Protective effects of sialylated oligosaccharides in immune complex-induced acute lung injury.

Using sialyl Lewisx (SLX) oligosaccharides derived from fucosyl transferase-expressing cells or generated synthetically, the ability of these compounds to protect against acute lung damage after deposition of immunoglobulin (Ig)G or IgA immune complexes has been determined. The synthetic compounds were tetra- and pentasaccharide derivates of SLX as well as the nonfucosylated forms of SLX as controls. In the IgG immune complex model of lung injury, which is E-selectin dependent, SLX preparations provided dose-dependent protective effects, as assessed by changes in lung vascular permeability and hemorrhage. Protective effects were associated with diminished tissue accumulation of neutrophils in lungs (as assessed by myeloperoxidase). Morphological assessment revealed reduced physical contact of neutrophils with the pulmonary vascular endothelium and reduced tissue accumulation of neutrophils. In the model of IgA immune complex-induced lung injury, which does not involve participation of neutrophils and is independent of the requirement for E-selectin, SLX preparations were not protective. These data suggest that, in neutrophil-mediated and E-selectin-dependent lung injury, SLX preparations provide significant, protective effects against inflammatory vascular injury. The ability to achieve antiinflammatory outcomes in vivo with appropriate oligosaccharides suggests a new approach to the blocking of acute inflammatory responses.

Evaluation of oncogene-related proteins in serum.

We hypothesize that the products of cellular oncogenes and antioncogenes are biomarkers of events related to cancer risk. This study uses monoclonal antibody technology to examine serum proteins which are immunologically related to ras oncogene and epidermal growth factor receptor proteins. We measured the prevalence of ras- and epidermal growth factor receptor-related proteins in stored and freshly frozen serum from cancer patients, male heavy smokers, and older healthy subjects. Work emphasized the attainment of inter- and intraobserver agreement between independent readings of immunoblot gels. Although we achieved acceptable levels of agreement, we uncovered evidence for blood collection and storage artifacts. Accounting for these artifacts, we compared 80 cancer patients and 188 middle-aged and older community controls and found a strong relationship (odds ratio = 11.1; 95% confidence interval, 6.0-20.6) between cancer and a M(r) 21,000 serum protein related to the ras oncogene product. These results indicate the need and importance of comprehensive pretesting of putative cancer biomarkers before use in applied or etiological epidemiological research.

Palladium catalysis in the synthesis of medicinal agents.

Palladium-catalyzed reactions are having a great impact on the synthesis of medicinal agents due to their ability to form carbon-carbon and carbon-heteroatom bonds effectively. Quite often the palladium-catalyzed step(s) in a synthesis is key to the overall strategy for preparing a drug candidate. The diversity of the coupling processes is being broadened by the availability of new functionalities for the oxidative addition and transmetalation steps. In addition, the development of new ligands, or the application of existing ligands, is playing a large role in expanding the choices of coupling partners. Traditionally, palladium reactions have constructed achiral systems, however, the number of successful asymmetric syntheses with palladium chemistry is growing. This review will cover the variety of coupling reactions that have been applied to drug synthesis, with representative examples highlighted from the recent literature.

Breast phantom for ion chamber dosimetry.

For studies of breast treatment techniques, a water phantom has been developed which allows high accuracy dose measurements using an ion chamber. The phantom is made from the torso of a female mannequin, which is supported so that it can be positioned either supine or prone. The back of the mannequin has been cut away to allow the phantom to be filled with water when positioned prone. The phantom can be simulated, planned, and treated in the manner of a patient. During "treatment" (prone rather than supine), ion chamber measurements can be made at any desired point within (or outside) the treatment volume. The ion chamber support system accurately assigns an (x, y, z) coordinate to each detector position within the phantom.

Technique to match mantle and para-aortic fields.

A technique is described to match the mantle and para-aortic fields used in treatment of Hodgkin's disease, when the patient is treated alternately in supine and prone position. The approach is based on referencing the field edges to a point close to the vertebral column, where uncontrolled motion is minimal and where accurate matching is particularly important. Fiducial surface points are established in the simulation process to accomplish this objective. Dose distributions have been measured to study the combined effect of divergence differences, changes in body angulation and setup errors. Even with the most careful technique, the use of small cord blocks of 50% transmission is an advisable precaution for the posterior fields.

Practice of 3-dimensional treatment planning at the Fox Chase Cancer Center, University of Pennsylvania.

The use of 3-dimensional (3-D) dose distributions and dose-volume histograms in radiation therapy treatment planning is illustrated on a patient with a head and neck tumor. The patient was immobilized in a rectangular tissue compensation bolus box. The treatment was planned with a 14 MeV D-T derived fast neutron therapy beam. The isodose distributions and the dose-volume histograms at multiple adjacent levels are used to evaluate the adequacy of coverage of target volumes and the doses to the normal tissues. Such dose-volume histograms are useful and practical in summarizing the dose distribution throughout the irradiated volume, assessing the degree of uniformity of the dose distribution within the target volume, quantifying the amount of normal tissue irradiated, and evaluating rival treatment plans for both particle and nonparticle beams.

Annulation of ketones with vinamidinium hexafluorophosphate salts: an efficient preparation of trisubstituted pyridines.

alpha-Aryl ketones react with vinamidinium hexafluorophosphate salts to give access to the corresponding 3-arylpyridines. The annulation reactions proceed in good to excellent yields with vinamidinium salts containing electron-withdrawing groups at the beta-position (R(2)). The reaction was applied to the preparation of the COX-2 specific inhibitor 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine (1), as well as a series of analogues.

Practical modifications and applications of the sharpless asymmetric aminohydroxylation in the one-pot preparation of chiral oxazolidin-2-ones.

[reaction: see text] Chiral oxazolidin-2-ones are synthetically valuable as chiral auxiliaries, and many have pharmaceutically interesting biological activity. This communication focuses on a convenient, practical one-pot preparation of chiral 4,5-disubstituted oxazolidan-2-ones in good yield with high enantioselectivities, using a modified Sharpless asymmetric aminohydroxylation of beta-substituted styrene derivatives followed by base-mediated ring closure. This procedure has been demonstrated on both small and large scale, utilizing 1, 3-dichloro-5,5-dimethyl hydantoin as an easily handled, commercially available substitute for tert-butyl hypochlorite.

The effect of flattening filter design on quality variations within an 8-MV primary x-ray beam.

Single material flattening filters supplied by manufacturers of medical linear accelerators are designed to produce the desired primary dose profile while maintaining output at a maximum level. This design criterion tends to produce substantial quality variations within the primary beam. Quality variations, as expressed by half-value layer in brass and polystyrene, were measured for an 8-MV primary beam both unfiltered and with the flattening filter supplied by the manufacturer. Most of the quality variation was introduced by the filter. Two approaches were then used to reduce this quality variation, each at a cost of a 25% reduction in output. First, a hardening filter was added to the manufacturer's flattening filter. The second approach was to design a new composite flattening filter made from brass and lead. For both approaches, the increase in quality variation over the intrinsic (no filter) variation was reduced by one-half.

Calculations for beam-flattening filters for high-energy x-ray machines.

A flattening filter is an important component in a medical accelerator to modify the photonbeam properties. To simplify the calculations of the flattening-filter profile, we have developed a computer program which sums primary and scatter and then makes iterations in the primary component to produce a desired total-dose profile. The program can account, to first order, for radial spectral changes by using an effective primary attenuation coefficient which varies with radius. Calculations made to model the Clinac-4 dose profiles using the measured variation of half-value layer with radius show good agreement with the measured data. It is shown that the variation of quality within the beam impairs the flatness that can be achieved over a range of depths. Since perfect flatness cannot be achieved for small and large fields with one flattening filter, one may choose a primary profile which is a compromise over a range of field sizes and depths. A compromise profile for a 4-MV beam is discussed.

Development of molecular approaches to estimating germinal mutation rates. I. Detection of insertion/deletion/rearrangement variants in the human genome.

DNA from 130 individuals was studied with up to 18 (primarily cDNA) probes for the frequency of variants in this initial experiment to determine the feasibility of this approach to screening for germinal gene mutations. This approach, a modification of the usual restriction enzyme mapping strategy, focuses on the detection of insertion/deletion/rearrangement (I/D/R) variants, because the DNA is digested with only two restriction enzymes before transfer to membranes and hybridization with an extensive series of unrelated probes. Some 4000 noncontiguous, independent DNA fragments ("loci"), functional loci, pseudogenes or anonymous fragments, (a total of approximately 77,400 kb) were screened. 19 different classes and 31 copies of presumably I/D/R variants were detected while 4 different classes and 24 individuals exhibiting base substitution variants were observed. 18 of the 19 I/D/R classes were rare variants, that is, each were observed at a frequency, within this population, of less than 0.01; 3 of the base substitution classes existed at polymorphic frequencies and only 1 was a rare variant. 10 of the I/D/R classes, occurring in a total of 18 individuals, were detected with probes which are not known to be associated with repetitive elements. This is a variant frequency for I/D/R variants without known repetitive elements of 0.15 classes and 0.23 copies for each 1000 kb screened; this would extrapolate to 1600 such variant sites in the genome of each individual. Within the context of a mutation screening program, the rare variants, either with or without repetitive elements, would have a higher probability of being de novo mutations than would polymorphic variants; this former group would be the focus of family studies to test for the heritability of the allele (fragment pattern). Sufficient DNA probes are available to screen a significant portion of the human genome for genetic variation and de novo mutations of this type.

Transmetacarpal amputations and replantation: the importance of the normal vascular anatomy.

Three transmetacarpal injuries are described in which the patency of one common digital vessel alone provided blood flow to all fingers. Transverse commissural vessels connect the digital vessels proximal to the proximal and distal interphalangeal joints. Retrograde flow to the adjacent common digital vessels revascularises the other digits. The volar metacarpal vessels, if not ligated, may allow continued bleeding into the palm following reattachment of a transmetacarpal amputation. These vessels may have been responsible for failure of the replantation in one case.