Dasatinib is a short-acting dual ABL/SRC family tyrosine kinase inhibitor (TKI), which is frequently used to treat chronic myeloid leukemia. Although very effective, patients taking dasatinib often ...display severe adverse effects, including pleural effusions and increased risk of bleeding primarily in the gastrointestinal tract. The actual causes of these side effects are currently undetermined. We hypothesize that endothelial cells (ECs) that line the inner walls of blood vessels and control the traffic to the underlying tissues might be involved.
The effects of TKIs on ECs were studied by various assays, such as real-time cell impedance measurements, live-cell microscopy, wound healing, Western blot, and an
model.
Dasatinib uniquely causes a profound, dose-dependent disorganization of the EC monolayers. Dasatinib promoted the disassembly of cell-cell contacts, altered cell-matrix contacts, and further altered the wound healing. A key observation is that this effect is fully reversible after drug washout. In line with these
observations, intraperitoneal administration of dasatinib to mice caused significant vascular leakage in the intestine. The underlying molecular mechanism of dasatinib-induced reorganization of the actin involves ROCK activation, which increases the amount of the phosphorylation of myosin light chain and consequently activates the non-muscle myosin II.
Our data are consistent with a scenario in which dasatinib triggers a transient increase in vascular leakage that probably contributes to adverse effects such as bleeding diathesis and pleural effusions.
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The impact of the newly discovered severe acute respiratory syndrome coronavirus 2 causing coronavirus disease‐19 (COVID‐19) in hemodialysis patients remains poorly characterized. Some hemodialysis ...techniques reduce systemic inflammation but their impact on COVID‐19 has not been addressed. The aim of this prospective study was to evaluate factors associated with mortality in COVID‐19 hemodialysis patients, including the impact of reducing interleukin‐6 using a cytokine adsorbent filter. This is a prospective single‐center study including 16 hemodialysis patients with COVID‐19. All were dialyzed using a polymethyl methacrylate (PMMA) filter. Interleukin‐6 levels were obtained before and after the first admission hemodialysis session and at 1 week. Baseline comorbidities, laboratory values, chest X‐ray, and treatments were recorded and compared between survivors and non‐survivors. Out of 16 patients (13 males, mean age 72 ± 15 years), 4 (25%) died. Factors associated with mortality were dialysis vintage (P = 0.01), chest X‐ray infiltrates (P = 0.032), serum C‐reactive protein (P = 0.05), and lactate dehydrogenase (P = 0.02) at 1 week, oxygen therapy requirement (P = 0.02) and anticoagulation (P < 0.01). At admission, non‐survivors had higher predialysis and postdialysis interleukin‐6 levels (P = 0.02 for both) and did not present the reduction of interleukin‐6 levels during the dialysis session with PMMA filter that was observed in survivors (survivors vs. non‐survivors: 25.0 17.5–53.2% vs. −2.8 −109.4–12.8% reduction, P = 0.04). A positive balance of interleukin‐6 during the admission dialysis was associated with mortality (P = 0.008). In conclusion, in hemodialysis COVID‐19 patients, a positive interleukin‐6 balance during the admission hemodialysis session was associated with higher mortality.
Naive B cells use the chemokine receptor CXCR5 to enter B cell follicles, where they scan CXCL13-expressing ICAM-1
VCAM-1
follicular dendritic cells (FDCs) for the presence of antigen. ...CXCL13-CXCR5-mediated motility is mainly driven by the Rac guanine exchange factor DOCK2, which contains a binding domain for phosphoinositide-3,4,5-triphosphate (PIP3) and other phospholipids. While p110δ, the catalytic subunit of the class IA phosphoinositide-3-kinase (PI3K) δ, contributes to CXCR5-mediated B cell migration, the precise interdependency of DOCK2, p110δ, or other PI3K family members during this process remains incompletely understood. Here, we combined
chemotaxis assays and
imaging to examine the contribution of these two factors during murine naïve B cell migration to CXCL13. Our data confirm that p110δ is the main catalytic subunit mediating PI3K-dependent migration downstream CXCR5, whereas it does not contribute to chemotaxis triggered by CXCR4 or CCR7, two other chemokine receptors expressed on naïve B cells. The contribution of p110δ activity to CXCR5-driven migration was complementary to that of DOCK2, and pharmacological or genetic interference with both pathways completely abrogated B cell chemotaxis to CXCL13. Intravital microscopy of control and gene-deficient B cells migrating on FDCs confirmed that lack of DOCK2 caused a profound migration defect, whereas p110δ contributed to cell speed and directionality. B cells lacking active p110δ also displayed defective adhesion to ICAM-1; yet, their migration impairment was maintained on ICAM-1-deficient FDCs. In sum, our data uncover two complementary signaling pathways mediated by DOCK2 and p110δ, which enable CXCR5-driven naïve B cell examination of FDCs.
SARS-CoV-2 is responsible for the development of coronavirus disease 2019 (COVID-19) in infected individuals, who can either exhibit mild symptoms or progress toward a life-threatening acute ...respiratory distress syndrome (ARDS). Exacerbated inflammation and dysregulated immune responses involving T and myeloid cells occur in COVID-19 patients with severe clinical progression. However, the differential contribution of specific subsets of dendritic cells and monocytes to ARDS is still poorly understood. In addition, the role of CD8+ T cells present in the lung of COVID-19 patients and relevant for viral control has not been characterized. Here, we have studied the frequencies and activation profiles of dendritic cells and monocytes present in the blood and lung of COVID-19 patients with different clinical severity in comparison with healthy individuals. Furthermore, these subpopulations and their association with antiviral effector CD8+ T cell subsets were also characterized in lung infiltrates from critical COVID-19 patients. Our results indicate that inflammatory transitional and nonclassical monocytes and CD1c+ conventional dendritic cells preferentially migrate from blood to lungs in patients with severe COVID-19. Thus, this study increases the knowledge of specific myeloid subsets involved in the pathogenesis of COVID-19 disease and could be useful for the design of therapeutic strategies for fighting SARS-CoV-2 infection.
In the analysis of biological time series, the state space is comprised of a framework for the study of systems with presumably deterministic and stationary properties. However, a physiological ...experiment typically captures an observable that characterizes the temporal response of the physiological system under study; the dynamic variables that make up the state of the system at any time are not available. Only from the acquired observations should state vectors be reconstructed to emulate the different states of the underlying system. This is what is known as the reconstruction of the state space, called the phase space in real-world signals, in many cases satisfactorily resolved using the method of delays. Each state vector consists of m components, extracted from successive observations delayed a time τ . The morphology of the geometric structure described by the state vectors, as well as their properties depends on the chosen parameters τ and m. The real dynamics of the system under study is subject to the correct determination of the parameters τ and m. Only in this way can be deduced features have true physical meaning, revealing aspects that reliably identify the dynamic complexity of the physiological system. The biological signal presented in this work, as a case study, is the photoplethysmographic (PPG) signal. We find that m is five for all the subjects analyzed and that τ depends on the time interval in which it is evaluated. The Hénon map and the Lorenz flow are used to facilitate a more intuitive understanding of the applied techniques.
The Bruton's tyrosine kinase inhibitor ibrutinib and the B‐cell lymphoma 2 anti‐apoptotic protein inhibitor venetoclax provide high response rates in chronic lymphocytic leukemia (CLL). However, ...there is a growing number of patients that relapse after treatment or show refractory disease, thus new targets and agents are still needed. We have previously reported the chemokine receptor CCR7 as a relevant deregulated target in CLL and have developed CAP‐100, a novel therapeutic anti‐CCR7 antibody that is under evaluation for relapse/refractory CLL (NCT04704323). While CCR7 expression has been shown to be down‐modulated in CLL patients treated with ibrutinib, whether venetoclax acts in a similar manner remains unaddressed. Here, we aimed to document the impact of venetoclax on CCR7 expression in CLL cells, as well as on the pre‐clinical activity of CAP‐100. To this end, we addressed CCR7 expression by flow cytometry and the antibody efficacy by means of in vitro chemotactic and antibody‐dependent cell‐mediated cytotoxicity (ADCC) assays. Our data indicate that venetoclax treatment did not significantly modify CCR7 expression pattern nor CAP‐100 mechanisms of action. Together, these findings support CAP‐100 as an adjuvant therapy to venetoclax that may introduce additional modes of action in CLL therapy.
This study developed a novel method for analyzing and decomposing a signal into its main dynamics for small and large timescales. Our proposal is based on a decoupled hybrid system of convolutional ...and recurrent neural networks that uses as inputs the power spectrum and spectrogram of a given signal, giving as output the dynamic behavior. We define the dynamic classification predicted of the signal using previously known dynamics characterized through training signals: periodic, quasi-periodic, aperiodic, chaotic, and randomness. We created a synthetic dataset comprising more than 50 training signals from different categories. For the real-world dataset, we used photoplethysmographic signals from 40 students obtained from a Spanish medical study. We tested the developed system's performance in real biological and synthetical signals, obtaining noteworthy results. All the results are evaluated qualitatively and quantitatively. Still, given the novelty and the lack of similar works, we cannot compare reliably and rigorously our results with other works, at least quantitatively. We can retrieve from the exposed results in this work three key ideas: the DNN-based solutions are capable of learning and generalizing the dynamics behavior of signals; the proposal learned correctly to distinguish between the reference dynamics provided and find some unidirectional similarities in the aperiodicity cases; and the results obtained using real-world PPG signals reveal that biological signals seem to exhibit a multi-dynamic behavior that changes depending on the used timescale, being quasi-periodically dominant in the short-term and aperiodically dominant in the long-term.
Is the PPG Signal Chaotic? De Pedro-Carracedo, Javier; Fuentes-Jimenez, David; Ugena, Ana M. ...
IEEE access,
2020, Letnik:
8
Journal Article
Recenzirano
Odprti dostop
PhotoPlethysmoGraphic (PPG) signal is an easily accessible biological signal that gives valuable diagnostic information. The novelty is the study procedure of the dynamic of the PPG signals, in our ...case of young and healthy individuals, with Deep Neural Network, which allows finding the dynamic behavior at different timescales. On a small timescale, the dynamic behavior of the PPG signal is predominantly quasi-periodic. On a large timescale, a more complex dynamic diversity emerges, but never a chaotic behavior as earlier studies had reported. The procedure that determines the dynamics of the PPG signal consists of contrasting the dynamics of a PPG signal with well-known dynamics-named reference signals in this study-, mostly present in physical systems, such as periodic, quasi-periodic, aperiodic, chaotic or random dynamics. For this purpose, this paper provides two methods of analysis based on Deep Neural Network (DNN) architectures. The former uses a Convolutional Neural Network (CNN) architecture model. Upon training with reference signals, the CNN model identifies the dynamics present in the PPG signal at different timescales, assigning, according to a classification process, an occurrence probability to each of them. The latter uses a Recurrent Neural Network (RNN) based on a Long Short-Term Memory (LSTM) architecture. With each of the signals, whether reference signals or PPG signals, the RNN model infers an evolution function (nonlinear regression model) based on training data, and considers its predictive capability over a relatively short time horizon.
Dasatinib is a dual SRC/ABL tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML) that is known to have unique immunomodulatory effects. In particular, dasatinib intake typically ...causes lymphocytosis, which has been linked to better clinical response. Since the underlying mechanisms are unknown and SRC family kinases are involved in many cell motility processes, we hypothesized that the movement and migration of lymphocytes is modulated by dasatinib.
Peripheral blood samples from CML patients treated with second-line dasatinib were collected before and 2 h after the first dasatinib intake, and follow-up samples from the same patients 3 and 6 months after the start of therapy. The migratory capacity and phenotype of lymphocytes and differential blood counts before and after drug intake were compared for all study time-points.
We report here for the first time that dasatinib intake is associated with inhibition of peripheral blood T-cell migration toward the homeostatic chemokines CCL19 and CCL21, which control the trafficking toward secondary lymphoid organs, mainly the lymph nodes. Accordingly, the proportion of lymphocytes in blood expressing CCR7, the chemokine receptor for both CCL19 and CCL21, decreased after the intake including both naïve CD45RA+ and central memory CD45RO+ T-cells. Similarly, naïve B-cells diminished with dasatinib. Finally, such changes in the migratory patterns did not occur in those patients whose lymphocyte counts remained unchanged after taking the drug.
We, therefore, conclude that lymphocytosis induced by dasatinib reflects a pronounced redistribution of naïve and memory populations of all lymphocyte subsets including CD4+ and CD8+ T-cells and B-cells.
Inhibition of the heterodimeric amino acid carrier SLC7A5/SLC3A2 (LAT1/CD98) has been widely studied in tumor biology but its role in physiological conditions remains largely unknown. Here we show ...that the SLC7A5/SLC3A2 heterodimer is constitutively present at different stages of erythroid differentiation but absent in mature erythrocytes. Administration of erythropoietin (EPO) further induces SLC7A5/SLC3A2 expression in circulating reticulocytes, as it also occurs in anemic conditions. Although Slc7a5 gene inactivation in the erythrocyte lineage does not compromise the total number of circulating red blood cells (RBCs), their size and hemoglobin content are significantly reduced accompanied by a diminished erythroblast mTORC1 activity. Furthermore circulating Slc7a5-deficient reticulocytes are characterized by lower transferrin receptor (CD71) expression as well as mitochondrial activity, suggesting a premature transition to mature RBCs. These data reveal that SLC7A5/SLC3A2 ensures adequate maturation of reticulocytes as well as the proper size and hemoglobin content of circulating RBCs.
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•Expression of SLC7A5/SLC3A2 amino acid carrier in immature erythroid cells•Erythropoietin regulates SLC7A5/SLC3A2 expression•Loss of SLC7A5 reduces size, hemoglobin and mTORC1 activity of erythroid cells•SLC7A5 sustains CD71 expression and mitochondrial activity in circulating reticulocytes
Molecular physiology; Cell biology.
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