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Augmented reality is one of the enabling technologies of the upcoming future. Its usage in working and learning scenarios may lead to a better quality of work and training by helping the operators during the most crucial stages of processes. Therefore, the automatic detection of stress during augmented reality experiences can be a valuable support to prevent consequences on people's health and foster the spreading of this technology. In this work, we present the design of a non-invasive stress assessment approach. The proposed system is based on the analysis of the head movements of people wearing a Head Mounted Display while performing stress-inducing tasks. First, we designed a subjective experiment consisting of two stress-related tests for data acquisition. Then, a statistical analysis of head movements has been performed to determine which features are representative of the presence of stress. Finally, a stress classifier based on a combination of Support Vector Machines has been designed and trained. The proposed approach achieved promising performances thus paving the way for further studies in this research direction.

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Here we evaluated the epigenomic and transcriptomic profile of XPO1 mutant chronic lymphocytic leukaemia (CLL) and their clinical phenotype. By ATAC-seq, chromatin regions that were more accessible in XPO1 mutated CLL were enriched of binding sites for transcription factors regulated by pathways emanating from the B-cell receptor (BCR), including NF-κB signalling, p38-JNK and RAS-RAF-MEK-ERK. XPO1 mutant CLL, consistent with the chromatin accessibility changes, were enriched with transcriptomic features associated with BCR and cytokine signalling. By combining epigenomic and transcriptomic data, MIR155HG, the host gene of miR-155, and MYB, the transcription factor that positively regulates MIR155HG, were upregulated by RNA-seq and their promoters were more accessible by ATAC-seq. To evaluate the clinical impact of XPO1 mutations, we investigated a total of 957 early-stage CLL subdivided into 3 independent cohorts (N = 276, N = 286 and N = 395). Next-generation sequencing analysis identified XPO1 mutations as a novel predictor of shorter time to first treatment (TTFT) in all cohorts. Notably, XPO1 mutations maintained their prognostic value independent of the immunoglobulin heavy chain variable status and early-stage prognostic models. These data suggest that XPO1 mutations, conceivably through increased miR-155 levels, may enhance BCR signalling leading to higher proliferation and shorter TTFT in early-stage CLL., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Constitutive activation of NOTCH1 -wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL., Methods: We performed a bioinformatics analysis of NOTCH1 -mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca 2+ , and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eμ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling., Results and Discussion: Bioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca 2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eμ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19 + /CD5 + cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Silva Barcelos, Rompietti, Adamo, Dorillo, De Falco, Del Papa, Baldoni, Nogarotto, Esposito, Capoccia, Geraci, Sorcini, Stella, Arcaleni, Tini, Imbroisi Valle Errera, Rosati and Sportoletti.)

Background: Chronic lymphocytic leukemia (CLL) is an incurable disorder associated with alterations in several pathways essential for survival and proliferation. Despite the advances made in CLL therapy with the new target agents, in some cases, relapses and resistance could occur, making the discovery of new alternatives to manage CLL refractoriness necessary. To provide new therapeutic strategies for CLL, we investigated the anti-leukemic activity of silver nanoparticles (AgNPs), whose impact on CLL cells has been poorly explored., Methods: We studied the action mechanisms of AgNPs in vitro through flow cytometry and molecular analyses. To improve the bioavailability of AgNPs, we generated AgNPs coated with the anti-CD20 antibody Rituximab (AgNPs@Rituximab) and carried out imaging-based approaches and in vivo experiments to evaluate specificity, drug uptake, and efficacy., Results: AgNPs reduced the viability of primary CLL cells and the HG-3 cell line by inducing an intrinsic apoptotic pathway characterized by Bax/Bcl-2 imbalance, caspase activation, and PARP degradation. Early apoptotic events triggered by AgNPs included enhanced Ca 2+ influx and ROS overproduction. AgNPs synergistically potentiated the cytotoxicity of Venetoclax, Ibrutinib, and Bepridil. In vitro, the AgNPs@Rituximab conjugates were rapidly internalized within CLL cells and strongly prolonged the survival of CLL xenograft models compared to each unconjugated single agent., Conclusions: AgNPs showed strong anti-leukemic activity in CLL, with the potential for clinical translation in combination with agents used in CLL. The increased specificity of AgNPs@Rituximab toward CLL cells could be relevant for overcoming in vivo AgNPs' non-specific distribution and increasing their efficacy.

NOTCH1 alterations have been associated with chronic lymphocytic leukemia (CLL), but the molecular mechanisms underlying NOTCH1 activation in CLL cells are not completely understood. Here, we show that GSK3β downregulates the constitutive levels of the active NOTCH1 intracellular domain (N1-ICD) in CLL cells. Indeed, GSK3β silencing by small interfering RNA increases N1-ICD levels, whereas expression of an active GSK3β mutant reduces them. Additionally, the GSK3β inhibitor SB216763 enhances N1-ICD stability at a concentration at which it also increases CLL cell viability. We also show that N1-ICD is physically associated with GSK3β in CLL cells. SB216763 reduces GSK3β/N1-ICD interactions and the levels of ubiquitinated N1-ICD, indicating a reduction in N1-ICD proteasomal degradation when GSK3β is less active. We then modulated the activity of two upstream regulators of GSK3β and examined the impact on N1-ICD levels and CLL cell viability. Specifically, we inhibited AKT that is a negative regulator of GSK3β and is constitutively active in CLL cells. Furthermore, we activated the protein phosphatase 2 A (PP2A) that is a positive regulator of GSK3β, and has an impaired activity in CLL. Results show that either AKT inhibition or PP2A activation reduce N1-ICD expression and CLL cell viability in vitro, through mechanisms mediated by GSK3β activity. Notably, for PP2A activation, we used the highly specific activator DT-061, that also reduces leukemic burden in peripheral blood, spleen and bone marrow in the Eµ-TCL1 adoptive transfer model of CLL, with a concomitant decrease in N1-ICD expression. Overall, we identify in GSK3β a key component of the network regulating N1-ICD stability in CLL, and in AKT and PP2A new druggable targets for disrupting NOTCH1 signaling with therapeutic potential., (© 2022. The Author(s).)

Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. Several immune effectors are impaired in CLL, including T and natural killer (NK) cells. The role of T cells in defense against CLL and in CLL progression and immunotherapy has been extensively studied. Less is known about the role of NK cells in this leukemia, and data on NK cell alterations in CLL are contrasting. Besides studies showing that NK cells have intrinsic defects in CLL, there is a large body of evidence indicating that NK cell dysfunctions in CLL mainly depend on the escape mechanisms employed by leukemic cells. In keeping, it has been shown that NK cell functions, including antibody-dependent cellular cytotoxicity (ADCC), can be retained and/or restored after adequate stimulation. Therefore, due to their preserved ADCC function and the reversibility of CLL-related dysfunctions, NK cells are an attractive source for novel immunotherapeutic strategies in this disease, including chimeric antigen receptor (CAR) therapy. Recently, satisfying clinical responses have been obtained in CLL patients using cord blood-derived CAR-NK cells, opening new possibilities for further exploring NK cells in the immunotherapy of CLL. However, notwithstanding the promising results of this clinical trial, more evidence is needed to fully understand whether and in which CLL cases NK cell-based immunotherapy may represent a valid, alternative/additional therapeutic option for this leukemia. In this review, we provide an overview of the current knowledge about phenotypic and functional alterations of NK cells in CLL and the mechanisms by which CLL cells circumvent NK cell-mediated immunosurveillance. Additionally, we discuss the potential relevance of using NK cells in CLL immunotherapy.

NOTCH1 mutations and deregulated signal have been commonly found in chronic lymphocytic leukemia (CLL) patients. Whereas the impact of NOTCH1 mutations on clinical course of CLL has been widely studied, the prognostic role of NOTCH1 activation in CLL remains to be defined. Here, we analyzed the activation of NOTCH1/NOTCH2 (ICN1/ICN2) and the expression of JAGGED1 (JAG1) in 163 CLL patients and evaluated their impact on TTFT (Time To First Treatment) and OS (Overall Survival). NOTCH1 activation (ICN1+) was found in 120/163 (73.6%) patients. Among them, 63 (52.5%) were NOTCH1 mutated (ICN1+/mutated) and 57 (47.5%) were NOTCH1 wild type (ICN1+/WT). ICN1+ patients had a significant reduction of TTFT compared to ICN1-negative (ICN1-). In the absence of NOTCH1 mutations, we found that the ICN1+/WT group had a significantly reduced TTFT compared to ICN1- patients. The analysis of IGHV mutational status showed that the distribution of the mutated/unmutated IGHV pattern was similar in ICN1+/WT and ICN1- patients. Additionally, TTFT was significantly reduced in ICN1+/ICN2+ and ICN1+/JAG1+ patients compared to ICN1-/ICN2- and ICN1-/JAG1- groups. Our data revealed for the first time that NOTCH1 activation is a negative prognosticator in CLL and is not correlated to NOTCH1 and IGHV mutational status. Activation of NOTCH2 and JAGGED1 expression might also influence clinical outcomes in this group, indicating the need for further dedicated studies. The evaluation of different NOTCH network components might represent a new approach to refine CLL risk stratification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Baldoni, Del Papa, De Falco, Dorillo, Sorrentino, Rompietti, Adamo, Nogarotto, Cecchini, Mondani, Silva Barcelos, Moretti, Mameli, Fabi, Sorcini, Stella, Giancola, Guardalupi, Ulbar, Plebani, Guarente, Rosati, Di Nicola, Marchioni, Di Ianni and Sportoletti.)

Background: Telemedicine involves medical practice and information and communications technology. It has been proven to be very effective for remote health care, especially in areas with poor provision of health facilities. However, implementation of these technologies is often hampered by various issues. Among these, ethical and legal concerns are some of the more complex and diverse ones. In this study, an analysis of scientific literature was carried out to identify the ethical and legal challenges of telemedicine. Materials and Methods: English literature, published between 2010 and 2019, was searched on PubMed, Scopus, and Web of Science by using keywords, including "Telemedicine," "Ethics," "Malpractice," "Telemedicine and Ethics," "Telemedicine and Informed consent," and "telemedicine and malpractice." Different types of articles were analyzed, including research articles, review articles, and qualitative studies. The abstracts were evaluated according to the selection criteria, using the Newcastle-Ottawa Scale criteria, and the final analysis led to the inclusion of 22 articles. Discussion: From the aforementioned sample, we analyzed elements that may be indicative of the efficacy of telemedicine in an adequate time frame. Ethical aspects such as informed consent, protection data, confidentiality, physician's malpractice, and liability and telemedicine regulations were considered. Conclusions: Our objective was to highlight the current status and identify what still needs to be implemented in telemedicine with respect to ethical and legal standards. Gaps emerged between current legislation, legislators, service providers, different medical services, and most importantly patient interaction with his/her data and the use of that data.

In the setting of T cell-depleted, full-haplotype mismatched transplantation, adoptive immunotherapy with regulatory T cells (Tregs) and conventional T cells (Tcons) can prevent graft-versus-host disease (GVHD) and improve post-transplantation immunologic reconstitution and is associated with a powerful graft-versus-leukemia effect. To improve the purity and the quantity of the infused Tregs, good manufacturing practices (GMP)-compatible expansion protocols are needed. Here we expanded Tregs using an automated, clinical-grade protocol. Cells were extensively characterized in vitro, and their efficiency was tested in vivo in a mouse model. Tregs were selected by CliniMacs (CD4 + CD25 + , 94.5 ± 6.3%; FoxP3 + , 63.7 ± 11.5%; CD127 + , 20 ± 3%; suppressive activity, 60 ± 7%), and an aliquot of 100 × 10 6 was expanded for 14 days using the CliniMACS Prodigy System, obtaining 684 ± 279 × 10 6 cells (CD4 + CD25 + , 99.6 ± 0.2%; FoxP3 + , 82 ± 8%; CD127 + , 1.1 ± 0.8%; suppressive activity, 75 ± 12%). CD39 and CTLA4 expression levels increased from 22.4 ± 12% to 58.1 ± 13.3% (P < .05) and from 20.4 ± 6.7% to 85.4 ± 9.8% (P < .01), respectively. TIM3 levels increased from .4 ± .05% to 29 ± 16% (P < .05). Memory Tregs were the prevalent population, whereas naive Tregs almost disappeared at the end of the culture. mRNA analysis displayed significant increases in CD39, IL-10, granzyme B, and IL-35 levels at the end of culture period (P < .05). Conversely, IFNγ expression decreased significantly by day +14. Expanded Tregs were sorted according to TIM3, CD39, and CD62L expression levels (purity >95%). When sorted populations were analyzed, TIM3 + cells showed significant increases in IL-10 and granzyme B (P < .01) .When expanded Tregs were infused in an NSG murine model, mice that received Tcons only died of GVHD, whereas mice that received both Tcons and Tregs survived without GVHD. GMP grade expanded cells that display phenotypic and functional Treg characteristics can be obtained using a fully automated system. Treg suppression is mediated by multiple overlapping mechanisms (eg, CTLA-4, CD39, IL-10, IL-35, TGF-β, granzyme B). TIM3 + cells emerge as a potentially highly suppressive population. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Internet represents a relevant source of information, but reliability of data that can be obtained by the web is still an unsolved issue. Non-reliable online information may have a relevance, especially in taking decisions related to health problems. Uncertainties on the quality of online health data may have a negative impact on health-related choices of citizens., Objective: This work consisted in a cross-sectional literature review of published papers on online health information. The two main research objectives consisted in the analysis of trends in the use of health web sites and in the quality assessment and reliability levels of web medical sites., Methods: Literature research was made using four digital reference databases, namely PubMed, British Medical Journal, Biomed, and CINAHL. Entries used were "trustworthy of medical information online," "survey to evaluate medical information online," "medical information online," and "habits of web-based health information users". Analysis included only papers published in English. The Newcastle Ottawa Scale was used to conduct quality checks of selected works., Results: Literature analysis using the above entries resulted in 212 studies. Twenty-four articles in line with study objectives, and user characteristics were selected. People more prone to use the internet for obtaining health information were females, younger people, scholars, and employees. Reliability of different online health sites is an issue taken into account by the majority of people using the internet for obtaining health information and physician assistance could help people to surf more safe health web sites., Conclusions: Limited health information and/or web literacy can cause misunderstandings in evaluating medical data found in the web. An appropriate education plan and evaluation tools could enhance user skills and bring to a more cautious analysis of health information found in the web., (© The Author(s) 2020.)

Epidemiological evidence from observational studies suggests that dietary polyphenols (PPs) - phytochemicals found in a variety of plant-based foods - can reduce the risk of developing type 2 diabetes mellitus (T2DM). Clinical trials have also indicated that PPs may help manage the two key features of T2DM, hyperglycemia and dyslipidemia. Since the incidence of T2DM is dramatically increasing worldwide, identifying food-based approaches that can reduce the risk of developing it and help manage its main risk factors in early-stage disease has clinical and socioeconomic relevance. After a brief overview of current epidemiological data on the incidence of T2DM in individuals consuming PP-rich diets, we review the evidence from clinical trials investigating PP-enriched foods and/or PP-based nutraceutical compounds, report their main results, and highlight the knowledge gaps that should be bridged to enhance our understanding of the role of PPs in T2DM development and management., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Telemedicine is defined as "the use of medical information exchanged from one site to another via electronic communications to improve a patient's health status". This relatively new concept of healthcare is based on the fusion between medical assistance and Information and Communication Technology (ICT) to provide support to people located in remote and underserved areas. It can be found not only in hospitals, but also in other healthcare facilities such as pharmacies. Starting from 2010, telemedicine or telehealth was formally introduced in the Italian pharmaceutical context with the "Pharmacy of Services Decree". In spite of this regulatory framework, the implementation of this technology was very slow and there are no data about the spreading and use of these services in Italian pharmacies., Objective: The present study has therefore developed a survey to collect information on the diffusion of telemedicine/telehealth services within Italian pharmacies., Methods: A two-part questionnaire in Italian was developed using SurveyMonkey, setting a mechanism aimed to have different outcomes according to the answers given. Six hundred eighty-three respondents returned the questionnaire. The results were then analysed statistically., Results: The questionnaire results have shown a limited diffusion of telemedicine/telehealth services among Italian pharmacies and an apparently limited interest of health authorities in supporting the integration of this technology., Conclusions: More efforts should be spent by national public health stakeholders to better analyse the contribution of telemedicine services available in public pharmacies and to find the best solutions to implement this innovative technology as an established service., Competing Interests: CONFLICT OF INTEREST Authors declare that there is no conflict of interests., (Copyright: © Pharmacy Practice and the Authors.)

Purpose: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), has improved the outcomes of chronic lymphocytic leukemia (CLL), but primary resistance or relapse are issues of increasing significance. While the predominant mechanism of action of BTKi is the B-cell receptor (BCR) blockade, many off-target effects are unknown. We investigated potential interactions between BCR pathway and NOTCH1 activity in ibrutinib-treated CLL to identify new mechanisms of therapy resistance and markers to monitor disease response., Experimental Design: NOTCH activations was evaluated either in vitro and ex vivo in CLL samples after ibrutinib treatment by Western blotting. Confocal proximity ligation assay (PLA) experiments and analyses of down-targets of NOTCH1 by qRT-PCR were used to investigate the cross-talk between BTK and NOTCH1., Results: In vitro ibrutinib treatment of CLL significantly reduced activated NOTCH1/2 and induced dephosphorylation of eIF4E, a NOTCH target in CLL. BCR stimulation increased the expression of activated NOTCH1 that accumulated in the nucleus leading to HES1, DTX1, and c-MYC transcription. Results of in situ PLA experiments revealed the presence of NOTCH1-ICD/BTK complexes, whose number was reduced after ibrutinib treatment. In ibrutinib-treated CLL patients, leukemic cells showed NOTCH1 activity downregulation that deepened over time. The NOTCH1 signaling was restored at relapse and remained activated in ibrutinib-resistant CLL cells., Conclusions: We demonstrated a strong clinical activity of ibrutinib in a real-life context. The ibrutinib clinical efficacy was associated with NOTCH1 activity downregulation that deepened over time. Our data point to NOTCH1 as a new molecular partner in BCR signaling with potential to further improve CLL-targeted treatments., (©2019 American Association for Cancer Research.)

Background and Objectives : The term "telepharmacy" indicates a form of pharmaceutical care in which pharmacists and patients are not in the same place and can interact using information and communication technology (ICT) facilities. Telepharmacy has been adopted to provide pharmaceutical services to underserved areas and to address the problem of pharmacist shortage. This paper has reviewed the multi-faceted phenomenon of telepharmacy, summarizing different experiences in the area. Advantages and limitations of telepharmacy are discussed as well. Materials and Methods : A literature analysis was carried out on PubMed, using as entry term "telepharmacy" and including articles on the topic published between 2012 and 2018. Results: The studies reviewed were divided into three categories of pharmacy practice, namely (1) support to clinical services, (2) remote education and handling of "special pharmacies", and (3) prescription and reconciliation of drug therapies. In general, different telepharmacy services were effective and accompanied by a satisfaction of their targets. Conclusion s : Nowadays, the shortage of health personnel, and in particular pharmacists, is a challenging issue that the health systems have to face. The use of a new technology such as telepharmacy can represent a possible option to solve these problems. However, there are unsolved limitations (e.g., legal implications) that make greater diffusion of telepharmacy difficult. Stronger data on the effectiveness of this area of pharmacy care, together with a critical evaluation of its limits, can make actors involved aware about the potentialities of it and could contribute to a larger diffusion of telepharmacy services in the interest of communities and citizens., Competing Interests: The author reports no conflicts of interest in this work.