1,396 research outputs found
A Construction-centered approach to the annotation of modality
No full textWe propose a comprehensive annotation framework for modality, which encompasses and supports existing annotation schemes, by adopting a construction-centered view. Rather than seeing modality as a feature of a trigger or of a target, we view it as a feature of the
triad “trigger-target-relation”, which we name construction. We motivate the need for such an approach from a theoretical perspective, and we also show that a construction-centered annotation scheme is operationally valid. We evaluate inter-annotator agreement via a pilot study, and find that modalised constructions identified by different annotators can be successfully aligned, as a first crucial step towards further agreement evaluations
Exploiting B-cell Receptor Stereotypy to Design Tailored Immunotherapy in Chronic Lymphocytic Leukemia
No full textData related to manuscript "Exploiting B-cell Receptor Stereotypy to Design Tailored Immunotherapy in Chronic Lymphocytic Leukemia" by Rovida A*, Maccalli C*, Scarfò L, Dellabona P, Stamatopoulos K, Ghia P. Clin Cancer Res. 2021 Feb 1;27(3):729-739. doi: 10.1158/1078-0432.CCR-20-1632. *Contributed equall
Detectability of Space-Time Fluctuations in Ultra High Energy Cosmic Ray Experiments
No full textIt is generally expected that quantum gravity affects the
structure of space-time by introducing stochastic fluctuations in the geometry,
and, ultimately, in the measurements of four-distances and fourmomenta.
These fluctuations may induce observable consequences on the
propagation of ultra high energy particles, mainly in the range of energies of
interest for cosmic ray physics, over large distances, leading to their detection
or constraining the underlying quantum gravitational structure. We argue
that the detectable effects of fluctuations may extend to energies much lower
than the threshold for proton photopion production (the so-called GZK cutoff),
so that lower energy observations may provide strong constraints on
the role of a fluctuating space-time structure
EZN-2208 treatment suppresses chronic lymphocytic leukaemia by interfering with environmental protection and increases response to fludarabine
No full textThe transcription factor HIF-1α is overexpressed in chronic lymphocytic leukaemia (CLL), where it promotes leukaemia progression by favouring the interaction of leukaemic cells with protective tissue microenvironments. Here, we tested the hypothesis that a pharmacological compound previously shown to inhibit HIF-1α may act as a chemosensitizer by interrupting protective microenvironmental interactions and exposing CLL cells to fludarabine-induced cytotoxicity. We found that the camptothecin-11 analogue EZN-2208 sensitizes CLL cells to fludarabine-induced apoptosis in cytoprotective in vitro cultures; in vivo EZN-2208 improves fludarabine responses, especially in early phases of leukaemia expansion, and exerts significant anti-leukaemia activity, thus suggesting that this or similar compounds may be considered as effective CLL therapeutic approaches
BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia
No full textInfections represent a cause of morbidity and mortality in patients affected by chronic lymphocytic leukemia (CLL). Introduction of new drugs in CLL clinical practice has showed impressive efficacy, in particular those targeting BTK. Among the consistent clinical data, an increasing number of reports describing the occurrence of unexpected opportunistic fungal infections has been reported during treatment with ibrutinib in the first 6 months of treatment. The reason underlying manifestations of invasive fungal infections in patients treated with ibrutinib is still under investigation. Our study aimed to understand the impact of BTK inhibition on immune response to fungal infection mediated by macrophages and CD14+ monocytic population obtained from CLL patients. Exposure to ibrutinib and acalabrutinib reduced signaling pathways activated by Aspergillus fumigatus determining an exacerbation of an immunosuppressive signature, a reduction of phagocytosis and a significant deficit in the secretion of inflammatory cytokines either in macrophages and monocytes isolated from CLL patients and healthy donors. These effects lead to a failure in completely counteracting conidia germination. In addition we investigated the biological effects of ibrutinib on monocyte counterpart in patients who were undergoing therapy. A significant impairment in cytokine secretion and a deficit of phagocytosis in circulating monocytes were detected after 3 months of treatment. Thus, our results uncover modifications in the innate response in CLL patients induced by ibrutinib that may impair the immunological response to fungal infection. BTK inhibition affects a productive immune response of CLL-associated macrophages (NLC) during Aspergillus fumigatus infection. Reduction of TNF-α secretion and phagocytosis are detected in monocytes isolated from CLL patients during ibrutinib therapy
Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2
No full textRecent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset # 1, # 2 and # 8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset # 2 (44%) versus subset # 1 and # 8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset # 2 was only 8%, lower than the frequency observed in either subset # 1 or # 8 (19% and 14%, respectively; P 0.04 for subset # 1 versus # 2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy
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