Modern systems evolve in unpredictable environments and have to continuously adapt their behaviour to changing conditions. The “DReAM” (Dynamic Reconfigurable Architecture Modelling) framework has ...been designed for modelling reconfigurable dynamic systems. It provides a rule-based language, inspired from Interaction Logic, which is expressive and easy to use encompassing all aspects of dynamicity including parametric multi-modal coordination with creation/deletion of components as well as mobility. Additionally, it allows the description of both endogenous/modular and exogenous/centralized coordination styles and sound transformations from one style to the other. The DReAM framework is implemented in the form of a Java API bundled with an execution engine. It allows us to develop runnable systems combining the expressiveness of the rule-based notation together with the flexibility of this widespread programming language.
Development of the highly selective targeted tyrosine kinase inhibitors (TKIs) has expanded the therapeutic options for chronic myeloid leukemia (CML). Patients undergoing TKI therapy should be ...closely monitored to ensure that the best therapeutic response and quality of life are achieved, and to control suboptimal responses and adverse events. Despite the high rate of response using current first‐line TKIs, treatment failure may still occur, and resistance is considered a challenge in the treatment of patients with CML. The third‐generation TKI, ponatinib, is a potent orally bioavailable pan BCR‐ABL inhibitor that inhibits both wild‐type and mutant BCR‐ABL1 kinase, including the “gatekeeper” T315I mutation, which is resistant to all other currently available TKIs. This paper reviews the effectiveness, feasibility, and safety of ponatinib in the real‐life clinical management of CML. Potential prognostic factors in identifying patients most likely to benefit from ponatinib treatment will be discussed, and case presentations illustrating situations encountered in real‐life clinical practice are described. Ponatinib is effective in patients who have received prior TKIs in clinical studies as well as under real‐life conditions. Nevertheless, the risk/benefit balance must be evaluated for each patient, particularly considering disease state, mutational status, treatment line, intolerance/resistance to prior TKIs, age, frailty, and specific comorbidities.
Treatment-free remission (TFR) has become a primary therapeutic goal in CML and is also considered feasible by international guidelines. TKIs dose reduction is often used in real-life practice to ...reduce adverse events, although its impact on TFR is still a matter of debate. This study aimed to explore the attitude of Italian hematologists towards prescribing TKIs at reduced doses and its impact on TFR. In September 2020, a questionnaire was sent to 54 hematology centers in Italy participating to the Campus CML network. For each patient, data on the main disease characteristics were collected. Most of the hematologists involved (64.4%) believed that low-dose TKIs should not influence TFR. Indeed, this approach was offered to 194 patients. At the time of TFR, all but 3 patients had already achieved a DMR, with a median duration of 61.0 months. After a median follow-up of 29.2 months, 138 (71.1%) patients were still in TFR. Interestingly, TFR outcome was not impaired by any of the variables examined, including sex, risk scores, BCR-ABL1 transcript types, previous interferon, type and number of TKIs used before treatment cessation, degree of DMR or median duration of TKIs therapy. On the contrary, TFR was significantly better after dose reduction due to AEs; furthermore, patients with a longer DMR duration showed a trend towards prolonged TFR. This survey indicates that low-dose TKI treatment is an important reality. While one third of Italian hematologists still had some uncertainties on TFR feasibility after using reduced doses of TKIs outside of clinical trials, TFR has often been considered a safe option even in patients treated with low-dose TKIs in the real-life setting. It should be noted that only 28.9% of our cases had a molecular recurrence, less than reported during standard dose treatment. Consequently, TFR is not impaired using low-dose TKIs.
An observational prospective study was conducted by the CML Italian network to analyze the role of baseline patient characteristics and first line treatments on overall survival and CML-related ...mortality in 1206 newly diagnosed CML patients, 608 treated with imatinib (IMA) and 598 with 2
nd
generation tyrosine kinase inhibitors (2GTKI). IMA-treated patients were much older (median age 69 years, IQR 58-77) than the 2GTKI group (52, IQR 41-63) and had more comorbidities. Estimated 4-year overall survival of the entire cohort was 89% (95%CI 85.9-91.4). Overall, 73 patients (6.1%) died: 17 (2.8%) in the 2GTKI vs 56 (9.2%) in the IMA cohort (adjusted HR=0.50; 95% CI=0.26-0.94), but no differences were detected for CML-related mortality (10 (1.7%) vs 11 (1.8%) in the 2GTKIs vs IMA cohort (sHR=1.61; 0.52-4.96). The ELTS score was associated to CML mortality (high risk vs low, HR=9.67; 95%CI 2.94-31.74; p<0.001), while age (per year, HR=1.03; 95%CI 1.00-1.06; p=0.064), CCI (4-5 vs 2, HR=5.22; 95%CI 2.56-10.65; p<0.001), ELTS score (high risk vs low, HR=3.11; 95%CI 1.52-6.35, p=0.002) and 2GTKI vs IMA (HR=0.26; 95%CI 0.10-0.65, p=0.004) were associated to an increased risk of non-related CML mortality. The ELTS score showed a better discriminant ability than the Sokal score in all comparisons.
Reverse takotsubo cardiomyopathy (rTTC) is a less frequent variant of takotsubo cardiomyopathy (TTC) with several differences about epidemiology and clinical aspects. While left ventricular outflow ...tract (LVOT) obstruction is relatively frequent in TTC patients, this complication has not been reported in the setting of rTTC yet. We describe the case of a female patient with rTTC complicated by LVOT obstruction and systolic anterior motion of mitral valve: the onset of these findings coincided with the regression of wall motion abnormalities. This dangerous “relay race” seems to be not casual but related to the characteristics of rTTC and should be always expected and prevented.
<Learning objective: Left ventricle outflow tract obstruction with systolic anterior motion of mitral valve is an insidious complication that may be associated with reverse takotsubo cardiomyopathy and not only with the classic takotsubo cardiomyopathy. This complication appears to be delayed and should be always expected. Close echocardiographic monitoring, careful fluid support and early start of beta-blocker therapy may prevent it.>
Achievement of deep molecular response following treatment with a tyrosine kinase inhibitor (TKI) allows for treatment-free remission (TFR) in many patients with chronic myeloid leukemia (CML). ...Successful TFR is defined as the achievement of a sustained molecular response after cessation of ongoing TKI therapy. The phase 3 ENESTPath study was designed to determine the required optimal duration of consolidation treatment with the second-generation TKI, nilotinib 300 mg twice-daily, to remain in successful TFR without relapse after entering TFR for 12 months. The purpose of this Italian 'patient's voice CML' substudy was to evaluate patients' psycho-emotional characteristics and quality of life through their experiences of stopping treatment with nilotinib and entering TFR. The purpose of the present contribution is to early present the study protocol of an ongoing study to the scientific community, in order to describe the study rationale and to extensively present the study methodology. Patients aged ≥18 years with a confirmed diagnosis of Philadelphia chromosome positive
+ CML in chronic phase and treated with front-line imatinib for a minimum of 24 months from the enrollment were eligible. Patients consenting to participate the substudy will have quality of life questionnaires and in-depth qualitative interviews conducted. The substudy will include both qualitative and quantitative design aspects to evaluate the psychological outcomes as assessed
patients' emotional experience during and after stopping nilotinib therapy. Randomization is hypothesized to be a timepoint of higher psychological alert or distress when compared to consolidation and additionally any improvement in health-related quality of life (HRQoL) due to nilotinib treatment is expected across the timepoints (from consolidation, to randomization, and TFR). An association is also expected between dysfunctional coping strategies, such as detachments and certain personality traits, and psychological distress and HRQoL impairments. Better HRQoL outcomes are expected in TFR compared to the end of consolidation. This substudy is designed for in-depth assessment of all potential psycho-emotional variables and aims to determine the need for personalized patient care and counselling, and also guide clinicians to consider the psychological well-being of patients who are considering treatment termination. NCT number: NCT01743989, EudraCT number: 2012-005124-15.
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The precise mechanisms that lead to orthopedic implant failure are not well understood; it is believed that the micromechanical environment at the bone-implant interface regulates ...structural stability of an implant. In this work, we seek to understand how the 3D mechanical environment of an implant affects bone formation during early osteointegration. We employed two-photon lithography (TPL) direct laser writing to fabricate 3-dimensional rigid polymer scaffolds with tetrakaidecahedral periodic geometry, herewith referred to as nanolattices, whose strut dimensions were on the same order as osteoblasts’ focal adhesions (∼2μm) and pore sizes on the order of cell size, ∼10μm. Some of these nanolattices were subsequently coated with thin conformal layers of Ti or W, and a final outer layer of 18nm-thick TiO2 was deposited on all samples to ensure biocompatibility. Nanomechanical experiments on each type of nanolattice revealed the range of stiffnesses of 0.7–100MPa.
Osteoblast-like cells (SAOS-2) were seeded on each nanolattice, and their mechanosensitve response was explored by tracking mineral secretions and intracellular f-actin and vinculin concentrations after 2, 8 and 12days of cell culture in mineralization media.
Experiments revealed that the most compliant nanolattices had ∼20% more intracellular f-actin and ∼40% more Ca and P secreted onto them than the stiffer nanolattices, where such cellular response was virtually indistinguishable.
We constructed a simple phenomenological model that appears to capture the observed relation between scaffold stiffness and f-actin concentration. This model predicts a range of optimal scaffold stiffnesses for maximum f-actin concentration, which appears to be directly correlated with osteoblast-driven mineral deposition.
This work suggests that three-dimensional scaffolds with titania-coated surfaces may provide an optimal microenvironment for cell growth when their stiffness is similar to that of cartilage (∼0.5–3MPa). These findings help provide a greater understanding of osteoblast mechanosensitivity and may have profound implications in developing more effective and safer bone prostheses.
Creating prostheses that lead to optimal bone remodeling has been a challenge for more than two decades because of a lack of thorough knowledge of cell behavior in three-dimensional (3D) environments. Literature has shown that 2D substrate stiffness plays a significant role in determining cell behavior, however, limitations in fabrication techniques and difficulties in characterizing cell-scaffold interactions have limited our understanding of how 3D scaffolds’ stiffness affects cell response.
The present study shows that scaffold structural stiffness affects osteoblasts cellular response. Specifically this work shows that the cells grown on the most compliant nanolattices with a stiffness of 0.7MPa expressed ∼20% higher concentration of intracellular f-actin and secreted ∼40% more Ca and P compared with all other nanolattices. This suggests that bone scaffolds with a stiffness close to that of cartilage may serve as optimal 3D scaffolds for new synthetic bone graft materials.
Lightweight materials that are simultaneously strong and stiff are desirable for a range of applications from transportation to energy storage to defense. Micro- and nanolattices represent some of ...the lightest fabricated materials to date, but studies of their mechanical properties have produced inconsistent results that are not well captured by existing lattice models. We performed systematic nanomechanical experiments on four distinct geometries of solid polymer and hollow ceramic (Al2O3) nanolattices. All samples tested had a nearly identical scaling of strength (σy) and Young's modulus (E) with relative density (ρ¯), ranging from σy∝ρ¯1.45 to ρ¯1.92 and E∝ρ¯1.41 to ρ¯1.83, revealing that changing topology alone does not necessarily have a significant impact on nanolattice mechanical properties. Finite element analysis was performed on solid and hollow lattices with structural parameters beyond those realized experimentally, enabling the identification of transition regimes where solid-beam lattices diverge from existing analytical theories and revealing the complex parameter space of hollow-beam lattices. We propose a simplified analytical model for solid-beam lattices that provides insight into the mechanisms behind their observed stiffness, and we investigate different hollow-beam lattice parameters that give rise to their aberrant properties. These experimental, computational and theoretical results uncover how architecture can be used to access unique lattice mechanical property spaces while demonstrating the practical limits of existing beam-based models in characterizing their behavior.
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