Genome-Wide Studies of Histone Demethylation Catalysed by the Fission Yeast Homologues of Mammalian LSD1

In order to gain a more global view of the activity of histone demethylases, we report here genome-wide studies of the fission yeast SWIRM and polyamine oxidase (PAO) domain homologues of mammalian LSD1. Consistent with previous work we find that the two S. pombe proteins, which we name Swm1 and Swm2 (after SWIRM1 and SWIRM2), associate together in a complex. However, we find that this complex specifically demethylates lysine 9 in histone H3 (H3K9) and both up- and down-regulates expression of different groups of genes. Using chromatin-immunoprecipitation, to isolate fragments of chromatin containing either H3K4me2 or H3K9me2, and DNA microarray analysis (ChIP-chip), we have studied genome-wide changes in patterns of histone methylation, and their correlation with gene expression, upon deletion of the swm1+ gene. Using hyper-geometric probability comparisons we uncover genetic links between lysine-specific demethylases, the histone deacetylase Clr6, and the chromatin remodeller Hrp1. The data presented here demonstrate that in fission yeast the SWIRM/PAO domain proteins Swm1 and Swm2 are associated in complexes that can remove methyl groups from lysine 9 methylated histone H3. In vitro, we show that bacterially expressed Swm1 also possesses lysine 9 demethylase activity. In vivo, loss of Swm1 increases the global levels of both H3K9me2 and H3K4me2. A significant accumulation of H3K4me2 is observed at genes that are up-regulated in a swm1 deletion strain. In addition, H3K9me2 accumulates at some genes known to be direct Swm1/2 targets that are down-regulated in the swm1¿ strain. The in vivo data indicate that Swm1 acts in concert with the HDAC Clr6 and the chromatin remodeller Hrp1 to repress gene expression. In addition, our in vitro analyses suggest that the H3K9 demethylase activity requires an unidentified post-translational modification to allow it to act. Thus, our results highlight complex interactions between histone demethylase, deacetylase and chromatin remodelling activities in the regulation of gene expression

Advantages of enteral nutrition over parenteral nutrition

It is a strong and commonly held belief among nutrition clinicians that enteral nutrition is preferable to parenteral nutrition. We provide a narrative review of more recent studies and technical reviews comparing enteral nutrition with parenteral nutrition. Despite significant weaknesses in the existing data, current literature continues to support the use of enteral nutrition in patients requiring nutrition support, over parenteral nutrition

OMA -AMO - Casa de la música de Oporto

La investigación de un “objeto arquitectónico” enlaza con los principios teóricos desde los que en ARKRIT-LAB se entiende la crítica la arquitectura: la obra antes que el autor y su descripción antes que su interpretación. Consecuentemente, se propuso estudiar un edificio relevante y considerado de gran impacto teórico y mediático, entrando primero de manera precisa en su respuesta al medio, al material, a la medida, a la morfología y a la misión -metodo M3- y proponiendo después, entre los investigadores del laboratorio diversas actividades: re exionar de manera abierta sobre las condiciones de su “arquitectura”, experimentar el edi cio, rastrear sus antecedentes e investigar en la materia concreta y en las formas utilizadas; actividades que buscaban nuevas realidades que pudieran mostrar otras visiones. En el laboratorio consideramos que como arquitectos y como críticos, no resulta super uo aprender a ver más, a oír más, a sentir más y a pensar más4. El edificio elegido para el curso 2010-2011 fue la “Casa da Musica” de Oporto, proyecto de OMA-Rem Koolhaas, siendo el texto que se convirtió en referencia para la primera aproximación el titulado “Otra Modernidad” de Rafael Moneo. Texto en el que se describe el proyecto como encarnación de los nuevos atributos de la arquitectura contemporánea5. “Otra Modernidad” entendida desde la Modernidad, como frontera considerada por Antonio Miranda como referente de progreso y faro de toda acción arquitectónica. Modernidad como anhelo de una sociedad nueva más justa

Data-Driven Approaches to NBA Team Evaluation and Building

Gemstone Team PROCESSIn the National Basketball Association (NBA), it has historically been difficult to build and sustain a team that can consistently compete for championships. Given this challenge, we have developed a series of analyses to support NBA teams in making data-driven decisions. Relying on a variety of datasets, we examined several facets related to the construction of NBA rosters and their performance. In our analysis of on-court performance, we have used clustering algorithms to classify teams in terms of play style, and determined which play styles tend to lead to success. In our analysis of roster construction and transactions, we have investigated the relative value of draft picks and the impact of trades involving draft picks, as well as the effect of roster continuity (i.e. maintaining the same players across seasons) on team success. Additionally, we have developed a model for predicting player contract values and performance versus contract value, which will help teams in identifying the most cost-effective players to acquire. Ultimately, this assembly of analyses, in conjunction, can be used to inform any NBA team’s decisions in its pursuit of success

Transcriptomic profiling of urine extracellular vesicles reveals alterations of CDH3 in prostate cancer

Extracellular vesicles (EV) are emerging structures with promising properties for intercellular communication. In addition, the characterization of EV in biofluids is an attractive source of non-invasive diagnostic, prognostic and predictive biomarkers. Here we show that urinary EV (uEV) from prostate cancer (PCa) patients exhibit genuine and differential physical and biological properties compared to benign prostate hyperplasia (BPH). Importantly, transcriptomics characterization of uEVs led us to define the decreased abundance of Cadherin 3, type 1 (CDH3) transcript in uEV from PCa patients. Tissue and cell line analysis strongly suggested that the status of CDH3 in uEVs is a distal reflection of changes in the expression of this cadherin in the prostate tumor. CDH3 was negatively regulated at the genomic, transcriptional, and epigenetic level in PCa. Our results reveal that uEVs could represent a non-invasive tool to inform about the molecular alterations in PCa

Sustained response off-treatment in eltrombopag-treated adult patients with ITP who are refractory or relapsed after first-line steroids: Primary, final, and ad-hoc analyses of the Phase II TAPER trial

Immune thrombocytopenia; Relapsed; SteroidsTrombocitopenia inmunitaria; Recaídas; EsteroidesTrombocitopènia immune; Recaiguda; EsteroidesImmune thrombocytopenia (ITP) is characterized by reduced platelet count due to increased destruction and is categorized according to the time following diagnosis (newly diagnosed, persistent, chronic). First-line corticosteroid therapy is associated with transient response, high relapse rates, and considerable toxicity. TAPER (NCT03524612) is a Phase II, prospective, single-arm trial investigating whether eltrombopag can induce a sustained response off-treatment (SRoT) in adult patients with ITP after first-line corticosteroid failure. This study defines SRoT as an off-treatment period wherein platelet count remains above 30 × 109/L in the absence of bleeding or rescue therapy. The primary endpoint was the proportion of patients who achieved SRoT until Month 12, which was 30.5% (n = 32/105; p 15%) following eltrombopag tapering and discontinuation, and median SRoT duration was ~8 months until Month 12. Median platelet count increased within 1 month of treatment and remained elevated until Month 12. Quality of life improved within 3 months and was maintained. Headache (21%) was the most common adverse event. None of the 4 deaths reported were considered treatment-related. In summary, ~one-third of patients achieved SRoT until Month 12 following eltrombopag tapering and discontinuation. An ad-hoc early-use analysis, stratified by ITP duration at baseline, assessed initial hematologic responses and safety. Results suggest that eltrombopag has similar efficacy in newly diagnosed and later stages of ITP. In follow-up until Month 24, a median SRoT duration of ~22 months was observed (n = 20). The safety profile was comparable across analyses and ITP duration groups and aligned with its well-established safety profile.Novartis Pharmaceuticals Corporation

Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML

Pevonedistat; Chronic myelomonocytic leukemiaPevonedistat; Leucemia mielomonocítica crónicaPevonedistat; Leucèmia mielomonocítica crònicaPANTHER is a global, randomized phase 3 trial of pevonedistat+azacitidine (n = 227) vs azacitidine monotherapy (n = 227) in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS; n = 324), higher-risk chronic myelomonocytic leukemia (n = 27), or acute myeloid leukemia (AML) with 20% to 30% blasts (n = 103). The primary end point was event-free survival (EFS). In the intent-to-treat population, the median EFS was 17.7 months with pevonedistat+azacitidine vs 15.7 months with azacitidine (hazard ratio [HR], 0.968; 95% confidence interval [CI], 0.757-1.238; P = .557) and in the higher-risk MDS cohort, median EFS was 19.2 vs 15.6 months (HR, 0.887; 95% CI, 0.659-1.193; P = .431). Median overall survival (OS) in the higher-risk MDS cohort was 21.6 vs 17.5 months (HR, 0.785; P = .092), and in patients with AML with 20% to 30% blasts was 14.5 vs 14.7 months (HR, 1.107; P = .664). In a post hoc analysis, median OS in the higher-risk MDS cohort for patients receiving >3 cycles was 23.8 vs 20.6 months (P = .021) and for >6 cycles was 27.1 vs 22.5 months (P = .008). No new safety signals were identified, and the azacitidine dose intensity was maintained. Common hematologic grade ≥3 treatment emergent adverse events were anemia (33% vs 34%), neutropenia (31% vs 33%), and thrombocytopenia (30% vs 30%). These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of continuing therapy for >3 cycles. The trial was registered on clinicaltrials.gov as #NCT03268954.This study was sponsored by Takeda Development Centers Inc (TDCA; Lexington, MA)

Multimedia Smart Process (MSP)

Traditional development processes do not include dynamic and creative aspects that exist in multimedia development environments. In these domains, creativity, design and animation are non-functional requirements that have great relevance in the final product and are often not considered in the implementation of traditional software. In this article, we make a comparison of the main traditional development processes and their suitability to the domains of multimedia software, proposing as an alternative Multimedia Smart Process (MSP)