Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

Introduction: Non-small cell lung cancer (NSCLC) is a highly lethal disease. During the past 20 years, the epidermal growth factor receptor (EGFR) has been a relevant target for anticancer drug-design, and a large family of EGFR tyrosine kinase inhibitors (TKI) were designed, which improved therapeutic outcomes compared to conventional chemotherapy in NSCLC patients with specific EGFR mutations. However, resistance to these inhibitors occurs; therefore, the debate on which inhibitor should be used first is still open. Dacomitinib was approved in 2018 for the first-line treatment of NSCLC with EGFR activating mutations. Areas covered: This manuscript reviews the properties of dacomitinib, including the current information from clinical trials and its potential application as stand-alone therapy, or in combination. Expert opinion: Dacomitinib is a second-generation EGFR-TKI that has demonstrated significant improvement in overall survival in a phase III randomized study compared with gefitinib, a first-generation TKI. However, the rapid development and approval of a new generation of TKIs (osimertinib), with better clinical profiles, raises the question of which role can dacomitinib play in NSCLC. Further studies are required to evaluate the efficacy of this drug on brain metastases, as a second-line treatment after third-generation TKIs, or in combination with other types of treatments

Commercial plant-probiotic microorganisms for sustainable organic tomato production systems

Selected plant-probiotic microorganisms, produced by the company CCS Aosta at a commercial scale, are being tested in the Italian Padana plain in open field conditions for their ability to provide adequate crop nutrition and to ensure durable soil fertility for organic tomato production. In this three-years-long project the QLIF-WP333 research team will investigate the potential of soil probiotics management as a tool to improve the quality of tomato fruits and the sustainability of organic tomato production systems

Drug resistance in pancreatic cancer: Impact of altered energy metabolism

Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer

Lactate dehydrogenase A inhibition by small molecular entities: steps in the right direction

Direct targeting of energy metabolism to defeat cancer is not a recent strategy. Although quite a few drugs use cellular metabolism for their antitumor effect, no direct inhibitors of energy metabolism have been approved by the FDA. Currently, several inhibitors of lactate dehydrogenase A (LDH-A), a key player in glycolysis, are in development. Earlier, we demonstrated the efficacy of N-hydroxyindole-based LDH-A inhibitors in different cancer types. In this study we describe the efficacy of NHI-Glc-2, which is designed to dual target cancer cells, by exploiting a simultaneous enhanced glucose uptake by overexpressed glucose transporter 1 (GLUT1) and by inhibition of LDH-A. NHI-Glc-2 inhibits LDH-A enzyme activity, PANC-1 cell growth and disrupts spheroid integrity, with an overall effect that is more pronounced when combined with gemcitabine

L'accertamento della responsabilita' dell'ente

A quindici anni dall’entrata in vigore della normativa sulla responsabilità amministrativa delle persone giuridiche, introdotta nel nostro ordinamento con il D.lgs. 231/2001, dottrina e giurisprudenza sono ormai consapevoli del fatto che tale materia si basa su categorie e concetti che necessitano di una rielaborazione in funzione del peculiare destinatario cui si rivolgono. L’elaborato si propone quindi di evidenziare quelli che sono i punti salienti riguardanti l’accertamento giurisdizionale di tale responsabilità, prendendo anzitutto le mosse da un quadro generale della disciplina, concentrandosi poi sull’analisi del fondamentale ruolo svolto dal Modello di organizzazione, gestione e controllo nella creazione di un sistema di tipo preventivo. Infine verranno evidenziate le problematiche relative al thema probandum, con particolare attenzione alla compatibilità della normativa “231” con i principi costituzionali. Gli approfondimenti presentati, oltre ad avere un taglio pratico, saranno sempre accompagnati da un’analisi di quelle che sono le pronunce della giurisprudenza, consentendo di verificare se teoria e prassi camminano sullo stesso sentiero

The role of Eph receptors in cancer and how to target them: novel approaches in cancer treatment.

Introduction: Erythropoietin-producing human hepatocellular (Eph) receptors are among the largest family of tyrosine kinases that are divided into two classes: EphA and EphB receptors. Over the past two decades, their role in cancer has become more evident. Areas covered: There is a need for new anticancer treatments and more insight in the emerging role of Eph receptors in cancer. Molecular mechanisms underlying the pro-tumorigenic effects of Eph receptors could be exploited for future therapeutic strategies. This review describes the variability in expression levels and different effects on oncogenic and tumor suppressive downstream signaling of Eph receptors in various cancer types, and the small molecules, antibodies and peptides that target these receptors. Expert opinion: The complexity of Eph signaling is a challenge for the definition of clear targets for cancer treatment. Nevertheless, numerous drugs that target EphA2 and EphB4 are currently in clinical trials. However, some Eph targeted drugs also inhibit other tyrosine kinases, so it is unclear to what extent the targeting of Eph receptors contributes to their efficacy. Future research is warranted for an improved understanding of the full network in which Eph receptors function. This will be critical for the improvement of the anticancer effects of drugs that target the Eph receptors

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers.

AbstractCancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of severa..

Sub-Saharan Africa in global trends of investment in renewable energy. Drivers and the challenge of the water-energy-land nexus

This paper explores recent patterns of domestic and foreign investments in renewable energies. It describes drivers and features of investment in renewable energies, with special attention to biofuels, highlighting that these forms of energy are likely to contribute to competition for land and water as the latter become increasingly scarce

On the pharmacogenetics of non-small cell lung cancer treatment

Abstract: Introduction. Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches