9 research outputs found
Gcn5p plays an important role in centromere kinetochore function in budding yeast
No full textWe report that the histone acetyltransferase Gcn5p is involved in cell cycle progression, whereas its absence induces several mitotic defects, including inefficient nuclear division, chromosome loss, delayed G(2) progression, and spindle elongation. The fidelity of chromosome segregation is finely regulated by the close interplay between the centromere and the kinetochore, a protein complex hierarchically assembled in the centromeric DNA region, while disruption of GCN5 in mutants of inner components results in sick phenotype. These synthetic interactions involving the ADA complex lay the genetic basis for the critical role of Gcn5p in kinetochore assembly and function. We found that Gcn5p is, in fact, physically linked to the centromere, where it affects the structure of the variant centromeric nucleosome. Our findings offer a key insight into a Gcn5p-dependent epigenetic regulation at centromere/kinetochore in mitosis
Chemogenomic profiling of the cellular effects associated with histone H3 acetylation impairment by a quinoline-derived compound
No full text
A Novel Histone Acetyltransferase Inhibitor Modulating Gcn5 Network: Cyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl)hydrazone
No full textAcetylation is a key modulator of genome accessibility through decondensation of the chromatin structure. The balance between acetylation and opposite deacetylation is, in fact, a prerequisite for several cell functions and differentiation. To find modulators of the histone acetyltransferase Gcn5p, we performed a phenotypic screening on a set of newly synthesized molecules derived from thiazole in budding yeast Saccharomyces cerevisiae. We selected compounds that induce growth inhibition in yeast strains deleted in genes encoding known histone acetyltransferases. A novel molecule CPTH2, cyclopentylidene-[4-(4?-chlorophenyl)thiazol- 2-yl)hydrazone, was selected based on its inhibitory effect on the growth of a gcn5? strain. We demonstrated a specific chemical-genetic interaction between CPTH2 and HAT Gcn5p, indicating that CPTH2 inhibits the Gcn5p dependent functional network. CPTH2 inhibited an in vitro HAT reaction, which is reverted by increasing concentration of histone H3. In vivo, it decreased acetylation of bulk histone H3 at the specific H3-AcK14 site. On the whole, our results demonstrate that CPTH2 is a novel HAT inhibitor modulating Gcn5p network in vitro and in vivo. Because genetic mutations and translocations in HAT genes have been found in a number of epithelial and hematological tumors, we believe that CPTH2 and future derived compounds will be of great interest, taking into account the selectivity toward the Gcn5p functional network here demonstrated in yeast
Harnessing Immune Response in Acute Myeloid Leukemia
No full textDespite the results achieved with the evolution of conventional chemotherapy and the inclusion of targeted therapies in the treatment of acute myeloid leukemia (AML), survival is still not satisfying, in particular in the setting of relapsed/refractory (R/R) disease or elderly/unfit patients. Among the most innovative therapeutic options, cellular therapy has shown great results in different hematological malignancies such as acute lymphoblastic leukemia and lymphomas, with several products already approved for clinical use. However, despite the great interest in also expanding the application of these new treatments to R/R AML, no product has been approved yet for clinical application. Furthermore, cellular therapy could indeed represent a powerful tool and an appealing alternative to allogeneic hematopoietic stem cell transplantation for ineligible patients. In this review, we aim to provide an overview of the most recent clinical research exploring the effectiveness of cellular therapy in AML, moving from consolidated approaches such as post- transplant donor’s lymphocytes infusion, to modern adoptive immunotherapies such as alloreactive NK cell infusions, engineered T and NK cells (CAR-T, CAR-NK) and novel platforms of T and NK cells engaging (i.e., BiTEs, DARTs and ANKETTM)
Comparing Outcomes Between CPX-351 and Fludarabine-Based Induction in Secondary Acute Myeloid Leukemia in the Real-World Setting: The Prognostic Role of Measurable Residual Disease
No full textSecondary acute myeloid leukemia (s-AML) is associated with inferior outcomes with conventional chemotherapy, and fludarabine combinations (FLAG-Ida) have been tested to improve results. More recently, CPX-351 resulted superior to conventional 3 + 7 in s-AML patients. In the UK NCRI AML19 trial, AML patients were randomized to receive either FLAG-Ida or CPX-351. Subgroup analysis revealed better overall survival (OS) with CPX-351 in patients with MDS-related gene mutations. Unfortunately, minimal residual disease (MRD) was evaluated only in a minority of patients. The aim of this study was to further disclose the mechanisms of higher efficacy of CPX-351 in s-AML, with a focus on MRD. We analyzed 183 consecutive s-AML elderly patients (median age 69, range 60-77) treated with CPX-351 (n = 82) or receiving FLAG-Ida (n = 101). Complete remission (CR) rate and MRD negativity probability were higher among patients receiving CPX-351 (MRD negative CR rate of 40/64, 62.5%, compared to 25/55, 45% in patients who received FLAG-Ida, p < 0.05). Extra-hematological toxicity was lower in CPX-351 arm, and 30 days mortality was 3.6% and 8% in patients receiving CPX-351 or FLAG-Ida, respectively. Notably, 21/64 (32.8%) CR patients treated with CPX 351 underwent allogeneic stem cell transplantation (HSCT), compared to 5/55 with FLAG-Ida (9%, p < 0.05). Overall, CPX-351 treatment resulted in higher OS (median OS 17.7 vs. 11.2 months with FLAG-Ida, p < 0.05). The better outcome of CPX-351 compared to FLAG-Ida in our cohort may be explained by a greater probability of MRD negativity, alongside with an improved tolerance, enabling more s-AML patients to undergo HSCT
Foreign influences on and innovation in English tomb sculpture in the first half of the sixteenth century
No full textThis study is an investigation of stylistic and iconographic
innovation in English tomb sculpture from the accession of King
Henry VIII through the first half of the sixteenth century, a
period during which Tudor society and Tudor art were in
transition as a result of greater interaction with continental
Europe. The form of the tomb was moulded by contemporary
cultural, temporal and spiritual innovations, as well as by the
force of artistic personalities and the directives of patrons.
Conversely, tomb sculpture is an inherently conservative art, and
old traditions and practices were resistant to innovation. The
early chapters examine different means of change as illustrated
by a particular group of tombs. The most direct innovations were
introduced by the royal tombs by Pietro Torrigiano in Westminster
Abbey. The function of Italian merchants in England as
intermediaries between Italian artists and English patrons is
considered. Italian artists also introduced terracotta to
England. A group of terracotta tombs in East Anglia, previously
attributed by tradition to Italian artists, is re-examined. A
less direct initiation of iconographic and stylistic innovation
occurred through English artists' use of foreign patterns. The
synthesis of such two-dimensional imagery by English sculptors is
examined in certain tombs in Hampshire and Sussex. The influence
of the Florentine royal tombs on English tomb sculpture in the
latter half of the period is illustrated by alabaster tombs from
an English workshop and by three other important tombs. The
abandoned Italian project for the tomb of Henry VIII is studied
in the context of the religious, political and economic changes
that contributed to the breakdown of a supportive environment for
Italian artists in England. Finally, the relevance of religious
Injunctions and iconoclasm to the evolution of English tomb
sculpture by the middle of the century is considered
