Tumor Angiogenesis Phenotyping by Nanoparticle-facilitated Magnetic Resonance and Near-infrared Fluorescence Molecular Imaging

One of the challenges of tailored antiangiogenic therapy is the ability to adequately monitor the angiogenic activity of a malignancy in response to treatment. The α_vβ₃ integrin, highly overexpressed on newly formed tumor vessels, has been successfully used as a target for Arg-Gly-Asp (RGD)-functionalized nanoparticle contrast agents. In the present study, an RGD-functionalized nanocarrier was used to image ongoing angiogenesis in two different xenograft tumor models with varying intensities of angiogenesis (LS174T > EW7). To that end, iron oxide nanocrystals were included in the core of the nanoparticles to provide contrast for T₂*-weighted magnetic resonance imaging (MRI), whereas the fluorophore Cy7 was attached to the surface to enable near-infrared fluorescence (NIRF) imaging. The mouse tumor models were used to test the potential of the nanoparticle probe in combination with dual modality imaging for in vivo detection of tumor angiogenesis. Pre-contrast and post-contrast images (4 hours) were acquired at a 9.4-T MRI system and revealed significant differences in the nanoparticle accumulation patterns between the two tumor models. In the case of the highly vascularized LS174T tumors, the accumulation was more confined to the periphery of the tumors, where angiogenesis is predominantly occurring. NIRF imaging revealed significant differences in accumulation kinetics between the models. In conclusion, this technology can serve as an in vivo biomarker for antiangiogenesis treatment and angiogenesis phenotyping.     

Carcinoid tumors: iodine-131 MIBG scintigraphy

Eighty-two patients with pathologically proved carcinoid tumors were examined with iodine-131 metaio-dobenzylguanidine (MIBG) scintigraphy. Localization scores of I-131 MIBG accumulation in the primary tumor or metastatic site ranged from 0 to 3+ on the basis of comparison with normal liver. I-131 MIBG uptake varied greatly in different patients with carcinoid tumors. The localization scores in known tumor sites were related to the location of the primary tumor in the stomach (1-3+ in two of five patients), pancreas (1-3+ in four of five patients), cecum (3+ in two of two patients), appendix (0 in one of one patient), jejunum (0 in one of one patient), Meckel diverticulum (3+ in one of one patient), terminal ileum (2-3+ in 19 of 28 patients), bronchus (3+ in one of nine patients), thymus (1+ in one of two patients), and unknown (2-3+ in 18 of 28 patients). Tumors of midgut origin concentrated I-131 MIBG more frequently than those of foregut origin. Uptake of I-131 MIBG was more likely if neurohumor levels, particularly serum serotonin, were elevated. There was no relationship of I-131 MIBG uptake to carcinoid syndrome. I-131 MIBG is useful in the determination of the location and extent of some carcinoid tumors, particularly those of midgut origin.     

Non-disjunction of chromosome 18

A sample of 100 trisomy 18 conceptuses analysed separately and together with a published sample of 61 conceptuses confirms that an error in maternal meiosis II (MII) is the most frequent cause of non-disjunction for chromosome 18. This is unlike all other human trisomies that have been studied, which show a higher frequency in maternal meiosis I (MI). Maternal MI trisomy 18 shows a low frequency of recombination in proximal p and medial q, but not the reduction in proximal q observed in chromosome 21 MI non-disjunction. Maternal MII non-disjunction does not fit the entanglement model that predicts increased recombination, especially near the centromere. Whereas recent data on MII trisomy 21 show the predicted increase in recombination proximally, maternal MII trisomy 18 has non-significantly reduced recombination. Therefore, chromosome-specific factors must complicate the simple model of susceptible chiasma distributions interacting with age-dependent deterioration of the meiotic mechanism. For chromosome 18, 30% of tetrads are nullichiasmate in maternal MI non-disjunction, but nullichiasmates are not observed in maternal MII non-disjunction. Chiasma distributions from normal chromosome 18 meioses provide no evidence for normal disjunction from nullichiasmate tetrads. We extend this study to examine the remaining autosomes and find no evidence for normal disjunction from nullichiasmate tetrads generally.      

Rett syndrome from quintuple and triple deletions within the MECP2 deletion hotspot region

Rett syndrome results from mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene, which are nearly always lethal in males and lead to regression and reduced life expectancy in females. Herein we report one propositus with five tandem deletions and a second propositus with three tandem deletions within MECP2 exon 4 that encode truncated protein products resulting in classic Rett syndrome. These deletion breakpoints and single deletions in 3 other patients were all found within a 185-bp region along with 64 of 69 other reported deletion breakpoints in the MECP2 gene. Illegitimate recombination resulting in deletion at a substantial proportion of the shared MECP2 sites is enhanced by repeated guanosine (G) DNA sequences in the antisense direction, consistent with reports at other gene loci that polypurine (multiple guanosine or adenosine (A)) basepairs enhance sequence deletion. Multiple deletions at the same poly G recombination sites confirm the existence of deletion hotspots in this gene region with numerous repeated antisense sites that are enriched 26- to 161-fold. Deletion by illegitimate recombination within a single allele can occur during mitotic or meiotic cell cycles. Although prone to disease-causing deletion, this region is unique in humans and highly conserved among mammals for the last 75 000 000 years to maintain the MECP2 gene's critical function.     

Association between asthma and an intragenic variant of CC16 on chromosome 11q13

The β subunit of high affinity immunoglobulin E (IgE) receptor (FcɛRIβ) and the Clara cell derived inflammatory molecule, CC16 have been cited as candidate genes for atopic asthma on chromosome 11q13. A genetic association study was performed with an intragenic microsatellite repeat of CC16 gene on chromosome 11q12–13 in relation to atopic and non-atopic asthma. Whereas variants of FcɛRIβ at chromosome 11q13 show association with atopy and asthma, no significant association was found between asthma and CC16 genotypes irrespective of atopic status. These data support the candidacy of FcɛRIβ rather than CC16 for the atopic asthma locus on chromosome 11q.     

Phone and e-mail counselling are effective for weight management in an overweight working population: a randomized controlled trial

Background  

The work setting provides an opportunity to introduce overweight (i.e., Body Mass Index ≥ 25 kg/m²) adults to a weight management programme, but new approaches are needed in this setting. The main purpose of this study was to investigate the effectiveness of lifestyle counselling by phone or e-mail on body weight, in an overweight working population. Secondary purposes were to establish effects on waist circumference and lifestyle behaviours, and to assess which communication method is the most effective.