The evidence that eicosanoids could be involved in endometrial function was gained over the 30 years after the initial observation that endometrium contained prostaglandins (PGs) and that the levels of PGs varied throughout the menstrual cycle. The changes observed in the capacity of endometrium to synthesize and metabolize eicosanoids during the menstrual cycle and the ability of ovarian steroids to alter PG synthesis in endometrium pointed to a role for PGs in the etiology of dysfunctional menstruation. Disorders of menstruation may be broadly divided into those arising from disturbances of cycle length, usually arising from changes of hypothalamo-pituitary-ovarian function, and those like menorrhagia, dysmenorrhea, and premenstrual syndrome, which occur most frequently with ovulatory cycles. Treatment of these problems by medical means is hampered by the limited knowledge of the underlying mechanisms of menstruation. The emphasis on disorders of eicosanoid synthesis should not deflect attention from the other paracrine and autocrine factors which may alter endometrial functions themselves or eicosanoid synthesis.

Abstract Mutations in estrogen receptor alpha (ERα) are detected in up to 30% of breast cancer patients who have relapsed during endocrine therapy. ERα mutations functionally confer resistance to existing classes of endocrine therapies, likely through gaining constitutive activity. The fact that current ER-directed therapies are only partially effective in the ERα mutant setting, and that a significant proportion of resistant breast cancer metastases continue to remain dependent on ERα signaling for growth/survival, highlights the critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Using structure-based drug design approaches we have identified a novel class of ERα antagonist referred to as Selective ERα Covalent Antagonist (SERCA) that inactivate both wild-type and mutant ERα by targeting a unique cysteine residue that is not conserved among other steroid hormone receptors. Biophysical, biochemical and cellular analyses confirm the covalent mechanism of action, specific binding to ER and selective inhibition of ERα-dependent transcription of SERCAs. H3B-6545 is a highly selective SERCA that potently antagonizes wild-type and mutant ERα in biochemical and cell based assays demonstrating increased potency over standard of care and other experimental agents. In vivo, H3B-6545 shows superior efficacy to fulvestrant in the MCF-7 xenograft model with once daily oral dosing, achieving maximal antitumor activity at doses >10x below the maximum tolerated dose in mice. In addition, H3B-6545 shows superior antitumor activity to both tamoxifen and fulvestrant in patient derived xenograft models of breast cancer carrying estrogen receptor mutations. In summary, H3B-6545 is a first-in-class, orally available and selective ER covalent antagonist with a compelling pre-clinical profile that is being developed for the treatment of ERα positive breast cancer. Citation Format: Korpal M, Puyang X, Furman C, Zheng GZ, Banka D, Wu J, Zhang Z, Thomas M, Mackenzie C, Yao H, Rimkunas V, Kumar P, Caleb B, Karr C, Subramanian V, Irwin S, Larsen N, Vaillancourt F, Nguyen T-V, Davis A, Chan B, Hao MH, O'Shea M, Prajapati S, Agoulnik S, Kuznetsov G, Kumar N, Yu Y, Lai G, Hart A, Eckley S, Fekkes P, Bowser T, Joshi JJ, Selvaraj A, Wardell S, Norris J, Smith S, Reynolds D, Mitchell L, Wang J, Yu L, Kim A, Rioux N, Sahmoud T, Warmuth M, Smith PG, Zhu P. Development of a first-in-class oral selective ERα covalent antagonist (SERCA) for the treatment of ERαWT and ERαMUT breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-08.

Introduction: The molecular pathways underlying the heterogeneous response to exercise in individuals at risk for cardiovascular disease remain unclear. Less is known about the molecular links to c...

Background:The effectiveness and efficiency of memory assessment services (MASs) is unknown. Our aim was to determine if a typology can be constructed, based on shared structural and process characteristics, as a basis for a non-randomized evaluation of their effectiveness and cost-effectiveness.Methods:Survey of random sample of 73 MASs in 2015; comparison of characteristics and investigation of inter-correlation.Results:It was not possible to group characteristics to form the basis of a typology of MASs. However, there was considerable variation in staff numbers (20-fold), new patients per whole-time equivalent (WTE) staff (20-fold), skill mix and the nurse:doctor ratio (1-10). The operational performance also varied: first appointments (50-120 minutes); time for first follow-up (2-12 weeks); frequency of follow-up in first year (1-5). These differences were not associated with the number of new patients per WTE staff or the accreditation status of the MAS. Post diagnosis, all MASs provided pharmacological treatment but the availability of non-pharmacological support varied, with half providing none or only one intervention while others providing four or more.Conclusions:In the absence of any clear typology, evaluation of MASs will need to focus on the impact of individual structural and process characteristics on outcomes.

Introduction and Objectives Tumour Necrosis Factor receptor 1 (TNFR1) transduces the pro-inflammatory activity of TNF-α, whereas signalling through TNFR2 may contribute to tissue repair. Attenuation of TNFR1 signalling, whilst simultaneously preserving the effects of TNFR2 signalling, may be beneficial in management of acute lung injury (ALI). GSK1995057 is a novel, fully human antibody fragment (domain antibody) that selectively binds TNFR1 and antagonises signalling of TNF-α via TNFR1. The aim of this clinical study was to investigate the effect of nebulised GSK1995057 on pulmonary and systemic inflammation and cell injury in an in vivo human model of lung injury induced by inhaled lipopolysaccharide (LPS). Methods Healthy subjects were enrolled in a double-blind, placebo-controlled study and randomised to nebulised GSK1995057 or placebo (1:1) administered 1 hour prior to LPS inhalation. Measurements were performed in bronchoalveolar lavage (BAL) fluid obtained at 6 hours after LPS challenge (7 hours after dosing) and in serum obtained over 24 hours post dosing of GSK1995057. The primary endpoint was BAL neutrophil count at 6 hours post LPS exposure. Data are geometric mean (95% CI). Results Thirty-seven healthy subjects were enrolled. One subject in the placebo group was excluded from the analysis of BAL markers as the BAL was technically poor. Pre-treatment with inhaled GSK1995057 significantly reduced pulmonary and systemic markers of inflammation. In addition, there was a reduction in pulmonary vWF reflecting reduced endothelial cell injury/activation (Table 1). The prevalence of LPS-induced clinical symptoms (e.g. fever, nausea) was also lower in GSK1995057 treated subjects compared with placebo treated subjects. There were no serious adverse events related to study drug. Conclusion This is the first report that inhalation of a novel human antibody fragment directed against the TNFR1 receptor attenuates mechanisms implicated in the pathophysiology of ALI. GSK1995057 may be a potential therapy for ALI. ClinicalTrials.gov identifier: NCT01587807. This work was funded by GlaxoSmithKline.

The present study determined whether a 5-d progesterone-based CO-Synch protocol with a single dose of prostaglandin F2α (PGF) at progesterone withdrawal on Day 5, would yield a timed AI pregnancy rate similar to two doses of PGF given 6 h apart on Day 5. Angus cross beef heifers (N = 562) at six locations were used. All heifers received 100 µg of gonadorelin hydrochloride (GnRH) and a controlled internal drug release (CIDR) insert on Day 0. Within farm, heifers were randomly allocated to receive one dose of 25 mg dinoprost (PGF) at CIDR removal on Day 5 (1 PGF; N = 264), or two doses of 25 mg PGF, with the first dose given on Day 5 at CIDR removal, and the second dose 6 h later (2 PGF; N = 298). Most heifers (N = 415) received a heat detector patch at CIDR removal. After CIDR removal, heifers were observed twice daily through Day 7 for estrus and heat detector aid status was recorded. On Day 8, heifers were given 100 µg of GnRH, heat detector aid status was recorded, and heifers were inseminated approximately 72 h after CIDR removal. Accounting for significant variables such as location (P < 0.01), heifers in estrus at or prior to AI (P < 0.001), and a treatment by location interaction (P < 0.01), two doses of PGF on Day 5 tended to have higher pregnancy rates to timed AI compared to those that received one dose of PGF (P = 0.06). In conclusion, heifers given two doses of PGF at CIDR removal on Day 5, in a 5-d CIDR-CO-Synch protocol, tended to have a higher pregnancy rate than those that received only one dose of PGF.

Gene regulatory networks inferred from RNA abundance data have generated significant interest, but despite this, gene network approaches are used infrequently and often require input from bioinformaticians. We have assembled a suite of tools for analysing regulatory networks, and we illustrate their use with microarray datasets generated in human endothelial cells. We infer a range of regulatory networks, and based on this analysis discuss the strengths and limitations of network inference from RNA abundance data. We welcome contact from researchers interested in using our inference and visualization tools to answer biological questions.

The most valuable asset that we possess is good health. Without it, individuals struggle to take advantage of education, and nations find it harder to develop, compete, and build a cohesive society.

Progesterone is essential for endometrial receptivity in primates. In studies previously performed using global gene profiling based on microarray technology, attempts have been made to identify changes in gene expression between early luteal-phase and mid-luteal-phase endometria. However, the issue of the putative impact of preimplantation embryo-derived signal in the process of endometrial receptivity was missing in the previous studies. In the present study, an attempt has been made to delineate the transcripts profile in implantation-stage endometrium under combinatorial regulation of progesterone and embryo-derived signal in the rhesus monkey. To this effect, we have compared transcript profiles for 409 known genes between control receptive stage (n=13), and mifepristone-induced desynchronized and non-receptive stage (n=12) monkey endometrial samples collected on days 4 (n=12) and 6 (n=13) after ovulation from mated, potential conception cycles, using cDNA arrays containing sequence-verified clones. Statistical analysis of correlation of estimated transcript abundance between arrays and qRT-PCR for nine selected gene products yielded significant (P<0.05) concordance. Of 409 genes, a total of 40 gene transcripts were seen to be affected, nine gene transcripts in endometrial samples were found to progressively increase between days 4 and 6 following mifepristone treatment, while an additional five genes showed differential expression profile depending on the day after treatment. Additionally, different sets of 12 and 14 gene products showed changes in days 4 and 6 post-ovulation samples respectively. A new cohort of 28 gene products in implantation-stage endometrium was seen to be affected by luteal-phase mifepristone.

Extended abstract of a paper presented at Microscopy and Microanalysis 2008 in Albuquerque, New Mexico, USA, August 3 – August 7, 2008