Acute myeloid leukemia (AML) progression is influenced by immune suppression induced by leukemia cells. ZEB1, a critical transcription factor in epithelial-to-mesenchymal transition, demonstrates ...immune regulatory functions in AML. Silencing ZEB1 in leukemic cells reduces engraftment and extramedullary disease in immune-competent mice, activating CD8 T lymphocytes and limiting Th17 cell expansion. ZEB1 in AML cells directly promotes Th17 cell development that, in turn, creates a self-sustaining loop and a pro-invasive phenotype, favoring transforming growth factor β (TGF-β), interleukin-23 (IL-23), and SOCS2 gene transcription. In bone marrow biopsies from AML patients, immunohistochemistry shows a direct correlation between ZEB1 and Th17. Also, the analysis of ZEB1 expression in larger datasets identifies two distinct AML groups, ZEB1high and ZEB1low, each with specific immunological and molecular traits. ZEB1high patients exhibit increased IL-17, SOCS2, and TGF-β pathways and a negative association with overall survival. This unveils ZEB1’s dual role in AML, entwining pro-tumoral and immune regulatory capacities in AML blasts.
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•ZEB1+ AML blasts are immune regulatory via Th17 expansion•IL-17 promotes proliferation and invasion of ZEB1+ cells•IL-17 promotes ZEB1 binding to target gene promoters•ZEB1 blast features combine immune regulation and chemoresistance
Bassani et al. show that ZEB1 drives immune suppression and pro-tumoral Th17 cell development in AML. Silencing ZEB1 in leukemic cells limits disease in mice. Clinical data identify a ZEB1high patient subgroup with poor outcomes, unveiling its significance in AML progression as both a pro-tumoral and immune regulatory factor.
In 2020 North Italy suffered the SARS-CoV-2-related pandemic with a high number of deaths and hospitalization. The effect of atmospheric parameters on the amount of hospital admissions (temperature, ...solar radiation, particulate matter, relative humidity and wind speed) is studied through about 8 months (May–December). Two periods are considered depending on different conditions: a) low incidence of COVID-19 and very few regulations concerning personal mobility and protection (“free/summer period”); b) increasing incidence of disease, social restrictions and use of personal protections (“confined/autumn period”). The “hospitalized people in medical area wards/100000 residents” was used as a reliable measure of COVID-19 spreading and load on the sanitary system. We developed a chemometric approach (multiple linear regression analysis) using the daily incidence of hospitalizations as a function of the single independent variables and of their products (interactions). Eight administrative domains were considered (altogether 26 million inhabitants) to account for relatively homogeneous territorial and social conditions.
The obtained models very significantly match the daily variation of hospitalizations, during the two periods. Under the confined/autumn period, the effect of non-pharmacologic measures (social distances, personal protection, etc.) possibly attenuates the virus diffusion despite environmental factors. On the contrary, in the free/summer conditions the effects of atmospheric parameters are very significant through all the areas. Particulate matter matches the growth of hospitalizations in areas with low chronic particulate pollution. Fewer hospitalizations strongly correspond to higher temperature and solar radiation. Relative humidity plays the same role, but with a lesser extent. The interaction between solar radiation and high temperature is also highly significant and represents surprising evidence. The solar radiation alone and combined with high temperature exert an anti-SARS-CoV-2 effect, via both the direct inactivation of virions and the stimulation of vitamin D synthesis, improving immune system function.
•Temperature, sun radiation, particulate matter, % humidity, wind vs hospitalization.•Multiple linear regression analysis has been performed to create multivariate models.•Two time periods free of restrictions and with restrictions has been considered.•Temperature, solar radiation, and their interaction match with fewer hospitalization.•Particulate matter matches higher hospitalization in areas with low chronic pollution.
The purpose of this study is to study the evolution of quality of life (QoL) in the first 5 years following Intensity-modulated radiation therapy (IMRT) for prostate cancer (PCa) and to determine ...possible associations with clinical/treatment data.
Patients were enrolled in a prospective multicentre observational trial in 2010-2014 and treated with conventional (74-80 Gy, 1.8-2 Gy/fr) or moderately hypofractionated IMRT (65-75.2 Gy, 2.2-2.7 Gy/fr). QoL was evaluated by means of EORTC QLQ-C30 at baseline, at radiation therapy (RT) end, and every 6 months up to 5 years after IMRT end. Fourteen QoL dimensions were investigated separately. The longitudinal evaluation of QoL was analysed by means of Analysis of variances (ANOVA) for multiple measures.
A total of 391 patients with complete sets of questionnaires across 5 years were available. The longitudinal analysis showed a trend toward the significant worsening of QoL at RT end for global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. QoL worsening was recovered within 6 months from RT end, with the only exception being physical functioning. Based on ANOVA, the most impaired time point was RT end. QoL dimension analysis at this time indicated that acute Grade ≥ 2 gastrointestinal (GI) toxicity significantly impacted global health, physical and role functioning, fatigue, appetite loss, diarrhoea, and pain. Acute Grade ≥ 2 genitourinary (GU) toxicity resulted in lower role functioning and higher pain. Prophylactic lymph-nodal irradiation (WPRT) resulted in significantly lower QoL for global health, fatigue, appetite loss, and diarrhoea; lower pain with the use of neoadjuvant/concomitant hormonal therapy; and lower fatigue with the use of an anti-androgen.
In this prospective, longitudinal, observational study, high radiation IMRT doses delivered for PCa led to a temporary worsening of QoL, which tended to be completely resolved at six months. Such transient worsening was mostly associated with acute GI/GU toxicity, WPRT, and higher prescription doses.
Despite the dramatic advancements in pelvic radiotherapy, urinary toxicity remains a significant side-effect. The assessment of clinico-dosimetric predictors of radiation cystitis (RC) based on ...clinical data has improved substantially over the last decade; however, a thorough understanding of the physiopathogenetic mechanisms underlying the onset of RC, with its variegated acute and late urinary symptoms, is still largely lacking, and data from pre-clinical research is still limited. The aim of this review is to provide an overview of the main open issues and, ideally, to help investigators in orienting future research. First, anatomy and physiology of bladder, as well as the current knowledge of dose and dose-volume effects in humans, are briefly summarized. Subsequently, pre-clinical radiobiology aspects of RC are discussed. The findings suggest that pre-clinical research on RC in animal models is a lively field of research with growing interest in the development of new radioprotective agents. The availability of new high precision micro-irradiators and the rapid advances in small animal imaging might lead to big improvement into this field. In particular, studies focusing on the definition of dose and fractionation are warranted, especially considering the growing interest in hypo-fractionation and ablative therapies for prostate cancer treatment. Moreover, improvement in radiotherapy plans optimization by selectively reducing radiation dose to more radiosensitive substructures close to the bladder would be of paramount importance. Finally, thanks to new pre-clinical imaging platforms, reliable and reproducible methods to assess the severity of RC in animal models are expected to be developed.
Background and Purpose
N‐Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme accountable for the breakdown of N‐acylethanolamines (NAEs) and its pharmacological inhibition has beneficial ...effects in inflammatory conditions. The knowledge of NAAA in cancer is fragmentary with an unclarified mechanism, whereas its contribution to colorectal cancer (CRC) is unknown to date.
Experimental Approach
CRC xenograft and azoxymethane models were used to assess the in vivo effect of NAAA inhibition. Further, the tumour secretome was evaluated by an oncogenic array, CRC cell lines were used for in vitro studies, cell cycle was analysed by cytofluorimetry, NAAA was knocked down with siRNA, human biopsies were obtained from surgically resected CRC patients, gene expression was measured by RT‐PCR and NAEs were measured by LC–MS.
Key Results
The NAAA inhibitor AM9053 reduced CRC xenograft tumour growth and counteracted tumour development in the azoxymethane model. NAAA inhibition affected the composition of the tumour secretome inhibiting the expression of EGF family members. In CRC cells, AM9053 reduced proliferation with a mechanism mediated by PPAR‐α and TRPV1. AM9053 induced cell cycle arrest in the S phase associated with cyclin A2/CDK2 down‐regulation. NAAA knock‐down mirrored the effects of NAAA inhibition with AM9053. NAAA expression was down‐regulated in human CRC tissues, with a consequential augmentation of NAE levels and dysregulation of some of their targets.
Conclusion and Implications
Our results show novel data on the functional importance of NAAA in CRC progression and the mechanism involved. We propose that this enzyme is a valid drug target for the treatment of CRC growth and development.
A study of aromatic maturity of Nerello Mascalese grapes from two districts (“Contrade”) of the Etna area was carried out using gas chromatography-mass spectrometry (GC-MS) and electronic nose ...(E-nose). To validate our hypothesis regarding the potential use of E-nose for aromatic maturity, two vineyards with different characteristics (08 Alto and Solicchiata) were used. Grapes were sampled at 18°, 21° and 23°Brix. Regarding the phenol maturity index, total anthocyanins reached a peak at the second sampling in 08 Alto grapes, while in Solicchiata they constantly increased. The ratio total anthocyanins: total polyphenols in 08 Alto grapes increased from 0.14 to 0.33, and in Solicchiata from 0.17 to 0.23. As regards grape volatile organic compounds (GVOCs) for the aromatic maturity index, in Solicchiata the concentrations of glycosylated benzenoids and C13-norisoprenoids were much higher than in 08 Alto, and the concentration decreased during maturity (opposite trend to the anthocyanins); by contrast, in 08 Alto, concentrations peaked at the second sampling time (as with the anthocyanins). The E-nose results did not completely coincide with the GVOCs pattern, but they discriminated the maturity stages very well. However, the different metallo-porphyrins responded differently depending on the class of GVOCs, highlighting very promising results in terms of GVOCs non-destructive prediction by means of principal component regression (PCR) application. E-nose shows potential for easy use with rapid PCR for the monitoring of the aromatic maturity of Nerello Mascalese grapes.
We hypothesised that the protection against oxygen (PAO) of must and wine during vinification by avoiding contact with air can preserve the primary volatile organic compounds (VOCs) of Nerello ...Mascalese. PAO was performed in two seasons (2020 and 2021) using carbon dioxide pellets (CO2,s) and gas (CO2,g), inactivated yeasts and ascorbic acid during fermentation; the control wine was made via traditional vinification without adding the aforementioned components. During fermentation, the two winemaking processes mainly differed in terms of the application of aeration during maceration/fermentation in the pump-over and délestage activities, and the care taken to avoid contact with oxygen during racking. In both years, higher concentrations of polyphenols and total anthocyanins were found in the PAO wine (about 16 % and 20 % respectively). The concentrations of nerol, citronellol and geraniol were significantly higher in the PAO wine in both seasons, albeit with small differences which affected the sensory evaluation. The free/bound terpenes ratio was 0.35 (PAO) and 0.55 (Control). Bound C13-norisoprenoids contents were higher than the free ones; in the PAO wine, free 3-oxo-α-ionol and bound vomifoliol concentrations were slightly higher than in the control wine. Thiols were measured in Nerello for the first time. In 2020 in particular, sulfanylhexan-1-ol was present in larger amounts in the PAO wine. Applying PAO in the production of Nerello Mascalese modified certain VOCs, as well as the overall free/bound ratio due to the increase in bound VOCs, thus influencing the aroma of the wine.
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