The ABC130 barrel module prototyping programme for the ATLAS strip tracker

For the Phase-II Upgrade of the ATLAS Detector, its Inner Detector, consisting of silicon pixel, silicon strip and transition radiation sub-detectors, will be replaced with an all new 100 % silicon tracker, composed of a pixel tracker at inner radii and a strip tracker at outer radii. The future ATLAS strip tracker will include 11,000 silicon sensor modules in the central region (barrel) and 7,000 modules in the forward region (end-caps), which are foreseen to be constructed over a period of 3.5 years. The construction of each module consists of a series of assembly and quality control steps, which were engineered to be identical for all production sites. In order to develop the tooling and procedures for assembly and testing of these modules, two series of major prototyping programs were conducted: an early program using readout chips designed using a 250 nm fabrication process (ABCN-25) and a subsequent program using a follow-up chip set made using 130 nm processing (ABC130 and HCC130 chips). This second generation of readout chips was used for an extensive prototyping program that produced around 100 barrel-type modules and contributed significantly to the development of the final module layout. This paper gives an overview of the components used in ABC130 barrel modules, their assembly procedure and findings resulting from their tests.Comment: 82 pages, 66 figure

Is exposure to formaldehyde in air causally associated with leukemia?—A hypothesis-based weight-of-evidence analysis

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde's reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case fora causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding

Preservation of differentiation and clonogenic potential of human hematopoietic stem and progenitor cells during lyophilization and ambient storage.

Progenitor cell therapies show great promise, but their potential for clinical applications requires improved storage and transportation. Desiccated cells stored at ambient temperature would provide economic and practical advantages over approaches employing cell freezing and subzero temperature storage. The objectives of this study were to assess a method for loading the stabilizing sugar, trehalose, into hematopoietic stem and progenitor cells (HPC) and to evaluate the effects of subsequent freeze-drying and storage at ambient temperature on differentiation and clonogenic potential. HPC were isolated from human umbilical cord blood and loaded with trehalose using an endogenous cell surface receptor, termed P2Z. Solution containing trehalose-loaded HPC was placed into vials, which were transferred to a tray freeze-dryer and removed during each step of the freeze-drying process to assess differentiation and clonogenic potential. Control groups for these experiments were freshly isolated HPC. Control cells formed 1450+/-230 CFU-GM, 430+/-140 BFU-E, and 50+/-40 CFU-GEMM per 50 microL. Compared to the values for the control cells, there was no statistical difference observed for cells removed at the end of the freezing step or at the end of primary drying. There was a gradual decrease in the number of CFU-GM and BFU-E for cells removed at different temperatures during secondary drying; however, there were no significant differences in the number of CFU-GEMM. To determine storage stability of lyophilized HPC, cells were stored for 4 weeks at 25 degrees C in the dark. Cells reconstituted immediately after lyophilization produced 580+/-90 CFU-GM ( approximately 40%, relative to unprocessed controls p<0.0001), 170+/-70 BFU-E (approximately 40%, p<0.0001), and 41+/-22 CFU-GEMM (approximately 82%, p = 0.4171), and cells reconstituted after 28 days at room temperature produced 513+/-170 CFU-GM (approximately 35%, relative to unprocessed controls, p<0.0001), 112+/-68 BFU-E (approximately 26%, p<0.0001), and 36+/-17 CFU-GEMM ( approximately 82%, p = 0.2164) These studies are the first to document high level retention of CFU-GEMM following lyophilization and storage for 4 weeks at 25 degrees C. This type of flexible storage stability would potentially permit the ability to ship and store HPC without the need for refrigeration

Is age an independent risk factor for chemically induced acute myelogenous leukemia in children?

Secondary or therapy-related acute myelogenous leukemia (t-AML) is a rare but unfortunate consequence of treatment with certain classes of cytotoxic chemotherapeutic agents or chronic exposure to high concentrations of benzene. Drugs known to produce AML following chemotherapy of primary malignancy are usually alkylating agents or topoisomerase II inhibitors. Both children and adults develop AML following treatment with these classes of antineoplastic drugs. In this review, the effect of age at treatment on a child's susceptibility to developing therapy related AML was investigated. The clinical literature describing pediatric cancer patients treated with cytotoxic chemotherapeutic agents was used to characterize risk factors associated with chemical leukemogenesis in children. As demonstrated in the published literature, the risk of developing AML following chemotherapy is not reliably correlated with the age of the pediatric patient. There is no consistent evidence that indicates that younger children will be at increased risk; in fact, some studies suggest that younger children might actually display a decreased susceptibility. The age dependency of treatment-related malignancies (all types) in children appears to vary considerably with the type of secondary neoplasm in question. For example, secondary solid tumors such as breast, central nervous system (CNS), bone, and thyroid cancer are highly dependent on the age of the patient at time of diagnosis and treatment; in contrast, an age dependency for t-AML risk was not observed in these same patient populations. Predictably, the induction of t-AML in children follows a rational dose-response relationship, with increasing doses of chemotherapy resulting in greater risk. Recent U.S. Environmental Protection Agency (EPA) cancer risk assessment guidance recommends a default assumption that children are inherently up to 10-fold more sensitive than adults to carcinogen exposures. Available scientific and medical literature does not support the hypothesis that children necessarily possess an increased risk of developing AML following leukemogenic chemical exposure. Copyrigh

Biomonitoring Equivalents for benzene

Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline such as a reference dose (RfD) or tolerable daily intake (TDI). BE values can be used as a screening tool for the evaluation of population-based biomonitoring data in the context of existing risk assessments. This study reviews available health based risk assessments and exposure guidance values for benzene from the United States Environmental Protection Agency (US EPA), Texas Commission on Environmental Quality (TCEQ), California's Office of Environmental Health Hazard Assessment (OEHHA) and the Agency for Toxic Substances and Disease Registry (ATSDR) to derive BE values for benzene in blood and urine. No BE values were derived for any of the numerous benzene metabolites or hemoglobin and albumin adducts. Using existing physiologically based pharmacokinetic (PBPK) models, government risk assessment values were translated into corresponding benzene levels in blood assuming chronic steady-state exposures. BEs for benzene in urine were derived using measured correlations between benzene in urine with benzene in blood. The BE values for benzene in blood range from 0.04 to 1.29 μg/L, depending upon the underlying non-cancer risk assessment used in deriving the BE. Sources of uncertainty relating to both the basis for the BE values and their use in evaluation of biomonitoring data, including the transience of the biomarkers relative to exposure frequency, are discussed. The BE values derived here can be used as screening tools for evaluation of population biomonitoring data for benzene in the context of the existing risk assessment and can assist in prioritization of the potential need for additional risk assessment efforts for benzene relative to other chemicals

HPC cell proliferation and differentiation of untreated and cryopreserved cells.

<p>Frequency of CFU-GM (Black Stripes), BFU-E, (Light Gray Stripes) and CFU-GEMM (Dark Gray Stripes) colonies following cryopreservation with trehalose were quantified using CFU assay (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012518#s2" target="_blank">Materials and Methods</a>). Values are represented as the mean ± standard deviation of the mean of 3 independent experiments for <i>n</i> = 3 subjects with 4 replicates and 4 individual culture plates for each control or treatment group (1 colony = ≥20 cells).</p

Storage stability of lyophilized HPC derived from umbilical cord as a function of clonogenic activity.

<p>HPC were lyophilized in a formulation containing 6.8% trehalose/2% HES/5% HSA (w/v) and stored at 25°C for 4 weeks in the dark. Stability of CFU-GM, BFU-E, and CFU-GEMM.</p

Frequency of CFU-GM, BFU-E and CFU-GEMM colonies obtained following lyophilization and reconstitution.

<p>A) HPC proliferation and differentiation of untreated and lyophilized cells were quantified by CFU assay (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012518#s2" target="_blank">Materials and Methods</a>). Colonies were scored as CFU-GM (Black Stripes), BFU-E (Light Gray Stripes), or CFU-GEMM (Dark Gray Stripes). Values are represented as the mean ± standard deviation of the mean (p<0.001) of 3 independent experiments for <i>n</i> = 3 subjects with 4 replicates and 4 individual culture plates for each control or treatment group. * = statistically different from control and other test groups, ** = statistically different from control, but not statistically different from each other. B) Thermal analysis of samples removed during lyophilization. FS = freezing step, PD = primary drying, SD = secondary drying.</p