Update on the use and management of lithium in neuropsychiatry / Actualización en el uso y el manejo del litio en neuropsiquiatría.

Lithium is an alkaline metal, used for more than 60 years in psychiatry, and currently considered the gold standard in the treatment of bipolar disorder (BD). According to recent evidence, this active ingredient is useful for the treatment of a wide spectrum of clinical varieties of affective disorders. In addition, it is estimated that lithium reduces the risk of suicide and suicidal behavior in people with mood disorders. On the other hand, some novel studies have shown that the cation has a potential efficacy for the treatment of other neuropsychiatric processes, such as the likelihood of reducing the risk of dementia and slowing down the development of neurodegenerative diseases. Despite the enormous evidence in favor of the use of lithium, it is known that, in Argentina, medications containing it are prescribed less than expected. In view of all this, the Asociación Argentina de Psiquiatría Biológica (Argentine Association of Biological Psychiatry) (AAPB or AABP) convened a group of experts to review the available scientific literature and prepare an updated document on the management and use of lithium in neuropsychiatry. In addition to the use of the ion in daily clinical practice, the scope of this review includes other contents that have been considered of interest for the psychiatrist, such as certain pharmacological and pharmacogenetic aspects, possible clinical predictors of response to treatment with lithium, management of ion during perinatal period, management of lithium in child and adolescent population, management of adverse effects linked to cation and interactions with drugs and other substances.

El litio es un metal alcalino, usado hace más de 60 años en psiquiatría, y actualmente es considerado el estándar de oro en el tratamiento del trastorno bipolar (TB). De acuerdo con la evidencia reciente, este principio activo es útil para el tratamiento de un amplio espectro de variedades clínicas de los trastornos afectivos. Además, se estima que desde hace tiempo el litio reduce el riesgo de suicidio y de comportamiento suicida en personas con trastornos del estado de ánimo. Por otro lado, algunos estudios novedosos han demostrado que el catión posee una potencial eficacia para el tratamiento de otros procesos neuropsiquiátricos, tales como la probabilidad de disminuir el riesgo de demencia y la de ralentizar el desarrollo de enfermedades neurodegenerativas. A pesar de la enorme evidencia a favor de la utilización del litio, se sabe que, en la Argentina, las especialidades medicinales que lo contienen se prescriben menos de lo esperado. En virtud de todo lo mencionado, la Asociación Argentina de Psiquiatría Biológica (AAPB) convocó a un grupo de expertos para revisar la literatura científica disponible y elaborar un documento actualizado sobre el manejo y el uso del litio en neuropsiquiatría. Además de la utilización del ion en la práctica clínica diaria, el alcance de esta revisión incluye otros contenidos que se han considerado de interés para el médico psiquiatra, tales como ciertos aspectos farmacológicos y farmacogenéticos, posibles predictores clínicos de la respuesta al tratamiento con litio, el manejo del ion durante el período perinatal, el manejo de litio en la población infantojuvenil, el manejo de los efectos adversos vinculados con el catión y las interacciones con medicamentos y otras sustancias.

Third Argentine Consensus statement on management Bipolar Disorders. Section 2 B / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Segunda Parte B.

This document constitutes the second section B of the Third Argentine Consensus on the Management of Bipolar Disorders, focused on synthesizing the most updated evidence on therapeutic approaches for adult patients. The scope of this section is to provide therapeutic recommendations for managing bipolar disorders in adults, (i) acute mania (ii) bipolar depression (iii) mixed stated (iv) suicidality and (vi) psychological interventions. In addition, the current manuscript outlines the assessment and management of side effects of pharmacotherapeutic treatments.

Este documento constituye la segunda parte B del Tercer Consenso Argentino sobre el Manejo de los Trastornos Bipolares llevada a cabo por la Asociación Argentina de Psiquiatría Biológica (AAPB). Siguiendo con el direccionamiento iniciado en el parte 2A sobre el tratamiento integral de los trastornos bipolares, esta sección se ha enfocado en sintetizar la evidencia más actualizada sobre abordajes terapéuticos para pacientes adultos. El alcance de esta sección es proporcionar recomendaciones terapéuticas para el manejo de los trastornos bipolares en adultos, (i) manía aguda, (ii) depresión bipolar, (iii) estado mixto, (iv) el suicidio en el trastorno bipolar, (v) intervenciones psicológicas. Además, el presente manuscrito aborda la evaluación y el manejo de los efectos secundarios de los tratamientos farmacoterapéuticos.

Third Argentine Consensus statement on management Bipolar Disorders. Section 2 A: Comprehensive treatment of the bipolar disorders in adults / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Segunda Parte A: Tratamiento integral de los trastornos bipolares en el adulto.

This document constitutes the second section A of the Third Argentine Consensus on the Management of Bipolar Disorders, focused on synthesizing the most updated evidence on therapeutic approaches for adult patients. The aim of this section (2A) is to provide therapeutic recommendations for managing bipolar disorders in adults. In addition, the scope of this current manuscript outlines recommendations on the use of treatment guidelines, levels of evidence available to support these recommendations, general considerations for the treatment of bipolar disorders, the so-called pseudoresistance and adherence to treatment, general considerations on psychological therapies, as well as long term treatment of bipolar disorders.

Este documento corresponde a la segunda parte del Tercer Consenso Argentino sobre el manejo de los trastornos bipolares, enfocada en sintetizar la evidencia actualizada sobre los abordajes terapéuticos de esta patología en los pacientes adultos. Siguiendo la metodología descripta en la primera parte del Consenso, el panel de expertos realizó una exhaustiva revisión de la bibliografía y, como consecuencia de un posterior debate sobre la información disponible, se generó esta sección A del segundo documento que abarca el tratamiento integral de las personas adultas que padecen este trastorno. Durante la etapa de debate y discusión de estas guías, se decidió incorporar algunos puntos que estimamos serán de gran utilidad para el equipo interdisciplinario encargado del manejo de pacientes con trastornos bipolares.  En tal sentido, en la sección A de la segunda parte de este documento, se podrán encontrar las recomendaciones generales para el uso de las guías de tratamiento, los niveles de evidencia disponibles para sustentar las recomendaciones, las consideraciones generales del tratamiento de los trastornos bipolares, el fenómeno de pseudorresistencia y adherencia al tratamiento, las consideraciones generales sobre el abordaje psicológico, así como el tratamiento a largo plazo de los trastornos bipolares.

Third Argentine Consensus statement on management Bipolar Disorders. Section3: Bipolar Disorder in the context of special situations / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Tercera parte: Manejo de los Trastornos Bipolares en el contexto de situaciones especiales.

This document constitutes the third and last part of the Third Argentine Consensus on the Management of Bipolar Disorders carried out by the Argentine Association of Biological Psychiatry (AAPB). Continuing with the initial objective, this section of the Consensus on the Management of Bipolar Disorders is focused on the management of bipolar disorders in special populations. This section constitutes a comprehensive review and expert consideration of the scientific evidence on: a) the management of bipolar disorders in treatment-resistant patients; b) the management of bipolar disorder in childhood and adolescence; c) the management of bipolar disorders in women during their perinatal period and, d) the management of bipolar disorders in older adults.

Este documento constituye la tercera y última parte del Tercer Consenso Argentino sobre el Manejo de los Trastornos Bipolares llevada a cabo por la Asociación Argentina de Psiquiatría Biológica (AAPB). Siguiendo con el objetivo propuesto por el comité de expertos, en la actual versión del Consenso sobre el manejo de los trastornos bipolares, esta sección está enfocada al abordaje de los Trastornos Bipolares en situaciones especiales. Esto configura una revisión exhaustiva de la evidencia científica  sobre: a) el manejo de los trastornos bipolares en pacientes resistentes al tratamiento, b) el manejo de los trastornos bipolares en la mujer en el período perinatal, c) el manejo del trastorno bipolar en la etapa infantojuvenil y d) el manejo de los trastornos bipolares en los adultos mayores.

Prevalence and Distribution of Human Papillomavirus Genotypes (1997-2019) and Their Association With Cervical Cancer and Precursor Lesions in Women From Southern Mexico.

BACKGROUND: Cervical cancer (CC) is the fourth most common malignancy of the female genital tract. Human Papillomavirus (HPV) is the main cause of precancerous lesions and CC cases worldwide. OBJECTIVE: We assessed the prevalence and distribution of HPV types and their association with precancerous lesions and CC. METHODS: HPV genotypes were detected by 3 methods depending on the year of in which the sample was analyzed: MY09/11 RFLPs (1997 to 2010), GP5+/6+ primer systems (2005 to 2010) and INNO-LiPA HPV Genotyping Extra (2010 to 2019) in cervical samples (No-IL: 4445; LSIL: 2464; HSILs: 151 and CC: 253) from women from southern Mexico. RESULTS: The overall HPV prevalence was 54.17%, and hpv-16 was the most common genotype. In single infection, the high-risk HPV genotypes (group 1) were associated with squamous intraepitelial lesions (LSIL: HPV-39 (OR = 10.58, 95% CI 4.09-27.36, P < .001); HSIL: HPV-31 (OR = 14.76, 95% CI 6.56-33.20, P < .001); and CC: HPV-16 (OR = 25.01, 95% CI 18.83-33.21, P < .001). In multiple infections, the HPV genotypes (HPV-16 and HPV-18) were also associated with a high risk of lesions [LSIL: HPV-18 (OR = 3.45; 95% CI 1.36-8.91; P = .009); HSIL: HPV-18 (OR = 5.12; 95% CI 1.21-21.68; P = .026); and CC: HPV-16 (OR = 3.03; 95% CI 1.72-5.32; P < .001)] compared to single infection. In the analysis adjusted for age, giving birth, and cigarette smoking, a significant increase in the risk of LSIL, HSIL, and CC was maintained. CONCLUSIONS: This study provides current data on the prevalence and distribution of HPV genotypes in women from southern Mexico, which could serve as a valuable reference to guide nationwide CC screening programs and provide scientific evidence that could be useful for vaccine development efforts. Likewise, it was identified that infection with carcinogenic HPV genotypes is an independent risk factor for LSIL, HSIL, and CC.

Third Argentine Consensus statement on management Bipolar Disorders. Section1: introduction and general concepts / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Primera Parte: introducción, método de trabajo y generalidades.

The Third Argentine Consensus on the management of bipolar disorders (TB) is an initiative of the Argentine Association of Biological Psychiatry (AAPB). As a reference document, this consensus pursues two main objectives: on the one hand, to summarize and systematize the best available evidence on the comprehensive management of this pathology; on the other, to provide a useful, up-to-date instrument for psychiatrists, multidisciplinary teams dedicated to mental health, and government agencies. During a period of approximately six months of work -that is, from May to October 2022- a committee of experts made up of 18 professionals and representatives of the three most important Psychiatry and Mental Health associations in Argentina (that is, the AAPB, the Argentine Association of Psychiatrists, AAP, and the Association of Argentine Psychiatrists, APSA) have focused on updating the information regarding TB. Finally, this document was prepared as a result of an exhaustive review of the bibliography published to date, which was strategically divided into three parts: the first deals with the generalities of TB; the second deals with the comprehensive treatment of the pathology; finally, the third analyzes TB in the context of special situations.

El Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares (TB) es una iniciativa de la Asociación Argentina de Psiquiatría Biológica (AAPB). Como documento de referencia, este consenso persigue dos objetivos principales: por un lado, resumir y sistematizar la mejor evidencia disponible sobre el manejo integral de esta patología; por el otro, proporcionar un instrumento útil y actualizado a psiquiatras, a equipos multidisciplinarios abocados a la salud mental y a organismos gubernamentales. Durante un período de aproximadamente seis meses de trabajo -desde mayo a octubre de 2022- un comité de expertos integrado por 18 profesionales y por representantes de las tres asociaciones de Psiquiatría y Salud Mental más importantes de la Argentina: la AAPB, la Asociación Argentina de Psiquiatras, (AAP) y la Asociación de Psiquiatras Argentinos (APSA), se abocaron a actualizar la información respecto de los TB. Finalmente, y como resultado de una exhaustiva revisión de la bibliográfica publicada hasta la actualidad, se confeccionó este documento que fue dividido estratégicamente en tres partes: la primera versa acerca de las generalidades del TB; la segunda aborda el  tratamiento integral de la patología; y, por último, la tercera analiza los TB en el contexto de situaciones especiales.

TOP2A/MCM2, p16INK4a, and cyclin E1 expression in liquid-based cytology: a biomarkers panel for progression risk of cervical premalignant lesions.

BACKGROUND: To improve the efficiency of early diagnosis systems for cervical cancer, the use of cellular and viral markers for identifying precancerous lesions with a greater probability to progress to cancer has been proposed. Several cellular proteins and markers of oxidative DNA damage have been suggested as possible biomarkers of cervical carcinogenesis; however, they have not been evaluated together. In this study, we analyzed the expression of the cellular markers p16INK4a, Ki-67, CyclinE1, TOP2A/MCM2, and telomerase, as well as the DNA oxidative damage markers ROS and 8-OHdG. The analyses were performed in liquid-based cervical cytology samples or biopsies with premalignant lesions or cervical cancer diagnosis, with the purpose of selecting a panel of biomarkers that allow the identification of precursor lesions with greater risk of progression to cervical cancer. METHODS: We analyzed 1485 liquid-based cytology samples, including 239 non-squamous intraepithelial lesions (NSIL), 901 low-grade squamous intraepithelial lesions (LSIL), 54 high-grade squamous intraepithelial lesions (HSIL), and 291 cervical cancers (CC). The biomarkers were analyzed by immunocytochemistry and Human Papilloma Virus (HPV) genotyping with the INNO-LiPA genotyping Extra kit. RESULTS: We found that all tested cellular biomarkers were overexpressed in samples with high risk-HPV infection, and the expression levels increased with the severity of the lesion. TOP2A/MCM2 was the best biomarker for discriminating between LSIL and HSIL, followed by p16INK4a and cyclinE1. Statistical analysis showed that TOP2A/MCM2 provided the largest explanation of HSIL and CC cases (93.8%), followed by p16INK4a (91%), cyclin E1 (91%), Ki-67 (89.3%), and telomerase (88.9%). CONCLUSIONS: We propose that the detection of TOP2A/MCM2, p16INK4a and cyclin E1 expression levels is useful as a panel of biomarkers that allow identification of cervical lesions with a higher risk for progression to CC with high sensitivity and precision; this can be done inexpensively, in a single and non-invasive liquid-based cytology sample.

Sensorless Speed Estimation for the Diagnosis of Induction Motors via MCSA. Review and Commercial Devices Analysis.

Sensorless speed estimation has been extensively studied for its use in control schemes. Nevertheless, it is also a key step when applying Motor Current Signature Analysis to induction motor diagnosis: accurate speed estimation is vital to locate fault harmonics, and prevent false positives and false negatives, as shown at the beginning of the paper through a real industrial case. Unfortunately, existing sensorless speed estimation techniques either do not provide enough precision for this purpose or have limited applicability. Currently, this is preventing Industry 4.0 from having a precise and automatic system to monitor the motor condition. Despite its importance, there is no research published reviewing this topic. To fill this gap, this paper investigates, from both theoretical background and an industrial application perspective, the reasons behind these problems. Therefore, the families of sensorless speed estimation techniques, mainly conceived for sensorless control, are here reviewed and thoroughly analyzed from the perspective of their use for diagnosis. Moreover, the algorithms implemented in the two leading commercial diagnostic devices are analyzed using real examples from a database of industrial measurements belonging to 79 induction motors. The analysis and discussion through the paper are synthesized to summarize the lacks and weaknesses of the industry application of these methods, which helps to highlight the open problems, challenges and research prospects, showing the direction in which research efforts have to be made to solve this important problem.

Power Quality Disturbance Tracking Based on a Proprietary FPGA Sensor with GPS Synchronization.

The study of power quality (PQ) has gained relevance over the years due to the increase in non-linear loads connected to the grid. Therefore, it is important to study the propagation of power quality disturbances (PQDs) to determine the propagation points in the grid, and their source of generation. Some papers in the state of the art perform the analysis of punctual measurements of a limited number of PQDs, some of them using high-cost commercial equipment. The proposed method is based upon a developed proprietary system, composed of a data logger FPGA with GPS, that allows the performance of synchronized measurements merged with the full parameterized PQD model, allowing the detection and tracking of disturbances propagating through the grid using wavelet transform (WT), fast Fourier transform (FFT), Hilbert-Huang transform (HHT), genetic algorithms (GAs), and particle swarm optimization (PSO). Measurements have been performed in an industrial installation, detecting the propagation of three PQDs: impulsive transients propagated at two locations in the grid, voltage fluctuation, and harmonic content propagated to all the locations. The results obtained show that the low-cost system and the developed methodology allow the detection of several PQDs, and track their propagation within a grid with 100% accuracy.

[Schizotypy and bipolar disorder]. / Trastorno bipolar y esquizotipia.

Bipolar disorder is a serious and chronic mood disorder, which in extreme forms can lead to psychosis, especially in manic states. In this sense, historically, the differentiation from schizophrenia has represented a real clinical challenge and a nosological dilemma. Categorical diagnostic approaches have promoted progress in the generation of consensus and the facilitation of scientific communication, but many times, they have done so to the detriment of the complexity and richness of clinical presentations. As a counterpart, the notion of the bipolar spectrum proposes a dimensional perspective, a continuum of severity in whose maximum expression alterations in the content of thought or sensory perception can stand out. Schizotype, where these manifestations can be found, has long been pointed out as a series of personality characteristics linked to schizophrenia. But its presence can be verified in other areas of psychopathology, even outside it. Regarding its presence in mood disorders, schizotypal traits, instead of being a marker of a worse prognosis, could be related to positive aspects such as creativity. The objective of this work is to investigate, through a bibliographic review, the association between schizotypy and bipolar disorder, mainly its possible role in the creative processes associated with this pathology.

[The features of insight in schizophrenia, a bibliographic review]. / Características del insight en la esquizofrenia. Una revisión bibliográfica.

Treatment of schizophrenia remains a huge challenge. Despite advances in recent decades in pathophysiology, genetics, and therapeutics, overall outcomes in the evolution of patients do not appear to have undergone such significant changes. Cognition is particularly important, bearing in mind that it is a determining factor in functionality, and this, in turn, in social, family, academic and work performance. Cognitive variables may include the ability to Insight as a form of self-recognition that goes beyond disease awareness. Like all cognitive functions, it is also impaired in patients and hinders, perhaps like no other, adherence to treatment, with the possibility of poor evolution, relapses and worse prognosis. The objective of this paper is to investigate, through a literature review, the characteristics of Insight and what is its importance in the clinical and prognostic of schizophrenia.

[A REVIEW ABOUT SPONTANEOUS MOVEMENTS DISORDERS IN SCHIZOPHRENIA]. / Una revisión sobre los Trastornos Espontáneos del Movimiento (TEM) en la esquizofrenia.

Spontaneous movements disorders are frequently observed in schizophrenia. Together with the negative and cognitive symptoms, they comprise manifestations more linked to the damage of this complex condition, although they are insufficient to make the diagnosis. When the psychotic symptoms express these phenomena, they have probably been causing deleterious effects for years. Within these intrinsic components, motor disorders are the most delayed, paradoxically, as a consequence of the progress of phar-macotherapy. Treatment with antipsychotics modified the clinical symptoms of schizophrenia by developing improvements in positive symptoms, disorganization and agitation, but also produced a change of another order, with the side effects that, many times, had difficulty in being distinguished from the pathology itself. Above all, the specific neuroleptics share to a greater or lesser extent of the production of extrapyramidal symptoms, classically expressed in motor alterations. Therefore, these abnormal movements are often mistakenly associated with antipsychotic medication in an exclusive manner, overshadowing primary motor manifestations.The objective of this work is to highlight the characteristics, importance and relationship with the conventional therapy of spon-taneous movements disorders in schizophrenia.

HOTAIR Knockdown Decreased the Activity Wnt/ß-Catenin Signaling Pathway and Increased the mRNA Levels of Its Negative Regulators in Hela Cells.

BACKGROUND/AIMS: HOTAIR is a long non-coding RNA that promotes the development of human cancer. TET1 enzyme is involved in DNA demethylation by oxidation of 5-methylcytocine and it is considered a tumor suppressor in some types of cancer. HOTAIR and TET1 are involved in modulation of the Wnt/ß-catenin signaling pathway, but their role in cervical cancer remains to be elucidated. The aim of this work was to analyze the effect of HOTAIR in TET1 expression, Wnt/ß-catenin signaling, and expression, methylation and hidroxymethylation of some negative regulators of this pathway in HeLa cells. METHODS: HOTAIR and TET expression were analyzed by RT-qPCR and western blot. The HOTAIR knockdown was done with DsiRNA and the activity of the Wnt/ß-catenin signaling pathway through luciferase assays and ß-catenin nuclear translocation. The mRNA levels of SNAIL, EDN3, CYCD1, SPRY2 (targets of Wnt/ß-catenin pathway) PCDH10, SOX17, AJAP1, and MAGI2 (negative regulators of Wnt/ß-catenin pathway) were evaluated by RT-qPCR. The DNA methylation and hidroxymethylation of negative regulators of the Wnt/ß-catenin pathway were evaluated by methylation-specific PCR and chemical modification, followed by digestion and quantitative PCR. RESULTS: HOTAIR knockdown in HeLa cells decreased the activity of Wnt/ß-catenin signaling pathway. It increased the mRNA levels of Wnt/ ß-catenin negative regulators through a decrease in their promoter's methylation pattern. TET1 enzyme was also down-regulated in HOTAIR knockdown cells. CONCLUSION: Our study suggests a mechanism in which HOTAIR promotes the over-activation of Wnt/ß-catenin signaling pathway by downregulation of PCDH10, SOX17, AJAP1 and MAGI2 and also TET.

Microwave-Assisted, Asymmetric Synthesis of 3-Amino-2,3-Dihydrobenzofuran Flavonoid Derivatives from Chalcones.

A route to access 3-amino-2,3-dihydrobenzofurans that utilizes microwave-assisted organic synthesis to rapidly generate analogues has been developed. The route begins with an acid-catalyzed, microwave-assisted aldol condensation to generate chalcone intermediates, followed by a Corey-Bakshi-Shibata reduction and subsequent Sharpless asymmetric epoxidation to access stereoisomeric epoxyalcohols. The final step is a one-pot, microwave-assisted, regioselective, acid-catalyzed epoxide opening with various amines followed by an intramolecular nucleophilic aromatic substitution reaction to generate the 3-amino-2,3-dihydrobenzofurans. This route provides ready access to stereochemically and structurally diverse analogues of these flavonoid scaffolds. Additionally, a pilot library was synthesized, and the biological activity diversity of the chalcones and dihydrobenzofurans was explored in human carcinoma cell lines.

Phenolic Compounds of Therapeutic Interest in Neuroprotection.

The number of elderly people is projected to double in the next 50 years worldwide, resulting in an increased prevalence of neurodegenerative diseases. Aging causes changes in brain tissue homeostasis, thus contributing to the development of neurodegenerative disorders. Current treatments are not entirely effective, so alternative treatments or adjuvant agents are being actively sought. Antioxidant properties of phenolic compounds are of particular interest for neurodegenerative diseases whose psychopathological mechanisms strongly rely on oxidative stress at the brain level. Moreover, phenolic compounds display other advantages such as the permeability of the blood-brain barrier (BBB) and the interesting molecular mechanisms that we reviewed in this work. We began by briefly outlining the physiopathology of neurodegenerative diseases to understand the mechanisms that result in irreversible brain damage, then we provided an overall classification of the phenolic compounds that would be addressed later. We reviewed in vitro and in vivo studies, as well as some clinical trials in which neuroprotective mechanisms were demonstrated in models of different neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), ischemia, and traumatic brain injury (TBI).

LncRNA SOX9-AS1 triggers a transcriptional program involved in lipid metabolic reprogramming, cell migration and invasion in triple-negative breast cancer.

At the molecular level, triple-negative breast cancer (TNBC) is frequently categorized as PAM50 basal-like subtype, but despite the advances in molecular analyses, the clinical outcome for these subtypes is uncertain. Long non-coding RNAs (lncRNAs) are master regulators of genes involved in hallmarks of cancer, which makes them suitable biomarkers for breast cancer (BRCA) diagnosis and prognosis. Here, we evaluated the regulatory role of lncRNA SOX9-AS1 in these subtypes. Using the BRCA-TCGA cohort, we observed that SOX9-AS1 was significantly overexpressed in basal-like and TNBC in comparison with other BRCA subtypes. Survival analyzes showed that SOX9-AS1 overexpression was associated with a favorable prognosis in TNBC and basal-like patients. To study the functions of SOX9-AS1, we determined the expression levels in a panel of nine BRCA cell lines finding increased levels in MDA-MB-468 and HCC1187 TNBC. Using subcellular fractionation in these cell lines, we ascertained that SOX9-AS1 was located in the cytoplasmic compartment. In addition, we performed SOX9-AS1 gene silencing using two short-harping constructs, which were transfected in both cell models and performed a genome-wide RNA-seq analysis. Data showed that 351 lncRNAs and 740 mRNAs were differentially expressed in MDA-MB-468 while 56 lncRNAs and 100 mRNAs were modulated in HCC1187 cells (Log2FC < - 1.5 and > 1.5, p.adj value < 0.05). Pathway analysis revealed that the protein-encoding genes potentially regulate lipid metabolic reprogramming, and epithelial-mesenchymal transition (EMT). Expression of lipid metabolic-related genes LIPE, REEP6, GABRE, FBP1, SCD1, UGT2B11, APOC1 was confirmed by RT-qPCR. Functional analysis demonstrated that the knockdown of SOX9-AS1 increases the triglyceride synthesis, cell migration and invasion in both two TNBC cell lines. In conclusion, high SOX9-AS1 expression predicts an improved clinical course in patients, while the loss of SOX9-AS1 expression enhances the aggressiveness of TNBC cells.

Aryl Hydrocarbon Receptor Involvement in the Sodium-Dependent Glutamate/Aspartate Transporter Regulation in Cerebellar Bergmann Glia Cells.

Glutamate, the major excitatory neurotransmitter in the vertebrate brain, exerts its functions through the activation of specific plasma membrane receptors and transporters. Overstimulation of glutamate receptors results in neuronal cell death through a process known as excitotoxicity. A family of sodium-dependent glutamate plasma membrane transporters is responsible for the removal of glutamate from the synaptic cleft, preventing an excitotoxic insult. Glial glutamate transporters carry out more than 90% of the brain glutamate uptake activity and are responsible for glutamate recycling through the GABA/Glutamate/Glutamine shuttle. The aryl hydrocarbon receptor is a ligand-dependent transcription factor that integrates environmental clues through its ability to heterodimerize with different transcription factors. Taking into consideration the fundamental role of glial glutamate transporters in glutamatergic synapses and that these transporters are regulated at the transcriptional, translational, and localization levels in an activity-dependent fashion, in this contribution, we explored the involvement of the aryl hydrocarbon receptor, as a model of environmental integrator, in the regulation of the glial sodium-dependent glutamate/aspartate transporter. Using the model of chick cerebellar Bergmann glia cells, we report herein that the aryl hydrocarbon receptors exert a time-dependent decrease in the transporter mRNA levels and a diminution of its uptake activity. The nuclear factor kappa light chain enhancer of the activated B cell signaling pathway is involved in this regulation. Our results favor the notion of an environmentally dependent regulation of glutamate removal in glial cells and therefore strengthen the notion of the involvement of glial cells in xenobiotic neurotoxic effects.

miR-218-5p, miR-124-3p and miR-23b-3p act synergistically to modulate the expression of NACC1, proliferation, and apoptosis in C-33A and CaSki cells.

Background: In cervical cancer (CC), miR-218-5p, -124-3p, and -23b-3p act as tumor suppressors. These miRNAs have specific and common target genes that modulate apoptosis, proliferation, invasion, and migration; biological processes involved in cancer. Methods: miR-218-5p, -124-3p, and -23b-3p mimics were transfected into C-33A and CaSki cells, and RT-qPCR was used to quantify the level of each miRNA and NACC1. Proliferation was assessed by BrdU and apoptosis by Annexin V/PI. In the TCGA and The Human Protein Atlas databases, the level of NACC1 mRNA and protein (putative target of the three miRNAs) was analyzed in CC and normal tissue. The relationship of NACC1 with the overall survival in CC was analyzed in GEPIA2. NACC1 mRNA and protein levels were higher in CC tissues compared with cervical tissue without injury. Results: An increased expression of NACC1 was associated with lower overall survival in CC patients. The levels of miR-218-5p, -124-3p, and -23b-3p were lower, and NACC1 was higher in C-33A and CaSki cells compared to HaCaT cells. The increase of miR-218-5p, -124-3p, and -23b-3p induced a significant decrease in NACC1 mRNA. The transfection of the three miRNAs together caused more drastic changes in the level of NACC1, in the proliferation, and in the apoptosis with respect to the individual transfections of each miRNA. Conclusion: The results indicate that miR-218-5p, -124-3p, and -23b-3p act synergistically to decrease NACC1 expression and proliferation while promoting apoptosis in C-33A and CaSki cells. The levels of NACC1, miR-218-5p, -124-3p, and -23b-3p may be a potential prognostic indicator in CC.

The 46359CT polymorphism of DNMT3B is associated with the risk of cervical cancer.

Abnormal methylation is related to cancer development. Since DNMT3B is an enzyme that modulates genomic methylation, we hypothesized that genetic variants of the promoter DNMT3B may be associated with an increased risk of developing cervical cancer. Our aim was to investigate the association between -579GT and 46359CT polymorphisms of DNMT3B and cervical cancer, high-grade squamous intraepithelial lesions (HSIL), and low-grade squamous intraepithelial lesions (LSIL). Samples from 200 healthy women and 130 women with squamous intraepithelial lesions (70 with cervical cancer, 30 with HSIL, and 30 with LSIL) were analyzed. Polymorphism genotyping was performed using PCR and restriction fragment length polymorphism. The -579GT polymorphism was not associated with cervical cancer, HSIL, or LSIL. The CT genotype of 46359CT polymorphism was significantly associated with cervical cancer risk (OR 8.75, CI 1.27-374.1), whereas the TT genotype was associated with a significantly decreased risk of HSIL (OR 0.66, CI 0.01-0.32) and LSIL (OR 0.11, CI 0.026-0.45). Our results suggest that genotyping the 46359CT polymorphism in DNMT3B may help identify women who are genetically susceptible to cervical cancer development. Additional studies with larger sample sizes are necessary to confirm our findings.

Discovery of a Small-Molecule Modulator of the Autophagy-Lysosome Pathway That Targets Lamin A/C and LAMP1, Induces Autophagic Flux, and Affects Lysosome Positioning in Neurons.

Autophagy is a major catabolic degradation and recycling process that maintains homeostasis in cells and is especially important in postmitotic neurons. We implemented a high-content phenotypic assay to discover small molecules that promote autophagic flux and completed target identification and validation studies to identify protein targets that modulate the autophagy pathway and promote neuronal health and survival. Efficient syntheses of the prioritized compounds were developed to readily access analogues of the initial hits, enabling initial structure-activity relationship studies to improve potency and preparation of a biotin-tagged pulldown probe that retains activity. This probe facilitated target identification and validation studies through pulldown and competition experiments using both an unbiased proteomics approach and western blotting to reveal Lamin A/C and LAMP1 as the protein targets of compound RH1115. Evaluation of RH1115 in neurons revealed that this compound induces changes to LAMP1 vesicle properties and alters lysosome positioning. Dysfunction of the autophagy-lysosome pathway has been implicated in a variety of neurodegenerative diseases, including Alzheimer's disease, highlighting the value of new strategies for therapeutic modulation and the importance of small-molecule probes to facilitate the study of autophagy regulation in cultured neurons and in vivo.