关键词： chronic lymphocytic leukemia   EMILIN-1   microenvironment   survival   VLA-4  

摘要： CD49d, the alpha 4 chain of the VLA-4 integrin, is a negative prognosticator in chronic lymphocytic leukemia (CLL) with a key role in CLL cell-microenvironment interactions mainly occurring via its ligands VCAM-1 and fibronectin. In the present study, we focused on EMILIN-1 (Elastin-MIcrofibriL-INterfacer-1), an alternative VLA-4 ligand whose role has been so far reported only in non-hematological settings, by investigating: i) the distribution of EMILIN-1 in CLL-involved tissues;ii) the capability of EMILIN-1 to operate, via its globular C1q (gC1q) domain, as additional adhesion ligand in CLL;iii) the functional meaning of EMILIN-1 gC1q/VLA-4 interactions in CLL. EMILIN-1 is widely present in the CLL-involved areas of bone marrow biopsies (BMBs) without difference between CD49d negative and positive cases, displaying at least three different expression patterns: "fibrillar", "dot-like" and "mixed". The lack in CLL-BMB of neutrophil elastase, whose proteolytic activity degrades EMILIN-1 and impairs EMILIN-1 function, suggests full functional EMILIN-1 in CLL independently of its expression pattern. Functionally, EMILIN-1 gC1q domain promotes adhesion of CLL cells through specific interaction with VLA-4, and releases pro-survival signals for CLL cells, as demonstrated by enhanced ERK and AKT phosphorylation and impairment of in-vitro-induced apoptosis. EMILIN-1/VLA-4 interaction can efficiently contribute to the maintenance of the neoplastic clone in CLL.

关键词： alternative high schools   mental health correlates   school policy  

摘要： Students in alternative high schools (AHSs) are an understudied population who experience disproportionate levels of risk factors that contribute to mental health problems. Using logistic regression, we explored associations between mental health problems and risk and protective factors among students in Texas AHSs (n = 515;mean age 17.1 years;51% female, 78% youth of color, 64% eligible for free/reduced lunch). Principals (n = 14) and lead health educators (n = 14) reported on school-level efforts to address mental health. Students reported, on average, 1.55 of 4 mental health problems in the past year. Logistic regression indicated that greater number of adverse childhood experiences, lower self-esteem, female gender, and sleep disruption (getting <8 h of sleep per night) were common contributors to symptoms of depression, anxiety, suicidal ideation, and PTSD with models showing medium-to-large effects (AUC: 0.73-0.81). We assessed school-level efforts to address mental health using descriptive statistics. At the school level, most (>50%) principals reported having policies and services to support student mental health, with the exception of having mental health/social services staff represented on school health councils (36%) and having Gay-Straight Alliances (21%). Most lead health educators (86%) reported educating AHS students about mental health, and many (57%) reported receiving professional development in mental health. Future research with a larger number of schools is needed to analyze whether school policies are statistically associated with student-level mental health outcomes. Such multi-level research can inform policies and practices for AHS student mental health.

关键词： COVID-19   VWF   ADAMTS13   Complement activation   Endotheliopathy   Microthrombosis  

摘要： ADAMTS13, a metalloproteinase, specifically cleaves unusually large multimers of von Willebrand factor (VWF), newly released from vascular endothelial cells. The ratio of ADAMTS13 activity to VWF antigen (ADAMTS13/VWF) and indicators of the alternative complement pathway (C3a and sC5b-9) are both related to the severity of COVID-19. The ADAMTS13/VWF ratio is generally moderately decreased (0.18-0.35) in patients with severe COVID-19. When these patients experience cytokine storms, both interleukin-8 and TNF alpha stimulate VWF release from vascular endothelial cells, while interleukin-6 inhibits both production of ADAMTS13 and its interaction with VWF, resulting in localized severe deficiency of ADAMTS13 activity. Platelet factor 4 and thrombospondin-1, both released upon platelet activation, bind to the VWF-A2 domain and enhance the blockade of ADAMTS13 function. Thus, the released unusually-large VWF multimers remain associated with the vascular endothelial cell surface, via anchoring with syndecan-1 in the glycocalyx. Unfolding of the VWF-A2 domain, which has high sequence homology with complement factor B, allows the domain to bind to activated complement C3b, providing a platform for complement activation of the alternative pathway. The resultant C3a and C5a generate tissue factor-rich neutrophil extracellular traps (NETs), which induce the mixed immunothrombosis, fibrin clots and platelet aggregates typically seen in patients with severe COVID-19.

关键词： elastic slab   Moutier theorem   solvent-induced stress  

摘要： Understanding the solvent-induced stresses in polymeric materials is of profound importance for drug release and soft robotics. This work presents an alternative method to obtain an analytical solution of solvent-induced stress in an elastic slab using the Moutier theorem under the framework of equilibrium thermodynamics and the elastic solution available in the literature. Using the analytical solution and the temporal evolution of the mass of organic solvents in polymeric slabs, we analyze the spatiotemporal evolution of the solvent-induced stress in the polymeric slabs and reveal the effects of the solvent transport on the stress evolution. The approach presented in this work provides a simple method to solve the decoupling problem involving diffusion and solvent-induced stresses.

摘要： Background and Aims The mechanism underlying HCC metastasis remains unclear, many oncogenes are known to regulate this process. However, the role of alternative splicing (AS) in pro-metastatic HCC is poorly understood. Approach and Results By performing RNA sequencing on nine pairs of primary HCC tissues with extrahepatic metastasis (EHMH) and nine pairs of metastasis-free HCC (MFH) tissues, we depicted the AS landscape in HCC and found a higher frequency of AS events in EHMH compared with MFH. Moreover, 28 differentially expressed splicing regulators were identified in EHMH compared with MFH. Among these, DEAD-box RNA helicase 17 (DDX17) was significantly up-regulated in EHMH and was strongly associated with patient outcome. Functional studies indicated that DDX17 knockout inhibited the degradation of the extracellular matrix, and diminished the invasive ability of HCC cells. A significant reduction in lung metastasis induced by DDX17 deficiency was also demonstrated in a diethylnitrosamine-induced DDX17(HKO) mouse model. Mechanistically, high DDX17 induced intron 3 retention of PXN-AS1 and produced a transcript (termed PXN-AS1-IR3). The transcript PXN-AS1-IR3 acted as an important promoter of HCC metastasis by inducing MYC transcription activation via recruiting the complex of testis expressed 10 and p300 to the MYC enhancer region, which led to transcriptional activation of several metastasis-associated downstream genes. Finally, the PXN-AS1-IR3 level was significantly higher in serum and HCC tissues with extrahepatic metastasis. Conclusions DDX17 and PXN-AS1-IR3 act as important metastatic promoters by modulating MYC signaling, suggesting that DDX17 and PXN-AS1-IR3 may be potential prognostic markers for metastatic HCC.

关键词： COVID-19   intensive care   nurses   nursing workforce   qualitative  

摘要： Aims To understand how COVID-19 affected nurse staffing in intensive care units (ICUs) in England, and to identify factors that influenced, and were influenced by, pandemic staffing models. Design Exploratory qualitative study. Methods Semi-structured, online interviews conducted July-September 2020 with regional critical care leaders including policy leads (n = 4) and directors/lead nurses (n = 10) across critical care networks in England. Findings The six themes emerging from the framework analysis illustrate how the pre-pandemic ICU culture influenced ICU staffing models during the pandemic. Changes in staffing impacted on the workforce and the care delivered, whilst it was necessary to learn from, and adjust to, a rapidly changing situation. Variation across and between networks necessitated variation in responses. The overwhelming outcome was that the pandemic has challenged the central tenets of ICU nurse staffing. Conclusions Pandemic nurse staffing models resulted in changes to ICU skill-mix and staffing numbers. Factors such as the impact of nurse staffing on care practices and on the workforce need to be taken into account when developing and testing future nurse staffing models for ICU. The extent to which ICUs will return to former staffing models is not yet known but there seems to be an appetite for change. Impact In common with many countries, nurse staffing in English ICUs was adapted to address surge requirements during the COVID-19 pandemic. Findings highlight the challenge COVID-19 presented to pre-pandemic ICU nurse staffing guidelines, the impact on patient and staff well-being and the potential legacy for future staffing models. Study findings have implications for ICU nurse managers, researchers and policy makers: nurse staffing models need to be adaptable to the local context of care and future research should investigate the impact of different models on patients, staff and health service outcomes.

关键词： Loss network   dynamic alternative routing   metastability   mixing times  

摘要： Consider N stations interconnected with links, each of capacity K, forming a complete graph. Calls arrive to each link at rate lambda and depart at rate 1. If a call arrives to a link xy, connecting stations x and y, which is at capacity, then a third station z is chosen uniformly at random and the call is attempted to be routed via z: if both links xz and zy have spare capacity, then the call is held simultaneously on these two;otherwise the call is lost. We analyse an approximation of this model. We show rigorously that there are three phases according to the traffic intensity alpha := lambda/K: for alpha is an element of (0, alpha(c)) boolean OR (1, infinity), the system has mixing time logarithmic in the number of links n := ((N)(2));for alpha is an element of (alpha(c), 1) the system has mixing time exponential in n, the number of links. Here alpha(c) := 1/3(5 root 10 - 13) approximate to 0.937 is an explicit critical threshold with a simple interpretation. We also consider allowing multiple rerouting attempts. This has little effect on the overall behaviour;it does not remove the metastability phase. Finally, we add trunk reservation: in this, some number sigma of circuits are reserved;a rerouting attempt is only accepted if at least sigma + 1 circuits are available. We show that if sigma is chosen sufficiently large, depending only on alpha, not K or n, then the metastability phase is removed.

关键词： Stem cell homing   Engraftment   The alternative pathway of the complement cascade   Factor B   Nlrp3 inflammasome   Proteomics  

摘要： We reported in the past that activation of the third (C3) and fifth element (C5) of complement cascade (ComC) is required for a proper homing and engraftment of transplanted hematopoietic stem/progenitor cells (HSPCs). Since myeloablative conditioning for transplantation triggers in recipient bone marrow (BM) state of sterile inflammation, we have become interested in the role of complement in this process and the potential involvement of alternative pathway of ComC activation. We noticed that factor B deficient mice (FB-KO) that do not activate properly alternative pathway, engraft poorly with BM cells from normal wild type (WT) mice. We observed defects both in homing and engraftment of transplanted HSPCs. To shed more light on these phenomena, we found that myeloablative lethal irradiation conditioning for transplantation activates purinergic signaling, ComC, and Nlrp3 inflammasome in WT mice, which is significantly impaired in FB-KO animals. Our proteomics analysis revealed that conditioned for transplantation lethally irradiated FB-KO compared to normal control animals have lower expression of several proteins involved in positive regulation of cell migration, transendothelial migration, immune system, cellular signaling protein, and metabolic pathways. Overall, our recent study further supports the role of innate immunity in homing and engraftment of HSPCs.

关键词： COVID-19   Medical education   e-learning   Learning behavior   Lectures   Remote learning  

摘要： Purpose The onset of the COVID-19 pandemic posed an eminent challenge for medical teachers worldwide. Face-to-face lectures and seminars were no longer possible, and alternatives had to be found. E-learning concepts quickly emerged as the only practicable solutions and also offered the opportunity to evaluate whether traditional face-to-face lectures could be translated into an online format, independent of the COVID-19 pandemic. Methods We offered an e-learning program consisting of lecture notes, screencasts with audio narration, and online webinars that covered topics normally taught in traditional lectures and seminars. To evaluate the learning behavior and quality of our e-learning program, we drafted a questionnaire that students completed at the end of the 2020 summer semester that had been designed to enable a comparative analysis of the different e-learning modules. Results Voluntary participation in the online courses was high. Survey analysis revealed high satisfaction with and a distinctive preference for the format, even under regular, COVID-19-independent conditions. In general, a positive appraisal of e-learning-especially as a substitute for regular lectures-was found. Students also reported higher studying efficiency. Exam results were equal to those of previous semesters. Conclusion Both acceptance of and satisfaction with our e-learning modules were high, and students displayed increased demand for this kind of e-learning format. We, therefore, conclude that e-learning offerings could serve as reasonable, efficient, student-orientated substitutes for certain medical courses, especially lectures. These curricular adaptations would correlate with the high digitalization seen in students' everyday lives. This correlation may also hold true independent of the ongoing COVID-19 pandemic.

关键词： Surgical Oncology   Oncology   Surgery  

摘要： Background Lymph node ratio (LNR) and the log odds of positive lymph nodes (LODDS) have been proposed as alternative lymph node (LN) classification schemes. Various cut-off values have been defined for each system, with the question of the most appropriate for patients with medullary thyroid cancer (MTC) still remaining open. We aimed to retrospectively compare the predictive impact of different LN classification systems and to define the most appropriate set of cut-off values regarding accurate evaluation of overall survival (OS) in patients with MTC. Methods 182 patients with MTC who were operated on between 1985 and 2018 were extracted from our medical database. Cox proportional hazards regression models and C-statistics were performed to assess the discriminative power of 28 LNR and 28 LODDS classifications and compare them with the N category according to the 8th edition of the AJCC/UICC TNM classification in terms of discriminative power. Regression models were adjusted for age, sex, T category, focality, and genetic predisposition. Results High LNR and LODDS are associated with advanced T categories, distant metastasis, sporadic disease, and male gender. In addition, among 56 alternative LN classifications, only one LNR and one LODDS classification were independently associated with OS, regardless of the presence of metastatic disease. The C-statistic demonstrated comparable results for all classification systems showing no clear superiority over the N category. Conclusion Two distinct alternative LN classification systems demonstrated a better prognostic performance in MTC patients than the N category. However, larger scale studies are needed to further verify our findings.