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The growing nanoparticulate pollution (e.g. engineered nanoparticles (NPs) or nanoplastics) has been shown to pose potential threats to human health. In particular, sensitive populations such as pregnant women and their unborn children need to be protected from harmful environmental exposures. However, developmental toxicity from prenatal exposure to pollution particles is not yet well studied despite evidence of particle accumulation in human placenta. Our study aimed to investigate how copper oxide NPs (CuO NPs; 10-20 nm) and polystyrene nanoplastics (PS NPs; 70 nm) impact on gene expression in ex vivo perfused human placental tissue. Whole genome microarray analysis revealed changes in global gene expression profile after 6 h of perfusion with sub-cytotoxic concentrations of CuO (10 µg/mL) and PS NPs (25 µg/mL). Pathway and gene ontology enrichment analysis of the differentially expressed genes suggested that CuO and PS NPs trigger distinct cellular response in placental tissue. While CuO NPs induced pathways related to angiogenesis, protein misfolding and heat shock responses, PS NPs affected the expression of genes related to inflammation and iron homeostasis. The observed effects on protein misfolding, cytokine signaling, and hormones were corroborated by western blot (accumulation of polyubiquitinated proteins) or qPCR analysis. Overall, the results of the present study revealed extensive and material-specific interference of CuO and PS NPs with placental gene expression from a single short-term exposure which deserves increasing attention. In addition, the placenta, which is often neglected in developmental toxicity studies, should be a key focus in the future safety assessment of NPs in pregnancy.
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Cobre , Nanopartículas , Embarazo , Humanos , Femenino , Cobre/toxicidad , Poliestirenos/toxicidad , Microplásticos , Transcriptoma , Placenta , Nanopartículas/toxicidad , ÓxidosRESUMEN
The varied transcriptomic response to nanoparticles has hampered the understanding of the mechanism of action. Here, by performing a meta-analysis of a large collection of transcriptomics data from various engineered nanoparticle exposure studies, we identify common patterns of gene regulation that impact the transcriptomic response. Analysis identifies deregulation of immune functions as a prominent response across different exposure studies. Looking at the promoter regions of these genes, a set of binding sites for zinc finger transcription factors C2H2, involved in cell stress responses, protein misfolding and chromatin remodelling and immunomodulation, is identified. The model can be used to explain the outcomes of mechanism of action and is observed across a range of species indicating this is a conserved part of the innate immune system.
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Nanoestructuras , Dedos de Zinc , Dedos de Zinc/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Perfilación de la Expresión Génica , Proteínas de PlantasRESUMEN
BACKGROUND: Chronic inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis (PSO) present major challenges in health care. Thus, biomarkers to identify disease trajectories and response to treatments to improve the lives of affected individuals warrant great research consideration. The requirements that these biomarkers must fulfil for use as practical clinical tools have not yet been adequately investigated. AIM: To identify the core elements of high-quality AD and PSO biomarkers to prepare recommendations for current biomarker research. METHOD: A cross-sectional two-round Delphi survey was conducted from August to October 2019 and October to November 2020. All participants were members of the BIOMAP project, an EU-funded consortium of clinicians, researchers, patient organizations and pharmaceutical industry partners. The first round consisted of three open-ended questions. Responses were qualitatively analysed, and 26 closed statements were developed. For the second round, 'agreement' was assumed when the responses of ≥70% of the participants were ≥5 points on a 7-point Likert scale for each statement. Priority classification was based on mean scores (<20th percentile = low, 20th to 60th percentile = medium, >60th percentile = high). RESULTS: Twenty-one and twenty-six individuals participated in rounds one and two, respectively. From 26 statements that were included in round 2, 18 achieved agreement (8 concerning the performance, 8 for the purpose and 2 on current obstacles). Seven statements were classified as high priority, e.g. those concerning reliability, clinical validity, a high positive predictive value, prediction of the therapeutic response and disease progression. Another seven statements were assigned medium priority, e.g. those about analytical validity, prediction of comorbidities and therapeutic algorithm. Low priority included four statements, like those concerning cost effectiveness and prediction of disease flares. CONCLUSION: The core requirements that experts agreed on being essential for high-quality AD and PSO biomarkers require rapid validation. Biomarkers can therefore be assessed based on these prioritized requirements.
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Dermatitis Atópica , Psoriasis , Biomarcadores , Consenso , Estudios Transversales , Técnica Delphi , Dermatitis Atópica/diagnóstico , Humanos , Motivación , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
BACKGROUND: A currently unsolved problem of open inguinal hernia repair (IHR) is chronic postoperative inguinal pain (CPIP), which affects 10-12% of patients after IHR. In the present paper, we explored the results of a newly designed partially absorbable mesh made of polypropylene and polylactic acid (HybridMesh®) for open hernia repair and its impact on postoperative safety, efficacy, comfort and pain. METHODS: A prospective multicentric pilot trial was conducted in third-referral centers across Italy (n = 5). Inclusion criteria were unilateral primary inguinal hernia in patients of both genders and BMI < 30 kg/m2. All patients were submitted to elective Lichtenstein mesh hernia repair under local anesthesia with HybridMesh. Primary outcome measure was the evaluation of Carolina Comfort Scale and modifications at 2 years after surgery and its correlation with surgical variables; secondary outcomes were postoperative early and late morbidity, recurrence and postoperative early quality of life. RESULTS: Between 2015 and 2016, 125 (5 female) patients were operated, 2-year follow-up rate was 100%. The surgical site occurrence rate was 28% without the need of procedural interventions. Twenty-four months after surgery, no case of severe CPIP was recorded and altered global CCS score was present in 16 patients (13.0%). At univariate analysis, CCS score was negatively affected by fixation with sutures (OR 3.949; 95% CI 1.334-13.300), with no effect shown on multivariate analysis. Alterations in pain and movement limitations domains of CCS were observed in 9.7% of patients, at univariate analysis; they occurred more frequently when the mesh was sutured (OR 4.437; 95% CI 1.387-17.025) and in patients suffering from SSO (ecchymosis: OR 3.269; 95% CI 1.032-10.405); however, no effect was shown on multivariate analysis. Two recurrences (1.6%) were identified within the first postoperative year. CONCLUSIONS: The results of this study support the safety, efficacy and good tolerability of HybridMesh as a device to treat primary unilateral inguinal hernia during open anterior approach. Further studies are needed to clarify its role in comparison to currently available devices at longer follow-ups.
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Hernia Inguinal/cirugía , Herniorrafia/métodos , Calidad de Vida/psicología , Mallas Quirúrgicas/normas , Femenino , Humanos , Masculino , Proyectos Piloto , Estudios ProspectivosRESUMEN
INTRODUCTION: Cri-du-Chat Syndrome (CdCS) is a genetic condition due to deletions showing different breakpoints encompassing a critical region on the short arm of chromosome 5, located between p15.2 and p15.3, first defined by Niebuhr in 1978. The classic phenotype includes a characteristic cry, peculiar facies, microcephaly, growth retardation, hypotonia, speech and psychomotor delay and intellectual disability. A wide spectrum of clinical manifestations can be attributed to differences in size and localization of the 5p deletion. Several critical regions related to some of the main features (such as cry, peculiar facies, developmental delay) have been identified. The aim of this study is to further define the genotype-phenotype correlations in CdCS with particular regards to the specific neuroradiological findings. PATIENTS AND METHODS: Fourteen patients with 5p deletions have been included in the present study. Neuroimaging studies were conducted using brain Magnetic Resonance Imaging (MRI). Genetic testing was performed by means of comparative genomic hybridization (CGH) array at 130 kb resolution. RESULTS: MRI analyses showed that isolated pontine hypoplasia is the most common finding, followed by vermian hypoplasia, ventricular anomalies, abnormal basal angle, widening of cavum sellae, increased signal of white matter, corpus callosum anomalies, and anomalies of cortical development. Chromosomal microarray analysis identified deletions ranging in size from 11,6 to 33,8 Mb on the short arm of chromosome 5. Then, we took into consideration the overlapping and non-overlapping deleted regions. The goal was to establish a correlation between the deleted segments and the neuroradiological features of our patients. CONCLUSIONS: Performing MRI on all the patients in our cohort, allowed us to expand the neuroradiological phenotype in CdCS. Moreover, possible critical regions associated to characteristic MRI findings have been identified.
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Encéfalo/diagnóstico por imagen , Encéfalo/patología , Síndrome del Maullido del Gato/diagnóstico por imagen , Síndrome del Maullido del Gato/patología , Adolescente , Adulto , Niño , Preescolar , Síndrome del Maullido del Gato/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética/métodos , Masculino , Adulto JovenRESUMEN
MOTIVATION: Omics technologies have the potential to facilitate the discovery of new biomarkers. However, only few omics-derived biomarkers have been successfully translated into clinical applications to date. Feature selection is a crucial step in this process that identifies small sets of features with high predictive power. Models consisting of a limited number of features are not only more robust in analytical terms, but also ensure cost effectiveness and clinical translatability of new biomarker panels. Here we introduce GARBO, a novel multi-island adaptive genetic algorithm to simultaneously optimize accuracy and set size in omics-driven biomarker discovery problems. RESULTS: Compared to existing methods, GARBO enables the identification of biomarker sets that best optimize the trade-off between classification accuracy and number of biomarkers. We tested GARBO and six alternative selection methods with two high relevant topics in precision medicine: cancer patient stratification and drug sensitivity prediction. We found multivariate biomarker models from different omics data types such as mRNA, miRNA, copy number variation, mutation and DNA methylation. The top performing models were evaluated by using two different strategies: the Pareto-based selection, and the weighted sum between accuracy and set size (w = 0.5). Pareto-based preferences show the ability of the proposed algorithm to search minimal subsets of relevant features that can be used to model accurate random forest-based classification systems. Moreover, GARBO systematically identified, on larger omics data types, such as gene expression and DNA methylation, biomarker panels exhibiting higher classification accuracy or employing a number of features much lower than those discovered with other methods. These results were confirmed on independent datasets. AVAILABILITY AND IMPLEMENTATION: github.com/Greco-Lab/GARBO. CONTACT: dario.greco@tuni.fi. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Variaciones en el Número de Copia de ADN , Neoplasias , Algoritmos , Biomarcadores , Humanos , Neoplasias/genética , Medicina de PrecisiónRESUMEN
BACKGROUND AND AIMS: Low vitamin D (vitD) has been linked to increased cardiovascular (CV) risk, but the effects of vitD supplementation are not clarified. We evaluated the impact of vitD normalization on HDL cholesterol efflux capacity (CEC), which inversely correlates with CV risk, the proatherogenic serum cholesterol loading capacity (CLC), adipokine profile and subclinical atherosclerosis. METHODS AND RESULTS: Healthy premenopausal women with vitD deficiency (n = 31) underwent supplementation. Subclinical atherosclerosis was evaluated by flow-mediated dilation (FMD), pulse wave velocity (PWV) and augmentation index (AIx), measured with standard techniques. HDL CEC and serum CLC were measured by a radioisotopic and fluorimetric assay, respectively. Malondialdehyde (MDA) in HDL was quantified by the TBARS assay. Pre-ß HDL was assessed by 2D-electrophoresis. Serum adipokines were measured by ELISA. VitD replacement restored normal levels of serum 25-hydroxyvitamin D (25OHD) and significantly improved FMD (+4%; p < 0.001), PWV (-4.1%: p < 0.001) and AIx (-16.1%; p < 0.001). Total CEC was significantly improved (+19.5%; p = 0.003), with a specific increase in the ABCA1-mediated CEC (+70.8%; p < 0.001). HDL-MDA slightly but significantly decreased (-9.6%; p = 0.027), while no difference was detected in pre-ß HDL. No change was observed in aqueous diffusion nor in the ABCG1-mediated CEC. Serum CLC was significantly reduced (-13.3%; p = 0.026). Levels of adiponectin were increased (+50.6%; p < 0.0001) and resistin levels were decreased (-24.3%; p < 0.0001). After vitD replacement, an inverse relationship was found linking the ABCA1-mediated CEC with pre-ß HDL (r2 = 0.346; p < 0.001) and resistin (r2 = 0.220; p = 0.009). CONCLUSION: Our data support vitD supplementation for CV risk prevention.
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Adipoquinas/sangre , Aterosclerosis/prevención & control , Colecalciferol/administración & dosificación , HDL-Colesterol/sangre , Suplementos Dietéticos , Lipoproteínas de Alta Densidad Pre-beta/sangre , Premenopausia/sangre , Deficiencia de Vitamina D/tratamiento farmacológico , Transportador 1 de Casete de Unión a ATP/metabolismo , Adulto , Enfermedades Asintomáticas , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Aterosclerosis/etiología , Biomarcadores/sangre , Colecalciferol/efectos adversos , Suplementos Dietéticos/efectos adversos , Femenino , Humanos , Prueba de Estudio Conceptual , Resistina/sangre , Factores de Tiempo , Resultado del Tratamiento , Turquía , Vitamina D/análogos & derivados , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/diagnósticoRESUMEN
Upper and lower respiratory symptoms and asthma are adverse health effects associated with moisture-damaged buildings. Quantitative measures to detect adverse health effects related to exposure to dampness and mold are needed. Here, we investigate differences in gene expression between occupants of moisture-damaged and reference buildings. Moisture-damaged (N = 11) and control (N = 5) buildings were evaluated for dampness and mold by trained inspectors. The transcriptomics cohort consisted of nasal brushings and peripheral blood mononuclear cells (PBMCs) from 86 teachers, with/without self-perceived respiratory symptoms. Subject categories comprised reference (R) and damaged (D) buildings with (S) or without (NS) symptoms, that is, R-S, R-NS, DS, and D-NS. Component analyses and k-means clustering of transcriptome profiles did not distinguish building status (R/D) or presence of respiratory symptoms (S/NS). Only one nasal mucosa gene (YBX3P1) exhibited a significant change in expression between D-S and D-NS. Nine other nasal mucosa genes were differentially expressed between R-S and D-S teachers. No differentially expressed genes were identified in PBMCs. We conclude that the observed mRNA differences provide very weak biological evidence for adverse health effects associated with subject occupancy of the specified moisture-damaged buildings. This emphasizes the need to evaluate all potential factors (including those not related to toxicity) influencing perceived/self-reported ill health in moisture-damaged buildings.
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BACKGROUND/AIM: Low dose rate brachytherapy has been used as salvage therapy for locally recurrent prostate cancer (PC) after primary external beam radiation therapy (EBRT), along with surgery and cryotherapy. All these techniques, in particular, when applied to the whole gland, involve a relatively high risk of toxicity and may worsen the patient's quality of life. Our aim is to evaluate the results of whole-gland salvage brachytherapy (SBT) after primary EBRT in terms of toxicity, functional outcomes, and efficacy. MATERIALS AND METHODS: We retrospectively reviewed clinical data on 19 patients consecutively treated with SBT at our institution between June 2012 and November 2015. Local recurrences were identified with 11C-choline positron emission tomography/computed tomography and pelvic magnetic resonance imaging after biochemical recurrence according to Phoenix criteria (prostate-specific antigen nadir + 2). Low dose rate brachytherapy was performed by 125I permanent seeds implantation to the whole prostate gland, with a prescription dose of 130 Gy. At the time of SBT, only 2 patients were receiving androgen deprivation therapy. Acute and late toxicities were recorded using the CTCAE 4.0 scoring system. Quality of life was assessed using IPSS (International Prostate Symptoms Score) and IIEF (International Index of Erectile Function) questionnaires at baseline and 6, 12, and 24 months after SBT, and the respective mean values were compared using Student t test. Biochemical relapse-free survival (BRFS) was also calculated. RESULTS: Median follow-up after SBT was 24 months. Of 19 patients, 2 patients experienced a G3 cystitis (10.2%) and 1 patient experienced a G4 proctitis (5.3%), respectively. Mean pre-SBT IPSS scores and 6, 12, and 24 months after SBT were 5.84, 10.22, 15.72, and 8.10, respectively. Mean pre-SBT IIEF scores and 6, 12, and 24 months after SBT were 8.42, 3.55, 7.89, and 6.40, respectively. At the time of analysis, only 2 patients showed a biochemical relapse (3-year BRFS 85.2%). The Student t test demonstrated a worsening of functional outcome 6 months and 1 year after treatment but a subsequent improvement 2 years after SBT. CONCLUSIONS: Salvage brachytherapy for recurrent PC after primary EBRT seems to be a feasible treatment for selected patients. Our series revealed a severe toxicity peak 6 months and 1 year after local re-treatment and then they decrease. Early BRFS rates are good. However, these are very preliminary results so further patient accrual, long-term follow-up, and prospective trials are needed in the future.
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Clinical pertussis resulting from infection with B. pertussis is a significant medical and public health problem, despite the huge success of vaccination that has greatly reduced its incidence. The whole cell vaccine had an undeniable success over the last 50 years, but its acceptance was strongly inhibited by fear, only partially justified, of severe side effects, but also, in the Western world, by the difficulty to enter in combination with other vaccines: today multi-vaccine formulations are essential to maintain a high vaccination coverage. The advent of acellular vaccines was greeted with enthusiasm by the public health world: in the Nineties, several controlled vaccine trials were carried out: they demonstrated a high safety and good efficacy of new vaccines. In fact, in the Western world, the acellular vaccines completely replaced the whole cells ones. In the last years, ample evidence on the variety of protection of these vaccines linked to the presence of different antigens of Bordetella pertussis was collected. It also became clear that the protection provided, on average around 80%, leaves every year a significant cohort of vaccinated susceptible even in countries with a vaccination coverage of 95%, such as Italy. Finally, it was shown that, as for the pertussis disease, protection decreases over time, to leave a proportion of adolescents and adults unprotected. Waiting for improved pertussis vaccines, the disease control today requires a different strategy that includes a booster at 5 years for infants, but also boosters for teenagers and young adults, re-vaccination of health care personnel, and possibly of pregnant women and of those who are in contact with infants (cocooning). Finally, the quest for better vaccines inevitably tends towards pertussis acellular vaccines with at least three components, which have demonstrated superior effectiveness and have been largely in use in Italy for fifteen years.
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Vacuna contra la Tos Ferina/administración & dosificación , Vacunas Acelulares/administración & dosificación , Tos Ferina/epidemiología , Adolescente , Adulto , Humanos , Inmunización Secundaria , Lactante , Italia , Vacuna contra la Tos Ferina/efectos adversos , Factores de Tiempo , Vacunación/tendencias , Vacunas Acelulares/efectos adversos , Tos Ferina/prevención & controlRESUMEN
BACKGROUND: Data from animal studies suggest that glucagon-like peptide-1 analogues should not be used in pregnancy, but there have been no reports to date of their effects in human pregnancy. The aim of the present report was to describe a case of exposure to liraglutide during the first trimester of pregnancy in a patient with Type 2 diabetes mellitus. CASE REPORT: A 37-year-old woman with Type 2 diabetes mellitus who had been taking liraglutide for 2 years was admitted in the 13(th) week of gestation. Liraglutide was immediately discontinued and intensive insulin therapy instituted. The woman gave birth to a healthy child after completing an uneventful gestation period. CONCLUSION: Although the present normal pregnancy outcome does not mean that glucagon-like peptide-1 analogues are safe to use in pregnancy, this report contributes to the limited knowledge regarding human exposure to these drugs during pregnancy in women with diabetes.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Liraglutida/uso terapéutico , Primer Trimestre del Embarazo , Embarazo en Diabéticas/tratamiento farmacológico , Adulto , Sustitución de Medicamentos , Femenino , Humanos , Recién Nacido , Insulina/uso terapéutico , Liraglutida/efectos adversos , Embarazo , Resultado del Embarazo , Primer Trimestre del Embarazo/sangre , Primer Trimestre del Embarazo/efectos de los fármacosRESUMEN
BRCA1 is a multifunctional protein best known for its role in DNA repair and association with breast and ovarian cancers. To uncover novel biologically significant molecular functions of BRCA1, we tested a panel of 198 approved and experimental drugs to inhibit growth of MDA-MB-231 breast cancer cells depleted for BRCA1 by siRNA. 26S proteasome inhibitors bortezomib and carfilzomib emerged as a new class of selective BRCA1-targeting agents. The effect was confirmed in HeLa and U2OS cancer cell lines using two independent siRNAs, and in mouse embryonic stem (ES) cells with inducible deletion of Brca1. Bortezomib treatment did not cause any increase in nuclear foci containing phosphorylated histone H2AX, and knockdown of BRCA2 did not entail sensitivity to bortezomib, suggesting that the DNA repair function of BRCA1 may not be directly involved. We found that a toxic effect of bortezomib on BRCA1-depleted cells is mostly due to deregulated cell cycle checkpoints mediated by RB1-E2F pathway and 53BP1. Similar to BRCA1, depletion of RB1 also conferred sensitivity to bortezomib, whereas suppression of E2F1 or 53BP1 together with BRCA1 reduced induction of apoptosis after bortezomib treatment. A gene expression microarray study identified additional genes activated by bortezomib treatment only in the context of inactivation of BRCA1 including a critical involvement of the ERN1-mediated unfolded protein response. Our data indicate that BRCA1 has a novel molecular function affecting cell cycle checkpoints in a manner dependent on the 26S proteasome activity.
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Proteína BRCA1/genética , Ácidos Borónicos/farmacología , Neoplasias de la Mama/genética , Regulación hacia Abajo , Inhibidores de Proteasoma/farmacología , Pirazinas/farmacología , Animales , Proteína BRCA1/metabolismo , Bortezomib , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Silenciador del Gen , Humanos , Ratones , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: In this prospective non-randomized observational cohort study we evaluated: the feasibility and effectiveness of primary umbilical hernia repair with open tension-free and sutureless technique using a porcine small intestinal submucosa (Surgisis) prosthesis, the quality of the treatment in terms of reduction of postoperative discomfort and the complications at early and long-term follow-up. METHODS: Thirty-six consecutive patients, mean age 45.25 +/- 12.19 years, affected by primary umbilical uncomplicated hernia with a defect size < or = 3 cm, were treated in a day-surgery setting. A tailored flat Surgisis graft was used to ensure an overlap of at least 2 cm; in all patients the mesh was fixed by fibrin glue. Collected data included: visual analogic scale (VAS) pain scores at 24 hours, 72 hours, and 7, 15, and 30 days and number of analgesic medications after operation, complications rate, the quality of life measured by Short Form 36 health survey questionnaire (SF-36) before the operation and at long term follow-up. RESULTS: The mean follow-up time was 5.6 +/- 1.4 years. Postoperative pain was low: the mean visual analogic scale (VAS) scores were 2.8 at 24 h, 1.8 at 72 h, and 0.9, 0.3, and 0.04 at 7, 15, and 30 days, respectively. 77.8% of the patients (28/36) did not use any analgesic drugs. Seroma was reported in 13.8% of the patients (5/36); there were no hematomas, infection, chronic pain and no major complications or mortality (< or = 30 days). Recurrence rate was 2.8% (1/36). Patient satisfaction showed a significant improvement in all SF-36 domain scores (P < 0.001). CONCLUSIONS: The biologic mesh seems to be a safe and reliable device for repairing primary umbilical hernia with high patient comfort, even if not yet an alternative to synthetic mesh.
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Colágeno/uso terapéutico , Hernia Umbilical/cirugía , Herniorrafia/instrumentación , Dolor Postoperatorio/prevención & control , Mallas Quirúrgicas , Adulto , Anciano , Estudios de Factibilidad , Femenino , Adhesivo de Tejido de Fibrina , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Prevención Secundaria , Técnicas de Sutura , Factores de Tiempo , Resultado del TratamientoRESUMEN
Neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells and express general and specific neuroendocrine markers. Neuropeptide S receptor 1 (NPSR1) is expressed in neuroendocrine cells and its ligand neuropeptide S (NPS) affects cell proliferation. Our aim was to study whether NPS/NPSR1 could be used as a biomarker for neuroendocrine neoplasms and to identify the gene pathways affected by NPS/NPSR1. We collected a cohort of NETs comprised of 91 samples from endocrine glands, digestive tract, skin, and lung. Tumor type was validated by immunostaining of chromogranin-A and synaptophysin expression and tumor grade was analyzed by Ki-67 proliferation index. NPS and NPSR1 expression was quantified by immunohistochemistry using polyclonal antibodies against NPS and monoclonal antibodies against the amino-terminus and carboxy-terminus of NPSR1 isoform A (NPSR1-A). The effects of NPS on downstream signaling were studied in a human SH-SY5Y neuroblastoma cell line which overexpresses NPSR1-A and is of neuroendocrine origin. NPSR1 and NPS were expressed in most NET tissues, with the exception of adrenal pheochromocytomas in which NPS/NPSR1 immunoreactivity was very low. Transcriptome analysis of NPSR1-A overexpressing cells revealed that mitogen-activated protein kinase (MAPK) pathways, circadian activity, focal adhesion, transforming growth factor beta, and cytokine-cytokine interactions were the most altered gene pathways after NPS stimulation. Our results show that NETs are a source of NPS and NPSR1, and that NPS affects cancer-related pathways.
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Neoplasias de las Glándulas Endocrinas/fisiopatología , Neoplasias Gastrointestinales/fisiopatología , Tumores Neuroendocrinos/fisiopatología , Receptores Acoplados a Proteínas G/fisiología , Transducción de Señal/fisiología , Neoplasias Cutáneas/fisiopatología , Adulto , Anciano , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/fisiología , Proliferación Celular , Neoplasias de las Glándulas Endocrinas/patología , Femenino , Neoplasias Gastrointestinales/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/patología , Neuropéptidos/inmunología , Neuropéptidos/fisiología , Receptores Acoplados a Proteínas G/inmunología , Estudios Retrospectivos , Neoplasias Cutáneas/patologíaRESUMEN
We examined the function of the oxysterol receptors (LXRs) in inflammatory bowel disease (IBD) through studying dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice and by elucidating molecular mechanisms underlying their anti-inflammatory action. We observed that Lxr-deficient mice are more susceptible to colitis. Clinical indicators of colitis including weight loss, diarrhea and blood in feces appeared earlier and were more severe in Lxr-deficient mice and particularly LXRß protected against symptoms of colitis. Addition of an LXR agonist led to faster recovery and increased survival. In contrast, Lxr-deficient mice showed slower recovery and decreased survival. In Lxr-deficient mice, inflammatory cytokines and chemokines were increased together with increased infiltration of immune cells in the colon epithelium. Activation of LXRs strongly suppressed expression of inflammatory mediators including TNFα. While LXRα had anti-inflammatory effects in CD11b(+) immune cell populations, LXRß in addition had anti-inflammatory effects in colon epithelial cells. Lack of LXRß also induced CD4(+)/CD3(+) immune cell recruitment to the inflamed colon. Expression of both LXRA and LXRB was significantly suppressed in inflamed colon from subjects with IBD compared with non-inflamed colon. Taken together, our observations suggest that the LXRs could provide interesting targets to reduce the inflammatory responses in IBD.
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Colitis/inducido químicamente , Colitis/inmunología , Colon/inmunología , Sulfato de Dextran/toxicidad , Receptores Nucleares Huérfanos/inmunología , Trinitrobencenos/toxicidad , Animales , Colitis/genética , Colitis/patología , Colitis/prevención & control , Colon/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Receptores X del Hígado , Ratones , Ratones Noqueados , Receptores Nucleares Huérfanos/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaAsunto(s)
Encefalopatías/diagnóstico , Disfonía/diagnóstico , Hiperalgesia/diagnóstico , Bulbo Raquídeo/fisiopatología , Anciano , Encefalopatías/patología , Encefalopatías/fisiopatología , Disfonía/patología , Disfonía/fisiopatología , Femenino , Humanos , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Bulbo Raquídeo/patología , SíndromeAsunto(s)
Antimetabolitos Antineoplásicos/farmacología , Azacitidina/farmacología , Metilación de ADN/efectos de los fármacos , Histonas/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Acetilación/efectos de los fármacos , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células Cultivadas , Epigénesis Genética/efectos de los fármacos , Epigenómica , HumanosRESUMEN
BACKGROUND: Hospital-acquired infections (HAI) are an important public health problem worldwide. Little information is available from African countries, but published data show that the burden of HAI is greater in Africa than in developed countries. In 2002, the World Health Organization (WHO) published guidelines for preventing HAI. AIM: To evaluate the impact of a hospital infection control programme on the prevalence of HAI among patients in a large Ugandan hospital. METHODS: A one-day cross-sectional prevalence survey and a ward procedure survey were performed in Lacor Hospital in March 2010 using standardized questionnaires. All patients admitted to hospital not less than two days before the survey were eligible to participate in the prevalence survey. Modified WHO criteria for HAI were used. The ward procedure survey examined the procedures to prevent HAI. Several hospital infection control measures were subsequently implemented, in accordance with WHO infection control guidelines, starting in October 2010. The prevalence survey and ward procedure survey were repeated in October 2011. FINDINGS: The prevalence of HAI was 34% in 2010 and 17% in 2011. The prevalence of infected patients reduced from 28% to 14%. The prevalence of HAI was lower in all age groups and for all types of HAI except urinary tract infections following the implementation of infection control activities. CONCLUSION: This study showed that HAI is an important problem in this large African hospital, and that the prevalence of HAI can be reduced effectively following the adoption of basic infection control procedures.