Approximate Profile Maximum Likelihood

We propose an efficient algorithm for approximate computation of the profile maximum likelihood (PML), a variant of maximum likelihood maximizing the probability of observing a sufficient statistic rather than the empirical sample. The PML has appealing theoretical properties, but is difficult to compute exactly. Inspired by observations gleaned from exactly solvable cases, we look for an approximate PML solution, which, intuitively, clumps comparably frequent symbols into one symbol. This amounts to lower-bounding a certain matrix permanent by summing over a subgroup of the symmetric group rather than the whole group during the computation. We extensively experiment with the approximate solution, and find the empirical performance of our approach is competitive and sometimes significantly better than state-of-the-art performance for various estimation problems

Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival

© 2021 by the authors.Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10–15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a KRAS somatic mutation. In addition, KRAS mutation negative cases harbor somatic mutations in potentially druggable genes such as KIT, PDGFR, MET, BRAF, and PIK3CA that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment.This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I+D+i 2013– 2016): ISCIII (PI09/02221, PI12/01635, PI15/02101, and PI18/0135) and co-financed by the European Development Regional Fund “A way to achieve Europe” (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073), La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016), Fundación Mutua Madrileña (FMM) / XVI Convocatoria de Ayudas a la Investigación en Salud 2019 and Asociación Cáncer de Páncreas (ACanPan); Asociación Española de Pancreatología (AESPANC) / IV Becas de Investigación Carmen Delgado/Miguel Pérez-Mateo 2019. The European Union’s Horizon 2020 research and innovation program under grant agreement No 857381, project VISION (Strategies to strengthen scientific excellence and innovation capacity for early diagnosis of gastrointestinal cancers).Peer reviewe

Nanomedicine and epigenetics: New alliances to increase the odds in pancreatic cancer survival

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers worldwide, primarily due to its robust desmoplastic stroma and immunosuppressive tumor microenvironment (TME), which facilitate tumor progression and metastasis. In addition, fibrous tissue leads to sparse vasculature, high interstitial fluid pressure, and hypoxia, thereby hindering effective systemic drug delivery and immune cell infiltration. Thus, remodeling the TME to enhance tumor perfusion, increase drug retention, and reverse immunosuppression has become a key therapeutic strategy. In recent years, targeting epigenetic pathways has emerged as a promising approach to overcome tumor immunosuppression and cancer progression. Moreover, the progress in nanotechnology has provided new opportunities for enhancing the efficacy of conventional and epigenetic drugs. Nano-based drug delivery systems (NDDSs) offer several advantages, including improved drug pharmacokinetics, enhanced tumor penetration, and reduced systemic toxicity. Smart NDDSs enable precise targeting of stromal components and augment the effectiveness of immunotherapy through multiple drug delivery options. This review offers an overview of the latest nano-based approaches developed to achieve superior therapeutic efficacy and overcome drug resistance. We specifically focus on the TME and epigenetic-targeted therapies in the context of PDAC, discussing the advantages and limitations of current strategies while highlighting promising new developments. By emphasizing the immense potential of NDDSs in improving therapeutic outcomes in PDAC, our review paves the way for future research in this rapidly evolving field.This research was funded by the European Union’s Horizon 2020 research and innovation program under grant agreement No 857381/VISION, the Spanish Biomedical Research Network in Cancer CIBERONC (CB16/12/00446), from the Slovak Research and Development Agency (APVV-21-0197, APVV-20-0143) and TRANSCAN-2 Program ERA-NET JTC 2017 “Translational research on rare cancers” within the project NExT.Peer reviewe

Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study

© 2021 by the authors.First-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.Financial support for this research was provided by Bayer Hispania, which had no role in the design of the study; the collection, analysis, and interpretation of data; and the writing of the manuscript.Peer reviewe

A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

Purpose: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients.Patients and methods: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm.Results: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: pop-ulation for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 pa-tients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C.Conclusions: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher nu-merical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles

Formación de los tutores de las prácticas externas como herramienta eficaz en la mejora del aprendizaje del estudiante y su inserción laboral

El objetivo del proyecto es mejorar la calidad de la tutorización de las prácticas externas y fomentar las buenas prácticas que garanticen el proceso de enseñanza-aprendizaje. Están implicados tutores académicos, externos, instituciones y estudiante

CARB-ES-19 Multicenter Study of Carbapenemase-Producing Klebsiella pneumoniae and Escherichia coli From All Spanish Provinces Reveals Interregional Spread of High-Risk Clones Such as ST307/OXA-48 and ST512/KPC-3

ObjectivesCARB-ES-19 is a comprehensive, multicenter, nationwide study integrating whole-genome sequencing (WGS) in the surveillance of carbapenemase-producing K. pneumoniae (CP-Kpn) and E. coli (CP-Eco) to determine their incidence, geographical distribution, phylogeny, and resistance mechanisms in Spain.MethodsIn total, 71 hospitals, representing all 50 Spanish provinces, collected the first 10 isolates per hospital (February to May 2019); CPE isolates were first identified according to EUCAST (meropenem MIC > 0.12 mg/L with immunochromatography, colorimetric tests, carbapenem inactivation, or carbapenem hydrolysis with MALDI-TOF). Prevalence and incidence were calculated according to population denominators. Antibiotic susceptibility testing was performed using the microdilution method (EUCAST). All 403 isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis.ResultsIn total, 377 (93.5%) CP-Kpn and 26 (6.5%) CP-Eco isolates were collected from 62 (87.3%) hospitals in 46 (92%) provinces. CP-Kpn was more prevalent in the blood (5.8%, 50/853) than in the urine (1.4%, 201/14,464). The cumulative incidence for both CP-Kpn and CP-Eco was 0.05 per 100 admitted patients. The main carbapenemase genes identified in CP-Kpn were blaOXA–48 (263/377), blaKPC–3 (62/377), blaVIM–1 (28/377), and blaNDM–1 (12/377). All isolates were susceptible to at least two antibiotics. Interregional dissemination of eight high-risk CP-Kpn clones was detected, mainly ST307/OXA-48 (16.4%), ST11/OXA-48 (16.4%), and ST512-ST258/KPC (13.8%). ST512/KPC and ST15/OXA-48 were the most frequent bacteremia-causative clones. The average number of acquired resistance genes was higher in CP-Kpn (7.9) than in CP-Eco (5.5).ConclusionThis study serves as a first step toward WGS integration in the surveillance of carbapenemase-producing Enterobacterales in Spain. We detected important epidemiological changes, including increased CP-Kpn and CP-Eco prevalence and incidence compared to previous studies, wide interregional dissemination, and increased dissemination of high-risk clones, such as ST307/OXA-48 and ST512/KPC-3

La celebración de días escolares

Se elaboran trece diseños didácticos que facilitan al profesorado de la enseñanza obligatoria a celebrar los 'días escolares' a los largo del curso. Se diseña material curricular para que los centros incluyan en el calendario escolar y en el proyecto curricular y concretamente en sus propósitos, objetivos y contenidos procedimentales y actitudinales, espacio y tiempo a unos temas exigidos por la conciencia ciudadana. Este tipo de educación ético-cívica consiste en la celebración de 'días didácticos' o 'días escolares' que la sociedad recuerda a la escuela. Se pretende celebrar estos 'días' de celebración con las áreas curriculares, contribuyendo a la educación en valores y a la creación de un diseño curricular más completo desde los temas transversales. En el proyecto se desarrolla la celebración de días como: 'día escolar de la no violencia y la paz'; 'día internacional de la mujer'; 'día internacional para la eliminación de todas las formas de discriminación racial'; 'día mundial de la salud'; 'día de Castilla y León'; 'día mundial de la telecomunicación'; 'día del medio ambiente'; 'día internacional de la paz'; 'día internacional del niño'; 'día mundial de la alimentación'; 'día de Santa Cecilia o día de la educación a través de la música'; 'día del maestro'; 'día de los Derechos Humanos'. La estructura del diseño de los 'días' es: historia del día y razón de su celebración; objetivos de celebración; contenidos a estudiar; relación con los temas transversales; actividades que se proponen; recursos didácticos o materiales complementarios; y evaluación de la celebración.Castilla y LeónConsejería de Educación. Dirección General de Universidades e Investigación ; Monasterio de Nuestra Señora de Prado, Autovía Puente Colgante s. n.; 47071 Valladolid; +34983411881; +34983411939;ES

Estudio científico didáctico y curricular sobre la celebración de días escolares

Proyecto realizado por siete maestros del Colegio Rural Agrupado de Sacramenia (Segovia), Colegio 'Santa Clara' de Cuéllar (Segovia), Colegio Rural Agrupado 'La Villa' de Peñafiel (Valladolid), Colegio 'Santa Teresa de Jesús' de Dueñas (Palencia), Colegio Público 'Tierno Galván' (Valladolid) y otros colaboradores. Los objetivos: 1) Elaborar diseños didácticos relativos a la celebración de días escolares. 2) Contribuir a la educación en valores enfatizando la importancia de los temas transversales. 3) Contribuir a la formación permanente del profesorado. Los sistemas de trabajo han sido: Búsqueda de materiales bibliográficos, selección de los días escolares, reuniones y trabajo conjunto para puestas en común y diseño del material curricular conforme a la opción de un modelo didáctico. Los materiales elaborados han sido los siguientes: Día de la paz; Día de la educación a través de la música; Prevención drogodepencias; Día de los derechos humanos; Día mundial del sida; Día mundial de la salud; Día del medio ambiente; Día del antiracismo. Sus características se ajustan al siguiente esquema: Historia del día, objetivos de la celebración, contenidos, actividades, recursos didácticos y se prevé la evaluación correspondiente. Los materiales utilizados han sido: Libros, videos y medios informáticos. El trabajo no ha sido publicado.Comunidad Autónoma de Castilla y León, Consejería de Educación y Cultura, Dirección General de EducaciónCastilla y LeónES