No surviving evolved companions to the progenitor of supernova SN 1006

Type Ia supernovae are thought to occur as a white dwarf made of carbon and oxygen accretes sufficient mass to trigger a thermonuclear explosion$^{1}$. The accretion could occur slowly from an unevolved (main-sequence) or evolved (subgiant or giant) star$^{2,3}$, that being dubbed the single-degenerate channel, or rapidly as it breaks up a smaller orbiting white dwarf (the double- degenerate channel)$^{3,4}$. Obviously, a companion will survive the explosion only in the single-degenerate channel$^{5}$. Both channels might contribute to the production of type Ia supernovae$^{6,7}$ but their relative proportions still remain a fundamental puzzle in astronomy. Previous searches for remnant companions have revealed one possible case for SN 1572$^{8,9}$, though that has been criticized$^{10}$. More recently, observations have restricted surviving companions to be small, main-sequence stars$^{11,12,13}$, ruling out giant companions, though still allowing the single-degenerate channel. Here we report the result of a search for surviving companions to the progenitor of SN 1006$^{14}$. None of the stars within 4' of the apparent site of the explosion is associated with the supernova remnant, so we can firmly exclude all giant and subgiant companions to the progenitor. Combined with the previous results, less than 20 per cent of type Iae occur through the single degenerate channel.Comment: Published as a letter in Nature (2012 September 27

Reporting reimbursement price decisions for onco-hematology drugs in Spain

Health technology assessment; Onco-hematologic prices; Price and reimbursement systemsAvaluació de tecnologies sanitàries; Preus onco-hematològics; Sistemes de preus i reemborsamentEvaluación de tecnologías sanitarias; Precios oncohematológicos; Sistemas de precios y reembolsosIntroduction: Even using well-established technology assessment processes, the basis of the decisions on drug price and reimbursement are sometimes perceived as poorly informed and sometimes may be seen as disconnected from value. The literature remains inconclusive about how Health Technology Assessment Bodies (HTAb) should report the determinants of their decisions. This study evaluates the relationship between oncology and hematology drug list prices and structured value parameters at the time of reimbursement decision in Spain. Methods: The study includes all new onco-hematological products (22), with a first indication authorized between January 2017 and December 2019 in Spain and pricing decisions published up until October 2022. For each product, 56 contextual and non-contextual indicators reflecting the structured multiple criteria decision analysis (MCDA) – Evidence-based Decision-Making (EVIDEM) framework were measured. The relationship between prices and the MCDA-EVIDEM framework was explored using univariate statistical analyses. Results: Higher prices were observed when the standard of care included for combinations, if there were references to long-lasting responses, for fixed-duration treatment compared to treatment until progression and treatment with lower frequencies of administration; lower prices were observed for oral administration compared to other routes of administration. Statistically significant associations were observed between prices and the median duration of treatment, the impact on patient autonomy, the ease of use of the drug, and the recommendations of experts. Discussion: The study suggests that indicators related to the type of standard of care, references to long-lasting responders, the convenience of the use of the drug, and the impact of treatment on patient autonomy, as well as contextual indicators such as the existence of previous clinical consensus, are factors in setting oncology drug prices in Spain. The implementation of MCDA-EVIDEM methodologies may be useful to capture the influence on pricing decisions of additional factors not included in legislation or consolidated assessment frameworks such as the European Network for Health Technology Assessment (EunetHTA) core model. It may be opportune to consider this in the upcoming revision of the Spanish regulation for health technology assessments and pricing and reimbursement procedures

Human saliva as a source of anti-malarial antibodies to examine population exposure to Plasmodium falciparum

BACKGROUND: Antibody responses to malaria antigens reflect exposure to parasites, and seroprevalence correlates with malaria transmission intensity. Antibodies are routinely measured in sera or on dried blood spots but a non-invasive method would provide extra utility in sampling general populations. Saliva is already in use in the detection of plasma-derived IgM and IgG to viral infections. In this study, antibodies to Plasmodium falciparum merozoite antigens were compared between blood and saliva samples from the same individuals in unlinked surveys conducted in Tanzania and The Gambia. METHODS: In Tanzania, 53 individuals provided paired fingerprick blood and saliva sample using two commercially available sampling devices. In the Gambia, archived plasma and saliva samples collected from 200 children in the Farafenni area in a cross-sectional survey were analyzed.IgG antibodies against P. falciparum antigens, Merozoite Surface Protein-1 (MSP-119) and Apical membrane Antigen (AMA-1) were measured by ELISA in paired saliva and blood samples from both sites. Antibody levels were compared as continuous optical density (OD) values and by sero-positivity. RESULTS: Significant correlations between saliva and plasma antibody levels were seen in Tanzania for both antigens, AMA-1(r2 range 0.93 to 0.89, p < 0.001) and MSP-119 (r2 range 0.93 to 0.75, p < 0.001), with a weaker correlation for results from The Gambia (r2range 0.64 to 0.63, p < 0.01). When assessed as seropositivity and compared with plasma, sensitivity and specificity were good with saliva antibody levels to both AMA-1 and MSP-1(19) (sensitivity range 64-77% and specificity range 91-100% & 47-67% and 90-97% respectively) over the different sample sets. CONCLUSIONS: These data demonstrate anti-malarial antibodies can be detected in saliva and correlate strongly with levels in plasma. This non-invasive relatively simple collection method will be potentially useful for general population surveys, and particularly in migratory populations or those with infrequent contact with health services or opposed to blood withdrawal. Further studies will be needed to optimize collection methods, standardize volumes and content and develop controls

Future care for long-term cancer survivors: towards a new model

Long cancer survivor; Multidisciplinary cancer careSobreviviente de cáncer; Atención multidisciplinar del cáncerSupervivent del càncer; Atenció multidisciplinària del càncerPurpose The increase in the prevalence "long-term cancer survivor” (LCS) patients is expected to increase the cost of LCS care. The aim of this study was to obtain information that would allow to optimise the current model of health management in Spain to adapt it to one of efficient LCS patient care. Methods This qualitative study was carried out using Delphi methodology. An advisory committee defined the criteria for participation, select the panel of experts, prepare the questionnaire, interpret the results and draft the final report. Results 232 people took part in the study (48 oncologists). Absolute consensus was reached in three of the proposed sections: oncological epidemiology, training of health professionals and ICT functions. Conclusion The role of primary care in the clinical management of LCS patients needs to be upgraded, coordination with the oncologist and hospital care is essential. The funding model needs to be adapted to determine the funding conditions for new drugs and technologies.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This project was funded by AZ. The funding party did not influence the opinion of the authors. All the authors have accepted the participation as advisers of the ASISTO group and give their consent for the publication of the document

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

A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer

Cetuximab; Colorectal cancer; MetastaticCetuximab; Càncer de còlon; MetastàticCetuximab; Cáncer de colon; MetastásicoBackground WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose-­escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions. Patients and Methods Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose–limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety. Results Twenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response. Conclusion Concerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated. Trial registration ClinicalTrials.gov, NCT02278133This study was sponsored by Array BioPharma in collaboration with Novartis. Array BioPharma was acquired by Pfizer in July 2019. For V.K.M., this work was supported by the generous philanthropic contributions to the Khalifa Scholars Programs (from the Khalifa Bin Zayed Al Nahyan Foundation), the Advanced Scholar Program (from the CG Johnson Foundation), and the NIH/NCI (award number K12 CA088084)

Advances in the systemic treatment of therapeutic approaches in biliary tract cancer

Biliary tract cancer; Molecular testing; Next-generation sequencingCáncer del tracto biliar; Pruebas moleculares; Secuenciación de nueva generaciónCàncer del tracte biliar; Proves moleculars; Seqüenciació de nova generacióIntroduction Biliary tract cancers (BTCs) are a rare and heterogenous group with an increasing incidence and high mortality rate. The estimated new cases and deaths of BTC worldwide are increasing, but the incidence and mortality rates in South East Asia are the highest worldwide, representing a real public health problem in these regions. BTC has a poor prognosis with a median overall survival <12 months. Thus, an urgent unmet clinical need for BTC patients exists and must be addressed. Results The backbone treatment of these malignancies is chemotherapy in first- and second-line setting, but in the last decade a rich molecular landscape has been discovered, expanding conceivable treatment options. Some druggable molecular aberrations can be treated with new targeted therapies and have already demonstrated efficacy in patients with BTC, improving clinical outcomes, such as the FGFR2 or IDH1 inhibitors. Many other molecular alterations are being discovered and the treatment of BTC will change in the near future from our current clinical practice. Conclusions In this review we discuss the epidemiology, molecular characteristics, present treatment approaches, review the recent therapeutic advances, and explore future directions for patients with BTC. Due to the rich molecular landscape of BTC, molecular profiling should be carried out early. Ongoing research will bring new targeted treatments and immunotherapy in the near future

Microorganisms as Shapers of Human Civilization, from Pandemics to Even Our Genomes: Villains or Friends? A Historical Approach

SARS-CoV-2; Influenza; MicrobiotaSARS-CoV-2; Influenza; MicrobiotaSARS-CoV-2; Influenza; MicrobiotaUniversal history is characterized by continuous evolution, in which civilizations are born and die. This evolution is associated with multiple factors, among which the role of microorganisms is often overlooked. Viruses and bacteria have written or decisively contributed to terrible episodes of history, such as the Black Death in 14th century Europe, the annihilation of pre-Columbian American civilizations, and pandemics such as the 1918 Spanish flu or the current COVID-19 pandemic caused by the coronavirus SARS-CoV-2. Nevertheless, it is clear that we could not live in a world without these tiny beings. Endogenous retroviruses have been key to our evolution and for the regulation of gene expression, and the gut microbiota helps us digest compounds that we could not otherwise process. In addition, we have used microorganisms to preserve or prepare food for millennia and more recently to obtain drugs such as antibiotics or to develop recombinant DNA technologies. Due to the enormous importance of microorganisms for our survival, they have significantly influenced the population genetics of different human groups. This paper will review the role of microorganisms as “villains” who have been responsible for tremendous mortality throughout history but also as “friends” who help us survive and evolve

The Gaia-ESO public spectroscopic survey: motivation, implementation, GIRAFFE data processing, analysis, and final data products star

Context. The Gaia-ESO Public Spectroscopic Survey is an ambitious project designed to obtain astrophysical parameters and elemental abundances for 100000 stars, including large representative samples of the stellar populations in the Galaxy, and a well-defined sample of 60 (plus 20 archive) open clusters. We provide internally consistent results calibrated on benchmark stars and star clusters, extending across a very wide range of abundances and ages. This provides a legacy data set of intrinsic value, and equally a large wide-ranging dataset that is of value for the homogenisation of other and future stellar surveys and Gaia’s astrophysical parameters. Aims. This article provides an overview of the survey methodology, the scientific aims, and the implementation, including a description of the data processing for the GIRAFFE spectra. A companion paper introduces the survey results. Methods. Gaia-ESO aspires to quantify both random and systematic contributions to measurement uncertainties. Thus, all available spectroscopic analysis techniques are utilised, each spectrum being analysed by up to several different analysis pipelines, with considerable effort being made to homogenise and calibrate the resulting parameters. We describe here the sequence of activities up to delivery of processed data products to the ESO Science Archive Facility for open use. Results. The Gaia-ESO Survey obtained 202000 spectra of 115000 stars using 340 allocated VLT nights between December 2011 and January 2018 from GIRAFFE and UVES. Conclusions. The full consistently reduced final data set of spectra was released through the ESO Science Archive Facility in late 2020, with the full astrophysical parameters sets following in 2022. A companion article reviews the survey implementation, scientific highlights, the open cluster survey, and data products