iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

: Induced pluripotent stem cells (iPSCs), obtained by reprogramming different somatic cell types, represent a promising tool for the study of drug toxicities, especially in the context of personalized medicine. Indeed, these cells retain the same genetic heritage of the donor, allowing the development of personalized models. In addition, they represent a useful tool for the study of adverse drug reactions (ADRs) in special populations, such as pediatric patients, which are often poorly represented in clinical trials due to ethical issues. Particularly, iPSCs can be differentiated into any tissue of the human body, following several protocols which use different stimuli to induce specific differentiation processes. Differentiated cells also maintain the genetic heritage of the donor, and therefore are suitable for personalized pharmacological studies; moreover, iPSC-derived differentiated cells are a valuable tool for the investigation of the mechanisms underlying the physiological differentiation processes. iPSCs-derived organoids represent another important tool for the study of ADRs. Precisely, organoids are in vitro 3D models which better represent the native organ, both from a structural and a functional point of view. Moreover, in the same way as iPSC-derived 2D models, iPSC-derived organoids are appropriate personalized models since they retain the genetic heritage of the donor. In comparison to other in vitro models, iPSC-derived organoids present advantages in terms of versatility, patient-specificity, and ethical issues. This review aims to provide an updated report of the employment of iPSCs, and 2D and 3D models derived from these, for the study of ADRs. This article is categorized under: Cancer > Stem Cells and Development

Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial

Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11

Uncontrolled headache induced by oxcarbazepine

Headache induced by acute exposure to a specific drug constitutes an idiosyncratic side effect. Metabolic imbalance appears as the leading aetiology, among several other hypotheses. Either primary headaches show a higher susceptibility to this idiosyncratic reaction or a drug-induced primary headache evolves in intensity and duration, becoming uncontrolled until the complete discontinuation of the drug in consideration. The goal of this study is to describe three patients diagnosed with migraine and epilepsy (both under control) who evolved into status migrainosus after the introduction of oxcarbazepine (OXC), as part of a switch off from carbamazepine (CBZ). Twenty-four to seventy-two hours following the switch, all patients developed intractable headache, despite the use of different symptomatic drugs. Complete recovery of the headache symptoms occurred only after OXC was discontinued. We discuss the potential mechanisms associated to OXC and status migrainosus, drug-induced headaches and uncontrolled headaches

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version

2-Aminotetraline derivative protects from ischemia/reperfusion brain injury with a broad therapeutic window

The effect of ST1942, a 2-aminotetraline derivative with anti-inflammatory properties, was evaluated in ischemia/reperfusion injury in CD1 and C57BL/6 mice. ST1942 or saline were injected intraperitoneally 30 min and 6, 24, 36 h after ischemia. Forty-eight hours after ischemia, ST1942 (25 mg/kg) reduced the infarct volume by 50% in CD1 and 61% in C57BL/6 mice. All subsequent data were obtained from the latter strain. The ischemic lesion was significantly reduced by 30% when the first injection was administered 6 h after ischemia, revealing a broad effective window. Degenerating neurons in striatum, cortex and hippocampus of ischemic mice were markedly decreased by ST1942. Also examined was the effect of ST1942 on general and focal neurological deficits for 4 days after ischemia. Mice receiving the drug twice daily showed constantly reduced deficits. We then investigated the cortical mRNA expression of some inflammatory and apoptotic genes by real-time PCR. Forty-eight hours after ischemia ST1942 treatment significantly counteracted ischemia-induced activation of IL-1β, TNFα, and Bax, and enhanced the expression of the antiapoptotic gene, Bcl-2, showing in vivo anti-inflammatory and antiapoptotic actions. The microglial activation/macrophage recruitment in the ischemic lesion was strongly prevented in mice receiving ST1942. In neuron-microglia cocultures, ST1942 significantly counteracted LPS-induced cytotoxicity. Binding data and experiments on microglial cell cultures indicate that the anti-inflammatory effect of ST1942 may be due to its action on 5-HT2B receptors, thus highlighting the possibility that this 5-HT receptor subtype may represent a novel target for neuroprotective drugs in ischemic injury. © 2007 Nature Publishing Group All rights reserved

A Multidisciplinary Study of Wild Grapevines in the River Crati Natural Reserve, South Italy (Calabria): Implications in Conservation Biology and Palaeoecological Reconstructions

Nowadays, wild grapevine populations are quite limited and sporadic mainly due to habitat destruction, land-use change, and the spread of pathogens that have reduced their distribution range. Palaeoecological, archaeobotanical, and genetic studies indicate that modern cultivars of Vitis vinifera are the results of the domestication of the dioecious, and sometimes hermaphrodite, wild species standing in riparian zones and wet environments. Wild grapevine populations have declined as a consequence of various forms of anthropogenic disturbance and were assigned by the IUCN Red List of Threatened Species to the Least Concern category. The River Crati Natural Reserve (Riserva Naturale Foce del Crati), located in southern Italy, hosts a population of Vitis vinifera subsp. sylvestris in a rewilding wet forest close to the Ionian Sea. These protected areas are of high scientific, biogeographic, and conservation interest in terms of Mediterranean biodiversity. Dendroecological and pollen morpho-biometric analyses of the wild grapevine are presented in this study. Palaeoecological perspectives for a landscape management strategy aimed at conserving and restoring the relic grapevine population are discussed

Pituitary metastases from neuroendocrine neoplasms: case report and narrative review

Pituitary metastases (PM) are uncommon findings and are mainly derived from breast and lung cancers. No extensive review of PM from neuroendocrine neoplasms (NENs) is on record. Here we describe a clinical case of PM from pancreatic NEN and review the clinical features of PM from NENs reported in the literature

Plasma and urinary metabolomic profiles of Down syndrome correlate with alteration of mitochondrial metabolism

Down syndrome (DS) is caused by the presence of a supernumerary copy of the human chromosome 21 (Hsa21) and is the most frequent genetic cause of intellectual disability (ID). Key traits of DS are the distinctive facies and cognitive impairment. We conducted for the first time an analysis of the Nuclear Magnetic Resonance (NMR)-detectable part of the metabolome in plasma and urine samples, studying 67 subjects with DS and 29 normal subjects as controls selected among DS siblings. Multivariate analysis of the NMR metabolomic profiles showed a clear discrimination (up to of 80% accuracy) between the DS and the control groups. The univariate analysis of plasma and urine revealed a significant alteration for some interesting metabolites. Remarkably, most of the altered concentrations were consistent with the 3:2 gene dosage model, suggesting effects caused by the presence of three copies of Hsa21 rather than two: DS/normal ratio in plasma was 1.23 (pyruvate), 1.47 (succinate), 1.39 (fumarate), 1.33 (lactate), 1.4 (formate). Several significantly altered metabolites are produced at the beginning or during the Krebs cycle. Accounting for sex, age and fasting state did not significantly affect the main result of both multivariate and univariate analysis

VENEZIA 2021 : indicatori condivisi per la costruzione del modello e del piano di monitoraggio e intervento : esiti di una ricerca interdisciplinare

La gestione degli interventi di restauro in un contesto complesso quale quello veneziano necessita di metodologie per il monitoraggio dello stato conservativo pre e post intervento che tengano in considerazione l’attuale situazione ambientale e quella che si prevede possa verificarsi in futuro, a seguito dei cambiamenti climatici e dell’entrata in funzione del sistema di dighe mobili “MOSE”. In questo contributo si presentano alcuni tra gli esiti preliminari del Programma di ricerca interdisciplinare “Venezia 2021”, relativi allo sviluppo di una metodologia basata su una serie di indicatori e descrittori atti a valutare la vulnerabilità degli elementi del patrimonio costruito e dunque utili per l’appropriata progettazione dell’intervento conservativo e del suo successivo monitoraggio negli anni

Venezia 2021. Piano di adattamento al cambiamento climatico e implementazione di strategie di intervento per la salvaguardia del patrimonio architettonico e ambientale. Primi esiti di una ricerca interdisciplinare

This research aims to provide a complete vision of the Venetian Lagoon system including both environmental and building aspects, with a specific focus on the interface between the mainland and the wetland of Venice. In particular, in perspective of climate change and MOSE infrastructure working and, consequently, in order to safeguard the city of Venice, all the peculiarities of the historical city, i.e. environment, economy, architecture, and cultural heritage, are being considered. Furthermore, the project will base all the proposals on the same set of data and analysis, designing comparative solutions and possible alternatives regarding the state of the urban environment, landscape, and state of conservation of historical heritage. The multidisciplinary approach, which combines architecture, urban planning, and disciplines applied to cultural heritage -chemistry, applied petrography, conservation science, technical physics, restoration, structural engineering- will set a foundation for an exhaustive vision, providing synergic, cost-effective and legitimized actions