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This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to Y-90-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m(2) every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving Y-90-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.

AIMS: The frequency of aggressive subtypes of B-cell non-Hodgkin lymphoma (B-NHL), such as high-grade B-cell lymphomas (HGBL) with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH/TH) or Burkitt-like lymphoma (BL) with 11q aberration is not well known in the HIV-setting. We aimed to characterize HIV-associated aggressive B-NHL according to the 2017 WHO criteria and to identify genotypic and phenotypic features with prognostic impact. Methods and results Seventy-five HIV-associated aggressive B-NHL were studied by immunohistochemistry (CD10, BCL2, BCL6, MUM1, MYC and CD30), EBERs, and FISH to evaluate the status of the MYC, BCL2 and BCL6 genes and chromosome 11q. The 2017 WHO classification criteria and the Hans algorithm, for the cell-of-origin classification of diffuse large B-cell lymphomas (DLBCL), were applied. In DLBCL cases, the frequencies of MYC and BCL6 rearrangements (14.9 and 27.7%, respectively) were similar to those described in HIV-negative patients, but BCL2 rearrangements were infrequent (4.3%). MYC expression was identified in 23.4% of DLBCL cases, and co-expression of MYC and BCL2 in 13.0%, which was associated with a worse prognosis. As for BL cases, the expression of MUM1 (30.4%) conferred a worse prognosis. Finally, the prevalence of HGBL-DH/TH and BL-like with 11q aberration are reported in the HIV-setting.; CONCLUSIONS: The phenotypic and genotypic characteristics of HIV-associated aggressive B-NHL are similar to those of the general population, except for the low frequency of BCL2 rearrangements in DLBCL. MYC and BCL2 co-expression in DLBCL, and MUM-1 expression in BL have negative prognostic impact in HIV-infected individuals. This article is protected by copyright. All rights reserved.

Although it has been reported that mesenchymal stem cells isolated from adult tissues can be induced to overcome their mesenchymal fate and transdifferentiate into neural cells, the findings and their interpretation have been challenged. The main argument against this process is that the cells rapidly adopt neuron-like morphologies through retraction of the cytoplasm rather than active neurite extension. In this study, we examined the sequence of biological events during neural differentiation of human periodontal ligament-derived stem cells (hPDLSCs), human bone marrow-derived stem cells (hBMSCs) and human dental pulp-derived stem cells (hDPSCs) by time-lapse microscopy. We have demonstrated that hPDLSCs, hBMSCs and hDPSCs can directly differentiate into neuron-like cells without passing through a mitotic stage and that they shrink dramatically and change their morphology to that of neuron-like cells through active neurite extension. Furthermore, we observed micronuclei movement and transient cell nuclei lobulation concurrent to in vitro neurogenesis from hBMSCs and hDPSCs. Our results demonstrate that the differentiation of hPDLSCs, hBMSCs and hDPSCs towards a neural lineage occurs through a dedifferentiation step followed by differentiation to neural phenotypes, and therefore we definitively confirm that the rapid acquisition of the neural phenotype is via a differentiation trait.

Plant and Animal Genome XXVII Conference (PAG XXVIII), 11-15 January 2020, San Diego, he marine environment is predicted to become warmer and more hypoxic over this century, and these conditions may become a challenge for cultured Atlantic salmon by negatively affecting their growth, immunology and welfare. DNA methylation mediates phenotypically plastic responses in gene expression that can potentially facilitate acclimatization responses. Thus, we measured DNA methylation from salmon that were subjected to: i) control conditions (normoxia, 12°C); ii) an incremental increase in temperature (12°C to 20°C, at 1°C per week) and then held at 20°C for 4 weeks; or iii) the former temperature regimen in combination with moderate hypoxia (~70% air saturation). DNA methylation levels were measured at CpG sites within a ~500 bp region (Promotor, 5’UTR, Exon, Intron) of six important liver biomarker genes (cribp, jund, pkd3, prdx6, serpinh1, and ucp2). Considering both experimental groups, we found 12 CpGs (out of 94 total) across the six genes that were differentially methylated when exposed to 20°C for 3 days, whereas only 6 CpGs from three genes (jund, prdx6 and ucp2) were affected after 4 weeks at 20°C. At both time points, we uncovered distinct DNA methylation profiles for fish of each treatment group, suggesting that high temperature and moderate hypoxia were inducing different CpG methylation changes in the liver of salmon. Further, we report significant relationships between CpG methylation and the mRNA expression of these genes that are complex and dynamic. These changes in DNA methylation may be an important regulatory mechanism allowing Atlantic salmon to quickly respond to new environmental challenges associated with global warming, This research was funded by the Ocean Frontier Institute, through the Canada First Research Excellence Fund

Resumen A pesar de ser una enfermedad rara, el cáncer es la primera causa de mortalidad por enfermedad durante la edad pediátrica en los países desarrollados. En este momento, la irrupción de nuevos tratamientos como la inmunoterapia constituye un nuevo paradigma clínico y regulatorio. Uno de estos tipos de inmunoterapia es la inmunoterapia celular. En particular, los medicamentos de terapia avanzada con receptores antigénicos quiméricos en los linfocitos T (CAR-T), y en concreto las células CAR-T19, han supuesto un nuevo escenario en el abordaje de los tumores hematológicos, como la leucemia aguda linfoblástica y los linfomas de células tipo B. La aprobación por las autoridades regulatorias de tisagenlecleucel y axicabtagene ciloleucel, ha impulsado la puesta en marcha del Plan Nacional de Terapias Avanzadas-Medicamentos CART en Espana, ˜ evidenciándose no solo la conveniencia de identificar los centros más adecuados para su administración, sino la necesidad de que estos sufran una profunda transformación para que su actividad asistencial se extienda en algunos casos a la capacidad de fabricación propia de este tipo de terapias. Los hospitales especializados en hematooncología pediátrica tienen por tanto el reto de evolucionar hacia un modelo asistencial que integre la inmunoterapia celular, dotándose de capacidad propia para gestionar todos los aspectos relativos al uso, fabricación y administración de estos nuevos tratamientos. Abstract Despite being a rare disease, cancer is the first cause of mortality due to disease during the paediatric age in the developed countries. The current, great increase in new treatments, such as immunotherapy, constitutes a new clinical and regulatory paradigm. Cellular immunotherapy is one of these types of immunotherapy. In particular, the advanced therapy drugs with chimeric antigen receptors in the T-lymphocytes (CAR-T), and particularly the CART19 cells, has opened up a new scenario in the approach to haematology tumours like acute lymphoblastic leukaemia and the B-Cell lymphomas. The approval of tisagenlecleucel and axicabtagene ciloleucel by the regulatory authorities has led to the setting up of the National Plan for Advanced Therapies-CAR-T drugs in Spain. There is evidence of, not only the advantage of identifying the centres most suitable for their administration, but also the need for these to undergo a profound change in order that their healthcare activity is extended, in some cases, to the ability for the in-house manufacture of these types of therapies. The hospitals specialised in paediatric haematology-oncology thus have the challenge of progressing towards a healthcare model that integrates cellular immunotherapy, having the appropriate capacity to manage all aspects relative to their use, manufacture, and administration of these new treatments.

Background Preclinical studies suggest that stem cells may be a valuable therapeutic tool in amyotrophic lateral sclerosis (ALS). As it has been demonstrated that there are molecular changes at the end-plate during the early stages of motorneuron degeneration in animal models, we hypothesize that the local effect of this stem cell delivery method could slow the progressive loss of motor units (MUs) in ALS patients. Methods We designed a Phase I/II clinical trial to study the safety of intramuscularly implanting autologous bone marrow mononuclear cells (BMMCs), including stem cells, in ALS patients and their possible effects on the MU of the tibialis anterior (TA) muscle. Twenty-two patients participated in a randomized, double-blind, placebo-controlled trial that consisted of a baseline visit followed by one intramuscular injection of BMNCs, follow-up visits at 30, 90, 180, and 360 days, and an additional year of clinical follow-up. In each patient, one TA muscle was injected with a single dose of BMMCs while the contralateral muscle was given a placebo; the sides were selected randomly. All visits included a complete EMG study of both TA muscles. Results Our results show that (1) the intramuscular injection of BMMCs is a safe procedure; (2) ALS patients show heterogeneities in the degree of TA injury; (3) a comparison of placebo-injected muscles with BMMC-injected muscles showed significant differences in only one parameter, the D50 index used to quantify the Compound Muscle Action Potential (CMAP) scan curve. This parameter was higher in the BMMC-injected TA muscle at both 90 days (placebo side: 29.55 +/- 2.89, n = 20; experimental side: 39.25 +/- 3.21, n = 20; p < 0.01) and 180 days (placebo side: 29.35 +/- 3.29, n = 17; experimental side: 41.24 +/- 3.34, n = 17; p < 0.01). Conclusion This procedure had no effect on the TA muscle MU properties, with the exception of the D50 index. Finding differences in just this index supports the fact that it may be much more sensitive than other electrophysiological parameters when studying treatment effects. Given the low number of patients and their heterogeneity, these results justify exploring the efficacy of this procedure in further patients and other muscles, through Phase II trials.

In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a successful collaborative public initiative funded by the Spanish government for the support of nationwide translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently form the network. Each program has three working packages focused on basic science, pre-clinical studies and clinical application. TerCel has contributed during this period to boost the translational research in cell therapy in Spain, setting up a network of Good Manufacturing Practicecertified cell manufacturing facilities and increasing the number of translational research projects, publications, patents and clinical trials of the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients. Crown Copyright (C) 2019. Published by Elsevier Inc. on behalf of International Society for Cell and Gene Therapy. All rights reserved.

International Conference & Exposition Aquaculture Europe 2019, Our Future Growing from Water, 7-10 October 2019, Berlin, Germany.-- 2 pages, 1 figure, Fish farmed for human consumption are reared in artificial environments that are very different from conditions that species experience in the wild. Consequently, the environment influences many aspects of the biology of cultured animals, including sexual phenotype through epigenetic mechanisms (Feeney et al., 2014). Disease outbreaks occur eventually in fish farms, causing economic loses. However, the epigenetic consequences that these reiterating infections can potentially cause in fish during their development and whether these can alter the reproductive system, remain unknown. Here we present a study for which two model research tools have been selected; the zebrafish as a suitable model for aquaculture research (Ribas and Piferrer, 2014) and the lipopolysaccharide (LPS) from Gram negative bacterial wall as a model to stimulate the immune system in fish(Forn-Cuní et al., 2017). The aim of this work is to develop a suitable in vivo system to study whether infections occurring in fishduring sex differentiation are able to alter the finalgonadal phenotype throughout epigenetic changes, This study was supported by the Spanish Ministry grant AGL2015-73864-JIN “Ambisex” to LR

12th Congress of the Iberian Association of Comparative Endocrinology (AIEC), 26-28 September 2019, Faro, Portugal

Functional annotation of the Atlantic salmon genome, translation to improved health and performance in Aquaculture, 26-27 August 2019, Canada

The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16years of age when diagnosed with FA, and underwent transplantation at a median age of 23years. Time between diagnosis and transplant was shortest (median 2years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76–87%), acute graft-versus-host disease (GvHD) grade II–IV in 22% (95% CI 16–28%) and the incidence of chronic GvHD at 96months was 26% (95% CI 20–33). Non-relapse mortality at 96months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow-up was 58months. Patients transplanted after 2000 had improved survival (84% at 36months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non-sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients.

Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P < .001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P < .001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Next Generation Sequencing (NGS 2018), 9-11 April 2018, Barcelona, Spain

11th International Symposium on Reproductive Physiology of Fish (ISRPF-2018), New frontiers in reproductive diversity in a changing environment, 3-8 June 2018, Manaus, Brazil.-- 1 page, Introduction. Stockpiling of molecules such as rRNAs in fish oocytes is essential to assist ribosomal assembly and protein synthesis in the newly formed embryo. In this way, the massive 5S rRNA expression during fish oogenesis serves as oocyte differentiation marker in the intersex testis formed after exposure to xenoestrogens. This 5S rRNA production is allowed by the general transcription factor IIIA (gtf3a) and as in Xenopusone single gtf3agene but two transcripts exist, one of them oocyte specific, we wanted to study the possible existence of paralog gtf3agenes in teleosts. Methods. Teleost genomes in ENSEMBL were analyzed to identify gtf3a orthologs. Two paralogs were identified so a synteny analysis was performed to understand the origin of the gene duplication event in teleosts. Then, transcription levels of gtf3aa and gtf3ab were analyzed by qPCR in tissues of adult zebrafish (D. rerio, ZF) and during the first 30 hours of embryo development. Transcription levels were also quantified in whole larvae (26 & 61 dpf), either masculinized or feminized after methyltestosterone (MT) and 17β-estradiol (E2) exposures, and compared to cyp19a1a, dmrt1 and amh levels. Finally, the promoter methylation level of both genes was studied in testis and ovary by bisulphite sequencing. Results and Discussion. Teleost genomes present two gtf3aparalog genes. Gtf3ab aroused from the teleost specific genome duplication event, with specific expression in ZF oocytes. Instead, gtf3aa is ubiquitously expressed in all tissues tested. No gonads were observable at 26 dpf in the ZF studied, exposed or not to E2 or MT, with no gtf3abtranscription but with detectable gtf3aalevels. 61 dpf E2 feminized ZF showed transcription of gtf3aband gtf3aain whole body analyses, while MT masculinized juveniles only transcribed gtf3aa. Female gtf3abtranscription coincided with that of ovarian cyp19a1aand opposite to that of amh and dmrt1. Maternal gtf3abtranscripts were present in zygote but disappeared after embryo genome activation. Opposite, the transcription of gtf3aabegan with the activation of the zygotic genome (~8 hpf). Bisulfite sequencing of the promoters of both gtf3agenes is currently ongoing. Conclusion. As 26 days exposure to E2 induced no gtf3abtranscription in whole juveniles, but transcripts were detected upon ovarian development at 61 dpf, we can consider that gtf3abtranscription is a consequence of oocyte production in fish and not a direct result of E2 exposure. Thus, gtf3abexpression constitutes a plausible marker of feminization in ZF, Funded: Basque Gov. (IT810-13), UPV/EHU (UFI 11/37), Spanish MINECO & EU-FEDER/ERDF (AGL2015-63936-R & AGL2015-73864)

Aquaculture Europe 2017 (AE2017), Cooperation for Growth, 17-20 October 2017, Dubrovnik, Croatia, Disease outbreaks are often found on aquaculture farms, being one of the major problems as they can cause serious economic losses due to their associated high mortalities. In the last years, special attention has been focused on the effects of infectious diseases in the reproductive system, which that can cause gonadal necrosis or infertility of adults. However, there are few studies describing the relationship between infections and their incidence on sex, as well as on the consequences that these temporary infections might cause in the reproductive system. The aim of this work is to develop a suitable in vivo system to study whether infections occurring in fish during sex differentiation are able to alter the final gonadal phenotype