The follicular lymphoma epigenome regulates its microenvironment

Follicular lymphoma (FL) is a B-cell non-Hodgkin lymphoma of germinal center (GC) origin with a distinctive tumor microenvironment (TME) and a unique spectrum of mutations. Despite the important therapeutic advances, FL is still incurable. During B-cell development, the GC reaction is a complex multistep process in which epigenetic regulators dynamically induce or suppress transcriptional programs. In FL, epigenetic gene mutations perturb the regulation of these programs, changing GC B-cell function and skewing differentiation towards tumor cells and altering the microenvironment interactions. FL pathogenesis and malignant transformation are promoted by epigenetic reprogramming of GC B cells that alters the immunological synapse and niche. Despite the extensive characterization of FL epigenetic signature and TME, the functional consequences of epigenetic dysregulation on TME and niche plasticity need to be better characterized. In this review, first we describe the most frequent epigenomic alterations in FL (KMT2D, CREBBP and EZH2) that affect the immunological niche, and their potential consequences on the informational transfer between tumor B cells and their microenvironment. Then, we discuss the latest progress to harness epigenetic targets for inhibiting the FL microenvironment. Finally, we highlight unexplored research areas and outstanding questions that should be considered for a successful long-term treatment of FL

Generalizabilty Probability: Importance in Clinical Research

International conference on harmonization (ICH) suggested that bridging study is important to extrapolate clinical results. and also us food and drug administration requires Substantial evidences regarding safety. The review explains about different approaches that are necessary for obtaining clinical results, various clinical results were performed between similar patient population within same or different regions. moreover no criteria on the  evaluation of similarity of clinical results between regions is given .It is important in regulatory submission of new drug application .Mainly this review explains about how clinical results are reproducible. Keywords: ICH, Generalizability, probability  Reproducibility, clinical trails, bridging study

The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2−/− ung−/− mice

Immunoglobulin (Ig) class switching is initiated by deamination of C→U within the immunoglobulin heavy chain locus, catalyzed by activation-induced deaminase (AID). In the absence of uracil-DNA glycosylase (UNG) and the homologue of bacterial MutS (MSH)–2 mismatch recognition protein, the resultant U:G lesions are not processed into switching events but are fixed by replication allowing sites of AID-catalyzed deamination to be identified by the resulting C→T mutations. We find that AID targets cytosines in both donor and acceptor switch regions (S regions) with the deamination domains initiating ∼150 nucleotides 3′ of the I exon start sites and extending over several kilobases (the IgH intronic enhancer is spared). Culturing B cells with interleukin 4 or interferon γ specifically enhanced deamination around Sγ1 and Sγ2a, respectively. Mutation spectra suggest that, in the absence of UNG and MSH2, AID may occasionally act at the μ switch region in an apparently processive manner, but there is no marked preference for targeting of the transcribed versus nontranscribed strand (even in areas capable of R loop formation). The data are consistent with switch recombination being triggered by transcription-associated, strand-symmetric AID-mediated deamination at both donor and acceptor S regions with cytokines directing isotype specificity by potentiating AID recruitment to the relevant acceptor S region

Asas Kebangsaan Dalam Perjanjian Nominee Untuk Memperoleh Hak Milik Atas Tanah

Perjanjian pinjam nama atau biasanya dikenal dengan istilah perjanjian nominee merupakan salah satu upaya dari warga asing agar bisa memperoleh hak kepemilikan tanah di Negara Kesatuan Republik Indonesia melalui cara meminjam nama warga Negara Indonesia, kemudian dimasukkan pada sertifikat kepemilikan yang mana seluruh pembiayaan ditanggung oleh pihak warga negara asing. Peraktik pinjam nama ini bukan suatu hal yang asing lagi oleh masyarakat Indonesia dan merupakan bentuk penyelundupan hukum tanah, mengingat adanya ketentuan Undang-Undang Nomor 5 Tahun 1960 Tentang Peraturan Dasar Pokok-Pokok Agraria pada Pasal 21 Ayat (1) yang menyebutkan “Hanya Warga Negara Indonesia yang mempunyai hak milikâ€.  Tujuan  penelitian   agar dapat memahami apakah Perjanjian nominee selaras dengan hukum positif Indonesia dan bagaimana penerapan asas kebangsaan dalam perjanjian nominee. Metode yang dipakai oleh penelitian ini adalah  metode penelitian normative yang lebih menitikberatkan pada pendekatan Perundang-undangan dan konseptual. Kesimpulan dari penelitian ini bahwa perjanjian nominee tidak selaras oleh peraturan yang berlaku di Negara Kesatuan Republik Indonesia disebabkan melanggar persyaratan suatu perjanjian berupa causa yang halal dan melanggar asas perjanjian yaitu asas kebebasan berkontrak dan berakibat batal demi hukum. Kemudian, penerapan asas kebangsaan dalam perjanjian nominee tidak tepat dan sangat bertentangan disebabkan tidak memenuhi syarat yang tertuang dalam Pasal 9 Ayat (1) dan (2)

Technology for large-scale translation of clinical practice guidelines : a pilot study of the performance of a hybrid human and computer-assisted approach

Background: The construction of EBMPracticeNet, a national electronic point-of-care information platform in Belgium, was initiated in 2011 to optimize quality of care by promoting evidence-based decision-making. The project involved, among other tasks, the translation of 940 EBM Guidelines of Duodecim Medical Publications from English into Dutch and French. Considering the scale of the translation process, it was decided to make use of computer-aided translation performed by certificated translators with limited expertise in medical translation. Our consortium used a hybrid approach, involving a human translator supported by a translation memory (using SDL Trados Studio), terminology recognition (using SDL Multiterm termbases) from medical termbases and support from online machine translation. This has resulted in a validated translation memory which is now in use for the translation of new and updated guidelines. Objective: The objective of this study was to evaluate the performance of the hybrid human and computer-assisted approach in comparison with translation unsupported by translation memory and terminology recognition. A comparison was also made with the translation efficiency of an expert medical translator. Methods: We conducted a pilot trial in which two sets of 30 new and 30 updated guidelines were randomized to one of three groups. Comparable guidelines were translated (a) by certificated junior translators without medical specialization using the hybrid method (b) by an experienced medical translator without this support and (c) by the same junior translators without the support of the validated translation memory. A medical proofreader who was blinded for the translation procedure, evaluated the translated guidelines for acceptability and adequacy. Translation speed was measured by recording translation and post-editing time. The Human Translation Edit Rate was calculated as a metric to evaluate the quality of the translation. A further evaluation was made of translation acceptability and adequacy. Results: The average number of words per guideline was 1,195 and the mean total translation time was 100.2 min/1,000 words. No meaningful differences were found in the translation speed for new guidelines. The translation of updated guidelines was 59 min/1,000 words faster (95% CI 2-115; P=.044) in the computer-aided group. Revisions due to terminology accounted for one third of the overall revisions by the medical proofreader. Conclusions: Use of the hybrid human and computer-aided translation by a non-expert translator makes the translation of updates of clinical practice guidelines faster and cheaper because of the benefits of translation memory. For the translation of new guidelines there was no apparent benefit in comparison with the efficiency of translation unsupported by translation memory (whether by an expert or non-expert translator

La abundancia y la ecología del comportamiento del blenny Ophioblennius trinitatis (Teleostei: Blenniidae) en un archipiélago oceánico de Brasil (Atlántico)

Local patterns of fish density, microhabitat use, feeding behaviour, bite rate, territory area and agonistic interactions were recorded for Ophioblennius trinitatis at an oceanic archipelago (southwestern Atlantic). Rugosity, number of crevices and benthic diversity positively predicted the distribution of O. trinitatis. Turf algae was the preferred food item at all sites, but given its high availability inside and outside territory boundaries, it did not seem to be a limiting factor on the density of this blenny, as opposed to substrate heterogeneity. Bite rate was higher in the afternoon and for smaller individuals (juveniles). Territory size showed local variation and, although larger territories may be an effect of density-dependent conditions (more available space in low-density areas), we propose that individuals expand territories to compensate for residing in areas of lower quality (i.e. of low structural complexity). Larger individuals defended larger territories and residents responded differently to intruders, with higher rates of agonistic interactions towards potential competitors. Higher agonistic rates were also observed in larger territories and at low-complexity sites.En este trabajo se han estudiado las pautas en la densidad, la utilización del micro hábitat, el comportamiento alimentario, las tasas de mordisqueo, la superficie del territorio y las interacciones agonísticas de Ophioblennius trinitatis en un archipiélago oceánico del SO Atlántico. Los mejores predictores de la distribución de O. trinitatus fueron la rugosidad, el número de grietas y la diversidad bentónica. El turf algal es el alimento preferido de este pez en todos los lugares, pero dada su elevada disponibilidad, dentro y fuera de los territorios, no pareció ser un factor limitante para este blénido como lo fue la heterogeneidad del substrato. La tasa de mordisqueo resultó ser más elevada entre los peces pequeños (juveniles) y especialmente por la tarde. La superficie del territorio presentó notables variaciones locales y, a pesar de que los territorios mayores pueden ser el resultado de un efecto denso-dependiente (al haber más espacio disponible en la zonas con densidades bajas), proponemos que los individuos expanden su territorio para compensar la baja calidad ambiental de ciertas zonas (una baja complejidad estructural). Los ejemplares mayores defendían territorios más extensos y respondían de manera diferente ante los intrusos, con una mayor tasa de interacciones agonísticas hacia los potenciales intrusos. Las interacciones agonísticas también fueron más elevadas en los territorios más amplios y con una baja complejidad

Sangrado rectal tras la administración de Dabigatrán

Presentamos el caso de tres pacientes intervenidos de prótesis total de cadera, que tras la administración protocolaria de tromboprofilaxis con Dabigatrán, presentaron un sangrado rectal importante, siendo este la primera manifestación de un cáncer colorrectal. Todos los casos se trataron durante el postoperatorio inmediato mediante cirugía tratamiento adyuvante. En el caso de un sangrado rectal tras la administración de los nuevos fármacos anticoagulantes es obligatorio descartar patología pre-existente antes de, simplemente, sustituir o suspender la medicación.We observed rectal bleeding in three asymptomatic patients after administration of Dabigatran in the postoperative period, being this the first manifestation of rectal cancer. In all cases Dabigatran was used as DVT prophylaxis. The cause of bleeding in the three cases was an asymptomatic and previously unknown colo-rectal cancer. All patients underwent tumoral resection surgery. With rectal bleeding in the inmediate postoperatory period after administration of oral anticoagulants, rectal cancer screening must be performed

Aeraulic behaviour of a biotrickling filter pilot plant: experiments and simulations

Trickling bed biofilters (or biotrickling filters, BTFs) are biological systems for polluted air treatment. Hydrodynamics of BTFs, and reactors in general, is of paramount importance for obtaining good performances. In fact, a non-uniform distribution of the pollutant into the bed brings to dead zones or bypass which reduce the bed working volume and, therefore, cause low removal efficiencies. The paper presents the preliminary results obtained regarding the aeraulic behavior of a BTF pilot plant with seashells as packing material. Experimental results of bed void fraction and pressure drop at several flow rates were used to obtain Ergun equation coefficients for dry bed. A numerical simulation of the reactor flow field carried out with a commercial CFD (Computational Fluid Dynamics) code, validated by the means of velocity measurements made with a Hot Wire Anemometer (HWA) completed the analysis of the reactor hydrodynamics