Relationship between hair and salivary cortisol and pregnancy in women undergoing IVF

Evidence for an association between cortisol and clinical pregnancy in women undergoing In Vitro Fertilisation (IVF) is mixed with previous studies relying exclusively on short term measures of cortisol in blood, saliva, urine, and/or follicular fluid. Hair sampling allows analysis of systemic levels of cortisol over the preceding 3–6 months. The present study sought to explore the relationship between cortisol and clinical pregnancy outcome in women undergoing IVF utilising multiple indices of cortisol derived from both saliva and hair measured prior to commencing gonadotrophin treatment. A total of 135 women (mean age 34.5 SD +/−4.8) were recruited from an English fertility clinic (December 2012–April 2014) 60% of whom became pregnant (n = 81). Salivary cortisol data were obtained over two days: upon awakening, 30 min post awakening, and at 22:00. A subsample (n = 88) of the women providing salivary samples were approached consecutively to provide hair samples for the measurement of cortisol. Independent Logistic regression analyses revealed that salivary cortisol measures including cortisol awakening response (CAR) (p = 0.485), area under the curve with respect to ground (AUCg) (p = 0.527), area under the curve with respect to increase (AUCi) (p = 0.731) and diurnal slope (p = 0.889) did not predict clinical pregnancy. In contrast, hair cortisol concentrations significantly predicted clinical pregnancy (p = 0.017). Associations between hair cortisol and clinical pregnancy remained when controlling for accumulations of salivary cortisol (p = 0.034) accounting for 26.7% of the variance in pregnancy outcome. These findings provide preliminary evidence that longer term systemic cortisol may influence reproductive outcomes; and in turn suggests that interventions to reduce cortisol prior to commencing IVF could improve treatment outcomes

FLIP: A Targetable Mediator of Resistance to Radiation in Non-Small Cell Lung Cancer

Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IRinduced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR

Realistic Medicine: changing culture and practice in the delivery of health and social care

Objective: Current models of health and social care services are stretched and do not always suit patients, their carers or the aspirations of the workforce. Realistic Medicine aims to improve patient care by ensuring that people receive appropriate, beneficial, evidence-based care aligned with their personal preferences. This paper builds on a keynote address delivered at ICCH 2018. Methods: We explore the six core principles of Realistic Medicine: (i) building a personalised approach to patient care; (ii) changing style to shared decision-making; (iii) reducing harm and waste; (iv) tackling unwarranted variation in practice and outcomes; (v) managing risk better; (vi) becoming improvers and innovators in healthcare. Results: Realistic Medicine is being embedded across Scotland, championed by local and national clinical leaders. There is particular focus on engaging patients around shared-decision making and improving value in healthcare. Conclusion: Realistic Medicine is the first example of these principles being articulated clearly and collectively as the essential components of a health and care system’s national improvement strategy. It reflects the care that most professional staff wish to provide. Practice implications: To deliver Realistic Medicine, all health and social care professionals must be empowered to work together in teams, networks and in partnership with people

Oncogenic Kras Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17.

Oncogenic mutations in Kras occur in 40%-45% of patients with advanced colorectal cancer (CRC). We have previously shown that chemotherapy acutely activates ADAM17 resulting in growth factor shedding, growth factor receptor activation and drug resistance in CRC tumours. In this study, we examined the role of mutant Kras in regulating growth factor shedding and ADAM17 activity using isogenic Kras mutant (MT) and wild type (WT) HCT116 CRC cells. Significantly higher levels of TGF-α and VEGF were shed from KrasMT HCT116 cells, both basally and following chemotherapy treatment, and this correlated with increased pErk1/2 levels and ADAM17 activity. Inhibition of Kras, MEK1/2 or Erk1/2 inhibition abrogated chemotherapy-induced ADAM17 activity and TGF-α shedding. Moreover, we found that these effects were not drug- or cell line-specific. In addition, MEK1/2 inhibition in KrasMT xenografts resulted in significant decreases in ADAM17 activity and growth factor shedding in vivo, which correlated with dramatically attenuated tumour growth. Furthermore, we found that MEK1/2 inhibition significantly induced apoptosis both alone and when combined with chemotherapy in KrasMT cells. Importantly, we found that sensitivity to MEK1/2 inhibition was ADAM17-dependent in vitro and in vivo. Collectively, our findings indicate that oncogenic Kras regulates ADAM17 activity and thereby growth factor ligand shedding in a MEK1/2/Erk1/2-dependent manner and that KrasMT CRC tumours are vulnerable to MEK1/2 inhibitors, at least in part due to their dependency on ADAM17 activity