In vivo epigenetic effects induced by engineered nanomaterials: A case study of copper oxide and laser printer-emitted engineered nanoparticles

Evidence continues to grow on potential environmental health hazards associated with engineered nanomaterials (ENMs). While the geno- and cytotoxic effects of ENMs have been investigated, their potential to target the epigenome remains largely unknown. The aim of this study is two-fold: 1) determining whether or not industry relevant ENMs can affect the epigenome in vivo and 2) validating a recently developed in vitro epigenetic screening platform for inhaled ENMs. Laser printer-emitted engineered nanoparticles (PEPs) released from nano-enabled toners during consumer use and copper oxide (CuO) were chosen since these particles induced significant epigenetic changes in a recent in vitro companion study. In this study, the epigenetic alterations in lung tissue, alveolar macrophages and peripheral blood from intratracheally instilled mice were evaluated. The methylation of global DNA and transposable elements (TEs), the expression of the DNA methylation machinery and TEs, in addition to general toxicological effects in the lung were assessed. CuO exhibited higher cell-damaging potential to the lung, while PEPs showed a greater ability to target the epigenome. Alterations in the methylation status of global DNA and TEs, and expression of TEs and DNA machinery in mouse lung were observed after exposure to CuO and PEPs. Additionally, epigenetic changes were detected in the peripheral blood after PEPs exposure. Altogether, CuO and PEPs can induce epigenetic alterations in a mouse experimental model, which in turn confirms that the recently developed in vitro epigenetic platform using macrophage and epithelial cell lines can be successfully utilized in the epigenetic screening of ENMs.     

Does a high Mandard score really define a poor response to chemotherapy in oesophageal adenocarcinoma?

Background A high Mandard score implies a non-response to chemotherapy in oesophageal adenocarcinoma. However, some patients exhibit tumour volume reduction and a nodal response despite a high score. This study examines survival and recurrence patterns in these patients.Methods Clinicopathological factors were analysed using multivariable Cox regression assessing time to death and recurrence. Computed tomography-estimated tumour volume change was examined in a subgroup of consecutive patients.Results Five hundred and fifty-five patients were included. Median survival was 55 months (Mandard 1–3) and 21 months (Mandard 4 and 5). In the Mandard 4 and 5 group (332 patients), comparison between complete nodal responders and persistent nodal disease showed improved survival (90 vs 18 months), recurrence rates (locoregional 14.75 vs 28.74%, systemic 24.59 vs 48.42%) and circumferential resection margin positivity (22.95 vs 68.11%). Complete nodal response independently predicted improved survival (hazard ratio 0.34 (0.16–0.74). Post-chemotherapy tumour volume reduction was greater in patients with a complete nodal response (−16.3 vs −7.7 cm³, p = 0.033) with no significant difference between Mandard groups.Conclusion Patients with a complete nodal response to chemotherapy have significantly improved outcomes despite a poor Mandard score. High Mandard score does not correspond with a non-response to chemotherapy in all cases and patients with nodal downstaging may still benefit from adjuvant chemotherapy.Subject terms: Oesophageal cancer, Surgical oncology     

Combining proteomics and lipid analysis to unravel Confidor stress response in Saccharomyces cerevisiae

The yeast Saccharomyces cerevisiae is a useful model for studying the influence of different stress factors on eukaryotic cells. In this work we used the pesticide imidacloprid, in the Confidor formulation, as the stress factor and analyzed its influence on the metabolic activity, proteome and lipid content and composition of Saccharomyces cerevisiae yeast. During the cultivation of yeast, the lowest recommended application dose of Confidor (0.025%, v/v) was added to the growth media and its influence on the mitochondria, cytosol with microsomes, and the whole yeast cells was monitored. The results show that under the stress provoked by the toxic effects of Confidor, yeast cells density significantly decreased and the percentage of metabolically disturbed cells significantly increased comparing with untreated control. Also, there was a downregulation of majority of glycolytic, gluconeogenesis, and TCA cycle enzymes (Fba1, Adh1, Hxk2, Tal1, Tdh1,Tdh3, Eno1) thus providing enough acetyl‐CoA for the lipid restructuring and accumulation mechanism since we have found the changes in the cell and mitochondrial lipid content and FA composition. This data suggest that lipids could be the molecules that orchestrate the answer of the cells in the stress response to the Confidor treatment.     

Anti-goat antibodies as a rare cause of high gonadotropin levels during menopausal transition

Abstract

Objective: To understand the origin of extremely high gonadotropin levels in a perimenopausal woman.

Methods: A 52-year-old woman with a 2?months of amenorrhea followed spontaneous menstrual cycles recovery was referred to our outpatient clinic with elevated follicle-stimulating hormone (FSH, 483 mUI/ml), luteinizing hormone (LH, 475 mUI/ml) and prolactin (PRL, 173?ng/ml). She was known to take levosulpiride. The gonadotropin levels did not fit with the clinical features.

Results: A gonadotroph tumor was ruled out. Further analysis confirmed constantly high FSH, LH and PRL levels. The measurements were repeated using different analytical platforms with different results. After serial dilutions, nonlinearity was present suggesting an immunoassay interference. After post-polyethylene glycol recovery, hormone levels appeared in the normal range. Anti-goat antibodies were recognized in the serum of the patient.

Conclusions: This case report shows a case of falsely abnormal high gonadotropin and PRL levels in a woman during menopause transition. In the clinical practice the evaluation of gonadotropin profile is not recommended at this age, but the abnormal levels stimulated further evaluation. An interference in the assay due to anti-goat antibodies resulted in abnormally high level of FSH and LH. A strict collaboration between clinicians and the laboratory is needed, when laboratory findings do not correspond to clinical findings.     

The Transient Receptor Potential Vanilloid 1 Antagonist Capsazepine Improves the Impaired Lung Mechanics during Endotoxemia

Acute lung injury (ALI) caused by systemic inflammatory response remains a leading cause of morbidity and mortality in critically ill patients. Management of patients with sepsis is largely limited to supportive therapies, reflecting an incomplete understanding of the underlying pathophysiology. Furthermore, there have been limited advances in the treatments for ALI. In this study, lung function and a histological analysis were performed to evaluate the impact of transient receptor potential vanilloid‐1 receptor (TRPV1) antagonist (capsazepine; CPZ) on the lipopolysaccharide (LPS)‐induced lung injury in mice. For this, adult mice pre‐treated with CPZ or vehicle received intraperitoneal injections of LPS or saline and 24 hr after, the mice were anaesthetized, and lung mechanics was evaluated. The LPS‐challenged mice exhibited substantial mechanical impairment, characterized by increases in respiratory system resistance, respiratory system elastance, tissue damping and tissue elastance. The pre‐treatment with CPZ prevented the increase in respiratory system resistance and decreased the increase in tissue damping during endotoxemia. In addition, mice pre‐treated with CPZ had an attenuated lung injury evidenced by reduction on collapsed area of the lung parenchyma induced by LPS. This suggests that the TRPV1 antagonist capsazepine has a protective effect on lung mechanics in ALI during endotoxemia and that it may be a target for enhanced therapeutic efficacy in ALI.