Centro Of Riferimento Oncologico Cro Irccs

Aviano, Italy

Centro Of Riferimento Oncologico Cro Irccs

Aviano, Italy

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Veljkovic V.,Vinča Institute of Nuclear Sciences | Glisic S.,Vinča Institute of Nuclear Sciences | Scotch M.,Arizona State University | Branch D.R.,Center for Innovation | And 4 more authors.
Frontiers in Microbiology | Year: 2015

The worst Ebola virus (EV) outbreak in history has hit Liberia, Sierra Leone and Guinea hardest and the trend lines in this crisis are grave, and now represents a global public health threat concern. Limited therapeutic and/or prophylactic options are available for people suffering from Ebola virus disease (EVD) and further complicate the situation. Previous studies suggested that the EV glycoprotein (GP) is the main determinant causing structural damage of endothelial cells that triggers the hemorrhagic diathesis, but molecular mechanisms underlying this phenomenon remains elusive. Using the informational spectrum method (ISM), a virtual spectroscopy method for analysis of the protein-protein interactions, the interaction of GP with endothelial extracellular matrix (ECM) was investigated. Presented results of this in silico study suggest that Elastin Microfibril Interface Located Proteins (EMILINs) are involved in interaction between GP and ECM. This finding could contribute to a better understanding of EV/endothelium interaction and its role in pathogenesis, prevention and therapy of EVD. © 2015 Veljkovic, Glisic, Muller, Scotch, Branch, Perovic, Sencanski, Veljkovic and Colombatti.


Golato M.,Patologia Clinica Aziendale | Moretti M.,Laboratorio Of Patologia Clinica | Martinotti S.,Unita Operativa di Medicina Predittiva e Biologia Molecolare Clinica | Toniato E.M.,Unita Operativa di Medicina Predittiva e Biologia Molecolare Clinica | And 16 more authors.
Rivista Italiana della Medicina di Laboratorio | Year: 2016

The colorectal cancer (CCR) is still one of the most important neoplastic pathologies whose mortality and metastatic progression is strictly connected to the structural and biological characteristics of the primary tumor. Compared with an overall increase in incidence, there has been a reduction in mortality by almost 35 percent in the last two decades. These features are undoubtedly due to the significant progress of predictive and preventative medicine that employs several new diagnostic tools and surgical exploration devices (i.e. endoscopy) allowing earlier diagnosis and intervention on patient injuries; in this way, the neoplastic transformation of dysplastic and polyposis lesions and invasiveness of the tumoral mass can be prevent. In particular, the review describes the progress achieved in the screening population programs. Of considerable importance is fecal occult blood test (SOF) survey, which allows the identification of areas of minimal bleeding in the gastroenteric district, hiding a putative neoplastic process. SOF has been highly successful in recent times and has allowed, in Regions where the screening process is applied, to significantly reduce the risk of metastatic disease and the associated mortality rate. Another important forward step is the use of new molecular techniques that allow to analyze mutations and epigenetic lesions of genes involved in the pathogenic mechanism of tumor induction (fecal DNA analyses) as a high sensitivity and specificity instrument for the detection of micro-cracks cancer. Is also discussed, according to the evidence-based medicine principles, the role played by serological markers like CEA and Ca 19.9 which represent prediction and prognostic values in the follow-up and monitoring of the therapeutic success. © 2016, Società Italiana di Patologia Clinica e Medicina di Laboratorio.


Veljkovic M.,Sveti Sava Hospital | Dopsaj V.,Institute of Medical Biochemistry | Dopsaj M.,University of Belgrade | Branch D.R.,Canadian Blood Services | And 5 more authors.
PLoS ONE | Year: 2011

Background: There is convincing evidence from numerous clinical and epidemiological studies that physical activity can reduce the risk for breast and prostate cancer. The biological mechanisms underlying this phenomenon remain elusive. Herein we suggest a role for naturally produced antibodies reactive with the vasoactive intestinal peptide (VIP) in the suppression of breast and prostate cancer, which we believe could offer a possible molecular mechanism underlying control of these cancers by physical exercise. Methodology and Results: We found that sera from individuals having breast and prostate cancers have decreased titers of VIP natural antibodies as demonstrated by a lower reactivity against peptide NTM1, having similar informational and structural properties as VIP. In contrast, sera collected from elite athletes, exhibited titers of natural NTM1-reactive antibodies that are significantly increased, suggesting that physical activity boosts production of these antibodies. Significance: Presented results suggest that physical exercise stimulates production of natural anti-VIP antibodies and likely results in suppression of VIP. This, in turn, may play a protective role against breast and prostate cancers. Physical exercise should be further investigated as a potential tool in the treatment of these diseases. © 2011 Veljkovic et al.


Negom Kouodom M.,University of Padua | Ronconi L.,University of Padua | Celegato M.,Centro Of Riferimento Oncologico Cro Irccs | Nardon C.,University of Padua | And 6 more authors.
Journal of Medicinal Chemistry | Year: 2012

Complexes [Au IIIX 2(dtc-Sar-AA-O(t-Bu))] (AA = Gly, X = Br (1)/Cl (2); AA = Aib, X = Br (3)/Cl (4); AA = l-Phe, X = Br (5)/Cl (6)) were designed on purpose in order to obtain gold(III)-based anticancer peptidomimetics that might specifically target two peptide transporters (namely, PEPT1 and PEPT2) upregulated in several tumor cells. All the compounds were characterized by means of FT-IR and mono- and multidimensional NMR spectroscopy, and the crystal structure of [Au IIIBr 2(dtc-Sar-Aib-O(t- Bu))] (3) was solved and refined. According to in vitro cytotoxicity studies, the Aib-containing complexes 3 and 4 turned out to be the most effective toward all the human tumor cell lines evaluated (PC3, DU145, 2008, C13, and L540), reporting IC 50 values much lower than that of cisplatin. Remarkably, they showed no cross-resistance with cisplatin itself and were proved to inhibit tumor cell proliferation by inducing either apoptosis or late apoptosis/necrosis depending on the cell lines. Biological results are here reported and discussed in terms of the structure-activity relationship. © 2012 American Chemical Society.


Vaisitti T.,University of Turin | Vaisitti T.,Human Genetics Foundation HuGeF | Audrito V.,University of Turin | Audrito V.,Human Genetics Foundation HuGeF | And 17 more authors.
Leukemia | Year: 2015

The ecto-enzyme CD38 is gaining momentum as a novel therapeutic target for patients with hematological malignancies, with several anti-CD38 monoclonal antibodies in clinical trials with promising results. In chronic lymphocytic leukemia (CLL) CD38 is a marker of unfavorable prognosis and a central factor in the pathogenetic network underlying the disease: activation of CD38 regulates genetic pathways involved in proliferation and movement. Here we show that CD38 is enzymatically active in primary CLL cells and that its forced expression increases disease aggressiveness in a xenograft model. The effect is completely lost when using an enzyme-deficient version of CD38 with a single amino-acid mutation. Through the enzymatic conversion of NAD into ADPR (ADP-ribose) and cADPR (cyclic ADP-ribose), CD38 increases cytoplasmic Ca 2+ concentrations, positively influencing proliferation and signaling mediated via chemokine receptors or integrins. Consistently, inhibition of the enzymatic activities of CD38 using the flavonoid kuromanin blocks CLL chemotaxis, adhesion and in vivo homing. In a short-term xenograft model using primary cells, kuromanin treatment traps CLL cells in the blood, thereby increasing responses to chemotherapy. These results suggest that monoclonal antibodies that block the enzymatic activities of CD38 or enzyme inhibitors may prove therapeutically useful. © 2015 Macmillan Publishers Limited All rights reserved


PubMed | University of Genoa, CNR Institute of Neuroscience, Human Genetics Foundation HuGeF, University of Turin and 2 more.
Type: Journal Article | Journal: Leukemia | Year: 2015

The ecto-enzyme CD38 is gaining momentum as a novel therapeutic target for patients with hematological malignancies, with several anti-CD38 monoclonal antibodies in clinical trials with promising results. In chronic lymphocytic leukemia (CLL) CD38 is a marker of unfavorable prognosis and a central factor in the pathogenetic network underlying the disease: activation of CD38 regulates genetic pathways involved in proliferation and movement. Here we show that CD38 is enzymatically active in primary CLL cells and that its forced expression increases disease aggressiveness in a xenograft model. The effect is completely lost when using an enzyme-deficient version of CD38 with a single amino-acid mutation. Through the enzymatic conversion of NAD into ADPR (ADP-ribose) and cADPR (cyclic ADP-ribose), CD38 increases cytoplasmic Ca(2+) concentrations, positively influencing proliferation and signaling mediated via chemokine receptors or integrins. Consistently, inhibition of the enzymatic activities of CD38 using the flavonoid kuromanin blocks CLL chemotaxis, adhesion and in vivo homing. In a short-term xenograft model using primary cells, kuromanin treatment traps CLL cells in the blood, thereby increasing responses to chemotherapy. These results suggest that monoclonal antibodies that block the enzymatic activities of CD38 or enzyme inhibitors may prove therapeutically useful.


Veljkovic M.,Sveti Sava Hospital | Branch D.R.,7 College Street | Dopsaj V.,Institute of Medical Biochemistry | Veljkovic V.,Vinča Institute of Nuclear Sciences | And 3 more authors.
Medical Hypotheses | Year: 2011

Objectives: The incidence of non-AIDS-defining cancer is remarkably higher in HIV-infected than in the general population. In contrast, breast cancer risk is significantly reduced in the HIV-infected population. The molecular mechanisms underlying the phenomenon of suppression of breast cancer in the HIV-infected population may serve as a basis for development of a new platform for prevention and treatment of breast cancer. Hypothesis: Various evidences indicate that vasoactive intestinal peptide (VIP) plays an important role in growth, and differentiation of breast cancer. We previously showed (i) that natural antibodies recognizing VIP and the gp120-derived peptide NTM significantly contribute to the control of HIV disease progression by suppression of VIP-like activity of HIV-1 gp120 and (ii) that physical exercise stimulates production of these natural antibodies. These findings suggest that natural anti-VIP/NTM antibodies could contribute to a decrease of breast cancer in the HIV-infected population by suppression of VIP, which may play a pro/oncogenic function. Aerobic exercise which stimulates production of anti-VIP/NTM antibodies could be used as prevention and supportive treatment of breast cancer. Impact: Immunotherapy based on natural anti-VIP/NTM antibodies could serve as an effective adjunct therapy for the treatment of breast cancer. Similarly, aerobic exercise, which stimulates production of these antibodies, should be considered as an inexpensive and safe preventive and supportive breast cancer therapy. Natural anti-VIP/NTM antibodies also represent promising prognostic marker for breast cancer. © 2011 Elsevier Ltd.


Ronconi L.,University of Padua | Aldinucci D.,Centro Of Riferimento Oncologico Cro Irccs | Dou Q.P.,Barbara Ann Karmanos Cancer Institute | Fregona D.,University of Padua
Anti-Cancer Agents in Medicinal Chemistry | Year: 2010

In this review paper we aim at giving a detailed overview on our research work devoted to the design of gold-based anticancer agents. In particular, during the last decade, we have been developing some gold(III)-dithiocarbamato derivates showing outstanding in vitro and in vivo antitumor properties and reduced, or even no, systemic and renal toxicity, compared to the reference clinically-established anticancer drug cisplatin. Starting from the rationale behind our investigations, we here summarize the results achieved so far, focusing on the latest in-depth mechanistic studies that have recently provided insights into their mechanism of action, thus opening up new prospects for further pharmacological testing and, hopefully, to enter clinical trials. © 2010 Bentham Science Publishers Ltd.


Cattaruzza L.,Centro Of Riferimento Oncologico Cro Irccs | Fregona D.,University of Padua | Mongiat M.,Centro Of Riferimento Oncologico Cro Irccs | Ronconi L.,University of Padua | And 3 more authors.
International Journal of Cancer | Year: 2011

Among the nonplatinum antitumor drugs, gold(III)-dithiocarbamato derivatives have recently attracted considerable attention due to their strong in vitro and in vivo antiproliferative activity and reduced renal toxicity. Some of them, namely [AuCl2(DMDT)] (compound 1) and [AuBr 2(ESDT)] (compound 2), have shown to be highly active against the androgen-resistant prostate cancer cell lines PC3 and DU145, both inhibiting cell proliferation in a dose-dependent way, and are more active than the reference drug cisplatin (cis-[PtCl2(NH3)2]). In particular, [AuCl2(DMDT)] was proved cytotoxic against cisplatin-resistant R-PC3 cells, with activity levels comparable to those induced on the parent cisplatin-sensitive PC3 cells, ruling out the occurrence of cross-resistance phenomena. Moreover, it causes early cell damage, slightly affecting the cell cycle, thus suggesting a different mechanism of action from clinically established platinum-based drugs. In fact, the investigated gold(III) complex alters mitochondrial functions, promoting mitochondrial membrane permeabilization and Cyt-c release, stimulating ROS generation, and strongly inhibiting the activity of the selenoenzyme TrxR, which is overexpressed in prostate cancer and associated with the onset of drug resistance. In addition, it induces apoptosis, caspase activation, Bcl-2 downregulation and Bax upregulation, reduces the expression of the phosphorylated form of the EGFR, and it inhibits PC3 cell migration. Finally, the treatment of PC3 prostate tumor-bearing nude mice with [AuCl2(DMDT)] significantly inhibited tumor growth in vivo, causing minimal systemic toxicity. Altogether, our results confirm that these gold(III)-dithiocarbamato derivatives have potential for the treatment of prostate cancer. © 2010 UICC.


Veljkovic V.,Vinča Institute of Nuclear Sciences | Glisic S.,Vinča Institute of Nuclear Sciences | Veljkovic N.,Vinča Institute of Nuclear Sciences | Bojic T.,Vinča Institute of Nuclear Sciences | And 3 more authors.
Vaccine | Year: 2014

Despite plausible evidence for beneficial effects of the vaccination against influenza in cardiovascular diseases (CVD) very limited studies have been carried out to explain the molecular mechanism of this phenomenon. Using the informational spectrum method (ISM), a virtual spectroscopy method for analysis of protein-protein interactions, the bradykinin 2 receptor (BKB2R) was identified as a principal host protein which could mediate molecular processes underlying the cardioprotective effect of influenza vaccines.Based on this finding we suggest that some antibodies elicited by influenza vaccines act as agonists, which activate a BKB2R-associated signaling pathway contributing to the protection against CVD. The ISM analysis of 14 influenza viruses, which were used as components of seasonal vaccines, revealed four vaccine viruses A/Beijing/262/95(H1N1), A/NewCaledonia/20/1999(H1N1), A/Christchurch/28/2003(H3N2) and A/Perth/16/2009(H3N2), which could be suited best for further studies on the cardioprotective effect of influenza vaccines. © 2014 Elsevier Ltd.

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