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Background: Prior to the introduction of tamoxifen, high dose estradiol was used to treat breast cancer patients with similar efficacy as tamoxifen, albeit with some undesirable side effects. There is renewed interest to utilize estradiol to treat endocrine resistant breast cancers, especially since findings from several preclinical models and clinical trials indicate that estradiol may be a rational second-line therapy in patients exhibiting resistance to tamoxifen and/or aromatase inhibitors. We and others reported that breast cancer patients bearing protein kinase C alpha (PKCα)- expressing tumors exhibit endocrine resistance and tumor aggressiveness. Our T47D:A18/PKCα preclinical model is tamoxifen-resistant, hormone-independent, yet is inhibited by 17β-estradiol (E2) in vivo. We previously reported that E2-induced T47D:A18/PKCα tumor regression requires extranuclear ERα and interaction with the extracellular matrix. Methods: T47D:A18/PKCα cells were grown in vitro using two-dimensional (2D) cell culture, three-dimensional (3D) Matrigel and in vivo by establishing xenografts in athymic mice. Immunofluoresence confocal microscopy and colocalization were applied to determine estrogen receptor alpha (ERα) subcellular localization. Co-immunoprecipitation and western blot were used to examine interaction of ERα with caveolin-1. Results: We report that although T47D:A18/PKCα cells are cross-resistant to raloxifene in cell culture and in Matrigel, raloxifene induces regression of tamoxifen-resistant tumors. ERα rapidly translocates to extranuclear sites during T47D: A18/PKCα tumor regression in response to both raloxifene and E2, whereas ERα is primarily localized in the nucleus in proliferating tumors. E2 treatment induced complete tumor regression whereas cessation of raloxifene treatment resulted in tumor regrowth accompanied by re-localization of ERα to the nucleus. T47D:A18/neo tumors that do not overexpress PKCα maintain ERα in the nucleus during tamoxifen-mediated regression. An association between ERα and caveolin-1 increases in tumors regressing in response to E2. Conclusions: Extranuclear ERα plays a role in the regression of PKCα-overexpressing tamoxifen-resistant tumors. These studies underline the unique role of extranuclear ERα in E2- and raloxifene-induced tumor regression that may have implications for treatment of endocrine-resistant PKCα-expressing tumors encountered in the clinic. [ABSTRACT FROM AUTHOR]

Objective: The PARENTS 1 study (Parents' Active Role and ENgagement in The review of their Stillbirth/perinatal death) found that parents would endorse the opportunity to give feedback into the perinatal mortality review (PNMR) process. In subsequent focus groups, healthcare professionals were positive about parental engagement, although they considered that there may be significant challenges. The objective of this study was to develop core principles and recommendations for parental engagement in PNMR in the UK.Methods: A two-round Delphi technique was followed to reach consensus on core principles for parental engagement in the PNMR process; Round 1 included a national consensus workshop and Round 2 an online questionnaire. The consensus meeting was attended by a national panel of stakeholders (clinical and academic experts, parent advocates, managers and commissioners) in stillbirth and neonatal and bereavement care. To develop recommendations for parental engagement, participants discussed four key areas comprising: communication with parents, including receiving feedback; the format of the PNMR meeting; the parental engagement pathway; and challenging aspects of engaging with parents in reviews. Content analysis was conducted to generate recommendations from the meeting for a subsequent anonymous web-based survey. Attendees of the consensus workshop and members of the PARENTS 2 Project Advisory Board were asked to rank recommendations using a 9-point Likert scale from 1 (not important) to 9 (critically important). It had been agreed a priori, in compliance with established Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria, that 'consensus' would be achieved if over 70% of participants scored the principle as 'critical' (score of 7-9) and fewer than 15% scored the principle as 'not important' (score of 1-3). Principles for which consensus was achieved were included in the core recommendations.Results: Of the 29 invited stakeholders, 22 participated in the consensus meeting and 25 (86% response rate) in the subsequent online questionnaire in June 2017. Consensus was agreed on 12 core principles. Of the 25 participants, 96% agreed that a face-to-face explanation of the PNMR process was of critical importance, 72% considered that parents should be offered the opportunity to nominate a suitable advocate, 92% believed that responses to parents' comments should be formally documented, 96% indicated that it was vital for action plans to be translated into lessons learnt and that this process should be monitored, and 100% of stakeholders voted that a plain-English summary should be produced for the parents following the meeting. There was good agreement on a further seven principles.Conclusions: Key national stakeholders were unanimously supportive of parental engagement in the PNMR process and agreed on core principles to make this process feasible, meaningful and robust. A 6-month pilot of parental engagement in the PNMR process (PARENTS 2 study) in two UK units took place after the consensus on core principles. In collaboration with the National Perinatal Epidemiology Unit, the findings will inform the national standardized PNMR tool. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Abstract Background: Periprosthetic fractures are a well-documented, serious complication of joint arthroplasty, occurring in up to 11% of hip replacements. We examined periprosthetic femoral fractures over an 8 year period to determine the demographics, fracture pattern and management options and associated outcomes. Furthermore, we sought to determine which comorbidities resulted in increased risk of 12 month mortality after periprosthetic fractures about hip replacements Methods: A retrospective review of a prospective fracture database was conducted for the years 2007–2015. The Fracture Outcomes Research Database (FORD) was interrogated for patients aged >60 years, admitted with periprosthetic hip fracture. Radiographic and Electronic Clinical Record review was performed to classify fractures, record treatments, comorbidies and 12 month mortality. A multivariate analysis was performed to determine comorbidities that significantly increased the risk of 12 month mortality. Results: A total of 189 patients were identified. The majority were Vancouver B1 fractures (61.9%); the operations were primarily cable plating (75.1%), with a smaller number of revision arthroplasties (21.2%) and only three proximal femoral replacement (1.6%). Four patients (2.1%) died before surgery. Only 27.3% returned to their usual residence post-discharge. Overall 30-day mortality was 2.1%, and one-year mortality was 11.6%. Patients who died tended to be older. In the multivariate analysis, ASA grade III/IV and active neoplasia were significant contributors to 12 month mortality. Conclusion(s): Our 12 month mortality (11.6%) is at the lower end of existing reported literature, and serves as a benchmark for UK practice. In the multivariate analysis, only ASA grade III/IV and an active neoplastic process were significantly associated with increased risk of mortality. Whilst large, multicenter trials, utilizing standardized treatment techniques are required to fully assess risk factors for 12-month mortality, it appears that those at significant risk are elderly, frail individuals with an active malignancy. [ABSTRACT FROM AUTHOR]

Renewable tissues exhibit heightened sensitivity to DNA damage, which is thought to result from a high level of p53. However, cell proliferation in renewable tissues requires p53 down-regulation, creating an apparent discrepancy between the p53 level and elevated sensitivity to DNA damage. Using a combination of genetic mouse models and pharmacologic inhibitors, we demonstrate that it is p53-regulated MDM2 that functions together with MDMX to regulate DNA damage sensitivity by targeting EZH2 (enhancer of zeste homolog 2) for ubiquitination/degradation. As a methyltransferase, EZH2 promotes H3K27me3, and therefore chromatin compaction, to determine sensitivity to DNA damage. We demonstrate that genetic and pharmacologic interference of the association between MDM2 and MDMX stabilizes EZH2, resulting in protection of renewable tissues from radio-/chemotherapy-induced acute injury. In cells with p53 mutation, there are diminished MDM2 levels, and thus accumulation of EZH2, underpinning the resistant phenotype. Our work uncovers an epigenetic mechanism behind tissue sensitivity to DNA damage, carrying important translation implications. [ABSTRACT FROM AUTHOR]

Abstract: Cyclodextrin (CD) is a well known drug carrier and excipient for enhancing aqueous solubility. CDs themselves are anticipated to have low membrane permeability because of relatively high hydrophilicity and molecular weight. CD derivatization with 17-beta estradiol (E2) was explored extensively using a number of different click chemistries and the cell membrane permeability of synthetic CD–E2 conjugate was explored by cell reporter assays and confocal fluorescence microscopy. In simile with reported dendrimer–E2 conjugates, CD–E2 was found to be a stable, extranuclear receptor selective estrogen that penetrated into the cytoplasm. [Copyright &y& Elsevier]

Background: Periprosthetic fractures are a well-documented, serious complication of joint arthroplasty, occurring in up to 11% of hip replacements. We examined periprosthetic femoral fractures over an 8 year period to determine the demographics, fracture pattern and management options and associated outcomes. Furthermore, we sought to determine which comorbidities resulted in increased risk of 12 month mortality after periprosthetic fractures about hip replacements Methods: A retrospective review of a prospective fracture database was conducted for the years 2007-2015. The Fracture Outcomes Research Database (FORD) was interrogated for patients aged >60 years, admitted with periprosthetic hip fracture. Radiographic and Electronic Clinical Record review was performed to classify fractures, record treatments, comorbidies and 12 month mortality. A multivariate analysis was performed to determine comorbidities that significantly increased the risk of 12 month mortality.Results: A total of 189 patients were identified. The majority were Vancouver B1 fractures (61.9%); the operations were primarily cable plating (75.1%), with a smaller number of revision arthroplasties (21.2%) and only three proximal femoral replacement (1.6%). Four patients (2.1%) died before surgery. Only 27.3% returned to their usual residence post-discharge. Overall 30-day mortality was 2.1%, and one-year mortality was 11.6%. Patients who died tended to be older. In the multivariate analysis, ASA grade III/IV and active neoplasia were significant contributors to 12 month mortality.Conclusion(s): Our 12 month mortality (11.6%) is at the lower end of existing reported literature, and serves as a benchmark for UK practice. In the multivariate analysis, only ASA grade III/IV and an active neoplastic process were significantly associated with increased risk of mortality. Whilst large, multicenter trials, utilizing standardized treatment techniques are required to fully assess risk factors for 12-month mortality, it appears that those at significant risk are elderly, frail individuals with an active malignancy. [ABSTRACT FROM AUTHOR]