RESUMEN
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the Activator Protein-1 (AP-1) (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens (Fra-) 1 and 2 is unknown. Here, we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis, and Pparγ-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently under direct regulation by AP-1 through a conserved distal 3' enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the Bromodomain and Extra-Terminal motif inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.
Asunto(s)
Carcinoma Hepatocelular , Antígeno 2 Relacionado con Fos , Neoplasias Hepáticas , Proteínas Proto-Oncogénicas c-fos , Proteínas Proto-Oncogénicas c-jun , Proteínas Proto-Oncogénicas c-myc , Factor de Transcripción AP-1 , Animales , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-1/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Ratones , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Proteínas Proto-Oncogénicas c-jun/metabolismo , Antígeno 2 Relacionado con Fos/metabolismo , Antígeno 2 Relacionado con Fos/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Humanos , Hepatocitos/metabolismo , Multimerización de Proteína , Regulación Neoplásica de la Expresión Génica , Ratones TransgénicosRESUMEN
BACKGROUND & AIMS: The aim of this study was to evaluate the efficacy of LT-02, a novel modified-release phosphatidylcholine (PC) formulation, for induction and maintenance of remission in patients with mild to moderate ulcerative colitis (UC) and inadequate response to mesalamine. METHODS: LT-02 was evaluated in a multicenter double-blind, randomized, placebo-controlled study comprising a 12-week induction trial (PCG-2), followed by a 48-week maintenance trial (PCG-4). In PCG-2, patients were randomized 1:1:1 to treatment with 0.8 g LT-02 4 times daily (QID), 1.6 g LT-02 twice daily (BID), or placebo, respectively. All patients continued to take a standard dose of oral mesalamine (≥2.4 g/day). The primary end point in PCG-2 was deep remission. Patients achieving remission at week 12 were randomly assigned 2:1:1 to 1.6 g LT-02 BID, placebo, or 500 mg mesalamine (3 times daily), respectively, in PCG-4; the primary end point was remission at 48 weeks. RESULTS: PCG-2 was terminated early for futility after a prespecified interim analysis; 466 patients (of 762 planned) were randomized. There was no statistically significant difference in deep remission at week 12 (placebo, 13.5%; LT-02 BID, 14.2%; LT-02 QID, 9.7%). In PCG-4, 150 patients (of approximately 400 planned) were randomized. There was no statistically significant difference in remission rates at week 48 (LT-02 BID, 49.3%; mesalamine, 50.0%; placebo, 43.2%). LT-02 was safe. CONCLUSIONS: Despite prior evidence of beneficial effects of PC in phase 2 trials, our induction study with LT-02 in patients with mild to moderate UC was terminated prematurely for futility. Signals of efficacy in maintenance therapy require confirmation in an adequately powered maintenance trial. LT-02 was safe and well-tolerated. CLINICALTRIALS: gov: NCT02280629, NCT02142725.
Asunto(s)
Colitis Ulcerosa , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Mesalamina/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Fosfatidilcolinas/uso terapéutico , Inducción de Remisión , Método Doble Ciego , Resultado del TratamientoRESUMEN
PURPOSE: About 15% of patients with common variable immunodeficiency (CVID) develop a small intestinal enteropathy, which resembles celiac disease with regard to histopathology but evolves from a distinct, poorly defined pathogenesis that has been linked in some cases to chronic norovirus (NV) infection. Interferon-driven inflammation is a prominent feature of CVID enteropathy, but it remains unknown how NV infection may contribute. METHODS: Duodenal biopsies of CVID patients, stratified according to the presence of villous atrophy (VA), IgA plasma cells (PCs), and chronic NV infection, were investigated by flow cytometry, multi-epitope-ligand cartography, bulk RNA-sequencing, and RT-qPCR of genes of interest. RESULTS: VA development was connected to the lack of intestinal (IgA+) PC, a T helper 1/T helper 17 cell imbalance, and increased recruitment of granzyme+CD8+ T cells and pro-inflammatory macrophages to the affected site. A mixed interferon type I/III and II signature occurred already in the absence of histopathological changes and increased with the severity of the disease and in the absence of (IgA+) PCs. Chronic NV infection exacerbated this signature when compared to stage-matched NV-negative samples. CONCLUSIONS: Our study suggests that increased IFN signaling and T-cell cytotoxicity are present already in mild and are aggravated in severe stages (VA) of CVID enteropathy. NV infection preempts local high IFN-driven inflammation, usually only seen in VA, at milder disease stages. Thus, revealing the impact of different drivers of the pathological mixed IFN type I/III and II signature may allow for more targeted treatment strategies in CVID enteropathy and supports the goal of viral elimination.
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Infecciones por Caliciviridae , Inmunodeficiencia Variable Común , Norovirus , Humanos , Atrofia/complicaciones , Atrofia/patología , Infecciones por Caliciviridae/inmunología , Linfocitos T CD8-positivos , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/inmunología , Inmunoglobulina A , Inflamación/complicaciones , Interferones , Norovirus/fisiologíaRESUMEN
BACKGROUND & AIMS: Exhaustion of CD8 T cells has been suggested to inform different clinical outcomes in Crohn's disease, but detailed analyses are lacking. This study aimed to identify the role of exhaustion on a single-cell level and identify relevant CD8 T cell populations in Crohn's disease. METHODS: Blood and intestinal tissue from 58 patients with Crohn's disease (active disease or remission) were assessed for CD8 T cell expression of exhaustion markers and their cytokine profile by highly multiplexed flow and mass cytometry. Key disease-associated subsets were sorted and analyzed by RNA sequencing. CD39 inhibition assays were performed in vitro. RESULTS: Activated CD39+ and CD39+PD-1+ CD8 T cell subsets expressing multiple exhaustion markers were enriched at low frequency in active Crohn's disease. Their cytokine production capacity was inversely linked to the Harvey-Bradshaw Index. Subset-level protein and transcriptome profiling revealed co-existence of effector and exhaustion programs in CD39+ and CD39+ PD-1+CD8 T cells, with CD39+ cells likely originating from the intestine. CD39 enzymatic activity controlled T cell cytokine production. Importantly, transcriptional exhaustion signatures were enriched in remission in CD39-expressing subsets with up-regulation of TOX. Subset-level transcriptomics revealed a CD39-related gene module that is associated with the clinical course. CONCLUSIONS: These data showed a role for the exhaustion of peripheral CD39-expressing CD8 T cell subsets in Crohn's disease. Their low frequency illustrated the utility of single-cell cytometry methods for identification of relevant immune populations. Importantly, the link of their exhaustion status to the clinical activity and their specific gene signatures have implications for exhaustion-based personalized medicine approaches.
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Apirasa , Linfocitos T CD8-positivos , Enfermedad de Crohn , Apirasa/sangre , Apirasa/genética , Apirasa/inmunología , Biomarcadores/sangre , Linfocitos T CD8-positivos/inmunología , Enfermedad de Crohn/sangre , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Citocinas/inmunología , Humanos , Pronóstico , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Subgrupos de Linfocitos TRESUMEN
Prevalence rates of delirium amount to 22.0% within acute-care settings. In contrast, 30-40% of patients with liver cirrhosis may develop hepatic encephalopathy, a condition that has been classified as a syndrome of delirium, based on recent pathophysiology findings. However, the prevalence of delirium in gastroenterology and hepatology units is unknown.The aims of the study were (i) to identify delirium prevalence rates in inpatients of gastroenterology/hepatology wards, (ii) to analyze the delirium motor subtype, and (iii) to assess associations between delirium and patient characteristics.In this monocentric, cross-sectional, epidemiological study, point prevalence was assessed at six time points in three gastroenterology/hepatology units within a German university hospital. Delirium was assessed using the 4 'As' Test (4AT) and delirium subtype by the delirium motor subtype scale. Patient characteristics were collected from patient charts.The sample consisted of 188 patients, aged 18 to 98 years (mean age 64, n=110 male). Of them, 18.1% of patients showed delirium symptoms (61.8% hypoactive, 29.4% mixed, and 8.8% hyperactive). For the participants aged ≥65 years (n=96), prevalence of delirium amounted to 26.0%. Significant associations were observed between delirium and the following characteristics: age (p=0.001), length of hospital stay until assessment (p=0.043), cerebrovascular disease (p=0.002), dementia (p=0.010), diabetes mellitus with chronic complications (p=0.012), and gender (nonsignificant trend, p=0.050), while no association was detected between moderate or severe liver disease and delirium (p=0.414).In conclusion, overall prevalence rates of delirium were rather low and did not increase in patients with liver disease.
Asunto(s)
Delirio , Encefalopatía Hepática , Cirrosis Hepática , Humanos , Masculino , Persona de Mediana Edad , Estudios Transversales , Delirio/diagnóstico , Delirio/epidemiología , Gastroenterología , Cirrosis Hepática/complicaciones , Prevalencia , Femenino , Adulto , Anciano , Anciano de 80 o más Años , Encefalopatía Hepática/complicacionesRESUMEN
Although the management of patients with ulcerative colitis (UC) is well defined by national and international guidelines, there are many debates and open questions related to daily care of UC patients. Here, we aimed to review topics with high clinical relevance including therapy algorithms, potential biomarkers for disease prognosis and response to therapy, the role of interventions targeting the gut microbiota, insights from head-to-head trials, novel UC medications, exit strategies, the impact of COVID19 on UC, care of patients with acute severe disease, cancer screening, and the role of surgery.
Asunto(s)
COVID-19 , Colitis Ulcerosa , Microbioma Gastrointestinal , Humanos , Colitis Ulcerosa/terapia , Colitis Ulcerosa/tratamiento farmacológico , Atención al PacienteRESUMEN
BACKGROUND AND AIMS: Self-expandable metal stent (SEMS) placement is routinely performed in a variety of benign and malignant GI diseases. One of the most frequent adverse events after esophageal SEMS placement is stent migration. We evaluated a novel over-the-scope clip device (stentfix OTSC; Ovesco Endoscopy, Tuebingen, Germany) designed and approved for SEMS fixation. METHODS: This single-center retrospective observational cohort study was performed to analyze stent migration rates before and after availability of the stentfix OTSC device. A cohort of patients who consecutively underwent SEMS fixation with the stentfix OTSC system (SF cohort) was compared with an historical cohort of patients who did not receive stentfix OTSC fixation or any other stent fixation method (NF cohort) before the stentfix OTSC system became available. Outcome variables including technical success, adverse events and clinical success were analyzed. RESULTS: Seventy-seven patients (SF cohort, 26; NF cohort, 51) underwent esophageal SEMS implantation for malignant (69%) and benign (31%) conditions. The technical success rate of stent fixation was 100%, and no procedure-related adverse events were observed. The stent migration rate was significantly lower in the SF cohort compared with the NF cohort (8.3% vs 35.4%, P < .001), indicating a relative risk reduction of 76.5% associated with stentfix OTSC application. Stent implantation across the gastroesophageal junction was identified as a predictor of stent migration. CONCLUSIONS: In patients with benign or malignant gastroesophageal diseases, there was a significantly lower stent migration rate in patients managed with the stentfix OTSC system compared with those without stent fixation. The application was technically successful in all cases, and no adverse events related to clip application or removal were observed.
Asunto(s)
Stents Metálicos Autoexpandibles , Instrumentos Quirúrgicos , Endoscopía Gastrointestinal/métodos , Humanos , Estudios Retrospectivos , Stents Metálicos Autoexpandibles/efectos adversos , Stents , Resultado del TratamientoRESUMEN
BACKGROUND: Diet-induced obesity can result in the development of a diverse spectrum of cardiovascular and metabolic diseases, including type 2 diabetes, dyslipidemia, non-alcoholic liver steatosis and atherosclerotic disease. MicroRNAs have been described to be important regulators of metabolism and disease development. METHODS: In the current study, we investigated the effects of ubiquitous miR-100 overexpression on weight gain and the metabolic phenotype in a newly generated transgenic mouse strain under normal chow and high fat diet and used microarray expression analysis to identify new potential target genes of miR-100. RESULTS: While transgenic overexpression of miR-100 did not significantly affect weight and metabolism under a normal diet, miR-100 overexpressing mice showed a reduced weight gain under a high fat diet compared to wildtype mice, despite an equal calorie intake. This was accompanied by less visceral and subcutaneous fat development and lover serum LDL cholesterol. In addition, transgenic miR-100 mice were more glucose tolerant and insulin sensitive and demonstrated increased energy expenditure under high fat diet feeding. A comprehensive gene expression profiling revealed the differential expression of several genes involved in lipid storage- and metabolism, among them CD36 and Cyp4A14. Our data showed a direct regulation of CD36 by miR-100, leading to a reduced fatty acid uptake in primary hepatocytes overexpressing miR-100 and the downregulation of several downstream mediators of lipid metabolism such as ACC1, FABP4, FAS and PPARγ in the liver. CONCLUSIONS: Our findings demonstrate a protective role of miR-100 in high fat diet induced metabolic syndrome and liver steatosis, partially mediated by the direct repression of CD36 and attenuation of hepatic lipid storage, implicating miR-100 as a possible therapeutic target in liver steatosis.
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Hipertrigliceridemia/etiología , Hipertrigliceridemia/metabolismo , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , MicroARNs/genética , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Regiones no Traducidas 3' , Animales , Biomarcadores , Células Cultivadas , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica , Glucosa/metabolismo , Hepatocitos/metabolismo , Insulina/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Transgénicos , Fenotipo , Interferencia de ARN , Transcriptoma , Aumento de PesoRESUMEN
OBJECTIVES: Chronic diarrhea, villous atrophy and/or increased intraepithelial T-lymphocytes (IEL) occur in many inflammatory disorders including celiac disease (CD). However, a definite diagnosis is difficult to make in some patients despite an extensive diagnostic work-up. Clinical outcomes and histological phenotypes of such patients we refer to as unclassifiable enteropathy (UEP) remain unclear. MATERIAL AND METHODS: We performed a retrospective single-center analysis of patients with chronic diarrhea, weight loss and increased IEL. Patients with defined etiologies including infections, CD, drugs, immunodeficiencies or neoplasms were excluded. Clinical and histologic/immunophenotypic parameters were analyzed. RESULTS: Nine patients with UEP were identified. Small intestinal damage ranged from minor villous abnormalities to complete atrophy while all patients displayed high numbers of CD103+ CD8+ IELs. In contrast to CD, these CD8+ T cells were not confined to the surface epithelium, but also infiltrated the crypts. Additional histological features included apoptotic crypt epithelial cells and mixed inflammatory infiltrates in the tunica propria. Involvement of other segments of the gastrointestinal tract was observed in 7/9 patients. A clonal intestinal T-cell lymphoproliferative disorder developed in 2 patients, one of which had a fatal disease course. The majority of patients responded to corticosteroids, while response to immunosuppressive medications yielded heterogeneous results. CONCLUSIONS: We report a patient population with 'difficult-to-classify' enteropathies characterized by various degrees of villous atrophy and strongly increased intraepithelial CD103+ CD8+ T cells in the small intestine which harbor an increased risk for T-cell lymphoproliferative disorders. Clinical course, histology, and response to immunosuppressive therapy all suggest an autoimmune pathogenesis.
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Linfocitos T CD8-positivos , Enfermedad Celíaca , Enfermedad Celíaca/diagnóstico , Humanos , Mucosa Intestinal , Intestino Delgado , Estudios RetrospectivosRESUMEN
INTRODUCTION: The influence of a SARS-CoV-2 infection on inflammatory bowel disease (IBD) has not yet been well characterized and it is unclear whether this requires an adaptation of the immunosuppressive therapy. METHODS: A national register was established for the retrospective documentation of clinical parameters and changes in immunosuppressive therapy in SARS-CoV-2 infected IBD patients. RESULTS: In total, only 3 of 185 IBD patients (1.6â%) were tested for SARS-CoV-2 infection because of abdominal symptoms. In the course of COVID-19 disease, 43.5â% developed diarrhea, abdominal pain or hematochezia (risk of hospitalization with vs. without abdominal symptoms: 20.0â% vs. 10.6â%, pâ<â0.01). With active IBD at the time of SARS-CoV-2 detection, there was an increased risk of hospitalization (remission 11.2â%, active IBD 23.3â% pâ<â0.05). IBD-specific therapy remained unchanged in 115 patients (71.4â%); the most common change was an interruption of systemic therapy (16.2â%). DISCUSSION: New abdominal symptoms often appeared in SARS-CoV-2 infected IBD patients. However, these only rarely led to SARS-CoV-2 testing. A high IBD activity at the time of SARS-CoV-2 detection was associated with an increased risk of hospitalization.
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COVID-19 , Enfermedades Inflamatorias del Intestino , COVID-19/complicaciones , Prueba de COVID-19 , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIM: The role of therapeutic drug monitoring (TDM) in ustekinumab (UST) therapy for Crohn's disease (CD) has not been established, as only few studies have analyzed the relationship between UST serum concentrations and clinical outcome. In this pilot study, we retrospectively examined the potential of UST-concentrations (cUST) 8 weeks after induction (cUSTw8) to predict clinical response at week 16. METHODS: Serum samples and clinical data from patients (nâ=â72) with moderate to severely active CD who received intravenous induction with UST were retrospectively analyzed. cUST were quantitated using liquid chromatography-tandem mass spectrometry (LC-MSMS). A receiver-operating characteristic (ROC) curve and area under ROC curve (AUROC) was computed to analyze the predictive potential of cUSTw8 for clinical response at week 16 and to determine the minimal therapeutic UST trough concentration. RESULTS: Forty-four patients (61â%) achieved clinical response to UST therapy at week 16. cUSTw8 was moderately effective to predict clinical response with a minimal therapeutic cUSTw8 of 2.0âmg/l (AUC 0.72, pâ=â0.001). CONCLUSION: Trough concentrations of UST 8 weeks after induction predict clinical response to therapy in week 16 with moderate sensitivity and specificity. TDMâusing LC-MSMS could prove beneficial in personalized UST therapy of patients with CD by identifying individuals with subtherapeutic concentrations who might benefit from dose escalation.
Asunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Factores Inmunológicos/farmacología , Ustekinumab/uso terapéutico , Biomarcadores/análisis , Cromatografía Liquida , Enfermedad de Crohn/sangre , Fármacos Dermatológicos/sangre , Humanos , Factores Inmunológicos/administración & dosificación , Proyectos Piloto , Curva ROC , Estudios Retrospectivos , Espectrometría de Masas en Tándem , Resultado del Tratamiento , Ustekinumab/sangreRESUMEN
Background: Although lichen planus (LP) is a common skin disorder, the prevalence of esophageal involvement (ELP) and its clinical manifestations are poorly defined. We aimed to establish diagnostic criteria and characterize disease outcomes of ELP.Methods: Clinical, endoscopic, histological, and immunofluorescence data from consecutive patients with known LP between 2013 and 2018 were analyzed. We established endoscopic (denudation and tearing of the mucosa, hyperkeratosis and trachealization) and histological criteria (mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis, dyskeratosis, and fibrinogen deposits along the basement membrane) to grade disease severity. Endoscopic findings were correlated with clinical symptoms. Response to medical therapy was monitored.Results: Fifty-two consecutive patients (median age 59.5 years) were analyzed. According to our grading system, 16 patients were considered as severe and 18 as mild ELP. Dysphagia was the only symptom which differentiated patients with severe (14/16) or mild ELP (8/18) from patients without ELP (1/18). Concomitant oral and genital involvement of LP was associated with the presence of ELP, while oral involvement alone was not. Follow-up of 14/16 patients with severe EPL for at least one year revealed that most of these patients responded to topical corticosteroids (budesonide: n = 9/10 or fluticasone n = 2/2). Three budesonide patients experienced a resolution of symptomatic esophageal stenosis.Conclusions: Esophageal involvement of LP is frequent, but may be asymptomatic. ELP can be diagnosed using the diagnostic criteria proposed here. Dysphagia and combined oral and genital manifestation are associated with ELP. Therapy with topical corticosteroids appears to be a prudent therapeutic approach for ELP.
Asunto(s)
Enfermedades del Esófago/diagnóstico , Liquen Plano/diagnóstico , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios/uso terapéutico , Enfermedades del Esófago/tratamiento farmacológico , Enfermedades del Esófago/patología , Esofagoscopía , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/uso terapéutico , Liquen Plano/tratamiento farmacológico , Liquen Plano/patología , Masculino , Persona de Mediana Edad , Diagnóstico Erróneo/prevención & control , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Juvenile polyposis syndrome is a rare autosomal-dominant disorder characterized by multiple hamartomatous polyps in the gastrointestinal tract. It is associated with an increased risk of gastrointestinal cancer. We report the case of a 49-year-old woman presenting with proximal muscle weakness, weight loss, severe anemia, and melena. One year before, the diagnosis of a "fundic gland polyposis" was presumed after endoscopic evaluation for iron deficiency anemia had shown numerous polyps limited to the gastric mucosa. On admission, the diagnosis of dermatomyositis was made based on laboratory results with a marked elevated creatine kinase as well as the presence of characteristic clinical findings and muscle histology. Upper endoscopy revealed multiple pedunculated, edematous polyps in the stomach without apparent cancerous lesions intraluminally. Infiltration of the muscular layer was not detectable on endoscopic ultrasound. Histopathological examination of the polyps showed smooth outer surfaces and multiple dilated cystic glands, consistent with hamartomatous juvenile-type polyps. Magnetic resonance imaging revealed a peritoneal mass close to the greater curvature of the stomach, which was identified as a poorly differentiated adenocarcinoma by laparoscopic sampling. Immunohistochemical analysis of resected polyps was remarkable for a loss of SMAD4 expression, a finding that is very commonly observed in patients with gastric juvenile polyposis syndrome. Despite initial treatment response to glucocorticoids and chemotherapy, the patient died 5 months later due to progressive illness. Patients with gastric juvenile polyposis and SMAD4 mutations are at a high risk of developing gastric cancer; hence, early gastrectomy should be considered.
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Dermatomiositis/complicaciones , Poliposis Intestinal/congénito , Poliposis Intestinal/diagnóstico por imagen , Síndromes Neoplásicos Hereditarios/diagnóstico por imagen , Pólipos/complicaciones , Pólipos/genética , Proteína Smad4/genética , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/genética , Adolescente , Dermatomiositis/patología , Endoscopía del Sistema Digestivo , Resultado Fatal , Femenino , Humanos , Poliposis Intestinal/patología , Imagen por Resonancia Magnética , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Gástricas/patologíaRESUMEN
Vedolizumab (VDZ) inhibits α4ß7 integrins and is used to target intestinal immune responses in patients with inflammatory bowel disease, which is considered to be relatively safe. Here we report on a fatal complication following VDZ administration. A 64-year-old female patient with ulcerative colitis (UC) refractory to tumor necrosis factor inhibitors was treated with VDZ. One week after the second VDZ infusion, she was admitted to hospital with severe diarrhea and systemic inflammatory response syndrome (SIRS). Blood stream infections were ruled out, and endoscopy revealed extensive ulcerations of the small intestine covered with pseudomembranes, reminiscent of invasive candidiasis or mesenteric ischemia. Histology confirmed subtotal destruction of small intestinal epithelia and colonization with Candida. Moreover, small mesenteric vessels were occluded by hyaline thrombi, likely as a result of SIRS, while perfusion of large mesenteric vessels was not compromised. Beta-D-glucan concentrations were highly elevated, and antimycotic therapy was initiated for suspected invasive candidiasis but did not result in any clinical benefit. Given the non-responsiveness to anti-infective therapies, an autoimmune phenomenon was suspected and immunosuppressive therapy was escalated. However, the patient eventually died from multi-organ failure. This case should raise the awareness for rare but severe complications related to immunosuppressive therapy, particularly in high risk patients.
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Anticuerpos Monoclonales Humanizados , Colitis Ulcerosa , Enteritis , Síndrome de Respuesta Inflamatoria Sistémica , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/mortalidad , Enteritis/complicaciones , Enteritis/tratamiento farmacológico , Enteritis/mortalidad , Femenino , Fármacos Gastrointestinales , Humanos , Intestino Delgado , Síndrome de Respuesta Inflamatoria Sistémica/etiologíaRESUMEN
Acute graft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic cell transplantation (allo-HCT); therefore, a better understanding of its biology may improve therapeutic options. We observed miR-146a up-regulation in T cells of mice developing acute GVHD compared with untreated mice. Transplanting miR-146a(-/-) T cells caused increased GVHD severity, elevated tumor necrosis factor (TNF) serum levels, and reduced survival. TNF receptor-associated factor 6 (TRAF6), a verified target of miR-146a, was up-regulated in miR-146a(-/-) T cells following alloantigen stimulation. Higher TRAF6 levels translated into increased nuclear factor-κB activity and TNF production in miR-146a(-/-) T cells. Conversely, the detrimental effect of miR-146a deficiency in T cells was antagonized by TNF blockade, whereas phytochemical induction of miR-146a or its overexpression using a miR-146a mimic reduced GVHD severity. In humans, the minor genotype of the single nucleotide polymorphism rs2910164 in HCT donors, which reduces expression of miR-146a, was associated with severe acute GVHD (grade III/IV). We show that miR-146a functions as a negative regulator of donor T cells in GVHD by targeting TRAF6, leading to reduced TNF transcription. Because miR-146a expression can be exogenously enhanced, our results provide a novel targeted molecular approach to mitigate GVHD.
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Enfermedad Injerto contra Huésped/metabolismo , MicroARNs/metabolismo , Linfocitos T/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Eliminación de Gen , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , MicroARNs/genética , Polimorfismo de Nucleótido Simple , Linfocitos T/trasplante , Factor de Necrosis Tumoral alfa/sangre , Regulación hacia ArribaRESUMEN
Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8+ T cell pool. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
Asunto(s)
Autofagia , Linfocitos T CD8-positivos , Humanos , Animales , Ratones , Dinoprostona , Genes Mitocondriales , GlutatiónRESUMEN
BACKGROUND & AIMS: During progression of liver disease, inflammation affects survival of hepatocytes. Endogenous release of adenosine triphosphate (ATP) in the liver activates purinergic P2 receptors (P2R), which regulate inflammatory responses, but little is known about the roles of these processes in the development of acute hepatitis. METHODS: We induced acute hepatitis in C57BL/6 mice by intravenous injection of concanavalin A and then analyzed liver concentrations of ATP and expression of P2R. We assessed P2Y(2)R(-/-) mice and C57BL/6 wild-type mice injected with suramin, a pharmacologic inhibitor of P2YR. Toxic liver failure was induced in mice by intraperitoneal injection of acetaminophen. Hepatocyte-specific functions of P2R signaling were analyzed in primary mouse hepatocytes. RESULTS: Induction of acute hepatitis in wild-type C57BL/6 mice released large amounts of ATP from livers and induced expression of P2Y(2)R. Liver damage and necrosis were greatly reduced in P2Y(2)R(-/-) mice and C57BL/6 mice given injections of suramin. Acetaminophen-induced liver damage was reduced in P2Y(2)R(-/-) mice. Analysis of liver-infiltrating immune cells during acute hepatitis revealed that expression of P2Y(2)R in bone marrow-derived cells was required for liver infiltration by neutrophils and subsequent liver damage. Hepatic expression of P2Y(2)R interfered with expression of genes that regulate cell survival, and promoted tumor necrosis factor-α-mediated cell death, in a cell-autonomous manner. CONCLUSIONS: Extracellular ATP and P2Y(2)R have cell-type specific, but synergistic functions during liver damage that regulate cellular immune responses and promote hepatocyte death. Reagents designed to target P2Y(2)R might be developed to treat inflammatory liver disease.
Asunto(s)
Apoptosis/fisiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hepatocitos/patología , Infiltración Neutrófila/fisiología , Receptores Purinérgicos P2Y2/fisiología , Enfermedad Aguda , Adenosina Trifosfato/metabolismo , Animales , Movimiento Celular/fisiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Concanavalina A/efectos adversos , Modelos Animales de Enfermedad , Hepatocitos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Purinérgicos P2Y2/deficiencia , Receptores Purinérgicos P2Y2/efectos de los fármacos , Suramina/farmacologíaRESUMEN
UNLABELLED: Endoplasmic reticulum (ER) stress due to accumulation of hepatoviral or misfolded proteins is increasingly recognized as an important step in the pathogenesis of inflammatory, toxic, and metabolic liver diseases. ER stress results in the activation of several intracellular signaling pathways including Jun N-terminal kinase (JNK). The AP-1 (activating protein 1) transcription factor c-Jun is a prototypic JNK target and important regulator of hepatocyte survival, proliferation, and liver tumorigenesis. Because the functions of c-Jun during the ER stress response are poorly understood, we addressed this issue in primary hepatocytes and livers of hepatocyte-specific c-Jun knockout mice. ER stress was induced pharmacologically in vitro and in vivo and resulted in a rapid and robust induction of c-Jun protein expression. Interestingly, ER-stressed hepatocytes lacking c-Jun displayed massive cytoplasmic vacuolization due to ER distension. This phenotype correlated with exacerbated and sustained activation of canonical ER stress signaling pathways. Moreover, sustained ER stress in hepatocytes lacking c-Jun resulted in increased cell damage and apoptosis. ER stress is also a strong inducer of macroautophagy, a cell-protective mechanism of self-degradation of cytoplasmic components and organelles. Interestingly, autophagosome numbers in response to ER stress were reduced in hepatocytes lacking c-Jun. To further validate these findings, macroautophagy was inhibited chemically in ER-stressed wildtype hepatocytes, which resulted in cytoplasmic vacuolization and increased cell damage closely resembling the phenotypes observed in c-Jun-deficient cells. CONCLUSION: Our findings indicate that c-Jun protects hepatocytes against excessive activation of the ER stress response and subsequent cell death and provide evidence that c-Jun functionally links ER stress responses and macroautophagy.
Asunto(s)
Estrés del Retículo Endoplásmico , Hepatocitos/fisiología , Proteínas Proto-Oncogénicas c-jun/fisiología , Animales , Apoptosis , Autofagia , Línea Celular Tumoral , Supervivencia Celular , Retículo Endoplásmico/ultraestructura , Humanos , Ratones , Ratones NoqueadosRESUMEN
Factors related to patient diversity may play a major role in the pathogenesis and clinical manifestation of intestinal and liver diseases and should be considered during diagnostic workup and therapeutic decisions. Here we discuss how diversity factors such as gender, ethnicity, age and socioeconomic parameters may affect the manifestation and disease course of inflammatory bowel diseases (IBD, i.e. Crohn's disease and ulcerative colitis). Consideration of such factors may help to pave the path towards personalized medicine approaches in clinical practice.
Asunto(s)
Colitis Ulcerosa , Enfermedad de Crohn , Gastroenterología , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/terapia , Colitis Ulcerosa/terapia , Enfermedad de Crohn/terapiaRESUMEN
Immune cells must adapt to different environments during the course of an immune response. We studied the adaptation of CD8 + T cells to the intestinal microenvironment and how this process shapes their residency in the gut. CD8 + T cells progressively remodel their transcriptome and surface phenotype as they acquire gut residency, and downregulate expression of mitochondrial genes. Human and mouse gut-resident CD8 + T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We found that the intestinal microenvironment is rich in prostaglandin E 2 (PGE 2 ), which drives mitochondrial depolarization in CD8 + T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE 2 sensing promotes CD8 + T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell population. Thus, a PGE 2 -autophagy-glutathione axis defines the metabolic adaptation of CD8 + T cells to the intestinal microenvironment, to ultimately influence the T cell pool.