Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers

PD-L1 checkpoint inhibitor; Atezolizumab; Solid tumorsInhibidor del punto de control PD-L1; Atezolizumab; Tumores sólidosInhibidor del punt de control PD-L1; Atezolizumab; Tumors sòlidsBackground The programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies. Patients and methods This phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated. Results Overall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively. Conclusions Atezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.This study was supported by F. Hoffmann-La Roche (no grant number) who provided financial support for the conduct of study and were involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. They also funded assistance with manuscript writing by a professional medical writer

Testing the chemical tagging technique with open clusters

Context. Stars are born together from giant molecular clouds and, if we assume that the priors were chemically homogeneous and well-mixed, we expect them to share the same chemical composition. Most of the stellar aggregates are disrupted while orbiting the Galaxy and most of the dynamic information is lost, thus the only possibility of reconstructing the stellar formation history is to analyze the chemical abundances that we observe today. Aims. The chemical tagging technique aims to recover disrupted stellar clusters based merely on their chemical composition. We evaluate the viability of this technique to recover co-natal stars that are no longer gravitationally bound. Methods. Open clusters are co-natal aggregates that have managed to survive together. We compiled stellar spectra from 31 old and intermediate-age open clusters, homogeneously derived atmospheric parameters, and 17 abundance species, and applied machine learning algorithms to group the stars based on their chemical composition. This approach allows us to evaluate the viability and efficiency of the chemical tagging technique. Results. We found that stars at different evolutionary stages have distinct chemical patterns that may be due to NLTE effects, atomic diffusion, mixing, and biases. When separating stars into dwarfs and giants, we observed that a few open clusters show distinct chemical signatures while the majority show a high degree of overlap. This limits the recovery of co-natal aggregates by applying the chemical tagging technique. Nevertheless, there is room for improvement if more elements are included and models are improved.Comment: accepted for publication in Astronomy and Astrophysics. Corrected typo

Has COVID-19 had a greater impact on female than male oncologists? Results of the ESMO Women for Oncology (W4O) Survey

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Desigualtats; DonaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Desigualdades; MujerCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV Inequalities; WomanBackground European Society for Medical Oncology Women for Oncology (ESMO W4O) research has previously shown under-representation of female oncologists in leadership roles. As early reports suggested disproportionate effects of the COVID-19 pandemic on women, the ESMO W4O Committee initiated a study on the impact of the pandemic on the lives of female and male oncologists. Methods A questionnaire was sent to ESMO members and put on the ESMO website between 8 June 2020 and 2 July 2020. Questions focused on the working (hospital tasks, laboratory tasks, science) and home (household management, childcare, parent care, personal care) lives of oncologists during and after COVID-19-related lockdowns. Results Of 649 respondents, 541 completed the questionnaire. Of these, 58% reported that COVID-19 had affected their professional career, 83% of whom said this was in a negative way (85% of women versus 76% of men). Approximately 86% reported that COVID-19 had changed their personal life and 82% their family life. Women were again significantly more affected than men: personal life (89% versus 78%; P = 0.001); family life (84% versus 77%; P = 0.037). During lockdowns, women reported increased time spent on hospital and laboratory tasks compared with men (53% versus 46% and 33% versus 26%, respectively) and a significantly higher proportion of women than men spent less time on science (39% versus 25%) and personal care (58% versus 39%). After confinement, this trend remained for science (42% versus 23%) and personal care (55% versus 36%). Conclusions The COVID-19 pandemic has adversely affected the professional and home lives of oncologists, especially women. Reduced research time for female oncologists may have long-lasting career consequences, especially for those at key stages in their career. The gender gap for promotion to leadership positions may widen further as a result of the pandemic.This work was supported by the European Society for Medical Oncology (ESMO)

Preconditioned iterative methods for convection diffusion and related boundary value problems

AbstractWe develop and analyze preconditioners for the iterative solution of the system of equations arising from the discretization of multi-dimensional singularity perturbed boundary value problems. This includes a class of convection diffusion models. The choice of preconditioner is crucial for the efficient solution of the system of equations. In particular, it is necessary to choose a preconditioner that substantially reduces the condition number κ both for small grid size h and for large values of the parameter K multiplying the convection terms. A class of preconditioners is analyzed that is inexpensive to implement and for which κ = 0(1) as h→0 and κ = (1 + K12) as K → ∞ for some convection diffusion problems with positive definite symmetric part. This result is then used to develop an algorithm with work estimate 0(1 + K12as K → ∞ for a more general class of convection diffusion problems including those with indefinite symmetric part. Numerical experiments using a symmetric multigrid preconditioner demonstrate the effectiveness of the numerical method even for large problems

HIF-1 and c-Src Mediate Increased Glucose Uptake Induced by Endothelin-1 and Connexin43 in Astrocytes

In previous work we showed that endothelin-1 (ET-1) increases the rate of glucose uptake in astrocytes, an important aspect of brain function since glucose taken up by astrocytes is used to supply the neurons with metabolic substrates. In the present work we sought to identify the signalling pathway responsible for this process in primary culture of rat astrocytes. Our results show that ET-1 promoted an increase in the transcription factor hypoxia-inducible factor-1α (HIF-1α) in astrocytes, as shown in other cell types. Furthermore, HIF-1α-siRNA experiments revealed that HIF-1α participates in the effects of ET-1 on glucose uptake and on the expression of GLUT-1, GLUT-3, type I and type II hexokinase. We previously reported that these effects of ET-1 are mediated by connexin43 (Cx43), the major gap junction protein in astrocytes. Indeed, our results show that silencing Cx43 increased HIF-1α and reduced the effect of ET-1 on HIF-1α, indicating that the effect of ET-1 on HIF-1α is mediated by Cx43. The activity of oncogenes such as c-Src can up-regulate HIF-1α. Since Cx43 interacts with c-Src, we investigated the participation of c-Src in this pathway. Interestingly, both the treatment with ET-1 and with Cx43-siRNA increased c-Src activity. In addition, when c-Src activity was inhibited neither ET-1 nor silencing Cx43 were able to up-regulate HIF-1α. In conclusion, our results suggest that ET-1 by down-regulating Cx43 activates c-Src, which in turn increases HIF-1α leading to the up-regulation of the machinery required to take up glucose in astrocytes. Cx43 expression can be reduced in response not only to ET-1 but also to various physiological and pathological stimuli. This study contributes to the identification of the signalling pathway evoked after Cx43 down-regulation that results in increased glucose uptake in astrocytes. Interestingly, this is the first evidence linking Cx43 to HIF-1, which is a master regulator of glucose metabolism

Brands in international and multi‐platform expansion strategies: economic and management issues

Powerful media branding has historically facilitated successful international expansion on the part of magazine and other content forms including film and TV formats. Multi-platform expansion is now increasingly central to the strategies of media companies and, as this chapter argues, effective use of branding in order to engage audiences effectively and to secure a prominent presence across digital platforms forms a core part of this. Drawing on original research into the experience of UK media companies, this chapter highlights some of the key economic, management and socio-cultural issues raised by the ever-increasing role of brands and branding in the strategies of international and multi-platform expansion that are increasingly common- place across media

The Gaia-ESO Survey: metallicity of the Chamaeleon I star forming region

Context. Recent metallicity determinations in young open clusters and star-forming regions suggest that the latter may be characterized by a slightly lower metallicity than the Sun and older clusters in the solar vicinity. However, these results are based on small statistics and inhomogeneous analyses. The Gaia-ESO Survey is observing and homogeneously analyzing large samples of stars in several young clusters and star-forming regions, hence allowing us to further investigate this issue. Aims. We present a new metallicity determination of the Chamaeleon I star-forming region, based on the products distributed in the first internal release of the Gaia-ESO Survey. Methods. 48 candidate members of Chamaeleon I have been observed with the high-resolution spectrograph UVES. We use the surface gravity, lithium line equivalent width and position in the Hertzsprung-Russell diagram to confirm the cluster members and we use the iron abundance to derive the mean metallicity of the region. Results. Out of the 48 targets, we confirm 15 high probability members. Considering the metallicity measurements for 9 of them, we find that the iron abundance of Chamaeleon I is slightly subsolar with a mean value [Fe/H]=-0.08+/-0.04 dex. This result is in agreement with the metallicity determination of other nearby star-forming regions and suggests that the chemical pattern of the youngest stars in the solar neighborhood is indeed more metal-poor than the Sun. We argue that this evidence may be related to the chemical distribution of the Gould Belt that contains most of the nearby star-forming regions and young clusters.Comment: 13 pages, 11 figures, 3 tables, Accepted for publication in Astronomy & Astrophysic

A longitudinal study on perceived health in cardiovascular patients. The role of conscientiousness, subjective wellbeing and cardiac self-efficacy

Cardiovascular disease (CVD) is the world’s most prevalent chronic disease and the leading chronic cause of morbidity. There are several psychosocial factors associated with quality of life during CVD. Our main objectives were to analyze the roles of conscientiousness, subjective wellbeing and self-efficacy beliefs. The sample comprised 514 patients (mean age 63.57 years) who were assessed twice over a nine-month interval. At Time 1, participants answered a questionnaire assessing conscientiousness, perceived subjective wellbeing (positive and negative affect, life satisfaction), cardiac self-efficacy and health-related quality of life (HRQoL). The same variables (except for conscientiousness) were re-assessed at Time 2. Results showed that conscientiousness had a positive relation with subjective wellbeing, cardiac self-efficacy, and HRQoL at Time 1. Moreover, cardiac self-efficacy at Time 1 had a positive longitudinal effect on HRQoL at Time 2, while controlling for autoregressive effects. Mediation analyses indicated that the relationship between conscientiousness and HRQoL was mediated by positive affect and cardiac self-efficacy. These results suggest the usefulness of psychosocial interventions aimed at promoting positive affect and self-efficacy beliefs among CVD patients

Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality

Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56low NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56low NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94hi/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality

Dynamical masses of two young transiting sub-Neptunes orbiting HD 63433

Although the number of exoplanets reported in the literature exceeds 5000 so far, only a few dozen of them are young planets ($\le$900 Myr). However, a complete characterization of these young planets is key to understanding the current properties of the entire population. Hence, it is necessary to constrain the planetary formation processes and the timescales of dynamical evolution by measuring the masses of exoplanets transiting young stars. We characterize and measure the masses of two transiting planets orbiting the 400 Myr old solar-type star HD\,63433, which is a member of the Ursa Major moving group. We analysed precise photometric light curves of five sectors of the TESS mission with a baseline of $\sim$750 days and obtained $\sim$150 precise radial velocity measurements with the visible and infrared arms of the CARMENES instrument at the Calar Alto 3.5 m telescope in two different campaigns of $\sim$500 days. We performed a combined photometric and spectroscopic analysis to retrieve the planetary properties of two young planets. The strong stellar activity signal was modelled by Gaussian regression processes. We have updated the transit parameters of HD\,63433\,b and c and obtained planet radii of R$_p^b$\,=\,2.140\,$\pm$\,0.087 R$_\oplus$ and R$_p^c$\,=\,2.692\,$\pm$\,0.108 R$_\oplus$. Our analysis allowed us to determine the dynamical mass of the outer planet with a 4$\sigma$ significance ($M_p^c$\,=\,15.54\,$\pm$\,3.86 M$_\oplus$) and set an upper limit on the mass of the inner planet at 3$\sigma$ ($M_p^b$\,$<$\,21.76 M$_\oplus$). According to theoretical models, both planets are expected to be sub-Neptunes, whose interiors mostly consist of silicates and water with no dominant composition of iron, and whose gas envelopes are lower than 2\% in the case of HD\,63433\,c. The envelope is unconstrained in HD\,63433\,b