The Nitric Oxide Donor [Zn(PipNONO)Cl] Exhibits Antitumor Activity through Inhibition of Epithelial and Endothelial Mesenchymal Transitions

Simple Summary Nitric oxide (NO) plays a critical pathophysiological role in cancer by modulating several processes, such as angiogenesis, tumor growth, and metastatic potential. The aim of this study was to characterize the antitumor effects of a novel NO donor, [Zn(PipNONO)Cl], on the processes of epithelial- and endothelial-mesenchymal transitions (EMT and EndMT), known to actively participate in cancer progression. Two tumor cells lines were used in this study: human lung cancer cells (A549) and melanoma cells (A375), alone and co-cultured with human endothelial cells. Our results demonstrate that both tumor and endothelial cells were targets of NO action, which impaired EMT and EndMT functional and molecular features. Further studies are needed to finalize the therapeutic use of the novel NO donor. Exogenous nitric oxide appears a promising therapeutic approach to control cancer progression. Previously, a nickel-based nonoate, [Ni(SalPipNONO)], inhibited lung cancer cells, along with impairment of angiogenesis. The Zn(II) containing derivatives [Zn(PipNONO)Cl] exhibited a protective effect on vascular endothelium. Here, we have evaluated the antitumor properties of [Zn(PipNONO)Cl] in human lung cancer (A549) and melanoma (A375) cells. Metastasis initiates with the epithelial-mesenchymal transition (EMT) process, consisting of the acquisition of invasive and migratory properties by tumor cells. At not cytotoxic levels, the nonoate significantly impaired A549 and A375 EMT induced by transforming growth factor-beta 1 (TGF-beta 1). Reduction of the mesenchymal marker vimentin, upregulated by TGF-beta 1, and restoration of the epithelial marker E-cadherin, reduced by TGF-beta 1, were detected in both tumor cell lines in the presence of Zn-nonoate. Further, the endothelial-mesenchymal transition achieved in a tumor-endothelial cell co-culture was assessed. Endothelial cells co-cultured with A549 or A375 acquired a mesenchymal phenotype with increased vimentin, alpha smooth muscle actin and Smad2/3, and reduced VE-cadherin. The presence of [Zn(PipNONO)Cl] maintained a typical endothelial phenotype. In conclusion, [Zn(PipNONO)Cl] appears a promising therapeutic tool to control tumor growth and metastasis, by acting on both tumor and endothelial cells, reprogramming the cells toward their physiologic phenotypes

Scoping Review on Platelets and Tumor Angiogenesis: Do We Need More Evidence or Better Analysis?

Platelets are an active component of the tumor microenvironment (TME), involved in the regulation of multiple tumor processes, including angiogenesis. They are generated rich in angiogenic factors in their granules to actively participate in the hemostatic process by megakaryocytes and further enriched in angiogenic factors by all components of the tumor microenvironment to control the angiogenic process because of their preferential relationship with the endothelial component of vessels. In recent decades, the literature has reported a great deal of evidence on the role of platelets in tumor angiogenesis; however, it is unclear whether the number or mean volume of platelets and/or their content and localization in TME may have clinical relevance in the choice and management of therapy for the cancer patient. In this scoping review, we collected and critically reviewed the scientific evidence supporting a close relationship between platelets, cancer, and angiogenesis. The aim of this work was to define the landscape of platelet-activated angiogenesis in cancer progression and analyze what and how much evidence is present in the last 20 years in the literature at both the preclinical and clinical levels, to answer whether platelets could be a useful determinant for analyzing tumor angiogenesis. In conclusion, this scoping review indicates that there is much evidence, both preclinical and clinical, but in the preclinical context, studies demonstrate the direct involvement of platelets in tumor angiogenesis; in the clinical context the evidence is indirect, though strong, and the indication of how and to what extent platelet content contributes to tumor angiogenesis is lacking. So, do we need more evidence or better analysis? More molecular and quali-quantitative data is needed to translate the results obtained in preclinical studies into the clinical setting. This information about platelets, if correlated with tumor type and its biology, including tumor vasculature, type of angiogenesis, and patient characteristics (age, sex, comorbidities, drug treatments for chronic diseases) could be an important pa- rameter for correlating platelet biology to angiogenesis, for personalizing cancer therapy, and for clinical prognosis

Imprese, i motori del cambiamento della società. Gucci e il primo Circular Hub in Toscana.

Il concetto di impresa nel corso degli anni ha assunto diverse accezioni. In passato lo scopo principale era prendere le materie prime come input, trasformarle e restituire prodotti finiti come output, oggi, ha anche una funzione sociale oltre che prettamente economica. Se un tempo si poteva affermare che lo scopo dell’azienda era quello di ottenere un profitto, oggi e soprattutto a seguito alla globalizzazione, non si può pensare alla stessa definizione, occorre individuare il ruolo che l’azienda ricopre all’interno della società globalizzata dove impresa significa anche avere delle responsabilità nei confronti di tutta la società, dipendenti, clienti, fornitori, azionisti e molto altro. Il concetto di sostenibilità e soprattutto di corporate sustainability nel corso del tempo si è evoluto e questo orientamento tende ad essere considerato con frequenza crescente, una risorsa strategica che può essere utilizzata anche per contribuire al miglioramento delle proprie performance economico-finanziarie. Per Responsabilità Sociale delle Imprese (e delle organizzazioni) o secondo l'acronimo inglese CSR, Corporate Social Responsibility, si intende l’inserimento di problematiche di natura sociale ed ecologica nelle operazioni commerciali delle imprese, più precisamente, è l'insieme di politiche, comportamenti e attività responsabili che un'impresa o altro soggetto business adotta, nelle proprie operazioni, su base volontaria, delle preoccupazioni sociali e ambientali. Essere socialmente responsabili significa non solo soddisfare pienamente gli obblighi giuridici applicabili, ma anche andare al di là investendo di più nel capitale umano, nell'ambiente e nei rapporti con le altre parti interessate. Il tradizionale concetto etico di Corporate Social Responsability (CSR), nel tempo, è transitato verso condotte e scelte d’impresa orientate ai fattori ESG (Sustainability, Environmental, Social and Governance) guidate da un legame tra sostenibilità e “profittabilità” dell’impresa. Questo acronimo viene utilizzato per comunicare a soggetti terzi l’impegno dell’azienda circa la sostenibilità e fa riferimento a un modello di business che unisce: pratiche politiche, comportamenti, interventi e massimizzazione dei profitti, attraverso azioni che rispettano le esigenze ambientali e sociali. A differenza della Responsabilità sociale d'impresa che non ha a disposizione dati solidi e misurabili, la ESG si basa su dati obiettivi e misurabili e attraverso di essi, è possibile valutare e confrontare le organizzazioni attraverso le performance ESG e inoltre, vengono utilizzati nelle decisioni di investimento e di allocazione del capitale. Gli ESG consentono di misurare la sostenibilità e quindi i progressi ottenuti nel tempo di un’azienda e sono collegati strettamente al modello CSR perché permettono di valutare i risultati e successi raggiunti dalle imprese che utilizzano questo modello di business. All’interno di un contesto che offre innumerevoli opportunità di innovazione e apprendimento, caratterizzato da profondi cambiamenti soprattutto negli ultimi anni, l’economia e la società hanno dovuto fare il conto con cambiamenti ecologici, tecnologici, politici e sociali. Individui e famiglie si sono sottoposti ad una pressante sfida su come adattarsi e sopravvivere, a causa dall’evoluzione dei presupposti del buon funzionamento dell’amministrazione. Se inizialmente la valutazione delle performance si basava sui compiti di organizzazione e controllo, ora comprende anche funzioni di individuazioni di strategie volte a migliorare il contesto e la cultura. Come espresso dalla prof.ssa Kranter (2009) i vecchi modelli di filantropia e CSR non sono più efficaci perché non hanno incentivi sufficientemente interessanti per le aziende. La logica del solo volontariato, per esempio, non è più sufficiente. È necessario individuare un modo nuovo per coinvolgere le imprese a collaborare con le istituzioni e con le non profit e trovare uno spazio proattivo all’interno delle comunità locali nelle quali agiscono con il loro business. Proprio per questo, è stato necessario passare dalla corporate social responsibility alla corporate social innovation, adottando un cambio di prospettiva, dove l’obiettivo principale diventa la creazione del valore sociale condiviso in modo da generare un impatto positivo sull’ambiente e sulla società in cui viviamo. L’innovazione sociale o in inglese social innovation, non rappresenta più solo una tendenza culturale ma la risposta alla crescente urgenza di offrire risposte di rinnovata efficacia a importanti bisogni sociali. Con innovazione sociale si intendono tutti i miglioramenti e innovazioni che rispondono alla necessità della collettività fornendo nuove idee utili a risolvere problemi sociali

Characterization of the Safety Profile of Sweet Chestnut Wood Distillate Employed in Agriculture

In organic agriculture, synthetic pesticides and treatments are substituted by natural remedies with interesting success for product yield and environmental outcomes, but the safety of these bio-based products needs to be assessed in vertebrate and human models. Therefore, in this paper we assessed the safety profile of sweet chestnut (Castanea sativa) wood distillate (WD) on the different cellular components of tissues implied in transcutaneous absorption. We investigated the viability of different cell lines mimicking the skin (HaCaT keratinocytes), mucosa (A431), connective (normal human dermal fibroblasts, NHDF) and vascular (human umbilical vein endothelial cells, HUVEC) tissues after exposure to increasing concentrations (0.04–0.5%, v/v, corresponding to 1:2800–1:200 dilutions) of WD. A short exposure to increasing doses of WD was well tolerated up to the highest concentration. Instead, following a prolonged treatment, a concentration dependent cytotoxic effect was observed. Notably, a different behavior was found with the various cell lines, with higher sensitivity to cytotoxicity by the cells with higher proliferation rate and reduced doubling time (human keratinocytes). Moreover, to exclude an inflammatory effect at the not cytotoxic WD concentrations, the expression of the main inducible markers of inflammation, cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), were assessed, and no improvement was found both after brief and prolonged exposure. In conclusion, our data exclude any inflammatory and cytotoxic effect at the lowest WD concentrations, namely 0.07% and 0.04%, mimicking some recommended dilutions of the product and the potential exposure doses for the operators in agriculture. Nevertheless, higher concentrations showed a safe profile for short time usage, but caution should be used by farmers following persistent product exposure

Characterization of the Safety Profile of Sweet Chestnut Wood Distillate Employed in Agriculture

In organic agriculture, synthetic pesticides and treatments are substituted by natural remedies with interesting success for product yield and environmental outcomes, but the safety of these bio-based products needs to be assessed in vertebrate and human models. Therefore, in this paper we assessed the safety profile of sweet chestnut (Castanea sativa) wood distillate (WD) on the different cellular components of tissues implied in transcutaneous absorption. We investigated the viability of different cell lines mimicking the skin (HaCaT keratinocytes), mucosa (A431), connective (normal human dermal fibroblasts, NHDF) and vascular (human umbilical vein endothelial cells, HUVEC) tissues after exposure to increasing concentrations (0.04–0.5%, v/v, corresponding to 1:2800–1:200 dilutions) of WD. A short exposure to increasing doses of WD was well tolerated up to the highest concentration. Instead, following a prolonged treatment, a concentration dependent cytotoxic effect was observed. Notably, a different behavior was found with the various cell lines, with higher sensitivity to cytotoxicity by the cells with higher proliferation rate and reduced doubling time (human keratinocytes). Moreover, to exclude an inflammatory effect at the not cytotoxic WD concentrations, the expression of the main inducible markers of inflammation, cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), were assessed, and no improvement was found both after brief and prolonged exposure. In conclusion, our data exclude any inflammatory and cytotoxic effect at the lowest WD concentrations, namely 0.07% and 0.04%, mimicking some recommended dilutions of the product and the potential exposure doses for the operators in agriculture. Nevertheless, higher concentrations showed a safe profile for short time usage, but caution should be used by farmers following persistent product exposure

State-of-the-Art in Antiangiogenic Agents in Cancer Therapy

Anti-angiogenesis is the therapeutic strategy designed to disrupt the vascular supply and starve tumors of nutrients and oxygen. This is achieved mainly by blocking the vascular endothelial growth factor (VEGF) actions, as the VEGF signaling pathway is considered the main angiogenesis promoter and is active in the tumor microenvironment (TME) under hypoxic conditions. A total of 16 anti-angiogenic agents, including anti-VEGF antibodies, anti-VEGF receptor (VEGFR) antibodies, as well as VEGFR tyrosine kinase inhibitors (TKIs), have been approved for certain types of cancer. However, despite the mechanistic rationale that strongly supports the benefit of antiangiogenics to stop cancer progression, both in monotherapy or in combination with chemotherapy or targeted therapies, the antiangiogenics demonstrated limited clinical benefits for most patients with cancer. A recent hypothesis is that the "normalization" of the entire TME through a combination of antiangiogenics with immune therapies and/or inhibitors of tumor-associated stromal cells could present a potential synergistic anti-tumor effect. The TME imprinting converges in epigenetic modifications in endothelial cells that switch to tumor pro-angiogenic endothelial cells and continue to support the aggressiveness of tumor cells, including resistance to antiangiogenic therapies. The present review summarizes the current status of antiangiogenic strategies, the molecular mechanisms underlying their failure, and we discuss some alternative mechanisms targeting angiogenesis

Molecular mechanisms of resistance to anti-angiogenic drugs

The problem of drug resistance in cancer patients has been well in mind from the beginning of modern medicine and oncology treatments with the so called conventional cytotoxic therapy. With the advent of target therapy against tumor angiogenesis and in particular against the vascular endothelial growth factor (VEGF)/VEGF receptor system, researchers thought that resistance could be no more a problem, since the low pattern of proliferation displayed by endothelial cells. However, beside the efficacy demonstrated by antiangiogenic drugs, resistance during prolonged drug treatments appears as a limiting feature. Nowadays, various mechanisms of resistance to antiangiogenic therapeutics have been discovered, either innate and depending on the host, or acquired by the tumor cells, especially as a consequence of induced hypoxia by antiangiogenic drugs and the redundancy of proangiogenic factors in the tumor microenvironment, and other forms of tumor neovascularization, than sprouting angiogenesis. Here, we have reviewed the preclinical and clinical evidence for mechanisms of resistance to antiangiogenic drugs reported so far. The knowledge of the mechanisms underneath antiangiogenic drug resistance could be of help in the choice of the more appropriate drug, the development of novel therapeutic strategies, the design of proper drug combination protocols or new formulations of antiangiogenic strategies

Pharmacological Inhibition of CA-IX Impairs Tumor Cell Proliferation, Migration and Invasiveness

Carbonic anhydrase IX (CA-IX) plays a pivotal role in regulation of pH in tumor milieu catalyzing carbonic acid formation by hydrating CO2. An acidification of tumor microenvironment contributes to tumor progression via multiple processes, including reduced cell-cell adhesion, increased migration and matrix invasion. We aimed to assess whether the pharmacological inhibition of CA-IX could impair tumor cell proliferation and invasion. Tumor epithelial cells from breast (MDA-MB-231) and lung (A549) cancer were used to evaluate the cytotoxic eect of sulfonamide CA-IX inhibitors. Two CA-IX enzyme blockers were tested, SLC-0111 (at present in phase Ib clinical trial) and AA-06-05. In these cells, the drugs inhibited cell proliferation, migration and invasion through shifting of the mesenchymal phenotype toward an epithelial one and by impairing matrix metalloprotease-2 (MMP-2) activity. The antitumor activity was elicited via apoptosis pathway activation. An upregulation of p53 was observed, which in turn regulated the activation of caspase-3. Inhibition of proteolytic activity was accompanied by upregulation of the endogenous tissue inhibitor TIMP-2. Collectively, these data confirm the potential use of CA-IX inhibitors, and in particular SLC-0111 and AA-06-05, as agents to be further developed, alone or in combination with other conventional anticancer drugs

Chapter 2. Antiangiogenic drugs: Chemosensitizers for combination cancer therapy

Angiogenesis is a key step in tumor progression and recurrence, and is known as a hallmark of solid tumors. The architecture of the tumor vasculature is deregulated, vessels are immature, and their functionality is defective, causing increase of interstitial pressure, hypoxia and acidity in the tumor microenvironment, and favouring an enhanced tumor dissemination and metastasis. The defective tumor vasculature as well as the modifications of tumor microenvironment are a barrier for the effective delivery and accumulation of either the anti-cancer drugs, including anti-angiogenic drugs, or immune competent T cells in tumor area, thus promoting tumor resistance to therapy. Among the various approaches for targeting tumor angiogenesis, vascular normalization and vessel maturation are considered the most promising approaches, which favour both an effective delivery of anticancer drugs and accumulation of immune competent T cells into the tumor area. Antiangiogenic therapy can downregulate continuous angiogenic signalling and result in vascular normalization, such as pruning, vascular maturation, and increased perfusion. Thus, antiangiogenic drugs are now considered promising chemosensitizers of anti-cancer strategies such as chemotherapy, target therapies and immune checkpoint inhibitors in several advanced tumors. This review summarizes the current understanding and clinical development of combination therapy with anti-angiogenic drugs and anticancer chemo-, targeted- and immune-therapies

The use of Berlin Heart EXCOR VAD in children less than 10kg: a single center experience

Objective: Despite the improvement in ventricular assist device (VAD) therapy in adults and in adolescents, in infant population only Berlin Heart EXCOR (BHE) is licensed as long term VAD to bridge children to Heart Transplantation (HTx). Particularly demanding in terms of morbidity and mortality are smallest patients namely the ones implanted in the first year of life or with a lower body surface area. This work aims at retrospective reviewing a single centre experience in using BHE in children with a body weight under 10kg. Methods: Data of all pediatric patients under 10kg undergoing BHE implantation in our institution from March 2002 to March 2016 were retrospectively reviewed Results: Of the 30 patients enrolled in the study, 53% were male, 87% were affected by a dilated cardiomyopathy with an average weight and age at the implantation of 6.75±2.16Kg and 11.57±10.12 months, respectively. Three patients (10%) required a BIVAD implantation. After the implantation, 7 patients (23%) required re-intervention for bleeding and 9 patients (30%) experienced BHE cannulas infection. A total of 56 BHE pump were changed for thrombus formation (1.86 BHE pump for patient). The average duration of VAD support was 132.8±94.4 days. Twenty patients (67%) were successfully transplanted and 10 patients (33%) died: 7 for major neurological complication and 3 for sepsis. Conclusion: Mechanical support in smaller children with end stage heart failure is an effective strategy for bridging patients to HTx. The need for BIVAD was relegated, in the last years, only to restrictive cardiomiopathy. Further efforts are required in small infants to improve anticoagulation strategy to reduce neurological events and BHE pump changes