Histone deacetylase 6 controls Notch3 trafficking and degradation in T-cell acute lymphoblastic leukemia cells

Several studies have revealed that endosomal sorting controls the steady-state levels of Notch at the cell surface in normal cells and prevents its inappropriate activation in the absence of ligands. However, whether this highly dynamic physiologic process can be exploited to counteract dysregulated Notch signaling in cancer cells remains unknown. T-ALL is a malignancy characterized by aberrant Notch signaling, sustained by activating mutations in Notch1 as well as overexpression of Notch3, a Notch paralog physiologically subjected to lysosome-dependent degradation in human cancer cells. Here we show that treatment with the pan-HDAC inhibitor Trichostatin A (TSA) strongly decreases Notch3 full-length protein levels in T-ALL cell lines and primary human T-ALL cells xenografted in mice without substantially reducing NOTCH3 mRNA levels. Moreover, TSA markedly reduced the levels of Notch target genes, including pT alpha, CR2, and DTX-1, and induced apoptosis of T-ALL cells. We further observed that Notch3 was post-translationally regulated following TSA treatment, with reduced Notch3 surface levels and increased accumulation of Notch3 protein in the lysosomal compartment. Surface Notch3 levels were rescued by inhibition of dynein with ciliobrevin D. Pharmacologic studies with HDAC1, 6, and 8-specific inhibitors disclosed that these effects were largely due to inhibition of HDAC6 in TALL cells. HDAC6 silencing by specific shRNA was followed by reduced Notch3 expression and increased apoptosis of TALL cells. Finally, HDAC6 silencing impaired leukemia outgrowth in mice, associated with reduction of Notch3 full-length protein in vivo. These results connect HDAC6 activity to regulation of total and surface Notch3 levels and suggest HDAC6 as a potential novel therapeutic target to lower Notch signaling in T-ALL and other Notch3-addicted tumor

Neuropsychiatric Symptoms, Endophenotypes, and Syndromes in Late-Onset Alzheimer's Disease: Focus on APOE Gene

Neuropsychiatric symptoms, previously denominated as behavioural and psychological symptoms of dementia, are common features of Alzheimer's disease (AD) and are one of the major risk factors for institutionalization. At present, the role of the apolipoprotein E (APOE) gene in the development of neuropsychiatric symptoms in AD patients is unclear. In this paper, we summarized the findings of the studies of neuropsychiatric symptoms and neuropsychiatric syndromes/endophenotypes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between APOE and neuropsychiatric symptoms in late-onset AD, other studies reported a significant association between the APOE ε4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. Furthermore, some negative studies that focused on the distribution of APOE genotypes between AD patients with or without neuropsychiatric symptoms further emphasized the importance of subgrouping neuropsychiatric symptoms in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies

Biomarkers for risk stratification and antibiotic stewardship in elderly patients

Elderly; Infection; ProcalcitoninAnciano; Infección; ProcalcitoninaAncià; infecció; ProcalcitoninaPurpose Optimal treatment of infections in the elderly patients population is challenging because clinical symptoms and signs may be less specific potentially resulting in both, over- and undertreatment. Elderly patients also have a less pronounced immune response to infection, which may influence kinetics of biomarkers of infection. Methods Within a group of experts, we critically reviewed the current literature regarding biomarkers for risk stratification and antibiotic stewardship in elderly patients with emphasis on procalcitonin (PCT). Results The expert group agreed that there is strong evidence that the elderly patient population is particularly vulnerable for infections and due to ambiguity of clinical signs and parameters in the elderly, there is considerable risk for undertreatment. At the same time, however, this group of patients is particularly vulnerable for off-target effects from antibiotic treatment and limiting the use of antibiotics is therefore important. The use of infection markers including PCT to guide individual treatment decisions has thus particular appeal in geriatric patients. For the elderly, there is evidence that PCT is a valuable biomarker for assessing the risk of septic complications and adverse outcomes, and helpful for guiding individual decisions for or against antibiotic treatment. There is need for additional educational efforts regarding the concept of “biomarker-guided antibiotic stewardship” for health care providers caring for elderly patients. Conclusion Use of biomarkers, most notably PCT, has high potential to improve the antibiotic management of elderly patients with possible infection for improving both, undertreatment and overtreatment. Within this narrative review, we aim to provide evidence-based concepts for the safe and efficient use of PCT in elderly patients.Open access funding provided by University of Basel

Frailty trajectories in community-dwelling older adults during COVID-19 pandemic: The PRESTIGE study

Background Frailty has been recognized as potential surrogate of biological age and relevant risk factor for COVID-19 severity. Thus, it is important to explore the frailty trajectories during COVID-19 pandemic and understand how COVID-19 directly and indirectly impacts on frailty condition. Methods We enrolled 217 community-dwelling older adults with available information on frailty condition as assessed by multidimensional frailty model both at baseline and at one-year follow-up using Multidimensional Prognostic Index (MPI) tools. Pre-frail/frail subjects were identified at baseline as those with MPI score >0.33 (MPI grades 2-3). Frailty worsening was defined by MPI difference between 12 months follow-up and baseline >= 0.1. Multivariable logistic regression was modelled to identify predictors of worsening of frailty condition. Results Frailer subjects at baseline (MPI grades 2-3 = 48.4%) were older, more frequently female and had higher rates of hospitalization and Sars-CoV-2 infection compared to robust ones (MPI grade 1). Having MPI grades 2-3 at baseline was associated with higher risk of further worsening of frailty condition (adjusted odd ratio (aOR): 13.60, 95% confidence interval (CI): 4.01-46.09), independently by age, gender and Sars-CoV-2 infection. Specifically, frail subjects without COVID-19 (aOR: 14.84, 95% CI: 4.26-51.74) as well as those with COVID-19 (aOR: 12.77, 95% CI: 2.66-61.40, p = 0.001) had significantly higher risk of worsening of frailty condition. Conclusions Effects of COVID-19 pandemic among community-dwelling frailer individuals are far beyond the mere infection and disease, determining a significant deterioration of frailty status both in infected and non-infected subjects

The role of prognostic stratification on prescription of anticoagulants in older patients with atrial fibrillation : a multicenter, observational, prospective European study (EUROSAF)

Background: Literature suggests that different risks of mortality could influence physicians in prescribing or not anticoagulants in older patients with atrial fibrillation (AF). The Multidimensional Prognostic Index (MPI) can be considered a tool for the detection of multidimensional frailty. The aim of this cross-sectional study was to evaluate whether prescription patterns of oral anticoagulants exist, based on MPI values. Methods: Older hospitalised patients (age >= 65 years) with non-valvular AF were included across 24 European centres. MPI was calculated using validated and standardised tools derived from a comprehensive geriatric assessment. Other functional and clinical information were collected to calculate indexes specific for haemorrhagic and thromboembolic risk in AF. Results: Altogether, 2,012 participants affected by AF (mean age was 83.2 +/- 7.5, range: 65-104 years), with a higher presence of women (57.0%), were included. Overall, 440 took vitamin K antagonists VKAs (22.0%), 667 (33.4%) direct oral anticoagulants (DOACs), whilst 44.6% did not take any anticoagulant treatment. Prescription of anticoagulants was associated with MPI values, with people taking anticoagulants having lower mean MPI values. Anticoagulant therapy was not used in 53.1% of the group with the highest risk of mortality, compared with 32.3% of those in the group with the lowest mortality risk. People with higher scores in MPI were less frequently treated with anticoagulant therapy, after adjusting for several potential confounders. Conclusions: The EURopean study of Older Subjects with Atrial Fibrillation (EUROSAF) suggested that almost half of the older persons with AF do not receive anticoagulants and that MPI is an important determinant in prescribing or not anticoagulants.Peer reviewe

Development and validation of an art-inspired multimodal interactive technology system for a multi-component intervention for older people: a pilot study

IntroductionThe World Health Organization (WHO) acknowledges the presence of a significant body of research on the positive effects of the arts on health, considering a variety of factors including physical well-being, quality of life, and social and community impact. The model that underlies cultural welfare puts the performing arts, visual arts, and cultural heritage at the service of people personal and societal well-being. The potential connections between movements of the body and artistic content have been extensively studied over time, considering movement as a non-verbal language with a universal character.MethodsThis pilot study presents the results of the validation of an innovative multimodal system, the DanzArTe-Emotional Wellbeing Technology, designed to support active and participative experience of older people providing physical and cognitive activation through a full-body physical interaction with a traditional visual work of art of religious subject. DanzArTe supports a replicable treatment protocol for multidimensional frailty, administered through a low cost and scalable technological platform capable of generating real-time visual and auditory feedback (interactive sonification) from the automated analysis of individual as well as joint movement expressive qualities. The study involved 45 participants, 23 of whom participated in the DanzArTe program and 22 who were included in the control group.ResultsThe two groups were similar in terms of age (p = 0.465) and gender (p = 0.683). The results showed that the DanzArTe program had a positive impact on participants' self-perceived psychological health and well-being (Mean Psychological General Well-Being Index—Short T1 = 19.6 ± 4.3 Vs. T2 = 20.8 ± 4.9; p = 0.029). The same trend was not observed in the control group (p = 0.389).DiscussionThe findings suggest that such programs may have a significant impact particularly on the mental and social well-being of older adults and could be a valuable tool for promoting healthy aging and improving quality of life

The Multidimensional Prognostic Index in general practice: One-year follow-up study.

BACKGROUND Older patients' health problems in general practice (GP) can often not be assigned to a specific disease, requiring a paradigm shift to goal-oriented, personalised care for clinical decision making. PURPOSE To investigate the predictive value of the comprehensive geriatric assessment (CGA)-based Multidimensional Prognostic Index (MPI) in a GP setting with respect to the main healthcare indicators during the 12 months following initial evaluation. METHODS One hundred twenty-five consecutive patients aged 70 years and older were enrolled in a GP and followed up to one year. All patients underwent a CGA based on which the MPI was calculated and subdivided into three risk groups (MPI-1, 0-0.33 = low risk, MPI-2, 0.34-0.66 = moderate risk and MPI-3, 0.67-1, severe risk). Grade of Care (GC), hospitalization rate, mortality, nursing home admission, use of home care services, falls, number of general practitioner contacts (GPC), of geriatric resources (GR) and geriatric syndromes (GS) during the 12 months following initial evaluation were collected. RESULTS The MPI was significantly associated with number of GS (P < .001), GR (P < .001), GC (P < .001) as well as with the average number of GPC per year (mean 10.4, P = .046). Interestingly, the clinical judgement of the general practitioner, in this case knowing his patients for 16 years on average, was associated with adverse outcomes to a similar extent than the prediction offered by the MPI (GP/adverse outcomes and MPI/adverse outcomes P < .001). CONCLUSION The MPI is strongly associated with adverse outcomes in older GP patients and strongly predicts the number of GPC up to one year after initial evaluation. Considering the feasibility and the strong clinimetric properties of the MPI, its collection should be encouraged as early as possible to disclose risk conditions, implement tailored preventive strategies and improve cost-effectiveness of healthcare resources use