The Past, Present, and Future of Non-Viral CAR T Cells

Adoptive transfer of chimeric antigen receptor (CAR) T lymphocytes is a powerful technology that has revolutionized the way we conceive immunotherapy. The impressive clinical results of complete and prolonged response in refractory and relapsed diseases have shifted the landscape of treatment for hematological malignancies, particularly those of lymphoid origin, and opens up new possibilities for the treatment of solid neoplasms. However, the widening use of cell therapy is hampered by the accessibility to viral vectors that are commonly used for T cell transfection. In the era of messenger RNA (mRNA) vaccines and CRISPR/Cas (clustered regularly interspaced short palindromic repeat-CRISPR-associated) precise genome editing, novel and virus-free methods for T cell engineering are emerging as a more versatile, flexible, and sustainable alternative for next-generation CAR T cell manufacturing. Here, we discuss how the use of non-viral vectors can address some of the limitations of the viral methods of gene transfer and allow us to deliver genetic information in a stable, effective and straightforward manner. In particular, we address the main transposon systems such as Sleeping Beauty (SB) and piggyBac (PB), the utilization of mRNA, and innovative approaches of nanotechnology like Lipid-based and Polymer-based DNA nanocarriers and nanovectors. We also describe the most relevant preclinical data that have recently led to the use of non-viral gene therapy in emerging clinical trials, and the related safety and efficacy aspects. We will also provide practical considerations for future trials to enable successful and safe cell therapy with non-viral methods for CAR T cell generation

Photovoltaic Pumps: Technical and Practical Aspects for Applications in Agriculture

The paper deals with a series of tests conducted on a PV-DC pump in Viterbo (42°24′ North, 12°06′ East). The tests lasted from January 2003 up to November 2004 and involved measurements of solar radiation, on both a horizontal surface and the tilted module surface, flow rates, volumes, and total dynamic heads. In total, up to 3000 data were collected every day whose analysis allowed us to find empirical relationships among system efficiencies, solar radiations, and total dynamic heads. In the second part of the paper we develop a simple method that allows both the assessment of performances of the whole system when installed in a different site from that in which the tests were performed and the optimal inclination angle of the panel to be determined in relation to annual or seasonal use (see irrigation)

La regionalizzazione biogeografica quale elemento per una migliore comprensione del valore degli habitat: il caso della Regione Marche

Habitat Directive provides the subdivision of the habitats indicated in Annex I in different biogegraphic regions on the basis of a classification of the U.E. territory extremely simplified. On the contrary, in the opinion of the Authors, a precise definition of the different hierarchical levels of the territory could allow to recognise, for each habitat, a more precise collocation and to make e new classification of them in the regional context. Within the REM Project, the biogeographical classification of the regional territory was done to the vegetation series level and the results are here presented. The hierarchical scheme utilised, follows that one proposed by Rivas-Martinez and for the upper hierarchical levels, from Region to subprovince, the unities defined in the European Biogeographic map have been taken. For Marche Region 5 sectors, 10 subsectors, 14 districts, 96 plant landscape units and 146 plant landscape elements within them a high number of tessera have been found. For the upper biogeographic levels, the maps are here presented while the plant landscape elements are listed following the hierarchical order

Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL

We performed sensitive polymerase chain reaction-based minimal residual disease (MRD) analyses on bone marrow samples at 9 follow-up time points in 71 children with T-lineage acute lymphoblastic leukemia (T-ALL) and compared the results with the precursor B-lineage ALL (B-ALL) results (n = 210) of our previous study. At the first 5 follow-up time points, the frequency of MRD-positive patients and the MRD levels were higher in T-ALL than in precursor-B-ALL, reflecting the more frequent occurrence of resistant disease in T-ALL. Subsequently, patients were classified according to their MRD level at time point 1 (TP1), taken at the end of induction treatment (5 weeks), and at TP2 just before the start of consolidation treatment (3 months). Patients were considered at low risk if TP1 and TP2 were MRD negative and at high risk if MRD levels at TP1 and TP2 were 10(-3) or higher; remaining patients were considered at intermediate risk. The relative distribution of patients with T-ALL (n = 43) over the MRD-based risk groups differed significantly from that of precursor B-ALL (n = 109). Twenty-three percent of patients with T-ALL and 46% of patients with precursor B-ALL were classified in the low-risk group (P =.01) and had a 5-year relapse-free survival (RFS) rate of 98% or greater. In contrast, 28% of patients with T-ALL were classified in the MRD-based high-risk group compared to only 11% of patients with precursor B-ALL (P =.02), and the RFS rates were 0% and 25%, respectively (P =.03). Not only was the distribution of patients with T-ALL different over the MRD-based risk groups, the prognostic value of MRD levels at TP1 and TP2 was higher in T-ALL (larger RFS gradient), and consistently higher RFS rates were found for MRD-negative T-ALL patients at the first 5 follow-up time points

Optical design of the SOXS spectrograph for ESO NTT

An overview of the optical design for the SOXS spectrograph is presented. SOXS (Son Of X-Shooter) is the new wideband, medium resolution (R>4500) spectrograph for the ESO 3.58m NTT telescope expected to start observations in 2021 at La Silla. The spectroscopic capabilities of SOXS are assured by two different arms. The UV-VIS (350-850 nm) arm is based on a novel concept that adopts the use of 4 ion-etched high efficiency transmission gratings. The NIR (800- 2000 nm) arm adopts the '4C' design (Collimator Correction of Camera Chromatism) successfully applied in X-Shooter. Other optical sub-systems are the imaging Acquisition Camera, the Calibration Unit and a pre-slit Common Path. We describe the optical design of the five sub-systems and report their performance in terms of spectral format, throughput and optical quality. This work is part of a series of contributions describing the SOXS design and properties as it is about to face the Final Design Review.Comment: 9 pages, 9 figures, published in SPIE Proceedings 1070

The Acquisition Camera System for SOXS at NTT

SOXS (Son of X-Shooter) will be the new medium resolution (R$\sim$4500 for a 1 arcsec slit), high-efficiency, wide band spectrograph for the ESO-NTT telescope on La Silla. It will be able to cover simultaneously optical and NIR bands (350-2000nm) using two different arms and a pre-slit Common Path feeding system. SOXS will provide an unique facility to follow up any kind of transient event with the best possible response time in addition to high efficiency and availability. Furthermore, a Calibration Unit and an Acquisition Camera System with all the necessary relay optics will be connected to the Common Path sub-system. The Acquisition Camera, working in optical regime, will be primarily focused on target acquisition and secondary guiding, but will also provide an imaging mode for scientific photometry. In this work we give an overview of the Acquisition Camera System for SOXS with all the different functionalities. The optical and mechanical design of the system are also presented together with the preliminary performances in terms of optical quality, throughput, magnitude limits and photometric properties.Comment: 9 pages, 7 figures, SPIE conferenc

Maturation signatures of conventional dendritic cell subtypes in COVID‐19 suggest direct viral sensing

Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19, which negatively affects T-cell activation. The presence of effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients suggests that adequate T-cell responses limit disease severity. Understanding how cDCs cope with SARS-CoV-2 can help elucidate how protective immune responses are generated. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures, with the upregulation of interferon-stimulated genes and interleukin (IL)-6 signaling pathways. Furthermore, comparison of cDCs between patients with severe and mild disease showed severely ill patients to exhibit profound downregulation of genes encoding molecules involved in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus, as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen presentation capacity. Moreover, DC3s showed upregulation of anti-apoptotic genes and accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the activation profile observed in vivo. Our findings suggest that SARS-CoV-2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T-cell activation

La Carta della vegetazione e degli elementi di paesaggio vegetale delle Marche (scala 1:50.000) per la progettazione e la gestione della rete ecologica regionale

A study regards 2 maps about actual vegetation and geosinphytosociological aspects of Marche Region territory is showed. This maps are carried out inside regional Ecological Network Project started by Biodiversity and Ecological Network Office at the end of 2003. Besides some possible applications are proposed

Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants

Acute bronchiolitis is the leading cause of lower respiratory tract infection and hospitalization in children less than 1 year of age worldwide. It is usually a mild disease, but some children may develop severe symptoms, requiring hospital admission and ventilatory support in the ICU. Infants with pre-existing risk factors (prematurity, bronchopulmonary dysplasia, congenital heart diseases and immunodeficiency) may be predisposed to a severe form of the disease. Clinical diagnosis of bronchiolitis is manly based on medical history and physical examination (rhinorrhea, cough, crackles, wheezing and signs of respiratory distress). Etiological diagnosis, with antigen or genome detection to identify viruses involved, may have a role in reducing hospital transmission of the infection. Criteria for hospitalization include low oxygen saturation (<90-92%), moderate-to-severe respiratory distress, dehydration and presence of apnea. Children with pre-existing risk factors should be carefully assessed. To date, there is no specific treatment for viral bronchiolitis, and the mainstay of therapy is supportive care. This consists of nasal suctioning and nebulized 3% hypertonic saline, assisted feeding and hydration, humidified O2 delivery. The possible role of any pharmacological approach is still debated, and till now there is no evidence to support the use of bronchodilators, corticosteroids, chest physiotherapy, antibiotics or antivirals. Nebulized adrenaline may be sometimes useful in the emergency room. Nebulized adrenaline can be useful in the hospital setting for treatment as needed. Lacking a specific etiological treatment, prophylaxis and prevention, especially in children at high risk of severe infection, have a fundamental role. Environmental preventive measures minimize viral transmission in hospital, in the outpatient setting and at home. Pharmacological prophylaxis with palivizumab for RSV bronchiolitis is indicated in specific categories of children at risk during the epidemic period. Viral bronchiolitis, especially in the case of severe form, may correlate with an increased incidence of recurrent wheezing in pre-schooled children and with asthma at school age. The aim of this document is to provide a multidisciplinary update on the current recommendations for the management and prevention of bronchiolitis, in order to share useful indications, identify gaps in knowledge and drive future research

Tropical Temperature Variability in the UTLS: New Insights from GPS Radio Occultation Observations

AbstractGlobal positioning system (GPS) radio occultation (RO) observations, first made of Earth's atmosphere in 1995, have contributed in new ways to the understanding of the thermal structure and variability of the tropical upper troposphere–lower stratosphere (UTLS), an important component of the climate system. The UTLS plays an essential role in the global radiative balance, the exchange of water vapor, ozone, and other chemical constituents between the troposphere and stratosphere, and the transfer of energy from the troposphere to the stratosphere. With their high accuracy, precision, vertical resolution, and global coverage, RO observations are uniquely suited for studying the UTLS and a broad range of equatorial waves, including gravity waves, Kelvin waves, Rossby and mixed Rossby–gravity waves, and thermal tides. Because RO measurements are nearly unaffected by clouds, they also resolve the upper-level thermal structure of deep convection and tropical cyclones as well as volcanic clouds. Their low biases and stability from mission to mission make RO observations powerful tools for studying climate variability and trends, including the annual cycle and intraseasonal-to-interannual atmospheric modes of variability such as the quasi-biennial oscillation (QBO), Madden–Julian oscillation (MJO), and El Niño–Southern Oscillation (ENSO). These properties also make them useful for evaluating climate models and detection of small trends in the UTLS temperature, key indicators of climate change. This paper reviews the contributions of RO observations to the understanding of the three-dimensional structure of tropical UTLS phenomena and their variability over time scales ranging from hours to decades and longer