Use of LC-MS/MS and Stable Isotopes to Differentiate Hydroxymethyl and Methyl DNA Adducts from Formaldehyde and Nitrosodimethylamine

Formaldehyde is a known human and animal carcinogen that forms DNA adducts, and causes mutations. While there is widespread exposure to formaldehyde in the environment, formaldehyde is also an essential biochemical in all living cells. The presence of both endogenous and exogenous sources of formaldehyde makes it difficult to develop exposure-specific DNA biomarkers. Furthermore, chemicals such as nitrosodimethylamine form one mole of formaldehyde for every mole of methylating agent, raising questions about potential co-carcinogenesis. Formaldehyde-induced hydroxymethyl DNA adducts are not stable and need to be reduced to stable methyl adducts for detection, which adds another layer of complexity to identifying the origins of these adducts. In this study, highly sensitive mass spectrometry methods and isotope labeled compounds were used to differentiate between endogenous and exogenous hydroxymethyl and methyl DNA adducts. We demonstrate that N2-hydroxymethyl-dG is the primary DNA adduct formed in cells following formaldehyde exposure. In addition, we show that alkylating agents induce methyl adducts at N2-dG and N6-dA positions, which are identical to the reduced forms of hydroxymethyl adducts arising from formaldehyde. The use of highly sensitive LC-MS/MS and isotope labeled compounds for exposure solves these challenges and provides mechanistic insights on the formation and role of these DNA adducts

Total-dose radiation effects data for semiconductor devices (1989 supplement)

Steady state, total dose radiation test data are provided for electronic designers and other personnel using semiconductor devices in a radiation environment. The data are presented in graphic and narrative formats. Two primary radiation source types were used: Cobalt-60 gamma rays and a Dynamitron electron accelerator capable of delivering 2.5 MeV electrons at a steady rate

Exploring the pedagogic culture of creative play in early childhood education

We present a conceptual analysis, grounded in empirical data, of how young children's creative play is framed by the 'pedagogic culture' within which the child is playing. Drawing on data from a research study with the broad aim of documenting children's creative play in Western play-based early childhood education, we gathered exploratory qualitative observations, self-initiated iPad video diaries and researcher-led activities to describe children's creative play. We adapted the Analysing Children's Creative Thinking Framework as a starting point for coding and the analyses focused on three contextual cues within the pedagogic culture – space, interpersonal collaborations and materials. We ground our discussion in a contextualist theoretical frame to demonstrate that in isolation, each contextual cue presents a degree of framing to children's creative play. When analysed as a synergy of contextual cues, however, we begin to see that the dynamic make-up of each of the contexts, and the interplay among them, create a 'pedagogic culture' that transforms children's creative play. We present 'stories' of each pedagogic culture that we observed, to describe how children's creative play manifested within each culture

A phase II study of the bispecific antibody MDX-H210 (anti-HER2 × CD64) with GM-CSF in HER2+ advanced prostate cancer

The proto-oncogene HER2 presents a novel therapeutic target. We report results in 25 patients with HER2+ advanced prostate cancer treated with the bispecific antibody MDX-H210 15 μg m−2by intravenous infusion plus GM-CSF 5 μg kg−1day−1by subcutaneous injection for 4 days repeated weekly for 6 weeks. Patients with stable disease or better received further cycles of treatment until disease progression or study withdrawal. 1 patient received no treatment and 4 received less than 1 cycle and are included in the toxicity analysis only. Median duration of follow up was 105+ (range 21–188) days. Toxicity was generally NCI-CTG 0–2. There were 2 grade 4 adverse events (heart failure and dyspnoea) and 1 grade 3 event (allergic reaction) resulting in discontinuation of the study medication. There were 9 further grade 3 events not resulting in trial withdrawal. There were no treatment-related deaths. 7/20 (35%) evaluable patients had a >50% PSA response of median duration 128 (range 71–184+) days. 7/12 (58%) patients with evaluable pain had improvements in pain scores. The PSA relative velocity on therapy decreased in 15/18 (83%) assessable patients compared to pre-study. GM-CSF and MDX-H210 is active in hormone refractory prostate carcinoma with acceptable toxicity; further studies are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.co

Efficacy of c-Met inhibitor for advanced prostate cancer

<p>Abstract</p> <p>Background</p> <p>Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer.</p> <p>Methods</p> <p>We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression.</p> <p>Results</p> <p>We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration.</p> <p>Conclusions</p> <p>The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer.</p

Hard exercise, affect lability, and personality among individuals with bulimia nervosa

The current study explores the personality traits of compulsivity (e.g., sense of orderliness and duty to perform tasks completely) and restricted expression (e.g., emotion expression difficulties) as potential moderators of the relation between affect lability and frequency of hard exercise episodes in a sample of individuals with bulimic pathology. Participants were 204 adult females recruited in five Midwestern cities who met criteria for threshold or subthreshold bulimia nervosa (BN). Compulsivity was found to significantly moderate the relation between affect lability and number of hard exercise episodes over the past 28 days, such that among those with high compulsivity, level of affect lability was associated with the number of hard exercise episodes; whereas, among those with low compulsivity, affect lability was not associated with the number of hard exercise episodes. The same pattern of findings emerged for restricted expression; however, this finding approached, but did not reach statistical significance. As such, it appears that affect lability is differentially related to hard exercise among individuals with BN depending upon the level of compulsivity and, to a more limited extent, restricted expression. These results suggest that, for individuals with BN with either compulsivity or restricted expression, focusing treatment on increasing flexibility and/or verbal expression of emotions may help them in the context of intense, fluctuating affect

An affinity matured minibody for PET imaging of prostate stem cell antigen (PSCA)-expressing tumors

PurposeProstate stem cell antigen (PSCA), a cell surface glycoprotein expressed in normal human prostate and bladder, is over-expressed in the majority of localized prostate cancer and most bone metastases. We have previously shown that the hu1G8 minibody, a humanized anti-PSCA antibody fragment (single-chain Fv-C(H)3 dimer, 80 kDa), can localize specifically and image PSCA-expressing xenografts at 21 h post-injection. However, the humanization and antibody fragment reformatting decreased its apparent affinity. Here, we sought to evaluate PET imaging contrast with affinity matured minibodies.MethodsYeast scFv display, involving four rounds of selection, was used to generate the three affinity matured antibody fragments (A2, A11, and C5) that were reformatted into minibodies. These three affinity matured anti-PSCA minibodies were characterized in vitro, and following radiolabeling with (124)I were evaluated in vivo for microPET imaging of PSCA-expressing tumors.ResultsThe A2, A11, and C5 minibody variants all demonstrated improved affinity compared to the parental (P) minibody and were ranked as follows: A2 &gt; A11 &gt; C5 &gt; P. The (124)I-labeled A11 minibody demonstrated higher immunoreactivity than the parental minibody and also achieved the best microPET imaging contrast in two xenograft models, LAPC-9 (prostate cancer) and Capan-1 (pancreatic cancer), when evaluated in vivo.ConclusionOf the affinity variant minibodies tested, the A11 minibody that ranked second in affinity was selected as the best immunoPET tracer to image PSCA-expressing xenografts. This candidate is currently under development for evaluation in a pilot clinical imaging study

An ecological exploration of the Internet of Toys in early childhood everyday life

Throughout this chapter, the focus is on the importance of children’s agency in their use of Internet of Toys (IoToys). We think about children’s capabilities as part of digitally mediated eco-communities. Informed by the socio-ecological model, children’s, practitioners’ and parents’ dispositions helped contextualise the factors that shape children’s use of IoToys. We provide the following key messages throughout the chapter: 1.A discussion of passivity or empowerment as part of children’s digital lives with IoToys, in line with Craft’s (2013) work. 2.A reanalysis of perceptions of childhood in the digital age, linking to the sociological models of childhood and the role of children as competent and agentic. 3.An account of socio-ecological influences on digital lives, likened to Rogoff’s (2008) three planes relating to individual, interpersonal and community alongside a discussion of how the interpersonal plane can be reimagined to include interactions between child and machine. 4.A note of caution against the passive child agenda and recurrent moral panic