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Abstract Microenvironmental signals strongly influence chronic lymphocytic leukemia (CLL) cells through the activation of distinct membrane receptors, such as B-cell receptors, and inflammatory receptors, such as Toll-like receptors (TLRs). Inflammatory pathways downstream of these receptors lead to NF-κB activation, thus protecting leukemic cells from apoptosis. Dimethyl fumarate (DMF) is an anti-inflammatory and immunoregulatory drug used to treat patients with multiple sclerosis and psoriasis in which it blocks aberrant NF-κB pathways and impacts the NRF2 antioxidant circuit. Our in vitro analysis demonstrated that increasing concentrations of DMF reduce ATP levels and lead to the apoptosis of CLL cells, including cell lines, splenocytes from Eµ-TCL1-transgenic mice, and primary leukemic cells isolated from the peripheral blood of patients. DMF showed a synergistic effect in association with BTK inhibitors in CLL cells. DMF reduced glutathione levels and activated the NRF2 pathway; gene expression analysis suggested that DMF downregulated pathways related to NFKB and inflammation. In primary leukemic cells, DMF disrupted the TLR signaling pathways induced by CpG by reducing the mRNA expression of NFKBIZ, IL6, IL10 and TNFα. Our data suggest that DMF targets a vulnerability of CLL cells linked to their inflammatory pathways, without impacting healthy donor peripheral blood mononuclear cells.

The spaceborne imaging spectroscopy mission PRecursore IperSpettrale della Missione Applicativa (PRISMA), launched on 22 March 2019 by the Italian Space Agency, opens new opportunities in many scientific domains, including precision farming and sustainable agriculture. This new Earth Observation (EO) data stream requires new-generation approaches for the estimation of important biophysical crop variables (BVs). In this framework, this study evaluated a hybrid approach, combining the radiative transfer model PROSAIL-PRO and several machine learning (ML) regression algorithms, for the retrieval of canopy chlorophyll content (CCC) and canopy nitrogen content (CNC) from synthetic PRISMA data. PRISMA-like data were simulated from two images acquired by the airborne sensor HyPlant, during a campaign performed in Grosseto (Italy) in 2018. CCC and CNC estimations, assessed from the best performing ML algorithms, were used to define two relations with plant nitrogen uptake (PNU). CNC proved to be slightly more correlated to PNU than CCC (R2 = 0.82 and R2 = 0.80, respectively). The CNC-PNU model was then applied to actual PRISMA images acquired in 2020. The results showed that the estimated PNU values are within the expected ranges, and the temporal trends are compatible with plant phenology stages.

The rice growing district in northwestern Italy, where paddies were traditionally flooded throughout spring, was interested by a general decrease of standing water presence caused by the adoption of dry seeding crop practices, with consequences for water management and for the ecology of breeding waterbirds. This communication analyses changes in flooding dynamics in the last four years, estimating them from MODIS data and comparing results with previous knowledge of the same study area. Results highlighted an intensification of the phenomenon in the north-western regions (–3.3 ± 0.6% per year in the period 2013–2021) and the almost complete loss of flooded surfaces east to the Ticino river (reaching in 2021 5% of the flooded extension estimated in 2000). Such findings highlight the importance of monitoring this phenomenon – considered by other authors as the biggest anthropogenic change in surface water of all Europe since 2000 – in near real time from remotely sensed data to monitor dynamics and support sustainable management of water usage at the district level.

Non-photosynthetic vegetation (NPV) plays a key role in soil conservation, which in turn is important in sustainable agriculture and carbon farming. For mapping NPV image spectroscopy proved to outperform multispectral sensors. PRISMA (PRecursore IperSpettrale della Missione Applicativa) is the forerunner of a new era of hyperspectral satellite missions, providing the proper spectral resolution for NPV mapping. This study takes advantage from both spectroscopy and machine-learning techniques. Exponential Gaussian Optimization was used for modelling known absorption bands (cellulose-lignin, pigments, water content and clays), resulting in a reduced feature space, which is split by a decision tree (DT) for mapping different field conditions (emerging, green and standing dead vegetation, crop residue and bare soil). DT training and validation exploited reference data, collected during PRISMA overpasses on a large farmland. Mapping results are accurate both at pixel and parcel level (O.A. > 90%; K > 0.9). Field status and crop rotation trajectories through time are derived by processing 12 images over 2020 and 2021. Results proved that PRISMA data are suitable for mapping field conditions at parcel scale with high confidence level. This is important in the perspective of other hyperspectral missions and is a premise toward quantitative estimates of NPV biophysical variable.

Objective: The main endpoint of the study was to evaluate if a daily intake of whey protein-based dietary supplement causes a worse response to levodopa in people with Parkinson's Disease (PWPD) Background: In PWPD, the competition between large neutral aminoacids and levodopa at intestinal absorption level may interfere with dopaminergic therapy's (DRT) effect; therefore, protein redistribution dietary regimen has been suggested. Many dietary supplementations are available to help people in balancing the protein intake and overcoming muscle mass loss. However, most of the products contain protein and could potentially affect levodopa action in PWPD. Methods: We performed a randomised single blind monocentric study on PWPD admitted in the rehabilitative unit for a 4-week multidisciplined intensive aerobic rehabilitation treatment. All patients received a standard protein redistribution dietary regimen plus a whey protein-based oral formula (N = 26) or Magnesium (N = 25) twice daily for 28 days. Neurological assessment and physical evaluation were conducted before (T0) and after (T1) rehabilitative treatment; DRT was recorded T0 and T1 as well. The delta of changes within groups in neurological (UPDRS III) and physical (TUG, 6 MW) evaluation scales was compared between groups. Results: Groups were comparable at baseline in clinical and demographic data; at T1, both groups showed a decrease in UPDRS III, TUG and 6 MWT and no differences between deltas were found. DRT remained stable in both groups. Conclusions: Our results show that whey protein supplementation does not interfere with DRT's efficacy and can be used in PWPD who need a protein supplementation without restrictions in intake hours. [ABSTRACT FROM AUTHOR]

BackgroundMicroenvironmental interactions of the malignant clone with T cells are critical throughout the natural history of chronic lymphocytic leukemia (CLL). Indeed, clonal expansions of T cells and shared clonotypes exist between different CLL patients, strongly implying clonal selection by antigens. Moreover, immunogenic neoepitopes have been isolated from the clonotypic B cell receptor immunoglobulin sequences, offering a rationale for immunotherapeutic approaches. Here, we interrogated the T cell receptor (TR) gene repertoire of CLL patients with different genomic aberration profiles aiming to identify unique signatures that would point towards an additional source of immunogenic neoepitopes for T cells.Experimental designTR gene repertoire profiling using next generation sequencing in groups of patients with CLL carrying one of the following copy-number aberrations (CNAs): del(11q), del(17p), del(13q), trisomy 12, or gene mutations in TP53 or NOTCH1.ResultsOligoclonal expansions were found in all patients with distinct recurrent genomic aberrations; these were more pronounced in cases bearing CNAs, particularly trisomy 12, rather than gene mutations. Shared clonotypes were found both within and across groups, which appeared to be CLL-biased based on extensive comparisons against TR databases from various entities. Moreover, in silico analysis identified TR clonotypes with high binding affinity to neoepitopes predicted to arise from TP53 and NOTCH1 mutations.ConclusionsDistinct TR repertoire profiles were identified in groups of patients with CLL bearing different genomic aberrations, alluding to distinct selection processes. Abnormal protein expression and gene dosage effects associated with recurrent genomic aberrations likely represent a relevant source of CLL-specific selecting antigens.

The breeding populations of colonial herons, egrets and allied waterbirds in Northwestern Italy increased since 1972, when a long-term monitoring was initiated, up to the end of the 20° century. Populations of continental importance for some heron species were concentrated mostly in the district of intensive rice cultivation, where the paddies offered wide foraging opportunities. After 2000, new cultivation techniques caused a progressive reduction in paddy flooding. We found a significant relationship between the post-2000 decrease in the number of nests of the three most abundant species of waterbirds, Grey Heron, Little Egret and Black-crowned Night-heron, and the diminishing extent of paddy flooding estimated on satellite-derived images. On the other hand, outside the paddies district the same three species continued to increase or remained mostly stable. The recent agronomic changes in the paddies of Northwestern Italy compromise their role as surrogates of natural wetlands and their importance for environmental conservation. The spread of dry rice fields, and the consequent loss of their value for conservation of aquatic biodiversity, call for a revision of the regulations and incentives to farmers under the Common Agriculture Policy by the European Union and by local authorities. Return to early-submerged rice fields and adoption of environmental-friendly practices, such as the creation of compensatory wetlands, should become mandatory for rice to maintain its status as “green” crop.

The spaceborne imaging spectroscopy mission PRecursore IperSpettrale della Missione Applicativa (PRISMA), launched on 22 March 2019 by the Italian Space Agency, opens new opportunities in many scientific domains, including precision farming and sustainable agriculture. This new Earth Observation (EO) data stream requires new-generation approaches for the estimation of important biophysical crop variables (BVs). In this framework, this study evaluated a hybrid approach, combining the radiative transfer model PROSAIL-PRO and several machine learning (ML) regression algorithms, for the retrieval of canopy chlorophyll content (CCC) and canopy nitrogen content (CNC) from synthetic PRISMA data. PRISMA-like data were simulated from two images acquired by the airborne sensor HyPlant, during a campaign performed in Grosseto (Italy) in 2018. CCC and CNC estimations, assessed from the best performing ML algorithms, were used to define two relations with plant nitrogen uptake (PNU). CNC proved to be slightly more correlated to PNU than CCC (R2 = 0.82 and R2 = 0.80, respectively). The CNC-PNU model was then applied to actual PRISMA images acquired in 2020. The results showed that the estimated PNU values are within the expected ranges, and the temporal trends are compatible with plant phenology stages. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) are multipotent cells with anti-inflammatory properties. Here we tested the safety of MSCs in patients with progressive supranuclear palsy (PSP; ClinicalTrials.gov: NCT01824121; Eudract No. 2011-004051-39). Seven patients were treated. To improve the safety, protocol adjustments were made during the performance of the study. The objectives of our work were: (1) to assess the safety of MSCs and (2) to identify critical issues in cell therapies for neurodegenerative diseases. Autologous MSCs from the bone marrow of PSP patients were administered through the internal carotid arteries. 1-year survival and number of severe adverse events were considered as safety endpoints. Clinical rating scales, neuropsychological assessments, gait and posture analysis, single-photon emission computed tomography, positron emission tomography, and brain magnetic resonance (BMR) were performed at different follow-up times. Peripheral blood levels of inflammatory cytokines were measured before and after cell infusion. Six of the seven treated patients were living 1 year after cell infusion. Asymptomatic spotty lesions were observed at BMR after 24 h in six of the seven treated patients. The last patient in the preliminary cohort (Case 5) exhibited transiently symptomatic BMR ischemic alterations. No severe adverse events were recorded in the last two treated patients. Interleukin-8 serum concentrations decreased in three patients (Case 2, 3, and 4). An adaptive study design, appropriate and up-to-date efficacy measures, adequate sample size estimation, and, possibly, the use of a cellular and/or allogeneic cell sources may help in performing phase II trials in the field.

Background: Mutations in ANO3 are a rare cause of autosomal dominant isolated or combined dystonia, mainly presenting in adulthood. Cases: We extensively characterize a new, large ANO3 family with six affected carriers. The proband is a young girl who had suffered from tremor and painful dystonic movements in her right arm since the age of 11 years. She later developed a diffuse dystonic tremor and mild extrapyramidal signs (ie, rigidity and hypodiadochokinesis) in her right arm. She also suffered from psychomotor delay and learning difficulties. Repeated structural and functional neuroimaging were unremarkable. A dystonic tremor was also present in her two sisters. Her paternal aunt, father, and a third older sister presented episodic postural tremor in the arms. The father and one sister also presented learning difficulties. The heterozygous p.G6V variant in ANO3 was identified in all affected subjects. Literature review: Stratification by age at onset divided ANO3 cases into two major groups, where younger patients displayed a more severe phenotype, probably due to variants near the scrambling domain. Conclusions: We describe the phenotype of a new ANO3 family and highlight the need for functional studies to explore the impact of ANO3 variants on its phospholipid scrambling activity. [ABSTRACT FROM AUTHOR]

The field related to mood disorders in Parkinson’s disease (PD) is fragmented. The aim of this cohort observational study was to evaluate whether the episodes of mood alteration could appear in different disease stages and to verify how nonmotor symptoms were led off into different stages. We enrolled 93 PD outpatients (three groups: drug naive—DN; not exhibiting motor fluctuations—n-MF; and exhibiting motor fluctuations—MF) and 50 healthy controls. Mood state was assessed through the Internal State Scale (ISS) while depressive symptoms were evaluated through the Beck Depression Inventory-II (BDI-II), nonmotor symptoms by means of the Non-Motor Symptoms Scale (NMSS), and the presence of impulse control disorders (ICDs) with the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP). Clinical and pharmacological data have also been recorded. No significant differences in mood state distribution between groups were observed. Nevertheless, as regards the mood state distribution within groups, in n-MF (47.6%) and MF patients (50%), (hypo)mania presence was significantly higher than other symptoms. In DN patients, hypomania showed a prevalence of 38.1% although it was not significant. At least one ICD was reported in 29.3% of n-MF and 50% of MF patients. In the MF group, a moderate positive correlation between ISS ACTivation subscale scores and the presence of ICDs and compulsive medication use emerged. Finally, MF patients reported higher BDI-II total scores than DN. Our results show that mood alterations in PD, considering both depressive symptoms and mood elevation, are related to the advanced stages of the disease as well as the presence of ICDs, and dopaminergic therapy would not always be able to restore a normal mood condition.

An immune suppressive tumor microenvironment (TME) is a limitation for immunotherapy. Here the authors show that, in a B cell acute lymphoblastic leukemia mouse model, gene-based delivery of IFNα reprograms the leukemia-induced immunosuppressive TME into immunostimulatory and enhances T-cell responses.

Non-photosynthetic vegetation (NPV) plays a key role in soil conservation, which in turn is important in sustainable agriculture and carbon farming. For mapping NPV image spectroscopy proved to outperform multispectral sensors. PRISMA (PRecursore IperSpettrale della Missione Applicativa) is the forerunner of a new era of hyperspectral satellite missions, providing the proper spectral resolution for NPV mapping. This study takes advantage from both spectroscopy and machine-learning techniques. Exponential Gaussian Optimization was used for modelling known absorption bands (cellulose-lignin, pigments, water content and clays), resulting in a reduced feature space, which is split by a decision tree (DT) for mapping different field conditions (emerging, green and standing dead vegetation, crop residue and bare soil). DT training and validation exploited reference data, collected during PRISMA overpasses on a large farmland. Mapping results are accurate both at pixel and parcel level (O.A. > 90%; K > 0.9). Field status and crop rotation trajectories through time are derived by processing 12 images over 2020 and 2021. Results proved that PRISMA data are suitable for mapping field conditions at parcel scale with high confidence level. This is important in the perspective of other hyperspectral missions and is a premise toward quantitative estimates of NPV biophysical variable. [ABSTRACT FROM AUTHOR]