Pancreatic ductal adenocarcinoma has a poor prognosis due to late diagnosis and a lack of effective therapeutic options. Thus, it is important to better understand its molecular mechanisms and to develop more effective treatments for the disease. The ternary complex factor Net, which exerts its strong inhibitory function on transcription of proto-oncogene gene c-fos by forming ternary complexes with a second transcription factor, has been suspected of being involved in pancreatic cancer and other tumors biology. In this study, we found that the majority of pancreatic ductal adenocarcinoma tissues and cell lines had weak or no expression of Net, whereas significantly high level of Net expression occurred in paired adjacent normal tissues we studied. Furthermore, using in vitro and in vivo model systems, we found that overexpression of Net inhibited cell growth and survival and induced cell apoptosis in human pancreatic ductal adenocarcinoma cell PL45; the mechanisms by which Net inhibited the cell cycle

TY - JOUR. T1 - Ex vivo organotypic culture system of precision-cut slices of human pancreatic ductal adenocarcinoma. AU - Misra, Sougat. AU - Moro, Carlos F.. AU - Del Chiaro, Marco. AU - Pouso, Soledad. AU - Sebestyén, A.. AU - Löhr, Matthias. AU - Björnstedt, Mikael. AU - Verbeke, Caroline S.. PY - 2019/12/1. Y1 - 2019/12/1. N2 - Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, which is mainly due to late diagnosis and profound resistance to treatment. The latter is to a large extent attributed to the tumor stroma that is exceedingly prominent in PDAC and engages in complex interactions with the cancer cells. Hence, relevant preclinical models of PDAC should also include the tumor stroma. We herein describe the establishment and functional validation of an ex vivo organotypic culture of human PDAC that is based on precision-cut tissue slices from surgical specimens and reproducibly recapitulates the complex cellular and acellular composition of PDAC, including its ...

In the present study, we found that the centrosomes in nearly all pancreatic ductal carcinomas displayed structural abnormalities, such as an increase in their number and size, and an irregular distribution. Quantitative analysis demonstrated a significant difference in centrosome number between normal and cancer cells. In addition, double-labeled immunofluorescence analysis of MIA PaCa-2 pancreatic cancer cells suggest that these aberrant centrosomes contribute to the assembly of multipolar spindles, which may result in the improper segregation of chromosomes during mitosis. These results are consistent with previous studies describing centrosome abnormalities in human malignant tumors of the breast, prostate, brain, lung, and colon (10 , 11) . To our knowledge, however, this is the first report to demonstrate centrosome abnormalities in pancreatic carcinoma.. The centrosome plays a key role in the organization of cytoplasmic microtubules, in the determination of cell polarity, and in the ...

TY - JOUR. T1 - Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. AU - Qian, Zhi Rong. AU - Rubinson, Douglas A.. AU - Nowak, Jonathan A.. AU - Morales-Oyarvide, Vicente. AU - Dunne, Richard F.. AU - Kozak, Margaret M.. AU - Welch, Marisa W.. AU - Brais, Lauren K.. AU - Da Silva, Annacarolina. AU - Li, Tingting. AU - Li, Wanwan. AU - Masuda, Atsuhiro. AU - Yang, Juhong. AU - Shi, Yan. AU - Gu, Mancang. AU - Masugi, Yohei. AU - Bui, Justin. AU - Zellers, Caitlin L.. AU - Yuan, Chen. AU - Babic, Ana. AU - Khalaf, Natalia. AU - Aguirre, Andrew. AU - Ng, Kimmie. AU - Miksad, Rebecca A.. AU - Bullock, Andrea J.. AU - Chang, Daniel T.. AU - Tseng, Jennifer F.. AU - Clancy, Thomas E.. AU - Linehan, David C.. AU - Findeis-Hosey, Jennifer J.. AU - Doyle, Leona A.. AU - Thorner, Aaron R.. AU - Ducar, Matthew. AU - Wollison, Bruce. AU - Laing, Angelica. AU - Hahn, William C.. AU - Meyerson, Matthew. AU - Fuchs, Charles S.. AU - Ogino, ...

TY - JOUR. T1 - Co-expression of mesothelin and CA125 correlates with unfavorable patient outcome in pancreatic ductal adenocarcinoma. AU - Einama, Takahiro. AU - Kamachi, Hirofumi. AU - Nishihara, Hiroshi. AU - Homma, Shigenori. AU - Kanno, Hiromi. AU - Takahashi, Kenta. AU - Sasaki, Ayami. AU - Tahara, Munenori. AU - Okada, Kuniaki. AU - Muraoka, Shunji. AU - Kamiyama, Toshiya. AU - Matsuno, Yoshihiro. AU - Ozaki, Michitaka. AU - Todo, Satoru. PY - 2011/11. Y1 - 2011/11. N2 - Objectives: Recent studies have shown that the high affinity of mesothelin-CA125 interaction might cause intracavitary tumor metastasis. We examined the clinicopathologic significance and prognostic implication of mesothelin and CA125 expression in pancreatic ductal adenocarcinoma. Methods: Tissue samples from 66 pancreatic ductal adenocarcinomas were immunohistochemically examined. Proportion and intensity of constituent tumor cells with mesothelin and CA125 expression were analyzed and classified as high-level ...

Osteopontin (OPN) is a secreted phospho-protein that confers on cancer cells a migratory phenotype. We have recently shown that nicotine, a risk factor in pancreatic ductal adenocarcinoma (PDA), induces an alpha7-nicotine acetylcholine receptor (α7-nAChR)-mediated increase of OPN in PDA cells. In this study, we tested nicotines effect on the expression of OPN splice variants (OPNa, b, c) in PDA cells. We also analyzed the correlation between patients smoking history with OPN and α7-nAChR levels. RT-PCR and UV-light-illumination of ethidium-bromide staining were used to examine the mRNA expression in tissue and PDA cells treated with or without nicotine (3-300 nM). Localization of total OPN, OPNc and α7-nAChR was analyzed by immunohistochemistry, and their mRNA tissue expression levels were correlated with the patients smoking history. PDA cells expressed varying levels of OPNa, OPNb, and α7-nAChR. Nicotine treatment selectively induced denovo expression of OPNc and increased α7-nAChR expression

Avarol is a sesquiterpenoid hydroquinone with potent cytotoxicity. Although resolving endoplasmic reticulum (ER) stress is essential for intracellular homeostasis, erratic or excessive ER stress can lead to apoptosis. Here, we reported that avarol selectively induces cell death in pancreatic ductal adenocarcinomas (PDAC), which are difficult to treat owing to the availability of few chemotherapeutic agents. Analyses of the molecular mechanisms of avarol-induced apoptosis indicated upregulation of ER stress marker BiP and ER stress-dependent apoptosis inducer CHOP in PDAC cells but not in normal cells, suggesting that avarol selectively induces ER stress responses. We also showed that avarol activated the PERK-eIF2α pathway but did not affect the IRE1 and ATF6 pathways. Moreover, CHOP downregulation was significantly suppressed by avarol-induced apoptosis. Thus, the PERK-eIF2α-CHOP signaling pathway may be a novel molecular mechanism of avarol-induced apoptosis. The present data indicate that avarol

Glycolytic cancer cells produce large quantities of lactate that must be removed to sustain metabolism in the absence of oxidative phosphorylation. The only venting mechanism described to do this at an adequate rate is H+-coupled lactate efflux on monocarboxylate transporters (MCTs). Outward MCT activity is, however, thermodynamically inhibited by extracellular acidity, a hallmark of solid tumours. This inhibition would feedback unfavourably on metabolism and growth, raising the possibility that other venting mechanisms become important in under-perfused tumours. We investigated connexin-assembled gap junctions as an alternative route for discharging lactate from pancreatic ductal adenocarcinoma (PDAC) cells. Diffusive coupling (calcein transmission) in vitro was strong between Colo357 cells, weaker yet hypoxia-inducible between BxPC3 cells, and very low between MiaPaCa2 cells. Coupling correlated with levels of connexin-43 (Cx43), a protein previously linked to late-stage disease. Evoked lactate

In February of this year the U.S. National Cancer Institute published an important overview of the state of the science and medicine of pancreatic cancer. We will comment on aspects of it from time to time in the future, but as it so comprehensive and precise, in a departure from our usual practice, we will show a copy it here (sans bibliography and figures) in our pancreatic cancer blog. The term Pancreatic Ductal Carcinoma is accurate and abbreviated PDAC in the original paper; here in the interests of a potential lay reader we will add in parentheses the term: pancreatic cancer.. Scientific Framework for Pancreatic Ductal Carcinoma Executive Summary Significant scientific progress has been made in the last decade in understanding the biology and natural history of pancreatic ductal adenocarcinoma (PDAC, pancreatic cancer); major clinical advances, however, have not occurred. Although PDAC (pancreatic cancer) shares some of the characteristics of other solid malignancies, such as mutations ...

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude ...

Telomerase activity was measured in surgically resected tissues of 20 human pancreatic ductal carcinomas, 12 adenomas, 5 pancreatitis tissues, 14 normal pancreatic ducts, and 13 normal pancreatic tissues (primarily made up of acinar cells) using a PCR-based telomerase assay. Relative telomerase activity was expressed as the equivalent telomerase intensity of the number of cells of a human pancreatic cancer cell line, MIA PaCa-2, per microgram of protein in the tissue samples. The median value (25th percentile, 75th percentile) of relative telomerase activity in pancreatic carcinomas was 13.2 (3.58, 244), which was significantly higher relative to normal tissues, normal ducts, pancreatitis tissues, and adenomas (P , 0.0001). When the cutoff value of relative telomerase activity was set at 1.00 and 3.00, the positivity rates of telomerase activity in pancreatic ductal carcinomas were 100 and 80%, respectively. Some of the adenoma samples displayed a weak telomerase ladder. However, when ...

TY - JOUR. T1 - Integrated stress response is critical for gemcitabine resistance in pancreatic ductal adenocarcinoma. AU - Palam, L. R.. AU - Gore, J.. AU - Craven, K. E.. AU - Wilson, J. L.. AU - Korc, M.. PY - 2015/10/1. Y1 - 2015/10/1. N2 - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with marked chemoresistance and a 5-year survival rate of 7%. The integrated stress response (ISR) is a cytoprotective pathway initiated in response to exposure to various environmental stimuli. We used pancreatic cancer cells (PCCs) that are highly resistant to gemcitabine (Gem) and an orthotopic mouse model to investigate the role of the ISR in Gem chemoresistance. Gem induced eIF2 phosphorylation and downstream transcription factors ATF4 and CHOP in PCCs, and these effects occurred in an eIF2a-S51 phosphorylation-dependent manner as determined using PANC-1 cells, and wild type and S51 mutant mouse embryo fibroblasts. Blocking the ISR pathway in PCCs with the ISR inhibitor ISRIB or ...

Growing tumors are hypoxic and respond to microenvironmental stress through increased expression of the hypoxia inducible factor-1α (HIF-1α) transcription factor, resulting in an adaptive switch to glycolytic metabolism, angiogenic signaling, survival, and metastasis. HIF-1α expression is associated with tumor resistance to cytotoxic therapy and inferior patient outcomes. Pancreatic cancer is the most hypoxic of all solid tumors and remains refractory to current chemoradiotherapy. We have seen nuclear HIF-1α in 88% of human pancreatic ductal carcinoma but in only 16% of normal pancreas. Stroma adjacent to the pancreatic ductal carcinoma also showed HIF-1α in 43% of cases. We investigated the novel selective HIF-1α inhibitor PX-478 on in vitro and in vivo radiation response of human pancreatic cancer models. Inhibition of HIF-1α by PX-478 increased cell killing by radiation. In mice with Panc-1, CF-PAC-1, or SU.86.86 pancreatic xenografts, concurrent administration of PX-478 potentiated ...

Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here, we determine the contribution of epigenetically silenced genes to the development of PDAC. We analyzed enriched, highly methylated DNAs from PDACs, chronic pancreatitis (CP) and normal tissues using CpG island microarrays and identified WNK2 as a prominent candidate tumor suppressor gene being downregulated early in PDAC development. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanIN), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in tumor than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein

TY - JOUR. T1 - Phosphoinositide 3-kinase signaling pathway in pancreatic ductal adenocarcinoma progression, pathogenesis, and therapeutics. AU - Murthy, Divya. AU - Attri, Kuldeep S.. AU - Singh, Pankaj K.. N1 - Funding Information: This work was supported in part by funding from the National Institutes of Health grant (R01 CA163649, R01 CA210439, and R01 CA216853, NCI) to PS and the Specialized Programs for Research Excellence (SPORE, 2P50 CA127297, NCI) to PS. We would also like to acknowledge the Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727, NCI) for supporting shared resources. Publisher Copyright: © 2018 Murthy, Attri and Singh.. PY - 2018/4/4. Y1 - 2018/4/4. N2 - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by its sudden manifestation, rapid progression, poor prognosis, and limited therapeutic options. Genetic alterations in key signaling pathways found in early pancreatic lesions are pivotal for the development and progression ...

The Wnt/β-catenin pathway has a key role in regulating cellular processes and its aberrant signaling can lead to cancer development. The role of β-catenin expression in pancreatic ductal adenocarcinoma is somewhat controversial. Transcription factor PROX1 is a target of Wnt/β-catenin signaling and it is involved in carcinogenesis through alterations in its expression. The actions can be either oncogenic or tumor suppressive depending on the tissue. The aim of this study was to investigate PROX1 and β-catenin expression in pancreatic ductal adenocarcinoma (PDAC). Expression of PROX1 and β-catenin were evaluated in 156 patients by immunohistochemistry of tissue microarrays. Associations between tumor marker expression and clinicopathological parameters were assessed by the Fischers exact-test or the linear-by-linear association test. The Kaplan-Meier method and log-rank test were used for survival analysis. Uni- and multivariate survival analyses were carried out by the Cox regression proportional

TY - JOUR. T1 - Pancreatic ductal adenocarcinoma radiology reporting template. T2 - Consensus statement of the society of abdominal radiology and the american pancreatic association. AU - Al-Hawary, Mahmoud M.. AU - Francis, Isaac R.. AU - Chari, Suresh T. AU - Fishman, Elliot K.. AU - Hough, David M.. AU - Lu, David S.. AU - Macari, Michael. AU - Megibow, Alec J.. AU - Miller, Frank H.. AU - Mortele, Koenraad J.. AU - Merchant, Nipun B.. AU - Minter, Rebecca M.. AU - Tamm, Eric P.. AU - Sahani, Dushyant V.. AU - Simeone, Diane M.. PY - 2014/1. Y1 - 2014/1. N2 - Pancreatic ductal adenocarcinoma is an aggressive malignancy with a high mortality rate. Proper determination of the extent of disease on imaging studies at the time of staging is one of the most important steps in optimal patient management. Given the variability in expertise and definition of disease extent among different practitioners as well as frequent lack of complete reporting of pertinent imaging findings at radiologic ...

Pancreatic cancer is among the most lethal malignancies worldwide. This study aimed to identify a novel prognostic biomarker, facilitating treatment selection, using mass spectrometry (MS)-based proteomic analysis with formalin-fixed paraffin-embedded (FFPE) tissue. The two groups with poor prognosis (n = 4) and with better prognosis (n = 4) had been carefully chosen among 96 resected cases of pancreatic cancer during 1998 to 2007 in Tohoku University Hospital. Although those 2 groups had adjusted background (UICC-Stage IIB, Grade2, R0, gemcitabine adjuvant), there was a significant difference in postoperative mean survival time (poor 21.0 months, better 58.1 months, P = 0.0067). Cancerous epithelial cells collected from FFPE tissue sections by laser micro-dissection (LMD) were processed for liquid chromatography-tandem mass spectrometry (LC-MS/MS). In total, 1099 unique proteins were identified and 6 proteins showed different expressions in the 2 groups by semi-quantitative comparison. Among these 6

A pancreatic adenocarcinoma cell line (Paca44) was treated with trichostatin-A (TSA), a potent inhibitor of histone deacetylases, in order to evaluate the effect of this drug on protein expression. Master maps of control and treated Paca44 cells were generated by analysis with the PDQuest software. The comparison between such maps showed up- and downregulation of 51 polypeptide chains, out of a total of 700 spots detected by a medium-sensitivity stain, micellar Coomassie Brilliant Blue. Fingerprinting by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)-mass spectrometry analysis enabled the identification of 22 of these spots. Among these proteins, of particular interest are the two downregulated proteins nucleophosmin and translationally controlled tumor protein, as well as the upregulated proteins programmed cell death protein 5 (also designated as TFAR19) and stathmin (oncoprotein 18). The modulation of these four proteins is consistent with our observation that TSA is ...

BACKGROUND: Characterization of molecular mechanisms underpinning development of pancreatic ductal adenocarcinoma (PDAC) may lead to the identification of novel therapeutic targets and biomarkers. SgK223, also known as Pragmin, is a pseudokinase and scaffolding protein closely related to SgK269/PEAK1. Both proteins are implicated in oncogenic tyrosine kinase signaling, but their mechanisms and function remain poorly characterized. METHODS: Expression of SgK223 in PDAC and PDAC cell lines was characterized using gene expression microarrays, mass spectrometry (MS)-based phosphoproteomics and Western blotting. SgK223 was overexpressed in human pancreatic ductal epithelial (HPDE) cells via retroviral transduction, and knocked down in PDAC cells using siRNA. Cell proliferation was determined using a colorimetric cell viability assay, and cell migration and invasion using transwells. Expression of markers of epithelial-mesenchyme transition (EMT) was assayed by quantitative PCR. SgK223 and Stat3 signaling was

Development of systems that reconstitute hallmark features of human pancreatic intraepithelial neoplasia (PanINs), the precursor to pancreatic ductal adenocarcinoma, could generate new strategies for early diagnosis and intervention. However, human cell-based PanIN models with defined mutations are unavailable. Here, we report that genetic modification of primary human pancreatic cells leads to development of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring oncogenic KRAS and induced mutations in CDKN2A, SMAD4 and TP53 expand in vitro as epithelial spheres. After pancreatic transplantation, mutant clones form lesions histologically similar to native PanINs, including prominent stromal responses. Gene expression profiling reveals molecular similarities of mutant clones with native PanINs, and identifies potential PanIN biomarker candidates including Neuromedin U, a circulating peptide hormone. Prospective reconstitution of human PanIN development from primary cells

Pancreatic ductal adenocarcinoma (PDAC) remains amongst the most lethal human cancers. PDAC is characterized by the tumor mass containing a paucity of malignant cells in association with a large desmoplastic reaction comprised of a variety of stromal components. Sporadic PDAC oncogenesis occurs as a result of the sequential acquisition of genetic aberrations occurring in core genetic pathways. Unfortunately, the average PDAC contains a large number of genetic aberrations that are not uniform between individual cancers. The interplay between the complex genetics and stromal component may represent a significant barrier to the development of effective therapy for this disease and ultimately be an important factor in PDAC lethality. The Wnt pathway has been identified as a one of the common pathways undergoing genetic alterations in PDAC. Wnt is a complex signal transduction pathway utilizing both a b-catenin dependent (canonical) and b-catenin independent (noncanonical) signals to affect a wide array of

CINTIA ELISABETH GOMEZ LIMIA. Modulation of survival, cell cycle, resistance signaling pathways and metastatic potential by ethoxzolamide in human pancreatic ductal adenocarcinoma cell line (PANC-1). 21 mar. 2013. Masters Dissertation - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging ...

Background Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer worldwide, as a result of a late diagnosis and limited therapeutic options. Tumour microenvironment (or stroma) plays a key role in cancer onset and progression and constitutes an intrinsic histological hallmark of PDAC. Thus we hypothesised that relevant prognostic biomarkers and therapeutic targets can be identified in the stroma. Methods Laser microdissection of the stroma from freshly frozen PDAC was combined to gene expression profiling. Protein expression of candidate biomarkers was evaluated by immunohistochemistry on tissue microarrays (n = 80 tumours) and by ELISA in plasma samples (n = 51 patients). Results A signature made of 1256 genes that significantly discriminate the stroma from the non-tumour fibrous tissue was identified. Upregulated genes were associated with inflammation and metastasis processes and linked to NF-Kappa B and TGF beta pathways. TMA analysis validated an increased expression of SFN, ADAMTS12 and CXCL3

The best treatment strategy for patients with locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC) remains the subject of considerable debate. This report presents a case of a 58-year-old woman with locally advanced unresectable PDAC who was treated with sequential FOLFIRINOX for 8 cycles followed by chemoradiation, and continues to show durable disease control 18 months later. The respective roles of systemic therapy and chemoradiation for locally advanced PDAC are discussed, including optimal sequencing of these modalities, recent improvements in chemotherapy, and the question of whether radiotherapy improves survival outcomes in this disease context. ...

Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear. Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival. Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019. Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine. Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence. Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9

To define the genetic requirements for pancreatic ductal adenocarcinoma (PDA), we have targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas, revealing the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disea …

The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDACs resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC ...

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumours with dismal prognosis. Although curative resection with adjuvant chemoradiotherapy is the most effective treatment, the

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with an overall five-year survival rate of 8%. Due to subtle texture changes of PDAC, pancreatic dual-phase imaging is...

TY - JOUR. T1 - The personalized medicine for pancreatic ductal adenocarcinoma patients: The oncologist perspective. AU - Peretti, U. AU - Zanon, Silvia. AU - Reni, M. PY - 2017. Y1 - 2017. N2 - No abstract available. AB - No abstract available. U2 - 10.4103/eus.eus_62_17. DO - 10.4103/eus.eus_62_17. M3 - Article. VL - 6. SP - S66-S68. JO - Endoscopic Ultrasound. JF - Endoscopic Ultrasound. SN - 2303-9027. IS - Suppl.3. ER - ...

Cancer has historically been considered as a genetic disease. Much effort have been dedicated to search for the one mutation causing normal cells to become cancer cells. But there is one property of cancer cells that is common for all cancers and that is the shift from oxidative phosphorylation in the mitochondria to aerobic glycolysis in the cytosol. The phenomena is called the Warburg effect, and it makes it possible for cells to aerobically, in a high rate, metabolize glucose to lactate. As a side effect the levels of reactive oxygen species (ROS) in the cell increases, which alters the normal homeostatic levels. In cancer cells elevated levels of ROS can also be caused by reduced activity of antioxidants, imbalanced levels of intracellular calcium, increased activity of certain receptors, higher levels of growth factors and increased intracellular production of ROS by NADPH oxidases (NOX).. PhD-project, Heléne Lindholm: NOX, ROS and metabolism in Pancreatic Ductal Adenocarcinoma. ...

Background Pancreatic ductal adenocarcinoma frequently recurs despite curative surgical resection. This study aims to investigate the patterns of recu..

Patterns and Determinants of Recurrence for Pancreatic Ductal Adenocarcinoma after Resection, Sia Kim, Malinda Itchins, Jennifer Arena, Chris Nahm, Nick

Enhancement parameters of contrast-enhanced computed tomography for pancreatic ductal adenocarcinoma: Correlation with pathologic grading

Chronic pancreatitis increases by 16 fold the risk of developing pancreatic ductal adenocarcinoma (PDAC), one of the deadliest human cancers. Activating Kras mutations have been detected in 30% of early pancreatic intraepithelial neoplasias (PanINs), increasing to 100% in advanced pancreatic ductal adenocarcinoma (PDAC).. We hypothesize that inflammatory cells recruited to the pancreas in response to chronic injury can interact with epithelial cells harboring activated KrasG12D and affect the progression of PanIN lesions. To test this hypothesis, we have used the inducible transgenic Mist1:CreERT2; LSL-KrasG12D (KCiMist1) adult mice in which the LSL KrasG12D allele is activated specifically in the acinar compartment. This model leads to rapid formation of PanINs with a classic ductal phenotype and the progression of lesions is further accelerated with the induction of chronic pancreatitis (CP) generated by recurrent injections of cerulein.. We have found that TH17 cells, a subtype of CD4+ ...

TY - JOUR. T1 - Phase 2 study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer. AU - Herman, Joseph M.. AU - Fan, Katherine Y.. AU - Wild, Aaron T.. AU - Hacker-Prietz, Amy. AU - Wood, Laura D.. AU - Blackford, Amanda L.. AU - Ellsworth, Susannah. AU - Zheng, Lei. AU - Le, Dung T.. AU - De Jesus-Acosta, Ana. AU - Hidalgo, Manuel. AU - Donehower, Ross C.. AU - Schulick, Richard D.. AU - Edil, Barish H.. AU - Choti, Michael A.. AU - Hruban, Ralph H.. AU - Pawlik, Timothy M.. AU - Cameron, John L.. AU - Laheru, Daniel A.. AU - Wolfgang, Christopher L.. PY - 2013/7/15. Y1 - 2013/7/15. N2 - Purpose: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine- erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of ...

Pancreatic cancer is lethal, as it is often detected late. Thus, novel biomarkers of precursor lesions are needed to devise timely therapies. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) are major precursors of pancreatic cancer. In normal gastric mucosa, gastric gland mucin-specific O-glycans are unique in having α1,4-linked N-acetylglucosamine (αGlcNAc) residues attached to MUC6. Recently we reported that αGlcNAc functions as a tumor suppressor for differentiated-type gastric adenocarcinoma (Karasawa et al., J Clin Invest 122, 923, 2012). MUC6 is also expressed in pancreatic neoplasms, including PanIN and IPMN, but the role of αGlcNAc expression in pancreatic neoplasms remains unknown. Here, we analyze expression patterns of αGlcNAc, MUC6 and MUC5AC in pancreatic neoplasms and compare them with progression from PanIN to invasive ductal adenocarcinoma (IDAC) (the PanIN-IDAC sequence; 20 cases) and from IPMN to IPMN with associated invasive

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N6-methyladenosine (m6A) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear.We first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene PIK3CB underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth.We identified a missense variant rs142933486 in PIK3CB that is significantly associated with the overall survival of PDAC by reducing the PIK3CB m6A level, which facilitated its mRNA and protein expression levels mediated by ...

Introduction IPMN is characterized by a predominantly noninvasive growth pattern with mucin production and cystic duct dilatation. The distinction between IPMN and pancreatic intraepithelial neoplasia (PanIN) ,which is the common precursor of invasive carcinomas

There is a lack of well-established clinical tools for predicting dendritic cell (DC) vaccination response of pancreatic ductal adenocarcinoma (PDAC). DC vaccine treatment efficiency was demonstrated using histological analysis in pre-clinical studies; however, its usage was limited due to invasiveness. In this study, we aimed to investigate the potential of MRI texture features for detection of early immunotherapeutic response as well as overall survival (OS) of PDAC subjects following dendritic cell (DC) vaccine treatment in LSL-KrasG12D;LSL-Trp53R172H;Pdx-1-Cre (KPC) transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC). KPC mice were treated with DC vaccines, and tumor growth was dynamically monitored. A total of a hundred and fifty-two image features of T2-weighted MRI images were analyzed using a kernel-based support vector machine model to detect treatment effects following the first and third weeks of the treatment. Moreover, univariate analysis was performed to describe the

There is a lack of well-established clinical tools for predicting dendritic cell (DC) vaccination response of pancreatic ductal adenocarcinoma (PDAC). DC vaccine treatment efficiency was demonstrated using histological analysis in pre-clinical studies; however, its usage was limited due to invasiveness. In this study, we aimed to investigate the potential of MRI texture features for detection of early immunotherapeutic response as well as overall survival (OS) of PDAC subjects following dendritic cell (DC) vaccine treatment in LSL-KrasG12D;LSL-Trp53R172H;Pdx-1-Cre (KPC) transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC). KPC mice were treated with DC vaccines, and tumor growth was dynamically monitored. A total of a hundred and fifty-two image features of T2-weighted MRI images were analyzed using a kernel-based support vector machine model to detect treatment effects following the first and third weeks of the treatment. Moreover, univariate analysis was performed to describe the

We immunohistochemically examined material from 36 pancreata (adenocarcinomas, 30 lesions; pancreatic intraepithelial neoplasia [PanIN], 65; normal pancreatic ducts, 30) for cyclooxygenase 2 (COX-2) with an automated platform. We analyzed 7 to 10 discrete foci and generated an average percentage of …

There will be two phases to this study. The lead-in phase will evaluate the safety, pharmacokinetics, and define the maximum tolerated dose (MTD) of momelotinib (MMB) combined with nab-paclitaxel and gemcitabine (nab-P + G) in adults with previously untreated metastatic pancreatic ductal adenocarcinoma. The randomized treatment phase will evaluate the efficacy, safety, and tolerability of nab-P + G with either MMB administered at the MTD or placebo in adults with previously untreated metastatic pancreatic ductal adenocarcinoma. Participants will continue study treatment until disease progression, unacceptable toxicity, consent withdrawal, or participants refusal of treatment. Following treatment, participants will be followed for safety for 30 days and for survival approximately every 3 months for up to 3 years ...

BACKGROUND & AIMS: Small nucleolar noncoding RNAs (snoRNAs) regulate function of ribosomes, and specific snoRNAs are dysregulated in some cancer cells. We investigated dysregulation of snoRNAs in pancreatic ductal adenocarcinoma (PDAC) cells. METHODS: We investigated snoRNA expression in PDAC cell lines by complementary DNA microarray and quantitative reverse transcription polymerase chain reaction. In PDAC (n = 133), intraductal papillary mucinous neoplasm (n = 16), mucinous cystic neoplasm-associated PDAC (n = 1), and non-tumor pancreas (n = 8) and liver (n = 3) tissues from subjects who underwent surgical resection, levels of snoRNA were measured by quantitative reverse transcription polymerase chain reaction and compared with clinicopathologic parameters and survival times determined by Kaplan-Meier analysis ...

BACKGROUND: The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results. METHODS: In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation. RESULTS: The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8

Depending on the cellular context, transforming growth factor β (TGFβ) has been observed to exert protumorigenic functions, such as inducing an epithelial-mesenchymal transition (EMT), or inhibit tumorigenesis by activating apoptosis. The proapoptotic functions of TGFβ have been linked with the transcription factor SMAD4, which acts downstream of TGFβ and is frequently deleted in pancreatic ductal carcinoma (PDAC). To elucidate the mechanism by which TGFβ promotes apoptosis, David and colleagues used a Kras-mutant/Smad4-deleted PDAC murine model and found that reintroduction of SMAD4 sensitized cells to TGFβ treatment and promoted changes in cell morphology and loss of E-cadherin consistent with EMT. Moreover, SNAIL was shown to be upregulated following TGFβ treatment, and genetic depletion of SNAIL inhibited TGFβ-induced EMT, apoptosis, and accelerated pancreatic carcinogenesis in SMAD4-wild-type cells, raising the unexpected possibility that EMT precedes apoptosis and is required for ...

Intraductal papillary mucinous neoplasm (IPMN) is a type of tumor that can occur within the cells of the pancreatic duct. IPMN tumors produce mucus, and this mucus can form pancreatic cysts. Although intraductal papillary mucinous neoplasms are benign tumors, they can progress to pancreatic cancer. As such IPMN is viewed as a precancerous condition. Once an intraductal papillary mucinous neoplasm has been found, the management options include close monitoring and pre-emptive surgery.[medical citation needed] Pathologists classify intraductal papillary mucinous neoplasms (IPMNs) into two broad groups - those that are associated with an invasive cancer and those that are not associated with an invasive cancer. This separation has critical prognostic significance. Patients with a surgically resected intraductal papillary mucinous neoplasm without an associated invasive cancer have an excellent prognosis (>95% will be cured), while patients with a surgically resected intraductal papillary mucinous ...

TY - JOUR. T1 - Invasive carcinoma derived from intestinal-type intraductal papillary mucinous neoplasm is associated with minimal invasion, colloid carcinoma, and less invasive behavior, leading to a better prognosis. AU - Nakata, Kohei. AU - Ohuchida, Kenoki. AU - Aishima, Shinichi. AU - Sadakari, Yoshihiko. AU - Kayashima, Tadashi. AU - Miyasaka, Yoshihiro. AU - Nagai, Eishi. AU - Mizumoto, Kazuhiro. AU - Tanaka, Masao. AU - Tsuneyoshi, Masazumi. AU - Oda, Yoshinao. PY - 2011/5/1. Y1 - 2011/5/1. N2 - Objectives: Although intestinal-type intraductal papillary mucinous carcinoma (IPMC) is reported to have a better prognosis, few studies have addressed its invasive pattern. The meaning of minimal invasion (MI) in IPMC also remains unclear. We investigated the prognosis of intraductal papillary mucinous neoplasm (IPMN) focusing on MI and subtypes. Methods: We evaluated 71 patients with IPMC among a total of 179 patients with resected IPMN. Results: Although 2 of 10 MI-IPMC patients had lymph ...

TY - JOUR. T1 - Is it necessary to follow patients after resection of a benign pancreatic intraductal papillary mucinous neoplasm?. AU - He, Jin. AU - Cameron, John L.. AU - Ahuja, Nita. AU - Makary, Martin A.. AU - Hirose, Kenzo. AU - Choti, Michael A.. AU - Schulick, Richard D.. AU - Hruban, Ralph H.. AU - Pawlik, Timothy M.. AU - Wolfgang, Christopher L.. PY - 2013/4. Y1 - 2013/4. N2 - Background: Little is known about the risk of subsequently developing a new or progressive intraductal papillary mucinous neoplasm (IPMN) after partial pancreatic resection of a noninvasive IPMN. Study Design: One hundred thirty patients with more than 1 year of follow-up after resection were included in this analysis. Results: At a median follow-up of 38 months, 22 (17%) developed imaging evidence of a new or progressive IPMN. Eleven (8%) underwent completion resection. Three of the 11 patients had invasive adenocarcinoma. Two other patients developed metastatic pancreatic adenocarcinoma and did not undergo ...

TY - JOUR. T1 - Circulating Leptin and Branched Chain Amino Acids-Correlation with Intraductal Papillary Mucinous Neoplasm Dysplastic Grade. AU - Yip-Schneider, Michele T.. AU - Simpson, Rachel. AU - Carr, Rosalie A.. AU - Wu, Huangbing. AU - Fan, Hao. AU - Liu, Ziyue. AU - Korc, Murray. AU - Zhang, Jianjun. AU - Schmidt, C. Max. PY - 2019/5/15. Y1 - 2019/5/15. N2 - Background: The most common type of mucinous pancreatic cyst that may progress to pancreatic cancer is intraductal papillary mucinous neoplasm (IPMN). Low-risk IPMN with low-/moderate-grade dysplasia may be safely watched, whereas high-risk IPMN with high-grade dysplasia or invasive components should undergo resection. However, there is currently no reliable means of making this distinction. We hypothesize that blood concentrations of insulin resistance biomarkers may aid in the differentiation of low- and high-risk IPMN. Methods: Plasma/serum was collected from consented patients undergoing pancreatic resection. IPMN diagnosis and ...

Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity.: Intraductal papillary mucinous neoplasms represe

Expression of MUC4 Mucin Is Observed Mainly in the Intestinal Type of Intraductal Papillary Mucinous Neoplasm of the PancreasExpression of MUC4 Mucin Is Observed Mainly in the Intestinal Type of Intraductal Papillary Mucinous Neoplasm of the Pancreas ...

Answer: Intraductal Papillary Mucinous Neoplasm. Histology: This papillary mucin-producing neoplasm involved a branch duct off of the main pancreatic duct. The main pancreatic duct was not involved. Ovarian stroma was not present.. Discussion: Intraductal papillary mucinous neoplasms (IPMNs) are characterized by involvement by one of the larger pancreatic ducts and by the presence of a papillary mucin-producing epithelium without associated ovarian-type stroma. Intraductal papillary mucinous neoplasms can be subcategorized into those which involve the main pancreatic duct and those which involve a branch of the main pancreatic duct. In this case, this intraductal papillary mucinous neoplasm did not involve the main pancreatic duct, but rather involved a branch duct. It is therefore a branch duct IPMN. The most important prognosticator for patients with intraductal papillary mucinous neoplasms is the presence or absence of an associated invasive carcinoma. In addition, it has been suggested that ...

We have previously shown that WW domain-containing oxidoreductase (WWOX) has tumour-suppressing effects and that its expression is frequently reduced in pancreatic carcinoma. In this study, we examined WWOX expression in intraductal papillary mucinous neoplasm of the pancreas (IPMN) to assess the function of WWOX in pancreatic duct tumourigenesis using immunohistochemistry and methylation-specific polymerase chain reaction analysis. Among 41 IPMNs including intraductal papillary mucinous adenomas (IPMAs) and intraductal papillary mucinous carcinomas (IPMCs), loss or reduced WWOX immunoreactivity was detected in 3 (15%) of 20 IPMAs and 17 (81%) of 21 IPMCs. In addition, hypermethylation of the WWOX regulatory site was detected in 1 (33%) of 3 WWOX(−) IPMAs and 9 (53%) of 17 WWOX(−) IPMCs, suggesting that hypermethylation may possibly be important in the suppression of WWOX expression. Reduction of WWOX expression was significantly correlated with a higher Ki-67 labelling index but was not correlated

Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T, Goggins M, Kato Y, Kloppel G, Longnecker DS, Luttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa S. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2004 Aug;28(8):977-87 ...

ASA 2018 Abstracts: Does Surgical Margin Impact Recurrence in Non-Invasive Intraductal Papillary Mucinous Neoplasms? A Multi-Institutional Study

article{41680afa-1eab-45c3-aa76-62b426b1b7aa, author = {Ansari, Daniel and Aronsson, Linus and Andersson, Roland}, issn = {1479-6694}, keyword = {biomarkers,gastrointestinal,molecular oncology,oncogenes,pancreatic biliary,surgery}, language = {eng}, month = {08}, number = {20}, pages = {1751--1753}, publisher = {Future Medicine Ltd.}, series = {Future Oncology}, title = {Biomarkers, imaging and multifocality in intraductal papillary mucinous neoplasms : Relevant for decision making?}, url = {http://dx.doi.org/10.2217/fon-2017-0244}, volume = {13}, year = {2017 ...

Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which plays a pivotal role in the progression of pancreatic ductal adenocarcinoma (PDAC). Therefore, we investigated the prognostic significance of GFPT1 expression in patients with resectable PDAC. We analyzed public datasets to compare GFPT1 expression in tumor tissues and normal/adjacent pancreatic tissues. We measured the relative GFPT1 expression of 134 resected PDAC specimens in our institution, using real-time polymerase chain reaction (PCR). Survival was compared between high and low GFPT1 expression groups using Kaplan-Meier curves and log-rank tests. Multivariate analyses were estimated using Cox regression and logistic regression models. GFPT1 is generally upregulated in PDAC tissues, according to the analysis of public datasets. The data from our institution shows that high GFPT1 expression was correlated with a high rate of lymph node (LN) metastasis (p = 0

Reliable methods are needed to identify patients with early-stage cancer or high-grade precancerous lesions in the pancreas. Analysis of pancreatic juice to detect somatic mutations could represent one such approach. Here we investigated the concordance between mutations found in the primary tumor and pancreatic juice from the same patient. Amplicon-based targeted deep sequencing was performed on samples from 21 patients with pancreatic ductal adenocarcinoma (PDAC) who had undergone Whipples operation. Mutation profiles were determined in formalin-fixed sections of the primary tumor and in pancreatic juice sampled from the main pancreatic duct during surgery. Using a cut-off of 3% for variant allele frequency, KRAS mutations were detected in 20/21 primary tumors (95%) and in 15/21 (71%) juice samples. When also considering low-frequency variants, KRAS mutations were found in 20/21 juice samples. Most juice samples exhibited multiple KRAS variants not seen in the primary tumor, and only in 11 cases (52%

BACKGROUND: Neoadjuvant chemoradiation before surgery is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC). However, analysis of prognostic factors is limited for patients with PDAC treated with neoadjuvant chemoradiation and pancreaticoduodenectomy (PD). METHODS: The study population was comprised of 240 consecutive patients with PDAC who received neoadjuvant chemoradiation and PD and was compared with 60 patients who had no neoadjuvant therapy between 1999 and 2007. Clinicopathologic features were correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: Among the 240 treated patients, the 1-year and 3- year DFS rates were 52% and 32%, with a median DFS of 15.1 months. The 1-year and 3-year OS rates were 95% and 47%, with a median OS of 33.5 months. By univariate analysis, DFS was associated with age, post-therapy tumor stage (ypT), lymph node status (ypN), number of positive lymph nodes, and American Joint Committee on Cancer (AJCC) stage, ...

TY - JOUR. T1 - Laparoscopic Pancreaticoduodenectomy. Is It an Effective Procedure for Pancreatic Ductal Adenocarcinoma?. AU - Tee, May C.. AU - Kendrick, Michael L.. AU - Farnell, Michael B.. PY - 2015/9/1. Y1 - 2015/9/1. KW - Laparoscopic pancreaticoduodenectomy/Whipple procedure. KW - Oncologic outcomes. KW - Technical safety. UR - http://www.scopus.com/inward/record.url?scp=84983127113&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=84983127113&partnerID=8YFLogxK. U2 - 10.1016/j.yasu.2015.03.003. DO - 10.1016/j.yasu.2015.03.003. M3 - Review article. C2 - 26299496. AN - SCOPUS:84983127113. VL - 49. SP - 143. EP - 156. JO - Advances in Surgery. JF - Advances in Surgery. SN - 0065-3411. IS - 1. ER - ...

Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals ...

Intraductal tubular adenoma of the pancreas, pyloric gland type (ITA), is an infrequent intraductal benign lesion located in the main duct and large branch duct of the pancreas. The purpose of this report is to introduce seven new cases and to compare their clinicopathologic features and KRAS mutations to gastric-type intraductal papillary mucinous neoplasms (IPMNs) and intraductal tubulopapillary neoplasms (ITPNs). Clinical findings, morphologic features, immunophenotypes and KRAS alterations were investigated in 7 patients with intraductal tubular adenomas, 16 patients with gastric-type intraductal papillary mucinous neoplasms and 6 patients with intraductal tubulopapillary neoplasms. There were more female patients in the ITA and gastric-type IPMN groups, whereas the opposite pattern was observed in the ITPN group. ITAs and gastric-type IPMNs were lined by columnar cells, similar to pyloric glands, with large extracellular deposits of mucin. ITPNs were polypoid and papillary mass located in the

Autori: Lefter LP, Sunamura M, Furukawa T, Yastsuoka T, Abe H, Inoue H, Abe T, Egawa S, Miura K, Morita R, Horii A, Matsuno S.. Editorial: Asian J Surg. 2004 Apr;27(2):85-92., 2004.. Rezumat:. BACKGROUND: In a previous work, we demonstrated that loss of heterozygosity of 18q is a frequent event significantly associated with poor prognosis in pancreatic cancer. We hypothesized that restoration of heterozygosity of chromosome 18 in pancreatic cancer cells would reduce their tumorigenicity. This study was intended to provide functional evidence for the existence of new tumour suppressor gene(s) located on chromosome 18. METHOD: Restoration of heterozygosity was achieved by introducing a normal copy of chromosome 18 into pancreatic ductal carcinoma using a microcell-mediated chromosome transfer technique. The tumorigenicity and metastatic ability of both the parental cells and resulting hybrids were assessed in vitro and in vivo. RESULTS: In vitro growth of hybrid clones was significantly delayed ...

An ASCO clinical practice guideline update, reported by Khorana et al in the Journal of Clinical Oncology, includes the recommendation of gemcitabine-capecitabine doublet therapy as an adjuvant therapy option in potentially curable pancreatic cancer. The updated recommendation (4.1) modifies the corresponding recommendation in the ASCO guideline published in May 2016. The remaining recommendations from the original 2016 ASCO guideline are unchanged.. New Evidence. The ASCO guideline expert panel based the update on findings in the recently reported phase III ESPAC-4 study, in which 730 evaluable patients with resected pancreatic ductal adenocarcinoma were randomized to receive gemcitabine plus capecitabine or gemcitabine alone. Median overall survival was 28.0 months in the doublet group vs 25.5 months in the gemcitabine-alone group (hazard ratio = 0.82, P = .032). Grade 3 and 4 adverse events were similar in both groups, although the doublet group had higher rates of hand-foot syndrome and ...

1240 The epidermal growth factor receptor (EGFR) is overexpressed in up to 60% of pancreatic cancer specimens. Recently, erlotinib (a small-molecule tyrosine kinase inhibitor, TKI) was approved for pancreatic cancer treatment. There is an association between TKI response in non-small cell lung cancer (NSCLC) and specific activating mutations in the EGFR tyrosine kinase (TK) domain. The applicability of this paradigm in pancreatic cancer was analyzed by evaluating the presence of activating EGFR TK mutations and EGFR pathway activation in a large cohort of pancreatic adenocarcinoma patients. Pancreatic adenocarcinoma is characterized by an exuberant desmoplastic reaction, masking precise analysis of tumor cells. State-of-the-art laser capture microdissection (LCM) allowed us to selectively isolate pancreatic ductal adenocarcinoma cells from their surrounding stromal elements. DNA, protein, and mRNA were extracted from 30 human frozen pancreatic cancer specimens following LCM of tissue sections ...

TY - JOUR. T1 - Culture and immortalization of pancreatic ductal epithelial cells.. AU - Lawson, Terence. AU - Ouellette, Michel M. AU - Kolar, Carol. AU - Hollingsworth, Michael A. PY - 2005. Y1 - 2005. N2 - Some populations of the epithelial cells from the duct and ductular network of the mammalian pancreas have been isolated and maintained in vitro for up to 3 mo. These cells express many of the surface factors that are unique to them in vivo. They also retain significant drug- and carcinogen-metabolizing capacity in vitro. In this chapter we review the progression of the methods for the isolation, culture and maintenance in vitro for these cells from the earliest when only duct/ductular fragments were obtainable to the current ones which provide epithelial cells. The critical steps in the isolation process are identified and strategies are provided to facilitate these steps. These include the selection of tissue digestive enzymes, the importance of extensive mincing before culture and the ...

The pseudokinase SgK223 promotes invasion of pancreatic ductal epithelial cells through JAK1-Stat3 signaling. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.

Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering « druggable » molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL17 functions during this transition are currently unclear. In this study, we demonstrate that IL17 induces the expression of REG3β, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia ...

Like weeds sprouting from cracks in the pavement, cancer often forms in sites of tissue damage. That damage could be an infection, a physical wound, or some type of inflammation. Common examples include stomach cancer caused by H. pylori infection, Barretts esophagus caused by acid reflux, and even smoking-induced lung cancer.. Exactly how tissue damage colludes with genetic changes to promote cancer isnt fully understood. Most of what scientists know about cancer concerns advanced stages of the disease. Thats especially true for cancers such as pancreatic cancer that are usually diagnosed very late.. Researchers in Scott Lowes lab at the Sloan Kettering Institute are now trying to zero in on the earliest stages of pancreatic cancer development.. If we understood how these tumors form, maybe we could catch them before the cancer has progressed to an incurable stage, says Direna Alonso Curbelo, a postdoctoral fellow in the Lowe lab who is the first author of a new paper published February 3 ...

Intraductal papillary mucinous neoplasm (IPMN), the most common pancreatic cystic neoplasm, is known to progress to invasive ductal adenocarcinoma. IPMNs commonly harbor activating somatic mutations in GNAS and KRAS, primarily GNAS(R201H) and KRAS(G12D). GNAS encodes the stimulatory G-protein α subunit (Gsα) that mediates a stimulatory signal to adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP), subsequently activating cAMP-dependent protein kinase A. The GNAS(R201H) mutation results in constitutive activation of Gsα. To study the potential role of GNAS in pancreatic tumorigenesis in vivo, we generated lines of transgenic mice in which the transgene consisted of Lox-STOP-Lox (LSL)-GNAS(R201H) under the control of the CAG promoter (Tg(CAG-LSL-GNAS)). These mice were crossed with pancreatic transcription factor 1a (Ptf1a)-Cre mice (Ptf1a(Cre/+)), generating Tg(CAG-LSL-GNAS);Ptf1a(Cre/+) mice. This mouse line showed elevated cAMP levels, small dilated tubular complex formation, ...

TY - JOUR. T1 - Long-term surgical outcome of noninvasive and minimally invasive intraductal papillary mucinous adenocarcinoma of the pancreas. AU - Nakagohri, Toshio. AU - Asano, Takehide. AU - Kenmochi, Takashi. AU - Urashima, Tetsuro. AU - Ochiai, Takenori. PY - 2002/9/1. Y1 - 2002/9/1. N2 - The objective of this study was to clarify the long-term outcome after surgical resection in patients with noninvasive and minimally invasive intraductal papillary mucinous adenocarcinoma. We performed a retrospective review of the clinicopathological features and outcome in patients who underwent pancreatic resection for noninvasive and minimally invasive intraductal papillary mucinous adenocarcinoma between November 1982 and December 1997 at Chiba University Hospital. Minimally invasive structures were pathologically observed in five cases. The mean age of patients with either noninvasive (n = 16) or minimally invasive (n = 5) adenocarcinoma was 61 years. Of the patients with minimally invasive ...

As reported by Vasen et al in the Journal of Clinical Oncology, surveillance for pancreatic ductal adenocarcinoma in high-risk individuals appears to be of benefit in individuals at risk due to CDKN2A mutation, with the advantage being less clear among individuals at risk due to familial clustering of pancreatic cancer.. Study Details. The study was a long-term prospective follow-up from three European expert centers. A total of 411 asymptomatic individuals, including 178 CDKN2A mutation carriers, 214 individuals with familial pancreatic cancer, and 19 BRCA1/2 or PALB2 mutation carriers, participated in a surveillance program consisting of annual magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography, or endoscopic ultrasound (EUS).. Individuals had a mean age of 56 years at the start of the program, and mean follow-up was 53 months (range = 0-169 months). In total, 866 MRIs and 106 EUSs were performed.. Surveillance Outcome. Pancreatic ductal adenocarcinoma was detected ...

Background Pancreatic ductal adenocarcinoma (PDAC) patients have the poorest 5-year survival rates of all cancer forms. It is difficult to diagnose at early disease stages, tumour relapse after surgery is common, and current chemotherapies are ineffective. Carbohydrate antigen 19-9 (Ca 19-9), the only clinically implemented PDAC biomarker, is insufficient for diagnostic and screening purposes.. PDAC tumours are characterised by a voluminous stroma that is rich in extracellular matrix (ECM) molecules such as collagens, hyaluronan (HA) and matricellular proteins. These stromal components have been suggested to promote PDAC cell migration, proliferation, evasion of apoptosis and chemotherapy resistance. Those events are mediated via interactions with adhesion receptors, such as integrins and CD44 receptors expressed on cancer cell surfaces.. Micro-RNAs (miRNA) post-transcriptionally regulate gene expression in health and disease. At the time of PDAC diagnosis, miRNA levels are altered both in ...

Mammalian target of rapamycin complicated 1 (mTORC1) is generally activated in individual cancers; however scientific studies of rapalog (the mTORC1 inhibitors) show that pancreatic ductal adenocarcinomas (PDACs) withstand to the procedure. overcome rapalog level of resistance in PDAC. and N-genes. K-or N-mutations play a crucial function in the rapalog level of resistance in PDAC. K-mutations donate to the rapalog-induced reviews activation of IGF-1-Ras-Raf-ERK pathway and inhibition from the mt K-Ras abolishes the reviews ERK signal decreases the rapalog level of resistance and therefore enhance inhibitory aftereffect of rapalog over the development of K-Ras mt PDAC cells-derived mouse xenografts. 2 Components and Strategies 2.1 Individual pancreatic carcinoma cell lines tissue and regular pancreatic tissues Individual PDAC cell lines BxPC-3 Capan-2 Hs 766T and PANC-1 had been extracted from the American Type Lifestyle Collection (Rockville MD). BxPC-3 was harvested in RPMI-1640 moderate ...

Burmi R, Maginn E, Gabra H, Stronach E, Wasan Het al., 2019, Combined inhibition of the PI3K/mTOR/MEK pathway induces Bim/Mcl-2-regulated apoptosis in pancreatic cancer cells, Cancer Biology and Therapy, Vol: 20, Pages: 21-30, ISSN: 1555-8576 Pancreatic ductal adenocarcinoma (PDAC) progression and chemotherapy insensitivity have been associated with aberrant PI3K/mTOR/MEK signalling. However, cell death responses activated by inhibitors of these pathways can differ - contextually varying with tumour genetic background. Here, we demonstrate that combining the dual PI3K/mTOR inhibitor PF5212384 (PF384) and MEK inhibitor PD325901 (PD901) more effectively induces apoptosis compared with either agent alone, independent of KRAS mutational status in PDAC cell lines. Additionally, a non-caspase dependent decrease in cell viability upon PF384 treatment was observed, and may be attributed to autophagy and G0/G1 cell cycle arrest. Using reverse phase protein arrays, we identify key molecular events ...

exocrine pancreatic cancer, pancreatic adenocarcinomas, pancreatic cancer; pancreas cancer Digital case JRC:10443 : cutaneous metastasis of a (...)

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions of pancreatic cancer. Misexpression of microRNAs (miRNAs) is commonly observed in pancreatic adenocarcinoma. In contrast, miRNA abnormalities in pancreatic cancer precursor lesions have not been documented.. EXPERIMENTAL DESIGN: Relative expression levels of a panel of twelve miRNAs upregulated in pancreatic cancers were assessed in 15 non-invasive IPMNs, using quantitative reverse transcription PCR (qRT-PCR). Two significantly overexpressed miRNAs-miR-155 and miR-21-were evaluated by locked nucleic acid in situ hybridization (LNA-ISH) in a panel of 64 archival IPMNs. The expression of miR-155 and miR-21 was also evaluated in pancreatic juice samples obtained from ten patients with surgically resected IPMNs and five patients with non-neoplastic pancreato-biliary disorders (disease controls).. RESULTS: Significant overexpression by qRT-PCR of ten of the twelve miRNAs was observed in the 15 IPMNs ...

The p63 gene is a recently discovered member of the p53 family located at chromosome 3q27Many studies have reported that overexpression of p63 can mimic p53 activities by binding DNA, activating transcription, and inducing apoptosis.. Various studies proved p63 as a marker of basal cells in normal salivary glands, breast, prostate, respiratory and squamous epithelia, and of tumor cells from various malignancies. Still, p63 has been the subject of relatively few studies in lung adenocarcinoma, and breast carcinoma, and no study has described the correlation of p63 with pancreatic ductal adenocarcinoma.. In the current study, we aim to evaluate the prognostic value of the expression of p63 in the lung adenocarcinoma, breast adenocarcinoma, and pancreatic ductal adenocarcinoma. We will achieve this aim by collecting clinical data retrospectively from the patients medical records as well as assessing the histological sections and performing immunohistochemical staining for p63. ...

PD‐L1 plays a central role in permitting cancer evasion, mainly by interfering with T‐cell functions, and inhibitors of the PD‐1/PD‐L1 axis have changed the paradigm in the management of melanoma patients (Clark et al, 2007). However, PDAC is characterized by a highly immunosuppressive stroma (Hiraoka et al, 2006; Lutz et al, 2014; Beatty et al, 2015; Diana et al, 2016b; Zhang et al, 2017) and immune checkpoint inhibitors alone were ineffective in the clinical setting (Royal et al, 2010; Brahmer et al, 2012). Evidence indicates potentially complementary roles for immunotherapy and RT (Sharabi et al, 2015a), but this combination has not been explored in PDAC. Here, we show that blockade of PD‐L1 strongly enhanced tumor response to high (12, 5 × 3, and 20 Gy) but not low (6 and 5 × 2 Gy) RT doses, albeit a trend was noted for low doses. In addition to sensitizing tumors to RT, anti‐PD‐L1 improved response after gemcitabine‐based chemoradiation. This is, to our knowledge, the ...

Design We developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA. ...

Authors: Pedro A Perez-Mancera, Alistair G Rust, Louise van der Weyden, Glen Kristiansen, Allen Li, Aaron L Sarver, Kevin AT Silverstein, Robert Gruetzmann, Daniela Aust, Petra Ruemmele, Thomas Knoesel, Colin Herd, Derek L Stemple, Ross Kettleborough, Jacqueline A Brosnan, Ang Li, Richard Morgan, Spencer Knight, Jun Yu, Shane Stegeman, Lara S Collier, Jelle J ten Hoeve, Jeroen de Ridder, Alison P Klein, Michael Goggins, Ralph H Hruban, David K Chang, Andrew V Biankin, Sean M Grimmond, Lodewyk FA Wessels, Stephen A Wood, Christine A Iacobuzio-Donahue, Christian Pilarsky, David A Largaespada, David J Adams, David A Tuveson

ESMO is a Swiss-registered not-for-profit organisation. All funding for this site is provided directly by ESMO or via grants from the sponsors and supporters.. Via L. Taddei 4, 6962 Viganello - Lugano - CH © Copyright 2017 European Society for Medical Oncology All rights reserved worldwide.. ...

Authors: Lindsey Stobie; Eve Karloski; Arlene Colvin; Cynthia Lim; Mary Linton Peters; Jill Krejdovsky; Kim DeLeonardis; Melissa Luna; Arthur J Moser; Kyle Allen; Virginia Speare; Jill Dolinsky; Erkut Borazanci; Nadine Tung; Randall Brand; Beth ...

Looking for branch duct? Find out information about branch duct. branch duct: installation branch duct An air duct which branches from a main duct; at this point the main duct is reduced in cross-sectional area Explanation of branch duct

The integrin αvβ6 is upregulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvβ6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-β1; this latter function complicates therapeutic targeting of αvβ6, since TGF-β1 has both tumour-promoting and -suppressive effects. It is unclear how these different αvβ6 functions are linked; both require actin cytoskeletal reorganisation, and it is suggested that tractive forces generated during cell migration activate TGF-β1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-β1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvβ6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-β1 activation depending on the ...