scholarly journals GnasR201C Induces Murine Pancreatic Cystic Neoplasms through Suppression of YAP1 Signaling and Transcriptional Reprogramming

2018 ◽  
Author(s):  
Noboru Ideno ◽  
Hiroshi Yamaguchi ◽  
Bidyut Ghosh ◽  
Sonal Gupta ◽  
Takashi Okumura ◽  
...  
Keyword(s):  
Protein A ◽  
Ductal Adenocarcinoma ◽  
Cystic Neoplasms ◽  
Transcriptional Reprogramming ◽  
Kaplan Meier ◽  
Stimulatory G Protein ◽  
Kinase Cascade ◽  
Well Differentiated ◽  
Underlying Mechanisms ◽  
Pancreatic Neoplasia

ABSTRACTBackground & AimsSomatic “hotspot” mutations of GNAS, which encodes for the alpha subunit of stimulatory G-protein, are present in ~60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. There are currently no cognate animal models that recapitulate the biology of mutant Gnas-induced IPMNs, and the underlying mechanisms that lead to the cystic pathway of neoplasia in the pancreas remain unknown.MethodsWe generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras; Gnas mice) where pancreas-specific GnasR201C expression was induced by doxycycline administration. In this model, mutant Kras is constitutively expressed, and control mice were produced through absence of doxycycline. Separate cohorts of mice were utilized for timed necropsies and for Kaplan-Meier survival analysis. Isogenic cell lines (with doxycycline inducible mutant Gnas expression) were propagated from the resulting pancreatic ductal adenocarcinoma (PDAC).ResultsCo-expression of KrasG12D and GnasR201C resulted in the development of pancreatic cystic lesions resembling human IPMNs in 100% of mice, with higher grades of epithelial dysplasia observed over time. Approximately one-third of Kras; Gnas mice developed PDAC at a median of 38 weeks post doxycycline induction. GnasR201C did not accelerate oncogenic transformation with KrasG12D, but rather, reprogrammed Ras-induced neoplasms towards a well-differentiated phenotype. GnasR201C induction led to activation of the inhibitory Hippo kinase cascade and cytoplasmic sequestration of phosphorylated YAP1 protein, a phenomenon that was also observed in human IPMN with GNAS mutations.ConclusionsGNASR201C functions not as a traditional oncogene, but rather as an “oncomodulator” of KRAS-mediated pancreatic neoplasia, through suppression of YAP1 and transcriptional reprogramming towards a differentiated (large ductal) phenotype.

Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323014
Author(s):  
Zhibo Xie ◽  
Ya Gao ◽  
Chiakang Ho ◽  
Lequn Li ◽  
Chen Jin ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Ductal Adenocarcinoma ◽  
Fibrotic Liver ◽  
Cd44 Variant ◽  
Logistic Regression Models ◽  
Tail Vein ◽  
Signalling Molecules ◽  
Kaplan Meier ◽  
Underlying Mechanisms ◽  
Complement C1q

ObjectivePancreatic ductal adenocarcinoma (PDAC) shows a remarkable predilection for liver metastasis. Pro-oncogenic secretome delivery and trafficking via exosomes are crucial for pre-metastatic microenvironment formation and metastasis. This study aimed to explore the underlying mechanisms of how PDAC-derived exosomes (Pex) modulate the liver microenvironment and promote metastasis.DesignC57BL/6 mice were ‘educated’ by tail vein Pex injection. The intrasplenic injection liver metastasis and PDAC orthotopic transplantation models were used to evaluate liver metastasis. Stable cell lines CD44v6 (CD44 variant isoform 6) or C1QBP (complement C1q binding protein) knockdown or overexpression was established using lentivirus transfection or gateway systems. A total of 142 patients with PDAC in Huashan Hospital were retrospectively enrolled. Prognosis and liver metastasis were predicted using Kaplan-Meier survival curves and logistic regression models.ResultsPex tail vein injection induced the deposition of liver fibrotic extracellular matrix, which promoted PDAC liver metastasis. Specifically, the exosomal CD44v6/C1QBP complex was delivered to the plasma membrane of hepatic satellite cells (HSCs), leading to phosphorylation of insulin-like growth factor 1 signalling molecules, which resulted in HSC activation and liver fibrosis. Expression of Pex CD44v6 and C1QBP in PDAC patients with liver metastasis was significantly higher than in PDAC patients without liver metastasis, and simultaneous high expression of exosomal CD44v6 and C1QBP correlated with a worse prognosis and a higher risk of postoperative PDAC liver metastasis.ConclusionThe Pex-derived CD44v6/C1QBP complex is essential for the formation of a fibrotic liver microenvironment and PDAC liver metastasis. Highly expressed exosomal CD44v6 and C1QBP are promising biomarkers for predicting prognosis and liver metastasis in patients with PDAC.

Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 377-377
Author(s):  
Matthew H. G. Katz ◽  
Qian Shi ◽  
Jeffrey P. Meyers ◽  
Joseph M. Herman ◽  
Michael Choung ◽  
...  
Keyword(s):  
Phase Ii ◽  
Interim Analysis ◽  
Historical Data ◽  
Ductal Adenocarcinoma ◽  
R0 Resection ◽  
Borderline Resectable ◽  
Novel Treatments ◽  
Kaplan Meier ◽  
Hypofractionated Radiation ◽  
Ecog Ps

377 Background: Neoadjuvant therapy has been associated with a median overall survival (OS) of 18 – 23 months (mo) in patients (pts) with BR pancreatic ductal adenocarcinoma (PDAC). To establish reference regimens to which novel treatments can be compared in future studies, we evaluated neoadjuvant mFOLFIRINOX with or without RT in BR PDAC in a phase II National Clinical Trials Network (NCTN) trial. Methods: Pts with ECOG PS 0-1 and BR PDAC confirmed by central real-time radiographic review after pre-registration were randomized to either arm A: 8 cycles of neoadjuvant mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours), or arm B: 7 cycles of mFOLFIRINOX followed by stereotactic body RT (SBRT, 33-40 Gy in 5 fractions [fx]) or hypofractionated image guided RT (HIGRT, 25 Gy in 5 fx). Pts in either arm without disease progression underwent pancreatectomy, then 4 cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours). The primary endpoint, 18-mo OS rate, of each arm was compared to a historical control of 50%. Planned interim analysis mandated closure of either arm in which <11 of first 30 accrued pts underwent R0 resection. Results: 155 pts pre-registered and 126 pts were enrolled to arm A (N=70; 54 randomized, 16 following closure of arm B) or arm B (N=56; closed at interim analysis, all pts randomized prior to closure). Median age (A: 63y, B: 67y), median CA 19-9 level (A: 171 U/ml, B: 248 U/ml) and ECOG PS (A: 51% PS 0, B: 57% PS 0) of registered pts were similar between arms (p > 0.05). Treatment detailed in Table. The 18-mo OS rate based on Kaplan Meier estimates was 67.9% (95%CI: 54.6 – 78.0) in arm A and 47.3% (95%CI: 33.7 – 59.7) in arm B. Among pts who underwent pancreatectomy, 18-mo OS rate was 93.1% (95%CI: 84.3 – 100) and 78.9% (95%CI: 62.6 – 99.6) in arm A and B, respectively. With median follow-up of 27 and 31 mo, median OS was 31.0 (95%CI: 22.2 – NE) mo and 17.1 (95%CI: 12.8 – 24.4) mo in arm A and B, respectively. Conclusions: Neoadjuvant mFOLFIRINOX was associated with favorable OS relative to historical data in pts with BL PDAC in this phase II NCTN trial. mFOLFIRINOX with hypofractionated RT did not improve OS compared to historical data. mFOLFIRINOX represents a reference regimen in this setting and a backbone on which to add novel agents. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org Clinical trial information: NCT02839343. [Table: see text]

scholarly journals Factors affecting overall survival in ductal adenocarcinoma of the pancreatic head. Experience of one center

2021 ◽  
Vol 11 (1) ◽  
pp. 20-28
Author(s):  
D.  M. Kuchin ◽  
Ya.  I. Kolesnik ◽  
H.  G. Torgomyan ◽  
V.  E. Zagainov
Keyword(s):  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Vascular Invasion ◽  
Survival Rates ◽  
Pancreatic Head ◽  
Ductal Adenocarcinoma ◽  
Factors Affecting ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
Major Factors

Purpose. To identify major factors affecting the overall survival (OS). To select the cohort of patients with the best prognosis.Materials and methods. A retrospective analysis included data of 268 patients, 128 men and 140 women, with median age of 59±10,53 (30 to 83) years. For multivariate analysis of survival, patients were selected who underwent pancreaticoduodenectomy (PD) for ductal adenocarcinoma of the pancreatic head.Results. Our study demonstrated that histologically verified vascular invasion (detected only in 30 % of patients who underwent PD with resection of the major vessels) statistically significantly affected the OS. The increased CA19-9 level over 500 U / L (detected in 32,3 % of cases) is the factor that significantly worsens the OS. Patients with high grade adenocarcinoma have significantly better survival rates compared with patients who have moderately or poorly differentiated adenocarcinoma (p = 0.014; median 26 months, 95 % CI 4.4–47.6 versus median 17 months, 95 % CI 15–19, an median: 13 months, 95 % CI 5–21, respectively). Also, the use of adjuvant chemotherapy has a positive effect on long-term outcomes (p = 0.0001; median 26 months, 95 % CI 21.7–30.3 versus median 13 months, 95 % CI 11.3–14.7).Conclusion. A well-differentiated tumor and the use of adjuvant chemotherapy significantly increase the OS of patients. Poorly differentiated tumor, CA19-9 level over 500 U / mL and the histologically confirmed vascular invasion significantly worsen the prognosis of these patients.

Effect of neoadjuvant radiotherapy on survival of non-metastatic Pancreatic Ductal Adenocarcinoma: A SEER Database Analysis

2020 ◽  
Author(s):  
Dan Wang ◽  
Chongshun Liu ◽  
Yuan Zhou ◽  
Tingyu Yan ◽  
Chenglong Li ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Adjuvant Radiotherapy ◽  
Risk Model ◽  
Ductal Adenocarcinoma ◽  
Seer Database ◽  
Database Analysis ◽  
Neoadjuvant Radiotherapy ◽  
Kaplan Meier ◽  
Stage T1 ◽  
Better Than

Abstract Background: Neoadjuvant radiotherapy has been shown to improve marginal negative resection and local control of Pancreatic Ductal Adenocarcinoma (PDAC). However, whether it improves overall survival (OS) in patients with non-metastatic PDAC remains controversial. Therefore, the purpose of this study was to analyze the benefits of only surgery, neoadjuvant radiotherapy, adjuvant radiotherapy, and surgery plus chemotherapy for OS in patients with non-metastatic PDAC. Methods: PDAC diagnosed by surgical histopathology in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016 was selected. Kaplan-Meier analysis was used to compare the prognosis of patients with different treatments. Cox proportional risk model was used to analyze independent predictors of OS.Propensity score matching (PSM) was used to analyze the tumor prognosis of different treatment methods. Results: Before PSM analysis, the OS of surgery plus chemotherapy (HRs = 0.896, 95%CIs, 0.827-0.970; P=0.007) were significantly better than the other three treatments for stage T1-3N0M0 PDAC patients. For stage T1-3N+M0 patients, adjuvant radiotherapy (HRs=0.613, 95% CIs, 0.579-0.649; P< 0.001) had significantly better OS than surgery plus chemotherapy and neoadjuvant radiotherapy. For stage T4N0M0 patients, neoadjuvant radiotherapy (HRs=0.482, 95% CIs, 0.347-0.670; P < 0.001) had significantly better OS than surgery plus chemotherapy and adjuvant radiotherapy. For stage T4N+M0 patients, neoadjuvant radiotherapy (HRs=0.338, 95% CIs, 0.215-0.532; P < 0.001) had significantly longer OS than adjuvant radiotherapy and surgery plus chemotherapy.Even after PSM, Chemotherapy plus surgery was still the best treatment for T1-3N0M0 patients. Postoperative adjuvant radiotherapy had the best prognosis among T1-3N+M0 patients, and neoadjuvant radiotherapy was the best treatment for T4 patients. Conclusions: For patients with non-metastatic PDAC, neoadjuvant radiotherapy, adjuvant radiotherapy and surgery plus chemotherapy were superior to only surgery in OS. For patients with stage T4 non-metastatic PDAC, neoadjuvant radiotherapy had the potential to be strongly recommended over adjuvant radiotherapy and surgery plus chemotherapy. However, neoadjuvant radiotherapy failed to benefit the survival of T1-3N0M0 stage patients, and surgery plus chemotherapy was preferred. For T1-3N+M0, neoadjuvant radiotherapy had no obvious advantage over adjuvant radiotherapy or surgery plus chemotherapy in OS, and adjuvant radiotherapy was more recommended.

scholarly journals Integrated Analyses Identify Immune-Related Signature Associated with Qingyihuaji Formula for Treatment of Pancreatic Ductal Adenocarcinoma Using Network Pharmacology and Weighted Gene Co-Expression Network

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Xiang Qian ◽  
Zhuo Chen ◽  
Sha Sha Chen ◽  
Lu Ming Liu ◽  
Ai Qin Zhang
Keyword(s):  
Expression Profiles ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Ductal Adenocarcinoma ◽  
Network Pharmacology ◽  
Active Ingredients ◽  
Kaplan Meier ◽  
Human Protein Atlas

The study aimed to clarify the potential immune-related targets and mechanisms of Qingyihuaji Formula (QYHJ) against pancreatic cancer (PC) through network pharmacology and weighted gene co-expression network analysis (WGCNA). Active ingredients of herbs in QYHJ were identified by the TCMSP database. Then, the putative targets of active ingredients were predicted with SwissTargetPrediction and the STITCH databases. The expression profiles of GSE32676 were downloaded from the GEO database. WGCNA was used to identify the co-expression modules. Besides, the putative targets, immune-related targets, and the critical module genes were mapped with the specific disease to select the overlapped genes (OGEs). Functional enrichment analysis of putative targets and OGEs was conducted. The overall survival (OS) analysis of OGEs was investigated using the Kaplan-Meier plotter. The relative expression and methylation levels of OGEs were detected in UALCAN, human protein atlas (HPA), Oncomine, DiseaseMeth version 2.0 and, MEXPRESS database, respectively. Gene set enrichment analysis (GSEA) was conducted to elucidate the key pathways of highly-expressed OGEs further. OS analyses found that 12 up-regulated OGEs, including CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 that could be utilized as potential diagnostic indicators for PC. Further, methylation analyses suggested that the abnormal up-regulation of these OGEs probably resulted from hypomethylation, and GSEA revealed the genes markedly related to cell cycle and proliferation of PC. This study identified CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 might be used as reliable immune-related biomarkers for prognosis of PC, which may be essential immunotherapies targets of QYHJ.

scholarly journals The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Katherine A. Michaelis ◽  
Mason A. Norgard ◽  
Xinxia Zhu ◽  
Peter R. Levasseur ◽  
Shamilene Sivagnanam ◽  
...  
Keyword(s):  
Knockout Mouse ◽  
Host Responses ◽  
Ductal Adenocarcinoma ◽  
Survival Duration ◽  
Murine Models ◽  
Tumor Mass ◽  
Treg Frequency ◽  
T Cell Infiltration ◽  
Pancreatic Neoplasia

Abstract A priority in cancer research is to innovate therapies that are not only effective against tumor progression but also address comorbidities such as cachexia that limit quality and quantity of life. We demonstrate that TLR7/8 agonist R848 induces anti-tumor responses and attenuates cachexia in murine models of pancreatic ductal adenocarcinoma (PDAC). In vivo, tumors from two of three cell lines were R848-sensitive, resulting in smaller tumor mass, increased immune complexity, increased CD8+ T-cell infiltration and activity, and decreased Treg frequency. R848-treated mice demonstrated improvements in behavioral and molecular cachexia manifestations, resulting in a near-doubling of survival duration. Knockout mouse studies revealed that stromal, not neoplastic, TLR7 is requisite for R848-mediated responses. In patient samples, we found Tlr7 is ubiquitously expressed in stroma across all stages of pancreatic neoplasia, but epithelial Tlr7 expression is relatively uncommon. These studies indicate immune-enhancing approaches including R848 may be useful in PDAC and cancer-associated cachexia.

scholarly journals Predictors of Peritonitis and the Impact of Peritonitis on Clinical Outcomes of Continuous Ambulatory Peritoneal Dialysis Patients in Taiwan—10 Years’ Experience in a Single Center

2014 ◽  
Vol 34 (1) ◽  
pp. 85-94 ◽  
Author(s):  
Yao-Peng Hsieh ◽  
Chia-Chu Chang ◽  
Yao-Ko Wen ◽  
Ping-Fang Chiu ◽  
Yu Yang
Keyword(s):  
Peritoneal Dialysis ◽  
Clinical Outcomes ◽  
Cox Regression ◽  
Drop Out ◽  
Kaplan Meier ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Impact ◽  
Technique Failure

ObjectivePeritoneal dialysis (PD) has become more prevalent as a treatment modality for end-stage renal disease, and peritonitis remains one of its most devastating complications. The aim of the present investigation was to examine the frequency and predictors of peritonitis and the impact of peritonitis on clinical outcomes.MethodsOur retrospective observational cohort study enrolled 391 patients who had been treated with continuous ambulatory PD (CAPD) for at least 90 days. Relevant demographic, biochemical, and clinical data were collected for an analysis of CAPD-associated peritonitis, technique failure, drop-out from PD, and patient mortality.ResultsThe peritonitis rate was 0.196 episodes per patient–year. Older age (>65 years) was the only identified risk factor associated with peritonitis. A multivariate Cox regression model demonstrated that technique failure occurred more often in patients experiencing peritonitis than in those free of peritonitis ( p < 0.001). Kaplan–Meier analysis revealed that the group experiencing peritonitis tended to survive longer than the group that was peritonitis-free ( p = 0.11). After multivariate adjustment, the survival advantage reached significance (hazard ratio: 0.64; 95% confidence interval: 0.46 to 0.89; p = 0.006). Compared with the peritonitis-free group, the group experiencing peritonitis also had more drop-out from PD ( p = 0.03).ConclusionsThe peritonitis rate was relatively low in the present investigation. Elderly patients were at higher risk of peritonitis episodes. Peritonitis independently predicted technique failure, in agreement with other reports. However, contrary to previous studies, all-cause mortality was better in patients experiencing peritonitis than in those free of peritonitis. The underlying mechanisms of this presumptive “peritonitis paradox” remain to be clarified.

scholarly journals Effects of Prednisolone on Serum and Tissue Fluid IGF-I Receptor Activation and Post-Receptor Signaling in Humans

2017 ◽  
Vol 102 (11) ◽  
pp. 4031-4040 ◽  
Author(s):  
Nilani Ramshanker ◽  
Maiken Aagaard ◽  
Rikke Hjortebjerg ◽  
Thomas Schmidt Voss ◽  
Niels Møller ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Protein A ◽  
Receptor Activation ◽  
Tissue Fluid ◽  
Igf Binding Proteins ◽  
Downstream Signaling ◽  
Specific Effects ◽  
Igf I ◽  
Underlying Mechanisms ◽  
Double Blinded

Abstract Context Short-term glucocorticoid exposure increases serum insulinlike growth factor I (IGF-I) concentrations but antagonizes IGF-I tissue signaling. The underlying mechanisms remain unknown. Objective To identify at which levels glucocorticoid inhibits IGF-I signaling. Design and Methods Nineteen healthy males received prednisolone (37.5 mg/d) and placebo for 5 days in a randomized, double-blinded, placebo-controlled crossover study. Serum was collected on days 1, 3, and 5, and abdominal skin suction blister fluid (SBF; ~interstitial fluid) was taken on day 5 (n = 9) together with muscle biopsy specimens (n = 19). The ability of serum and SBF to activate the IGF-I receptor (IGF-IR) (bioactive IGF) and its downstream signaling proteins was assessed using IGF-IR–transfected cells. Results Prednisolone increased IGF-I concentrations and bioactive IGF in serum (P ≤ 0.001) but not in SBF, which, compared with serum, contained less bioactive IGF (~28%) after prednisolone (P &lt; 0.05). This observation was unexplained by SBF concentrations of IGFs and IGF-binding proteins (IGFBPs) 1 to 4. However, following prednisolone treatment, SBF contained less IGFBP-4 fragments (P &lt; 0.05) generated by pregnancy-associated plasma protein A (PAPP-A). Concomitantly, prednisolone increased SBF levels of stanniocalcin 2 (STC2) (P = 0.02) compared with serum. STC2 blocks PAPP-A from cleaving IGFBP-4. Finally, prednisolone suppressed post–IGF-IR signaling pathways at the level of insulin receptor substrate 1 (P &lt; 0.05) but did not change skeletal muscle IGF-IR, IGF-I, or STC2 messenger RNA. Conclusion Prednisolone increased IGF-I concentrations and IGF bioactivity in serum but not in tissue fluid. The latter may relate to a STC2-mediated inhibition of PAPP-A in tissue fluids. Furthermore, prednisolone induced post–IGF-IR resistance. Thus, glucocorticoid may exert distinct, compartment-specific effects on IGF action.

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