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Breast cancer (BC) is the most diagnosed cancer in women worldwide. In estrogen receptor (ER)-positive disease, anti-estrogens and aromatase inhibitors (AI) improve patient survival; however, many patients develop resistance. Dysregulation of apoptosis is a common resistance mechanism; thus, agents that can reinstate the activity of apoptotic pathways represent promising therapeutics for advanced drug-resistant disease. Emerging targets in this scenario include microRNAs (miRs). To identify miRs modulating apoptosis in drug-responsive and -resistant BC, a high-throughput miR inhibitor screen was performed, followed by high-content screening microscopy for apoptotic markers. Validation demonstrated that miR-361-3p inhibitor significantly increases early apoptosis and reduces proliferation of drug-responsive (MCF7), plus AI-/antiestrogen-resistant derivatives (LTED, TamR, FulvR), and ER- cells (MDA-MB-231). Importantly, proliferation-inhibitory effects were observed in vivo in a xenograft model, indicating the potential clinical application of miR-361-3p inhibition. RNA-seq of tumour xenografts identified FANCA as a direct miR-361-3p target, and validation suggested miR-361-3p inhibitor effects might be mediated in part through FANCA modulation. Moreover, miR-361-3p inhibition resulted in p53-mediated G1 cell cycle arrest through activation of p21 and reduced BC invasion. Analysis of publicly available datasets showed miR-361-3p expression is significantly higher in primary breast tumours vspaired normal tissue and is associated with decreased overall survival. In addition, miR-361-3p inhibitor treatment of BC patient explants decreased levels of miR-361-3p and proliferation marker, Ki67. Finally, miR-361-3p inhibitor showed synergistic effects on BC growth when combined with PARP inhibitor, Olaparib. Together, these studies identify miR-361-3p inhibitor as a potential new treatment for drug-responsive and -resistant advanced BC.

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BACKGROUND: Psoriasis is a common long-term, immune-mediated skin condition associated with behavioural factors (e.g. smoking, excess alcohol, obesity), which increase the risk of psoriasis onset, flares and comorbidities. Motivational interviewing (MI) is an evidence-based approach to health-related behaviour change that has been used successfully for patients with long-term conditions. This study assessed change in clinicians' MI skills and psoriasis knowledge following Psoriasis and Wellbeing (Pso Well® ) training. OBJECTIVES: To investigate whether the Pso Well training intervention improves clinicians' MI skills and knowledge about psoriasis-related comorbidities and risk factors; and to explore the acceptability and feasibility of the Pso Well training content, delivery and evaluation. METHODS: Clinicians attended the 1-day training programme focused on MI skills development in the context of psoriasis. MI skills were assessed pre- and post-training using the Behaviour Change Counselling Index. Knowledge about psoriasis-related comorbidity and risk factors was assessed with a novel 22-point measure developed for the study. Interviews with clinicians were analysed qualitatively to identify perceptions about the feasibility and acceptability of the training. RESULTS: Sixty-one clinicians completed the training (35 dermatology nurses, 23 dermatologists and three primary-care clinicians). Clinicians' MI skills (P < 0·001) and knowledge (P < 0·001) increased significantly post-training. Clinicians found the training valuable and relevant to psoriasis management. CONCLUSIONS: Attendance at the Pso Well training resulted in improvements in clinicians' knowledge and skills to manage psoriasis holistically. Clinicians deemed the training itself and the assessment procedures used both feasible and acceptable. Future research should investigate how this training may influence patient outcomes.

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BACKGROUND: Psoriasis frequently requires lifetime control and current therapies vary significantly in price. High-quality economic evaluations are necessary to determine if higher-cost treatments are value for money. OBJECTIVES: This review aims to identify the cost-effectiveness of psoriasis care (whether more expensive interventions are associated with savings in health care and psoriasis management and/or improve patients' health); assess the level of uncertainty and transferability of this evidence to policy and practice; and, identify future research needs. METHODS: Searches of electronic databases Embase, MEDLINE and NHS EED for full economic evaluations were conducted in January 2012 (updated April 2014). Included articles were screened, selected and critically appraised using predefined inclusion criteria and data extraction forms: 1355 articles were identified; 37 papers reporting 71 comparisons met the inclusion criteria. Treatments evaluated were systemic (n = 45), topical (n = 22), phototherapies (n = 14) and combination (n = 4). RESULTS: Despite a significant number of recent economic evaluations, the cost-effectiveness of all therapies remains unclear. This uncertainty arises from a diversity in settings, perspective and design. Economic evaluations were constrained by limited availability of high-quality short- and long-term head-to-head comparisons of the effectiveness, safety and adherence of different interventions. CONCLUSIONS: The economic evidence is dominated by comparisons of interventions to placebo, with implicit comparisons of different therapies. There is a lack of evaluations of service model innovations to deliver complex packages of care for psoriasis. Primary and secondary integrated clinical and economic research is needed to address the limitations and to identify patient preferences and barriers/facilitators to treatment.

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Various protocols of ovarian stimulation have been proposed for optimising IVF/ICSI results in women presenting with a poor response to controlled ovarian stimulation; however, achieving a good response to stimulation for this category of patients still remains a challenge. The most extensively employed strategy to improve follicular response in these so-called 'poor responders' involves the use of high doses of gonadotrophins. A small number of randomised controlled trials and retrospective studies have evaluated the effectiveness of the high-dose FSH regimes over a 300 IU threshold. The results of these studies have shown these approaches to be of little or no clinical benefit, although both the costs of treatment and side-effects were higher. There are other studies that have examined 450 IU FSH regimens or even more. This paper presents an overview in all these clinical trials, trying to evaluate the safest and most effective upper limit of FSH that may be used for controlled ovarian hyperstimulation.

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BACKGROUND: Intracytoplasmic sperm injection (ICSI) is a more invasive option than conventional in-vitro fertilisation (IVF), which can be successful even when semen characteristics are poor. Reports of higher fertilisation rates after ICSI suggest that this technique may be better than the conventional method for all couples seeking IVF. We undertook a multicentre randomised controlled trial comparing clinical outcome after ICSI or traditional IVF in couples with non-male-factor infertility. METHODS: 415 eligible and consenting couples at four UK centres were randomly assigned IVF or ICSI (total 435 treatment cycles: IVF 224; ICSI 211). Usual clinical and laboratory protocols for the two treatment procedures were followed in each of four participating centres. The primary outcome was the implantation rate (number of gestation sacs per embryo replaced expressed as a percentage). Secondary outcomes were pregnancy and fertilisation rates associated with each treatment. Analyses were by intention to treat. FINDINGS: The implantation rate was higher in the IVF group than in the ICSI group (95/318 [30%] vs 72/325 [22%]; relative risk 1.35 [95% CI 1.04-1.76]). The pregnancy rate per cycle was also higher after IVF (72 [33%] vs 53 [26%]; 1.17 [0.97-1.35]). Mean associated laboratory time was significantly shorter with IVF than with ICSI (22.9 [SD 12.1] vs 74.0 [38.1] min; 95% CI for difference 45.6-56.6). INTERPRETATION: ICSI offers no advantage over IVF in terms of clinical outcome in cases of non-male-factor infertility. Our results support the current practice of reserving ICSI only for severe male-factor problems.

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To compare the efficacy and acceptability of conventional intravenous sedation with patient-controlled inhalational isodesox, 57 women undergoing outpatient oocyte recovery were randomly allocated to receive isodesox by face mask, while 55 women were given intravenous fentanyl and midazolam. Women's satisfaction with pain relief, peroperative pain, clouding of memory and the surgeons' assessment of operating conditions were evaluated. Thirty-eight women in the inhalation group (67%) and 41 (75%) women in the intravenous group were 'very satisfied' with their analgesia (p = 0. 41). The mean (SD) pain score in women given isodesox was 46.8 (34. 7), while in the intravenous group it was 34.1 (21.3) (p = 0.02). Oxygen saturation levels < 94% were recorded in one woman using isodesox and in 16 (29%) women given intravenous analgesia. Despite higher pain scores, in comparison with the conventional analgesia, patient-controlled isodesox offers a safer method of pain relief with comparable satisfaction rates.

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Although the conventional method of pain relief during outpatient oocyte recovery involves physician-administered drugs, patient-controlled analgesia (PCA) offers an alternative technique with the potential to give women more control over peroperative analgesia. We conducted a prospective randomized study to compare the effect of fentanyl administered either through a PCA delivery system or by a physician. Thirty-nine women were randomized to PCA during egg collection while 42 were allocated to receive intermittent doses administered by a physician. Pain was evaluated by means of a 100 mm linear analogue scale. The mean (SD) pain score in the PCA group was 38.5 (19.8) while in the other group it was 46.1 (21.3) (P = 0.1). In the PCA group, 64% of women felt very satisfied with their analgesia as compared with 57% in the non-PCA group (P = 0.6). Among the PCA users, 39% of demands were successful. Significantly more fentanyl (97.5 microg) was used in the PCA group than in the other group (84.6 microg) (P = 0.03). Though intraoperative PCA with fentanyl is an effective alternative to physician-administered techniques, many women still feel the need for more analgesia during the procedure.

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Human oocyte cryopreservation results in poor survival and subsequent fertilization rates. It has been suggested that freeze-thaw-induced changes in the zona pellucida may impair sperm penetration or attachment. The aim of this study was to compare fertilization and cleavage rates in cryopreserved oocytes inseminated by conventional in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). A total of 220 oocytes, obtained from volunteers who had undergone ovarian stimulation, were cryopreserved using a slow freeze-rapid thaw protocol with 1.5 M propanediol as the cryoprotectant. Surviving oocytes (n = 74, 34.4%) were randomly allocated for fertilization by conventional IVF (group 1) or ICSI (group 2) using cryopreserved spermatozoa from a single donor of proven fertility. Fertilization was achieved in five (13.5%) of the oocytes in group 1 and 17 (45.9%) in group 2 (P < 0.005), with only one oocyte in group 1 exhibiting normal fertilization as opposed to 16 (43.2%) in group 2 (P < 0.001). Similarly, one oocyte fertilized by IVF cleaved, while all fertilized with ICSI cleaved (P < 0.001). We conclude that although the survival of oocytes is poor following cryopreservation, fertilization and cleavage rates can be enhanced significantly using ICSI. These data also suggest that the method of cryopreservation used in this study affected the zona pellucida, such that normal sperm attachment or penetration was impaired.

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Recent widespread concern has led to legislation in the UK preventing the use of fetal ovarian tissue for the treatment of infertile women. This questionnaire-based study aimed to assess the attitudes of both fertile and infertile men and women as well as egg donors and recipients towards the use of donated eggs for treatment, diagnosis and research. Fertile individuals were significantly less aware of egg donation but the majority in both the fertile and the infertile groups approved the use of eggs for research (89 and 95% of women and 88 and 92% of men respectively) and treatment (similar percentages). However, fetal sources of oocytes were acceptable to only 15% of women in the fertile, 21% in the infertile, 35% in the recipient and 19% in the donor groups. Cadaveric sources of oocytes were slightly more acceptable (28% fertile, 28% infertile, 50% recipient and 42% donors). Both these sources of oocytes were slightly more acceptable to men. Education had little influence on attitudes, although men and women of tertiary education level said they would be less likely to have gamete donation themselves. Thus there would appear to be widespread approval for the use of donor eggs in research and treatment but not if the source of eggs is fetal or cadaveric.

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The aim of this study was to investigate the effects of two different biopsy strategies, zona slitting and zona piercing, on the post-thaw survival and subsequent in-vitro development of 8-cell mouse embryos. From control experiments it was determined that neither biopsy by zona slitting nor zona piercing adversely affected embryo development in vitro, as similar rates of blastocyst formation and hatching were found between biopsied and zona-intact embryos; there was, however, a trend towards a lower rate of blastocyst hatching in embryos biopsied by zona piercing (78.3% compared with 91.9% of zona-intact embryos). When biopsy was followed by cryopreservation a different picture was seen: similar rates of freeze-thaw survival were found for zona-slit, zona-pierced and zona-intact embryos (84.2, 88.5 and 87.2% respectively), but this was superseded by a significant (P < 0.05) reduction in the blastocyst formation rates (61.4% zona-slit and 63.9% zona-pierced versus 78.7% zona-intact) and hatching rates (51% zona-slit and 52.5% zona-pierced versus 72.3% zona-intact) of the biopsied embryos. When the effects of zona slitting and piercing were considered in isolation, i.e. without performing biopsy, it was found that the larger holes produced by zona slitting rendered embryos more susceptible to freeze-thaw damage.(ABSTRACT TRUNCATED AT 250 WORDS)

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The anti-oestrogens, clomiphene citrate, tamoxifen and cyclofenil are commonly used in the treatment of female infertility. Their role in the management of anovulation is well established but there is continuing controversy about their relevance to other areas of management. We have studied the effects of each of these drugs on cervical mucus and sperm-cervical mucus interaction among 23 patients with unexplained infertility. Each patient received all three drugs in an alternative month treatment regime and in addition acted as her own control. The starting point in each patient was randomized. Luteinizing hormone (LH) and oestradiol were measured daily from day 10, and follicle scanning was also undertaken. Cervical mucus quality and sperm-cervical mucus interaction were studied on the day of onset of the LH surge. The use of clomiphene and tamoxifen resulted in a significant reduction in cervical mucus score and sperm-cervical mucus interaction as judged by the distance travelled by the vanguard spermatozoa. Cyclofenil had no effect on these parameters.

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Serial ovarian ultrasound and daily assessments of plasma concentrations of pituitary and ovarian hormones were used to investigate ovarian function in 175 women with unexplained infertility. Their endocrine and ultrasound profiles were compared with similarly derived data from 43 normal volunteers. Fifty-one (29.1%) of the study group showed subnormal luteal phase rises in progesterone concentrations, described as poor progesterone surge (PPS) cycles. Within this group, 23 women (45.1%) demonstrated luteal cyst formation, a pattern not seen in any of the control cycles. High concentrations of follicle stimulating hormone (FSH) and reduced concentrations of oestradiol (E2) were observed in the follicular phases of the PPS cycles suggesting that the phenomenon is a product of abnormal follicular metabolism. An association of PPS with infertility exists, perhaps related to a combination of disturbances in the follicular micro-environment compromising oocyte quality, a failure of oocyte release, and impaired endometrial receptivity.

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A prospective, controlled study of ovarian function using ovarian ultrasound and daily plasma hormone estimations (estradiol, progesterone [P], follicle-stimulating hormone [FSH], luteinizing hormone [LH]) was carried out on 175 spontaneously cycling patients with unexplained infertility. Forty-one (23.4%) demonstrated luteal phase cyst formation. In 21 cycles the dominant follicle reduced in size after the LH peak (cystic corpus luteum cycles), and in 20 no shrinkage was seen (luteinized unruptured follicles). Progesterone concentrations in the early luteal phase were significantly reduced in the luteinized unruptured follicle cycles. Elevation in plasma FSH was seen in the early follicular and luteal phases of both cyst forming groups and may be due to disturbances in ovarian metabolism. Follicular rupture is important for efficient P release by the corpus luteum.

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Infertile women with oligomenorrhoea and elevated LH concentrations (presumed polycystic ovary disease, PCO) were treated with exogenous gonadotrophins, HMG and HCG, for induction of follicular growth and ovulation, respectively. This was effected in the absence or presence of a gonadotrophin releasing hormone analogue (GnRH-A) to suppress basal LH and the positive feedback surge of LH. Analyses of the duration of HMG therapy required to attain the degree of stimulation for HCG to be administered showed no difference between those with and without LH suppression. Analyses of the ultrasound estimations of rates of follicle growth and continued recruitment during the course of HMG also failed to show any effect of LH suppression. These data show that the high sensitivity of these patients to HMG is not related to the circulating LH concentrations.

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The patient was 8 years subfertile and had failed other forms of treatment when she was enrolled in the GIFT program. Of the total of 16 oocytes recovered 4 were transferred and the remaining 12 inseminated with her husband's sperm. Four resulting embryos were frozen. When she did not conceive, the 4 embryos were thawed 3 months later and replaced into her. She conceived and recently delivered a pair of twins. The protocol will be discussed in detail. Cryopreservation of embryos therefore may increase the patient's chance of pregnancy in a GIFT program.

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