Hemodynamic Effects of Anthrax Toxins in the Rabbit Model and the Cardiac Pathology Induced by Lethal Toxin

Anthrax lethal toxin (LeTx) and edema toxin (EdTx) have been shown to alter hemodynamics in the rodent model, while LeTx primarily is reported to induce extensive tissue pathology. However, the rodent model has limitations when used for comparison to higher organisms such as humans. The rabbit model, on the other hand, has gained recognition as a useful model for studying anthrax infection and its pathophysiological effects. In this study, we assessed the hemodynamic effects of lethal toxin (LeTx) and edema toxin (EdTx) in the rabbit model using physiologically relevant amounts of the toxins. Moreover, we further examine the pathological effects of LeTx on cardiac tissue. We intravenously injected Dutch-belted rabbits with either low-dose and high-dose recombinant LeTx or a single dose of EdTx. The animals’ heart rate and mean arterial pressure were continuously monitored via telemetry until either 48 or 72 h post-challenge. Additional animals challenged with LeTx were used for cardiac troponin I (cTnI) quantitation, cardiac histopathology, and echocardiography. LeTx depressed heart rate at the lower dose and mean arterial pressure (MAP) at the higher dose. EdTx, on the other hand, temporarily intensified heart rate while lowering MAP. Both doses of LeTx caused cardiac pathology with the higher dose having a more profound effect. Lastly, left-ventricular dilation due to LeTx was not apparent at the given time-points. Our study demonstrates the hemodynamic effects of anthrax toxins, as well as the pathological effects of LeTx on the heart in the rabbit model, and it provides further evidence for the toxins’ direct impact on the heart

Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma : preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates

Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.Peer reviewe

Expression Profiling Reveals Novel Hypoxic Biomarkers in Peripheral Blood of Adult Mice Exposed to Chronic Hypoxia

Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO) mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX), exposed for two weeks to normobaric chronic hypoxia (CH) or two weeks of CH followed by two weeks of normoxic recovery (REC). Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off), 230 genes were identified and separated into four distinct temporal categories. Class I) contained 1 transcript up-regulated in both CH and REC; Class II) contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III) contained 9 transcripts down-regulated both in CH and REC; Class IV) contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1) by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia

Performance of an endcap prototype of the Atlas accordion electromagnetic calorimeter

The design and construction of a lead-liquid argon endcap calorimeter prototype using an accordion geometry and conceived as a sector of the inner wheel of the endcap calorimeter of the future ATLAS experiment at the LHC is described. The performance obtained using electron beam data is presented. The main results are an energy resolution with a sampling term below $11\%/\sqrt{E(\rm GeV)}$ and a small local constant term, a good linearity of the response with the incident energy and a global constant term of 0.8\% over an extended area in the rapidity range of $2.2\eta 2.9$. These properties make the design suitable for the ATLAS electromagnetic endcap calorimeter

Construction and test of a fine-grained liquid argon preshower prototype

A separate liquid argon preshower detector consisting of two layers featuring a fine granularity of 2.5~10$^{\mathrm{-3}}$ was studied by the RD3 collaboration. A prototype covering approximately 0.8 in pseudo-rapidity and 9 degrees in azimuth was built and tested at CERN in July 94. CMOS and GaAs VLSI preamplifiers were designed and tested for this occasion. The combined response of this detector and an accordion electromagnetic calorimeter prototype to muons, electrons and photons is presented. For minimum ionizing tracks a signal-to-noise ratio of 4.5 per preshower layer was measured. Above 150~GeV the space resolution for electrons is better than 250~$\mu$m in both directions. The precision on the electromagnetic shower direction, determined together with the calorimeter, is better than 4 mrad above 50~GeV. It is concluded that the preshower detector would adequately fulfil its role for future operation at CERN Large Hadron Collider

Performance of a large scale prototype of the ATLAS accordion electromagnetic calorimeter

A 2 m long prototype of a lead-liquid argon electromagnetic calorimeter with accordion-shaped electrodes, conceived as a sector of the barrel calorimeter of the future ATLAS experiment at the LHC, has been tested with electron and pion beams in the energy range 10 to 287 GeV. A sampling term of 10%/root E(GeV) was obtained for electrons in the rapidity range 0 < eta < 1, while the constant term measured over an area of about 1 m(2) is 0.69%. With a cell size of 2.7 cm the position resolution is. about 4 mm/root E(GeV)

Construction and test of a fine-grained liquid argon preshower prototype

A separate liquid argon preshower detector consisting of two layers featuring a fine granularity of 2.5~10$^{\mathrm{-3}}$ was studied by the RD3 collaboration. A prototype covering approximately 0.8 in pseudo-rapidity and 9 degrees in azimuth was built and tested at CERN in July 94. CMOS and GaAs VLSI preamplifiers were designed and tested for this occasion. The combined response of this detector and an accordion electromagnetic calorimeter prototype to muons, electrons and photons is presented. For minimum ionizing tracks a signal-to-noise ratio of 4.5 per preshower layer was measured. Above 150~GeV the space resolution for electrons is better than 250~$\mu$m in both directions. The precision on the electromagnetic shower direction, determined together with the calorimeter, is better than 4 mrad above 50~GeV. It is concluded that the preshower detector would adequately fulfil its role for future operation at CERN Large Hadron Collider

Performance of an endcap prototype of the ATLAS accordion electromagnetic calorimeter

The design and construction of a lead-liquid argon endcap calorimeter prototype using an accordion geometry and conceived as a sector of the inner wheel of the endcap calorimeter of the future ATLAS experiment at the LHC is described. The performance obtained using electron beam data is presented. The main results are an energy resolution with a sampling term below $11\%/\sqrt{E(\rm GeV)}$ and a small local constant term, a good linearity of the response with the incident energy and a global constant term of 0.8\% over an extended area in the rapidity range of $2.2 < \eta <2.9$. These properties make the design suitable for the ATLAS electromagnetic endcap calorimeter

Test beam results of a stereo preshower integrated in the liquid argon accordion calorimeter

This paper describes the construction of an integrated preshower within the RD3 liquid argon accordion calorimeter. It has a stereo view which enables the measurement of two transverse coordinates. The prototype was tested at CERN with electrons, photons and muons to validate its capability to work at LHC ( Energy resolution, impact point resolution, angular resolution, $\pi^o$/$\gamma$ rejection )

Test beam results of a stereo preshower integrated in the liquid argon accordion calorimeter

This paper describes the construction of an integrated preshower within the RD3 liquid argon accordion calorimeter. It has a stereo view which enables the measurement of two transverse coordinates. The prototype was tested at CERN with electrons, photons and muons to validate its capability to work at LHC (Energy resolution, impact point resolution, angular resolution, π o γ rejection). (Elsevier