5 results on '"Daniel, Diolaiti"'
Search Results
2. Validation of a non-oncogene encoded vulnerability to exportin 1 inhibition in pediatric renal tumors
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Diego F. Coutinho, Prabhjot S. Mundi, Lianna J. Marks, Chelsey Burke, Michael V. Ortiz, Daniel Diolaiti, Lauren Bird, Kelly L. Vallance, Glorymar Ibáñez, Daoqi You, Matthew Long, Nestor Rosales, Adina Grunn, Andoyo Ndengu, Armaan Siddiquee, Ervin S. Gaviria, Allison R. Rainey, Ladan Fazlollahi, Hajime Hosoi, Andrea Califano, Andrew L. Kung, and Filemon S. Dela Cruz
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Child, Preschool ,Cell Line, Tumor ,Humans ,General Medicine ,Child ,Xenograft Model Antitumor Assays ,Kidney Neoplasms - Abstract
Malignant rhabdoid tumors (MRTs) and Wilms' tumors (WTs) are rare and aggressive renal tumors of infants and young children comprising ∼5% of all pediatric cancers. MRTs are among the most genomically stable cancers, and although WTs are genomically heterogeneous, both generally lack therapeutically targetable genetic mutations.Comparative protein activity analysis of MRTs (n = 68) and WTs (n = 132) across TCGA and TARGET cohorts, using metaVIPER, revealed elevated exportin 1 (XPO1) inferred activity. In vitro studies were performed on a panel of MRT and WT cell lines to evaluate effects on proliferation and cell-cycle progression following treatment with the selective XPO1 inhibitor selinexor. In vivo anti-tumor activity was assessed in patient-derived xenograft (PDX) models of MRTs and WTs.metaVIPER analysis identified markedly aberrant activation of XPO1 in MRTs and WTs compared with other tumor types. All MRT and most WT cell lines demonstrated baseline, aberrant XPO1 activity with in vitro sensitivity to selinexor via cell-cycle arrest and induction of apoptosis. In vivo, XPO1 inhibitors significantly abrogated tumor growth in PDX models, inducing effective disease control with sustained treatment. Corroborating human relevance, we present a case report of a child with multiply relapsed WTs with prolonged disease control on selinexor.We report on a novel systems-biology-based comparative framework to identify non-genetically encoded vulnerabilities in genomically quiescent pediatric cancers. These results have provided preclinical rationale for investigation of XPO1 inhibitors in an upcoming investigator-initiated clinical trial of selinexor in children with MRTs and WTs and offer opportunities for exploration of inferred XPO1 activity as a potential predictive biomarker for response.This work was funded by CureSearch for Children's Cancer, Alan B. Slifka Foundation, NIH (U01 CA217858, S10 OD012351, and S10 OD021764), Michael's Miracle Cure, Hyundai Hope on Wheels, Cannonball Kids Cancer, Conquer Cancer the ASCO Foundation, Cycle for Survival, Paulie Strong Foundation, and the Grayson Fund.
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- 2022
3. Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers
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Miho Nakajima, Maša Alečković, Linda Bojmar, Avigdor Scherz, Benjamin A. Garcia, Jacqueline Bromberg, Irit Sagi, Pernille Lauritzen, Yuan Liu, Michael F. Berger, Kayleen A. Bailey, Kofi Ennu Gyan, Moshe Oren, Kei Sugiura, Charles M. Rudin, Zoe Posner, Shakeel Modak, Milica Tesic Mark, Joshua S. Jolissant, Irina Matei, Henrik Molina, Constantinos P. Zambirinis, Mark A. LaBarge, G. Praveen Raju, Srikanth R. Ambati, Jeanine Baisch, Mariel Marrano, Tanya M. Trippett, Caitlin Williams, Alexander J. Chou, Ayako Hashimoto, David J. Pisapia, Michele Cioffi, Stephanie Vitolano, Norman J. Lacayo, Yves A. DeClerck, Geraldine P. Wright, Michael A. Hollingsworth, Joe DeStefano, Vinod P. Balachandran, Michael H.A. Roehrl, Mary Petriccione, Mary S. Brady, Kim Kramer, Héctor Peinado, Guillermo García-Santos, David R. Jones, Haiying Zhang, Mina J. Bissell, Jonathan M. Hernandez, Naoko Takahashi, Yonathan Ararso, L. Miles Schaeffer, Daniela Freitas, Enrico Danzer, David P. Kelsen, Ben Z. Stanger, Paul A. Meyers, Stephen S. Roberts, Cyrus M. Ghajar, Angela Di Giannatale, Jack D. Bui, William R. Jarnagin, Virginia Pascual, Eileen M. O'Reilly, Todd E. Heaton, David Lyden, Amber L. Simpson, Michael P. La Quaglia, Arti Shukla, Serena Lucotti, Vinagolu K. Rajasekhar, Amina Ahmed, John H. Healey, Robert E. Schwartz, Candia M. Kenific, Emily K. Slotkin, Laura Nogués, Kristy A. Brown, Søren Heissel, Daniel Diolaiti, Loïc Steiner, Ruth Scherz-Shouval, Yosef Yarden, Theresa C. Vincent, Martin R. Weiser, Fatima Cardoso, Han Sang Kim, Ayuko Hoshino, Huajuan Wang, Sujit Sheth, Fanny A. Pelissier Vatter, Yibin Kang, Maria Donzelli, Laurence Blavier, Benjamin A. Krantz, Alexander E. Davies, Thomas C. Caffrey, Yusuke Ogitani, Cheryl Fischer, Maria de Sousa, Gonçalo Rodrigues, Ellen M. Basu, Weston Buehring, Surinder K. Batra, Maneesh Jain, Diane M. Simeone, Leonard H. Wexler, Alberto Benito-Martin, Yasmin Khakoo, Lee Ganshaw, Katharine Offer, Paul M. Grandgenett, Bruno Costa-Silva, Kevin C. De Braganca, Mahathi Malladi, and Ashton Harris
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Proteomics ,Cancer microenvironment ,Proteome ,Biology ,Sensitivity and Specificity ,Exosome ,Article ,Tetraspanin 29 ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Machine Learning ,Tumour biomarkers ,Plasma ,Extracellular Vesicles ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Liquid biopsy ,030304 developmental biology ,0303 health sciences ,Proteomic Profile ,Microfilament Proteins ,HSC70 Heat-Shock Proteins ,Cancer ,Extracellular vesicle ,medicine.disease ,Research Highlight ,Mice, Inbred C57BL ,rap GTP-Binding Proteins ,Cancer research ,Biomarkers ,030217 neurology & neurosurgery ,Cancer of unknown primary origin - Abstract
Summary There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
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- 2020
4. Functional cooperation between TrkA and p75NTR accelerates neuronal differentiation by increased transcription of GAP-43 and p21(CIP/WAF) genes via ERK1/2 and AP-1 activities
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Giuliano Della Valle, Daniel Diolaiti, Roberto Bernardoni, Antonio Porro, Françoise Bono, Giovanni Perini, Stefania Trazzi, Jean Marc Herbert, Antonella Papa, Daniel Diolaiti, Roberto Bernardoni, Stefania Trazzi, Antonella Papa, Antonio Porro, Françoise Bono, Jean-Marc Herbert, Giovanni Perini, and Giuliano Della Valle
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Cyclin-Dependent Kinase Inhibitor p21 ,animal structures ,Transcription, Genetic ,Neurite ,Cellular differentiation ,NF-KAPPA-B ,SIGNAL-TRANSDUCTION ,Biology ,Tropomyosin receptor kinase A ,Receptor, Nerve Growth Factor ,GAP-43 Protein ,Nerve Growth Factor ,Tumor Cells, Cultured ,HUMAN NEUROBLASTOMA-CELLS ,Animals ,Humans ,Low-affinity nerve growth factor receptor ,PC12 CELL-DIFFERENTIATION ,Phosphorylation ,Receptor, trkA ,Mitogen-Activated Protein Kinase 1 ,Neurons ,Mitogen-Activated Protein Kinase 3 ,NERVE GROWTH-FACTOR ,Autophosphorylation ,Cell Differentiation ,AFFINITY NGF BINDING ,PROTEIN-KINASE ACTIVITY ,Cell Biology ,MAP KINASE ,Cell biology ,Enzyme Activation ,Transcription Factor AP-1 ,SYMPATHETIC NEURONS ,Nerve growth factor ,nervous system ,biology.protein ,P75 NEUROTROPHIN RECEPTOR ,Signal transduction ,Signal Transduction ,Neurotrophin - Abstract
The biological complexity of NGF action is achieved by binding two distinct neurotrophin receptors, TrkA and p75(NTR). While several reports have provided lines of evidence on the interaction between TrkA and p75(NTR) at the plasma membrane, much fewer data are available on the consequence of such an interaction in terms of intracellular signaling. In this study, we have focused on how p75(NTR) may affect TrkA downstream signaling with respect to neuronal differentiation. Here, we have shown that cooperation between p75(NTR) and TrkA results in an increased NGF-mediated TrkA autophosphorylation, leads to a sustained activation of ERK1/2 and accelerates neurite outgrowth. Interestingly, neurite outgrowth is concomitant with a selective enhancement of the AP-1 activity and the transcriptional activation of genes such as GAP-43 and p21(CIP/WAF), known to be involved in the differentiation process. Collectively, our results unveil a functional link between the specific expression profile of neurotrophin receptors in neuronal cells and the NGF-mediated regulation of the differentiation process possibly through a persistent ERKs activation and the selective control of the AP-1 activity. The biological complexity of NGF action is achieved by binding two distinct neurotrophin receptors, TrkA and p75(NTR). While several reports have provided lines of evidence on the interaction between TrkA and p75(NTR) at the plasma membrane, much fewer data are available on the consequence of such an interaction in terms of intracellular signaling. In this study, we have focused on how p75(NTR) may affect TrkA downstream signaling with respect to neuronal differentiation. Here, we have shown that cooperation between p75(NTR) and TrkA results in an increased NGF-mediated TrkA autophosphorylation, leads to a sustained activation of ERK1/2 and accelerates neurite outgrowth. Interestingly, neurite outgrowth is concomitant with a selective enhancement of the AP-1 activity and the transcriptional activation of genes such as GAP-43 and p21(CIP/WAF), known to be involved in the differentiation process. Collectively, our results unveil a functional link between the specific expression profile of neurotrophin receptors in neuronal cells and the NGF-mediated regulation of the differentiation process possibly through a persistent ERKs activation and the selective control of the AP-1 activity.
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- 2007
5. In vivo functional dissection of human inner kinetochore protein CENP-C
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Giuliano Della Valle, Daniel Diolaiti, William C. Earnshaw, Valeria Politi, Roberto Bernardoni, Giovanni Perini, Stefania Trazzi, Trazzi, S, Bernardoni, R, Diolaiti, D, Politi, V, Earnshaw, Wc, Perini, G, and Della Valle, G.
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Chromosomal Proteins, Non-Histone ,Immunoprecipitation ,Blotting, Western ,Centromere ,macromolecular substances ,DNA, Satellite ,Biology ,α-Satellite DNA ,DNA binding domain ,Protein structure ,Structural Biology ,Formaldehyde ,Humans ,Kinetochores ,Peptide sequence ,Centromere localization domain ,Kinetochore ,DNA-binding domain ,Precipitin Tests ,Chromatin ,Protein Structure, Tertiary ,Cell biology ,Cross-Linking Reagents ,Microscopy, Fluorescence ,Structural biology ,Biochemistry ,Mutation ,Electrophoresis, Polyacrylamide Gel ,CENP-C - Abstract
CENP-C is a fundamental component of the inner kinetochore plate and contributes to the formation of functional centromeres in eukaryotic organisms. Recruitment of CENP-C to kinetochore requires other centromere proteins, particularly CENP-A, CENP-H, and CENP-I. However, how CENP-C is correctly localized at the kinetochore is not clearly determined, mainly due to the functional variety of its domains, which hints at a complex recruitment mechanism. Here, by both immunofluorescent labeling and chromatin/immunoprecipitation we could show that human CENP-C contains two distinct domains, one in the central region, between amino acids 426 and 537, and the second one in the carboxyl terminal region, between amino acids 638 and 943, which are both capable of localizing at centromeres and binding α-satellite DNA. The presence of two domains that iterate the same function despite being significantly different in their amino acid sequence and structure suggests that CENP-C may target the centromere by establishing multiple contacts with both the DNA and protein constituents of the kinetochore. © 2002 Elsevier Science (USA). All rights reserved.
- Published
- 2002
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