The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

Identifying characteristic features of the retinal and choroidal vasculature in choroideremia using optical coherence tomography angiography

PURPOSE: Using optical coherence tomography angiography (OCTA) to investigate the area with flow in the superficial retinal vessel network (SVRN) and choriocapillaris (CC) layer among male subjects with choroideremia (CHM), female carriers, and normal controls to identify vascular changes. PATIENTS AND METHODS: Images of SRVN and CC layer were acquired in 9 affected males, 5 female carriers, and 14 age- and gender-matched controls using the Angiovue software of the RTVue XR Avanti. RESULTS: The mean age was 33 years for affected male CHM patients (median 30 years), 46 years for female carriers (median 53 years), and 39 years for controls (median 38.5). Mean SRVN area±SD in subjects with CHM was 12.93±2.06 mm², in carrier subjects 15.36±0.60 mm², and in controls 15.30±1.35 mm² (P<0.01). The mean CC area±SD with flow was 6.97±5.26 mm² in CHM subjects, 21.65±0.17 mm² in carriers and 21.36±0.76 mm² in controls (P<0.01). SRVN and CC area with flow showed a negative correlation in CHM subjects with the age (r=−0.86; P<0.003 and r=−0.77; P<0.01, respectively). CC area with flow had a positive correlation with SRVN (r=0.83, P<0.001). Overall, visual acuity had a negative correlation with SRVN and CC area with flow (r=−0.67, P<0.001 and r=−0.57, P<0.002, respectively). CONCLUSIONS: This is the first study to highlight changes in the SRVN in CHM subjects. OCTA detected a reduced area with flow in both retinal and choroidal circulations, and may be a useful tool for monitoring natural history and disease progression in forthcoming clinical trials

Diabetic retinopathy: current and future methods for early screening from a retinal hemodynamic and geometric approach

Diabetic retinopathy (DR) is a major disease and is the number one cause of blindness in the UK. In England alone, 4200 new cases appear every year and 1280 lead to blindness. DR is a result of diabetes mellitus, which affects the retina of the eye and specifically the vessel structure. Elevated levels of glucose cause a malfunction in the cell structure, which affects the vessel wall and, in severe conditions, leads to their breakage. Much research has been carried out on detecting the different stages of DR but not enough versatile research has been carried out on the detection of early DR before the appearance of any lesions. In this review, the authors approach the topic from the functional side of the human eye and how hemodynamic factors that are impaired by diabetes affect the vascular structur

Global delivery models: the role of talent, speed and time zones in the global outsourcing industry

Global delivery models (GDMs) are transforming the global IT and business process outsourcing industry. GDMs are a new form of client-specific investment promoting service integration with clients by combining client proximity with time-zone spread for 24/7 service operations. We investigate antecedents and contingencies of setting up GDM structures. Based on comprehensive data we show that providers are likely to establish GDM location configurations when clients value access to globally distributed talent and speed of service delivery, in particular when services are highly commoditized. Findings imply that coordination across time zones increasingly affects international operations in business-to-business and born-global industries

Role of genetic polymorphisms in tumour angiogenesis

Angiogenesis plays a crucial role in the development, growth and spread of solid tumours. Pro- and anti-angiogenic factors are abnormally expressed in tumours, influencing tumour angiogenesis, growth and progression. Polymorphisms in genes encoding angiogenic factors or their receptors may alter protein expression and/or activity. This article reviews the literature to determine the possible role of angiogenesis-related polymorphisms in cancer. Further research studies in this potentially crucial area of tumour biology are proposed

Identification of S100A8-correlated genes for prediction of disease progression in non-muscle invasive bladder cancer

<p>Abstract</p> <p>Background</p> <p><it>S100 calcium binding protein A8 </it>(<it>S100A8</it>) has been implicated as a prognostic indicator in several types of cancer. However, previous studies are limited in their ability to predict the clinical behavior of the cancer. Here, we sought to identify a molecular signature based on <it>S100A8 </it>expression and to assess its usefulness as a prognostic indicator of disease progression in non-muscle invasive bladder cancer (NMIBC).</p> <p>Methods</p> <p>We used 103 primary NMIBC specimens for microarray gene expression profiling. The median follow-up period for all patients was 57.6 months (range: 3.2 to 137.0 months). Various statistical methods, including the leave-one-out cross validation method, were applied to identify a gene expression signature able to predict the likelihood of progression. The prognostic value of the gene expression signature was validated in an independent cohort (n = 302).</p> <p>Results</p> <p>Kaplan-Meier estimates revealed significant differences in disease progression associated with the expression signature of <it>S100A8</it>-correlated genes (log-rank test, <it>P </it>< 0.001). Multivariate Cox regression analysis revealed that the expression signature of <it>S100A8</it>-correlated genes was a strong predictor of disease progression (hazard ratio = 15.225, 95% confidence interval = 1.746 to 133.52, <it>P </it>= 0.014). We validated our results in an independent cohort and confirmed that this signature produced consistent prediction patterns. Finally, gene network analyses of the signature revealed that <it>S100A8</it>, <it>IL1B</it>, and <it>S100A9 </it>could be important mediators of the progression of NMIBC.</p> <p>Conclusions</p> <p>The prognostic molecular signature defined by <it>S100A8</it>-correlated genes represents a promising diagnostic tool for the identification of NMIBC patients that have a high risk of progression to muscle invasive bladder cancer.</p

Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3

Dysregulation of matrix degrading metalloproteinase enzymes (MMPs) leads to increased extracellular matrix turnover, a key event in the local invasion and metastasis of many tumours. The tissue inhibitors of metalloproteinases (TIMPs) limit the activity of MMPs, which suggests their use in gene therapy. We have previously shown that overexpression of TIMP-1, -2 or -3 inhibits vascular smooth muscle and melanoma cell invasion, while TIMP-3 uniquely promotes apoptosis. We have therefore sought to determine whether TIMP-3 can inhibit invasion and promote apoptosis in other cancer cell types. Adenoviral-mediated overexpression of TIMP-3 inhibited invasion of HeLa and HT1080 cells through artificial basement membrane to similar levels as that achieved by TIMP-1 and -2. However, TIMP-3 uniquely promoted cell cycle entry and subsequent death by apoptosis. Apoptosis was confirmed by morphological analysis, terminal dUTP nick end labelling (TUNEL) and flow cytometry. The apoptotic phenotype was mimicked by addition of exogenous recombinant TIMP-3 to uninfected cultures demonstrating that the death signal is initiated extracellularly and that a bystander effect exists. These results show that TIMP-3 inhibits invasion in vitro and promotes apoptosis in cancer cell type of differing origin. This clearly identifies the potential of TIMP-3 for gene therapy of multiple cancer types. © 1999 Cancer Research Campaig