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The ERBB tyrosine kinase receptors and their ligands belong to a complex family that has diverse biological effects and expression profiles in the developing mammary glands, where its members play an essential role in translating hormone signals into local effects. While our understanding of these processes stems mostly from mouse models, there is the potential for differences in how this family functions in the mammary glands of other species, particularly in light of their unique histomorphological features. Herein we review the postnatal distribution and function of ERBB receptors and their ligands in the mammary glands of rodents and humans, as well as for livestock and companion animals. Our analysis highlights the diverse biology for this family and its members across species, the regulation of their expression, and how their roles and functions might be modulated by varying stromal composition and hormone interactions. Given that ERBB receptors and their ligands have the potential to influence processes ranging from normal mammary development to diseased states such as cancer and/or mastitis, both in human and veterinary medicine, a more complete understanding of their biological functions should help to direct future research and the identification of new therapeutic targets.

IntroductionAromatase inhibitors are effective in lowering breast cancer incidence among postmenopausal women, but adverse events represent a barrier to their acceptability and adherence as a preventive treatment. This study aims to assess whether lowering exemestane schedule may retain biological activity while improving tolerability in breast cancer patients.Methods/designWe are conducting a, pre-surgical, non-inferiority phase IIb study in postmenopausal women with newly diagnosed estrogen receptor-positive breast cancer. Participants are randomized to receive either exemestane 25 mg/day or 25 mg/three times-week or once a week for 4 to 6 weeks prior to surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery comparing the three arms. Sample size of 180 women was calculated assuming a 6% non-inferiority of the percent change of estradiol in the lower dose arms compared with the 80% decrease predicted in the full dose arm, with 80% power and using a one-sided 5% significance level and a two-sample t-test. Main secondary outcomes are: safety; change in Ki-67 in cancer and adjacent pre-cancer tissue, circulating sex hormones, adipokines, lipid profile, insulin and glucose changes, in correlation with drug and metabolites concentrations.Results and discussionThe present paper is focused on methodology and operational aspects of the study. A total of 180 participants have ben enrolled. The trial is still blinded, and the analyses are ongoing. Despite the short term duration, results may have relevant implications for clinical management of women at increased risk of developing a ER positive breast cancer.

During the early stage of pregnancy trophoblast cells adapt to adverse uterine environments characterized by oxygen and nutrient deprivation. Autophagy is an intracellular degradation process that aims to promote cell survival in response to stressful conditions. Autophagy activation passes through the mechanistic target of rapamycin (mTOR), also known as a placental nutrient sensor. Here, we tested the hypothesis that ovine trophoblast cells may adapt to a suboptimal environment through an mTOR dependent regulation of cell survival with relevant implications for key placental functionality. Primary ovine trophoblast cells subjected to mTOR inhibitor and low-nutrient conditions were used to explore how autophagy affects cellular functionality and expression of solute carriers' genes (SLCs). Autophagy activation was confirmed both in rapamycin-treated and low-nutrient conditions, through the detection of specific autophagic markers. However, p-mTOR activation seems to be severely modified only following rapamycin treatment whereas 24h of starvation allowed p-mTOR reactivation. Starvation promoted migration compared to normal culture conditions whereas all trophoblast functional activities were decreased in rapamycin treatment. Interestingly in both conditions, the autophagy-activated environment did not affect the progesterone release. mRNA expression of amino acid transporters remains largely undisturbed except for SLC43A2 and SLC38A4 which are downregulated in starved and rapamycin-treated cells, respectively. The study demonstrates that sheep trophoblast cells can adapt to adverse conditions in the early stage of placentation by balancing, in an mTOR dependent manner, nutrient recycling and transport with relevant effects for in vitro functional properties, which could potentially impact conceptus development and survival. • Sheep trophoblast cells display uncommon responses to pro-autophagic stimuli. • mTOR inhibition interferes with stress adaptive response of trophoblast cells. • Low nutrient environment improves in vitro trophoblast migration. • Long-term starvation induces trophoblast mTOR reactivation in an autophagy-dependent manner. [ABSTRACT FROM AUTHOR]

We estimated childhood risk of developing selected DSM-IV Disorders, including Attention-Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), and Separation Anxiety Disorder (SAD), in children with prenatal cocaine exposure (PCE). Children were enrolled prospectively at birth (n = 476) with prenatal drug exposures documented by maternal interview, urine and meconium assays. Study participants included 400 African-American children from the birth cohort, 208 cocaine-exposed (CE) and 192 non-cocaine-exposed (NCE), who attended a 5-year follow-up assessment and whose caregiver completed the Computerized Diagnostic Interview Schedule for Children. Under a generalized linear model (logistic link), Fisher's exact methods were used to estimate the PCE-associated relative risk (RR) of these disorders. Our results indicated a modest but statistically robust elevation of ADHD risk associated with increasing levels of PCE (p less than 0.05). Binary comparison of CE versus NCE children indicated no PCE-associated RR. Estimated cumulative incidence proportions among CE children were 2.9% for ADHD (vs 3.1% NCE); 1.4% for SAD (vs 1.6% NCE); and 4.3% for ODD (vs 6.8% NCE). Our findings suggest evidence of increased risk of ADHD (but not ODD or SAD) in relation to an increasing gradient of PCE during gestation.

During the early stage of placentation in sheep, normal conceptus development is affected by trophoblast cell functionality, whose dysregulation results in early pregnancy loss. Trophoblast metabolism is supported mainly by histotrophic factors, including fibroblast growth factor-2 (FGF2), which are involved in cell differentiation and function through the modulation of specific cellular mechanisms. The mechanistic target of rapamycin (mTOR) is known as a cellular 'nutrient sensor', but its downstream regulation remains poorly understood. The hypothesis was that during trophoblast development, the FGF2 effect is mediated by mTOR signalling pathway modulation. Primary trophoblast cells from 21-day-old sheep placenta were characterised and subjected to FGF2 and rapamycin treatment to study the effects on cell functionality and gene and protein expression profiles. The model showed mainly mononuclear cells with epithelial cell-like growth and placental morphological properties, expressing typical trophoblast markers. FGF2 promoted cell proliferation and migration under normal culture conditions, whereas mTOR inhibition reversed this effect. When the mTOR signalling pathway was activated, FGF2 failed to influence invasion activity. mTOR inhibition significantly reduced cell motility, but FGF2 supplementation restored motility even when mTOR was inhibited. Interestingly, mTOR inhibition influenced endocrine trophoblast marker regulation. Although FGF2 supplementation did not affect ovine placenta lactogen expression, as observed in the control, interferon-tau was drastically reduced. This study provides new insights into the mechanism underlying mTOR inhibitory effects on trophoblast cell functionality. In addition, as mTOR is involved in the expression of hormonal trophoblast markers, it may play a crucial role in early placenta growth and fetal-maternal crosstalk. [ABSTRACT FROM AUTHOR]

Abstract Echinacea spp. are popularly used as an herbal medicine or food supplement for enhancing the immune system and activating biological property in different tissues. In this study we show [...]