129 research outputs found
Therapeutic targeting of Hedgehog signalling pathway in T-cell acute lymphoblastic leukemia (T-ALL)
No full textT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological tumour arising from the malignant transformation of T-cell precursors. Notwithstanding intensified therapy, ~40% of adult and ~20% of pediatric patients face a dismal prognosis due to primary resistance to treatment and relapse, raising the need for more efficient and targeted therapies. Hedgehog (HH) signalling is a major developmental pathway frequently deregulated in cancer, for which a role in T-ALL is recently emerging. The therapeutic targeting of HH signalling in T-ALL by specific inhibitors in vitro and in vivo was shown to be partially effective when used as monotherapy and seems to suggest an important role for the non-canonical activation of the pathway (i.e. independent of upstream Smoothened receptor). This noncanonical activation of GLI1 transcription factor, the main HH downstream effector, underscores the necessity of dissecting the complex regulatory network upstream of GLI1 in T-ALL. In this study, we evaluated gene and protein expression of HH pathway components in T-ALL cell lines, patient-derived xenografts (PDX) and Notch1-dependent T-ALL murine models, confirming their expression in the majority of the tested samples. A significant fraction of T-ALL cell lines and PDX-derived cells were sensitive to HH pathway inhibition by GANT61 (GLI1/2 inhibitor), much less so to cyclopamine (Smoothened inhibitor). Interestingly, in a Notch1-induced T-ALL murine model, pharmacological combinations targeting commonly deregulated oncogenic pathways in T-ALL revealed a therapeutically relevant synergism between GANT61 and glucocorticoids (GCs). Combined treatment of T-ALL cell lines and PDXderived cells with GANT61 plus Dexamethasone (Dexa) showed a synergistic anti-leukemic effect, affecting both cell proliferation and survival. In order to gain mechanistic insights of the found crosstalk between the HH pathway and the GC receptor pathway, we studied the impact of synthetic GCs on GLI1 function. GCs impaired GLI1 transcriptional activity in transfected HEK293T cells stably expressing the GC receptor; however, gene expression data and Western blot analysis seemed to exclude a transcriptional effect of GCs on GLI1, but rather suggested a post-translational mechanism of action. Cell fractionation analysis did not reveal significant re-distribution of GLI1 upon Dexa treatment, while GLI1 stability was shown to be impaired, revealing a reduced protein half-life after treatment. Finally, GLI1 and the GC receptor were shown to interact, with the GC receptor recruiting the acetyltransferase PCAF and dissociating from the deacetylase HDAC1 upon Dexa treatment, thus leading to GLI1 hyperacetylation and reduced transcriptional activity. In conclusion, we demonstrated that HH pathway is active in a subset of TALLs and the differential sensitivity to HH inhibitors suggests a ligandindependent non-canonical mechanism of activation. We also collected evidence of a crosstalk between the GC receptor and HH pathway, with the GC receptor acting as a negative regulator of GLI1 transcription factor, setting the therapeutic rationale for combining GLI1 inhibitors and GCs
Aberrant signaling pathways in t-cell acute lymphoblastic leukemia
No full textAbstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therap
New Dimensions in a Classic Novel: James Joyce
No full textJames Joyce is a fascinating writer, but he can be a most difficult author to teach. In her dissertation, Lynn Bongiovanni brings a recent viewpoint – empire theory – to bear on this most singular author and finds an interesting paradox. While Joyce inveighed against imperial rule – in this case, Ireland’s “colonization” by the British – he was capable of celebrating the fruits of empire in his writings. Just as you and I may deplore the consequences of what might be called the modern technology “empire,” even as we happily use our refrigerators and computers, Joyce had his own conflicted attitude towards empire.
In this brief excerpt from Prof. Bongionvanni’s full dissertation¸ and in her interview, the author begins to set out the structure and overview of Joyce’s conflicted politics. In the later parts of her dissertation, she goes into detail, using specific passages from Joyce’s prose to illustrate her thesis
Crosstalk between Hedgehog pathway and the glucocorticoid receptor pathway as a basis for combination therapy in T-cell acute lymphoblastic leukemia
No full textEurope and the End of the Age of Innocence [electronic resource] /
No full text“Europe is no longer fit for purpose. With his trademark style, Bongiovanni takes an unflinching look at what led the continent to this moment. Do not read this book if you’re optimistic about Europe’s future – but read this book if you care about that future.” —Ian Bremmer, President and Founder of Eurasia Group “A valuable and timely wake-up call Europeans ignore at their own peril.” —Kishore Mahbubani, Author of Has the West Lost It?: A Provocation Francesco M. Bongiovanni returns with a sequel to The Decline and the Fall of Europe, a book Guardian journalist Nils Pratley labelled ‘a wake-up call for the twenty-first century’. Since 2012 Europe hasbeen confronted with new, unexpected game-changing challenges such as the refugee crisis and its human tsunami, the surprise of Brexit and the explosion of ‘alternative’ politics. Europeans have finally come to realize that the open-societies that they have been comfortably living in are under threat and fragmenting, leaving their survival uncertain. Minorities are falling prey to an Islamist ideology that conveys values and customs diametrically opposed to European ones. Terrorist acts have become the ‘new normal’, part of daily life. The North-South cleavage brought about by the eurozone crisis is now completed by a deep East-West cleavage born from the refugee crisis. Against this backdrop, a Germany that is not all that it seems has become Europe’s de-facto ruler, but is unfit to lead, while Trump’s America cannot be counted on as it once used to be, forcing Europe to fend for itself. A beacon of stability and prosperity in the past, a naive and unprepared Europe, facing new and terrifying challenges is today more than ever torn apart, increasingly unstable and adrift. Francesco M. Bongiovanni holds an MBA from Harvard, USA, and a doctorate in engineering. He has lived in Europe, Asia, the USA and the Arab World. A former investment banker in Wall Street and London, he subsequently worked as an entrepreneur and advisor in direct investments and private equity. He has been made a Knight of the Order of St Charles for his contribution to humanitarian endeavours and biodiversity protection. Bongiovanni is also an author and composer of classical symphonic music and jazz.Chapter 1: Introduction -- Part I: The Trilogy -- Chapter 2: The Awakening -- Chapter 3: The Tsunami -- Chapter 4: Barbarians in the City -- Chapter 5: The Rise of Alternative Politics -- Chapter 6: Ensuring the Survival of a 'Europe of Values' -- Part II: A Brief History of How to Mess Things Up -- Chapter 7: The Island that Couldn't get Far Enough -- Chapter 8: Uber Alles... Not so Fast! -- Chapter 9: The More it Changes, the More it Stays the Same -- Chapter 10: The Gas Wars -- Chapter 11: The Trump Card -- Chapter 12: Conclusion.“Europe is no longer fit for purpose. With his trademark style, Bongiovanni takes an unflinching look at what led the continent to this moment. Do not read this book if you’re optimistic about Europe’s future – but read this book if you care about that future.” —Ian Bremmer, President and Founder of Eurasia Group “A valuable and timely wake-up call Europeans ignore at their own peril.” —Kishore Mahbubani, Author of Has the West Lost It?: A Provocation Francesco M. Bongiovanni returns with a sequel to The Decline and the Fall of Europe, a book Guardian journalist Nils Pratley labelled ‘a wake-up call for the twenty-first century’. Since 2012 Europe hasbeen confronted with new, unexpected game-changing challenges such as the refugee crisis and its human tsunami, the surprise of Brexit and the explosion of ‘alternative’ politics. Europeans have finally come to realize that the open-societies that they have been comfortably living in are under threat and fragmenting, leaving their survival uncertain. Minorities are falling prey to an Islamist ideology that conveys values and customs diametrically opposed to European ones. Terrorist acts have become the ‘new normal’, part of daily life. The North-South cleavage brought about by the eurozone crisis is now completed by a deep East-West cleavage born from the refugee crisis. Against this backdrop, a Germany that is not all that it seems has become Europe’s de-facto ruler, but is unfit to lead, while Trump’s America cannot be counted on as it once used to be, forcing Europe to fend for itself. A beacon of stability and prosperity in the past, a naive and unprepared Europe, facing new and terrifying challenges is today more than ever torn apart, increasingly unstable and adrift. Francesco M. Bongiovanni holds an MBA from Harvard, USA, and a doctorate in engineering. He has lived in Europe, Asia, the USA and the Arab World. A former investment banker in Wall Street and London, he subsequently worked as an entrepreneur and advisor in direct investments and private equity. He has been made a Knight of the Order of St Charles for his contribution to humanitarian endeavours and biodiversity protection. Bongiovanni is also an author and composer of classical symphonic music and jazz
Responsiveness to hedgehog pathway inhibitors in t-cell acute lymphoblastic leukemia cells is highly dependent on 5′ amp-activated kinase inactivation
No full textNumerous studies have shown that hedgehog inhibitors (iHHs) only partially block the growth of tumor cells, especially in vivo. Leukemia often expands in a nutrient-depleted environment (bone marrow and thymus). In order to identify putative signaling pathways implicated in the adaptive response to metabolically adverse conditions, we executed quantitative phospho-proteomics in T-cell acute lymphoblastic leukemia (T-ALL) cells subjected to nutrient-depleted conditions (serum starvation). We found important modulations of peptides phosphorylated by critical signaling pathways including casein kinase, mammalian target of rapamycin, and 5′ AMP-activated kinase (AMPK). Surprisingly, in T-ALL cells, AMPK signaling was the most consistently downregulated pathway under serum-depleted conditions, and this coincided with increased GLI1 expression and sensitivity to iHHs, especially the GLI1/2 inhibitor GANT-61. Increased sensitivity to GANT-61 was also found following genetic inactivation of the catalytic subunit of AMPK (AMPKα1) or pharmacological inhibition of AMPK by Compound C. Additionally, patient-derived xenografts showing high GLI1 expression lacked activated AMPK, suggesting an important role for this signaling pathway in regulating GLI1 protein levels. Further, joint targeting of HH and AMPK signaling pathways in T-ALL cells by GANT-61 and Compound C significantly increased the therapeutic response. Our results suggest that metabolic adaptation that occurs under nutrient starvation in T-ALL cells increases responsiveness to HH pathway inhibitors through an AMPK-dependent mechanism and that joint therapeutic targeting of AMPK signaling and HH signaling could represent a valid therapeutic strategy in rapidly expanding tumors where nutrient availability becomes limiting
Targeted Genomic Profiling and Chemotherapy Outcomes in Grade 3 Gastro-Entero-Pancreatic Neuroendocrine Tumors (G3 GEP-NET)
No full textBackground: Grade 3 gastro-entero-pancreatic neuroendocrine tumors (G3 GEP-NET) are poorly characterized in terms of molecular features and response to treatments. Methods: Patients with G3 GEP-NET were included if they received capecitabine and temozolomide (CAPTEM) or oxaliplatin with either 5-fluorouracile (FOLFOX) or capecitabine (XELOX) as first-line treatment (chemotherapy cohort). G3 NET which successfully undergone next-generation sequencing (NGS) were included in the NGS cohort. Results: In total, 49 patients were included in the chemotherapy cohort: 15 received CAPTEM and 34 received FOLFOX/XELOX. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were 42.9%, 9.0 months, and 33.6 months, respectively. Calculating a Ki67 cutoff using ROC curve analysis, tumors with Ki67 ≥ 40% had lower ORR (51.2% vs. 0%; p = 0.007) and shorter PFS (10.6 months vs. 4.4 months; p < 0.001) and OS (49.4 months vs. 10.0 months; p = 0.023). In patients who received FOLFOX/XELOX as a first-line treatment, ORR, PFS, and OS were 38.2%, 7.9 months, and 30.0 months, respectively. In the NGS cohort (N = 13), the most mutated genes were DAXX/ATRX (N = 5, 38%), MEN1 (N = 4, 31%), TP53 (N = 4, 31%), AKT1 (N = 2, 15%), and PIK3CA (N = 1, 8%). Conclusions: FOLFOX/XELOX chemotherapy is active as the first-line treatment of patients with G3 GEP-NET. The mutational landscape of G3 NET is more similar to well-differentiated NETs than NECs
Analysis of spatial effects in vine crop across Portuguese regions
No full textThe consideration of spatial effects at a regional level is becoming increasingly frequent and the work of Anselin (1988), among others, has contributed to this. This study analyses, through cross-section estimation methods, the influence of spatial effects in the NUTs III vine crop of mainland Portugal, in 1999 (the last data available), considering the Verdoorn relationship as a base of study. To analyse the data, by using Moran I statistics, and estimation results, considering the spatial lag and spatial error component, it is stated that there are positive spatial autocorrelation (variables of each of the regions develop in a similar manner to each of the neighbouring regions), in the vine crop.spatial econometrics; vine crop; Portuguese regions
Earliest mechanisms of dopaminergic neurons sufferance in a novel slow progressing ex vivo model of parkinson disease in rat organotypic cultures of substantia nigra
No full textThe current treatments of Parkinson disease (PD) are ineffective mainly due to the poor understanding of the early events causing the decline of dopaminergic neurons (DOPAn). To overcome this problem, slow progressively degenerating models of PD allowing the study of the pre-clinical phase are crucial. We recreated in a short ex vivo time scale (96 h) all the features of human PD (needing dozens of years) by challenging organotypic culture of rat substantia nigra with low doses of rotenone. Thus, taking advantage of the existent knowledge, the model was used to perform a time-dependent comparative study of the principal possible causative molecular mechanisms undergoing DOPAn demise. Alteration in the redox state and inflammation started at 3 h, preceding the reduction in DOPAn number (pre-diagnosis phase). The number of DOPAn declined to levels compatible with diagnosis only at 12 h. The decline was accompanied by a persistent inflammation and redox imbalance. Significant microglia activation, apoptosis, a reduction in dopamine vesicle transporters, and the ubiquitination of misfolded protein clearance pathways were late (96 h, consequential) events. The work suggests inflammation and redox imbalance as simultaneous early mechanisms undergoing DOPAn sufferance, to be targeted for a causative treatment aimed to stop/delay PD. © 2019 by the author
Analysis of spatial effects in vine and olive crops across Portuguese regions
No full textThe consideration of spatial effects at a regional level is becoming increasingly frequent and the work of Anselin (1988), among others, has contributed to this. This study analyses, through cross-section estimation methods, the influence of spatial effects in the NUTs III vine and olive crops of mainland Portugal, in 1999 (the last data available), considering the Verdoorn relationship as a base of study. To analyse the data, by using Moran I statistics, and estimation results, considering the spatial lag and spatial error component, it is stated that there are positive spatial autocorrelation (variables of each of the regions develop in a similar manner to each of the neighbouring regions), above all in vine.spatial econometrics; vine and olive crops; Portuguese regions
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