Transient over-expression of estrogen receptor-�� in breast cancer cells promotes cell survival and estrogen-independent growth

Estrogen receptor-?? (ER??) positive breast cancer frequently responds to inhibitors of ER?? activity, such as tamoxifen, and/or to aromatase inhibitors that block estrogen biosynthesis. However, many patients become resistant to these agents through mechanisms that remain unclear. Previous studies have shown that expression of ER?? in ER??-negative breast cancer cell lines frequently inhibits their growth. In order to determine the consequence of ER?? over-expression in ER??-positive breast cancer cells, we over-expressed ER?? in the MCF-7 breast cancer cell line using adenovirus gene transduction. ER?? over-expression led to ligand-independent expression of the estrogen-regulated genes pS2 and PR and growth in the absence of estrogen. Interestingly, prolonged culturing of these cells in estrogen-free conditions led to the outgrowth of cells capable of growth in cultures from ER?? transduced, but not in control cultures. From these cultures a line, MLET5, was established which remained ER??-positive, but grew in an estrogen-independent manner. Moreover, MLET5 cells were inhibited by anti-estrogens showing that ER?? remains important for their growth. Gene expression microarray analysis comparing MCF-7 cells with MLET5 highlighted apoptosis as a major functional grouping that is altered in MLET5 cells, such that cell survival would be favoured. This conclusion was further substantiated by the demonstration that MLET5 show resistance to etoposide-induced apoptosis. As the gene expression microarray analysis also shows that the apoptosis gene set differentially expressed in MLET5 is enriched for estrogen-regulated genes, our findings suggest that transient over-expression of ER?? could lead to increased cell survival and the development of estrogen-independent growth, thereby contributing to resistance to endocrine therapies in breast cancer patients.     

A graduate student mentoring program to develop interest in research

Objective. To assess the impact of a graduate student mentoring program on student interest in research and postgraduate education and on graduate student confidence in mentoring.Methods. Undergraduate and pharmacy students (mentees) and graduate students (mentors) were matched and participated in the study, which required them to engage in at least 2 discussions regarding research and careers. Mentees completed a pre- and post-assessment of their perceptions of research, postgraduate training plans, and perceptions about mentors. Mentors completed a pre- and post-assessment of their perceptions about themselves as mentors and their confidence in mentoring.Results. Although there were no significant differences among the mentees' perceptions of research or the mentors' confidence in mentoring, qualitative analysis indicated that the mentees' perceptions of research improved and that the mentors believed their mentoring skills improved.Conclusions. Based on the results of the qualitative analysis, implementing a graduate student mentoring program may help improve students' perceptions of research and graduate students' confidence in mentoring, which could increase student interest in postgraduate education and prepare mentors for future leadership roles.     

Circulating CD4+ CD25 high FoxP3+ T cells vary in different clinical forms of leprosy

Background CD4⁺ CD25^highFoxP3⁺ regulatory T cells (T‐regs) were reported to increase in chronic infections. We aimed at studying their frequency in leprosy to investigate their role during Mycobacterium leprae infection. Methods Using flow cytometry, the frequency and FoxP3 expression of circulating T‐regs was assessed in 38 leprosy patients and 38 healthy controls. Patients were divided into; group I tuberculoid (TT), group II borderline cases [borderline tuberculoid (BT), borderline (BB), and borderline lepromatous (BL)], group III lepromatous (LL), and group IV erythema nodosum leprosum (ENL). Results Mean T‐regs% and FoxP3 expression were significantly elevated in patients (particularly TT) compared to controls (3.8 ± 2.5% vs. 2.5 ± 0.8% and 78.8 ± 56.2% vs. 55.8 ± 15.7%, respectively) (P < 0.05). Comparing the four disease groups, T‐regs% was significantly different (median 5.3% in group I, 3.4% in group II, 2.8% in group III, and 1.2% in group IV; P = 0.005). FoxP3% on T‐regs was not significantly different between them [median 71.5% in TT, 62.3% in borderline categories, 67.75% in LL, and 85.75% in ENL; P = 0.149). Notably FoxP3 expression was significantly higher in ENL than controls (P = 0.011). Conclusion The frequency and suppressive marker of circulating T‐regs are elevated in TT patients. Patients with LL and ENL express significantly lower frequency of T‐regs and higher FoxP3 expression (in ENL), consistent with disease progression and immune hyper‐activation in these disease categories. Thus, rather than being detrimental to immunity, intact T‐regs activity may be beneficial to leprosy patients.     

Cumulative administrations of gadolinium-based contrast agents: risks of accumulation and toxicity of linear vs macrocyclic agents

Abstract

Ever since gadolinium was found to deposit in the brain of patients with normal kidney function by Kanda et al. in 2014, several studies have been conducted to evaluate its effect on the patients’ health. However, conflicting results were obtained regarding imaging in gadolinium retention. These finding were attributed to the chelating structure of the administered gadolinium-based contrast agent (GBCA): linear agents were found to accumulate in the dentate nucleus (DN) and the globus pallidus (GP) of subjects even after one dose. There are some contradictory results when assessing macrocyclic agents. In the following article, we review the basis of GBCAs characteristics and their side effects, as well as, the MRI studies that assessed the accumulation of gadolinium in the brain. Based on the results of several studies, in 2017, the European Medicine Agency requested the suspension of the marketing authorizations for three linear GBCAs: gadodiamide (Omniscan®), gadoversetamide (Optimark®) and gadopentate dimeglimine (Magnevist®) and limited the use of gadoxetate disodium (Primovist/Eovist®) and gadobenate dimeglumine (MultiHance®) to hepatic uptake for imaging poorly vascularized hepatic lesions. Accordingly, the FDA did not restrict GBCA use, but will continue to study their safety and urged clinicians to use these agents sparingly. All macrocyclic GBCAs continued however to be used as no available valid evidence linked them to brain gadolinium retention. Regardless of possible accumulation in the brain, there is no evidence to-date that gadolinium retention leads to any disease or disorders in subjects with normal renal function. Further investigations with long-term follow-up are needed.     

A new isoflavone from Blepharis ciliaris of an Egyptian origin

A phytochemical study of the aerial parts of Blepharis ciliaris (L.) B.L. Burtt. led to the isolation of one new isoflavone glycoside caffeic acid ester: genistein-7-O-(6″-O-E-caffeoyl-β-d-glucopyranoside) (4), along with seven known compounds: methyl veratrate (1), methyl vanillate (2), protocatechuic acid (3), naringenin-7-O-(3″-acetyl-6″-E-p-coumaroyl-β-d-glucopyranoside) (5), naringenin-7-O-(6″-E-p-coumaroyl-β-d-glucopyranoside) (6), apigenin-7-O-(6″-E-p-coumaroyl-β-d-glucopyranoside) (7), and acteoside (8). Their structures were established on the basis of detailed analyses of physical, chemical, and spectral data. Compounds 1, 2, 3, 6, and 8 were isolated for the first time from this plant. The antioxidant activity of the different extracts as well as for some of the isolated compounds was evaluated.