Investigating the molecular mechanism of h3b‐8800: A splicing modulator inducing preferential lethality in spliceosome‐mutant cancers

The SF3B1 protein, part of the SF3b complex, recognizes the intron branch point sequence of precursor messenger RNA (pre‐mRNA), thus contributing to splicing fidelity. SF3B1 is frequently mutated in cancer and is the target of distinct families of splicing modulators (SMs). Among these, H3B‐8800 is of particular interest, as it induces preferential lethality in cancer cells bearing the frequent and highly pathogenic K700E SF3B1 mutation. Despite the potential of H3B‐8800 to treat myeloid leukemia and other cancer types hallmarked by SF3B1 mutations, the molecular mechanism underlying its preferential lethality towards spliceosome‐mutant cancer cells remains elusive. Here, microsecond‐long all‐atom simulations addressed the binding/dissociation mechanism of H3B‐8800 to wild type and K700E SF3B1‐containing SF3b (K700ESB3b) complexes at the atomic level, unlocking that the K700E mutation little affects the thermodynamics and kinetic traits of H3B‐8800 binding. This supports the hypothesis that the selectivity of H3B‐8800 towards mutant cancer cells is unrelated to its preferential targeting ofK700ESB3b. Nevertheless, this set of simulations discloses that the K700E mutation and H3B‐8800 binding affect the overall SF3b internal motion, which in turn may influence the way SF3b interacts with other spliceosome components. Finally, we unveil the existence of a putative druggable SF3b pocket in the vicinity of K700E that could be harnessed in future rational drug‐discovery efforts to specifically target mutant SF3b

Disclosing the impact of carcinogenic SF3b mutations on pre-mRNA recognition via all-atom simulations

The spliceosome accurately promotes precursor messenger-RNA splicing by recognizing specific noncoding intronic tracts including the branch point sequence (BPS) and the 3'-splice-site (3\u2018SS). Mutations of Hsh155 (yeast)/SF3B1 (human), which is a protein of the SF3b factor involved in BPS recognition and induces altered BPS binding and 3\u2018SS selection, lead to mis-spliced mRNA transcripts. Although these mutations recur in hematologic malignancies, the mechanism by which they change gene expression remains unclear. In this study, multi-microsecond-long moleculardynamics simulations of eighth distinct ~700,000 atom models of the spliceosome Bact complex, and gene sequencing of SF3B1, disclose that these carcinogenic isoforms destabilize intron binding and/or affect the functional dynamics of Hsh155/SF3B1 only when binding non-consensus BPSs, as opposed to the non-pathogenic variants newly annotated here. This pinpoints a cross-talk between the distal Hsh155 mutation and BPS recognition sites. Our outcomes unprecedentedly contribute to elucidating the principles of pre-mRNA recognition, which provides critical insights on the mechanism underlying constitutive/alternative/aberrant splicing

Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload

Between 2002 and 2008, a number of consensus statements and guidelines were developed by various groups around the world to educate healthcare professionals on the treatment of myelodysplastic syndromes (MDS), including the management of transfusional iron overload with iron chelation therapy. Guidelines have been developed by The Italian Society of Hematology, The UK MDS Guidelines Group, The Nagasaki Group, The National Comprehensive Cancer Network, and The MDS Foundation. These guidelines show that the approaches to managing iron overload in patients with MDS are region specific, differing in their recommendations for when iron chelation therapy should be initiated and strategies for the ongoing management of iron overload. The guidelines all agree that red blood cell transfusions are clinically beneficial to treat the symptomatic anemia in MDS, and that patients with low-risk MDS receiving transfusions are the most likely to benefit from iron chelation therapy

Riqualificazione di alcune piazze e vie a Trezzano Rosa (Milano). Progetto 1° classificato.

Pubblicazione del progetto primo classificato al concorso per la "Riqualificazione di alcune piazze e vie a Trezzano Rosa (Milano)". Questo concorso ha avuto lo scopo di promuovere la riqualificazione della zona centrale e nevralgica del paese della provincia di Milano. La piazza San Gottardo dovrà tornare ad essere uno spazio ad intenso uso collettivo, con un nuovo sagrato e accessi alla chiesa. Il progetto vincitore ha come obiettivo quello di rafforzare l’identità del luogo e consolidarne i caratteri distintivi di insediamento rurale dal punto di vista morfologico e della qualità dello spazio. All’interno di una strategia urbana unitaria e riconoscibile, il lavoro si è concentrato in particolare su tre questioni principali: gli assi stradali (via Roma, via Dante, via Madonna); il sistema delle piazze (piazza San Gottardo, piazza XXV Aprile); il sistema del verde pubblico e il viale di circonvallazione

Starting from scratch: patient-reported outcome questionnaires & their role in an integrative medicine primary care minimum-dataset

Aim This research explored the use of patient questionnaires for evaluating integrative medicine (IM) clinics in the primary care setting. Background Integrative medicine (IM) combines traditional, complementary, and alternative medicine with conventional biomedicine. With more clinics in Australia offering IM, it is important to evaluate outcomes. Methods Mixed methods were used. This included a case study of an IM clinic in Sydney, Australia; interviews with 20 patients and 13 staff at the clinic; and a systematic literature review of patient questionnaires. Results Challenges for meausring IM outcomes limitations with routine clinical data collection, selecting appropriate questionnaires able to measure the wide range of IM outcomes whilst minimizing responder burden, patient recruitment and practitioner support. Electronic questionnaires have many advantages. Alternative formats such as paper are still needed. Not all interviewees were interested in cohort results or research and instead wanted to access their individual patient results. Discussion The results from the studies were synthesised and a set of recommendations are offered. Conclusions Patient questionnaires could be used to establish a minimum dataset for use in research, health service development, and informing and improving individual patient care. A bottom-up approach that adresses stakeholders’ needs for a dataset is essential

LOFT - a Large Observatory For x-ray Timing

The high time resolution observations of the X-ray sky hold the key to a number of diagnostics of fundamental physics, some of which are unaccessible to other types of investigations, such as those based on imaging and spectroscopy. Revealing strong gravitational field effects, measuring the mass and spin of black holes and the equation of state of ultradense matter are among the goals of such observations. At present prospects for future, non-focused X-ray timing experiments following the exciting age of RXTE/PCA are uncertain. Technological limitations are unavoidably faced in the conception and development of experiments with effective area of several square meters, as needed in order to meet the scientific requirements. We are developing large-area monolithic Silicon Drift Detectors offering high time and energy resolution at room temperature, which require modest resources and operation complexity (e.g., read-out) per unit area. Based on the properties of the detector and read-out electronics that we measured in the lab, we developed a realistic concept for a very large effective area mission devoted to X-ray timing in the 2-30 keV energy range. We show that effective areas in the range of 10-15 square meters are within reach, by using a conventional spacecraft platform and launcher of the small-medium class.Comment: 13 pages, 8 figures, 1 table, Proceedings of SPIE Vol. 7732, Paper No. 7732-66, 201

Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet

Chronic myelomonocytic leukemia (CMML) is a disease of the elderly, and by far the most frequent overlap myelodysplastic/myeloproliferative neoplasm in adults. Aside from the chronic monocytosis that remains the cornerstone of its diagnosis, the clinical presentation of CMML includes dysplastic features, cytopenias, excess of blasts, or myeloproliferative features including high white blood cell count or splenomegaly. Prognosis is variable, with several prognostic scoring systems reported in recent years, and treatment is poorly defined, with options ranging from watchful waiting to allogeneic stem cell transplantation, which remains the only curative therapy for CMML. Here, we present on behalf of the European Hematology Association and the European LeukemiaNet, evidence- and consensus-based guidelines, established by an international group of experts, from Europe and the United States, for standardized diagnostic and prognostic procedures and for an appropriate choice of therapeutic interventions in adult patients with CMML