Specific Profile Research Articles

Aberrant nuclear β-catenin distribution does not prognosticate recurrences of endometrioid endometrial cancers – A retrospective single-institutional study

ObjectiveAberrant β-catenin distribution has been theorized as a predictive biomarker for recurrence in early stage, low grade endometrioid endometrial cancer. MethodsThis retrospective single-institution cohort study reviewed 410 patients with endometrial cancer from May 2018 to May 2022. Only endometrioid histology was included. Demographic and clinicopathological data were collected from the medical records. Univariate and multivariate logistic regressions, and sensitivity analyses for early stage, low grade and no specific molecular profile (NSMP) tumors were performed. Results297 patients were included for analysis. Most patients were over 60 years old, White, and with a BMI >30 and early stage low grade disease. Aberrant β-catenin distribution was found in 135 patients (45.5%) and wild type membranous β-catenin distribution in 162 (54.5%). While TP53 mutation correlated with endometrial cancer recurrence in this cohort (OR = 4.78), aberrant β-catenin distribution did not correlate in the overall population (OR = 0.75), the early stage low grade cancers (OR = 0.84), or the NSMP group (OR = 1.41) on univariate or multivariate analysis. No correlation between β-catenin distribution and local (OR = 0.61) or distant recurrences (OR = 0.90) was detected. ConclusionsAberrant β-catenin distribution did not significantly correlate with recurrence in endometrioid endometrial cancer, nor in the early stage, low grade and NSMP sub-cohorts.

Investigating an extended multiphase flow model that includes specific interfacial area

Niessner and Hassnaizadeh (2008) proposed a set of governing equations to model multiphase flow in porous media based on first principles that includes fluid/fluid specific interfacial area as a state variable. Herein, we shed light on the lesser-discussed aspects of their proposed model, referred to as the extended model. Firstly, we show how the extended model facilitates real-time tracking of specific interfacial area. Secondly, we compare numerical solutions of the extended model to that of the traditional multiphase flow model with capillary dispersion and the analytical Buckley–Leverett solution. Thirdly, we provide a sensitivity analysis for the additional unknown parameters of the extended model - specific interfacial permeability and specific interfacial area generation. Lastly, a stability analysis is performed for the numerical solutions. As an auxiliary outcome, we provide an approach to solve the non-linear partial differential equations of the extended model by using torch.autograd as the automatic differentiation engine of PyTorch. Our results demonstrate that the extended model can provide saturation profiles similar to those generated by traditional models, but with the added benefit of real-time tracking of specific interfacial area. The generated specific interfacial area profiles were comparable to expected trends from previous numerical and experimental studies and highlighted the importance of the capillary pressure relationship and specific interfacial area generation term. The results also demonstrate an important balance between the permeability of the porous media and the interfacial permeability that must be maintained; otherwise, generated profiles become physically unrealistic. Overall, the extended model explains the evolution of specific interfacial area during multiphase flow at the cost of additional non-linearity and unknown parameters.

Abstract 16780: Single Cell Profiles of Human Heart Failure and Myocardial Diseases

Background: Heart failure represents the end-stage of a range of diseases which adversely impact the heart muscle. The extent by which cellular and molecular mechanisms differ between myocardial diseases in heart failure remains incompletely understood. Methods: We performed isolation and droplet-based RNA-sequencing of 394 247 single nuclei from 103 explanted hearts from transplant and ventricular assist device recipients and 7 unused donor hearts without heart disease. After sample and nuclei level quality control, doublet removal and sample integration; principal component analysis and shared nearest neighbor clustering were used to identify distinct cell populations. Cell type composition and transcriptomic profiles were compared across donor hearts and 10 myocardial diseases (hypertrophic, dilated, ischemic, restrictive, arrythmogenic and non-compaction cardiomyopathy; rheumatic and congenital heart disease; cardiac amyloidosis and graft rejection; n=1-45/group). Results: We identified and manually annotated 14 distinct cell populations that were present across controls and myocardial diseases, including transcriptionally diverse subgroups of cardiomyocytes, endothelial cells and pericytes. Compared to controls, we observed disease-specific differences in cell populations with regards to composition, heterogeneity, and specific transcriptional profiles. Conclusions: Our results reveal differences in single cell profiles of individual heart muscle diseases compared to controls without heart disease.

Genome-Wide Identification and Characterization of CLAVATA3/EMBRYO SURROUNDING REGION (CLE) Gene Family in Foxtail Millet (Setaria italica L.).

The CLAVATA3/EMBRYO-SURROUNDING REGION (CLE) genes encode signaling peptides that play important roles in various developmental and physiological processes. However, the systematic identification and characterization of CLE genes in foxtail millet (Setaria italica L.) remain limited. In this study, we identified and characterized 41 SiCLE genes in the foxtail millet genome. These genes were distributed across nine chromosomes and classified into four groups, with five pairs resulting from gene duplication events. SiCLE genes within the same phylogenetic group shared similar gene structure and motif patterns, while 34 genes were found to be single-exon genes. All SiCLE peptides harbored the conserved C-terminal CLE domain, with highly conserved positions in the CLE core sequences shared among foxtail millet, Arabidopsis, rice, and maize. The SiCLE genes contained various cis-elements, including five plant hormone-responsive elements. Notably, 34 SiCLE genes possessed more than three types of phytohormone-responsive elements on their promoters. Comparative analysis revealed higher collinearity between CLE genes in maize and foxtail millet, which may be because they are both C4 plants. Tissue-specific expression patterns were observed, with genes within the same group exhibiting similar and specific expression profiles. SiCLE32 and SiCLE41, classified in Group D, displayed relatively high expression levels in all tissues except panicles. Most SiCLE genes exhibited low expression levels in young panicles, while SiCLE6, SiCLE24, SiCLE25, and SiCLE34 showed higher expression in young panicles, with SiCLE24 down-regulated during later panicle development. Greater numbers of SiCLE genes exhibited higher expression in roots, with SiCLE7, SiCLE22, and SiCLE36 showing the highest levels and SiCLE36 significantly down-regulated after abscisic acid (ABA) treatment. Following treatments with ABA, 6-benzylaminopurine (6-BA), and gibberellic acid 3 (GA3), most SiCLE genes displayed down-regulation followed by subsequent recovery, while jasmonic acid (JA) and indole-3-acetic acid (IAA) treatments led to upregulation at 30 min in leaves. Moreover, identical hormone treatments elicited different expression patterns of the same genes in leaves and stems. This comprehensive study enhances our understanding of the SiCLE gene family and provides a foundation for further investigations into the functions and evolution of SiCLE genes in foxtail millet.

Cognition, academic achievement, and adaptive behavior in school-aged girls with fragile X syndrome

BackgroundFragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism in males and females. Females with FXS typically display a milder cognitive phenotype than males, despite experiencing significant developmental, behavioral, and social-emotional issues. AimsTo measure and distinguish the cognitive-behavioral profile of girls with FXS relative to verbal IQ-matched peers. Methods and proceduresNinety-seven participants (NFXS=55, Ncomparison=42) six to 16 years of age completed assessments evaluating cognition, academic achievement, and adaptive behavior. The comparison group consisted of age-, sex-, and verbal IQ-matched peers. Outcomes and resultsConsistent with previous studies, the FXS group demonstrated mean cognitive skills, academic achievement, and adaptive behavior in the borderline to low average range. On average, the FXS group showed poorer nonverbal reasoning, visual pattern recognition, verbal abstraction, math abilities, attention, inhibitory control, and working memory than the comparison group. There were no significant group differences in adaptive behavior. Different patterns of associations between cognition and selected outcomes emerged in each group. Conclusions and implicationsResults highlight the importance of identifying specific cognitive-behavioral profiles in girls with FXS to inform more targeted interventions for optimizing outcomes and quality of life in this population.

Concurrent features of sarcoidosis and hypersensitivity pneumonitis in two patients exposed to fungal antigens

BackgroundSarcoidosis and hypersensitivity pneumonitis (HP) are two distinct clinical entities that share granulomatous inflammation, although each of them has specific clinical, radiologic and pathologic profiles. Coexistence of the two diseases have been described, suggesting, at least in some cases, a common biologic background.Case presentationWe describe two patients showing the concurrent diagnosis of sarcoidosis and hypersensitivity pneumonitis. Case 1: a 51-year old never smoker man had a history of occupational exposure, episodes of acute exacerbations and positive serum precipitins to Penicillium spp suggestive of HP, while the positivity of serum angiotensin converting enzyme (ACE) favored sarcoidosis. Case 2: a 42-year old non-smoker woman with occasional finding of enlarged mediastinal lymph nodes had a history of domestic exposure to molds and positive serum precipitins to Aspergillus spp suggestive of HP.In both cases high resolution computed tomography (HRCT) together with broncoscopy findings allowed to maintain both the diagnoses: HRCT showed both enlarged hilar/mediastinal limph nodes and intersitial lung involvement typical of HP; bronchoalveolar lavage presented marked lymphocytosis and granulomatous nodal lesions were observed at transbronchial needle aspiration.ConclusionsSarcoidosis and HP share some clinical findings and the differential diagnosis may be difficult. Our cases suggest that a common trait may be responsible for the concurrent diagnosis of sarcoidosis and hypersensitivity pneumonitis in the same patient.

Influence of Maternal Cognitions on Child Mental Health and Educational Experiences at Home During COVID-19

ABSTRACT Suboptimal parenting characterized by low self-efficacy and perceived impact is associated with poor child mental health and academic outcomes, especially for at-risk families. This study capitalized on a longitudinal study conducted prior to and after the onset of the COVID-19 pandemic to test how prior parenting cognitions and environmental risk factors predict mental health and educational challenges faced by children during the pandemic. Pre-pandemic parenting and environmental risk data are available for a sample of 252 low-income mother-child dyads in Toronto, Canada. Research Findings: Mothers who had lower parental self-efficacy, but higher perceived parental impact prior to COVID-19 reported that their children faced educational challenges during the pandemic. In addition, mothers who reported lower levels of pre-pandemic parental self-efficacy reported that their children were more likely to have emotional and conduct problems greater than the sample average during COVID-19. Practice or Policy: Parents with specific profiles of parenting cognitions may need additional support to help their children cope during the pandemic.

Attention challenges in Kabuki syndrome.

Understanding the specific neurobehavioural profile of rare genetic diseases enables clinicians to provide the best possible care for patients and families, including prognostic and treatment advisement. Previous studies suggested that a subset of individuals with Kabuki syndrome (KS), a genetic disorder causing intellectual disability and other neurodevelopmental phenotypes, have attentional deficits. However, these studies looked at relatively small numbers of molecularly confirmed cases and often used retrospective clinical data instead of standardised assessments. Fifty-five individuals or caregivers of individuals with molecularly confirmed KS completed assessments to investigate behaviour and adaptive function. Additionally, information was collected on 23 unaffected biological siblings as controls. Attention Problems in children was the only behavioural category that, when averaged, was clinically significant, with the individual scores of nearly 50% of the children with KS falling in the problematic range. Children with KS scored significantly higher than their unaffected sibling on nearly all behavioural categories. A significant correlation was found between Attention Problems scores and adaptive function scores (P=0.032), which was not explained by lower general cognitive ability. We found that the rates of children with attentional deficits are much more elevated than would be expected in the general population, and that attention challenges are negatively correlated with adaptive function. When averaged across KS participants, none of the behavioural categories were in the clinically significant range except Attention Problems for children, which underscores the importance of clinicians screening for attention deficit hyperactivity disorder (ADHD) in children with KS.

Optimizing the Integration of Genetic Testing in AML Care in Community Practice: Insights from a Quality Improvement Initiative

Background The treatment landscape for acute myeloid leukemia (AML) is rapidly evolving, and with many of the more recently FDA approved treatments being targeted therapies, timely and actionable molecular and cytogenetic testing is critical to the management of AML patients. However, many challenges and barriers to optimal testing workflows impede clinicians' ability to integrate genetic testing in treatment decision-making. To improve quality care related to genetic testing in AML, we conducted a quality improvement (QI) study focused on evidence-based integration of genetic testing into routine practice for AML patients in community oncology clinics. Methods This QI initiative is comprised of baseline (N = 72) and follow-up provider surveys, and pre- and post-surveys of providers participating in small-group, team-based audit-feedback (AF) sessions across 5 community clinics. Survey questions were designed to assess knowledge, confidence, and experiences with genetic testing in AML. Care teams from each clinic, along with an expert AML oncologist and a hematopathologist, participated in AF sessions to (a) assess system-specific practice gaps identified via the provider surveys, (b) prioritize areas for improvement, and (c) develop action plans for addressing root causes. Results Provider Surveys: Providers top reported challenges encountered with integrating genetic testing into routine practice include determining whether to begin treatment prior to receipt of genetic testing result (56%)and applying genetic testing results to treatment decision-making (29%). For patients with AML, 70% of providers stated they were likely to start treatment prior to receiving testing results. When asked to report routine molecular testing practice patterns, 72% of providers reported testing for FLT3 mutations, 62% for IDH1/2 mutations, 65% for TP53 mutations, and 63% for NPM1 mutations; with further suboptimal reported practices in the use of NGS panels (58%; average turnaround time 15 days) and PCR (52%; average turnaround time 8 days). Overall, providers reported a 56% satisfaction rate with the processes implemented in the clinic related to sample preparation, timely review, and turnaround time of molecular diagnostics testing reports. AF Sessions: Providers participating in the AF sessions also reported determining whether to begin treatment prior to receipt of molecular testing results, long turnaround times and deciding on the appropriate molecular tests as top barriers to integrating testing in routine AML care. Clinicians reported improvements in high/very high confidence in their ability to select appropriate genetic tests to order for patients with AML (35% to 50%) and select targeted therapies based on genetic test results for AML patients (34% to 59%). Care teams set goals to improve turnaround times and testing workflows with pathology partners, as well as to maximize opportunities for patients to receive AML therapies for their specific mutation profile. Action plans to achieve these goals include improve team skills in choosing guideline-based genetic testing methods and targeted therapies and collaborate among clinical teams to improve ordering workflow and diagnostic sample preparation for genetic testing. Follow-Up Surveys: In 90-day follow up surveys, 100% of clinic champions reported upshifts in patients with targetable driver mutations receiving guideline-recommended treatment based on genetic testing results, and 4/5 clinics reported improved selection of guideline-recommended genetic testing prior to treatment initiation for AML patients. Conclusions Through this QI initiative, clinical teams identified barriers to integrating genetic testing into routine AML care, creating and implementing action plans to optimize genetic testing workflows and guideline-recommended targeted therapy selection. While meaningful confidence and action plan gains were demonstrated, these data underscore clinical practice gaps to address in future initiatives to support the integration of evidence-based genetic testing into AML care, including integrated education sessions with clinicians and pathologists. Study Sponsor Statement The study reported in this abstract was funded by independent educational grants from AbbVie, Inc. and Astellas Pharma Global Development, Inc., who had no role in the study design, execution, analysis, or reporting.

Metabolome and Transcriptome Analyses Provide Insights into Glucosinolate Accumulation in the Novel Vegetable Crop Cardamine violifolia

Cardamine violifolia, a species belonging to the Brassicaceae family, is a novel vegetable crop that is rich in glucosinolates. However, the specific glucosinolate profiles in this species remain unknown. In the present study, four parts of C. violifolia were collected including central leaves (CLs), outer leaves (OLs), petiole (P), and root (R). The highest level of total glucosinolate was observed in the R. A total of 19 glucosinolates were found in C. violifolia. The predominant glucosinolate compounds were 3-methylbutyl glucosinolate, 6-methylsulfinylhexyl glucosinolate, Indol-3-ylmethyl glucosinolate, 4-methoxyglucobrassicin, and neoglucobrassicin. A transcriptome analysis showed that 16 genes, including BCAT1, BCAT3-6, CYP79A2, CYP79B2-3, CYP83A1, CYP83B1, and SOT17-18, and nine metabolites, such as valine, tryptophan, and 1-methylpropyl glucosinolate, were enriched in the glucosinolate biosynthesis pathway. These genes may be involved in the regulation of glucosinolate accumulation among the four parts. A weighted gene co-expression analysis showed that five genes were predicted to regulate glucosinolate accumulation, including ABC transporter G family member 19, 3-ketoacyl-CoA synthase 19, and pyruvate decarboxylase 1. This study deepens our understanding of the nutrient quality of C. violifolia and provides insights into the regulatory mechanism of glucosinolate accumulation in C. violifolia.

The Specific Transcriptional Signature and Clonal Selection of MGUS-like Profile Predict an Exceptionally Favorable Prognosis in Patients with Newly-Diagnosed Multiple Myeloma

Background: Achieving undetectable minimal residual disease (MRD) has been considered a functional cure in multiple myeloma (MM), emphasizing the clinical importance of depth and duration of remission. Interestingly, a subset of myeloma patients presents with an MGUS-like status, characterized by persistent M-component or detectable MRD despite systematic treatment. Surprisingly, these patients exhibit an indolent disease course and experience unexpectedly long survival (PFS ≥ 5 years). Nevertheless, the specific genomic characteristics of their tumor cells, immune microenvironment, and clonal evolution patterns are still inadequately explored. Methods: This study utilizes data from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199) to investigate the unique MGUS-like cohort. This cohort comprises patients who achieved functional cure (PFS ≥ 5 years) but retained MGUS-like features. We conducted DNA and RNA sequencing of sorted plasma cells to elucidate the specific transcriptional and genomic profiles and clonal evolution patterns, aiming to shed light on the underlying mechanisms and enable individualized treatment approaches. Results: In the study cohort, only 6.4% (35/548) exhibited the MGUS-like profile, characterized by younger age, low tumor burden, infrequent anemia and bone lesions, and stable cytogenetics. Intriguingly, the MGUS-like cohort demonstrated consistently favorable prognoses regardless of response depth, unlike classical MM patients. Analysis of the intrinsic features of tumor cells revealed a distinct transcriptome for the MGUS-like group compared to classical MM. Subsequently, we identified a MGUS-like transcriptional gene signature that effectively discriminated a rare cohort with excellent survival, irrespective of remission depth, in the MMRF database. Notably, gene set enrichment analysis (GSEA) analysis revealed the upregulation of genes involved in the adaptive immune response, T cell activation, natural killer cell-mediated immunity, and erythrocyte differentiation, along with the downregulation of genes involved in protein folding. These biological differences potentially account for the unprecedented favorable prognosis due to an activated immune microenvironment and distinct clinical features such as reduced anemia and low tumor burden. Furthermore, genomic analysis of sequential samples from MGUS-like patients demonstrated that most mutations and copy number alterations became undetectable in residual tumor cells or during relapse, suggesting clonal selection of indolent tumor clones in MGUS-like patients. Conclusions: The rare MGUS-like population exhibits unique clinical features and an exceptionally favorable prognosis with limited treatment. Utilizing the distinct tumor transcriptome and specific clonal selection pattern, early identification of MGUS-like patients could facilitate precise individualized treatment strategies.

Collegiality Competence Profiles of Social- and Healthcare Educators – Cross-sectional Study

This study focuses on collegiality competence among social and healthcare educators, aiming to identify profiles and factors linked to these profiles. The importance of collegiality for educators' career growth and workplace well-being has been recognized, but less attention has been given to specific profiles and their underlying factors. Data from educators in vocational institutions and universities of applied sciences were collected using the CollegialityComp instrument, assessing five competence areas: 1) individual-centered collaboration, 2) educator action and fairness, 3) collaboration among colleagues, 4) collaboration outside the organization, and 5) communication and trust. Three educator profiles emerged: Profile A displayed high competence in all areas, Profile B showed strong competence in certain areas, and Profile C demonstrated intermediate competence across all. Education and job title significantly linked to specific profiles. Educators with doctoral degrees had lower collegiality levels. The findings suggest the importance of facilitating external collaboration for educators and providing extra support for high-degree educators to enhance their collegial behavior. Additional resources may be needed to bolster the collegiality competence of educators with significant responsibilities.

Behavioural design of gamification elements and exploration of player types in youth basketball training

In Mainland China, the sports training process of most players is highly homogenized, the convergence of which makes them ineffectively be identified with their individual and specific profile and difficult for them to play the sports according to their strengths and characteristics. Moreover, existing sports training software does not differentiate between player types to provide customized persona. Therefore, efficient and personalized methods need to be provided to guide players towards more autonomous sports training. Current research shows that gamification design in the process of sports training can transform players' unique conscious behaviors into habits, thus increasing their autonomy. However, the current gamification design in sports training is only based on uniform gamification elements and does not take into account the player's motivation and gamification experience, which is one of the main reasons for the homogenization of sports training. Therefore, this study aimed to identify factors that contribute to the design of gamification systems in the field of sports training, as well as to determine the relationship between players' gamification experiences during sport. It will help the researchers to explore in depth the possibilities of learning environments for youth basketball training with the development of gamified experiences. This design-driven study performed both offline and online questionnaire research (N = 198), which was analyzed with the method of a 7-point Likert scale as well as the assistance of SPSS, identified potential for the establishment of a framework for analysing preferences for gamification design elements in the context of basketball training for young players. Based on the results, this paper finds that there is a correlation between immersion and achievement in gamification experiences and proposes a framework for gamification system design in the field of sports training and offers insight that may enable the development of gamification designs that can motivate players.

3 Latent Wechsler Profiles in Presurgical Pediatric Epilepsy

Objective:The Pediatric Epilepsy Research Consortium (PERC) Epilepsy Surgery Database Project is a multisite collaborative that includes neuropsychological evaluations of children presenting for epilepsy surgery. There is some evidence for specific neuropsychological phenotypes within epilepsy (Hermann et al, 2016); however, this is less clear in pediatric patients. As a first step, we applied an empirically-based subtyping approach to determine if there were specific profiles using indices from the Wechsler scales [Verbal IQ (VIQ), Nonverbal IQ (NVIQ), Processing Speed Index (PSI), Working Memory Index (WMI)]. We hypothesized that there would be at least four profiles that are distinguished by slow processing speed and poor working memory as well as profiles with significant differences between verbal and nonverbal reasoning abilities.Participants and Methods:Our study included 372 children (M=12.1 years SD=4.1; 77.4% White; 48% male) who completed an age-appropriate Wechsler measure, enough to render at least two index scores. Epilepsy characteristics included 84.4% with focal epilepsy (evenly distributed between left and right focus) and 13.5% with generalized or mixed seizure types; mean age of onset = 6.7 years, SD = 4.5; seizure frequency ranged from daily to less than monthly; 53% had structural etiology; 71% had an abnormal MRI; and mean number of antiseizure medications was two. Latent profile analysis was used to identify discrete underlying cognitive profiles based on intellectual functioning. Demographic and epilepsy characteristics were compared among profiles.Results:Based on class enumeration procedures, a 3-cluster solution provided the best fit for the data, with profiles characterized by generally Average, Low Average, or Below Average functioning. 32.8% were in the Average profile with mean index scores ranging from 91.7-103.2; 47.6% were in the Low Average profile with mean index ranging from 80.7 to 84.5; and 19.6% were in the Below Average profile with mean index scores ranging from 55.0-63.1. Across all profiles, the lowest mean score was the PSI, followed by WMI. VIQ and NVIQ represented relatively higher scores for all three profiles. Mean discrepancy between indices within a profile was as large as 11.5 IQ points. No demographics or epilepsy characteristics were significantly different across cognitive phenotypes.Conclusions:Latent cognitive phenotypes in a pediatric presurgical cohort were differentiated by general level of functioning; however, across profiles, processing speed was consistently the lowest index followed by working memory. These findings across phenotypes suggest a common relative weakness which may result from a global effect of antiseizure medications and/or the widespread impact of seizures on neural networks even in a largely focal epilepsy cohort; similar to adult studies with temporal lobe epilepsy (Hermann et al, 2007). Future work will use latent profile analysis to examine phenotypes across other domains relevant to pediatric epilepsy including attention, naming, motor, and memory functioning. These findings are in line with collaborative efforts towards cognitive phenotyping which is the aim of our PERC Epilepsy Surgery Database Project that has already established one of the largest pediatric epilepsy surgery cohorts.

Effects of senescence on the tumour microenvironment and response to therapy.

Cellular senescence is a state of durable cell arrest that has been identified both in vitro and in vivo. It is associated with profound changes in gene expression and a specific secretory profile that includes pro-inflammatory cytokines, growth factors and matrix-remodelling enzymes, referred to as the senescence-associated secretory phenotype (SASP). In cancer, senescence can have anti- or pro-tumour effects. On one hand, it can inhibit tumour progression in a cell autonomous manner. On the other hand, senescence can also promote tumour initiation, progression, metastatic dissemination and resistance to therapy in a paracrine manner. Therefore, despite efforts to target senescence as a potential strategy to inhibit tumour growth, senescent cancer and microenvironmental cells can eventually lead to uncontrolled proliferation and aggressive tumour phenotypes. This can happen either through overcoming senescence growth arrest or through SASP-mediated effects in adjacent tumour cells. This review will discuss how senescence affects the tumour microenvironment, including extracellular matrix remodelling, the immune system and the vascular compartment, to promote tumourigenesis, metastasis and resistance to DNA-damaging therapies. It will also discuss current approaches used in the field to target senescence: senolytics, improving the immune clearance of senescent cells and targeting the SASP.

Emodin Ameliorates Severe Acute Pancreatitis-Associated Acute Lung Injury in Rats by Modulating Exosome-Specific miRNA Expression Profiles.

Numerous preclinical investigations have exhibited the beneficial impact of emodin (EMO) on the management of severe acute pancreatitis (SAP)-associated acute lung injury (ALI). However, the potential of EMO to mitigate organ damage through the modulation of exosome (Exo)-specific miRNA expression profiles remains unclear. The SAP rat model was established by retrograde injection of 5% sodium taurocholate into the pancreatic bile duct. Rats received intragastric administration of EMO at 2 h and 12 h post-modeling. Plasma and bronchoalveolar lavage fluid (BALF)-derived exosomes were isolated and purified from SAP rats treated with EMO. The therapeutic effects of these Exos in SAP rats were assessed using hematoxylin-eosin staining and measurement of inflammatory factor levels. MicroRNA (miRNA) sequencing was conducted on plasma and BALF-derived Exos, and rescue experiments were performed to investigate the function of NOVEL miR-29a-3p in the treatment of SAP using EMO. EMO exhibits ameliorative effects on pancreatic and lung injury and inflammation in rats with SAP. Plasma/BALF-derived Exos from EMO-treated SAP rats also have therapeutic effects on SAP rats. The miRNA expression profile of plasma and BALF-derived Exos in SAP rats underwent significant changes upon exposure to EMO. In particular, 34 differentially expressed miRNAs (DEmiRNAs) were identified when comparing BALF-SAP+EMO-Exo and BALF-SAP-Exo. 39 DEmiRNAs were identified when comparing plasma-SAP+EMO-Exo to plasma-SAP-Exo. We found that SAP rats treated with Exos derived from BALF exhibited a more potent therapeutic response than those treated with Exos derived from plasma. EMO may rely on NOVEL-rno-miR-29a-3p expression to prevent pulmonary injury in SAP rats. The mechanism of action of EMO is observed to have a significant impact on the miRNA expression profile of Exos derived from plasma and BALF in SAP rats. NOVEL-rno-miR-29a-3p, which is specific to Exos, and is derived from BALF, may play a crucial role in the therapeutic efficacy of EMO.

Pharmaceutical industry payments to NHS trusts in England: A four-year analysis of the Disclosure UK database.

Although hospitals are key health service providers, their financial ties to drug companies are little understood. We examine non-research pharmaceutical industry payments to English National Health Service (NHS) trusts-hospital groupings providing secondary and tertiary care. We extracted data from the industry-run Disclosure UK database, analysing it descriptively and using the Jonckheere-Terpstra test to establish whether a statistically significant time trend existed in the median values of individual payments. We explained payment value and number per trust with random effects models, using selected trust characteristics as predictors. Drug companies reported paying £60,253,421 to 234 trusts, representing between 90.0% and 92.0% of all trusts in England between 2015 and 2018. As a share of payments to all healthcare organisations, the number of payments rose from 38.6% to 39.5%, but their value dropped from 33.0% to 23.6%. The number of payments for fees for service and consultancy and contributions to costs of events increased by 61.5% and 29.4%. The median payment value decreased significantly for trusts overall (from £2,250.8 to £1,758.5), including those with lower autonomy from central government; providing acute services; and from half of England's regions. The random effects model showed that acute trusts received significantly more money on average than trusts with all other service profiles; and trusts from East England received significantly less than those from London. However, trusts enjoying greater autonomy from government did not receive significantly more money than others. Trusts also received significantly less money in 2018 than in 2015. NHS trusts had extensive pharmaceutical industry ties but were losing importance as payment targets relative to other healthcare organisations. Industry payment strategies shifted towards events sponsorship, consultancies, and smaller payments. Trusts with specific service and geographical profiles were prioritised. Understanding corporate payments across the health system requires more granular disclosure data.

Laminar organization of neocortical activities during systemic anoxia

The neocortex is highly susceptible to metabolic dysfunction. When exposed to global ischemia or anoxia, it suffers a slowly propagating wave of collective neuronal depolarization that ultimately impairs its structure and function. While the molecular signature of anoxic depolarization (AD) is well documented, little is known about the brain states that precede and follow AD onset. Here, by means of multisite extracellular local field potentials and intracellular recordings from identified pyramidal cells, we investigated the laminar expression of cortical activities induced by transient anoxia in rat primary somatosensory cortex. Soon after the interruption of brain oxygenation, we observed a well-organized sequence of stereotyped activity patterns across all cortical layers. This sequence included an initial period of beta-gamma activity, rapidly replaced by delta-theta oscillations followed by a decline in all spontaneous activites, marking the entry into a sustained period of electrical silence. Intracellular recordings revealed that cortical pyramidal neurons were depolarized and highly active during high-frequency activity, became inactive and devoid of synaptic potentials during the isoelectric state, and showed subthreshold composite synaptic depolarizations during the low-frequency period. Contrasting with the strong temporal coherence of pre-AD activities along the vertical axis of the cortical column, the onset of AD was not uniform across layers. AD initially occurred in layer 5 or 6 and then propagated bidirectionally in the upward and downward direction. Conversely, the post-anoxic waves that indicated the repolarization of cortical neurons upon brain reoxygenation did not exhibit a specific spatio-temporal profile. Pyramidal neurons from AD initiation site had a more depolarized resting potential and higher spontaneous firing rate compared to superficial cortical cells. We also found that the propagation pattern of AD was reliably reproduced by focal injection of an inhibitor of sodium‑potassium ATPases, suggesting that cortical AD dynamics could reflect layer-dependent variations in cellular metabolic regulations.

35 MoCA performance as an indicator of NSAb positivity in focal epilepsy: A preliminary analysis

Objective:Researchers are increasingly finding that the presence of neuronal surface antibodies (NSAb) may account for a larger percentage of outpatient epilepsy cases than previously thought (Elisak et al., 2018; Brenner et al., 2013). However, systematic NSAb screening is not included in standard epilepsy care (Kambadja et al., 2022). The Montreal Cognitive Assessment (MoCA; Nasreddine, 2005) is one of the most commonly used screening tools among physicians (Judge et al., 2019) across various neurological conditions, and has previously been validated in populations with autoimmune encephalitis (Hebert et al., 2018). Because patients with NSAb associated epilepsy often present with cognitive dysfunction (Greco et al., 2006), a MoCA is often administered as part of standard clinical care. The present analysis compared MoCA performance profiles in epilepsy patients with and without the presence of serum NSAbs. We explored what specific cognitive profile, as defined by the MoCA, may predict NSAb positivity.Participants and Methods:Forty-eight epilepsy patients were enrolled through an outpatient epilepsy clinic or during non-intensive or elective hospital stays. Participants were eligible if they met one of three diagnostic categories: focal epilepsy of unknown cause (n = 33), lesional focal epilepsy (n = 5), or generalized epilepsy (n = 4). All participants signed consent, underwent a comprehensive interview, which included MoCA testing, and serum NSAb testing paralleling standard clinical practice. Mann-U Whitney tests were run to compare overall MoCA and subgroup domain performance between groups.Results:Six patients (13%), all with focal epilepsy of unknown cause, had positive NSAb panels (LGI1: n = 3; GAD65: n = 2; CASPR2: n = 1). There was no significant difference in overall MoCA scores between participants with focal epilepsy of unknown cause who were antibody positive versus negative, and antibody positive versus antibody negative lesional or generalized epilepsy. However, when analyzing by MoCA subgroup, we found that antibody positive patients performed significantly worse on delayed recall than antibody negative patients with focal epilepsy of unknown cause (Mdn = 1.5 vs 3), U(Nantibodynegative=27, Nantibodypositive=6) = 69.00, p = .02. There was no significant difference in other MoCA cognitive domain tests, and delayed recall scores did not significantly differ between antibody positive patients and those with lesional focal and generalized epilepsy.Conclusions:These preliminary findings suggest that episodic memory impairment, as measured by delayed recall on the MoCA, may predict NSAb antibody positivity among patients with focal epilepsy of unknown cause. This may relate to specific predilection of the hippocampal regions in antibody-mediated epileptogenesis and pathology.

Antiproliferative and Apoptosis Effects of Hybrid Varieties of Vitis vinifera L. Sweet Sapphire and Sweet Surprise on Human Prostate Cancer Cells Using In Vitro and In Silico Approaches.

Grape hybrids are characterized by different chemical compositions; often with high hybrids are characterized by different chemical compositions, often with a high phenolic content and a specific profile of anthocyanins. The aim of study was to characterize the constituents of hybrid Vitis vinifera L. varieties Sweet Sapphire (SA) and Sweet Surprise (SU) extracts and their influence on apoptosis induction and antiproliferative effects on human prostate cancer cells. We used the MTT assay to evaluate the cytotoxic effect of extracts of SA and SU, on the prostate adenocarcinoma cell lines PC-3 and DU-145. To analyze the inhibiting impact by flow cytometry, used 24 and 48 hours. Anthocyanins were quantified by liquid chromatography and analysed by their absorption rate, hepatotoxicity, blood concentration, blood-brain barrier passage ability and maximum recommended dose by in silico approaches. Our results showed that malvidin derivatives present the highest content in both cultivars. We identified 14.46mg/100g malvidin-3-O-glycoside in SA and 2.76 mg/100 g in SU. A reduction in cell viability of DU-145 (45 and 65%) and PC-3 (63 and 67%) cells after 48h treatment with SA and SU, respectively, was found via MTT assay. Flow cytometry showed that the treatment with extracts from SA and SU had an inhibitory impact on cell development due to G2/M arrest and caused a rise in apoptotic cells compared to control group. None of the anthocyanin presented hepatotoxicity as well as blood-brain barrier passage ability. Peonidin 3-O-glucoside had the lower maximum recommended dose as well as the highest intestinal absorption rate. However, delphinidin 3-O-glucoside had the highest blood concentration values. The findings of this study highlight the potential of hybrid Vitis vinifera L. varieties as an important source of natural antioxidants and their protective effect against prostate cancer cells as well as elucidate in part their anthocyanin's metabolism.