Instituto Europeo Of Oncologia

Milano, Italy

Instituto Europeo Of Oncologia

Milano, Italy
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Di Fiore P.P.,Instituto Europeo Of Oncologia | Di Fiore P.P.,University of Milan | von Zastrow M.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2014

The endocytic network comprises a vast and intricate system of membrane-delimited cell entry and cargo sorting routes running between biochemically and functionally distinct intracellular compartments. The endocytic network caters to the organization and redistribution of diverse subcellular components, and mediates appropriate shuttling and processing of materials acquired from neighboring cells or the extracellular milieu. Such trafficking logistics, despite their importance, represent only one facet of endocytic function. The endocytic network also plays a key role in organizing, mediating, and regulating cellular signal transduction events. Conversely, cellular signaling processes tightly control the endocytic pathway at different steps. The present article provides a perspective on the intimate relationships that exist between particular endocytic and cellular signaling processes in mammalian cells, within the context of understanding the impact of this nexus on integrated physiology. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Bogani G.,University of Insubria | Cliby W.A.,Gynecologic Surgery Unit | Aletti G.D.,Instituto Europeo Of Oncologia
Gynecologic Oncology | Year: 2015

Objective. To reviewthe current evidence on the effects of intra-abdominalmorcellation on survival outcomes of patients affected by unexpected uterine leiomyosarcoma (ULMS) and to estimate the risk of recurrence in those patients. Methods. PubMed (MEDLINE), Scopus, Embase, Web of Science databases as well as, were searched for data evaluating the effects of intra-abdominal morcellation on survival outcomes of patients with undiagnosed ULMS. Studies were evaluated per the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) and the American College of Obstetricians and Gynecologists (ACOG) guidelines. Results. Sixty manuscripts were screened, 11 (18%) were selected and four (7%) were included. Overall, 202 patients were included: 75 (37%) patients had morcellation of ULMS, while 127 (63%) patients had not. A meta-analysis of these studies showed that morcellation increased the overall (62% vs. 39%; OR: 3.16 (95% CI: 1.38, 7.26)) and intra-abdominal (39% vs. 9%; OR: 4.11 (95% CI: 1.92, 8.81)) recurrence rates as well as death rate (48% vs. 29%; OR: 2.42 (95% CI: 1.19, 4.92)). No between-group difference in cumulative extra-abdominal recurrence (OR: 0.34 (95% CI: 0.07, 1.59)) rate was observed. Conclusions. Our data support a significant correlation between uterinemorcellation and an increased risk of intra-abdominal recurrence in patients affected by unexpected ULMS. However, the limited data on this issue and the absence of high level of evidence suggest the need of further studies designed to estimate the risk to benefit ratio of morcellation in patients with uterine fibroids and undiagnosed ULMS. © 2014 Elsevier Inc. All rights reserved.

Sabo A.,Italian Institute of Technology | Amati B.,Italian Institute of Technology | Amati B.,Instituto Europeo Of Oncologia
Cold Spring Harbor Perspectives in Medicine | Year: 2014

MYC dimerizes with MAX to bind DNA, with a preference for the E-box consensus CACGTG and several variant motifs. In cells, MYC binds DNA preferentially within transcriptionally active promoter regions. Although several thousand promoters are bound under physiological (low MYC) conditions, these represent only a fraction of all accessible, active promoters. MYC overexpression-as commonly observed in cancer cells-leads to invasion of virtually all active promoters, as well as of distal enhancer elements.We summarize here what is currently known about the mechanisms that may guide this process. We propose that binding site recognition is determined by low-affinity protein-protein interactions between MYC/MAX dimers and components of the basal transcriptional machinery, other chromatin-associated protein complexes, and/or DNA-bound transcription factors. DNA binding occurs subsequently, without an obligate requirement for sequence recognition. Local DNA scanning then leads to preferential stabilization of the MYC/MAX dimer on high-affinity DNA elements. This model is consistent with the invasion of all active promoters that occurs at elevated MYC levels, but posits that important differences in affinity persist between physiological target sites and the newly invaded elements, which may not all be bound in a productive regulatory mode. The implications of this model for transcriptional control by MYC in normal and cancer cells are discussed in the light of the latest literature. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Curigliano G.,Instituto Europeo Of Oncologia
Breast | Year: 2011

Summary: Evading immune destruction should be considered an emerging hallmark of cancer. Highly immunogenic cancer cells can be eliminated in immunocompetent hosts as a result of the "immunoediting" process. Weakly immunogenic variants can grow and generate solid tumors. Regulatory T cells (Tregs) were found to be involved in the maintenance of the immune tolerance both preventing autoimmune disease and curtailing antitumour immune response. Modulation of immune response in cancer patients is the result of a balanced activity of Tregs and T effector cells. In cancer patients increased number of Tregs was found in blood and tumour tissue: it was demonstrated that Tregs suppress T-cell response and natural killer (NK) cells proliferation and function, thus interfering both with acquired and innate immunity. Upregulation of Tregs in tumor bed can be associated with worse prognosis. Drugs blocking function of Tregs increase activity of T effectors and, as side effect, induce an autoimmune disease. Issues of biology and prognosis of breast cancer in the presence of a deregulation of the immune system needs to be studied. The identification of immunological and genetic features affecting immune response in patients with minimal tumor burden are the optimal background for development of clinical studies in the adjuvant setting. © 2011 Elsevier Ltd.

Curigliano G.,Instituto Europeo Of Oncologia | Criscitiello C.,Instituto Europeo Of Oncologia | Gelao L.,Instituto Europeo Of Oncologia | Goldhirsch A.,Instituto Europeo Of Oncologia
Clinical Cancer Research | Year: 2013

Human leukocyte antigen G (HLA-G) is a nonclassical MHC class I molecule that exerts important tolerogenic functions. Its main physiologic expression occurs in the placenta, where it participates in the maternal tolerance toward the fetus. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. It is expressed in various types of primary solid (melanoma, head and neck, lung, urogenital, gastrointestinal, and breast cancers) and hematologic malignancies (acute leukemia, lymphomas) and metastases. HLA-G ectopic expression is observed in cancer, suggesting that its expression is one strategy used by tumor cells to escape immune surveillance. In this review, we will focus on HLA-G expression in cancers and its association with the prognosis. We will highlight the underlying molecular mechanisms of impaired HLA-G expression, the immune tolerant function of HLA-G in tumors, and the potential diagnostic use of membrane-bound and soluble HLA-G as a biomarker to identify tumors and to monitor disease stage. As HLA-G is a potent immunoinhibitory molecule, its blockade remains an attractive therapeutic strategy against cancer. Elimination of HLA-G-expressing cancer cells would be important in the efficacy of anticancer therapies. ©2013 AACR.

Tsilingiri K.,Instituto Europeo Of Oncologia | Rescigno M.,Instituto Europeo Of Oncologia
Beneficial Microbes | Year: 2013

The use of probiotics and synbiotics in the food industry or as food supplements for a balanced diet and improved gut homeostasis has been blooming for the past decade. As feedback from healthy consumers is rather enthusiastic, a lot of effort is currently directed in elucidating the mechanisms of interaction between beneficial microbes and barrier and immune function of the host. The use of probiotics or synbiotics for treating certain pathologies has also been examined, however, the outcome has not always been favourable. In most cases, the effect of the administered probiotic is evident when the bacteria are still alive at the time they reach the small and large intestine, suggesting that it is dependent on the metabolic activity of the bacteria. Indeed, in some occasions it has been shown that the culture supernatant of these bacteria mediates the immunomodulatory effect conferred to the host. Recent work on relevant probiotic strains has also led to the isolation and characterisation of certain probiotic-produced, soluble factors, here called postbiotics, which were sufficient to elicit the desired response. Here, we summarise these recent findings and propose the use of purified and well characterised postbiotic components as a safer alternative for clinical applications, especially in chronic inflammatory conditions like inflammatory bowel disease, where probiotics have not yet given encouraging results as far as induction of remission is concerned. © 2013 Wageningen Academic Publishers.

Colombo N.,Instituto Europeo Of Oncologia
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society | Year: 2011

The results of the OVA-301 study show that trabectedin in combination with pegylated liposomal doxorubicin (PLD) results in improved progression-free survival and response rate in patients with advanced ovarian cancer. The trial has also demonstrated a trend toward improvement in overall survival. A subgroup analysis indicates that in the subset of patients with platinum-free interval (PFI) of 6 to 12 months, the combined treatment resulted in a 6-month improvement in overall survival. Furthermore, in the patients who have received third-line treatment with a platinum agent, it was found that the survival was better in those who had received trabectedin and PLD. These results suggest that prolonging the PFI by a nonplatinum-effective regimen improves the outcome with subsequent, third-line platinum treatment. This strategy may also have positive effects in treatment tolerability, as it allows extra time to recover from platinum-induced toxicities. This hypothesis is currently been tested in the INOVATYON (INternational OVArian Cancer Patients Trial With YONdelis) phase III study.

Criscitiello C.,Instituto Europeo Of Oncologia | Esposito A.,Instituto Europeo Of Oncologia | Curigliano G.,Instituto Europeo Of Oncologia
Current Opinion in Oncology | Year: 2014

Purpose of review: Combinatorial strategies in cancer medicine will not only target cancer cell-intrinsic pathways, but also cancer cell-extrinsic cells, pathways, and mediators of the tumor microenvironment. The aim of the present review is to define the roles of the tumor microenvironment in primary and metastatic breast cancer progression. Recent findings: The cancer microenvironment is composed of nontransformed host stromal cells, such as endothelial cells, fibroblasts, various immune cells, and a complex extracellular matrix secreted by both the normal and neoplastic cells embedded in it. The stromal constituents contribute to the core and emergent hallmarks of cancer. In particular, they can boost sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction. Summary: The stromal cells play a role in enabling or enhancing multiple hallmark capabilities in tumor microenvironment. This is a background for therapeutic-targeting strategies aimed to abrogate the stroma's contribution. Targeting tumor-associated fibroblasts, macrophages, angiogenesis and enhancing immune response may represent a paradigm-shifting approach to treating human cancer in the near future. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Criscitiello C.,Instituto Europeo Of Oncologia | Curigliano G.,Instituto Europeo Of Oncologia
Current Opinion in Oncology | Year: 2013

PURPOSE OF REVIEW: We review recent advances leading to a new understanding of immunology of breast cancer with its potential clinical applications. RECENT FINDINGS: With the exception of antibody-based HER2 targeting, immunotherapy in breast cancer has largely been an unsatisfying experience. To improve the efficacy of breast cancer immunotherapeutics, a better understanding of the relation between innate and adaptive immune responses, of the immune escape mechanisms, the discovery of mechanisms underlying immunological tolerance, and the acknowledgment of the importance of both cell-mediated and humoral adaptive immunity for the control of tumor growth are needed. SUMMARY: Cancer takes advantage of the ability to hide from the immune system by exploiting a series of immune escape mechanisms. Among these mechanisms are the hijackings of immune cell-intrinsic checkpoints that are induced on T-cell activation. Blockade of these checkpoints - cytotoxic T-lymphocyte-associated antigen 4 or the programmed death 1 receptor - recently provided the first evidence of activity of an immune-modulation approach in the treatment of solid tumors. The future frontier in the immunotherapeutics of breast cancer requires identification of predictive factors. The immune system remembers what it targets, so once the system is correctly activated, it may mediate a long-lasting tumor response. © 2013 Wolters Kluwer Health Lippincott Williams & Wilkins.

Curigliano G.,Instituto Europeo Of Oncologia | Goldhirsch A.,Instituto Europeo Of Oncologia
Journal of the National Cancer Institute - Monographs | Year: 2011

Triple-negative breast cancer accounts for about 15%-20% of all breast cancers. Patients with triple-negative subtype have a significantly increased risk of relapse and death. A panel of specific molecular alterations like high rate of p53 mutations, frequent loss of function of BRCA1, and several tyrosine kinase activations has been shown in this specific phenotype. An optimal chemotherapy regimen for these cancers remains to be determined, representing a major challenge for patient management. DNA alkylating agents, as cisplatin, were shown to be particularly effective in the neoadjuvant setting for patients with the disease. Targeted therapies are being successfully developed. Poly (ADP-ribose) polymerase-1 inhibitors induce tumor response as a single agent in BRCA1-mutated breast cancer and might sensitize cancer cells to cisplatin in the triple-negative subpopulation. Chemotherapy is a cornerstone of current clinical practice for this type of disease. Progress might derive from refined biology-driven phase II trials that will also integrate targeted agents with chemotherapy. © The Author 2011. Published by Oxford University Press. All rights reserved.

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