Pre-clinical Models for Studying the Interaction between Mesenchymal Stromal Cells and Cancer Cells and the Induction of Stemness

Mesenchymal stromal cells (MSC) have essential functions in building and supporting the tumour microenvironment, providing metastatic niches, and maintaining cancer hallmarks, and it is increasingly evident that the study of the role of MSC in cancer is crucial for paving the way to clinical opportunities for novel anti-cancer therapies. To date, the vast majority of preclinical models that have been used for studying the effect of reactive MSC on cancer growth, metastasis, and response to therapy has been mainly based on in vitro flat biology, including the co-culturing with cell compartmentalization or with cell-to-cell contact, and on in vivo cancer models with different routes of MSC inoculation. More complex in vitro 3D models based on spheroid structures that are formed by intermingled MSC and tumour cells are also capturing the interest in cancer research. These are innovative culture systems tailored on the specific tumour type and that can be combined with a synthetic extracellular matrix, or included in in silico technologies, to more properly mimic the in vivo biological, spatial, biochemical, and biophysical features of tumour tissues. In this review, we summarized the most popular and currently available preclinical models for evaluating the role of MSC in cancer and their specific suitability, for example, in assaying the MSC-driven induction of epithelial-to-mesenchymal transition or of stem-like traits in cancer cells. Finally, we enlightened the need to carefully consider those parameters that might unintentionally strongly affect the secretome in MSC-cancer interplay and introduce confounding variables for the interpretation of results

Endogenous extracellular matrix regulates the response of osteosarcoma 3D spheroids to doxorubicin

The extracellular matrix (ECM) modulates cell behavior, shape, and viability as well as mechanical properties. In recent years, ECM disregulation and aberrant remodeling has gained considerable attention in cancer targeting and prevention since it may stimulate tumorigenesis and metastasis. Here, we developed an in vitro model that aims at mimicking the in vivo tumor microenvironment by recapitulating the interactions between osteosarcoma (OS) cells and ECM with respect to cancer progression. We long-term cultured 3D OS spheroids made of metastatic or non-metastatic OS cells mixed with mesenchymal stromal cells (MSCs); confirmed the deposition of ECM proteins such as Type I collagen, Type III collagen, and fibronectin by the stromal component at the interface between tumor cells and MSCs; and found that ECM secretion is inhibited by a neutralizing anti-IL-6 antibody, suggesting a new role of this cytokine in OS ECM deposition. Most importantly, we showed that the cytotoxic effect of doxorubicin is reduced by the presence of Type I collagen. We thus conclude that ECM protein deposition is crucial for modelling and studying drug response. Our results also suggest that targeting ECM proteins might improve the outcome of a subset of chemoresistant tumors

A New COL3A1 Mutation in Ehlers-Danlos Syndrome Vascular Type with Different Phenotypes in the Same Family

Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe connective tissue disorder caused by mutations in the collagen type III alpha I chain (COL3A1) gene. We describe a pathogenetic heterozygous COL3A1 mutation c.3140 G>A, p. Gly1047Asp, identified using next-generation sequencing, in a 40-year-old Italian female. The genetic test performed on her relatives, which present different clinical phenotypes, confirmed that they carry the same mutation in heterozygous state. This finding confirms that mutations causing vEDS have an incomplete penetrance

Repetitive element hypermethylation in multiple sclerosis patients

Background: Multiple sclerosis (MS) is a complex disorder of the central nervous system whose cause is currently unknown. Evidence is increasing that DNA methylation alterations could be involved in inflammatory and neurodegenerative diseases and could contribute to MS pathogenesis. Repetitive elements Alu, LINE-1 and SAT-\u3b1, are widely known as estimators of global DNA methylation. We investigated Alu, LINE-1 and SAT-\u3b1 methylation levels to evaluate their difference in a case-control setup and their role as a marker of disability. Results: We obtained blood samples from 51 MS patients and 137 healthy volunteers matched by gender, age and smoking. Methylation was assessed using bisulfite-PCR-pyrosequencing. For all participants, medical history, physical and neurological examinations and screening laboratory tests were collected. All repetitive elements were hypermethylated in MS patients compared to healthy controls. A lower Expanded Disability Status Scale (EDSS) score was associated with a lower levels of LINE-1 methylation for 'EDSS = 1.0' and '1.5 64 EDSS 64 2.5' compared to an EDSS higher than 3, while Alu was associated with a higher level of methylation in these groups: 'EDSS = 1.0' and '1.5 64 EDSS 64 2.5'. Conclusions: MS patients exhibit an hypermethylation in repetitive elements compared to healthy controls. Alu and LINE-1 were associated with degree of EDSS score. Forthcoming studies focusing on epigenetics and the multifactorial pathogenetic mechanism of MS could elucidate these links further

A New Academic Quality at Work Tool (AQ@workT) to Assess the Quality of Life at Work in the Italian Academic Context

The present study provides evidence for a valid and reliable tool, the Academic Quality at Work Tool (AQ@workT), to investigate the quality of life at work in academics within the Italian university sector. The AQ@workT was developed by the QoL@Work research team, namely a group of expert academics in the field of work and organizational psychology affiliated with the Italian Association of Psychologists. The tool is grounded in the job demands-resources model and its psychometric properties were assessed in three studies comprising a wide sample of lecturers, researchers, and professors: a pilot study (N = 120), a calibration study (N = 1084), and a validation study (N = 1481). Reliability and content, construct, and nomological validity were supported, as well as measurement invariance across work role (researchers, associate professors, and full professors) and gender. Evidence from the present study shows that the AQ@workT represents a useful and reliable tool to assist university management to enhance quality of life, to manage work-related stress, and to mitigate the potential for harm to academics, particularly during a pandemic. Future studies, such as longitudinal tests of the AQ@workT, should test predictive validity among the variables in the tool

Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer's disease

Progranulin (GRN) mutations are associated with different clinical phenotypes, including Frontotemporal Lobar Degeneration (FTLD), Corticobasal Degeneration and Alzheimer's disease (AD). In addition, the range of age at onset is very wide and patients presenting initial symptoms around eighty years have been described. Previous studies demonstrated that progranulin plasma levels determination may be a reliable method to identify GRN deletion carriers. We thus evaluated progranulin plasma levels in all patients followed at our Alzheimer's Centre whose plasma was available (n = 176) and found four patients displaying low values. Three of them carried the CACT deletion in exon 7 and their clinical diagnosis was behavioral variant Frontotemporal Dementia. We also identified a patient carrying a previously reported CAGT deletion in exon 5. Here, we report on this case. The onset of symptoms was at 77 years and the initial diagnosis was of amnestic Mild Cognitive Impairment (aMCI), which converted to AD six months later. In the following years, the patient also developed behavioral disturbances, gait apraxia and parkinsonian symptoms. At present, she is 84 years old and is still followed-up periodically. This case confirms progranulin plasma levels as a reliable biomarker to identify GRN deletion carriers and discriminate between FTLD and other dementias which may mimic it. We thus encourage the inclusion of this non-invasive and easy test in clinical practice

Luminous Red Novae: Stellar Mergers or Giant Eruptions?

We present extensive datasets for a class of intermediate-luminosity optical transients known as luminous red novae. They show double-peaked light curves, with an initial rapid luminosity rise to a blue peak (at -13 to -15 mag), which is followed by a longer-duration red peak that sometimes is attenuated, resembling a plateau. The progenitors of three of them (NGC 4490-2011OT1, M 101-2015OT1, and SNhunt248), likely relatively massive blue to yellow stars, were also observed in a pre-eruptive stage when their luminosity was slowly increasing. Early spectra obtained during the first peak show a blue continuum with superposed prominent narrow Balmer lines, with P Cygni profiles. Lines of Fe II are also clearly observed, mostly in emission. During the second peak, the spectral continuum becomes much redder, H alpha is barely detected, and a forest of narrow metal lines is observed in absorption. Very late-time spectra (similar to 6 months after blue peak) show an extremely red spectral continuum, peaking in the infrared (IR) domain. H alpha is detected in pure emission at such late phases, along with broad absorption bands due to molecular overtones (such as TiO, VO). We discuss a few alternative scenarios for luminous red novae. Although major instabilities of single massive stars cannot be definitely ruled out, we favour a common envelope ejection in a close binary system, with possibly a final coalescence of the two stars. The similarity between luminous red novae and the outburst observed a few months before the explosion of the Type IIn SN 2011ht is also discussed

Violent behavior of patients living in psychiatric residential facilities: A comparison of male patients with different violence histories

People with severe mental disorders and a history of violence are often seen as a difficult-to-manage segment of the population. In addition, this group is usually characterized by a high risk of crime recidivism, and poor compliance with community and aftercare programs. To investigate a sample of male patients living in Residential Facilities (RFs) with a history of violent behavior against people and to compare their characteristics with those of never-violent residents; to analyze the associations between aggressive behaviors in the last two years and a history of previous violence; and, to assess the predictors of aggressive behaviors. This study is part of a prospective observational cohort study which involved 23 RFs in Northern Italy. A comprehensive set of sociodemographic, clinical, and treatment-related information was gathered, and standardized assessments were administered to each participant. Also a detailed assessment of aggressive behaviors in the past two years was carried out. The study involved 268 males: 81 violent and 187 never-violent. Compared to never-violent patients, violent patients were younger, with a higher proportion of personality disorders, and have displayed an increased number of aggressive behaviors in the last two years. The presence of a history of violent behavior in the past significantly increases the probability of committing aggressive acts in the future

Dead or Alive? Long-term evolution of SN 2015bh (SNhunt275)

This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/mnras/stw2253Supernova (SN) 2015bh (or SNhunt275) was discovered in NGC 2770 on 2015 February with an absolute magnitude of M$_r$ ~ −13.4 mag, and was initially classified as an SN impostor. Here, we present the photometric and spectroscopic evolution of SN 2015bh from discovery to late phases (~1 yr after). In addition, we inspect archival images of the host galaxy up to ~21 yr before discovery, finding a burst ~1 yr before discovery, and further signatures of stellar instability until late 2014. Later on, the luminosity of the transient slowly increases, and a broad light-curve peak is reached after about three months. We propose that the transient discovered in early 2015 could be a core-collapse SN explosion. The pre-SN luminosity variability history, the long-lasting rise and faintness first light-curve peak suggests that the progenitor was a very massive, unstable and blue star, which exploded as a faint SN because of severe fallback of material. Later on, the object experiences a sudden brightening of 3 mag, which results from the interaction of the SN ejecta with circumstellar material formed through repeated past mass-loss events. Spectroscopic signatures of interaction are however visible at all epochs. A similar chain of events was previously proposed for the similar interacting SN 2009ip.European Research Council under the European Union's Seventh Framework Programme, Science and Technology Facilities Counci

Italian pool of asbestos workers cohorts: asbestos related mortality by industrial sector and cumulative exposure

Objective. Italy has been a large user of asbestos and asbestos containing materials until the 1992 ban. We present a pooled cohort study on long-term mortality in exposed workers. Methods. Pool of 43 Italian asbestos cohorts (asbestos cement, rolling stock, shipbuilding, glasswork, harbors, insulation and other industries). SMRs were computed by industrial sector for the 1970-2010 period, for the major causes, using reference rates by age, sex, region and calendar period. Results. The study included 51 801 subjects (5741 women): 55.9% alive, 42.6% died (cause known for 95%) and 1.5% lost to follow-up. Asbestos exposure was estimated at the plant and period levels. Asbestos related mortality was significantly increased. All industrial sectors showed increased mortality from pleural malignancies, and most als