A Survey of Interaction Techniques and Devices for Large High Resolution Displays

Innovations in large high-resolution wall-sized displays have been yielding benefits to visualizations in industry and academia, leading to a rapidly growing increase of their implementations. In scenarios such as these, the displayed visual information tends to be larger than the users field of view, hence the necessity to move away from traditional interaction methods towards more suitable interaction devices and techniques. This paper aspires to explore the state-of-the-art with respect to such technologies for large high-resolution displays

A Novel Flow Cytometric HTS Assay Reveals Functional Modulators of ATP Binding Cassette Transporter ABCB6

ABCB6 is a member of the adenosine triphosphate (ATP)-binding cassette family of transporter proteins that is increasingly recognized as a relevant physiological and therapeutic target. Evaluation of modulators of ABCB6 activity would pave the way toward a more complete understanding of the significance of this transport process in tumor cell growth, proliferation and therapy-related drug resistance. In addition, this effort would improve our understanding of the function of ABCB6 in normal physiology with respect to heme biosynthesis, and cellular adaptation to metabolic demand and stress responses. To search for modulators of ABCB6, we developed a novel cell-based approach that, in combination with flow cytometric high-throughput screening (HTS), can be used to identify functional modulators of ABCB6. Accumulation of protoporphyrin, a fluorescent molecule, in wild-type ABCB6 expressing K562 cells, forms the basis of the HTS assay. Screening the Prestwick Chemical Library employing the HTS assay identified four compounds, benzethonium chloride, verteporfin, tomatine hydrochloride and piperlongumine, that reduced ABCB6 mediated cellular porphyrin levels. Validation of the identified compounds employing the hemin-agarose affinity chromatography and mitochondrial transport assays demonstrated that three out of the four compounds were capable of inhibiting ABCB6 mediated hemin transport into isolated mitochondria. However, only verteporfin and tomatine hydrochloride inhibited ABCB6’s ability to compete with hemin as an ABCB6 substrate. This assay is therefore sensitive, robust, and suitable for automation in a high-throughput environment as demonstrated by our identification of selective functional modulators of ABCB6. Application of this assay to other libraries of synthetic compounds and natural products is expected to identify novel modulators of ABCB6 activity

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Selectivity and validation of HTS identified compounds by hemin agarose affinity chromatography.

<p>(a) verteporfin and (b) tomatine hydrochloride potently disrupt the interaction between ABCB6 and hemin-agarose compared with (c) succinylacetone. (d, e and f) image J analysis of ABCB6 band intensity treated with (d) verteporfin, (e) tomatine hydrochloride and (f) succinylacetone averaged over three independent experiments. Mitochondria isolated from K562 cells expressing ABCB6-Flag or the empty vector were incubated in the presence or absence of increasing concentration of the indicated compound and hemin-agarose and the resulting complex was immunoblotted using a monoclonal antibody to the flag-tag. Results are representative of 3 independent experiments. ‘*’ significantly different from untreated controls. P<0.05. ‘NS’ differences are non-significant compared to untreated control.</p

SDS-PAGE analysis of purified ABCB6 and selectivity and validation of HTS identified compounds by hemin-agarose affinity chromatography using purified ABCB6.

<p>(a) Purified ABCB6 sample was analyzed by SDS-PAGE. The figure shows coomassie brilliant blue staining of SDS gel (lane legends are 1, protein marker; 2, purified ABCB6-flag 2 µg protein; 3, purified ABCB6-flag 5 µg protein; 4, protein marker; and 5, bovine serum albumin control). b) verteporfin and (c) tomatine hydrochloride potently disrupt the interaction between purified ABCB6 protein and hemin-agarose compared with (d) succinylacetone. Three hundred nanograms of purified ABCB6-flag protein was incubated in the presence or absence of increasing concentration of the indicated compound and hemin-agarose and the resulting complex was immunoblotted using a monoclonal antibody to the flag-tag. Results are representative of three independent experiments.</p

Topology and homology model of ABCB6 dimer with the docked ligands.

<p>(a) far and (b) close view of docking poses of selected ligands to the human ABCB6 transporter. Coproporphyrinogen III – blue; verteporfin – green; benzethonium chloride– magenta; piperlongumine - light blue; and tomatine hydrochloride - yellow. The Gly426-Val429, and Phe545-Pro555 parts from one ABCB6 monomer were hidden in order to better see the ligands.</p

Verteporfin and tomatine hydrochloride are ABCB6 transport substrates.

<p>(a) verteporfin and (b) tomatine hydrochloride are transported by transport competent ABCB6 protein (ABCB6) in the presence of ATP which is significantly higher than transport by transport incompetent ABCB6 protein (ABCB6-MT) in the presence of ATP in mitochondria isolated from ABCB6 or ABCB6-MToverexpressing cells. Results are representative of three independent experiments. ‘*’ significantly different from ABCB6-MT and AMP treated ABCB6 expressing mitochondria; P<0.05. ‘**’ significantly different from ABCB6-MT and AMP treated ABCB6 expressing mitochondria; P<0.01. (c) and (d) vanadate sensitive ATPase activity (fold change relative to basal activity) was stimulated by (c) verteporfin and (d) tomatine hydrochloride in mitochondria from cells expressing transport competent ABCB6 protein (ABCB6) relative to mitochondria isolated from transport incompetent ABCB6 protein (ABCB6-MT). Values are means +/− SEM. ‘*’ significantly different from ABCB6-MT cells at each time point; P<0.05.</p