Agencia Estatal De Investigacion Research Articles

Iadademstat in combination with azacitidine in patients with newly diagnosed acute myeloid leukaemia (ALICE): an open-label, phase 2a dose-finding study

Iadademstat is a potent, selective, oral inhibitor of both the enzymatic and scaffolding activities of the transcriptional repressor lysine-specific demethylase 1 (LSD1; also known as KDM1A) that showed promising early activity and safety in a phase 1 trial and strong preclinical synergy with azacitidine in acute myeloid leukaemia cell lines. Therefore, we aimed to investigate the combination of iadademstat and azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukaemia. The open-label, phase 2a, dose-finding ALICE study was conducted at six hospitals in Spain and enrolled patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy and an ECOG performance status of 0-2. In the dose escalation portion of the trial, patients received a starting dose of iadademstat at 90 μg/m2 per day (with de-escalation to 60 μg/m2 per day and escalation up to 140 μg/m2 per day) orally, for 5 days on, 2 days off weekly, with azacitidine 75 mg/m2 subcutaneously, for seven of 28 days. The primary objectives were safety (analysed in the safety analysis set; all patients who received at least one dose of study treatment) and establishing the recommended phase 2 dose; secondary objectives included response rates in the efficacy analysis set (all patients who had at least one efficacy assessment). This study is registered on EudraCT (EudraCT 2018-000482-36) and has been completed. Between Nov 12, 2018, and Sept 30, 2021, 36 patients with newly diagnosed acute myeloid leukaemia were enrolled; the median age was 76 (IQR 74-79) years, all patients were White, 18 (50%) were male, and 18 (50%) were female, and all had intermediate-risk or adverse-risk acute myeloid leukaemia. The median follow-up was 22 (IQR 16-31) months. The most frequent (≥10%) adverse events considered to be related to treatment were decreases in platelet (25 [69%]) and neutrophil (22 [61%]) counts (all grade 3-4) and anaemia (15 [42%]; of which ten [28%] were grade 3-4). Three patients had treatment-related serious adverse events (one fatal grade 5 intracranial haemorrhage, one grade 3 differentiation syndrome, and one grade 3 febrile neutropenia). Based on safety, pharmacokinetic and pharmacodynamic data, and efficacy, the recommended phase 2 dose of iadademstat was 90 μg/m2 per day with azacitidine. 22 (82%; 95% CI 62-94) of 27 patients in the efficacy analysis set had an objective response. 14 (52%) of 27 patients had complete remission or complete remission with incomplete haematological recovery; of these, ten of 11 evaluable for measurable residual disease achieved negativity. In the safety analysis set, 22 (61%) of 36 patients had an objective response. The combination of iadademstat and azacitidine has a manageable safety profile and shows promising responses in patients with newly diagnosed acute myeloid leukaemia, including those with high-risk prognostic factors. Oryzon Genomics and Spain's Ministerio de Ciencia, Innovacion y Universidades (MICIU)-Agencia Estatal de Investigacion (AEI).

Global Financial Cycle, Household Credit, and Macroprudential Policies

We show that macroprudential policies dampen the impact of global financial conditions on local bank credit cycles. For identification, we exploit variation in the U.S. volatility index (VIX) and household and business credit registers in an emerging market economy in which banks depend on foreign funding and macroprudential measures vary over the full cycle. Our results suggest that when the VIX is low, tighter macroprudential policies reduce household lending, notably for riskier (foreign currency (FX) and high debt-service-to-income) loans and by banks dependent on foreign funding. Moreover, they increase (less regulated) local currency lending to real estate firms. Such periods are associated with less subsequent total lending to households and firms and with a lower share of FX loans at the local level. Consistently, when the VIX is low, tighter macroprudential policies dampen house prices and economic activity. This paper was accepted by Victoria Ivashina, finance. Funding: M. Epure acknowledges support from the Serra Húnter program. This project received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program [Grant 648398], from the Agencia Estatal de Investigacion [Grants PID2020-115660GB-I00 and PGC2018-102133-B-I00], and the Severo Ochoa Program for Centers of Excellence in Research and Development [Grant CEX2019-000915-S]. Supplemental Material: The online appendix and data files are available at https://doi.org/10.1287/mnsc.2024.4981 .

Energy Allocation Design for the Satellite Return Channel of a Massive NOMA System With Interference Cancellation

Work supported in part by Agencia Estatal de Investigacion (AEI, Spain) and by European Regional Development Fund (ERDF) through project RODIN (PID2019-105717RB-C22), and in part by the Catalan administration (AGAUR) under Grant 2017 SGR 578 and Fellowship 2020FI B2 00062.

Lateral Interactions and Order–Disorder Phase Transitions of Metal Phthalocyanines on Ag(111)

We gratefully acknowledge support from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Project ID 223848855-SFB 1083 “Structure and Dynamics of Internal Interfaces”. L.F. acknowledges financial support from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement MagicFACE no. 797109. D.S.-P. and A.X.B.-R. acknowledge the Spanish Agencia Estatal de Investigacion (grant nos. MAT2016-78293-C6-4-R and PID2019-107338RB-C66) and Dep. Educacion of the Basque Government and UPV/EHU (grant no. IT1246-19) for support.

Toward the Recycling of Low-GWP Hydrofluorocarbon/Hydrofluoroolefin Refrigerant Mixtures Using Composite Ionic Liquid–Polymer Membranes

Authors fully acknowledge the financial support received from Project KET4F-Gas-SOE2/P1/P0823, which is cofinanced by the European Regional Development Fund within the framework of Interreg Sudoe Programme, and project PID2019-105827RB-I00—Agencia Estatal de Investigacion, Spain. F.P. acknowledges the postdoctoral fellowship (FJCI-2017-32884 Juan de la Cierva Formacion) awarded by the Spanish Ministry of Science, Innovation and Universities.

Computationally Driven Rational Design of Substrate Promiscuity on Serine Ester Hydrolases

This work was funded by grant ‘INMARE’ from the European Union’s Horizon 2020 (grant agreement no. 634486), grants PCIN-2017-078 (within the Marine Biotechnology ERA-NET), and BIO2017-85522-R and PID2019-106370RB-I00 grants from the Spanish Ministry of Science and Innovation, Ministerio de Economia y Competitividad, Ministerio de Ciencia, Innovacion y Universidades, Agencia Estatal de Investigacion (AEI), Fondo Europeo de Desarrollo Regional (FEDER) and European Union (EU). This work has also been supported by a predoctoral fellowship from the Spanish Ministry of Science and Innovation (FPU19/00608).

New macaque fossil remains from Morocco

This work has been funded by Palarq Foundation, Spanish Ministry of Culture and Sport (42-T002018042853 and 170-T002019038589), Direction of Cultural Heritage (Ministry of Culture and Communication, Morocco), Faculty of Sciences (Mohamed 1r University of Oujda, Morocco), INSAP (Institut National des Sciences de l’Archeologie et du Patrimoine), Agencia Estatal de Investigacion (Spanish Ministry of Science, Innovation and Universities: CGL2016-76431-P, CGL2016-80975-P, CGL2016-80000-P, CGL2017-82654-P, PGC2018-095489-B-I00, and PGC2018-093925-B-C31, AEI/FEDER-UE), and Research Group Support of the Generalitat de Catalunya (2017 SGR 116, 2017 SGR836, and 2017 SGR 859). The research by D.M.A., R.S-R, M.G.C., P.S., C.L., and E.D. is funded by CERCA Programme/Generalitat de Catalunya. A.M.A and M.F. are beneficiaries of a fellowship from the Erasmus Mundus Program to do the Master in Quaternary and Prehistory at the Universitat Rovia i Virgili (Tarragona, Spain). A.R.-H. is the beneficiary of a postdoctoral scholarship from the MICINN, Subprograma Juan de la Cierva (IJC-037447-I), and member of theconsolidated research group 2017 SGR 1040 of the Generalitat de Catalunya. The Institut Catala de Paleoecologia Humana i Evolucio Social (IPHES-CERCA) has received financial support from the Spanish Ministry of Science and Innovation through the ‘Maria de Maeztu’ program for Units of Excellence (CEX2019-000945-M).

Banking stability and borrower discouragement: a multilevel analysis for SMEs in the EU-28

The authors acknowledge financial support from Agencia Estatal de Investigacion (https://doi.org/10.13039/501100011033), research project PID2019-106314GB-I00/AEI/10.13039/501100011033. We also acknowledge financial support from Fundacion UCEIF and Santander Financial Institute (SANFI).

Effects of including endurance and speed sessions within small-sided soccer games periodization on physical fitness.

The main aim of this study was to analyse the effects of including additional speed and endurance sessions during small-sided games (SSG) training periodization on physical fitness in professional soccer players. Sixteen outfield players (age = 25.6 ± 7.6 years) who competed in the First Division of a European League participated in this study. Players were randomly assigned to perform only the SSG periodization (G-SSG group) or to add endurance and speed training contents to the SSG (ES-SSG group). Before and after the 6-week experimental period, a Yo-Yo Intermittent Recovery Test level 1 (YYIR1) and a 40 m sprinting test were performed. Rating of perceived exertion (RPE) was also measured after each training session. The G-SSG group showed a large improvement in the YYIR1 performance (p = 0.018–0.028; ES = 0.521–0.576) after the training programme, whereas no significant changes were observed for the ES-SSG group (p = 0.763–1.000; ES = 0.000–0.014). In addition, no significant differences (p > 0.05, ES = 0.005–361, trivial to small) in sprint performance at 5 and 10 m intervals up to 40 m were observed at post-training in comparison to pre-training evaluation in G-SSG and ES-SSG groups. No significant differences (p > 0.05) between groups were observed at baseline in the YYIR1 test. The 6-week SSG training supported with only six endurance and speed training sessions was no more effective than well-organized SSG alone for improving running endurance in professional soccer players.

Why westillneed permanent plots for vegetation science

This study was supported by the projects from the Czech Science Foundation (Grant Number: GA16‐15012S) and from the Agencia Estatal de Investigacion (Plan Nacional de I+D+i, project c). EV was funded by the Program for attracting and retaining talent of ‘Comunidad de Madrid’ (Grant Number: 2017‐T2/AMB‐5406). DW recognizes support from the Herrick Trust, Kent State University.

Confocal Raman imaging as a useful tool to understand the internal microstructure of multicomponent aerogels

AbstractThis work shows the characterization of (nano)cellulosic aerogels prepared from Posidonia oceanica waste biomass by means of confocal Raman microscopy (CRM). For this aim, aerogels were prepared by simple freeze‐drying of aqueous dispersions of four (nano)cellulosic fractions with different purification degrees, tested at two different concentrations (0.5% and 2%). These were then coated with polylactic acid (PLA) in order to improve their hydrophobicity and subjected to oil sorption–desorption experiments. Both univariate and multivariate analyses, including an approach based on comparing the spectra with those of reference materials and another one based on automatic detection of components, were compared in terms of the quality and the accuracy of the information provided. Univariate analysis only provided accurate information in the simplest systems (native (nano)cellulosic aerogels), while multivariate analyses facilitated the detection of the different components even for the most complex structures. Automatic identification of components was selected as the optimal methodology, although it also underestimated the abundance of the components with the least intense Raman spectra (cellulosic clusters) in the presence of PLA and oil. Comparison with the reference materials resulted in unrealistic images for the most complex systems. Micron‐sized regions of concentrated cellulose were detected using CRM, being more abundant in the denser aerogels. Results also confirmed that PLA was preferentially located close to the surface, while oil could penetrate deeper along the matrix. Overall, the results showed the potential of Raman imaging as a novel approach for the characterization of complex biopolymeric aerogels.

Discussion on "Assessing the goodness of fit of logistic regression models in large samples: A modification of the Hosmer-Lemeshow test" by Giovanni Nattino, Michael L. Pennell, and Stanley Lemeshow.

This work was supported by the Marsden Fund (Award Num-ber E2987-3648) administrated by the Royal Society of NewZealand and also supported by grant RTI2018-100927-J-I00 administrated by Ministerio de Ciencia e Innovacion (MCI,Spain), by the Agencia Estatal de Investigacion (AEI, Spain),and by the European Regional Development Fund FEDER(FEDER, UE). We are grateful to Dr Louise McMillan for helpful comments.

Discussion on “Assessing the goodness of fit of logistic regression models in large samples: A modification of the Hosmer‐Lemeshow test” by Giovanni Nattino, Michael L. Pennell, and Stanley Lemeshow

This work was supported by the Marsden Fund (Award Num-ber E2987-3648) administrated by the Royal Society of NewZealand and also supported by grant RTI2018-100927-J-I00 administrated by Ministerio de Ciencia e Innovacion (MCI,Spain), by the Agencia Estatal de Investigacion (AEI, Spain),and by the European Regional Development Fund FEDER(FEDER, UE). We are grateful to Dr Louise McMillan for helpful comments.

Toothpicking in early Homo OH 62 from Olduvai Gorge (Tanzania): An indirect evidence of intensive meat consumption?

A.E. is a Juan de la Cierva postdoctoral fellow (grant number: FJCI-2016-30122). This study has been partially funded by project CGL2012-36682 and project CGL2016-75109-P (Spanish Ministry of Economy and Competitivity, Agencia Estatal de Investigacion (AEI) and FEDER EU).

On Factorised Finite Groups

The first and third authors are supported by the grant PGC2018-095140-B-I00 from the Ministerio de Ciencia, Innovacion y Universidades and the Agencia Estatal de Investigacion, Spain, and FEDER, European Union and by Prometeo/2017/057 of Generalitat (Valencian Community, Spain). Funding was provided by National Natural Science Foundation of China (Grant no. 11401597).

SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications

Background: Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cell (CSC) subpopulations. The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Methods: shRNA and cDNA lentiviral constructions were used to deplete and overexpress SOX2 in a model of undifferentiated pleomorphic sarcoma (UPS). In addition, we introduced a reporter system (SORE6) which allows to detect and isolate viable cells expressing SOX2 and/or OCT4 in the UPS model and patient-derived chondrosarcoma lines. Functional CSC characterization included tumorsphere formation, in vivo xenograft growth assays, and pharmacologic testing of the effects of doxorubicin, placlitaxel, trabectedin or the mithramycin analogue EC8042. Immunohistochemical analysis of a cohort of 88 formalin-fixed and paraffin-embedded sarcoma samples was performed to correlate SOX2 expression with clinical parameters. Findings: SOX2 depletion dramatically reduced the ability of sarcoma cells to form tumorspheres and to initiate tumor growth in vivo. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. In sarcoma patients, SOX2 expression was associated to advanced disease stages, aggressive phenotypes and lower survival. Finally, SORE6+ cells were significantly more tumorigenic than the SORE6- population and EC-8042 effectively targeted SORE6+ cells in vitro and in vivo. Interpretation: SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations. Funding Statement: This work was supported by the Agencia Estatal de Investigacion (AEI) [MINECO/Fondo Europeo de Desarrollo Regional (FEDER) (SAF-2016-75286-R to R.R.), ISC III/FEDER (Miguel Servet Program CPII16/00049 to R.R., Sara Borrell Program CD16/00103 to S.T.M. and PI16/00280 and PI19/00560 to J.M.G-P) and Consorcio CIBERONC CB16/12/00390)] and the Plan de Ciencia Tecnologia e Innovacion del Principado de Asturias/FEDER (IDI/2018/155) to J.P.R. PharmaMar and EntreChem also provided support. Finally, the authors acknowledge the Principado de Asturias BioBank (PT17/0015/0023), financed jointly by Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III and Fundacion Bancaria Cajastur and integrated in the Spanish National Biobanks Network, for its collaboration. Declaration of Interests: The authors declare they have no competing interests. Ethics Approval Statement: All experimental protocols have been performed in accordance with institutional review board guidelines and were approved by the Institutional Ethics Committee of the Principado de Asturias. All samples from human origin were obtained upon signed informed consent. All experimental protocols were carried out in accordance with the institutional guidelines of the University of Oviedo and were approved by the Animal Research Ethical Committee of the University of Oviedo prior to the study.

Factorization theorems for some new classes of multilinear operators

The research was supported by National Science Centre of Poland, project 2015/17/B/ST1/00064. The research was supported by the Ministerio de Ciencia, Innovacion y Universidades, Agencia Estatal de Investigacion (Spain) and FEDER under project MTM2016-77054-C2-1-P.

Building Decentralized Fog Computing-Based Smart Parking Systems: From Deterministic Propagation Modeling to Practical Deployment

This work was supported in part by the School of Engineering and Sciences, Tecnologico de Monterrey, in part by the Xunta de Galicia under Grant ED431G2019/01, in part by the Agencia Estatal de Investigacion of Spain under Grant TEC2016-75067-C4-1-R, Grant RED2018-102668-T, and Grant PID2019-104958RB-C42, in part by the European Regional Development Fund (ERDF) funds of the European Union (EU) (AEI/FEDER, UE), and in part by the Ministerio de Ciencia, Innovacion y Universidades, Gobierno de Espana (MCI-U/AEI/FEDER,UE) under Grant RTI2018-095499-B-C31.

Measurement of the integrated luminosity of the Phase 2 data of the Belle II experiment * * This work was supported by the following funding sources: Science Committee of the Republic of Armenia Grant No. 18T-1C180; Australian Research Council and research grant Nos. DP180102629, DP170102389, DP170102204, DP150103061, FT130100303, and FT130100018; Austrian Federal Ministry of Education, Science and Research, and Austrian

From April to July 2018, a data sample at the peak energy of the resonance was collected with the Belle II detector at the SuperKEKB electron-positron collider. This is the first data sample of the Belle II experiment. Using Bhabha and digamma events, we measure the integrated luminosity of the data sample to be ( , where the first uncertainty is statistical and the second is systematic. This work provides a basis for future luminosity measurements at Belle II.

On large orbits of supersoluble subgroups of linear groups

The research of this paper has been supported by the grant MTM2014-54707-C3-1-P from the Ministerio de Economia y Competitividad, Spain, and FEDER, European Union, by the grant PGC2018-095140-B-I00 from the Ministerio de Ciencia, Innovacion y Universidades and the Agencia Estatal de Investigacion, Spain, and FEDER, European Union, and by the grant PROMETEO/2017/057 from the Generalitat, Valencian Community, Spain. The first author is supported by the predoctoral grant 201606890006 from the China Scholarship Council. The second author is supported by the grant 11401597 from the National Science Foundation of Chin