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BACKGROUND: Respiratory syncytial virus (RSV) infection is the primary cause of lower respiratory tract infections in children <5 years of age. Monocytes, especially in the respiratory tract, are suggested to contribute to RSV pathology, but their role is incompletely understood. With transcriptomic profiling of blood and airway monocytes, we describe the role of monocytes in severe RSV infection. METHODS: Tracheobronchial aspirates and blood samples were collected from control patients (n = 9) and those infected with RSV (n = 14) who were admitted to the pediatric intensive care unit. Monocytes (CD14+) were sorted and analyzed by RNA sequencing for transcriptomic profiling. RESULTS: Peripheral blood and airway monocytes of patients with RSV demonstrated increased expression of antiviral and interferon-responsive genes as compared with controls. Cytokine signaling showed a shared response between blood and airway monocytes while displaying responses that were more pronounced according to the tissue of origin. Airway monocytes upregulated additional genes related to migration and inflammation. CONCLUSIONS: We found that the RSV-induced interferon response extends from the airways to the peripheral blood. Moreover, RSV induces a migration-promoting transcriptional program in monocytes. Unraveling the monocytic response and its role in the immune response to RSV infection could help the development of therapeutics to prevent severe disease.
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Infecciones por Virus Sincitial Respiratorio , Niño , Lactante , Humanos , Infecciones por Virus Sincitial Respiratorio/genética , Monocitos , Sistema Respiratorio , Perfilación de la Expresión Génica , Interferones , Fenotipo , Antivirales/farmacología , Antivirales/uso terapéuticoRESUMEN
We report the case of a young patient with unknown, genetically caused thrombophilia in whom thrombosis of the main portal vein developed as well as of the hepatic branches and the superior mesenteric vein with necrosis of the small intestine. Partial resection of the small intestine was performed and conservative management of portal vein thrombosis with a therapeutic dose of LMWH was indicated. Key words: thrombophilia - thrombosis of the portal vein.
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Abdomen Agudo/etiología , Trombofilia/complicaciones , Trombosis de la Vena/etiología , Venas Hepáticas , Humanos , Intestino Delgado/patología , Masculino , Venas Mesentéricas , Necrosis , Vena Porta , Adulto JovenRESUMEN
The rapid advancements in genome-scale (omics) techniques has created significant opportunities to investigate complex disease mechanisms in tissues and cells. Nevertheless, interpreting -omics data can be challenging, and pathway enrichment analysis is a frequently used method to identify candidate molecular pathways that drive gene expression changes. With a growing number of -omics studies dedicated to atherosclerosis, there has been a significant increase in studies and hypotheses relying on enrichment analysis. This brief review discusses the benefits and limitations of pathway enrichment analysis within atherosclerosis research. We highlight the challenges of identifying complex biological processes, such as cell phenotypic switching, within -omics data. Additionally, we emphasize the need for more comprehensive and curated gene sets that reflect the biological complexity of atherosclerosis. Pathway enrichment analysis is a valuable tool for gaining insights into the molecular mechanisms of atherosclerosis. Nevertheless, it is crucial to remain aware of the intrinsic limitations of this approach. By addressing these weaknesses, enrichment analysis in atherosclerosis can lead to breakthroughs in identifying the mechanisms of disease progresses, the identification of key driver genes, and consequently, advance personalized patient care.
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Aterosclerosis , Humanos , Aterosclerosis/genéticaRESUMEN
Radionecrosis (RN) in children treated for brain tumors represents a potentially severe long-term complication. Its diagnosis is challenging, since magnetic resonance imaging (MRI) cannot clearly discriminate between RN and tumor recurrence. A retrospective single-center study was undertaken to describe the incidence and clinical course of RN in a cohort of 107 children treated with external radiotherapy (RT) for various brain tumors between 1992 and 2012. During a median follow-up of 4.6 years (range 0.29-20.1 years), RN was implied by suspicious MRI findings in in 5 children (4.7 %), 5-131 months after RT. Suspicion was confirmed histologically (1 patient) or substantiated by FDG positron-emission tomography (FDG-PET, 2 patients) or by FDG-PET and MR spectroscopy (1 patient). Before developing RN, all 5 patients had received cytotoxic chemotherapy in addition to RT. In addition to standard treatment protocols, 2 patients had received further chemotherapy for progression or relapse. Median radiation dose expressed as the biologically equivalent total dose applied in 2 Gy fractions (EQD2) was 51.7 Gy (range 51.0-60.0 Gy). At RN onset, 4 children presented with neurological symptoms. Treatment of RN included resection (n = 1), corticosteroids (n = 2) and a combination of corticosteroids, hyperbaric oxygen (HBO) and bevacizumab (n = 1). One patient with asymptomatic RN was not treated. Complete radiological regression of the lesions was observed in all patients. Clinical symptoms normalized in 3 patients, whereas 2 developed permanent severe neurological deficits. RN represents a severe long-term treatment complication in children with brain tumors. The spectrum of clinical presentation is wide; ranging from asymptomatic lesions to progressive neurological deterioration. FDG-PET and MR spectroscopy may be useful for distinguishing between RN and tumor recurrence. Treatment options in patients with symptomatic RN include conservative management (steroids, HBO, bevacizumab) and surgical resection.
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Lesiones Encefálicas/epidemiología , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/radioterapia , Traumatismos por Radiación/epidemiología , Radioterapia Conformacional/estadística & datos numéricos , Adolescente , Austria/epidemiología , Niño , Preescolar , Comorbilidad , Femenino , Humanos , Incidencia , Lactante , Estudios Longitudinales , Masculino , Medición de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Cholesterol granulomas are benign lesions that sometimes occur on the petrous apex (PA). We report our experience using an endoscopic endonasal approach to remove PA cholesterol granulomas. MATERIAL AND METHODS: A retrospective patient chart analysis was conducted at a tertiary care university hospital. RESULTS: Four patients (3 females, 1 male) were included in this study. Patients' ages ranged from 27 to 78 years. Computed tomography (CT) and magnetic resonance imaging (MRI) for diagnosis and computer-assisted navigation were performed. The most common symptom was abducens nerve palsy. The largest granuloma measured 5 x 2 cm and was located on the left side. An endoscopic endonasal approach was chosen and navigation was applied (3/4 patients) to identify the optimal area for opening the granuloma. No complications occurred, and patients were free from recurrence during the follow-up period. CONCLUSION: The endoscopic endonasal approach to PA cholesterol granulomas is feasible and safe. Intra-operative navigation is recommended to identify the position of the internal carotid artery and determine the safest area for opening the granuloma without damaging the artery. Another advantage of this approach is an easier follow-up through diagnostic nasal endoscopy.
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Enfermedades Óseas/cirugía , Colesterol , Drenaje/métodos , Endoscopía/métodos , Granuloma de Cuerpo Extraño/cirugía , Procedimientos Quirúrgicos Otorrinolaringológicos/métodos , Hueso Petroso/cirugía , Adulto , Anciano , Enfermedades Óseas/diagnóstico , Diagnóstico Diferencial , Femenino , Granuloma de Cuerpo Extraño/diagnóstico , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Aim of the present study was to investigate survival rates of unselected patients with glioblastoma after multimodal treatment and estimation of prognostic factors. Data of 189 patients (118 men; 71 women; median age: 59 years) with histologically confirmed glioblastoma treated from 1999 to 2009 were analyzed retrospectively. Complete tumor resection was performed in 99 patients (52%), subtotal excision in 65 patients (34%), and stereotactic biopsy in 25 patients (13%). In 135 patients (71%), residual tumors were detectable in post-surgical imaging. All patients underwent three-dimensional conformal radiotherapy of the tumor region in shrinking-field technique to a total dose of 60 Gy. Beginning in 2002, 124 patients (66%) received concomitant temozolomide (TMZ) treatment, 76 patients among them were additionally treated with adjuvant TMZ. After disease progression, 74 patients underwent salvage therapy (salvage chemotherapy, n=61; local therapy, n=30). Actuarial 1- and 2- year progression-free survival (PFS) rates were 32% and 7%, overall survival (OS) rates were 54% and 22%, respectively. Without TMZ, 1- and 2- year OS rates were 47% and 11%, with concomitant TMZ 57% and 28%, and with concomitant and adjuvant TMZ 72% and 44%. In multivariate Cox proportional hazards regression models, age (p<0.001), extent of resection (p = 0.001), and TMZ (p < 0.001) were significantly associated with OS. Furthermore, a significant association between salvage therapy and improved survival was observed (p=0.020). RT with concomitant TMZ was well tolerated in the majority of patients and completed as scheduled in 78% of patients. Multimodal treatment including extensive surgical resection, radiotherapy and chemotherapy significantly improves prognosis of patients with glioblastoma and is feasible with acceptable toxicity in routine practice. To achieve optimal results, close coordination among all disciplines is required.
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Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/mortalidad , Terapia Combinada , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Femenino , Glioblastoma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Radioterapia Conformacional , Tasa de Supervivencia , TemozolomidaAsunto(s)
Adenoma/cirugía , Endoscopía , Piezocirugía , Neoplasias Hipofisarias/cirugía , Base del Cráneo/cirugía , Adenoma/diagnóstico por imagen , Adenoma/patología , Adulto , Anciano , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/patología , Calidad de Vida , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
The authors present the case of a patient with an abdominal puncture wound who developed, in two weeks, perforation of the colon with an unrecognized foreign body in the abdominal cavity.
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Traumatismos Abdominales/complicaciones , Colon Sigmoide/lesiones , Cuerpos Extraños/complicaciones , Perforación Intestinal/etiología , Heridas Punzantes/complicaciones , Pared Abdominal , Femenino , Vidrio , Humanos , Persona de Mediana EdadRESUMEN
INTRODUCTION: Arnold Chiari Malformation Type II can be associated with basilar invagination through an elongated retroflexed odontoid process (dens axis). Traditionally, decompression surgery has been performed transorally under microscopic vision or via transcutaneous latero-cervical/posterior approaches. Endoscopic approaches were introduced a few years ago. CASE REPORT: We report of an eleven-year-old girl with Arnold Chiari Malformation Type II who had undergone surgery eight years ago for posterior cranial fossa decompression at the department of neurosurgery. At that time, an external transcutaneous median approach was performed to resect the posterior arch of the atlas. The patient now presented with the initial symptoms of brainstem compression as a result of an elongated retroflexed odontoid process and craniocervical instability. SURGICAL TECHNIQUE: An endoscopic transoral/transnasal approach was chosen for the resection of the dens. CONCLUSION: Endoscopic surgery was successful and the complete resection of the dens was achieved without any complications. In a second intervention, orthopaedic surgeons performed cranio-cervical arthrodesis.
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Malformación de Arnold-Chiari/cirugía , Endoscopía/métodos , Apófisis Odontoides/cirugía , Artrodesis , Vértebras Cervicales/cirugía , Niño , Femenino , Humanos , Cirugía Asistida por ComputadorRESUMEN
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. However, little is known about the upstream pathways and key regulators causing the disease. Therefore, we employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts. RESULTS: Using H3K27ac ChIP-seq and RNA-seq we obtained 9310 differentially acetylated regions and 2033 differentially expressed genes, respectively, between 13 HCM and 10 control hearts. We obtained 441 differentially expressed proteins between 11 HCM and 8 control hearts using proteomics. By integrating multi-omics datasets, we identified a set of DNA regions and genes that differentiate HCM from control hearts and 53 protein-coding genes as the major contributors. This comprehensive analysis consistently points toward altered extracellular matrix formation, muscle contraction, and metabolism. Therefore, we studied enriched transcription factor (TF) binding motifs and identified 9 motif-encoded TFs, including KLF15, ETV4, AR, CLOCK, ETS2, GATA5, MEIS1, RXRA, and ZFX. Selected candidates were examined in stem cell-derived cardiomyocytes with and without mutated MYBPC3. Furthermore, we observed an abundance of acetylation signals and transcripts derived from cardiomyocytes compared to non-myocyte populations. CONCLUSIONS: By integrating histone acetylome, transcriptome, and proteome profiles, we identified major effector genes and protein networks that drive the pathological changes in HCM with mutated MYBPC3. Our work identifies 38 highly affected protein-coding genes as potential plasma HCM biomarkers and 9 TFs as potential upstream regulators of these pathomechanisms that may serve as possible therapeutic targets.
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Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Proteínas Portadoras/genética , Metilación de ADN , Expresión Génica , Genes Homeobox , Histonas/genética , Humanos , Mutación , TranscriptomaRESUMEN
Traumatic injury to the back wall of the duodenum is a rare injury now. Due to rapid development of retroperitoneal flegmona from unknown damage to retroperitoneal wall of the duodenum it is necessary its early diagnosis. In the mentioned case we recall the perforating injury of the abdominal cavity with a back injury of the duodenal wall and its successful treatment by primary suture.
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Duodeno/lesiones , Heridas Punzantes , Adulto , Duodeno/patología , Duodeno/cirugía , Humanos , Masculino , Intento de Suicidio , Heridas Punzantes/patología , Heridas Punzantes/cirugíaRESUMEN
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. The authors present the rare common case localisation tumor in hepatal flexure of colon, witch presented as acute abdominal situation.
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Abdomen Agudo/etiología , Neoplasias del Colon/cirugía , Tumores del Estroma Gastrointestinal/diagnóstico , Adulto , Neoplasias del Colon/complicaciones , Neoplasias del Colon/patología , Tumores del Estroma Gastrointestinal/complicaciones , Tumores del Estroma Gastrointestinal/patología , Humanos , MasculinoRESUMEN
Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To increase our understanding of the transcriptional and epigenetic events associated with autophagy, we performed extensive genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human autophagy-proficient and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux. As a proof of principle that this resource can be used to identify novel autophagy regulators, we followed up on one identified target: EGR1 (early growth response 1), which indeed appears to be a central transcriptional regulator of autophagy by affecting autophagy-associated gene expression and autophagic flux. Taken together, these data stress the relevance of transcriptional and epigenetic regulation of autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation.
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Autofagia/fisiología , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Epigénesis Genética , Perfilación de la Expresión Génica , Lisosomas/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Regulación de la Expresión Génica , Células HEK293 , Humanos , NutrientesRESUMEN
One possibility of verifying malabsorbtion is by doing a biopsy of the duodenal mucosa for a histochemical examination. The authors present a complicated biopsy with a duodenal intramural haematoma, with caused signs of an ileus condition and of haemoperitoneum.
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Abdomen Agudo/etiología , Biopsia con Aguja/efectos adversos , Obstrucción Duodenal/etiología , Duodeno/patología , Hematoma/etiología , Niño , Hemoperitoneo/etiología , Humanos , MasculinoRESUMEN
Background: Posttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP-seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes. Results: Analysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions. Of the corresponding transcription factors, four were upregulated, SP1, ARNT2, HEY2, and VDR, and two downregulated, FOSL and NR4A1. Conclusion: We demonstrate a key role for genome-wide alterations in H3K27ac in FGR placentas corresponding with changes in transcription profiles of regions relevant to placental function. Future studies on the role of H3K27ac in FGR and placental-fetal development may help to identify novel targets for therapy of this currently incurable disease.
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Retardo del Crecimiento Fetal/genética , Histonas/metabolismo , Placenta/metabolismo , Acetilación , Inmunoprecipitación de Cromatina/métodos , Epigénesis Genética , Femenino , Desarrollo Fetal , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Embarazo , Procesamiento Proteico-Postraduccional , Receptores de Somatotropina/metabolismo , Análisis de Secuencia de ARN , Factores de TranscripciónRESUMEN
Adverse remodeling after myocardial infarction (MI) is strongly influenced by T cells. Stem cell therapy after MI, using mesenchymal stem cells (MSC) or cardiomyocyte progenitor cells (CMPC), improved cardiac function, despite low cell retention and limited differentiation. As MSC secrete many factors affecting T cell proliferation and function, we hypothesized the immune response could be affected as one of the targets of stem cell therapy. Therefore, we studied the immunosuppressive properties of human BM-MSC and CMPC and their extracellular vesicles (EVs) in co-culture with activated T cells. Proliferation of T cells, measured by carboxyfluorescein succinimidyl ester dilution, was significantly reduced in the presence of BM-MSC and CMPC. The inflammatory cytokine panel of the T cells in co-culture, measured by Luminex assay, changed, with strong downregulation of IFN-gamma and TNF-alpha. The effect on proliferation was observed in both direct cell contact and transwell co-culture systems. Transfer of conditioned medium to unrelated T cells abrogated proliferation in these cells. EVs isolated from the conditioned medium of BM-MSC and CMPC prevented T cell proliferation in a dose-dependent fashion. Progenitor cells presence induces up- and downregulation of multiple previously unreported pathways in T cells. In conclusion, both BM-MSC and CMPC have a strong capacity for in vitro immunosuppression. This effect is mediated by paracrine factors, such as extracellular vesicles. Besides proliferation, many additional pathways are influenced by both BM-MSC and CMPC.
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INTRODUCTION: The optimal parameters of low level laser therapy (LLLT) are still under debate. It has been documented that a dose or 5 J/cm2 would be capable to accelerate the wound healing process in patients. However, the optimal delivering form, i.e. power intensity, is unknown. Therefore, the aim of our study was to compare different power densities of LLLT. MATERIALS AND METHODS: Sixteen male Sprague-Dawley rats were included in this experiment and randomized into two groups, normal healthy group and streptozotocine induced diabetic group. In general anesthesia four full thickness skin incisions were performed under standard aseptic conditions on the back of each rat and immediately closed using intradermal running suture. Three wounds were stimulated with diode laser (wavelength: 635 nm; daily dose 5 J/cm2; power densities: 1 mW/cm2, 5 mW/cm2 and 15 mW/cm2) each with different power density while the fourth wound served as control. Six days after surgery animals were sacrificed and samples removed for histological evaluation. RESULTS: Our study demonstrated that LLLT positively influences wound healing. The most significant changes were observed in wounds stimulated at the highest power density 15 mW/cm2. Since using the highest power density the shortest time is needed to achieve the optimal daily dose of 5 J/cm2, it can be suggested that 15 mW/cm2 might be optimal parameter for such a therapy in patients.
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Diabetes Mellitus Experimental/fisiopatología , Terapia por Luz de Baja Intensidad , Cicatrización de Heridas , Animales , Masculino , Dosificación Radioterapéutica , Ratas , Ratas Sprague-Dawley , Piel/lesionesRESUMEN
Biocompatible iron chelators are currently under extensive investigation as promising drug candidates. Pyridoxal isonicotinoyl hydrazone (PIH) is a lead compound of the aroylhydrazone group of novel iron chelating agents. In this study, the precise and accurate HPLC analytical methods were used for the stability evaluation of water-soluble PIH salt (PIH x 2HCl) in aqueous media of different pH (2.0, 3.9, 7.0, 9.0 and 12.0) as well as in two selected pharmaceutical co-solvents at both laboratory and elevated (40 degrees C) temperatures. The susceptibility of PIH x 2HCl to oxidative decomposition was studied in the solutions of hydrogen peroxide (3 and 30%). Furthermore, the solid substance of PIH x 2HCl was exposed to UV, dry and wet heat. Our experiments revealed that PIH was considerably sensitive to hydrolytic decomposition in aqueous media, resulting in the splitting of the hydrazone bond. The elevated temperature significantly accelerated the hydrolytic reaction. The lowest rate of hydrolysis of PIH was observed in the phosphate buffer of pH 7.0 and in the pharmaceutical co-solvents (30% PEG-300 and 10% Cremophor EL). No special degradation products were detected in the samples exposed to either hydrogen peroxide or co-solvents. The solid substance of PIH x 2HCl was stable when exposed to UV, dry or wet heat for 33 h.
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Química Farmacéutica/métodos , Cromatografía Líquida de Alta Presión/métodos , Isoniazida/análogos & derivados , Piridoxal/análogos & derivados , Calibración , Técnicas de Química Analítica , Cromatografía , Relación Dosis-Respuesta a Droga , Hidrazonas/química , Peróxido de Hidrógeno/química , Concentración de Iones de Hidrógeno , Hidrólisis , Hierro/química , Quelantes del Hierro/farmacología , Isoniazida/análisis , Isoniazida/química , Cinética , Modelos Químicos , Oxígeno/química , Piridoxal/análisis , Piridoxal/química , Solventes/química , Temperatura , Factores de Tiempo , Rayos UltravioletaRESUMEN
The specific aim of this study was to measure the TS of rat skin wounds during the first week following surgical injury. Biomechanical and histological data were collected daily (days 1 to 7 following surgery) from separate groups of Sprague-Dawley rats (N = 12) each with two 3 cm long parallel skin incisions on the back. The wounds were immediately closed by four simple sutures. A control group (N = 15) was used to obtain TS measurements of unwounded skin. TS was measured by applying a ramp load until wound separation and estimated by dividing the yield strength by the wound area. The time course of biomechanical recovery followed a step-plateau pattern with the largest increase in TS observed one day after surgery (0 - 1.60 g/cm(2)). The plateau stage extended from day 1 to 5 (1.60 - 3.88 g/cm(2)). The final step (day 5-7) indicated a period of rapid rise in wound TS (3.88 - 11.57 g/cm(2)). Since even on day 7 the mean TS was only 4% of unwounded skin, the wound had to be protected from tensile loads. Histological analysis confirmed that the early changes in TS (day 1) correlated with the fibrin accumulation of the wound edges followed by a plateau stage caused by the tissue proliferation. The rapid increase in wound TS was characterized by cross-linking the incisions with collagen fibres with escalating organization. We conclude that from a biomechanical perspective, sutures can be removed during the "plateau phase", but the wound must be protected from tensile loads.
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Piel/patología , Piel/fisiopatología , Suturas/efectos adversos , Cicatrización de Heridas/fisiología , Heridas y Lesiones/patología , Heridas y Lesiones/fisiopatología , Animales , Femenino , Queratinas/metabolismo , Músculo Esquelético/fisiología , Ratas , Ratas Sprague-Dawley , Regeneración , Resistencia a la Tracción/fisiología , Heridas y Lesiones/etiologíaRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) frequently involves aberrant expression of TAL1 (T-cell acute lymphocytic leukemia 1) and LMO2, oncogenic members of the TAL1 transcriptional complex. Transcriptional activity of the TAL1-complex is thought to have a pivotal role in the transformation of thymocytes and is associated with a differentiation block and self-renewal. The transcription factor Forkhead Box P3 (FOXP3) was recently described to be expressed in a variety of malignancies including T-ALL. Here we show that increased FOXP3 levels negatively correlate with expression of genes regulated by the oncogenic TAL1-complex in human T-ALL patient samples as well as a T-ALL cell line ectopically expressing FOXP3. In these cells, FOXP3 expression results in altered regulation of cell cycle progression and reduced cell viability. Finally, we demonstrate that FOXP3 binds LMO2 in vitro, resulting in decreased interaction between LMO2 and TAL1, providing a molecular mechanism for FOXP3-mediated transcriptional modulation in T-ALL. Collectively, our findings provide initial evidence for a novel role of FOXP3 as a tumor suppressor in T-ALL through modulation of TAL1 transcriptional activity.