Mitigating effect of organic matter on the in vivo toxicity of metal oxide nanoparticles in the marine environment

This is the final version of the article. Available from the Royal Society of Chemistry via the DOI in this recordMajor constituents of seawater, i.e. ions and natural organic matter (NOM), can influence the environmental and toxicological behaviour of nanoparticles (NPs) in aquatic systems. By adsorbing-ligating-reacting to NP surface reactive sites, they can modify the NP surface structure and overall physico-chemical proprieties. This study explored the fate and in vivo toxicity of ZnO and MnO2NPs under artificial seawater conditions. These two nanomaterials are representative of metal oxide NPs inducing harm via dissolution and bandgap mechanisms, respectively. To gain a comprehensive understanding of the overall toxicological outcome, we traced the behaviour of NPs in the test systems (i.e. aggregation, sedimentation, dissolution, sorption), their fate in the model organism (i.e. ingestion and cellular internalization by oyster larvae), and the induction of a toxicological pathway (i.e. oxidative stress) up to pathogenesis. We found that ZnO NPs induced harm to oyster larvae under seawater conditions, but NOM mitigated its intensity. In contrast, MnO2NPs were not toxic at the tested concentrations (up to 200 μM), and their toxicological stasis was not modified by the presence of organic matter. We propose that strong ion sorption on the MnO2NP surface blocked redox-active sites thus preventing their bandgap mode of action.his project was funded by the European Union Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement No 655134 (SOS-Nano project, Structure – Oxidative Stress relationships of metal oxide nanoparticles in the aquatic environment) and NERC FENAC access grant No PR120021. TG was further supported through NERC NE/N006178

Dissolution and bandgap paradigms for predicting the toxicity of metal oxide nanoparticles in the marine environment: an in vivo study with oyster embryos

This is the author accepted manuscript. The final version is available from Taylor & Francis via the DOI in this recordDissolution and bandgap paradigms have been proposed for predicting the ability of metal oxide nanoparticles (NPs) to induce oxidative stress in different in vitro and in vivo models. Here, we addressed the effectiveness of these paradigms in vivo and under conditions typical of the marine environment, a final sink for many NPs released through aquatic systems. We used ZnO and MnO2 NPs as models for dissolution and bandgap paradigms, respectively, and CeO2 NPs to assess reactive oxygen radical (ROS) production via Fenton-like reactions in vivo. Oyster embryos were exposed to 0.5-500 μM of each test NP over 24 h and oxidative stress was determined as a primary toxicity pathway across successive levels of biological complexity, with arrested development as the main pathological outcome. NPs were actively ingested by oyster larvae and entered cells. Dissolution was a viable paradigm for predicting the toxicity of NPs in the marine environment, whereas the surface reactivity based paradigms (i.e. bandgap and ROS generation via Fenton-like reaction) were not supported under seawater conditions. Bio-imaging identified potential cellular storage-disposal sites of solid particles that could ameliorate the toxicological behavior of non-dissolving NPs, whilst abiotic screening of surface reactivity suggested that the adsorption-complexation of surface active sites by seawater ions could provide a valuable hypothesis to explain the quenching of the intrinsic oxidation potential of MnO2 NPs in seawater.This project was funded by the European Union Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement No 655134 and NERC FENAC access grant No PR120021. TG acknowledges support from NERC grant NE/N006178/1

Pre and post anti Her-2 therapy era: a mono-institutional analysis of the outcome in patients with residual disease after neoadjuvant therapy for Her-2 positive locally advanced breast cancer.

Background: Anti Her-2+ therapies (aH2Tx) have changed the outcome of women with Her2 positive (Her2+) breast cancer and its activity showed a considerable impact in the neoadjuvant setting in which a higher rate of pathologic complete response (pCR) was observed. Of interest is the difference in outcome of patients who did not achieved a pCR and the analysis of the residual disease (RD) represents a relevant issue to explore to identify the subset of patients ( pts) with different outcome. Methods: 67 consecutive Her-2+ pts with locally advanced breast cancer (LABC) treated since 1993 to 2015 and who did not reached a pCR were evaluated. A minimum of three years of follow up was requested for the outcome analysis. Overall survival (OS) and disease free survival (DFS) has been explored in the two cohorts and the type of RD after neoadjuvant aH2Tx was also examined. Immunochemistry expression for estrogen and progesterone receptors (ER/PR) in the primary tumor for the aH2Tx-not-receiving pts was: 8 pts was ER/PR negative, 10 were ER/PR positive, 6 were ER-/PR + , 1 ER + /PR-. In the aH2Tx-receiving group: 26 were ER/PR + , 6 were ER + /PR-, 10 were ER/PR negative. Results: 25 pts did not receive aH2Tx in the neoadjuvant and 19 did not in adjuvant setting. 42 pts received aH2Tx in the neoadjuvant and 35 also in the adjuvant setting. Eleven pts in the aH2Tx-non-receiving group had recurrent disease compared with five recurrences in the aH2Tx-receiving group. The subtypes of RD in the aH2Tx not-receiving group were as follow: 4 had Luminal A like disease, 2 Luminal B like, 1 was triple negative, 18 were Her2+. For the aH2Tx-receiving group: 4 were Luminal A like, 5 Luminal B like, 30 were Her2+. The subtype of RD in the aH2Tx-not-receiving group with recurrent disease it has changed in 2 out of 11 pts if compared to primary tumor and in 2 out of 5 pts of the aH2Tx-receiving group. Conclusion: Recurrent disease was observed more often in the non-receiving aH2Tx pts, the analysis of impact of RD on outcome is still pending and will be presented at the meeting. Optimizing the selection of aH2Tx by identifying subpopulations of Her-2+ pts who need more or less therapy could be cost effective and would spare some patients unnecessary exposure to ineffective treatments

Pet ownership and cognitive decline in older people

Animals can have a positive influence on human health. However, it is not yet known whether pet ownership can prevent cognitive decline. Therefore, we aimed to investigate cross-sectional and prospective associations between pet ownership and cognitive function in a large, representative sample of older adults. Data were from the English Longitudinal Study of Ageing (ELSA) using data collected in wave 5 and six years later in wave 8. Pet ownership was categorized as no pet, dog, cat or other pet. Cognitive function was assessed using tests of verbal fluency (assessed by asking how many different animals the participants could name in 60 seconds) and memory (sum of immediate and delayed verbal recall). Multiple linear regression, adjusted for potential confounders, was used to test the associations between pet ownership and cognitive function. A total of 8291 people (mean age: 66.72 years) were included. In cross-sectional analyses, dog owners had better verbal fluency than individuals with no pet, but there was no significant difference between cat or other pet owners and those with no pet. In prospective analyses, dog owners had a significantly larger decline in recall than those with no pet, whilst cat owners had a significantly smaller decline in verbal fluency. These results provide some evidence to suggest that pet ownership may have positive effects on cognition in later life. However, benefits of pet ownership were not unilaterally observed across different types of pet and measures of cognitive function suggesting that further research is required

Epigenetic and genetic landscape of uterine leiomyomas: a current view over a common gynecological disease

Purpose: Despite the numerous studies on the factors involved in the genesis and growth of uterine leiomyomas, the pathogenesis of these tumors remains unknown. Intrinsic abnormalities of the myometrium, abnormal myometrial receptors for estrogen, and hormonal changes or altered responses to ischemic damage during the menstrual period may be responsible for the initiation of (epi)genetic changes found in these tumors. Considering these elements, we aimed to offer an overview about epigenetic and genetic landscape of uterine leiomyomas. Methods: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. Results: Several studies showed that leiomyomas have a monoclonal origin. Accumulating evidence converges on the risk factors and mechanisms of tumorigenesis: the translocation t (12;14) and deletion of 7q were found in the highest percentages of recurrence; dysregulation of the HMGA2 gene has been mapped within the critical 12q14-q15 locus. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has been poorly explored. The growth factors with mitogenic activity, such as transforming growth factor-β3, fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I are elevated in fibroids and may have a role as effectors of the tumor promotion. Conclusion: The new clues on genetics and epigenetics, as well as about the growth factors that control normal and pathological myometrial cellular biology may be of great help for the development of new effective and less invasive therapeutic strategies in the near future

Endometrial Cancer Risk Prediction According to Indication of Diagnostic Hysteroscopy in Post-Menopausal Women

We conducted a prospective observational study investigating the clinical relevance of endometrial thickness (ET) and abnormal uterine bleeding (AUB) on endometrial cancer (EC) risk in a cohort of postmenopausal patients undergoing diagnostic hysteroscopy and endometrial biopsy. Patients were divided into two groups according to the indication of diagnostic hysteroscopy: ET_Group (asymptomatic patients with endometrial thickness 4 mm) and AUB_Group (patients with a history of abnormal uterine bleeding). We further divided the AUB_Group into two subgroups based on endometrial thickness (AUB_Subgroup1: ET < 4 mm; AUB_Subgroup2: ET 4 mm). The primary outcome was the risk of endometrial cancer and atypical hyperplasia according to the indications of diagnostic hysteroscopy (AUB, ET 4 mm or both). The secondary outcome was to determine the best cut-o value of endometrial thickness to predict endometrial cancer in asymptomatic postmenopausal women. The prevalence of endometrial cancer and atypical hyperplasia in AUB_Group and ET_Group was 21% and 6.7% respectively. As well as for EC alone, higher prevalence of both conditions was observed in AUB_Subgroup2 (29.3%) in comparison to AUB_Subgroup1 (10.6%; p < 0.001). In asymptomatic patients the cut-o of endometrial thickness that showed the best sensitivity and specificity to diagnose endometrial cancer (100% and 80% respectively) was 11 mm (AUC of 91.4%; Exp : 1067; CI 95%). In conclusion, considering the high risk of neoplasia, diagnostic hysteroscopy with endometrial biopsy should be mandatory in cases of abnormal uterine bleeding in postmenopausal patients. Moreover, we want to emphasize the need for further evidence stating the clinical relevance of endometrial thickness value in asymptomatic patients and the impact of individual risk factors on endometrial cancer development

Pituitary block with gonadotrophin-releasing hormone antagonist during intrauterine insemination cycles: a systematic review and meta-analysis of randomised controlled trials

BACKGROUND: Several randomised controlled trials (RCTs) have investigated the usefulness of pituitary block with gonadotrophin-releasing hormone (GnRH) antagonists during intrauterine insemination (IUI) cycles, with conflicting results. OBJECTIVE: The aim of the present systematic review and meta-analysis of RCTs was to evaluate the effectiveness of GnRH antagonist administration as an intervention to improve the success of IUI cycles. SEARCH STRATEGY: Electronic databases (MEDLINE, Scopus, EMBASE, Sciencedirect) and clinical registers were searched from their inception until October 2017. SELECTION CRITERIA: Randomised controlled trials of infertile women undergoing one or more IUI stimulated cycles with GnRH antagonists compared with a control group. DATA COLLECTION AND ANALYSIS: The primary outcomes were ongoing pregnancy/live birth rate (OPR/LBR) and clinical pregnancy rate (CPR). Pooled results were expressed as odds ratio (OR) or mean differences with 95% confidence interval (95% CI). Sources of heterogeneity were investigated through sensitivity and subgroups analysis. The body of evidence was rated using GRADE methodology. Publication bias was assessed with funnel plot, Begg's and Egger's tests. MAIN RESULTS: Fifteen RCTs were included (3253 IUI cycles, 2345 participants). No differences in OPR/LBR (OR 1.14, 95% CI 0.82-1.57, P = 0.44) and CPR (OR 1.28, 95% CI 0.97-1.69, P = 0.08) were found. Sensitivity and subgroup analyses did not provide statistical changes in pooled results. The body of evidence was rated as low (GRADE 2/4). No publication bias was detected. CONCLUSION: Pituitary block with GnRH antagonists does not improve OPR/LBR and CPR in women undergoing IUI cycles. TWEETABLE ABSTRACT: Pituitary block with GnRH antagonists does not improve the success of IUI cycles

Fertility-sparing approach in women affected by stage i and low-grade endometrial carcinoma: An updated overview

Endometrial cancer (EC) is a deleterious condition which strongly affects a woman’s quality of life. Although aggressive interventions should be considered to treat high-grade EC, a conservative approach should be taken into consideration for women wishing to conceive. In this scenario, we present an overview about the EC fertility-sparing approach state of art. Type I EC at low stage is the only histological type which can be addressed with a fertility-sparing approach. Moreover, no myometrium and/or adnexal invasion should be seen, and lymph-vascular space should not be involved. Regarding the pharmaceutical target, progestins, in particular medroxyprogesterone acetate (MPA) or megestrol acetate (MA), are the most employed agent in conservative treatment of early-stage EC. The metformin usage and hysteroscopic assessment is still under debate, despite promising results. Particularly strict and imperious attention should be given to the follow-up and psychological wellbeing of women, especially because of the double detrimental impairment: both EC and EC-related infertility consequences

Mutational analysis of EGFR, c-KIT, PDGFRs, BRAF and KRAS, and expression of ALK and PD-L1 in a series of 103 thymic epithelial tumors with different histology

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