

Epithelial ovarian cancer (EOC) is the sixth most common malignancy in women. Ovarian tumors consist of several clinical and pathological entities that share an anatomic site. The gold standard treatment, both in front-line and in adjuvant setting, is represented by carboplatin/paclitaxel combination. Conversely, the second-line treatment is not well defined. The response to platinum is the major prognostic factor for survival. In this review we discuss the current views on platinum-refractory/resistant patient treatment only, which includes patients progressing or relapsing within 6 months from the last platinum-based course. Concerning this subgroup, the activity of several conventional drugs was confirmed in different trials without a significant impact in terms of overall survival. In the last years particular emphasis was given to targeted anti-angiogenetic therapy which produced a survival improvement with an acceptable toxicity profile. New “ad hoc” approaches, with a major attention to outcome-predictive factors, are eagerly awaited.