Bayesian Uncertainty Directed Trial Designs

Most Bayesian response-adaptive designs unbalance randomization rates toward the most promising arms with the goal of increasing the number of positive treatment outcomes during the study, even though the primary aim of the trial is different. We discuss Bayesian uncertainty directed designs (BUD), a class of Bayesian designs in which the investigator specifies an information measure tailored to the experiment. All decisions during the trial are selected to optimize the available information at the end of the study. The approach can be applied to several designs, ranging from early stage multi-arm trials to biomarker-driven and multi-endpoint studies. We discuss the asymptotic limit of the patient allocation proportion to treatments, and illustrate the finite-sample operating characteristics of BUD designs through examples, including multi-arm trials, biomarker-stratified trials, and trials with multiple co-primary endpoints. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.The work of SB was partially supported by funding from the Cantab Capital Institute for the Mathematics of Information. LT has been supported by a Burroughs Wellcome Fund Award for Innovation in Regulatory Science and the The Claudia Adams Barr Program in Innovative Basic Cancer Research

Novel antiproliferative biphenyl nicotinamide: NMR metabolomic study of its effect on the MCF-7 cell in comparison with cisplatin and vinblastine

A 1H-NMR-based metabolomic study was performed on MCF-7 cell lines treated with a novel nicotinamide derivative (DT-8) in comparison with two drugs characterized by a well-established mechanism of action, namely the DNA-metalating drug cisplatin (cis-diamminedichloridoplatinum(II), CDDP) and the antimitotic drug vinblastine (vinblastine, VIN). The effects of the three compounds, each one at the concentration corresponding to the IC50 value, were investigated, with respect to the controls (K), by the 1H-NMR of cells lysates and multivariate analysis (MVA) of the spectroscopic data. Relevant differences were found in the metabolic profiles of the different treatments with respect to the controls. A large overlap of the metabolic profiles in DT-8 vs. K and VIN vs. K suggests a similar biological response and mechanism of action, significantly diverse with respect to CDDP. On the other hand, DT8 seems to act by disorganizing the mitotic spindle and ultimately blocking the cell division, through a mechanism implying methionine depletion and/or S-adenosylmethionine (SAM) limitation

Synthesis and Biological Evaluation of Dantrolene-Like Hydrazide and Hydrazone Analogues as Multitarget Agents for Neurodegenerative Diseases

Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAO B over either MAO A or AChE, with the secondary aldimine 9 and phenylhydrazone 20 attaining IC50 values of 0.68 and 0.81 μM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAO B. Finally, further in vitro investigations revealed cell protection from oxidative insult and activation of carnitine/acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series

Annelated medium-sized azaheterocycles as attractive scaffolds for CNS targeted leads.

Medium-sized nitrogen heterocycles (7-to-15-membered) have widespread interest in organic synthesis and medicinal chemistry. Indeed, such heterocyclic rings are found as subunits or core structures in natural and bioactive molecules, including pharmaceutical products, whereas on the other hand they often can serve as key intermediates in the synthesis of bicyclic compounds by selective transformations (e.g., transannular ring-contractions, cycloadditions). These molecular frameworks, particularly annelated 7-to-10-membered aza-heterocycles, have long drawn our attention as potential scaffolds for developing new multitarget- directed ligands (MTDLs) for treating Alzheimer's disease (AD) and other neurodegenerative syndromes.AD, the most common form of dementia affecting people worldwide, is a progressive neurodegenerative disorder, whose multifactorial pathogenesis is still not completely understood. The main histopathological changes include synaptic dysfunction and neuronal loss resulting from intracellular and extracellular fibrillar aggregates of Beta-amyloid (Abeta),hyperphosphorilated and beta-folded tau proteins, cholinergic impairment, oxidative stress, neuroinflammation, metal dys-homeostasis and mitochondrial damage. Among others, N- methyl-D-aspartate receptors (NMDARs) play a major role in learning and memory, and their overactivation causes excessive calcium influx and consequent excitotoxicity, which is associated with CNS diseases, including Parkinson's disease. Starting from our old1,2 and recent 3 findings on the suitability of partially hydrogenated benzo-, chromane-4- one- and indole-fused azepine and azocine derivatives targeted at enzymes, receptors and biochemical pathways involved in the pathogenesis of AD, we extended the investigation to novel derivatives of annelated azonines and azecines. Herein, our recent advances of benzo- and indol-fused 7-to-10-membered nitrogen heterocycles as molecular tools for AD-associated targets (e.g., butyryl- and acetylcholinesterase, monoamine oxidases A and B, Abeta aggregation, ROS insult, NMDAR antagonist), along with the results from investigation on cell and ex vivo/in vivo animal models, will be presented and discussed in an effort of rationalizing structure-activity relationships and progressing drug optimization of the examined CNS-targeted lead compounds

Hydroxy-propil-β-cyclodextrin inclusion complexes of two biphenylnicotinamide derivatives: Formulation and anti-proliferative activity evaluation in pancreatic cancer cell models

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for systemic PDAC treatment by the utilization of two newly synthesized biphenylnicotinamide derivatives, PTA73 and PTA34, with remarkable antitumor activity in an in vitro PDAC model. Given their poor water solubility, inclusion complexes of PTA34 and PTA73 in Hydroxy-Propil-β-Cyclodextrin (HP-β-CD) were prepared in solution and at the solid state. Complexation studies demonstrated that HP-β-CD is able to form stable host–guest inclusion complexes with PTA34 and PTA73, characterized by a 1:1 apparent formation constant of 503.9 M−1 and 369.2 M−1, respectively (also demonstrated by the Job plot), and by an increase in aqueous solubility of about 150 times (from 1.95 µg/mL to 292.5 µg/mL) and 106 times (from 7.16 µg/mL to 762.5 µg/mL), in the presence of 45% w/v of HP-β-CD, respectively. In vitro studies confirmed the high antitumor activity of the complexed PTA34 and PTA73 towards PDAC cells, the strong G2/M phase arrest followed by induction of apoptosis, and thus their eligibility for PDAC therapy

Measurement of the angular correlation between the two gamma rays emitted in the radioactive decays of a 60^{60}Co source with two NaI(Tl) scintillator

We implemented a didactic experiment to study the angular correlation between the two gamma rays emitted in typical $^{60}$Co radioactive decays. We used two NaI(Tl) scintillators, already available in our laboratory, and a low-activity $^{60}$Co source. The detectors were mounted on two rails, with the source at their center. The first rail was fixed, while the second could be rotated around the source. We performed several measurements by changing the angle between the two scintillators in the range from $90^\circ$ to $180^\circ$. Dedicated background runs were also performed, removing the source from the experimental setup. We found that the signal rate increases with the angular separation between the two scintillators, with small discrepancies from the theoretical expectations.Comment: 15 pages, 12 figure

Extraordinary Molecular Evolution in the PRDM9 Fertility Gene

Recent work indicates that allelic incompatibility in the mouse PRDM9 (Meisetz) gene can cause hybrid male sterility, contributing to genetic isolation and potentially speciation. The only phenotype of mouse PRDM9 knockouts is a meiosis I block that causes sterility in both sexes. The PRDM9 gene encodes a protein with histone H3(K4) trimethyltransferase activity, a KRAB domain, and a DNA-binding domain consisting of multiple tandem C2H2 zinc finger (ZF) domains. We have analyzed human coding polymorphism and interspecies evolutionary changes in the PRDM9 gene. The ZF domains of PRDM9 are evolving very rapidly, with compelling evidence of positive selection in primates. Positively selected amino acids are predominantly those known to make nucleotide specific contacts in C2H2 zinc fingers. These results suggest that PRDM9 is subject to recurrent selection to change DNA-binding specificity. The human PRDM9 protein is highly polymorphic in its ZF domains and nearly all polymorphisms affect the same nucleotide contact residues that are subject to positive selection. ZF domain nucleotide sequences are strongly homogenized within species, indicating that interfinger recombination contributes to their evolution. PRDM9 has previously been assumed to be a transcription factor required to induce meiosis specific genes, a role that is inconsistent with its molecular evolution. We suggest instead that PRDM9 is involved in some aspect of centromere segregation conflict and that rapidly evolving centromeric DNA drives changes in PRDM9 DNA-binding domains

The impact of digital technologies on the school-family relationship during distance learning

Nel contesto formativo la tecnologia è percepita sempre di più come un elemento chiave di grande rinnovamento didattico. Per questa ragione il suo utilizzo deve essere versatile e dinamico e adattarsi a diversi fattori quali: il singolo docente, il livello specifico di istruzione, gli elementi caratterizzanti della disciplina, l’età degli studenti, il background culturale delle famiglie e la disponibilità di risorse tecnologiche e finanziarie. Il saggio propone una riflessione sul rapporto scuola-famiglia durante il periodo di didattica a distanza, attraverso l’analisi dei dati emersi da una indagine condotta su un campione di 1326 genitori, per verificare in che modo le tecnologie hanno trovato spazio nelle case, se sono state di aiuto o meno nel portare avanti le attività didattiche, oppure se hanno rappresentato per le famiglie un ostacolo per la mancanza di adeguate competenze digitali.Abstract: In the educational context, technology is increasingly perceived as a key element of great educational renewal. For this reason, its use must be versatile and dynamic and adapt to various factors such as the teacher, the specific level of education, the characterising elements of the discipline, the age of the students, the cultural background of the families, and the availability of technological and financial resources. The essay proposes a reflection on the school-family relationship during the period of distance learning, through the analysis of the data that emerged from a survey conducted on a sample of 1326 parents, to verify how technologies found their way into the home, whether or not they were of help in carrying out teaching activities, or whether they represented an obstacle for families due to the lack of adequate digital competences

Editoriale: un nuovo orizzonte di senso per la scuola del 2050

L’accesso ai dati che la digitalizzazione permette e la loro fruibilità per tutti, viene a costituire un patrimonio comune sul quale costruire, oltre che saperi, anche occasioni di collaborazione, di condivisione di idee e di confronto. Non ci sembra ardito ipotizzare che queste opportunità possano favorire la creazione di un ambiente e di un clima democratico senza il quale formule come riduzione dei divari, inclusione, promozione sociale e individuale farebbero non poca fatica a trovare un reale spazio di affermazione, ma anche un preciso senso etico