BU Oncology

Nerviano, Italy

BU Oncology

Nerviano, Italy

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Russo M.,BU Oncology | Invernizzi A.,Instituto Zooprofilattico Sperimentale della Lombardia e dellEmila Romagna | Gobbi A.,Italian National Cancer Institute | Radaelli E.,University of Milan | Radaelli E.,Fondazione Filarete
Veterinary Pathology | Year: 2013

This report describes the clinicopathological features of a case of diffuse scaling dermatitis that occurred in a 16-week-old female athymic nude (CrTac:NCr-Foxn1nu) mouse. Gross presentation was suggestive of Corynebacterium bovis infection (scaly skin disease). However, C. bovis was not isolated from the skin of the affected animal or from the skin of unaffected CrTac:NCr-Foxn1nu mice housed in the same cage or room. Staphylococcus xylosus was instead isolated in high numbers from the skin lesion, whereas only a few colonies were recovered from the skin of unaffected mice. Microscopically, the affected skin was characterized by chronic hyperplastic and hyperkeratotic dermatitis with focal ulcerations, extensive serocellular crusts, and intralesional clusters of Gram-positive coccoid bacteria. Although gross presentation of the reported case was suggestive of C. bovis infection, epidemiological, histopathological, and bacteriological findings definitively ruled out an outbreak of scaly skin disease. A diagnostic hypothesis of hyperplastic and hyperkeratotic dermatitis associated with opportunistic S. xylosus infection was formulated based on increased bacterial burden and presence of intralesional Gram-positive coccoid bacteria. © The Author(s) 2012.


Martelli C.,University of Milan | Borelli M.,University of Milan | Ottobrini L.,University of Milan | Rainone V.,University of Milan | And 10 more authors.
Molecular Imaging and Biology | Year: 2012

Purpose: The authors present a protocol for the in vivo evaluation, using different imaging techniques, of lymph node (LN) homing of tumor-specific dendritic cells (DCs) in a murine breast cancer model. Procedures: Bone marrow DCs were labeled with paramagnetic nanoparticles (MNPs) or 111In- oxine. Antigen loading was performed using tumor lysate. Mature DCs were injected into the footpads of transgenic tumor-bearing mice (MMTV-Ras) and DC migration was tracked by magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT). Ex vivo analyses were performed to validate the imaging data. Results: DC labeling, both with MNPs and with 111In-oxine, did not affect DC phenotype or functionality. MRI and SPECT allowed the detection of iron and 111In in both axillary and popliteal LNs. Immunohistochemistry and γ-counting revealed the presence of DCs in LNs. Conclusions: MRI and SPECT imaging, by allowing in vivo dynamic monitoring of DC migration, could further the development and optimization of efficient anti-cancer vaccines. © Academy of Molecular Imaging and Society for Molecular Imaging, 2011.


Libani I.V.,University of Milan | Lucignani G.,University of Milan | Gianelli U.,University of Milan | Degrassi A.,BU Oncology | And 5 more authors.
Molecular Imaging and Biology | Year: 2012

Purpose: We propose herein labeling protocols for multimodal in vivo visualization of human skeletal muscle cells (HSkMCs) by MRI and BLI to investigate the survival, localization, and proliferation/differentiation of these cells in cell-mediated therapy. Procedures: HSkMCs were labeled with different quantities of Endorem® and transfection agents or infected with lentiviral vector expressing the luciferase gene under the myogenin promoter. Cells were evaluated before and after intra-arterial injection in NUDE mice with N 2-induced muscle inflammation. Results: Neither iron labeling nor infection affected cell features; the number of iron-positive cells increased proportionally to the iron content in the medium and in the presence of transfection agents. Loaded cells were detected for up to 1 month by MRI and 2 months by BLI. Conclusions: These protocols could be used to visualize new stem cells, in vivo and over time, in preclinical studies of cell-based treatments for myopathies of different etiologies. © Academy of Molecular Imaging and Society for Molecular Imaging, 2011.


Albanese C.,BU Oncology | Alzani R.,BU Oncology | Amboldi N.,BU Oncology | Avanzi N.,BU Oncology | And 15 more authors.
Molecular Cancer Therapeutics | Year: 2010

Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC50. PHA-848125-treated cells show cell cycle arrest in G1 and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment. ©2010 AACR.


Degrassi A.,BU Oncology | Russo M.,BU Oncology | Nanni C.,Policlinico S. Orsola Malpighi | Patton V.,BU Oncology | And 6 more authors.
Molecular Cancer Therapeutics | Year: 2010

K-ras is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), the most common form of lung cancer. Recent studies indicate that NSCLC patients with mutant K-ras do not respond to epidermal growth factor receptor inhibitors. In the attempt to find alternative therapeutic regimes for such patients, we tested PHA-848125, an oral pan cyclin-dependent kinase inhibitor currently under evaluation in phase II clinical trial, on a transgenic mouse model, K-RasG12DLA2, which develops pulmonary cancerous lesions reminiscent of human lung adenocarcinomas.We used magnetic resonance imaging and positron emission tomography to follow longitudinally disease progression and evaluate therapeutic efficacy in this model. Treatment of K-RasG12DLA2 mice with 40 mg/kg twice daily for 10 days with PHA-848125 induced a significant tumor growth inhibition at the end of treatment (P < 0.005) and this was accompanied by a reduction in the cell membrane turnover, as seen by 11C-Choline-positron emission tomography (P < 0.05). Magnetic resonance imaging data were validated versus histology and the mechanism of action of the compound was verified by immunohistochemistry, using cyclin-dependent kinase-related biomarkers phospho-Retinoblastoma and cyclin A. In this study, multimodality imaging was successfully used for the preclinical assessment of PHA-848125 therapeutic efficacy on a lung adenocarcinoma mouse model. This compound induced a volumetric and metabolic anticancer effect and could represent a valid therapeutic approach for NSCLC patients with mutant K-ras. ©2010 AACR.


PubMed | BU Oncology and University of Milan
Type: Journal Article | Journal: PloS one | Year: 2016

Dendritic cells play a key role as initiators of T-cell responses, and even if tumour antigen-loaded dendritic cells can induce anti-tumour responses, their efficacy has been questioned, suggesting a need to enhance immunization strategies.We focused on the characterization of bone marrow-derived dendritic cells pulsed with whole tumour lysate (TAA-DC), as a source of known and unknown antigens, in a mouse model of breast cancer (MMTV-Ras). Dendritic cells were evaluated for antigen uptake and for the expression of MHC class I/II and costimulatory molecules and markers associated with maturation.Results showed that antigen-loaded dendritic cells are characterized by a phenotypically semi-mature/mature profile and by the upregulation of genes involved in antigen presentation and T-cell priming. Activated dendritic cells stimulated T-cell proliferation and induced the production of high concentrations of IL-12p70 and IFN- but only low levels of IL-10, indicating their ability to elicit a TH1-immune response. Furthermore, administration of Antigen loaded-Dendritic Cells in MMTV-Ras mice evoked a strong anti-tumour response in vivo as demonstrated by a general activation of immunocompetent cells and the release of TH1 cytokines.Data herein could be useful in the design of antitumoral DC-based therapies, showing a specific activation of immune system against breast cancer.


PubMed | BU Oncology
Type: Journal Article | Journal: British journal of pharmacology | Year: 2013

Malignant gliomas, the most common primary brain tumours, are highly invasive and neurologically destructive neoplasms with a very bad prognosis due to the difficulty in removing the mass completely by surgery and the limited activity of current therapeutic agents. PHA-848125 is a multi-kinase inhibitor with broad anti-tumour activity in pre-clinical studies and good tolerability in phase 1 studies, which could affect two main pathways involved in glioma pathogenesis, the G1-S phase progression control pathway through the inhibition of cyclin-dependent kinases and the signalling pathways mediated by tyrosine kinase growth factor receptors, such as tropomyosin receptors. For this reason, we tested PHA-848125 in glioma models.PHA-848125 was tested on a panel of glioma cell lines in vitro to evaluate inhibition of proliferation and mechanism of action. In vivo efficacy was evaluated on two glioma models both as single agent and in combination with standard therapy.When tested on a subset of representative glioma cell lines, PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell cycle and signal transduction markers. Relevantly, PHA-848125 was also able to induce cell death through autophagy in all cell lines. Good anti-tumour efficacy was observed by oral route in different glioma models both with s.c. and intracranial implantation. Indeed, we demonstrate that the drug is able to cross the blood-brain barrier. Moreover, the combination of PHA-848125 with temozolomide resulted in a synergistic effect, and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide.All the pre-clinical data obtained so far suggest that PHA-848125 may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in phase 2 trials for this indication.


PubMed | BU Oncology
Type: Journal Article | Journal: Molecular cancer therapeutics | Year: 2010

Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC(50). PHA-848125-treated cells show cell cycle arrest in G(1) and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment.


PubMed | BU Oncology
Type: Case Reports | Journal: Veterinary pathology | Year: 2013

This report describes the clinicopathological features of a case of diffuse scaling dermatitis that occurred in a 16-week-old female athymic nude (CrTac:NCr-Foxn1(nu)) mouse. Gross presentation was suggestive of Corynebacterium bovis infection (scaly skin disease). However, C. bovis was not isolated from the skin of the affected animal or from the skin of unaffected CrTac:NCr-Foxn1(nu) mice housed in the same cage or room. Staphylococcus xylosus was instead isolated in high numbers from the skin lesion, whereas only a few colonies were recovered from the skin of unaffected mice. Microscopically, the affected skin was characterized by chronic hyperplastic and hyperkeratotic dermatitis with focal ulcerations, extensive serocellular crusts, and intralesional clusters of Gram-positive coccoid bacteria. Although gross presentation of the reported case was suggestive of C. bovis infection, epidemiological, histopathological, and bacteriological findings definitively ruled out an outbreak of scaly skin disease. A diagnostic hypothesis of hyperplastic and hyperkeratotic dermatitis associated with opportunistic S. xylosus infection was formulated based on increased bacterial burden and presence of intralesional Gram-positive coccoid bacteria.


PubMed | BU Oncology
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2013

In vitro approaches using human cancer cell lines aimed to identify and validate oncology targets, have pinpointed a number of key targets and signalling pathways which control cell growth and cell death. However, tumors are more than insular masses of proliferating cancer cells. Instead they are complex tissues composed of multiple distinct cell types that participate in homotypic and heterotypic interactions and depend upon each other for their growth. Therefore, many targets in oncology need to be validated in the context of the whole animal. This review provides an overview on how animal models can be generated and used for target identification and validation in vivo.

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