SACM - United Kingdom
Permanent URI for this collectionhttps://drepo.sdl.edu.sa/handle/20.500.14154/9667
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Item Restricted Investigation of mechanisms and predictive markers of immune checkpoint inhibitor-induced immune-related adverse events.(Saudi Digital Library, 2025-01-30) Aboheimed, Nourah; Dan, Carr; Dean, Naisbittbstract: Introduction: Immune-related adverse events (irAEs) are significant limitations to the use of immune checkpoint inhibitors (ICIs). Over half of the patients on these medications experience irAEs, which vary in severity and affected organ. The identification of susceptible patients through biological biomarkers and genetic variations, along with an understanding of the immune mechanisms underlying these reactions, is a crucial goal in this field. Method: Our study utilized various methods to detect serum biomarkers, including ELISA, immunohistochemistry, and transcriptomic RNA analyses. We employed in vitro assays to elucidate the modulating effects of HMGB1 on T-cell and Treg suppression functions that affect the immune response. Additionally, TaqMan assays and genome-wide association studies (GWAS) were used to identify single nucleotide polymorphisms (SNPs) of interest. Results: HMGB1 was significantly elevated in the serum of patients with ICI-induced irAEs, particularly in those with gastrointestinal (GI) irAEs. Colon biopsies from these patients showed marked decreases in nuclear staining, indicating cellular death and HMGB1 translocation. Different HMGB1 isoforms varied in their effects on CTLA4 expression on CD3+ T cells, with dsHMGB1 notably reducing it. The effect of dsHMGB1 on CTLA4 expression in Treg populations showed intra-variability between donors and influenced the suppression function of Tregs on CD8+ and CD4+ T cells, which relates back to CTLA4 expression on these cells. Unfortunately, SNPs in the main receptor of dsHMGB1 (TLR4/MD2) were not significantly associated with the phenotype. However, female patients and those with a history of allergic reactions were significantly more likely to develop irAEs. ARG1 – a marker for MDSC and M2, was found to be significantly expresses in patients experiencing irAE. In our GWAS 14 snps exceeded our suggestive threshol d, these SNPs were mapped to regions of genes related to autoimmune disease and cancer. Discussion: Our findings highlight HMGB1's significant role in mediating immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors. Elevated HMGB1 levels, particularly noted in gastrointestinal irAEs, suggest its potential as a biomarker for irAE risk. Additionally, the influence of HMGB1 on CTLA4 expression in T cells and Tregs underscores 6 its impact on immune modulation. Despite the lack of significant associations with TLR4/MD2 SNPs, the identification of other genetic variants related to autoimmune conditions hints at a complex genetic underpinning that warrants further investigation to enhance irAE management strategies.20 0Item Restricted Biomarkers, Metagenomics, and Metabolomics in Grade C Molar Incisor Pattern Periodontitis: A Multidimensional Approach to Understand C/MIP Pathogenesis(King's College University, 2025) Alamri, Meaad Mohammed; Proctor, Gordon; Nibali, LuigiObjective: This project aimed to clarify grade C molar incisor pattern periodontitis (C/MIP) pathogenesis in young cases by comparing them to age-matched periodontitis-free controls in a multidimensional approach. Material and Methods: (1) The literature on saliva, GCF, serum, and blood biomarkers in systemically healthy and non-smoking young C/MIP (≤25 years old) was systematically searched for promising biomarkers. Six databases were searched, including PubMed, Embase, Web of Science, Scopus, Virtual Health Library and ProQuest, for cross-sectional, case-control, and cohort studies with more than 10 subjects in the cases group. Meta-analysis was done on biomarkers that were assessed using the same detection methods and sample type in at least two papers. (2) After that, a case series on 31 C/MIP young cases (≤25 years old) was compiled to evaluate grade C periodontitis through clinical data and radiographs. Following that, a series of four analyses were conducted on the same group of patients, the 31 C/MIP young cases in which (3) human total immunoglobulin G (IgG) levels were investigated in saliva, gingival crevicular fluid (GCF), and serum using an Enzyme-Linked Immunosorbent Assay (ELISA); (4) the saliva and serum metabolites profiles of C/MIP and controls were analysed using a combination of nuclear magnetic resonance (NMR) and mass spectrometry (MS) respectively; (5) DNA was extracted from plaque and saliva of the same group using Qigen PowerSoil kit. (6) metabolomics and metagenomics data were then integrated using R software and Cytoscape to identify significant microbe–metabolite interactions. Results: (1) Eighty-seven biomarkers were assessed, with the majority being higher in cases than in controls. Only the meta-analysis of total serum IgG with low heterogeneity value revealed a statistically significant increase in its levels in C/MIPs compared to controls (standardised mean difference: 1.08; 95% CI: 0.76, 1.40). (2) A considerable portion of MIPs were female, and almost half of the MIPs were Afro/Caribbean, with more than half reported having a family history of periodontitis with tooth loss in either siblings, parents, and/or grandparents at a young age. Most affected incisors and molars had grade 1 mobility and class I furcation involvement, with most cases having vertical bone loss in at least one molar. (3) After adjusting for covariates, cases had higher Immunoglobulin G levels in saliva (p=0.005) and gingival crevicular fluid (p<0.001) than controls; however, serum IgG levels did not reach the significance threshold (p=0.137) for differences between test and controls. Among other factors contributing to IgG levels, males had higher serum IgG than females (p=0.018), and serum IgG levels increased with age (p= 0.033). (4) Of the 42 salivary metabolites detected by NMR, dimethylamine, proline, and glycine were significantly lower in C/MIP than controls after adjusting for covariates. Conversely, the MS method detected 349 metabolites in serum, among which Bis(hydroxymethyl) propionic acid, 1-[(9Z)-octadecenoyl]-2-tetradecanoyl-sn-glycero-3-phosphocholine, decanoylcarnitine, 4-Picoline, tranexamic acid, 2-Hydroxy-5-vinylphenyl hydrogen sulfate, and L-Serine were lower in C/MIP compared to controls, whereas methyl indole-3-acetate, N-(3-acetamidopropyl) pyrrolidin-2-one, 4-Ethyl-2-hydroxy-6-methoxyphenyl hydrogen sulfate, and sulfosalicylic acid were higher in C/MIP than controls (5) C/MIP had a more diverse and distinct bacterial profile than controls in plaque and saliva. A novel unknown group of bacteria, labelled GGB, showed significant associations with C/MIP. The following bacteria were consistently identified in all analyses: C/MIP-associated taxa in plaque: Desulfobulbus oralis, Anaerolineaceae bacterium oral taxon 439, GGB4333 SGB5935, Treponema SGB3604, Campylobacter rectus, Treponema denticola, Eubacterium nodatum, Parvimonas micra, Eubacterium brachy, Slackia exigua, and Fretibacterium fastidiosum. Oral-health-associated taxa: Rothia mucilaginosa in saliva, and GGB10485 SGB49305 and Leptotrichia hongkongensis in plaque. Desulfobulbus oralis and GGB10485 SGB49305 showed considerable power as biomarkers in plaque. (6) Notable clusters of key periodontal pathogens were noticed including Porphyromonas gingivalis, Tannerella forsythia, Filifactor alocis and Abiotrophia defectiva and among metabolites, taurine, glutamine, N-Phenylacetylglutamine, and tetraacetylethylenediamine. Conclusion: This study identified for the first time the critical microbial and metabolic signatures associated with the pathogenesis of C/MIP in young cases using a combination of omics techniques. Integration of metagenomics and metabolomics revealed new insights into host-microbe interaction and metabolic pathways driving the disease, thus opening up new avenues for better diagnostic and therapeutic approaches.17 0Item Restricted MAJOR ADVERSE EVENTS IN CRITICALLY ILL PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME(Saudi Digital Library, 2021) Alenezi, Faraj; Thickett, David; Parekh, Dhruv; Mahida, Rahul; Patel, JaiminAcute kidney injury (AKI) is common among patients with COVID-19 or sepsis. The incidence of AKI may increase when these patients develop acute respiratory distress syndrome (ARDS), which is often associated with poorer patient outcomes and higher mortality rates. Major adverse kidney events (MAKEs) - a composite of the need for renal replacement therapy (RRT), a decline in eGFR of <75% from baseline, or all- cause mortality - are considered a reliable long-term measure of AKI's impact on patient outcomes. This thesis aimed to evaluate the existing evidence regarding the incidence and risk factors of AKI in COVID-19 patients with ARDS. Additionally, it sought to determine the incidence and clinical risk factors of MAKE-365 in patients with AKI, both with and without COVID-19 ARDS. The thesis also examined the associations between novel kidney biomarkers (including plasma Cystatin C, urinary NGAL, urinary [TIMP- 2]*[IGFBP-7], and urinary CCL-14) and MAKE-365 in ICU patients with sepsis and AKI. Lastly, it evaluated the predictive capabilities of these kidney biomarkers in combination with clinical predictive models for MAKE-365. Firstly, a systematic review and meta-analysis were conducted to examine the incidence and risk factors of AKI in COVID-19 patients with ARDS. This review, which included 31 studies, found a higher incidence of AKI in COVID-19 patients with ARDS compared to those without. The study identified several risk factors associated with worse outcomes, including advanced age, male gender, and pre-existing conditions such as hypertension, diabetes, obesity, and CKD. Secondly, a retrospective cohort study was carried out on ARDS patients to assess the occurrence of MAKEs up to 365 days post-ICU admission in both non-COVID-19 and COVID-19 cohorts. The incidence of MAKE-365 was more common in the non- COVID-19 cohort. CKD and high bilirubin levels were identified as predictors for MAKE-365 in both cohorts, with additional risk factors such as older age and diabetes in the COVID-19 cohort and lower albumin levels in the non-COVID-19 cohort. Finally, another retrospective cohort study was conducted to assess MAKE-365 development and evaluate the predictive ability of kidney biomarkers for MAKE-365 in septic patients, regardless of ARDS status. The prevalence of MAKE-365 was higher in septic patients with AKI, irrespective of ARDS status. Among the evaluated biomarkers, urinary [TIMP-2]*[IGFBP-7] showed the most promise for predicting MAKE-365, particularly when combined with the clinical prediction model. Overall, this thesis underscores the importance of identifying patients at risk of MAKE- 365 development in critically ill patients using clinical predictors in conjunction with kidney biomarkers. However, the utility of these biomarker combinations must be confirmed in larger, external prospective cohorts to ensure the findings' generalizability and specificity to the patient population used in this study.21 0Item Restricted Characterisation of physiological and blood biomarker changes in paediatric congenital cardiac interventions(2022-11-01) Alablani, Fatmah Jamal; Chung, EmmaBackground: Physiological and blood biomarker changes could give new insights into brain injury mechanisms associated with paediatric congenital heart disease (CHD) surgery. Objectives: This thesis aimed to characterise physiological and blood biomarker changes associated with paediatric CHD interventions. Methods: A systematic review was performed to investigate the incidence of perioperative brain MRI findings from studies that had conducted both pre- and post-surgery brain MRI. As preparation for our clinical study, a neonatal TCD probe holder was developed, and the accuracy of our TCD equipment was verified through development of a Doppler phantom mimicking the middle cerebral artery. Finally, a prospective observational study was conducted involving measurement of pre-, intra- and post-operative cerebral blood flow velocity (CBFV), physiological monitoring, analysis of blood-based brain injury and inflammatory biomarkers, and brain MRI in infants undergoing CHD interventions (on-pump, off-pump, and catheterisation). Results: Our systematic review demonstrated that new brain MRI findings are typically present in 51% of infants following CHD surgery. Our in vitro study provided a better understand of TCD CBFV measurements and revealed differences between manufacturers at high velocities. CBFV monitoring using TCD at various perioperative time-points in 38 CHD infants revealed differences in cerebral haemodynamics between CHD repair groups. Analysis of 12 blood-based brain injury and inflammatory biomarkers in 20 infants revealed high levels of biomarkers, especially in infants undergoing on-pump surgery. Finally, a case-study is reported, which includes brain MRI findings in a 3-month-old infant who underwent trans-catheter CHD repair. Conclusion: TCD monitoring, blood biomarkers, and MRI, could be valuable in addressing knowledge gaps around perioperative brain injury and have the potential to support the evaluation of methods for improving outcome. Further work should also assess neurodevelopmental outcome for comparison with TCD, blood biomarkers, and brain MRI outcomes around the time of surgery in a larger group of patients.12 0