New Cepheid variables in the young open clusters Berkeley 51 and Berkeley 55

As part of a wider investigation of evolved massive stars in Galactic open clusters, we have spectroscopically identified three candidate classical Cepheids in the little-studied clusters Berkeley 51, Berkeley 55 and NGC 6603. Using new multi-epoch photometry, we confirm that Be 51 #162 and Be 55 #107 are bona fide Cepheids, with pulsation periods of 9.83±0.01 d and 5.850±0.005 d respectively, while NGC 6603 star W2249 does not show significant photometric variability. Using the period-luminosity relationship for Cepheid variables, we determine a distance to Be 51 of 5.3 +1.0 −0.8 kpc and an age of 44 +9 −8 Myr, placing it in a sparsely-attested region of the Perseus arm. For Be 55, we find a distance of 2.2±0.3 kpc and age of 63 +12 −11 Myr, locating the cluster in the Local arm. Taken together with our recent discovery of a long-period Cepheid in the starburst cluster VdBH222, these represent an important increase in the number of young, massive Cepheids known in Galactic open clusters. We also consider new Gaia (data release 2) parallaxes and proper motions for members of Be 51 and Be 55; the uncertainties on the parallaxes do not allow us to refine our distance estimates to these clusters, but the well-constrained proper motion measurements furnish further confirmation of cluster membership. However, future final Gaia parallaxes for such objects should provide valuable independent distance measurements, improving the calibration of the period-luminosity relationship, with implications for the distance ladder out to cosmological scales

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

A new family of phosphoinositide phosphatases in microorganisms: identification and biochemical analysis

<p>Abstract</p> <p>Background</p> <p>Phosphoinositide metabolism is essential to membrane dynamics and impinges on many cellular processes, including phagocytosis. Modulation of phosphoinositide metabolism is important for pathogenicity and virulence of many human pathogens, allowing them to survive and replicate in the host cells. Phosphoinositide phosphatases from bacterial pathogens are therefore key players in this modulation and constitute attractive targets for chemotherapy. MptpB, a virulence factor from <it>Mycobacterium tuberculosis</it>, has phosphoinositide phosphatase activity and a distinct active site P-loop signature HCXXGKDR that shares characteristics with eukaryotic lipid phosphatases and protein tyrosine phosphatases. We used this P-loop signature as a "diagnostic motif" to identify related putative phosphatases with phosphoinositide activity in other organisms.</p> <p>Results</p> <p>We found more than 200 uncharacterised putative phosphatase sequences with the conserved signature in bacteria, with some related examples in fungi and protozoa. Many of the sequences identified belong to recognised human pathogens. Interestingly, no homologues were found in any other organisms including Archaea, plants, or animals. Phylogenetic analysis revealed that these proteins are unrelated to classic eukaryotic lipid phosphatases. However, biochemical characterisation of those from <it>Listeria monocytogenes </it>and <it>Leishmania major</it>, demonstrated that, like MptpB, they have phosphatase activity towards phosphoinositides. Mutagenesis studies established that the conserved Asp and Lys in the P-loop signature (HCXXG<b>KD</b>R) are important in catalysis and substrate binding respectively. Furthermore, we provide experimental evidence that the number of basic residues in the P-loop is critical in determining activity towards poly-phosphoinositides.</p> <p>Conclusion</p> <p>This new family of enzymes in microorganisms shows distinct sequence and biochemical characteristics to classic eukaryotic lipid phosphatases and they have no homologues in humans. This study provides a foundation for examining the biological role of this new family of phosphatases and their potential as pharmaceutical targets against infectious diseases.</p

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

Bioconversion of polyphenols and organic acids by gut microbiota of predigested Hibiscus sabdariffa L. calyces and Agave (A. tequilana Weber) fructans assessed in a dynamic in vitro model (TIM-2) of the human colon

The present work aimed at understanding gut microbiota bioconversion of phenolic compounds (PC) and organic acids in predigested Hibiscus sabdariffa (Hb) calyces and the mixture of Hb and Agave (Agave tequilana Weber) fructans (AF). With this purpose, dried Hb and Hb/AF were predigested with enzymatic treatment, and then fermented in a dynamic in vitro model of the human colon (TIM-2). After HPLC-ESI-QToF-MS analysis of samples taken at 0, 24, 48 and 72 h of fermentation, it was observed that hydroxycinnamic acids, flavanols, flavonols, and anthocyanins were mainly transformed into derivatives of hydroxyphenylpropionic, hydroxyphenylacetic and hydroxybenzoic acids. Moreover, organic acids, such as hydroxycitric and hibiscus acids, were formed along with unidentified lactones and reduced compounds. Interestingly, no differences were observed between microbial-derived metabolites formed after the fermentation of Hb and Hb/AF. In conclusion, colonic fermentation of polyphenol-rich Hb yields a wide range of microbial phenolic metabolites with potential effects on health.RMB and SGSA acknowledge to Science and Technology for Development Program (CYTED) through the Ibero-American Network of Underutilized Autonomous Foods (ALSUB-CYTED, 118RT0543). SGSA acknowledges CONACYT-Mexico for the sabbatical grant 260935. The Spanish Ministry of Science, Innovation and Universities (Project AGL2015-69986-R) is also acknowledged. This research has been made possible with the support of the Dutch Province of Limburg.Peer reviewe

Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer

Metastatic colorectal cancer; Renal impairment; SafetyCáncer colorrectal metastásico; Insuficiencia renal; SeguridadCàncer colorectal metastàtic; Insuficiència renal; SeguretatBackground Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. Patients and methods Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. Results TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. Conclusions These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.This work was supported by Taiho Oncology, Inc. and Taiho Pharmaceutical (no grant number). This analysis was funded by Taiho Oncology, Inc. Professional medical writing and editorial assistance were provided by Vasupradha Vethantham, Meredith Kalish, and Jennifer L. Robertson at Ashfield MedComms, an Inizio company, funded by Taiho Oncology, Inc

Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study

Metastatic gastric cancer; Overall survival; Trifluridine/tipiracilCàncer gàstric metastàtic; Supervivència global; Trifluridina/tipiracilCáncer gástrico metastásico; Supervivencia global; Trifluridina/tipiraciloBackground Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment. Patients and methods Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety. Results Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups. Conclusions This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.The TAGS study was funded by Taiho Oncology and Taiho Pharmaceutical (no grant number). This exploratory subgroup analysis was funded by Servier (no grant number)

Napabucasin plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine in previously untreated metastatic pancreatic adenocarcinoma: an adaptive multicentre, randomised, open-label, phase 3, superiority trial

Adenocarcinoma; Napabucasin; Pancreatic cancerAdenocarcinoma; Napabucasin; Càncer de pàncreesAdenocarcinoma; Napabucasin; Cáncer de páncreasBackground Compared with normal cells, tumour cells contain elevated levels of reactive oxygen species (ROS). Increased levels of the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) correlate negatively with the survival of patients with pancreatic cancer. Napabucasin is an investigational, orally administered ROS generator bioactivated by NQO1. Methods In the open-label, phase 3 CanStem111P study (NCT02993731), adults with previously untreated metastatic pancreatic adenocarcinoma (mPDAC) were randomised (1:1) to napabucasin plus nab-paclitaxel with gemcitabine or nab-paclitaxel with gemcitabine alone. The primary endpoint was overall survival (OS). In exploratory analyses, OS was evaluated in the subgroup of patients with tumours positive for pSTAT3 (biomarker-positive). Findings Between 30 January 2017 and 20 February 2019, a total of 1779 patients were screened across 165 study sites in Austria, Australia, Belgium, Canada, China, Czech Republic, France, Germany, Italy, Japan, Korea, Netherlands, Poland, Portugal, Russia, Singapore, Spain, Taiwan, Ukraine, and the US. Of the 565 and 569 patients randomised to the napabucasin and control treatment arms, respectively, 206 and 176 were biomarker-positive. Median (95% confidence interval [CI]) OS in the napabucasin and control treatment arms was 11.4 (10.5–12.2) and 11.7 (10.7–12.7) months, respectively (hazard ratio, 1.07; 95% CI, 0.93–1.23). Due to the lack of OS improvement in the napabucasin arm, CanStem111P was terminated due to futility. In the biomarker-positive subgroup, no difference between treatment arms was found for OS. Grade ≥3 adverse events were reported in 85.4% and 83.9% of napabucasin-treated and control-treated patients, respectively. The incidence of gastrointestinal-related grade ≥3 events was higher with napabucasin (diarrhoea: 11.6% vs 4.9%; abdominal pain: 10.0% vs 4.8%). Interpretation Our findings suggested that although the addition of napabucasin to nab-paclitaxel with gemcitabine did not improve efficacy in patients with previously untreated mPDAC, the safety profile of napabucasin was consistent with previous reports. CanStem111P represents the largest cohort of patients with mPDAC administered nab-paclitaxel with gemcitabine in the clinical trial setting. Our data reinforce the value of nab-paclitaxel plus gemcitabine as a platform for novel therapeutics approaches in mPDAC.This study was supported by Sumitomo Pharma Oncology, Inc

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)