This article focuses on the transformations and changes in the area of state aid control prompted by the COVID-19 pandemic. It attempts to provide a first assessment on the European Commission ...Temporary Framework on state aid measures to support the economy in the outbreak. It discusses whether the measures adopted have been effective and managed to guarantee on the one side the possibility of Member States to take swift and effective action as to ensure short and long term liquidity to undertakings affected by COVID 19 and on the other to preserve fair competition respect of state aid rules control.
The article focuses on the analysis of seven Lombard weapons datable between the end of 6th and the 7th century C.E. and present in the Archaeological Museum of Fiesole, in the north-eastern area of ...Tuscany in Italy. These objects, only partially published, and coming both from the Lombard necropolis of Area Garibaldi and from unknown contexts, have been compared with similar materials on national scale of the 6th-7th century C.E. and represent a relevant term of archaeological analysis for the transition between Late Antiquity Era and Lombard domination in Fiesole.
In recent years, digital technology and wearable devices applied to seizure detection have progressively become available. In this study, we investigated the perspectives of people with epilepsy ...(PWE), caregivers (CG), and healthcare professionals (HP). We were interested in their current use of digital technology as well as their willingness to use wearables to monitor seizures. We also explored the role of factors influencing engagement with technology, including demographic and clinical characteristics, data confidentiality, need for technical support, and concerns about strain or increased workload.
An online survey drawing on previous data collected via focus groups was constructed and distributed via a web link. Using logistic regression analyses, demographic, clinical, and other factors identified to influence engagement with technology were correlated with reported use and willingness to use digital technology and wearables for seizure tracking.
Eighty-seven surveys were completed, fifty-two (59.7%) by PWE, 13 (14.4%) by CG, and 22 (25.3%) by HP. Responders were familiar with multiple digital technologies, including the Internet, smartphones, and personal computers, and the use of digital services was similar to the UK average. Moreover, age and disease-related factors did not influence access to digital technology. The majority of PWE were willing to use a wearable device for long-term seizure tracking. However, only a limited number of PWE reported current regular use of wearables, and nonusers attributed their choice to uncertainty about the usefulness of this technology in epilepsy care. People with epilepsy envisaged the possibility of understanding their condition better through wearables and considered, with caution, the option to send automatic emergency calls. Despite concerns around accuracy, data confidentiality, and technical support, these factors did not limit PWE's willingness to use digital technology. Caregivers appeared willing to provide support to PWE using wearables and perceived a reduction of their workload and anxiety. Healthcare professionals identified areas of application for digital technologies in their clinical practice, pending an appropriate reorganization of the clinical team to share the burden of data reviewing and handling.
Unlike people who have other chronic health conditions, PWE appeared not to be at risk of digital exclusion. This study highlighted a great interest in the use of wearable technology across epilepsy service users, carers, and healthcare professionals, which was independent of demographic and clinical factors and outpaced data security and technology usability concerns.
•Epilepsy service users are interested in the application of wearables in routine care.•Uncertainty about the usefulness of wearable devices limited their current use.•Commonly used, discrete multimodal devices were preferred for long-term use.•An automated device-generated alarm feature should be considered with caution.•Specific epilepsy care team personnel should be dedicated to digital data handling.
Chimeric antigen receptor (CAR)-redirected T lymphocytes are a promising immunotherapeutic approach and object of pre-clinical evaluation for the treatment of acute myeloid leukemia (AML). We ...developed a CAR against CD123, overexpressed on AML blasts and leukemic stem cells. However, potential recognition of low CD123-positive healthy tissues, through the on-target, off-tumor effect, limits safe clinical employment of CAR-redirected T cells. Therefore, we evaluated the effect of context-dependent variables capable of modulating CAR T cell functional profiles, such as CAR binding affinity, CAR expression, and target antigen density. Computational structural biology tools allowed for the design of rational mutations in the anti-CD123 CAR antigen binding domain that altered CAR expression and CAR binding affinity without affecting the overall CAR design. We defined both lytic and activation antigen thresholds, with early cytotoxic activity unaffected by either CAR expression or CAR affinity tuning but later effector functions impaired by low CAR expression. Moreover, the anti-CD123 CAR safety profile was confirmed by lowering CAR binding affinity, corroborating CD123 is a good therapeutic target antigen. Overall, full dissection of these variables offers suitable anti-CD123 CAR design optimization for the treatment of AML.
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In the context of CAR T cell immunotherapy, a proper balance between safety and efficacy should be evaluated before reaching the clinic. Arcangeli et al. demonstrated how context-dependent variables, i.e., CAR binding affinity, CAR expression, and target antigen density, modulate CAR T cell functionality in the context of AML targeting by an anti-CD123 CAR.
Background Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease affecting mostly children but also adults and characterized by hyperinflammatory features. A subset of patients, ...referred to as having familial hemophagocytic lymphohistiocytosis (FHL), have various underlying genetic abnormalities, the frequencies of which have not been systematically determined previously. Objective This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. Methods From our registry, we have analyzed a total of 500 unselected patients with HLH. Results Biallelic pathogenic mutations defining FHL were found in 171 (34%) patients; the proportion of FHL was much higher (64%) in patients given a diagnosis during the first year of life. Taken together, mutations of the genes PRF1 (FHL2) and UNC13D (FHL3) accounted for 70% of cases of FHL. Overall, a genetic diagnosis was possible in more than 90% of our patients with FHL. Perforin expression and the extent of degranulation have been more useful for diagnosing FHL than hemophagocytosis and the cytotoxicity assay. Of 281 (56%) patients classified as having “sporadic” HLH, 43 had monoallelic mutations in one of the FHL-defining genes. Given this gene dosage effect, FHL is not strictly recessive. Conclusion We suggest that the clinical syndrome HLH generally results from the combined effects of an exogenous trigger and genetic predisposition. Within this combination, different weights of exogenous and genetic factors account for the wide disease spectrum that ranges from HLH secondary to severe infection to FHL.
To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents.
A review of English literature on childhood ...ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups.
With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome-positive, and Philadelphia chromosome-like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL.
The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL.
Brain responses to transcranial magnetic stimulation (TMS) as measured with electroencephalography (EEG) have so far been assessed either by TMS-evoked EEG potentials (TEPs), mostly reflecting ...phase-locked neuronal activity, or time-frequency-representations (TFRs), reflecting oscillatory power arising from a mixture of both evoked (i.e., phase-locked) and induced (i.e., non-phase-locked) responses. Single-pulse TMS of the human primary motor cortex induces a specific pattern of oscillatory changes, characterized by an early (30–200 ms after TMS) synchronization in the α- and β-bands over the stimulated sensorimotor cortex and adjacent lateral frontal cortex, followed by a late (200–400 ms) α- and β-desynchronization over the stimulated and contralateral sensorimotor cortex. As GABAergic inhibition plays an important role in shaping oscillatory brain activity, we sought here to understand if GABAergic inhibition contributes to these TMS-induced oscillations. We tested single oral doses of alprazolam, diazepam, zolpidem (positive modulators of the GABAA receptor), and baclofen (specific GABAB receptor agonist). Diazepam and zolpidem enhanced, and alprazolam tended to enhance while baclofen decreased the early α-synchronization. Alprazolam and baclofen enhanced the early β-synchronization. Baclofen enhanced the late α-desynchronization, and alprazolam, diazepam and baclofen enhanced the late β-desynchronization. The observed GABAergic drug effects on TMS-induced α- and β-band oscillations were not explained by drug-induced changes on corticospinal excitability, muscle response size, or resting-state EEG power. Our results provide first insights into the pharmacological profile of TMS-induced oscillatory responses of motor cortex.
•The response to TMS of M1 is composed of evoked and induced oscillatory activity.•TMS induced early α-/β-synchronization and late α-/β-desynchronization in M1.•GABAAergic vs. GABABergic drugs had opposite effects on early α-synchronization.•GABAAergic and GABABergic drugs enhanced the late β-desynchronization.
Adoptive T cell therapy (ACT) is a rapidly evolving therapeutic approach designed to harness T cell specificity and function to fight diseases. Based on the evidence that T lymphocytes can mediate a ...potent anti-tumor response, initially ACT solely relied on the isolation,
expansion, and infusion of tumor-infiltrating or circulating tumor-specific T cells. Although effective in a subset of cases, in the first ACT clinical trials several patients experienced disease progression, in some cases after temporary disease control. This evidence prompted researchers to improve ACT products by taking advantage of the continuously evolving gene engineering field and by improving manufacturing protocols, to enable the generation of effective and long-term persisting tumor-specific T cell products. Despite recent advances, several challenges, including prioritization of antigen targets, identification, and optimization of tumor-specific T cell receptors, in the development of tools enabling T cells to counteract the immunosuppressive tumor microenvironment, still need to be faced. This review aims at summarizing the major achievements, hurdles and possible solutions designed to improve the ACT efficacy and safety profile in the context of liquid and solid tumors.
Although adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has achieved unprecedented response rates in patients with certain hematological malignancies, this therapeutic ...modality is still far from fulfilling its remarkable potential, especially in the context of solid cancers. Antigen escape variants, off-tumor destruction of healthy tissues expressing tumor-associated antigens (TAAs), poor CAR-T cell persistence, and the occurrence of functional exhaustion represent some of the most prominent hurdles that limit CAR-T cell ability to induce long-lasting remissions with a tolerable adverse effect profile. In this review, we summarize the main approaches that have been developed to face such bottlenecks, including the adapter CAR (AdCAR) system, Boolean-logic gating, epitope editing, the modulation of cell-intrinsic signaling pathways, and the incorporation of safety switches to precisely control CAR-T cell activation. We also discuss the most pressing issues pertaining to the selection of co-stimulatory domains, with a focus on strategies aimed at promoting CAR-T cell persistence and optimal antitumor functionality.
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