Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2–advanced breast cancer: GEICAM/2014–12 (FLIPPER)

Background The potential benefit of adding palbociclib to fulvestrant as first-line treatment in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative endocrine-sensitive advanced breast cancer (ABC) patients remains uncharacterized. Patients and methods In this randomized (1:1), double-blind, phase II study, postmenopausal women with HR-positive, HER2-negative ABC with de novo metastatic disease or those who relapsed after >12 months of adjuvant endocrine therapy received palbociclib/fulvestrant or placebo/fulvestrant. Stratification was based on recurrent versus de novo metastatic disease and visceral involvement. The primary objective was one-year progression-free survival (PFS-1y) rate. The sample size was 190 patients. The two-sided alpha of 0.2, 80% of power to detect a difference between the arms, assuming PFS rates of 0.695 and 0.545 for palbociclib/fulvestrant and placebo/fulvestrant, respectively. Results In total, 189 patients were randomized to palbociclib/fulvestrant ([n = 94] or placebo/fulvestrant [n = 95]). 45.5% and 60.3% of patients had de novo metastatic disease and visceral involvement, respectively. PFS-1y rates were 83.5% and 71.9% in the palbociclib/fulvestrant and placebo/fulvestrant arms, (HR 0.55, 80% CI 0.36–0.83, P = 0.064). The median PFS were 31.8 and 22.0 months for the palbociclib/fulvestrant and placebo/fulvestrant arms (aHR 0.48, 80% CI 0.37–0.64, P = 0.001). The most frequent grade 3–4 adverse events were neutropenia (68.1% vs. 0%), leucopenia (26.6% vs. 0%), anemia (3.2% vs. 0%), and lymphopenia (14.9% vs. 2.1%) for the palbociclib/fulvestrant and placebo/fulvestrant, respectively. The most frequent non-hematologic grade 3–4 adverse event was fatigue (4.3% vs. 0%). Conclusions Palbociclib/fulvestrant demonstrated better PFS-1y rates and median PFS than placebo/fulvestrant in HR-positive/HER2-negative endocrine-sensitive ABC patients

A high-throughput screening identifies microRNA inhibitors that influence neuronal maintenance and/or response to oxidative stress

Oxidative stress; Small RNA sequencing; NeurodegenerationEstrés oxidativo; Secuenciación de ARN pequeño; NeurodegeneraciónEstrès oxidatiu; Seqüenciació d'ARN petit; NeurodegeneracióSmall non-coding RNAs (sncRNAs), including microRNAs (miRNAs) are important post-transcriptional gene expression regulators relevant in physiological and pathological processes. Here, we combined a high-throughput functional screening (HTFS) platform with a library of antisense oligonucleotides (ASOs) to systematically identify sncRNAs that affect neuronal cell survival in basal conditions and in response to oxidative stress (OS), a major hallmark in neurodegenerative diseases. We considered hits commonly detected by two statistical methods in three biological replicates. Forty-seven ASOs targeting miRNAs (miRNA-ASOs) consistently decreased cell viability under basal conditions. A total of 60 miRNA-ASOs worsened cell viability impairment mediated by OS, with 36.6% commonly affecting cell viability under basal conditions. In addition, 40 miRNA-ASOs significantly protected neuronal cells from OS. In agreement with cell viability impairment, damaging miRNA-ASOs specifically induced increased free radical biogenesis. miRNAs targeted by the detrimental ASOs are enriched in the fraction of miRNAs downregulated by OS, suggesting that the miRNA expression pattern after OS contributes to neuronal damage. The present HTFS highlighted potentially druggable sncRNAs. However, future studies are needed to define the pathways by which the identified ASOs regulate cell survival and OS response and to explore the potential of translating the current findings into clinical applications.This work was supported by the Spanish Ministry of Economy and Competitiveness and FEDER funds (SAF2014-60551-R and SAF2017-88452-R). We acknowledge the support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership and the Centro de Excelencia Severo Ochoa 2013-2017 (SEV-2012-0208). We acknowledge the support of the Spanish Ministry of Science Innovation and Universities, Maria Maeztu Unit of Excellence Programme. We thank the staff of the Genomics Unit for the preparation of sRNA libraries and sequencing and the staff of the Biomolecular Screening and Protein Technologies Unit for their help in the setting up the high-throughput screening

Positive effect of spring advance on the diet quality of an alpine herbivore

Funding: Govern d'Andorra (ATC015 AND 2015/2016, 2016/2017, and 2017/2018).Altres ajuts: Acord transformatiu CRUE-CSICChanges in vegetation phenology related to global warming are having alarming effects on the life history traits of many herbivore species. Such changes are particularly critical in alpine ecosystems, where strong climate limitations on plant growth make seasonal synchronization imperative for the growth, reproduction and survival of herbivores. However, despite the pivotal role of resource-use strategies on the performances of such species, few studies have explicitly assessed the mechanistic impact of climate change on their diets. We aimed to fill this gap by studying the effect of spring onset on the dietary composition and quality of a medium-size alpine herbivore while considering density-dependent processes and age- and sex-specific differences in foraging behavior. Using an exceptional, long-term (24 years) direct individual-based dietary monitoring of a Pyrenean chamois population (Rupicapra pyrenaica pyrenaica), we showed that ongoing earlier onsets of spring are leading to an earlier access to high-quality forage and therefore a higher diet quality at a fixed date, without apparent changes in diet composition. We also showed that at high densities, intraspecific competition reduced diet quality by driving animals to feed more on woody plants and less on nutritious forbs and graminoids. By assessing the mechanistic effects of global warming on the dietary patterns of species at the center of trophic networks, this study is an essential step for predictive models aiming at understanding the ongoing ecosystem consequences of the global climatic crisis

Evangelical Visitor- October 2, 1911. Vol. XXV. No. 20.

Evangelical Visitor published in Harrisburg, Pa., for the exposition of true, practical piety and devoted to the spread of evangelical truths and the unity of the church. Published in the interest of the church of the Brethren in Christ on October 2, 1911. Vol. XXV. No. 20

Involving Children and Teenagers With Bilateral Cochlear Implants in the Design of the BEARS (Both EARS) Virtual Reality Training Suite Improves Personalization

Older children and teenagers with bilateral cochlear implants often have poor spatial hearing because they cannot fuse sounds from the two ears. This deficit jeopardizes speech and language development, education, and social well-being. The lack of protocols for fitting bilateral cochlear implants and resources for spatial-hearing training contribute to these difficulties. Spatial hearing develops with bilateral experience. A large body of research demonstrates that sound localisation can improve with training, underpinned by plasticity-driven changes in the auditory pathways. Generalizing training to non-trained auditory skills is best achieved by using a multi-modal (audio-visual) implementation and multi-domain training tasks (localisation, speech-in-noise, and spatial music). The goal of this work was to develop a package of virtual-reality games (BEARS, Both EARS) to train spatial hearing in young people (8–16 years) with bilateral cochlear implants using an action-research protocol. The action research protocol used formalized cycles for participants to trial aspects of the BEARS suite, reflect on their experiences, and in turn inform changes in the game implementations. This participatory design used the stakeholder participants as co-creators. The cycles for each of the three domains (localisation, spatial speech-in-noise, and spatial music) were customized to focus on the elements that the stakeholder participants considered important. The participants agreed that the final games were appropriate and ready to be used by patients. The main areas of modification were: the variety of immersive scenarios to cover age range and interests, the number of levels of complexity to ensure small improvements were measurable, feedback, and reward schemes to ensure positive reinforcement, and an additional implementation on an iPad for those who had difficulties with the headsets due to age or balance issues. The effectiveness of the BEARS training suite will be evaluated in a large-scale clinical trial to determine if using the games lead to improvements in speech-in-noise, quality of life, perceived benefit, and cost utility. Such interventions allow patients to take control of their own management reducing the reliance on outpatient-based rehabilitation. For young people, a virtual-reality implementation is more engaging than traditional rehabilitation methods, and the participatory design used here has ensured that the BEARS games are relevant

Phase III Trial of Everolimus in Metastatic Renal Cell Carcinoma: Subgroup Analysis of Japanese Patients from RECORD-1

Objective: To assess the efficacy and safety of everolimus in Japanese patients with metastatic renal cell carcinoma. Methods: A subgroup analysis of the pivotal Phase III, randomized, double-blind, placebocontrolled trial of everolimus 10 mg/day in patients with disease progression after treatment with sorafenib, sunitinib or both assessed outcomes in Japanese participants. Results were compared with those for the overall study population. Results: The final trial analysis included 24 Japanese patients (everolimus, n 15; placebo, n 9). Median progression-free survival in the Japanese subpopulation was 5.75 months (95% confidence interval, 4.90 months to not reached) with everolimus and 3.61 months (95 % confidence interval, 1.91–9.03 months) with placebo (hazard ratio, 0.19; 95 % confidence interval, 0.05–0.83). Median overall survival was not reached with everolimus and was 14.9 month

Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer

Background. Immunotherapy has shown efficacy in small cell lung cancer (SCLC), but only a subset of patients benefits. Surrogate biomarkers are urgently needed. Our aim was to evaluate serum Th1, Th2, and proinflammatory cytokines in two cohorts of SCLC patients before and during treatment with chemotherapy with or without ipilimumab and to correlate them with survival. Patients and methods. Two cohorts of SCLC patients were studied: patients treated with chemotherapy (n = 47), and patients treated with chemotherapy plus ipilimumab (n = 37). Baseline, on-treatment and after-treatment serum samples were evaluated for the presence of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha, GM-CSF, and Mip-1alpha using a Luminex assay. Differential changes in cytokines between cohorts were analyzed. Associations between cytokine levels and their changes with overall survival were evaluated. Results. Patients treated with ipilimumab showed a global increase of all cytokines after treatment initiation. A high level of IL-8 at baseline was associated with worse prognosis regardless of treatment. Baseline increased IL-2 levels predicted sensitivity to ipilimumab, while high IL-6 and TNF-alpha predicted resistance. An on-treatment increase in IL-4 levels in patients treated with immune-chemotherapy was associated with a better overall survival. Conclusions. The addition of ipilimumab to standard chemotherapy in SCLC modulates the serum levels of cytokines. Baseline levels and their change over time relate to overall survival. Blood-based biomarkers are convenient for patients, and our results support prospective validation of cytokines as predictive biomarkers for ipilimumab in SCLC

FISH and immunohistochemical status of the hepatocyte growth factor receptor (c-Met) in 184 invasive breast tumors

Grants PI05/0961 and PI06/1513 from Ministerio de Sanidad y Consumo ISCIII and RTICC 06/0020/1

Plucked human hair as a tissue in which to assess pharmacodynamic end points during drug development studies

We have demonstrated the feasibility of detecting and quantifying six cell-cycle-related nuclear markers (Ki67, pRb, p27, phospho-p27 (phosphorylated p27), phospho-pRb (phosphorylated pRb), phospho-HH3 (phosphorylated histone H3)) in plucked human scalp and eyebrow hair. Estimates of the proportion of plucked hairs that are lost or damaged during processing plus the intra- and intersubject variability of each nuclear marker with these techniques are provided to inform sizing decisions for intervention studies with drugs potentially impacting on these markers in the future