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Background: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. Methods: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III–IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016–004403–31). Findings: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2–29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7–12·1) in the standard group and 9·6 months (7·2–17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65–0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3–4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). Interpretation: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted.

Background and Purpose: Airway remodelling is a critical feature of chronic lung diseases. Epithelial-mesenchymal transition (EMT) represents an important source of myofibroblasts, contributing to airway remodelling. Here, we investigated the sphingosine-1-phosphate (S1P) role in EMT and its involvement in asthma-related airway dysfunction. Experimental Approach: A549 cells were used to assess the S1P effect on EMT and its interaction with TGF-β signalling. To assess the S1P role in vivo and its impact on lung function, two experimental models of asthma were used by exposing BALB/c mice to subcutaneous administration of either S1P or ovalbumin (OVA). Key Results: Following incubation with TGF-β or S1P, A549 acquire a fibroblast-like morphology associated with an increase of mesenchymal markers and down-regulation of the epithelial. These effects are reversed by treatment with the TGF-β receptor antagonist LY2109761. Systemic administration of S1P to BALB/c mice induces asthma-like disease characterized by mucous cell metaplasia and increased levels of TGF-β, IL-33 and FGF-2 within the lung. The bronchi harvested from S1P-treated mice display bronchial hyperresponsiveness associated with overexpression of the mesenchymal and fibrosis markers and reduction of the epithelial.The S1P-induced switch from the epithelial toward the mesenchymal pattern correlates to a significant increase of lung resistance and fibroblast activation. TGF-β blockade, in S1P-treated mice, abrogates these effects. Finally, inhibition of sphingosine kinases by SK1-II in OVA-sensitized mice, abrogates EMT, pulmonary TGF-β up-regulation, fibroblasts recruitment and airway hyperresponsiveness. Conclusion and Implications: Targeting S1P/TGF-β axis may hold promise as a feasible therapeutic target to control airway dysfunction in asthma. © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

This presentation was part of a webinar introduced by the International GLAM Labs Community in October 25th, 2022 and brought together theory and practice on how to make available GLAM digital collections as datasets for publication and re-use by researchers, GLAM professionals, creative workers and other users. As the options for preparing collections as data are nearly endless, starting the implementation of the Collections as Data principle may be daunting. To support GLAM institutions to start on this journey, the presentation gives a practical overview of the steps that can be taken and presents some of the choices to be made. You will also learn about real-life examples from the National Library of Scotland, the German National Library, the Library of Congress, Europeana, KBR - Royal Library of Belgium, the Royal Danish Library and Meemoo., Additional information available at https://glamlabs.io/events/collections-data/

Study question Could 448KHz electrostimulation be beneficial in the endometrial preparation for transfer in pre-menopausal or menopausal women? Summary answer Few women had adequate endometrium (8.3%) with standard treatments, which increased to 54.1% when combined with aspirin-sildenafyl, while when combined with 448KHz is over 75% What is known already We know that electrical stimulation is used in tissue engineering as a new regenerative medicine approach, which promotes cell proliferation and differentiation. In addition, it improves cell membrane permeability and cell metabolism. Study design, size, duration In the retrospective clinical study a total of 96 patients were considered, all in premenopausal or menopausal state, with inadequate endometrial response to common therapies and failure to transfer. In the following cycle, attempts were made to optimize the level of endometrial preparation by various approaches. Participants/materials, setting, methods The instrument used for electrostimulation was INDIBA. The 96 patients were divided into 4 groups: group A received estrogen therapy and 448KHz electrostimulation, group B received estrogen therapy, group C received estrogen therapy, aspirin and sildenafyl support, group D received estrogen therapy, aspirin-sildenafyl support and 448KHz electrostimulation. Main results and the role of chance Electrostimulation was found to be beneficial in group A (with electro-stimulation) where 75% of patients had an endometrium suitable for transfer compared to group B (without electro-stimulation) with only 8.3%. Similarly, group C (without electro-stimulation) had 54.1% of patients with a suitable endometrium, while group D (with electro-stimulation) had 87.5%. Limitations, reasons for caution The limitations are related to the nature of the study, which is retrospective, so although the starting conditions were evaluated to reduce bias, we suggest confirmation with a prospective randomized clinical trial to validate these data, which will be our next objective. Wider implications of the findings The common therapeutic approach of endometrial preparation, when combined with electrostimulation, leads to a drastic decrease in cancelled cycles due to an inadequate endometrium. Trial registration number not applicable

Abstract Alteration of neuronal protein processing is often associated with neurological disorders and is highly dependent on cellular protein trafficking. A prime example is the amyloidogenic processing of amyloid precursor protein (APP) in intracellular vesicles, which plays a key role in age-related cognitive impairment. Most approaches to correct this altered processing aim to limit enzymatic activities that lead to toxic products, such as protein cleavage by β-secretase and the resulting amyloid β production. A viable alternative is to direct APP to cellular compartments where non-amyloidogenic mechanisms are favored. To this end, we exploited the molecular properties of the herpes simplex virus 1 (HSV-1) transport protein US9 to guide APP interaction with preferred endogenous targets. Specifically, we generated a US9 chimeric construct that facilitates APP processing through the non-amyloidogenic pathway and tested it in primary cortical neurons. In addition to reducing amyloid β production, our approach controls other APP-dependent biochemical steps that lead to neuronal deficits, including phosphorylation of APP and tau proteins. Notably, it also promotes the release of neuroprotective soluble αAPP. In contrast to other neuroprotective strategies, these US9-driven effects rely on the activity of endogenous neuronal proteins, which lends itself well to the study of fundamental mechanisms of APP processing/trafficking. Overall, this work introduces a new method to limit APP misprocessing and its cellular consequences without directly targeting secretase activity, offering a novel tool to reduce cognitive decline in pathologies such as Alzheimer’s disease and HIV-associated neurocognitive disorders.

As a response to COVID-19 and while the onset of the pandemic was still in its very earlystages, in April 2020 the Digital Curation Unit (DCU), Research and Innovation Center"Athena", as co-ordinator of APOLLONIS, the Greek Infrastructure for Digital Arts, Humanitiesand Language Research and Innovation, organized a Twitter Conference under the title “DHin the Time of Virus”.This event aimed at battling academic isolation and facilitating and supportingcommunity building and osmosis in DH research and education. Due to its sensitive timing,with Italy going through extreme difficulties and Europe and the US entering quarantine andwork-from-home regimes, the Twitter Conference provided a platform of communication of DH research pursuits as well as of expression of an unprecedented human experience. With the support of a DARIAH Theme grant, a year later, in 2021, we designed and organized a digital workshop in which we reunitedthe Twitter Conference participants alongside further DH researchers who were selectedthrough an open call. The outcome of these events is an electronicas well as a printed publication monitoring the effects ofthe pandemic on e-Education, e-Research and digital tools, methods and platforms, thedevelopments the pandemic has expedited and the delays it may have caused in DH researchand the distance covered and toils endured by DH researchers and practitioners to keep trackof their work.

Opioid use has substantially increased over recent years and remains a major driver of new HIV infections worldwide. Clinical studies indicate that opioids may exacerbate the symptoms of HIV-associated neurocognitive disorders (HAND), but the mechanisms underlying opioid-induced cognitive decline remain obscure. We recently reported that the μ-opioid agonist morphine increased neuronal iron levels and the levels of ferritin proteins that store iron, suggesting that opioids modulate neuronal iron homeostasis. Additionally, increased iron and ferritin heavy chain protein were necessary for morphine’s ability to reduce the density of thin and mushroom dendritic spines in cortical neurons, which are considered critical mediators of learning and memory respectively. As altered iron homeostasis has been reported in HAND and related neurocognitive disorders like Alzheimer’s, Parkinson’s, and Huntington’s disease, understanding how opioids regulate neuronal iron metabolism may help identify novel drug targets in HAND with potential relevance to these other neurocognitive disorders. Here, we review the known mechanisms of opioid mediated regulation of neuronal iron and the corresponding cellular response and discuss the implications of these findings for patients with HAND. Furthermore, we will discuss a new molecular approach that can be used to understand if opioid modulation of iron affects the expression and processing of amyloid precursor protein and the contributions of this pathway to HAND.

The increase in couple sterility and the average increase in the age of women seeking pregnancy has placed the scientific community in front of the need to improve the quality of oocytes and the percentage of the embryonic implantation. The oxygen- ozone therapy seems to be able to help in this research thanks to its modes of action. A therapeutic protocol, identified with the acronym H.A.R.O.T (Human assisted reproduction ozone therapy) has been developed, the first results of which seem to be considerably encouraging in order to obtain a greater number and quality of oocytes and improve the percentage of embryonic implantation.

Preimplantation genetic diagnosis (PGD) was introduced in the late 1980s and represents an option for couples at risk of transmitting an inherited, debilitating or neurological disorder to their children. From a cleavage or blastocyst stage embryo, cell(s) are collected and then genetically analyzed for disease; enabling an unaffected embryo to be transferred into the uterus cavity. Nowadays, PGD has been carried out for several hundreds of heritable conditions including myotonic dystrophy, and for susceptibility genes involved in cancers of the nervous system. Currently, advanced molecular technologies with better resolution, such as array comparative genomic hybridisation, quantitative polymerase chain reaction, and next generation sequencing, are on the verge of becoming the gold standard in embryo preimplantation screening. Given this, it may be time for neurological societies to consider the published evidence to develop new guidelines for the integration of PGD into modern preventative neurology. Therefore, the main aim of this review is to illustrate the option of PGD to enable conception of an unaffected baby, and to assist clinicians and neurologists in the counseling of the patient at risk of transmitting an inherited disease, to explore the genetic journey throughout in vitro fertilization IVF with PGD.

Les situations de desastres patrimoniaux, en particulier la destruction de monuments et de sites emblematiques, conduisent a questionner la facon d’outiller politiquement et juridiquement la lutte contre les differentes formes de criminalite culturelle, de repenser aussi les modes operatoires, les deux aspects sont intimement lies. Le corpus des instruments de prevention et de lutte contre cette forme de criminalite s’est considerablement etoffe ces dernieres annees, que ce soit sur le terrai...

Synaptodendritic pruning is a common cause of cognitive decline in neurological disorders, including HIV-associated neurocognitive disorders (HAND). HAND persists in treated patients as a result of chronic inflammation and low-level expression of viral proteins, though the mechanisms involved in synaptic damage are unclear. Here, we report that the chemokine CXCL12 recoups both cognitive performance and synaptodendritic health in a rodent model of HAND, which recapitulates the neuroinflammatory state of virally controlled individuals and the associated structural/functional deficiencies. CXCL12 preferentially regulates plastic thin spines on layer II/III pyramidal neurons of the medial prefrontal cortex via CXCR4-dependent stimulation of the Rac1/PAK actin polymerization pathway, leading to increased spine density and improved flexible behavior. Our studies unveil a critical role of CXCL12/CXCR4 signaling in spine dynamics and cognitive flexibility, suggesting that HAND - or other diseases driven by spine loss - may be reversible and upturned by targeting Rac1-dependent processes in cortical neurons.

Stress granules are nonmembranous organelles that function as a stress-adaptation mechanism. We have recently shown that stress granules are mobilized by mutant KRAS pancreatic cancer cells under stress to enhance tumor fitness and survival. In this chapter, we outline a method for inducing, detecting, and quantifying stress granules in pancreatic cancer cells in vitro and in vivo. This method can be utilized to better understand the mechanisms driving stress granule formation and their role in pancreatic tumorigenesis.

Colorectal Carcinoma (CRC) is the second most common malignant tumor in the Western world. It has been well documented that the tumor microenvironment plays an important role in tumor progression via the co-evolution of tumor cells and tumor stroma. The extracellular matrix (ECM) is the major component of stroma and acts as a key regulator of cell and tissue functions. During cancer progression, the ECM is deregulated and becomes disorganized, resulting in an abnormal ECM that promotes cellular transformation and metastasis, deregulates behavior of stromal cells, and facilitates inflammation and angiogenesis. This thesis aims at the elucidation of the origin and role of collagen X, which has been unexpectedly discovered in the stroma of malignant colorectal carcinomas. Collagen-X (Col-X) is a network-forming collagen with a short triple-helical core flanked by two non-collagenous domains: C-terminal NC1 and N-terminal NC2. Its expression is normally limited to hypertrophic chondrocytes in the growth plate cartilage in long bones, ribs and vertebrate, but under pathological conditions. It is also expressed in osteoarthritic cartilage and chondrosarcomas. At present, only incomplete information is available regarding Col-X and cancer. Chapman et al. showed in 2012 that Col-X expression is elevated in diverse solid tumor types, and others proposed Col-X as a new biomarker for colon cancer. The exact cellular origin of type X collagen in CRC tissues and the putative role of Col-X in tumor progression, however, remains undefined. In this thesis I present data confirming a correlation of high levels of Col-X protein and Col10A1 mRNA expression in two cohorts of human CRC samples with poor tumor prognosis. Immunohistochemical staining of CRC tissues indicated that Col-X was primarily deposited in the stroma, suggesting stroma cells as the main source of the protein. This was confirmed by in situ hybridization analysis using a COL10A1 specific probe which revealed intense signals exclusively in stromal cells, displaying the typical spindle-shaped morphology of fibroblast like cells. Immunofluorescence co-localization studies of Col-X with Vimentin and alpha-SMA antibodies indicated that fibroblast –like cells and smooth muscle cells were the main source of the protein. First indications for a tumor-promoting role of Col-X were obtained from in vitro cell motility assays showing that recombinant purified Col-X enhances the motility of colorectal cancer cells. Altogether the results show that Col-X represents a novel specific biomarker for the detection of malignant colorectal carcinomas and opens the prospective that COL10A1 analysis could be used in routinely processed primary tumor tissues as prognostic profiler to identify high risk patients. Further studies are required to clarify its specific role in tumor progression.

HIV-associated neurocognitive disorders (HAND) remain prevalent and are aggravated by µ-opioid use. We have previously shown that morphine and other µ-opioids may contribute to HAND by inhibiting the homeostatic and neuroprotective chemokine receptor CXCR4 in cortical neurons, and this novel mechanism depends on upregulation of the protein ferritin heavy chain (FHC). Here, we examined the cellular events and potential mechanisms involved in morphine-mediated FHC upregulation using rat cortical neurons of either sex in vitro and in vivo. Morphine dose dependently increased FHC protein levels in primary neurons through µ-opioid receptor (µOR) and Gαi-protein signaling. Cytoplasmic FHC levels were significantly elevated, but nuclear FHC levels and FHC gene expression were unchanged. Morphine-treated rats also displayed increased FHC levels in layer 2/3 neurons of the prefrontal cortex. Importantly, bothin vitroandin vivoFHC upregulation was accompanied by loss of mature dendritic spines, which was also dependent on µOR and Gαi-protein signaling. Moreover, morphine upregulated ferritin light chain (FLC), a component of the ferritin iron storage complex, suggesting that morphine altered neuronal iron metabolism. Indeed, prior to FHC upregulation, morphine increased cytoplasmic labile iron levels as a function of decreased endolysosomal iron. In line with this, chelation of endolysosomal iron (but not extracellular iron) blocked morphine-induced FHC upregulation and dendritic spine reduction, whereas iron overloading mimicked the effect of morphine on FHC and dendritic spines. Overall, these data demonstrate that iron mediates morphine-induced FHC upregulation and consequent dendritic spine deficits and implicate endolysosomal iron efflux to the cytoplasm in these effects.

The study of the secondary metabolites contained in the organic extract of Caribbean sponge Smenospongia aurea led to the isolation of smenothiazole A (3) and B (4), hybrid peptide/polyketide compounds. Assays performed using four solid tumor cell lines showed that smenothiazoles exert a potent cytotoxic activity at nanomolar levels, with selectivity over ovarian cancer cells and a pro-apoptotic mechanism.

L’evoluzione morfo-strutturale delle colline di Napoli si correla alle eruzioni flegree tardo-Pleistoceniche, all’attivita della fault zone che borda a NE la piana del Sebeto ed a N il Golfo di Napoli, a rimodellamenti fluvio-denudazionali ed alla nascita di falesie e piane durante la trasgressione post glaciale. All’apice di quest’ultima una baia di sommersione occupa il settore Municipio; ad E una piattaforma di abrasione si arresta sotto la scarpata di faglia del Pendino e la costa si articola fino al profondo seno nella piana del F. Sebeto. Tale assetto favorisce gli insediamenti umani fin dalla preistoria. Tracce di frequentazione si datano al Bronzo Medio nel settore Duomo, mentre nelle insenature costiere esse risalgono almeno al v-iv sec. a.C. La baia di Municipio viene scelta come area portuale a partire dalla fine del iv sec. a.C. restando attiva fino al Tardo Antico, quando, nei diversi settori, si registrano condizioni di progressivo impaludamento. Una subsidenza tardo-olocenica stimata tra 4 e 7 m circa si manifesta con ritmi diversi nei vari settori indagati.