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PURPOSE OF REVIEW: Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders characterized by increased susceptibility to infection and/or aberrant regulation of immunological pathways. This review summarizes and highlights the new IEI disorders in the International Union of Immunological Societies (IUIS) 2022 report and current trends among new PIDs. RECENT FINDINGS: Since the 2019 IUIS report and the 2021 IUIS interim update, the IUIS IEI classification now includes 485 validated IEIs. Increasing utilization of genetic testing and advances in the strategic evaluation of genetic variants has continued to drive the identification of, not only novel IEI disorders, but additional genetic etiologies for known IEI disorders and phenotypes. SUMMARY: The recognition of new IEIs continues to advance at a rapid pace, which is due in part to increased performance and application of genetic modalities as well as expansion of the underlying science that is applied to convincingly establish causality. These disorders, as a whole, continue to emphasize the specificity of immunity, complexity of immune mechanisms, and the fine balance that defines immune homeostasis.
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Pruebas Genéticas , Humanos , Homeostasis , FenotipoRESUMEN
Current practices vary widely regarding the immunological work-up and management of patients affected with defects in thymic development (DTD), which include chromosome 22q11.2 microdeletion syndrome (22q11.2del) and other causes of DiGeorge syndrome (DGS) and coloboma, heart defect, atresia choanae, retardation of growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome. Practice variations affect the initial and subsequent assessment of immune function, the terminology used to describe the condition and immune status, the accepted criteria for recommending live vaccines, and how often follow-up is needed based on the degree of immune compromise. The lack of consensus and widely varying practices highlight the need to establish updated immunological clinical practice guidelines. These guideline recommendations provide a comprehensive review for immunologists and other clinicians who manage immune aspects of this group of disorders.
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Síndrome CHARGE , Síndrome de DiGeorge , Cardiopatías Congénitas , Humanos , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Deleción Cromosómica , Cromosomas , Cardiopatías Congénitas/genéticaRESUMEN
INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterised by loss of microvessels. The Wnt pathways control pulmonary angiogenesis but their role in PAH is incompletely understood. We hypothesised that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH. METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a -/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx). RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with the formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced vascular endothelial growth factor (VEGF)-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signalling by facilitating Y1175 tyrosine phosphorylation in vascular endothelial growth factor receptor 2 (VEGFR2) through receptor tyrosine kinase-like orphan receptor 2 (ROR2), a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a -/- mice under either chronic hypoxia or SuHx, global Wnt7a +/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodelling. Similar to PAH, Wnt7a +/- PMVECs exhibited an insufficient angiogenic response to VEGF-A that improved with Wnt7a. CONCLUSIONS: Wnt7a promotes VEGF signalling in lung PMVECs and its loss is associated with an insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.
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Hipertensión Arterial Pulmonar , Ratones , Animales , Hipertensión Arterial Pulmonar/complicaciones , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células Endoteliales/metabolismo , Hipertensión Pulmonar Primaria Familiar/metabolismo , Hipoxia/metabolismoRESUMEN
BACKGROUND: Patients exquisitely sensitive to cashew/pistachio are at risk for allergic reactions to citrus seeds and pectin. OBJECTIVE: In this study, we sought to evaluate whether pectin is contaminated with citrus seeds, to identify a culprit antigen in citrus seeds, and to assess for cross-reactivity among allergens in citrus seeds, citrus pectin, and cashew or pistachio. METHODS: Proteins from orange seed coats, orange seed endosperms, lemon seeds, grapefruit seeds, citrus pectin, apple pectin, and grapefruit pectin were extracted. Protein concentrations in all extracts were determined and visualized using sodium dodecyl sulfate-polyacrylamide gel electrophoresis technique. Immunoglobulin E-binding capacity was determined with Western blot analyses and tandem mass spectrometry for the identification of the culprit allergen in citrus seeds and pectin. RESULTS: In subjects with citrus seed, pectin, and cashew allergies, there was strong immunoglobulin E-reactivity to bands between 17 to 28 kDa and 28 to 38 kDa. The tandem mass spectrometry analysis of these bands indicated the presence of citrin as the culprit allergen. Citrin and Ana o 2 are both 11S globulins belonging to the cupin superfamily, and significant homology was found between these proteins. CONCLUSION: Citrus pectin may be contaminated with citrus seeds. Citrin, a newly identified allergen in citrus seeds, seems to be the culprit antigen in citrus seeds and contaminated citrus pectin. Citrin is highly homologous with Ana o 2 in cashew and Pis v 2 in pistachio, suggesting potential for cross-reactivity and providing an explanation for co-allergenicity of cashew or pistachio, citrus seeds, and citrus pectin.
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Anacardium , Citrus , Hipersensibilidad a los Alimentos , Hipersensibilidad a la Nuez , Pistacia , Humanos , Alérgenos/química , Citrus/química , Inmunoglobulina E , Pectinas , Pistacia/química , Proteínas de Plantas , Semillas/químicaRESUMEN
PURPOSE OF REVIEW: Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders classically characterized by an increased susceptibility to infection and/or disruption in the regulation of an immunologic pathway. This review summarizes and highlights the new IEI disorders in the IUIS 2019 report and 2020 interim report and discusses the directions for the future management of PIDs. RECENT FINDINGS: Since 2017, the International Union of Immunologic Societies (IUIS) IEI committee has updated the IUIS classification of IEIs with 88 new gene defects and 75 new immune disorders. The increased utilization of genetic testing and advances in the strategic evaluation of genetic variants have identified, not only novel IEI disorders, but additional genetic causes for known IEI disorders. Investigation of potential immune susceptibilities during the ongoing COVID-19 pandemic suggests that defects in Type I interferon signalling may underlie more severe disease. SUMMARY: The rapid discovery of new IEIs reflects the growing trend of applying genetic testing modalities as part of medical diagnosis and management.In turn, elucidating the pathophysiology of these novel IEIs have enhanced our understanding of how genetic mutations can modulate the immune system and their consequential effect on human health and disease.
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COVID-19 , Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/terapia , Pandemias , SARS-CoV-2RESUMEN
Pulmonary artery smooth muscle cells (PASMCs) and pericytes are NG2+ mural cells that provide structural support to pulmonary arteries and capillaries. In pulmonary arterial hypertension (PAH), both mural cell types contribute to PA muscularization, but whether similar mechanisms are responsible for their behavior is unknown. RNA-seq was used to compare the gene profile of pericytes and PASMCs from PAH and healthy lungs. NG2-Cre-ER mice were used to generate NG2-selective reporter mice (NG2tdT) for cell lineage identification and tamoxifen-inducible mice for NG2-selective SDF1 knockout (SDF1NG2-KO). Hierarchical clustering of RNA-seq data demonstrated that the genetic profile of PAH pericytes and PASMCs is highly similar. Cellular lineage staining studies on NG2tdT mice in chronic hypoxia showed that, similar to PAH, tdT+ cells accumulate in muscularized microvessels and demonstrate significant upregulation of SDF1, a chemokine involved in chemotaxis and angiogenesis. Compared with control mice, SDF1NG2-KO mice in chronic hypoxia had reduced muscularization and lower abundance of NG2+ cells around microvessels. SDF1 stimulation in healthy pericytes induced greater contractility and impaired their capacity to establish endothelial-pericyte communications. In contrast, SDF1 knockdown reduced PAH pericyte contractility and improved their capacity to associate with vascular tubes in coculture. SDF1 is upregulated in NG2+ mural cells and is associated with PA muscularization. Targeting SDF1 could help prevent and/or reverse muscularization in PAH.
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Quimiocina CXCL12/fisiología , Hipertensión Pulmonar/etiología , Hipoxia/complicaciones , Miocitos del Músculo Liso/metabolismo , Pericitos/metabolismo , Animales , Antígenos/análisis , Bencilaminas , División Celular , Linaje de la Célula , Quimiocina CXCL12/genética , Enfermedad Crónica , Ciclamas , ADN Nucleotidilexotransferasa/análisis , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/uso terapéutico , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/prevención & control , Hipoxia/metabolismo , Ratones , Ratones Transgénicos , Modelos Biológicos , Proteoglicanos/análisis , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores CXCR4/antagonistas & inhibidores , Proteínas Recombinantes/farmacología , Transducción de Señal , VasoconstricciónRESUMEN
PURPOSE OF REVIEW: Primary immunodeficiency diseases (PIDs) are genetic disorders classically characterized by impaired host defense and an increased susceptibility to infections. It is now appreciated that these conditions broadly include variations in the genetic code that cause dysregulated immune function. This review highlights the newly defined PIDs in the 2017 International Union of Immunologic Societies (IUIS) report, current approaches to diagnosing PIDs, and the implications for the future management of PIDs. RECENT FINDINGS: With the advances in and increased commercial availability of genetic testing and the adoption of the TREC assay into the US Newborn Screening program, the number of identified PIDs has exponentially risen in the past few decades, reaching over 350 disorders. The IUIS Inborn Errors of Immunity committee acknowledged at least 50 new disorders between 2015 and 2017. Furthermore, given the greater recognition of disorders with primarily immune dysregulation, the committee proposed a more inclusive term of 'inborn errors of immunity' to encompass primary immunodeficiencies and immune dysregulation disorders. SUMMARY: This latest IUIS report underscores the rapid expansion in the PID field with technologic advancements in immunogenetics and clinical screening discovering new genetic diseases, and therefore, paving the way to novel therapeutics and precision medicine.
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Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/tendencias , Síndromes de Inmunodeficiencia/clasificación , Autoinmunidad , Niño , Manejo de la Enfermedad , Medicina Basada en la Evidencia , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Recién Nacido , Tamizaje Neonatal/tendenciasRESUMEN
The dramatic rise in the prevalence of food allergy and food allergy-associated anaphylaxis in the past few decades has fueled investigative interest into understanding this puzzling trend. Here, we review the question as to whether important external environmental determinants beyond dietary habits and exposure to food allergens are involved. This review will summarize our current understanding of these environment determinants, derived from the latest experimental and epidemiological research. Specifically, we will review the role of exposures that affect skin barrier function, development of a diverse microbiome, and food processing. Additional exposures of concern are insufficient sunlight, endocrine disrupting chemicals and pesticides, and use of specific pharmaceutical agents that may drive or modify the risk for food allergy. Despite limitations in the quantity and quality of research to date, many new epidemiological associations and experimental data in support of this paradigm have emerged.
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Ambiente , Hipersensibilidad a los Alimentos , Alérgenos/inmunología , Dieta , Hipersensibilidad a los Alimentos/epidemiología , Hipersensibilidad a los Alimentos/inmunología , Humanos , MicrobiotaRESUMEN
At care transitions, patients are susceptible to adverse events and medication errors that can lead to harm or hospital readmission. This study describes the services provided by an interprofessional discharge clinic (IDC) aimed to improve these transitions and the impact on 30-day readmission rate, medication errors, and interventions documented. Data were collected retrospectively using an electronic medical record and analysed using SAS data system. Among 167 discharged patients, 154 patients were seen by a physician only (PO) and 13 patients were seen in the IDC. Thirty-day readmission rates were 26.6% and 7.7% for patients in the PO and IDC groups, respectively (p = 0.19). Seventy patients (45.5%) in the PO group and 11 patients (84.6%) in the IDC group (p = 0.0082) were found to have at least one medication error. All patients seen at the IDC had an intervention made, while 68 (44.2%) seen by a PO received no intervention (p = 0.0009). While sample size was a major limitation, a statistically significant increase in identified medication errors and intervention documentation was found in the IDC group. It is critical that healthcare systems continue to develop new strategies, such as IDCs, to reduce hospital readmissions.
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Continuidad de la Atención al Paciente/organización & administración , Relaciones Interprofesionales , Grupo de Atención al Paciente/organización & administración , Alta del Paciente , Readmisión del Paciente/estadística & datos numéricos , Atención Primaria de Salud/organización & administración , Adolescente , Adulto , Anciano , Instituciones de Atención Ambulatoria/organización & administración , Conducta Cooperativa , Registros Electrónicos de Salud , Femenino , Humanos , Masculino , Conciliación de Medicamentos/organización & administración , Conciliación de Medicamentos/estadística & datos numéricos , Persona de Mediana Edad , Estudios Retrospectivos , Factores Socioeconómicos , Adulto JovenRESUMEN
BACKGROUND: microRNAs (miRNAs) are emerging as key regulators of the immune system, but their role in CD8+ T cell differentiation is not well explored. Some evidence suggests that signals from cell surface receptors influence the expression of miRNAs in CD8+ T cells, and may have consequent effects on cell phenotype and function. We set out to investigate whether common gamma chain cytokines modulated human CD8+ T cell expression of miR-146a, which previous studies have associated with different stages of CD8+ differentiation. We also investigated how changes in miR-146a related to other miRNAs that alter with CD8+ differentiation status. METHODS: We treated human CD8+ T cells with the cytokines IL-2, IL-7 or IL-15 either at rest or after stimulation with anti-CD3 and anti-CD28. For some experiments we also purified human CD8+ T cell subsets ex vivo. Flow cytometry was used in parallel to assess cell surface memory marker expression. Total RNA from these cells was subjected to microarray analysis and real-time PCR for miRNA expression. Nucleofection studies were performed to assess potential mRNA targets of miR-146a. RESULTS: We find that miR-146a is up-regulated in naïve CD8+ T cells exposed to IL-2 or IL-15, even in the absence of an activating T cell receptor stimulus, but not when IL-7 is also present. miR-146a expression correlates with a memory phenotype in both ex vivo and in vitro cultured cells although in our hands overexpression of miR-146a was not sufficient alone to drive a full memory phenotype. In ex vivo analysis, miR-146a was one of a small number of miRNAs that was differentially expressed between naïve and memory CD8+ T cells. CONCLUSIONS: miR-146a is emerging as a critical regulator of immune system. Our data shows that miR-146a expression is strongly influenced by the cytokine milieu even in the absence of a T cell receptor stimulus. Our results have implications for studies designed to assess the function of miR-146a, help to define a fingerprint of miRNA expression in CD8+ T cell subsets and may be useful when designing optimal protocols for T cell expansion as efficacy of T cell immunotherapy is correlated with an 'early' memory phenotype.
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Linfocitos T CD8-positivos/metabolismo , Citocinas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , MicroARNs/genética , Subgrupos de Linfocitos T/metabolismo , Antígenos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Perfilación de la Expresión Génica , Humanos , Memoria Inmunológica , Interleucina-15/farmacología , Interleucina-2/farmacología , Interleucina-7/farmacología , MicroARNs/metabolismo , Fenotipo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CCR7/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Factor 6 Asociado a Receptor de TNF/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
PURPOSE OF STUDY: Thirty-day readmission is associated with increased morbidity and mortality among postoperative coronary artery bypass graft (CABG) surgery patients. Interventions such as case management and follow-up care may reduce 30-day readmission. The purpose of this article is to report a study on modifiable factors that may have significant implications for case management in the prevention of readmission after CABG surgery. PRIMARY PRACTICE SETTINGS: The study population included all the adult patients who underwent first-time CABG surgery from January 1, 2013, to January 1, 2016, from a Mid-South hospital. METHODOLOGY AND SAMPLE: A retrospective case-control study was employed to examine 1,712 patients who underwent CABG surgery. RESULTS: The results revealed that patients readmitted within 30 days had a significantly shorter length of stay (LOS) (6 days vs. 10 days; p < .0001), more days in intensive care unit (6 days vs. 4 days; p = .0391), and significantly higher diabetes/renal (4% vs. 1%), infection (17% vs. 2%), and respiratory-related diagnoses (10% vs. 1%; p < .0001). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Among these factors, hospital LOS is a major factor that can be addressed through case management in addition to other modifiable risk factors. Understanding modifiable factors associated with higher readmission risk is crucial for effective intervention and case management planning.
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To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA4 and PD1, we leveraged Phase 1/2 multicenter open-label trial NCT01896999 that enrolled patients with refractory or relapsed HL (R/R HL). Using peripheral blood, we assessed soluble proteins, cell composition, T-cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. NCT01896999 reported high (>75%) overall objective response rates with brentuximab vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed a durable increase in soluble PD1 and plasmacytoid dendritic cells as well as decreases in plasma CCL17, ANGPT2, MMP12, IL13, and CXCL13 in N-containing regimens (BV + N and BV + I + N) compared with BV + I (P < 0.05). Nonresponders and patients with short progression-free survival showed elevated CXCL9, CXCL13, CD5, CCL17, adenosine-deaminase, and MUC16 at baseline or after one treatment cycle and a higher prevalence of NY-ESO-1-specific autoantibodies (P < 0.05). The results suggest a circulating tumor-immune-derived signature of BV ± I ± N treatment resistance that may be useful for patient stratification in combination checkpoint therapy. SIGNIFICANCE: Identification of multi-omic immune markers from peripheral blood may help elucidate resistance mechanisms to checkpoint inhibitor and antibody-drug conjugate combinations with potential implications for treatment decisions in relapsed HL.
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Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotina , Resistencia a Antineoplásicos , Enfermedad de Hodgkin , Ipilimumab , Nivolumab , Humanos , Brentuximab Vedotina/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/sangre , Nivolumab/uso terapéutico , Nivolumab/administración & dosificación , Ipilimumab/uso terapéutico , Ipilimumab/administración & dosificación , Ipilimumab/farmacología , Femenino , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Persona de Mediana Edad , Anciano , Adulto JovenRESUMEN
Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.
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Neuroblastoma , Receptores Quiméricos de Antígenos , Niño , Adulto Joven , Humanos , Receptores Quiméricos de Antígenos/genética , Receptores de Antígenos de Linfocitos T/genética , Proteómica , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfocitos T , Neuroblastoma/patología , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. CONCLUSIONS: The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Nivolumab , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Multiómica , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Inmunoterapia , Pulmón/patología , Células Epiteliales/patología , Ipilimumab/uso terapéutico , Microambiente TumoralRESUMEN
BACKGROUND: Bruton tyrosine kinase (BTK) is a component of signaling pathways downstream from Toll-like receptors (TLRs) 2, 4, 7, 8, and 9. Previous work in BTK-deficient mice, cell lines, and cultured cells from patients with X-linked agammaglobulinemia (XLA) suggested defective TLR-driven cytokine production. OBJECTIVE: We sought to compare TLR-4-, TLR-7-, and TLR-8-induced cytokine production of primary cells from patients with XLA with that seen in control cells. METHODS: PBMCs from patients with XLA, freshly isolated plasmacytoid dendritic cells, monocytes, and monocytoid dendritic cells were activated with TLR-4, TLR-7, and TLR-8 agonists. Signaling intermediates and intracellular and secreted cytokine levels were compared with those seen in control cells. RESULTS: Although TLR-4, TLR-7, and TLR-8 activation of nuclear factor κB and mitogen-activated protein kinase pathways in cells from patients with XLA and control cells were comparable, TLR-activated freshly isolated monocytes and monocytoid dendritic cells from patients with XLA produced significantly more TNF-α, IL-6, and IL-10 than control cells. TLR-7/8-activated plasmacytoid dendritic cells produced normal amounts of IFN-α. In murine models BTK regulates the degradation of Toll-IL-1 receptor domain-containing adaptor protein, terminating TLR-4-induced cytokine production. Although this might explain the heightened TLR-4-driven cytokine production we observed, Toll-IL-1 receptor domain-containing adaptor protein degradation is intact in cells from patients with XLA, excluding this explanation. CONCLUSION: In contrast to previous studies with BTK-deficient mice, cell lines, and cultured cells from patients with XLA suggesting impaired TLR-driven cytokine production, these data suggest that BTK inhibits TLR-induced cytokine production in primary human cells.
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Agammaglobulinemia/inmunología , Citocinas/biosíntesis , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Mediadores de Inflamación/metabolismo , Células Mieloides/inmunología , Receptores Toll-Like/metabolismo , Adolescente , Adulto , Agammaglobulinemia Tirosina Quinasa , Amidas/farmacología , Niño , Preescolar , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Lactante , Masculino , Glicoproteínas de Membrana/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , FN-kappa B/metabolismo , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptores de Interleucina-1/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismo , Adulto JovenRESUMEN
While post-transcriptional control is thought to be required at the periphery of neurons and glia, its extent is unclear. Here, we investigate systematically the spatial distribution and expression of mRNA at single molecule sensitivity and their corresponding proteins of 200 YFP trap lines across the intact Drosophila nervous system. 97.5% of the genes studied showed discordance between the distribution of mRNA and the proteins they encode in at least one region of the nervous system. These data suggest that post-transcriptional regulation is very common, helping to explain the complexity of the nervous system. We also discovered that 68.5% of these genes have transcripts present at the periphery of neurons, with 9.5% at the glial periphery. Peripheral transcripts include many potential new regulators of neurons, glia, and their interactions. Our approach is applicable to most genes and tissues and includes powerful novel data annotation and visualization tools for post-transcriptional regulation.
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Proteínas de Drosophila , ARN Mensajero , Animales , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Factores de Transcripción/metabolismo , ARN Mensajero/genética , Procesamiento Postranscripcional del ARNRESUMEN
Common variable immune deficiency (CVID) B cells have impaired responses to TLR7 and TLR9 agonists including poor cell proliferation, loss of cytokine production, and failure to produce IgG or IgA. We show that TLR7- or 9-activated B cells from CVID subjects with >0.5% peripheral isotype-switched CD27(+) B cells (group 2) have increased mature Cγ1 and Cγ2 heavy-chain mRNA transcripts compared to subjects who have <0.5% isotype-switched cells (group 1). While TLR-stimulated CVID plasmacytoid dendritic cells for all subjects had impaired IFN-α production, TLR7 or TLR9 stimulation in the presence IFN-α normalized isotype-switched CD27(+) B cells, enhanced activation-induced cytidine deaminase mRNA, and significantly improved IgG production only for group 2 subjects. IFN-α also upregulated TLR7 and TLR9 mRNA expression comparable to normal levels in B cells of group 2 subjects, indicating that the loss of IFN-α could be a significant component of the B-cell defect for these subjects.
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Linfocitos B/inmunología , Inmunodeficiencia Variable Común/inmunología , Interferón-alfa/biosíntesis , Receptores Toll-Like/metabolismo , Adolescente , Adulto , Anciano , Linfocitos B/metabolismo , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/metabolismo , Citidina Desaminasa/genética , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Inmunoglobulina A/metabolismo , Cambio de Clase de Inmunoglobulina , Inmunoglobulina G/metabolismo , Cadenas gamma de Inmunoglobulina/genética , Activación de Linfocitos/inmunología , Persona de Mediana Edad , ARN Mensajero/biosíntesis , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/genética , Adulto JovenAsunto(s)
Asma , Leche , Animales , Granjas , Humanos , Lactante , Hipersensibilidad a la Leche , Proteínas de la LecheRESUMEN
INTRODUCTION: Antihyperglycemic agents are significant contributors to adverse drug events, responsible for emergency department visits, hospitalizations, and death. Nationally, the rate of serious hypoglycemic events associated with these agents remains high despite widespread efforts to improve drug safety. Transitions of care between healthcare settings can lead to communication challenges between care professionals and increase the risk of adverse drug events. System-based improvements are needed to assure the safe transitions for patients with diabetes who are on antihyperglycemic agents. The objective of this study was to develop a consensus list of requisite elements that should be communicated between care settings during transitions of patients who are prescribed antihyperglycemic agents. METHODS: The Island Peer Review Organization (IPRO) Hypoglycemia Coalition identified suboptimal transitions of care as a barrier to improving patient safety and quality of diabetes care. The Coalition formed a multidisciplinary Task Force with experts in the field of diabetes care. The Task Force created a draft list of requisite communication elements through literature review and deliberation on monthly conference calls. A blinded iterative Delphi process was subsequently performed to generate a consensus list of requisite communication elements that participating experts agreed were necessary to safely and effectively assume the management of patients with diabetes upon care transitions. RESULTS: The Task Force completed a series of four iterative polls from September 2015 to August 2016, resulting in a final list of 22 requisite communication elements (the Diabetes Management Discharge Communication List), with the elements conceptually categorized into three domains: diagnosis and treatment, factors affecting glycemic control or patient risk, and patient self-management. CONCLUSIONS: The Diabetes Management Discharge Communication List provides an initial framework for the development of diabetes-specific resources to improve clinical communication between care settings.