Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors

BACKGROUND: The Hedgehog (Hh) signaling pathway regulates a variety of developmental processes, including vasculogenesis, and can also induce the expression of pro-angiogenic factors in fibroblasts postnatally. Misregulation of the Hh pathway has been implicated in a variety of different types of cancer, including pancreatic and small-cell lung cancer. Recently a putative antagonist of the pathway, Hedgehog-interacting protein (HIP), was identified as a Hh binding protein that is also a target of Hh signaling. We sought to clarify possible roles for HIP in angiogenesis and cancer. METHODS: Inhibition of Hh signaling by HIP was assayed by measuring the induction of Ptc-1 mRNA in TM3 cells treated with conditioned medium containing Sonic hedgehog (Shh). Angiogenesis was assayed in vitro by EC tube formation on Matrigel. Expression of HIP mRNA was assayed in cells and tissues by Q-RT-PCR and Western blot. HIP expression in human tumors or mouse xenograft tumors compared to normal tissues was assayed by Q-RT-PCR or hybridization of RNA probes to a cancer profiling array. RESULTS: We show that Hedgehog-interacting protein (HIP) is abundantly expressed in vascular endothelial cells (EC) but at low or undetectable levels in other cell types. Expression of HIP in mouse epithelial cells attenuated their response to Shh, demonstrating that HIP can antagonize Hh signaling when expressed in the responding cell, and supporting the hypothesis that HIP blocks Hh signaling in EC. HIP expression was significantly reduced in tissues undergoing angiogenesis, including PC3 human prostate cancer and A549 human lung cancer xenograft tumors, as well as in EC undergoing tube formation on Matrigel. HIP expression was also decreased in several human tumors of the liver, lung, stomach, colon and rectum when compared to the corresponding normal tissue. CONCLUSION: These results suggest that reduced expression of HIP, a naturally occurring Hh pathway antagonist, in tumor neo-vasculature may contribute to increased Hh signaling within the tumor and possibly promote angiogenesis

Hereditary palmoplantar keratoderma - phenotypes and mutations in 64 patients

Background Hereditary palmoplantar keratodermas (PPK) represent a heterogeneous group of rare skin disorders with epidermal hyperkeratosis of the palms and soles, with occasional additional manifestations in other tissues. Mutations in at least 69 genes have been implicated in PPK, but further novel candidate genes and mutations are still to be found. Objectives To identify mutations underlying PPK in a cohort of 64 patients. Methods DNA of 48 patients was analysed on a custom-designed in-house panel for 35 PPK genes, and 16 patients were investigated by a diagnostic genetic laboratory either by whole-exome sequencing, gene panels or targeted single-gene sequencing. Results Of the 64 PPK patients, 32 had diffuse (50%), 19 focal (30%) and 13 punctate (20%) PPK. None had striate PPK. Pathogenic mutations in altogether five genes were identified in 31 of 64 (48%) patients, the majority (22/31) with diffuse PPK. Of them, 11 had a mutation in AQP5, five in SERPINB7, four in KRT9 and two in SLURP1. AAGAB mutations were found in nine punctate PPK patients. New mutations were identified in KRT9 and AAGAB. No pathogenic mutations were detected in focal PPK. Variants of uncertain significance (VUS) in PPK-associated and other genes were observed in 21 patients that might explain their PPK. No suggestive pathogenic variants were found for 12 patients. Conclusions Diffuse PPK was the most common (50%) and striate PPK was not observed. We identified pathogenic mutations in 48% of our PPK patients, mainly in five genes: AQP5, AAGAB, KRT9, SERPINB7 and SLURP1.Peer reviewe

Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a hereditary condition characterized by a wide range of developmental abnormalities and a predisposition to neoplasms

Predicting biomass partitioning to root versus shoot in corn and velvetleaf (\u3ci\u3eAbutilon theophrasti\u3c/i\u3e)

Knowledge of how plants will partition their new biomass will aid in understanding competition between crops and weeds. This study determined if the amount of biomass partitioned to the root versus the shoot can be predicted from tissue carbon [C] and nitrogen [N] concentrations and the daily gain in C (GC) and N (GN) for each unit shoot and root biomass, respectively. Pots measuring 28 cm diameter and 60 cm deep were embedded in the ground, and each contained one plant of either corn or velvetleaf. Each plant received one of three nitrogen treatments: 0, 1, or 3 g of nitrogen applied as ammonium nitrate in 2001 and 0, 2, or 6 g of nitrogen in 2002. Measurements of total above- and below-ground biomass and tissue [C] and [N] were made at 10 different sample dates during the growing season. Fraction of biomass partitioned to roots (Pr) was predicted from [C], [N], GC, and GN. Accurate prediction of the fraction of biomass partitioned to roots versus shoots was evaluated by comparing observed and predicted Pr across all treatments. The coordination model has potential as a reliable tool for predicting plant biomass partitioning. Normalized error values were close to zero for corn in 2001 and 2002 and for velvetleaf in 2001, indicating that biomass partitioning was correctly predicted

Effects of Nitrogen Supply on the Root Morphology of Corn and Velvetleaf

Root morphology will affect interplant competition for soil nutrients. Research was conducted to assess fine root fraction, mean root radius, specific root length, root length density, and nitrogen (N) uptake per unit fine root biomass of corn and velvetleaf over time and in response to nitrogen supply. Pots containing either corn or velvetleaf were embedded in the ground and received one of three N treatments. Plants were destructively sampled on 10 dates during each of two years and root subsamples analyzed using root scanning software. While corn root morphology was more responsive to N supply than velvetleaf, velvetleaf N uptake per unit fine root length was greater than that of corn at similar biomass. Results suggest that, in lieu of modifying root morphology to increase uptake efficiency when N is deficient, velvetleaf may invest more root biomass to produce a deeper tap root to reach nutrients deeper in the profile

Nitrogen supply affects root:shoot ratio in corn and velvetleaf (Abutilon theophrasti)

Competitive outcome between crops and weeds is affected by partitioning of new biomass to above- and below-ground plant organs in response to nutrient supply. This study determined the fraction of biomass partitioned to roots vs. shoots in corn and velvetleaf in response to nitrogen (N) supply. Pots measuring 28 cm in diam and 60 cm deep were embedded in the ground and each contained one plant of either corn or velvetleaf. Each plant received one of three N treatments: 0, 1, or 3 g N applied as ammonium nitrate in 2001, and 0, 2, or 6 g N in 2002. Measurements of total above- and below-ground biomass were made at 10 sampling dates during each growing season. The root:shoot ratio decreased over time for both corn and velvetleaf as a result of normal plant growth and as N supply increased. Root: shoot ratio was greater for corn than for velvetleaf at comparable stages of development and at all levels of N supply. Both corn and velvetleaf display true plasticity in biomass partitioning patterns in response to N supply. Velvetleaf root:shoot ratio increased by 46 to 82% when N was limiting in 2001 and 2002, respectively, whereas corn root:shoot ratio increased by only 29 to 45%. The greater increase in biomass partitioned to roots by velvetleaf might negatively impact its ability to compete with corn for light when N supply is limited

NAUTILE: a safe environment for silicon compilation

This paper deals with an environment for IC's layout, to act as a framework for the design of module generators for behavioral silicon compilation.It is built around an object oriented data manager that handles hierarchical design, and multiple representations, with emphasis on a safe design methodology. This manager also allows the use of externally defined elements, and the integration of tools written for other systems