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  1. Article ; Online: How to study and overcome tumor heterogeneity with circulating biomarkers: The breast cancer case.

    Appierto, Valentina / Di Cosimo, Serena / Reduzzi, Carolina / Pala, Valentina / Cappelletti, Vera / Daidone, Maria Grazia

    Seminars in cancer biology

    2017  Volume 44, Page(s) 106–116

    Abstract: Breast cancer ranks first among female cancer-related deaths in Western countries. As the primary tumor can often be controlled by surgical resection, the survival of women with breast cancer is closely linked to the incidence of distant metastases. ... ...

    Abstract Breast cancer ranks first among female cancer-related deaths in Western countries. As the primary tumor can often be controlled by surgical resection, the survival of women with breast cancer is closely linked to the incidence of distant metastases. Molecular screening by next generation sequencing highlighted the spatial and temporal heterogeneity of solid tumors as well as the clonal evolution of cancer cells during progression and under treatment pressure. Such findings question whether an optimal assessment of disease progression and a screening for druggable mutations should be based on molecular features of primary or recurrent/metastatic lesions and therefore represent a crucial element for failure or success of personalized medicine. In fact, new targeted therapies may induce only short-term benefit annulled by the emergence of resistant clones with new driver mutations which would need to be rapidly and reliably identified. Serial tissue sampling is therefore essential but, unfortunately, also represents a problem since biopsies from solid lesions, which are invasive and potentially painful and risky, cannot be easily repeatedly sampled, are inaccessible or may not fully reflect tumor heterogeneity. The need to early detect and strike this "moving target" is now directing the scientific community toward liquid biopsy-based biomarkers, which include circulating tumor cells (CTC) and cell-free circulating tumor DNA (ctDNA), can be repeatedly assessed through non-invasive and easy-to-perform procedures and may act as reliable read-outs of functional and molecular features of recurrent/metastatic lesions. In this review we summarize the outcome of CTCs and ctDNA in breast cancer, with special reference on their role on unveiling and overcoming tumor heterogeneity, on their potential relevance for tumor surveillance and monitoring, and for the selection of therapeutic options. Finally, we propose integration between blood-based molecular and clinical approaches for monitoring disease progression according to the specific pattern of recurrence of the most aggressive breast cancer molecular subtypes.
    Language English
    Publishing date 2017-06
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1033980-2
    ISSN 1096-3650 ; 1044-579X
    ISSN (online) 1096-3650
    ISSN 1044-579X
    DOI 10.1016/j.semcancer.2017.04.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Implications of stemness-related signaling pathways in breast cancer response to therapy.

    Angeloni, Valentina / Tiberio, Paola / Appierto, Valentina / Daidone, Maria Grazia

    Seminars in cancer biology

    2015  Volume 31, Page(s) 43–51

    Abstract: There is accumulating evidence that breast cancer may arise from a small subpopulation of transformed mammary stem/progenitor cells, termed breast cancer-initiating cells (BCICs), responsible for initiation and maintenance of cancer. BCICs have been ... ...

    Abstract There is accumulating evidence that breast cancer may arise from a small subpopulation of transformed mammary stem/progenitor cells, termed breast cancer-initiating cells (BCICs), responsible for initiation and maintenance of cancer. BCICs have been identified in clinical specimens based on CD44(+)/CD24(-/low) membrane expression and/or enzymatic activity of aldehyde dehydrogenase 1 (ALDH1+), or isolated and in vitro propagated as non-adherent spheres. This cell population has been demonstrated to be able to recreate, when injected in mice even at very low concentrations, the same histopathological features of the tumor they were derived from and to escape from current therapeutic strategies. Alterations in genes involved in stemness-related pathways, such as Wnt, Notch, and Sonic Hedgehog, have been proven to play a role in breast cancer progression. Targeting these key elements represents an attractive option, with a solid rationale, although possible concerns may derive from the poor knowledge of tolerance and efficacy of inhibiting these mechanisms without inducing severe side effects. In addition, efforts to develop alternative BCIC-targeted therapies against stemness markers (CD44 and ALDH1) and molecules involved in regulating EMT- and HER2-related pathways, or able to reverse the multi-drug resistance phenotype, or to induce differentiation and to control cell survival pathways are currently ongoing and encouraging results from pre-clinical studies have already been obtained using in vitro and in vivo models.
    MeSH term(s) Animals ; Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/antagonists & inhibitors ; Biomarkers, Tumor/metabolism ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Disease Progression ; Humans ; Mice ; Molecular Targeted Therapy/methods ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Signal Transduction
    Chemical Substances Antineoplastic Agents ; Biomarkers, Tumor
    Language English
    Publishing date 2015-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1033980-2
    ISSN 1096-3650 ; 1044-579X
    ISSN (online) 1096-3650
    ISSN 1044-579X
    DOI 10.1016/j.semcancer.2014.08.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Challenges in using circulating miRNAs as cancer biomarkers.

    Tiberio, Paola / Callari, Maurizio / Angeloni, Valentina / Daidone, Maria Grazia / Appierto, Valentina

    BioMed research international

    2015  Volume 2015, Page(s) 731479

    Abstract: In the last years, circulating miRNAs have emerged as a new class of promising cancer biomarkers. Independent studies have shown the feasibility of using these small RNAs as tools for the diagnosis and prognosis of different types of malignancies as well ...

    Abstract In the last years, circulating miRNAs have emerged as a new class of promising cancer biomarkers. Independent studies have shown the feasibility of using these small RNAs as tools for the diagnosis and prognosis of different types of malignancies as well as for predicting and possibly monitoring treatment response. However, despite an initial enthusiasm for their possible clinical application, widespread inconsistencies have been observed among the studies, and miRNA-based tools still represent the object of research within clinical diagnostic or treatment protocols. The poor overlap of results could be explained, at least in part, by preanalytical and analytical variables and donor-related factors that could generate artefacts, impairing an accurate quantification of circulating miRNAs. In fact, critical issues are represented by nonuniform sample choice, handling, and processing, as well as by blood cell contamination in sample preparation and lack of consensus for data normalization. In this review, we address the potential technical biases and individual-related parameters that can influence circulating miRNA studies' outcome. The exciting potential of circulating miRNAs as cancer biomarkers could confer an important advance in the disease management, but their clinical significance might not be proven without a global consensus of procedures and standardized protocols for their accurate detection.
    MeSH term(s) Biomarkers, Tumor/blood ; Humans ; MicroRNAs/blood ; Neoplasms/blood ; Neoplasms/pathology ; Neoplasms/therapy ; RNA, Neoplasm/blood
    Chemical Substances Biomarkers, Tumor ; MicroRNAs ; RNA, Neoplasm
    Language English
    Publishing date 2015
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2698540-8
    ISSN 2314-6141 ; 2314-6133
    ISSN (online) 2314-6141
    ISSN 2314-6133
    DOI 10.1155/2015/731479
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Sodium 4-Carboxymethoxyimino-(4-HPR) a Novel Water-Soluble Derivative of 4-Oxo-4-HPR Endowed with

    Tiberio, Paola / Cavadini, Elena / Cleris, Loredana / Dallavalle, Sabrina / Musso, Loana / Daidone, Maria G / Appierto, Valentina

    Frontiers in pharmacology

    2017  Volume 8, Page(s) 226

    Abstract: 4-oxo- ...

    Abstract 4-oxo-
    Language English
    Publishing date 2017-04-26
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2017.00226
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Challenges in Using Circulating miRNAs as Cancer Biomarkers

    Paola Tiberio / Maurizio Callari / Valentina Angeloni / Maria Grazia Daidone / Valentina Appierto

    BioMed Research International, Vol

    2015  Volume 2015

    Abstract: In the last years, circulating miRNAs have emerged as a new class of promising cancer biomarkers. Independent studies have shown the feasibility of using these small RNAs as tools for the diagnosis and prognosis of different types of malignancies as well ...

    Abstract In the last years, circulating miRNAs have emerged as a new class of promising cancer biomarkers. Independent studies have shown the feasibility of using these small RNAs as tools for the diagnosis and prognosis of different types of malignancies as well as for predicting and possibly monitoring treatment response. However, despite an initial enthusiasm for their possible clinical application, widespread inconsistencies have been observed among the studies, and miRNA-based tools still represent the object of research within clinical diagnostic or treatment protocols. The poor overlap of results could be explained, at least in part, by preanalytical and analytical variables and donor-related factors that could generate artefacts, impairing an accurate quantification of circulating miRNAs. In fact, critical issues are represented by nonuniform sample choice, handling, and processing, as well as by blood cell contamination in sample preparation and lack of consensus for data normalization. In this review, we address the potential technical biases and individual-related parameters that can influence circulating miRNA studies’ outcome. The exciting potential of circulating miRNAs as cancer biomarkers could confer an important advance in the disease management, but their clinical significance might not be proven without a global consensus of procedures and standardized protocols for their accurate detection.
    Keywords Medicine ; R
    Subject code 610
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article: Targeted-Gene Sequencing to Catch Triple Negative Breast Cancer Heterogeneity before and after Neoadjuvant Chemotherapy.

    Di Cosimo, Serena / Appierto, Valentina / Silvestri, Marco / Pruneri, Giancarlo / Vingiani, Andrea / Perrone, Federica / Busico, Adele / Folli, Secondo / Scaperrotta, Gianfranco / de Braud, Filippo Guglielmo / Bianchi, Giulia Valeria / Cavalieri, Stefano / Daidone, Maria Grazia / Dugo, Matteo

    Cancers

    2019  Volume 11, Issue 11

    Abstract: Triple negative breast cancer (TNBC) patients not attaining pathological Complete Response (pCR) after neo-adjuvant chemotherapy (NAC) have poor prognosis. We characterized 19 patients for somatic mutations in primary tumor biopsy and residual disease ( ... ...

    Abstract Triple negative breast cancer (TNBC) patients not attaining pathological Complete Response (pCR) after neo-adjuvant chemotherapy (NAC) have poor prognosis. We characterized 19 patients for somatic mutations in primary tumor biopsy and residual disease (RD) at surgery by 409 cancer-related gene sequencing (IonAmpliSeqTM Comprehensive Cancer Panel). A median of four (range 1-66) genes was mutated in each primary tumor biopsy, and the most common mutated gene was
    Language English
    Publishing date 2019-11-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers11111753
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Involvement of AF1q/MLLT11 in the progression of ovarian cancer.

    Tiberio, Paola / Lozneanu, Ludmila / Angeloni, Valentina / Cavadini, Elena / Pinciroli, Patrizia / Callari, Maurizio / Carcangiu, Maria Luisa / Lorusso, Domenica / Raspagliesi, Francesco / Pala, Valentina / Daidone, Maria Grazia / Appierto, Valentina

    Oncotarget

    2017  Volume 8, Issue 14, Page(s) 23246–23264

    Abstract: The functional role of AF1q/MLLT11, an oncogenic factor involved in a translocation t(1;11)(q21;q23) responsible for acute myeloid leukaemia, has been investigated in hematological and solid malignancies and its expression was found to be linked to tumor ...

    Abstract The functional role of AF1q/MLLT11, an oncogenic factor involved in a translocation t(1;11)(q21;q23) responsible for acute myeloid leukaemia, has been investigated in hematological and solid malignancies and its expression was found to be linked to tumor progression and poor clinical outcome. In addition to its oncogenic function, AF1q has been shown to play a role in the onset of basal and drug-induced apoptosis in cancer cells of different histotypes, including ovarian cancer. Through in vitro, ex vivo, and in silico approaches, we demonstrated here that AF1q is also endowed with protumorigenic potential in ovarian cancer. In ovarian cancer cell lines, stable AF1q overexpression caused activation of epithelial-to-mesenchymal transition and increased motility/migratory/invasive abilities accompanied by gene expression changes mainly related to Wnt signaling and to signaling pathways involving in ERK/p38 activation. The potential role of AF1q in ovarian cancer progression was confirmed by immunohistochemical and in silico analyses performed in ovarian tumor specimens which revealed that the protein was absent in normal ovarian epithelium and became detectable when atypical proliferation was present. Moreover, AF1q was significantly lower in borderline ovarian tumors (i.e., tumors of low malignant potential without stromal invasion) than in invasive tumors, thus corroborating the association between high AF1q expression and increased migratory/invasive cell behavior and confirming its potential role in ovarian cancer progression. Our findings demonstrated, for the first time, that AF1q is endowed with protumorigenic activity in ovarian cancer, thus highlighting a dual behavior (i.e., protumorigenic and proapoptotic functions) of the protein in the malignancy.
    Language English
    Publishing date 2017-04-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.15574
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Circulating Biomarkers for Prediction of Treatment Response.

    Cappelletti, Vera / Appierto, Valentina / Tiberio, Paola / Fina, Emanuela / Callari, Maurizio / Daidone, Maria Grazia

    Journal of the National Cancer Institute. Monographs

    2015  Volume 2015, Issue 51, Page(s) 60–63

    Abstract: For cancer management, predicting and monitoring response to treatment and disease progression longitudinally is crucial due to changes in tumor biology and therapy responsiveness over time. However, solid tumors are usually sampled only at time of ... ...

    Abstract For cancer management, predicting and monitoring response to treatment and disease progression longitudinally is crucial due to changes in tumor biology and therapy responsiveness over time. However, solid tumors are usually sampled only at time of initial diagnosis, as obtaining tissue biopsies is an invasive procedures with associated risks. Thus, there is a pressing need for approaches able to serially detect function-related reliable biomarkers reflecting treatment response and/or disease progression through easy noninvasive procedures, amenable for longitudinal analysis of tumor molecular features. Recent evidences indicate that blood and other body fluids could replace invasive surgical biopsies and represent a "liquid biopsy" containing cells and nucleic acids released by primary and metastatic lesions, reflecting their biological features and allowing identification of clinically useful biomarkers and treatment-induced cancer adaption processes. The development of new and highly sensitive technologies that allow to detect and characterize circulating tumor cells, to identify cell-free nucleic acids (circulating tumor-associated microRNAs and cancer-specific mutations in circulating DNA) and to measure their eventual dynamic changes represents therefore a major achievement for disease monitoring. However, notwithstanding preliminary findings support the prognostic and/or predictive role of this new generation of biomarkers, there are a number of technical and biological caveats that still require additional studies to demonstrate and validate their clinical utility. A unique opportunity to rapidly assess the contribution of circulating tumor cells and cell-free nucleic acids to patient management and to personalized medicine could derive by their combined consideration in the neoadjuvant setting.
    MeSH term(s) Biomarkers, Tumor/blood ; DNA, Neoplasm/blood ; Disease Progression ; Humans ; MicroRNAs/blood ; Neoplasms/blood ; Neoplasms/diagnosis ; Neoplasms/therapy ; Neoplastic Cells, Circulating/pathology ; Outcome Assessment (Health Care)/methods ; Prognosis ; Reproducibility of Results ; Sensitivity and Specificity
    Chemical Substances Biomarkers, Tumor ; DNA, Neoplasm ; MicroRNAs
    Language English
    Publishing date 2015-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1745-6614
    ISSN (online) 1745-6614
    DOI 10.1093/jncimonographs/lgv006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Proposal of supervised data analysis strategy of plasma miRNAs from hybridisation array data with an application to assess hemolysis-related deregulation.

    Landoni, Elena / Miceli, Rosalba / Callari, Maurizio / Tiberio, Paola / Appierto, Valentina / Angeloni, Valentina / Mariani, Luigi / Daidone, Maria Grazia

    BMC bioinformatics

    2015  Volume 16, Page(s) 388

    Abstract: Background: Plasma miRNAs have the potential as cancer biomarkers but no consolidated guidelines for data mining in this field are available. The purpose of the study was to apply a supervised data analysis strategy in a context where prior knowledge is ...

    Abstract Background: Plasma miRNAs have the potential as cancer biomarkers but no consolidated guidelines for data mining in this field are available. The purpose of the study was to apply a supervised data analysis strategy in a context where prior knowledge is available, i.e., that of hemolysis-related miRNAs deregulation, so as to compare our results with existing evidence.
    Results: We developed a structured strategy with innovative applications of existing bioinformatics methods for supervised analyses including: 1) the combination of two statistical (t- and Anderson-Darling) test results to detect miRNAs with significant fold change or general distributional differences in class comparison, which could reveal hidden differential biological processes worth to be considered for building predictive tools; 2) a bootstrap selection procedure together with machine learning techniques in class prediction to guarantee the transferability of results and explore the interconnections among the selected miRNAs, which is important for highlighting their inherent biological dependences. The strategy was applied to develop a classifier for discriminating between hemolyzed and not hemolyzed plasma samples, defined according to a recently published hemolysis score. We identified five miRNAs with increased expression in hemolyzed plasma samples (miR-486-5p, miR-92a, miR-451, miR-16, miR-22).
    Conclusions: We identified four miRNAs previously reported in the literature as hemolysis related together with a new one (miR-22).which needs further investigations. Our findings confirm the validity of the proposed strategy and, in parallel, the hemolysis score capability to be used as pre-analytic hemolysis detector. R codes for implementing the approaches are provided.
    MeSH term(s) Biomarkers, Tumor/blood ; Biomarkers, Tumor/genetics ; Breast Neoplasms/blood ; Breast Neoplasms/genetics ; Breast Neoplasms/prevention & control ; Case-Control Studies ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Hemolysis/genetics ; Humans ; MicroRNAs/blood ; MicroRNAs/genetics
    Chemical Substances Biomarkers, Tumor ; MicroRNAs
    Language English
    Publishing date 2015-11-18
    Publishing country England
    Document type Comparative Study ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2041484-5
    ISSN 1471-2105 ; 1471-2105
    ISSN (online) 1471-2105
    ISSN 1471-2105
    DOI 10.1186/s12859-015-0820-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: A lipemia-independent NanoDrop(®)-based score to identify hemolysis in plasma and serum samples.

    Appierto, Valentina / Callari, Maurizio / Cavadini, Elena / Morelli, Daniele / Daidone, Maria Grazia / Tiberio, Paola

    Bioanalysis

    2014  Volume 6, Issue 9, Page(s) 1215–1226

    Abstract: Background: The identification and management of hemolyzed samples are crucial issues in the development of new blood-based biomarkers.: Results: Using experiments of controlled hemolysis and lipemia and two plasma series from cancer patients, we ... ...

    Abstract Background: The identification and management of hemolyzed samples are crucial issues in the development of new blood-based biomarkers.
    Results: Using experiments of controlled hemolysis and lipemia and two plasma series from cancer patients, we developed and validated a lipemia-independent hemolysis score (HS). HS resulted strictly associated with the amount of lysed erythrocytes and with serum index measurement (reference method), highly reproducible, and able to identify as hemolyzed plasma/serum samples containing ≥6.1 mg/dl of free hemoglobin.
    Conclusion: We developed a simple, robust, sensitive, cost-effective, spectrophotometrically-based system to identify hemolyzed plasma/serum specimens. The procedure requires only 2 μl of sample, thus representing a useful tool for research studies and an essential pre-analytical quality control for an optimal biobanking of liquid biopsies.
    MeSH term(s) Adult ; Biomarkers/blood ; Erythrocytes/cytology ; Hemolysis ; Humans ; Hyperlipidemias/blood ; Nanoparticles/chemistry ; Neoplasms/blood ; Quality Control ; Spectrophotometry
    Chemical Substances Biomarkers
    Language English
    Publishing date 2014-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1757-6199
    ISSN (online) 1757-6199
    DOI 10.4155/bio.13.344
    Database MEDical Literature Analysis and Retrieval System OnLINE

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