The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent ...novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.
The targeting of two independent but synergistic enzymatic activities, histone deacetylases (HDACs, class I and HDAC6) and phosphodiesterase 5 (PDE5), has recently been validated as a potentially ...novel therapeutic approach for Alzheimer's disease (AD). Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission. Thus, CM-414 may serve as the starting point to discover balanced dual inhibitors with an optimal efficacy and safety profile for clinical testing on AD patients.
Training and assessment paradigms for laparoscopic surgical skills are evolving from traditional mentor–trainee tutorship towards structured, more objective and safer programs. Accreditation of ...surgeons requires reaching a consensus on metrics and tasks used to assess surgeons’ psychomotor skills. Ongoing development of tracking systems and software solutions has allowed for the expansion of novel training and assessment means in laparoscopy. The current challenge is to adapt and include these systems within training programs, and to exploit their possibilities for evaluation purposes. This paper describes the state of the art in research on measuring and assessing psychomotor laparoscopic skills. It gives an overview on tracking systems as well as on metrics and advanced statistical and machine learning techniques employed for evaluation purposes. The later ones have a potential to be used as an aid in deciding on the surgical competence level, which is an important aspect when accreditation of the surgeons in particular, and patient safety in general, are considered. The prospective of these methods and tools make them complementary means for surgical assessment of motor skills, especially in the early stages of training. Successful examples such as the Fundamentals of Laparoscopic Surgery should help drive a paradigm change to structured curricula based on objective parameters. These may improve the accreditation of new surgeons, as well as optimize their already overloaded training schedules.
The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between ...fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.
Nutritional support of surgical and critically ill patients has undergone significant advances since 1936 when Studley demonstrated a direct relationship between pre-operative weight loss and ...operative mortality. The advent of total parenteral nutrition followed by the extraordinary progress in parenteral and enteral feedings, in addition to the increased knowledge of cellular biology and biochemistry, have allowed clinicians to treat malnutrition and improve surgical patient's outcomes. We reviewed the literature for the current status of perioperative nutrition comparing parenteral nutrition with enteral nutrition. In a surgical patient with established malnutrition, nutritional support should begin at least 7-10 days prior to surgery. Those patients in whom eating is not anticipated beyond the first five days following surgery should receive the benefits of early enteral or parenteral feeding depending on whether the gut can be used. Compared to parenteral nutrition, enteral nutrition is associated with fewer complications, a decrease in the length of hospital stay, and a favorable cost-benefit analysis. In addition, many patients may benefit from newer enteral formulations such as Immunonutrition as well as disease-specific formulations.
► We studied the phase reddening on near-Earth asteroids and lab samples spectra. ► Phase reddening has no significant impact on the mineralogical analysis. ► Phase reddening is comparable to certain ...degree of space weathering. ► Phase reddening can lead to an ambiguous taxonomic classification.
Phase reddening is an effect that produces an increase of the spectral slope and variations in the strength of the absorption bands as the phase angle increases. In order to understand its effect on spectroscopic observations of asteroids, we have analyzed the visible and near-infrared spectra (0.45–2.5μm) of 12 near-Earth asteroids observed at different phase angles. All these asteroids are classified as either S-complex or Q-type asteroids. In addition, we have acquired laboratory spectra of three different types of ordinary chondrites at phase angles ranging from 13° to 120°. We have found that both, asteroid and meteorite spectra show an increase in band depths with increasing phase angle. In the case of the asteroids the Band I depth increases in the range of ∼2°<g<70° and the Band II depth increases in the range of ∼2°<g<55°. Using this information we have derived equations that can be used to correct the effect of phase reddening in the band depths. Of the three meteorite samples, the (olivine-rich) LL6 ordinary chondrite is the most affected by phase reddening. The studied ordinary chondrites have their maximum spectral contrast of Band I depths at a phase angle of ∼60°, followed by a decrease between 60° and 120° phase angle. The Band II depths of these samples have their maximum spectral contrast at phase angles of 30–60° which then gradually decreases to 120° phase angle. The spectral slope of the ordinary chondrites spectra shows a significant increase with increasing phase angle for g>30°. Variations in band centers and band area ratio (BAR) values were also found, however they seems to have no significant impact on the mineralogical analysis. Our study showed that the increase in spectral slope caused by phase reddening is comparable to certain degree of space weathering. In particular, an increase in phase angle in the range of 30–120° will produce a reddening of the reflectance spectra equivalent to exposure times of ∼0.1×106–1.3×106years at about 1AU from the Sun. This increase in spectral slope due to phase reddening is also comparable to the effects caused by the addition of different fractions of SMFe. Furthermore, we found that under some circumstances phase reddening could lead to an ambiguous taxonomic classification of asteroids.
•Forest structure modulates Scots pine growth responses to climate.•Tree-to-tree competition and radial growth were negatively related.•Tree growth is strongly modulated by competition.•Competition ...overrides climate as a driver of tree growth.•Climate–growth sensitivity increases as competition decreases.
Understanding the relative contributions of competition and climate on individual tree growth is critical to project realistic forest dynamics under projected climate scenarios. Furthermore, present competition levels may reflect legacies of past use. Here, we analyze the effects of climate, site conditions and competition on radial growth in three Scots pine stands located along an altitudinal gradient in central Spain. Current stand structure and retrospective analyses of radial growth (basal area increment, BAI) were used to model changes in tree growth as a function of a spatially-explicit competition index (CI) and climate. Linear mixed-effects models were employed to model BAI and to quantify the growth responses to climate of trees under low and high competition levels. Competition effects on growth were steady over time regardless of tree age. High competition levels negatively affected growth since negative exponential functions characterized the CI–BAI relationships. Tree growth sensitivity to climate increased with decreasing competition intensity. Growth at high elevations was mainly limited by low winter temperatures, whereas warm spring enhanced growth at middle elevations and warm late summer temperatures constrained growth at low elevation. Growth responsiveness to climate is enhanced under low competition levels. Overall, current competition is a more relevant driver of recent growth than climate. Proactive forest management should be adopted to reduce the vulnerability of Scots pine forests currently subjected to higher competition levels and warmer and drier conditions.
Silk fibroin (SF) is a biocompatible natural protein with excellent mechanical characteristics. SF-based biomaterials can be structured using a number of techniques, allowing the tuning of materials ...for specific biomedical applications. In this study, SF films, porous membranes, and electrospun membranes were produced using solvent-casting, salt-leaching, and electrospinning methodologies, respectively. SF-based materials were subjected to physicochemical and biological characterizations to determine their suitability for tissue regeneration applications. Mechanical analysis showed stress–strain curves of brittle materials in films and porous membranes, while electrospun membranes featured stress–strain curves typical of ductile materials. All samples showed similar chemical composition, melting transition, hydrophobic behavior, and low cytotoxicity levels, regardless of their architecture. Finally, all of the SF-based materials promote the proliferation of human umbilical vein endothelial cells (HUVECs). These findings demonstrate the different relationship between HUVEC behavior and the SF sample’s topography, which can be taken advantage of for the design of vascular implants.
Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We ...found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1
T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4
T cells, which prevented activation, reduced T
1-polarization and directed T
17-differentiation. PD-L1 signaling also induced an anergic T-bet
IFN-γ
phenotype in CD8
T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1
T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1
T cells engaged PD-1
macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1
T cells have diverse tolerogenic effects on tumor immunity.
BACKGROUND: This study aims to implement a set of wearable technologies to record and analyze the surgeon’s physiological and ergonomic parameters during the performance of conventional and ...robotic-assisted laparoscopic surgery, comparing the ergonomics and stress levels of surgeons during surgical procedures. METHODS: This study was organized in two different settings: simulator tasks and experimental model surgical procedures. The participating surgeons performed the tasks and surgical procedures in both laparoscopic and robotic-assisted surgery in a randomized fashion. Different wearable technologies were used to record the surgeons’ posture, muscle activity, electrodermal activity and electrocardiography signal during the surgical practice. RESULTS: The simulator study involved six surgeons: three experienced (>100 laparoscopic procedures performed; 36.33 ± 13.65 years old) and three novices (<100 laparoscopic procedures; 29.33 ± 8.39 years old). Three surgeons of different surgical specialties with experience in laparoscopic surgery (>100 laparoscopic procedures performed; 37.00 ± 5.29 years old), but without experience in surgical robotics, participated in the experimental model study. The participating surgeons showed an increased level of stress during the robotic-assisted surgical procedures. Overall, improved surgeon posture was obtained during robotic-assisted surgery, with a reduction in localized muscle fatigue. CONCLUSIONS: A set of wearable technologies was implemented to measure and analyze surgeon physiological and ergonomic parameters. Robotic-assisted procedures showed better ergonomic outcomes for the surgeon compared to conventional laparoscopic surgery. Ergonomic analysis allows us to optimize surgeon performance and improve surgical training.
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