Immune by Heart: Unexpected Observations Inspiring Perspective Therapeutic/Preventive Strategies against Cancer

We often overlook ordinary events that take place right in front of our eyes. However, such events might be inspiring sources of revolutionary scientific discovery. Simple observations, such as those regarding the substantial immunity of the heart to cancer or the noninvasive behavior of plant tumors, are just the tips of icebergs hiding profound mechanistic causes that deserve deeper investigation. Several current or unprecedented approaches aimed at improving both the prevention and treatment of tumors are discussed on these bases herein. This viewpoint is not intended to give definitive answers, but rather to provide cues for discussion and motivation to pursue unexplored and accessible strategies to fight cancer

Rocking of freestanding objects: theoretical and experimental comparisons

The methodical study of safeguard of artistic heritage and other devices subjected to earthquake and, in general, to time-dependent forces has considerably spreaded in the last years, thus increasing researchers' interest in problems concerning motions of rigid objects simply supported on a base plane. The behaviour of piece of equipments, statues, storage tanks, or even tall buildings has been in fact studied as that of rigid bodies with relation to different base excitations. In some cases, the possibility of influencing the quality of motion can be a strong tool to reduce vulnerability, like in the cases in which rocking motion is to be avoided and sliding motion is welcome. This paper focuses the attention on this last problem. This is the same large class of both non-structural and structural elements that can lose their functionality because of earthquake motions. The results of numerical modelling of sliding and rocking motion in presence of both different excitations and mechanical parameters are presented and compared with experimental data performed by the authors. The results developed are in good agreement with the laboratory tests, and this assures the reliability of both the analytical procedure and the determination of the parameters involved

Tackling tumors by exploiting their glucose avidity and high rate of glycolysis

Most cancers of various tissue origin show large portions suffering from permanent or transient hypoxia, which takes place during tumor development. This situation leads to an increase of the glycolytic metabolism leading to the production of lactate, which provides cancer cells with adequate amounts of energy. In order to do so, cancer cells often display an overexpression of glucose transporters (GLUTs), in particular of GLUT1, which results in an augmented glucose uptake. This is due to the fact that neoplastic cells need enhanced glucose supply to support their less efficient energy production by means of anaerobic glycolysis (Warburg effect). This peculiar metabolic switch can be effectively utilized for both diagnostic and therapeutic purposes. As a matter of fact, a widely diffused clinical application that exploits the increased uptake of glucose into cancerous over normal tissues consists in the administration of the radiolabeled glucose analogue 18F-FDG as an ubiquitous imaging tool for cancer diagnosis. Furthermore, therapeutic interventions aimed at reducing cancer glycolysis may be implemented by several strategies, such as, for example: 1) reduction of glucose uptake (calorie-restricted ketogenic diet, physical exercise, inhibitors of glucose transporters); 2) inhibition of enzymes involved in key-steps of glycolysis (hexokinase, phosphofructokinase, lactate dehydrogenase); 3) block of the cellular trafficking of lactate (monocarboxylate transporters); 4) enhancement of the mitochondrial oxidative metabolism (hyperbaric oxygen therapy, removal of inhibition of the Krebs cycle). We have developed various classes of compounds that produce an anti-proliferative effect in cancer cells by specific interventions on cancer metabolism. For examples, some compounds proved to be able to inhibit lactate dehydrogenase (LDH) activity, or to reduce glucose uptake through GLUTs. Furthermore, some of these compounds demonstrated a remarkable synergism with other antineoplastic agents with different mechanisms of action

By Degrees

By Degrees, a play in three acts that depicts a woman who slowly learns her life lessons over three time periods: the 1850s, the 1950s, and the 1610s. Although each era presents very different expectations for women, the character\u27s journey toward independence occurs despite the limitations of the time period. The character becomes more conscious of her choices; each time she becomes slightly more aware of her power to choose, her limitations become freedoms, responsibilities become pleasure, discontent becomes fulfillment. As she progresses through the different time periods, she changes from Susannah to Suzanne to Lady Susan, and experiences different kinds of relationships, both romantic and maternal, to eventually discover that she has found serenity in love, in motherhood, and especially in herself. She learns of her own capabilities by degrees ; in each act she becomes increasingly cognizant of her choices; consequently, in her last lifetime, she chooses what is most appropriate for herself and becomes more content with her surroundings and circumstances. In structure and style, each of the three acts of the play works toward increasing enlightenment. Drawing from literature of the 19 century, Act I weaves together both sentimentalism and naturalism. Act I chronicles the life of a commonplace housewife of the 1850s who is controlled by her environment. Susannah must sustain her family on a barren island many miles offshore while her husband keeps the lighthouse; her inner anguish over seeking sustenance , both physical and emotional, culminates in desperation and an attempt to exercise her free will. Her environment and her family manage to thwart her feeble attempts at trying to provide herself with a solution for her yearnings. Melodramatic in style, Act I presents us with our heroine at the bottom of the spiral, a place I from where she cannot yet see her way out. Susannah is propelled into Act 11 as Suzanne, a young black student at Ohio State University. To parallel her new surroundings of slightly fewer limitations than Susannah had, the melodrama of Act I leads into modem drama of Act II. Act II\u27s structure specifically mirrors Adrienne Kennedy\u27s play The Ohio State Murders, with the present Suzanne Alexander narrating her experiences of the past. The structure works as a transition phase for our heroine: the inaction of Susannah in Act I moves into the passive action of Act 11. Suzanne of 1950, like Susannah, is still dangerously vulnerable and her decisions reflect this. The tension of Act 11 provides the drama required to force the protagonist to her next phase. Act 111 differs stylistically from the first two acts. Where the first two acts reveal the protagonist as she is caught up in the drama of her own life, Act 111 unveils Lady Susan, a woman in Renaissance England who is resolute in the protection of herself and her daughters. The comedic style reflects a much lighter situation; Lady Susan\u27s emergence as an individual allows for a less conventional, less stringent plot line. Caryl Churchill\u27s plays Top Girls and Cloud Nine have inspired the structure and style of By Degrees; the product reflects character movement over three time periods and three dramatic styles: melodramatic, dramatic, and comedic, respectively

Strategic Choice and Firm Performance during COVID-19

This paper aims to identify successful strategies for private companies to increase liquidity during times of crisis. We define four strategic choices based on an introduction and/or discontinuation of new products or services: cannibalization, retrenchment, expansion, or entrenchment. We use a micro data set from a worldwide survey of 10,349 companies conducted between April and September 2020 by the World Bank. Our results show that for most companies liquidity during COVID-19 decreased or at best stayed the same. Due to the pandemic, firms applied one of the four strategies, with the majority of the firms applying an intrench strategy. The Chi-square test was used to assess which strategy is associated with increased liquidity during the COVID-19 pandemic. Results indicate that liquidity increased or stayed the same for the companies using the expansion strategy, followed by cannibalization, intrench, and retrench strategies. Expansion and cannibalization strategies are both associated with the introduction of new products and/or services, suggesting that innovation is the key to surviving a pandemic crisis

A multi-level methodology for the automated translation of a coreference resolution dataset: an application to the Italian language

In the last decade, the demand for readily accessible corpora has touched all areas of natural language processing, including coreference resolution. However, it is one of the least considered sub-fields in recent developments. Moreover, almost all existing resources are only available for the English language. To overcome this lack, this work proposes a methodology to create a corpus for coreference resolution in Italian exploiting knowledge of annotated resources in other languages. Starting from OntonNotes, the methodology translates and refines English utterances to obtain utterances respecting Italian grammar, dealing with language-specific phenomena and preserving coreference and mentions. A quantitative and qualitative evaluation is performed to assess the well-formedness of generated utterances, considering readability, grammaticality, and acceptability indexes. The results have confirmed the effectiveness of the methodology in generating a good dataset for coreference resolution starting from an existing one. The goodness of the dataset is also assessed by training a coreference resolution model based on BERT language model, achieving the promising results. Even if the methodology has been tailored for English and Italian languages, it has a general basis easily extendable to other languages, adapting a small number of language-dependent rules to generalize most of the linguistic phenomena of the language under examination

Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53 independent pathways

Most cancer cells use aerobic glycolysis to fuel their growth. The enzyme lactate dehydrogenase-A (LDH-A) is key to cancer’s glycolytic phenotype, catalysing the regeneration of nicotinamide adenine dinucleotide (NAD þ ) from reduced nicotinamide adenine dinucleotide (NADH) necessary to sustain glycolysis. As such, LDH-A is a promising target for anticancer therapy. Here we ask if the tumour suppressor p53, a major regulator of cellular metabolism, influences the response of cancer cells to LDH-A suppression. LDH-A knockdown by RNA interference (RNAi) induced cancer cell death in p53 wild-type, mutant and p53-null human cancer cell lines, indicating that endogenous LDH-A promotes cancer cell survival irrespective of cancer cell p53 status. Unexpectedly,however,weuncoveredanovelroleforp53intheregulationofcancercellNADþ anditsreducedformNADH.Thus, LDH-A silencing by RNAi, or its inhibition using a small-molecule inhibitor, resulted in a p53-dependent increase in the cancer cell ratioofNADH:NADþ.Thiseffectwasspecificforp53þ/þ cancercellsandcorrelatedwith(i)reducedactivityofNADþ-dependent deacetylase sirtuin 1 (SIRT1) and (ii) an increase in acetylated p53, a known target of SIRT1 deacetylation activity. In addition, activation of the redox-sensitive anticancer drug EO9 was enhanced selectively in p53 þ / þ cancer cells, attributable to increased activity of NAD(P)H-dependent oxidoreductase NQO1 (NAD(P)H quinone oxidoreductase 1). Suppressing LDH-A increased EO9-inducedDNAdamageinp53þ/þ cancercells,butimportantlyhadnoadditiveeffectinnon-cancercells.Ourresultsidentifya unique strategy by which the NADH/NADþ cellular redox status can be modulated in a cancer-specific, p53-dependent manner and we show that this can impact upon the activity of important NAD(H)-dependent enzymes. To summarise, this work indicates two distinct mechanisms by which suppressing LDH-A could potentially be used to kill cancer cells selectively, (i) through induction of apoptosis, irrespective of cancer cell p53 status and (ii) as a part of a combinatorial approach with redox-sensitive anticancer drugs via a novel p53/NAD(H)-dependent mechanism

ESA, iron therapy and new drugs: Are there new perspectives in the treatment of anaemia?

Anemia is a well-known consequence of chronic kidney disease (CKD); it is mainly due to a relative insufficiency of erythropoietin synthesis by the failing kidneys. Over the years, the combination of erythropoiesis stimulating agents (ESA) and iron has become the standard of care of anemia. All ESAs effectively increase hemoglobin (Hb) levels in a substantial percentage of patients. However, in the last decade, their use has been surrounded by safety issues in increased cardiovascular risk, especially when used at high doses in inflamed and hyporesponsive patients. This has led to the definition of a more cautious Hb target. Iron deficiency is very frequent in CKD patients, with a higher frequency in non-dialysis patients. Traditionally, iron supplementation is mostly used as supportive therapy for anemia control. However, the concept is growing that intravenous iron therapy per se could be beneficial in the presence of heart failure. A new class of drugs, prolyl hydroxylase domain (PHD) inhibitors (PHD inhibitors) is becoming available for the treatment of anemia in CKD patients. Theoretically, these agents have a number of advantages, the main ones being that of stimulating the synthesis of endogenous erythropoietin and increasing iron avail-ability. The impact of their future use in clinical practice is still to be defined. Another possible strategy could be targeting serum hepcidin and its related pathways. This possibility is fascinating from the scientific point of view, but at present its development phase is still far from clinical application

Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy

Bcr-Abl inhibitors paved the way of targeted therapy epoch. Imatinib was the first tyrosine kinase inhibitor to be discovered with high specificity for Bcr-Abl protein resulting from t(9, 22)-derived Philadelphia chromosome. Although the specific targeting of that oncoprotein, several Bcr-Abl-dependent and Bcr-Abl-independent mechanisms of resistance to imatinib arose after becoming first-line therapy in chronic myelogenous leukemia (CML) treatment. Consequently, new specific drugs, namely dasatinib, nilotinib, bosutinib, and ponatinib, were rationally designed and approved for clinic to override resistances. Imatinib fine mechanisms of action had been elucidated to rationally develop those second- and third-generation inhibitors. Crystallographic and structure-activity relationship analysis, jointly to clinical data, were pivotal to shed light on this topic. More recently, preclinical evidence on bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole derivatives lay promising foundations for better inhibitors to be approved for clinic in the near future. Notably, structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics