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Two field trials (2017 and 2018) evaluated the performance of barley–pea mixed cropping by comparing different sowing densities (replacement design) and tailoring N fertilization on barley sowing density (split-plot design). High and Low N inputs were applied to whole plots whereas barley and pea, as pure and in mixed crops, were applied to subplots. The 2017 trial suggested the occurrence of an interaction between soil physical properties and N fertilization. Therefore, in 2018 a pedological survey allowed the soil effect to be included in the ANOVA model applied to evaluate crop performance parameters, showing that N fertilization positively affected barley performance only in the soil unit located downslope. A significantly lower presence of weeds was observed in mixed crops rather than in pea pure crops. Overall, increasing pea density and reducing barley density in mixed crops, and tailoring N fertilization were effective approaches to obtain a more balanced mixed grain at harvest. The combination of crop performance evaluation and assessments of soil conditions suggested that more sustainable agricultural systems, based on mixed cropping and a significant reduction of N fertilizers and herbicides, can be achieved with barley–pea mixed cropping as an alternative to pure cropping systems.

Background Triple negative breast cancer (TNBC) is an aggressive disease characterized by high risk of relapse and development of resistance to different chemotherapy agents. Several targeted therapies have been investigated in TNBC with modest results in clinical trials. Among these, PI3K/AKT inhibitors have been evaluated in addition to standard therapies, yielding conflicting results and making attempts on elucidating inherent mechanisms of resistance of great interest. Increasing evidences suggest that PI3K/AKT inhibitors can induce autophagy in different cancers. Autophagy represents a supposed mechanism of drug-resistance in aggressive tumors, like TNBC. We, therefore, investigated if two PI3K/AKT inhibitors, ipatasertib and taselisib, could induce autophagy in breast cancer models, and whether chloroquine (CQ), a well known autophagy inhibitor, could potentiate ipatasertib and taselisib anti-cancer effect in combination with conventional chemotherapy. Methods The induction of autophagy after ipatasertib and taselisib treatment was evaluated in MDAMB231, MDAM468, MCF7, SKBR3 and MDAB361 breast cancer cell lines by assaying LC3-I conversion to LC3-II through immunoblotting and immunofluorescence. Other autophagy-markers as p62/SQSTM1 and ATG5 were evaluated by immunoblotting. Synergistic antiproliferative effect of double and triple combinations of ipatasertib/taselisib plus CQ and/or paclitaxel were evaluated by SRB assay and clonogenic assay. Anti-apoptotic effect of double combination of ipatasertib/taselisib plus CQ was evaluated by increased cleaved-PARP by immunoblot and by Annexin V- flow cytometric analysis. In vivo experiments were performed on xenograft model of MDAMB231 in NOD/SCID mice. Results Our results suggested that ipatasertib and taselisib induce increased autophagy signaling in different breast cancer models. This effect was particularly evident in PI3K/AKT resistant TNBC cells, where the inhibition of autophagy by CQ potentiates the therapeutic effect of PI3K/AKT inhibitors in vitro and in vivo TNBC models, synergizing with taxane-based chemotherapy. Conclusion These data suggest that inhibition of authophagy with CQ could overcome mechanism of drug resistance to PI3K/AKT inhibitors plus paclitaxel in TNBC making the evaluation of such combinations in clinical trials warranted.

Hyperglycemia, obesity and metabolic syndrome are negative prognostic factors in breast cancer patients. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies. However, ICIs are associated with immune-related adverse events involving cardiotoxicity. We aimed to study if hyperglycemia could affect ipilimumab-induced anticancer efficacy and enhance its cardiotoxicity. Human cardiomyocytes and estrogen-responsive and triple-negative breast cancer cells (MCF-7 and MDA-MB-231 cell lines) were exposed to ipilimumab under high glucose (25 mM); low glucose (5.5 mM); high glucose and co-administration of SGLT-2 inhibitor (empagliflozin); shifting from high glucose to low glucose. Study of cell viability and the expression of new putative biomarkers of cardiotoxicity and resistance to ICIs (NLRP3, MyD88, cytokines) were quantified through ELISA (Cayman Chemical) methods. Hyperglycemia during treatment with ipilimumab increased cardiotoxicity and reduced mortality of breast cancer cells in a manner that is sensitive to NLRP3. Notably, treatment with ipilimumab and empagliflozin under high glucose or shifting from high glucose to low glucose reduced significantly the magnitude of the effects, increasing responsiveness to ipilimumab and reducing cardiotoxicity. To our knowledge, this is the first evidence that hyperglycemia exacerbates ipilimumab-induced cardiotoxicity and decreases its anticancer efficacy in MCF-7 and MDA-MB-231 cells. This study sets the stage for further tests on other breast cancer cell lines and primary cardiomyocytes and for preclinical trials in mice aimed to decrease glucose through nutritional interventions or administration of gliflozines during treatment with ipilimumab.

The Arctic region is characterized by severe temperatures and a unique ecosystem with largely unexplored microbiomes. Whereas soil microbiomes in temperate regions play key roles in nutrient cycling, organic matter decomposition, greenhouse gas fluxes, and overall ecosystem functioning, Arctic microbiomes remain poorly understood, highlighting the need for a thorough characterization to better predict and manage soil health and resilience. In this study, we compared the microbial profiles of three raised beaches on Devon Island (Nunavut, Canadian Arctic Archipelago), which emerged sequentially between eight and two thousand years ago, to assess their similarities and differences. Samples were collected by genetic horizons along excavations from the top layer to the permafrost. For each horizon, total soil DNA, 16S gene copies dPCR quantification, 16S metabarcoding, and functional prediction were carried out. Total DNA quantification revealed a consistently comparable concentration of genetic material across the three soil beaches (AB2 μ = 2.28 ± 5.44 μg ∙ g -1 , AB1 μ = 4.71 ± 2.35 μg ∙ g -1 , AB3 μ = 5.44 ± 2.91 μg ∙ g -1 ), regardless of site age (AB2 = 2,360 YBP, AB1 = 6,726 YBP, AB3 = 8,410 YBP). Conversely, clear differences emerged by comparing the different horizons at each site. The hierarchical cluster analysis based on the Bray-Curtis dissimilarity matrix revealed a clear separation between surface and deep horizons. The core microbiome analysis highlighted Actinobacteria, Proteobacteria, and Firmicutes as the three predominant phyla accounting for relative abundances of 42%, 22%, and 18%, respectively. Remarkable evidence was the unexpectedly high taxonomic diversity that was recorded in these sites and that surprisingly matched with the commonly observed values in soils of temperate regions. Since these stony shores developed under cold, life-limiting conditions, their apparent microbial richness raises doubts about the potential biases in inferring physiological contexts and active biodiversity directly inferred from culture-independent DNA-based studies. The reason is that such inventories can be possibly inflated, in all environments, by chronically accumulated cells from passive immigration events through atmospheric discharge.

Chronic exposure to polychlorinated biphenyls (PCBs), ubiquitous environmental contaminants, can adversely affect the development and function of the nervous system. Here we evaluated the effect of PCB exposure on mitochondrial function using the PCB mixture Aroclor-1254 (A1254) in SH-SY5Y neuroblastoma cells. A 6-hour exposure to A1254 (5 μg/ml) reduced cellular ATP production by 45%±7, and mitochondrial membrane potential, detected by TMRE, by 49%±7. Consistently, A1254 significantly decreased oxidative phosphorylation and aerobic glycolysis measured by extracellular flux analyzer. Furthermore, the activity of mitochondrial protein complexes I, II, and IV, but not V (ATPase), measured by BN-PAGE technique, was significantly reduced after 6-hour exposure to A1254. The addition of pyruvic acid during exposure to A1254 significantly prevent A1254-induced cell injury, restoring resting mitochondrial membrane potential, ATP levels, oxidative phosphorylation and aerobic glycolysis. Furthermore, pyruvic acid significantly preserved the activity of mitochondrial complexes I, II and IV and increased basal activity of complex V. Collectively, the present results indicate that the neurotoxicity of A1254 depends on the impairment of oxidative phosphorylation, aerobic glycolysis, and mitochondrial complexes I, II, and IV activity and it was counteracted by pyruvic acid.

Land set-up systems in Italy were and, in a few cases, still are integral parts of agricultural landscapes. The soils of Italy mirror a wide variety of climates and morphologies and derive from a great diversity of parent materials influenced by different soil temperature and moisture regimes. Furthermore, their development was influenced by several anthropogenic activities over time including land settings. Land set-up systems have been widely used throughout the Italian soilscape to regulate surface and underground water and to improve the physical soil features in a way that ensures mixed herbaceous and tree-crops cultivation. In recent times, new technologies have been introduced in agroforestry exploitation of the land, while the ancient but tested hydraulic soil systems have been abandoned. As a result, a great part of Italian soilscapes is prone to water erosion and floods, an unforeseen impact, which can be counterbalanced by good soil management practices. Moreover, new pedotechniques have been recently adopted, transforming soils and landscapes, but generating sometimes soil degradation issues. After presenting the main features characterizing Italian soils and landscapes, we describe all the historical land set-up systems adopted over time, highlighting their positive functions in terms of both soil conservation and agricultural production. We also emphasise the importance of maintaining such land settings both as distinctive parts of cultural landscapes and strategies of soil conservation, and the need of developing new systems based on the principles of environmental sustainability.   Highlights - Italy shows different morphological regions that are characterized by different soilscapes. - Historical land set-up systems are distinctive constituents of the Italian cultural landscapes. - Land settings have been adopted over time to protect soil and increase agricultural production. - New pedotechniques have been recently adopted in large scale farming with no consideration of soil conservation. - Maintenance of historical land set-up systems and development of new systems is needed.

Background: The introduction of trastuzumab biosimilars in clinical practice plays an important role in promoting the sustainability of healthcare systems. By contrast, the switching process can be challenging to the clinics. This survey describes the switching process at a National Cancer Institute over a period of 2 years. Methods: Data regarding all trastuzumab-based regimens for breast cancer (BC) from 1 January 2019 and 31 December 2020 were extracted from both adverse drug reactions (ADRs) reporting systems and electronic systems involved in inventory management, prescribing, dispensing, and administration. Both patients under monotherapy and combination treatment regimens were included. There were no exclusion criteria. Results and Conclusions: Overall 354 patients received at least one trastuzumab-based regimen for a total of 493 lines of treatment and 5769 administrations. Biosimilar were used in 34.3% of trastuzumab-based treatments. No differences between biosimilars and reference drug have been observed in terms of ADRs. The effective cost-saving of the first 2 years is greater than EUR 800,000 and it is estimated to increase over time.

Land reclamation and drainage networks represent one of the most ancient human modifications of the Italian soilscape, where tailored land set-up systems were developed in agro- and forestecosystems in three millennia of man’s activity. Most of once manually maintained land settings are currently scarcely working or even disappeared because of the cost needed for their maintenance and the advent of mechanization that have simplified the field organization. The scarce attention to the soil experienced in the last decades, has accelerated soil erosion and flooding events, which entailed high costs in terms of money and human lives, but also caused reduction of soil thickness, water holding capacity, and fertility. In view of a sustainable agriculture, it is mandatory to assess the role of land set-up systems, which for centuries have been key in protecting soil from erosion, but also in increasing soil fertility. Such an effort cannot be made without considering the different pedo-climatic conditions and land uses of the Italian territory, which is different with respect to the past because of the multiple transformations made to favour the mechanization of agriculture. In this review we discuss the main effect of Italian land settings on the soilscape and on soil physicochemical conditions. Since land settings were developed centuries ago, detailed information about their effect on specific soil parameters is scarce in the scientific literature; thus, in some case, we provide information gathered in places where land set-up systems are still present.

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors characterized by aggressive behavior, high risk of distant recurrence, and poor survival. Chemotherapy is still the main therapeutic approach for this subgroup of patients, therefore, progress in the treatment of TNBC remains an important challenge. Data derived from molecular technologies have identified TNBCs with different gene expression and mutation profiles that may help developing targeted therapies. So far, however, only a few of these have shown to improve the prognosis and outcomes of TNBC patients. Robust predictive biomarkers to accelerate clinical progress are needed. Herein, we review prognostic and predictive biomarkers in TNBC, discuss the current evidence supporting their use, and look at the future of this research field.