Background Inflammatory arthritis is a recognised complication of cystic fibrosis (CF) with an estimated prevalence of 2.3[i] to 8.5%[ii] of CF patients. Cystic fibrosis associated arthritis (CFA) constitutes the majority of this, but other there may be other co-morbid rheumatic disease. Concerns about use of immunosuppression in the context of chronic pulmonary infection, and consequent risk of destabilisation, may limit use of these medications when clinically indicated. Immunosuppressive therapy is used in patients with CF lung disease who have inflammatory rheumatic disease, inflammatory bowel disease, or who have had a liver transplant for CF-related liver disease. Some data on those receiving immunosuppression post-transplant has been published and reassuringly reported fewer courses of intravenous antibiotics following transplant.[iii] Reports of immunosuppressants being used in other contexts, including arthritis, are more sporadic. Objectives To assess prior use and safety outcomes of immunosuppressant therapy in adults with CF. Methods A retrospective case note review of patients with CF receiving disease modifying anti-rheumatic drugs from 2 large adult CF centres (total >700 patients) from electronic records spanning 3–10 years. Results 41 patients were identified: 7 post liver transplant, 1 with inflammatory bowel disease, 1 with IgA nephropathy; 32 with inflammatory arthritis.Abstract AB1149 – Table 1 Medication Number of patients Cumulative months of treatment Stopped due to side effects Azathioprine 4 239 0 Hydroxychloroquine 27 726 3 Sulfasalazine 7 98 3 Tacrolimus 7 900 0 Methotrexate 6 192 1 Cyclophosphamide 1 1 0 Etanercept (with methotrexate, sulfasalazine, hydroxychloroquine) 1 7 0 There was one possible case of increased pulmonary exacerbation associated with methotrexate; they remained on treatment at the time of the study. There was no evidence that immunosuppression resulted in a fall in lung function necessitating cessation of treatment in any of these cases. Three patients stopped hydroxychloroquine and 1 patient stopped methotrexate due to non-respiratory side effects. Four of 7 patients responded to treatment with sulfasalazine for inflammatory arthritis, 3 stopped due to non-respiratory side effects. Conclusions No patients had immunosuppression stopped because of deterioration in lung disease. Steroids were not included in this analysis because duration and dose varied widely. However, it is important to note that they are frequently used in CF (particularly for allergic bronchopulmonary aspergillosis). Indeed 14% of all CF patients in these centres have had steroids in the last 6 months, of whom nearly half received a course of more than 6 months duration. Whilst our results are reassuring, the numbers remain small. Decisions must be made in conjunction with the multidisciplinary team, but CF in itself should not delay or stop treatment with immunosuppression where it is indicated. References [1] Rush, P. J., A. Shore, et al. (1986). [2] Bourke, S., M. Rooney, et al. (1987). [3] Dowman, J. K., D. Watson, et al. (2012). Disclosure of Interest None declared

questions relating to emotional wellbeing.Participants were contacted by the nurse practitioner if they answered yes to any questions, and their care was triaged accordingly.The primary outcome measure was courses and days of IVAB.Results: Sixty participants (29 female, aged [mean ± SD] 31 ± 9 years, FEV 1 60 ± 18% predicted) were recruited for the study, with 29 (48%) allocated to the intervention group.Preliminary analysis in 46 (77%) participants who have completed the study demonstrated no difference in the number of IVAB courses (median [IQR] intervention 1 [0 to 1] vs. control 0.5 [0 to 1]; incidence rate ratio [IRR] 1.1) or days of IVAB (intervention 14 [0 to 21] vs. control 6 [0 to 16]; IRR 1.1).Conclusion: Preliminary analyses suggest no effect of the app on courses and days of IVAB.

Abstract Cell lines represent a valuable model system for the study of breast cancer, as they capture the cellular diversity, mutational spectrum, expression subtypes, and genomic alterations that are observed in clinical specimens. However, like any model system, cell lines are imperfect, particularly when it comes to capturing the effects of the myriad of signals and interactions they encounter in their microenvironment (ME). We are utilizing a technology known as microenvironment microarrays (MEMA) to begin to unravel the consequences of interactions of breast cancer cells with the ME. MEMA consist of thousands of unique combinations of insoluble matrix proteins that are printed to form growth pads with ligands added to the media. Cells are grown on the MEMA spots and the effects of the specific ME that they are exposed to can be read out using immunofluorescent stains of interest. When combined with automated imaging and sophisticated image processing and analysis, the MEMA platform enables the identification of specific ME conditions that alter the phenotypes of cells. We have applied MEMA to understand both baseline responses to the ME as well as how the ME might mediate response to therapeutics. We performed a pilot experiment to investigate the effects of the ME on the response to the HER2-targeted inhibitor lapatinib. We found that HCC1954 cells continued to proliferate robustly in the presence of HGF when treated with 500 nM lapatinib. In contrast, AU565 cells were proliferative in the presence of NRG1 and lapatinib, but not HGF. Focused follow up studies showed that HGF is effective in rescuing only basal HER2+ cells, while NRG1 is effective in rescuing only luminal subtype HER2+cells. Rescue with the relevant growth factor was also observed in 3-d matrigel studies, showing this was not an artifact of the 2-d culture system. We investigated the effects of drug combinations using lapatinib plus drugs that target either MET (Crizotinib) or HER3-HER2 dimers (pertuzumab). These drug combinations were able to overcome the resistance mediated by HGF and NRG1 in basal and luminal cells respectively. We found the effectiveness of pertuzumab particularly interesting, given that lapatinib should still be inhibiting HER2 kinase activity. Parallel studies found that inhibitors targeting other kinase receptors such as IGF1R partially restored sensitivity to HER2 in the presence of NRG1, suggesting a role for such receptors in the resistance. Immunoprecipitation studies showed that IGF1R co-immunoprecipitated with HER2/HER3 when pertuzumab was absent, but that additional of pertuzumab abrogated the binding of IGF1R to HER3, suggesting the formation of HER2-dependent higher order structures that can signal even when HER2 is inhibited. These studies highlight the importance of understanding the effects of the ME on cancer cells, and demonstrate the differences between ME factors that can confer resistance to HER2 targeted inhibitors in basal and luminal HER2+ cells. These findings suggest that both subtype and ME composition may be important in determining response to combinatorial treatments and may be useful to inform clinical decision making. Citation Format: Korkola JE, Watson S, Smith R, Thompson W, Dame M, Liby T, Bucher E, Sudar D, Nederlof M, Heiser L, Gray JW. Microenvironment microarrays show that microenvironment mediated resistance mechanisms to lapatinib differ between basal and luminal HER2+ cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD5-01.

Non-small cell lung cancer (NSCLC) represents 85% of all lung cancer cases, with early-stage accounting for 18% of NSCLC cases. While surgical resection remains the primary treatment for early stage NSCLC for lesions 5 cm or less, stereotactic body radiation therapy (SBRT) has become an excellent alternative. Recent studies had shown that SBRT achieved excellent local control rates of 80-90%, and impressive overall survival rates of up to 95% in early-stage NSCLC patients with a 3-5 year follow-up. Adenocarcinomas, followed by squamous cell carcinomas (SCC) are the most common histological subtypes of NSCLC. The significance of tumor cell histology for locoregional control is largely unknown. From the limited publications, factors associated with locoregional failure include presence of serum carcinoembryonic antigen, lymphovascular invasion, and tumor size >2.7 cm. This study was designed to investigate the relevance of lung tumor cell histology/subtypes for local tumor control by retrospectively analyzing cases of NSCLC treated with SBRT. One hundred seventeen early stage NSCLC (135 nodules) cases treated at a single institution from 12/2008 to 11/2012 were analyzed. The median age of our patients was 81(49-95) years and median follow-up was 3.1 years (0.5-5.8). A 4D CT simulation was done prior to the treatment. The treatment volume included respiratory motion (ITV) with a 5mm margin (PTV). The treatment dose was 50 Gy over 5 consecutive days. The tumor subtypes in this group included adenocarcinomas (81.5%), SCC (12.5%), and unknown (6%). The overall rate of local recurrence was 10.4%, which is consistent with published literature. Cases with squamous cell histology showed a significantly higher rate of local recurrence as compared to adenocarcinoma (35.3% vs 7.3% respectively, P<0.01). In addition, the regional recurrence rate was also higher in SCC cases (23.5% vs 3.6%, P<0.05). There was no difference in the rates of distal recurrence between these histological tumor subtypes (17.3% for adenocarcinoma vs 17.6% for SCC). In addition, no differences were identified in patient age, mean follow-up time, sex, tumor size or stage, maximum SUV, or dose delivered. However, there was a trend (P >0.05) towards a larger lesion size (mean of 23.7 mm for SCC vs 21.0 mm for adenocarcinomas) and more advanced tumor stage (T1b of 41.2% for SCC vs 30.9% for adenocarcinoma) in SCC subgroup. With a conservative dose scheme of SBRT for NSCLC, squamous cell carcinomas showed higher local and regional recurrence rates as compared to adenocarcinomas. The results of this study should be taken with caution given the relatively small numbers of patients, and the trends toward larger lesion sizes and more advanced tumor stages in the SCC subgroup. Nevertheless, the findings in this study may suggest a more aggressive approach for squamous cell histology. We initiated a central boost of an additional 5Gy at our institution since 2013. We plan to analyze these data for future reporting.

Produced water (PW) generated from oil exploration requires rigorous removal of suspended matter (free oil and particulate solids) as tertiary treatment (downstream of hydrocyclone and gas flotation) if it is to be re-injected into low-permeability reservoirs. The viability of membrane filtration for this duty is largely dependent on sustaining a high membrane flux to minimise the process footprint.A pilot-scale study of PW filtration using crossflow multi-channel ceramic membrane technology has been conducted to identify the appropriate membrane characteristics for sustaining the flux whilst maintaining the required treated water quality. Membranes based on two materials (silicon carbide, SiC, and titanium dioxide, TiO2) and two different pore sizes were challenged with real PW samples taken from oil platforms operating on the Arabian Gulf. The membranes were characterised according to the overall permeability decline rate and the end permeability.Results suggest that SiC membranes outperform TiO2 ones with respect to sustainable permeability under the same operating and maintenance conditions. The SiC microfiltration membrane provided anomalously high permeabilities but also the highest fouling propensity. Results suggest that whilst the high fluxes (1300-1800 L m(-2) h(-1)) are attainable for the technology, this is contingent upon the application of an effective chemical clean. (C) 2016 Elsevier B.V. All rights reserved.

We describe an algorithm for generating panoramic video from unstructured camera arrays. Artifact‐free panorama stitching is impeded by parallax between input views. Common strategies such as multi‐level blending or minimum energy seams produce seamless results on quasi‐static input. However, on video input these approaches introduce noticeable visual artifacts due to lack of global temporal and spatial coherence. In this paper we extend the basic concept of local warping for parallax removal. Firstly, we introduce an error measure with increased sensitivity to stitching artifacts in regions with pronounced structure. Using this measure, our method efficiently finds an optimal ordering of pair‐wise warps for robust stitching with minimal parallax artifacts. Weighted extrapolation of warps in non‐overlap regions ensures temporal stability, while at the same time avoiding visual discontinuities around transitions between views. Remaining global deformation introduced by the warps is spread over the entire panorama domain using constrained relaxation, while staying as close as possible to the original input views. In combination, these contributions form the first system for spatiotemporally stable panoramic video stitching from unstructured camera array input.

Produced water (PW) is wastewater generated from oil exploration, and requires treating for oil and suspended solids removal. The viability of an effluent treatment unit process for this duty is dependent both on its efficacy, in terms of oil removal and - for offshore applications especially - its size, in terms of its area (F-A, m/h) and volume (F-V, h(-1)) footprint per unit volume flow. The incurred footprint applies to both the individual unit (vessel, column or tank) and the collection (or array) of units/vessels in a skid.An assessment of unit process footprint based on available information has been conducted, in particular to the case where high-quality treated water is required for reinjection. The analysis encompasses technical data from specific proprietary technologies as well as generic information for process technology types. Technologies considered comprised hydrocyclones (HCs), induced gas flotation (IGF), media (nutshell) filtration (NSF), and crossflow membrane filtration (CMF).The analysis revealed the HC to incur the smallest area footprint, less than half that of an IGF, notwithstanding only similar to 0.15% of the total skid volume being used for the actual separation process. The CMF had a slightly smaller area footprint and less than half the volumetric footprint of the NSF, if the requirement for backflushing is considered. The fitting of the modular HC and CMF technologies to a skid incurs a considerable increase in the footprint, particularly for the HC where the volume occupancy is increased by an order of magnitude. It was concluded that spatial efficiency gains could be attained for modular processes if spacing of the HC vessels or membrane modules can be reduced, contributing significantly to the viability of CMF in particular. (C) 2014 Elsevier B.V. All rights reserved.

Failure of high level waste/spent fuel containers is most likely to occur as a result of mechanical overload following a period of corrosion that results in a reduction of the wall thickness and/or the degradation of the material properties. There can be significant interaction between the mechanical loads and the corrosion processes to which a disposal container is subjected which, in turn, can influence the mode and time of failure. Here, these interactions are illustrated for a single shell, carbon steel spent fuel container during its entire life cycle, from the time of manufacture through to the long term behaviour in a bentonite backfilled geological disposal facility. The evolution of the structural integrity of the container is illustrated through the use of failure assessment diagrams.

The aim of the study was to design bilayer tablets containing Telmisartan for immediate release and Metformin hydrochloride for sustained release. Telmisartan has the strongest binding affinity to AT1 receptor among various ARBs and also has positive effects on insulin resistance syndrome because of the partial agonistic activity towards peroxisome proliferator-activated receptor-gamma (PPARγ). Metformin is an antihyperglycemic not a hypoglycemic. Combinations of both drugs effect the treatment of hypertension in Type-II diabetes mellitus patients and improve the patient compliance. Telmisartan belongs to class II drug in BCS classification. Enhancement of solubility of Telmisartan was observed with physical mixture of drug with beta (β)-Cyclodextrin. Immediate release layers were prepared by wet granulation method using various concentration of sodium starch glycolate as superdisintegrant. SR layers were prepared by wet granulation method using swellable polymer HPMC K4 M and HPMC K100 M in different ratios. Both Immediate (L1, L2 and L3) and Sustained release (F1, F2, F3, F4 and F5) tablets were formulated and evaluated. All the values were found to be satisfactory and were within limits. From the results obtained I3 and S5 were selected and finally compressed into bilayer tablets. In vitro release studies were carried out using USP type II paddle apparatus in 0.1M HCl for first 2 hours and pH 6.8 phosphate buffer solution for next 8 hours as dissolution medium. Stability studies were carried out at 40 ± 2°c and 75± 5% RH for a period of three months.

Recurrent head and neck squamous cell carcinoma (HNSCC) carries a dismal prognosis, similar to that of distant metastatic disease, of 10.1 months with first line chemotherapy. The underlying mechanisms driving recurrent disease and associated treatment resistance are unknown. One proposed mechanism is the persistence of chemo- and radio-resistant tumor-initiating cells (TICs or cancer stem cells) after definitive therapy. We hypothesize that specific interactions between these TICs and the recurrent tumor microenvironment provide a nurturing bed for HNSCC regrowth. To evaluate whether radiation produces a relative increase in TICs, we compared pre- and post-irradiation samples for TIC markers, including a novel HNSCC TIC marker CD166. We examined TIC marker expression both in vitro with flow cytometry and in vivo with immunofluorescence using an orthotopic xenograft model and patient samples. To evaluate the role of the microenvironment in supporting HNSCC TIC maintenance and survival, we plated HNSCC TICs on microenvironment microarrays (MEarrays), which are a novel platform allowing for combinatorial evaluation of extracellular matrix proteins and growth factors relevant to HNSCC. We then stained cells bound to the MEarray spots with proliferation marker ki67 and TIC markers CD44 and CD166 to determine which protein combinations allow for TIC maintenance and proliferation. We found that in post-irradiation samples, cells expressed increased levels of TIC markers both in vitro by increased mean fluorescent intensity and in our orthotopic xenograft model by increased CD166 immunofluorescence staining. We correlated this with human specimens from our HNSCC tumor bank and found that patient HNSCC samples that had received prior irradiation showed increased numbers of CD166 positive tumor cells compared to those without prior radiation (6% compared to 3%, p < 0.05). Using our MEarrays, we were able to identify several stromal proteins that promote the maintenance and proliferation of HNSCC TICs that we are currently validating. These results indicate that radiation may select for aggressive TICs and/or selectively kill off non-TICs, which support our hypothesis that TICs are responsible for recurrent HNSCC. Dual targeting of both TIC and microenvironment molecular alterations could improve therapeutic efficacy and the prognosis of recurrent HNSCC. This is a novel proposal as TICs have not been adequately characterized in recurrent HNSCC and the microenvironment microarrays I will be using to characterize the TIC niche are a unique and powerful platform. This proposal is significant because there are limited treatment options for recurrent HNSCC and the diagnosis is associated with a guarded prognosis.