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Background and purpose: To review available data on toxicity during and/or after treatment of abdominal-pelvic lymph node oligometastases (A-P LN) with stereotactic body radiation therapy (SBRT) and to provide an overview of adverse events and its relation to dose or fractionation. Material and methods: For this systematic review, we searched MEDLINE, Embase, Web of Science Core Collection, and CINAH for studies published between the database inception and October 3rd, 2023. Inclusion criteria were (1) patients with 1–5 A-P LN oligometastases, (2) treatment with SBRT to a median prescribed dose of ≥55 Gy BED10, and (3) description of acute and/or late toxicity. There were no language or date restrictions. Results: A total of 35 studies, including 1,512 patients, were selected. Late grade 3 and 4 adverse events occurred in 0.6% and 0.1% of the patients treated for A-P LN oligometastases. All late adverse events grade ≥ 3 occurred after treatment of the tumor with a minimum BED10 of 72 Gy. Of the 11 patients with severe late toxicity, five patients were re-irradiated. Late grade 2 and 1 toxicity was reported in 3.4% and 8.3% of the patients. Acute toxicity grades 4, 3, 2, and 1 occurred in 0.1%, 0.2%, 4.4%, and 19.8% of the patients, respectively. Interpretation: SBRT for A-P LN oligometastases show low toxicity rates. Nearly 50% of late adverse events ≥ grade 3 were associated with re-irradiation.

Anthocyanins are a large group of water-soluble flavonoid pigments. These specialized metabolites are ubiquitous in the plant kingdom and play an essential role not only in plant reproduction and dispersal but also in responses to biotic and abiotic stresses. Anthocyanins are recognized as important health-promoting and chronic-disease-preventing components in the human diet. Therefore, interest in developing food crops with improved levels and compositions of these important nutraceuticals is growing. This review focuses on work conducted to elucidate the genetic control of the anthocyanin pathway and modulate anthocyanin content in eggplant (Solanum melongena L.) and tomato (Solanum lycopersicum L.), two solanaceous fruit vegetables of worldwide relevance. While anthocyanin levels in eggplant fruit have always been an important quality trait, anthocyanin-based, purple-fruited tomato cultivars are currently a novelty. As detailed in this review, this difference in the anthocyanin content of the cultivated germplasm has largely influenced genetic studies as well as breeding and transgenic approaches to improve the anthocyanin content/profile of these two important solanaceous crops. The information provided should be of help to researchers and breeders in devising strategies to address the increasing consumer demand for nutraceutical foods.

Abstract The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and potentially lethal metastatic disease remains unclear. DNA sequencing studies have revealed a massive mutational burden but have yet to illuminate mechanisms of disease progression. Here we perform RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation, dynamic modulation of the epidermal differentiation complex, remodelling of the immune landscape and an increase in the preponderance of tumour specific keratinocytes. Comparative systems analysis of human cSCC coupled with the generation of genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genes Tgfbr2, Trp53, and Notch1 coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis. Taken together we provide a comprehensive map of the cSCC disease continuum and reveal potentially actionable events that promote and accompany disease progression.

Cellular plasticity defines the capacity of cells to adopt distinct identities during development, tissue homeostasis and regeneration. Dynamic fluctuations between different states, within or across lineages, are regulated by changes in chromatin accessibility and in gene expression. When deregulated, cellular plasticity can contribute to cancer initiation and progression. Cancer cells are remarkably plastic which contributes to phenotypic and functional heterogeneity within tumours as well as resistance to targeted therapies. It is for these reasons that the scientific community has become increasingly interested in understanding the molecular mechanisms governing cancer cell plasticity. The purpose of this mini-review is to discuss different examples of cellular plasticity associated with metaplasia and epithelial-mesenchymal transition with a focus on therapy resistance.

Google Earth Engine has deeply changed the way in which Earth observation data are processed, allowing the analysis of wide areas in a faster and more efficient way than ever before. Since its inception, many functions have been implemented by a rapidly expanding community, but none so far has focused on the computation of phenological metrics in mountain areas with high-resolution data. This work aimed to fill this gap by developing an open-source Google Earth Engine algorithm to map phenological metrics (PMs) such as the Start of Season, End of Season, and Length of Season and detect the Peak of Season in mountain areas worldwide using high-resolution free satellite data from the Landsat collection and Sentinel-2. The script was tested considering the entire Alpine chain. The validation was performed by the cross-computation of PMs using the R package greenbrown, which permits land surface phenology and trend analysis, and the Moderate-Resolution Imaging Spectroradiometer (MODIS) in homogeneous quote and land cover alpine landscapes. MAE and RMSE were computed. Therefore, this algorithm permits one to compute with a certain robustness PMs retrieved from higher-resolution free EO data from GEE in mountain areas worldwide.

It remains critical to identify colorectal cancers (CRC) that will disseminate as early as possible. Here, the authors identify CRC tumours that are aggressive and prone to early dissemination, characterised by epithelial TGFβ and growth-factor signalling - which could be targeted with MEK/EGFR inhibitors.

Abstract Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment.

The influence of mRNA splicing on colon cancer development and progression is unclear. In this study, the authors demonstrate that the SRSF1 splicing factor is essential to sustain the stem cell phenotype of WNT-activated colorectal cancers.

Abstract RAC1B is a tumour-related alternative splice isoform of the small GTPase RAC1, found overexpressed in a large number of tumour types. Building evidence suggests it promotes tumour progression but compelling in vivo evidence, demonstrating a role in driving tumour invasion, is currently lacking. In the present study, we have overexpressed RAC1B in a colorectal cancer mouse model with potential invasive properties. Interestingly, RAC1B overexpression did not trigger tumour invasion, rather it led to an acceleration of tumour initiation and reduced mouse survival. By modelling early stages of adenoma initiation we observed a reduced apoptotic rate in RAC1B overexpressing tumours, suggesting protection from apoptosis as a mediator of this phenotype. RAC1B overexpressing tumours displayed attenuated TGFβ signalling and functional analysis in ex vivo organoid cultures demonstrated that RAC1B negatively modulates TGFβ signalling and confers resistance to TGFβ-driven cell death. This work defines a novel mechanism by which early adenoma cells can overcome the cytostatic and cytotoxic effects of TGFβ signalling and characterises a new oncogenic function of RAC1B in vivo.

RAC1 is a downstream target of the Wnt signaling that promotes intestinal stem cell expansion and tumorigenesis. Here, the authors identify the specific splice variant RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment.

European long shelf-life (LSL) tomato landraces can be classified into two main groups: the Italian group, including ‘Piennolo’ landraces, and the Spanish group, including the ‘Penjar’ and ‘Ramellet’ landraces. In this study, a partially common set of ‘Piennolo’ and ‘Penjar-Ramellet’ varieties was grown in Italy and Spain to evaluate the effect of different agro-environmental and storage conditions on fruit quality and shelf-life. Overall, both Italian and Spanish LSL genotypes lost their peculiar phenotype in terms of physicochemical properties and shelf-life behavior when not grown in their original agro-environment. To better understand the sensory attributes that drive consumers’ preferences, all varieties were characterized using descriptive sensory analysis combined with hedonic tests. The evaluations were conducted postharvest on raw and processed products according to the country’s culinary tradition (baked in Italy; spread on bread in Spain). Sensory description by trained panels conducted on raw and processed products highlighted different sensory profiles between the two LSL tomato groups. In the ‘Piennolo’ group, a reduction in sensory diversity among the genotypes was observed in the baked products compared to the raw ones, while this trend was not observed for the ‘Penjar-Ramellet’ group. None of the varieties fully met the consumers’ preferences.

Earth observation data have assumed a key role in environmental monitoring, as well as in risk assessment. Rising temperatures and consequently heat waves due to ongoing climate change represent an important risk considering the population, as well as animals, exposed. This study was focused on the Aosta Valley Region in NW Italy. To assess population exposure to these patterns, the following datasets have been considered: (1) HDX Meta population dataset refined and updated in order to map population distribution and its features; (2) Landsat collection (missions 4 to 9) from 1984 to 2022 obtained and calibrated in Google Earth Engine to model LST trends. A pixel-based analysis was performed considering Aosta Valley settlements and relative population distribution according to the Meta population dataset. From Landsat data, LST trends were modelled. The LST gains computed were used to produce risk exposure maps considering the population distribution and structure (such as ages, gender, etc.). To check the consistency and quality of the HDX population dataset, MAE was computed considering the ISTAT population dataset at the municipality level. Exposure-risk maps were finally realized adopting two different approaches. The first one considers only LST gain maximum by performing an ISODATA unsupervised classification clustering in which the separability of each class obtained and was checked by computing the Jeffries–Matusita (J-M) distances. The second one was to map the rising temperature exposure by developing and performing a risk geo-analysis. In this last case the input parameters considered were defined after performing a multivariate regression in which LST maximum was correlated and tested considering (a) Fractional Vegetation Cover (FVC), (b) Quote, (c) Slope, (d) Aspect, (e) Potential Incoming Solar Radiation (mean sunlight duration in the meteorological summer season), and (f) LST gain mean. Results show a steeper increase in LST maximum trend, especially in the bottom valley municipalities, and especially in new built-up areas, where more than 60% of the Aosta Valley population and domestic animals live and where a high exposure has been detected and mapped with both approaches performed. Maps produced may help the local planners and the civil protection services to face global warming from a One Health perspective.

Kras is often mutated in colorectal cancer but how this oncogenic mutation alters signalling pathways globally is undetermined. Here, the authors analyse how this mutation affects protein interaction networks and signal flow showing an extensive re‐wiring of signalling in response to KRas mutation

Land cover (LC) maps are crucial to environmental modeling and define sustainable management and planning policies. The development of a land cover mapping continuous service according to the new EAGLE legend criteria has become of great interest to the public sector. In this work, a tentative approach to map land cover overcoming remote sensing (RS) limitations in the mountains according to the newest EAGLE guidelines was proposed. In order to reach this goal, the methodology has been developed in Aosta Valley, NW of Italy, due to its higher degree of geomorphological complexity. Copernicus Sentinel-1 and 2 data were adopted, exploiting the maximum potentialities and limits of both, and processed in Google Earth Engine and SNAP. Due to SAR geometrical distortions, these data were used only to refine the mapping of urban and water surfaces, while for other classes, composite and timeseries filtered and regularized stack from Sentinel-2 were used. GNSS ground truth data were adopted, with training and validation sets. Results showed that K-Nearest-Neighbor and Minimum Distance classification permit maximizing the accuracy and reducing errors. Therefore, a mixed hierarchical approach seems to be the best solution to create LC in mountain areas and strengthen local environmental modeling concerning land cover mapping.

Earth Observation services guarantee continuous land cover mapping and are becoming of great interest worldwide. The Google Earth Engine Dynamic World represents a planetary example. This work aims to develop a land cover mapping service in geomorphological complex areas in the Aosta Valley in NW Italy, according to the newest European EAGLE legend starting in the year 2020. Sentinel-2 data were processed in the Google Earth Engine, particularly the summer yearly median composite for each band and their standard deviation with multispectral indexes, which were used to perform a k-nearest neighbor classification. To better map some classes, a minimum distance classification involving NDVI and NDRE yearly filtered and regularized stacks were computed to map the agronomical classes. Furthermore, SAR Sentinel-1 SLC data were processed in the SNAP to map urban and water surfaces to improve optical classification. Additionally, deep learning and GIS updated datasets involving urban components were adopted beginning with an aerial orthophoto. GNSS ground truth data were used to define the training and the validation sets. In order to test the effectiveness of the implemented service and its methodology, the overall accuracy was compared to other approaches. A mixed hierarchical approach represented the best solution to effectively map geomorphological complex areas to overcome the remote sensing limitations. In conclusion, this service may help in the implementation of European and local policies concerning land cover surveys both at high spatial and temporal resolutions, empowering the technological transfer in alpine realities.

Wnt ligands are essential for intestinal homoeostasis and stem cell maintenance. Here, the authors show that reduction in Wnt secretion reduces the number of intestinal stem cells; this results in rapid fixation of mutated stem cells and accelerated adenoma formation due to lack of cell competition.

Consumer dissatisfaction with the flavor quality of many modern fresh market tomato varieties has fostered breeders’ interest in sensory quality improvement, and the demand for traditional varieties, which are generally associated with better flavor. To achieve further knowledge on the factors influencing the sensory quality and consumers’ preferences and perception, European traditional and modern fresh market tomato varieties were grown and evaluated in France, Italy, and Spain. Different growing conditions were tested in France (soilless vs. soil) and in Spain (open field vs. greenhouse), while in Italy fruits were evaluated at two ripening stages. Fruit quality was assessed by integrating physicochemical analyses, sensory profiles, and consumer tests. In all three countries, overall modern varieties were perceived as having more intense “tomato flavor” and “overall flavor” than traditional ones. In France and Spain, consumers’ preferences were more oriented towards modern varieties than traditional ones. Significant growing condition effects were found on sensory and physicochemical traits, while the effect on consumers’ overall liking was not significant, largely depending on the genotype. A fair agreement between product configurations from descriptive analysis by trained assessors and Check-All-That-Apply (CATA) questions by consumers was observed. Penalty-lift analysis based on CATA allowed identifying positive and negative drivers of liking.

Abstract Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc. The increased levels of DNA damage sensitised Huwe1‐deficient tumours to DNA‐damaging agents and to deletion of the anti‐apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a potential vulnerability of HUWE1‐mutated tumours to DNA‐damaging agents and inhibitors of anti‐apoptotic proteins.

Plant specialized metabolites (SMs) play an important role in the interaction with the environment and are part of the plant defense response. These natural products are volatile, semi-volatile and non-volatile compounds produced from common building blocks deriving from primary metabolic pathways and rapidly evolved to allow a better adaptation of plants to environmental cues. Specialized metabolites include terpenes, flavonoids, alkaloids, glucosinolates, tannins, resins, etc. that can be used as phytochemicals, food additives, flavoring agents and pharmaceutical compounds. This review will be focused on Mediterranean crop plants as a source of SMs, with a special attention on the strategies that can be used to modulate their production, including abiotic stresses, interaction with beneficial soil microorganisms and novel genetic approaches.

Exotic libraries have proven a powerful tool for the exploitation of wild relatives and quantitative trait loci (QTLs) detection in crop species. In early 2000, an introgression line (IL) population of the wild tomato Solanum habrochaites (SH) acc. LA1777 was developed and made publicly available. Despite the potentiality of the donor parent, so far, these lines have been poorly explored for their agronomic performance and for the identification of genomic regions underlying the variation of quantitative traits (QTLs). Here, we report the evaluation of 19 morpho-agronomic and chemical traits on a set of 39 ILs grown in three consecutive field seasons with the aim to: (a) Determine the overall phenotypic performances of the studied collection, (b) estimate the influence of the genotype (G) and the year of cultivation (Y) and their interaction on the traits analyzed, (c) investigate the plasticity of the traits, and (d) identify whole-genome QTLs in the wild SH background. The ILs showed lower productivity compared to the control genotype, while no major effects were found for the morphological fruit-related traits. Instead, a general increase in the soluble solids content was observed. The combined analysis of G × Y highlighted a major effect of the genotype on trait variation, although yield-related traits were more influenced by environmental factors. In total, 75 associations for 17 traits were detected. Major QTLs increasing soluble solids, pericarp thickness, and trichome density were respectively found on chromosomes 1, 5, and 11 with a percentage variation (PV) of 24.01%, 32.49%, and 200%. Furthermore, different QTLs increasing the color intensity and fruit shape were detected. These results suggest that SH could be a potential source of favorable alleles for qualitative traits despite its inferior phenotype compared to the cultivated parent. The evaluated set of SH LA1777 ILs is a potential for novel allele discovery in wild tomatoes and for breeding purposes towards the exploitation of the available introgressions and for the pyramiding of traits.

Cutaneous squamous cell carcinomas is a growing problem but the driver genes causing this remain poorly defined. Here, the authors demonstrate that inactivating driver mutations in TGFBR1 and TGFBR2occur in vemurafenib-induced and sporadic cutaneous squamous cell carcinomas.

An understanding of the mechanisms determining MYC’s transcriptional and proliferation-promoting activities in vivo could facilitate approaches for MYC targeting. However, post-translational mechanisms that control MYC function in vivo are poorly understood. Here, we demonstrate that MYC phosphorylation at serine 62 enhances MYC accumulation on Lamin A/C-associated nuclear structures and that the protein phosphatase 2A (PP2A) inhibitor protein CIP2A is required for this process. CIP2A is also critical for serum-induced MYC phosphorylation and for MYC-elicited proliferation induction in vitro. Complementary transgenic approaches and an intestinal regeneration model further demonstrated the in vivo importance of CIP2A and serine 62 phosphorylation for MYC activity upon DNA damage. However, targeting of CIP2A did not influence the normal function of intestinal crypt cells. These data underline the importance of nuclear organization in the regulation of MYC phosphorylation, leading to an in vivo demonstration of a strategy for inhibiting MYC activity without detrimental physiological effects.

The Wnt pathway is abnormally activated in the majority of colorectal cancers, and significant knowledge has been gained in understanding its role in tumor initiation. However, the mechanisms of metastatic outgrowth in colorectal cancer remain a major challenge. We report that autophagy-dependent metabolic adaptation and survival of metastatic colorectal cancer cells is regulated by the target of oncogenic Wnt signaling, homeobox transcription factor PROX1, expressed by a subpopulation of colon cancer progenitor/stem cells. We identify direct PROX1 target genes and show that repression of a pro-apoptotic member of the BCL2 family, BCL2L15, is important for survival of PROX1+ cells under metabolic stress. PROX1 inactivation after the establishment of metastases prevented further growth of lesions. Furthermore, autophagy inhibition efficiently targeted metastatic PROX1+ cells, suggesting a potential therapeutic approach. These data identify PROX1 as a key regulator of the transcriptional network contributing to metastases outgrowth in colorectal cancer.