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Gall TMH, Gerrard G, Frampton AE, et al., 2019, Can we predict long-term survival in resectable pancreatic ductal adenocarcinoma?, Oncotarget, Vol: 10, Pages: 696-706, ISSN: 1949-2553
Objective: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumour associated with poor 5-year survival. We aimed to determine factors which differentiate short and long-term survivors and identify a prognostic biomarker. Methods: Over a ten-year period, patients with resected PDAC who developed disease recurrence within 12 months (Group I) and those who had no disease recurrence for 24 months (Group II) were identified. Clinicopathological data was analysed. Ion Torrent high-throughput sequencing on DNA extracted from FFPE tumour samples was used to identify mutations. Additionally, peripheral blood samples were analysed for variants in cell-free DNA, circulating tumour cells (CTCs), and microRNAs. Results: Multivariable analysis of clinicopathological factors showed that a positive medial resection margin was significantly associated with short disease-free survival (p = 0.007). Group I patients (n = 21) had a higher frequency of the KRAS mutant mean variant allele (16.93% ± 11.04) compared to those in Group II (n = 13; 7.55% ± 5.76, p = 0.0078). Group I patients also trended towards having a KRAS c.35G>A p.Gly12Asp mutation in addition to variants in other genes, such as TP53, CDKN2A, and SMAD4. Mutational status of cell-free DNA, and number of CTCs, was not found to be useful in this study. A circulating miRNA (hsa-miR-548ah-5p) was found to be significantly differentially expressed. Conclusions: Medial resection margin status and the frequency of KRAS mutation in the tumour tissue are independent prognostic indicators for resectable PDAC. Circulating miRNA hsa-miR-548ah-5p has the potential to be used as a prognostic biomarker.
Reccia I, Kumar J, Habib N, et al., 2018, The use of radiofrequency ablation in pancreatic cancer in the midst of the dawn of immuno-oncology, MEDICAL ONCOLOGY, Vol: 35, ISSN: 1357-0560
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- Citations: 8
Blagden SP, Rizzuto I, Suppiah P, et al., 2018, Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study, British Journal of Cancer, Vol: 119, Pages: 815-822, ISSN: 0007-0920
BackgroundGemcitabine is used to treat a wide range of tumours, but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms.MethodsSixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess the safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed.ResultsSixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate. Cmax levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle.ConclusionsNUC-1031 was well tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive.
Reccia I, Kumar J, Kusano T, et al., 2018, Radiofrequency-assisted liver resection: Technique and results, Surgical Oncology, Vol: 27, Pages: 415-420, ISSN: 0960-7404
BackgroundRadiofrequency (RF)-assisted liver resection allows non-anatomical liver resection with reduced blood loss and offers the opportunity for a combination of resection and ablation. However, there are still concerns with regard to postoperative complications related to this technique. In the present study, we discuss the technical aspects of RF-assisted liver resections and analyse the rate of perioperative complications, focusing on post-hepatectomy liver failure (PLF), bile leak and abscess, and mortality.MethodsBetween 2001 and 2015, 857 consecutive open and laparoscopic elective RF-assisted liver resections for benign and malignant liver tumours were reviewed retrospectively to assess perioperative outcomes.ResultsMedian intraoperative blood loss was 130 mL, with 9.8% of patients requiring blood transfusion. Intra-abdominal collections requiring percutaneous drainage developed in 8.7% of all patients, while bile leak at resection margin developed in 2.8% of the cases. Major liver resection was performed in 34% of patients and the incidence of PLF was 1.5% with one directly related mortality (0.1%).ConclusionRF-assisted liver resection has evolved into a feasible and safe technique of liver resection with an acceptable incidence of perioperative morbidity and a low incidence of PLF and related mortality.
Mazmishvili K, Jayant K, Janikashvili N, et al., 2018, Study to evaluate the immunomodulatory effects of radiofrequency ablation compared to surgical resection for liver cancer, Journal of Cancer, Vol: 9, Pages: 3187-3195, ISSN: 1837-9664
Introduction: Hepatic cancer is a highly lethal tumour with increasing worldwide incidence. These tumours are characterized by the proliferation of malignant cells, generalised immunosuppression and chronic inflammation marked with an increase in inflammatory markers as a neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and overexpression of CD4+CD39+ on T lymphocytes. The studies have outlined immunomodulatory changes in liver cancer patients as the plausible explanation for the better survival. The aim of this pilot study was understand the possible immunomodulatory effect of radiofrequency (RF) energy and liver resection (non-radiofrequency based devices; non-RF device) in relation to NLR, PLR and expression of CD4+CD39+ T lymphocytes and compare the magnitude of these changes.Material and Methods: In the present study, 17 patients with hepatic cancer were prospectively divided into treatment groups radiofrequency ablation (RFA group) and Liver resection using non-RF devices (LR group). A blood sample was collected from each patient, one month before and after the procedure and compared with the blood samples of age-matched healthy volunteers for group wise comparison. The Mann-Whitney U test, Mc Nemar test and Wilcoxon rank test were used for statistical comparisons as appropriate.Results: A decrease in NLR was reported after RFA from 4.7±3.3 to 3.8±1.8 (P=0.283), in contrary to an increase from 3.5±2.8 to 4.5±3.2 (P=0.183) in LR group. Likewise, a decrease was discerned in PLR following RFA from 140.5±79.5 to 137±69.2 respectively (P=0.386) and increase in the LR group from 116±42.2 to 120.8±29 respectively (P=0.391). A significant decrease in CD4+CD39+ lymphocytes from 55.8±13.8 to 24.6±21.1 (P=0.03) was observed in RFA group whilst a significant increase was reported in LR group from 47.6±8.8 to 55.7±33.2 (P=0.38).Conclusion: Studies have shown that
Setten RL, Lightfoot HL, Habib NA, et al., 2018, Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocellular Carcinoma, Current Pharmaceutical Biotechnology, Vol: 19, Pages: 611-621, ISSN: 1389-2010
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.
Reccia I, Sodergren MH, Jayant K, et al., 2018, The journey of radiofrequency-assisted liver resection, Surgical Oncology, Vol: 27, Pages: A16-A18, ISSN: 0960-7404
Sarker D, Plummer ER, Basu B, et al., 2018, Preliminary results of a first-in-human, first-in-class phase I study of MTL-CEBPA, a small activating RNA (saRNA) targeting the transcription factor C/EBP-α in patients with advanced liver cancer., Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
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- Citations: 2
Wong JK, Seifalian A, Mohseni R, et al., 2018, Emerging <i>In Vitro</i> 3D Tumour Models in Nanoparticle-Based Gene and Drug Therapy, TRENDS IN BIOTECHNOLOGY, Vol: 36, Pages: 477-480, ISSN: 0167-7799
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- Citations: 3
Frampton AE, Mato Prado M, Lopez Jimenez ME, et al., 2018, Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden, Oncotarget, Vol: 9, Pages: 19006-19013, ISSN: 1949-2553
Background: Glypican-1 (GPC1) is expressed in pancreatic ductal adenocarcinoma (PDAC) cells and adjacent stroma fibroblasts. Recently, GPC1 circulating exosomes (crExos) have been shown to be able to detect early stages of PDAC. This study 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 high 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, ISSN: 1949-2553
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.
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, Vol: 37, Pages: 3216-3228, ISSN: 0950-9232
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.
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
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- Citations: 14
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, Pages: e9106-e9106, ISSN: 0025-7974
RATIONALE: An isolated splenic metastasis is a rare phenomenon noted in advanced stage melanoma. We report the role of radiofrequency (RF) -based splenic-preserving splenectomy in a patient with a solitary splenic metastasis from advanced stage melanoma that was managed with checkpoint inhibitors. PATIENT CONCERNS: We report a case of a 60-year-old man who presented with multiple lung metastases and a solitary splenic metastasis with advanced stage melanoma following excision of primary from his trunk 2.3 years back. DIAGNOSIS: Considering the diagnosis of advanced stage melanoma with multiple lung metastases and a solitary splenic metastasis, and its ongoing progressive nature. This case was discussed in the tumour board meeting. INTERVENTIONS: A decision was made to commence treatment with immunotherapy in the form of PD-1 inhibitor (programmed cell death 1 receptor) pembrolizumab. Follow-up restaging computer tomography (CT) scan of the abdomen and chest showed a significant reduction in the lung and chest wall lesions, but the splenic lesion remained unchanged. Given the lack of response to treatment in the splenic metastasis and the significant decrease in lung metastases, the multidisciplinary team decided that a partial splenectomy combined with continued immunotherapy treatment would be appropriate as the success of immunotherapy was imminent within the splenic preservation. OUTCOMES: The postoperative recovery was smooth and the patient was discharged from hospital on the sixth postoperative day with normal platelets and white blood cells. The histopathological analysis of the resected specimen showed a metastatic melanoma with negative margins.At 10-month follow-up after the splenic resection the patient had not experienced further tumour recurrences. LESSONS: Spleen-preserving resection for an isolated, solitary splenic metastasis of melanoma is a feasible approach as it not only preserves the ongoing efficacy of checkpoint inhibitors by preserving the ph
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
Background: The aim of this study was to evaluate the oncological outcomes of hepatocellular carcinoma patients undergoing liver resection using cavitron ultrasonic surgical aspirator (CUSA) or radiofrequency (RF) based device Habib-4X.Study Design: We prospectively analyzed the data of 280 patients who underwent liver resection for hepatocellular carcinoma at our institution from 2010–2012 with follow up till August 2016. The CUSA was used in the 163 patients whilst Habib-4X in 117 patients. The end points of analysis were oncological outcomes as disease recurrence, disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan–Meier method, which has been compared with all other existing literature on the survival study.Results: Compared with CUSA the reported incidence of recurrence was significantly lower, in Habib-4X group; p < 0.01. The median DFS was significantly better in Habib-4X group than CUSA group (50.80 vs 45.87 months, p = 0.03). The median OS was better in Habib-4X group than CUSA group (60.57 vs 57.17 months, p = 0.12) though the lesser difference in OS between the groups might be explained by the use of palliative therapies as TACE, percutaneous RFA, etc. in case of recurrence.Conclusions: RF based device Habib-4X, is safe and effective device for resection of hepatocellular carcinoma, in comparison to CUSA with better oncological outcomes, i.e., significantly lesser tumour recurrence and better DFS. This could be explained on the basis of systemic and local immunomodulatory effect involving induction of kupffer cells and effector CD-8 T cells that help in minimizing postoperative complications and bring more advantageous oncological outcomes.
Vavra P, Roman J, Zonca P, et al., 2017, Recent Development of Augmented Reality in Surgery: A Review, Journal of Healthcare Engineering, Vol: 2017, ISSN: 2040-2309
Introduction. The development augmented reality devices allow physicians to incorporate data visualization into diagnostic and treatment procedures to improve work efficiency, safety, and cost and to enhance surgical training. However, the awareness of possibilities of augmented reality is generally low. This review evaluates whether augmented reality can presently improve the results of surgical procedures. Methods. We performed a review of available literature dating from 2010 to November 2016 by searching PubMed and Scopus using the terms “augmented reality” and “surgery.” Results. The initial search yielded 808 studies. After removing duplicates and including only journal articles, a total of 417 studies were identified. By reading of abstracts, 91 relevant studies were chosen to be included. 11 references were gathered by cross-referencing. A total of 102 studies were included in this review. Conclusions. The present literature suggest an increasing interest of surgeons regarding employing augmented reality into surgery leading to improved safety and efficacy of surgical procedures. Many studies showed that the performance of newly devised augmented reality systems is comparable to traditional techniques. However, several problems need to be addressed before augmented reality is implemented into the routine practice.
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
Organic nanoparticle-based (ONP) gene therapy is a potential strategy to cure human cancer. However, there are still many practical barriers before the promising results from in vitro and preclinical studies can be translated to clinical success. We discuss the reasons behind the hesitant uptake by the clinic.
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
Small activating RNAs (saRNAs) are short double-stranded oligonucleotides that selectively increase gene transcription. Here, we describe the development of an saRNA that upregulates the transcription factor CCATT/enhancer binding protein alpha (CEBPA), investigate its mode of action, and describe its development into a clinical candidate. A bioinformatically directed nucleotide walk around the CEBPA gene identified an saRNA sequence that upregulates CEBPA mRNA 2.5-fold in human hepatocellular carcinoma cells. A nuclear run-on assay confirmed that this upregulation is a transcriptionally driven process. Mechanistic experiments demonstrate that Argonaute-2 (Ago2) is required for saRNA activity, with the guide strand of the saRNA shown to be associated with Ago2 and localized at the CEBPA genomic locus using RNA chromatin immunoprecipitation (ChIP) assays. The data support a sequence-specific on-target saRNA activity that leads to enhanced CEBPA mRNA transcription. Chemical modifications were introduced in the saRNA duplex to prevent activation of the innate immunity. This modified saRNA retains activation of CEBPA mRNA and downstream targets and inhibits growth of liver cancer cell lines in vitro. This novel drug has been encapsulated in a liposomal formulation for liver delivery, is currently in a phase I clinical trial for patients with liver cancer, and represents the first human study of an saRNA therapeutic.
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
PURPOSE: The aim of this study is to provide a technical detail and feasibility of percutaneous image-guided pancreatic duct (PD) drainage and to discuss its subtleties in a series of patients with obstructed PD. MATERIALS AND METHODS: Thirty patients presenting with PD obstruction from pancreatic head tumour or pancreatitis were subjected to percutaneous image-guided PD drainage under a guidance of ultrasound or computed tomography. Following the successful puncture of PD, a locking loop drainage catheter was placed using conventional guidewire techniques under real-time fluoroscopy guidance. RESULTS: The percutaneous drainage of obstructed PD was completed in 29 (96.7%) patients as an independent therapeutic intent or as a bridge to further percutaneous procedures. Clinical improvement following drainage was documented by the gradual reduction in clinical symptoms, including pain, nausea and fever and improved blood test results, showing the significant decrease of amylase concentration. The amount of pancreatic fluid drained post procedure was between 300 and 900 mL/day. No major procedure-related complications were observed. Subsequently, 14 of 29 patients underwent further procedures, including endoluminal placement of metal stent with or without radiofrequency ablation, balloon assisted percutaneous descending litholapaxy (BAPDL), endoluminal biopsy and balloon dilatation using the same drainage tract. CONCLUSION: The percutaneous PD drainage appears to be a safe and effective procedure. It should be considered in patients with obstructed PD secondary to malignancy, pancreatitis etc., where endoscopic retrograde cannulation has been failed or impracticable. The procedure can also be contemplated either as an independent treatment option or as an initial step for the subsequent therapeutic endoluminal procedures.
Habib N, Reebye V, Zhao X, et al., 2017, MTL-CEBPA activates the transcription factor CEBPalpha leading to inhibition of hepatocellular cancer growth, CANCER RESEARCH, Vol: 77, ISSN: 0008-5472
Zhao X, Voutila J, Ghobrial S, et al., 2017, Treatment of liver cancer by C/EBPA-saRNA., Advances in Experimental Medicine and Biology
Reccia I, Kumar J, Tomokazu K, et al., 2017, A systemic review on radiofrequency assisted laparoscopic liver resection: Challenges and window to excel, Surgical Oncology, Vol: 26, Pages: 296-304, ISSN: 1879-3320
Laparoscopic liver resection has progressively gained acceptance as a safe and effective procedure in the treatment of benign and malignant liver neoplasms. However, blood loss remains the major challenge in liver surgery. Several techniques and devices have been introduced in liver surgery in order to minimize intraoperative haemorrhage during parenchymal transection. Radiofrequency (RF)-assisted liver resection has been shown to be an effective method to minimize bleeding in open and laparoscopic liver resection. A number of RF devices for parenchymal transection have been designed to assist laparoscopic liver resections. Here we have reviewed the results of various RF devices in laparoscopic liver resection. A total 15 article were considered relevant for the evaluation of technical aspects and outcomes of RF-assisted liver resections in laparoscopic procedures. In these studies, 176 patients had laparoscopic liver resection using RF-assisted parenchymal coagulation. Two monopolar and three bipolar devices were employed. Blood loss was limited in most of the studies. The need of blood transfusions was limited to two cases in all the series. Conversion was necessary due to bleeding in 3 cases. Operative and transection times varied between studies. However, RF-assisted resection with bipolar devices appeared to have taken less time in comparison to other RF devices. RF-related complications were minimum, and only one case of in-hospital death due to hepatic failure was reported. Although RF has been used in a small minority of laparoscopic liver resections, laparoscopic RF-assisted liver resection for benign and malignant disease is a safe and feasible procedure associated with reduction in blood loss, low morbidity, and lower hospital mortality rates.
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: Elsevier (Cell Press), Pages: 34-34, ISSN: 1525-0024
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: Elsevier (Cell Press), Pages: 43-43, ISSN: 1525-0024
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
Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and leading cause of cirrhosis in the United States and developed countries. NAFLD is closely associated with obesity, insulin resistance and metabolic syndrome, significantly contributing to the exacerbation of the latter. Although NAFLD represents the hepatic component of metabolic syndrome, it can also be found in patients prior to their presentation with other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly involved in its pathogenesis and progression. In this review, we bring together the current understanding of the pathogenesis that makes NAFLD a systemic disease.
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
Identifying targets that are exposed on the plasma membrane of tumor cells, but expressed internally in normal cells, is a fundamental issue for improving the specificity and efficacy of anticancer therpeutics. Using blind cell Systemic Evolution of Ligands by EXponetial enrichment (SELEX), which is untargeted SELEX, we have identified an aptamer, P15, which specifically bound to the human pancreatic adenocarcinoma cells. To identify the aptamer binding plasma membrane protein, liquid chromatography tandem mass spectrometry (LC-MS/MS) was used. The results of this unbiased proteomic mass spectrometry approach identified the target of P15 as the intermediate filament vimentin, biomarker of epithelial–mesenchymal transition (EMT), which is an intracellular protein but is specifically expressed on the plasma membrane of cancer cells. As EMT plays a pivotal role to transit cancer cells to invasive cells, tumor cell metastasis assays were performed in vitro. P15-treated pancreatic cancer cells showed the significant inhibition of tumor metastasis. To investigate the downstream effects of P15, EMT-related gene expression analysis was performed to identify differently expressed genes (DEG). Among five DEGs, P15-treated cells showed the downregulated expression of matrix metallopeptidase 3 (MMP3), which is involved in cancer invasion. These results, for the first time, demonstrate that P15 binding to cell surface vimentin inhibits the tumor cell invasion and is associated with reduced MMP3 expression. Thus, suggesting that P15 has potential as an anti-metastatic therapy in pancreatic cancer.
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
Habib N, Zhao XY, Voutila J, et al., 2017, Treatment of Liver Cancer by CEBPA saRNA, RNA Activation Innovative Medicine Advances in Experimental Medicine and Biology, Publisher: Springer, ISBN: 978-981-10-4310-9
Mintz P, Sætrom P, Reebye V, et al., 2016, MicroRNA-181a* targets Nanog in a subpopulation of CD34+ cells isolated from peripheral blood, Molecular Therapy - Nucleic Acids, Vol: 1, ISSN: 2162-2531
Exploiting the properties of stem cells by microRNA (miRNA) profiling offers an attractive approach to identify new regulators of stem cell fate. Although numerous miRNA have been screened from hematopoietic stem cells (HSC), the targets corresponding to many of these miRNA have not yet been fully elucidated. By miRNA profiling in a subpopulation of CD34+ cells isolated from peripheral blood, we have identified eight clusters of miRNA that were differentially expressed. Further analysis of one of the clusters by bioinformatics revealed that a miRNA, miR-181a*, which is highly expressed in the adherent CD34+ cells, affects the expression levels of Nanog, a stem cell surrogate marker. We show specifically by reporter assay and mutational analysis that miR-181a* targets a seedless 3′ compensatory site in the 3′UTR of Nanog and affects gene expression. We demonstrate that inhibiting miR-181a* upregulates the Nanog expression level, in addition to an increase in alkaline phosphatase activity. Our studies suggest that miR-181a* may be important in controlling the expression level of Nanog in a subpopulation of CD34+ cells.
Reebye V, Saetrom P, Mintz PJ, et al., 2016, A short-activating RNA oligonucleotide targeting the islet beta-cell transcriptional factor MafA in CD34(+) cells, MOLECULAR THERAPY-NUCLEIC ACIDS, Vol: 2, ISSN: 2162-2531
Upon functional loss of insulin producing islet β-cells, some patients with diabetes become dependent on life-long insulin supplementation therapy. Bioengineering surrogate insulin producing cells is an alternative replacement strategy. We have developed a novel approach using short-activating RNA oligonucleotides to differentiate adult human CD34+ cells into insulin-secreting cells. By transfecting RNA to increase transcript levels of the master regulator of insulin biosynthesis, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), several pancreatic endodermal genes were upregulated during the differentiation procedure. These included Pancreatic and duodenal homeobox gene-1 (PDX1), Neurogenin 3, NeuroD, and NK6 homeobox 1 (NKx6-1). Differentiated CD34+ cells also expressed glucokinase, glucagon-like peptide 1 receptor (GLP1R), sulfonylurea receptor-1 (SUR1) and phogrin'all essential for glucose sensitivity and insulin secretion. The differentiated cells appropriately processed C-peptide and insulin in response to increasing glucose stimulation as shown by enzyme-linked immunosorbent assay (ELISA), fluorescence-activated cell sorting analysis, western blotting, and immunofluorescence staining. We provide a new approach using short-activating RNA in developing insulin producing surrogate cells for treating diabetes.
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