Molecular profiling of the “plexinome” in melanoma and pancreatic cancer

Plexins are transmembrane high‐affinity receptors for semaphorins, regulating cell guidance, motility, and invasion. Functional evidences implicate semaphorin signals in cancer progression and metastasis. Yet, it is largely unknown whether plexin genes are genetically altered in human tumors. We performed a comprehensive gene copy analysis and mutational profiling of all nine members of the plexin gene family (plexinome), in melanomas and pancreatic ductal adenocarcinomas (PDACs), which are characterized by high metastatic potential and poor prognosis. Gene copy analysis detected amplification of PLXNA4 in melanomas, whereas copy number losses of multiple plexin genes were seen in PDACs. Somatic mutations were detected in PLXNA4, PLXNB3, and PLXNC1; providing the first evidence that these plexins are mutated in human cancer. Functional assays in cellular models revealed that some of these missense mutations result in loss of plexin function. For instance, c.1613G>A, p.R538H mutation in the extracellular domain of PLXNB3 prevented binding of the ligand Sema5A. Moreover, although PLXNA4 signaling can inhibit tumor cell migration, the mutated c.5206C>T, p.H1736Y allele had lost this activity. Our study is the first systematic analysis of the “plexinome” in human tumors, and indicates that multiple mutated plexins may be involved in cancer progression. Hum Mutat 30,1–8, 2009. © 2009 Wiley‐Liss, Inc.     

Reverse ventricular remodelling after cardiac resynchronization therapy is associated with a reduction in serum tenascin-C and plasma matrix metalloproteinase-9 levels

BACKGROUND: In heart failure patients, cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling. AIM: The aim of this study was to evaluate whether changes in levels of circulating biomarkers of extracellular matrix metabolism correlate with the response to CRT. METHODS AND RESULTS: Clinical parameters, left ventricular (LV) volumes, and circulating levels of tenascin-C (TNC), matrix metalloproteinase-2 (MMP-2), MMP-9, and amino-terminal propeptide of brain natriuretic peptide (NT-proBNP) were assessed in 64 patients at baseline and 6 months follow-up. The majority of patients (72%) showed a >10% reduction in LV end-systolic volume at follow-up, and were classified as responders to CRT. The remaining patients were classified as non-responders. In responders, a significant decrease in circulating levels of TNC (from 60+/-40 ng/mL to 47+/-30 ng/mL, p<0.01), MMP-9 (from 55+/-30 AU to 44+/-27 AU, p<0.01), and NT-proBNP (from 2106+/-1805 pg/mL to 1132+/-1289 pg/mL, p<0.001) were observed at follow-up; MMP-2 levels were unchanged. In non-responders TNC, NT-proBNP, MMP-9 and MMP-2 levels remained unchanged. CONCLUSION: At 6 months follow-up, CRT was associated with reverse LV remodelling, and a significant decrease in TNC, MMP-9, and NT-proBNP levels. This suggests an important role of ECM modulation in the process of reverse ventricular remodelling in patients responding to CRT.     

Synthesis of methoxypoly(ethylene glycol) carbonate prodrugs of zidovudine and penetration through human skin in vitro

Objectives The aim of this study was to synthesise a series of novel methoxypoly (ethylene glycol) carbonate prodrugs of the antiretroviral drug zidovudine (azidothymidine, AZT) in an attempt to enhance the physicochemical properties for transdermal delivery, which may reduce the severe side‐effects and toxicity associated with high oral doses of AZT. Methods Methoxypoly(ethylene glycol) carbonates of AZT were synthesised in two steps: activation of the relevant methoxypoly(ethylene glycol) with p‐nitrophenyl chloroformate, followed by reaction with AZT. Analysis of the hydrolytic stability in phosphate buffer at pH 5.0 and 7.4 revealed that all the carbonates were markedly more stable at pH 5.0 than at pH 7.4 (0.01 m), with half‐lives ranging from 15 to 44 days at pH 5.0 and from 6 to 24 days at pH 7.4. The potential of the series to penetrate the skin was evaluated in vitro by measuring diffusion through excised abdominal female human skin at pH 5.0. Key findings Prodrugs with 1–3 or 8 oxyethylene units in the methoxypoly(ethylene glycol) moiety were found to permeate the skin whereas those with 12 or 17 units did not. The prodrug with eight oxyethylene units was the most effective penetrant, permeating the skin with a mean flux of 53.3 ± 46.5 nmol/cm² per h, which is 2.4–10.1 times that of AZT (8.55 ± 5.3 nmol/cm² per h). Conclusions The bioreversible conjugation of the methoxypoly(ethylene glycol) promoiety to AZT appears to be a promising strategy for the transdermal delivery of AZT at a therapeutic dose.     

Noninvasive imaging in cardiac resynchronization therapy--part 1: selection of patients

Cardiac resynchronization therapy (CRT) is an established therapy for patients with advanced heart failure, depressed left ventricular function, and wide QRS complex. However, individual response varies, and a substantial amount of patients do not respond to CRT. Recent studies observed that assessment of inter- and particularly intraventricular dyssynchrony may allow identification of potential responders to CRT. In addition, presence of scar tissue and venous anatomy may play a role in the selection of candidates. In this review, an extensive overview of the available dyssynchrony measurements is provided using echocardiography as well as magnetic resonance imaging (MRI) and nuclear imaging. Furthermore, other information derived from MRI, nuclear imaging, and computed tomography useful for the selection of potential candidates for CRT will be discussed.     

Activation of neurospecific gene expression by antennapedia homeobox peptide

Antennapedia homeobox peptide has been reported to enhance neurite outgrowth and branching. Thus it is of interest to investigate whether antennapedia peptide is capable of modulating the expression of genes related to different events of neuronal development. In this paper we report the enhancement of a 68 KDa neurofilament subunit, choline acetyltransferase and acetylcholinesterase expression in spinal cord neurons, elicited by antennapedia peptide. Modulation of gene expression is different with respect to each gene product analyzed, suggesting a specific action of the peptide on diverse genes controlling different events of neuronal differentiation.     

The health of women treated for breast cancer: A challenge in primary care

At least one in a hundred consultations in general practice in Australia involves women being treated for breast cancer. The challenges presented during these consultations test the quality of primary care. Firstly, women are reported to prefer to discuss their breast cancer-related problems with a specialist even though research suggests that patients generally prefer to consult with a general practitioner (GP). The extent to which these patients will have maintained or return to their previous level of functioning will be a reflection on the quality of primary care, as some breast cancer-related health issues may persist beyond the time period when they are undergoing specialist review. Further, psychosocial matters, sexuality and relationships may require repeated review and perhaps consultations involving family members and would therefore be better addressed by a GP. An increasingly urgent need exists to review how best to support people who are successfully treated for life limiting illnesses, such as breast cancer.     

Antigenicity of legume proteins

In the food and feed industry, large amounts of agro‐industrial basic materials are used for the formulation of end‐products meant for human or animal nutrition. These basic ingredients and the final end‐products often have to fulfil special requirements regarding nutritional and anti‐nutritional factors (ANFs). A special need therefore exists for the identification and characterization of these factors. As there is increasing interest in the use of legume seeds as protein and energy sources in various foods and feedstuffs, a number of methods for the immunochemical detection and quantification of proteinaceous ANFs in legumes have been developed. Current knowledge of the immunochemical detection and analysis of antigenic proteins in legume seeds and some of the phenomena of these proteinaceous ANFs in young animals are described in this paper.