Circulating immunome fingerprint in eosinophilic esophagitis is associated with clinical response to proton pump inhibitor treatment.

Objectives: The aim of the study was to characterize the circulating immunome of patients with EoE before and after proton pump inhibitor (PPI) treatment in order to identify potential non-invasive biomarkers of treatment response. Methods: PBMCs from 19 healthy controls and 24 EoE patients were studied using a 39-plex spectral cytometry panel. The plasmacytoid dendritic cell (pDC) population was differentially characterized by spectral cytometry analysis and immunofluorescence assays in esophageal biopsies from 7 healthy controls and 13 EoE patients. Results: Interestingly, EoE patients at baseline had lower levels of circulating pDC compared with controls. Before treatment, patients with EoE who responded to PPI therapy had higher levels of circulating pDC and classical monocytes, compared with non-responders. Moreover, following PPI therapy pDC levels were increased in all EoE patients, while normal levels were only restored in PPI-responding patients. Finally, circulating pDC levels inversely correlated with peak eosinophil count and pDC count in esophageal biopsies. The number of tissue pDCs significantly increased during active EoE, being even higher in non-responder patients when compared to responder patients pre-PPI. pDC levels decreased after PPI intake, being further restored almost to control levels in responder patients post-PPI. Conclusions: We hereby describe a unique immune fingerprint of EoE patients at diagnosis. Moreover, circulating pDC may be also used as a novel non-invasive biomarker to predict subsequent response to PPI treatment.

Swallowed topical corticosteroids for eosinophilic esophagitis: Utilization and real-world efficacy from the EoE CONNECT registry.

BACKGROUND: Swallowed topical corticosteroids (tC) are common therapy for patients with eosinophilic esophagitis (EoE). Widely heterogeneous results have occurred due to their active ingredients, formulations and doses. OBJECTIVE: To assess the effectiveness of topical corticosteroid therapy for EoE in real-world practice. METHODS: Cross-sectional study analysis of the multicentre EoE CONNECT registry. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom scores; histological remission was defined as a peak eosinophil count below 15 per high-power field. The effectiveness in achieving clinico-histological remission (CHR) was compared for the main tC formulations. RESULTS: Overall, data on 1456 prescriptions of tC in monotherapy used in 866 individual patients were assessed. Of those, 904 prescriptions with data on formulation were employed for the induction of remission; 234 reduced a previously effective dose for maintenance. Fluticasone propionate formulations dominated the first-line treatment, while budesonide was more common in later therapies. A swallowed nasal drop suspension was the most common formulation of fluticasone propionate. Doses ≥0.8 mg/day provided a 65% CHR rate and were superior to lower doses. Oral viscous solution prepared by a pharmacist was the most common prescription of budesonide; 4 mg/day provided no benefit over 2 mg/day (CHR rated being 72% and 80%, respectively). A multivariate analysis revealed budesonide orodispersible tablets as the most effective therapy (OR 18.9, p < 0.001); use of higher doses (OR 4.3, p = 0.03) and lower symptom scores (OR 0.9, p = 0.01) were also determinants of effectiveness. CONCLUSION: Reduced symptom severity, use of high doses, and use of budesonide orodispersible tablets particularly were all independent predictors of tC effectiveness.

Sobrecrecimiento bacteriano intestinal. Documento de posicionamiento ASENEM-SEPD / Small intestinal bacterial overgrowth. A position paper of ASENEM-SEPD

El sobrecrecimiento bacteriano intestinal (SIBO, por sus siglas en inglés) es una entidad descrita desde hace varias décadas, pero que en los últimos años ha cobrado un especial interés por parte de los profesionales médicos y por la población general, probablemente por el aumento de la disponibilidad de pruebas diagnósticas y por la extensa difusión que se le ha dado a esta enfermedad a través de los medios de comunicación y redes sociales. En vista de la gran cantidad de información disponible en la actualidad y en ocasiones discrepante, entre la Sociedad Española de Patología Digestiva (SEPD) y la Asociación Española de Neurogastroenterología y Motilidad (ASENEM) hemos realizado un documento de posicionamiento para establecer líneas de diagnóstico y tratamiento del SIBO con la información científica actualizada.(AU)

Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation.

Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.

The adaptive antioxidant response during fasting-induced muscle atrophy is oppositely regulated by ZEB1 and ZEB2.

Reactive oxygen species (ROS) serve important homeostatic functions but must be constantly neutralized by an adaptive antioxidant response to prevent supraphysiological levels of ROS from causing oxidative damage to cellular components. Here, we report that the cellular plasticity transcription factors ZEB1 and ZEB2 modulate in opposing directions the adaptive antioxidant response to fasting in skeletal muscle. Using transgenic mice in which Zeb1 or Zeb2 were specifically deleted in skeletal myofibers, we show that in fasted mice, the deletion of Zeb1, but not Zeb2, increased ROS production and that the adaptive antioxidant response to fasting essentially requires ZEB1 and is inhibited by ZEB2. ZEB1 expression increased in fasted muscles and protected them from atrophy; conversely, ZEB2 expression in muscles decreased during fasting and exacerbated muscle atrophy. In fasted muscles, ZEB1 reduces mitochondrial damage and increases mitochondrial respiratory activity; meanwhile, ZEB2 did the opposite. Treatment of fasting mice with Zeb1-deficient myofibers with the antioxidant triterpenoid 1[2-cyano-3,12-dioxool-eana-1,9(11)-dien-28-oyl] trifluoro-ethylamide (CDDO-TFEA) completely reversed their altered phenotype to that observed in fasted control mice. These results set ZEB factors as potential therapeutic targets to modulate the adaptive antioxidant response in physiopathological conditions and diseases caused by redox imbalance.

Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation.

Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.

Small intestinal bacterial overgrowth. A position paper of ASENEM-SEPD.

Small intestinal bacterial overgrowth (SIBO) is a condition that was described decades ago and has recently aroused special interest among both medical professionals and the general population, likely because of increased availability of diagnostic testing and extensive coverage by the media and social networks. In view of the large amount of-often conflicting-information available, the need has arisen to develop a joint position paper of the Sociedad Española de Patología Digestiva (SEPD) and Asociación Española de Neurogastroenterología y Motilidad (ASENEM) to discuss up-to-date scientific information.

Proteomic analysis of the esophageal epithelium reveals key features of eosinophilic esophagitis pathophysiology.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic non-IgE-mediated allergic disease of the esophagus. An unbiased proteomics approach was performed to investigate pathophysiological changes in esophageal epithelium. Additionally, an RNAseq-based transcriptomic analysis in paired samples was also carried out. METHODS: Total proteins were purified from esophageal endoscopic biopsies in a cohort of adult EoE patients (n = 25) and healthy esophagus controls (n = 10). Differentially accumulated (DA) proteins in EoE patients compared to control tissues were characterized to identify altered biological processes and signaling pathways. Results were also compared with a quantitative proteome dataset of the human esophageal mucosa. Next, results were contrasted with those obtained after RNAseq analysis in paired samples. Finally, we matched up protein expression with two EoE-specific mRNA panels (EDP and Eso-EoE panel). RESULTS: A total of 1667 proteins were identified, of which 363 were DA in EoE. RNA sequencing in paired samples identified 1993 differentially expressed (DE) genes. Total RNA and protein levels positively correlated, especially in DE mRNA-proteins pairs. Pathway analysis of these proteins in EoE showed alterations in immune and inflammatory responses for the upregulated proteins, and in epithelial differentiation, cornification and keratinization in those downregulated. Interestingly, a set of DA proteins, including eosinophil-related and secreted proteins, were not detected at the mRNA level. Protein expression positively correlated with EDP and Eso-EoE, and corresponded with the most abundant proteins of the human esophageal proteome. CONCLUSIONS: We unraveled for the first time key proteomic features involved in EoE pathogenesis. An integrative analysis of transcriptomic and proteomic datasets provides a deeper insight than transcriptomic alone into understanding complex disease mechanisms.

Codependencia laboral: análisis factorial confirmatorio

El objetivo de esta investigación es validar un instrumento para medir la codependencia laboral. El método implementado fue un enfoque cuantitativo, de diseño no experimental transeccional, utilizando un análisis factorial confirmatorio basado en ecuaciones estructurales. Los resultados mostraron que el modelo presentó un ajuste adecuado NC =1.86; ρ=0.000; NFI=.979; IFI=.990; CFI=.990; MFI=.925 Y RMSEA=.68. Se concluye que los factores relacionados con la falta de confianza y los comportamientos abusivos son los elementos que describen la codependencia en el ámbito laboral.

The objective of this research is to validate an instrument to measure labor co-dependency, using a quantitative approach of non-experimental trans-sectional design, via a Confirmatory Factor Analysis based on structural equations. Results showed that the model presented an adequate adjustment NC = 1.86; p = 0.000; NFI = .979; IFI = .990; CFI = .990; MFI = .925, and RMSEA = .68. It is concluded that the factors related to lack of trust and abusive behaviors are the elements that describe co-dependency in the workplace.

Accurate and timely diagnosis of Eosinophilic Esophagitis improves over time in Europe. An analysis of the EoE CONNECT Registry.

BACKGROUND: Poor adherence to clinical practice guidelines for eosinophilic esophagitis (EoE) has been described and the diagnostic delay of the disease continues to be unacceptable in many settings. OBJECTIVE: To analyze the impact of improved knowledge provided by the successive international clinical practice guidelines on reducing diagnostic delay and improving the diagnostic process for European patients with EoE. METHODS: Cross-sectional analysis of the EoE CONNECT registry based on clinical practice. Time periods defined by the publication dates of four major sets of guidelines over 10 years were considered. Patients were grouped per time period according to date of symptom onset. RESULTS: Data from 1,132 patients was analyzed and median (IQR) diagnostic delay in the whole series was 2.1 (0.7-6.2) years. This gradually decreased over time with subsequent release of new guidelines (p < 0.001), from 12.7 years up to 2007 to 0.7 years after 2017. The proportion of patients with stricturing of mixed phenotypes at the point of EoE diagnosis also decreased over time (41.3% vs. 16%; p < 0.001), as did EREFS scores. The fibrotic sub-score decreased from a median (IQR) of 2 (1-2) to 0 (0-1) when patients whose symptoms started up to 2007 and after 2017 were compared (p < 0.001). In parallel, symptoms measured with the Dysphagia Symptoms Score reduced significantly when patients with symptoms starting before 2007 and after 2012 were compared. A reduction in the number of endoscopies patients underwent before the one that achieved an EoE diagnosis, and the use of allergy testing as part of the diagnostic workout of EoE, also reduced significantly over time (p = 0.010 and p < 0.001, respectively). CONCLUSION: The diagnostic work-up of EoE patients improved substantially over time at the European sites contributing to EoE CONNECT, with a dramatic reduction in diagnostic delay.

Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most frequent, and still incurable, form of leukemia in the Western World. It is widely accepted that cancer results from an evolutionary process shaped by the acquisition of driver mutations which confer selective growth advantage to cells that harbor them. Clear examples are missense mutations in classic RAS genes (KRAS, HRAS and NRAS) that underlie the development of approximately 13% of human cancers. Although autonomous B cell antigen receptor (BCR) signaling is involved and mutations in many tumor suppressor genes and oncogenes have been identified, an oncogenic driver gene has not still been identified for CLL. METHODS: Conditional knock-in mice were generated to overexpress wild type RRAS2 and prove its driver role. RT-qPCR analysis of a human CLL sample cohort was carried out to measure RRAS2 transcriptional expression. Sanger DNA sequencing was used to identify a SNP in the 3'UTR region of RRAS2 in human CLL samples. RNAseq of murine CLL was carried out to identify activated pathways, molecular mechanisms and to pinpoint somatic mutations accompanying RRAS2 overexpression. Flow cytometry was used for phenotypic characterization and shRNA techniques to knockdown RRAS2 expression in human CLL. RESULTS: RRAS2 mRNA is found overexpressed in its wild type form in 82% of the human CLL samples analyzed (n = 178, mean and median = 5-fold) as well as in the explored metadata. A single nucleotide polymorphism (rs8570) in the 3'UTR of the RRAS2 mRNA has been identified in CLL patients, linking higher expression of RRAS2 with more aggressive disease. Deliberate overexpression of wild type RRAS2 in mice, but not an oncogenic Q72L mutation in the coding sequence, provokes the development of CLL. Overexpression of wild type RRAS2 in mice is accompanied by a strong convergent selection of somatic mutations in genes that have been identified in human CLL. R-RAS2 protein is physically bound to the BCR and mediates BCR signals in CLL. CONCLUSIONS: The results indicate that overexpression of wild type RRAS2 is behind the development of CLL.

A programme for early diagnosis of atrial fibrillation: a multi-centre study in primary care.

BACKGROUND: Atrial fibrillation (AF) is a morbid disease whose complications can be prevented if prompt and correctly treated. OBJECTIVE: To assess the usefulness of an early AF diagnosis programme in at-risk individuals in primary care centres. METHODS: In an open-label, multi-centre, controlled interventional study, individuals with one or more risk factors for AF but without known AF were enrolled. They were allocated to intervention and control groups in a 1:2 ratio. Participants in the intervention group had three clinical and educational visits (0, 6 and 12 months). In intervention subgroup A, an electrocardiogram (ECG) was performed at each visit and in subgroup B, only if arrhythmia was detected on auscultation. After 2 years, the medical records of all participants were reviewed. Participants diagnosed with AF were followed for two additional years. RESULTS: Of the total 2231 participants enrolled, 1503 (67.36%) were allocated to the control group and 728 (32.63%) to the intervention groups (355 in subgroup A, 373 subgroup B). The groups showed similar clinical characteristics. New-onset AF was diagnosed in 38 patients. Early detection in subgroup B was similar to subgroup A and superior to control group (3.2% versus 1.2%, hazard ratio 3.149, 95% confidence interval 1.503-6.597, P = 0.002). AF patients in subgroups A and B had similar long-term complications and a tendency for fewer complications than AF patients in the control group. CONCLUSIONS: An intervention programme consisting of health education, systematic auscultation and opportunistic ECG by a primary care provider is a useful method for the early diagnosis of AF.

Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice.

Diffuse large B-cell lymphomas (DLBCLs) are clinically and genetically heterogeneous tumors. Deregulation of diverse biological processes specific to B cells, such as B-cell receptor (BCR) signaling and motility regulation, contribute to lymphomagenesis. Human germinal center associated lymphoma (HGAL) is a B-cell-specific adaptor protein controlling BCR signaling and B lymphocyte motility. In normal B cells, it is expressed in germinal center (GC) B lymphocytes and promptly downregulated upon further differentiation. The majority of DLBCL tumors, primarily GC B-cell types, but also activated types, express HGAL. To investigate the consequences of constitutive expression of HGAL in vivo, we generated mice that conditionally express human HGAL at different stages of hematopoietic development using 3 restricted Cre-mediated approaches to initiate expression of HGAL in hematopoietic stem cells, pro-B cells, or GC B cells. Following immune stimulation, we observed larger GCs in mice in which HGAL expression was initiated in GC B cells. All 3 mouse strains developed DLBCL at a frequency of 12% to 30% starting at age 13 months, leading to shorter survival. Immunohistochemical studies showed that all analyzed tumors were of the GC B-cell type. Exon sequencing revealed mutations reported in human DLBCL. Our data demonstrate that constitutive enforced expression of HGAL leads to DLBCL development.

Pathogenic SREK1 decrease in Huntington's disease lowers TAF1 mimicking X-linked dystonia parkinsonism.

Huntington's disease and X-linked dystonia parkinsonism are two monogenic basal ganglia model diseases. Huntington's disease is caused by a polyglutamine-encoding CAG repeat expansion in the Huntingtin (HTT) gene leading to several toxic interactions of both the expanded CAG-containing mRNA and the polyglutamine-containing protein, while X-linked dystonia parkinsonism is caused by a retrotransposon insertion in the TAF1 gene, which decreases expression of this core scaffold of the basal transcription factor complex TFIID. SRSF6 is an RNA-binding protein of the serine and arginine-rich (SR) protein family that interacts with expanded CAG mRNA and is sequestered into the characteristic polyglutamine-containing inclusion bodies of Huntington's disease brains. Here we report decreased levels of the SRSF6 interactor and regulator SREK1-another SR protein involved in RNA processing-which includes TAF1 as one of its targets. This led us to hypothesize that Huntington's disease and X-linked dystonia parkinsonism pathogeneses converge in TAF1 alteration. We show that diminishing SRSF6 through RNA interference in human neuroblastoma cells leads to a decrease in SREK1 levels, which, in turn, suffices to cause diminished TAF1 levels. We also observed decreased SREK1 and TAF1 levels in striatum of Huntington's disease patients and transgenic model mice. We then generated mice with neuronal transgenic expression of SREK1 (TgSREK1 mice) that, interestingly, showed transcriptomic alterations complementary to those in Huntington's disease mice. Most importantly, by combining Huntington's disease and TgSREK1 mice we verify that SREK1 overexpression corrects TAF1 deficiency and attenuates striatal atrophy and motor phenotype of Huntington's disease mice. Our results therefore demonstrate that altered RNA processing upon SREK1 dysregulation plays a key role in Huntington's disease pathogenesis and pinpoint TAF1 as a likely general determinant of selective vulnerability of the striatum in multiple neurological disorders.

Linfomas de colon: análisis de nuestra experiencia en los últimos 23 años / Colon lymphomas: an analysis of our experience over the last 23 years

Introducción: el linfoma de colon (LC) es una variedad poco frecuente de los linfomas no Hodgkin (LNH) que representa menos del 0,6% de todas las neoplasias primarias del colon. Realizar un diagnóstico precoz es difícil debido a que las manifestaciones clínicas son inespecíficas. El objetivo de esta revisión fue presentar nuestra experiencia en los últimos años en cuanto a características clínicas, endoscópicas, histológicas, diagnóstico, tratamiento y evolución de los LC. Pacientes y métodos: se realizó un análisis retrospectivo y descriptivo de pacientes con LC diagnosticados desde 1994 hasta 2016 en el Hospital Universitario de la Princesa, Madrid. Resultados: se identificaron 29 pacientes con LC (mediana de edad 67 años, 18 hombres [62%]). Las manifestaciones clínicas más comunes fueron dolor abdominal, síndrome constitucional, diarrea y masa abdominal palpable. Ocho (27,6%) pacientes se encontraban asintomáticos y seis (20,6%) debutaron con complicaciones quirúrgicas. En 24 pacientes se realizó colonoscopia y los hallazgos más frecuentes fueron infiltración difusa y tumoración. La localización más común fue el colon descendente y sigma. Los subtipos histológicos más frecuentes fueron: LNH de células B del manto y linfoma difuso de células grandes tipo B. Se trató con quimioterapia a 28 pacientes (96,5%), con cirugía a seis (20,7%) y uno recibió quimio y radioterapia. La mediana del tiempo de supervivencia fue de 156 meses. La supervivencia al año fue del 100,0% y a los diez años, del 55,0%. Conclusiones: debido al aspecto endoscópico variable del LC, es necesario el estudio histológico de todos los segmentos del colon. El tratamiento de elección es la quimioterapia y en casos de complicaciones es necesaria la cirugía urgente con quimioterapia posterior. Los principales factores asociados a peor supervivencia son la edad mayor de 65 años, la existencia de recidiva y las respuestas parciales o nulas

Introduction: colon lymphoma (CL) is an uncommon variety of non-Hodgkin lymphoma (NHL) that represents less than 0.6% of all primary colonic neoplasms. Early diagnosis is challenging as clinical manifestations are non-specific. The goal of this review was to discuss our experience over the last few years regarding the clinical, endoscopic, histological, diagnostic, therapeutic and evolutionary characteristics of CL. Patients and methods: a retrospective, descriptive analysis of patients with CL diagnosed from 1994 to 2016 at the Hospital Universitario de La Princesa (Madrid, Spain) was performed. Results: a total of 29 patients with CL were identified, with a median age of 67 years; 18 were male (62%). The most common clinical manifestations included abdominal pain, constitutional syndrome, diarrhea and a palpable abdominal mass. Eight (27.6%) patients were asymptomatic and six (20.6%) initially presented with surgical complications. A colonoscopy was performed in 24 patients and the most common findings included diffuse infiltration and solid growth. The most common location was the descending and sigmoid colon. The most common histological subtypes included mantle B-cell NHL and diffuse large B-cell lymphoma. Chemotherapy was administered to 28 patients (96.5%), surgery was performed in six (20.7%) and combined chemo-radiotherapy was administered to one patient. Median survival was 156 months. Survival was 100.0% at one year and 55.0% at ten years. Conclusions: due to the variable aspects of CL on endoscopy, a histological study of all colonic segments is required. Chemotherapy is the treatment of choice and emergency surgery followed by chemotherapy is required for complications. Primary factors associated with poorer survival include age above 65 years, relapsing disease and partial or nil responses

Colon lymphomas: an analysis of our experience over the last 23 years.

INTRODUCTION: colon lymphoma (CL) is an uncommon variety of non-Hodgkin lymphoma (NHL) that represents less than 0.6% of all primary colonic neoplasms. Early diagnosis is challenging as clinical manifestations are non-specific. The goal of this review was to discuss our experience over the last few years regarding the clinical, endoscopic, histological, diagnostic, therapeutic and evolutionary characteristics of CL. PATIENTS AND METHODS: a retrospective, descriptive analysis of patients with CL diagnosed from 1994 to 2016 at the Hospital Universitario de La Princesa (Madrid, Spain) was performed. RESULTS: a total of 29 patients with CL were identified, with a median age of 67 years; 18 were male (62%). The most common clinical manifestations included abdominal pain, constitutional syndrome, diarrhea and a palpable abdominal mass. Eight (27.6%) patients were asymptomatic and six (20.6%) initially presented with surgical complications. A colonoscopy was performed in 24 patients and the most common findings included diffuse infiltration and solid growth. The most common location was the descending and sigmoid colon. The most common histological subtypes included mantle B-cell NHL and diffuse large B-cell lymphoma. Chemotherapy was administered to 28 patients (96.5%), surgery was performed in six (20.7%) and combined chemo-radiotherapy was administered to one patient. Median survival was 156 months. Survival was 100.0% at one year and 55.0% at ten years. CONCLUSIONS: due to the variable aspects of CL on endoscopy, a histological study of all colonic segments is required. Chemotherapy is the treatment of choice and emergency surgery followed by chemotherapy is required for complications. Primary factors associated with poorer survival include age above 65 years, relapsing disease and partial or nil responses.

Lmo2 expression defines tumor cell identity during T-cell leukemogenesis.

The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of Lmo2 at different stages of B-cell development induces systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T-ALL to current therapies.

N-terminal acetylation modulates Bax targeting to mitochondria.

The pro-apoptotic Bax protein is the main effector of mitochondrial permeabilization during apoptosis. Bax is controlled at several levels, including post-translational modifications such as phosphorylation and S-palmitoylation. However, little is known about the contribution of other protein modifications to Bax activity. Here, we used heterologous expression of human Bax in yeast to study the involvement of N-terminal acetylation by yNaa20p (yNatB) on Bax function. We found that human Bax is N-terminal (Nt-)acetylated by yNaa20p and that Nt-acetylation of Bax is essential to maintain Bax in an inactive conformation in the cytosol of yeast and Mouse Embryonic Fibroblast (MEF) cells. Bax accumulates in the mitochondria of yeast naa20Δ and Naa25-/- MEF cells, but does not promote cytochrome c release, suggesting that an additional step is required for full activation of Bax. Altogether, our results show that Bax N-terminal acetylation by NatB is involved in its mitochondrial targeting.