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BACKGROUND: The survival benefit of sentinel lymph node biopsy (SLNB) in immunocompetent and immunosuppressed patients with high-risk cutaneous squamous cell carcinoma (cSCC) has not been established. OBJECTIVE: To determine whether SLNB improves disease-specific survival (DSS) in high-risk cSCC. Secondary objectives were to analyse disease-free survival, nodal recurrence-free survival and overall survival (OS). METHODS: Multicentre, retrospective, observational cohort study comparing survival outcomes in immunosuppressed and immunocompetent patients treated with SLNB or watchful waiting. Inverse probability of treatment weighting was used to adjust for possible confounding effects. RESULTS: We studied 638 tumours in immunocompetent patients (SLNB n = 42, observation n = 596) and 173 tumours in immunosuppressed patients (SLNB n = 28, observation n = 145). Overall, SLNB was positive in 15.7% of tumours. SLNB was associated with a reduced risk of nodal recurrence (NR) (hazard ratio [HR], 0.05 [95% CI, 0.01-0.43]; p = 0.006), disease specific mortality (HR, 0.17 [95% CI, 0.04-0.72]; p = 0.016) and all-cause mortality (HR, 0.33 [95% CI, 0.15-0.71]; p = 0.004) only in immunocompetent patients. CONCLUSIONS: SLNB was associated with improvements in NR, DSS and OS in immunocompetent but not in immunosuppressed patients with high-risk cSCC.
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Carcinoma de Células Escamosas , Huésped Inmunocomprometido , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/mortalidad , Masculino , Estudios Retrospectivos , Femenino , Anciano , Persona de Mediana Edad , Inmunocompetencia , Anciano de 80 o más Años , Espera Vigilante , Supervivencia sin EnfermedadRESUMEN
BACKGROUND: Gallbladder cancer (GBC) is a prevalent and deadly biliary tract carcinoma, often diagnosed at advanced stages with limited treatment options. The 5-year survival rate varies widely from 4 to 60%, mainly due to differences in disease stage detection. With only a small fraction of patients having resectable tumors and a high incidence of metastasis, advanced GBC stages are characterized by significant chemoresistance. Identification of new therapeutic targets is crucial, and recent studies have shown that the Endothelin-1 (ET-1) signaling pathway, involving ETAR and/or ETBR receptors (ETRs), plays a crucial role in promoting tumor aggressiveness in various cancer models. Blocking one or both receptors has been reported to reduce invasiveness and chemoresistance in cancers like ovarian, prostate, and colon. Furthermore, transcriptomic studies have associated ET-1 levels with late stages of GBC; however, it remains unclear whether its signaling or its inhibition has implications for its aggressiveness. Although the role of ET-1 signaling in gallbladder physiology is minimally understood, its significance in other tumor models leads us to hypothesize its involvement in GBC malignancy. RESULTS: In this study, we investigated the expression of ET-1 pathway proteins in three GBC cell lines and a primary GBC culture. Our findings demonstrated that both ETAR and ETBR receptors are expressed in GBC cells and tumor samples. Moreover, we successfully down-regulated ET-1 signaling using a non-selective ETR antagonist, Macitentan, which resulted in reduced migratory and invasive capacities of GBC cells. Additionally, Macitentan treatment chemosensitized the cells to Gemcitabine, a commonly used therapy for GBC. CONCLUSION: For the first time, we reveal the role of the ET-1 pathway in GBC cells, providing insight into the potential therapeutic targeting of its receptors to mitigate invasion and chemoresistance in this cancer with limited treatment options. These findings pave the way for further exploration of Macitentan or other ETR antagonists as potential therapeutic strategies for GBC management. In summary, our study represents a groundbreaking contribution to the field by providing the first evidence of the ET 1 pathway's pivotal role in modulating the behavior and aggressiveness of GBC cells, shedding new light on potential therapeutic targets.
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BACKGROUND: Histopathological analysis of tissue samples is an ancillary complementary diagnostic tool in tuberculosis (TB) with variable sensitivity and specificity according to different clinical settings. We evaluated the spectrum of histological findings, their diagnostic sensitivity, diagnostic utility, and requests over time in a sample of archival biopsies. METHODS: Analysis of biopsies of confirmed TB cases between years 2011-2019 at a reference hospital in Chile. RESULTS: The series included patients with a histological study for TB confirmed by culture (88.9%) or PCR (11.1%). In total, 34 samples were available for analysis, most of them of extrapulmonary origin (82.4%). Biopsies were taken before the start of treatment in 26 cases (76.5%) or after the start-end of treatment for different reasons in 8 cases (23.5%). Restricting the analysis to the group with pretreatment biopsies, the prevalence/diagnostic sensitivity of granulomas was 93.3%, 69.2% for caseous necrosis, 26.9% for granulomas with caseous necrosis without acid-fast bacilli (AFB), and 46.2% for AFB in any histological context. A histological score was constructed to evaluate the homogeneity of lesions, observing that 76.9% had at least four of the six components of the score. The request for biopsies was maintained over time despite the increase in the use of molecular techniques. The presence of AFB contributed to the diagnosis before microbiological results in 23.1% of the cases. CONCLUSIONS: Histological study continues to contribute to the diagnosis of TB, especially in extrapulmonary forms.
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Sensibilidad y Especificidad , Tuberculosis , Humanos , Biopsia/métodos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Tuberculosis/diagnóstico , Tuberculosis/patología , Tuberculosis/microbiología , Chile , Mycobacterium tuberculosis/aislamiento & purificación , Mycobacterium tuberculosis/genética , Anciano , Adulto Joven , Estudios Retrospectivos , Adolescente , Granuloma/patología , Granuloma/microbiología , Granuloma/diagnósticoRESUMEN
OBJECTIVES: To characterize clinical aspects, evaluate the diagnostic opportunity, and identify factors associated with mortality in patients hospitalized for tuberculosis (TB). METHODS: Retrospective study of patients admitted for TB to a Regional Hospital in Chile between 2011 and 2019. RESULTS: 142 TB events required hospitalization in this period (38.2% of total cases). All risk groups were identified, with a significant increase in patients with diabetes mellitus. The pulmonary location was the most frequent (71.1%), followed by disseminated forms (16.2%). The sensitivity of microscopy smear in cases of pulmonary TB (isolated or combined) was 78.8% and lower in cases of bronchoalveolar lavage (58.3%). PCR was only occasionally applied (< 10%) with a sensitivity of 100% in sputum samples. Its use increased progressively and reached a positivity of 33% (6 out of 18 cases) in cases with negative sputum staining. The median time between symptom onset and diagnosis was prolonged (9 weeks), and 32.5% of all regional events were diagnosed at the hospital. Dose adjustments (22.1%), corticosteroid use (25%), and treatment interruptions were frequent (11%). Lethality reached 19%, and by multivariate analysis, only shock was associated with a fatal outcome. CONCLUSIONS: In this case series, the diagnosis of TB cases was delayed, scarcely diagnosed by molecular methods, highly concentrated at the hospital level, required admission in a large percentage of cases, and had a high case-fatality rate.
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Tuberculosis Pulmonar , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Chile/epidemiología , Adulto , Factores de Riesgo , Anciano , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/mortalidad , Adulto Joven , Hospitalización/estadística & datos numéricos , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tuberculosis/mortalidad , Adolescente , Esputo/microbiologíaRESUMEN
Poor response to current treatments for glioblastoma has been attributed to the presence of glioblastoma stem-like cells (GSCs). GSCs are able to expel antitumor drugs to the extracellular medium using the multidrug resistance-associated protein 1 (MRP1) transporter. Tacrolimus (FK506) has been identified as an MRP1 regulator in differentiated glioblastoma (GBM) cells (non-GSCs); however, the effect of FK506 on GSCs is currently unknown. The objective of the following research is to evaluate the effect of FK506 on the MRP1-related chemo-resistant phenotype of GSCs. For this, U87MG and C6 glioma cell lines were used to generate non-GSCs and GSCs. mRNA and MRP1-positive cells were evaluated by RT-qPCR and flow cytometry, respectively. A Carboxyfluorescein Diacetate (CFDA)-retention assay was performed to evaluate the MRP1 activity. Apoptosis and MTT assays were employed to evaluate the cytotoxic effects of FK506 plus Vincristine (MRP1 substrate). GSC-derived subcutaneous tumors were generated to evaluate the in vivo effect of FK506/Vincristine treatment. No differences in transcript levels and positive cells for MRP1 were observed in FK506-treated cells. Lesser cell viability, increased apoptosis, and CFDA-retention in the FK506/Vincristine-treated cells were observed. In vivo, the FK506/Vincristine treatment decreased the tumor size as well as ki67, Glial Fibrillary Acidic Protein (GFAP), and nestin expression. We conclude that FK506 confers a chemo-sensitive phenotype to MRP1-drug substrate in GSCs.
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Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Células Madre Neoplásicas/efectos de los fármacos , Tacrolimus/uso terapéutico , Vincristina/uso terapéutico , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Masculino , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fenotipo , Ratas Sprague-Dawley , Tacrolimus/farmacología , Vincristina/farmacologíaRESUMEN
BACKGROUND: It is accepted that T regulatory cells (Treg) control different types of immune responses. In connection with this role, we have recently described an important increase in CD4+, CD25high, Foxp3+ lymphocytes in the airway system of horses coursing with an exacerbation of severe equine asthma (EA). To explore the potential role of this population in the resolution of EA inflammation, we used a murine experimental model in which airway neutrophilic inflammation, which is similar to that observed in EA, is induced in mice by continual exposure to Aspergillus fumigatus contaminated hay. This model has the advantage that in mice we may induce a reduction of the Treg population using low doses of cyclophosphamide (Cy). RESULTS: The results indicated that the percentage of Treg cells increased with allergen exposure, as in horses; and animals partially depleted of Treg cells by treatment with Cy showed increased airway inflammation, demonstrated by an increased percentage of neutrophils and specific immunoglobulins in bronchoalveolar lavage fluid (BALF). Furthermore, a histopathologic study of animals that were pretreated with Cy before antigenic challenge showed higher cellular infiltration in the lung and deeper remodeling changes in the bronchi, including epithelial and goblet cell hyperplasia as well as airway smooth muscle hypertrophy. CONCLUSION: In this murine model of EA, the reduced number and function of Treg induced by low doses of Cy, which directly correlates with increased airway inflammation and lung infiltration, indicates that Treg may play a major role in the regulation and resolution of EA.
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Asma/veterinaria , Enfermedades de los Caballos/inmunología , Linfocitos T Reguladores/fisiología , Enfermedad Aguda , Alérgenos/inmunología , Alimentación Animal/microbiología , Animales , Aspergillus fumigatus/inmunología , Asma/inmunología , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Femenino , Caballos , Ratones , Linfocitos T Reguladores/inmunologíaRESUMEN
The most aggressive type of brain tumor is glioblastoma multiforme, which to date remains incurable. Thuja occidentalis is used in homeopathy for the treatment of cancer, however, its mechanism of action remains unknown. We set out to study the effects of thujone fractions of Thuja on glioblastoma using in vitro and in vivo models. We found that the α/ ß-thujone fraction decrease the cell viability and exhibit a potent anti-proliferative, pro-apoptotic and anti-angiogenic effects in vitro. In vivo assays showed that α /ß-thujone promotes the regression of neoplasia and inhibits the angiogenic markers VEGF, Ang-4 and CD31 into the tumor.
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Antineoplásicos/farmacología , Glioblastoma/tratamiento farmacológico , Monoterpenos/farmacología , Fitoterapia , Extractos Vegetales/farmacología , Thuja , Inhibidores de la Angiogénesis/farmacología , Animales , Apoptosis/efectos de los fármacos , Monoterpenos Bicíclicos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Glioblastoma/irrigación sanguínea , Glioblastoma/patología , Glioblastoma/fisiopatología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Masculino , Trasplante de Neoplasias , Ratas Sprague-DawleyRESUMEN
Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.
Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal networktargeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.
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Although the general location of functional neural networks is similar across individuals, there is vast person-to-person topographic variability. To capture this, we implemented precision brain mapping functional magnetic resonance imaging methods to establish an open-source, method-flexible set of precision functional network atlases-the Masonic Institute for the Developing Brain (MIDB) Precision Brain Atlas. This atlas is an evolving resource comprising 53,273 individual-specific network maps, from more than 9,900 individuals, across ages and cohorts, including the Adolescent Brain Cognitive Development study, the Developmental Human Connectome Project and others. We also generated probabilistic network maps across multiple ages and integration zones (using a new overlapping mapping technique, Overlapping MultiNetwork Imaging). Using regions of high network invariance improved the reproducibility of executive function statistical maps in brain-wide associations compared to group average-based parcellations. Finally, we provide a potential use case for probabilistic maps for targeted neuromodulation. The atlas is expandable to alternative datasets with an online interface encouraging the scientific community to explore and contribute to understanding the human brain function more precisely.
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Encéfalo , Conectoma , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Encéfalo/fisiología , Encéfalo/diagnóstico por imagen , Adolescente , Masculino , Femenino , Adulto , Adulto Joven , Red Nerviosa/fisiología , Red Nerviosa/diagnóstico por imagen , Mapeo Encefálico/métodos , Atlas como Asunto , Niño , Probabilidad , Vías Nerviosas/fisiologíaRESUMEN
BACKGROUND: the masseteric nerve is one of the main options to neurotize free muscle flaps in irreversible long-term facial paralysis. Several preoperative skin marking techniques for the masseteric nerve have been proposed to limit the surgical dissection area, shorten the surgical time, and enable a safer dissection. However, these have shown variability amongst them and cannot preoperatively visualize the nerve. Thus, we aim to design an observational study to validate a high-frequency ultrasound (HFUS) nerve identification technique. METHODS: a systematic HFUS examination was designed and performed to visualize the masseteric nerve in 64 hemifaces of healthy volunteers. One-third were randomly selected to undergo an additional HFUS-guided needle electrostimulation to validate the HFUS image. RESULTS: the masseteric nerve was identified by HFUS in 96,9% of hemifaces (95% CI 0.89 to >0.99) and showed almost perfect agreement with direct needle stimulation as calculated with Cohen's kappa coefficient; 0.95 (CI 0.85 to 1.00). It was found within the masseter muscle, in between the deeper muscle bellies, at 18,3 mm (SD ±2,2) from the skin. Only in 12,9% of cases (95 CI 0.06 to 0.24) its course became adjacent to the mandible periosteum. Other important features, such as disposition in relation to the parotid gland or whether the nerve was directly covered by a thick intramuscular aponeurosis, could be well observed by HFUS. CONCLUSIONS: HFUS enables masseteric nerve identification and can give the surgeon specific information on anatomical relations for each examined individual prior to surgery.
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We reported mono and bimetallic ferrocene-based 1,2,3-triazolyl compounds as potential burning rate catalysts in their neutral and ionic forms. All complexes reported here were characterized using 1H and 13C NMR, elemental analysis, and Mössbauer spectroscopy, which was performed for neutral and oxide compounds. The complexes present quasireversible redox potentials with higher oxidative ability than ferrocene and catocene under the same conditions. The complexes were tested as catalysts on the thermal decomposition of ammonium perchlorate (AP) and examined by a differential scanning calorimetry technique to gain further knowledge about their catalytic behavior. Compound 1 causes a decrease of the high-temperature decomposition (HTD) of AP positively, decreasing the decomposition temperature of AP to 345 °C and consequently increasing the energy release to 1939 J·g-1. We took the residues from the pans after testing from the DSC to elucidate the underlying reaction pathways. We obtained the size of the nanostructures formed after thermal decomposition of AP determined by the TEM technique. The diameter and size distribution of iron oxide nanoparticles formed depend on the alkyl sidechain of the triazolium ring, which induces the formation of nanoparticles with a double diameter and size distribution compared to their neutral analogues, suggesting that the possible intermediate for the mechanism degradation of AP by ferrocene derivatives is nanoscale Fe2O3 or similar oxides.
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Gallbladder cancer (GBC) is commonly diagnosed at late stages when conventional treatments achieve only modest clinical benefit. Therefore, effective treatments for advanced GBC are needed. In this context, the administration of T cells genetically engineered with chimeric antigen receptors (CAR) has shown remarkable results in hematological cancers and is being extensively studied for solid tumors. Interestingly, GBC tumors express canonical tumor-associated antigens, including the carcinoembryonic antigen (CEA). However, the potential of CEA as a relevant antigen in GBC to be targeted by CAR-T cell-based immunotherapy has not been addressed. Here we show that CEA was expressed in 88% of GBC tumors, with higher levels associated with advanced disease stages. CAR-T cells specifically recognized plate-bound CEA as evidenced by up-regulation of 4-1BB, CD69 and PD-1, and production of effector cytokines IFN-γ and TNF-α. In addition, CD8+ CAR-T cells up-regulated the cytotoxic molecules granzyme B and perforin. Interestingly, CAR-T cell activation occurred even in the presence of PD-L1. Consistent with these results, CAR-T cells efficiently recognized GBC cell lines expressing CEA and PD-L1, but not a CEA-negative cell line. Furthermore, CAR-T cells exhibited in vitro cytotoxicity and reduced in vivo tumor growth of GB-d1 cells. In summary, we demonstrate that CEA represents a relevant antigen for GBC that can be targeted by CAR-T cells at the preclinical level. This study warrants further development of the adoptive transfer of CEA-specific CAR-T cells as a potential immunotherapy for GBC.
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Neoplasias de la Vesícula Biliar , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/genética , Antígeno Carcinoembrionario/genética , Inmunoterapia Adoptiva/métodos , Antígeno B7-H1 , Neoplasias de la Vesícula Biliar/terapia , Inmunoterapia , Linfocitos TRESUMEN
Gallbladder cancer (GBC) is a rare pathology in Western countries. However, it constitutes a relevant health problem in Asia and Latin America, with a high mortality in middle-aged Chilean women. The limited therapeutic options for GBC require the identification of targetable proteins with prognostic value for improving clinical management support. We evaluated the expression of targetable proteins, including three epithelial tumor markers, four proteins associated with multidrug and apoptosis resistance, and eleven immunological markers in 241 primary gallbladder adenocarcinomas. We investigated correlations between tumor marker expression, the primary tumor staging, and GBC patients' survival using automated immunohistochemistry, a semi-automatic method for image analysis, univariate and multivariate statistical analyses, and machine learning algorithms. Our data show a significant association between the expression of MRP2 (p = 0.0028), CXCR4 (p = 0.0423), and PD-L1 (p = 0.0264), and a better prognosis for patients with late-stage primary tumors. The expression of the MRP2/CXCR4/PD-L1 cluster of markers discriminates among short-, medium-, and long-term patient survival, with an ROC of significant prognostic value (AUC = 0.85, p = 0.0012). Moreover, a high MRP2/CXCR4/PD-L1 co-expression is associated with increased survival time (30 vs. 6 months, p = 0.0025) in GBC patients, regardless of tumor stage. Hence, our results suggest that the MRP2/CXCR4/PD-L1 cluster could potentially be a prognostic marker for GBC.
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The characterization of individual functional brain organization with Precision Functional Mapping has provided important insights in recent years in adults. However, little is known about the ontogeny of inter-individual differences in brain functional organization during human development, but precise characterization of systems organization during periods of high plasticity might be most influential towards discoveries promoting lifelong health. Collecting and analyzing precision fMRI data during early development has unique challenges and emphasizes the importance of novel methods to improve data acquisition, processing, and analysis strategies in infant samples. Here, we investigate the applicability of two such methods from adult MRI research, multi-echo (ME) data acquisition and thermal noise removal with Noise reduction with distribution corrected principal component analysis (NORDIC), in precision fMRI data from three newborn infants. Compared to an adult example subject, T2* relaxation times calculated from ME data in infants were longer and more variable across the brain, pointing towards ME acquisition being a promising tool for optimizing developmental fMRI. The application of thermal denoising via NORDIC increased tSNR and the overall strength of functional connections as well as the split-half reliability of functional connectivity matrices in infant ME data. While our findings related to NORDIC denoising are coherent with the adult literature and ME data acquisition showed high promise, its application in developmental samples needs further investigation. The present work reveals gaps in our understanding of the best techniques for developmental brain imaging and highlights the need for further developmentally-specific methodological advances and optimizations, towards precision functional imaging in infants.
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Resting-state functional connectivity (RSFC) is a powerful tool for characterizing brain changes, but it has yet to reliably predict higher-order cognition. This may be attributed to small effect sizes of such brain-behavior relationships, which can lead to underpowered, variable results when utilizing typical sample sizes (Nâ¼25). Inspired by techniques in genomics, we implement the polyneuro risk score (PNRS) framework - the application of multivariate techniques to RSFC data and validation in an independent sample. Utilizing the Adolescent Brain Cognitive Development® cohort split into two datasets, we explore the framework's ability to reliably capture brain-behavior relationships across 3 cognitive scores - general ability, executive function, learning & memory. The weight and significance of each connection is assessed in the first dataset, and a PNRS is calculated for each participant in the second. Results support the PNRS framework as a suitable methodology to inspect the distribution of connections contributing towards behavior, with explained variance ranging from 1.0 % to 21.4 %. For the outcomes assessed, the framework reveals globally distributed, rather than localized, patterns of predictive connections. Larger samples are likely necessary to systematically identify the specific connections contributing towards complex outcomes. The PNRS framework could be applied translationally to identify neurologically distinct subtypes of neurodevelopmental disorders.
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Mapeo Encefálico , Cognición , Adolescente , Humanos , Mapeo Encefálico/métodos , Encéfalo , Factores de Riesgo , Función Ejecutiva , Imagen por Resonancia Magnética/métodosRESUMEN
Bicarbonate secretion is a fundamental process involved in maintaining acid-base homeostasis. Disruption of bicarbonate entry into airway lumen, as has been observed in cystic fibrosis, produces several defects in lung function due to thick mucus accumulation. Bicarbonate is critical for correct mucin deployment and there is increasing interest in understanding its role in airway physiology, particularly in the initiation of lung disease in children affected by cystic fibrosis, in the absence of detectable bacterial infection. The current model of anion secretion in mammalian airways consists of CFTR and TMEM16A as apical anion exit channels, with limited capacity for bicarbonate transport compared to chloride. However, both channels can couple to SLC26A4 anion exchanger to maximise bicarbonate secretion. Nevertheless, current models lack any details about the identity of the basolateral protein(s) responsible for bicarbonate uptake into airway epithelial cells. We report herein that the electrogenic, sodium-dependent, bicarbonate cotransporter, SLC4A4, is expressed in the basolateral membrane of human and mouse airways, and that it's pharmacological inhibition or genetic silencing reduces bicarbonate secretion. In fully differentiated primary human airway cells cultures, SLC4A4 inhibition induced an acidification of the airways surface liquid and markedly reduced the capacity of cells to recover from an acid load. Studies in the Slc4a4-null mice revealed a previously unreported lung phenotype, characterized by mucus accumulation and reduced mucociliary clearance. Collectively, our results demonstrate that the reduction of SLC4A4 function induced a CF-like phenotype, even when chloride secretion remained intact, highlighting the important role SLC4A4 plays in bicarbonate secretion and mammalian airway function.
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Proteína 1 de Intercambio de Anión de Eritrocito/metabolismo , Fibrosis Quística , Animales , Bicarbonatos/metabolismo , Cloruros/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Mamíferos/metabolismo , Ratones , Fenotipo , Sodio/metabolismo , Simportadores de Sodio-Bicarbonato/genéticaRESUMEN
The solid-pseudopapillary tumors of the pancreas (TSPP) are a uncommon neoplasm (1- 2% of exocrine tumors). Are more frequent in young women and presents a low malignant potential (15% develop metastases). Its preoperative diagnosis is very difficult, because these tumors haven`t radiological features that makes distinguish from the other pancreatic cysts tumors. Usually are a histopathological finding. Surgical therapy provides good survival, even in the presence of metastases. We present 3 cases with clinical, imaging, treatment and histopathology to provide more information about this rare disease.
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Neoplasias Pancreáticas , Adulto , Femenino , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirugía , Adulto JovenRESUMEN
Gallbladder cancer (GBC) is an aggressive and highly lethal disease with relatively low global incidence, but one that constitutes a major health problem in Asian and Latin American countries, particularly in Chile. The identification of new tumor-associated markers with potential prognosis value is required for GBC clinical practice. Using immunohistochemistry/tumor tissue microarray, we evaluated the expression of 17 gastrointestinal tumor-associated protein markers (CK7, CK17, CK19, CK20, CKLMW, CKHMW, MUC1, MUC2, MUC5AC, MUC6, CA125, CD10, CEA, vimentin, villin, claudin-4, and CDX2) in primary gallbladder adenocarcinomas from 180 Chilean patients and analyzed potential associations with their pathological and clinical characteristics. Younger female patients with well- to moderately differentiated tumors had a better prognosis than that of older female or male patients with tumors with a similar tumor differentiation grade. Among all analyzed markers, MUC6 expression was associated with better prognosis in patients with well- to moderately differentiated tumors, whereas CK17 or CD10 was associated with worse prognosis in patients with poorly differentiated tumors. In addition, the MUC6+CK17- expression pattern was strongly associated with better prognosis in patients with well- to moderately differentiated tumors, whereas patients with poorly differentiated tumors and with the CK17+CD10+ expression pattern showed worse prognosis. Our results suggest that tumor MUC6, CK17, and CD10 can be considered as potential prognosis markers for GBC.
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Epstein-Barr virus (EBV) is a ubiquitous herpes virus with a widespread infection in the world's adult population. EBV has been associated with human malignancies, mainly the nasal type NK/T cell lymphoma. The disease is more frequent in Asian than in Western countries. However, there are few studies from Latin American countries. The aim of this study was to determine the prevalence of EBV in patients with nasal lymphomas diagnosed in the Regional Hospital of Valdivia, southern Chile, during 1987-2005. Immunohistochemistry was done on paraffin sections using anti-CD3epsilon, anti-CD20, and anti-CD56. The presence of small ribonucleic acids (RNAs) of EBV was detected in paraffin sections by in situ hybridization using oligonucleotides targeting EBV-encoded small RNAs. The present study revealed a prevalence of 27.7% of Hodgkin's lymphomas and 72.3% of non-Hodgkin's lymphomas. From the latter group, there was a prevalence of 2.9% (10 cases) of nasal lymphoma. From these 10 cases, 6 (60%) were NK/T cell lymphomas, nasal type; 1 case (10%) was a T-cell phenotype; and 3 cases (30%) were B-cell phenotype. The prevalence was higher than reports from Western countries, but lower than the reports from Asian countries. These results agreed with previous reports suggesting that EBV is strongly associated with T lymphomas. This study contributes new epidemiological data on EBV in Chile.
Asunto(s)
Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4/aislamiento & purificación , Linfoma/virología , Neoplasias Nasales/virología , Adulto , Anciano , Chile/epidemiología , Infecciones por Virus de Epstein-Barr/virología , Hospitales , Humanos , Inmunohistoquímica , Hibridación in Situ , Linfoma/patología , Masculino , Persona de Mediana Edad , Neoplasias Nasales/patología , Prevalencia , ARN Viral/genéticaRESUMEN
In South America Andes hantavirus (ANDV) is hosted by the rodent Oligoryzomys longicaudatus (also known as pygmy rice rat). In humans, ANDV causes Hantavirus Pulmonary Syndrome (HPS), with a fatality rate of about 40%. Epidemiologic and molecular evidence has shown that ANDV can be transmitted from person to person. Sin Nombre hantavirus, occurring in North America, and ANDV are genetically related, and both cause HPS with similar clinical evolution and mortality rate. However, only ANDV is transmitted from person to person. A recent hantavirus outbreak in a small village in Southern Argentine, with 29 HPS cases and 11 deaths has brought to mind that person-to-person transmission continues to be a public health emergency. The present investigation was aimed to understand how does ANDV actually spread between persons. Tissue samples of lung and salivary glands from infected Oligoryzomys longicaudatus and lethal cases of human HPS were investigated by bright field immunocytochemistry, multichannel immunofluorescence, and transmission electron microscopy. The findings are consistent with ANDV infection and replication in the lung alveolar epithelium and macrophages, and in the secretory cells of the submandibular salivary glands. In the lung of infected Oligoryzomys longicaudatus and human cases HPS, the bulk of immunoreactive hantavirus antigens was localized in epithelial cells of the alveolar walls and macrophages. The ultrastructural study supports that in the lung of HPS patients the virus replicates in the alveolar epithelial cells with virus particles being discharged into the alveolar lumen. Virus-like particles were seen within vacuoles of the lung macrophages. Considering that these macrophages can reach the conductive segments of the airways, their expectoration becomes a deadly bullet for ANDV transmission. In the submandibular glands of infected rodents and HPS cases, ANDV antigens were in capillary endothelium, the secretory cells and filling the lumen of the excretory pathway. It is proposed that in patients with HPS caused by ANDV the alveolar epithelium and macrophages would be the gate for the airway spreading of the virus, while the salivary glands are a target for virus replication and an exit pathway through saliva.