Targeted proteomics of plasma extracellular vesicles uncovers MUC1 as combinatorial biomarker for the early detection of high-grade serous ovarian cancer.

BACKGROUND: The five-year prognosis for patients with late-stage high-grade serous carcinoma (HGSC) remains dismal, underscoring the critical need for identifying early-stage biomarkers. This study explores the potential of extracellular vesicles (EVs) circulating in blood, which are believed to harbor proteomic cargo reflective of the HGSC microenvironment, as a source for biomarker discovery. RESULTS: We conducted a comprehensive proteomic profiling of EVs isolated from blood plasma, ascites, and cell lines of patients, employing both data-dependent (DDA) and data-independent acquisition (DIA) methods to construct a spectral library tailored for targeted proteomics. Our investigation aimed at uncovering novel biomarkers for the early detection of HGSC by comparing the proteomic signatures of EVs from women with HGSC to those with benign gynecological conditions. The initial cohort, comprising 19 donors, utilized DDA proteomics for spectral library development. The subsequent cohort, involving 30 HGSC patients and 30 control subjects, employed DIA proteomics for a similar purpose. Support vector machine (SVM) classification was applied in both cohorts to identify combinatorial biomarkers with high specificity and sensitivity (ROC-AUC > 0.90). Notably, MUC1 emerged as a significant biomarker in both cohorts when used in combination with additional biomarkers. Validation through an ELISA assay on a subset of benign (n = 18), Stage I (n = 9), and stage II (n = 9) plasma samples corroborated the diagnostic utility of MUC1 in the early-stage detection of HGSC. CONCLUSIONS: This study highlights the value of EV-based proteomic analysis in the discovery of combinatorial biomarkers for early ovarian cancer detection.

Large-scale coupling of prefrontal activity patterns as a mechanism for cognitive control in health and disease: evidence from rodent models.

Cognitive control of behavior is crucial for well-being, as allows subject to adapt to changing environments in a goal-directed way. Changes in cognitive control of behavior is observed during cognitive decline in elderly and in pathological mental conditions. Therefore, the recovery of cognitive control may provide a reliable preventive and therapeutic strategy. However, its neural basis is not completely understood. Cognitive control is supported by the prefrontal cortex, structure that integrates relevant information for the appropriate organization of behavior. At neurophysiological level, it is suggested that cognitive control is supported by local and large-scale synchronization of oscillatory activity patterns and neural spiking activity between the prefrontal cortex and distributed neural networks. In this review, we focus mainly on rodent models approaching the neuronal origin of these prefrontal patterns, and the cognitive and behavioral relevance of its coordination with distributed brain systems. We also examine the relationship between cognitive control and neural activity patterns in the prefrontal cortex, and its role in normal cognitive decline and pathological mental conditions. Finally, based on these body of evidence, we propose a common mechanism that may underlie the impaired cognitive control of behavior.

Tandem SERS and MS/MS Profiling of Plasma Extracellular Vesicles for Early Ovarian Cancer Biomarker Discovery.

Extracellular vesicles (EVs) are vectors of biomolecular cargo that play essential roles in intercellular communication across a range of cells. Protein, lipid, and nucleic acid cargo harbored within EVs may serve as biomarkers at all stages of disease; however, the choice of methodology may challenge the specificity and reproducibility of discovery. To address these challenges, the integration of rigorous EV purification methods, cutting-edge spectroscopic technologies, and data analysis are critical to uncover diagnostic signatures of disease. Herein, we demonstrate an EV isolation and analysis pipeline using surface-enhanced Raman spectroscopy (SERS) and mass spectrometry (MS) techniques on plasma samples obtained from umbilical cord blood, healthy donor (HD) plasma, and plasma from women with early stage high-grade serous carcinoma (HGSC). Plasma EVs were purified by size exclusion chromatography and analyzed by surface-enhanced Raman spectroscopy (SERS), mass spectrometry (MS), and atomic force microscopy. After determining the fraction of highest EV purity, SERS and MS were used to characterize EVs from HDs, pooled donors with noncancerous gynecological ailments (n = 6), and donors with early stage [FIGO (I/II)] with HGSC. SERS spectra were subjected to different machine learning algorithms such as PCA, logistic regression, support vector machine, naïve Bayes, random forest, neural network, and k nearest neighbors to differentiate healthy, benign, and HGSC EVs. Collectively, we demonstrate a reproducible workflow with the potential to serve as a diagnostic platform for HGSC.

Enhanced Astrocyte Activity and Excitatory Synaptic Function in the Hippocampus of Pentylenetetrazole Kindling Model of Epilepsy.

Epilepsy is a chronic condition characterized by recurrent spontaneous seizures. The interaction between astrocytes and neurons has been suggested to play a role in the abnormal neuronal activity observed in epilepsy. However, the exact way astrocytes influence neuronal activity in the epileptogenic brain remains unclear. Here, using the PTZ-induced kindling mouse model, we evaluated the interaction between astrocyte and synaptic function by measuring astrocytic Ca2+ activity, neuronal excitability, and the excitatory/inhibitory balance in the hippocampus. Compared to control mice, hippocampal slices from PTZ-kindled mice displayed an increase in glial fibrillary acidic protein (GFAP) levels and an abnormal pattern of intracellular Ca2+-oscillations, characterized by an increased frequency of prolonged spontaneous transients. PTZ-kindled hippocampal slices also showed an increase in the E/I ratio towards excitation, likely resulting from an augmented release probability of excitatory inputs without affecting inhibitory synapses. Notably, the alterations in the release probability seen in PTZ-kindled slices can be recovered by reducing astrocyte hyperactivity with the reversible toxin fluorocitrate. This suggests that astroglial hyper-reactivity enhances excitatory synaptic transmission, thereby impacting the E/I balance in the hippocampus. Altogether, our findings support the notion that abnormal astrocyte-neuron interactions are pivotal mechanisms in epileptogenesis.

Alteraciones de la masticación en usuarios de prótesis dental removible. Revisión sistemática / Chewing alterations in removable dental prosthesis users: systematic review

Resumen:Tras el paso de los años, la pérdida de dientes genera la necesidad de recurrir al uso de prótesis dental. Específicamente, las alteraciones en el proceso de masticación en usuarios de prótesis dental removible se consideran un problema no sólo en relación a las modificaciones a nivel morfofuncional, sino que también en la propia satisfacción en cuanto a la masticación y funcionalidad de este proceso. El propósito de esta revisión es compilar y analizar los artículos científicos sobre la relación de la masticación y prótesis dental removible en adultos y adultos mayores. Se realizó una búsqueda integrativa de artículos en las bases de datos SCIELO, LILACS y PUBMED, seleccionando artículos publicados entre el año 2005 a 2014. Los artículos de revisión incluyeron estudios que identificaran la relación entre el uso de prótesis dental removible y la masticación en adultos usuarios de dicha prótesis dental. En la búsqueda se encontraron 21 documentos para potencial revisión. Finalmente, aplicando criterios de inclusión y exclusión se seleccionaron11artículos, los cuales tomaban diferentes variables de estudio, entre ellas, nivel de satisfacción, rendimiento, eficiencia y parámetros masticatorios. La satisfacción, el rendimiento, la eficiencia y los parámetros masticatorios fueron las variables que se encontraban afectadas en usuarios de prótesis dental removible.

Abstract:In aging process, the tooth loss generates the need to use a dental prosthesis. Specific alterations in mastication process of denture-users can be considered a problem not only in relation to the morphofunctional structures modification, but also in personal satisfaction associated to chewing and its functionality. The proposal of this review is to compile and analyze scientific articles about the relation between chewing and removable dental prostheses in adults and older adult's users. An integrative search of all articles on data from SCIELO, PUBMED and LILACS databases selected articles published 2006 to 2014, whose topic focused mastication and removable dental prosthesis in adults. The search presented 21 potential articles and, after applying criteria of inclusion and exclusion, 11 were selected. The satisfaction, performance, efficiency and masticatory parameters were the variables, which found to be effected in users of removable dental prosthesis.