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BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Inestabilidad de Microsatélites , Mutación , Paclitaxel , Humanos , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación , Anciano , Carboplatino/administración & dosificación , Carboplatino/farmacología , Carboplatino/uso terapéutico , Inmunoterapia/métodos , Fosfohidrolasa PTEN/genética , Adulto , Supervivencia sin Progresión , Biomarcadores de Tumor/genética , Proteína p53 Supresora de Tumor/genética , Proteínas de Unión al ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Factores de Transcripción , Fosfatidilinositol 3-Quinasa Clase IRESUMEN
PURPOSE: Radioiodine I-131 (RAI) is the therapy of choice for differentiated thyroid cancer (DTC). Between 5% and 15% of DTC patients become RAI refractory, due to the loss of expression/function of iodide metabolism components, especially the Na/I symporter (NIS). We searched for a miRNA profile associated with RAI-refractory DTC to identify novel biomarkers that could be potential targets for redifferentiation therapy. METHODS: We analyzed the expression of 754 miRNAs in 26 DTC tissues: 12 responsive (R) and 14 non-responsive (NR) to RAI therapy. We identified 15 dysregulated miRNAs: 14 were upregulated, while only one (miR-139-5p) was downregulated in NR vs. R tumors. We investigated the role of miR-139-5p in iodine uptake metabolism. We overexpressed miR-139-5p in two primary and five immortalized thyroid cancer cell lines, and we analyzed the transcript and protein levels of NIS and its activation through iodine uptake assay and subcellular protein localization. RESULTS: The finding of higher intracellular iodine levels and increased cell membrane protein localization in miR-139-5p overexpressing cells supports the role of this miRNA in the regulation of NIS function. CONCLUSIONS: Our study provides evidence of miR-139-5p involvement in iodine uptake metabolism and suggests its possible role as a therapeutic target in restoring iodine uptake in RAI-refractory DTC.
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Yodo , MicroARNs , Simportadores , Neoplasias de la Tiroides , Humanos , Radioisótopos de Yodo/uso terapéutico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Simportadores/genéticaRESUMEN
We investigate the relaxation dynamics of protein-polymer conjugates by neutron scattering spectroscopy to understand to which extent the coating of a protein by a polymer can replace water in promoting thermal structural fluctuations. For this purpose, we compare the dynamics of protein-polymer mixtures to that of conjugates with a variable number of polymers covalently attached to the protein. Results show that the flexibility of the protein is larger in protein-polymer mixtures than in native protein or in conjugates, even in the dry state. Upon hydration, both the native protein and the conjugate show equivalent dynamics, suggesting that the polymer grafted on the protein surface adsorbs all water molecules.
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Organofosfatos/química , Poliésteres/química , Albúmina Sérica Bovina/química , Animales , Bovinos , Docilidad , Agua/químicaRESUMEN
Photodynamic Therapy (PDT) is a minimally invasive approach that has shown promising results in management of oral, head and neck lesions. PDT can be used alone or in combination with other conventional treatments (surgery, chemotherapy, radiotherapy). Oral Lichen Planus (OLP) is a mucosal and cutaneous chronic disease characterized by an autoimmune insult of basal keratinocytes. We aim to evaluate the feasibility of topical toluidine blue-mediated PDT for the treatment of oral cavity multifocal homogeneous white lesions by oral lichen planus without dysplastic features.
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Liquen Plano Oral/tratamiento farmacológico , Fotoquimioterapia , Cloruro de Tolonio/uso terapéutico , Enfermedad Crónica , Humanos , Fármacos FotosensibilizantesRESUMEN
PURPOSE: Aim of this study was to evaluate the association between body mass index (BMI) and aggressive features of differentiated thyroid cancer (DTC) in a prospective cohort. METHODS: Patients with DTC were prospectively enrolled at a tertiary referral center and grouped according to their BMI. Aggressive clinic-pathological features were analyzed following the American Thyroid Association Initial Risk Stratification System score. RESULTS: The cohort was composed of 432 patients: 5 (1.2%) were underweight, 187 (43.3%) normal weight, 154 (35.6%) overweight, 68 (15.7%) grade 1 obese, 11 (2.5%) grade 2 obese and 7 (1.6%) grade 3 obese. No single feature of advanced thyroid cancer was more frequent in obese patients than in others. No significant correlation was found between BMI, primary tumor size (Spearman's ρ - 0.02; p = 0.71) and ATA Initial Risk Stratification System score (ρ 0.03; p = 0.49), after adjustment for age. According to the multivariate logistic regression analysis, male gender and pre-surgical diagnosis of cancer were significant predictors of cancer with high or intermediate-high recurrence risk according to the ATA system (OR 2.06 and 2.51, respectively), while older age at diagnosis was a protective factor (OR 0.98), and BMI was not a predictor. BMI was a predictor of microscopic extrathyroidal extension only (OR 1.06). CONCLUSIONS: Obesity was not associated with aggressive features in this prospective, European cohort of patients with DTC.
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Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Obesidad/diagnóstico , Obesidad/epidemiología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/epidemiología , Adulto , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estudios ProspectivosRESUMEN
Intrasellar plasmacytoma is a rare pituitary tumor, which originates from monoclonal plasma cells in a single lesion. Knowledge of its features comes from case reports only. Here, we present an interesting case of a 77-year-old woman with a presumptive diagnosis of non-functioning pituitary adenoma, as based on both clinical and radiological examinations. Following endoscopic endonasal transsphenoidal surgery, the definitive diagnosis of intrasellar plasmacytoma was made by immunohistochemical analysis of the sellar mass. Intrasellar plasmacytoma is rare, but it should be evaluated in the differential diagnosis of a pituitary mass due to its different therapeutic approach and prognosis, since it can frequently progress to multiple myeloma.
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BACKGROUND: Mycosis fungoides (MF) is the major subtype of cutaneous T-cell lymphomas (CTCL). It usually has a prolonged indolent clinical course with a minority of cases acquiring a more aggressive biological profile and resistance to conventional therapies, partially attributed to the persistent activation of nuclear factor-kappa B (NF-κB) pathway. In the last decade, several papers suggested an important role for the FK506-binding protein 51 (FKBP51), an immunophilin initially cloned in lymphocytes, in the control of NF-κB pathway in different types of human malignancies. OBJECTIVES: We aimed to investigate the possible value of FKBP51 expression as a new reliable marker of outcome in patients with MF. METHODS: We assessed by immunohistochemistry (IHC) FKBP51 expression in 44 patients with MF, representative of different stages of the disease. Immunohistochemical results were subsequently confirmed at mRNA level with quantitative PCR (qPCR) in a subset of enrolled patients. In addition, IHC and qPCR served to study the expression of some NF-κB-target genes, including the tumour necrosis factor receptor-associated factor 2 (TRAF2). RESULTS: Our results show that FKBP51 was expressed in all evaluated cases, with the highest level of expression characterizing MFs with the worst prognosis. Moreover, a significant correlation subsisted between FKBP51 and TRAF2 IHC expression scores. CONCLUSIONS: We hypothesize a role for FKBP51 as a prognostic marker for MF and suggest an involvement of this immunophilin in deregulated NF-κB pathway of this CTCL.
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Micosis Fungoide/metabolismo , ARN Mensajero/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismo , Proteínas de Unión a Tacrolimus/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Dermatitis/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Micosis Fungoide/genética , Pronóstico , Piel/metabolismo , Factor 2 Asociado a Receptor de TNF/genética , Proteínas de Unión a Tacrolimus/genética , Timo/metabolismoRESUMEN
Introduced species represent a threat to native wildlife worldwide, due to predation, competition, and disease transmission. Concurrent introduction of parasites may also add a new dimension of competition, i.e. parasite-mediated competition, through spillover and spillback dynamics. Urban areas are major hotspots of introduced species, but little is known about the effects of urban habitat structure on the parasite load and diversity of introduced species. Here, we investigated such environmental effects on the ectoparasite load, richness, and occurrence of spillback in two widespread invasive parakeets, Psittacula krameri and Myiopsitta monachus, in the metropolitan area of Rome, central Italy. We tested 231 parakeets and found that in both species parasite load was positively influenced by host abundance at local scale, while environmental features such as the amount of natural or urban habitats, as well as richness of native birds, influenced parasite occurrence, load, and richness differently in the two host species. Therefore, we highlight the importance of host population density and habitat composition in shaping the role of introduced parakeets in the spread of both native and introduced parasites, recommending the monitoring of urban populations of birds and their parasites to assess and manage the potential occurrence of parasite-mediated competition dynamics as well as potential spread of vector-borne diseases.
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Enfermedades de las Aves/parasitología , Enfermedades de las Aves/transmisión , Especies Introducidas , Carga de Parásitos , Psittacula/parasitología , Animales , Ecosistema , Especificidad del Huésped , Italia , Parásitos/clasificación , Parásitos/aislamiento & purificación , Densidad de PoblaciónRESUMEN
PURPOSE: C-peptide has been shown to exert several, previously unknown, biological effects. A recent cross-sectional study demonstrated an association between low C-peptide serum levels and low lumbar bone density of postmenopausal women not affected by diabetes. To date, very little research attention has been directed toward the association between C-peptide and osteoporotic fractures. To contribute toward filling this gap, we investigated the association between C-peptide and fractures in postmenopausal women. METHODS: A cohort of 133 non-diabetic postmenopausal women with and without a history of fractures was evaluated in this cross-sectional investigation. Standardized interviews were performed to gather information on the patients' fracture history. All of the participants underwent a bone mineral density assessment by DXA, radiographs, and a serum C-peptide measurement. RESULTS: Thirty-four women presented fractures. Bivariate analysis revealed an inverse correlation between C-peptide and fractures (r = -0.27, p = 0.002). A significant difference in mean C-peptide levels was also found between women with vs. without fractures (p = 0.01, adjusted for age, BMI and glucose). Logistic regression analysis showed that C-peptide levels, femoral and vertebral BMD were all negatively associated with fracture status (B = -1.097, ES = 0.401, p = 0.006, 95% CI 0.15-0.73; B = -15.6, SE = 4.17, p < 0.001, CI 0.001-0.002; B = -24.8, SE = 5.23, p < 0.001, CI 0001-0.002; respectively). CONCLUSIONS: This study confirms an inverse association between serum C-peptide levels and a history of fractures in postmenopausal women without diabetes. These results suggest that C-peptidemay exert an effect on bone mineral density. However, further large-scale studies are needed to corroborate this finding and investigate the potential underlying mechanisms involved.
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Biomarcadores/sangre , Densidad Ósea , Péptido C/deficiencia , Diabetes Mellitus , Osteoporosis Posmenopáusica/diagnóstico , Fracturas Osteoporóticas/diagnóstico , Anciano , Péptido C/sangre , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Italia/epidemiología , Persona de Mediana Edad , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/epidemiología , Fracturas Osteoporóticas/sangre , Fracturas Osteoporóticas/epidemiología , Posmenopausia , Prevalencia , Pronóstico , Factores de RiesgoRESUMEN
Urbanisation and climate change are two global change processes that affect animal distributions, posing critical threats to biodiversity. Due to its versatile ecology and synurbic habits, Kuhl's pipistrelle (Pipistrellus kuhlii) offers a unique opportunity to explore the relative effects of climate change and urbanisation on species distributions. In a climate change scenario, this typically Mediterranean species is expected to expand its range in response to increasing temperatures. We collected 25,132 high-resolution occurrence records from P. kuhlii European range between 1980 and 2013 and modelled the species' distribution with a multi-temporal approach, using three bioclimatic variables and one proxy of urbanisation. Temperature in the coldest quarter of the year was the most important factor predicting the presence of P. kuhlii and showed an increasing trend in the study period; mean annual precipitation and precipitation seasonality were also relevant, but to a lower extent. Although urbanisation increased in recently colonised areas, it had little effect on the species' presence predictability. P. kuhlii expanded its geographical range by about 394 % in the last four decades, a process that can be interpreted as a response to climate change.
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Distribución Animal/fisiología , Quirópteros/fisiología , Cambio Climático , Urbanización , Animales , Modelos Biológicos , Lluvia , Estaciones del Año , TemperaturaRESUMEN
BACKGROUND: The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage. PATIENTS AND METHODS: To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period. RESULTS: Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011). CONCLUSIONS: The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome. CLINICAL TRIAL NUMBERS: NCT00510926, NCT00514488, NCT00769327, NCT00481052.
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Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Esplenomegalia/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Bazo/patología , Adulto JovenRESUMEN
Protein low-frequency vibrational modes are an important portion of a proteins' dynamical repertoire. Yet, it is notoriously difficult to isolate specific vibrational features in the spectra of proteins. Given an appropriately chosen model peptide, and using different experimental conditions, we can simplify the system and gain useful insights into the protein vibrational properties. Combining neutron scattering, depolarized light scattering, and molecular dynamics simulations, we analyse the low frequency vibrations of biological molecules, comparing the results from a small globular protein, lysozyme, and an amphiphilic peptide, NALMA, both in solution and in powder states. Lysozyme and NALMA present similar spectral features in the frequency range between 1 and 10 THz. With the aid of MD simulations, we assign the spectral features to methyl groups' librations (1-5 THz) and hindered torsions (5-10 THz) in NALMA. Our data also show that, while proteins display boson peak vibrations in both powder and solution forms, NALMA exhibits boson peak vibrations in powder form only. This provides insight into the nature of this feature, suggesting a connection of BP collective motions to a characteristic length scale of heterogeneities present in the system. These results provide context for the use of model peptide systems to study protein dynamics; demonstrating both their utility, and the great care that has to be used in extrapolating results observed in powder to solutions.
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Leucina/análogos & derivados , Muramidasa/química , Vibración , Leucina/química , Simulación de Dinámica Molecular , Muramidasa/metabolismoRESUMEN
BACKGROUND: Non-functioning (NF) pancreatic neuroendocrine tumors (pNET) often have an indolent outcome. A consensus to submit patients with large (>2 cm) NF-pNET to surgery already exists; but a conservative approach for small (≤2 cm) NF neoplasms has been proposed. AIM: To identify prognostic factors for survival and progression free survival (PFS) of NF-pNET, evaluating whether surgery may be avoided for small NF-pNET. SUBJECTS AND METHODS: Retrospective study of 77 consecutive patients with pNET submitted to surgery, of which 60 were NF. Pathological tissues were revised according to the 2000 and 2010 WHO classifications. Risk factors for survival and PFS were evaluated using the Kaplan-Meier method and the Cox regression model. RESULTS: The 8-year cause-specific survival of NF-pNET was 79.3%. At univariate analysis, high grading, high staging, large tumors, angioinvasion and peri-pancreatic infiltration were significantly associated with a shorter survival; at multivariate analysis only peri-pancreatic infiltration was significantly associated with a shorter NF-pNET survival. Most small NF-pNET were grade 1 (74%), compared to large NF-pNET (27%). Distant metastases were present in 29.7% (n = 11) and 17.4% (n = 4) of patients with large or small NF-pNET, respectively; among the 19 small NF-pNET without metastasis, five had a local malignancy (lymph node metastasis or local infiltration); thus, 39% of the 23 NF-pNET, turned out to have a malignant potential. CONCLUSIONS: Among NF-pNET, large neoplasms were associated with worse outcomes; however, small NF-pNET do not seem to have an invariable benign behavior. Whether surgery should be avoided in all patients with small NF-pNET is questionable.
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Metástasis Linfática/patología , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Individuals at clinical high risk (CHR) for psychosis represent a heterogeneous group with a high rate of comorbid psychiatric disorders. There is little information on whether certain qualitative aspects of psychotic symptoms among CHR individuals may be predictive of future psychosis. This study focused on describing the prevalence of first-rank symptoms (FRS) among a sample of CHR individuals and its association with future transition to psychosis and, from a neurodevelopmental perspective, the level of adjustment of individuals at CHR during their childhood was also analysed. SAMPLING AND METHODS: Participants comprised 60 individuals at CHR (according to the Comprehensive Assessment of At-Risk Mental States, CAARMS) at the time of their referral to an early intervention service and 60 healthy volunteers (HVs). All subjects were assessed by senior research clinicians using the Mini International Neuropsychiatric Interview (MINI), and the Positive and Negative Syndrome Scale (PANSS). FRS were defined according to Kurt Schneider's original classification, and information was collected from PANSS, CAARMS and clinical reports. Early premorbid functioning was measured using the Premorbid Adjustment Scale (PAS). We grouped individuals by number and type of FRS and analysed transitions to full-blown psychosis over a 2-year follow-up period. We also correlated the general social and functional adjustment of these individuals during their childhood (6-11 years of age) with the future development of mental states at CHR and FRS. RESULTS: Over 69% of CHR individuals had more than one DSM-IV psychiatric diagnosis, mainly within the affective and anxiety diagnostic spectra. At least one FRS was present in 43.3% of CHR individuals, and 21.6% of these had more than one. Auditory hallucinations and passivity experiences were the most commonly reported. Only 10% of individuals at CHR made a transition to first-episode psychosis (FEP) over 2 years and, except for passivity experiences, the presence of one or more FRS was not significantly associated with the transition to FEP. CHR individuals, especially those with FRS, had poorer premorbid functioning and adjustment as children across educational, social and peer relationship domains than HVs. However, this was not associated with FEP 2 years later. CONCLUSIONS: FRS might not be indicators of psychosis alone but of different psychiatric disorders. In line with the neurodevelopmental model of psychosis, individuals at CHR might be exhibiting several vulnerability traits and manifestations of abnormal developmental processes that might predict a future psychiatric disorder and/or long-term impairment.
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Adaptación Psicológica , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/psicología , Ajuste Social , Adolescente , Adulto , Ansiedad/psicología , Trastornos de Ansiedad/psicología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Incidencia , Masculino , Servicios de Salud Mental , Prevalencia , Trastornos Psicóticos/prevención & control , Medición de Riesgo , Factores de Riesgo , Reino Unido , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Vesicle-associated membrane-protein-associated protein B (VAPB) is an endoplasmic reticulum (ER) resident protein participating in ER function, vesicle trafficking, calcium homeostasis and lipid transport. Its N-terminal domain, named MSP, is cleaved and secreted, serving as an extracellular ligand. VAPB mutations are linked to autosomal-dominant motor neuron diseases, including amyotrophic lateral sclerosis (ALS) type 8. An altered VAPB function is also suspected in sporadic ALS (SALS). METHODS: The expression pattern of VAPB cleavage and secreted products in the peripheral blood leukocytes (PBL) and cerebrospinal fluid (CSF) of SALS patients and neurological controls was assessed. PBL from healthy controls were also analyzed. Assays were carried out through western blotting, using an anti-VAPB (N-terminal) antibody. RESULTS: Two VAPB fragments containing the MSP domain (17 kDa and 14 kDa molecular sizes) were identified in PBL of SALS and controls, with no significant differences amongst groups. In CSF, only the 14 kDa VAPB MSP fragment was expressed and a corresponding VAPA fragment was not detected. The CSF VAPB fragment was absent in 58.7% of SALS patients, of whom 79.2% were bulbar onset (P = 0.001, bulbar versus spinal). CONCLUSIONS: The absence of the CSF VAPB MSP fragment from most bulbar-onset SALS patients suggests a specific alteration of brain-derived VAPB cleavage and secretion in this group of patients, and hints at a role of VAPB in the pathophysiology of this motor neuron disease.
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Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/patología , Leucocitos/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Peso Molecular , Mutación/genética , Estadísticas no Paramétricas , Proteínas de Transporte Vesicular/genéticaRESUMEN
BACKGROUND: Bacterial, fungal, and viral infections often affect non-relapse mortality after allogeneic stem cell transplantation (alloSCT). Recovery from infections depends on a balanced integration between innate and adaptive immune responses. In this complex interplay, a key role is played by Toll-like receptors (TLRs), which are sensors of pathogen-associated molecular patterns. To our knowledge, no previous study deals with both expression and function of all human TLRs together, in relation to infections in the setting of alloSCT. METHODS: We prospectively evaluated 9 TLRs by flow cytometry on T lymphocytes and monocytes of 35 patients in relation to infectious events from day +30 to day +120. Tumor necrois factor-alpha, interleukin-4, interferon-gamma, and monocyte chemoattractant protein-1 induction upon TLR activation was assessed by enzyme-linked immunosorbent assay on cell supernatants. RESULTS: In multivariate Cox regression analysis, levels of TLR-9 expression on T lymphocytes (P = 0.01) and values of natural killer cells (P = 0.01) correlated negatively with bacterial infections, whereas cytomegalovirus (CMV) infection resulted as a positive predictor. We observed a trend for negative correlation between TLR-7 levels on T lymphocytes and fungal infections (P = 0.07). Values of monocytes were negatively associated with CMV infection (P = 0.03), whereas levels of TLR-5 on T lymphocytes were positive predictors (P = 0.01). Age (P = 0.03) and bacterial infections (P = 0.006) negatively influenced overall survival. Monocyte values were positive predictors of survival (P = 0.003). CONCLUSIONS: Bacterial, fungal, and CMV infections were associated with a different expression of some TLRs on T lymphocytes. The protective role of TLR-7 and TLR-9 seemed dominant over other TLRs involved in recognizing fungi and bacteria. We also observed an atypical involvement of TLR-5 in CMV infection. The dominant and atypical role of some TLRs could depend on their pleiotropic functions and the changing inflammatory environment of transplanted patients. A specific TLR profile and an adequate count of monocytes could improve survival, promoting an effective control of infections, and balanced immune responses. If our findings will be confirmed by further studies, these immunological variables could be useful as parameters to predict susceptibility to infections.