Does a Screening Trial for Spinal Cord Stimulation in Patients with Chronic Pain of Neuropathic Origin have Clinical Utility and Cost-Effectiveness? (TRIAL-STIM Study): study protocol for a randomised controlled trial

Abstract Background The TRIAL-STIM Study aims to assess the diagnostic performance, clinical outcomes and cost-effectiveness of a screening trial prior to full implantation of a spinal cord stimulation (SCS) device. Methods/design The TRIAL-STIM Study is a superiority, parallel-group, three-centre, randomised controlled trial in patients with chronic neuropathic pain with a nested qualitative study and economic evaluation. The study will take place in three UK centres: South Tees Hospitals NHS Foundation Trust (The James Cook University Hospital); Basildon and Thurrock University Hospitals NHS Foundation Trust; and Leeds Teaching Hospitals NHS Trust. A total of 100 adults undergoing SCS implantation for the treatment of neuropathy will be included. Subjects will be recruited from the outpatient clinics of the three participating sites and randomised to undergo a screening trial prior to SCS implant or an implantation-only strategy in a 1:1 ratio. Allocation will be stratified by centre and minimised on patient age (≥ 65 or < 65 years), gender, presence of failed back surgery syndrome (or not) and use of high frequency (HF10™) (or not). The primary outcome measure is the numerical rating scale (NRS) at 6 months compared between the screening trial and implantation strategy and the implantation-only strategy. Secondary outcome measures will include diagnostic accuracy, the proportion of patients achieving at least 50% and 30% pain relief at 6 months as measured on the NRS, health-related quality-of-life (EQ-5D), function (Oswestry Disability Index), patient satisfaction (Patients’ Global Impression of Change) and complication rates. A nested qualitative study will be carried out in parallel for a total of 30 of the patients recruited in each centre (10 at each centre) to explore their views of the screening trial, implantation and overall use of the SCS device. The economic evaluation will take the form of a cost–utility analysis. Discussion The TRIAL-STIM Study is a randomised controlled trial with a nested qualitative study and economic evaluation aiming to determine the clinical utility of screening trials of SCS as well as their cost-effectiveness. The nested qualitative study will seek to explore the patient’s view of the screening trials, implantation and overall use of SCS. Trial registration ISRCTN, ISRCTN60778781. Registered on 15 August 2017

Down-Regulation of GEP100 Causes Increase in E-Cadherin Levels and Inhibits Pancreatic Cancer Cell Invasion

AIMS: Invasion and metastasis are major reasons for pancreatic cancer death and identifying signaling molecules that are specifically used in tumor invasion is of great significance. The purpose of this study was to elucidate the role of GEP100 in pancreatic cancer cell invasion and metastasis and the corresponding molecular mechanism. METHODS: Stable cell lines with GEP100 knocked-down were established by transfecting GEP100 shRNA vector into PaTu8988 cells and selected by puromycin. qRT-PCR and Western blot were performed to detect gene expression. Matrigel-invasion assay was used to detect cancer cell invasion in vitro. Liver metastasis in vivo was determined by splenic injection of indicated cell lines followed by spleen resection. Immunofluorescence study was used to detect the intracellular localization of E-cadherin. RESULTS: We found that the expression level of GEP100 protein was closely related to the invasive ability of a panel of 6 different human pancreatic cancer cell lines. Down-regulation of GEP100 in PaTu8988 cells significantly decreased invasive activity by Matrigel invasion assay, without affecting migration, invasion and viability. The inhibited invasive activity was rescued by over-expression of GEP100 cDNA. In vivo study showed that liver metastasis was significantly decreased in the PaTu8988 cells with GEP100 stably knocked-down. In addition, an epithelial-like morphological change, mimicking a mesenchymal to epithelial transition (MET) was induced by GEP100 down-regulation. The expression of E-cadherin protein was increased 2-3 folds accompanied by its redistribution to the cell-cell contacts, while no obvious changes were observed for E-cadherin mRNA. Unexpectedly, the mRNA of Slug was increased by GEP100 knock-down. CONCLUSION: These findings provided important evidence that GEP100 plays a significant role in pancreatic cancer invasion through regulating the expression of E-cadherin and the process of MET, indicating the possibility of it becoming a potential therapeutic target against pancreatic cancer

The Anti-Tumor Effect of HDAC Inhibition in a Human Pancreas Cancer Model Is Significantly Improved by the Simultaneous Inhibition of Cyclooxygenase 2

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date. In this study, we tested whether the combined inhibition of cyclooxygenase-2 (COX-2) and class I histone deacetylase (HDAC) may results in a better control of pancreatic ductal adenocarcinoma. The impact of the concomitant HDAC and COX-2 inhibition on cell growth, apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC-3, PANC-1 or CFPAC-1 cells treated with chemical inhibitors (SAHA, MS-275 and celecoxib) or HDAC1/2/3/7 siRNA. To test the potential antitumoral activity of this combination in vivo, we have developed and characterized, a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma. The combination of HDAC1/3 and COX-2 inhibition significantly impaired proliferation of BxPC-3 cells in vitro and stalled entirely the BxPC-3 cells tumor growth onto the chorioallantoic membrane in vivo. The combination was more effective than either drug used alone. Consistently, we showed that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 via the NF-kB pathway. Our data demonstrate, for the first time in a Pancreatic Ductal Adenocarcinoma (PDAC) model, a significant action of HDAC and COX-2 inhibitors on cancer cell growth, which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients.Peer reviewe

The first samples from Almahata Sitta showing contacts between ureilitic and chondritic lithologies: implications for the structure and composition of asteroid 2008 TC 3

Almahata Sitta (AhS), an anomalous polymict ureilite, is the first meteorite observed to originate from a spectrally classified asteroid (2008 TC3). However, correlating properties of the meteorite with those of the asteroid is not straightforward because the AhS stones are diverse types. Of those studied prior to this work, 70–80% are ureilites (achondrites) and 20–30% are various types of chondrites. Asteroid 2008 TC3 was a heterogeneous breccia that disintegrated in the atmosphere, with its clasts landing on Earth as individual stones and most of its mass lost. We describe AhS 91A and AhS 671, which are the first AhS stones to show contacts between ureilitic and chondritic materials and provide direct information about the structure and composition of asteroid 2008 TC3. AhS 91A and AhS 671 are friable breccias, consisting of a C1 lithology that encloses rounded to angular clasts (<10 μm to 3 mm) of olivine, pyroxenes, plagioclase, graphite, and metal‐sulfide, as well as chondrules (~130–600 μm) and chondrule fragments. The C1 material consists of fine‐grained phyllosilicates (serpentine and saponite) and amorphous material, magnetite, breunnerite, dolomite, fayalitic olivine (Fo 28‐42), an unidentified Ca‐rich silicate phase, Fe,Ni sulfides, and minor Ca‐phosphate and ilmenite. It has similarities to CI1 but shows evidence of heterogeneous thermal metamorphism. Its bulk oxygen isotope composition (δ18O = 13.53‰, δ17O = 8.93‰) is unlike that of any known chondrite, but similar to compositions of several CC‐like clasts in typical polymict ureilites. Its Cr isotope composition is unlike that of any known meteorite. The enclosed clasts and chondrules do not belong to the C1 lithology. The olivine (Fo 75‐88), pyroxenes (pigeonite of Wo ~10 and orthopyroxene of Wo ~4.6), plagioclase, graphite, and some metal‐sulfide are ureilitic, based on mineral compositions, textures, and oxygen isotope compositions, and represent at least six distinct ureilitic lithologies. The chondrules are probably derived from type 3 OC and/or CC, based on mineral and oxygen isotope compositions. Some of the metal‐sulfide clasts are derived from EC. AhS 91A and AhS 671 are plausible representatives of the bulk of the asteroid that was lost. Reflectance spectra of AhS 91A are dark (reflectance ~0.04–0.05) and relatively featureless in VNIR, and have an ~2.7 μm absorption band due to OH− in phyllosilicates. Spectral modeling, using mixtures of laboratory VNIR reflectance spectra of AhS stones to fit the F‐type spectrum of the asteroid, suggests that 2008 TC3 consisted mainly of ureilitic and AhS 91A‐like materials, with as much as 40–70% of the latter, and <10% of OC, EC, and other meteorite types. The bulk density of AhS 91A (2.35 ± 0.05 g cm−3) is lower than bulk densities of other AhS stones, and closer to estimates for the asteroid (~1.7–2.2 g cm−3). Its porosity (36%) is near the low end of estimates for the asteroid (33–50%), suggesting significant macroporosity. The textures of AhS 91A and AhS 671 (finely comminuted clasts of disparate materials intimately mixed) support formation of 2008 TC3 in a regolith environment. AhS 91A and AhS 671 could represent a volume of regolith formed when a CC‐like body impacted into already well‐gardened ureilitic + impactor‐derived debris. AhS 91A bulk samples do not show a solar wind component, so they represent subsurface layers. AhS 91A has a lower cosmic ray exposure (CRE) age (~5–9 Ma) than previously studied AhS stones (11–22 Ma). The spread in CRE ages argues for irradiation in a regolith environment. AhS 91A and AhS 671 show that ureilitic asteroids could have detectable ~2.7 μm absorption bands