Homogeneous immunoconjugates for boron neutron-capture therapy: design, synthesis, and preliminary characterization

The application of immunoprotein-based targeting strategies to the boron neutron-capture therapy of cancer poses an exceptional challenge, because viable boron neutron-capture therapy by this method will require the efficient delivery of 10(3) boron-10 atoms by each antigen-binding protein. Our recent investigations in this area have been focused on the development of efficient methods for the assembly of homogeneous immunoprotein conjugates containing the requisite boron load. In this regard, engineered immunoproteins fitted with unique, exposed cysteine residues provide attractive vehicles for site-specific modification. Additionally, homogeneous oligomeric boron-rich phosphodiesters (oligophosphates) have been identified as promising conjugation reagents. The coupling of two such boron-rich oligophosphates to sulfhydryls introduced to the CH2 domain of a chimeric IgG3 has been demonstrated. The resulting boron-rich immunoconjugates are formed efficiently, are readily purified, and have promising in vitro and in vivo characteristics. Encouragingly, these studies showed subtle differences in the properties of the conjugates derived from the two oligophosphate molecules studied, providing a basis for the application of rational design to future work. Such subtle details would not have been as readily discernible in heterogeneous conjugates, thus validating the rigorous experimental design employed here.     

COLD STERILE FILTRATION: A SMALL SCALE FILTRATION TEST AND INVESTIGATION OF MEMBRANE PLUGGING

Beer brewed from 24 commercially and bag malted samples by a small scale brewing method was assessed by a micro-filtration efficiency (MFE) test designed to emulate the cold-sterile (membrane or micro-) filtration process. The level of malt derived beer components with the potential to reduce MFE, such as β-glucan, arabinoxylan, protein and polyphenol, were consistent over duplicate beer batches suggesting that beer quality was reproducible using the small scale method. The small scale MFE test was able to differentiate (P<0.001) between beer brewed from distinct malt samples in a reproducible fashion, suggesting that the test is effective in assessing beer MFE in the laboratory. Subsequently, the effects of various malt derived beer components on micro-filtration were investigated. MFE (measured as <i>V_max) was negatively correlated with beer arabinoxylan content (r=–0.62, P<0.01), suggesting that the arabinoxylan content of malt, and subsequently beer, may influence MFE. Total beer β-glucan was not significantly related to beer MFE (r=-0.36). However, it was likely that β-glucan molecules of high molecular weight influenced MFE more so than the total β-glucan content. Beer viscosity, which was correlated to both beer β-glucan and arabinoxylan content (r=0.86, P<0.001 and r=0.68, P<0.05, respectively), correlated with V_max (r=-0.81, P<0.001) .     

Carborane‐Derived Local Anesthetics are Isomer Dependent

Clinically there is a need for local anesthetics with a greater specificity of action on target cells and longer duration. We have synthesized a series of local anesthetic derivatives we call boronicaines in which the aromatic phenyl ring of lidocaine was replaced with ortho‐, meta‐, C,C’‐dimethyl meta‐ and para‐carborane clusters. The boronicaine derivatives were tested for their analgesic activity and compared with lidocaine using standard procedures in mice following a plantar injection. The compounds differed in their analgesic activity in the following order: ortho‐carborane = C,C’‐dimethyl meta‐carborane > para‐carborane > lidocaine > meta‐carborane derivative. Both ortho‐boronicaine and C,C’‐dimethyl meta‐boronicaine had longer durations of analgesia than lidocaine. Differences in analgesic efficacies are rationalized by variations in chemical structure and protein binding characteristics.     

PREPARATION OF TRANS-ISO-ALPHA ACIDS AND USE OF THEIR DICYCLOHEXYLAMINE SALTS AS A STANDARD FOR ISO-ALPHA ACIDS ANALYSIS

The reaction between dicyclohexylamine and iso-alpha acids yields a crystalline product which consists of the dicyclohexylamine salts of trans-iso-cohumulone, trans-isohumulone and trans-iso-adhumulone. The presence of only the trans-isomers in the crystalline product was established by proton and carbon NMR. Pure trans-iso-alpha acids can be regenerated from the salt either by treatment with acid or in situ by the use of acidic buffers during HPLC analysis. The dicyclohexylamine salts of the trans-iso-alpha acids are stable for extended periods at room temperature, unlike the purified trans-iso-alpha acids, and are thus suitable for use as a standard for iso-alpha acids analysis.     

Hydrodynamic analysis of a 10 kWth Calcium Looping Dual Fluidized Bed for post-combustion CO2 capture

Calcium Looping (CaL) in a Dual Fluidized Bed (DFB), utilizing a carbonator and a regenerator, is a post-combustion CO₂ capture technology currently under development. At IFK, University of Stuttgart, a 10 kW_th CaL DFB system has been built consisting of a carbonator riser and a Bubbling Fluidized Bed (BFB) regenerator. A major novelty of this facility is the implementation of a cone valve to control the sorbent looping rate between the two beds. This study presents detailed results of tests conducted on a hydrodynamically scaled cold model of the 10 kW_th CaL DFB facility. The performance of the cold model was compared with CaL process boundary conditions in order to determine the suitability of the 10 kW_th CaL DFB system. The resulting qualitative conclusions regarding DFB hydrodynamics may be of aid to other DFB processes, such as Chemical Looping Combustion (CLC) and Fast Internally Circulating Fluidized Bed (FICFB) gasification. All important operational parameters of the cold model DFB system, namely the Total Solid Inventory (TSI), riser superficial velocity, loop seal aeration, BFB overpressure, cone valve opening and mean particle size were varied in order to fully characterize the DFB operation. A stable operating region, bordered by two unstable regions, has been identified for the cold model riser. The cold model riser pressure drop profile, solid fraction profile, solid flow structure and their variation with respect to operational parameters have been analyzed in order to draw conclusions regarding axial inventory allocation and gas–solid contacting which are important criteria for the CFB carbonator's CO₂ capture efficiency. Finally, empirical correlations regarding the cold model riser entrainment and the solid looping rate have been derived.     

Dechlorination of lindane, dieldrin, tetrachloroethane, trichloroethene, and PVC in subcritical water

Pure water has been used to dechlorinate aliphatic organics without the need for catalysts or other additives. Dehydrohalogenation (loss of HCI with the formation of a double bond) occurred at temperatures as low as 105-200 degrees C for 1,1,2,2-tetrachloroethane, lindane (1,2,3,4,5,6-hexachlorocyclohexane, gamma-isomer), and dieldrin (1,2,3,4,10,10-hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-endo, exo-1,4:5,8-dimethanonaphthalene). Complete loss of the parent compounds was achieved in less than 1 h at 150, 200, and 300 degrees C for 1,1,2,2-tetrachloroethane, lindane, and dieldrin, respectively. The initial dechlorination of lindane had an activation energy of 84 kJ mol(-1) with an Arrhenius pre-exponential factor of 1.5 x 10(6) s(-1). Dehydrohalogenation of lindane formed trichlorobenzenes, followed by subsequent hydrolysis and hydride/chloride exchange to form chlorophenols, lower chlorobenzenes, and phenol as the major final product. Reaction of poly(vinyl chloride) at 300 degrees C for 1 h formed aromatic hydrocarbons ranging from benzene to anthracene and a char residue with a ca. 1:1 carbon-to-hydrogen ratio (mol/mol). The residue contained <1 wt % of chlorine compared to 57 wt % chlorine in the original polymer. All compounds tested yielded chloride ion as the major product (at higher temperatures), indicating that complete dechlorination of some aliphatic organochlorines may be feasible.     

Drug abuse in an obstetric population of a midsized city

Drug abuse during pregnancy has attracted national attention, but most studies are from large cities. This study is concerned with the indigent pregnant patients in a midsized city in the southeastern United States. In a 23-month study, 2,442 patients were delivered of neonates. Using specific criteria, 511 patients were tested for drug abuse. A positive test was identified in 156 (31%), cocaine being the most common agent. During 2 months of random testing, 15 patients (16%) had positive drug screens. Comparison of drug-positive pregnant patients with general obstetric patients identified many adverse obstetric and perinatal outcome data. Drug-positive patients weighed less, were older, were prone to not seek prenatal care, and were more likely to deliver prematurely and have a growth-retarded infant. Drug abuse in this population had significant impact on the health of the patient and her unborn infant.     

LC/MS/MS determination of omapatrilat, a sulfhydryl-containing vasopeptidase inhibitor, and its sulfhydryl- and thioether-containing metabolites in human plasma

Omapatrilat, the most clinically advanced member of a new class of cardiovascular agents, vasopeptidase inhibitors, is under development at Bristol-Myers Squibb Pharmaceutical Research Institute for the treatment of hypertension and heart failure. An electrospray LC/MS/MS method has been developed and validated for the simultaneous determination of omapatrilat and its four metabolites in human plasma. Since omapatrilat and two of the metabolites are sulfhydryl-containing compounds, methyl acrylate was used to stabilize these compounds in human blood and plasma samples. Methyl acrylate reacted instantly with the sulfhydryl group to form a derivative that was stable in blood and plasma. Extraction of the analytes from plasma samples was achieved by semiautomated liquid-liquid extraction, where a robotic liquid handler performed the liquid-transferring steps. The mass spectrometer was operated in the negative ion selected-reaction-monitoring mode. The calibration curve ranges were 0.5-250 ng/mL for omapatrilat and one metabolite and 2.0-250 ng/mL for the other three metabolites.