Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk

Common genetic variation could alter the risk for developing bladder cancer. We conducted a large-scale evaluation of single nucleotide polymorphisms (SNPs) in candidate genes for cancer to identify common variants that influence bladder cancer risk. An Illumina GoldenGate assay was used to genotype 1,433 SNPs within or near 386 genes in 1,086 cases and 1,033 controls in Spain. The most significant finding was in the 5′ UTR of VEGF (rs25648, p for likelihood ratio test, 2 degrees of freedom = 1 × 10⁻⁵). To further investigate the region, we analyzed 29 additional SNPs in VEGF, selected to saturate the promoter and 5′ UTR and to tag common genetic variation in this gene. Three additional SNPs in the promoter region (rs833052, rs1109324, and rs1547651) were associated with increased risk for bladder cancer: odds ratio (95% confidence interval): 2.52 (1.06–5.97), 2.74 (1.26–5.98), and 3.02 (1.36–6.63), respectively; and a polymorphism in intron 2 (rs3024994) was associated with reduced risk: 0.65 (0.46–0.91). Two of the promoter SNPs and the intron 2 SNP showed linkage disequilibrium with rs25648. Haplotype analyses revealed three blocks of linkage disequilibrium with significant associations for two blocks including the promoter and 5′ UTR (global p = 0.02 and 0.009, respectively). These findings are biologically plausible since VEGF is critical in angiogenesis, which is important for tumor growth, its elevated expression in bladder tumors correlates with tumor progression, and specific 5′ UTR haplotypes have been shown to influence promoter activity. Associations between bladder cancer risk and other genes in this report were not robust based on false discovery rate calculations. In conclusion, this large-scale evaluation of candidate cancer genes has identified common genetic variants in the regulatory regions of VEGF that could be associated with bladder cancer risk.     

Energetics and dynamics of SNAREpin folding across lipid bilayers

Membrane fusion occurs when SNAREpins fold up between lipid bilayers. How much energy is generated during SNAREpin folding and how this energy is coupled to the fusion of apposing membranes is unknown. We have used a surface forces apparatus to determine the energetics and dynamics of SNAREpin formation and characterize the different intermediate structures sampled by cognate SNAREs in the course of their assembly. The interaction energy-versus-distance profiles of assembling SNAREpins reveal that SNARE motifs begin to interact when the membranes are 8 nm apart. Even after very close approach of the bilayers (approximately 2-4 nm), the SNAREpins remain partly unstructured in their membrane-proximal region. The energy stabilizing a single SNAREpin in this configuration (35 k(B)T) corresponds closely with the energy needed to fuse outer but not inner leaflets (hemifusion) of pure lipid bilayers (40-50 k(B)T).     

Many genomic regions are required for normal embryonic programmed cell death in Caenorhabditis elegans

To identify genes involved in programmed cell death (PCD) in Caenorhabditis elegans, we screened a comprehensive set of chromosomal deficiencies for alterations in the pattern of PCD throughout embryonic development. From a set of 58 deficiencies, which collectively remove approximately 74% of the genome, four distinct classes were identified. In class I (20 deficiencies), no significant deviation from wild type in the temporal pattern of cell corpses was observed, indicating that much of the genome does not contain zygotic genes that perform conspicuous roles in embryonic PCD. The class II deficiencies (16 deficiencies defining at least 11 distinct genomic regions) led to no or fewer-than-normal cell corpses. Some of these cause premature cell division arrest, probably explaining the diminution in cell corpse number; however, others have little effect on cell proliferation, indicating that the reduced cell corpse number is not a direct result of premature embryonic arrest. In class III (18 deficiencies defining at least 16 unique regions), an excess of cell corpses was observed. The developmental stage at which the extra corpses were observed varied among the class III deficiencies, suggesting the existence of genes that perform temporal-specific functions in PCD. The four deficiencies in class IV (defining at least three unique regions), showed unusually large corpses that were, in some cases, attributable to extremely premature arrest in cell division without a concomitant block in PCD. Deficiencies in this last class suggest that the cell death program does not require normal embryonic cell proliferation to be activated and suggest that while some genes required for cell division might also be required for cell death, others are not. Most of the regions identified by these deficiencies do not contain previously identified zygotic cell death genes. There are, therefore, a substantial number of as yet unidentified genes required for normal PCD in C. elegans.     

Re-examination of the "3/4-law" of metabolism

We examine the scaling law B is proportional to M(alpha)which connects organismal resting metabolic rate B with organismal mass M, where alpha is commonly held to be 3/4. Since simple dimensional analysis suggests alpha = 2/3, we consider this to be a null hypothesis testable by empirical studies. We re-analyse data sets for mammals and birds compiled by Heusner, Bennett and Harvey, Bartels, Hemmingsen, Brody, and Kleiber, and find little evidence for rejecting alpha = 2/3 in favor of alpha = 3/4. For mammals, we find a possible breakdown in scaling for larger masses reflected in a systematic increase in alpha. We also review theoretical justifications of alpha = 3/4 based on dimensional analysis, nutrient-supply networks, and four-dimensional biology. We find that present theories for alpha = 3/4 require assumptions that render them unconvincing for rejecting the null hypothesis that alpha = 2/3.     

Delta opioid binding selectivity of 3-ether analogs of naltrindole

Masking of the 3-phenol of naltrindole as a range of ethers caused a decrease in binding affinity at all three opiate receptors (μ, κ, δ), however for the methyl ether, the reduction in affinity at both μ and κ was greater than at δ, thereby increasing δ binding selectivity.     

Treatment of a bifurcation lesion at the anastomosis of a vein graft by true 'Y' stenting

We describe the treatment of a bifurcation lesion at the anastomosis of a vein graft by 'true Y' stenting which preserved both antegrade and retrograde flow away from the graft.     

Diaryldimethylpiperazine ligands with mu- and delta-opioid receptor affinity: Synthesis of (+)-4-[(alphaR)-alpha-(4-allyl-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide and (-)-4-[(alphaR)-alpha-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide

We have explored the synthesis of compounds that have good affinity for both mu- and delta-opioid receptors from the (alphaR,2S,5S) class of diaryldimethylpiperazines. These non-selective compounds were related to opioids that have been found to interact selectively with mu- or delta-opioid receptors as agonists or antagonists. In our initial survey, we found two compounds, (+)-4-[(alphaR)-alpha-(4-allyl-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide (14) and its N-H relative, (-)-4-[(alphaR)-alpha-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide (15), that interacted with delta-receptors with good affinity, and, as we hoped, with much higher affinity at mu-receptors than SNC80. The relative configuration of the benzylic position in (+)-4-[(alphaR)-alpha-(4-allyl-(2S,5S)-dimethyl-1-piperazinyl)-(3-methoxyphenyl)methyl]-benzyl alcohol (10) was determined by X-ray crystallographic analysis of a crystal that was an unresolved twin. The absolute stereochemistry of that benzylic stereogenic center was unequivocally derived by the X-ray crystallographic analysis from the two other centers of asymmetry in the molecule that were known. Those were established from the synthesis via a dipeptide cyclo-L-Ala-L-Ala in which the absolute stereochemistry was established.     

Intravascular ultrasound assessment of culotte stent deployment for the treatment of stenoses at major coronary bifurcations

BACKGROUND: The mechanism for the disappointing late outcome following stenting of bifurcation lesions is unclear. This prospective observational study aims to evaluate culotte stent deployment and dimensions with intravascular ultrasound (IVUS). PATIENTS AND METHODS: Patients with bifurcation stenoses were treated using two stents in a culotte configuration. After optimizing the angiographic appearance of both stents, IVUS was used to evaluate both limbs of the culotte. The main outcome measures were cross-sectional area (CSA) and minimal lumen diameter (MLD) assessed by IVUS. RESULTS: Within the culotte stent, the final mean CSA in the main limb was 6.1 mm(2) (97% of reference) and in the side-limb was 5.9 mm(2) (97% of reference). However, in each case, the minimum CSA and IVUS MLD of both limbs was at the bifurcation point. For all patients, the final mean CSA at the bifurcation point of the main limb was 4.3 mm(2) (70% of main stent) and of the side-limb was 4.4 mm(2) (75% of side stent). The IVUS MLD at the bifurcation point of the main limb was 2.1 mm (78% of main stent) and of the side-limb was 2.1 mm (84% of the side stent). Importantly, this significant residual stenosis was not detectable with quantitative coronary angiography. CONCLUSIONS: IVUS evaluation of culotte stents is feasible. The minimum IVUS CSA and MLD of both limbs of the culotte stent is at the bifurcation point. Despite an optimal angiographic appearance a significant residual stenosis was noted with IVUS at each bifurcation point.