Development Of Pancreatic Cancer Research Articles

Abstract A038: High-dimensional, multi-omics analyses of proteins, metabolites, transcripts, and genes enable biomarker discovery in early- and late-stage pancreatic cancer

Abstract Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Disease biomarkers quantified from blood-based assays may help reduce mortality by enabling early detection, treatment selection, or response and resistance assessment. PrognomiQ has developed a multi-omics assay and analysis platform that comprehensively profiles blood samples to detect proteins, metabolites, lipids, mRNA, miRNA, cfDNA fragments, and methylation at CpG sites. This platform can provide deep insights into the biology of pancreatic cancer and could enable the development of high sensitivity and specificity tests for the early detection of pancreatic cancer. We conducted a case-control study comprising 196 subjects: 92 with untreated pancreatic cancer and 104 matched controls without pancreatic cancer. For each subject, blood was collected in assay-specific tubes and processed to provide 7 different `omics readouts. cfDNA and mRNA were isolated from samples and assayed following standard NGS protocols. cfDNA fragments were processed to estimate fragment-length disorder and copy-number variation along with CpG site methylation. In addition, targeted and untargeted LCMS were used to detect and quantify proteins, metabolites, and lipids. After normalization, non-parametric univariate analyses of cases versus controls were performed to identify differentially abundant features on all available samples for each assay. Unsupervised learning was used to investigate the separation of subjects into groups based on disease status for the subset of 157 subjects for which complete data on all 7 readouts were available. We detected 2,812 proteins, 811 lipids, 373 metabolites, and 110,864 mRNA transcripts in all samples where data for each assay was available. Of these, 275 proteins, 232 lipids, 49 metabolites, and 3385 mRNA transcripts were significantly different (FWER < 0.05) in cases versus controls. From cfDNA data, we identified 35 non-contiguous genomic regions associated with fragment-length disorder, 557 with copy-number variation, and 5 with multiple, differentially methylated CpGs (FWER < 0.05) that aggregately span 307 protein-coding genes; of these, the overlap with the differentially expressed proteins included E-cadherin (tumor suppressor) and N-cadherin (involved in epithelial-to-mesenchymal transition). Statistically significant genes and proteins were found to be associated with processes including Wnt signaling, regulation of focal adhesion assembly, and actin cytoskeleton organization. Multi-omics, unsupervised learning showed separation of early- and late-stage cases and controls. High-dimensional bioinformatics analyses systematically decomposed each `omics data type into joint and orthogonal components associated with pancreatic cancer. Ongoing multivariate analyses, including supervised machine learning, will further elucidate the biology of pancreatic cancer development, and serve as the foundation for high-sensitivity blood tests for the early detection and monitoring of pancreatic cancer. Citation Format: Ehdieh Khaledian, Preethi Prasad, John Blume, Ghristine Bundalian, Connie Chao-Shern, Jinlyung Choi, Rea Cuaresma, Jared Deyarmin, Jun Heok Jang, Manoj Khadka, Thidar Khin, Yuya Kodama, Ajinkya Kokate, Joon-Yong Lee, Manway Liu, Nithya Mudaliar, Madhuvanthi Ramaiah, Saividya Ramaswamy, Peter Spiro, Kavya Swaminathan, Preston Williams, Mi Yang, James Yee, Brian Young, Robert Zawada, Susan Zhang, Chinmay Belthangady, Bruce Wilcox, Philip Ma. High-dimensional, multi-omics analyses of proteins, metabolites, transcripts, and genes enable biomarker discovery in early- and late-stage pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A038.

Histone Chaperones and Digestive Cancer: A Review of the Literature.

The global burden of digestive cancer is expected to increase. Therefore, crucial for the prognosis of patients with these tumors is to identify early diagnostic markers or novel therapeutic targets. There is accumulating evidence connecting histone chaperones to the pathogenesis of digestive cancer. Histone chaperones are now broadly defined as a class of proteins that bind histones and regulate nucleosome assembly. Recent studies have demonstrated that multiple histone chaperones are aberrantly expressed and have distinct roles in digestive cancers. The purpose of this review is to present the current evidence regarding the role of histone chaperones in digestive cancer, particularly their mechanism in the development and progression of esophageal, gastric, liver, pancreatic, and colorectal cancers. In addition, the prognostic significance of particular histone chaperones in patients with digestive cancer is discussed. According to PRISMA guidelines, we searched the PubMed, Embase, and MEDLINE databases to identify studies on histone chaperones and digestive cancer from inception until June 2022. A total of 104 studies involving 21 histone chaperones were retrieved. This review confirms the roles and mechanisms of selected histone chaperones in digestive cancer and suggests their significance as potential prognostic biomarkers and therapeutic targets. However, due to their non-specificity, more research on histone chaperones should be conducted in the future to elucidate novel strategies of histone chaperones for prognosis and treatment of digestive cancer.

Loss of p53 and genetic evolution in pancreatic cancer: Ordered chaos after the guardian is gone.

A recent Nature study delineates a stepwise genomic evolution during pancreatic cancer development, employing an engineered mutant Kras and heterozygous Trp53 mouse model that identifies cells undergoing Trp53 loss of heterozygosity (LOH). Genetic progression post-Trp53 LOH involves clonal deletions, then genome doubling and subsequent accumulation of subclonal gains and amplifications.

KRAS G12D mutation eliminates reactive oxygen species through the Nrf2/CSE/H 2S axis and contributes to pancreatic cancer growth.

In pancreatic cancer, KRAS G12D can trigger pancreatic cancer initiation and development. Rapid tumor growth is often accompanied by excess intracellular reactive oxygen species (ROS) production, which is unfavorable to tumor. However, the regulation of intracellular ROS levels in KRAS mutant pancreatic cancer remains unclear. In this study, we establish BxPC3 stable cell strains expressing KRAS wild type (WT) and G12D mutation and find unchanged ROS levels despite higher glycolysis and proliferation viability in KRAS mutant cells than KRAS WT cells. The key hydrogen sulfide (H 2S)-generating enzyme cystathionine-γ-lyase (CSE) is upregulated in KRAS mutant BxPC3 cells, and its knockdown significantly increases intracellular ROS levels and decreases cell glycolysis and proliferation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by KRAS mutation to promote CSE transcription. An Nrf2 binding site (‒47/‒39 bp) in the CSE promoter is verified. CSE overexpression and the addition of NaHS after Nrf2 knockdown or inhibition by brusatol decreases ROS levels and rescues cell proliferation. Our study reveals the regulatory mechanism of intracellular ROS levels in KRAS mutant pancreatic cancer cells, which provides a potential target for pancreatic cancer therapy.

The Role of Selected Serpins in Gastrointestinal (GI) Malignancies.

Gastrointestinal (GI) cancers, which are a diverse group of malignant diseases, represent a major healthcare problem around the world. Due to the lack of specific symptoms in the early stages as well as insufficient diagnostic possibilities, these malignancies occupy the leading position in the causes of death worldwide. The currently available tests have too many limitations to be part of routine diagnostics. Therefore, new potential biomarkers that could be used as diagnostic and prognostic factors for these cancers are still being sought. Among the proteins that might fit this role are serpins, which are serine protease inhibitors. Although the serpins themselves have been known for many years, they have recently become the centre of attention for many authors, especially due to the fact that a number of proteins in this family are involved in many stages of neoplasia formation, from angiogenesis through tumour growth to progression. Therefore, the aim of this review is to present the current knowledge about the significance of serpins in GI malignancies, especially their involvement in the development and progression of oesophageal, gastric, pancreatic and colorectal cancers. This review summarises and confirms the important roles of selected serpins in the pathogenesis of various GI cancers and also points to their promising roles as therapeutic targets. However, due to the relatively nonspecific nature of serpins, future research should be carried out to elucidate the mechanisms involved in tumour pathogenesis in more detail.

Neutrophils in pancreatic cancer: Potential therapeutic targets

Pancreatic cancer is a digestive system malignancy and poses a high mortality worldwide. Traditionally, neutrophils have been thought to play a role in acute inflammation. In contrast, their importance during tumor diseases has been less well studied. Generally, neutrophils are recruited into the tumor microenvironment and exert inflammation and tumor-promoting effects. As an essential part of the tumor microenvironment, neutrophils play diverse roles in pancreatic cancer, such as angiogenesis, progression, metastasis and immunosuppression. Additionally, neutrophils can be a new potential therapeutic target in cancer. Inhibitors of cytokines, chemokines and neutrophil extracellular traps can exert antitumor effects. In this review, we describe the role of neutrophils in the development and progression of pancreatic cancer, discuss their potential as therapeutic targets, and aim to provide ideas for improving the prognosis of patients with this malignant tumor disease.

The Emerging Role of MicroRNAs and Autophagy Mechanism in Pancreatic Cancer Progression: Future Therapeutic Approaches.

Pancreatic cancer constitutes the fourth most frequent cause of death due to malignancy in the US. Despite the new therapeutic modalities, the management of pancreatic ductal adenocarcinoma (PDAC) is considered a difficult task for clinicians due to the fact that is usually diagnosed in already advanced stages and it is relatively resistant to the current chemotherapeutic agents. The molecular background analysis of pancreatic malignant tumors, which includes various epigenetic and genetic alterations, opens new horizons for the development of novel diagnostic and therapeutic strategies. The interplay between miRNAs, autophagy pathway, and pancreatic carcinogenesis is in the spotlight of the current research. There is strong evidence that miRNAs take part in carcinogenesis either as tumor inhibitors that combat the oncogene expression or as promoters (oncomiRs) by acting as oncogenes by interfering with various cell functions such as proliferation, programmed cell death, and metabolic and signaling pathways. Deregulation of the expression levels of various miRNAs is closely associated with tumor growth, progression, and dissemination, as well as low sensitivity to chemotherapeutic agents. Similarly, autophagy despite constituting a pivotal homeostatic mechanism for cell survival has a binary role in PDAC, either as an inhibitor or promoter of carcinogenesis. The emerging role of miRNAs in autophagy gets a great deal of attention as it opens new opportunities for the development of novel therapeutic strategies for the management of this aggressive and chemoresistant malignancy. In this review, we will shed light on the interplay between miRNAs and the autophagy mechanism for pancreatic cancer development and progression.

Modeling Obesity-Driven Pancreatic Carcinogenesis-A Review of Current In Vivo and In Vitro Models of Obesity and Pancreatic Carcinogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy with a 5-year survival rate below 10%, thereby exhibiting the worst prognosis of all solid tumors. Increasing incidence together with a continued lack of targeted treatment options will cause PDAC to be the second leading cause of cancer-related deaths in the western world by 2030. Obesity belongs to the predominant risk factors for pancreatic cancer. To improve our understanding of the impact of obesity on pancreatic cancer development and progression, novel laboratory techniques have been developed. In this review, we summarize current in vitro and in vivo models of PDAC and obesity as well as an overview of a variety of models to investigate obesity-driven pancreatic carcinogenesis. We start by giving an overview on different methods to cultivate adipocytes in vitro as well as various in vivo mouse models of obesity. Moreover, established murine and human PDAC cell lines as well as organoids are summarized and the genetically engineered models of PCAC compared to xenograft models are introduced. Finally, we review published in vitro and in vivo models studying the impact of obesity on PDAC, enabling us to decipher the molecular basis of obesity-driven pancreatic carcinogenesis.

Exosomal DNAJB11 promotes the development of pancreatic cancer by modulating the EGFR/MAPK pathway

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with invasive and metastatic characteristics and poor prognosis. Intracellular protein homeostasis is associated with invasion and metastasis of pancreatic cancer, but the specific molecular mechanism remains unclear. Our previous studies have revealed that DNAJB11, a key protein in protein homeostasis, is secreted by exosomes in the supernatant of dissociated pancreatic cancer cells with high metastasis. The results from transcriptome sequencing and co-immunoprecipitation (Co-IP)-based liquid chromatography with tandem mass spectrometry (LC–MS/MS) showed that depletion of DNAJB11 levels could increase HSPA5 expression and induce endoplasmic reticulum stress through the PRKR-like endoplasmic reticulum kinase signaling pathway in pancreatic cancer cells. Furthermore, exosomal DNAJB11 promoted cell development of PC cells in vitro and in vivo. In addition, exosomal DNAJB11 could regulate the expression of EGFR and activate the downstream MAPK signaling pathway. Clinical blood samples were collected to evaluate the potential of exosome DNAJB11 as a diagnostic biomarker and therapeutic target for the treatment of pancreatic cancer. This study could provide a new theoretical basis and potential molecular targets for the treatment of pancreatic cancer.

Risk factors modification as a preventive strategy in mortality reduction caused by digestive organs malignant neoplasms

Purpose of this study is to research contribution of chronic non-communicable diseases (CNCDs) risk factors (RF) to the prevalence rate of digestive organs diseases and risks of digestive system malignant neoplasms development in the context of Omsk region municipal districts. Material and methods: the analysis includes following risk factors (RF): unhealthy diets, overweight, harmful use of alcohol, physical inactivity with proved causal relationship with of digestive organs diseases such as stomach and duodenal ulcer, gastritis and duodenitis, liver fibrosis and liver cirrhosis, and with digestive organs malignant neoplasms (MNP): esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer and intrahepatic bile ducts cancer. This research used Russian Federation Federal State Statistics Service statistic material. Statistic material processing was conducted using traditional correlation analysis and the estimation of reliability of data differences method. Correlation analysis was carried out using online-calculator of statistics on the www.medstatistic.ru website. Results: the group of region municipal districts with the most unfavorable population mortality rates for malignant neoplasms has “unhealthy diets” RF associated with high risk of stomach cancer development, “overweight” RF associated with high risk of colorectal cancer and liver cancer development, “harmful use of alcohol” RF associated with high risk of stomach cancer and pancreatic cancer development, “physical inactivity” RF associated with high risk of stomach cancer development. Conclusion: the analysis made it possible to determine priorities in primary prevention of oncological diseases strategy in Omsk region municipal districts and to form key MNP development risk groups among region population to be targeted by preventive measures.

Does Chronic Use of High Dose Proton Pump Inhibitors Increase Risk for Pancreatic Cancer?

To analyze whether use of proton pump inhibitors increase the risk for pancreatic cancer in a mouse model and human clinical cohorts. p48-Cre/LSL-KrasG12D mice that develop precancerous pancreatic intraepithelial neoplasia (PanINs) were treated with low- or high-dose proton pump inhibitors (PPIs) orally for 1 and 4 months. The mechanism for the cholecystokinin receptor 2 (CCK-2R) activation was investigated in vitro. Two resources were employed to analyze the risk of pancreatic cancer in human subjects with PPI use. Serum gastrin levels were increased 8-fold (P < 0.0001) in mice treated with chronic high-dose PPIs, and this change correlated with an increase (P = 0.02) in PanIN grade and the development of microinvasive cancer. The CCK-2R expression was regulated by microRNA-148a in the p48-Cre/LSL-KrasG12D mice pancreas and in human pancreatic cancer cells in vitro. Proton pump inhibitor consumption in human subjects was correlated with pancreatic cancer risk (odds ratio, 1.54). A validation analysis conducted using the large-scale United Kingdom Biobank database confirmed the correlation (odds ratio, 1.9; P = 0.00761) of pancreatic cancer risk with PPI exposure. This investigation revealed in both murine models and human subjects, PPI use is correlated with a risk for development of pancreatic cancer.

New lead compounds identification against KRas mediated cancers through pharmacophore-based virtual screening and in vitro assays

Cancer remains the leading cause of mortality and morbidity in the world, with 19.3 million new diagnoses and 10.1 million deaths in 2020. Cancer is caused due to mutations in proto-oncogenes and tumor-suppressor genes. Genetic analyses found that Ras (Rat sarcoma) is one of the most deregulated oncogenes in human cancers. The Ras oncogene family members including NRas (Neuroblastoma ras viral oncogene homolog), HRas (Harvey rat sarcoma) and KRas are involved in different types of human cancers. The mutant KRas is considered as the most frequent oncogene implicated in the development of lung, pancreatic and colon cancers. However, there is no efficient clinical drug even though it has been identified as an oncogene for 30 years. Therefore there is an emerging need to develop potent, new anticancer drugs. In this study, computer-aided drug designing approaches as well as experimental methods were employed to find new and potential anti-cancer drugs. The pharmacophore model was developed from an already known FDA approved anti-cancer drug Bortezomib using the software MOE. The validated pharmacophore model was then used to screen the in-house and commercially available databases. The pharmacophore-based virtual screening resulted in 26 and 86 hits from in-house and commercial databases respectively. Finally, 6/13 (in-house database) and 24/64 hits (commercial databases) were selected with different scaffolds having good interactions with the significant active residues of KRasG12D protein that were predicted as potent lead compounds. Finally, the results of pharmacophore-based virtual screening were further validated by molecular dynamics simulation analysis. The 6 hits of the in-house database were further evaluated experimentally. The experimental results showed that these compounds have good anti-cancer activity which validate the protocol of our in silico studies. KRasG12D protein is a very important anti-cancer target and potent inhibitors for this target are still not available, so small lead compound inhibitors were identified to inhibit the activity of this protein by blocking the GTP-binding pocket. Communicated by Ramaswamy H. Sarma

Cellular and transcriptional dynamics of human neutrophils at steady state and upon stress.

Traditionally viewed as poorly plastic, neutrophils are now recognized as functionally diverse; however, the extent and determinants of neutrophil heterogeneity in humans remain unclear. We performed a comprehensive immunophenotypic and transcriptome analysis, at a bulk and single-cell level, of neutrophils from healthy donors and patients undergoing stress myelopoiesis upon exposure to growth factors, transplantation of hematopoietic stem cells (HSC-T), development of pancreatic cancer and viral infection. We uncover an extreme diversity of human neutrophils in vivo, reflecting the rates of cell mobilization, differentiation and exposure to environmental signals. Integrated control of developmental and inducible transcriptional programs linked flexible granulopoietic outputs with elicitation of stimulus-specific functional responses. In this context, we detected an acute interferon (IFN) response in the blood of patients receiving HSC-T that was mirrored by marked upregulation of IFN-stimulated genes in neutrophils but not in monocytes. Systematic characterization of human neutrophil plasticity may uncover clinically relevant biomarkers and support the development of diagnostic and therapeutic tools.

LncRNA MALAT1 regulates METTL3-mediated PD-L1 expression and immune infiltrates in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. The main methods of treating pancreatic cancer are surgery and chemotherapy, but the treatment efficacy is low with a poor prognosis. Immunotherapy represented by PD-1/PD-L1 has brought a milestone progress in the treatment of pancreatic cancer. However, the unique tumor microenvironment of pancreatic cancer presents challenges for immunotherapy. In addition, m6A is a common RNA modification and a potential molecular target in tumor therapy. The expression pattern of m6A in pancreatic cancer is still unclear. LncRNAs also play an essential role in pancreatic cancer development and treatment. In this study, we found that some m6A regulators were significantly elevated in pancreatic cancer and associated with the expression of PD-1/PD-L1. Moreover, we observed that METTL3 can increase the expression of PD-L1. Notably, METTL3 positively regulates the expression of lncRNA MALAT1 in pancreatic cancer cells. Strikingly, lncRNA MALAT1 increased the expression of PD-L1 in pancreatic cancer cells. This finding indicated that METTL3 regulated the expression of PD-L1 possibly via targeting lncRNA MALAT1 in pancreatic cancer cells. Lastly, MALAT1 governed the viability of pancreatic cancer cells. Taken together, lncRNA MALAT1 is involved in METTL3-mediated promotion of PD-L1 expression in pancreatic cancer.

Stratification Based on Risk Factors at Diagnosis Could Predict Progression in Patients with Pancreatic Cysts.

Predicting the risk of malignant transformation in pancreatic cyst patients is challenging. We retrospectively investigated the risk factors for malignant transformation in pancreatic cyst patients. Patients with pancreatic cysts diagnosed using imaging tests were followed from November 2008 to December 2021. A significant change was defined as the additional development of high-risk stigmata (HRS), worrisome features (WFs), or pancreatic cancer during monitoring. In total, 479 patients were analyzed, with a median observation period of 50months. Forty-four patients (9.2%) showed significant changes, and eight (1.7%) developed pancreatic cancer. The univariate analysis showed that the cyst diameter at diagnosis (≥ 14mm), main pancreatic duct (MPD) diameter at diagnosis (≥ 3mm), presence of multilocular cysts, and an inconsistent MPD caliber were significant predictive factors for a significant change. One point was assigned for each significant factor. We grouped the patients into three groups: the low-risk group (total score 0), medium-risk group (score 1-2), and high-risk group (score 3-4). The high-risk group had a higher risk of a significant change than the medium- and low-risk groups (age-adjusted HRs for the medium-risk and high-risk groups were 3.0 and 5.2 compared with the low-risk group). Stratification based on risk factors may help predict the development of significant changes in pancreatic cyst patients.

MAIN EPIDEMIOLOGICAL ASPECTS OF PANCREATIC CANCER IN KAZAKHSTAN

According to GLOBOCAN (2020), pancreatic cancer (PC) is in 12th place among oncopathology in terms of incidence - 4.9 cases per 100,000 population. Most cases of pancreatic cancer are registered in China, the USA, Japan, and Germany. In the structure of mortality among oncological diseases, pancreatic cancer occupies 9th place - 4.5 cases per 100 thousand of the population. According to epidemiological studies, by 2040, a 79.9% increase in mortality from pancreatic cancer is predicted. According to statistics, in the United States, there is an increase in the incidence of cancer in the distal pancreas. In addition, early stages of pancreatic cancer were diagnosed more often and less often - the 4th. One of the trends in the epidemiology of pancreatic cancer is an increase in the incidence of this pathology among young people. Factors contributing to the development of pancreatic cancer in people under 50 years of age are genetic mutations, smoking, and obesity. A retrospective statistical analysis of the epidemiological state of pancreatic cancer in Kazakhstan over 3 years was carried out (standardized WHO World indicators per 100,000 population and intensive indicators of morbidity, mortality, distribution by stage, age, and sex), and regional features of pancreatic cancer were studied.

Pancreatic fibrosis by extracellular volume fraction using Contrast-enhanced computed tomography and relationship with pancreatic cancer

PurposeThis study aimed to assess the relationship between pancreatic fibrosis measured by the extracellular volume fraction (ECV) using contrast-enhanced computed tomography (CT) and the histologic pancreatic fibrosis fraction and investigate the relationship between pancreatic fibrosis and pancreatic cancer. MethodThe study included 88 consecutive patients (48 males, 40 females; median age, 69 years; range, 17–89 years); 47 had pancreatic cancer, and 41 had other diseases. Fifty-two cases were evaluated pathologically for pancreatic fibrosis. The histologic pancreatic fibrosis fraction was quantified using image analysis software in nontumorous pancreatic tissue at the resection stump using 2-µm-thick Azan-stained slides. Two board-certified radiologists measured ECV in the pancreatic parenchyma at an estimated transection line. The correlation between histologic pancreatic fibrosis fraction and ECV was investigated, and whether the ECV value could be used as a biomarker for pancreatic cancer was investigated. ResultsThe histologic pancreatic fibrosis fraction was significantly correlated with the ECV (r = 0.64, P < 0.01). Pancreatic fibrosis evaluated by ECV was higher in pancreatic cancer patients than in other patients (P < 0.01). On receiver-operating characteristic curve analysis, the ECV had good diagnostic accuracy for the development of pancreatic cancer (cut-off value 32.8%; sensitivity 61.0%, specificity 85.1%). ECV was identified on multivariate analysis as an independent risk factor for pancreatic cancer (odds ratio 1.16; P < 0.01). ConclusionsExtracellular volume fraction was strongly related to the histologic pancreatic fibrosis fraction, which was independently associated with pancreatic cancer. Thus, extracellular volume fraction is an imaging biomarker that reflects the progression of pancreatic fibrosis and may potentially help predict the development of pancreatic cancer, although further investigation will be needed.

Previous hepatitis B viral infection-an underestimated cause of pancreatic cancer.

BACKGROUNDThe etiology of pancreatic cancer remains unclear. This limits the possibility of prevention and effective treatment. Hepatitis B virus (HBV) is responsible for the development of different types of cancer, but its role in pancreatic cancer is still being discussed.AIMTo assess the prevalence of previous HBV infection and to identify viral biomarkers in patients with pancreatic ductal adenocarcinoma (PDAC) to support the role of the virus in etiology of this cancer.METHODSThe data of 130 hepatitis B surface antigen-negative subjects were available for the final analysis, including 60 patients with PDAC confirmed by cytology or histology and 70 sex- and age-matched controls. All the participants were tested for HBV biomarkers in blood [antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs) and HBV DNA], and for those with PDAC, biomarkers in resected pancreatic tissues were tested (HBV DNA, HBV pregenomic RNA and covalently closed circular DNA). We performed immunohistochemistry staining of pancreatic tissues for hepatitis B virus X antigen and Ki-67 protein. Non-parametric statistics were used for the analysis.RESULTSAnti-HBc was detected in 18/60 (30%) patients with PDAC and in 9/70 (13%) participants in the control group (P = 0.029). Accordingly, the odds of PDAC in anti-HBc-positive subjects were higher compared to those with no previous HBV infection (odds ratio: 2.905, 95% confidence interval: 1.191-7.084, standard error 0.455). HBV DNA was detected in 8 cases of PDAC and in 6 of them in the pancreatic tumor tissue samples only (all patients were anti-HBc positive). Blood HBV DNA was negative in all subjects of the control group with positive results of the serum anti-HBc test. Among 9 patients with PDAC, 5 revealed signs of replicative competence of the virus (covalently closed circular DNA with or without pregenomic RNA) in the pancreatic tumor tissue samples. Hepatitis B virus X antigen expression and active cell proliferation was revealed by immunohistochemistry in 4 patients with PDAC in the pancreatic tumor tissue samples.CONCLUSIONWe found significantly higher risks of PDAC in anti-HBc-positive patients. Detection of viral replication and hepatitis B virus X protein expression in the tumor tissue prove involvement of HBV infection in pancreatic cancer development.

Risk Factors of Pancreatic Cancer in Patients With Type 2 Diabetes Mellitus: The Hong Kong Diabetes Study.

ContextDiabetes mellitus (DM) is associated with the development of pancreatic cancer (PaC), but few large-scale studies have examined its predictive risk factors.ObjectiveThe present study aims to examine the predictors for PaC in patients with type 2 diabetes mellitus (T2DM) in a territory-wide, retrospective cohort study.MethodsThis was a territory-wide, retrospective cohort study of patients with T2DM mellitus older than 40 years with no prior history of PaC. Baseline demographics, use of antidiabetic medications, comorbidities, and biochemical parameters were extracted. Cox regression was used to calculate hazard ratios (HR) with 95% CI. Subgroup analyses based on chronic kidney disease (CKD) stages were performed.ResultsThis study consisted of 273 738 patients (age = 65.4 ± 12.7 years, male = 48.2%, follow-up duration = 3547 ± 1207 days, disease duration = 4.8 ± 2.3 years), of whom 1148 developed PaC. The number of antidiabetic medications prescribed (HR: 1.20; 95% CI, 1.01-1.42; P = .040), diabetic microvascular complications (HR: 1.91; 95% CI, 1.30-2.81; P < .001), chronic kidney disease (HR: 1.81; 95% CI, 1.25-2.64; P = .002), use of acarbose (HR: 2.24; 95% CI, 1.35-3.74; P = .002), and use of glucagon-like peptide-1 receptor agonist (HR: 4.00; 95% CI: 1.28-12.53, P = .017) were associated with PaC development on multivariable Cox regression adjusting for the duration of DM, mean glycated hemoglobin A1c, and history of pancreatic diseases. Stage 3A CKD or below was associated with PaC but not stage 3B or beyond.ConclusionDiabetic microvascular complications, especially stage 1, 2, and 3A CKD, were associated with PaCs.

To Explore the Molecular Mechanism of Acupuncture Alleviating Inflammation and Treating Obesity Based on Text Mining.

Objective To explore the related mechanism of acupuncture affecting obesity by regulating inflammation using bioinformatics methods. Methods The genes related to obesity, inflammation, and acupuncture and inflammation were mined using GenCLiP 3, and the intersecting genes were extracted using Venn diagram. The DAVID database was employed for pathway enrichment analysis and functional annotation of coexpressed genes. Then, the protein-protein interaction (PPI) network was constructed with the STRING database and visualized by the Cytoscape software and screened out important hub genes. Finally, the Boxplot and Survival Analysis of the hub genes in various cancers were performed by GEPIA. Results 755 genes related to obesity and inflammation and 38 genes related to acupuncture and inflammation were identified, and 24 coexpressed genes related to obesity, inflammation, and acupuncture were extracted from the Venn diagram. Eight hub genes including interleukin-6 (IL-6), interleukin-10 (IL-10), Toll-like receptor 4 (TLR4), signal transduction and transcriptional activation factor 3 (STAT3), C-X-C motif chemokine 10 (CXCL10), interleukin-17A (IL-17A), prostaglandin peroxide synthesis-2 (PTGS2), signal transistors, and transcriptional activation factor 6 (STAT6) were identified by gene ontology (GO), Kyoto Encyclopedia of Genes (KEGG), and PPI network analysis. Among them, IL-6 is suggested to play an essential role in the treatment of obesity and inflammation by acupuncture, and IL-6 was significant in both Boxplot and Survival Analysis of pancreatic cancer (PAAD). Therefore, in this study, the core gene, IL-6 was used as the breakthrough point to explore the possible mechanism of acupuncture in treating obesity and pancreatic cancer by regulating IL-6. Conclusion (1) Acupuncture can regulate the expression of IL-6 through the TLR4/nuclear factor-κB (NF-κB) pathway, thereby alleviating inflammation, which can be used as a potential strategy for the treatment of obesity. (2) IL-6/STAT3 is closely related to the occurrence, development, and metastasis of pancreatic cancer. Acupuncture affecting pancreatic cancer through TLR4/NF-κB/IL-6/STAT3 pathway may be a potential method for the treatment of pancreatic cancer.