Next-generation sequencing reveals remarkable genetic stability in primary and corresponding recurrent intestinal-type sinonasal adenocarcinoma.

BACKGROUND: Recurrent intestinal-type sinonasal adenocarcinoma (ITAC) can occur several years after primary treatment and with different histology. We aimed to clarify if such recurrences could be second primary tumors and to identify actionable mutations as targets for personalized treatment of recurrent ITAC. METHODS: Twelve pairs of primary and recurrent ITAC were histologically examined and analyzed by next-generation sequencing. RESULTS: Histological differences between primary and recurrent tumor pairs were observed in five cases. Frequent mutations included TP53, APC, TSC2, ATM, EPHA2, BRCA2, LRP1B, KRAS, and KMT2B. There was 86% concordance of somatic mutations between the tumor pairs, while four cases carried additional mutations in the recurrence. CONCLUSIONS: We found all cases to be clonal recurrences and not second primary tumors. Moreover, tumor pairs showed a remarkable genomic stability, suggesting that personalized treatment of a recurrence may be based on actionable molecular genetic targets observed in the primary tumor.

Sinusitis originada por patologías o tratamientos dentales: revisión de la literatura / Sinusitis caused by dental treatment or pathology: a literature review

Introducción: la sinusitis odontogénica (SO) es una condición infradiagnosticada de la esfera otorrinolaringológica a pesar de su frecuencia que se estima entre 10 y el 40% de la rinosinusitis crónica. La SO representa hasta 75% de los casos de sinusitis maxilar unilateral y sigue pasando desapercibida en las guías más actuales de rinosinusitis, ocasionando una falta de consenso sobre los criterios diagnósticos y las pautas terapéuticas a observar. La dificultad en identificar el foco odontogénico en otorrinolaringología (ORL), y la de estimar la magnitud de la sinusitis en consultas de odontología, conduce frecuentemente a la persistencia de los síntomas y al fracaso de las terapias conducidas, impactando considerablemente en la calidad de vida de los pacientes. Por lo tanto, se elaboró esta revisión de la literatura para entender los desafíos que esta condición supone, a la luz de los estudios recientes en el tema. Métodos: se ha realizado una búsqueda exhaustiva de la literatura en Pubmed, Scopus y Google Scholar con términos relativos a las secciones y subsecciones de esta revisión. Resultados y conclusiones: el diagnóstico y el manejo de la SO plantean, por tanto, un desafío importante debido a la falta de protocolos estandarizados de diagnóstico y de procedimientos terapéuticos multidisciplinares consensuados. Se recomienda un enfoque interdisciplinar personalizado para lograr la resolución de la sintomatología y se precisan estudios bien diseñados, con estratificación según los causantes dentales y iatrogénicos, para generar una evidencia que respalde los futuros protocolos. (AU)

Introduction: Despite it being responsible for 10-40% of chronic rhinosinusitis cases, odontogenic sinusitis (OS) is an underdiagnosed otorhinolaryngological condition. OS represents up to 75% of cases of unilateral maxillary sinusitis and is still overlooked in most current rhinosinusitis guidelines. This leads to a lack of consensus on the diagnostic criteria and therapeutic guidelines to be observed. The difficulty in identifying the odontogenic focus in ENT consultations as well as estimating the magnitude of sinusitis in dental consultations frequently leads to the persistence of symptoms and the failure of the therapies undertaken, considerably impacting the quality of life of patients. This literature review was implemented to understand the challenges that this condition poses, in the light of recent studies on the subject. Methods: An exhaustive search of the literature in PubMed, Scopus and Google Scholar with terms related to the sections and subsections of this review. Results and conclusions: The diagnosis and management of OS therefore poses a significant challenge due to the lack of standardised diagnostic protocols and consensual multidisciplinary therapeutic procedures. A personalised interdisciplinary approach is recommended to achieve resolution of symptoms along with well-designed studies, stratified according to dental and iatrogenic causes, to provide evidence to support future protocols. (AU)

Sinusitis originada por patologías o tratamientos dentales: revisión de la literatura / Sinusitis caused by dental treatment or pathology: a literature review

Introducción: la sinusitis odontogénica (SO) es una condición infradiagnosticada de la esfera otorrinolaringológica a pesar de su frecuencia que se estima entre 10 y el 40% de la rinosinusitis crónica. La SO representa hasta 75% de los casos de sinusitis maxilar unilateral y sigue pasando desapercibida en las guías más actuales de rinosinusitis, ocasionando una falta de consenso sobre los criterios diagnósticos y las pautas terapéuticas a observar. La dificultad en identificar el foco odontogénico en otorrinolaringología (ORL), y la de estimar la magnitud de la sinusitis en consultas de odontología, conduce frecuentemente a la persistencia de los síntomas y al fracaso de las terapias conducidas, impactando considerablemente en la calidad de vida de los pacientes. Por lo tanto, se elaboró esta revisión de la literatura para entender los desafíos que esta condición supone, a la luz de los estudios recientes en el tema. Métodos: se ha realizado una búsqueda exhaustiva de la literatura en Pubmed, Scopus y Google Scholar con términos relativos a las secciones y subsecciones de esta revisión. Resultados y conclusiones: el diagnóstico y el manejo de la SO plantean, por tanto, un desafío importante debido a la falta de protocolos estandarizados de diagnóstico y de procedimientos terapéuticos multidisciplinares consensuados. Se recomienda un enfoque interdisciplinar personalizado para lograr la resolución de la sintomatología y se precisan estudios bien diseñados, con estratificación según los causantes dentales y iatrogénicos, para generar una evidencia que respalde los futuros protocolos. (AU)

Introduction: Despite it being responsible for 10-40% of chronic rhinosinusitis cases, odontogenic sinusitis (OS) is an underdiagnosed otorhinolaryngological condition. OS represents up to 75% of cases of unilateral maxillary sinusitis and is still overlooked in most current rhinosinusitis guidelines. This leads to a lack of consensus on the diagnostic criteria and therapeutic guidelines to be observed. The difficulty in identifying the odontogenic focus in ENT consultations as well as estimating the magnitude of sinusitis in dental consultations frequently leads to the persistence of symptoms and the failure of the therapies undertaken, considerably impacting the quality of life of patients. This literature review was implemented to understand the challenges that this condition poses, in the light of recent studies on the subject. Methods: An exhaustive search of the literature in PubMed, Scopus and Google Scholar with terms related to the sections and subsections of this review. Results and conclusions: The diagnosis and management of OS therefore poses a significant challenge due to the lack of standardised diagnostic protocols and consensual multidisciplinary therapeutic procedures. A personalised interdisciplinary approach is recommended to achieve resolution of symptoms along with well-designed studies, stratified according to dental and iatrogenic causes, to provide evidence to support future protocols. (AU)

Signaling Pathways mTOR and ERK as Therapeutic Targets in Sinonasal Intestinal-Type Adenocarcinoma.

Despite advances in surgery and radiotherapy, the overall prognosis of sinonasal intestinal-type adenocarcinoma (ITAC) is poor, and new treatment options are needed. Recent studies have indicated alterations in cellular signaling pathways that may serve as targets for modern inhibitors. Our aim was to evaluate the frequency of mTOR and ERK pathway upregulation in a retrospective series of 139 ITAC and to test the efficacy and mechanism of action of candidate targeted inhibitors in cell line ITAC-3. An immunohistochemical analysis on p-AKT, p-mTOR, p-S6, p-4E-BP1, and p-ERK indicated, respectively, a 68% and 57% mTOR and ERK pathway activation. In vitro studies using low doses of mTOR inhibitor everolimus and ERK inhibitor selumetinib showed significant growth inhibition as monotherapy and especially as combined therapy. This effect was accompanied by the downregulation of mTOR and ERK protein expression. Our data open a new and promising possibility for personalized treatment of ITAC patients.

Sox2 and ßIII-Tubulin as Biomarkers of Drug Resistance in Poorly Differentiated Sinonasal Carcinomas.

Poorly differentiated sinonasal carcinomas (PDCs) are tumors that have a poor prognosis despite advances in classical treatment. Predictive and prognostic markers and new personalized treatments could improve the oncological outcomes of patients. In this study, we analyzed SOX2 and ßIII-tubulin as biomarkers that could have prognostic and therapeutic impacts on these tumors. The cohort included 57 cases of PDCs: 36 sinonasal undifferentiated carcinoma (SNUC) cases, 13 olfactory neuroblastoma (ONB) cases, and 8 sinonasal neuroendocrine carcinoma (SNEC) cases. Clinical follow-up data were available for 26 of these cases. Sox2 expression was detected using immunohistochemistry in 6 (75%) SNEC cases, 19 (53%) SNUC cases, and 6 (46%) ONB cases. The absence of Sox2 staining correlated with a higher rate of recurrence (p = 0.015), especially distant recurrence. The majority of cases showed ßIII-tubulin expression, with strong positivity in 85%, 75%, and 64% of SNEC, ONB, and SNUC cases, respectively. Tumors with stronger ßIII-tubulin expression demonstrated longer disease-free survival than those with no expression or low expression (p = 0.049). Sox2 and ßIII-tubulin expression is common in poorly differentiated sinonasal tumors and has prognostic and therapeutic utility.

Corrigendum: Intrafamilial variability in SLC6A1-related neurodevelopmental disorders.

[This corrects the article DOI: 10.3389/fnins.2023.1219262.].

Intrafamilial variability in SLC6A1-related neurodevelopmental disorders.

Introduction: Phenotypic spectrum of SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, beginning from early infancy or after seizure onset, and other neurological features such as hypotonia and movement disorders. Data on familial phenotypic heterogeneity have been rarely reported, thus in our study we aimed to investigate intrafamilial phenotypic variability in families with SLC6A1 variants. Methods: We collected clinical, laboratory and genetic data on 39 individuals, including 17 probands, belonging to 13 families harboring inherited variants of SLC6A1. Data were collected through an international network of Epilepsy and Genetic Centers. Results: Main clinical findings in the whole cohort of 39 subjects were: (a) epilepsy, mainly presenting with generalized seizures, reported in 71% of probands and 36% of siblings or first/second-degree relatives. Within a family, the same epilepsy type (generalized or focal) was observed; (b) ID reported in 100% and in 13% of probands and siblings or first/second-degree relatives, respectively; (c) learning disabilities detected in 28% of the SLC6A1 carriers, all of them were relatives of a proband; (d) around 51% of the whole cohort presented with psychiatric symptoms or behavioral disorders, including 82% of the probands. Out of the 19 patients with psychiatric symptoms, ASD were diagnosed in 40% of them; (e) neurological findings (primarily tremor and speech difficulties) were observed 38.5% of the whole cohort, including 10 probands. Our families harbored 12 different SLC6A1 variants, one was a frameshift, two stop-gain, while the remaining were missense. No genotype-phenotype associations were identified. Discussion: Our study showed that first-or second-degree relatives presented with a less severe phenotype, featuring mainly mild intellectual and/or learning disabilities, at variance with the probands who suffered from moderate to severe ID, generalized, sometimes intractable, epileptic seizures, behavioral and psychiatric disorders. These findings may suggest that a proportion of individuals with mild SLC6A1-NDD might be missed, in particular those with an older age where genetic testing is not performed. Further studies on intrafamilial phenotypic variability are needed to confirm our results and possibly to expand the phenotypic spectrum of these disorders and benefit genetic counseling.

Efficacy and safety of a new medicated nail hydrolacquer in the treatment of adults with toenail onychomycosis: A randomised clinical trial.

BACKGROUND: A new water-soluble formulation with ciclopirox has shown a higher penetration than other ciclopirox nail lacquers currently marketed, thus providing a higher concentration of ciclopirox into the nail. OBJECTIVE: To evaluate the efficacy and safety of a new ciclopirox nail hydrolacquer compared with its vehicle and an active comparator (hydroxypropyl chitosan-based 80 mg/g ciclopirox nail lacquer) for the treatment of toenail fungal infection. METHODS: Phase III, multicenter, randomised, double-blind, clinical trial in patients with distal mild to moderate toenail onychomycosis due to dermatophyte fungi. Patients were randomised to apply topically a ciclopirox nail hydrolacquer, its vehicle or a reference product once daily for 48 weeks with a follow-up period of 4 weeks up to week 52. RESULTS: A total of 381 patients were included. No statistically significant differences were observed between patient groups in the proportion of subjects achieving a complete cure. At week 52, a higher percentage of patients in the ciclopirox nail hydrolacquer group achieved a mycological cure (negative for culture and DTS/KOH test, with results: 32.0% ciclopirox nail hydrolacquer, 23.2% vehicle and 27% reference product, respectively), and similar results were found for improvement (mycological cure and reduction of diseased nail ≥20%, with results: 27.2% ciclopirox nail hydrolacquer, 21.6% vehicle and 20.6% reference product, respectively). Regarding mycological results, only ciclopirox nail hydrolacquer demonstrated significant statistical superiority versus vehicle negativizing dermatophyte culture (p = .039) with no recurrences, relapses or re-infections in a four-week follow-up patients with complete cure. The safety profile was comparable to the vehicle and reference product and consistent with the previously reported. CONCLUSIONS: A new water-soluble formulation for a ciclopirox nail lacquer showed similar efficacy to the reference product to eradicate toenail onychomycosis and superiority in the mycological cure defined by negative culture, thus preventing reinfections and recurrences. Efficacy and safety data demonstrate the positive benefit-risk profile of this new topical antifungal preparation. [Correction added on 13 April 2023, after first online publication: The results and conclusions in the Abstract contained incorrect information and were revised in this version.].

A Novel External Auditory Canal Squamous Cell Carcinoma Cell Line Sensitive to CDK4/6 Inhibition.

OBJECTIVE: To characterize cell line CAE606 derived from a squamous cell carcinoma (SCC) of the external auditory canal (EAC) and to show its usefulness as a model for testing candidate therapeutic agents. STUDY DESIGN: Preclinical translational research. SETTING: Biomedical research institute. METHODS: The cell line was initiated from a moderately differentiated T2N0M0 EAC SCC. We studied its histologic and genetic features as well as growth and invasion parameters. Sensitivity to cell CDK4/6 cell cycle inhibitor palbociclib was analyzed. RESULTS: CAE606 cells expressed heavy molecular weight cytokeratin, p63, and vimentin. The population doubling time was 25.8 hours, and the cells showed fast collective cell migration in a wound-healing assay. Short tandem repeat analysis confirmed it to be derived from the primary tumor of the patient. Next-generation sequencing revealed alterations in cell cycle regulation genes, including inactivating mutations in CDKN2A and TP53 and high-level amplification of CCND1 and EGFR. CAE606 showed a strong decrease of phospo-Rb expression upon exposure to the CDK4/6 inhibitor palbociclib, causing significant growth inhibition with an IC50 of 0.46 µM. CONCLUSION: This is the first report of a stable EAC SCC cell line. Its genetic features make it a useful tool for preclinical testing of new therapeutic agents for EAC SCC, particularly those targeting cell cycle regulation in combination with radio- and chemotherapy or other specific signaling pathway inhibitors.

Characterization of a Preclinical In Vitro Model Derived from a SMARCA4-Mutated Sinonasal Teratocarcinosarcoma.

Sinonasal teratocarcinosarcoma (TCS) is a rare tumor that displays a variable histology with admixtures of epithelial, mesenchymal, neuroendocrine and germ cell elements. Facing a very poor prognosis, patients with TCS are in need of new options for treatment. Recently identified recurrent mutations in SMARCA4 may serve as target for modern therapies with EZH1/2 and CDK4/6 inhibitors. Here, we present the first in vitro cell line TCS627, established from a previously untreated primary TCS originating in the ethmoid sinus with invasion into the brain. The cultured cells expressed immunohistochemical markers, indicating differentiation of epithelial, neuroepithelial, sarcomatous and teratomatous components. Whole-exome sequencing revealed 99 somatic mutations including SMARCA4, ARID2, TET2, CDKN2A, WNT7A, NOTCH3 and STAG2, all present both in the primary tumor and in the cell line. Focusing on mutated SMARCA4 as the therapeutic target, growth inhibition assays showed a strong response to the CDK4/6 inhibitor palbociclib, but much less to the EZH1/2 inhibitor valemetostat. In conclusion, cell line TCS627 carries both histologic and genetic features characteristic of TCS and is a valuable model for both basic research and preclinical testing of new therapeutic options for treatment of TCS patients.

Recolonization origin and reproductive locations, but not isolation from the sea, lead to genetic structure in migratory lagoonal fishes.

The assessment of connectivity in marine ecosystems is a requirement to adequate fisheries management. In this study we have selected two commercially exploited migratory species, European perch (Perca fluviatilis) and European smelt (Osmerus eperlanus), to evaluate the connectivity between the Curonian Lagoon and the coastal Baltic Sea. Our results indicate that isolation between the coastal lagoon and the adjacent sea area does not lead to the formation of genetic structure in migratory fish species. However, both species do register subpopulations coexisting in the area without interbreeding. This indicates that the fisheries management for migratory fishes in coastal lagoons affects a wider area than just the coastal lagoon. European perch, being a postglacial recolonizer from various refugees, has four different subpopulations, while the mechanism that maintains this division remains unexplored. The feeding migrations of European perch to the coastal zone suggest that the reproduction might occur elsewhere and that the factors for genetic structure suggested at the Baltic Sea scale might operate during these migrations. For European smelt, we discuss the existence of two different ecotypes, one lagoonal and one diadromous, and the different registered spawning locations as explicative causes for the maintenance of two genetically divergent clusters. The lagoonal ecotype reproduces and spawns inside the Curonian Lagoon while the diadromous one lives in the open Baltic Sea, performing spawning migrations to the lagoon and the mouth of Nemunas river, thus, maintaining the genetic divergence among them. However, our results indicate that there are no differences in size between both clusters, while the lagoonal population is expected to be smaller, forbidding the determination of two genetically different ecotypes. We conclude that there are no geographically and genetically separated populations of these two species in the lagoon-sea- terrestrial inlets continuum, and unified stock management for the coastal Baltic Sea and the Curonian lagoon is required.

Biomarkers for Immunotherapy in Poorly Differentiated Sinonasal Tumors.

The sinonasal cavities harbor a wide variety of rare cancer types. Histopathological classification can be challenging, especially for poorly differentiated tumors. Despite advances in surgery and radio-chemotherapy, the 5-year survival rate is still very low. Thus, there is an unmet clinical need for new therapeutic options. We retrospectively evaluated poorly differentiated tumors of 9 different histological subtypes from 69 patients who had received conventional treatments for the presence of CD8+ tumor-infiltrating lymphocytes (TILs), as well as the expression of PD-L1 and microsatellite instability (MSI) markers MLH1, MSH2, MSH6 and PMS2, as biomarkers for immunotherapy. CD8+ TILs were present in 23/69 (33%) cases, PD-L1 expression was observed in 23/69 (33%), and markers for MSI positivity in 5/69 (7%) cases. CD8+ TILs correlated with PD-L1 positivity, while both were mutually exclusive with MSI markers. None of the biomarkers were associated with clinical features as age, gender or tumor stage. Cases with CD8+ TILs and PD-L1 positivity showed a tendency toward worse disease-specific survival. Immune checkpoint inhibitors are emerging as new options for treatment of many tumor types. Our results indicate that also a substantial subset of patients with poorly differentiated sinonasal tumors may be a candidate to be treated with this promising new therapy.

Nursing students faced with organ donation: Multicenter stratified national study.

AIM: To analyze the attitude of university nursing students at Spanish universities toward organ donation and transplantation and the factors affecting to their attitude. BACKGROUND: The opinion of future nurses toward organ transplant donation could have an important influence on the population. Knowing that opinion and what factors influence it is important to improve the attitude towards organ donation and transplantation. DESIGN: A multicenter, sociological, interdisciplinary and observational study including university nursing diploma students in a complete academic year. METHODS: Selected and randomized sample was taken of students from 52 of the 111 faculties and nursing schools and faculties in Spain with teaching activity PARTICIPANTS: A sample of 10,566 students was selected stratified by geographical area and year. MEASUREMENT INSTRUMENT: The instrument used was a validated questionnaire of attitude toward organ donation and transplantation, self-administered and completed anonymously. RESULTS: Completion rate: 85 % (n = 9001). Of the students surveyed, 78 % (n = 7040) would donate their organs after dying. Variables related to a favourable attitude: (1) Interest in listening to a talk about organ donation and transplantation [Odds ratio 1.66, 95 % confidence interval 2.05-1.35]; (2) Family discussion [Odds ratio 2.30, 95 % confidence interval 2.79-1.90] or discussion with friends about organ donation and transplantation [Odds ratio 1.56, 95 % confidence interval 1.86-1.31]; (3) Knowing that one's father [Odds ratio 1.54, 95 % confidence interval 1.94-1.22], mother's [Odds ratio 1.44, 95 % confidence interval 1.82-1.13] or partner [Odds ratio 1.28, 95 % confidence interval 1.60-1.03] has a favourable opinion; (4) Having a good self-assessment of information about organ donation and transplantation [Odds ratio 2.94, 95 % confidence interval 4.90-1.78]; (5) Not being worried about possible mutilation of the body after donation [Odds ratio 2.73, 95 % confidence interval 3.36-1.72]. CONCLUSIONS: Nursing students in Spain tend to have a favourable attitude toward organ donation and transplantation although more than 20 % of those surveyed are not in favour. TWEETABLE ABSTRACT: To maintain a high rate of organ donation for organ transplantation, it is necessary to improve the social awareness of future generations of nurses towards organ donation.

Interatrial Block Predicts Life-Threatening Arrhythmias in Dilated Cardiomyopathy.

Background Interatrial block (IAB) has been associated with supraventricular arrhythmias and stroke, and even with sudden cardiac death in the general population. Whether IAB is associated with life-threatening arrhythmias (LTA) and sudden cardiac death in dilated cardiomyopathy (DCM) remains unknown. This study aimed to determine the association between IAB and LTA in ambulant patients with DCM. Methods and Results A derivation cohort (Maastricht Dilated Cardiomyopathy Registry; N=469) and an external validation cohort (Utrecht Cardiomyopathy Cohort; N=321) were used for this study. The presence of IAB (P-wave duration>120 milliseconds) or atrial fibrillation (AF) was determined using digital calipers by physicians blinded to the study data. In the derivation cohort, IAB and AF were present in 291 (62%) and 70 (15%) patients with DCM, respectively. LTA (defined as sudden cardiac death, justified shock from implantable cardioverter-defibrillator or anti-tachypacing, or hemodynamic unstable ventricular fibrillation/tachycardia) occurred in 49 patients (3 with no IAB, 35 with IAB, and 11 patients with AF, respectively; median follow-up, 4.4 years [2.1; 7.4]). The LTA-free survival distribution significantly differed between IAB or AF versus no IAB (both P<0.01), but not between IAB versus AF (P=0.999). This association remained statistically significant in the multivariable model (IAB: HR, 4.8 (1.4-16.1), P=0.013; AF: HR, 6.4 (1.7-24.0), P=0.007). In the external validation cohort, the survival distribution was also significantly worse for IAB or AF versus no IAB (P=0.037; P=0.005), but not for IAB versus AF (P=0.836). Conclusions IAB is an easy to assess, widely applicable marker associated with LTA in DCM. IAB and AF seem to confer similar risk of LTA. Further research on IAB in DCM, and on the management of IAB in DCM is warranted.

Density thresholds and the incorporation of biocontrol into decision-making to enhance the control of Cacopsylla pyri in pear (cv. Ercolini) orchards.

BACKGROUND: Economic injury level (EIL) and economic threshold (ET) are customary tools for integrated pest management. Cacopsylla pyri L. is a major pest in pear orchards. The aim of this work was to establish EIL and ET for the optimization of the use of insecticides to control this psyllid, considering biocontrol and two spraying strategies (low-toxicity versus broad spectrum chemicals). This research was conducted over 4 years in five commercial pear, cv. Ercolini, orchards in south-eastern Spain. RESULTS: Psyllids and ant populations were followed using periodic sampling, and the russet on fruits was quantified. The effect of spray intensity and ant exclusion on psyllid abundance and yield were also tested: both had a significant effect on the cumulative number of C. pyri (CNP), yield and fruit weight. Yield was found to be negatively correlated with CNP. The russet index (RI) increased in a sigmoidal fashion as a function of CNP, being significantly higher with than without ant exclusion. The commercial categorization of fruits was explained satisfactorily as a function of CNP and the cumulative number of ants (CNA). The quantitative EIL was established at a CNP of 427.2 for spraying with paraffinic oil and 425.7 for abamectin. As for the cosmetic EIL, when CNA was zero, this EIL was 24.2, at a CNP of 16.6 for spraying with paraffinic oil or abamectin. CONCLUSIONS: The use of products of low toxicity, for the conservation of ants, is expected to increase ET and, thus, reduce the intensity of spraying. © 2021 Society of Chemical Industry.

Physical exercise shapes the mouse brain epigenome.

OBJECTIVE: To analyze the genome-wide epigenomic and transcriptomic changes induced by long term resistance or endurance training in the hippocampus of wild-type mice. METHODS: We performed whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) of mice hippocampus after 4 weeks of specific training. In addition, we used a novel object recognition test before and after the intervention to determine whether the exercise led to an improvement in cognitive function. RESULTS: Although the majority of DNA methylation changes identified in this study were training-model specific, most were associated with hypomethylation and were enriched in similar histone marks, chromatin states, and transcription factor biding sites. It is worth highlighting the significant association found between the loss of DNA methylation in Tet1 binding sites and gene expression changes, indicating the importance of these epigenomic changes in transcriptional regulation. However, endurance and resistance training activate different gene pathways, those being associated with neuroplasticity in the case of endurance exercise, and interferon response pathways in the case of resistance exercise, which also appears to be associated with improved learning and memory functions. CONCLUSIONS: Our results help both understand the molecular mechanisms by which different exercise models exert beneficial effects for brain health and provide new potential therapeutic targets for future research.

Dysregulation of Translation Factors EIF2S1, EIF5A and EIF6 in Intestinal-Type Adenocarcinoma (ITAC).

Intestinal-type adenocarcinoma (ITAC) is a rare cancer of the nasal cavity and paranasal sinuses that occurs sporadically or secondary to exposure to occupational hazards, such as wood dust and leather. Eukaryotic translation initiation factors have been described as promising targets for novel cancer treatments in many cancers, but hardly anything is known about these factors in ITAC. Here we performed in silico analyses, evaluated the protein levels of EIF2S1, EIF5A and EIF6 in tumour samples and non-neoplastic tissue controls obtained from 145 patients, and correlated these results with clinical outcome data, including tumour site, stage, adjuvant radiotherapy and survival. In silico analyses revealed significant upregulation of the translation factors EIF6 (ITGB4BP), EIF5, EIF2S1 and EIF2S2 (p < 0.05) with a higher arithmetic mean expression in ITAC compared to non-neoplastic tissue (NNT). Immunohistochemical analyses using antibodies against EIF2S1 and EIF6 confirmed a significantly different expression at the protein level (p < 0.05). In conclusion, this work identifies the eukaryotic translation initiation factors EIF2S1 and EIF6 to be significantly upregulated in ITAC. As these factors have been described as promising therapeutic targets in other cancers, this work identifies candidate therapeutic targets in this rare but often deadly cancer.

Prevalence of Neural Autoantibodies in Paired Serum and Cerebrospinal Fluid in Adult Patients with Drug-Resistant Temporal Lobe Epilepsy of Unknown Etiology.

In order to determine the prevalence of neural autoantibodies in adult patients with drug-resistant temporal lobe epilepsy (DRTLE) of unknown etiology, we compared the characteristics of patients with and without autoantibodies and applied antibody predictive scores to the patients. Patients aged ≥18 years with DRTLE of unknown etiology and ≥12 months of evolution were prospectively recruited. Neural autoantibodies in serum and CSF were systematically determined in all patients. We created the ARTE (antibody in drug-resistant temporal lobe epilepsy) score based on the variables associated with the presence of neural autoantibodies. Twenty-seven patients were included. The mean (SD) age in years at the index date was 52 (±14.2) and at epilepsy onset was 32 (±17.1). The mean epilepsy duration was 19 (±12.5) years. Neural autoantibodies were detected in 51.85% (14/27) of patients. The presence of bitemporal, independent, interictal epileptiform discharges (BIIED) had a higher frequency in patients with neural autoantibodies (57.1% vs. 15.4%; p = 0.025) as well as those patients with a previous history of status epilepticus (49.2% vs. 0.0%; p = 0.007). The ARTE score showed an area under the curve (AUC) of 0.854. Using a cut-off point of ≥1, the sensitivity was 100% and the specificity was 46.1%, whereas when using a cut-off point of ≥3, the results were 35.7% and 100%, respectively. We found a high prevalence of neural autoantibodies in patients with DRTLE of unknown etiology, indicating an autoimmune mechanism. The presence of BIIED and a history of SE in DRTLE of unknown etiology are possible markers for autoimmune-associated epilepsy. The proposed ARTE score requires future validation in larger independent cohorts.

An Uncommon Presentation of Darier-White Disease with Hystrix-like Palmoplantar Keratoderma.

Darier-White disease is a relatively common autosomal dominant genodermatosis caused by mutation in the ATP2A2 gene. It is characterized by multiple warty papules coalescing into plaques in the seborrheic areas and by specific histological skin changes. Palm and sole involvement in Darier-White disease is usually mild, mainly featuring discrete and small keratotic papules. We present a unique case of Darier-White disease presenting with a diffuse, mutilating hystrix-like palmoplantar keratoderma.

A Real-World Study of the Association between a Brief Group Psychoeducation and the Course of Bipolar Disorder.

Although pharmacotherapy is considered the first-line treatment for bipolar disorders (BD), adjunctive psychoeducation has proven its effectiveness in improving self-management of the disease and reducing relapse rates. Few studies have evaluated the effect of brief group psychoeducation on pragmatic variables, such as the number of hospitalizations. The aim of the present study was to assess the mid-term effect of a four-session group psychoeducation on course-related variables in BD. Thirty-two individuals with BD were included in the study. Sixteen were exposed to psychoeducation and were matched to sixteen nonexposed individuals who received their usual treatment. Both groups were compared on insight, treatment adherence, change in the number of hospitalizations and visits to the emergency services, occurrence rate after intervention, and time to the first psychiatric hospitalization and the first urgent attendance. There was a significant reduction in the mean number of hospitalizations and urgent attendances in the exposed group in comparison to the nonexposed group. The first urgent attendance was significantly sooner in the nonexposed cohort. There were no differences between groups in any of the other variables. This intervention has shown benefits for pragmatic variables of the disease course and may be a feasible and cost-effective intervention to routinely implement in the management of BD.