A compact solution for ion beam therapy with laser accelerated protons

The recent advancements in the field of laser-driven particle acceleration have made Laser-driven Ion Beam Therapy (L-IBT) an attractive alternative to the conventional particle therapy facilities. To bring this emerging technology to clinical application, we introduce the broad energy assorted depth dose deposition model which makes efficient use of the large energy spread and high dose-per-pulse of Laser Accelerated Protons (LAP) and is capable of delivering homogeneous doses to tumors. Furthermore, as a key component of L-IBT solution, we present a compact iso-centric gantry design with 360° rotation capability and an integrated shot-to-shot energy selection system for efficient transport of LAP with large energy spread to the patient. We show that gantry size could be reduced by a factor of 2–3 compared to conventional gantry systems by utilizing pulsed air-core magnets.     

Targeted catalytic inactivation of angiotensin converting enzyme by lisinopril-coupled transition-metal chelates

A series of compounds that target reactive transition-metal chelates to somatic angiotensin converting enzyme (sACE-1) have been synthesized. Half-maximal inhibitory concentrations (IC(50)) and rate constants for both inactivation and cleavage of full-length sACE-1 have been determined and evaluated in terms of metal chelate size, charge, reduction potential, coordination unsaturation, and coreactant selectivity. Ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and tripeptide GGH were linked to the lysine side chain of lisinopril by 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride/N-hydroxysuccinimide coupling. The resulting amide-linked chelate-lisinopril (EDTA-lisinopril, NTA-lisinopril, DOTA-lisinopril, and GGH-lisinopril) conjugates were used to form coordination complexes with iron, cobalt, nickel, and copper, such that lisinopril could mediate localization of the reactive metal chelates to sACE-1. ACE activity was assayed by monitoring cleavage of the fluorogenic substrate Mca-RPPGFSAFK(Dnp)-OH, a derivative of bradykinin, following preincubation with metal chelate-lisinopril compounds. Concentration-dependent inhibition of sACE-1 by metal chelate-lisinopril complexes revealed IC(50) values ranging from 44 to 4500 nM for Ni-NTA-lisinopril and Ni-DOTA-lisinopril, respectively, versus 1.9 nM for lisinopril. Stronger inhibition was correlated with smaller size and lower negative charge of the attached metal chelates. Time-dependent inactivation of sACE-1 by metal chelate-lisinopril complexes revealed a remarkable range of catalytic activities, with second-order rate constants as high as 150,000 M(-1) min(-1) (Cu-GGH-lisinopril), while catalyst-mediated cleavage of sACE-1 typically occurred at much lower rates, indicating that inactivation arose primarily from side chain modification. Optimal inactivation of sACE-1 was observed when the reduction potential for the metal center was poised near 1000 mV, reflecting the difficulty of protein oxidation. This class of metal chelate-lisinopril complexes possesses a range of high-affinity binding to ACE, introduces the advantage of irreversible catalytic turnover, and marks an important step toward the development of multiple-turnover drugs for selective inactivation of sACE-1.     

Glutathione complexed Fe-S centers

Glutathione (γ-glutamyl-cysteinyl-glycine, GSH) is a major thiol-containing peptide with cellular levels of up to 10 mM. (1) Several recent reports have demonstrated glutaredoxins (Grx) to form [Fe(2)S(2)] cluster-bridged dimers, where glutathione provides two exogenous thiol ligands, and have implicated such species in cellular iron sulfur cluster biosynthesis. We report the finding that glutathione alone can coordinate and stabilize an [Fe(2)S(2)] cluster under physiological conditions, with optical, redox, M?ssbauer, and NMR characteristics that are consistent with a [Fe(2)S(2)](GS)(4) composition. The Fe-S assembly protein ISU catalyzes formation of [Fe(2)S(2)](GS)(4) from iron and sulfide ions in the presence of glutathione, and the [Fe(2)S(2)] core undergoes reversible exchange between apo ISU and free glutathione.