Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules

Tubulin-targeting molecules are widely used cancer therapeutic agents. They inhibit microtubule-based structures, including the mitotic spindle, ultimately preventing cell division. The final fates of microtubule-inhibited cells are however often heterogeneous and difficult to predict. While recent work has provided insight into the cell response to inhibitors of microtubule dynamics (taxanes), the cell response to tubulin polymerization inhibitors remains less well characterized. Arylthioindoles (ATIs) are recently developed tubulin inhibitors. We previously identified ATI members that effectively inhibit tubulin polymerization in vitro and cancer cell growth in bulk cell viability assays. Here we characterise in depth the response of cancer cell lines to five selected ATIs. We find that all ATIs arrest mitotic progression, yet subsequently yield distinct cell fate profiles in time-lapse recording assays, indicating that molecules endowed with similar tubulin polymerization inhibitory activity in vitro can in fact display differential efficacy in living cells. Individual ATIs induce cytological phenotypes of increasing severity in terms of damage to the mitotic apparatus. That differentially triggers MCL-1 down-regulation and caspase-3 activation, and underlies the terminal fate of treated cells. Collectively, these results contribute to define the cell response to tubulin inhibitors and pinpoint potentially valuable molecules that can increase the molecular diversity of tubulin-targeting agents

The Role of Water in the Photocatalytic Degradation of Acetonitrile and Toluene in Gas-Solid and Liquid-Solid Regimes

Photocatalytic degradation of acetonitrile and toluene was carried out both in gas-solid and in liquid-solid regimes by using commercial TiO2 samples ( Merck and Degussa P25). The investigation was mainly aimed to study the influence of water present in the reaction environment on the mechanism and degradation rate of two probe molecules. In gas-solid regime, the reacting mixture consisted of toluene or acetonitrile, oxygen, nitrogen, and water vapour. The main degradation product of toluene was CO2 with small amounts of benzaldehyde. In the presence of water vapour, the activity of TiO2 Merck remained stable but greatly decreased if water was absent. TiO2 Degussa P25 continuously deactivated, even in the presence of water vapour. With both catalysts, the photodegradation products of acetonitrile were CO2 and HCN; the activity was stable and was independent of the presence of water vapour in the reacting mixture. The production of HCN represents a drawback of acetonitrile photocatalytic degradation but the elimination of HCN is not actually a problem. In liquid-solid regime, the main intermediates of toluene photodegradation were p-cresol and benzaldehyde; traces of pyrogallol and benzyl alcohol were also found. Benzoic acid, hydroquinone, and trans, trans muconic acid were detected only when TiO2 Merck was used. The photodegradation products of acetonitrile were cyanide, cyanate, formate, nitrate, and carbonate ions

Effect of mofezolac-galactose distance in conjugates targeting cyclooxygenase (COX)-1 and CNS GLUT-1 carrier

Neuroinflammation is the earliest stage of several neurological and neurodegenerative diseases. In the case of neurodegenerative disorders, it takes place about 15â 20 years before the appearance of specific neurodegenerative clinical symptoms. Constitutive microglial COX-1 is one of the pro-inflammatory players of the neuroinflammation. Novel compounds 3, 14 and 15 (Galmof0, Galmof5and Galmof11, respectively) were projected, and their synthetic methodologies developed, by linking by an ester bond, directly or through a C5 or C11 unit linker the highly selective COX-1 inhibitor mofezolac (COXs selectivity index > 6000) to galactose in order to obtain substances capable to cross blood-brain barrier (BBB) and control the CNS inflammatory response. 3, 14 and 15 (Galmofs) were prepared in good to fair yields. Galmof0(3) was found to be a selective COX-1 inhibitor (COX-1 IC50= 0.27 μM and COX-2 IC50= 3.1 μM, selectivity index = 11.5), chemically and metabolically stable, and capable to cross Caco-2 cell monolayer, resembling BBB, probing that its transport is GLUT-1-mediated. Furthermore, Galmof0(3) powerfully inhibits PGE2release higher than mofezolac (1) in LPS-stimulated mouse BV2 microglial cell line, a worldwide recognized neuroinflammation model. In addition, Fingerprints for Ligands and Proteins (FLAP) was used to explain the different binding interactions of Galmofs with the COX-1 active site

Bibliometric Network Analysis on Rapid-Onset Opioids for Breakthrough Cancer Pain Treatment

Background and Objectives. Proper breakthrough cancer pain (BTcP) management is of pivotal importance. Although rapid-acting, oral and nasal transmucosal, fentanyl formulations (rapid-onset opioids, ROOs) are licensed for BTcP treatment, not all guidelines recommend their use. Presumably, some research gaps need to be bridged to produce solid evidence. We present a bibliometric network analysis on ROOs for BTcP treatment.Methods. Documents were retrieved from the Web of Science (WOS) online database. The string was "rapid onset opioids" or "transmucosal fentanyl" and "breakthrough cancer pain". Year of publication, journal metrics (impact factor and quartile), title, document type, topic, and clinical setting (in-patients, outpatients, and palliative care) were extracted. The software tool VOSviewer (version 1.6.17) was used to analyze the semantic network analyzes, bibliographic coupling, journals analysis, and research networks.Results. 502 articles were found in WOS. A declining trend in published articles from 2014 to 2021 was observed. Approximately 50% of documents regard top quartile (Q1) journals. Most articles focused on ROOs efficacy, but abuse and misuse issues are poorly addressed. With respect to article type, we calculated 132 clinical investigations. The semantic network analysis found interconnections between the terms "breakthrough cancer pain," "opioids," and "cancers." The top co-cited article was published in 2000 and addressed pain assessment. The largest number of partnerships regarded the United States, Italy, and England.Conclusion. In this research area, most articles are published in top-ranked journals. Nevertheless, paramount topics should be better addressed, and the implementation of research networks is needed. (C) 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Multiple Scenario Generation of Subsurface Models:Consistent Integration of Information from Geophysical and Geological Data throuh Combination of Probabilistic Inverse Problem Theory and Geostatistics

Neutrinos with energies above 1017 eV are detectable with the Surface Detector Array of the Pierre Auger Observatory. The identification is efficiently performed for neutrinos of all flavors interacting in the atmosphere at large zenith angles, as well as for Earth-skimming \u3c4 neutrinos with nearly tangential trajectories relative to the Earth. No neutrino candidates were found in 3c 14.7 years of data taken up to 31 August 2018. This leads to restrictive upper bounds on their flux. The 90% C.L. single-flavor limit to the diffuse flux of ultra-high-energy neutrinos with an E\u3bd-2 spectrum in the energy range 1.0 7 1017 eV -2.5 7 1019 eV is E2 dN\u3bd/dE\u3bd < 4.4 7 10-9 GeV cm-2 s-1 sr-1, placing strong constraints on several models of neutrino production at EeV energies and on the properties of the sources of ultra-high-energy cosmic rays

Factors affecting the presence of women on firms’ board from an institutional/cultural perspective

This paper is voted to study if cultural/institutional environment among different countries can affect the presence of women on boards. The analysis is focused on a statistical model to observe over the period 2007–2017 (11 years) a cross-sectional sample of MSCI Index-listed companies (476 firms). Grounding on Institutional Theory, we select several variables which represent cultural and institutional contexts in which firms do operate. As per female presence on boards, we collect data from Bloomberg database. To select institutional/cultural variables, we use well-acknowledged sources (Polity IV Project, PRS Group, World Bank). Our hypothesis is that among context variables, the most important one is the rule of law on gender quotas. To study the relationship between institutional factors and female presence on board, we use a multivariate regression model to test the effects on the female board presence to variables presenting cultural, legal, and institutional country’s context. In particular, we will perform a fixed effects regression, using also control variables selected from extant literature on this topic (i.e., financial and dimension variables). Our hypothesis is that among context variables, the most important one is the legislation on gender (a law which obliges the appointment of women by firms). Our first contribution is to show a descriptive analysis of the presence of female leaders in the sample. We want to provide a picture for the period of the MSCI Index firms’ situation regarding gender distribution among the sample boards. The second contribution is to test if the female presence is affected by the abovementioned cultural/ institutional variables. Our work finally provides a new insight on analyzing the phenomenon of women on boards from a cultural/institutional point of view. We contribute to literature adopting a methodology that allows us to explain if the presence of women is depending on institutional and cultural factors. The empirical results of this study bring evidence that the presence of a law on gender quota in corporate board has a positive effect on the presence of women on boards. Moreover, the results show, in addition to coercive pressures, that there are also several normative pressures that have an influence on the representation of women on boards in a given country

The theory of new business models innovation and sustainability. Toward new investigations of smart technologies

The aim of this chapter is to define the theory of BM providing an updated overview of new business models, focusing on BM innovation and sustainability toward the investigation of smart technologies. Using a bibliometric investigating the years 2018–2020, our results enrich existing studies with a primary set of relevant keywords and streams directed to support BM innovation, sustainability, and smart technologies

Business model and sustainability: the state of the art

Our paper consist of a literature review about business model research in academia, which represents a premise to identify the main topics, as well as the evolution of the studies. As for the methodology, we used EBSCO database, searching for academic papers having ―business model‖ in the title and in the abstract published from 1975 until now. This paper contributes to the literature in two ways. First, it provides a wide analysis of the extant literature on business models. Besides the classification by main topics, we aim to outline the trend of these studies over time. Moreover, by this review we propose to understand how much literature has already investigated, and to identify new roots for future research on empirical and practical application of business model in business studies. Our work is the first step of a project. In order to contribute to previous literature, we propose to view corporate business models as the crossroads of different disciplines, as management and accounting and finance are. Further developments of our research, actually, could concern the study of the characteristics of sustainable business models applied by firms, in order to select which key factors of firms‘ business model positively affect their performance and their valu