The relationship between body growth, retinal blood vessel development and the incidence of retinopathy of prematurity: a clinical and laboratory investigation

The relationship between body growth, retinal blood vessel development and the incidence of retinopathy of prematurity: a clinical and laboratory investigationBACKGROUND: Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina in preterm infants and an important cause of childhood blindness. The incidence of ROP has varied over time and across the world as a result of changes in clinical neonatal practice. ROP is a multifactorial disease with low birth weight, low gestational age and exposure to supplemental oxygen being key risk factors. Prenatal and postnatal body growth together with availability of growth factors may also be involved in the pathogenesis. Premature infants undergo eye screening using binocular indirect ophthalmoscopy (BIO) or wide-field digital retinal imaging (WFDRI) in order to identify those infants with sight-threatening disease that require treatment with laser photocoagulation. Eye screening is a painful and distressing procedure for infants.AIMS: (i) To report the trends in incidence of ROP within Lothian, Scotland (ii) To report the incidence of ROP in small-for-gestational (SGA) infants (iii) To study retinal vascular development in growth-restricted rat pups (iv) To carry out a prospective randomised study comparing the diagnostic accuracy of WFDRI with BIO for ROP eye examinations (v) To compare the pain experienced by infants undergoing WFDRI and BIOMETHODS: Data from eye screening examinations within Lothian between 1990 and 2004 were analysed and epidemiological data were obtained from the Scottish Health Service. Dams of rat pups were fed either a 'normal' (18%) or 'low' (9%) protein diet. Dams and pups were exposed to either room air or a fluctuating oxygen profile for 14 days. Retinas were dissected and blood vessels were stained using immunohistochemistry. The extent of vascular development was measured and compared between animal groups. Serum was collected from pups and levels of insulin-like growth factor-1 (IGF-1) were measured using an enzyme-linked immunosorbent assay. Infants from Edinburgh Neonatal Unit undergoing routine ROP screening were recruited and screened by both WFDRI and BIO in random order. The sensitivity and specificity of WFDRI compared to BIO was calculated. The pain experienced by infants was scored using the Premature Infant Pain Profile (PIPP) and compared between the two techniques.RESULTS: There has been an increase in survival of preterm infants, a reduction in the incidence of any degree of ROP, severe ROP and a marked reduction in treatment for ROP in Lothian from 1990-2004. The prevalence of ROP and severe ROP were higher in SGA infants than their appropriately sized peers. Pups of dams fed the 9% protein diet were born growth restricted. The growth restricted rat pups had significantly larger retinal avascular areas and lower serum IGF-1 levels than 'normal' sized pups. The sensitivity of WFDRI in detecting any ROP, stage 3 ROP and plus disease was 60%, 57% and 80% respectively with a specificity of 91%, 98% and 98% respectively. ROP screening using WFDRI and BIO was painful but the pain experienced by infants was similar for both techniques (WFDRI PIPP score 15.0, BIO PIPP score 15.2).CONCLUSIONS: Advances in obstetric and neonatal care within the developed world over the last two decades are likely responsible for the increased survival of premature infants and the overall decreasing incidence of ROP seen in Lothian. Body growth and IGF-1 are important in the pathogenesis of ROP. Further work is required to identify a mechanism for this association and clinical trials of nutritional therapies are needed. WFDRI is a useful examination technique for ROP eye screening but has some technical limitations which need to be improved. Further work is required to implement adequate analgesia regimes for ROP screening

Quantitative Proteomic Profiling of Pleomorphic Human Sarcoma Identifies CLIC1 as a Dominant Pro-Oncogenic Receptor Expressed in Diverse Sarcoma Types

Sarcomas are rare forms of cancer with a high unmet clinical need that develop in connective tissue, such as muscle, bone, nerves, cartilage, and fat. The outcome for patients is poor, with surgery and postoperative radiotherapy the standard treatment for patients. A better understanding of the molecular pathology of sarcoma may allow for the development of novel therapeutics. There are dozens of sarcoma subtypes where there is a need for targetted therapeutics, with the most commonly studied including Ewing’s sarcoma and osteosarcoma. Here we initiate a proteomics-based target-discovery program to define “dominant” pro-oncogenic signaling targets in the most common sarcoma in adults: high-grade pleiomorphic soft tissue sarcoma. We have carried out a proteome screen using tandem mass tag isobaric labeling on three high-grade undifferentiated pleomorphic sarcoma biopsies from different tissue sites. We identified the commonly dysregulated proteins within the three sarcomas and further validated the most penetrant receptor as CLIC1, using immunohistochemistry arising from two different population cohorts representing over 300 patients. The dominant expression of CLIC1 in a broad range of human sarcomas suggests that studying this relatively unexplored signaling pathway might provide new insights into disease mechanism and facilitate the development of new CLIC1 targeted therapeutics

Quantitative Proteomic Profiling of Pleomorphic Human Sarcoma Identifies CLIC1 as a Dominant Pro-Oncogenic Receptor Expressed in Diverse Sarcoma Types

Sarcomas are rare forms of cancer with a high unmet clinical need that develop in connective tissue, such as muscle, bone, nerves, cartilage, and fat. The outcome for patients is poor, with surgery and postoperative radiotherapy the standard treatment for patients. A better understanding of the molecular pathology of sarcoma may allow for the development of novel therapeutics. There are dozens of sarcoma subtypes where there is a need for targetted therapeutics, with the most commonly studied including Ewing’s sarcoma and osteosarcoma. Here we initiate a proteomics-based target-discovery program to define “dominant” pro-oncogenic signaling targets in the most common sarcoma in adults: high-grade pleiomorphic soft tissue sarcoma. We have carried out a proteome screen using tandem mass tag isobaric labeling on three high-grade undifferentiated pleomorphic sarcoma biopsies from different tissue sites. We identified the commonly dysregulated proteins within the three sarcomas and further validated the most penetrant receptor as CLIC1, using immunohistochemistry arising from two different population cohorts representing over 300 patients. The dominant expression of CLIC1 in a broad range of human sarcomas suggests that studying this relatively unexplored signaling pathway might provide new insights into disease mechanism and facilitate the development of new CLIC1 targeted therapeutics