Comparative immune profiling of pancreatic ductal adenocarcinoma progression among South African patients.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer characterized by an immunosuppressive microenvironment. Patients from specific ethnicities and population groups have poorer prognoses than others. Therefore, a better understanding of the immune landscape in such groups is necessary for disease elucidation, predicting patient outcomes and therapeutic targeting. This study investigated the expression of circulating key immune cell markers in South African PDAC patients of African ancestry. METHODS: Blood samples were obtained from a total of 6 healthy volunteers (HC), 6 Chronic Pancreatitis (CP) and 34 PDAC patients consisting of 22 resectable (RPC), 8 locally advanced (LAPC) and 4 metastatic (MPC). Real-time Quantitative Polymerase Chain reactions (RT-qPCR), Metabolomics, Enzyme-Linked Immunosorbent Assay (ELISA), Reactive Oxygen Species (ROS), and Immunophenotyping assays were conducted. Statistical analysis was conducted in R (v 4.3.2). Additional analysis of single-cell RNA data from 20 patients (16 PDAC and 4 controls) was conducted to interrogate the distribution of T-cell and Natural Killer cell populations. RESULTS: Granulocyte and neutrophil levels were significantly elevated while lymphocytes decreased with PDAC severity. The total percentages of CD3 T-cell subpopulations (helper and double negative T-cells) decreased when compared to HC. Although both NK (p = 0.014) and NKT (p < 0.001) cell levels increased as the disease progressed, their subsets: NK CD56dimCD16- (p = 0.024) and NKTs CD56+ (p = 0.008) cell levels reduced significantly. Of note is the negative association of NK CD56dimCD16- (p < 0.001) cell levels with survival time. The gene expression analyses showed no statistically significant correlation when comparing the PDAC groups with the controls. The inflammatory status of PDAC was assessed by ROS levels of serum which were elevated in CP (p = 0.025), (RPC (p = 0.003) and LAPC (p = 0.008)) while no significant change was observed in MPC, compared to the HC group. ROS was shown to be positively correlated with GlycA (R = 0.45, p = 0.0096). Single-cell analyses showed a significant difference in the ratio of NKT cells per total cell counts in LAPC (p < 0.001) and MPC (p < 0.001) groups compared with HC, confirming observations in our sample group. CONCLUSION: The expression of these immune cell markers observed in this pilot study provides insight into their potential roles in tumour progression in the patient group and suggests their potential utility in the development of immunotherapeutic strategies.

Exploiting the molecular subtypes and genetic landscape in pancreatic cancer: the quest to find effective drugs.

Pancreatic Ductal Adenocarcinoma (PDAC) is a very lethal disease that typically presents at an advanced stage and is non-compliant with most treatments. Recent technologies have helped delineate associated molecular subtypes and genetic variations yielding important insights into the pathophysiology of this disease and having implications for the identification of new therapeutic targets. Drug repurposing has been evaluated as a new paradigm in oncology to accelerate the application of approved or failed target-specific molecules for the treatment of cancer patients. This review focuses on the impact of molecular subtypes on key genomic alterations in PDAC, and the progress made thus far. Importantly, these alterations are discussed in light of the potential role of drug repurposing in PDAC.

MetChem: a new pipeline to explore structural similarity across metabolite modules.

Summary: Computational analysis and interpretation of metabolomic profiling data remains a major challenge in translational research. Exploring metabolic biomarkers and dysregulated metabolic pathways associated with a patient phenotype could offer new opportunities for targeted therapeutic intervention. Metabolite clustering based on structural similarity has the potential to uncover common underpinnings of biological processes. To address this need, we have developed the MetChem package. MetChem is a quick and simple tool that allows to classify metabolites in structurally related modules, thus revealing their functional information. Availabilityand implementation: MetChem is freely available from the R archive CRAN (http://cran.r-project.org). The software is distributed under the GNU General Public License (version 3 or later).

Corrigendum: KODAMA exploratory analysis in metabolic phenotyping.

[This corrects the article DOI: 10.3389/fmolb.2022.1070394.].

Influence of GSTM1, T1 genes polymorphisms on oxidative stress and liver enzymes in rural and urban pesticides-exposed workers.

Several studies discussed the relationship between the toxicity of organophosphates (OPs) and carbamates pesticides and oxidative stress which affects human health. This study aimed to evaluate the effects of pesticides on the induction of oxidative stress and hepatotoxicity. It was also focused on glutathione-S-transferase gene polymorphism in the modulation of these effects. In addition, the role of the educational level of exposed workers was studied. Acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), liver enzymes, malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and glutathione S transferase (GST) were estimated at 100 pesticide-exposed workers (50 urban researchers (UE) and 50 rural sprayers (RE)), and 100 matched controls (50 urban controls (UC)and 50 rural controls (RC)). AChE and BuChE were decreased in RE and UE compared to RC. Aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activity were elevated in UE and UC compared to the RE and RC. Alanine aminotransferase (ALT) was elevated in UE compared to RE. MDA in RE and UE showed elevation compared to RC. There was a significant reduction in the levels of GSH, GST, and GPx in UE compared to RE and RC. The most sensitive pesticide-induced hepatotoxicity group were exposed workers with the GSTT1 genotype. Within these workers, ALT and ALP were significantly correlated with MDA and inversely correlated with AChE and BuChE, while AST was inversely correlated with AChE and BuChE only in UE. Conclusion: GST gene polymorphisms appeared to have a significant role in workers' susceptibility to hepatotoxic effects due to occupational exposure to pesticides; GSTT1 was the most sensitive genotype.

Early prediction of liver carcinogenicity due to occupational exposure to pesticides.

Several studies linked between pesticides exposure and development of liver cancer, through several mechanisms inform of genotoxicity, cytotoxicity, tumor promotion, immunotoxicity and hormonal actions. This study aimed to estimate novel biomarkers for early prediction of liver malignancy due to occupational exposure to pesticides in two groups of workers with different socioeconomic standard (highly educated urban researchers and low educated rural pesticides sprayers). This study included 50 urban researchers and 50 rural pesticides sprayers occupationally exposed to pesticides. They were compared with 50 non-exposed urban researchers and 50 non-exposed rural subjects. Several tumor biomarkers were estimated; P53 protein, Alfa fetoprotein (AFP), and Alpha-L-fucosidase (AFU). Additionally, telomerase enzyme activity, Relative telomere length (RTL), and DNA damage using comet assay were measured. Furthermore, the glutathione-S-Transferase (GST) gene polymorphisms were identified for both exposed groups. Statistical analysis revealed elevated level of tumor biomarkers among exposed subjects relative to control groups in spite of being within the normal range. Increase in the DNA damage was detected, with shortening of telomere length and decrease in telomerase enzyme activity in pesticides-exposed subjects compared to their controls. Most of these changes were related to the levels of butyrylcholinesterase. Subjects with GSTT1 genotype were suggested to be more susceptible to hepatic carcinogenicity. Telomere relative length and comets assay together with GST genes polymorphisms could be used as early predictors for liver cancer susceptibility among pesticides exposed workers.

GSTP1 and XRCC1 polymorphisms and DNA damage in agricultural workers exposed to pesticides.

Pesticide exposure may be associated with increased risk of genotoxicity and carcinogenesis. These risks may be affected by polymorphisms of genes for glutathione transferase-dependent metabolism of pesticides and for DNA repair. We studied the prevalence of GSTP1 and XRCC1 polymorphisms and their possible correlation with DNA damage following prolonged pesticide exposure. DNA damage was estimated by the comet assay in peripheral blood samples from 51 pesticide-exposed workers and 50 controls. GSTP1 (105) and XRCC1 (399 and 194) genotypes were identified by restriction fragment length analysis. Individuals carrying theGSTP1 Ile-Ile or XRCC1399 Arg-Arg genotypes showed greater DNA damage than observed for other alleles.