Blood gene expression biomarkers of response to anti-TNF drugs in pediatric inflammatory bowel diseases before initiation of treatment

Inflammatory bowel disease; Pediatrics; PharmacogenomicsEnfermedad inflamatoria intestinal; Pediatría; FarmacogenómicaMalaltia inflamatòria intestinal; Pediatria; FarmacogenòmicaBackground/aims Changes in gene expression profiles among individuals with inflammatory bowel diseases (IBDs) could potentially influence the responsiveness to anti-TNF treatment. The aim of this study was to identify genes that could serve as predictors of early response to anti-TNF therapies in pediatric IBD patients prior to the initiation of treatment. Methods We conducted a prospective, longitudinal, and multicenter study, enrolling 24 pediatric IBD patients aged less than 18 years who were initiating treatment with either infliximab or adalimumab. RNA-seq from blood samples was analyzed using the DESeq2 library by comparing responders and non-responders to anti-TNF drugs. Results Bioinformatic analyses unveiled 102 differentially expressed genes, with 99 genes exhibiting higher expression in responders compared to non-responders prior to the initiation of anti-TNF therapy. Functional enrichment analyses highlighted defense response to Gram-negative bacteria (FDR = 2.3 ×10–7) as the most significant biological processes, and hemoglobin binding (FDR = 0.002), as the most significant molecular function. Gene Set Enrichment Analysis (GSEA) revealed notable enrichment in transcriptional misregulation in cancer (FDR = 0.016). Notably, 13 genes (CEACAM8, CEACAM6, CILP2, COL17A1, OLFM4, INHBA, LCN2, LTF, MMP8, DEFA4, PRTN3, AZU1, and ELANE) were selected for validation, and a consistent trend of increased expression in responders prior to drug administration was observed for most of these genes, with findings for 4 of them being statistically significant (CEACAM8, LCN2, LTF2, and PRTN3). Conclusions We identified 102 differentially expressed genes involved in the response to anti-TNF drugs in children with IBDs and validated CEACAM8, LCN2, LTF2, and PRTN3. Genes participating in defense response to Gram-negative bacterium, serine-type endopeptidase activity, and transcriptional misregulation in cancer are good candidates for anticipating the response to anti-TNF drugs in children with IBDs.Instituto de Salud Carlos III (ISCIII), "PI19/00792 and PI22/00584", co-funded by the European Union (L.L-F); Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), grant number 2021-II-postdoc-01 (S.S-M.), and by Consejería de Educación, Ciencia y Universidades Comunidad de Madrid, grant number PEJ-2021-AI/BMD-21866 and PIPF2022/SAL-GL-24790 (P.Z-C.)

Generation and characterization of a defective HIV-1 Virus as an immunogen for a therapeutic vaccine

Background The generation of new immunogens able to elicit strong specific immune responses remains a major challenge in the attempts to obtain a prophylactic or therapeutic vaccine against HIV/AIDS. We designed and constructed a defective recombinant virus based on the HIV-1 genome generating infective but non-replicative virions able to elicit broad and strong cellular immune responses in HIV-1 seropositive individuals. Results Viral particles were generated through transient transfection in producer cells (293-T) of a full length HIV-1 DNA carrying a deletion of 892 base pairs (bp) in the pol gene encompassing the sequence that codes for the reverse transcriptase (NL4-3/ΔRT clone). The viral particles generated were able to enter target cells, but due to the absence of reverse transcriptase no replication was detected. The immunogenic capacity of these particles was assessed by ELISPOT to determine γ-interferon production in a cohort of 69 chronic asymptomatic HIV-1 seropositive individuals. Surprisingly, defective particles produced from NL4-3/ΔRT triggered stronger cellular responses than wild-type HIV-1 viruses inactivated with Aldrithiol-2 (AT-2) and in a larger proportion of individuals (55% versus 23% seropositive individuals tested). Electron microscopy showed that NL4-3/ΔRT virions display immature morphology. Interestingly, wild-type viruses treated with Amprenavir (APV) to induce defective core maturation also induced stronger responses than the same viral particles generated in the absence of protease inhibitors. Conclusions We propose that immature HIV-1 virions generated from NL4-3/ΔRT viral clones may represent new prototypes of immunogens with a safer profile and stronger capacity to induce cellular immune responses than wild-type inactivated viral particles

Inhibidores de bomba de protones vs. antagonistas del receptor 2 de histamina en la protección gástrica en el paciente anticoagulado: ¿qué ha definido la evidencia?

Objetivo: evaluar la evidencia más reciente sobre la diferencia de la gastroprotección generada por los inhibidores de bomba de protones (IBP) y antagonistas del receptor de histamina 2 (ARH2) en el paciente anticoagulado, así como del riesgo de sangrado gastrointestinal asociado. Métodos: revisión narrativa. Se realizó una búsqueda bibliográfica en las bases de datos PubMed, ScienceDirect, Web of Science, y MEDLINE. Resultados: dentro de los mecanismos descritos que explican un sangrado en el tracto gastrointestinal, se encuentran el daño a mucosa, alteraciones en el pH local, inhibición plaquetaria y alteración de factores de la coagulación, y lesiones vasculares. Dependiendo del grupo farmacológico, los anticoagulantes pueden actúan a nivel de diferentes dianas de la vía de la coagulación, alterando los factores involucrados en esta vía, y pudiendo desencadenar sangrado. Por su parte, los antisecretores gástricos, tienen como objetivo inhibir o reducir la secreción de ácido gástrico por medio de la interacción con sistemas enzimáticos, alterando el pH local. De esta forma, estos fármacos influyen sobre el riesgo de sangrado. No obstante, la evidencia más reciente demuestra que los IBP reducen la probabilidad de sangrado gastrointestinal hasta en un 33%, comparado con los ARH2, sin impactar en otros desenlaces como mortalidad u hospitalización. Conclusión: aunque la evidencia es escasa y heterogénea, se pudo observar mayor respaldo científico y beneficio gastroprotector contra la frecuencia de sangrado gastrointestinal, con el uso de IBP comparado a ARH2, en pacientes anticoagulados que concomitantemente, utilizan antisecretores gástricos

Inhibidores de bomba de protones vs. antagonistas del receptor 2 de histamina en la protección gástrica en el paciente anticoagulado: ¿qué ha definido la evidencia?

Objective: to evaluate the latest evidence on the difference in gastroprotection generated by proton pump inhibitors (PPIs) and histamine receptor 2 antagonists (H2RAs) in anticoagulated patients, as well as the associated risk of gastrointestinal bleeding. Methods: narrative review. A literature search was conducted in the PubMed, ScienceDirect, Web of Science, and MEDLINE databases. Results: Among the described mechanisms explaining bleeding in the gastrointestinal tract are mucosal damage, alterations in local pH, platelet inhibition, coagulation factor alteration, and vascular lesions. Depending on the pharmacological group, anticoagulants can act on different targets in the coagulation pathway, altering the factors involved in this pathway and potentially triggering bleeding. Antisecretory drugs, on the other hand, aim to inhibit or reduce gastric acid secretion through interaction with enzymatic systems, altering the local pH. Thus, these drugs influence the risk of bleeding. However, the latest evidence shows that PPIs reduce the likelihood of gastrointestinal bleeding by up to 33% compared to H2RAs, without impacting other outcomes such as mortality or hospitalization. Conclusion: Although the evidence is scarce and heterogeneous, it was observed that there is greater scientific support and gastroprotective benefit against the frequency of gastrointestinal bleeding with the use of PPIs compared to H2RAs in anticoagulated patients who concurrently use gastric acid suppressants.Objetivo: evaluar la evidencia más reciente sobre la diferencia de la gastroprotección generada por los inhibidores de bomba de protones (IBP) y antagonistas del receptor de histamina 2 (ARH2) en el paciente anticoagulado, así como del riesgo de sangrado gastrointestinal asociado. Métodos: revisión narrativa. Se realizó una búsqueda bibliográfica en las bases de datos PubMed, ScienceDirect, Web of Science, y MEDLINE. Resultados: dentro de los mecanismos descritos que explican un sangrado en el tracto gastrointestinal, se encuentran el daño a mucosa, alteraciones en el pH local, inhibición plaquetaria y alteración de factores de la coagulación, y lesiones vasculares. Dependiendo del grupo farmacológico, los anticoagulantes pueden actúan a nivel de diferentes dianas de la vía de la coagulación, alterando los factores involucrados en esta vía, y pudiendo desencadenar sangrado. Por su parte, los antisecretores gástricos, tienen como objetivo inhibir o reducir la secreción de ácido gástrico por medio de la interacción con sistemas enzimáticos, alterando el pH local. De esta forma, estos fármacos influyen sobre el riesgo de sangrado. No obstante, la evidencia más reciente demuestra que los IBP reducen la probabilidad de sangrado gastrointestinal hasta en un 33%, comparado con los ARH2, sin impactar en otros desenlaces como mortalidad u hospitalización. Conclusión: aunque la evidencia es escasa y heterogénea, se pudo observar mayor respaldo científico y beneficio gastroprotector contra la frecuencia de sangrado gastrointestinal, con el uso de IBP comparado a ARH2, en pacientes anticoagulados que concomitantemente, utilizan antisecretores gástricos

The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever

Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. The incidence of NF among the groups was reduced (64%, 44%, and 24%; P2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age �60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05. G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial

Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci

Objective. Five loci—the shared epitope (SE) of HLA-DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region—have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone

Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies

BACKGROUND: Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. OBJECTIVES: The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. METHODS: FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. RESULTS: Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. CONCLUSIONS: Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.Instituto de Salud Carlos III [PI11/0699, PI14/0967, PI14/01477, RD012/0042/0029, RD012/0042/0049, RD012/0042/0066, RD12/0042/0069]; Spanish Ministry of Economy and Competitiveness [SAF2015-71863-REDT]; Plan Nacional de I+D+I; Plan Estatalde I+D+I, European Regional Development Fund; Health in Code SLS

Generation and characterization of a defective HIV-1 Virus as an immunogen for a therapeutic vaccine

BACKGROUND: The generation of new immunogens able to elicit strong specific immune responses remains a major challenge in the attempts to obtain a prophylactic or therapeutic vaccine against HIV/AIDS. We designed and constructed a defective recombinant virus based on the HIV-1 genome generating infective but non-replicative virions able to elicit broad and strong cellular immune responses in HIV-1 seropositive individuals. RESULTS: Viral particles were generated through transient transfection in producer cells (293-T) of a full length HIV-1 DNA carrying a deletion of 892 base pairs (bp) in the pol gene encompassing the sequence that codes for the reverse transcriptase (NL4-3/ΔRT clone). The viral particles generated were able to enter target cells, but due to the absence of reverse transcriptase no replication was detected. The immunogenic capacity of these particles was assessed by ELISPOT to determine γ-interferon production in a cohort of 69 chronic asymptomatic HIV-1 seropositive individuals. Surprisingly, defective particles produced from NL4-3/ΔRT triggered stronger cellular responses than wild-type HIV-1 viruses inactivated with Aldrithiol-2 (AT-2) and in a larger proportion of individuals (55% versus 23% seropositive individuals tested). Electron microscopy showed that NL4-3/ΔRT virions display immature morphology. Interestingly, wild-type viruses treated with Amprenavir (APV) to induce defective core maturation also induced stronger responses than the same viral particles generated in the absence of protease inhibitors. CONCLUSIONS: We propose that immature HIV-1 virions generated from NL4-3/ΔRT viral clones may represent new prototypes of immunogens with a safer profile and stronger capacity to induce cellular immune responses than wild-type inactivated viral particles.This study was supported by grants FIS PI050265, FIS PI040503, FIS PI070291, FIS Intrasalud 080752, FIS PS09/01297, FIS PI10/02984, SAF2006-26667-E, FIT 09-010-205-9, FIPSE 36780/08, Fundación Mútua Madrileña, TRA-094, EC10-153, ISCIII-RETIC RD06/0006, HIVACAT–HIV Development Program in Catalonia, FIPSE 36630/07, UE Program Health 2009 CHAARM. Spanish Health Institute Carlos III (ISCIII) and the Health Department of the Catalan Government (Generalitat de Catalunya). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

A US perspective on closing the carbon cycle to defossilize difficult-to-electrify segments of our economy

Electrification to reduce or eliminate greenhouse gas emissions is essential to mitigate climate change. However, a substantial portion of our manufacturing and transportation infrastructure will be difficult to electrify and/or will continue to use carbon as a key component, including areas in aviation, heavy-duty and marine transportation, and the chemical industry. In this Roadmap, we explore how multidisciplinary approaches will enable us to close the carbon cycle and create a circular economy by defossilizing these difficult-to-electrify areas and those that will continue to need carbon. We discuss two approaches for this: developing carbon alternatives and improving our ability to reuse carbon, enabled by separations. Furthermore, we posit that co-design and use-driven fundamental science are essential to reach aggressive greenhouse gas reduction targets

Plant trait and vegetation data along a 1314 m elevation gradient with fire history in Puna grasslands, Perú

Alpine grassland vegetation supports globally important biodiversity and ecosystems that are increasingly threatened by climate warming and other environmental changes. Trait-based approaches can support understanding of vegetation responses to global change drivers and consequences for ecosystem functioning. In six sites along a 1314 m elevational gradient in Puna grasslands in the Peruvian Andes, we collected datasets on vascular plant composition, plant functional traits, biomass, ecosystem fluxes, and climate data over three years. The data were collected in the wet and dry season and from plots with different fire histories. We selected traits associated with plant resource use, growth, and life history strategies (leaf area, leaf dry/wet mass, leaf thickness, specific leaf area, leaf dry matter content, leaf C, N, P content, C and N isotopes). The trait dataset contains 3,665 plant records from 145 taxa, 54,036 trait measurements (increasing the trait data coverage of the regional flora by 420%) covering 14 traits and 121 plant taxa (ca. 40% of which have no previous publicly available trait data) across 33 families