Age-Dependent Behavioral and Synaptic Dysfunction Impairment Are Improved with Long-Term Andrographolide Administration in Long-Lived Female Degus (Octodon degus).

In Octodon degus, the aging process is not equivalent between sexes and worsens for females. To determine the beginning of detrimental features in females and the ways in which to improve them, we compared adult females (36 months old) and aged females (72 months old) treated with Andrographolide (ANDRO), the primary ingredient in Andrographis paniculata. Our behavioral data demonstrated that age does not affect recognition memory and preference for novel experiences, but ANDRO increases these at both ages. Sociability was also not affected by age; however, social recognition and long-term memory were lower in the aged females than adults but were restored with ANDRO. The synaptic physiology data from brain slices showed that adults have more basal synaptic efficiency than aged degus; however, ANDRO reduced basal activity in adults, while it increased long-term potentiation (LTP). Instead, ANDRO increased the basal synaptic activity and LTP in aged females. Age-dependent changes were also observed in synaptic proteins, where aged females have higher synaptotagmin (SYT) and lower postsynaptic density protein-95 (PSD95) levels than adults. ANDRO increased the N-methyl D-aspartate receptor subtype 2B (NR2B) at both ages and the PSD95 and Homer1 only in the aged. Thus, females exposed to long-term ANDRO administration show improved complex behaviors related to age-detrimental effects, modulating mechanisms of synaptic transmission, and proteins.

Clinical and Descriptive Study of Orofacial Clefts in Colombia: 2069 Patients From Operation Smile Foundation.

OBJECTIVE: To describe the population of patients with cleft lip and/or palate (CL/P) in terms of cleft phenotypes, gender, age, ethnic group, family history, clinical presentation (syndromic vs nonsyndromic), some environmental and behavioral factors, and some clinical features. DESIGN: Descriptive retrospective study. SETTING: Patients attending the genetics counseling practice in Operation Smile Foundation, Bogotá, Colombia, for over 8 years. PARTICIPANTS: No screening was conducted. All patients requiring clinical genetics assessment in Operation Smile Foundation were included in the study. RESULTS: Left cleft lip and palate (CLP) and nonsyndromic forms were the most frequent types of malformations in this population. Psychomotor retardation and heart disease were the most frequent comorbidities in these patients. A low proportion of mothers exposed to passive smoking during pregnancy was observed and low birth weight accounted for an important number of cases. Aarskog, velocardiofacial, and orofaciodigital syndromes were the most frequent syndromic forms of CLP in this population. CONCLUSIONS: In this study, the most frequent type of CL/P was the nonsyndromic complete left CLP. Aarskog, velocardiofacial, and orofaciodigital syndromes were the most frequent syndromic forms of CL/P in this population.

What is the quality of life of adults with vitiligo in Mexico?

INTRODUCTION: Vitiligo is an incurable, slowly progressive skin condition, the prevalence of which ranges from 0.4 to 2.0%. Health-related quality of life (HRQoL) refers to self-perceived well-being associated with the presence of a disease and its treatment. METHODS: Cross-sectional study at a dermatological center. Adults with non-segmental vitiligo (NSV) were included, while patients with other pigmentary disorders and other types of vitiligo were excluded. The VitiQoL questionnaire (0 = no skin involvement, 90 = maximum skin involvement), the Vitiligo Extent Score (VES) and the Vitiligo Area Scoring Index (VASI) were applied. RESULTS: 492 patients did participate; 63% were women. An average score of 32.6 was obtained on VitiQoL (95% CI = 30.6-34.5). Self-perception of severity and HRQoL were correlated (r = 0.568, p < 0.001). Age, the female gender, lower education and higher self-perceived severity were associated with poorer HRQoL. The proportion of subjects who reported an addiction was similar in the worst and best HRQoL groups (28% vs. 32%, p = 0.23). CONCLUSION: Poorer HRQoL is explained by severity self-perception, concern about disease progression, appearance of the skin and necessary actions to avoid sun exposure during recreation.

INTRODUCCIÓN: El vitiligo es incurable, lentamente progresivo, su prevalencia varía de 0.4 a 2.0 %. La calidad de vida relacionada con la salud (CVRS) se refiere al bienestar autopercibido asociado a la presencia de una enfermedad y su tratamiento. MÉTODOS: Estudio transversal en un centro dermatológico. Se incluyeron adultos con vitiligo no segmentario (VNS), en tanto que se excluyeron pacientes con otros trastornos pigmentarios y otros tipos de vitiligo. Se aplicó el cuestionario VitiQoL (0 = sin afectación, 90 = máxima afectación), el Vitiligo Extent Score (VES) y el Vitiligo Area Scoring Index (VASI). RESULTADOS: Participaron 492 pacientes, 63 % mujeres. Se obtuvieron 32.6 puntos de promedio en el VitiQoL (IC 95 % = 30.6-34.5). La autopercepción de gravedad y la CVRS se correlacionaron (r = 0.568, p < 0.001). La edad, el sexo femenino, la menor educación y la mayor gravedad autopercibida se asociaron a peor CVRS. La proporción de personas que reportaron una adicción fue similar en los grupos con peor y mejor CVRS (28 % versus 32 %, p = 0.23). CONCLUSIÓN: La peor CVRS se explica por la autopercepción de gravedad, preocupación por la progresión de la enfermedad, aspecto de la piel y acciones necesarias para evitar la exposición al sol durante la recreación.

Simvastatin Improves Cardiac Function through Notch 1 Activation in BALB/c Mice with Chronic Chagas Cardiomyopathy.

Chagas disease, caused by the protozoan Trypanosoma cruzi, endemic in Latin America but distributed worldwide because of migration. Without appropriate treatment, the disease progresses from an acute asymptomatic phase to a chronic, progressive inflammatory cardiomyopathy causing heart failure and death. Despite specific trypanocidal therapy, heart damage progression cannot be stopped or reversed. Statins, as part of their pleiotropic actions, can modulate chagasic myocarditis by inducing the production of 15-epi-lipoxin A4 (15-epi-LXA4), a proresolution lipid mediator in inflammation. Furthermore, several reports suggest that simvastatin activates the Notch pathway after stroke in cerebral endothelial cells, enhancing blood flow by promoting angiogenesis. Thus, statins are an attractive therapeutic strategy for modulating the Notch pathway to reverse the chronic heart damage induced by T. cruzi BALB/c mice chronically infected with T. cruzi were treated with 1 mg/kg/day simvastatin or 25 µg/kg/day 15-epi-LXA4 for 20 days. During the treatment period, cardiac function was evaluated by echocardiography. At 80 days postinfection, the heart tissues were assessed for Notch 1 activity. T. cruzi infection activated the Notch 1 pathway, and simvastatin (but not 15-epi-lipoxin A4) produced a further increase in that activity, correlating with improvement in the ejection fraction and histopathologic findings typical of T. cruzi infection, including improvements in inflammation and fibrosis. Moreover, simvastatin increased the number of isolectin B4-positive cells, suggesting active angiogenesis in the chronically infected hearts without alteration of the parasitic load. Simvastatin, probably acting through the Notch 1 pathway, decreases inflammation, improving cardiac function in mice chronically infected with T. cruzi.

Notch receptor expression in Trypanosoma cruzi-infected human umbilical vein endothelial cells treated with benznidazole or simvastatin revealed by microarray analysis.

Chagas disease is a vector-borne disease caused by the protozoan parasite Trypanosoma cruzi. Current therapy involves benznidazole. Benznidazole and other drugs can modify gene expression patterns, improving the response to the inflammatory influx induced by T. cruzi and decreasing the endothelial activation or immune cell recruitment, among other effects. Here, we performed a microarray analysis of human umbilical vein endothelial cells (HUVECs) treated with benznidazole and the anti-inflammatory drugs acetylsalicylic acid or simvastatin and infected with T. cruzi. Parasitic infection produces differential expression of a set of genes in HUVECs treated with benznidazole alone or a combination with simvastatin or acetylsalicylic acid. The differentially expressed genes were involved in inflammation, adhesion, cardiac function, and remodeling. Notch1 and high mobility group B1 were genes of interest in this analysis due to their importance in placental development, cardiac development, and inflammation. Quantitative polymerase chain reaction confirmation of these two genes indicated that both are upregulated in the presence of benznidazole.

Amyloid-ß Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory.

High levels of amyloid-ß peptide (Aß) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Aß are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Aß levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors sildenafil and vardenafil induces a parallel release of Aß due to a change in the approximation of amyloid precursor protein (APP) and the ß-site APP cleaving enzyme 1. Moreover, electrophysiological and behavioral studies performed on animals of both sexes showed that blocking Aß function, by using anti-murine Aß antibodies or APP knock-out mice, prevents the cGMP-dependent enhancement of LTP and memory. Our data suggest that cGMP positively regulates Aß levels in the healthy brain which, in turn, boosts synaptic plasticity and memory.SIGNIFICANCE STATEMENT Amyloid-ß (Aß) is a key pathogenetic factor in Alzheimer's disease. However, low concentrations of endogenous Aß, mimicking levels of the peptide in the healthy brain, enhance hippocampal long-term potentiation (LTP) and memory. Because the second messenger cGMP exerts a central role in LTP mechanisms, here we studied whether cGMP affects Aß levels and function during LTP. We show that cGMP enhances Aß production by increasing the APP/BACE-1 convergence in endolysosomal compartments. Moreover, the cGMP-induced enhancement of LTP and memory was disrupted by blockade of Aß, suggesting that the physiological effect of the cyclic nucleotide on LTP and memory is dependent upon Aß.

[Fecal microbiota transplantation through colonoscopy for Clostridium difficile recurrent infection. Report of eight cases]. / Experiencia del trasplante de microbiota fecal a través de colonoscopía en el tratamiento de la infección por Clostridium difficile recurrente.

BACKGROUND: Most cases of Clostridium difficile infection (CDI) respond to a standard course of antibiotics, however recurrent CDI is becoming common and alternative therapeutic strategies are needed. In this scenario, fecal microbiota transplantation (FMT) has been suggested. AIM: To describe the efficacy and safety of FMT for the treatment of recurrent CDI. PATIENTS AND METHODS: Review of medical records of all patients with recurrent CDI treated with FMT between April 2013 and April 2017. Demographic and clinical data were abstracted including details of treatment prior to FMT, rate of FMT treatment success and clinical course during follow-up period. Telephone surveys were conducted to determine patient satisfaction. RESULTS: Eight patients aged 19 to 82 years (six women) underwent FMT. They experienced a median of four previous episodes of CDI (range 3-8). The mean duration of CDI was 18 days (range 3-36) before FMT. All procedures were performed by colonoscopy. Effectiveness with one session of FMT was 100%. During the follow-up period (median 24 months, range 7-55), two patients developed CDI, one of them after using antibiotics. Adverse events were reported in three patients. Two had bloating and one patient with Crohn's disease and a history of bacteremia had an episode of Escherichia coli bacteremia. All patients would use FMT again if necessary. CONCLUSIONS: FMT through colonoscopy appears to be a safe, effective and long-lasting therapy in cases of recurrent CDI.

Destabilization of mitochondrial functions as a target against breast cancer progression: Role of TPP(+)-linked-polyhydroxybenzoates.

Mitochondrion is an accepted molecular target in cancer treatment since it exhibits a higher transmembrane potential in cancer cells, making it susceptible to be targeted by lipophilic-delocalized cations of triphenylphosphonium (TPP(+)). Thus, we evaluated five TPP(+)-linked decyl polyhydroxybenzoates as potential cytotoxic agents in several human breast cancer cell lines that differ in estrogen receptor and HER2/neu expression, and in metabolic profile. Results showed that all cell lines tested were sensitive to the cytotoxic action of these compounds. The mechanism underlying the cytotoxicity would be triggered by their weak uncoupling effect on the oxidative phosphorylation system, while having a wider and safer therapeutic range than other uncouplers and a significant lowering in transmembrane potential. Noteworthy, while the TPP(+)-derivatives alone led to almost negligible losses of ATP, when these were added in the presence of an AMP-activated protein kinase inhibitor, the levels of ATP fell greatly. Overall, data presented suggest that decyl polyhydroxybenzoates-TPP(+) and its derivatives warrant future investigation as potential anti-tumor agents.

On cognitive ecology and the environmental factors that promote Alzheimer disease: lessons from Octodon degus (Rodentia: Octodontidae).

Cognitive ecologist posits that the more efficiently an animal uses information from the biotic and abiotic environment, the more adaptive are its cognitive abilities. Nevertheless, this approach does not test for natural neurodegenerative processes under field or experimental conditions, which may recover animals information processing and decision making and may explain, mechanistically, maladaptive behaviors. Here, we call for integrative approaches to explain the relationship between ultimate and proximate mechanisms behind social behavior. We highlight the importance of using the endemic caviomorph rodent Octodon degus as a valuable natural model for mechanistic studies of social behavior and to explain how physical environments can shape social experiences that might influence impaired cognitive abilities and the onset and progression of neurodegenerative disorders such as Alzheimer disease. We consequently suggest neuroecological approaches to examine how key elements of the environment may affect neural and cognitive mechanisms associated with learning, memory processes and brain structures involved in social behavior. We propose the following three core objectives of a program comprising interdisciplinary research in O. degus, namely: (1) to determine whether diet types provided after weaning can lead to cognitive impairment associated with spatial memory, learning and predisposing to develop Alzheimer disease in younger ages; (2) to examine if early life social experience has long term effects on behavior and cognitive responses and risk for development Alzheimer disease in later life and (3) To determine if an increase of social interactions in adult degu reared in different degree of social stressful conditions alter their behavior and cognitive responses.

A novel mechanism for cyclic adenosine monophosphate-mediated memory formation: Role of amyloid beta.

Cyclic adenosine monophosphate (cAMP) regulates long-term potentiation (LTP) and ameliorates memory in healthy and diseased brain. Increasing evidence shows that, under physiological conditions, low concentrations of amyloid ß (Aß) are necessary for LTP expression and memory formation. Here, we report that cAMP controls amyloid precursor protein (APP) translation and Aß levels, and that the modulatory effects of cAMP on LTP occur through the stimulation of APP synthesis and Aß production.

Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors.

A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.

[Fecal microbiota transplantation in recurrent Clostridium difficile infection. Report of one case]. / Trasplante de microbiota fecal en infección recurrente por Clostridium difficile. Experiencia local a partir de un caso clínico.

Fecal microbiota transplantation (FMT) has an incomparable efficacy to treat recurrent Clostridium difficile infection, with near 90% of success. We report a 57 years old woman who developed an antibiotic associated diarrhea with a positive polymerase chain reaction test for Clostridium Difficile toxin. She was successfully treated with Vancomycin trice but diarrhea recurred. Therefore a fecal microbiota transplant was performed using solid stools from a relative, diluted in saline and instilled in the distal ileon, with a good clinical response, without recurrence of diarrhea, during a 6-month follow-up.

[Fecal microbiota transplantation: first case report in Chile and review]. / Trasplante de microbiota fecal: primer caso reportado en Chile y revisión de la literatura.

Clostridium difficile (CD) infection is increasing in frequency and severity in in-hospital and outpatient clinical settings, with a recurrence that can reach 30% after first episode. The recurrences are usually treated with longer courses of metronidazole or vancomycin. Other treatments have been used, such as probiotics, fidaxomicin, rifaximin, immunoglobulins and monoclonal antibodies against toxins A and B. Fecal microbiota transplantation (FMT) has emerged as a promising strategy in this group of patients, with effectiveness greater than 90%. We present the first case reported in Chile of this therapeutic strategy in a patient with Crohn's disease and recurrent CD infection who presented after the fecal transplantation an Escherichia coli bacteremia, suggesting the need for caution in the use of this strategy. 10 months after the FMT the patient presented a new episode of E. coli bacteremia and two episodes of diarrhea due to CD infection, treated both of them with vancomycin with good clinical response.

Insights into the Gut Microbiome of the South American Leaf-Toed Gecko (Phylodactylus gerropygus) Inhabiting the Core of the Atacama Desert.

Living in arid environments presents unique challenges to organisms, including limited food and water, extreme temperatures, and UV exposure. Reptiles, such as the South American leaf-toed gecko (Phyllodactylus gerrhopygus), have evolved remarkable adaptations to thrive in such harsh conditions. The gut microbiome plays a critical role in host adaptation and health, yet its composition remains poorly characterized in desert reptiles. This study aimed to characterize the composition and abundance of the gut microbiome in P. gerrhopygus inhabiting the hyperarid Atacama Desert, taking into account potential sex differences. Fecal samples from adult female and male geckos were analyzed by 16S rRNA gene amplicon sequencing. No significant differences in bacterial alpha diversity were observed between the sexes. However, the phylum Bacteroidota was more abundant in females, while males had a higher Firmicutes/Bacteroidota ratio. The core microbiome was dominated by the phyla Bacteroidota, Firmicutes, and Proteobacteria in both sexes. Analysis of bacterial composition revealed 481 amplicon sequence variants (ASVs) shared by female and male geckos. In addition, 108 unique ASVs were exclusive to females, while 244 ASVs were unique to males. Although the overall bacterial composition did not differ significantly between the sexes, certain taxa exhibited higher relative abundances in each sex group. This study provides insight into the taxonomic structure of the gut microbiome in a desert-adapted reptile and highlights potential sex-specific differences. Understanding these microbial communities is critical for elucidating the mechanisms underlying host resilience in Earth's most arid environments, and for informing conservation efforts in the face of ongoing climate change.

Mitochondrial bioenergetics as a cell fate rheostat for responsive to Bcl-2 drugs: New cues for cancer chemotherapy.

Pro-survival BCL-2 proteins prevent the initiation of intrinsic apoptosis (mitochondria-dependent pathway) by inhibiting the pro-apoptotic proteins BAX and BAK, while BH3-only proteins promote apoptosis by blocking pro-survival BCL-2 proteins. Disruptions in this delicate balance contribute to cancer cell survival and chemoresistance. Recent advances in cancer therapeutics involve a new generation of drugs known as BH3-mimetics, which are small molecules designed to mimic the action of BH3-only proteins. Promising effects have been observed in patients with hematological and solid tumors undergoing treatment with these agents. However, the rapid emergence of mitochondria-dependent resistance to BH3-mimetics has been reported. This resistance involves increased mitochondrial respiration, altered mitophagy, and mitochondria with higher and tighter cristae. Conversely, mutations in isocitrate dehydrogenase 1 and 2, catalyzing R-2-hydroxyglutarate production, promote sensitivity to venetoclax. This evidence underscores the urgency for comprehensive studies on bioenergetics-based adaptive responses in both BH3 mimetics-sensitive and -resistant cancer cells. Ongoing clinical trials are evaluating BH3-mimetics in combination with standard chemotherapeutics. In this article, we discuss the role of mitochondrial bioenergetics in response to BH3-mimetics and explore potential therapeutic opportunities through metabolism-targeting strategies.

Impact of prolonged chronic social isolation stress on behavior and multifractal complexity of metabolic rate in Octodon degus.

Social interaction can improve animal performance through the prevention of stress-related events, the provision of security, and the enhancement of reproductive output and survival. We investigated the effects of prolonged chronic social isolation stress on behavioral, cognitive, and physiological performance in the social, long-lived rodent Octodon degus. Degu pups were separated into two social stress treatments: control (CTRL) and chronically isolated (CI) individuals from post-natal and post-weaning until adulthood. We quantified anxiety-like behavior and cognitive performance with a battery of behavioral tests. Additionally, we measured their basal metabolic rate (BMR) and analyzed the multifractal properties of the oxygen consumption time series using Multifractal Detrended Fluctuation Analysis, a well-known method for assessing the fractal characteristics of biological signals. Our results showed that CI induced a significant increase in anxiety-like behaviors and led to a reduction in social and working memory in male degus. In addition, CI-treated degus reduced the multifractal complexity of BMR compared to CTRL, which implies a decrease in the ability to respond to environmental stressors and, as a result, an unhealthy state. In contrast, we did not observe significant effects of social stress on BMR. Multivariate analyses showed a clear separation of behavior and physiological variables into two clusters, corresponding to CI and CTRL degus. This study provides novel insights into the effects of prolonged chronic social isolation stress on behavior, cognitive performance, and metabolic complexity in this rodent animal model. To the best of our knowledge, it is the first study to integrate cognitive-behavioral performance and multifractal dynamics of a physiological signal in response to prolonged social isolation. These findings highlight the importance of social interactions for the well-being and overall performance of social animals.

Porcine fungal mock community analyses: Implications for mycobiome investigations.

Introduction: The gut microbiome is an integral partner in host health and plays a role in immune development, altered nutrition, and pathogen prevention. The mycobiome (fungal microbiome) is considered part of the rare biosphere but is still a critical component in health. Next generation sequencing has improved our understanding of fungi in the gut, but methodological challenges remain. Biases are introduced during DNA isolation, primer design and choice, polymerase selection, sequencing platform selection, and data analyses, as fungal reference databases are often incomplete or contain erroneous sequences. Methods: Here, we compared the accuracy of taxonomic identifications and abundances from mycobiome analyses which vary among three commonly selected target gene regions (18S, ITS1, or ITS2) and the reference database (UNITE - ITS1, ITS2 and SILVA - 18S). We analyze multiple communities including individual fungal isolates, a mixed mock community created from five common fungal isolates found in weanling piglet feces, a purchased commercial fungal mock community, and piglet fecal samples. In addition, we calculated gene copy numbers for the 18S, ITS1, and ITS2 regions of each of the five isolates from the piglet fecal mock community to determine whether copy number affects abundance estimates. Finally, we determined the abundance of taxa from several iterations of our in-house fecal community to assess the effects of community composition on taxon abundance. Results: Overall, no marker-database combination consistently outperformed the others. Internal transcribed space markers were slightly superior to 18S in the identification of species in tested communities, but Lichtheimia corymbifera, a common member of piglet gut communities, was not amplified by ITS1 and ITS2 primers. Thus, ITS based abundance estimates of taxa in piglet mock communities were skewed while 18S marker profiles were more accurate. Kazachstania slooffiae displayed the most stable copy numbers (83-85) while L. corymbifera displayed significant variability (90-144) across gene regions. Discussion: This study underscores the importance of preliminary studies to assess primer combinations and database choice for the mycobiome sample of interest and raises questions regarding the validity of fungal abundance estimates.

Pyrosequencing Assay for BRCA1 Methylation Analysis: Results from a Cross-Validation Study.

Epithelial ovarian cancers (EOCs) harboring germline or somatic pathogenic variants in BRCA1 and BRCA2 genes show sensitivity to poly(ADP-ribose) polymerase inhibition. It has been suggested that BRCA1 promoter methylation is perhaps a better determinant of therapy response, because of its intrinsic dynamic feature, with respect to genomic scars or gene mutation. Conflicting evidence was reported so far, and the lack of a validated assay to measure promoter methylation was considered a main confounding factor in data interpretation. To contribute to the validation process of a pyrosequencing assay for BRCA1 promoter methylation, 109 EOCs from two Italian centers were reciprocally blindly investigated. By comparing two different pyrosequencing assays, addressing a partially overlapping region of BRCA1 promoter, an almost complete concordance of results was obtained. Moreover, the clinical relevance of this approach was also supported by the finding of BRCA1 transcript down-regulation in BRCA1-methylated EOCs. These findings could lead to the development of a simple and cheap pyrosequencing assay for diagnostics, easily applicable to formalin-fixed, paraffin-embedded tissues. This technique may be implemented in routine clinical practice in the near future to identify EOCs sensitive to poly(ADP-ribose) polymerase inhibitor therapy, thus increasing the subset of women affected by EOCs who could benefit from such treatment.

The Advantages of Next-Generation Sequencing Molecular Classification in Endometrial Cancer Diagnosis.

Endometrial cancer (EC) is the most frequent gynecological cancer. The ESGO/ESTRO/ESP 2020 guidelines identify prognostic groups based on morpho-molecular characteristics. This study aims to evaluate the clinical applicability of NGS analysis to define an appropriate risk class and to improve the diagnostic and prognostic stratification of ECs. Cases of serous carcinoma (OHEC) and high- (HGEC) and low-grade (LGEC) endometrioid carcinoma diagnosed with the morphological and immunohistochemical (IHC) protocols were considered. After a standardized pre-analytical phase, tumor DNA was semi-automatically extracted and analyzed using NGS with a panel of 14 genes. A total of 63 cases were considered. NGS analysis was successful in 60 cases; all of these were classified according to the new diagnostic algorithm. The molecular risk classification showed a good correlation with the morphological (k = 0.8). The study showed that the protocols of the pre-analytical and analytical phases used are robust and can lead to molecular results that fall within the standards required, which can be used in clinical practice for more precise diagnostic-therapeutic management of patients. The implementation of the classification is particularly relevant for better prognostic stratification of HGECs. In addition, the identification of a suspicious VUS in POLE questions the classification of truncating variants.

Long-term social isolation stress exacerbates sex-specific neurodegeneration markers in a natural model of Alzheimer's disease.

Social interactions have a significant impact on health in humans and animal models. Social isolation initiates a cascade of stress-related physiological disorders and stands as a significant risk factor for a wide spectrum of morbidity and mortality. Indeed, social isolation stress (SIS) is indicative of cognitive decline and risk to neurodegenerative conditions, including Alzheimer's disease (AD). This study aimed to evaluate the impact of chronic, long-term SIS on the propensity to develop hallmarks of AD in young degus (Octodon degus), a long-lived animal model that mimics sporadic AD naturally. We examined inflammatory factors, bioenergetic status, reactive oxygen species (ROS), oxidative stress, antioxidants, abnormal proteins, tau protein, and amyloid-ß (Aß) levels in the hippocampus of female and male degus that were socially isolated from post-natal and post-weaning until adulthood. Additionally, we explored the effect of re-socialization following chronic isolation on these protein profiles. Our results showed that SIS promotes a pro-inflammatory scenario more severe in males, a response that was partially mitigated by a period of re-socialization. In addition, ATP levels, ROS, and markers of oxidative stress are severely affected in female degus, where a period of re-socialization fails to restore them as it does in males. In females, these effects might be linked to antioxidant enzymes like catalase, which experience a decline across all SIS treatments without recovery during re-socialization. Although in males, a previous enzyme in antioxidant pathway diminishes in all treatments, catalase rebounds during re-socialization. Notably, males have less mature neurons after chronic isolation, whereas phosphorylated tau and all detectable forms of Aß increased in both sexes, persisting even post re-socialization. Collectively, these findings suggest that long-term SIS may render males more susceptible to inflammatory states, while females are predisposed to oxidative states. In both scenarios, the accumulation of tau and Aß proteins increase the individual susceptibility to early-onset neurodegenerative conditions such as AD.