Search

PURPOSE:KRAS is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells. EXPERIMENTAL DESIGN:We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. In addition, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignant-specific vulnerabilities. RESULTS:Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies. CONCLUSIONS:Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models, pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT, and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both in vitro and in vivo.

We report on a search for a spin-zero non-standard model particle in proton-antiproton collisions collected by the Collider Detector at Fermilab at a center-of-mass-energy of 1.96 TeV. This particle, the φ boson, is expected to decay into a bottom-antibottom quark pair and to be produced in association with at least one bottom quark. The data sample consists of events with three jets identified as initiated by bottom quarks and corresponds to 5.4 fb-1 of integrated luminosity. In each event, the invariant mass of the two most energetic jets is studied by looking for deviations from the multijet background, which is modeled using data. No evidence is found for such a particle. Exclusion upper limits ranging from 20 to 2 pb are set for the product of production cross sections times branching fraction for the hypothetical φ boson with mass between 100 and 300 GeV/c2. These are the most stringent constraints to date.

Objective Hip fractures are associated with significant morbidity and mortality. Ultrasound-guided peripheral nerve blocks are a safe method to manage pain and decrease opioid usage. The pericapsular nerve group (PENG) block is a novel, potentially superior block because of its motor-sparing effects. Through training, simulation, and supervision, we aim to determine whether it is feasible to perform the PENG block in the emergency department. Methods Phase 1 consisted of emergency physicians attending a workshop to demonstrate ultrasound proficiency, anatomical understanding, and procedural competency using a low-fidelity model. Phase 2 consisted of a prospective, observational, feasibility study of 10 patients with hip fractures. Pain scores, side effects, and opioid usage data were collected. Results The median pain score at time 0 (time of block) was 9 (interquartile range [IQR], 6.5–9). The median pain score at 30 minutes was 4 (IQR, 2.0–6.8) and 3.5 (IQR, 1.0–4.8) at 4 hours. All 10 patients required narcotics prior to the initiation of the PENG block with a median dosage of 6.25 morphine milligram equivalents (MME; IQR, 4.25–7.38 MME). After the PENG block, only 30% of the patients required further narcotics with a median dosage of 0 MME (IQR, 0–0.6 MME) until operative fixation. Conclusion In this feasibility study, PENG blocks were safely administered by trained emergency physicians under supervision. We demonstrated data suggesting a trend of pain relief and decreased opiate requirements, and further investigation is necessary to measure efficacy.

Abstract The interest for the discovery of blood biomarkers for several neurological disorders, including Ischemic Stroke (IS), is growing and their identification in blood samples would be revolutionary allowing a fast and better pathology prediction or outcome and to collect information on patient recovery. The increased permeability of the blood–brain barrier, following a brain infarct, allows the detection of brain proteins in the blood flow. In this work, we analyzed the expression levels of two synaptic proteins Syntaxin (STX)-1a and Synaptosomal Associated Protein, 25 kDa (SNAP-25), in Peripheral Blood Mononuclear Cell (PBMC), serum and in Neuronal Derived Extracellular vesicles (NDEs) of IS patients, age and sex matched healthy control (HC) and younger HC (Y-HC). Interestingly, we identified STX-1a protein in the cytoplasm of PBMC and both STX-1a and SNAP-25 expression levels were significantly augmented in all IS patient’s blood fractions compared to control subjects. In addition, STX-1a blood levels correlated with the IS clinical scales National Institutes of Health Stroke Scale (NIH-SS) and the modified Barthel Index (BI). These results prompted us to speculate that STX-1a and SNAP-25 hematic fluctuations depict the brain damage after an ischemic attack and that their hematic detection could represent a novel and accessible IS biomarkers.

Gut microbiota is a complex ecosystem, strictly linked to health and disease, as a balanced composition (referred as eubiosis) is necessary for several physiological functions, while an unbalanced composition (dysbiosis) is often associated to pathological conditions and/or diseases. An altered microbiota could be positively affected and partially restored through probiotic supplementation, among others. This review addresses the effects of probiotics in several conditions, used as case-studies (colorectal cancer, neuro-psychiatric diseases, intestinal diseases, obesity, diabetes, metabolic syndrome, immune system, and musculoskeletal system disorders) by pointing out the clinical outcomes, the mode of action, mainly related to the production of short chain fatty acids (SCFA), the impact of probiotic dose and mode of supplementation, as well as trying to highlight a hit of the most used genera.

BackgroundAlzheimer disease (AD) and Parkinson disease (PD) are the 2 most common neurodegenerative diseases affecting millions of people worldwide. The Personalized Integrated Care Promoting Quality of Life for Older People (PC4L) project proposes an integrated, scalable, and interactive care ecosystem that can be easily adapted to the needs of several neurodegenerative and chronic diseases, care institutions, and end user requirements. ObjectiveThe study protocol developed within the framework of the PC4L project aims to iteratively test the integrated platform and its modules, and focuses primarily on assessing the impact of the proposed solution (ie, the PC4L platform) on patients’ quality of life, as well as its usability and feasibility on a large-scale sample size in 3 different scenarios (home, neurorehabilitation, and day care centers). MethodsA prospective multicenter clinical study is conducted in 5 European countries (Germany, Italy, Portugal, Romania, and Spain) at 6 different pilot centers, for 3 months, in patients with PD, Parkinsonism, AD, and other dementias (ODs). Patients were randomized in a ratio of 1:1 to the intervention group (use of the PC4L system) or the control group (no intervention). The PC4L system consists mainly of a wristband for monitoring parameters such as steps and levels of physical activity, and the PC4L app, which includes different engaging functionalities. Both groups are assessed through baseline and end-of-study clinical evaluations, including assessment of quality of life through the EQ-5D-3L scale. ResultsThe study protocol is part of a project approved and funded by the European Commission Horizon 2020 (grant agreement number 875221). The ethics committees of all involved centers reviewed and approved the study protocol. The study began with the recruitment phase in September 2022, and enrollment ended in February 2023. Recruitment is now closed (April 2023). The results of this study are expected to be published in summer 2023. A total of 558 patients, 279 per study group, were recruited. The results will allow to clarify the impact of PC4L on quality of life, will assess the empowerment of patients and the medical resources use, as well as the usability of the final version of the PC4L system. It will also provide information on the support of the system as a tool to facilitate the decision-making process. ConclusionsThe PC4L project intends to test a technology-based, integrated, scalable, and interactive care platform on patients with neurodegenerative diseases and proposes a good coordinated care model between all involved actors. Future developments of the PC4L solution may involve caregivers and socio-health professionals in the decision-making process in order to facilitate efficient communication between all stakeholders and ensure reliable and protected access to data within Europe. Trial RegistrationClinicalTrials.gov NCT05538455; https://clinicaltrials.gov/study/NCT05538455 International Registered Report Identifier (IRRID)DERR1-10.2196/47916

The dense tumor stroma of pancreatic ductal adenocarcinoma (PDAC) and its secreted immune active molecules provide a barrier for chemotherapy treatment as well as for immune cell infiltration to the tumor core, providing a challenge for immunotherapeutic strategies. Consequently, the investigation of processes underlying the interaction between the tumor stroma, particularly activated pancreatic stellate cells (PSCs), and immune cells may offer new therapeutic approaches for PDAC treatment. In this study, we established a 3D PDAC model cultured under flow, consisting of an endothelial tube, PSCs and PDAC organoids. This was applied to study the role of the tumor microenvironment (TME) on immune cell recruitment and its effect on partly preventing their interaction with pancreatic cancer cells. We observed that stromal cells form a physical barrier, partly shielding the cancer cells from migrating immune cells, as well as a biochemical microenvironment, that seems to attract and influence immune cell distribution. In addition, stromal targeting by Halofuginone led to an increase in immune cell infiltration. We propose that the here developed model setups will support the understanding of the cellular interplay influencing the recruitment and distribution of immune cells, and contribute to the identification of key players in the PDAC immunosuppressive TME as well as support the discovery of new strategies to treat this immune unresponsive tumor.

BackgroundChronic pain (CP) and its management are critical issues in the care pathway of patients with breast cancer. Considering the complexity of CP experience in cancer, the international scientific community has advocated identifying cutting-edge approaches for CP management. Recent advances in the field of health technology enable the adoption of a novel approach to care management by developing integrated ecosystems and mobile health apps. ObjectiveThe primary end point of this pilot study is to evaluate patients’ usability experience at 3 months of a new digital and integrated technological ecosystem, PainRELife, for CP in a sample of patients with breast cancer. The PainRELife ecosystem is composed of 3 main technological assets integrated into a single digital ecosystem: Fast Healthcare Interoperability Resources–based cloud platform (Nu platform) that enables care pathway definition and data collection; a big data infrastructure connected to the Fast Healthcare Interoperability Resources server that analyzes data and implements dynamic dashboards for aggregate data visualization; and an ecosystem of personalized applications for patient-reported outcomes collection, digital delivery of interventions and tailored information, and decision support of patients and caregivers (PainRELife app). MethodsThis is an observational, prospective pilot study. Twenty patients with early breast cancer and chronic pain will be enrolled at the European Institute of Oncology at the Division of Medical Senology and the Division of Pain Therapy and Palliative Care. Each patient will use the PainRELife mobile app for 3 months, during which data extracted from the questionnaires will be sent to the Nu Platform that health care professionals will manage. This pilot study is nested in a large-scale project named “PainRELife,” which aims to develop a cloud technology platform to interoperate with institutional systems and patients' devices to collect integrated health care data. The study received approval from the Ethical Committee of the European Cancer Institute in December 2021 (number R1597/21-IEO 1701). ResultsThe recruitment process started in May 2022 and ended in October 2022. ConclusionsThe new integrated technological ecosystems might be considered an encouraging affordance to enhance a patient-centered approach to managing patients with cancer. This pilot study will inform about which features the health technological ecosystems should have to be used by cancer patients to manage CP. International Registered Report Identifier (IRRID)DERR1-10.2196/41216

EphrinB2 and its receptor EphB4 are highly expressed in head and neck squamous cell carcinoma (HNSCC) and disrupting EphB4-ephrinB2 interaction generates sub-optimal outcomes. Here, compartmental targeting of EphB4 and ephrinB2 in HNSCC cancer cell and endothelial compartments suggests that ephrinB2 acts as a tumor promoter and EphB4 as a tumor suppressor.

Background: Metabolic syndrome represents a pancreatic ductal adenocarcinoma (PDAC) risk factor. Metabolic alterations favor PDAC onset, which occurs early upon dysmetabolism. Pancreatic neoplastic lesions evolve within a dense desmoplastic stroma, consisting in abundant extracellular matrix settled by cancer associated fibroblasts (CAFs). Hereby, dysmetabolism and PDAC association was analyzed focusing on CAF functions. Methods: PDAC development upon dysmetabolic conditions was investigated in: 1) high fat diet fed wild type immunocompetent syngeneic mice by orthotopic transplantation of pancreatic intraepithelial neoplasia (PanIN) organoids; and 2) primary pancreatic CAFs isolated from chemotherapy naïve PDAC patients with/without an history of metabolic syndrome. Results: The dysmetabolic-associated higher PDAC aggressiveness was paralleled by collagen fibril enrichment due to prolyl 4-hydroxylase subunit alpha 1 (P4HA1) increased function. Upon dysmetabolism, P4HA1 boosts collagen proline hydroxylation, intensifies collagen contraction strength, precluding PDAC infiltration. Noteworthy, semaglutide, an incretin agonist, prevents the higher dysmetabolism-dependent PDAC stromal deposition and allows T lymphocyte infiltration, reducing tumor development. Conclusions: These results shed light on novel therapeutic options for PDAC patients with metabolic syndrome aimed at PDAC stroma reshape. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly type of cancer, with an extremely low five-year overall survival rate. To date, current treatment options primarily involve various chemotherapies, which often prove ineffective and are associated with substantial toxicity. Furthermore, immunotherapies utilizing checkpoint inhibitors have shown limited efficacy in this context, highlighting an urgent need for novel therapeutic strategies. This study investigates the preclinical efficacy of an innovative targeted therapy based on antibody-cytokine fusion proteins, specifically interleukin-2 (IL-2), a pivotal driver of cell-mediated immunity, fused to L19 antibody, which selectively binds to extra domain B of fibronectin (EDB-FN1) expressed in the tumor microenvironment. Methods: We tested the effectiveness of different immunocytokines through in vivo characterization in syngeneic C57BL/6J orthotopic mouse models of PDAC. Based on these results, we decided to focus on L19-IL2. To assess the efficacy of this immunocytokine we developed an ex-vivo immune-spheroid interaction platform derived from murine 3D pancreatic cultures, and telomerase reverse transcriptase (TERT) specific T-lymphocytes. Moreover, we evaluated the anti-cancer effect of L19-IL2 in combination with standard therapy in vivo experiments in PDAC mouse models. Tumor samples collected after the treatments were characterized for tumor infiltrating immune cell components by bulk RNA sequencing (RNA-seq) and spatial transcriptomics (Stereo-seq) analysis. Results: The tumor-targeted L19-IL2 fusion protein demonstrated potent, dose-dependent anti-tumor activity in mice with pancreatic tumors resistant to standard chemotherapy. Spatial Transcriptomics (ST) and RNA-seq analyses indicated that L19-IL2 treatment induced a significant influx of immune cells into the tumor microenvironment, with these cells expressing activation markers like granzymes, perforins, and the IL-2 receptors. Conclusions: Our results demonstrated that L19-IL2 enhances immune infiltration and cytotoxicity, remodeling the "cold" tumor microenvironment (TME) in PDAC. This innovative antibody-cytokine fusion protein improves therapeutic outcomes, paving the way for novel targeted treatment strategies in PDAC. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin-induced neuropathy (OIN) is a severe painful condition that strongly affects the patient's quality of life and cannot be counteracted by the available drugs or adjuvants. Thus, several efforts are devoted to discovering substances that can revert or reduce OIN, including natural compounds. The carob tree, Ceratonia siliqua L., possesses several beneficial properties. However, its antalgic properties have not been substantially investigated and only a few investigations have been conducted on the unripe carob (up-CS) pods. Thus, the aims of this study were to evaluate for the first time the unripe variety of Apulian carob, chemically characterized and profiled as antioxidant potential of polyphenolic compounds as well as to investigate the ability of up-CS to reduce the neurotoxicity in a mouse model of oxaliplatin-induced neuropathic pain. Methods: By UHPLC-HRMS/MS analyses, 50 phenolic compounds, belonging mainly to n-galloylated glucoses and flavonoids were detected. Results: In a mouse model of oxaliplatin-induced neurotoxicity (2.4 mg/kg, 10 injections over two weeks), acute per os treatment with up-CS provoked a dose-dependent pain-relieving effect that completely counteracted oxaliplatin hypersensitivity at the dose of 200 mg/kg. Repeated oral administration of up-CS (100 mg/kg), concomitantly with oxaliplatin injection, exerted a protective effect against the development of thermal and mechanical allodynia. In addition, up-CS exerted a neuroprotective role against oxaliplatin-induced astrocytes activation in the spinal cord measured as GFAP-fluorescence intensity. Conclusions: Overall, our study contributes to the knowledge on up-CS properties by highlighting its protective activity in the painful condition related to the administration of oxaliplatin. [ABSTRACT FROM AUTHOR]

The gut microbiota plays a key role in health and disease, but it could be affected by various factors (diet, lifestyle, environment, genetics, etc.). Focusing on diet, while the role of the different styles and choices (Mediterranean vs. Western diet, vegan or vegetarian diets) has been extensively studied, there are a few comprehensive papers on the effects of additives and food processing. Therefore, the main goal of this manuscript is to propose an overview of the link between ultra-processed foods and the gut microbiota based on papers and data available in the literature. The literature search was performed on PubMed and Clinicaltrials.gov, and after the selection of the most relevant articles, the paper proposes a synopsis of the effects of some classes of additives (sweeteners, preservatives, emulsifiers, glutamate, etc.), as well as of some treatments, on the gut microbiota and some pathological conditions. [ABSTRACT FROM AUTHOR]

Background: The Italian Fund for Alzheimer's and other dementias approved in 2020 enabled the conducting of a survey in the Italian Centers for Cognitive Disorders and Dementias (CCDDs) to analyse the organization, the administrative features and the professionals' characteristics. Aims: To investigate the current use of neuropsychological (NP) tests in Italian CCDDs and the association between the use of a basic set of tests for neuropsychological assessment (NPA) and organizational/structural characteristics of CCDDs. Methods: A survey was conducted with an online questionnaire in all CCDDs between July 2022 and February 2023. To verify the use of a comprehensive NPA in the diagnosis of cognitive disorders and dementia, we identified a minimum core test (MCT). Results: The CCDDs using a Minimum Core Test (MCT) significantly increased from 45.7% in 2015 to the current 57.1%. Territorial CCDDs using MCT significantly increased from 24.9% in 2015 to 37% in 2022 (p = 0.004). As multivariable results, the presence of psychologist/neuropsychologist in the staff and the University-based/IRCCS CCDDs increased the probability of using MCT (OR = 9.2; 95% CI 5.6–15.0; p < 0.001 and OR = 5.4; 95% CI 1.9–15.9; p = 0.002, respectively), while CCDDs in Southern Italy-Islands showed a lower probability than those in the North (OR = 0.4; 95% CI 0.2–0.7; p = 0.001). Discussion: Almost half of CCDDs (43%) do not use MCT in their clinical practice. The presence of the psychologist/neuropsychologist on the staff has a key role in the adoption of MCT and regional differences have increased over the past years. NPA is crucial in the diagnostic process and in characterizing risk profiles in order to implement targeted interventions for risk reduction. Conclusions: Our results could help to identify good practices aimed at improving dementia diagnosis. An intervention by health policymakers is urgently needed with the aim of improving diagnostic appropriateness and overcoming regional differences. [ABSTRACT FROM AUTHOR]

The view that there is something inherently wrong with the ways in which police are held accountable when a person dies in their custody has been expressed across several national contexts, most often with a focus on Indigenous people and people of colour. This is so even when processes typically seen as accountability mechanisms are engaged. With a view to garnering some understanding of this dissatisfaction, this paper focuses on the question, How is police accountability understood by those discussing deaths of Indigenous people in police custody in an Australian context? A narrative review method identified key themes from textual sources that discussed police accountability in the specific context of an Aboriginal and Torres Strait Islander person dying in police custody. The findings indicated three key elements of how police accountability is understood, namely: independent investigation of police actions, criminal prosecution, and public giving of honest evidence, with these themes emerging against a background of claims that police accountability does not exist when Indigenous people die in police custody. Of particular interest are findings as to what the narrative review did not show about police accountability and what that might mean for developing police accountability processes that better meet the needs and expectations of Australia’s First Nations people and the broader community. It is proposed that, in contrast to police being ‘held accountable’, the complementary position of police ‘being accountable’ may yield better accountability-related outcomes in policing contexts, both systemically and individually. [ABSTRACT FROM AUTHOR]

Introduction: Top-down mechanisms that regulate attentional control are influenced by task demands and individuals' goals, while bottom-up processes are influenced by salient stimuli. Analogous networks are involved in both processes (e.g., frontostriatal areas). However, they are affected differently by the emotional salience of stimuli, which determines the allocation of attention. This study aims to determine whether the recent pandemic experience continues to exert an influence on cognitive processes. To this end, the study will determine attentional biases toward pandemic-related stimuli compared to negative and neutral stimuli. Furthermore, the study will investigate whether pandemic-related stimuli influence top-down and bottom-up attentional processes and whether the latter affect autonomic control as indexed by Heart Rate Variability (HRV). Methods: Ninety-six undergraduate students completed a Flicker Task with stimuli categorized by emotional valence (neutral, negative non-COVID, negative COVID-related). This paradigm involves the presentation of two different pictures, which are identical except for a specific detail. The task required to detect the specific detail that has been changed. Given that the task employs images of natural scenes, participants tend to focus more on specific areas of the scene than others. As a result, changes in central interest (CI) areas are detected more rapidly than changes in marginal interest (MI) areas. Participants' response times (RTs) at the task and their HRV data were used to assess attentional performance and the associated autonomic nervous system activity. Results: The results indicate slower responses to COVID-related stimuli than negative and neutral stimuli for both CI and MI changes, requiring the involvement of bottom-up (CI changes) and top-down (MI changes) processes. The HRV was associated with a slower detection of CI changes in COVID-related scenes. Discussion: These findings highlight the intricate interplay between emotional salience, attentional mechanisms, and physiological responses to threatening stimuli. Contextual factors, particularly those related to pandemic-related stress, influence attentional processing and its relationship with autonomic activity. [ABSTRACT FROM AUTHOR]

We used engagement marketing and human-centered design principles to cocreate a digital decision support tool for research participation with LGBTQIA+ community members to help them make an informed decision about joining the All of Us Research Program. Building on results from the research phase, we conducted eight problem validation and solutioning workshops with 48 LGBTQIA+ community members. Community members validated barriers to engagement with All of Us and brainstormed 47 potential digital solutions. We developed potential solutions into 27 concepts (descriptive text and visual storyboards) and assessed acceptability, appropriateness, feasibility, and engagement in a set of 10 concept testing workshops with 57 community members. We developed one of the highest rated concepts, the "Decide Later Tool," into a prototype and tested it with 45 LGBTQIA+ community members and 14 community advisory group members to assess acceptability, appropriateness, feasibility, usability, and engagement. Prototype testing participants indicated that the tool provides information to help with decision making, provides a clear value or benefit to them, was designed for someone like them, provides the right amount of information, and is easy to use; they also offered constructive feedback to improve it. Across the design and development phases, community members indicated that the process of engaging them demonstrated integrity, competence, dependability, trust, and collaboration; fostered a sense of connection to All of Us; and will enhance future engagement with All of Us. Our next steps are to develop the prototype into a fully functioning web tool and pilot test it in community and health care settings. [ABSTRACT FROM AUTHOR]

This paper explores the application of Airborne Laser Scanning (ALS) technology in the investigation of the medieval Norman site of Castel Fenuculus, in the lower Calore Valley, Southern Italy. This research aims to assess the actual potential of the ALS dataset provided by the Italian Ministry of the Environment (MATTM) for the detection and visibility of archaeological features in a difficult environment characterised by dense vegetation and morphologically complex terrain. The study focuses on improving the detection and interpretation of archaeological features through a systematic approach that includes the acquisition of ALS point clouds, the implementation of classification algorithms, and the removal of vegetation layers to reveal the underlying terrain and ruined structures. Furthermore, the aim was to test different classification and filtering techniques to identify the best one to use in complex contexts, with the intention of providing a comprehensive and replicable methodological framework. Finally, the Digital Elevation Model (DTM), and various LiDAR-derived models (LDMs), were generated to visualise and highlight topographical features potentially related to archaeological remains. The results obtained demonstrate the significant potential of LiDAR in identifying and documenting archaeological features in densely vegetated and wooded landscapes. [ABSTRACT FROM AUTHOR]

Simple Summary: Because of the treatments they have undergone, survivors of childhood brain tumors have a greater risk of cardiovascular disease and sarcopenia compared to the general population. The objective of this study was to analyze differences in a bioelectrical impedance analysis (BIA) of body composition between male childhood brain tumor cancer survivors and healthy controls and to evaluate the correlation between the BIA results and the treatments performed (chemotherapy, radiotherapy, and steroid therapy). Our analysis indicates the presence of several body composition indexes at the BIA that point towards the presence of sarcopenia in childhood brain tumor survivors, showing also a significant correlation between some of these indexes and total dose of carboplatin received. Background. Childhood brain tumor survivors (CCSs) are at high risk of developing metabolic syndrome (MetS) and sarcopenia. To date, a tool able to predict any body composition changes or detect them early and increased adiposity (and, therefore, increased likelihood of MetS onset) is still lacking in this population. Objective. The objective was to analyze differences in a bioelectrical impedance analysis (BIA) of body composition between male childhood brain tumor cancer survivors and healthy controls. Methods. In this pilot, prospective, observational study, 14 male CCSs were compared to 14 healthy controls matched for sex and age. Results. CCSs showed statistically significant lower mean values in terms of their body metabolic rate (BMR), body cell mass index (BCMI), fat-free mass (FFM), skeleton muscle mass (SM), skeletal muscle mass index (SMI), and appendicular skeletal muscular mass (ASMM). CCSs also showed a statistically significantly higher mean value of resistance when compared with controls. The BMR, BCM, FFM, and ASMM were significantly correlated with total doses of carboplatin (Tau = −0.601; p = 0.018; Tau = −0.599, p = 0.025; Tau = −0.601, p = 0.018; Tau = −0.509, p = 0.045, respectively). Conclusion. A BIA allows for the detection of changes in body composition in survivors of childhood brain tumors, revealing either the presence of central obesity correlated with the risk of MetS or signs of sarcopenia that deserve early treatment. [ABSTRACT FROM AUTHOR]

Background and objective: It is commonly known that there is a connection between heart disease and depression symptoms. Compared to heart failure patients without concurrent depression, those with depressive symptoms are more likely to have longer hospital stays and more outpatient visits following discharge. Although the exact neurobiological mechanisms causing the correlation between heart disease and depression symptoms are unknown, it is thought that vascular abnormalities may be a major factor. The purpose of this review was to examine the connection between brain networks linked to depression and heart failure (HF). Methods: PRISMA guidelines were followed. We included studies that reported both heart failure as well as depression and neuroimaging. Results: We identified 159 papers, but only 12 articles were included. Our findings show that reduced cerebral blood flow (CBF) following HF, along with other contributing factors such as chronic inflammation and neurovascular dysfunction, can lead to significant brain tissue damage and disruption of neural networks. The resulting alteration in the brain increases the risk of developing depression, as the neural circuits responsible for emotional regulation become compromised. Conclusions: Individuals with heart failure (HF) exhibit reduced regional cerebral blood flow across multiple brain areas, many of which are critical for mood regulation and are commonly implicated in depression, such as the left frontal cortex and right hippocampus. [ABSTRACT FROM AUTHOR]

The role of transcription factors in photoreceptor gene regulation is fairly well understood, but knowledge of the cell-type-specific function of transcriptional cofactors remains incomplete. Here, we show that the transcriptional corepressor samd7 promotes rod differentiation and represses short-wavelength cone genes in long-wavelength cones in zebrafish. In samd7-/- retinas, red cones are transformed into hybrid red/ultraviolet (UV) cones, green cones are absent, the number of blue cones is approximately doubled, and the number of rods is greatly reduced. We also find that mouse Samd7 represses S-opsin expression in dorsal M-cones--analogous to its role in repressing UV cone genes in zebrafish red cones. Thus, samd7 plays a key role in ensuring appropriate patterns of gene expression in rods and cone subtypes of both zebrafish and mice. [ABSTRACT FROM AUTHOR]

Human milk (HM) is a complex biofluid rich in nutrients and bioactive compounds essential for infant health. Recent advances in omics technologies—such as proteomics, metabolomics, and transcriptomics—have shed light on the influence of HM on bone development and health. This review discusses the impact of various HM components, including proteins, lipids, carbohydrates, and hormones, on bone metabolism and skeletal growth. Proteins like casein and whey promote calcium absorption and osteoblast differentiation, supporting bone mineralization. Long-chain polyunsaturated fatty acids like docosahexaenoic acid (DHA) contribute to bone health by modulating inflammatory pathways and regulating osteoclast activity. Additionally, human milk oligosaccharides (HMOs) act as prebiotics, improving gut health and calcium bioavailability while influencing bone mineralization. Hormones present in HM, such as insulin-like growth factor 1 (IGF-1), leptin, and adiponectin, have been linked to infant growth, body composition, and bone density. Research has shown that higher IGF-1 levels in breast milk are associated with increased weight gain, while leptin and adiponectin influence fat mass and bone metabolism. Emerging studies have also highlighted the role of microRNAs (miRNAs) in regulating key processes like adipogenesis and bone homeostasis. Furthermore, microbiome-focused techniques reveal HM's role in establishing a balanced infant gut microbiota, indirectly influencing bone development by enhancing nutrient absorption. Although current findings are promising, comprehensive longitudinal studies integrating omics approaches are needed to fully understand the intricate relationships among maternal diet, HM composition, and infant bone health. Bridging these gaps could offer novel dietary strategies to optimize skeletal health during infancy, advancing early-life nutrition science. [ABSTRACT FROM AUTHOR]

Background: Visuo-perceptual and visuo-attentional disorders, such as global processing deficit and simultanagnosia, are not routinely investigated in prodromal forms of typical Alzheimer's disease, as amnestic mild cognitive impairment (MCI). Objective: This study evaluated global processing abilities through Navon's classical paradigm in individuals with amnestic MCI and investigated the related visuo-perceptual and attentional components involved in simultanagnosia. Methods: Sixteen consecutive patients with amnestic MCI (6 single-domain, 10 multiple-domain) and 16 matched controls were requested to identify global and local elements of hierarchical Navon letters, and to name large and small solid letters. Results: While correctly identifying solid letters, patients with multiple-domain amnestic MCI were less accurate in processing the global level of hierarchical stimuli compared to controls. Single-case analyses suggested that global processing may also be impaired in single-domain amnestic MCI. In addition, patients with pathological performance in the Navon task showed perceptual and/or visual focal attention deficits. Conclusions: Early dysfunction of holistic processing can be detected in amnestic MCI. Visuo-perceptual and/or visual focal attention mechanisms, which have been shown to be damaged in Posterior Cortical Atrophy patients with simultanagnosia, may be impaired in individuals with amnestic MCI. Investigation and identification of global processing deficits in MCI could contribute to early diagnosis and longitudinal monitoring of the disease. [ABSTRACT FROM AUTHOR]

Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded GAA repeat in the first intron of the FXN gene. Objective: The aim of this study was to analyze leukocyte telomeres length (LTL) in FRDA to verify the possible relationships between LTL and disease progression. We investigated LTL in a cohort of FRDA biallelic patients (n = 61), heterozygous (n = 29), and age‐matched healthy subjects (n = 87). Methods: LTL was measured by real‐time polymerase chain reaction quantitative analysis (qPCR). Results: The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. This picture mirrors what has been previously observed in vitro in FRDA cultured fibroblasts, showing significantly longer telomeres at early passages because of activation of an alternative lengthening of telomeres (ALT)‐like mechanism, but showing accelerated telomere shortening as population doubling increases. GAA1 repeat length is positively correlated with the LTL and negatively correlated with the age at blood sampling. The relationship of LTL with clinical parameters (cardiomyopathy, diabetes, dependence on a wheelchair) was also analyzed. Significantly shorter leukocyte telomeres were associated with the presence of cardiomyopathy, but not with diabetes and the dependence on a wheelchair. Conclusions: Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]