Stimulus-Evoked Activity Modulation of In Vitro Engineered Cortical and Hippocampal Networks

The delivery of electrical stimuli is crucial to shape the electrophysiological activity of neuronal populations and to appreciate the response of the different brain circuits involved. In the present work, we used dissociated cortical and hippocampal networks coupled to Micro-Electrode Arrays (MEAs) to investigate the features of their evoked response when a low-frequency (0.2 Hz) electrical stimulation protocol is delivered. In particular, cortical and hippocampal neurons were topologically organized to recreate interconnected sub-populations with a polydimethylsiloxane (PDMS) mask, which guaranteed the segregation of the cell bodies and the connections among the sub-regions through microchannels. We found that cortical assemblies were more reactive than hippocampal ones. Despite both configurations exhibiting a fast (<35 ms) response, this did not uniformly distribute over the MEA in the hippocampal networks. Moreover, the propagation of the stimuli-evoked activity within the networks showed a late (35-500 ms) response only in the cortical assemblies. The achieved results suggest the importance of the neuronal target when electrical stimulation experiments are performed. Not all neuronal types display the same response, and in light of transferring stimulation protocols to in vivo applications, it becomes fundamental to design realistic in vitro brain-on-a-chip devices to investigate the dynamical properties of complex neuronal circuits

Modularity and neuronal heterogeneity: Two properties that influence in vitro neuropharmacological experiments

IntroductionThe goal of this work is to prove the relevance of the experimental model (in vitro neuronal networks in this study) when drug-delivery testing is performed. MethodsWe used dissociated cortical and hippocampal neurons coupled to Micro-Electrode Arrays (MEAs) arranged in different configurations characterized by modularity (i.e., the presence of interconnected sub-networks) and heterogeneity (i.e., the co-existence of neurons coming from brain districts). We delivered increasing concentrations of bicuculline (BIC), a neuromodulator acting on the GABAergic system, and we extracted the IC50 values (i.e., the effective concentration yielding a reduction in the response by 50%) of the mean firing rate for each configuration. ResultsWe found significant lower values of the IC50 computed for modular cortical-hippocampal ensembles than isolated cortical or hippocampal ones. DiscussionAlthough tested with a specific neuromodulator, this work aims at proving the relevance of ad hoc experimental models to perform neuropharmacological experiments to avoid errors of overestimation/underestimation leading to biased information in the characterization of the effects of a drug on neuronal networks

Stakeholder Participation in Planning of a Sustainable and Competitive Tourism Destination: The Genoa Integrated Action Plan

The outbreak of COVID-19 confronted the international community with critical health, social, and economic challenges. Travel and tourism were among the hardest affected sectors. In 2020 and 2021 new travel trends emerged, emphasizing local destinations, short distances, and consequently, lower-carbon transportation (proximity tourism). Post-pandemic recovery represents an opportunity to bounce back better by rethinking the sector’s economic model for the sake of sustainability and innovation. This paper disseminates the research that led to the structuring of guidelines for a breakthrough and inclusive municipal-level action plan for the promotion of sustainable tourism, as part of the Tourism Friendly Cities project. An operational methodology is discussed here, whereby key stakeholder participation, conceptualized through a sextuple helix model, is the foundation of the planning process. A small-scale action and a qualitative assessment tool of the participatory process are also illustrated. The proposed methodology corroborates the vast positive effects deriving from stakeholder participation in terms of trust, ownership, planning quality, innovativeness and sustainability of interventions. In applying the methodology, although the digital framework was evaluated positively in terms of the number of participants that could be involved, data collection, and confidentiality of activities, the evaluation shows that hybrid modes of participation are more desirable

Management of young women with early breast cancer

Breast cancer is still the most frequent cancer diagnosed in women aged 6440 years and the primary cause of death in this age group. The management of these patients needs a dedicated approach involving a multidisciplinary team that takes into account their treatment and survivorship issues. The present review aims to provide a perspective on the many challenges associated with treatment of young women with early breast cancer. We will focus on the standard (neo)adjuvant treatment, highlighting the paucity of age-specific results about the available genomic signatures, the groundbreaking landscape of adjuvant endocrine therapy and the relevant issue of the fertility preservation

Potential Mechanisms of Ovarian Protection with Gonadotropin-Releasing Hormone Agonist in Breast Cancer Patients: A Review

The use of chemotherapy in premenopausal cancer patients may lead to chemotherapy-induced premature ovarian failure. Pharmacological temporary ovarian suppression obtained with the gonadotropin-releasing hormone agonist (GnRHa) administered concomitantly with chemotherapy has been investigated as a technique capable to reduce the gonadotoxicity, reducing the risk of developing premature menopause. In recent years, important evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients. However, in women interested in fertility preservation, this is not an alternative to cryopreservation strategies, which remains the first option to be proposed. The purpose of this review is to summarize the mechanisms of GnRHa in the preservation of fertility in premenopausal cancer patient candidates to receive chemotherapy, highlighting the areas of doubt that require further investigation

Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis

Single-agent poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved as the first targeted therapy available for patients with BRCA-mutated HER2-negative metastatic breast cancer. This meta-analysis aimed to better evaluate activity, efficacy and safety of single-agent PARPi in this population. A systematic search of Medline, Embase and conference proceedings up to 31 January 2018 was conducted to identify randomised controlled trials (RCTs) investigating single-agent PARPi versus monochemotherapy in patients with BRCA-mutated HER2-negative metastatic breast cancer. Using the random-effect model, we calculated summary risk estimates (pooled HR and OR with 95% CI) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3-4 adverse events (AEs), treatment discontinuation rate and time to deterioration in quality of life (QoL). Two RCTs (n=733) were included. As compared with monochemotherapy, single-agent PARPi significantly improved PFS (HR 0.56(95% CI 0.45 to 0.70)) and ORR (OR 4.15 (95% CI 2.82 to 6.10)), with no difference in OS (HR 0.82 (95% CI 0.64 to 1.05)). Single-agent PARPi significantly increased risk of anaemia and any grade headache, but reduced risk of neutropenia and any grade palmar-plantar erythrodysesthesia syndrome as compared with monochemotherapy. No significant differences in other AEs and treatment discontinuation rate were observed. Patients treated with PARPi experienced a significant delayed time to QoL deterioration (HR 0.40 (95% CI 0.29 to 0.54)). Single-agent PARPi showed to be an effective, well tolerated and useful treatment in maintaining QoL of patients with BRCA-mutated HER2-negative metastatic breast cancer

The role of dose-dense (DD) adjuvant chemotherapy (CT) in HER2-positive (HER2+) early breast cancer (BC) patients (pts) before and after the introduction of trastuzumab (T): Exploratory analysis of the GIM2 trial

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The cerium content of the Milky Way as revealed by Gaia DR3 GSP-Spec abundances

[Abstract]: The recent Gaia third data release contains a homogeneous analysis of millions of high-quality Radial Velocity Spectrometer (RVS) stellar spectra by the GSP-Spec module. This led to the estimation of millions of individual chemical abundances and allows us to chemically map the Milky Way. The published GSP-Spec abundances include three heavy elements produced by neutron-captures in stellar interiors: Ce, Zr, and Nd. Aims. We study the Galactic content in cerium based on these Gaia/RVS data and discuss the chemical evolution of this element. Methods. We used a sample of about 30 000 local thermal equilibrium Ce abundances, selected after applying different combinations of GSP-Spec flags. Based on the Gaia DR3 astrometric data and radial velocities, we explore the cerium content in the Milky Way and, in particular, in its halo and disc components. Results. The high quality of the Ce GSP-Spec abundances is quantified through literature comparisons. We found a rather flat [Ce/Fe] versus [M/H] trend. We also found a flat radial gradient in the disc derived from field stars and, independently, from about 50 open clusters. This agrees with previous studies. The [Ce/Fe] vertical gradient was also estimated. We also report an increasing [Ce/Ca] versus [Ca/H] in the disc, illustrating the late contribution of asymptotic giant branch stars with respect to supernovae of type II. Our cerium abundances in the disc, including the young massive population, are well reproduced by a new three-infall chemical evolution model. In the halo population, the M 4 globular cluster is found to be enriched in cerium. Moreover, 11 stars with cerium abundances belonging to the Thamnos, Helmi Stream, and Gaia-Sausage-Enceladus accreted systems were identified from chemo-dynamical diagnostics. We found that the Helmi Stream might be slightly underabundant in cerium compared to the two other systems. Conclusions. This work illustrates the high quality of the GSP-Spec chemical abundances, which significantly contribute to unveiling the heavy-element evolution history of the Milky Way.We thank the referee for their valuable comments. ES received funding from the European Union’s Horizon 2020 research and innovation program under SPACE-H2020 grant agreement number 101004214 (EXPLORE project). ARB also acknowledges support from this Horizon program. PAP and EP thanks the Centre National d’Etudes Spatiales (CNES) for funding support. VG acknowledges support from the European Research Council Consolidator Grant funding scheme (project ASTEROCHRONOMETRY, G.A. n. 772293, http://www.asterochronometry.eu ). Special thanks to Niels Nieuwmunster and Botebar for grateful comments on figures. This work has made use of data from the European Space Agency (ESA) mission Gaia ( https://www.cosmos.esa.int/gaia ), processed by the Gaia Data Processing and Analysis Consortium (DPAC, https://www.cosmos.esa.int/web/gaia/dpac/consortium ). Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement

Modularity and neuronal heterogeneity: Two properties that influence in vitro neuropharmacological experiments

IntroductionThe goal of this work is to prove the relevance of the experimental model (in vitro neuronal networks in this study) when drug-delivery testing is performed.MethodsWe used dissociated cortical and hippocampal neurons coupled to Micro-Electrode Arrays (MEAs) arranged in different configurations characterized by modularity (i.e., the presence of interconnected sub-networks) and heterogeneity (i.e., the co-existence of neurons coming from brain districts). We delivered increasing concentrations of bicuculline (BIC), a neuromodulator acting on the GABAergic system, and we extracted the IC50 values (i.e., the effective concentration yielding a reduction in the response by 50%) of the mean firing rate for each configuration.ResultsWe found significant lower values of the IC50 computed for modular cortical-hippocampal ensembles than isolated cortical or hippocampal ones.DiscussionAlthough tested with a specific neuromodulator, this work aims at proving the relevance of ad hoc experimental models to perform neuropharmacological experiments to avoid errors of overestimation/underestimation leading to biased information in the characterization of the effects of a drug on neuronal networks

Hormonal therapy followed by chemotherapy or the reverse sequence as first-line treatment of hormone-responsive, human epidermal growth factor receptor-2 negative metastatic breast cancer patients: Results of an observational study

Introduction Although hormonal-therapy is the preferred first-line treatment for hormone-responsive, HER2 negative metastatic breast cancer, no data from clinical trials support the choice between hormonal-therapy and chemotherapy. Methods Patients were divided into two groups according to the treatment: chemotherapy or hormonal-therapy. Outcomes in terms of clinical benefit and median overall survival (OS) were retrospectively evaluated in the two groups. To calculate the time spent in chemotherapy with respect to OS in the two groups, the proportion of patients in chemotherapy relative to those present in either group was computed at every day from the start of therapy. Results From 1999 to 2013, 119 patients received first-line hormonal-therapy (HT-first group) and 100 first-line chemotherapy (CT-first group). Patients in the CTfirst group were younger and with poorer prognostic factors as compared to those in HT-first group. Clinical benefit (77 vs 81%) and median OS (50.7 vs 51.1 months) were similar in the two groups. Time spent in chemotherapy was significantly longer during the first 3 years in CT-first group (54-34%) as compared to the HT-first group (11-18%). This difference decreased after the third year and overall was 28% in the CT-first group and 18% in the HT-first group. Conclusions The sequence first-line chemotherapy followed by hormonal-therapy, as compared with the opposite sequence, is associated with a longer time of OS spent in chemotherapy. However, despite the poorer prognostic factors, patients in the CTfirst group had a superimposable OS than those in the HT-first group