European expert panel consensus on the clinical management of BRAFV600E-mutant metastatic colorectal cancer

Consensus; Metastatic colorectal cancer; TreatmentConsens; Càncer colorectal metastàtic; TractamentConsenso; Cáncer colorrectal metastásico; TratamientoMetastatic colorectal cancer (mCRC) is a heterogenous disease caused by various genetic alterations. The BRAFV600E mutation occurs in approximately 8–12% of patients and is characterised by an aggressive clinical course and poor prognosis. Here we review the current knowledge on BRAFV600E-mutant mCRC and provide a series of consensus statements on its clinical management. The treatment landscape for BRAFV600E-mutant mCRC has changed greatly due to the emergence of molecular targeted therapies (including BRAF inhibitors) and immune checkpoint inhibitors. A scientific literature search identified available data on molecular testing, treatments, and clinical monitoring of patients with BRAFV600E-mutant mCRC. Consensus statements were discussed and developed by a European expert panel. This manuscript provides consensus management guidance for different clinical presentations of BRAFV600E-mutant mCRC and makes recommendations regarding treatment sequencing choices. To guide appropriate clinical management and treatment decisions for mCRC patients, tumour tissue analysis for DNA mismatch repair/microsatellite status and, at a minimum, KRAS, NRAS, and BRAF mutational status is mandatory at the time of diagnosis. Finally, we discuss the rapidly evolving treatment landscape for BRAFV600E-mutant mCRC and define priorities for the development of novel therapeutic strategies that are needed to improve patient outcomes.This work was supported by an unrestricted medical education grant from Pierre Fabre, whose only involvement was to select the chair and to fund LiNK Health Group to provide independent medical writing support to the author group. Pierre Fabre had no sight of the article during development and no editorial involvement

Fine-tuning genomic and pedigree inbreeding rates in equine population with a deep and reliable stud book: the case of the Pura Raza Española horse

Background: Estimating inbreeding, which is omnipresent and inevitable in livestock populations, is a primary goal for management and animal breeding especially for those interested in mitigating the negative consequences of inbreeding. Inbreeding coefficients have been historically estimated by using pedigree information; however, over the last decade, genome-base inbreeding coefficients have come to the forefront in this field. The Pura Raza Española (PRE) horse is an autochthonous Spanish horse breed which has been recognised since 1912. The total PRE population (344,718 horses) was used to estimate Classical (F), Ballou’s ancestral, Kalinowski’s ancestral, Kalinowski’s new and the ancestral history coefficient values. In addition, genotypic data from a selected population of 805 PRE individuals was used to determine the individual inbreeding coefficient using SNP-by-SNP-based techniques (methods of moments -FHOM-, the diagonal elements of the genomic -FG-, and hybrid matrixes -FH-) and ROH measures (FRZ). The analyse of both pedigree and genomic based inbreeding coefficients in a large and robust population such as the PRE horse, with proven parenteral information for the last 40 years and a high degree of completeness (over 90% for the last 70 years) will allow us to understand PRE genetic variability better and the correlations between the estimations will give the data greater reliability. Results: The mean values of the pedigree-based inbreeding coefficients ranged from 0.01 (F for the last 3 generations -F3-) to 0.44 (ancestral history coefficient) and the mean values of genomic-based inbreeding coefficients varied from 0.05 (FRZ for three generations, FH and FHOM) to 0.11 (FRZ for nine generations). Significant correlations were also found between pedigree and genomic inbreeding values, which ranged between 0.58 (F3 with FHOM) and 0.79 (F with FRZ). In addition, the correlations between FRZ estimated for the last 20 generations and the pedigree-based inbreeding highlight the fact that fewer generations of genomic data are required when comparing total inbreeding values, and the opposite when ancient values are calculated. Conclusions: Ultimately, our results show that it is still useful to work with a deep and reliable pedigree in pedigree-based genetic studies with very large effective population sizes. Obtaining a satisfactory parameter will always be desirable, but the approximation obtained with a robust pedigree will allow us to work more efficiently and economically than with massive genotyping.Fil: Perdomo González, Davinia Isabel. Universidad de Sevilla; EspañaFil: Laseca, Nora. Universidad de Córdoba; EspañaFil: Demyda-peyrás, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; ArgentinaFil: Valera, Mercedes. Universidad de Sevilla; EspañaFil: Cervantes, Isabel. Universidad Complutense de Madrid; EspañaFil: Molina, Antonio. Universidad de Córdoba; Españ

Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer’s disease Ibero-American cohort

INTRODUCTION: Some familial Alzheimer's disease (AD) cases are caused by rare and highly-penetrant mutations in APP, PSEN1, and PSEN2. Mutations in GRN and MAPT, two genes associated with frontotemporal dementia (FTD), have been found in clinically diagnosed AD cases. Due to the dramatic developments in next-generation sequencing (NGS), high-throughput sequencing of targeted genomic regions of the human genome in many individuals in a single run is now cheap and feasible. Recent findings favor the rare variant-common disease hypothesis by which the combination effects of rare variants could explain a large proportion of the heritability. We utilized NGS to identify rare and pathogenic variants in APP, PSEN1, PSEN2, GRN, and MAPT in an Ibero-American cohort. METHODS: We performed pooled-DNA sequencing of each exon and flanking sequences in APP, PSEN1, PSEN2, MAPT and GRN in 167 clinical and 5 autopsy-confirmed AD cases (15 familial early-onset, 136 sporadic early-onset and 16 familial late-onset) from Spain and Uruguay using NGS. Follow-up genotyping was used to validate variants. After genotyping additional controls, we performed segregation and functional analyses to determine the pathogenicity of validated variants. RESULTS: We identified a novel G to T transition (g.38816G>T) in exon 6 of PSEN1 in a sporadic early-onset AD case, resulting in a previously described pathogenic p.L173F mutation. A pathogenic p.L392V mutation in exon 11 was found in one familial early-onset AD case. We also identified a novel CC insertion (g.10974_10975insCC) in exon 8 of GRN, which introduced a premature stop codon, resulting in nonsense-mediated mRNA decay. This GRN mutation was associated with lower GRN plasma levels, as previously reported for other GRN pathogenic mutations. We found two variants in MAPT (p.A152T, p.S318L) present only in three AD cases but not controls, suggesting that these variants could be risk factors for the disease. CONCLUSIONS: We found pathogenic mutations in PSEN1, GRN and MAPT in 2.33% of the screened cases. This study suggests that pathogenic mutations or risk variants in MAPT and in GRN are as frequent in clinical AD cases as mutations in APP, PSEN1 and PSEN2, highlighting that pleiotropy of MAPT or GRN mutations can influence both FTD and AD phenotypic traits

The altered transcriptome and DNA methylation profiles of docetaxel resistance in breast cancer PDX models

Taxanes are standard therapy in clinical practice for metastatic breast cancer; however, primary or acquired chemoresistance are a common cause of mortality. Breast cancer patient-derived xenografts (PDX) are powerful tools for the study of cancer biology and drug treatment response. Specific DNA methylation patterns have been associated to different breast cancer subtypes but its association with chemoresistance remains unstudied. Aiming to elucidate docetaxel resistance mechanisms, we performed genome-wide DNA methylation in breast cancer PDX models, including luminal and triple-negative breast cancer (TNBC) models sensitive to docetaxel, their matched models after emergence of chemoresistance and residual disease after short-term docetaxel treatment. We found that DNA methylation profiles from breast cancer PDX models maintain the subtype-specific methylation patterns of clinical samples. Two main DNA methylation clusters were found in TNBC PDX and remain stable during the emergence of docetaxel resistance; however, some genes/pathways were differentially methylated according to docetaxel response. A DNA methylation signature of resistance able to segregate TNBC based on chemotherapy response was identified. Transcriptomic profiling of selected sensitive/resistant pairs and integrative analysis with methylation data demonstrated correlation between some differentially methylated and expressed genes in docetaxel-resistant TNBC PDX models. Multiple gene expression changes were found after the emergence of docetaxel resistance in TNBC. DNA methylation and transcriptional changes identified between docetaxel-sensitive and -resistant TNBC PDX models or residual disease may have predictive value for chemotherapy response in TNBC. IMPLICATIONS: Subtype-specific DNA methylation patterns are maintained in breast cancer PDX models. While no global methylation changes were found, we uncovered differentially DNA methylated and expressed genes/pathways associated with the emergence of docetaxel resistance in TNBC

Modelo prolab: Mantay, tienda virtual que facilita la venta de la mayor variedad de artículos de artesanía peruana

La presente tesis se desarrolla alrededor de la artesanía peruana, partiendo de las dificultades que ha generado la pandemia COVID-19, la cual evidenció la necesidad de brindarle una mayor exposición al artesano para que obtenga nuevas fuentes de ingreso, al mismo tiempo que se promueve la tradición artesanal y cultural peruana. Esta situación se aborda de distintas perspectivas, desde los artesanos, las asociaciones y/o agrupaciones artesanales en cada región del Perú, hasta los consumidores y sus necesidades específicas alrededor del rubro. Ante ello, se desarrolló un ecommerce llamado Mantay, en homenaje a las madres que transmiten la tradición del trabajo artesanal a sus hijos. Mantay es una tienda virtual que facilita la venta de productos artesanales provenientes de las ciudades de Cuzco, Piura y Puno. Además, se realizaron estudios de mercado cuyos resultados concluyen que existe un interés genuino de 83.68% de compra por los usuarios potenciales. En la deseabilidad de Mantay, se obtuvo que la satisfacción superó el criterio mínimo propuesto logrando un 70% de NPS. Mientras que la factibilidad fue validada a través del plan de marketing con una eficiencia de 100% al evaluar la relación del valor tiempo de vida del cliente y su costo de adquisición. Adicionalmente, para la viabilidad financiera se tomó en cuenta inversión inicial de S/1,100,000.00 con una VAN promedio de S/ S/4,596,036.04 para los cinco primeros años y una tasa de retorno (TIR) de 72.40%. Finamente, en la viabilidad social y ambiental, se estimaron los beneficios y costos en el ahorro de tiempo en la movilización para que el usuario final compre artesanía y el aumento de los ingresos de los artesanos, logrando un VANS de S/10,481,560.64. Por ello, Mantay es una propuesta sostenible alineada los ODS 1, 8 y 12, generando un mayor impacto económico y de conocimiento tanto técnico como de gestión en los artesanos del Perú.This thesis is concerned with the Peruvian craftworks, starting from the difficulties generated by COVID-19, which has revealed that is necessary to provide artisans more exposure giving them new sources of income, while it becomes essential to give greater notoriety to the Peruvian artisanal and cultural tradition. This situation is approached from different perspectives, from artisans, associations, and artisan groups in each region of Peru, to consumers and their specific needs about this artisanal sector. The solution is an ecommerce called Mantay, a name that honors mothers who pass on the tradition of craftsmanship to their children. Mantay is an ecommerce platform that has the largest variety of handcrafted products from the cities of Cuzco, Piura, and Puno. In addition, market studies were carried out and the results conclude that there is a genuine interest of 83.68% in purchase by potential users. In Mantay’s desirability, the satisfaction exceeded the proposed minimum criterion achieving 70% NPS. While the feasibility was validated through the marketing plan with an efficiency of 100% when evaluating the relationship between the customer's lifetime value and its acquisition cost. Additionally, for financial viability, an initial investment of S/1,100,000.00 was taken account with an average NPV of S/4,596,036.04 for the first five years and a rate of return (IRR) of 72.40%. Finally, in social and environmental viability, the benefits and costs were estimated in saving time in mobilization so the final user buys handicrafts and the increase in the income of artisans, achieving a VANS of S/10,481,560.64. For this reason, Mantay is a sustainable proposal that is aligned with SDG 1, 8 and 12, generating a greater economic and both technical and management knowledge in the artisans of Peru

High content live cell imaging for the discovery of new antimalarial marine natural products

<p>Abstract</p> <p>Background</p> <p>The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, <it>Plasmodium falciparum</it>.</p> <p>Methods</p> <p>A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown <it>in vitro </it>in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope.</p> <p>Results</p> <p>Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts.</p> <p>Conclusion</p> <p>Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.</p

AUMENTO DEL TRANSPORTE DE CALOR MEDIANTE ONDAS ELECTROMAGNÉTICAS SUPERFICIALES

Como es conocido, la conductividad térmica de una película delgada generalmente disminuye a medida que su&nbsp;espesor se reduce a través de valores nanométricos (Liu &amp; M. Asheghi, 2006); esto genera el sobrecalentamiento y la&nbsp;reducción de la vida útil de procesadores y otros componentes electrónicos (Pop, 2010). Sin embargo, dado que las&nbsp;películas más delgadas tienen mayores cocientes área/volumen, los predominantes efectos superficiales en&nbsp;nanopelículas permiten el transporte de energía térmica no solo dentro de sus volúmenes, sino también a lo largo de&nbsp;sus interfaces. En nanopelículas polares, este transporte superficial es impulsado por fonones-polaritones de&nbsp;superficie, los cuales son ondas electromagnéticas generadas por el acoplamiento de fonones y fotones a lo largo de&nbsp;sus superficies. Modelos teóricos predicen que estos polaritones pueden contribuir significativamente a la&nbsp;conductividad térmica en el plano de películas de SiO con espesores menores a 200 nm (Chen et al., 2005; Ordonez- 2&nbsp;Miranda et al., 2013). En el presente trabajo demostramos experimentalmente este aumento de la conductividad&nbsp;térmica, mediante las técnicas 3 y rejilla transitoria. Los resultados medidos a través de estas dos técnicas son consistentes y muestran que la conductividad térmica en el plano de una película de SiO de 20 nm de espesor a 2&nbsp;temperatura ambiente es el doble de su contraparte debida a fonones solamente. Mediciones adicionales de la&nbsp;difusividad térmica de películas de SiO revelan que esta propiedad térmica también aumenta para películas más 2&nbsp;delgadas, de tal manera que la relación (conductividad térmica)/(difusividad térmica) = capacidad calorífica&nbsp;volumétrica se mantiene independiente del espesor de la película. Los resultados experimentales obtenidos aquí&nbsp;abren una nueva vía para desarrollar nanomateriales térmicamente conductores útiles para una refrigeración&nbsp;electrónica eficiente

Intravenous tPA for Acute Ischemic Stroke in Patients with COVID-19

BACKGROUND/PURPOSE: Coronavirus disease 2019 (COVID-19) is associated with increased risk of acute ischemic stroke (AIS), however, there is a paucity of data regarding outcomes after administration of intravenous tissue plasminogen activator (IV tPA) for stroke in patients with COVID-19. METHODS: We present a multicenter case series from 9 centers in the United States of patients with acute neurological deficits consistent with AIS and COVID-19 who were treated with IV tPA. RESULTS: We identified 13 patients (mean age 62 (±9.8) years, 9 (69.2%) male). All received IV tPA and 3 cases also underwent mechanical thrombectomy. All patients had systemic symptoms consistent with COVID-19 at the time of admission: fever (5 patients), cough (7 patients), and dyspnea (8 patients). The median admission NIH stroke scale (NIHSS) score was 14.5 (range 3-26) and most patients (61.5%) improved at follow up (median NIHSS score 7.5, range 0-25). No systemic or symptomatic intracranial hemorrhages were seen. Stroke mechanisms included cardioembolic (3 patients), large artery atherosclerosis (2 patients), small vessel disease (1 patient), embolic stroke of undetermined source (3 patients), and cryptogenic with incomplete investigation (1 patient). Three patients were determined to have transient ischemic attacks or aborted strokes. Two out of 12 (16.6%) patients had elevated fibrinogen levels on admission (mean 262.2 ± 87.5 mg/dl), and 7 out of 11 (63.6%) patients had an elevated D-dimer level (mean 4284.6 ±3368.9 ng/ml). CONCLUSIONS: IV tPA may be safe and efficacious in COVID-19, but larger studies are needed to validate these results

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected