Hedgehog Signaling in Prostate Cancer and Its Therapeutic Implication

Activation of Hedgehog (Hh) signaling is implicated in the development and progression of several tumor types, including prostate cancer, which is still the most common non-skin malignancy and the third leading cause of cancer-related mortality in men in industrialized countries worldwide. Several studies have indicated that the Hh pathway plays a crucial role in the development as well as in the progression of this disease to more aggressive and even therapy-resistant disease states. Moreover, preclinical data have shown that inhibition of Hh signaling has the potential to reduce prostate cancer invasiveness and metastatic potential. Clinical trials investigating the benefit of Hh inhibitors in patients with prostate cancer have recently been initiated. However, acquired drug resistance has already been observed in other tumor types after long-term Hh inhibition. Therefore, combining Hh inhibitors with ionizing radiation, chemotherapy or other molecular targeted agents could represent an alternative therapeutic strategy. In this review, we will highlight the role of Hh signaling in the development and progression of prostate cancer and summarize the different therapeutic applications of Hedgehog inhibition.     

Analysis of Low Molecular Weight Lignin-Derived Sulphonates by Capillary Zone Electrophoresis

A fast and simple analytical procedure, based on capillary zone electrophoresis (CZE), for separation of underivatized low molecular weight lignin-derived sulphonates has been developed. Optimal CZE-operatipn conditions for the separation and detection of several lignin-derived sulphonic acids was found when using a low pH (pH 1.7) phosphate buffer system, an applied voltage of 20 kV and UV-detection at the anode-side. At these conditions the electroosmotic flow is negligible and the analytes are transported through the capillary column by electromigration. The sulphonation and subsequent degradation of the lignin-model compound 1-(4-hydroxy-3-methoxyphenyl)-2-O-(2-methoxyphenyl)-glycerol has been studied by CZE-analysis of aliquots taken from a sulphite reaction mixture No sample pretreatment was needed before analyzing the sulphite reaction mixture with CZE. The method has also been found to be useful for detection of sulphonic acids in samples from sulphite cooking. Crude extracts of a sulphite cooking liquor could be directly analysed by using the technique developed. Based on migration time data and comparison with an authentic sample, 1-(4-hydroxy-3-meth6xyphenyl)-prop-2-ene-1-sulphonate was identified as one of the sulphonic acids present in the sulphite cooking liquor.     

Cleavable surfactants

Cleavable surfactants are of interest for several reasons. Above all, the development of surfactants with weak bonds deliberately built into the structure is driven by the need for improved biodegradability of amphiphiles. The breakdown may be catalyzed by enzymes, and biodegradation would be the normal mechanism in sewage plants. Alternatively, the surfactant may degrade by chemical means, e.g., induced by acid, alkali, ultraviolet (UV) light, heat, or ozone. Acid- and alkali-labile surfactants have attracted particular attention, and there is often a compromise between required stability at one stage and ease of breakdown at a subsequent stage. The paper reviews the main routes used to prepare cleavable surfactants and points out advantages and disadvantages of the different approaches. Emphasis is placed on the development during recent years. Cyclic and acyclic acetals, ketals, and ortho esters are the most important types of bonds for the preparation of acid-labile surfactants, whereas alkali-labile amphiphiles usually are based on ester bonds. The ester bond approach has been particularly important for cationic surfactants, and so-called ester quats have rapidly taken a large share of the traditional market for quats. Betaine esters constitute a special class of ester with very pronounced pH dependence. UV-labile surfactants based, for instance, on an azo bond, offer promise for the future.     

Colour research with architectural relevance: How can different approaches gain from each other?

Colour research from different scientific traditions start from different basic questions and use different methods and concepts. This makes it difficult to communicate and to judge result relevance in a wider perspective. Here we start from architects' need of colour knowledge and discuss recent studies of colour appearance and colour emotion, with and without explicit connection to architecture. We stress the need for further development and clarification of concepts and conclude that the multitude of studies with different approaches can be seen as cases, jointly adding to a widened and deepened understanding of colour. © 2010 Wiley Periodicals, Inc. Col Res Appl, 2010     

Effect of NiO-to-Ni Transformation on Conductivity and Structure of Yttria-Stabilized ZrO2

The conductivity and structure of 8-mol%-yttria-stabilized zirconia with additions of nickel oxide has been investigated, both in the as-prepared state and after reduction of NiO in hydrogen. During reduction at 1000°C, the conductivity decreases by 40%–50% and most of the NiO dissolved in the zirconia is exsolved in the form of nickel particles. This is accompanied by the formation of tetragonal zirconia precipitates of size 10–40 nm and by an increase in the lattice parameter. On reoxidation in air at 1000°C, the change in lattice parameter is partly reversed, but the conductivity shows no further changes.     

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.     

Tocotrienol-rich fraction from palm oil affects gene expression in tumors resulting from MCF-7 cell inoculation in athymic mice

It has recently been shown that tocotrienols are the components of vitamin E responsible for inhibiting the growth of human breast cancer cells in vitro, through an estrogen-independent mechanism. Although tocotrienols act on cell proliferation in a dose-dependent manner and can induce programmed cell death, no specific gene regulation has yet been identified. To investigate the molecular basis of the effect of tocotrienols, we injected MCF-7 breast cancer cells into athymic nude mice. Mice were fed orally with 1 mg/d of tocotrienol-rich fraction (TRF) for 20 wk. At end of the 20 wk, there was a significant delay in the onset, incidence, and size of the tumors in nude mice supplemented with TRF compared with the controls. At autopsy, the tumor tissue was excised and analyzed for gene expression by means of a cDNA array technique. Thirty out of 1176 genes were significantly affected. Ten genes were down-regulated and 20 genes up-regulated with respect to untreated animals, and some genes in particular were involved in regulating the immune system and its function. The expression of the interferon-inducible transmembrane protein-1 gene was significantly up-regulated in tumors excised from TRF-treated animals compared with control mice. Within the group of genes related to the immune system, we also found that the CD59 glycoprotein precursor gene was up-regulated. Among the functional class of intracellular transducers/effectors/modulators, the c-myc gene was significantly down-regulated in tumors by TRF treatment. Our observations indicate that TRF supplementation significantly and specifically affects MCF-7 cell response after tumor formation in vivo and therefore the host immune function. The observed effect on gene expression is possibly exerted independently from the antioxidant activity typical of this family of molecules.