436 results found
Frampton AE, Prado MM, López-Jiménez E, et al., 2018, Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden., Oncotarget, Vol: 9, Pages: 19006-19013
Background: Glypican-1 (GPC1) is expressed in pancreatic ductal adenocarcinoma (PDAC) cells and adjacent stromal fibroblasts. Recently, GPC1 circulating exosomes (crExos) have been shown to be able to detect early stages of PDAC. In this study, we investigated the usefulness of crExos GPC1 as a biomarker for PDAC. Methods: Plasma was obtained from patients with benign pancreatic disease (n = 16) and PDAC (n = 27) prior to pancreatectomy, and crExos were isolated by ultra-centrifugation. Protein was extracted from surgical specimens (adjacent normal pancreas, n = 13; and PDAC, n = 17). GPC1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: There was no significant difference in GPC1 levels between normal pancreas and PDAC tissues. This was also true when comparing matched pairs. However, GPC1 levels were enriched in PDAC crExos (n = 11), compared to the source tumors (n = 11; 97 ± 54 vs. 20.9 ± 12.3 pg/mL; P < 0.001). In addition, PDACs with high GPC1 expression tended to have crExos with higher GPC1 levels. Despite these findings, we were unable to distinguish PDAC from benign pancreatic disease using crExos GPC1 levels. Interestingly, we found that in matched pre and post-operative plasma samples there was a significant drop in crExos GPC1 levels after surgical resection for PDAC (n = 11 vs. 11; 97 ± 54 vs. 77.8 ± 32.4 pg/mL; P = 0.0428). Furthermore, we found that patients with high crExos GPC1 levels have significantly larger PDACs (>4 cm; P = 0.012). Conclusions: High GPC1 crExos may be able to determine PDAC tumor size and disease burden. However, further efforts are needed to elucidate its role as a diagnostic and/or prognostic biomarker using larger cohorts of PDAC patients.
Kumar J, Reccia I, Sodergren MH, et al., 2018, Radiofrequency assisted pancreaticoduodenectomy for palliative surgical resection of locally advanced pancreatic adenocarcinoma., Oncotarget, Vol: 9, Pages: 15732-15739
Background: Despite careful patient selection and preoperative investigations curative resection rate (R0) in pancreaticoduodenectomy ranges from 15% to 87%. Here we describe a new palliative approach for pancreaticoduodenectomy using a radiofrequency energy device to ablate tumor in situ in patients undergoing R1/R2 resections for locally advanced pancreatic ductal adenocarcinoma where vascular reconstruction was not feasible. Results: There was neither postoperative mortality nor significant morbidity. Each time the ablation lasted less than 15 minutes. Following radiofrequency ablation it was observed that the tumor remnant attached to the vessel had shrunk significantly. In four patients this allowed easier separation and dissection of the ablated tumor from the adherent vessel leading to R1 resection. In the other two patients, the ablated tumor did not separate from vessel due to true tumor invasion and patients had an R2 resection. The ablated remnant part of the tumor was left in situ. Conclusion: Whenever pancreaticoduodenectomy with R0 resection cannot be achieved, this new palliative procedure could be considered in order to facilitate resection and enable maximum destruction in remnant tumors. Method: Six patients with suspected tumor infiltration and where vascular reconstruction was not warranted underwent radiofrequency-assisted pancreaticoduodenectomy for locally advanced pancreatic ductal adenocarcinoma. Radiofrequency was applied across the tumor vertically 5-10 mm from the edge of the mesenteric and portal veins. Following ablation, the duodenum and the head of pancreas were removed after knife excision along the ablated line. The remaining ablated tissue was left in situ attached to the vessel.
Mizandari M, Kumar J, Pai M, et al., 2018, Interventional radiofrequency ablation: A promising therapeutic modality in the management of malignant biliary and pancreatic duct obstruction, JOURNAL OF CANCER, Vol: 9, Pages: 629-637, ISSN: 1837-9664
Reccia I, Sodergren MH, Jayant K, et al., 2018, The journey of radiofrequency-assisted liver resection., Surg Oncol
Reebye V, Huang K-W, Lin V, et al., 2018, Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer., Oncogene
Liver diseases are a growing epidemic worldwide. If unresolved, liver fibrosis develops and can lead to cirrhosis and clinical decompensation. Around 5% of cirrhotic liver diseased patients develop hepatocellular carcinoma (HCC), which in its advanced stages has limited therapeutic options and negative survival outcomes. CEPBA is a master regulator of hepatic function where its expression is known to be suppressed in many forms of liver disease including HCC. Injection of MTL-CEBPA, a small activating RNA oligonucleotide therapy (CEBPA-51) formulated in liposomal nanoparticles (NOV340- SMARTICLES) upregulates hepatic CEBPA expression. Here we show how MTL-CEBPA therapy promotes disease reversal in rodent models of cirrhosis, fibrosis, hepatosteatosis, and significantly reduces tumor burden in cirrhotic HCC. Restoration of liver function markers were observed in a carbon-tetrachloride-induced rat model of fibrosis following 2 weeks of MTL-CEBPA therapy. At 14 weeks, animals showed reduction in ascites and enhanced survival rates. MTL-CEBPA reversed changes associated with hepatosteatosis in non-alcoholic methionine and cholic-deficient diet-induced steaotic liver disease. In diethylnitrosamine induced cirrhotic HCC rats, MTL-CEBPA treatment led to a significant reduction in tumor burden. The data included here and the rapid adoption of MTL-CEBPA into a Phase 1 study may lead to new therapeutic oligonucleotides for undruggable diseases.
Setten RL, Lightfoot HL, Habib NA, et al., 2018, Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocellular Carcinoma., Curr Pharm Biotechnol
BACKGROUND: Oligonucleotide drug development has revolutionised the drug discovery field allowing the notoriously "undruggable" genome to potentially become "druggable". Within this field, 'small' or 'short' activating RNAs (saRNA) are a more recently discovered category of short double stranded RNA with clinical potential. SaRNAs promote endogenous transcription from target loci, a phenomenon widely observed in mammals known as RNA activation (RNAa). The ability to target a particular gene is dependent on the sequence of the saRNA. Hence, the potential clinical application of saRNA is to increase target gene expression in a sequence specific manner. SaRNA based oligonucleotide therapeutics present great promise in expanding the "druggable" genome with particular areas of interest including transcription factor activation and haploinsufficency. Review and Conclusion: In this mini-review, we describe the pre-clinical development of the first saRNA drug to enter the clinic. This saRNA, referred to as MTL-CEBPA, induces transcription of the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα), a tumour suppressor and critical regulator of hepatocyte function. MTL-CEBPA is presently in Phase I clinical trials for hepatocellular carcinoma (HCC). The clinical development of MTL-CEBPA will demonstrate "proof of concept", showing that saRNAs can provide the basis for drugs which enhance targeted gene expression and consequently improve disease outcome in patients.
Wong JK, Seifalian A, Mohseni R, et al., 2018, Emerging In Vitro 3D Tumour Models in Nanoparticle-Based Gene and Drug Therapy, TRENDS IN BIOTECHNOLOGY, Vol: 36, Pages: 477-480, ISSN: 0167-7799
Huang K-W, Lee P-H, Kusano T, et al., 2017, Impact of cavitron ultrasonic surgical aspirator (CUSA) and bipolar radiofrequency device (Habib-4X) based hepatectomy for hepatocellular carcinoma on tumour recurrence and disease-free survival, ONCOTARGET, Vol: 8, Pages: 93644-93654, ISSN: 1949-2553
Mizandari M, Azrumelashvili T, Kumar J, et al., 2017, Percutaneous Image-Guided Pancreatic Duct Drainage: Technique, Results and Expected Benefits, CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY, Vol: 40, Pages: 1911-1920, ISSN: 0174-1551
Mudan S, Kumar J, Mafalda NC, et al., 2017, Case report on the role of radiofrequency-assisted spleen-preserving surgery for splenic metastasis in the era of check-point inhibitors, MEDICINE, Vol: 96, ISSN: 0025-7974
Reccia I, Kumar J, Akladios C, et al., 2017, Non-alcoholic fatty liver disease: A sign of systemic disease, METABOLISM-CLINICAL AND EXPERIMENTAL, Vol: 72, Pages: 94-108, ISSN: 0026-0495
Reccia I, Kumar J, Kusano T, et al., 2017, A systematic review on radiofrequency assisted laparoscopic liver resection: Challenges and window to excel, SURGICAL ONCOLOGY-OXFORD, Vol: 26, Pages: 296-304, ISSN: 0960-7404
Vavra P, Roman J, Zonca P, et al., 2017, Recent Development of Augmented Reality in Surgery: A Review, JOURNAL OF HEALTHCARE ENGINEERING, ISSN: 2040-2295
Voutila J, Reebye V, Roberts T, et al., 2017, Mechanism and In Vivo Activity of a Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Disease, 20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: CELL PRESS, Pages: 34-34, ISSN: 1525-0016
Voutila J, Reebye V, Roberts TC, et al., 2017, Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer, MOLECULAR THERAPY, Vol: 25, Pages: 2705-2714, ISSN: 1525-0016
Wong JKL, Mohseni R, Hamidieh AA, et al., 2017, Will Nanotechnology Bring New Hope for Gene Delivery?, TRENDS IN BIOTECHNOLOGY, Vol: 35, Pages: 434-451, ISSN: 0167-7799
Wong JKL, Mohseni R, Hamidieh AA, et al., 2017, Limitations in Clinical Translation of Nanoparticle-Based Gene Therapy, TRENDS IN BIOTECHNOLOGY, Vol: 35, Pages: 1124-1125, ISSN: 0167-7799
Yoon S, Armstrong B, Habib N, et al., 2017, RNA Aptamers Selected Through Blind-SELEX Inhibit Pancreatic Cancer Cell Metastasis and Invasion by Regulating Epithelial Mesenchymal Transition(EMT), 20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: CELL PRESS, Pages: 43-43, ISSN: 1525-0016
Yoon S, Armstrong B, Habib N, et al., 2017, Blind SELEX Approach Identifies RNA Aptamers That Regulate EMT and Inhibit Metastasis, MOLECULAR CANCER RESEARCH, Vol: 15, Pages: 811-820, ISSN: 1541-7786
Yoon S, Huang K-W, Reebye V, et al., 2017, Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth, MOLECULAR THERAPY-NUCLEIC ACIDS, Vol: 6, Pages: 80-88, ISSN: 2162-2531
The prognosis for hepatocellular carcinoma (HCC) remains poor and has not improved in over two decades. Most patients with advanced HCC who are not eligible for surgery have limited treatment options due to poor liver function or large, unresectable tumors. Although sorafenib is the standard-of-care treatment for these patients, only a small number respond. For the remaining, the outlook remains bleak. A better approach to target "undruggable" molecular pathways that reverse HCC is therefore urgently needed. Small activating RNAs (saRNAs) may provide a novel strategy to activate expression of genes that become dysregulated in chronic disease. The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα), a critical regulator of hepatocyte function, is suppressed in many advanced liver diseases. By using an saRNA to activate C/EBPα, we can exploit the cell's own transcription machinery to enhance gene expression without relying on exogenous vectors that have been the backbone of gene therapy. saRNAs do not integrate into the host genome and can be modified to avoid immune stimulation. In preclinical models of liver disease, treatment with C/EBPα saRNA has shown reduction in tumor volume and improvement in serum markers of essential liver function such as albumin, bilirubin, aspartate aminotransferase (AST), and alanine transaminase (ALT). This saRNA that activates C/EBPα for advanced HCC is the first saRNA therapy to have entered a human clinical trial. The hope is that this new tool will help break the dismal 20-year trend and provide a more positive prognosis for patients with severe liver disease.
Blakey D, Reebye V, Voutila J, et al., 2016, Small activating RNA to CEBPA as a novel therapeutic approach to treat patients with liver cancer, 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Publisher: ELSEVIER SCI LTD, Pages: S149-S149, ISSN: 0959-8049
Clift A, Pai M, Habib N, et al., 2016, Endoscopic Ultrasound-Guided Radiofrequency Ablation for Pancreatic Neoplasms, 13th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 91-91, ISSN: 0028-3835
Frampton AE, Krell J, Prado MM, et al., 2016, Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies, ONCOTARGET, Vol: 7, Pages: 28556-28569, ISSN: 1949-2553
Giglio MC, Giakoustidis A, Draz A, et al., 2016, Oncological Outcomes of Major Liver Resection Following Portal Vein Embolization: A Systematic Review and Meta-analysis, ANNALS OF SURGICAL ONCOLOGY, Vol: 23, Pages: 3709-3717, ISSN: 1068-9265
Giglio MC, Spalding DRC, Giakoustidis A, et al., 2016, Meta-analysis of drain amylase content on postoperative day 1 as a predictor of pancreatic fistula following pancreatic resection, BRITISH JOURNAL OF SURGERY, Vol: 103, Pages: 328-336, ISSN: 0007-1323
Huan H, Wen X, Chen X, et al., 2016, C/EBP alpha Short-Activating RNA Suppresses Metastasis of Hepatocellular Carcinoma through Inhibiting EGFR/beta-Catenin Signaling Mediated EMT, PLOS ONE, Vol: 11, ISSN: 1932-6203
Reebye V, Huang K-W, Czysz K, et al., 2016, Hepatocellular Nuclear Factor 4 alpha (HNF-4 alpha) activation by saRNA rescues dyslipidemia and promotes favorable metabolic profile in a high fat diet (HFD) fed rat model., 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY, Pages: 794A-794A, ISSN: 0270-9139
Reebye V, Voutila J, Blakey D, et al., 2016, The clinical candidate MTL-CEBPA leads to significant reduction in ascites and improvement in overall survival in a CCl4-induced acute liver failure model., 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY, Pages: 1045A-1046A, ISSN: 0270-9139
Yoon S, Huang K-W, Habib N, et al., 2016, Potent Anti-Tumor Effects of ApDCs (Aptamer Drug Conjugates) for Targeted Therapeutics in Pancreatic Cancer, 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: NATURE PUBLISHING GROUP, Pages: S265-S265, ISSN: 1525-0016
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