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Pancreatic cancer - Top 30 Publications

APE1/Ref-1 knockdown in pancreatic ductal adenocarcinoma: Characterizing gene expression changes and identifying novel pathways using single-cell RNA sequencing.

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer-related pathways. Because APE1 is essential for cell viability, generation of APE1 knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single-cell RNA Sequencing to identify differentially expressed genes in relation to APE1 protein levels within the cell. Using a straight forward yet novel statistical design, we identified 2,837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mTOR pathways and a number of mitochondrial-related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the differentially expressed genes along with siRNA knockdown and qRT-PCR. Testing additional patient-derived pancreatic cancer cells reveal particular genes (ITGA1, TNFAIP2, COMMD7, RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor sub-type specificity. These findings will allow for hypothesis driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.

Sweet Sixteen: The Prospective Clinical Trials of John L. Cameron, MD-The Clinician-Scientist: From Alternate-Allocation to Randomized Controlled Trials.

: The era of randomized controlled trials was ushered in by the British epidemiologist-statistician Austin Bradford Hill, with his work on the use of streptomycin in patients with tuberculosis. John L. Cameron, can be linked to 16 prospective clinical trials over his career thus far, starting with alternate-allocation trials and transitioning to prospective, randomized, placebo-controlled trials. These trials studied various topics in surgery-from pancreatitis to surgical site infections, to drain trials, a trial in Crohn disease and multiple trials in pancreatic surgery and cancer. Herein are described the "sweet sixteen" prospective clinical trials of Dr Cameron.

Impact of Advanced Age on Survival in Patients Undergoing Resection of Hepatocellular Carcinoma: Report of a Japanese Nationwide Survey.

The impact of age on survival after hepatic resection for hepatocellular carcinoma (HCC) has not been thoroughly examined. We reviewed the data of a nationwide follow-up survey to determine the outcomes of hepatectomy for HCC in elderly patients.

Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women.

Nitrate and nitrite are precursors of N-nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by-products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986-2011). We used historical monitoring and treatment data to estimate levels of long-term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one-half the maximum contaminant level (>½ MCL; nitrate-nitrogen 5mg/L, 40µg/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N=15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HRp95vs.Q1 =1.16, 95%CI: 0.51-2.64). Associations with average TTHM levels were also null (HRQ4vsQ1 =0.70, 95%CI:0.42-1.18). We observed no trend with increasing years of exposure to either contaminant at levels >½ MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HRp95vs.Q1 =1.66, 95% CI 1.00-2.75;ptrend =0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer. This article is protected by copyright. All rights reserved.

A naive Bayes algorithm for tissue origin diagnosis (TOD-Bayes) of synchronous multifocal tumors in the hepatobiliary and pancreatic system.

Synchronous multifocal tumors are common in the hepatobiliary and pancreatic system but because of similarities in their histological features, oncologists have difficulty in identifying their precise tissue clonal origin through routine histopathological methods. To address this problem and assist in more precise diagnosis, we developed a computational approach for tissue origin diagnosis based on naive Bayes algorithm (TOD-Bayes) using ubiquitous RNA-Seq data. Massive tissue-specific RNA-Seq data sets were first obtained from The Cancer Genome Atlas (TCGA) and ∼1,000 feature genes were used to train and validate the TOD-Bayes algorithm. The accuracy of the model was > 95% based on 10-fold cross validation by the data from TCGA. A total of 18 clinical cancer samples (including 6 negative controls) with definitive tissue origin were subsequently used for external validation and 17 of the 18 samples were classified correctly in our study (94.4%). Furthermore, we included as cases studies seven tumor samples, taken from two individuals who suffered from synchronous multifocal tumors across tissues, where the efforts to make a definitive primary cancer diagnosis by traditional diagnostic methods had failed. Using our TOD-Bayes analysis, the two clinical test cases were successfully diagnosed as pancreatic cancer (PC) and cholangiocarcinoma (CC), respectively, in agreement with their clinical outcomes. Based on our findings, we believe that the TOD-Bayes algorithm is a powerful novel methodology to accurately identify the tissue origin of synchronous multifocal tumors of unknown primary cancers using RNA-Seq data and an important step towards more precision-based medicine in cancer diagnosis and treatment. This article is protected by copyright. All rights reserved.

Radiation overexposure from repeated CT scans in young adults with acute abdominal pain.

The purpose of this study is to assess the dose of ionizing radiation caused by repeated CT scans performed to investigate non-traumatic acute abdominal conditions in young adults.

Impact of pancreaticoduodenal arcade dilation on postoperative outcomes after pancreaticoduodenectomy.

The aim of this study was to investigate the impact of pancreaticoduodenal arcade (PDA) dilation on postoperative outcomes after pancreaticoduodenectomy.

Hepatic Tmem30a deficiency causes intrahepatic cholestasis by impairing expression and localization of bile salt transporters.

Mutations in ATP8B1 or ATP11C (members of P4-type ATPases) cause progressive familial intrahepatic cholestasis type 1 (PFIC1) in human or intrahepatic cholestasis in mice. Transmembrane protein 30A (TMEM30A), as a β-subunit, is essential for the function of P4-type ATPases including ATP8B1 and ATP11C, however, its role in the etiology of cholestasis remains poorly understood. To investigate the function of TMEM30A in bile salt homeostasis, we developed Tmem30a liver-specific knockout (LKO) mice. Tmem30a LKO mice suffered from hyperbilirubinaemia, hypercholanaemia, inflammatory infiltration, ductular proliferation and liver fibrosis. The expression and membrane localization of ATP8B1 and ATP11C were significantly reduced in Tmem30a LKO mice, which correlated with the impaired expression and localization of BS transporters, such as OATP1A4, OATP1B2, NTCP, BSEP, and MRP2. The proteasome inhibitor bortezomib partially restored total protein levels of BS transporters but not the localization of BS transporters in the membrane. Furthermore, the expression of nuclear receptors, including FXRα, RXRα, HNF4α, LRH-1, and SHP, was also down-regulated. A cholic acid-supplemented diet further exacerbated the liver damage in Tmem30a LKO mice. TMEM30A deficiency led to intrahepatic cholestasis in mice by impairing the expression and localization of BS transporters and the expression of related nuclear receptors. Therefore, TMEM30A may be a novel genetic determinant of intrahepatic cholestasis.

Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.

A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product.

Targeted cancer therapies that use genetics are successful, but principles for selectively targeting tumor metabolism that is also dependent on the environment remain unknown. We now show that differences in rate-controlling enzymes during the Warburg effect (WE), the most prominent hallmark of cancer cell metabolism, can be used to predict a response to targeting glucose metabolism. We establish a natural product, koningic acid (KA), to be a selective inhibitor of GAPDH, an enzyme we characterize to have differential control properties over metabolism during the WE. With machine learning and integrated pharmacogenomics and metabolomics, we demonstrate that KA efficacy is not determined by the status of individual genes, but by the quantitative extent of the WE, leading to a therapeutic window in vivo. Thus, the basis of targeting the WE can be encoded by molecular principles that extend beyond the status of individual genes.

mTOR Inhibition Restores Amino Acid Balance in Cells Dependent on Catabolism of Extracellular Protein.

Scavenging of extracellular protein via macropinocytosis is an alternative to monomeric amino acid uptake. In pancreatic cancer, macropinocytosis is driven by oncogenic Ras signaling and contributes substantially to amino acid supply. While Ras signaling promotes scavenging, mTOR signaling suppresses it. Here, we present an integrated experimental-computational method that enables quantitative comparison of protein scavenging rates across cell lines and conditions. Using it, we find that, independently of mTORC1, amino acid scarcity induces protein scavenging and that under such conditions the impact of mTOR signaling on protein scavenging rate is minimal. Nevertheless, mTOR inhibition promotes growth of cells reliant on eating extracellular protein. This growth enhancement depends on mTORC1's canonical function in controlling translation rate: mTOR inhibition slows translation, thereby matching protein synthesis to the limited amino acid supply. Thus, paradoxically, in amino acid-poor conditions the pro-anabolic effects of mTORC1 are functionally opposed to growth.

Recurrence of Barcelona Clinic Liver Cancer Stage A Hepatocellular Carcinoma After Hepatectomy.

The Barcelona Clinic Liver Cancer (BCLC) staging system is widely used to classify hepatocellular carcinoma (HCC). This study was performed to investigate the prognostic factors for patients with BCLC stage A HCC after R0 hepatectomy.

Endoscopic Ultrasonography with Fine-needle Aspiration: New Techniques for Interpretation of Endoscopic Ultrasonography Cytology and Histology Specimens.

Significant advances have been made in the last few years in the technologies for sampling pancreatic masses, and in the understanding of the biology of pancreatic cancer. Better and more targeted treatments are likely to become available. Because most pancreatic cancers are likely to remain unresectable at diagnosis, high-quality, high-cellularity specimens are essential. A tailored approach that considers indication, location, and treatment possibilities needs to be taken before embarking on a pancreatic biopsy. Because the demand from oncologists and patients for increasingly personalized therapy is likely to grow, optimal sampling beyond diagnostic accuracy is likely to become increasingly critical.

New Imaging Techniques for Endoscopic Ultrasonography: Contrast-Enhanced Endoscopic Ultrasonography.

Conventional endoscopic ultrasonography (EUS) has limitations in the diagnosis of solid masses. Because most are depicted as a hypoechoic mass, without cytology or biopsy, it can be difficult to distinguish inflammatory masses from malignancy. Recently developed, contrast-enhanced harmonic EUS (CH-EUS) has improved characterization of digestive lesions by depicting microvessels and parenchymal perfusion, particularly for differentiating pancreatic cancer from other pancreatic solid lesions, identifying mural nodules in intraductal papillary mucinous neoplasms, and estimating malignant potential of gastrointestinal stromal tumors. CH-EUS is complementary to EUS-guided fine-needle aspiration for diagnosing pancreatic lesions, staging, and predicting chemotherapy response.

The anticancer functions of RIG-I-like receptors, RIG-I, and MDA5 and their applications in cancer therapy.

Cancer is a major cause of death worldwide, and its incidence and mortality continuously increase in China. Nowadays, cancer heavily influences our health and constitutes enormous burden on society and families. Although there are many tools for cancer treatment, but the overall therapeutic effect is poor. In addition, cancer cells often develop resistance to therapy due to defective cell death or immune escape mechanisms. Therefore, it is a promising way for cancer treatment to effectively activate apoptosis and conquer immunosuppression. RIG-I-like receptors (RLRs) belong to RNA-sensing pattern recognition receptors (PRRs), one of the major subsets of PRRs, and play a critical role in sensing RNA viruses and initiate host antiviral responses such as the production of type I interferons (IFNs), proinflammatory cytokines, and other immune response molecules. Recent studies have demonstrated that tumor cells could mimic viral infection to activate viral recognition of immune system and the activation of interferon response pathway. RIG-I and MDA5, two members of RLRs family, could induce growth inhibition or apoptosis of multiple types of cancer cells on the activation by RNA ligands in IFN-dependent or IFN-independent approach. Previous studies have reviewed PRRs as promising immunotherapy targets for colorectal cancer and pancreatic cancer. However, until now, a comprehensive review on the role of RLRs in the development and treatment of various cancers is still lacking. In this article, we reviewed the latest studies on the roles as well as the mechanisms of RIG-I and MDA5 in the development of various cancers and therapeutic potentials of targeting RIG-I and MDA5 for cancer treatment.

PEGylated thermosensitive lipid-coated hollow gold nanoshells for effective combinational chemo-photothermal therapy of pancreatic cancer.

Pancreatic cancer has extremely poor prognosis with an 85% mortality rate that results from aggressive and asymptomatic growth, high metastatic potential, and rapid development of resistance to already ineffective chemotherapy. In this study, plasmonic hollow gold nanoshells (GNS) coated with PEGylated thermosensitive lipids were prepared as an efficient platform to ratiometrically co-deliver two drugs, bortezomib and gemcitabine (GNS-L/GB), for combinational chemotherapy and photothermal therapy of pancreatic cancer. Bortezomib was loaded within the lipid bilayers, while gemcitabine was loaded into the hydrophilic interior of the porous GNS via an ammonium sulfate-driven pH gradient method. Physicochemical characterizations and biological studies of GNS-L/GB were performed, with the latter using cytotoxicity assays, cellular uptake and apoptosis assays, live/dead assays, and western blot analysis of pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). The nanoshells showed remotely controllable drug release when exposed to near-infrared laser for site-specific delivery. GNS-L/GB showed synergistic cytotoxicity and improved internalization by cancer cells. High-powered near-infrared continuous wave laser (λ=808nm) effectively killed cancer cells via the photothermal effect of GNS-L/GB, irrespective of cell type in a power density-, time-, and GNS dose-dependent manner. These results suggest that this method can provide a novel approach to achieve synergistic combinational chemotherapy and photothermal therapy, even with resistant pancreatic cancer.

Identification of the S100 fused-type protein hornerin as a regulator of tumor vascularity.

Sustained angiogenesis is essential for the development of solid tumors and metastatic disease. Disruption of signaling pathways that govern tumor vascularity provide a potential avenue to thwart cancer progression. Through phage display-based functional proteomics, immunohistochemical analysis of human pancreatic ductal carcinoma (PDAC) specimens, and in vitro validation, we reveal that hornerin, an S100 fused-type protein, is highly expressed on pancreatic tumor endothelium in a vascular endothelial growth factor (VEGF)-independent manner. Murine-specific hornerin knockdown in PDAC xenografts results in tumor vessels with decreased radii and tortuosity. Hornerin knockdown tumors have significantly reduced leakiness, increased oxygenation, and greater apoptosis. Additionally, these tumors show a significant reduction in growth, a response that is further heightened when therapeutic inhibition of VEGF receptor 2 (VEGFR2) is utilized in combination with hornerin knockdown. These results indicate that hornerin is highly expressed in pancreatic tumor endothelium and alters tumor vessel parameters through a VEGF-independent mechanism.Angiogenesis is essential for solid tumor progression. Here, the authors interrogate the proteome of pancreatic cancer endothelium via phage display and identify hornerin as a critical protein whose expression is essential to maintain the pancreatic cancer vasculature through a VEGF-independent mechanism.

The NQO1 bioactivatable drug, β-Lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism.

Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. β-Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. β-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide, then peroxide formation, which damages DNA and causes hyperactivation of poly (ADP-ribose) polymerase (PARP), resulting in extensive NAD+/ATP depletion. However, the effects of this drug on energy metabolism due to NAD+ depletion were never described. The futile redox cycle rapidly consumes O2, rendering standard assays of Krebs cycle turnover unusable. In this study, a multimodal analysis, including metabolic imaging using hyperpolarized pyruvate, points to reduced oxidative flux due to NAD+ depletion after β-lapachone treatment of NQO1+ human pancreatic cancer cells. NAD+-sensitive pathways, such as glycolysis, flux through lactate dehydrogenase, and the citric acid cycle (as inferred by flux through pyruvate dehydrogenase) were down-regulated by β-lapachone treatment. Changes in flux through these pathways should generate biomarkers useful for in vivo dose-responses of β-lapachone treatment in humans, avoiding toxic side effects. Targeting the enzymes in these pathways for therapeutic treatment may, have the potential to synergize with β-lapachone treatment, creating unique NQO1-selective combinatorial therapies for specific cancers. These findings warrant future studies of intermediary metabolism in patients treated with β-lapachone.

Monoclonal antibodies directed against cadherin RGD exhibit therapeutic activity against melanoma and colorectal cancer metastasis.

New targets are required for the control of advanced metastatic disease. We investigated the use of cadherin RGD motifs, which activate the α2β1integrin pathway, as targets for the development of therapeutic monoclonal antibodies (mAbs).

The prognostic value of long noncoding RNAs in prostate cancer: a systematic review and meta-analysis.

The abnormally expressed LncRNAs played irreplaceable roles in the prognosis of prostate cancer (PCa). Therefore, we conducted this systematic review and meta-analysis to summarize the association between the expression of LncRNAs, prognosis and clinicopathology of PCa. 18 eligible studies were recruited into our analysis, including 18 on prognosis and 9 on clinicopathological features. Results indicated that aberrant expression of LncRNAs was significantly associated with biochemical recurrence-free survival (BCR-FS) (HR = 1.55, 95%CI: 1.01-2.37, P < 0.05), recurrence free survival (RSF) (HR = 3.07, 95%CI: 1.07-8.86, P < 0.05) and progression free survival (PFS) (HR = 2.34, 95%CI: 1.94-2.83, P < 0.001) in PCa patients. LncRNAs expression level was correlated with several vital clinical features, like tumor size (HR = 0.52, 95%CI: 0.28-0.95, P = 0.03), distance metastasis (HR = 4.55, 95%CI: 2.26-9.15, P < 0.0001) and histological grade (HR = 6.23, 95% CI: 3.29-11.82, P < 0.00001). Besides, down-regulation of PCAT14 was associated with the prognosis of PCa [over survival (HR = 0.77, 95%CI: 0.63-0.95, P = 0.01), BCR-FS (HR = 0.61, 95%CI: 0.48-0.79, P = 0.0001), prostate cancer-specific survival (HR = 0.64, 95%CI: 0.48-0.85, P = 0.002) and metastasis-free survival (HR = 0.61, 95%CI: 0.50-0.74, P < 0.00001)]. And, the increased SChLAP1 expression could imply the worse BCR-FS (HR = 2.54, 95%CI: 1.82-3.56, P < 0.00001) and correlate with Gleason score (< 7 vs ≥ 7) (OR = 4.11, 95% CI: 1.94-8.70, P = 0.0002). Conclusively, our present work demonstrated that LncRNAs transcription level might be potential prognostic markers in PCa.

Biological effects and epidemiological consequences of arsenic exposure, and reagents that can ameliorate arsenic damage in vivo.

Through contaminated diet, water, and other forms of environmental exposure, arsenic affects human health. There are many U.S. and worldwide "hot spots" where the arsenic level in public water exceeds the maximum exposure limit. The biological effects of chronic arsenic exposure include generation of reactive oxygen species (ROS), leading to oxidative stress and DNA damage, epigenetic DNA modification, induction of genomic instability, and inflammation and immunomodulation, all of which can initiate carcinogenesis. High arsenic exposure is epidemiologically associated with skin, lung, bladder, liver, kidney and pancreatic cancer, and cardiovascular, neuronal, and other diseases. This review briefly summarizes the biological effects of arsenic exposure and epidemiological cancer studies worldwide, and provides an overview for emerging rodent-based studies of reagents that can ameliorate the effects of arsenic exposure in vivo. These reagents may be translated to human populations for disease prevention. We propose the importance of developing a biomarker-based precision prevention approach for the health issues associated with arsenic exposure that affects millions of people worldwide.

Cbl-b predicts postoperative survival in patients with resectable pancreatic ductal adenocarcinoma.

Casitas B-lineage lymphoma b (Cbl-b) is a ubiquitin-protein ligase and a signal transducing adaptor protein involved in immune regulation, and it may be involved in the development and progression of cancer. We investigated the association between Cbl-b expression and prognosis in patients with resectable pancreatic ductal adenocarcinoma (PDAC). The clinicopathological characteristics and survival data of 134 patients with surgery for PDAC between January 2009 and February 2012 were retrospectively evaluated, and Cbl-b expression was assayed by immunohistochemical staining. The association of Cbl-b expression with clinicopathological features and postoperative prognosis was analyzed. Cbl-b expression was strongly associated with the pathological primary tumor (pT) category (P = 0.005) and pathological TNM (pTNM) stage (P = 0.035), but not with other clinicopathological characteristics (all P > 0.05). In addition to current markers including pathological regional lymph nodes (pN) category, CA19-9, and histological differentiation, univariate and multivariate analysis found that Cbl-b was independently associated with overall survival (OS) of patients with resectable PDAC. Cbl-b was predictive of OS in a subgroup of patients with serum CA19-9 ≥ 37 U/mL. Cbl-b expression combined with pN, histological differentiation, and CA19-9 level could be used as a novel clinical model predictive of OS for patients with resectable PDAC. In conclusion, Cbl-b in resectable PDAC was an independent predictor of adverse prognosis. Cbl-b expression together with pN, histological differentiation, and CA19-9 level might lead to improved risk stratification and prognosis for patients with resectable PDAC.

Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells.

Pancreatic ductal adenocarcinoma (PDAC) is the 4(th) leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC). The potency of IL-15 to promote NK cell-mediated killing was evaluated phenotypically and functionally. In addition, NK cell and immune checkpoint ligands on PSC were charted. We demonstrate that IL-15 activated NK cells kill both PCC and PSC lines (range 9-35% and 20-50%, respectively) in a contact-dependent manner and significantly higher as compared to resting NK cells. Improved killing of these pancreatic cell lines is, at least partly, dependent on IL-15 induced upregulation of TIM-3 and NKG2D. Furthermore, we confirm significant killing of primary PSC by IL-15 activated NK cells in an ex vivo autologous system. Screening for potential targets for immunotherapeutic strategies, we demonstrate surface expression of both inhibitory (PD-L1, PD-L2) and activating (MICA/B, ULBPs and Galectin-9) ligands on primary PSC. These data underscore the therapeutic potential of IL-15 to promote NK cell-mediated cytotoxicity as a treatment of pancreatic cancer and provide promising future targets to tackle remaining PSC.

Role of glucose metabolism related gene GLUT1 in the occurrence and prognosis of colorectal cancer.

Colorectal cancer (CRC) ranks the third most commonly diagnosed cancer in males and the second in females worldwide. However, the functional and causal SNPs for CRC remain to be mined. Glucose transporter 1 (GLUT1), a pivotal rate-limiting element in the transport of glucose in malignancy cells, has been identified to be associated with many cancers. Here, we aim to explore the role of GLUT1 in the occurrence and prognosis of colorectal cancer in a Chinese population. We found that GLUT1 expression levels in CRC tumor tissues were significantly higher than those in the corresponding adjacent normal tissues, and Cox multivariate analysis demonstrated that the GLUT1 expression was an independent prognostic factor for CRC (HR = 2.11, 95% CI = 1.33-3.34, P=0.001). For a functional polymorphism of GLUT1 (rs710218), we found that individuals with TT genotype (OR = 1.68, 95% CI = 1.02-2.75, P = 0.041) or AT genotype (OR = 1.47, 95% CI = 1.09-1.99, P = 0.012) of rs710218 had a significantly increased risk of CRC compared to those with AA homozygote. These findings strongly suggest that glucose metabolism related gene GLUT1, and its functional SNP, rs710218 might contribute to CRC susceptibility and prognosis, and the exact biological mechanism awaits further research.

Selection of optimal molecular targets for tumor-specific imaging in pancreatic ductal adenocarcinoma.

Discrimination of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) or peritumoral inflammation is challenging, both at preoperative imaging and during surgery, but it is crucial for proper therapy selection. Tumor-specific molecular imaging aims to enhance this discrimination and to help select and stratify patients for resection. We evaluated various biomarkers for the specific identification of PDAC and associated lymph node metastases. Using immunohistochemistry (IHC), expression levels and patterns were investigated of integrin αvβ6, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), Cathepsin E (Cath E), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), thymocyte differentiation antigen 1 (Thy1), and urokinase-type plasminogen activator receptor (uPAR). In a first cohort, multiple types of pancreatic tissue were evaluated (n=62); normal pancreatic tissue (n=8), CP (n=7), PDAC (n=9), tumor associated lymph nodes (n=32), and PDAC after neoadjuvant radiochemotherapy (n=6). In a second cohort, tissues were investigated (n=55) with IHC and immunofluorescence (IF) for concordance of biomarker expression in all tissue types, obtained from an individual patient. Integrin αvβ6 and CEACAM5 showed significantly higher expression levels in PDAC versus normal pancreatic tissue (P=0.001 and P<0.001, respectively) and CP (P=0.003 and P<0.001, respectively). Avβ6 and CEACAM5 expression identified tumor-positive lymph nodes correctly in 84% and 68%, respectively, and in 100% of tumor-negative nodes for both biomarkers. In conclusion, αvβ6 and CEACAM5 are excellent biomarkers to differentiate PDAC from surrounding tissue and to identify lymph node metastases. Individually or combined, these biomarkers are promising targets for tumor-specific molecular imaging of PDAC.

Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells.

Metformin is most widely prescribed for type 2 diabetes. Recently, evidences have shown that metformin has anticancer effects on pancreatic-, colorectal-, ovarian-, and other cancers. Because metformin has less adverse effects and is inexpensive, it could be a useful chemo-therapeutic agent with anticancer effects. In this study, we demonstrated metformin inhibited by cell proliferation, cell migration ability, clonogenic ability, and cancer stem cell population. Metformin also induced cell cycle arrest in parental-(SNU-C5), and 5-Fu resistant-colorectal cancer cell line (SNU-C5_5FuR). Moreover, a treatment that combines 5-Fu and metformin was found to have a synergistic effect on the cell proliferation rate, especially in SNU-C5_5FuR, which was mediated by the activation of AMPK pathway and NF-ƙB pathway, well-known metformin mechanisms. In this study, we suggested novel anticancer mechanism of metformin that inhibited DNA replication machinery, such as the MCM family in SNU-C5_5FuR. In conclusion, we provided that how metformin acts as not only a chemo-sensitizer, but also as a synergistic effector of 5-Fu in the 5-Fu resistant-cell line. We speculate that metformin used for adjuvant therapy is effective on 5-Fu resistant cancer cells.

Increased expression of calponin 2 is a positive prognostic factor in pancreatic ductal adenocarcinoma.

Calponin 2 plays an important role in regulating actin cytoskeleton, which is critical for cell division and migration. Previous studies have demonstrated that calponin 2 inhibits prostate cancer cell proliferation and metastasis. However, the role of calponin 2 in pancreatic tumor growth, metastasis and patient survival remains unclear. Here, we demonstrate that the level of calponin 2 is a positive prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC). Patients with high calponin 2 expression in the tumor presented less lymph node metastasis and longer survival. Knockdown of calponin 2 facilitated pancreatic cancer cell proliferation and metastasis. Further experiments suggested that PI3K/AKT, NF-κB, Vimentin, Fibronectin, Snail and Slug were upregulated and E-cadherin was downregulated after calponin 2 was knocked down, implicating altered functions in PDAC proliferation and metastasis. In addition, we verified that calponin 2 functioned through inhibiting PI3K/AKT and NF-κB pathways. Our study suggests that the upregulation of calponin 2 in PDAC correlates to lower malignancy and presents a novel target for the development of new treatment.

Baicalein inhibits pancreatic cancer cell proliferation and invasion via suppression of NEDD9 expression and its downstream Akt and ERK signaling pathways.

Baicalein, a flavone ingredient of Scutellaria baicalensis Georgi, is a promising anti-cancer agent. However, its potential anti-pancreatic cancer effects and the underlying mechanisms are still unclear. In this study, we showed that Baicalein not only induced apoptosis, but also suppressed proliferation, migration and invasion of two pancreatic cancer cell lines BxPC-3 and PANC-1 in a dose- and time-dependent manner. Notably, Baicalein exhibited low toxicity to normal human liver or kidney cells. We further discovered that Baicalein suppressed BxPC-3 and PANC-1 cell proliferation and invasion through targeting the expression of NEDD9, a Cas scaffolding protein, to decrease Akt and ERK activities. Especially, Baicalein decreased Akt phosphorylation at T-308 via lowering NEDD9-dependent PDK1 expression. Overexpression of NEDD9 effectively rescued proliferation and invasion of BxPC-3 and PANC-1 cells dampened by Baicalein. Taken together, our findings suggest that Baicalein is a potent remedy applied to pancreatic cancer treatment in the future.

Up-regulation of LINC00161 correlates with tumor migration and invasion and poor prognosis of patients with hepatocellular carcinoma.

Accumulating evidence suggested that long non-coding RNAs (lncRNAs) play essential roles in various biological processes, including tumorigenesis. Aberrant expression of LINC00161 has been reported in some cancer types, however, the association of LINC00161 and hepatocellular carcinoma (HCC) has not been evaluated. Here, we measured the expression of LINC00161 in HCC tissues and corresponding normal liver tissues using real-time PCR. The result showed that the expression level of LINC00161 was significantly higher in HCC tissues. Further analysis indicated that HCC patients with higher LINC00161 expression have shorter survival. Multivariate Cox regression analysis showed that LINC00161 expression was an independent prognostic factor for the overall survival. Furthermore, our result indicated that knock-down of LINC00161 can significantly inhibit liver cancer cell migration and invasion. The present work indicated that LINC00161 might serve as an oncogenic gene and play a pivotal role in promoting tumor migration and invasion in HCC. Our work implicates the promising effect of LINC00161 on the prognosis of HCC.

Cytotoxic Evaluation of (2S)-5,7-Dihydroxy-6-prenylflavanone Derivatives Loaded PLGA Nanoparticles against MiaPaCa-2 Cells.

The search for new alternatives for the prevention and treatment of cancer is extremely important to minimize human mortality. Natural products are an alternative to chemical drugs, since they are a source of many potential compounds with anticancer properties. In the present study, the (2S)-5,7-dihydroxy-6-prenylflavanone (semi-systematic name), also called (2S)-5,7-dihydroxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one (CAS Name registered) (1) was isolated from Eysenhardtia platycarpa leaves. This flavanone 1 was considered as the lead compound to generate new cytotoxic derivatives 1a, 1b, 1c and 1d. These compounds 1, 1a, 1b, 1c, and 1d were then loaded in nanosized drug delivery systems such as polymeric nanoparticles (NPs). Small homogeneous spherical shaped NPs were obtained. Cytotoxic activity of free compounds 1, 1a, 1b, 1c, and 1d and encapsulated in polymeric NPs (NPs1, NPs1a, NPs1b, NPs1c and NPs1d) were evaluated against the pancreatic cancer cell line MiaPaCa-2. The obtained results demonstrated that NPs1a and NPs1b exhibited optimal cytotoxicity, and an even higher improvement of the cytotoxic efficacy was exhibited with the encapsulation of 1a. Based on these results, NPs1a were proposed as promising anticancer agent candidates.