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Female participation rates in ultra-running is considerably lower than that of males, but the reasons for this are not fully understood. In this study, online questionnaire responses were collected from ultra-runners taking part in the Scottish Jedburgh 3 Peaks ultra and Highland Fling race. One-to-one-semi-structured phone interviews were conducted with a subset of runners to further explore themes from questionnaire responses. Similar experiences among male and female ultra-runners were identified. Enablers were: wanting a challenge, nature/outdoors, and the friendliness of the ultra-community. The main barrier was training time. Qualitative responses suggested negotiation-efficacy was important for factoring in training around work and family commitments, and although a greater proportion of males had dependants compared to females, female participation was considerably lower than males. This may be due to the historical influences of traditional gender roles however this effect may be diminishing as female participation in Scottish ultra-races appears to be increasing. [ABSTRACT FROM AUTHOR]

Inclusive and modified sport promotes opportunities for participation usually for older people or people with disabilities, physical and or mental health issues. Walking sports, a form of modified sport, is often designed to support engagement in physical and social activity amongst people over 50 years. This qualitative study explored how walking football sessions were designed and delivered for, and experienced by people living with dementia and their family carers. We thematically analysed 18 qualitative interviews and identified three main themes (1) social impact, (2) embodied memories and (3) flexible carer respite. The findings increase our understanding of how walking sports such as football can be viewed as a psychosocial intervention and be modified to promote the inclusion and agency of people living with dementia and respite for family carers. The study offers best practice recommendations for those organising modified sports activities for older people living with dementia. [ABSTRACT FROM AUTHOR]

When assessing a reservoir's Hydrocarbon Initially In Place (HIIP) volumes there are often many uncertain input factors. If they are discretized into low, mid and high case scenarios, this can result in tens of thousands of possible combinations of factors and it is often necessary to reduce the amount of uncertain factors to a manageable number. This can reduce the range of model outcomes, and the confidence in the predicted volumes will be overestimated. Experimental design allows a reduced representative set of models to be constructed for uncertainty analysis when it would take too long to construct all possible realizations. This paper uses a case study to demonstrate a refined application of experimental design, whereby uncertain factors were first identified and experts were consulted to specify high, mid and low values with associated probabilities. The analysis was completed in two parts: a screening phase, whereby non-significant factors were eliminated; and an optimization phase, whereby a limited number of model runs were used to train a proxy model for use in a Monte Carlo procedure to generate a probability distribution of HIIP. The key advantage of the method is the comprehensive treatment of uncertainty with a reduced amount of modelling effort. [ABSTRACT FROM AUTHOR]

Impaired sensorimotor synchronization (SMS) to acoustic rhythm may be a marker of atypical language development. Here, Motion Capture was used to assess gross motor rhythmic movement at six time points between 5- and 11 months of age. Infants were recorded drumming to acoustic stimuli of varying linguistic and temporal complexity: drumbeats, repeated syllables and nursery rhymes. Here we show, for the first time, developmental change in infants' movement timing in response to auditory stimuli over the first year of life. Longitudinal analyses revealed that whilst infants could not yet reliably synchronize their movement to auditory rhythms, infant spontaneous motor tempo became faster with age, and by 11 months, a subset of infants decelerate from their spontaneous motor tempo, which better accords with the incoming tempo. Further, infants became more regular drummers with age, with marked decreases in the variability of spontaneous motor tempo and variability in response to drumbeats. This latter effect was subdued in response to linguistic stimuli. The current work lays the foundation for using individual differences in precursors of SMS in infancy to predict later language outcomes. RESEARCH HIGHLIGHT: We present the first longitudinal investigation of infant rhythmic movement over the first year of life Whilst infants generally move more quickly and with higher regularity over their first year, by 11 months infants begin to counter this pattern when hearing slower infant-directed song Infant movement is more variable to speech than non-speech stimuli In the context of the larger Cambridge UK BabyRhythm Project, we lay the foundation for rhythmic movement in infancy to predict later language outcomes., (© 2024 The Authors. Developmental Science published by John Wiley & Sons Ltd.)

Cognitive control is a predictor of later-life outcomes and may underpin higher order executive processes. The present study examines the development of early cognitive control during the first 24-month. We evaluated a tablet-based assessment of cognitive control among infants aged 18- and 24-month. We also examined concurrent and longitudinal associations between attentional disengagement, general cognitive skills and cognitive control. Participants (N = 60, 30 female) completed the tablet-task at 18- and 24-month of age. Attentional disengagement and general cognitive development were assessed at 5-, 8-, 12-, 18- and 24-month using an eye-tracking measure and the Mullen Scales of Early Learning (MSEL), respectively. The cognitive control task demonstrated good internal consistency, sensitivity to age-related change in performance and stable individual differences. No associations were found between infant cognitive control and MSEL scores longitudinally or concurrently. The eye-tracking task revealed that slower attentional disengagement at 8-month, but faster disengagement at 18-month, predicted higher cognitive control scores at 24-month. This task may represent a useful tool for measuring emergent cognitive control. The multifaceted relationship between attention and infant cognitive control suggests that the rapid development of the attentional system in infancy results in distinct attentional skills, at different ages, being relevant for cognitive control development., (© 2024 The Authors. Infancy published by Wiley Periodicals LLC on behalf of International Congress of Infant Studies.)

Introduction: The aim of this study was to evaluate noise exposure to the operating room staff consisting of the surgeon, assistant, anaesthetist and Mako Product Specialist (MPS) during Mako robotic-arm assisted total knee arthroplasty (TKA) and total hip arthroplasty (THA). We aimed to determine whether employees were exposed to noise at or above a lower exposure action value (LEAV) set out by the Noise at Work Regulations 2005, Health and Safety Executive (HSE), UK., Materials and Methods: We prospectively recorded intra-operative noise levels in Mako robotic-arm assisted TKA and THA over a period of two months using the MicW i436 connected to an iOS device (Apple), using the Sound Level Meter App (iOS) by the National Institute for Occupation Safety and Health (NIOSH). Data obtained was then used to calculate "worst case" daily exposure value to assess if sound levels were compliant with UK guidelines. Comparison between operating room staff groups was performed with ANOVA testing., Results: A total of 19 TKA and 11 THA operations were recorded. During TKA, for the primary surgeon and the assistant, the equivalent continuous sound pressure level (L Aeq ) was over 80 dB, exceeding the LEAV set out by the Noise at Work Regulations by HSE. During THA, the average L Aeq and peak sound pressure levels did not exceed the LEAV. The calculated daily exposure for the primary surgeon in TKA was 82 dB. A Tukey post hoc test revealed that L Aeq was statistically significantly lower in the anaesthetist and MPS (p < .001) compared to the primary surgeon and assistant in both TKA and THA., Conclusions: Operating room staff, particularly the primary surgeon and assistant are exposed to significant levels of noise during Mako robotic-arm assisted TKA and THA. Formal assessments should be performed to further assess the risk of noise induced hearing loss in robotic-arm assisted arthroplasty., (© 2024. The Author(s).)

Objectives: CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in utilizing CpG ODN as an adjuvant to improve clinical efficacy of current treatments and immunogenicity of breast cancers not traditionally responsive to active immunotherapy, such as those that are human epidermal growth factor receptor 2 (HER2)-positive. This study aimed to study the efficacy and safety of combination CpG ODN plus anti-HER2 antibody trastuzumab treatment in patients with advanced/metastatic breast cancer., Methods: This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response., Results: Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment., Conclusions: CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Neonatal units across the world have altered their policies to prevent the spread of infection during the COVID-19 pandemic. Our aim was to report parental experience in two European neonatal units during the pandemic., Methods: Parents of infants admitted to each neonatal unit were asked to complete a questionnaire regarding their experience during the COVID-19 pandemic. At King's College Hospital, UK (KCH), data were collected prospectively between June 2020 and August 2020 (first wave). At the Hospital Clínic Barcelona (HCM), data were collected retrospectively from parents whose infants were admitted between September 2020 and February 2021 (second and third wave)., Results: A total of 74 questionnaires were completed (38 from KCH and 36 from HCM). The parents reported that they were fully involved or involved in the care of their infants in 34 (89.4%) responses in KCH and 33 (91.6%) responses in HCM. Quality time spent with infants during the pandemic was more negatively affected at KCH compared with HCM (n=24 (63.2%) vs n=12 (33.3%)). Parents felt either satisfied or very satisfied with the updates from the clinical care team in 30 (79.0%) responses at KCH and 30 (83.4%) responses in HCM. The parents felt that the restrictions negatively affected breast feeding in six (15.8%) responses at KCH and two (5.6%) responses in HCM. Travelling to the hospital was reported overall to be sometimes difficult (39.2%); this did not differ between the two units (14 (36.8%) respondents at KCH and 15 (41.6%) from HCM). Furthermore, the self-reported amount of time spent giving kangaroo care also did not differ between the two countries., Conclusion: Restrictive policies implemented due to the COVID-19 pandemic had a negative impact on the perception of quality of time spent by parents with their newborns admitted to neonatal units., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Furthermore, the BROCADE studies demonstrated benefit of adding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay., Materials and Methods: Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3'-deoxythymidine ( 18 FLT) positron emission tomography (PET) imaging., Results: Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n = 1), and G3 akathisia (n = 1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUV max ) of target lesions between baseline and early in cycle 1 based on 18 FLT-PET (day 7-21; p trend  = .006)., Conclusion: The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUV max on 18 FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response., Implications for Practice: The BROCADE studies suggest that breast cancer patients with BRCA mutation benefit from addition of veliparib to carboplatin plus paclitaxel. This study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, the authors demonstrate that decrease in [18]fluoro-3'-deoxythymidine positron emission tomography (FLT-PET) SUV max during cycle 1 of therapy is associated with response. Collectively, this study established a safety profile of veliparib and carboplatin in advanced breast cancer while also providing additional data on the potential for FLT-PET imaging modality in monitoring therapy response., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: While combinations of immune checkpoint (ICP) inhibitors and neo-adjuvant chemotherapy (NAC) have begun testing in patients with breast cancer (BC), the effects of chemotherapy on ICP expression in circulating T cells and within the tumor microenvironment are still unclear. This information could help with the design of future clinical trials by permitting the selection of the most appropriate ICP inhibitors for incorporation into NAC., Methods: Peripheral blood samples and/or tumor specimens before and after NAC were obtained from 24 women with operable BC. The expression of CTLA4, PD-1, Lag3, OX40, and Tim3 on circulating T lymphocytes before and at the end of NAC were measured using flow cytometry. Furthermore, using multi-color immunohistochemistry (IHC), the expression of immune checkpoint molecules by stromal tumor-infiltrating lymphocytes (TILs), CD8+ T cells, and tumor cells was determined before and after NAC. Differences in the percentage of CD4+ and CD8+ T cells expressing various checkpoint receptors were determined by a paired Student's t-test., Results: This analysis showed decreased ICP expression by circulating CD4+ T cells after NAC, including significant decreases in CTLA4, Lag3, OX40, and PD-1 (all p values < 0.01). In comparison, circulating CD8+ T cells showed a significant increase in CTLA4, Lag3, and OX40 (all p values < 0.01). Within tumor samples, TILs, CD8+ T cells, and PD-L1/PD-1 expression decreased after NAC. Additionally, fewer tumor specimens were considered to be PD-L1/PD-1 positive post-NAC as compared to pre-NAC biopsy samples using a cutoff of 1% expression., Conclusions: This work revealed that NAC treatment can substantially downregulate CD4+ and upregulate CD8+ T cell ICP expression as well as deplete the amount of TILs and CD8+ T cells found in breast tumor samples. These findings provide a starting point to study the biological significance of these changes in BC patients., Trial Registration: NCT04022616.

Objective: The English Bowel Cancer Screening Programme (BCSP) recommends 3 yearly colonoscopy surveillance for patients at intermediate risk of colorectal cancer (CRC) postpolypectomy (those with three to four small adenomas or one ≥10 mm). We investigated whether faecal immunochemical tests (FITs) could reduce surveillance burden on patients and endoscopy services., Design: Intermediate-risk patients (60-72 years) recommended 3 yearly surveillance were recruited within the BCSP (January 2012-December 2013). FITs were offered at 1, 2 and 3 years postpolypectomy. Invitees consenting and returning a year 1 FIT were included. Participants testing positive (haemoglobin ≥40 µg/g) at years one or two were offered colonoscopy early; all others were offered colonoscopy at 3 years. Diagnostic accuracy for CRC and advanced adenomas (AAs) was estimated considering multiple tests and thresholds. We calculated incremental costs per additional AA and CRC detected by colonoscopy versus FIT surveillance., Results: 74% (5938/8009) of invitees were included in our study having participated at year 1. Of these, 97% returned FITs at years 2 and 3. Three-year cumulative positivity was 13% at the 40 µg/g haemoglobin threshold and 29% at 10 µg/g. 29 participants were diagnosed with CRC and 446 with AAs. Three-year programme sensitivities for CRC and AAs were, respectively, 59% and 33% at 40 µg/g, and 72% and 57% at 10 µg/g. Incremental costs per additional AA and CRC detected by colonoscopy versus FIT (40 µg/g) surveillance were £7354 and £180 778, respectively., Conclusions: Replacing 3 yearly colonoscopy surveillance in intermediate-risk patients with annual FIT could reduce colonoscopies by 71%, significantly cut costs but could miss 30%-40% of CRCs and 40%-70% of AAs., Trial Registration Number: ISRCTN18040196; Results., Competing Interests: Competing interests: WSA received non-financial support from Eiken Co. Ltd (MAST is UK distributor). SM is a member of the NIHR Health Services and Delivery Research (HS&DR) Funding Board. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Context: Walking football (soccer) has recently emerged as a physical activity option targeted at older males to enhance health and wellbeing., Design: This pilot study aimed to examine the feasibility of recruiting and retaining males aged 50 years and over to an 8-week walking football programme in a professional football club., Intervention: Participants were recruited via social media and assigned to an intervention group or a wait-list control group. The intervention group engaged in 1 h of walking football a week led by a community coach from the professional football club, followed by an optional social session in the club facility. Physiological and psychological outcome measures were obtained onsite at the football club facility (aiding compliance and retention) at baseline and following 8-weeks, from both groups. Semi-structured interviews were conducted after the 8-week programme and 1 year later, to explore motivations for engagement and the social impact., Results: The opportunity to engage in football and the link to a professional football club were key attractions. All participants recruited were overweight, sedentary, exhibited blood pressures outside normal ranges, and all but two were hypertensive. Adherence to the programme was 90% over 8 weeks, and of the participants who were contacted after one year, all (n = 6) had maintained engagement in walking football. Walking football is therefore a feasible, cost-effective method of recruiting and retaining males aged 50 years and over to a physical activity programme, though attrition is to be expected., (Copyright © 2018 Elsevier Inc. All rights reserved.)

New Zealand (NZ) is a small country with an export-led economy with above 90% of primary production exported. Plant-based primary commodities derived from the pastoral, horticultural and forestry sectors account for around half of the export earnings. Productivity is characterized by a history of innovation and the early adoption of advanced technologies. Gene editing has the potential to revolutionize breeding programmes, particularly in NZ. Here, perennials such as tree crops and forestry species are key components of the primary production value chain but are challenging for conventional breeding and only recently domesticated. Uncertainty over the global regulatory status of gene editing products is a barrier to invest in and apply editing techniques in plant breeding. NZs major trading partners including Europe, Asia and Australia are currently evaluating the regulatory status of these technologies and have not made definitive decisions. NZ is one of the few countries where the regulatory status of gene editing has been clarified. In 2014, the NZ Environmental Protection Authority ruled that plants produced via gene editing methods, where no foreign DNA remained in the edited plant, would not be regulated as GMOs. However, following a challenge in the High Court, this decision was overturned such that NZ currently controls all products of gene editing as GMOs. Here, we illustrate the potential benefits of integrating gene editing into plant breeding programmes using targets and traits with application in NZ. The regulatory process which led to gene editing's current GMO classification in NZ is described and the importance of globally harmonized regulations, particularly to small export-driven nations is discussed.

Background: Colorectal cancer is the third most common cancer worldwide. Previous analyses have only reported follow-up after flexible sigmoidoscopy for a maximum of 12 years. We aimed to examine colorectal cancer incidence and mortality after a single flexible sigmoidoscopy screening and 17 years of follow-up., Methods: In this multicentre randomised trial (UK Flexible Sigmoidoscopy Screening Trial), done between Nov 14, 1994, and March 30, 1999, 170 432 eligible men and women, who had indicated on a previous questionnaire that they would probably attend screening if invited, were randomly assigned (1:2) to an intervention group (offered flexible sigmoidoscopy screening) or a control group (not contacted). Randomisation was done centrally in blocks of 12, and stratified by trial centre, general practice, and household type. The nature of the intervention did not allow the staff to be masked to arm of the trial; however, randomisation was done in batches so that the control group and participants not yet randomised were unaware of their allocation status. The primary outcomes were incidence and mortality of colorectal cancer. Hazard ratios (HRs) and 95% CIs for colorectal cancer incidence and mortality were estimated for intention-to-treat and per-protocol analyses. The trial is registered with ISRCTN, number 28352761., Findings: Our cohort analysis included 170 034 people: 112 936 in the control group and 57 098 in the intervention group, 40 621 (71%) of whom were screened and 16 477 (29%) were not screened. During screening and a median of 17·1 years' follow-up, colorectal cancer was diagnosed in 1230 individuals in the intervention group and 3253 in the control group, and 353 individuals in the intervention group versus 996 individuals in the control group died from colorectal cancer. In intention-to-treat analyses, colorectal cancer incidence was reduced by 26% (HR 0·74 [95% CI 0·70-0·80]; p<0·0001) in the intervention group versus the control group and colorectal cancer mortality was reduced by 30% (0·70 [0·62-0·79]; p<0·0001) in the intervention group versus the control group. In per-protocol analyses, adjusted for non-compliance, colorectal cancer incidence and mortality were 35% (HR 0·65 [95% CI 0·59-0·71]) and 41% (0·59 [0·49-0·70]) lower in the screened group., Interpretation: A single flexible sigmoidoscopy continues to provide substantial protection from colorectal cancer diagnosis and death, with protection lasting at least 17 years., Funding: National Institute for Health Research Efficacy and Mechanism Evaluation., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Background: To assess public preferences for colorectal cancer (CRC) surveillance tests for intermediate-risk adenomas, using a hypothetical scenario., Methods: Adults aged 45-54 years without CRC were identified from three General Practices in England (two in Cumbria, one in London). A postal survey was carried out during a separate study on preferences for different first-line CRC screening modalities (non- or full-laxative computed tomographic colonography, flexible sigmoidoscopy, or colonoscopy). Individuals were allocated at random to receive a pack containing information on one first-line test, and a paragraph describing CRC surveillance recommendations for people who are diagnosed with intermediate-risk adenomas during screening. All participants received a description of two surveillance options: annual single-sample, home-based stool testing (consistent with Faecal Immunochemical Tests; FIT) or triennial colonoscopy. Invitees were asked to imagine they had been diagnosed with intermediate-risk adenomas, and then complete a questionnaire on their surveillance preferences., Results: 22.1 % (686/3,100) questionnaires were returned. 491 (15.8 %) were eligible for analysis. The majority of participants stated a surveillance preference for the stool test over colonoscopy (60.8 % vs 31.0 %; no preference: 8.1 %; no surveillance: 0.2 %). Women were more likely to prefer the stool test than men (66.7 % vs. 53.6 %; p = .011). The primary reason for preferring the stool test was that it would be done more frequently. The main reason to prefer colonoscopy was its superiority at finding polyps., Conclusions: A majority of participants stated a preference for a surveillance test resembling FIT over colonoscopy. Future research should test whether this translates to greater adherence in a real surveillance setting., Trial Registration: International Standard Randomised Controlled Trial Number registry, ISRCTN85697880 , prospectively registered on 25/04/2013.

Purpose: To develop recommendations about endocrine therapy for women with hormone receptor (HR) -positive metastatic breast cancer (MBC)., Methods: The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of evidence from 2008 through 2015 to create recommendations informed by that evidence. Outcomes of interest included sequencing of hormonal agents, hormonal agents compared with chemotherapy, targeted biologic therapy, and treatment of premenopausal women. This guideline puts forth recommendations for endocrine therapy as treatment for women with HR-positive MBC., Recommendations: Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC. Except in cases of immediately life-threatening disease, hormone therapy, alone or in combination, should be used as initial treatment. Patients whose tumors express any level of hormone receptors should be offered hormone therapy. Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and organ function. Tumor markers should not be the sole criteria for determining tumor progression; use of additional biomarkers remains experimental. Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women. For postmenopausal women, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the cyclin-dependent kinase inhibitor palbociclib. As second-line therapy, fulvestrant should be administered at 500 mg with a loading schedule and may be administered with palbociclib. The mammalian target of rapamycin inhibitor everolimus may be administered with exemestane to postmenopausal women with MBC whose disease progresses while receiving nonsteroidal AIs. Among patients with HR-positive, human epidermal growth factor receptor 2-positive MBC, human epidermal growth factor receptor 2-targeted therapy plus an AI can be effective for those who are not chemotherapy candidates., (© 2016 by American Society of Clinical Oncology.)

Purpose: Paclitaxel-based chemotherapy continues to be an integral component of breast cancer treatment. Prolonged use of paclitaxel may result in repeated doses of premedications that can have unwanted side effects. Infusion hypersensitivity reactions occurring beyond the second dose of paclitaxel are infrequent and not well characterized. We previously published the results of a small, prospective pilot trial demonstrating the safety and feasibility of discontinuing premedications in patients who received the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction. In this study, we aimed to retrospectively characterize the incidence of rescue medication using this abbreviated premedication regimen in our institution following the publication of the pilot study., Methods: Patients with stages I-IV breast cancer who received paclitaxel from January 2011 through June 2013 were screened for eligibility. Patients who did not experience an infusion hypersensitivity reaction with their first or second dose of paclitaxel and discontinued paclitaxel premedication for subsequent doses were included in this analysis. The primary endpoint was to estimate the incidence of rescue medication use for the treatment of paclitaxel infusion hypersensitivity during doses three to six of paclitaxel in the study population., Results: In total, 449 patients received paclitaxel-based chemotherapy for the treatment of breast cancer during the interval time period. After receiving the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction, 234 breast cancer patients had their premedications discontinued for all remaining paclitaxel doses. These patients tolerated future paclitaxel doses without severe or life-threatening complications related to infusion hypersensitivity. The majority of patients did not have any symptoms of an infusion reaction, with only two of these patients requiring rescue medication to treat an infusion hypersensitivity reaction with subsequent paclitaxel doses (0.85; 95 % confidence interval (CI), 0.10-3.05 %)., Conclusions: Discontinuation of paclitaxel premedications in breast cancer patients who have not experienced an infusion hypersensitivity reaction with the first two doses of paclitaxel is not associated with increased rate of rescue medication use for infusion hypersensitivity.

The mitogen-activated protein kinase (MAPK) pathway is aberrantly activated in many human cancers, including breast cancer. Activation of MAPK signaling is associated with the increased expression of a wide range of genes that promote cell survival, proliferation, and migration. This report investigated the influence of MAPK signaling on the regulation and expression of JUNB in human breast cancer cell lines. JUNB has been associated with tumor suppressor and oncogenic functions, with most reports describing JUNB as an oncogene in breast cancer. Our results indicated that JUNB expression is elevated in MCF10A(met), SKBR3, and MDA-MB-231 human breast cancer cell lines compared to nontransformed MCF10A mammary epithelial cells. Increased RAS/MAPK signaling in MCF10A(met) cells correlates with the increased association of RNA polymerase II (Pol II) phosphorylated on serine 5 (Pol IIser5p) with the JUNB proximal promoter. Pol IIser5p is the "transcription initiating" form of Pol II. Treatment with U0126, a MAPK pathway inhibitor, reduces Pol IIser5p association with the JUNB proximal promoter and reduces JUNB expression. Oncostatin M (OSM) enhances MAPK and STAT3 signaling and significantly induces JUNB expression. U0126 treatment reduces OSM-induced Pol IIser5p binding to the JUNB proximal promoter and JUNB expression, but does not reduce pSTAT3 levels or the association of pSTAT3 with the JUNB proximal promoter. These results demonstrate that the MAPK pathway plays a primary role in the control of JUNB gene expression by promoting the association of Pol IIser5p with the JUNB proximal promoter.