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Phase Ⅱ trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/CDKN2A

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5518-5527页

作者： Javier Martin-Broto Jeronimo Martinez-Garcia David SMoura Andres Redondo Antonio Gutierrez Antonio lopez-Pousa Javier Martinez-Trufero Isabel Sevilla Roberto Diaz-Beveridge Maria pilar Solis-Hernandez Amancio Carnero Marco Perez David Marcilla Jesus Garcia-Foncillas Pablo Romero Javier Fernandez-Jara Daniel lopez-lopez Ivan Arribas Nadia Hindi Health Research Institute-Fundación Jiménez Díaz University Hospital Universidad Autónoma de Madrid(IIS-FJDUAM)28040MadridSpain Medical Oncology Department Fundación Jimenez Diaz University Hospital28040MadridSpain General de Villalba University Hospital 28400MadridSpain Medical Oncology Department University Hospital Virgen de la Arrixaca30120MurciaSpain Department of Medical Oncology Hospital Universitario La Paz-IdiPAZP.Castellana26128046MadridSpain Hematology Department University Hospital Son Espases07120MallorcaSpain Medical Oncology Department Sant Pau Hospital08025BarcelonaSpain Medical Oncology Department University Hospital Miguel Servet50009ZaragozaSpain Investigación Clínica y Traslacional en Cáncer/Instituto de Investigaciones Biomédicas de Malaga(IBIMA)/Hospitales Universitarios Regional y Virgen de la Victoria de Malaga MalagaSpain Medical Oncology Department Hospital Universitari i Politècnic La Fe46026ValenciaSpain Medical Oncology Department Central University Hospital of Asturias33011OviedoSpain Instituto de Biomedicina de Sevilla(IBiS HUVRCSICUS)41013SevillaSpain Pathology Department Virgen del Rocio University Hospital41013SevillaSpain Radiology Department Fundación Jimenez Diaz University Hospital28040MadridSpain Computational Medicine Platform Fundación progreso y salud(FPS)Hospital Virgen del Rocío41013SevilleSpain Bioinformatics in Rare Diseases(BiER).Centro de Investigación Biomédica en Red de Enfermedades Raras(CIBERER) FPSHospital Virgen del RocioSevillaSpain Universitat de València-ERI-CES 46010ValenciaSpain

Cyclin-dependent kinases 4 and 6(CDK4/6)inhibitors demonstrated activity in terms of progression-free survival(PFS)in advanced dedifferentiated liposarcoma(DD-LPS),a sarcoma with CDK4 amplification.CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors.Preclinical investigators of this study found that CDK4 overexpression,while not of CDKN2A,was the most consistent predictive factor for palbociclib efficacy in sarcomas.Advanced adult-type soft-tissue sarcoma,excluding DD-LPS,or bone sarcoma patients,progressing after at least one systemic line,whose tumors overexpressed CDK4,but not CDKN2A at baseline biopsy,were accrued in this single-arm phase II trial(EudraCT number:2016-004039-19).With the main endpoint of a 6-month PFS rate,40%was considered promising in this population.Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles.A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening,archival material(141),and screening,baseline biopsy(95).There were 28(29%)with favorable mRNA profiles from 95 screened patients at baseline.From 23 enrolled patients,21 evaluable,the 6-month PFS rate was 29%(95%CI 9–48),and there were 6 patients out of 21 with a PFS longer than 6 months.The median PFS and overall survival were 4.2(95%CI 3.6–4.8)and 12(95%CI 8.7–15.4)months,respectively.Translational research showed a significant correlation between CDK4 mRNA and protein expression.Palbociclib was active in a variety of sarcoma subtypes,selected by CDK4/CDKN2A,and deserves further investigation in the sarcoma context.

关键词： CDKN2A sarcoma CDK4

Female mate choice based on pheromone content may inhibit reproductive isolation between distinct populations of Iberian wall lizards

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Current Zoology 2013年第2期59卷 210-220页

作者： Marianne GABIROT pilar lopez Jose MARTIN Departement Ecologie Comportementale (U.M.R. 5175) CEFE-CNRS 1919 Route de Mende F34293 Montpellier Cedex 5 France Departamento de Ecologia Evolutiva Museo Naeional de Ciencias Naturales C.S.I.C. Jos6 Guti6rrez Abascal 2 28006 Madrid Spain

The Iberian wall lizardPodarcis hispanicaforms part of a species complex with several morphologically and genetically distinct types and populations, which may or may not be reproductively isolated. We analyzed whether female mate choice based on males’ chemical signals may contribute to a current pre-mating reproductive isolation between two distinct populations ofP. hispanicafrom central Spain. We experimentally examined whether females choose to establish territories on areas scent-marked by males of their own population, versus areas marked by males of the other population. Results showed that females did not prefer scent-marks of males from their own population. In contrast, females seemed to attend mostly to among-individual variation in males’ pheromones that did not differ between populations. Finally, to test for strong premating reproductive isolation, we staged intersexual encounters between males and females. The population of origin of males and females did not affect the probability nor the duration of copulations. We suggest that the different environmental conditions in each population might be selecting for different morphologies and different chemical signals of males that maximize efficiency of communication in each environment. However, females in both populations based mate choice on a similar condition-dependent signal of males. Thus, male signals and female mate choice criteria could be precluding premating reproductive isolation between these phenotypically “distinct” populations.

关键词：生殖隔离女性择偶人群蜥蜴信息素化学信号气味标记

Microengineering double layer hydrogel structures towards the recapitulation of the hematopoietic stem cell niche

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Science Bulletin 2018年第20期63卷 1319-1323页

作者： pilar Carreras Rodrigo Cortrim Chaves Miguel Gallardo Alejandra Ortiz Joaquin Martinez lopez Samuel K.Sia Department of Biomedical Engineering Columbia UniversityNew YorkNY 10032USA Hematology Department Research Institute i+12Hospital 12 OctubreMadrid 2804Spain Hematological Malignancies Clinical Research Unit H120 CNIOMadrid 28029Spain

Adult stem cells,especially from bone marrow,have a tremendous therapeutic potential,and its application in regenerative medicine has been increasingly studied [1,2].It is well known that three-dimensional (3D)cell culture matrix promotes many biological relevant functions not observed in two-dimensional (2D) monolayer cell culture [3]and therefore,engineering 3D cell culture platforms to mimic the native in vivo biological systems represents a realistic approach for studies of bone marrow stem cells. High-throughput microfluidics constitutes a promising technology to generate hydrogel three dimensional constructs [4,5],however, its application to host adult stem cells remains still a challenge.

关键词： hydrogel hematopoietic stem cell

Functions of Bounded （p（·), 2)-Variation in De la Vallee Poussin-Wiener’s Sense with Variable Exponent

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Advances in Pure Mathematics 2017年第9期7卷 507-532页

作者： Odalis Mejia pilar Silvestre Maria Valera-lopez Departamento de Matematica Universidad Central de Venezuela Caracas Venezuela University of Barcelona Spain

In this paper we establish the notion of the space of bounded ?(p(⋅), 2)variation in De la Vallée Poussin-Wiener’s sense with variable exponent. We show some properties of this space and we show that any uniformly bounded composition operator that maps this space into itself necessarily satisfies the so-called Matkowski’s conditions.

关键词： Generalized Variation De la Vallee Poussin (p(·) 2)-Variation in Wiener’s Sense Variable Exponent Composition Operator Matkowski’s Condition

Pulmonary arterial hypertension related to human immunodeficiency virus infection:A case series

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World Journal of Cardiology 2014年第6期6卷 495-501页

作者： Inês Araújo Cristina Enjuanes-Grau Carmen Jimenez lopez-Guarch Dariusz Narankiewicz Maria J Ruiz-Cano Teresa Velazquez-Martin Juan Delgado pilar Escribano 3~(rd) Medicine Department S?o Francisco Xavier HospitalCHLO1449-005 LisboaPortugal Cardiology Department University Hospital of Canarias38320 La LagunaTenerifeSpain Teresa Velazquez-Martin Juan DelgadoPilar EscribanoPulmonary Hypertension UnitUniversity Hospital of 12 de Octubre28041 MadridSpain Internal Medicine Department Carlos Haya Hospital29010 MálagaSpain Pulmonary Hypertension Unit University Hospital of 12 de Octubre28041 MadridSpain

AIM: To present 18 new cases of human immunodeficiency virus(HIV)-related pulmonary arterial hypertension(PAH) with presenting features,treatment options and follow-up data.METHODS: This is a single-centre,retrospective,observational study that used prospectively collected data,conducted during a 14-year period on HIV-related PAH patients who were referred to a pulmonary hy-pertension unit. All patients infected with HIV were consecutively admitted for an initial evaluation of PAH during the study period and included in our study. Right heart catheterisation was used for the diagnosis of PAH. Specific PAH treatment was started according to the physician's judgment and the recommendations for idiopathic PAH. The data collected included demographic characteristics,parameters related to both HIV infection and PAH and disease follow-up.RESULTS: Eighteen patients were included. Intravenous drug use was the major risk factor for HIV infection. Risk factors for PAH,other than HIV infection,were present in 55.5% patients. The elapsed time between HIV infection and PAH diagnoses was 12.2 ± 6.9 years. At PAH diagnosis,94.1% patients had a CD4 cell count > 200 cells/μL. Highly active antiretroviral therapy(present in 47.1% patients) was associated with an accelerated onset of PAH. Survival rates were 93.8%,92.9% and 85.7% at one,two and three years,respectively. Concerning specific therapy,33.3% of the patients were started on a prostacyclin analogue,and the rest were on oral drugs,mainly phosphodiesterase-5 inhibitors. During the follow-up period,specific therapy was de-escalated to oral drugs in all of the living patients.CONCLUSION: The survival rates of HIV-related PAH patients were higher,most likely due to new aggressive specific therapy. The majority of patients were on oral specific therapy and clinically stable. Moreover,sildenafil appears to be a safe therapy for less severe HIVrelated PAH.

关键词：人的免疫不全病毒感染肺的动脉的高血压处理

Replacement of Cereal with Low Starch Fibrous By-Products on Nutrients Utilization and Methane Emissions in Dairy Goats

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Open Journal of Animal Sciences 2015年第2期5卷 198-209页

作者： Carla Ibanez Vicente Javier Moya Haritz Arriaga Diana Maria lopez pilar Merino Carlos Fernandez Research Group ACUMA Animal Science DepartmentPolytechnic University of ValenciaValenciaSpain Institute for Animal Science and Technology Universitat Politecnica de ValenciaValenciaSpain Neiker-Tecnalia Basque Institute for Agricultural Research and DevelopmentBizkaiaSpain

Feeding systems for dairy ruminants need to ensure high intake of energy to achieve maximum milk production potential. This might be accomplished by raising the dietary concentration of cereal grain. Increasing the concentration of starch in diets can lead to undesirable ruminal fermentation, and to prevent it, the partial replacement of cereal grain with low starch by-product feeds is recommended. The purpose of the present study was to compare the effect of fed two mixed diets to dairy goats differing in the type of carbohydrate (starch vs. easily degradable fiber). Energy and nitrogen balance, short chain fatty acids in rumen liquor and milk performance in dairy goats during mid lactation were determined. Enteric methane (CH4) emissions and CH4 production from manure were determined as well. Ten multiparous Muciano-Granadina goats were assigned to two isoenergetic and isoproteic diets (19.1 MJ/kg dry matter (DM) and 18.1% of CP, DM basis) in a crossover design. One group was fed a mixed ration with 21.9% of starch (HS diet) and the other (LS diet) with 7.0% of starch. HS diet had 36% of barley (as source of starch) and it was replaced with soy hulls and corn gluten feed in LS diet (as potentially digestible fiber). No differences were observed for dry matter intake in both diets (2.05 kg/d, on average). A significant increase of ruminal acetic acid was found for low starch diet (66.4 and 56.6 mol/100 mol for LS and HS diet, respectively). No significant effect was found among diets for enteric CH4 emissions (28.5 g/d, on average). Manure derived maximum potential yield was (Bo) higher in HS diet, with 5.9 L CH4/kg OM vs. 0.28 L CH4/kg OM for LS diet, probably associated with the low ADF digestibility. Differences among diets were found for milk production (2.4 vs. 2.2 kg/d for HS and LS, respectively), and greater milk fat was observed with LS diet compared with HS (6.4% vs. 5.5%, respectively).

关键词： Goats Starch Enteric Methane Manure CH_(4)0. Potential Production

Prospective application of a bleeding and ischemic risks-adjusted antithrombotic protocol in elderly patients revascularized with everolimus-eluting stents:EPIC05-Sierra75 study

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Journal of Geriatric Cardiology 2022年第5期19卷 354-366页

作者： Jose M de la Torre Hernandez Ramon lopez Palop Jesus M Jimenez Mazuecos pilar Carrillo Sáez Alejandro Gutierez-Barrios Eduardo Pinar Belen Cid Luis Fernandez Tamara Garcia Camarero Cristóbal Urbano-Carrillo Juan F Oteo Dominguez Victor A Jimenez Diaz Antonio EGomez Menchero Eladio Galindo Fernández Juan GCórdoba Soriano Raymundo Ocaranza Eduardo ArroyoÚcar Koldobika Garcia San Roman Silvio Leal Ginés Martínez Cáceres Jose A Linares Vicente Georgina Fuertes Ferre Xavier Carrillo Juan CRama Merchán Catia Costa Juan Sanchis Renato Fernandes Alberto Rodrigues Jose M Vegas Valle Hélder Pereira Armando Perez de Prado Cardiology Department Hospital Universitario Marqués de ValdecillaIDIVALSantanderSpain Cardiology Department Hospital Universitario San JuanAlicanteSpain Cardiology Department Complejo Hospitalario Universitario de AlbaceteAlbaceteSpain Cardiology Department Hospital Universitario Puerta del MarCadizSpain Cardiology Department Hospital Clínico Universitario Virgen de la ArrixacaMurciaSpain Cardiology Department Hospital Clinico Universitario de SantiagoCIBERCVSantiago de CompostelaSpain Cardiology Department Hospital Universitario de CrucesBilbaoSpain Cardiology Department Hospital Regional Universitario de MálagaMalagaSpain Cardiology Department Hospital Universitario Puerta de HierroMadridSpain Cardiology Department Hospital Alvaro CunqueiroVigoSpain Cardiology Department Hospital Juan Ramon JimenezHuelvaSpain Cardiology Department Hospital Universitario de BadajozBadajozSpain Cardiology Department Hospital Universitario Lucus AugustiLugoSpain Cardiology Department Hospital de Torrevieja/VinalopóRibera SaludTorreviejaSpain Cardiology Department Hospital Santa CruzLisboaPortugal Cardiology Department Hospital Clínico Universitario Lozano BlesaZaragozaSpain Cardiology Department Hospital Universitario Miguel ServetZaragozaSpain Cardiology Department Hospital Germans Trias i PujolBadalonaSpain Cardiology Department Hospital de MeridaMeridaSpain Cardiology Department Hospital São BernardoSetúbalPortugal Cardiology Department Hospital Clinico Universitario de ValenciaUniversidad de ValenciaCIBERCVValenciaSpain Cardiology Department Hospital do Espirito SantoEvoraPortugal Cardiology Department Centro Hospitalar de Vilanova de GaiaVilanova de GaiaPortugal Cardiology Department Hospital de CabueñesGijonSpain Cardiology Department Hospital Garcia de OrtaAlmadaPortugal Cardiology Department Complejo Asistencial Universitario de LeónLeonSpain

OBJECTIVES Elderly patients show a higher incidence of ischemic and bleeding events after percutaneous transluminal coron-ary intervention(PCI).We sought to investigate outcomes in elderly patients treated with antithrombotic strategy guided by bleeding and ischemic risks after revascularization with last generation everolimus-eluting stent(EES).METHODS Prospective multicenter registry including patients over 75 years revascularized with EES and antithrombotic ther-apy guided by clinical presentation,PCI complexity and PRECISE DAPT score.Co-primary safety endpoints were:(1)composite of cardiac death,myocardial infarction and stent thrombosis and;(2)bleeding(BARC 2-5).Primary efficacy endpoint was target lesion revascularization.A matched group of patients revascularized with current drug-eluting stents and no such tailored antith-rombotic therapy was used as control.RESULTS Finally,1064 patients were included in SIERRA-75 cohort,80.8±4.2 years,36.6%women,71%acute coronary syn-dromes(ACS)and 53.6%complex PCI.Co-primary safety endpoint of major adverse cardiovascular events was met in 6.2%,co-primary safety endpoint of bleeding in 7.8%and primary efficacy endpoint of TKLR in 1.5%.The multivariable adjusted model showed no significant association of the prescribed short/long dual antiplatelet therapy(DAPT)durations with any endpoint suggesting a well tailored therapy.No stent thrombosis reported in the subgroup with 1-3 months DAPT duration.As compared to control group,bleeding BARC 2-5 was significantly lower in SIERRA-75 group(7.4%vs.10.2%,P=0.04)as well as the net safety-efficacy endpoint(14.3%vs.18.5%,P=0.02).CONCLUSIONS In elderly population,the application of this risks-adjusted antithrombotic protocol after revascularization with last generation EES seems to be associated with an improved prognosis in terms of ischemic and bleeding outcomes.

关键词： patients bleeding antithrombotic

Rare germline copy number variants in colorectal cancer predisposition characterized by exome sequencing analysis

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Journal of Genetics and Genomics 2018年第1期45卷 41-45页

作者： Sebastia Franch-Exposito Clara Esteban-Jurado pilar Garre Isabel Quintanilla Saray Duran-Sanchon Marcos Diaz-Gay Laia Bonjoch Miriam Cuatrecasas Esther Samper Jenifer Munoz Teresa Ocana Sabela Carballal Maria lopez-Ceron Antoni Castells Maria Vila-Casadesus Sophia Derdak Steven Laurie Sergi Beltran Jaime carvajal Luis Bujanda Clara Ruiz-Ponte Jordi Camps Meritxell Gironella Juan Jose Lozano Francesc Balaguer Joaquin Cubiella Trinidad Caldes Sergi Castellvi-Bel Gastroenterology Department Hospital Clinic de Barcelona August Pi i Sunyer Biomedical Research Institute CIBER of Hepatic and Digestive Diseases University of Barcelona Barcelona 08036 Spain Molecular Oncology Laboratory Hospital Clinico San Carlos Health Research Institute of the Hospital Clinico San Carlos Madrid 28040 Spain Department of Pathology Hospital Clinic de Barcelona Barcelona 08036 Spain EPICOLON consortium Bioinformatics Platform CIBER of Hepatic and Digestive Diseases Barcelona 08036 Spain National Center of Genomic Analysis Science Park of Barcelona Barcelona 08028 Spain Andalusian Developmental Biology Institute CSIC-Pablo de Olavide University-Andalusian Regional Government SeviUa 41013 Spain Gastroenterology Department Hospital Donostia-Biodonostia Institute CIBER of Hepatic and Digestive Diseases University of the Basque Country (UPV/EHU) San Sebastian 20080 Spain Galician Public Foundation of Genomic Medicine (FPGMX) CIBER of Rare Diseases Genomics Medicine Group Hospital Clinico Universitario University of Santiago de Compostela Santiago de Cornpostela 15706 Spain Castroenterology Department Complexo Hospitalario Universitario de Ourense Ourense Biomedical Research Institute Ourense 32005 Spain

Colorectal cancer （CRC） is one of the most common neoplasms and an important cause of mortality worldwide （http：//globocan. iarc.fr]）. Approximately 35% of the variation in CRC susceptibility is likely due to heritable factors （Lichtenstein et al., 2000}. Genetic variations in the human genome include single nucleotide variants （SNVs）, short insertions and deletions, and larger structural variants resulting in gain or loss of genomic DNA larger than 1 kb, such as copy number variants （CNVs）. Leaving aside the importance of CNVs in sporadic tumor development, these variants can also be present in the germline DNA of healthy individuals from the general population and be considered polymorphic.

关键词： WHOLE-EXOME GENE

A High-Resolution Modeling Strategy to Assess Impacts of Climate Change for Mesoamerica and the Caribbean

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American Journal of Climate Change 2016年第2期5卷 202-228页

作者： Robert Oglesby Clinton Rowe Alfred Grunwaldt Ines Ferreira Franklyn Ruiz Jayaka Campbell Luis Alvarado Francisco Argenal Berta Olmedo Alejandro del Castillo pilar lopez Edwards Matos Yosef Nava Carlos Perez Joel Perez Department of Earth and Atmospheric Sciences University of Nebraska Lincoln NE USA Climate Change and Sustainability Division Inter-American Development Bank Washington DC USA Instituto de Hidrología Meteorología y Estudios Ambientales de Colombia Bogota Colombia University of the West Indies Kingston Jamaica Instituto Meteorológico Nacional Costa Rica San Jose Costa Rica Servicio Meteorológico Nacional de Honduras Dirección General de Aeronáutica Civil Tegucigalpa Honduras Empresa de Transmisión Eléctrica Paname?a Ciudad de Panamá Panamá Water Center for the Humid Tropics of Latin America and the Caribbean (CATHALAC) Ciudad de Panamá Panamá Unidad de Análisis Meteorológico Empresa de Transmisión Eléctrica Paname?a Ciudad de Panamá Panamá Instituto Nacional de Ecología y Cambio Climático Mexico City Mexico National Weather Service MARN San Salvador El Salvador

Mesoamerica and the Caribbean are low-latitude regions at risk for the effects of climate change. Global climate models provide large-scale assessment of climate drivers, but, at a horizontal resolution of 100 km, cannot resolve the effects of topography and land use as they impact the local temperature and precipitation that are keys to climate impacts. We developed a robust dynamical downscaling strategy that used the WRF regional climate model to downscale at 4 - 12 km resolution GCM results. Model verification demonstrates the need for such resolution of topography in order to properly simulate temperatures. Precipitation is more difficult to evaluate, being highly variable in time and space. Overall, a 36 km resolution is inadequate;12 km appears reasonable, especially in regions of low topography, but the 4 km resolution provides the best match with observations. This represents a tradeoff between model resolution and the computational effort needed to make simulations. A key goal is to provide climate change specialists in each country with the information they need to evaluate possible future climate change impacts.

关键词： Regional Climate Models Dynamical Downscaling Strategy Mesoamerica and Caribbean Climate Change