First Reported Case of Malignant Ectomesenchymoma with p.Leu122Arg Mutation in MYOD1 Gene: Extensive Intra- and Extracranial Tumor in a 15-Year-Old Female.

BACKGROUND: Ectomesenchymomas (EMs) are extremely rare neoplasms composed of malignant mesenchymal components and neuroectodermal derivatives. They are described in a wide variety of locations, with the head and neck region being one of the most frequently involved areas. EMs are usually managed as high-risk rhabdomyosarcomas and have similar outcomes. METHODS: We present the case of a 15-year-old female with an EM that arose in the parapharyngeal space and extended into the intracranial space. RESULTS: Histologically, the tumor presented an embryonal rhabdomyosarcomatous mesenchymal component and the neuroectodermal component was constituted by isolated ganglion cells. Next-generation sequencing (NGS) revealed a p.Leu122Arg (c.365 T > G) mutation in the MYOD1 gene, a p.Ala34Gly mutation in the CDKN2A gene, and CDK4 gene amplification. The patient was treated with chemotherapy. She died 17 months after the debut of symptoms. CONCLUSION(S): To our knowledge, this is the first reported case in English literature of an EM with this MYOD1 mutation. We suggest combining PI3K/ATK pathway inhibitors in these cases. NGS should be performed in EMs cases to detect mutations with potential treatment options.

COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models.

One year into the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), effective treatments are still needed 1-3 . Monoclonal antibodies, given alone or as part of a therapeutic cocktail, have shown promising results in patients, raising the hope that they could play an important role in preventing clinical deterioration in severely ill or in exposed, high risk individuals 4-6 . Here, we evaluated the prophylactic and therapeutic effect of COVA1-18 in vivo , a neutralizing antibody isolated from a convalescent patient 7 and highly potent against the B.1.1.7. isolate 8,9 . In both prophylactic and therapeutic settings, SARS-CoV-2 remained undetectable in the lungs of COVA1-18 treated hACE2 mice. Therapeutic treatment also caused a dramatic reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg - 1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 had a very strong antiviral activity in the upper respiratory compartments with an estimated reduction in viral infectivity of more than 95%, and prevented lymphopenia and extensive lung lesions. Modelling and experimental findings demonstrate that COVA1-18 has a strong antiviral activity in three different preclinical models and could be a valuable candidate for further clinical evaluation.

Rare earth elements recovery from secondary wastes by solid-state chlorination and selective organic leaching.

Processing of end-of-life products (EoL) containing rare earth elements (REE) has gained increasing importance in recent years with the aim of avoiding supply risks. In addition, circular economy renders complete recirculation of technology metals mandatory. Fluorescent lamp wastes are an important source for REE recovery since they contain significant amounts, up to 55 wt%, of Y and Eu in red phosphors. For these purposes, solid-state chlorination (SSC) is an economically attractive alternative to wet acid leaching treatment, which profits from a considerable reduction of chemicals consumption and process costs. Chlorination takes place with dry HCl(g) produced from thermal decomposition of NH4Cl(s), not only converting the REE content of the Hg-free phosphor waste into water soluble REE metal chlorides, but also avoiding the implications of aqueous complex chemistry of REE. To establish an industrial process viable on a commercial scale, the SSC process has been optimized by (i) using a design of experiment (DOE) varying temperature, residence time, and gNH4Cl/gsolid ratio and (ii) improved leaching of the chlorinated metals with an organic mixture selective for REE. As a result, 95.7% of the Y and 92.2% of the Eu were selectively recovered at 295.9 °C, 67 min and a ratio of 1.27 gNH4Cl/gsolid, followed by quantitative selective leaching of the REE. Owed to its low chemicals consumption and operation costs, the current process allows for valorizing lamp waste even when raw material prices are low.

Is it possible to eliminate hepatitis C from the prisons of Catalonia, Spain, in 2021?

AIM: Predict the elimination of chronic hepatitis C in Catalan prisons. MATERIAL AND METHOD: We analyzed the trend of the prevalence of HCV-RNA and anti-hepatitis C treatments prescribed in Catalonia in the period 2002-2016. Using linear exponential smoothing from the historical values in the time series, we estimate the time required to eliminate hepatitis C as a public health problem in prisons (prevalence of hepatitis C virus RNA<1%). RESULTS: A total of 1264 treatments were administered by 12/31/2016. The prevalence of hepatitis C virus RNA was 31.2% in 2002, decreasing to 8.81% in 2016. We estimate that prevalence will reach 0-0.5% in 5 years (second half 2021; 95% CI: 2019-2025). DISCUSSION: Appropriate actions can eliminate hepatitis C infection in prisoners. We estimate that by 2021 hepatitis C infection will no longer be a public health problem in Catalonia prisons.

¿Es posible eliminar la hepatitis C en las prisiones de Cataluña en el 2021? / Is it possible to eliminate hepatitis C from the prisons of Catalonia, Spain, in 2021?

Objetivo: predecir la eliminación de la hepatitis C crónica en las prisiones de Cataluña. Material y método: se analiza la tendencia de la prevalencia de ácido ribonucleico (ARN)-virus de la hepatitis C (VHC) y los tratamientos antihepatitis C prescritos en Cataluña en el periodo 2002-2016. Mediante un alisado exponencial de los valores históricos de la serie, se calcula el tiempo en que podrá eliminarse la hepatitis C en Cataluña como problema de salud pública (prevalencia ARN-VHC<1%). Resultados: hasta el 31 de diciembre de 2016, se habían prescrito 1.264 tratamientos. La prevalencia de ARN-VHC fue del 31,2% en 2002, y drecreció hasta el 8,8% en 2016. Se estima que la prevalencia alcanzará una tasa del 0-0,5% en cinco años (segundo semestre de 2021; intervalo de confianza, IC, del 95%: 2019-2025). Discusión: con las acciones adecuadas, puede y debe eliminarse la hepatitis C en los presos. En Cataluña, esta enfermedad dejaría de ser un problema de salud pública en 2021

Aim: predict the elimination of chronic hepatitis C in Catalan prisons. Material and method: we analyzed the trend of the prevalence of HCV-RNA and anti-hepatitis C treatments prescribed in Catalonia in the period 2002-2016. Using linear exponential smoothing from the historical values in the time series, we estimate the time required to eliminate hepatitis C as a public health problem in prisons (prevalence of hepatitis C virus RNA<1%). Results: a total of 1264 treatments were administered by 12/31/2016. The prevalence of hepatitis C virus RNA was 31.2% in 2002, decreasing to 8.81% in 2016. We estimate that prevalence will reach 0-0.5% in 5 years (second half 2021; 95% CI: 2019-2025). Discussion: appropriate actions can eliminate hepatitis C infection in prisoners. We estimate that by 2021 hepatitis C infection will no longer be a public health problem in Catalonia prisons

Rare earths separation from fluorescent lamp wastes using ionic liquids as extractant agents.

Processing of end-of-life products has become essential in the rare earth elements (REEs) recovery field because the demand for these metals has increased over the last years due to their intensive use in advanced technologies. Fluorescent lamp wastes are considered one of the most interesting end-of-life products for investigation due to their high REEs content, mainly yttrium and europium. As a result, red phosphors (Y2O3:Eu3+ - YOX) have been chosen for evaluating their REEs' recovery potential. The REEs from a YOX reach liquor, coming from a soft leaching process have been precipitated adding oxalic acid and calcined to get the REEs in oxide form. Cyanex 572, D2EHPA and the ionic liquids, Primene 81R·Cyanex 572 IL and Primene 81R·D2EHPA IL, have been chosen to investigate the efficiency of REEs separation in chloride media. Yttrium, europium and cerium have been individually recovered by a four stages cross-flow solvent extraction process using the Primene 81R·D2EHPA IL and the Primene 81R·Cyanex 572 IL as extractants. Ce(III), Eu(III) and Y(III) have been obtained at high purities ≥ 99.9%. 4 mol/L HCl has been used to recover the yttrium and the europium from the organic phases.

Neodymium recovery from NdFeB magnet wastes using Primene 81R·Cyanex 572 IL by solvent extraction.

The necessity of Rare Earth Elements (REEs) recycling is crucial to minimizing their supply risk and provide an alternative to greener technologies. Hence, the REEs recovery from NdFeB magnet wastes using cationic extractants by solvent extraction technique has been investigated in this research. Due to the difficulty in maintaining the aqueous pH in the industrial counter-current devices when extractants like Cyanex 272 or Cyanex 572 are used, the Primene 81R·Cyanex 572 ionic liquid has been synthesised to overcome this. 99.99% Nd(III) recovery with a purity of 99.7% from an aqueous mixture of Nd/Tb/Dy in chloride medium, the three representative REEs present in the NdFeB magnets wastes, has been achieved after two stages counter-current extraction process using 0.30 M of Primene 81R·Cyanex 572 ionic liquid (1:4 A:O ratio) diluted in Solvesso 100, without any aqueous pH conditioning.

Safety of immunotherapy with glutaraldehyde modified allergen extracts in children and adults

BACKGROUND: Glutaraldehyde-modified natural allergen extracts show significant reduction in the IgE-binding capacity and proteolytic activity. This allows the administration of higher doses in a shorter period of time, and to mix different allergen extracts. OBJECTIVE: Evaluate the safety of different concentrations and mixtures of glutaraldehyde-modified allergen extracts in a large group of paediatric and adult patients undergoing specific immunotherapy treatment. MATERIALS AND METHODS: 1855 patients (1156 adults and 699 children), suffering from rhinoconjunctivitis and/or asthma, participated in an observational multicentre cohort study, to evaluate the safety of immunotherapy using vaccines containing modified allergen extracts. Patients were monosensitised, or polysensitised, and received a therapeutic vaccine containing polymerised allergen extracts adsorbed onto aluminium hydroxide. Safety was assessed by recording all side reactions related to immunotherapy. RESULTS: The clinically relevant local reactions totalled 120, (90 immediate and 30 delayed) (1.02% of injections). Of them, 31 (0.26% of injections) occurred in children (26 immediate and 5 delayed) and 89 (0.76% of injections) in adults (64 immediate and 25 delayed). There were 38 systemic reactions. Eleven reactions were immediate (9 of grade 1 and 2 of grade 2) and 27 delayed (22 of grade 1 and 5 of grade 2). There were seven grade 2 systemic reactions (0.06% of the injections). No differences (P>0.05) in the number of reactions were observed between adults and children and between treatments were found in systemic reactions. All systemic reactions were mild and resolved spontaneously without the need of medication. CONCLUSION: Specific immunotherapy using natural modified allergen vaccines is safe to treat allergic patients, even at higher doses and in mixtures of unrelated allergen extracts. The percentage of adverse reactions detected is lower than those reported in the literature with native unmodified allergen extracts

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Safety of immunotherapy with glutaraldehyde modified allergen extracts in children and adults.

BACKGROUND: Glutaraldehyde-modified natural allergen extracts show significant reduction in the IgE-binding capacity and proteolytic activity. This allows the administration of higher doses in a shorter period of time, and to mix different allergen extracts. OBJECTIVE: Evaluate the safety of different concentrations and mixtures of glutaraldehyde-modified allergen extracts in a large group of paediatric and adult patients undergoing specific immunotherapy treatment. MATERIALS AND METHODS: 1855 patients (1156 adults and 699 children), suffering from rhinoconjunctivitis and/or asthma, participated in an observational multicentre cohort study, to evaluate the safety of immunotherapy using vaccines containing modified allergen extracts. Patients were monosensitised, or polysensitised, and received a therapeutic vaccine containing polymerised allergen extracts adsorbed onto aluminium hydroxide. Safety was assessed by recording all side reactions related to immunotherapy. RESULTS: The clinically relevant local reactions totalled 120, (90 immediate and 30 delayed) (1.02% of injections). Of them, 31 (0.26% of injections) occurred in children (26 immediate and 5 delayed) and 89 (0.76% of injections) in adults (64 immediate and 25 delayed). There were 38 systemic reactions. Eleven reactions were immediate (9 of grade 1 and 2 of grade 2) and 27 delayed (22 of grade 1 and 5 of grade 2). There were seven grade 2 systemic reactions (0.06% of the injections). No differences (P>0.05) in the number of reactions were observed between adults and children and between treatments were found in systemic reactions. All systemic reactions were mild and resolved spontaneously without the need of medication. CONCLUSION: Specific immunotherapy using natural modified allergen vaccines is safe to treat allergic patients, even at higher doses and in mixtures of unrelated allergen extracts. The percentage of adverse reactions detected is lower than those reported in the literature with native unmodified allergen extracts.

Subcellular Localizations of RIG-I, TRIM25, and MAVS Complexes.

The retinoic acid-inducible gene 1 (RIG-I) signaling pathway is essential for the recognition of viruses and the initiation of host interferon (IFN)-mediated antiviral responses. Once activated, RIG-I interacts with polyubiquitin chains generated by TRIM25 and binds mitochondrial antiviral signaling protein (MAVS), leading to the production of type I IFN. We now show specific interactions among these key partners in the RLR pathway through the use of bimolecular fluorescence complementation (BiFC) and super-resolution microscopy. Dimers of RIG-I, TRIM25, and MAVS localize into different compartments. Upon activation, we show that TRIM25 is redistributed into cytoplasmic dots associated with stress granules, while RIG-I associates with TRIM25/stress granules and with mitochondrial MAVS. In addition, MAVS competes with TRIM25 for RIG-I binding, and this suggests that upon TRIM25-mediated activation of RIG-I, RIG-I moves away from TRIM25 to interact with MAVS at the mitochondria. For the first time, the distribution of these three proteins was analyzed at the same time in virus-infected cells. We also investigated how specific viral proteins modify some of the protein complexes in the pathway. The protease NS3/4A from hepatitis C virus redistributes the complexes RIG-I/MAVS and MAVS/MAVS but not RIG-I/TRIM25. In contrast, the influenza A virus NS1 protein interacts with RIG-I and TRIM25 in specific areas in the cell cytoplasm and inhibits the formation of TRIM25 homocomplexes but not the formation of RIG-I/TRIM25 heterocomplexes, preventing the formation of RIG-I/MAVS complexes. Thus, we have localized spatially in the cell different complexes formed between RIG-I, TRIM25, and MAVS, in the presence or absence of two viral IFN antagonistic proteins. IMPORTANCE: The first line of defense against viral infections is the innate immune response. Viruses are recognized by pathogen recognition receptors, such as the RIG-I like receptor family, that activate a signaling cascade that induces IFN production. In the present study, we visualized, for the first time in cells, both in overexpression and endogenous levels, complexes formed among key proteins involved in this innate immune signaling pathway. Through different techniques we were able to analyze how these proteins are distributed and reorganized spatially within the cell in order to transmit the signal, leading to an efficient antiviral state. In addition, this work presents a new means by how, when, and where viral proteins can target these pathways and act against the host immune system in order to counteract the activation of the immune response.

EWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma.

Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene. EWS-FLI1 knockdown specifically increased the expression of SPRY1, while other Sprouty family members remained unaffected. Analysis of SPRY1 expression in a panel of Ewing sarcoma cells showed that SPRY1 was not expressed in Ewing sarcoma cell lines, suggesting that it could act as a tumor suppressor gene in these cells. In agreement, induction of SPRY1 in three different Ewing sarcoma cell lines functionally impaired proliferation, clonogenic growth and migration. In addition, SPRY1 expression inhibited extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling induced by serum and basic FGF (bFGF). Moreover, treatment of Ewing sarcoma cells with the potent FGFR inhibitor PD-173074 reduced bFGF-induced proliferation, colony formation and in vivo tumor growth in a dose-dependent manner, thus mimicking SPRY1 activity in Ewing sarcoma cells. Although the expression of SPRY1 was low when compared with other tumors, SPRY1 was variably expressed in primary Ewing sarcoma tumors and higher expression levels were significantly associated with improved outcome in a large patient cohort. Taken together, our data indicate that EWS-FLI1-mediated repression of SPRY1 leads to unrestrained bFGF-induced cell proliferation, suggesting that targeting the FGFR/MAPK pathway can constitute a promising therapeutic approach for this devastating disease.

Up and Down Quark Masses and Corrections to Dashen's Theorem from Lattice QCD and Quenched QED.

In a previous Letter [Borsanyi et al., Phys. Rev. Lett. 111, 252001 (2013)] we determined the isospin mass splittings of the baryon octet from a lattice calculation based on N_{f}=2+1 QCD simulations to which QED effects have been added in a partially quenched setup. Using the same data we determine here the corrections to Dashen's theorem and the individual up and down quark masses. Our ensembles include 5 lattice spacings down to 0.054 fm, lattice sizes up to 6 fm, and average up-down quark masses all the way down to their physical value. For the parameter which quantifies violations to Dashen's theorem, we obtain ϵ=0.73(2)(5)(17), where the first error is statistical, the second is systematic, and the third is an estimate of the QED quenching error. For the light quark masses we obtain, m_{u}=2.27(6)(5)(4) and m_{d}=4.67(6)(5)(4) MeV in the modified minimal subtraction scheme at 2 GeV and the isospin breaking ratios m_{u}/m_{d}=0.485(11)(8)(14), R=38.2(1.1)(0.8)(1.4), and Q=23.4(0.4)(0.3)(0.4). Our results exclude the m_{u}=0 solution to the strong CP problem by more than 24 standard deviations.

Landscape of early clinical trials for childhood and adolescence cancer in Spain

Purpose: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. Methods: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. Results: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. Conclusions: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer (AU)

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Identification of genetic variants in pharmacokinetic genes associated with Ewing Sarcoma treatment outcome.

BACKGROUND: Despite the effectiveness of current treatment protocols for Ewing sarcoma (ES), many patients still experience relapse, and survival following recurrence is <15%. We aimed to identify genetic variants that predict treatment outcome in children diagnosed with ES. PATIENTS AND METHODS: We carried out a pharmacogenetic study of 384 single-nucleotide polymorphisms (SNPs) in 24 key transport or metabolism genes relevant to drugs used to treat in pediatric patients (<30 years) with histologically confirmed ES. We studied the association of genotypes with tumor response and overall survival (OS) in a discovery cohort of 106 Spanish children, with replication in a second cohort of 389 pediatric patients from across Europe. RESULTS: We identified associations with OS (P < 0.05) for three SNPs in the Spanish cohort that were replicated in the European cohort. The strongest association observed was with rs7190447, located in the ATP-binding cassette subfamily C member 6 (ABCC6) gene [discovery: hazard ratio (HR) = 14.30, 95% confidence interval (CI) = 1.53-134, P = 0.020; replication: HR = 9.28, 95% CI = 2.20-39.2, P = 0.0024] and its correlated SNP rs7192303, which was predicted to have a plausible regulatory function. We also replicated associations with rs4148737 in the ATP-binding cassette subfamily B member 1 (ABCB1) gene (discovery: HR = 2.96, 95% CI = 1.08-8.10, P = 0.034; replication: HR = 1.60, 95% CI = 1.05-2.44, P = 0.029), which we have previously found to be associated with poorer OS in pediatric osteosarcoma patients, and rs11188147 in cytochrome P450 family 2 subfamily C member 8 gene (CYP2C8) (discovery : HR = 2.49, 95% CI = 1.06-5.87, P = 0.037; replication: HR = 1.77, 95% CI = 1.06-2.96, P = 0.030), an enzyme involved in the oxidative metabolism of the ES chemotherapeutic agents cyclophosphamide and ifosfamide. None of the associations with tumor response were replicated. CONCLUSION: Using an integrated pathway-based approach, we identified polymorphisms in ABCC6, ABCB1 and CYP2C8 associated with OS. These associations were replicated in a large independent cohort, highlighting the importance of pharmacokinetic genes as prognostic markers in ES.

Aspectos inmunológicos de la leucemia mieloblástica aguda / An immunological approach to acute myeloid leukaemia

INTRODUCCIÓN: La leucemia mieloblástica aguda (LMA) constituye la segunda hemopatía maligna en la población pediátrica y una de las principales causas de mortalidad por cáncer infantil. La supervivencia se sitúa alrededor del 60% sin haber mejorado en las últimas décadas, por lo que son necesarios nuevos enfoques terapéuticos. El efecto antileucémico ejercido por los linfocitos y las células natural killer (NK) del sistema inmunológico está bien establecido en el trasplante de células madre hematopoyéticas pero también como estrategia de inmunoterapia adoptiva tras la quimioterapia de consolidación. PACIENTES Y MÉTODOS: De manera retrospectiva, se analizan las características clínicas de los pacientes diagnosticados de LMA en nuestro centro durante el período 1996-2014. Además en 10 leucemias agudas, 5 linfoides y 5 mieloides, se analizaron la intensidad media de fluorescencia de HLA-I, MICA-B, ULBP1-4, ligandos para los receptores de las células NK. RESULTADOS: Un total de 67 pacientes formaron parte de este análisis. La supervivencia libre de eventos con una mediana de seguimiento de 25 meses fue del 62% (IC del 95%, 55-67). Las LMA con menor supervivencia fueron las secundarias, las no M3 y las carentes de marcadores citogenéticos favorables. La probabilidad de recaída fue del 38% (IC del 95%, 31-45). La expresión de HLA-I y ULBP-4 fue significativamente menor en los blastos mieloides que en los linfoides. CONCLUSIONES: Nuestros resultados clínicos son similares a los descritos en la literatura. No se ha modificado significativamente la supervivencia en las últimas décadas y la probabilidad de recaída sigue siendo elevada. Los blastos mieloides podrían ser más susceptibles a las células NK al expresar menos HLA-I, por lo que estrategias de terapia celular podrían ser eficaces tal y como reportan otros grupos

INTRODUCTION: Acute myeloid leukaemia (AML) is the second haematological malignancy in the paediatric population, and one of the leading causes of childhood cancer mortality. Survival is currently around 60%, with no improvement in last decades, suggesting that new therapeutic approaches are needed. The anti-leukaemia effect mediated by the lymphocytes and natural killer (NK) cells of the immune system has been established in haematopoietic stem cell transplantation, and also as adoptive immunotherapy after consolidation chemotherapy schemes. PATIENTS AND METHODS: A retrospective study was conducted on the clinical characteristics of patients diagnosed and treated for AML in our centre during 1996-2014. The mean fluorescence intensities of HLA-I, MICA/B and ULBP1-4, ligands for NK cell receptors, were also analysed in ten new diagnosed leukaemia cases, five myeloid and five lymphoid. RESULTS: A total of 67 patients were used in this analysis. With a median follow up of 25 months, the event-free survival was 62% (95% CI: 55-67). Secondary AML, non-M3 phenotype, and the absence of favourable cytogenetic markers had a lower survival. The probability of relapse was 38% (95% CI: 31-45). The expression of HLA-I and ULBP-4 was significantly lower in myeloid than in lymphoid blast cells. CONCLUSIONS: Our clinical results are similar to those described in the literature. Survival did not significantly change in recent decades, and the likelihood of relapse remains high. Myeloid blasts might be more susceptible to the cytotoxicity of NK cells through their lower expression of HLA-I. NK therapy strategies in minimal disease situation could be effective, as reported by other groups

[An immunological approach to acute myeloid leukaemia]. / Aspectos inmunológicos de la leucemia mieloblástica aguda.

INTRODUCTION: Acute myeloid leukaemia (AML) is the second haematological malignancy in the paediatric population, and one of the leading causes of childhood cancer mortality. Survival is currently around 60%, with no improvement in last decades, suggesting that new therapeutic approaches are needed. The anti-leukaemia effect mediated by the lymphocytes and natural killer (NK) cells of the immune system has been established in haematopoietic stem cell transplantation, and also as adoptive immunotherapy after consolidation chemotherapy schemes. PATIENTS AND METHODS: A retrospective study was conducted on the clinical characteristics of patients diagnosed and treated for AML in our centre during 1996-2014. The mean fluorescence intensities of HLA-I, MICA/B and ULBP1-4, ligands for NK cell receptors, were also analysed in ten new diagnosed leukaemia cases, five myeloid and five lymphoid. RESULTS: A total of 67 patients were used in this analysis. With a median follow up of 25 months, the event-free survival was 62% (95% CI: 55-67). Secondary AML, non-M3 phenotype, and the absence of favourable cytogenetic markers had a lower survival. The probability of relapse was 38% (95% CI: 31-45). The expression of HLA-I and ULBP-4 was significantly lower in myeloid than in lymphoid blast cells. CONCLUSIONS: Our clinical results are similar to those described in the literature. Survival did not significantly change in recent decades, and the likelihood of relapse remains high. Myeloid blasts might be more susceptible to the cytotoxicity of NK cells through their lower expression of HLA-I. NK therapy strategies in minimal disease situation could be effective, as reported by other groups.

Landscape of early clinical trials for childhood and adolescence cancer in Spain.

PURPOSE: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. METHODS: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. RESULTS: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. CONCLUSIONS: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer.

Model of influenza A virus infection: dynamics of viral antagonism and innate immune response.

Viral antagonism of host responses is an essential component of virus pathogenicity. The study of the interplay between immune response and viral antagonism is challenging due to the involvement of many processes acting at multiple time scales. Here we develop an ordinary differential equation model to investigate the early, experimentally measured, responses of human monocyte-derived dendritic cells to infection by two H1N1 influenza A viruses of different clinical outcomes: pandemic A/California/4/2009 and seasonal A/New Caledonia/20/1999. Our results reveal how the strength of virus antagonism, and the time scale over which it acts to thwart the innate immune response, differs significantly between the two viruses, as is made clear by their impact on the temporal behavior of a number of measured genes. The model thus sheds light on the mechanisms that underlie the variability of innate immune responses to different H1N1 viruses.

Hemagglutinin stalk-based universal vaccine constructs protect against group 2 influenza A viruses.

Current influenza virus vaccines contain H1N1 (phylogenetic group 1 hemagglutinin), H3N2 (phylogenetic group 2 hemagglutinin), and influenza B virus components. These vaccines induce good protection against closely matched strains by predominantly eliciting antibodies against the membrane distal globular head domain of their respective viral hemagglutinins. This domain, however, undergoes rapid antigenic drift, allowing the virus to escape neutralizing antibody responses. The membrane proximal stalk domain of the hemagglutinin is much more conserved compared to the head domain. In recent years, a growing collection of antibodies that neutralize a broad range of influenza virus strains and subtypes by binding to this domain has been isolated. Here, we demonstrate that a vaccination strategy based on the stalk domain of the H3 hemagglutinin (group 2) induces in mice broadly neutralizing anti-stalk antibodies that are highly cross-reactive to heterologous H3, H10, H14, H15, and H7 (derived from the novel Chinese H7N9 virus) hemagglutinins. Furthermore, we demonstrate that these antibodies confer broad protection against influenza viruses expressing various group 2 hemagglutinins, including an H7 subtype. Through passive transfer experiments, we show that the protection is mediated mainly by neutralizing antibodies against the stalk domain. Our data suggest that, in mice, a vaccine strategy based on the hemagglutinin stalk domain can protect against viruses expressing divergent group 2 hemagglutinins.