Biology subjects

Jorgensen, A.

Publications and source records attributed to Jorgensen, A..

6 recordsLinked to original sources

bioRxiv2024

HCV- and HBV-mediated liver cancer converge on similar transcriptomic landscapes and immune profiles.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, and a large proportion of HCC is attributable to viral causes including hepatitis B (HBV) and C virus (HCV). The pathogenesis of viral-mediated HCC can differ between HBV and HCV, but it is unclear how much these differences influence the tumors final molecular and immune profiles. Additionally, there are known sex differences in the molecular etiology of HCC, but sex differences have not been explored in the context of viral-mediated HCC. To determine the extent to which the viral status and sex impact the molecular and immune profiles of HCC, we performed differential expression and immune cell deconvolution analyses. We identified a large number of differentially expressed genes unique to the HBV or HCV tumor:tumor-adjacent comparison. Pathway enrichment analyses demonstrated that the changes unique to the HCV tumor:tumor-adjacent tissue were predominated by changes in the immune pathways. Immune cell deconvolution demonstrated that HCV tumor-adjacent tissue had the largest immune cell infiltrate, with no difference in the immune profiles within HBV and HCV tumor samples. We subsequently segregated the differential expression analyses by sex, but demonstrated that the low number of female samples led to an overestimate of differentially expressed genes unique to male tumors. This limitation highlights the importance of additional sampling of female HCC tumors to allow for a more complete analysis of the sex differences in HCC. Overall, this work demonstrates the convergence of HBV- and HCV-mediated HCC on a similar transcriptomic landscape and immune profile despite differences in the surrounding tissue. Author SummaryHepatocellular carcinoma (HCC) is a significant worldwide health challenge. The majority of cases are attributable to infection with hepatitis B (HBV) or C (HCV). HBV and HCV differ in their methods of transmission and how they cause cancer. Despite these differences, most treatment guidelines are ambivalent to the underlying viral etiology of the tumor. In the age of personalized medicine, we sought to determine how similar or different HCC was when mediated by HBV or HCV. Additionally, since previous work has demonstrated biological differences in the tumors between males and females, we sought to characterize the sex differences within viral-mediated HCC. We found that, although there are several genes with differences in HBV- and HCV-mediated tumors, the tumors appear to be more biologically similar than the corresponding tumor-adjacent tissue. This suggests a convergence on common pathways toward cancers even when the starting point differs. The lower number of female samples inhibits a full understanding of the biological differences between HCC in males and females. This presents a critical need in the field to increase the sampling of female cancers to enable a full understanding of the sex differences in HCC.

genetics↗

bioRxiv2024

Exploring the functional, protective, and transcriptomic effects of GIP on cytokine-exposed human pancreatic islets and EndoC-βH5 cells

Immune-mediated beta-cell destruction and lack of alpha-cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects, as well as its beta-cell protective effects shown in rodent islets. Here, we examined the functional, protective, and transcriptomic effects of GIP treatment upon diabetogenic cytokine exposure to interleukin (IL)-1{beta} {+/-} interferon (IFN)-{gamma} in human EndoC-{beta}H5 beta cells and isolated human islets, respectively. GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-{beta}H5 cells and increased insulin and glucagon secretion from human islets during high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-{beta}H5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis or cytokine-induced functional impairment of human EndoC-{beta}H5 cells. GIP also did not prevent cytokine-induced apoptosis in human islets. GIP treatment of human islets with or without cytokines for 24 hours did not significantly impact the transcriptome. GIP potentiated cytokine-induced secretion of IL-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-{beta}H5 cells, GIP reduced IFN-{gamma}-induced secretion of tumor necrosis factor (TNF)-, IL-2, IL-6, and IL-10 but increased the secretion of CXCL8, CCL2, CCL4, and CCL11. In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our results indicate that GIP does not provide substantial cytoprotective effects against diabetogenic cytokine challenge or significantly modulate the transcriptome of human islets when applied at a supraphysiological level. GIP may, however, still exert selective inflammation-modulatory effects upon diabetogenic cytokine exposure.

cell biology↗

bioRxiv2023

Role of transporters and enzymes in metabolism and distribution of 4-chlorokynurenine and metabolites

4-chlorokynurenine (4-Cl-KYN) is in clinical development for potential CNS indications. We have sought to further understand the distribution and metabolism of 4-Cl-KYN as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite had the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

pharmacology and toxicology↗

bioRxiv2021

rareSurvival: rare variant association analysis for time-to-event outcomes.

SummaryRare variants have been proposed as contributing to the "missing heritability" of complex human traits. There has been much recent development of methodology to investigate association of complex traits with multiple rare variants within pre-defined "units" from sequence and array-based studies of the exome or genome. However, software for modelling time to event outcomes for rare variant associations has been under developed in comparison with binary and quantitative traits. We introduce a new command line application, rareSurvival, used for the analysis of rare variants with time to event outcomes. The program is compatible with high performance computing (HPC) clusters for batch processing. rareSurvival implements statistical methodology, which are a combination of widely used survival and gene-based analysis techniques such as the Cox proportional hazards model and the burden test. We introduce a novel piece of software that will be at the forefront of efforts to discover rare variants associated with a variety of complex diseases with survival endpoints. Availability & ImplementationrareSurvival is implemented in C#, available on Linux, Windows and Mac OS X operating systems. It is freely available (GNU General Public License, version 3) to download from https://www.liverpool.ac.uk/translational-medicine/research/statistical-genetics/software/. Download Mono for Linux or Mac OS X to run software. Contacthamzah.syed@liverpool.ac.uk Supplementary informationLinks to additional figures and tables are available at Bioinformatics online.

bioinformatics↗

bioRxiv2021

Germaphobia! Does our Relationship with, and Knowledge of Biodiversity Affect our Attitudes Towards Microbes?

Germaphobia -- a pathological aversion to microorganisms -- could be contributing to an explosion in human immune-related disorders via mass sterilisation of surfaces and reduced exposure to biodiversity. Loss of biodiversity and our connectedness to nature, along with poor microbial literacy may be augmenting the negative consequences of germaphobia on ecosystem health. In this study, we created an online questionnaire to acquire data on attitudes towards, and knowledge of microbes. We collected data on nature connectedness and interactions with nature and explored the relationships between these variables. We found a significant association between attitudes towards microbes and both duration and frequency of visits to natural environments. A higher frequency of visits to nature per week, and a longer duration spent in nature per visit, significantly associated with positive attitudes towards microbes. We found no association between nature connectedness and attitudes towards microbes. We found a significant relationship between knowledge of lesser known microbial groups (e.g., identifying that fungi, algae, protozoa, and archaea are microbes) and positive attitudes towards microbes. However, we also found that people who correctly identified viruses as being microbes expressed less positive views of microbes overall -- this could potentially be attributed to a COVID-19 effect. Our results suggest that basic microbial literacy and nature engagement may be important in reducing/preventing germaphobia. The results also suggest that a virus-centric phenomenon (e.g., COVID-19) could increase broader germaphobia. As the rise of immune-related disorders and mental health conditions have been linked to germaphobia, reduced biodiversity, and non-targeted sterilisation, our findings point to a feasible strategy to potentially help ameliorate these negative consequences. A greater emphasis on microbial literacy and promoting time spent in nature could be useful in promoting resilience in human health and more positive/constructive attitudes towards the foundations of our ecosystems - the microorganisms.

scientific communication and education↗

bioRxiv2019

Radiographic and clinical risk factors of total knee arthroplasty in asymptomatic knees; a 15-year follow-up study

BackgroundRadiographic signs of osteoarthritis (OA) are frequent in knees without symptoms. The long-term impact of these findings is not completely elucidated. We wanted to evaluate whether radiographic or clinical baseline findings are associated with the risk of total knee arthroplasty (TKA) in knees without symptomatic OA but with clinical OA of the other knee during a mean follow-up period of 15 years. MethodsA follow-up analysis was performed in 100 persons with unilateral, clinical knee OA according to the ACR (American College of Rheumatology) criteria, who participated in a clinical trial between 2000 and 2002. Baseline radiographs of the contralateral, non-symptomatic knee were available in 88 participants at follow-up. Data on TKA procedures were extracted from the Danish National Patient Register at follow-up. Radiographic and clinical findings were analyzed for associations with subsequent TKA. ResultsAt follow-up, 40% had received a TKA in their non-symptomatic knee. The risk of TKA was significantly associated with baseline joint space narrowing (risk ratio (RR) 1.6 (95% confidence interval (95% CI) 1.4 to 1.9)), osteophytes (RR 1.5 (95% CI 1.3 to 1.8)) and subchondral sclerosis (RR 2.4 (95% CI 1.6 to 3.7)). Among the clinical findings, only baseline body mass index (BMI) was significantly associated with the risk of TKA (RR 1.4 (95& CI 1.1 to 1.8)). ConclusionsRadiographic OA changes and BMI at baseline were significantly associated with the long-term risk of TKA in persons without symptomatic knee OA but with symptomatic OA in the contralateral knee, implying that radiographic OA findings are important prognostic factors regardless of symptoms.

pathology↗