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Metabolites Jun 2024Intratumoral heterogeneity (ITH) complicates the diagnosis and treatment of glioma, partly due to the diverse metabolic profiles driven by underlying genomic...
Intratumoral heterogeneity (ITH) complicates the diagnosis and treatment of glioma, partly due to the diverse metabolic profiles driven by underlying genomic alterations. While multiparametric imaging enhances the characterization of ITH by capturing both spatial and functional variations, it falls short in directly assessing the metabolic activities that underpin these phenotypic differences. This gap stems from the challenge of integrating easily accessible, colocated pathology and detailed genomic data with metabolic insights. This study presents a multifaceted approach combining stereotactic biopsy with standard clinical open-craniotomy for sample collection, voxel-wise analysis of MR images, regression-based GAM, and whole-exome sequencing. This work aims to demonstrate the potential of machine learning algorithms to predict variations in cellular and molecular tumor characteristics. This retrospective study enrolled ten treatment-naïve patients with radiologically confirmed glioma. Each patient underwent a multiparametric MR scan (T1, T1, T2, T2-FLAIR, DWI) prior to surgery. During standard craniotomy, at least 1 stereotactic biopsy was collected from each patient, with screenshots of the sample locations saved for spatial registration to pre-surgical MR data. Whole-exome sequencing was performed on flash-frozen tumor samples, prioritizing the signatures of five glioma-related genes: IDH1, TP53, EGFR, PIK3CA, and NF1. Regression was implemented with a GAM using a univariate shape function for each predictor. Standard receiver operating characteristic (ROC) analyses were used to evaluate detection, with AUC (area under curve) calculated for each gene target and MR contrast combination. Mean AUC for five gene targets and 31 MR contrast combinations was 0.75 ± 0.11; individual AUCs were as high as 0.96 for both IDH1 and TP53 with T2-FLAIR and ADC, and 0.99 for EGFR with T2 and ADC. These results suggest the possibility of predicting exome-wide mutation events from noninvasive, in vivo imaging by combining stereotactic localization of glioma samples and a semi-parametric deep learning method. The genomic alterations identified, particularly in IDH1, TP53, EGFR, PIK3CA, and NF1, are known to play pivotal roles in metabolic pathways driving glioma heterogeneity. Our methodology, therefore, indirectly sheds light on the metabolic landscape of glioma through the lens of these critical genomic markers, suggesting a complex interplay between tumor genomics and metabolism. This approach holds potential for refining targeted therapy by better addressing the genomic heterogeneity of glioma tumors.
PubMed: 38921472
DOI: 10.3390/metabo14060337 -
Healthcare (Basel, Switzerland) Jun 2024In an era of global interdependence, universities play a crucial role in promoting social responsibility and sustainable development. The United Nations Convention on...
In an era of global interdependence, universities play a crucial role in promoting social responsibility and sustainable development. The United Nations Convention on the Rights of Persons with Disabilities emphasizes the empowerment of individuals with disabilities, a key aspect of inclusion. The COVID-19 pandemic underscored the necessity of digital platforms to ensure equitable opportunities, particularly for those with disabilities. It highlighted challenges in transitioning to remote operations and stressed the importance of accessible digital tools in maintaining inclusivity during disruptions. This study investigates how university websites promote social responsibility and empower individuals with disabilities in Saudi Arabia, the UK, and the US. It also examines how these websites foster inclusivity, advocate for disability rights, and contribute to societal change. Using a qualitative case study design, the study evaluated university websites focusing on accessibility services, inclusive policies, and academic accommodations. Qualitative content and thematic analyses identified recurring themes and variations. The findings reveal diverse strategies in empowerment initiatives, website maintenance practices, community engagement approaches, the accessibility of support services, and the presentation of success stories. Despite differences among websites, this study underscores their significance in empowering individuals with disabilities. Recommendations aim to guide universities worldwide in enhancing their digital platforms, ensuring inclusivity, especially during challenges like the COVID-19 pandemic.
PubMed: 38921326
DOI: 10.3390/healthcare12121212 -
Cells Jun 2024Neurological and neuropsychiatric disorders pose substantial challenges to public health, necessitating a comprehensive understanding of the molecular mechanisms... (Review)
Review
Neurological and neuropsychiatric disorders pose substantial challenges to public health, necessitating a comprehensive understanding of the molecular mechanisms underlying their pathogenesis. In recent years, the focus has shifted toward the intricate world of non-coding RNAs (ncRNAs), a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. This review explores the emerging significance of ncRNAs in the context of neurological and neuropsychiatric disorders, shedding light on their diverse functions and regulatory mechanisms. The dysregulation of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has been implicated in the pathophysiology of conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and mood disorders. This review delves into the specific roles these ncRNAs play in modulating key cellular processes, including synaptic plasticity, neuroinflammation, and apoptosis, providing a nuanced understanding of their impact on disease progression. Furthermore, it discusses the potential diagnostic and therapeutic implications of targeting ncRNAs in neurological and neuropsychiatric disorders. The identification of specific ncRNA signatures holds promise for the development of novel biomarkers for early disease detection, while the manipulation of ncRNA expression offers innovative therapeutic avenues. Challenges and future directions in the field are also considered, highlighting the need for continued research to unravel the complexities of ncRNA-mediated regulatory networks in the context of neurological and neuropsychiatric disorders. This review aims to provide a comprehensive overview of the current state of knowledge and stimulate further exploration into the fascinating realm of ncRNAs in the brain's intricate landscape.
Topics: Humans; RNA, Untranslated; Nervous System Diseases; Mental Disorders; RNA, Circular; Animals; RNA, Long Noncoding; Gene Expression Regulation; MicroRNAs
PubMed: 38920691
DOI: 10.3390/cells13121063 -
Cells Jun 2024Serine/threonine kinase AKT isoforms play a well-established role in cell metabolism and growth. Most pancreatic adenocarcinomas (PDACs) harbor activation mutations of...
Serine/threonine kinase AKT isoforms play a well-established role in cell metabolism and growth. Most pancreatic adenocarcinomas (PDACs) harbor activation mutations of KRAS, which activates the PI3K/AKT signaling pathway. However, AKT inhibitors are not effective in the treatment of pancreatic cancer. To better understand the role of AKT signaling in mutant-KRAS pancreatic tumors, this study utilized proteolysis-targeting chimeras (PROTACs) and CRISPR-Cas9-genome editing to investigate AKT proteins. The PROTAC down-regulation of AKT proteins markedly slowed the growth of three pancreatic tumor cell lines harboring mutant KRAS. In contrast, the inhibition of AKT kinase activity alone had very little effect on the growth of these cell lines. The concurrent genetic deletion of all AKT isoforms (AKT1, AKT2, and AKT3) in the KPC (; ; ) pancreatic cancer cell line also dramatically slowed its growth in vitro and when orthotopically implanted in syngeneic mice. Surprisingly, insulin-like growth factor-1 (IGF-1), but not epidermal growth factor (EGF), restored KPC cell growth in serum-deprived conditions, and the IGF-1 growth stimulation effect was AKT-dependent. The RNA-seq analysis of AKT1/2/3-deficient KPC cells suggested that reduced cholesterol synthesis may be responsible for the decreased response to IGF-1 stimulation. These results indicate that the presence of all three AKT isoforms supports pancreatic tumor cell growth, and the pharmacological degradation of AKT proteins may be more effective than AKT catalytic inhibitors for treating pancreatic cancer.
Topics: Proto-Oncogene Proteins c-akt; Pancreatic Neoplasms; Animals; Cell Line, Tumor; Mice; Humans; Down-Regulation; Proto-Oncogene Proteins p21(ras); Mutation; Cell Proliferation; Signal Transduction; Gene Expression Regulation, Neoplastic
PubMed: 38920688
DOI: 10.3390/cells13121061 -
International Journal of Nanomedicine 2024Nanoscale metal-organic frameworks (MOFs) offer high biocompatibility, nanomaterial permeability, substantial specific surface area, and well-defined pores. These... (Review)
Review
Nanoscale metal-organic frameworks (MOFs) offer high biocompatibility, nanomaterial permeability, substantial specific surface area, and well-defined pores. These properties make MOFs valuable in biomedical applications, including biological targeting and drug delivery. They also play a critical role in tumor diagnosis and treatment, including tumor cell targeting, identification, imaging, and therapeutic methods such as drug delivery, photothermal effects, photodynamic therapy, and immunogenic cell death. The diversity of MOFs with different metal centers, organics, and surface modifications underscores their multifaceted contributions to tumor research and treatment. This review is a summary of these roles and mechanisms. The final section of this review summarizes the current state of the field and discusses prospects that may bring MOFs closer to pharmaceutical applications.
Topics: Metal-Organic Frameworks; Humans; Neoplasms; Nanocomposites; Drug Delivery Systems; Animals; Photochemotherapy; Antineoplastic Agents; Nanomedicine
PubMed: 38919774
DOI: 10.2147/IJN.S463144 -
BMC Research Notes Jun 2024Asthma is an airways inflammatory disease and the most common chronic disease of childhood, which causes most hospital visits and placing a heavy financial burden on...
Asthma is an airways inflammatory disease and the most common chronic disease of childhood, which causes most hospital visits and placing a heavy financial burden on families and communities. Interleukins 4, 5 and 13, play a central role in the pathogenesis of asthma. Given the importance of oral hygiene in asthmatic patients and IL-4 and 5 are involved in the inflammatory process of periodontitis, the effect of chlorhexidine as mouthwash on asthma attacks in children on serum cytokines is necessary. In this study, 375 children with asthma were divided into two groups using or non-using chlorhexidine. Blood samples were taken and cytokines were measured by ELISA. From 375 patients, 17 patients were excluded. In this study, 171 males and 187 females participated and there were 180 patients in asthma group and 178 patients in asthma/Chlorhexidine group. The levels of IL-4, IL-5 and IL-13 had no significant difference (p > 0.05) between Asthma and Asthma/Chlorhexidine groups. Using chlorhexidine as mouthwash in children with asthma had no effect on the type 2 cytokines and may not trigger an asthma attack via allergo-inflammatory mechanism.
Topics: Humans; Chlorhexidine; Asthma; Mouthwashes; Female; Male; Child; Interleukin-4; Interleukin-13; Interleukin-5; Cytokines; Child, Preschool; Anti-Infective Agents, Local; Adolescent
PubMed: 38918842
DOI: 10.1186/s13104-024-06831-7 -
European Journal of Medical Research Jun 2024Multiple Sclerosis (MS) is a complex autoimmune disorder that significantly impacts the central nervous system, leading to a range of complications. While intracranial... (Review)
Review
Multiple Sclerosis (MS) is a complex autoimmune disorder that significantly impacts the central nervous system, leading to a range of complications. While intracranial haemorrhage (ICH) is a rare but highly morbid complication, more common CNS complications include progressive multifocal leukoencephalopathy (PML) and other CNS infections. This severe form of stroke, known for its high morbidity and mortality rates, presents a critical challenge in the management of MS. The use of disease-modifying drugs (DMDs) in treating MS introduces a nuanced aspect to patient care, with certain medications like Dimethyl Fumarate and Fingolimod showing potential in reducing the risk of ICH, while others such as Alemtuzumab and Mitoxantrone are associated with an increased risk. Understanding the intricate relationship between these DMDs, the pathophysiological mechanisms of ICH, and the individualised aspects of each patient's condition is paramount. Factors such as genetic predispositions, existing comorbidities, and lifestyle choices play a crucial role in tailoring treatment approaches, emphasising the importance of a personalised, vigilant therapeutic strategy. The necessity for ongoing and detailed research cannot be overstated. It is crucial to explore the long-term effects of DMDs on ICH occurrence and prognosis in MS patients, aiming to refine clinical practices and promote patient-centric, informed therapeutic decisions. This approach ensures that the management of MS is not only comprehensive but also adaptable to the evolving understanding of the disease and its treatments.
Topics: Humans; Multiple Sclerosis; Cerebral Hemorrhage; Immunosuppressive Agents; Mitoxantrone; Fingolimod Hydrochloride; Dimethyl Fumarate
PubMed: 38918831
DOI: 10.1186/s40001-024-01945-x -
Journal of Neuroinflammation Jun 2024The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for...
The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases.
Topics: Nucleotidyltransferases; Membrane Proteins; Animals; Humans; Mice; Neuroinflammatory Diseases; Mice, Inbred C57BL; Choroidal Neovascularization; Signal Transduction; Mice, Knockout; Diabetic Retinopathy
PubMed: 38918759
DOI: 10.1186/s12974-024-03155-y -
BMC Psychiatry Jun 2024Children and adolescents, after natural and man-made disasters, often exhibit various psychological, emotional, and behavioral issues, showing a range of clinical... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Children and adolescents, after natural and man-made disasters, often exhibit various psychological, emotional, and behavioral issues, showing a range of clinical symptoms related to post-traumatic stress disorder (PTSD) and depression. This review used a network meta-analysis (NMA) approach to compare and rank psychological interventions for PTSD and depression in children and adolescents after exposure to natural and man-made disasters.
METHODS
Randomized studies of psychosocial interventions for PTSD and depression in children and adolescents exposed to natural and man-made disasters were identified. PTSD and depression symptoms at postintervention and 1-12 month follow-up are the outcomes. The standardized mean differences (SMDs) between pairs of interventions at postintervention and follow-up were pooled. Mean effect sizes with 95% credible intervals (CI) were calculated, and the ranking probabilities for all interventions were estimated using the surface under the cumulative ranking curve. Study quality was assessed with version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2).
RESULTS
In total, 26 studies with 4331 participants were included in this NMA. Eye movement desensitization and reprocessing therapy (EMDR) (SMD = - 0.67; 95% CI - 1.17 to - 0.17), exposure therapy (ET) (SMD = - 0.66; 95% CI - 1.11 to - 0.22), and cognitive behavioral therapy (CBT) (SMD = - 0.62; 95% CI - 0.90 to - 0.34) were significantly more effective for PTSD at postintervention than inactive intervention. EMDR (SMD = - 0.72; 95% CI - 1.11 to - 0.33) and ET (SMD = - 0.62; 95% CI - 0.97 to - 0.27) were associated with a higher reduction in PTSD symptoms at follow-up than inactive intervention. EMDR (SMD = - 0.40; 95% CI - 0.78 to - 0.03) and play therapy (PT) (SMD = - 0.37; 95% CI - 0.62 to - 0.12) were significantly more effective for depression at postintervention than inactive intervention. For all psychological interventions in reducing depression symptoms at follow-up compared with inactive intervention, the differences were not significant.
CONCLUSION
EMDR appears to be most effective in reducing PTSD and depression in children and adolescents exposed to natural and man-made disasters. In addition, ET and CBT are potentially effective in reducing PTSD symptoms at postintervention, while PT is beneficial in managing depression symptoms at the treatment endpoint.
Topics: Humans; Stress Disorders, Post-Traumatic; Adolescent; Child; Network Meta-Analysis; Psychosocial Intervention; Disasters; Eye Movement Desensitization Reprocessing; Depression; Natural Disasters; Randomized Controlled Trials as Topic; Cognitive Behavioral Therapy
PubMed: 38918741
DOI: 10.1186/s12888-024-05924-8 -
Asian Pacific Journal of Cancer... Jun 2024The alterations of EGFR and HER2/neu as growth factor receptors and the cytoplasmic signal transduction proteins of RAS/RAF/MAP kinases including its end effector...
Evaluation of the Expression EGFR, HER2/NEU and the End Effector ERK of the RAS/RAF/MAP Kinase Pathway in Prostatic Adenocarcinoma for a Possible Role as New Target Therapy.
UNLABELLED
The alterations of EGFR and HER2/neu as growth factor receptors and the cytoplasmic signal transduction proteins of RAS/RAF/MAP kinases including its end effector molecule (ERK) are important in the carcinogenesis of many tumors. The activation of these protooncogenes in prostate cancer is still under investigation. The aim of this work was to study EGFR, HER2- neu, inactive (non-phosphorylated) and active (phosphorylated) ERK expression in prostatic adenocarcinomas in correlation to the clinical and pathological parameters.
METHODS
Immunohistochemistry- using tissue microarrays- for EGFR, HER2/neu, non-phosphorylated, and phosphor-ERK, was performed on tissues from 166 patients- with primary prostatic adenocarcinoma with no prior treatment-. The results of different markers expression were correlated with the clinical and pathological parameters and were analyzed statistically.
RESULTS
The prostatic tissue showed EGFR, HER2 neu, phosphorylated and non-phosphorylated ERK expression in 8.4%, 1.4%, 78.2%, and 83.4% respectively whether low (patchy) or high expression (diffuse). There were no significant correlations found between patient characteristics and expression of the tested markers. The negative immune reactivity for non-phosphorylated ERK and EGFR- was significantly correlated with high tumor stage (p values 0.03 and 0.01, respectively).
CONCLUSION
EGFR and HER2/neu may play a limited role in prostatic adenocarcinoma as they showed positive expression in a limited number of the examined tissues specifically HER2neu. The expression of non-phosphorylated ERK (mostly weak to moderate) and phosphorylated ERK (mostly moderate to strong)- was appreciated in most cases. Thus, we suggest that anti-EGFR drugs may have a limited role in the treatment of castrate-resistant prostate cancer, but anti-MEK/ERK drugs may have more promising role as a target therapy. It is recommended to perform further molecular testing to elucidate the exact mechanism and significance of these markers.
Topics: Humans; Male; Prostatic Neoplasms; ErbB Receptors; Receptor, ErbB-2; Adenocarcinoma; Biomarkers, Tumor; Aged; Middle Aged; Prognosis; Phosphorylation; raf Kinases; Follow-Up Studies; MAP Kinase Signaling System; ras Proteins; Aged, 80 and over; Extracellular Signal-Regulated MAP Kinases; Signal Transduction
PubMed: 38918683
DOI: 10.31557/APJCP.2024.25.6.2193