Serum and tissue metallome of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) patients have late presentation at the time of diagnosis and a poor prognosis. Metal dyshomeostasis is known to play a role in cancer progression. However, the blood and tissue metallome of PDAC patients has not been assessed. This study aimed to determine the levels of essential and toxic metals in the serum and pancreatic tissue from PDAC patients. Serum samples were obtained from PDAC patients before surgical resection. Tissue (tumor and adjacent normal pancreas) were obtained from the surgically resected specimen. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis was performed to quantify the levels of 10 essential and 3 toxic metals in these samples. Statistical analysis was performed to identify dysregulated metals in PDAC and their role as potential diagnostic and prognostic biomarkers. Significantly decreased serum levels of magnesium, potassium, calcium, iron, zinc, selenium, arsenic, and mercury and increased levels of molybdenum were shown to be associated with PDAC. There were significantly decreased levels of zinc, manganese and molybdenum, and increased levels of calcium and selenium in the pancreatic tumor tissue compared with the adjacent normal pancreas. Notably, lower serum levels of calcium, iron, and selenium, and higher levels of manganese, were significantly associated with a poor prognosis (i.e., overall survival) in PDAC patients. In conclusion, this is the first study to comprehensively assess the serum and tissue metallome of PDAC patients. It identified the association of metals with PDAC diagnosis and prognosis.

Novel serum protein biomarker panel for early diagnosis of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Late presentation of disease at the time of diagnosis is one of the major reasons for dismal prognostic outcomes for PDAC patients. Currently, there is a lack of clinical biomarkers, which can be used to diagnose PDAC patients at an early resectable stage. This study performed proteomic mass spectrometry to identify novel blood-based biomarkers for early diagnosis of PDAC. Serum specimens from 88 PDAC patients and 88 healthy controls (60 discovery cohort and 28 validation cohort) were analyzed using data independent acquisition high resolution mass spectrometry to identify candidate biomarker proteins. A total of 249 proteins were identified and quantified by the mass spectrometric analysis. Six proteins were markedly (>1.5 fold) and significantly (p < .05; q < 0.1) increased in PDAC patients compared to healthy controls in discovery cohort. Notably, four of these six proteins were significantly upregulated in an independent validation cohort. The top three upregulated proteins (i.e., Polymeric Immunoglobulin Receptor [PIGR], von Willebrand Factor [vWF], and Fibrinogen) were validated using enzyme linked immunosorbent assay, which led to selection of PIGR and vWF as a diagnostic biomarker panel for PDAC. The panel showed high ability to diagnose early stage (stage I and II) PDAC patients (area under the curve [AUC]: 0.8926), which was further improved after the addition of clinically used prognostic biomarker (Ca 19-9) to the panel (AUC: 0.9798). In conclusion, a novel serum protein biomarker panel for early diagnosis of PDAC was identified.

Heterogeneous tumor microenvironment in pancreatic ductal adenocarcinoma: An emerging role of single-cell analysis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies in the world, for which the mortality is almost as high as the disease incidence and is predicted to be the second-highest cause of cancer-related deaths by 2030. These cancerous tumors consist of diversified gene expressions within the different cellular subpopulations that include neoplastic ductal cells, cancer-associated fibroblasts, and immune cells, all of which collectively facilitate cellular heterogeneity in the PDAC tumor microenvironment (TME). Active intratumoral interaction within the cell populations in TME induces the proliferation of cancerous cells, accounting for tumorigenesis and rapid metastasis. METHODS: This review will focus on novel findings uncovering PDAC heterogeneity in different cellular subpopulations using single-cell RNA-sequencing (scRNA-seq) and other single-cell analysis technologies. It will further explore the emerging role of single-cell technologies in assessing the role of different subpopulations of neoplastic ductal cells, cancer-associated fibroblasts, and immune cells in PDAC progression. RESULTS AND CONCLUSION: The application of scRNA-seq in PDAC has started to unveil associations between disease progression and heterogeneity in pancreatic TME and could influence future PDAC treatment. Recent advances in scRNA-seq have uncovered comprehensive analyses of heterogeneous ecosystems present within the TME. These emerging findings underpins further need for a more in-depth understanding of intratumoral heterogeneity in the PDAC microenvironment.

Gene expression profiling of pancreatic ductal adenocarcinomas in response to neoadjuvant chemotherapy.

AIM: Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers. Chemotherapy is the mainstay systemic therapy for PDAC, and chemoresistance is a major clinical problem leading to therapeutic failure. This study aimed to identify key differences in gene expression profile in tumors from chemoresponsive and chemoresistant patients. METHODS: Archived formalin-fixed paraffin-embedded tumor tissue samples from patients treated with neoadjuvant chemotherapy were obtained during surgical resection. Specimens were macrodissected and gene expression analysis was performed. Multi- and univariate statistical analysis was performed to identify differential gene expression profile of tumors from good (0%-30% residual viable tumor [RVT]) and poor (>30% RVT) chemotherapy-responders. RESULTS: Initially, unsupervised multivariate modeling was performed by principal component analysis, which demonstrated a distinct gene expression profile between good- and poor-chemotherapy responders. There were 396 genes that were significantly (p < 0.05) downregulated (200 genes) or upregulated (196 genes) in tumors from good responders compared to poor responders. Further supervised multivariate analysis of significant genes by partial least square (PLS) demonstrated a highly distinct gene expression profile between good- and poor responders. A gene biomarker of panel (IL18, SPA17, CD58, PTTG1, MTBP, ABL1, SFRP1, CHRDL1, IGF1, and CFD) was selected based on PLS model, and univariate regression analysis of individual genes was performed. The identified biomarker panel demonstrated a very high ability to diagnose good-responding PDAC patients (AUROC: 0.977, sensitivity: 82.4%; specificity: 87.0%). CONCLUSION: A distinct tumor biological profile between PDAC patients who either respond or not respond to chemotherapy was identified.

Kynurenic acid as a biochemical factor underlying the association between Western-style diet and depression: A cross-sectional study.

Consumption of a Western-style diet (WS-diet), high in saturated fat and added sugar, is associated with increased depression risk. However, the physiological mechanisms underlying the relationship requires elucidation. Diet can alter tryptophan metabolism along the kynurenine pathway (KP), potentially linking inflammation and depression. This study aimed to examine whether urinary inflammatory markers and KP metabolites differed according to WS-diet consumption and depression severity. Depression symptoms and habitual WS-diet consumption were assessed in 169 healthy adults aged 17-35 recruited from two experimental studies. Targeted metabolomics profiling of seven KP metabolites, ELISA-based assays of interleukin-6 (IL-6) and C-reactive protein (CRP) were performed using urine samples collected from the participants. Parametric tests were performed for group comparison and associations analysis. Multilevel mixed-effect modelling was applied to control for biases. Higher intake of WS-diet was associated with lower levels of neuroprotective kynurenic acid (KA; R = -0.17, p = 0.0236). There were no differences in IL-6 or CRP across diet groups (p > 0.05). Physical activity had negative associations with most KP metabolites. Mixed-effects regression analysis showed the glutamatergic inhibitor, KA, was the only biomarker to have a significant association with depression symptoms in a model adjusted for demographic and lifestyle variables: a unit increase in KA was associated with 0.21 unit decrease in Depression Anxiety and Stress Scale-21 depression score (p = 0.009). These findings suggest that urinary KA is associated with both habitual WS-diet intake, and levels of depression symptoms, independent of inflammation. Findings support the role of neuroprotection and glutamatergic modulation in depression. We propose that KA may act as endogenous glutamatergic inhibition in regulating depression severity in the absence of inflammation. Further comparison with blood-based markers will assist in validating the utility of non-invasive urine samples for measuring KP metabolites.