Intervención nutricional en el paciente oncohematológico

Background: Oncohematological diseases such as lymphoma or leukaemia affect an increasing number of newly diagnosed patients in Spain and other countries. Both disease and treatment may have a negatively impact in the nutritional status of the patient. Malnutrition is not uncommon among oncohematological patients. This situation can compromised the course of the disease, the clinical response of the treatment and the patient’s quality of life. Method: The implementation of a multidisciplinary approach and a systematic and protocolled nutritional assessment would be useful when dealing with haematological malignancies. Results: We present a proposal of protocol for nutritional intervention in oncohematological patients. This proposal is been developed from the analysis of the published literature as well as clinical practice of a multidisciplinary team specialized in the management of patients with haematological malignanciesObjetivos: Las enfermedades oncohematológicas como el Linfoma o la Leucemia afectan a un número importante y creciente de personas en España. Tanto la enfermedad como las distintas modalidades de tratamiento que puede llegar a precisar el paciente a lo largo del curso de la misma impactan negativamente en el estado nutricional del paciente, no siendo infrecuente el desarrollo de desnutrición, situación que compromete la evolución, la respuesta al tratamiento y la calidad de vida del paciente. Método: La implementación de una estrategia multidisciplinar, sistematizada y protocolizada de valoración nutricional puede resultar de utilidad a la hora de abordar a los pacientes con enfermedades oncohematológicas. Resultados: Se presenta una propuesta de protocolo de evaluación y soporte nutricional en el paciente oncohematológico elaborada a partir del análisis de la literatura publicada al respecto, así como de la práctica clínica habitual de un equipo sanitario multidisciplinar especialmente implicado en el manejo de los pacientes con enfermedades oncohematológica

Genotype, environment and their interaction on olive

Resumen del trabajo presentado en la 6th International Conference on the Olive Tree and Olive Products, celebrada en Sevilla (España) del 15 al 19 de octubre de 2018.The wide olive genetic patrimony has revealed high variability for most of the agronomic and oil quality traits of interest in olive growing. Few studies, however, have addressed the interaction of this variability with the environment, a subject of particular interest considering the natural high instability of the Mediterranean climate and the challenge of the predicted climate change. The current work presents results on the interaction between genotype and environment from multi-environment trials of olive cultivars and breeding selections, planted in different edaphoclimatic conditions of Andalusia, Southern Peninsular Spain and Canary Islands. For most of the agronomic and oil quality characters evaluated (flowering phenology, flower quality, pattern of oil accumulation, fatty acid composition and phenol content and composition), significant genotype and environment effects have been observed. For example, olive cultivars grown in Tenerife under much milder winter temperatures than in the Iberian Peninsula showed substantially earlierflowering and oil accumulation. Only in the case of flowering phenology was no significant genotype effect found. Furthermore, a strong genotype x environment effect was highly consistent in all characters considered. Regarding resistance to disease, such as Verticillium wilt, the variability of results from both natural and artificial inoculations also tends to indicate a considerable environmental effect and the need for careful testing of disease evolution. All this information strongly suggests the necessity of comparative trials of olive cultivars for both adequate choice of cultivar and final selection in breeding programs

Deletion Mutants of VPg Reveal New Cytopathology Determinants in a Picornavirus

BACKGROUND: Success of a viral infection requires that each infected cell delivers a sufficient number of infectious particles to allow new rounds of infection. In picornaviruses, viral replication is initiated by the viral polymerase and a viral-coded protein, termed VPg, that primes RNA synthesis. Foot-and-mouth disease virus (FMDV) is exceptional among picornaviruses in that its genome encodes 3 copies of VPg. Why FMDV encodes three VPgs is unknown. METHODOLOGY AND PRINCIPAL FINDINGS: we have constructed four mutant FMDVS that encode only one VPG: either VPg(1), VPg(3), or two chimeric versions containing part of VPg(1) and VPg(3). All mutants, except that encoding only VPg(1), were replication-competent. Unexpectedly, despite being replication-competent, the mutants did not form plaques on BHK-21 cell monolayers. The one-VPg mutant FMDVs released lower amounts of encapsidated viral RNA to the extracellular environment than wild type FMDV, suggesting that deficient plaque formation was associated with insufficient release of infectious progeny. Mutant FMDVs subjected to serial passages in BHK-21 cells regained plaque-forming capacity without modification of the number of copies of VPg. Substitutions in non-structural proteins 2C, 3A and VPg were associated with restoration of plaque formation. Specifically, replacement R55W in 2C was repeatedly found in several mutant viruses that had regained competence in plaque development. The effect of R55W in 2C was to mediate an increase in the extracellular viral RNA release without a detectable increase of total viral RNA that correlated with an enhanced capacity to alter and detach BHK-21 cells from the monolayer, the first stage of cell killing. CONCLUSIONS: The results link the VPg copies in the FMDV genome with the cytopathology capacity of the virus, and have unveiled yet another function of 2C: modulation of picornavirus cell-to-cell transmission. Implications for picornaviruses pathogenesis are discussed

Fumarate Analogs Act as Allosteric Inhibitors of the Human Mitochondrial NAD(P)+-Dependent Malic Enzyme

Human mitochondrial NAD(P)+-dependent malic enzyme (m-NAD(P)-ME) is allosterically activated by the four-carbon trans dicarboxylic acid, fumarate. Previous studies have suggested that the dicarboxylic acid in a trans conformation around the carbon-carbon double bond is required for the allosteric activation of the enzyme. In this paper, the allosteric effects of fumarate analogs on m-NAD(P)-ME are investigated. Two fumarate-insensitive mutants, m-NAD(P)-ME_R67A/R91A and m-NAD(P)-ME_K57S/E59N/K73E/D102S, as well as c-NADP-ME, were used as the negative controls. Among these analogs, mesaconate, trans-aconitate, monomethyl fumarate and monoethyl fumarate were allosteric activators of the enzyme, while oxaloacetate, diethyl oxalacetate, and dimethyl fumarate were found to be allosteric inhibitors of human m-NAD(P)-ME. The IC50 value for diethyl oxalacetate was approximately 2.5 mM. This paper suggests that the allosteric inhibitors may impede the conformational change from open form to closed form and therefore inhibit m-NAD(P)-ME enzyme activity

ALPs effective field theory and collider signatures

We study the leading effective interactions between the Standard Model fields and a generic singlet CP-odd (pseudo-) Goldstone boson. Two possible frameworks for electroweak symmetry breaking are considered: linear and non-linear. For the latter case, the basis of leading effective operators is determined and compared with that for the linear expansion. Associated phenomenological signals at colliders are explored for both scenarios, deriving new bounds and analyzing future prospects, including LHC and High Luminosity LHC sensitivities. Mono-Z, mono-W, W-photon plus missing energy and on-shell top final states are most promising signals expected in both frameworks. In addition, non-standard Higgs decays and mono-Higgs signatures are especially prominent and expected to be dominant in non-linear realisations

A Multi-Step Process of Viral Adaptation to a Mutagenic Nucleoside Analogue by Modulation of Transition Types Leads to Extinction-Escape

Resistance of viruses to mutagenic agents is an important problem for the development of lethal mutagenesis as an antiviral strategy. Previous studies with RNA viruses have documented that resistance to the mutagenic nucleoside analogue ribavirin (1-β-D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) is mediated by amino acid substitutions in the viral polymerase that either increase the general template copying fidelity of the enzyme or decrease the incorporation of ribavirin into RNA. Here we describe experiments that show that replication of the important picornavirus pathogen foot-and-mouth disease virus (FMDV) in the presence of increasing concentrations of ribavirin results in the sequential incorporation of three amino acid substitutions (M296I, P44S and P169S) in the viral polymerase (3D). The main biological effect of these substitutions is to attenuate the consequences of the mutagenic activity of ribavirin —by avoiding the biased repertoire of transition mutations produced by this purine analogue—and to maintain the replicative fitness of the virus which is able to escape extinction by ribavirin. This is achieved through alteration of the pairing behavior of ribavirin-triphosphate (RTP), as evidenced by in vitro polymerization assays with purified mutant 3Ds. Comparison of the three-dimensional structure of wild type and mutant polymerases suggests that the amino acid substitutions alter the position of the template RNA in the entry channel of the enzyme, thereby affecting nucleotide recognition. The results provide evidence of a new mechanism of resistance to a mutagenic nucleoside analogue which allows the virus to maintain a balance among mutation types introduced into progeny genomes during replication under strong mutagenic pressure

Adoptive NK cell transfer as a treatment in colorectal cancer patients: analyses of tumour cell determinants correlating with efficacy in vitro and in vivo

6 figures.-- Supplementary material available.Background: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC.Methods: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity.Results: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control.Conclusions: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.Work in the JP laboratory is funded by ASPANOA, CIBER (CB 2021; Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación and Union Europea.NextGenerationEU), Fundacion Inocente, Carrera de la Mujer Monzón, FEDER/Gobierno de Aragón (Group B29_17R), and Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación (SAF2017‐83120‐C2‐1‐R and PID2020-113963RB-I00). Predoctoral grants/contracts from Gobierno de Aragon (IU-M and JP) are supported by ARAID Foundation. EG is funded by Ministerio de Ciencia, Innovación y Universidades (MCNU), and Agencia Estatal de Investigación (PID2020-113963RB-I00). MA and LS are funded by Postdoctoral Juan de la Cierva Contract. SR, LC, SH, and IU-M are funded by predoctoral contracts from Aragon Government. PL is funded by FPU predoctoral grants from Ministerio de Ciencia, Innovación e Universidades. Work at the Catalan Institute of Oncology is funded by the entity, the Instituto de Salud Carlos III and Ministerio de Economia y Competitividad, and co-funded by FEDER funds—a way to build Europe (PI20/00767), CIBERESP (grant CB07/02/2005), H2020 grant MoTriColor, and the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723. This work is supported by COST Action CA17118.Peer reviewe

Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: A prospective observational study

Background: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. Methods: In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with =2 clinical signs/symptoms of NP-C were considered ''suspected NP-C'' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI =70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. Results: In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores =70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients. Conclusion: This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis

Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location