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Bellinzona, Switzerland

Conconi A.,University of Piemonte Orientale | Franceschetti S.,University of Piemonte Orientale | Lobetti-Bodoni C.,University of Turin | Stathis A.,Oncology Institute of Southern Switzerland IOSI | And 9 more authors.
Leukemia and Lymphoma | Year: 2013

Central nervous system (CNS) relapse has not been extensively studied in mantle cell lymphoma (MCL). We retrospectively analyzed the risk factors and pattern of CNS relapse in consecutive patients with MCL. We identified 142 cases of MCL treated from 1980 to 2011. Median age at diagnosis was 68 years; 82% of patients had advanced stage; extranodal disease was reported in 89% of cases and high serum lactate dehydrogenase (LDH) in 40%. Fourteen patients (10%) did not receive treatment at diagnosis. Chemotherapy was administered to 125 patients (88%), in 21 cases (15%) including drugs penetrating into the CNS or given intrathecally; 49 patients (35%) had rituximab. Ten patients had front-line autologous transplant. After a median follow-up of 7.9 years, CNS relapse occurred in 11 cases (7.8%) at a median of 13.8 months. Actuarial risk of CNS relapse was higher in patients with elevated LDH (p = 0.002), higher International Prognostic Index (IPI) score (p = 0.018) and blastoid histology (p < 0.0001). Blastoid histology retained significance at multivariate analysis. Median survival after CNS relapse was 6.3 months. No front-line treatment reduced the risk of CNS relapse. Our analysis confirms the poor outcome of MCL after CNS relapse and may allow the identification of patients needing prophylaxis of CNS relapse. © 2013 Informa UK, Ltd.

Lobetti-Bodoni C.,Oncology Institute of Southern Switzerland IOSI | Bertoni F.,Oncology Institute of Southern Switzerland IOSI | Bertoni F.,Institute of Oncology Research IOR | Stussi G.,Oncology Institute of Southern Switzerland IOSI | And 2 more authors.
European Journal of Internal Medicine | Year: 2013

B cell-chronic lymphocytic leukemia (CLL), the commonest adult leukemia in western world, is today most often diagnosed at early-stage, following the accidental detection of lymphocytosis during a routine blood analysis. Moreover, the expectations of CLL patients have dramatically changed in the past decade and for the first time a significant overall survival improvement has been demonstrated in the disease - at least in the younger and fit patients - with the use of the FCR regimen, which combines rituximab fludarabine and cyclophosphamide. New drugs and new regimens are currently being developed for the relapsed patients and for those too old or too frail to receive aggressive treatments. Some of these promising compounds will likely be part of the future front-line treatments. Additionally, the increasing knowledge on the molecular features that predict the clinical outcome may soon result in a molecular classification of the disease. These acquisitions are producing a migration from palliative care to a curative and individually-tailored approach. In this review we tried to summarize the advances achieved in the past decade and help the specialists in internal medicine and the general practitioners to understand the completely changed scenario in which the disease should nowadays be managed. © 2013 European Federation of Internal Medicine.

Zovko A.,Karolinska Institutet | Viktorsson K.,Karolinska Institutet | Ha a g P.,Karolinska Institutet | Kovalerchick D.,Tel Aviv University | And 6 more authors.
Molecular Cancer Therapeutics | Year: 2014

Marine-derived compounds have been explored and considered as possible antitumor agents. In this study, we analyzed extracts of the sponge Cribrochalina vasculum for their ability to inhibit tumor cell proliferation. Screening identified two acetylenic compounds of similar structure that showed strong tumor-specific toxicity in non-small cell lung carcinoma (NSCLC) cells and small-cell lung carcinoma cells, and less prominent toxicity in ovarian carcinoma, while having no effect on normal cells. These acetylenic compounds were found to cause a time-dependent increase in activation of apoptotic signaling involving cleavage of caspase-9, caspase-3, and PARP, as well as apoptotic cell morphology in NSCLC cells, but not in normal fibroblasts. Further analysis demonstrated that these compounds caused conformational change in Bak and Bax, and resulted in loss of mitochondrial potential and cytochrome c release in NSCLC cells. Moreover, a decreased phosphorylation of the growth factor signaling kinases Akt, mTOR, and ERK was evident and an increased phosphorylation of JNK was observed. Thus, these acetylenic compounds hold potential as novel therapeutic agents that should be further explored for NSCLC and other tumor malignancies. ©2014 AACR.

Brambilla L.,Institute of Oncology Research IOR | Brambilla L.,New York University | Genini D.,Institute of Oncology Research IOR | Laurini E.,University of Trieste | And 8 more authors.
Molecular Oncology | Year: 2015

STAT3 is a key element in many oncogenic pathways and, like other transcription factors, is an attractive target for development of novel anticancer drugs. However, interfering with STAT3 functions has been a difficult task and very few small molecule inhibitors have made their way to the clinic. OPB-31121, an anticancer compound currently in clinical trials, has been reported to affect STAT3 signaling, although its mechanism of action has not been unequivocally demonstrated. In this study, we used a combined computational and experimental approach to investigate the molecular target and the mode of interaction of OPB-31121 with STAT3. In parallel, similar studies were performed with known STAT3 inhibitors (STAT3i) to validate our approach. Computational docking and molecular dynamics simulation (MDS) showed that OPB-31121 interacted with high affinity with the SH2 domain of STAT3. Interestingly, there was no overlap of the OPB-31121 binding site with those of the other STAT3i. Computational predictions were confirmed by in vitro binding assays and competition experiments along with site-directed mutagenesis of critical residues in the STAT3 SH2 domain. Isothermal titration calorimetry experiments demonstrated the remarkably high affinity of OPB-31121 for STAT3 with Kd (10 nM) 2-3 orders lower than other STAT3i. Notably, a similar ranking of the potency of the compounds was observed in terms of inhibition of STAT3 phosphorylation, cancer cell proliferation and clonogenicity. These results suggest that the high affinity and efficacy of OPB-31121 might be related to the unique features and mode of interaction of OPB-31121 with STAT3. These unique characteristics make OPB-31121 a promising candidate for further development and an interesting lead for designing new, more effective STAT3i. © 2015 Federation of European Biochemical Societies.

Akhmedov M.,Dalle Molle Institute for Artificial Intelligence | Akhmedov M.,Institute of Oncology Research IOR | Kwee I.,Dalle Molle Institute for Artificial Intelligence | Kwee I.,Institute of Oncology Research IOR | Montemanni R.,Dalle Molle Institute for Artificial Intelligence
Computers and Operations Research | Year: 2016

The Prize-collecting Steiner Tree Problem (PCSTP) is a well-known problem in graph theory and combinatorial optimization. It has been successfully applied to solve real problems such as fiber-optic and gas distribution networks design. In this work, we concentrate on its application in biology to perform a functional analysis of genes. It is common to analyze large networks in genomics to infer a hidden knowledge. Due to the NP-hard characteristics of the PCSTP, it is computationally costly, if possible, to achieve exact solutions for such huge instances. Therefore, there is a need for fast and efficient matheuristic algorithms to explore and understand the concealed information in huge biological graphs. In this study, we propose a matheuristic method based on clustering algorithm. The main target of the method is to scale up the applicability of the currently available exact methods to large graph instances, without loosing too much on solution quality. The proposed matheuristic method is composed of a preprocessing procedures, a heuristic clustering algorithm and an exact solver for the PCSTP, applied on sub-graphs. We examine the performance of the proposed method on real-world benchmark instances from biology, and compare its results with those of the exact solver alone, without the heuristic clustering. We obtain solutions in shorter execution time and with negligible optimality gaps. This enables analyzing very large biological networks with the currently available exact solvers. © 2015 Elsevier Ltd. All rights reserved.

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