CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response

Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature

Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) = 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb = 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years

Diet quality index as a predictor of treatment efficacy in overweight and obese adolescents: The EVASYON study

Background & aim: A diet quality index (DQI) is a tool that provides an overall score of an individual''s dietary intake when assessing compliance with food-based dietary guidelines. A number of DQIs have emerged, albeit their associations with health-related outcomes are debated. The aim of the present study was to assess whether adherence to dietary intervention, and the overall quality of the diet, can predict body composition changes. Methods: To this purpose, overweight/obese adolescents (n = 117, aged: 13–16 years; 51 males, 66 females) were recruited into a multi-component (diet, physical activity and psychological support) family-based group treatment programme. We measured the adolescents’ compliance and body composition at baseline and after 2 months (intensive phase) and 13 months (extensive phase) of follow-up. Also, at baseline, after 6 months, and at the end of follow-up we calculated the DQI. Results: Global compliance with the dietary intervention was 37.4% during the intensive phase, and 14.3% during the extensive phase. Physical activity compliance was 94.1% at 2-months and 34.7% at 13months and psychological support compliance were growing over the intervention period (10.3% intensive phase and 45.3% during extensive phase). Adolescents complying with the meal frequency criteria at the end of the extensive phase had greater reductions in FMI z-scores than those did not complying (Cohen''s d = 0.53). A statistically significant association was observed with the diet quality index. DQI-A variation explained 98.1% of BMI z-score changes and 95.1% of FMI changes. Conclusions: We conclude that assessment of changes in diet quality could be a useful tool in predicting body composition changes in obese adolescents involved in a diet and physical activity intervention programme backed-up by psychological and family support

Effectiveness of Motivational Interviewing in improving lipid level in patients with dyslipidemia assisted by general practitioners: Dislip-EM study protocol

<p>Abstract</p> <p>Background</p> <p>The non-pharmacological approach to cholesterol control in patients with hyperlipidemia is based on the promotion of a healthy diet and physical activity. Thus, to help patients change their habits, it is essential to identify the most effective approach. Many efforts have been devoted to explain changes in or adherence to specific health behaviors. Such efforts have resulted in the development of theories that have been applied in prevention campaigns, and that include brief advice and counseling services. Within this context, Motivational Interviewing has proven to be effective in changing health behaviors in specific cases. However, more robust evidence is needed on the effectiveness of Motivational Interviewing in treating chronic pathologies -such as dyslipidemia- in patients assisted by general practitioners. This article describes a protocol to assess the effectiveness of MI as compared with general practice (brief advice), with the aim of improving lipid level control in patients with dyslipidemia assisted by a general practitioner.</p> <p>Methods/Design</p> <p>An open, two-arm parallel, multicentre, cluster, controlled, randomized, clinical trial will be performed. A total of 48-50 general practitioners from 35 public primary care centers in Spain will be randomized and will recruit 436 patients with dyslipidemia. They will perform an intervention based either on Motivational Interviewing or on the usual brief advice. After an initial assessment, follow-ups will be performed at 2, 4, 8 and 12 months. Primary outcomes are lipid levels (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides) and cardiovascular risk. The study will assess the degree of dietary and physical activity improvement, weight loss in overweight patients, and adherence to treatment guidelines.</p> <p>Discussion</p> <p>Motivational interview skills constitute the primary strategies GPs use to treat their patients. Having economical, simple, effective and applicable techniques is essential for primary care professionals to help their patients change their lifestyle and improve their health. This study will provide scientific evidence on the effectiveness of Motivational interviewing, and will be performed under strict control over the data collected, ensuring the maintenance of therapeutic integrity.</p> <p>Trials Registration</p> <p>ClinicalTrials.gov (<a href="http://www.clinicaltrials.gov/ct2/show/NCT01282190">NCT01282190</a>).</p

Oestradiol-17β plasma concentrations after intramuscular injection of oestradiol benzoate or oestradiol cypionate in llamas (Lama glama)

<p>Abstract</p> <p>Background</p> <p>Llamas (<it>Lama glama</it>) are induced ovulators and the process of ovulation depends on dominant follicular size. In addition, a close relationship between behavioural estrus and ovulation is not registered in llamas. Therefore, the exogenous control of follicular development with hormones aims to predict the optimal time to mate. Oestradiol-17β (E₂) and its esters are currently used in domestic species, including camelids, in synchronization treatments. But, in llamas, there is no reports regarding the appropriate dosages to be used and most protocols have been designed by extrapolation from those recommended for other ruminants. The aim of the present study was to characterize plasma E₂concentrations in intact female llamas following a single intramuscular (i.m.) injection of two oestradiol esters: oestradiol benzoate (EB) and oestradiol cypionate (ECP).</p> <p>Methods</p> <p>Twelve non pregnant and non lactating sexually mature llamas were i.m. injected on day 0 with 2.5 mg of EB (EB group, n = 6) or ECP (ECP group, n = 6). Blood samples were collected immediately before injection, at 1, 6, 12, 24 h after treatment and then daily until day 14 post injection. Changes in hormone concentrations with time were analyzed in each group by analysis of variance (ANOVA) using a repeated measures (within-SS) design. Plasma E₂concentrations and area under the concentration-time curve (AUC) values were compared between groups by ANOVA. In all cases a Least-Significant Difference test (LSD) was used to determine differences between means. Hormonal and AUC data are expressed as mean ± S.E.M.</p> <p>Results</p> <p>Peak plasma E₂concentrations were achieved earlier and were higher in EB group than in ECP group. Thereafter, E₂returned to physiological concentrations earlier in EB group (day 5) than in ECP group (day 9). Although plasma E₂profiles differed over time among groups there were no differences between them on AUC values.</p> <p>Conclusions</p> <p>The i.m. injection of a single dose of both oestradiol esters resulted in plasma E₂concentrations exceeding physiological values for a variable period. Moreover, the plasma E₂profiles observed depended on the derivative of oestradiol administered. This basic information becomes relevant at defining treatment protocols including oestrogens in llamas.</p

Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients with Inflammatory Bowel Disease: Results from the Eneida Registry

Background: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn''s disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response

The High Cadence Transient Survey (HITS). I. Survey Design and Supernova Shock Breakout Constraints

We present the first results of the High Cadence Transient Survey (HiTS), a survey for which the objective is to detect and follow-up optical transients with characteristic timescales from hours to days, especially the earliest hours of supernova (SN) explosions. HiTS uses the Dark Energy Camera and a custom pipeline for image subtraction, candidate filtering and candidate visualization, which runs in real-time to be able to react rapidly to the new transients. We discuss the survey design, the technical challenges associated with the real-time analysis of these large volumes of data and our first results. In our 2013, 2014, and 2015 campaigns, we detected more than 120 young SN candidates, but we did not find a clear signature from the short-lived SN shock breakouts (SBOs) originating after the core collapse of red supergiant stars, which was the initial science aim of this survey. Using the empirical distribution of limiting magnitudes from our observational campaigns, we measured the expected recovery fraction of randomly injected SN light curves, which included SBO optical peaks produced with models from Tominaga et al. (2011) and Nakar & Sari (2010). From this analysis, we cannot rule out the models from Tominaga et al. (2011) under any reasonable distributions of progenitor masses, but we can marginally rule out the brighter and longer-lived SBO models from Nakar & Sari (2010) under our best-guess distribution of progenitor masses. Finally, we highlight the implications of this work for future massive data sets produced by astronomical observatories, such as LSST

Challenges of adapting English médium instruction into the Spanish university curricula and some novel solutions

The integration of the Spanish university system in the European Higher Education Area (EHEA) demands a series of concrete proposals. As we advance in the implementation of the process of Bologna, it is necessary to contemplate a new paradigm of teaching/learning. Central to this new paradigm is the adaptation of the curricula into the English language medium (EMI). Among many strategies for internationalization of the Universidad Politécnica de Madrid (UPM) under adoption, this university has funded a project TechEnglish intends to facilitate the conversion of subjects and eventually degree programs into the delivery in the English Language. This paper details a work in progress and describes the collaboration between content teachers and applied linguistics. The three collaborative actions are currently underway: observation of classes by applied linguists, seminar delivery on topics requested by the content teachers, and materials development with the help of teaching assistants. We are convinced that this collaboration is the necessary ingredient to promote teaching and learning through English at our university