Radiotherapy for Canine Apocrine Gland Anal Sac Adenocarcinoma: Survival Outcomes and Side Effects of a Palliative Treatment Protocol of 20 Gy in Five Consecutive Fractions.

This research aims to evaluate the outcomes of a radiotherapy protocol, consisting of five fractions of 4 Gy each, resulting in a total dose of 20 Gy for apocrine gland anal sac tumors and local lymph nodes in canines. This protocol was assessed as a palliative treatment for macroscopic tumors alone, or in combination with additional therapies under different scenarios. Medical records from fifty canine patients met the inclusion criteria and were divided into different treatment groups: radiotherapy alone (n = 22, 44%), radiotherapy with chemotherapy or targeted therapy with toceranib (n = 18, 36%), surgery with radiotherapy (n = 5, 10%), and surgery with radiotherapy and chemotherapy or targeted therapy with toceranib (n = 5, 10%). Patients who received radiotherapy alone had a median survival time of 384 days (95% CI 198-569) and 628 days (95% CI 579-676) for RT + additional therapies. The median time to progression for patients with radiotherapy alone was 337 days (95% CI 282-391 days), and 402 days (95% CI 286-517 days) for radiotherapy plus additional treatments. Acute side effects were mild, with the majority having diarrhea (61%), and only one patient developed grade III late effects VRTOG v2 classification; however, this happened 22 months after the first radiotherapy protocol after re-irradiation. The results demonstrate that radiotherapy alone under this protocol provided a comparable median time to progression vs. radiotherapy plus additional treatments while maintaining acceptable side effects. The combination of this protocol with other treatment modalities offers attractive results for local disease control and survival while maintaining acceptable toxicities. Overall, these findings contribute to the growing evidence supporting the role of radiotherapy in managing apocrine gland anal sac adenocarcinoma in dogs.

Schlafen14 Impairs HIV-1 Expression in a Codon Usage-Dependent Manner.

Schlafen (SLFN) is a family of proteins upregulated by type I interferons with a regulatory role in translation. Intriguingly, SLFN14 associates with the ribosome and can degrade rRNA, tRNA, and mRNA in vitro, but a role in translation is still unknown. Ribosomes are important regulatory hubs during translation elongation of mRNAs rich in rare codons. Therefore, we evaluated the potential role of SLFN14 in the expression of mRNAs enriched in rare codons, using HIV-1 genes as a model. We found that, in a variety of cell types, including primary immune cells, SLFN14 regulates the expression of HIV-1 and non-viral genes based on their codon adaptation index, a measurement of the synonymous codon usage bias; consequently, SLFN14 inhibits the replication of HIV-1. The potent inhibitory effect of SLFN14 on the expression of the rare codon-rich transcript HIV-1 Gag was minimized by codon optimization. Mechanistically, we found that the endoribonuclease activity of SLFN14 is required, and that ribosomal RNA degradation is involved. Therefore, we propose that SLFN14 impairs the expression of HIV-1 transcripts rich in rare codons, in a catalytic-dependent manner.

The MUC1-HIF-1α signaling axis regulates pancreatic cancer pathogenesis through polyamine metabolism remodeling.

Dysregulation of polyamine metabolism has been implicated in cancer initiation and progression; however, the mechanism of polyamine dysregulation in cancer is not fully understood. In this study, we investigated the role of MUC1, a mucin protein overexpressed in pancreatic cancer, in regulating polyamine metabolism. Utilizing pancreatic cancer patient data, we noted a positive correlation between MUC1 expression and the expression of key polyamine metabolism pathway genes. Functional studies revealed that knockdown of spermidine/spermine N1-acetyltransferase 1 (SAT1), a key enzyme involved in polyamine catabolism, attenuated the oncogenic functions of MUC1, including cell survival and proliferation. We further identified a regulatory axis whereby MUC1 stabilized hypoxia-inducible factor (HIF-1α), leading to increased SAT1 expression, which in turn induced carbon flux into the tricarboxylic acid cycle. MUC1-mediated stabilization of HIF-1α enhanced the promoter occupancy of the latter on SAT1 promoter and corresponding transcriptional activation of SAT1, which could be abrogated by pharmacological inhibition of HIF-1α or CRISPR/Cas9-mediated knockout of HIF1A. MUC1 knockdown caused a significant reduction in the levels of SAT1-generated metabolites, N1-acetylspermidine and N8-acetylspermidine. Given the known role of MUC1 in therapy resistance, we also investigated whether inhibiting SAT1 would enhance the efficacy of FOLFIRINOX chemotherapy. By utilizing organoid and orthotopic pancreatic cancer mouse models, we observed that targeting SAT1 with pentamidine improved the efficacy of FOLFIRINOX, suggesting that the combination may represent a promising therapeutic strategy against pancreatic cancer. This study provides insights into the interplay between MUC1 and polyamine metabolism, offering potential avenues for the development of treatments against pancreatic cancer.

Psychometric Properties of the Acoso Sexual en las Instituciones de Educación Superior Scale (ASIES) in an Ecuadorian Sample.

Sexual harassment has become increasingly common in Ecuador's higher education centers. However, due to the lack of instruments that evaluate sexual harassment, the magnitude of this phenomenon in Ecuador is unknown. This research aims to analyze the construct validity and internal consistency reliability of a sexual harassment measurement scale in higher education institutions (ASIES). The instrument analyzes 21 behaviors related to sexual harassment. The sample consisted of 4628 people. A descriptive analysis of the items, item-total correlation analysis, and both exploratory and confirmatory factor analysis are performed to test the internal structure of the scale. It was found that the 4-factor model and a second-order factor presented a better fit (CFI = .99, TLI = .99, SRMR = .075, and RMSEA = .018). The results confirm the four dimensions proposed.

El acoso sexual constituye un fenómeno que se evidencia cada vez con mayor frecuencia en la educación superior. Sin embargo, debido a la falta de instrumentos que evalúen el acoso sexual, se desconoce la magnitud de este fenómeno en el Ecuador. El objetivo de esta investigación es analizar la validez de constructo y la confiabilidad por consistencia interna de una escala de medición de acoso sexual en instituciones de educación superior (ASIES). El instrumento analiza 21 comportamientos relacionados con el acoso sexual. Se aplicó en 4.628 personas. Se realizó un análisis descriptivo de los ítems, un análisis de correlación ítem-total y un análisis factorial, tanto exploratorio como confirmatorio, para probar la estructura interna de la escala. Se encontró que el modelo de 4 factores y un factor de segundo orden fueron los que presentaron mejor ajuste (CFI = .99, TLI = .99, SRMR = .075 y RMSEA = .018). Los resultados confirman las cuatro dimensiones planteadas para la medición del acoso sexual.

Effect of moderate prenatal ethanol exposure on the differential expression of two histamine H3 receptor isoforms in different brain regions of adult rat offspring.

We have reported that prenatal alcohol exposure (PAE) elevates histamine H3 receptor (H3R) agonist-mediated inhibition of glutamatergic neurotransmission in the dentate gyrus. Here, we hypothesized that PAE alters the expression of two prominent H3R isoforms namely, the rH3A and rH3C isoforms, which have differing intrinsic activities for H3R agonists, in a manner that may contribute to heightened H3R function in PAE rats. In contrast to our predictions, we found different effects of sex and PAE in various brain regions with significant interactions between sex and PAE in dentate gyrus and entorhinal cortex for both isoforms. Subsequently, to confirm the PAE-and sex-induced differences on H3R isoform mRNA expression, we developed a polyclonal antibody selective for the rH3A inform. Western blots of rH3A mRNA-transfected HEK-293 cells identified a ~ 48 kDa band of binding consistent with the molecular weight of rH3A, thus confirming antibody sensitivity for rH3A protein. In parallel, we also established a pan-H3R knockout mice line to confirm antibody specificity in rodent brain membranes. Both qRT-PCR and H3R agonist-stimulated [35S]-GTPγS binding confirmed the absence of mH3A mRNA and H3 receptor-effector coupling in H3R knockout (KO) mice. Subsequent western blotting studies in both rat and mouse brain membranes were unable to detect rH3A antibody binding at ~48 kDa. Rather, the H3RA antibody bound to a ~ 55 kDa band in both rat and mouse membranes, including H3R KO mice, suggesting H3RA binding was not specific for H3Rs in rodent membranes. Subsequent LC/MS analysis of the ~55 kDa band in frontal cortical membranes identified the highly abundant beta subunit of ATPase in both WT and KO mice. Finally, LC/MS analysis of the ~48 kDa band from rH3A mRNA-transfected HEK-293 cell membranes was able to detect rH3A protein, but its presence was below the limits of quantitative reliability. We conclude that PAE alters rH3A and rH3C mRNA expression in some of the same brain regions where we have previously reported PAE-induced alterations in H3R-effector coupling. However, interpreting the functional consequences of altered H3R isoform expression was limited given the technical challenges of measuring the relatively low abundance of rH3A protein in native membrane preparations.

Retrospective comparison of side effects and outcomes of three-dimensional conformal vs. intensity-modulated radiation therapy in the palliative-intent treatment (4 Gy × 5 daily fractions) of canine intranasal tumors (2010-2017).

Objective: To compare the occurrence of radiation side effects and treatment outcomes in dogs with intranasal tumors treated with a total dose of 20 Gy delivered in 5 daily 4 Gy fractions using computer-based 3D conformal (3DCRT) or intensity-modulated (IMRT) radiation therapy plans. Design: Retrospective case series. Materials and methods: Medical records for dogs with intranasal tumors treated with 4 Gy × 5 fractions between 2010 and 2017 were reviewed. Radiation side effects, time to local progression (TTLP), progression-free survival (PFS) and survival time (OS) were evaluated. Results: Thirty-six dogs (24 carcinomas, 10 sarcomas and 2 others) met the inclusion criteria. Sixteen were treated with 3DCRT and 20 with IMRT. Clinical signs improvement or resolution were reported in 84% of dogs. The median time to clinical signs improvement was 12 days (1-88 days) after the end of treatment. Eight dogs treated with 3DCRT (8/16, 50%) and 5 with IMRT (5/20, 25%) were documented acute radiation side effects. Almost all were classified as grade 1 skin, oral or ocular acute side effects. Only one dog in 3DCRT group was demonstrated grade 2 skin acute effects. The median TTLP for dogs treated with 3DCRT or IMRT was 238 days and 179 days, respectively (p = 0.967). The median PFS for 3DCRT or IMRT was 228 days and 175 days, respectively (p = 0.940). The median OS for 3DCRT or IMRT was 295 days and 312 days, respectively (p = 0.787). No significantly differences were observed in side effects, TTLP, PFS and OS between 3DCRT and IMRT groups. Conclusions: Palliative-intent conformal radiation therapy given in five daily 4 Gy fractions relieved clinical signs with minimal radiation side effects, with no statistical difference in occurrence between 3DCRT and IMRT dogs.

Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover.

Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, we executed unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discovered a previously unappreciated mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism is dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of SEL1L. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus cell-autonomous, rheostatic collagen clearance is a previously unidentified pathway of tissue homeostasis.

The positive allosteric modulator of NMDA receptors, GNE-9278, blocks the ethanol-induced decrease of excitability in developing retrosplenial cortex neurons from mice.

Binge-like exposure to ethanol during the brain growth spurt triggers apoptotic neurodegeneration in multiple brain regions, including the retrosplenial cortex, a brain region that is part of the hippocampal-diencephalic-cingulate memory network. This is mediated, in part, by reduced Ca2+ influx through N-methyl-d-aspartate (NMDA) receptors followed by a decrease in the activation of pro-survival genes. Here, we tested whether a positive allosteric modulator of NMDA receptors could counteract the inhibitory effect of ethanol on developing retrosplenial cortex pyramidal neurons. We used patch-clamp electrophysiological techniques in acute slices from postnatal day 6-8 mice to test the effect of the positive allosteric modulator GNE-9278 on ethanol-induced inhibition of NMDA receptor function. GNE-9278 dose-dependently increased the amplitude, decay time, and total charge of NMDA excitatory postsynaptic currents. At a concentration of 5 µmol L-1 , GNE-9278 significantly reduced the 90 mmol L-1 ethanol-induced inhibition of NMDA excitatory postsynaptic current amplitude, decay time, and total charge. Current-clamp experiments showed that 5 µmol L-1 GNE-9278 ameliorated the 90 mmol L-1 ethanol-induced inhibition of synaptically-evoked action potential firing and compound excitatory postsynaptic potential amplitude. These findings indicate that positive allosteric modulators mitigate ethanol-induced hypofunction of NMDA receptors in developing cerebral cortex neurons, an effect that could ameliorate its pro-apoptotic effects during the late stages of fetal development.

Single institution study of the immune landscape for canine oral melanoma based on transcriptome analysis of the primary tumor.

Introduction: Understanding a tumor's immune context is paramount in the fight against cancer. Oral melanoma in dogs serves as an excellent translational model for human immunotherapy. However, additional study is necessary to comprehend the immune landscape of dog oral melanomas, including their similarity to human melanomas in this context. Methods: This retrospective study utilizes formalin-fixed paraffin-embedded (FFPE) tissue samples to analyze RNA sequences associated with oral melanoma in dogs. Nanostring Technologies was used for conducting RNA sequencing. The focus is on understanding the differences between melanoma tumors restricted to the oral cavity (OL) and the same primary oral tumors with a history of metastasis to the lymph nodes or other organs (OM). Normal buccal mucosa samples are also included as a normal tissue reference. Results: In the OM patient group, gene signatures exhibit significant changes relative to the OL patient group, including significantly decreased expression of S100, BRAF, CEACAM1, BCL2, ANXA1, and tumor suppressor genes (TP63). Relative to the OL tumors, the OM tumors had significantly increased expression of hypoxia-related genes (VEGFA expression), cell mobility genes (MCAM), and PTGS2 (COX2). The analysis of the immune landscape in the OM group indicates a shift from a possible "hot" tumor suppressed by immune checkpoints (PDL1) to significantly heightened expression not only of those checkpoints but also the inclusion of other immune blockades such as PD1 and IDO2. In addition, the OM group had significantly reduced expression of Toll-like receptors (TLR4) and IL-18 relative to the OL group, contributing to the tumor's immune escape. Additionally, signs of immune cell exhaustion are evident in both the OM and OL groups through significantly increased expression of TIGIT relative to normal tissue. Both the OM and OL groups had significantly increased expression of the immune cell marker CD4 expression relative to normal tissue. Further, CD4 expression significantly decreased in OM relative to OL; however, this study cannot determine the specific cell types expressing CD4 in OM and OL tumors. Discussion: This preliminary study reports significant changes in gene expression for oral melanoma between canine patients with localized disease relative to those with metastatic disease. In the future, a more in-depth investigation involving immunohistochemistry analysis and single-cell RNA expression is necessary to confirm our findings.

Two novel piperidones induce apoptosis and antiproliferative effects on human prostate and lymphoma cancer cell lines.

Cancer remains the second most common cause of death in the US. Due to a recurrent problem with anticancer drug resistance, there is a current need for anticancer drugs with distinct modes of action for combination drug therapy We have tested two novel piperidone compounds, named 2608 (1-dichloroacetyl - 3,5-bis(3,4-difluorobenzylidene)-4-piperidone) and 2610 (1-dichloroacetyl-3,5-bis(3,4-dichlorobenzylidene)-4-piperidone), for their potential cytotoxicity on numerous human cancer cell lines. We found that both compounds were cytotoxic for breast, pancreatic, leukemia, lymphoma, colon, and fibroblast cell lines, with a cytotoxic concentration 50% (CC50) in the low micromolar to nanomolar concentration range. Further assays focused primarily on an acute lymphoblastic lymphoma and colon cancer cell lines since they were the most sensitive and resistant to the experimental piperidones. The cell death mechanism was evaluated through assays commonly used to detect the induction of apoptosis. These assays revealed that both 2608 and 2610 induced reactive oxygen species (ROS) accumulation, mitochondrial depolarization, and activated caspase-3/7. Our findings suggest that the piperidones induced cell death via the intrinsic apoptotic pathway. Additional assays revealed that both piperidones cause cell cycle alteration in lymphoma and colon cell lines. Both piperidones elicited DNA fragmentation, as evidenced by an increment in the sub-G0/G1 subpopulation in both cell lines. Similar to other related compounds, both piperidones were found to act as proteasome inhibitors by increasing the levels of poly-ubiquitinated proteins in both lymphoma and colon cell lines. Hence, the two piperidones exhibited attractive cytotoxic properties and suitable mechanisms of action, which makes them good candidates as anticancer drugs.

Participación, apoyo social y expectativas en la integración social de población venezolana en Ecuador / Participation, social support and expectations in the social integration of the Venezuelan population in Ecuador / Participação, apoio social e expectativas na integração social da população venezuelana no Equador

La integración social (IS) de población venezolana que se ha movilizado por América Latina resulta compleja, por el contexto político, social, laboral, económico y recientemente sanitario adverso, que les expone a dinámicas de discriminación, exclusión y vulneración de derechos. El presente trabajo tiene por objetivo analizar, desde un enfoque psicosocial, la participación social y el apoyo social como dimensiones de IS de venezolanas/os residentes en Quito, Ecuador. Para ello, se aplica una encuesta a 50 participantes (25 hombres y 25 mujeres) que evalúa los problemas y el vínculo con la sociedad de acogida, la participación social y el apoyo social percibido. Los resultados revelan que la población venezolana presenta diversas limitaciones en la IS, especialmente, en la incorporación laboral y el ámbito económico, pero que se están creando canales a nivel socio-comunitario que posibilitan mayores vínculos con la población local, a la vez que presenta una valoración positiva de las expectativas previas al proceso migratorio, que está incidiendo en un apoyo social. Se discuten estos hallazgos y la necesidad de que los Estados latinoamericanos generen políticas públicas que faciliten la IS de población venezolana.

The social integration (SI) of the Venezuelan population that has been moving through Latin America is complex, in an adverse political, social, labor, economic and recently health context, which exposes them to dynamics of discrimination, exclusion and violation of rights. The aim of this paper is to analyze, from a psychosocial approach, social participation and social support as dimensions of SI of Venezuelan residents in Quito, Ecuador. For this purpose, a survey was applied to 50 participants (25 men and 25 women) that evaluated the problems and the link with the host society, social participation and perceived social support, through group meetings. The results reveal that the Venezuelan population presents several limitations in the SI, especially in labor and economic incorporation, but that it is creating channels at the socio-community level that enable greater links with the local population, while presenting a positive appraisal of expectations prior to the migration process, which is influencing social support. These findings and the need for Latin American states to generate public policies that facilitate the SI of the Venezuelan population are discussed.

A integração social (SI) da população venezuelana que se deslocou pela América Latina é complexa, devido ao contexto adverso político, social, trabalhista, econômico e de saúde recente, o que os expõe a dinâmicas de discriminação, exclusão e violação de direitos. O objetivo deste documento é analizar, a partir de uma abordagem psicosocial, a participação social e o apoio social como dimensões da SI entre os venezuelanos residentes em Quito, Equador. Para este fim, uma pesquisa foi aplicada a 50 participantes (25 homens e 25 mulheres) para avaliar problemas e vínculos com a sociedade anfitriã, participação social e apoio social percebido. Os resultados revelam que a população venezuelana apresenta várias limitações no SI, especialmente no mercado de trabalho e na esfera econômica, mas que está criando canais em nível sócio-comunitário que permitem maiores vínculos com a população local, ao mesmo tempo em que apresenta uma avaliação positiva das expectativas antes do processo migratório, o que está tendo um impacto no apoio social. Estas descobertas e a necessidade dos estados latino-americanos de gerar políticas públicas que facilitem a SI da população venezuelana são discutidas.

El sesgo atencional en los trastornos relacionados con sustancias. Aspectos teóricos, evaluativos y de tratamiento / Attentional bias in substance-related disorders. Theoretical, evaluative and treatment aspects

Resumen En la actualidad, existe mayor interés sobre los estudios acerca de la cognición implícita y su función en la conducta. Los modelos explicativos actuales de la psicopatología tienen como limitante la escasa consideración de los procesos cognitivos automáticos en la conducta psicopatológica, como la relacionada con el consumo de sustancias. En este estudio, se revisa al sesgo atencional en los trastornos por consumo y sus implicaciones en la psicopatología, la medición del fenómeno y su aplicación para la intervención. El sesgo atencional hacia las señales críticas de sustancias o drogas es un mecanismo disfuncional de la atención selectiva que opera frecuentemente a nivel automático o implícito y en el que la asignación y focalización de la atención es desproporcionada en el tiempo, entre un estímulo específico (imagen o palabra relacionada con una droga) versus un estímulo neutro. Atrae la atención de la persona al estímulo crítico del que, posteriormente, resulta difícil de desacoplarse y facilita otros procesos cognitivos subsecuentes al consumo. Se presenta evidencia de la incidencia del sesgo atencional en el consumo, el curso, la gravedad, el craving (necesidad intensa de consumo), la abstinencia, la recaída y la probabilidad de fracaso en el tratamiento. Además, explica sobre el fenómeno del consumo, desde la cognición implícita, el inconsciente y la neurociencia cognitiva. Finalmente, en este estudio, se revisan propuestas de intervención sobre los problemas de consumo con técnicas de modificación del sesgo atencional complementarias a los tratamientos cognitivo-conductuales actuales. Se considera necesario explorar sobre esta línea de investigación y su relación con los trastornos por consumo de sustancias dentro de la región.

Abstract The objective of this work is to investigate attentional bias as an automatic cognitive process and its implications in substance use disorders. Cognitive processes are fundamental in the formulation of the different explanatory models about psychopathology. Of the various cognitive processes, attention is a significant determinant, because although it fulfils various activities such as orientation and wakefulness, it is cognitive control that arouses relevant interest for it. This is due to the fact that it fulfills a task of linking between signal uptake and the achievement of other cognitive processes that intervene in the behavioral response mechanism. When a cognitive process like attention is markedly altered it will trigger impaired sequential cognitive functioning, along with the emission of disturbing behavior. Psychology considers that cognitive processes operate consciously (voluntarily) and automatically (implicitly); that is, in a dual way in which these processes such as attention maintain a continuum of coordinated gradual variations that regulate behavior. Failure to consider automatic cognitive processes is a notorious limitation for current explanatory models of psychopathological behavior (including compulsive substance use); given that many of these underlying cognitive processes are often not considered to influence higher mental processes and therefore behavior, without the individual necessarily being aware of this. In fact, this can help to understand pathological behaviors that for the investigator or the professional of psychology can be incomprehensible or paradoxical. Among the various underlying and altered processes, the attentional bias towards critical signals associated with substances has investigative relevance. Since it is a dysfunctional mechanism of selective attention, which operates frequently at an automatic level and in which the allocation and focus of attention are disproportionate in time, between a specific stimulus (image or word related to a drug) versus a neutral stimulus. And it attracts a person's focus of attention to the critical stimulus, from which it later becomes difficult to decouple. This later facilitates other altered cognitive processes subsequent to consumption. The generation of an attentional bias towards a specific signal has its origin in the association between the signal and the behavior, which can be avoidant (recurrent in phobias) or attractive (frequent in substance or food consumption) and that is conditioned until becoming an automatic process of difficult voluntary control. Although it is true that attention bias may be present in all individuals, the evidence reveals the marked and recurrent presence in various pathologies such as mood disorders (depressive), anxiety, food intake, phobias, of personality among others. And also included in substance use disorders. The findings show that attention bias has an impact on substance use, course, the severity of the disorder, craving, withdrawal, relapse, and the probability of treatment failure. Working with an attentional bias for specific signals on substances can generate difficulty, in the case of evaluation because it is assessed through software that usually measures the eye-hand reaction time or eye movement when faced with neutral and critical signals, which can be a limitation for the usual clinic; while at the intervention level, it is required to formulate bias retraining processes that require continuous exercise as a complementary technique to the usual cognitive-behavioral treatment. It is considered necessary to explore this line of research and its relationship with substance use disorders within the region.

Three novel piperidones exhibit tumor-selective cytotoxicity on leukemia cells via protein degradation and stress-mediated mechanisms.

BACKGROUND: Cancer is an ongoing worldwide health problem. Although chemotherapy remains the mainstay therapy for cancer, it is not always effective and has detrimental side effects. Here, we present piperidone compounds P3, P4, and P5 that selectively target cancer cells via protein- and stress-mediated mechanisms. METHODS: We assessed typical apoptotic markers including phosphatidylserine externalization, caspase-3 activation, and DNA fragmentation through flow cytometry. Then, specific markers of the intrinsic pathway of apoptosis including the depolarization of the mitochondria and the generation of reactive oxygen species (ROS) were investigated. Finally, we utilized western blot techniques, RT-qPCR, and observed the cell cycle profile after compound treatment to evaluate the possible behavior of these compounds as proteasome inhibitors. For statistical analyses, we employed the one-way ANOVA followed by Bonferroni post hoc test. RESULTS: P3, P4, and P5 induce cytotoxic effects towards tumorigenic cells, as opposed to non-cancerous cells, at the low micromolar range. Compound treatment leads to the activation of the intrinsic pathway of apoptosis. The accumulation of poly-ubiquitinated proteins and the pro-apoptotic protein Noxa, both typically observed after proteasome inhibition, occurs after P3, P4, and P5 treatment. The stress-related genes PMAIP1, ATF3, CHAC1, MYC, and HMOX-1 were differentially regulated to contribute to the cytotoxic activity of P3-P5. Finally, compound P5 causes cell cycle arrest at the G2/M phase. CONCLUSION: Taken together, compounds P3, P4, and P5 exhibit strong potential as anticancer drug candidates as shown by strong cytotoxic potential, activation of the intrinsic pathway of apoptosis, and show typical proteasome inhibitor characteristics.

The mediating role of emotions in offline and online political participation: A post-social outbreak study in Ecuador and Chile.

Introduction: In 2019, there was a period of social outbreaks in several Latin American countries, which share a background of social inequality, distrust in authorities, a crisis of representativeness, and discontent towards social and economic policies. In October 2019, in Ecuador and Chile, participation in these protests was characterized by street protests and broad political participation in social networks and alternative media, which were followed or interrupted by the COVID-19 pandemic. These facts have been deeply researched, addressing causal and structural factors of the phenomenon, the alternatives of political participation, and the role of emotions as determinants of action in these contexts. The objective of this study is to explore offline and online political participation (Facebook) after the social outbreak of 2019 in both countries, based on political interest, and how emotions intervene, especially negative ones, in a context of high demobilization. Methods: A descriptive, correlational ex post facto and cross-sectional methodology was used, with the participation of 367 people, 210 from Ecuador (57.2%) and 157 from Chile (42.8%), aged between 17 and 48 years (M = 22.13, SD = 3.73). The measurement was carried out from 2020 to 2021. Results: A mediation analysis showed that people who are more interested in politics are more likely to experience anger and anxiety with the political and economic situation, which motivates conventional political participation (Model 1). In Model 2 people who showed greater concern about the political and economic impacts of the COVID-19 pandemic and together with anger, favor online political participation, especially local support. Discussion: These results suggest the influence of emotions on political participation, which occurs when there is an increase in social discontent due to government policies adopted during the pandemic and which represents a continuity of the discontent that was expressed in the October 2019 social outbreak.

Persistent myelin abnormalities in a third trimester-equivalent mouse model of fetal alcohol spectrum disorder.

BACKGROUND: Abnormal diffusion within white matter (WM) tracts has been linked to cognitive impairment in children with fetal alcohol spectrum disorder. Whether changes to myelin organization and structure underlie the observed abnormal diffusion patterns remains unknown. Using a third trimester-equivalent mouse model of alcohol exposure, we previously demonstrated acute loss of oligodendrocyte lineage cells with persistent loss of myelin basic protein and lower fractional anisotropy (FA) in the corpus callosum (CC). Here, we tested whether these WM deficits are accompanied by changes in: (i) axial diffusion (AD) and radial diffusion (RD), (ii) myelin ultrastructure, or (iii) structural components of the node of Ranvier. METHODS: Mouse pups were exposed to alcohol or air vapor for 4 h daily from postnatal day (P)3 to P15 (BEC: 160.4 ± 12.0 mg/dl; range = 128.2 to 185.6 mg/dl). Diffusion tensor imaging (DTI) and histological analyses were performed on brain tissue isolated at P50. Diffusion parameters were measured with Paravision™ 5.1 software (Bruker) following ex vivo scanning in a 7.0 T MRI. Nodes of Ranvier were identified using high-resolution confocal imaging of immunofluorescence for Nav 1.6 (nodes) and Caspr (paranodes) and measured using Imaris™ imaging software (Bitplane). Myelin ultrastructure was evaluated by calculating the G-ratio (axonal diameter/myelinated fiber diameter) on images acquired using transmission electron microscopy. RESULTS: Consistent with our previous study, high resolution DTI at P50 showed lower FA in the CC of alcohol-exposed mice (p = 0.0014). Here, we show that while AD (diffusion parallel to CC axons) was similar between treatment groups (p = 0.30), RD (diffusion perpendicular to CC axons) in alcohol-exposed subjects was significantly higher than in controls (p = 0.0087). In the posterior CC, where we identified the highest degree of abnormal diffusion, node of Ranvier length did not differ between treatment groups (p = 0.41); however, the G-ratio of myelinated axons was significantly higher in alcohol-exposed animals than controls (p = 0.023). CONCLUSIONS: High resolution DTI revealed higher RD at P50 in the CC of alcohol-exposed animals, suggesting less myelination of axons, particularly in the posterior regions. In agreement with these findings, ultrastructural analysis of myelinated axons in the posterior CC showed reduced myelin thickness in alcohol-exposed animals, evidenced by a higher G-ratio.

Teleconsulta médica. Análisis y recomendaciones del Departamento de Ética del Colegio Médico de Chile

The possibility of allowing patients access to health professionals, has been greatly facilitated by advances in technology. Indeed, nowadays it is possible not only direct contact between one health professional with another, but also the possibility of sending images and other tests to consult distant colleagues. This has undoubtedly enabled better health care for many patients. It is also possible for a patient to consult a doctor directly in a remote and synchronous way with oral and visual contact, thus establishing a new form of medical consultation. It is this last way of relationship, which has already spread as a practice in normal times, which arouses apprehensions about the ethical requirements that a consultation must meet. This work by the Ethics Department of the Chilean Medical Association seeks to reflect on the ethical demands of a medical consultation and on the shortcomings that teleconsultation has. It also aims to propose several recommendations, so that this new form of doctor-patient relationship serves as a complement to traditional care, without jeopardizing the objectives of a medical action.

Bienestar Subjetivo en contextos de desigualdad y derrota social en jóvenes universitarios de Chile y Ecuador

Resumen Los estudios macroeconómicos evidencian que países con mayor desigualdad social presentan peores indicadores de salud mental y bienestar, sin embargo, otros mecanismos intervinientes no están del todo claro. Recientes investigaciones han propuesto que la percepción de derrota social configura una variable clave para comprender los impactos de las desigualdades. El objetivo de este estudio fue explorar el rol predictor de la derrota social en el bienestar subjetivo de estudiantes universitarios provenientes de países latinoamericanos que exhiben niveles de desigualdad social. Los participantes fueron 347 estudiantes universitarios de Chile y 246 de Ecuador, en los cuales se evaluó la percepción de derrota social, fatalismo, participación social, bienestar social, y bienestar subjetivo. Los resultados del modelo de regresión muestran que la predicción del bienestar subjetivo mejora al incluir las dimensiones de derrota social en el modelo (r2 = .38). Se propone la derrota social como una variable que ayuda a comprender cómo un contexto de desigualdad social puede impactar en el bienestar percibido de jóvenes universitarios.

Abstract Macroeconomic studies show that countries with greater social inequality have worse indicators of mental health and well-being; however, other intervening mechanisms are not entirely clear. Recent research has proposed that the perception of social defeat is a key variable in understanding the impacts of inequalities. The aim of this study was to explore the predictive role of social defeat in the subjective well-being of university students from Latin American countries that exhibit levels of social inequality. The participants were 347 university students from Chile and 246 from Ecuador, in whom the perception of social defeat, fatalism, social participation, social well-being, and subjective well-being were evaluated. The results of the regression model show that the prediction of subjective well-being improves when including the dimensions of social defeat in the model (r2 = .38) Social defeat is proposed as a variable that helps to understand how a context of social inequality can impact the perceived well-being of young university students.

Cifosis patológica en la columna pediátrica / Pathologic kyphosis in the pediatric spine

En este manuscrito se revisan las diferentes causas que producen aumento de la cifosis torácica (dorso curvo), específicamente en niños y adolescentes. Las causas del dorso curvo que se analizan en este artículo son: Dorso curvo postural, idiopático, neuromuscular, congénito y enfermedad de Scheuermann. Se centra en los factores que producen su aparición, características de su evolución y tratamiento.

This manuscript reviews the different causes that lead to increased thoracic kyphosis, specifically in children and adolescents. The causes of increased thoracic kyphosis that will be discussed in this article are: postural, idiopathic, neuromuscular, congenital, and Scheuermann's disease. This paper focuses on the factors that produce its appearance, characteristics of its evolution, and treatment.

Social Sharing of Emotions and Communal Appraisal as Mediators Between the Intensity of Trauma and Social Well-Being in People Affected by the 27F, 2010 Earthquake in the Biobío Region, Chile.

The psychosocial impacts of natural disasters are associated with the triggering of negative and positive responses in the affected population; also, such effects are expressed in an individual and collective sphere. This can be seen in several reactions and behaviors that can vary from the development of individual disorders to impacts on interpersonal relationships, cohesion, communication, and participation of the affected communities, among others. The present work addressed the psychosocial impacts of the consequences of natural disasters considering individual effects via the impact of trauma and community effects, through the perception of social well-being, the valuation of the community and the social exchange of emotions. The aim of this study was to assess the relationship between individual reactions (i.e., intensity of trauma) and the evaluation of social and collective circumstances (i.e., social well-being) after the earthquake of 27F 2010 in Chile, through collective-type intervention variables not used in previous studies (i.e., social sharing of emotions and community appraisal). For this purpose, a descriptive, ex post facto correlational and cross-sectional methodology was carried on, with the participation of 487 people affected by the 2010 earthquake, 331 women (68%) and 156 men (32%), between 18 and 58 years old (M = 21.09; SD = 5.45), from the provinces of Ñuble and Biobío, VIII region, Chile. The measurement was carried out 4 years after the earthquake and the results show that greater individual than collective involvements were found, mainly in the coastal zone of the region. The mediation analysis showed that the relationship between the intensity of the trauma and social well-being occurs through a route that considers social sharing of emotions and community appraisal. These results indicate that the overcoming of individual affectations to achieve social well-being occurs when in the immediate post-disaster phases the affected communities activate shared emotional and cognitive processes, which allow them to jointly face subsequent threats and abrupt changes.

Tomografía computarizada de haz cónico como examen concluyente de hiperplasia de procesos coronoides bilateral. Reporte de tres casos / Cone beam computed tomography as a conclusive examination of bilateral coronoid process hyperplasia. Report of three cases

RESUMEN La hiperplasia del proceso coronoides (HPC) es un crecimiento exagerado del proceso coronoides. La HPC es poco frecuente y genera limitación asintomática de la apertura bucal debido a la impactación del proceso coronoides con el segmento posterior del hueso cigomático. La HPC es un posible diagnóstico en pacientes con limitación progresiva tanto de la apertura bucal como del movimiento protrusivo mandibular. En el presente artículo, se reportan tres casos de pacientes con limitación de apertura bucal. Mediante examen de tomografía computarizada de haz cónico (TCHC), se observó un aumento de tamaño uniforme de los procesos coronoides, confirmando el diagnóstico de HPC bilateral. La TCHC con campo de visión grande determinó el diagnóstico final, pues mostró la impactación del proceso coronoides con el segmento posterior del hueso cigomático en apertura bucal. Además, la TCHC permitió distinguir entre una HPC y una neoplasia del proceso coronoides y/o estructuras anatómicas vecinas.

SUMMARY Coronoid process hyperplasia (CPH) is an excessive coronoid process growing. CPH is infrequent and produces an asymptomatic mouth opening limitation due to the impaction of the coronoid process in the posterior portion of the zygomatic bone. CPH is a possible diagnosis in patients with both progressive mouth opening and protrusive movement limitations. In the present article, cases of three patients with mouth opening limitation are reported. In cone-beam computed tomography (CBCT) examination, a uniform growing of coronoid processes was observed, which confirmed the diagnosis of bilateral CPH. CBCT with large field of view allowed the determination of the final diagnosis, because the impaction of the coronoid process in the posterior portion of the zygomatic bone during mouth opening could be observed. Furthermore, CBCT allowed to distinguish between CPH and neoplasia of coronoid process and/or neighboring anatomical structures.