Development Of Pathology Research Articles

Two universal school-based prevention programs for depression and anxiety: 24-Month follow-up of an RCT

Background and objectivesTransdiagnostic approaches have been promoted as a means of maximising preventative effects across multiple problems with depression and anxiety suitable targets as they appear to have highly interconnected systems in pathology development and maintenance. This study investigated long-term effects of two universal school-based programs, Emotion Regulation (ER) and Behavioral Activation (BA), that sought to prevent depression and anxiety by targeting worry (a transdiagnostic feature) to promote resilience. MethodsThis follow-up study captured data from 162 of 316 initial students (aged 8–13; 52.2% female), from six Australian schools. The original study design cluster randomised students by school into BA, ER, or a usual class control. Intervention conditions consisted of 8 × 50-min weekly sessions. This study measured the effects of these interventions after 24 months on resilience, worry, depression, and anxiety. Resilience was also examined as a potential mediator. ResultsAt 24-month follow-up, there was no significant effect of either intervention on depression, anxiety, worry, or resilience levels. Significantly fewer participants in ER and BA met clinical thresholds for separation anxiety disorder (SAD) and obsessive-compulsive disorder (OCD) in the 24-month follow-up compared with baseline. No mediation effects were found. LimitationsAlthough self-report measures are common in universal, school-based research, this represents a study limitation. ConclusionsBoth interventions may provide limited long-term protective effects on SAD and OCD symptoms, which appear to have a shelf-life shorter than 24 months. To maintain program effects, refresher sessions at shorter intervals may be a consideration for future research.

Update on Effects of the Prophylactic HPV Vaccines on HPV Type Prevalence and Cervical Pathology.

Most national prophylactic HPV vaccination programs started in approximately 2008, with either the bivalent Cervarix HPV16/18 or quadrivalent Gardasil (HPV6/11/16/18) vaccines, which were then followed by introduction of the nonavalent Gardasil 9 (HPV6/11/16/18/ 31/33/45/52/58) vaccine from 2015. Since that time, these products have demonstrated their ability to prevent infection with vaccine-covered HPV types and subsequent development of HPV-related cervical and genital pathologies. The data indicate that vaccination of young girls prior to sexual debut is more effective than vaccination of older HPV+ve women. Although some studies have shown a decline in the prevalence of vaccine-covered HPV types, there are national and regional differences in overall vaccine efficacy. Furthermore, several recently published studies show an increase in the prevalence of non-vaccine-covered HPV types in vaccinated populations, which is indicative of HPV type-replacement. It is also notable that vaccine-related changes in HPV type prevalence spread between vaccinated and unvaccinated women at the same geographical location-presumably via sexual transmission. In conclusion, it is not yet clear what effect dissemination of vaccine-associated changes in HPV type prevalence will have on vaccine efficacy and cervical pathology, particularly in mixed populations of vaccinated and unvaccinated women. However, it is very clear these observations do underscore the need for long-term continuation of cervical screening combined with regular reassessment of testing practices.

Abstract Tu027: Impact of Atherosclerosis-Related Small Cerebral Vessel Damages on Tau Pathology in Atherosclerosis Mouse Model

Background: The linkage between atherosclerosis and vascular dementia, including its ties to Alzheimer’s disease (AD), is well-established. This research explores how small cerebral vessel damages, a less recognized consequence of atherosclerosis, contribute to the development of tau pathology, a key AD hallmark. Methods and Results: Through the ApoE-/- mouse model, we evaluated the impact of hypercholesterolemia and AngII infusion on tau pathology. The regimen included an atherogenic diet for three months and subsequent AngII infusion (1mg/kg/min) for 28 days in three-month-old mice. Key outcomes measured were phosphorylated tau (AT8), cerebral microbleeds, blood component deposition, and oxidative stress markers. Results indicated a synergistic effect of diet and AngII on increasing microbleeds, vascular leakage, and oxidative stress, which coincided with heightened p-tau in affected brain regions. A specific focus on endothelial glutaredoxin-1 (Glrx) deficiency revealed its critical role in moderating these pathological changes, linking endothelial oxidative stress directly with tau pathology. Conclusion: Our research highlights the significant role of small cerebral vessel damage in advancing tau pathology in atherosclerosis, with endothelial oxidative stress as a key mediator. This underscores novel pathways through which vascular health influences AD pathology.

Long-read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer’s disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts – including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 – associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology.

Developments and Opportunities for 3D Bioprinted Organoids.

Organoids developed from pluripotent stem cells or adult stem cells are three-dimensional cell cultures possessing certain key characteristics of their organ counterparts, and they can mimic certain biological developmental processes of organs in vitro. Therefore, they have promising applications in drug screening, disease modeling, and regenerative repair of tissues and organs. However, the construction of organoids currently faces numerous challenges, such as breakthroughs in scale size, vascularization, better reproducibility, and precise architecture in time and space. Recently, the application of bioprinting has accelerated the process of organoid construction. In this review, we present current bioprinting techniques and the application of bioinks and summarize examples of successful organoid bioprinting. In the future, a multidisciplinary combination of developmental biology, disease pathology, cell biology, and materials science will aid in overcoming the obstacles pertaining to the bioprinting of organoids. The combination of bioprinting and organoids with a focus on structure and function can facilitate further development of real organs.

TLR2 immunotherapy suppresses neuroinflammation, tau spread, and memory loss in rTg4510 mice

In Alzheimer’s disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer’s disease.

Role of BDNF Signaling in the Neuroprotective and Memory-enhancing Effects of Flavonoids in Alzheimer's Disease.

Foods rich in flavonoids are associated with a reduced risk of various chronic diseases, including Alzheimer's disease (AD). In fact, growing evidence suggests that consuming flavonoid- rich foods can beneficially affect normal cognitive function. Animal models have shown that many flavonoids prevent the development of AD-like pathology and improve cognitive deficits. Identifying the molecular causes underlying the memory-enhancing effect of flavonoid-rich foods makes it possible to provide the best diet to prevent cognitive decline associated with aging and Alzheimer's disease. Based on the most recent scientific literature, this review article critically examines the therapeutic role of dietary flavonoids in ameliorating and preventing the progression of AD and enhancement of memory with a focus on the role of the BDNF signaling pathway. The databases of PubMed, Web of Science, Google Scholar, and Scopus were searched up to March 2023 and limited to English language. Search strategies were using the following keywords in titles and abstracts: (Flavonoid-rich foods OR Flavonoids OR Polyphenols); AND (Brain-Derived Neurotrophic Factor OR BDNF OR CREB OR) AND (Alzheimer's disease OR memory OR cognition OR). Flavonoid-rich foods including green tea, berries, curcumin and pomegranate exert their beneficial effects on memory decline associated with aging and Alzheimer's disease mostly through the direct interaction with BDNF signaling pathway. The neuroprotective effects of flavonoid-rich foods through the CREB-BDNF mechanism have the potential to prevent or limit memory decline due to aging and Alzheimer's disease, so their consumption throughout life may prevent age-related cognitive impairment.

Nesfatin-1 inhibits cerebral aneurysms by activating Nrf2 and inhibiting NF-κB signaling.

Cerebral aneurysm (CA) has been considered one of the most common cerebrovascular diseases, affecting millions of people worldwide. A therapeutic agent is currently missing for the treatment of CA. Nesfatin-1 (Nes-1) is an 82-amino acid adipokine which possesses a wide range of biological functions. However, the physiological function of Nes-1 in CA is still unknown. Here, we aimed to assess the preventive effects of Nes-1 in the pathological development of CA and elucidate the mechanisms behind this. We used an elastase-induced CA model, accompanied by a high-salt diet to induce hypertension. Additionally, diverse experimental techniques, including Verhoeff-Van Gieson staining, real time PCR, enzyme-linked immuno sorbent assay (ELISA), and immunofluorescence staining, were employed to assess CA formation, gene and protein expression, as well as the macrophage infiltration. Our results indicate that administration of Nes-1 significantly decreased the aneurysm size. Additionally, Nes-1 prevented inflammatory response by inhibiting the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein 1 (MCP-1) at both the mRNA and protein levels in the Circle of Willis (COW) region. Also, the increased levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in the COW region were reduced by Nes-1. We found that Nes-1 administration suppressed the invasion of macrophages. Mechanistically, Nes-1 activated Nrf-2 by promoting its nuclear translocation but prevented the activation of the IκBα/NF-κB signaling pathway. These findings suggest that Nes-1 might be used as a promising agent for the prevention of CA.

Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment

Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ. To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels <40 Centiloids) at baseline. This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024. Baseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Cross-sectional and longitudinal PET and CSF measures of brain Aβ pathology. This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aβ42/40: β = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aβ42/40: β = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P = .002; Aβ42/40: β = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Results of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.

Prevention of vision disorders at school age: view of secondary school teachers on the problem

Background. The relevance of the study is due to the importance of maintaining full vision functions from childhood, which allows for having healthy visual perception for a quality life, learning and work capacity in adolescence and adulthood. The problem is gaining global importance, because according to the forecasts of international experts, the spread of ophthalmic pathology in 2050 will reach such a scale that almost a third of the planet’s population will have impaired vision, with most of cases diagnosed already in childhood. Scientific studies reveal an increase in the frequency of visual impairment among school-aged children. Thus, 8–10 % of the first-graders are diagnosed with ophthalmic pathology, and upon completion of schooling, this indicator can increase to 30–50 %. The purpose was to study the awareness of teachers and lecturers of secondary educational institutions (schools, lyceums) regarding the problems of visual impairment among schoolchildren, their attitude to the problem and willingness to participate in preventive measures. Materials and methods. The materials for the research were the results of a sociological survey of educators of secondary educational institutions from all regions of Ukraine (lecturers, teachers at schools and lyceums), a total of 6,215 questionnaires were subject to analy­sis. The tool for conducting sociological research was the deve­loped Questionnaire of secondary school educators regarding their awareness and willingness to participate in preventive programs to preserve eyesight from childhood. The procedure for filling out the questionnaire included an interview with an interviewer, who verbally informed about the purpose, tasks of sociological research, and its anonymity. Only after obtaining preliminary voluntary verbal consent to participate in the study, respondents were offered to proceed to filling out the questionnaire, which took an average of 15–20 minutes. The research methods were sociological survey, analytical-synthetic, medical-statistical methods, in particular the latter was used to calculate the representativeness and reliability of the survey results. Results. The results of the study prove the importance of the participation of secondary school educators in measures to prevent impairment of visual functions in school-aged children. Despite the high readiness of lecturers and secondary school teachers to engage in preventive activities, their awareness of preventing visual impairment among schoolchildren was found to be insufficient, as was the level of preventive work of medical personnel in schools. It was found that most educators are convinced that a school education worker should be aware of the signs of visual impairment in children (90.46 ± 0.37 %), participate in preventive measures and be familiar with the hygienic norms of visual stress in children (86.39 ± 0.43 %). Most respondents expressed the feasibility of introducing regular systematic supervision of vision functions in school-aged children (99.40 ± 0.10 %) and supporting the implementation of state preventive programs to preserve vision from childhood in Ukraine (97.38 ± 0.20 %), self-critically recognizing the need for informational support regarding the detection of signs and symptoms of these diseases in children (71.70 ± 0.57 %). Conclusions. Visual impairments in children of different ages are of great medical and social importance, as they affect the formation of disorders of socialization and human performance. The results of the study open the prospect of involving secondary school educators in the activities of interdisciplinary comprehensive programs to prevent the development of ophthalmic pathology among school-aged children. The search for effective ways of informational support for educators on the issues of modern preventive technologies, risk factors for the formation of visual impairments in schoolchildren in order to prevent the formation of stigma about children with disabilities and visual impairments in their environment requires scientific justification.

Systematic Cholecystectomy During Cytoreductive Surgery Plus HIPEC: A Critical Analysis of an Empirical Tradition.

Some procedures performed during cytoreductive surgery (CRS) and hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) are based on empirical data. One of these procedures is systematic cholecystectomy. This study aimed to perform a critical analysis of the need for systematic cholecystectomy during CRS+HIPEC of patients with peritoneal carcinomatosis using long-term follow-up data. Patients with peritoneal surface malignancies who were candidates for CRS+HIPEC and underwent surgery between January 2008 and December 2022 were analyzed. For patients with gallbladder involvement due to the disease or for patients whose preoperative study showed the presence of cholelithiasis, cholecystectomy was performed as part of the surgery, which was avoided for the remaining patients. All postoperative adverse events that occurred in the first 90 days were recorded, and clinical records focused on the development of biliary pathology during the follow-up period were studied. The results from a consecutive series of 443 patients with peritoneal surface malignancies who underwent surgery between January 2008 and December 2022 were analyzed. The average age of the cohort was 50 years. The median follow-up period for the cohort was 41 months (range, 12-180 months), with a disease-free survival of 17 months. For 373 of the patients, CRS+HIPEC was completed without an associated cholecystectomy, and in 16 of them, the appearance of cholelithiasis was detected during the follow-up period. Only two patients in the series showed complications derived from gallstones and required a delayed cholecystectomy. Although cholecystectomy is a safe procedure in the context of CRS+HIPEC, it is not risk free, and its routine performance may be unnecessary.

The value of direct child observation in a therapeutic parent-toddler group, for students of psychoanalysis

ABSTRACT Starting in Vienna in the 1920s, Anna Freud’s first tentative attempts at observing children became a crucial component of the ‘double approach’ which integrated direct child observation with psychoanalytic reconstruction. This approach enabled the detailed study of unfolding developmental processes and the construction of a theory of normative as well as pathological child development. Direct child observation was an integral component in the curriculum of the Psychoanalytic Master’s degree at Anna Freud’s Hampstead Clinic (later, the Anna Freud Centre) in London. The process, experience and value of observation for students of psychoanalysis is described, focussing on observers in a therapeutic parent-toddler group. The experience of observing or being observed is discussed from the perspective of staff facilitating the group, students, parents and children.

The life and legacy of Yakov Lvovich Rapoport: the great pathologist and his contribution to medicine

Yakov Lvovich Rapoport is an outstanding Soviet pathologist, professor, who made a significant contribution to the development of medical science, and also left an indelible mark in the literature with his memoirs about the Doctors' Trial of 1953. This article discusses his contribution to the development of pathology, as well as examples of his scientific achievements. The authors of the article analyze the works by Ya. L. Rapoport, devoted to the study of immunopathological processes in the human body, pathomorphosis, as well as cardiomyopathies. The article describes the contribution of Ya. L. Rapoport to the development of new methods for diagnosing various diseases, as well as to the creation of new approaches to the study of pathological processes. The experience of scientific research and teaching at various medical institutes of Ya. L. Rapoport makes his research multifaceted. Separately, the article describes the turning points in the life of Ya. L. Rapoport. The early years of Ya. L. Rapoport’s life are interesting because of the choice between a creative career and medicine. In addition, participation in the Great Patriotic War left a big imprint on the scientist’s personal life and career. Also, a great tragedy - appearing in the Doctors' Trial of 1953 - changed the personality of Ya. L. Rapoport himself, as well as the relationships within his family, according to the descriptions in his memoirs. The scientific career and research interests of Ya. L. Rapoport from that moment also proceeded differently. The daughters of Yakov Lvovich Rapoport, Noemi Yakovlevna and Natalya Yakovlevna, in their articles, notes and books, cited vivid memories of various moments in their father’s life, which was also reflected in the text of the article.

The odyssey of the TR(i)P journey to the cellular membrane.

Ion channels are integral membrane proteins mediating ion flow in response to changes in their environment. Among the different types of ion channels reported to date, the super-family of TRP channels stands out since its members have been linked to many pathophysiological processes. The family comprises 6 subfamilies and 28 members in mammals, which are widely distributed throughout most tissues and organs and have an important role in several aspects of cellular physiology. It has been evidenced that abnormal expression, post-translational modifications, and channel trafficking are associated with several pathologies, such as cancer, cardiovascular disease, diabetes, and brain disorders, among others. In this review, we present an updated summary of the mechanisms involved in the subcellular trafficking of TRP channels, with a special emphasis on whether different post-translational modifications and naturally occurring mutagenesis affect both expression and trafficking. Additionally, we describe how such changes have been associated with the development and progress of diverse pathologies associated with the gain or loss of functional phenotypes. The study of these processes will not only contribute to a better understanding the role of TRP channels in the different tissues but will also present novel possible therapeutic targets in diseases where their activity is dysregulated.

The relationship between intervertebral disc pathologies and the use of digital devices and lack of physical activity in adolescents

Background/Aim: Existing research on herniated discs in adolescents primarily focuses on surgical interventions and outcomes, with fewer studies investigating the effectiveness of non-surgical therapies. The correlation between obesity, facet tropism, lumbosacral transitional vertebrae, trauma, certain sports activities, and herniated discs in adolescents is well-documented. Comparable to adults, a sedentary lifestyle in adolescents potentially carries a significant risk of developing disc degeneration and herniation. Consequently, this study aims to examine the relationship between increased digital device usage, decreased physical activity, and the onset of disc pathologies in adolescents. Methods: The study group included 94 patients aged between 10 and 16 years diagnosed with cervical (CDH), thoracic (TDH), and lumbar (LDH) disc disease. For each participant, the individual daily usage time spent on desktop computers, tablets, laptops, and mobile phones and the total time spent on all digital devices were evaluated. Their level of physical activity was also assessed using the International Physical Activity Questionnaire – Short Form (IPAQ-SF). The study eliminated causes such as listhesis, facet tropism, lumbosacral transitional vertebra, trauma, and sports injuries that could prompt the development of these spinal pathologies. Additionally, other conditions that might cause spinal pain, such as scoliosis, rheumatological diseases with spinal involvement, tumors, and myofascial pain, were also ruled out. Results: The average age of all patients was 13.44 (2.07) years. A majority were women (n=55), comprising 58.50% of the sample. Of the patients, 60.64% had CDH, 12.77% had TDH, and 75.53% had LDH. The amount of physical activity and time spent on digital devices were similar across both genders (P=0.194 and P=0.770). A significant correlation was found between CDH and the time spent on tablets, laptops, and mobile phones (P&lt;0.001). Again, a significant correlation was observed between LDH, usage of desktop computers, total time spent on all digital devices, and the IPAQ-SF score for low physical activity (P&lt;0.001). Conclusion: The prevalence and duration of digital device use among adolescents are increasing, while physical activity is decreasing. Our study indicates that this situation may be linked to the development of disc degeneration and hernias. Understanding this association can help reduce treatment and rehabilitation costs and prevent the potential loss of workability and quality of life resulting from a herniated disc. Consequently, additional comparative research on this topic is crucial.

Major clinical and metabomic approaches to childhood obesity: a systematic review

Introduction: In the context of childhood obesity, of children under 5 years of age in Brazil, 7% are overweight and 3% meet the criteria for obesity. Globally, according to a report from the World Health Organization (WHO), it is estimated that the total number of overweight and obese children in the world could reach 75 million by the year 2025. Objective: It was to carry out a systematic review to present the main approaches to clinical and metabolomics of childhood obesity. Methods: The PRISMA Platform systematic review rules were followed. The research was carried out from February to April 2024 in the Scopus, PubMed, Science Direct, Scielo and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: 110 articles were recruited for the initial evaluation. A total of 41 articles were evaluated and 19 were included in this systematic review. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 28 studies with a high risk of bias and 28 studies that did not meet GRADE. Most studies showed homogeneity in their results, with X2=58.7%&gt;50%. It was concluded that miRNAs are potential biomarkers for the development of pathologies, such as obesity. A heterogeneous group of these molecules was found to be associated with obesity in children. miR-15b-5p, miR-486-5p and hsa-miR-122-5p were considered good candidates for childhood obesity biomarkers. MiRNA-dependent mechanisms regulate up to 60% of all human genes. MiRNAs influence multiple pathways, including insulin signaling, immune-mediated inflammation, adipokine expression, adipogenesis, lipid metabolism, and regulation of food intake.

Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models.

Finding successful therapies for individuals with Alzheimer's disease (AD) remains an ongoing challenge. One contributing factor is that the mouse models commonly used in preclinical research primarily mimic the familial form of AD, whereas the vast majority of human cases are sporadic. Accordingly, for a sporadic mouse model of AD, incorporating the multifactorial aspects of the disease is of utmost importance. In the current study, we exposed humanized Aβ knock-in mice (hAβ-KI) to weekly low-dose lipopolysaccharide (LPS) injections until 24 weeks of age and compared the development of AD pathologies to the familial AD mouse model known as the J20 mice. At the early time point of 24 weeks, hAβ-KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hAβ-KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of Aβ plaques in hAβ-KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hAβ-KI mice compared to WT, and LPS exposure in hAβ-KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology. The study highlights the potential of hAβ-KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of Aβ plaque formation. These findings underscore the importance of considering multifactorial influences in sporadic AD pathogenesis and the need for innovative models to advance our understanding and treatment strategies for this complex disease.

Reproducibility of c-Met Immunohistochemical Scoring (Clone SP44) for Non-Small Cell Lung Cancer Using Conventional Light Microscopy and Whole Slide Imaging.

Emerging therapies for non-small cell lung cancer targeting c-Met overexpression have recently demonstrated promising results. However, the evaluation of c-Met expression can be challenging. We aimed to study the inter and intraobserver reproducibility of c-Met expression evaluation. One hundred ten cases with non-small cell lung cancer (40 biopsies and 70 surgical specimens) were retrospectively selected in a single laboratory (LPCE) and evaluated for c-Met expression. Six pathologists (4 seniors and 2 juniors) evaluated the H-score and made a 3-tier classification of c-Met expression for all cases, using conventional light microscopy (CLM) and whole slide imaging (WSI). The interobserver reproducibility with CLM gave global Cohen Kappa coefficients (ƙ) ranging from 0.581 (95% CI: 0.364-0.771) to 0.763 (95% CI: 0.58-0.92) using the c-Met 3-tier classification and H-score, respectively. ƙ was higher for senior pathologists and biopsy samples. The interobserver reproducibility with WSI gave a global ƙ ranging from 0.543 (95% CI: 0.33-0.724) to 0.905 (95% CI: 0.618-1) using the c-Met H-score and 2-tier classification (≥25% 3+), respectively. ƙ for intraobserver reproducibility between CLM and WSI ranged from 0.713 to 0.898 for the c-Met H-score and from 0.600 to 0.779 for the c-Met 3-tier classification. We demonstrated a moderate to excellent interobserver agreement for c-Met expression with a substantial to excellent intraobserver agreement between CLM and WSI, thereby supporting the development of digital pathology. However, some factors (scoring method, type of tissue samples, and expertise level) affect reproducibility. Our findings highlight the importance of establishing a consensus definition and providing further training, particularly for inexperienced pathologists, for c-Met immunohistochemistry assessment in clinical practice.

Nutrient and Hormonal Effects on Long Bone Growth in Healthy and Obese Children: A Literature Review.

Longitudinal bone growth is mediated through several mechanisms including macro- and micronutrients, and endocrine and paracrine hormones. These mechanisms can be affected by childhood obesity as excess adiposity may affect signaling pathways, place undue stress on the body, and affect normal physiology. This review describes the physiology of the epiphyseal growth plate, its regulation under healthy weight and obesity parameters, and bone pathology following obesity. A literature review was performed utilizing PubMed, PMC, NIH, and the Cochrane Database of Systematic Reviews pertinent to hormonal and nutritional effects on bone development, child obesity, and pathologic bone development related to weight. The review indicates a complex network of nutrients, hormones, and multi-system interactions mediates long bone growth. As growth of long bones occurs during childhood and the pubertal growth spurt, pediatric bones require adequate levels of minerals, vitamins, amino acids, and a base caloric supply for energy. Recommendations should focus on a nutrient-dense dietary approach rather than restrictive caloric diets to maintain optimal health. In conclusion, childhood obesity has profound multifaceted effects on the developing musculoskeletal system, ultimately causing poor nutritional status during development. Weight loss, under medical supervision, with proper nutritional guidelines, can help counteract the ill effects of childhood obesity.

P-309 Injectable “homing-like” bioactive short-fibers for endometrial repair and efficient live births

Abstract Study question To develop effective therapeutic interventions to promote endometrial growth and facilitate the restoration of the damaged endometrium of rats with intrauterine adhesion (IUA). Summary answer We have developed injectable “homing-like” bioactive decellularized extracellular matrix short-fibers which can achieve efficient endometrial repair and live births of rats with IUA. What is known already The prevalence of infertility caused by endometrial defects has been steadily increasing, posing a significant challenge to women’s reproductive health. Various factors, such as infection and intrauterine surgery, can lead to damage to the basal layer of the endometrium, which hinders functional endometrial repair and results in the pathological development of IUA. However, there is currently no effective clinical treatment strategy for IUA. Therefore, it is imperative to develop effective therapeutic interventions to promote endometrial growth and receptivity, ameliorate endometrial fibrosis, and facilitate the restoration of the damaged endometrium that ultimately reverses the poor pregnancy outcomes of patients with IUA. Study design, size, duration We have developed an innovative method for creating injectable acellular extracellular matrix short fibers (DEFs) from porcine skin. We investigated the effects of DEFs by in vitro and in vivo experiments over a period of two years. Participants/materials, setting, methods In vitro, we investigated the pro-proliferative, anti-fibrosis and angiogenesis effects of DEFs in human primary endometrial stromal cells (HESCs) and human umbilical vein endothelial cells (HUVECs). In vivo, we constructed a rat IUA model to investigate the promotion of endometrial repair and fertility remodeling by DFEs. Main results and the role of chance The DEFs can effectively attract endometrial cells, enabling cell adhesion, spreading, and proliferation on their surface. DEFs are rich in bioactive growth factors, which creates a nourishing microenvironment for endometrial recovery while attracting and recruiting endogenous endometrial cells for in situ regeneration. Initially, DEFs formed stable bonds with the surface of endometrial cells via electrostatic interactions after injection into the uterine cavity, which acted as a physical barrier to prevent intrauterine adhesions. Subsequently, DEFs effectively facilitated the proliferation and angiogenesis of HESCs and HUVECs, and inhibited fibrosis of pretreated HESCs. Next, DEFs could decrease endometrial collagen deposition and promote endometrial repair and endometrial angiogenesis by releasing growth factors. Therefore, bioactive DEFs could efficiently improve endometrial receptivity, promote endometrial repair, and achieve efficient live births in endometrium-injured rats. Limitations, reasons for caution The composition of DEFs is complex. The mechanism by which DEFs promotes endometrial repair remains unclear. In our future endeavors, our primary aim is to conduct a proteomic analysis of the DEFs to pinpoint the vital proteins responsible for their ability to induce tissue growth. Wider implications of the findings The DEFs can achieve efficient live births and the preparation method is suitable for mass production. In addition, the injectability of DEFs can achieve non-invasive intrauterine injection, which can reduce the risk of endometrial re-injury. Therefore, the DEFs system provides a new promising clinical strategy for endometrial factor infertility. Trial registration number enter ‘not applicable