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Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure-activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L1. Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.
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Endorribonucleasas , MicroARNs , ARN Mensajero , Humanos , Genes jun/genética , Genes myc/genética , MicroARNs/antagonistas & inhibidores , MicroARNs/química , MicroARNs/genética , MicroARNs/metabolismo , Conformación de Ácido Nucleico , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/química , ARN Mensajero/genética , ARN Mensajero/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato , Endorribonucleasas/química , Endorribonucleasas/metabolismo , TranscriptomaRESUMEN
Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis.
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Genes Supresores de Tumor , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Tristetraprolina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Linfocitos B/metabolismo , Línea Celular Tumoral , Transformación Celular Neoplásica , Células HeLa , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Estabilidad del ARN , ARN Mensajero/químicaRESUMEN
Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17 cells. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against Citrobacter rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that ILC3-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as exacerbates autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.
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Colitis , Infecciones por Enterobacteriaceae , Ratones , Animales , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Interleucina-17 , Ornitina Descarboxilasa/genética , Inmunidad Innata , Putrescina , Colitis/genética , Infecciones por Enterobacteriaceae/genética , Células Th17/metabolismo , Ornitina , Antibacterianos , Interleucina-22RESUMEN
Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.
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Encéfalo , Cardiopatías Congénitas , Imagen por Resonancia Magnética , Humanos , Cardiopatías Congénitas/patología , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/genética , Femenino , Masculino , Niño , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Adolescente , Adulto Joven , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto , Preescolar , Imagen de Difusión por Resonancia Magnética , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/patología , Trastornos del Neurodesarrollo/genéticaRESUMEN
OBJECTIVE: Patients with complete atrioventricular canal have a variable clinical course prior to repair. Many patients balance their circulations well prior to elective repair. Others manifest clinically significant pulmonary over circulation early in life and require either palliative pulmonary artery banding or complete repair. The objective of this study was to assess anatomic features that impact the clinical course of patients. METHODS: In total, 222 patients underwent complete atrioventricular canal repair between 2012 and 2022 at a single institution. Twenty-seven (12%) patients underwent either pulmonary artery banding (n = 15) or complete repair (n = 12) at less than 3 months of age (Group 1). The remaining 195 (88%) underwent repair after 3 months of age (Group 2). Patient records and imaging were reviewed. RESULTS: The median post-operative length of stay following complete repair was 25 [7,46] days for those patients in Group 1 and 7 [5,12] days for those in Group 2 (p < 0.0001). There was relative hypoplasia of left-sided structures in Group 1 versus Group 2. Mean z-score for the ascending aorta was -1.2 (±0.8) versus -0.3 (±0.9) (p < 0.0001), the aortic isthmus was -2.1 (±0.8) versus -1.4 (±0.8) (p = 0.005). The pulmonary valve to aortic valve diameter ratio was median 1.47 [1.38,1.71] versus 1.38 [1.17,1.53] (p 0.008). CONCLUSIONS: Echocardiographic evaluation of the systemic and pulmonary outflow of patients with complete atrioventricular canal may assist in predicting the clinical course and need for early repair vs pulmonary artery banding.
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Defectos del Tabique Interventricular , Defectos de los Tabiques Cardíacos , Humanos , Lactante , Defectos de los Tabiques Cardíacos/diagnóstico por imagen , Defectos de los Tabiques Cardíacos/cirugía , Ecocardiografía , Defectos del Tabique Interventricular/cirugía , Progresión de la Enfermedad , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
BACKGROUND: Perioperative immunisation administration surrounding congenital heart surgery is controversial. Delayed immunisation administration results in children being at risk of vaccine-preventable illnesses and is associated with failure to complete immunisation schedules. Among children with CHD, many of whom are medically fragile, vaccine-preventable illnesses can be devastating. Limited research shows perioperative immunisation may be safe and effective. METHODS: We surveyed Pediatric Acute Care Cardiology Collaborative member centres and explored perioperative immunisation practices. We analysed responses using descriptive statistics. RESULTS: Complete responses were submitted by 35/46 (76%) centres. Immunisations were deferred for any period prior to surgery by 23 (66%) centres and after surgery by 31 (89%) centres. Among those who deferred post-operative immunisation, 20 (65%) required deferral only for patients whose operations required cardiopulmonary bypass. Duration of deferral in the pre- and post-operative periods was variable. Many centres included exceptions to their policy for specific vaccine-preventable illnesses. Almost all (34, 97%) centres administer routine childhood immunisation to patients who remain admitted for prolonged periods. CONCLUSIONS: Most centres defer routine childhood immunisation for some period before and after congenital heart surgery. Centre specific practices vary. Immunisation deferral confers risk to patients and may not be warranted in this population. Further research would be necessary to understand the immunologic impact of these practices.
RESUMEN
The unique amino acid hypusine [Nε-(4-amino-2-hydroxybutyl)lysine] is exclusively formed on the translational regulator eukaryotic initiation factor 5A (eIF5A) via a process coined hypusination. Hypusination is mediated by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), and hypusinated eIF5A (eIF5AHyp) promotes translation elongation by alleviating ribosome pauses at amino acid motifs that cause structural constraints, and it also facilitates translation initiation and termination. Accordingly, eIF5AHyp has diverse biological functions that rely on translational control of its targets. Homozygous deletion of Eif5a, Dhps, or Dohh in mice leads to embryonic lethality, and heterozygous germline variants in EIF5A and biallelic variants in DHPS and DOHH are associated with rare inherited neurodevelopmental disorders, underscoring the importance of the hypusine circuit for embryonic and neuronal development. Given the pleiotropic effects of eIF5AHyp, a detailed understanding of the cell context-specific intrinsic roles of eIF5AHyp and of the chronic versus acute effects of eIF5AHyp inhibition is necessary to develop future strategies for eIF5AHyp-targeted therapy to treat various human health problems. Here, we review the most recent studies documenting the intrinsic roles of eIF5AHyp in different tissues/cell types under normal or pathophysiological conditions and discuss these unique aspects of eIF5AHyp-dependent translational control.
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Factor 5A Eucariótico de Iniciación de Traducción , Lisina , Factores de Iniciación de Péptidos , Proteínas de Unión al ARN , Factores de Iniciación de Péptidos/metabolismo , Factores de Iniciación de Péptidos/genética , Humanos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Animales , Lisina/metabolismo , Lisina/análogos & derivados , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Biosíntesis de Proteínas , RatonesRESUMEN
We have reported previously that CD33hi myeloid-derived suppressor cells (MDSCs) play a direct role in the pathogenesis of myelodysplastic syndromes (MDSs) and that their sustained activation contributes to hematopoietic and immune impairment, including modulation of PD1/PDL1. MDSCs can also limit the clinical activity of immune checkpoint inhibition in solid malignancies. We hypothesized that depletion of MDSCs may ameliorate resistance to checkpoint inhibitors and, hence, targeted them with AMV564 combined with anti-PD1 in MDS bone marrow (BM) mononuclear cells (MNCs) enhanced activation of cytotoxic T cells. AMV564 was active in vivo in a leukemia xenograft model when co-administered with healthy donor peripheral blood MNCs (PBMCs). Our findings provide a strong rationale for clinical investigation of AMV564 as a single agent or in combination with an anti-PD1 antibody and in particular for treatment of cancers resistant to checkpoint inhibitors.
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Anticuerpos Biespecíficos , Antineoplásicos , Melanoma , Síndromes Mielodisplásicos , Células Supresoras de Origen Mieloide , Animales , Anticuerpos Biespecíficos/farmacología , Antineoplásicos/farmacología , Humanos , Melanoma/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Linfocitos TRESUMEN
In this retrospective analysis of men who have sex with men with human immunodeficiency virus (HIV) in the South from 2014 through 2019, incident bacterial sexually transmitted infections (STIs) increased regardless of virologic control. Clinicians should prioritize STI screening and management in primary HIV care.
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Infecciones por VIH , Homosexualidad Masculina , Enfermedades Bacterianas de Transmisión Sexual , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Incidencia , Masculino , Estudios Retrospectivos , Minorías Sexuales y de Género , Enfermedades Bacterianas de Transmisión Sexual/tratamiento farmacológico , Enfermedades Bacterianas de Transmisión Sexual/epidemiología , Enfermedades Bacterianas de Transmisión Sexual/prevención & controlRESUMEN
Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.
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Leucemia Mieloide Aguda , Mutación , Síndromes Mielodisplásicos , Células Supresoras de Origen Mieloide/inmunología , Linfocitos T Reguladores/inmunología , Proteína p53 Supresora de Tumor , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Terapia de Inmunosupresión , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Masculino , MicroARNs/genética , MicroARNs/inmunología , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/patología , Células Supresoras de Origen Mieloide/patología , ARN Neoplásico/genética , ARN Neoplásico/inmunología , Linfocitos T Reguladores/patología , Proteína p53 Supresora de Tumor/inmunologíaRESUMEN
Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known "neosubstrates," such as IKAROS, AIOLOS, and CK1α, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN. We report that CRBN functions in a feedback loop that harnesses antigen-specific CD8+ T-cell effector responses. Specifically, Crbn deficiency in murine CD8+ T cells augments their central metabolism manifested as elevated bioenergetics, with supraphysiological levels of polyamines, secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Treatment with CRBN-modulating compounds similarly augments central metabolism of human CD8+ T cells. Notably, the metabolic control of CD8+ T cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn-deficient T cells have augmented antigen-specific cytolytic activity vs melanoma tumor cells, ex vivo and in vivo, and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of CD8+ T cells, and this phenotype can be exploited by treatment with drugs.
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Proteínas Adaptadoras Transductoras de Señales/fisiología , Linfocitos T CD8-positivos/fisiología , Metabolismo Energético/genética , Activación de Linfocitos/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Inmunomodulación/genética , Melanoma Experimental/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Rates of chronic pain and cigarette smoking are each substantially higher among people living with HIV (PLWH) than in the general population. The goal of these analyses was to examine the prevalence and impact of comorbid chronic pain and cigarette smoking among PLWH. Participants included 3289 PLWH (83% male) who were recruited from five HIV clinics. As expected, the prevalence of smoking was higher among PLWH with chronic pain (41.9%), than PLWH without chronic pain (26.6%, p < .0001), and the prevalence of chronic pain was higher among current smokers (32.9%), than among former (23.6%) or never (17%) smokers (ps < .0001). PLWH who endorsed comorbid chronic pain and smoking (vs. nonsmokers without chronic pain) were more likely to report cocaine/crack and cannabis use, be prescribed long-term opioid therapy, and have virologic failure, even after controlling for relevant sociodemographic and substance-related variables (ps < .05). These results contribute to a growing empirical literature indicating that chronic pain and cigarette smoking frequently co-occur, and extend this work to a large sample of PLWH. Indeed, PLWH may benefit from interventions that are tailored to address bidirectional pain-smoking effects in the context of HIV.
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Dolor Crónico , Fumar Cigarrillos , Infecciones por VIH , Cese del Hábito de Fumar , Dolor Crónico/epidemiología , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Humanos , Masculino , Prevalencia , Fumar/epidemiologíaRESUMEN
The MDM2 homolog MDMX oncoprotein is indispensable for inhibition of p53 during normal embryonic development and malignant transformation, yet how MDMX harnesses p53 functions is unclear. In addition to a canonical N-terminal p53-binding domain, recent work suggests the central acidic domain of MDMX regulates p53 interaction through intramolecular mimicry and engages in second-site interaction with the p53 core domain in vitro. To test the physiological relevance of these interactions, we generated an MDMX knockin mouse having substitutions in a conserved WW motif necessary for these functions (W201S/W202G). Notably, MDMXSG cells have normal p53 level but increased p53 DNA binding and target gene expression, and rapidly senesce. In vivo, MDMXSG inhibits early-phase disease in Eµ-Myc transgenic mice but accelerates the onset of lethal lymphoma and shortens overall survival. Therefore, MDMX is an important regulator of p53 DNA binding, which complements the role of MDM2 in regulating p53 level. Furthermore, the results suggest that the WW motif has dual functions that regulate p53 and inhibit Myc-driven lymphomas independent of p53.
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Carcinogénesis/metabolismo , Linfoma/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Carcinogénesis/genética , Transformación Celular Neoplásica , Femenino , Genes myc , Humanos , Linfoma/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , Dominios Proteicos , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genéticaRESUMEN
OBJECTIVE: To assess whether insurance payer, comorbidity, and income are associated with total elbow arthroplasty (TEA) outcomes. METHODS: We used the 1998-2014 US National Inpatient Sample. Multivariable logistic regression adjusted for demographics and underlying diagnosis to estimate odds ratio (OR) and 95% confidence intervals (CI) of insurance payer, comorbidity, and income with TEA outcomes. RESULTS: The mean age was 60 (SE, 0.29) years, 68% were female, and 62% were white among the 7992 TEA procedures. Compared with private insurance, Medicaid was associated with significantly higher ORs (95% CI) of (1) hospital charges above the median, 1.25 (95% CI, 1.01-1.53); (2) discharge to a rehabilitation facility, 1.64 (95% CI, 1.16-2.31); (3) hospital stay >2 days, 1.63 (95% CI, 1.32-2.00); (4) fracture, 1.71 (95% CI, 1.14-2.56). Medicare payer was associated with higher ORs (95% CI) of (1) discharge to a rehabilitation facility, 1.80 (95% CI, 1.42-2.28); and (2) hospital stay >2 days, 1.29 (95% CI, 1.12-1.50). Compared with Deyo-Charlson score of zero, odds of health care utilization outcomes were higher by 14% to 20% for score of 1 and by 62% to 146% for score of 2 or higher, and by 36% to 257% for transfusion. The lowest income quartile had significantly higher OR of 1.51 (95% CI, 1.31-1.73) of hospital charges above the median versus the highest quartile. CONCLUSIONS: Payer type, comorbidity, and income were associated with higher health care utilization and complications post-TEA. Further investigation into potentially modifiable mediators is needed.
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Codo , Medicaid , Anciano , Artroplastia , Comorbilidad , Femenino , Humanos , Medicare , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
PURPOSE OF REVIEW: Cardiac transplant remains the most effective therapy for children with end-stage heart disease. Outcomes remain better than any alternative therapy for this condition, but its use is limited by donor organ availability. As a result, waitlist times and mortality on the waiting list remain unacceptably high. Novel approaches are necessary to address this problem. RECENT FINDINGS: Organ Procurement and Transplant Network/United Network for Organ Sharing readjusted the pediatric heart allocation system in 2016 to prioritize children at highest risk of mortality, encourage judicious listing, and improve appropriate donor organ utilization. Subsequent studies have aligned with these priorities to help risk-stratify patients at the time of listing and identify the importance that should be assigned to donor-specific factors. In addition, many authors are advocating for increased utilization of hearts donated after cardiac death. Pediatric Ventricular Assist Device (VAD) application has also been increasing to help decrease waitlist mortality. Although results have significantly improved, there remain important limitations to widespread use of VADs in the pediatric population. This has prompted novel techniques such as pulmonary artery banding to improve cardiac function and, in some cases, promote recovery. The demand for cardiac replacement continues to increase with an ageing population of patients with congenital heart disease, presenting new challenges and stressors to the system. SUMMARY: Pediatric cardiac transplant outcomes are excellent but remain plagued by the limited supply of donor organs. Recent strategies to combat this problem have focused on judicious listing, maximal utilization of available donor organs, and safely extending the lives of patients on the waitlist. New demands on the organ supply chain will continue to stress the system, making these efforts of the highest importance.Clinical Trial Registry Number not applicable.
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Trasplante de Corazón , Niño , Corazón Auxiliar , Humanos , Donantes de Tejidos , Obtención de Tejidos y Órganos , Listas de EsperaRESUMEN
BACKGROUND: Polyamine catabolism plays a key role in maintaining intracellular polyamine pools, yet its physiological significance is largely unexplored. Here, we report that the disruption of polyamine catabolism leads to severe cerebellar damage and ataxia, demonstrating the fundamental role of polyamine catabolism in the maintenance of cerebellar function and integrity. METHODS: Mice with simultaneous deletion of the two principal polyamine catabolic enzymes, spermine oxidase and spermidine/spermine N1-acetyltransferase (Smox/Sat1-dKO), were generated by the crossbreeding of Smox-KO (Smox-/-) and Sat1-KO (Sat1-/-) animals. Development and progression of tissue injury was monitored using imaging, behavioral, and molecular analyses. RESULTS: Smox/Sat1-dKO mice are normal at birth, but develop progressive cerebellar damage and ataxia. The cerebellar injury in Smox/Sat1-dKO mice is associated with Purkinje cell loss and gliosis, leading to neuroinflammation and white matter demyelination during the latter stages of the injury. The onset of tissue damage in Smox/Sat1-dKO mice is not solely dependent on changes in polyamine levels as cerebellar injury was highly selective. RNA-seq analysis and confirmatory studies revealed clear decreases in the expression of Purkinje cell-associated proteins and significant increases in the expression of transglutaminases and markers of neurodegenerative microgliosis and astrocytosis. Further, the α-Synuclein expression, aggregation, and polyamination levels were significantly increased in the cerebellum of Smox/Sat1-dKO mice. Finally, there were clear roles of transglutaminase-2 (TGM2) in the cerebellar pathologies manifest in Smox/Sat1-dKO mice, as pharmacological inhibition of transglutaminases reduced the severity of ataxia and cerebellar injury in Smox/Sat1-dKO mice. CONCLUSIONS: These results indicate that the disruption of polyamine catabolism, via coordinated alterations in tissue polyamine levels, elevated transglutaminase activity and increased expression, polyamination, and aggregation of α-Synuclein, leads to severe cerebellar damage and ataxia. These studies indicate that polyamine catabolism is necessary to Purkinje cell survival, and for sustaining the functional integrity of the cerebellum.
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Acetiltransferasas/deficiencia , Ataxia/enzimología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/deficiencia , Células de Purkinje/enzimología , Acetiltransferasas/genética , Animales , Apoptosis/fisiología , Ataxia/genética , Ataxia/patología , Cerebelo/enzimología , Cerebelo/patología , Inflamación/enzimología , Inflamación/genética , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Células de Purkinje/patología , Poliamino OxidasaRESUMEN
OBJECTIVE: To assess the risk of hypersensitivity reactions (HSRs) with allopurinol and febuxostat in a population-based study. METHODS: We used the 5% Medicare beneficiary sample (≥65 years) from 2006 to 2012 to identify people with a newly filled prescription for allopurinol, febuxostat or colchicine. We used multivariable-adjusted Cox regression analyses to compare the hazard ratio (HR) of incident HSRs with allopurinol or febuxostat use versus colchicine use; separate analyses were done in people exposed to allopurinol. Propensity-matched analyses (5:1) compared hazards with allopurinol versus febuxostat. RESULTS: Crude incidence rates of HSRs were as follows: allopurinol, 23.7; febuxostat, 30.7; and colchicine, 25.6 per 1000 person-years. Compared with colchicine, allopurinol, febuxostat and febuxostat+colchicine were associated with significantly higher HRs of HSRs, 1.32 (95% CI: 1.10 to 1.60) and 1.54 (95% CI: 1.12 to 2.12) and 2.17 (95% CI: 1.18 to 3.99), respectively. In propensity-matched analyses, febuxostat did not significantly differ from allopurinol; HR for HSRs was 1.25 (95% CI: 0.93 to 1.67). Compared with allopurinol start dose <200 mg/day, allopurinol start dose ≥300 mg/day, diabetes and female sex were associated with significantly higher hazard of HSRs, 1.27 (95% CI: 1.12 to 1.44), 1.21 (95% CI: 1.00 to 1.45) and 1.32 (95% CI: 1.17 to 1.48), respectively. The majority (69%) of HSRs occurred in the outpatient setting. CONCLUSIONS: Compared with colchicine, allopurinol and febuxostat similarly increased the risk of HSRs. Allopurinol and febuxostat did not differ from each other. In allopurinol users, starting dose, female sex and diabetes increased this risk, findings that need further study.
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Alopurinol/efectos adversos , Colchicina/efectos adversos , Hipersensibilidad a las Drogas/epidemiología , Febuxostat/efectos adversos , Supresores de la Gota/efectos adversos , Factores de Edad , Anciano , Anciano de 80 o más Años , Diabetes Mellitus/epidemiología , Relación Dosis-Respuesta a Droga , Hipersensibilidad a las Drogas/etiología , Quimioterapia Combinada , Femenino , Humanos , Incidencia , Masculino , Medicare , Análisis Multivariante , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Factores Sexuales , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVES: To study the incidence, time-trends and outcomes of serious infections in Sjögren's syndrome (SS). METHODS: We examined the epidemiology, time-trends and outcomes of five serious infections (opportunistic infections (OI), skin and soft tissue infections (SSTI), urinary tract infection (UTI), pneumonia, and sepsis/bacteremia) in hospitalised patients with SS, using the 1998-2016 U.S. National Inpatient Sample. Multivariable-adjusted logistic regression analyses analysed the association of patient, comorbidity and hospital characteristics with healthcare utilisation (hospital charges, length of hospital stay, discharge to non-home setting), and in-hospital mortality. RESULTS: We found 49,897,331 hospitalisations with serious infections in general population and 69,239 in patients with SS. Compared to serious infections hospitalisations in people without SS, SS patients were older, and more likely to be female, white or have Deyo-Charlson index score ≥2. Serious infections during the study period 1998-2016 were: OI, 3%; SSTI, 19%; UTI, 6%; pneumonia, 37%; and sepsis, 34%. Serious infection rates/100,000 NIS hospitalisations increased from 1998-2000 to 2015-2016: OI, 0.16 to 0.46; SSTI, 0.55 to 2.90; UTI, 0.25 to 1.96; pneumonia, 2.78 to 5.43; sepsis, 0.63 to 10.71. In multivariable-adjusted analyses, older age, Deyo-Charlson index score ≥2 and medium or large hospital bed size were associated with higher healthcare utilisation and in-hospital mortality. Medicare insurance, Northeast region, non-rural hospital were associated with higher healthcare utilisation outcomes only. CONCLUSIONS: We quantified the increasing disease burden of serious infections in people with SS, and described its epidemiology. Association of factors with serious infection hospitalisation outcomes identifies potential targets for future interventions.
Asunto(s)
Síndrome de Sjögren , Infecciones Urinarias , Anciano , Femenino , Mortalidad Hospitalaria , Hospitalización , Humanos , Tiempo de Internación , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/epidemiología , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/epidemiologíaRESUMEN
BACKGROUND: To assess whether Sjogren's Syndrome (SS) is associated with outcomes after total knee or hip arthroplasty (TKA/THA). METHODS: We used the 1998-2014 U.S. National Inpatient Sample data. We performed multivariable-adjusted logistic regression analyses to assess the association of SS with healthcare utilization (hospital charges, length of hospital stay, discharge to non-home setting), and in-hospital complications (implant infection, revision, transfusion, mortality), controlling for important covariates and confounders. In sensitivity analyses, we additionally adjusted the main models for hospital location/teaching status, bed size, and region. RESULTS: We examined 4,116,485 primary THAs and 8,127,282 primary TKAs performed from 1998 to 2014; 12,772 (0.2%) primary TKAs and 6222 (0.2%) primary THAs were done in people with SS. In multivariable-adjusted models, SS was associated with a statistically significant higher odds ratio (OR; 95% confidence interval (CI)) of discharge to a rehabilitation/inpatient facility post-THA, 1.13 (1.00, 1.28), but not post-TKA, 0.93 (0.86, 1.02). We noted no differences in the length of hospital stay or hospital charges. SS was associated with significantly higher adjusted odds of in-hospital transfusion post-THA, 1.37 (1.22, 1.55) and post-TKA, 1.21 (1.10, 1.34). No significant differences by SS diagnosis were seen in hospital stay, hospital charges implant infection, implant revision or mortality rates. CONCLUSIONS: People with SS had higher transfusion rate post-TKA/THA, and higher rate of discharge to non-home setting post-THA. The lack of association of SS with post-arthroplasty complications should reassure patients, surgeons and policy-makers about the utility of TKA/THA in people with SS undergoing these procedures.
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Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Síndrome de Sjögren , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Estudios de Cohortes , Humanos , Tiempo de Internación , Alta del Paciente , Complicaciones Posoperatorias/cirugía , Factores de Riesgo , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/epidemiologíaRESUMEN
Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection. Myeloid-specific Odc deletion significantly increased gastric and colonic inflammation, respectively, and enhanced M1 activation. Add-back of putrescine, the product of ODC, reversed the increased macrophage activation, indicating that ODC and putrescine are regulators of macrophage function. Odc-deficient macrophages had increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 acetylation, accompanied by decreased H3K9 di/trimethylation both in vivo and ex vivo in primary macrophages. These alterations in chromatin structure directly resulted in up-regulated gene transcription, especially M1 gene expression. Thus, ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms.