NADPH oxidases as regulators of tumor angiogenesis : current and emerging concepts

Significance Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and peroxynitrite are generated ubiquitously by all mammalian cells and have been understood for many decades as inflicting cell damage and as causing cancer by oxidation and nitration of macromolecules, including DNA, RNA, proteins, and lipids. Recent Advances A current concept suggests that ROS can also promote cell signaling pathways triggered by growth factors and transcription factors that ultimately regulate cell proliferation, differentiation, and apoptosis, all of which are important hallmarks of tumor cell proliferation and angiogenesis. Moreover, an emerging concept indicates that ROS regulate the functions of immune cells that infiltrate the tumor environment and stimulate angiogenesis, such as macrophages and specific regulatory T cells. Critical Issues In this article, we highlight that the NADPH oxidase family of ROS-generating enzymes are the key sources of ROS and, thus, play an important role in redox signaling within tumor, endothelial, and immune cells thereby promoting tumor angiogenesis. Future Directions Knowledge of these intricate ROS signaling pathways and identification of the culprit NADPH oxidases is likely to reveal novel therapeutic opportunities to prevent angiogenesis that occurs during cancer and which is responsible for the revascularization after current antiangiogenic treatment.

Tumor-suppressor gene promoter hypermethylation in saliva of head and neck cancer patients

Head and neck squamous cell carcinoma (HNSCC) accounts for a bulk of the oral and laryngeal cancers, the majority (70%) of which are associated with smoking and excessive drinking, major known risk factors for the development of HNSCC. In contrast to reports that suggest an inverse relationship between smoking and global DNA CpG methylation, hypermethylation of promoters of a number of genes was detected in saliva collected from patients with HNSCC. Using a sensitive methylation-specific polymerase chain reaction (MSP) assay to determine specific methylation events in the promoters of RASSF1A, DAPK1, and p16 genes, we demonstrate that we can detect tumor presence with an overall accuracy of 81% in the DNA isolated from saliva of patients with HNSCC (n = 143) when compared with the DNA isolated from the saliva of healthy nonsmoker controls (n = 31). The specificity for this MSP panel was 87% and the sensitivity was 80%(with a Fisher exact test P < .0001). In addition, the test panel performed extremely well in the detection of the early stages of HNSCCs, with a sensitivity of 94% and a specificity of 87%, and a high. concordance value of 0.8, indicating an excellent overall agreement between the presence of HNSCC and a positive MSP panel result. In conclusion, we demonstrate that the promoter methylation of RASSF1A, DAPK1, and p16 MSP panel is useful in detecting hypermethylation events in a noninvasive manner in patients with HNSCC.

Exploring location-dependency in process modeling

Purpose – Context-awareness has emerged as an important principle in the design of flexible business processes. The goal of the research is to develop an approach to extend context-aware business process modeling toward location-awareness. The purpose of this paper is to identify and conceptualize location-dependencies in process modeling. Design/methodology/approach – This paper uses a pattern-based approach to identify location-dependency in process models. The authors design specifications for these patterns. The authors present illustrative examples and evaluate the identified patterns through a literature review of published process cases. Findings – This paper introduces location-awareness as a new perspective to extend context-awareness in BPM research, by introducing relevant location concepts such as location-awareness and location-dependencies. The authors identify five basic location-dependent control-flow patterns that can be captured in process models. And the authors identify location-dependencies in several existing case studies of business processes. Research limitations/implications – The authors focus exclusively on the control-flow perspective of process models. Further work needs to extend the research to address location-dependencies in process data or resources. Further empirical work is needed to explore determinants and consequences of the modeling of location-dependencies. Originality/value – As existing literature mostly focusses on the broad context of business process, location in process modeling still is treated as “second class citizen” in theory and in practice. This paper discusses the vital role of location-dependencies within business processes. The proposed five basic location-dependent control-flow patterns are novel and useful to explain location-dependency in business process models. They provide a conceptual basis for further exploration of location-awareness in the management of business processes.

A Memetic Algorithm for the location-based continuously operating reference stations placement problem in Network Real-Time Kinematic

Network Real-Time Kinematic (NRTK) is a technology that can provide centimeter-level accuracy positioning services in real time, and it is enabled by a network of Continuously Operating Reference Stations (CORS). The location-oriented CORS placement problem is an important problem in the design of a NRTK as it will directly affect not only the installation and operational cost of the NRTK, but also the quality of positioning services provided by the NRTK. This paper presents a Memetic Algorithm (MA) for the location-oriented CORS placement problem, which hybridizes the powerful explorative search capacity of a genetic algorithm and the efficient and effective exploitative search capacity of a local optimization. Experimental results have shown that the MA has better performance than existing approaches. In this paper we also conduct an empirical study about the scalability of the MA, effectiveness of the hybridization technique and selection of crossover operator in the MA.

Tissue-engineered 3D tumor angiogenesis models : potential technologies for anti-cancer drug discovery

Angiogenesis is indispensable for solid tumor expansion, and thus it has become a major target of cancer research and anti-cancer therapies. Deciphering the arcane actions of various cell populations during tumor angiogenesis requires sophisticated research models, which could capture the dynamics and complexity of the process. There is a continuous need for improvement of existing research models, which engages interdisciplinary approaches of tissue engineering with life sciences. Tireless efforts to develop a new model to study tumor angiogenesis result in innovative solutions, which bring us one step closer to decipher the dubious nature of cancer. This review aims to overview the recent developments, current limitations and future challenges in three-dimensional tissue-engineered models for the study of tumor angiogenesis and for the purpose of elucidating novel targets aimed at anti-cancer drug discovery.

Influences of luminance and accommodation stimuli on pupil size and pupil center location

PURPOSE. To investigate effects of luminance and accommodation stimuli on pupil size and pupil center location and their implications for progressive addition lens wear. METHODS. Participants were young and older adult groups (n=20, 22±2 years, age range 18-25 years; n=19, 49±4 years, 45-58 years). A wave aberrometer included a relay system to allow a 12.5°x11° background for the internal fixation target. Participants viewed the target under a matrix of conditions with luminance levels 0.01, 3.7, 120 and 6100 cd/m² and with accommodation stimuli up to 6 diopters in 2 diopter steps. Pupil sizes and their centers, relative to limbus centers, were determined from anterior eye images. RESULTS. With luminance increase, reduction in pupil size was accentuated by increase in accommodation stimulus in the young, but not in the older, group. As luminance increased, pupil center location altered. This was nasally in both groups with an average shift of approximately 0.12mm. Relative to the lowest stimulus condition, the mean of the maximum absolute pupil center shifts was 0.26±0.08mm for both groups with individual shifts up to 0.5mm, findings consistent with previous studies. There was no significant effect of accommodation on pupil center locations for either age group, or evidence that location was influenced by the combination of luminance and accommodation stimulus that resulted in any particular pupil size. CONCLUSIONS. Variations in luminance and accommodation influence pupil size, but only the former affects pupil center location significantly. Pupil center shifts are too small to be of concern in fitting progressive addition lenses.

Chirp-spread-spectrum-based real time location system for construction safety management: A case study

Observing the working procedure of construction workers is an effective means of maintaining the safety performance of a construction project. It is also difficult to achieve due to a high worker-to-safety-officer ratio. There is an imminent need for the development of a tool to assist in the real-time monitoring of workers, in order to reduce the number of construction accidents. The development and application of a real time locating system (RTLS) based on the Chirp Spread Spectrum (CSS) technique is described in this paper for tracking the real-time position of workers on construction sites. Experiments and tests were carried out both on- and off-site to verify the accuracy of static and dynamic targets by the system, indicating an average error of within one metre. Experiments were also carried out to verify the ability of the system to identify workers’ unsafe behaviours. Wireless data transfer was used to simplify the deployment of the system. The system was deployed in a public residential construction project and proved to be quick and simple to use. The cost of the developed system is also reported to be reasonable (around 1800USD) in this study and is much cheaper than the cost of other RTLS. In addition, the CCS technique is shown to provide an economical solution with reasonable accuracy compared with other positioning systems, such as ultra wideband. The study verifies the potential of the CCS technique to provide an effective and economical aid in the improvement of safety management in the construction industry.

Cone location and correction of keratoconus with rigid gas-permeable contact lenses

Purpose To evaluate the influence of cone location and corneal cylinder on RGP corrected visual acuities and residual astigmatism in patients with keratoconus. Methods In this prospective study, 156 eyes from 134 patients were enrolled. Complete ophthalmologic examination including manifest refraction, Best spectacle visual acuity (BSCVA), slit-lamp biomicroscopy was performed and corneal topography analysis was done. According to the cone location on the topographic map, the patients were divided into central and paracentral cone groups. Trial RGP lenses were selected based on the flat Sim K readings and a ‘three-point touch’ fitting approach was used. Over contact lens refraction was performed, residual astigmatism (RA) was measured and best-corrected RGP visual acuities (RGPVA) were recorded. Results The mean age (±SD) was 22.1 ± 5.3 years. 76 eyes (48.6%) had central and 80 eyes (51.4%) had paracentral cone. Prior to RGP lenses fitting mean (±SD) subjective refraction spherical equivalent (SRSE), subjective refraction astigmatism (SRAST) and BSCVA (logMAR) were −5.04 ± 2.27 D, −3.51 ± 1.68 D and 0.34 ± 0.14, respectively. There were statistically significant differences between central and paracentral cone groups in mean values of SRSE, SRAST, flat meridian (Sim K1), steep meridian (Sim K2), mean K and corneal cylinder (p-values < 0.05). Comparison of BSCVA to RGPVA shows that vision has improved 0.3 logMAR by RGP lenses (p < 0.0001). Mean (±SD) RA was −0.72 ± 0.39 D. There were no statistically significant differences between RGPVAs and RAs of central and paracentral cone groups (p = 0.22) and (p = 0.42), respectively. Pearson's correlation analysis shows that there is a statistically significant relationship between corneal cylinder and BSCVA and RGPVA, However, the relationship between corneal cylinder and residual astigmatism was not significant. Conclusions Cone location has no effect on the RGP corrected visual acuities and residual astigmatism in patients with keratoconus. Corneal cylinder and Sim K values influence RGP-corrected visual acuities but do not influence residual astigmatism.

Location and labor: Critical crossroads in global film and television

I approached the editorial prompt as an opportunity to work through some of the concerns driving my current research on creative labor in emergent or ‘peripheral’ media hubs, centers of production activity outside established media capitals that are nevertheless increasingly integrated into a global production apparatus. It builds from my research on the role that film, television and digital media production have played in the economic and cultural strategies of Glasgow, Scotland, and extends the focus on media work to other locations, including Prague and Budapest. I am particularly drawn to the spatial dynamics at play in these locations and how local producers, writers, directors and crew negotiate a sense of place and creative identity against the flows and counter-flows of capital and culture. This means not only asking questions about the growing ensemble of people, places, firms and policies that make international productions possible, but also studying the more quotidian relationships between media workers and the locations (both near and far) where they now find work. I do not see these tasks as unrelated. On the one hand, such queries underscore how international production depends on a growing constellation of interchangeable parts and is facilitated by various actors whose agendas may or may not converge. On the other hand, these questions also betray an even more complicated dynamic, a process that is shifting the spatial orientation of both location and labor around uneven and contested scales. As local industries reimagine themselves as global players, media practitioners are caught up in a new geography of creative labor: not only are personnel finding it increasingly necessary to hop from place to place to follow the work, but also place itself is changing, as locations morph into nebulous amalgamations of tax rebates, subsidized facilities, production services and (when it still matters) natural beauty.

A mouse with an N-ethyl-N-nitrosourea (ENU) induced Trp589Arg Galnt3 mutation represents a model for hyperphosphataemic familial tumoural calcinosis

Mutations of UDP-N-acetyl-alpha-D-galactosamine polypeptide N-acetyl galactosaminyl transferase 3 (GALNT3) result in familial tumoural calcinosis (FTC) and the hyperostosis-hyperphosphataemia syndrome (HHS), which are autosomal recessive disorders characterised by soft-tissue calcification and hyperphosphataemia. To facilitate in vivo studies of these heritable disorders of phosphate homeostasis, we embarked on establishing a mouse model by assessing progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU), and identified a mutant mouse, TCAL, with autosomal recessive inheritance of ectopic calcification, which involved multiple tissues, and hyperphosphataemia; the phenotype was designated TCAL and the locus, Tcal. TCAL males were infertile with loss of Sertoli cells and spermatozoa, and increased testicular apoptosis. Genetic mapping localized Tcal to chromosome 2 (62.64-71.11 Mb) which contained the Galnt3. DNA sequence analysis identified a Galnt3 missense mutation (Trp589Arg) in TCAL mice. Transient transfection of wild-type and mutant Galnt3-enhanced green fluorescent protein (EGFP) constructs in COS-7 cells revealed endoplasmic reticulum retention of the Trp589Arg mutant and Western blot analysis of kidney homogenates demonstrated defective glycosylation of Galnt3 in Tcal/Tcal mice. Tcal/Tcal mice had normal plasma calcium and parathyroid hormone concentrations; decreased alkaline phosphatase activity and intact Fgf23 concentrations; and elevation of circulating 1,25-dihydroxyvitamin D. Quantitative reverse transcriptase-PCR (qRT-PCR) revealed that Tcal/Tcal mice had increased expression of Galnt3 and Fgf23 in bone, but that renal expression of Klotho, 25-hydroxyvitamin D-1α-hydroxylase (Cyp27b1), and the sodium-phosphate co-transporters type-IIa and -IIc was similar to that in wild-type mice. Thus, TCAL mice have the phenotypic features of FTC and HHS, and provide a model for these disorders of phosphate metabolism. © 2012 Esapa et al.

Social capital or ethnic enclave location? A multilevel explanation of immigrant business growth

The rapid increase in migration into host countries and the growth of immigrant-owned business enterprises has revitalized research on ethnic business. Does micro (individual)-level social capital, or meso (group)-level location within the ethnic enclave lead to immigrant business growth? Or do you need both? We analyze quantitative data collected from 110 Chinese restaurants in Australia, a major host country. At the micro level we find that coethnic (same ethnic group) networks are critical to the growth of an immigrant entrepreneur's business, particularly in the early years. But non-coethnic (different ethnic group) social capital only has a positive impact on business growth for immigrant businesses outside the ethnic enclave. Our findings are relevant, not only to host-country policymakers, but also for future immigrant business owners and ethnic community leaders trying to better understand how to promote healthy communities and sustainable economic growth.

Prognostic value of BRAF mutations in localized cutaneous melanoma

BACKGROUND: BRAF mutations are frequent in melanoma but their prognostic significance remains unclear. OBJECTIVE: We sought to further evaluate the prognostic value of BRAF mutations in localized cutaneous melanoma. METHODS: We undertook an observational retrospective study of 147 patients with localized invasive (stages I and II) cutaneous melanomas to determine the prognostic value of BRAF mutation status. RESULTS: After a median follow-up of 48 months, patients with localized melanomas with BRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype (hazard ratio 2.2, 95% confidence interval 1.1-4.3) even after adjustment for Breslow thickness, tumor ulceration, location, age, sex, and tumor mitotic rate. LIMITATIONS: The retrospective design and the small number of events are limitations. CONCLUSIONS: Our findings suggest that reappraisal of clinical treatment approaches for patients with localized melanoma harboring tumors with BRAF mutation might be warranted

Tumor-associated mutations inO6-methylguanine DNA-methyltransferase (MGMT) reduce DNA repair functionality

MGMT is the primary vehicle for cellular removal of alkyl lesions from the O-6 position of guanine and the O-4 position of thymine. While key to the maintenance of genomic integrity, MGMT also removes damage induced by alkylating chemotherapies, inhibiting the efficacy of cancer treatment. Germline variants of human MGMT are well-characterized, but somatic variants found in tumors were, prior to this work, uncharacterized. We found that MGMT G132R, from a human esophageal tumor, and MGMT G156C, from a human colorectal cancer cell line, are unable to rescue methyltransferase-deficient Escherichia coli as well as wild type (WT) human MGMT after treatment with a methylating agent. Using pre-steady state kinetics, we biochemically characterized these variants as having a reduced rate constant. G132R binds DNA containing an O6-methylguanine lesion half as tightly as WT MGMT, while G156C has a 40-fold decrease in binding affinity for the same damaged DNA versus WT. Mammalian cells expressing either G132R or G156C are more sensitive to methylating agents than mammalian cells expressing WT MGMT. G132R is slightly resistant to O6-benzylguanine, an inhibitor of MGMT in clinical trials, while G156C is almost completely resistant to this inhibitor. The impared functionality of expressed variants G132R and G156C suggests that the presence of somatic variants of MGMT in a tumor could impact chemotherapeutic outcomes.

Suggestive linkage of the parathyroid receptor type 1 to osteoporosis

We have investigated the role of 23 candidate genes in the control of bone mineral density (BMD) by linkage studies in families of probands with osteoporosis (lumbar spine [LS] or femoral neck [FN] BMD T score < -2.5) and low BMD relative to an age- and gender-matched cohort (Z score < -2.0). One hundred and fifteen probands (35 male, 80 female) and 499 of their first- or second-degree relatives (223 males and 276 females) were recruited for the study. BMD was measured at the LS and FN using dual-energy X-ray absorptiometry and expressed as age- and gender-matched Z scores corrected for body mass index. The candidate genes studied were the androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony-stimulating factor 1, calcium-sensing receptor, epidermal growth factor (EGF), estrogen receptor 1 (ESR1), fibrillin type 1, insulin-like growth factor 1, interleukin-1 alpha (IL-1α), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-11 (IL-11), osteopontin, parathyroid hormone (PTH), PTH-related peptide, PTH receptor type 1 (PTHR1), transforming growth factor-beta 1, and tumor necrosis factors alpha and beta. Sixty-four microsatellites lying close to or within these genes were investigated for linkage with BMD. Using the program MapMaker/Sibs there was suggestive evidence of linkage between BMD and PTHR1 (maximum LOD score obtained [MLS] 2.7-3.5). Moderate evidence of linkage was also observed with EGF (MLS 1.8), COLIA1 (MLS 1.7), COLIIA1/VDR (MLS 1.7), ESR1 (MLS 1.4), IL-1α (MLS 1.4), IL-4 (MLS 1.2), and IL-6 (MLS 1.2). Variance components analysis using the program ACT, correcting for proband-wise ascertainment, also showed evidence of linkage (p ≤0.05) at markers close to or within the candidate genes IL- 1α, PTHR1, IL-6, and COLIIA1/VDR. Further studies will be required to confirm these findings, to refine the location of gene responsible for the observed linkage, and to screen the candidate genes targeted at these loci for mutations.