Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspar-tate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the as-partate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention

Extracting actionable knowledge to increase business utility in sport services

The increase in retention of customer in gyms and health clubs is nowadays a challenge that requires concrete and personalized actions. Traditional data mining studies focused essentially on predictive analytics, neglecting the business domain. This work presents an actionable knowledge discovery system which uses the following pipeline (data collection, predictive model, loyalty actions). In the first step, it extracts and transforms existing real data from databases of the sports facilities. In a second step, predictive models are applied to identify user profiles more susceptible to dropout. Actionable rules are generated based on actionable attributes that should be avoided, in order to increase retention. Finally, in the third step, based on the previous actionable knowledge, experimental planning is carried out, with test and control groups, in order to find the best loyalty actions for customer retention. This document presents a simulation and the measure of the business utility of an actions sequence to avoid dropout.info:eu-repo/semantics/publishedVersio

Co-infections and multiple stressors in fish

Fish are typically exposed to multiple physical, chemical and biological stressors. The cumulative impact of co-infections between parasites, bacteria, viruses and (a)biotic environmental pressures may trigger complex interactions, eliciting different pathological and immunological outcomes than those classically assessed. New cross-disciplinary studies attempt to measure the impact of environmental stressors in modulating the host response to pathogens. Scientific advances are needed to reduce pressure on natural populations, improve fish stock management, and to design more efficient diagnostic tools or vaccination strategies. An EAFP-promoted workshop, held on 10th September 2019 in Porto, Portugal, was dedicated to sharing research experiences on the interaction between heterogenous pathogens and multiple stressors in fish. The workshop involved around 200 attendants, opened by a keynote talk (Fast), and followed by a further twelve oral presentations, including three in the format of lash poster presentations. Contributions illustrated cross-disciplinary approaches to study complex host-pathogen and stressors interactions

An actionable knowledge discovery system in regular sports services

This work presents an actionable knowledge discovery system for real user needs with three steps. In the first step, it extracts and transforms existing data in the databases of the ERP and CRM systems of the sports facilities and loads them into a Data Warehouse. In a second phase, predictive models are applied to identify profiles more susceptible to abandonment. Finally, in the third phase, based on the previous models, experimental planning is carried out, with test and control groups, in order to find concrete actions for customer retention.info:eu-repo/semantics/publishedVersio

New Insight on the Bioactivity of Solanum aethiopicum Linn. Growing in Basilicata Region (Italy): Phytochemical Characterization, Liposomal Incorporation, and Antioxidant Effects

Food extract’s biological effect and its improvement using nanotechnologies is one of the challenges of the last and the future decades; for this reason, the antioxidant effect of scarlet eggplant extract liposomal incorporation was investigated. Scarlet eggplant (Solanum aethiopicum L.) is a member of the Solanaceae family, and it is one of the most consumed vegetables in tropical Africa and south of Italy. This study investigated the antioxidant activity and the phytochemical composition of S. aethiopicum grown in the Basilicata Region for the first time. The whole fruit, peel, and pulp were subjected to ethanolic exhaustive maceration extraction, and all extracts were investigated. The HPLC-DAD analysis revealed the presence of ten phenolic compounds, including hydroxycinnamic acids, flavanones, flavanols, and four carotenoids (one xanthophyll and three carotenes). The peel extract was the most promising, active, and the richest in specialized metabolites; hence, it was tested on HepG2 cell lines and incorporated into liposomes. The nanoincorporation enhanced the peel extract’s antioxidant activity, resulting in a reduction of the concentration used. Furthermore, the extract improved the expression of endogenous antioxidants, such as ABCG2, CAT, and NQO1, presumably through the Nrf2 pathway

Misure di radioattività naturale nel sito preistorico di Grotta dei Cervi in Porto Badisco (LE)

Nel presente lavoro sono riportati I risultati di una campagna di misure finalizzata alle determinazione della concentrazione di radon all’interno di Grotta dei Cervi di Porto Badisco (LE). Grotta dei Cervi è una cavità carsica caratterizzata da un complesso pittorico neolitico imponente

Determination of Unbound Partition Coefficient and in Vitro-in Vivo Extrapolation for SLC13A Transporter-Mediated Uptake.

ABSTRACT Unbound partition coefficient (K puu ) is important to an understanding of the asymmetric free drug distribution of a compound between cells and medium in vitro, as well as between tissue and plasma in vivo, especially for transporter-mediated processes. K puu was determined for a set of compounds from the SLC13A family that are inhibitors and substrates of transporters in hepatocytes and transportertransfected cell lines. Enantioselectivity was observed, with (R)-enantiomers achieving much higher K puu (>4) than the (S)-enantiomers (<1) in human hepatocytes and SLC13A5-transfected human embryonic 293 cells. The intracellular free drug concentration correlated directly with in vitro pharmacological activity rather than the nominal concentration in the assay because of the high K puu mediated by SLC13A5 transporter uptake. Delivery of the diacid PF-06649298 directly or via hydrolysis of the ethyl ester prodrug PF-06757303 resulted in quite different K puu values in human hepatocytes (K puu of 3 for diacid versus 59 for prodrug), which was successfully modeled on the basis of passive diffusion, active uptake, and conversion rate from ester to diacid using a compartmental model. K puu values changed with drug concentrations; lower values were observed at higher concentrations possibly owing to a saturation of transporters. Michaelis-Menten constant (K m ) of SLC13A5 was estimated to be 24 mM for PF-06649298 in human hepatocytes. In vitro K puu obtained from rat suspension hepatocytes supplemented with 4% fatty acid free bovine serum albumin showed good correlation with in vivo K puu of liver-to-plasma, illustrating the potential of this approach to predict in vivo K puu from in vitro systems

KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth

The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis1,2. Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production2. The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRASmut cell lines display decreased glutaminolysis, lower NADPH/NADP+ and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRASWT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRASmut PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRASmut rewired glutamine metabolism2, and thus it should be considered a key metabolic target for the treatment of this refractory tumour

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery