Gene assessment of pancreatic adenocarcinoma disease via protein-protein interaction (PPI) Network Analysis.

Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, it is reported that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating roles in the activation of MAPK pathways and the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. The findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.

Metabolic diseases, including type 2 diabetes, have long been considered incurable, chronic conditions resulting from a variety of pathological conditions in obese patients. Growing evidence suggests the Wnt/β-catenin pathway is a major pathway in adipose tissue remodelling, pancreatic β-cell regeneration and energy expenditure through regulation of key metabolic target genes in various tissues. CXXC5-type zinc finger protein 5 (CXXC5) is identified negative feedback regulator of the Wnt/β-catenin pathway that functions via Dishevelled (Dvl) binding.

Exocrine pancreatic cancer is an aggressive disease with an exceptionally high mortality rate. Genetic analysis suggests a causative role for environmental factors, but consistent epidemiological support is scarce and no biomarkers for monitoring the effects of chemical pancreatic carcinogens are available. With the objective to identify common traits for chemicals inducing pancreatic tumors we studied the National Toxicology Program (NTP) bioassay database. We found that male rats were affected more often than female rats and identified eight chemicals that induced exocrine pancreatic tumors in males only. For a hypothesis generating process we used a text mining tool to analyse published literature for suggested mode of actions (MOA). The resulting MOA analysis suggested inflammatory responses as common feature. In cell studies we found that all the chemicals increased protein levels of the inflammatory protein autotaxin (ATX) in Panc-1, MIA PaCa-2 or Capan-2 cells. Induction of MMP-9 and increased invasive migration were also frequent effects, consistent with ATX activation. Testosterone has previously been implicated in pancreatic carcinogenesis and we found that it increased ATX levels. Our data show that ATX is a target for chemicals inducing pancreatic tumors in rats. Several lines of evidence implicate ATX and its product lysophosphatidic acid in human pancreatic cancer. Mechanisms of action may include stimulated invasive growth and metastasis. ATX may interact with hormones or onco- or suppressor-genes often deregulated in exocrine pancreatic cancer. Our data suggest that ATX is a target for chemicals promoting pancreatic tumor development.

The impact of postoperative pancreatic fistula (POPF) on survival after resection for pancreatic ductal adenocarcinoma (PDAC) remains unclear.

Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs). Our immunohistochemistry (IHC) studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type); MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type); High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4) expression in cancer cell line was regulated by DNA methylation. We have developed a novel 'methylation-specific electrophoresis (MSE)' method to analyze the DNA methylation status of mucin genes by high sensitivity and resolution. By using the MSE method, we evaluated pancreatic juice samples from 45 patients with various pancreatic lesions. The results were compared with final diagnosis of the pancreatic lesions including IHC of mucin expression in the paired pancreatic tissues. The results indicated that the DNA methylation status of MUC1, MUC2 and MUC4 in pancreatic juice matched with the mucin expression in tissue. Analyses of the DNA methylation status of MUC1, MUC2 and MUC4 were useful for differential diagnosis of human pancreatic neoplasms, with specificity and sensitivity of 87% and 80% for PDAC; 100% and 88% for intestinal-type IPMN; and 88% and 77% for gastric-type IPMN, respectively. In conclusion, MSE analysis of human pancreatic juice may provide useful information for selection of treatment for pancreatic neoplasms.

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.

Several factors could lead to lipid disturbances observed in cystic fibrosis (CF). This study aimed to assess sterol homeostasis in CF and define potential exogenous and endogenous determinants of lipid dysregulation.

This meta-analysis aims to identify the diagnostic accuracy of mutations in the Kirsten Rat Sarcoma (KRAS) oncogene in the diagnosis of pancreatic ductal adenocarcinoma (PDAC). The survival of PDAC remains poor often due to the fact that disease is advanced at diagnosis. We analysed 22 studies, with a total of 2156 patients, to identify if the detection of KRAS mutations from pancreatic exocrine secretions yields sufficient specificity and sensitivity to detect patients with PDAC amongst healthy individuals. The majority of the studies were retrospective, samples were obtained endoscopically or surgically, and included comparator populations of patients with chronic pancreatitis and pre-malignant pancreatic lesions (PanIN) as well as healthy controls. We performed several analyses to identify the diagnostic accuracy for PDAC among these patient populations. Our results highlighted that the diagnostic accuracy of KRAS mutation for PDAC was of variable sensitivity and specificity when compared with PanINs and chronic pancreatitis, but had a higher specificity among healthy individuals. The sensitivity of this test must be improved to prevent missing early PDAC or PanINs. This could be achieved with rigorous prospective cohort studies, in which high-risk patients with normal cross-sectional imaging undergo surveillance following KRAS mutation testing.

Pancreatic cancer (PC) represents an unresolved therapeutic challenge, due to the poor prognosis and the reduced response to currently available treatments. Pancreatic cancer is the most lethal type of digestive cancers, with a median survival of 4-6 months. Only a small proportion of PC patients is curative by surgical resection, whilst standard chemotherapy for patients in advanced disease generates only modest effects with considerable toxic damages. Thus, new therapeutic approaches, specially specific treatments such as immunotherapy, are needed. In this paper we analyze recent preclinical and clinical efforts towards immunotherapy of pancreatic cancer, including passive and active immunotherapy approaches, designed to target pancreatic-cancer-associated antigens and to elicit an antitumor response in vivo.

Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote β cell proliferation have been elusive. We previously reported that the liver is a source for such factors in the liver insulin receptor knockout (LIRKO) mouse, an insulin resistance model that manifests islet hyperplasia. Using proteomics we show that serpinB1, a protease inhibitor, which is abundant in the hepatocyte secretome and sera derived from LIRKO mice, is the liver-derived secretory protein that regulates β cell proliferation in humans, mice, and zebrafish. Small-molecule compounds, that partially mimic serpinB1 effects of inhibiting elastase activity, enhanced proliferation of β cells, and mice lacking serpinB1 exhibit attenuated β cell compensation in response to insulin resistance. Finally, SerpinB1 treatment of islets modulated proteins in growth/survival pathways. Together, these data implicate serpinB1 as an endogenous protein that can potentially be harnessed to enhance functional β cell mass in patients with diabetes.

On 31 December 2019, the WHO China Country Office was informed of cases of pneumonia of unknown etiology detected in Wuhan (Hubei Province of China). In January 2020, a new coronavirus named SARS-CoV2 was isolated and, since that time, SARS-CoV2 related disease (COVID-19) rapidly spread all over the world becoming pandemic in March 2020. The COVID-19 outbreak dramatically affected the public-health and the health-care facilities organization. Bilio-pancreatic endoscopy is considered a high-risk procedure for cross-contamination and, even though it is not directly involved in COVID-19 diagnosis and management, its reorganization is crucial to guarantee high standards of care minimizing the risk of SARS-CoV2 transmission among patients and health-care providers. Bilio-pancreatic endoscopic procedures often require a short physical distance between the endoscopist and the patient for a long period of time, a frequent exchange of devices, the involvement of a large number of personnel, the use of complex endoscopes difficult to reprocess. On this basis, endoscopic units should take precautions with adjusted management of bilio-pancreatic endoscopy. The aim of this article is to discuss the approach to bilio-pancreatic endoscopy in the COVID-19 era with focus on diagnostic algorithms, indications, management of the endoscopic room, proper use of Personal Protective Equipment and correct reprocessing of instrumentation.

Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancer types where the 5-year survival rate shows no improvement. Despite conflicting evidence, the majority of data points to an essential role for autophagy in PDAC growth and survival, in particular constitutively activated autophagy, can provide crucial fuel to PDAC tumor cells in their nutrient-deprived environment. Autophagy, which is required for cell homeostasis, can both suppress and promote tumorigenesis and tumor survival in a context-dependent manner. Protein by protein, the mystery of how PDAC abuses the cell's homeostasis system for its malignant growth has recently begun to be unraveled. In this review, we focus on how autophagy is responsible for growth and development of PDAC tumors and where autophagy and the mechanisms controlling it fit into PDAC metabolism. Understanding the range of pathways controlling autophagy and their interplay in PDAC could open the way for new therapeutic avenues.

Pancreatic β cells are essential in the maintenance of glucose homeostasis during the progression to type 2 Diabetes Mellitus (T2DM), generating compensatory hyperinsulinemia to counteract insulin resistance. It is well known, that throughout the process there is an increased mTORC1 signaling pathway, with an impairment in different quality control systems including ubiquitin-proteasome system and autophagy. In addition, under this situation, pancreatic β cells start to accumulate amylin protein (IAPP) in aggregates, and this accumulation contributes to the failure of autophagy, damaging different organelles such as plasma membrane, endoplasmic reticulum, mitochondria, and others. Here, we report that IAPP can be incorporated to multivesicular bodies (MVB) and secreted into exosomes, a mechanism responsible for the exportation of these toxic aggregates as vehicles of cell to cell communication. On this regard, we have demonstrated that the exosomes bearing toxic hIAPP released from pancreatic β cells are capable to induce hyperactivation of mTORC1 signaling, a failure in the autophagic cellular quality control, and favor pro-fission status of the mitochondrial dynamics in hippocampal cells. In summary, our results show that harmful accumulation of hIAPP in pancreatic β cells may be detoxified by the release of exosomes, which may be captured by endocytosis mechanism damaging neuronal hippocampal cells, which suggest an underlying molecular mechanism to the link between type 2 diabetes and neurodegenerative diseases.

Standard treatments for autoimmune and autoinflammatory disorders rely mainly on immunosuppression. These are predominantly symptomatic remedies that do not affect the root cause of the disease and are associated with multiple side effects. Immunotherapies are being developed during the last decades as more specific and safer alternatives to small molecules with broad immunosuppressive activity, but they still do not distinguish between disease-causing and protective cell targets and thus, they still have considerable risks of increasing susceptibility to infections and/or malignancy. Antigen-specific approaches inducing immune tolerance represent an emerging trend carrying the potential to be curative without inducing broad immunosuppression. These therapies are based on antigenic epitopes derived from the same proteins that are targeted by the autoreactive T and B cells, and which are administered to patients together with precise instructions to induce regulatory responses capable to restore homeostasis. They are not personalized medicines, and they do not need to be. They are precision therapies exquisitely targeting the disease-causing cells that drive pathology in defined patient populations. Immune tolerance approaches are truly transformative options for people suffering from autoimmune diseases.

We previously reported that transient overexpression of reprogramming factors can be used to generate induced pluripotent stem (iPS) cells, induced tissue-specific stem (iTS) cells, and fibroblast-like (iF) cells from pancreatic tissue. iF cells have tumorigenic ability and behave similarly to pancreatic cancer cells. In this study, we analyzed gene expression in iF cells and iTS-P cells (iTS cells from pancreatic tissue) via microarray analysis and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression levels of the Mybl2 and Lyn genes, which are reported to be oncogenes, were significantly higher in iF cells than in iTS-P cells. The expression level of Nestin, which is expressed in not only pancreatic progenitor cells but also pancreatic ductal adenocarcinomas, was also higher in iF cells than in iTS-P cells. Itgb6 and Fgf13, which are involved in the pathogenesis of diseases such as cancer, exhibited higher expression levels in iF cells than in iTS-P cells. Unexpectedly, the expression levels of genes related to epithelial-mesenchymal transition (EMT), except Bmp4, were lower in iF cells than in iTS-P cells. These data suggest that the Mybl2, Lyn, Nestin, Itgb6, and Fgf13 genes could be important biomarkers to distinguish iTS-P cells from iF cells.

Pancreatic ductal adenocarcinoma accounts for the primary type of pancreatic cancer (PC) with a 5-year survival rate of only about 10% in the United States. Early diagnosis will improve chances for curative treatment. To date, a broadly used serum marker for PC diagnosis is carbohydrate antigen 19-9, which is the only approved biomarker currently by the United States Food and Drug Administration. However, it has low specificity; therefore, development of novel biomarkers is urgently needed. Clinical trials are ongoing to evaluate candidate biomarkers for PC diagnosis, and the use of a multi-biomarker panel with current PC diagnostic biomarkers appears promising.

The optimal nutritional therapy in the field of pancreatic surgery is still debated.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a median survival below 6 months and a 5-year survival rate below 1%. Effective therapies for locally advanced or metastatic tumours are missing and curatively resected patients relapse in over 80% of the cases. Although histone deacetylases (HDACs) are involved in the control of proliferation, apoptosis, differentiation, migration and angiogenesis of cancer cells, knowledge about the expression patterns and functions of individual HDAC isoenzymes in pancreatic cancer is sparse. This review summarizes the roles of HDACs as novel therapeutic targets and the molecular mode of action of HDAC-inhibitors (HDACI) in PDACs. Success of HDACI in clinical settings will depend on an increased knowledge of HDAC functions as well as on a better understanding of the mode of action of HDACI. Pre-clinical experimental data that constitute the basis for rational therapeutic strategies to treat PDAC are described here. Translating these rational-based therapies into the clinic will finally increase our chance to establish an effective HDACI-containing combination therapy effective against PDAC.

Treatment of pancreatic metastases (PM) from renal cell carcinoma (RCC) is still an issue between surgeons and oncologists, in the era of target-therapy.