0000000001293115
AUTHOR
Daniele Caracciolo
Additional file 5: of Trabectedin triggers direct and NK-mediated cytotoxicity in multiple myeloma
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 MI…
Immunomodulatory activity of microRNAs: potential implications for multiple myeloma treatment
Multiple myeloma (MM) is an incurable plasma cell neoplasm accounting for about 10% of all hematologic malignancies. Recently, emerging evidence is disclosing the complexity of bone marrow interactions between MM cells and infiltrating immune cells, which have been reported to promote proliferation, survival and drug resistance of tumor cells. MicroRNAs (miRNAs) are small non-coding RNA molecules with regulatory functions in the cell, whose expression has predictive and prognostic value in different malignancies. MiRNAs are gaining increasing interest due to their capability to polarize the immune-response through different mechanisms, which include the molecular reprogramming of immune cel…
Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: in vitro and in vivo anti-tumor activity
// Lavinia Raimondi 1 , Nicola Amodio 1 , Maria Teresa Di Martino 1 , Emanuela Altomare 1 , Marzia Leotta 1 , Daniele Caracciolo 1 , Annamaria Gulla 1 , Antonino Neri 2 , Simona Taverna 3 , Patrizia D’Aquila 4 , Riccardo Alessandro 3 , Antonio Giordano 5 , Pierosandro Tagliaferri 1 and Pierfrancesco Tassone 1,5 . 1 Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy 2 Department of Medical Sciences University of Milan, Hematology1, IRCCS Policlinico Foundation, Milan, Italy 3 Department of Pathology and Forensic and Medical Biotechnology, Section of Biology and…
miR-22 suppresses DNA ligase III addiction in multiple myeloma
Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of…
Eltrombopag treatment for severe immune thrombocytopenia during pregnancy: a case report
Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia (platelet count <100 × 109/l) in the absence of other causes or disorders associated. The incidence of ITP in pregnancy is one to two cases per 1000 gestations. ITP could be diagnosed before or during pregnancy; sometimes a relapse of a previously diagnosed ITP can occur. Intravenous immune globulins (IVIg) and corticosteroids are the standard frontline therapy because of their well known safety profile either for the mother or for the neonate. Treatments for refractory patients are limited by potential fetal risk. We report the case of a patient with ITP along pregnancy, refractory…
Assessment of the 4-factor score: Retrospective analysis of 586 CLL patients receiving ibrutinib. A campus CLL study
Not Available
Additional file 3: of Trabectedin triggers direct and NK-mediated cytotoxicity in multiple myeloma
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. …
Additional file 4: of Trabectedin triggers direct and NK-mediated cytotoxicity in multiple myeloma
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)
miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma
Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis…
The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma
Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CAL…
Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts.
// Maria Rita Pitari 1 , Marco Rossi 1 , Nicola Amodio 1 , Cirino Botta 1 , Eugenio Morelli 1 , Cinzia Federico 1 , Annamaria Gulla 1 , Daniele Caracciolo 1 , Maria Teresa Di Martino 1 , Mariamena Arbitrio 2 , Antonio Giordano 3, 4 , Pierosandro Tagliaferri 1 , Pierfrancesco Tassone 1, 4 1 Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy 2 ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy 3 Department of Human Pathology and Oncology, University of Siena, Siena, Italy 4 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology,…
Replacement of miR-155 Elicits Tumor Suppressive Activity and Antagonizes Bortezomib Resistance in Multiple Myeloma
Aberrant expression of microRNAs (miRNAs) has been associated to the pathogenesis of multiple myeloma (MM). While miR-155 is considered a therapeutic target in several malignancies, its role in MM is still unclear. The analysis of miR-155 expression indicates its down-regulation in MM patient-derived as compared to healthy plasma cells, thus pointing to a tumor suppressor role in this malignancy. On this finding, we investigated miR-155 replacement as a potential anti-tumor strategy in MM. The miR-155 enforced expression triggered anti-proliferative and pro-apoptotic effects in vitro. Given the lower miR-155 levels in bortezomib-resistant as compared to sensitive MM cells, we analyzed the p…
Therapeutic afucosylated monoclonal antibody and bispecific T-cell engagers for T-cell acute lymphoblastic leukemia
BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a poor cure rate for relapsed/resistant patients. Due to the lack of T-cell restricted targetable antigens, effective immune-therapeutics are not presently available and the treatment of chemo-refractory T-ALL is still an unmet clinical need. To develop novel immune-therapy for T-ALL, we generated an afucosylated monoclonal antibody (mAb) (ahuUMG1) and two different bispecific T-cell engagers (BTCEs) against UMG1, a unique CD43-epitope highly and selectively expressed by T-ALL cells from pediatric and adult patients.MethodsUMG1 expression was assessed by immunohistochemistry (IHC) on a wide panel of normal t…
MiR-29b antagonizes the pro-inflammatory tumor-promoting activity of multiple myeloma-educated dendritic cells
Dendritic cells (DCs) have a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their microRNA (miRNA) network. By analyzing six different miRNA-profiling data sets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor-associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients. In DCs co-cultured with MM cells, enforced expression of miR-29b counteracted pro-inflammatory pathways, includin…
Additional file 2: of Trabectedin triggers direct and NK-mediated cytotoxicity in multiple myeloma
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 1: of Trabectedin triggers direct and NK-mediated cytotoxicity in multiple myeloma
Table S1. List of genes included in DNA repair systems. (XLSX 11 kb)