bluuebunny/crossref_metadata_2025 huggingface dataset:
Variation of Threshold Voltage and ON-Cell Current Caused by Cell Gate Length Fluctuation in Virtual Source/Drain NAND Flash Memory
Authors: Kim Wandong , Kim Yoon , Park Se Hwan , Seo Joo Yun , Kim Do Bin , Park Byung-Gook
Published: June 2012

In this study, we investigate the variation of threshold voltage and ON-cell current caused by cell gate length fluctuation in silicon–oxide–nitride–oxide–silicon (SONOS) NAND flash memory with virtual source and drain (VSD). The fluctuation in cell gate length caused by process errors such as line edge roughness, etch slope variation, and lithography resolution-induced error affects threshold voltage and ON-cell current considerably. Our results show that three-dimensional (3D) structures have robust immunity to the cell gate length fluctuation effect. From the viewpoint of array design, threshold voltage and ON-cell current variation due to cell gate length fluctuation can be reasonably mitigated by enlarging the cell gate length in a word line (WL) pitch and reducing the body doping concentration. In addition, the tendency of the variation by technology node scaling and the comparison with the junctionless NAND flash memory structure are also investigated.
Effect of Surface Elasticity on the Piezoelectric Potential of a Bent ZnO Nanowire
Authors: Yao Haiyan , Yun Guohong , Bai Narsu , Li Jiangang
Published: June 2012

The influence of surface elasticity on the piezoelectric potential distribution of a deformed ZnO nanowire is investigated by the effective Young's modulus based upon elastic and piezoelectric theory. When the nanowire in radius 25 nm subjects to an lateral applied force 5 nN, the maximum piezoelectric potential of the nanowire we derived is about 13.8 mV, which approaches much more closely to the experiment measurement value (∼10 mV) [Z. L. Wang and J. H. Song: Science 312 (2006) 242]. Moreover, a comprehensive analysis of maximum piezoelectric potential between the cases with and without the effect of surface elasticity is analyzed. The results show that the values of piezoelectric potential generated in ZnO nanowires are decreased due to the surface stiffening. From the theoretical analysis, the effect of surface elasticity has a significant impact on the piezoelectric potential for a bent ZnO nanowire, actually it reduces the gap between theoretical estimation and experiment measurements.
CS and popular culture; learning from console games
Authors: Guzdial Mark , Robertson Judy
Published: June 2012

The
Communications
Web site, http://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
, we'll publish selected posts or excerpts.

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Mark Guzdial writes about why computer science should permeate popular culture. Judy Robertson discusses the educational benefits of using console games in the classroom.
Lost and found
Authors: Hyman Paul
Published: June 2012

Researchers discover computer pioneer Konrad Zuse's long-forgotten Z9, the world's first program-controlled binary relay calculator using floating-point arithmetic.
Can online piracy be stopped by laws?
Authors: Samuelson Pamela
Published: June 2012

Considering the legal responsibilities of Internet intermediaries in the aftermath of the Stop Online Privacy Act controversy.
Controlling queue delay
Authors: Nichols Kathleen , Jacobson Van
Published: June 2012

A modern AQM is just one piece of the solution to bufferbloat.
Computational folkloristics
Authors: Abello James , Broadwell Peter , Tangherlini Timothy R.
Published: June 2012

A searchable meta-graph can connect even troublesome house elves and other supernatural beings to scholarly folk categories.
Intrinsic robustness of the price of anarchy
Authors: Roughgarden Tim
Published: June 2012

The price of anarchy, defined as the ratio of the worst-case objective function value of a Nash equilibrium of a game and that of an optimal outcome, quantifies the inefficiency of selfish behavior. Remarkably good bounds on this measure are known for a wide range of application domains. However, such bounds are meaningful only if a game's participants successfully reach a Nash equilibrium. This drawback motivates inefficiency bounds that apply more generally to weaker notions of equilibria, such as mixed Nash equilibria and correlated equilibria, or to sequences of outcomes generated by natural experimentation strategies, such as simultaneous regret-minimization.

We prove a general and fundamental connection between the price of anarchy and its seemingly more general relatives. First, we identify a "canonical sufficient condition" for an upper bound on the price of anarchy of pure Nash equilibria, which we call a
smoothness argument
. Second, we prove an "extension theorem": every bound on the price of anarchy that is derived via a smoothness argument
extends automatically
, with no quantitative degradation in the bound, to mixed Nash equilibria, correlated equilibria, and the average objective function value of every no-regret sequence of joint repeated play. Third, we prove that in routing games, smoothness arguments are "complete" in a proof-theoretic sense: despite their automatic generality, they are guaranteed to produce an optimal worst-case upper bound on the price of anarchy.
Do small IT firms benefit from higher process capability?
Authors: Swinarski Matthew , Parente Diane H. , Kishore Rajiv
Published: June 2012

Evidence suggests small firms can reap rewards from developing a high level of formal process capability.
Phosphorylation of adipose triglyceride lipase Ser404is not related to 5′-AMPK activation during moderate-intensity exercise in humans
Authors: Mason Rachael R. , Meex Ruth C. R. , Lee-Young Robert , Canny Benedict J. , Watt Matthew J.
Published: June 2012

Intramyocellular triacylglycerol provides fatty acid substrate for ATP generation in contracting muscle. The protein adipose triglyceride lipase (ATGL) is a key regulator of triacylglycerol lipolysis and whole body energy metabolism at rest and during exercise, and ATGL activity is reported to be enhanced by 5′-AMP-activated protein kinase (AMPK)-mediated phosphorylation at Ser406in mice. This is a curious observation, because AMPK activation reduces lipolysis in several cell types. We investigated whether the phosphorylation of ATGL Ser404(corresponding to murine Ser406) was increased during exercise in human skeletal muscle and with pharmacological AMPK activation in myotubes in vitro. In human experiments, skeletal muscle and venous blood samples were obtained from recreationally active male subjects before and at 5 and 60 min during exercise. ATGL Ser404phosphorylation was not increased from rest during exercise, but ATGL Ser404phosphorylation correlated with myosin heavy chain 1 expression, suggesting a possible fiber type dependency. ATGL Ser404phosphorylation was not related to increases in AMPK activity, and immunoprecipitation experiments indicated no interaction between AMPK and ATGL. Rather, ATGL Ser404phosphorylation was associated with protein kinase A (PKA) signaling. ATGL Ser406phosphorylation in C2C12myotubes was unaffected by 5-aminoimidazole-4-carboxaminde-1-β-d-ribofuranoside, an AMPK activator, and the PKA activator forskolin. Our results demonstrate that ATGL Ser404phosphorylation is not increased in mixed skeletal muscle during moderate-intensity exercise and that AMPK does not appear to be an activating kinase for ATGL Ser404/406in skeletal muscle.
Progression of type 2 diabetes in GK rats affects muscle and liver mitochondria differently: pronounced reduction of complex II flux is observed in liver only
Authors: Jørgensen Wenche , Jelnes Peter , Rud Kasper A. , Hansen Lillian L. , Grunnet Niels , Quistorff Bjørn
Published: June 2012

Impaired mitochondrial function is implicated in the development of type 2 diabetes mellitus (T2DM). This was investigated in mitochondria from skeletal muscle and liver of the Goto-Kakizaki (GK) rat, which spontaneously develops T2DM with age. The early and the manifest stage of T2DM was studied in 6- and 16-wk-old GK rats, respectively. In GK16 compared with GK6 animals, a decrease in state 3 respiration with palmitoyl carnitine (PC) as substrate was observed in muscle. Yet an increase was seen in liver. To test the complex II contribution to the state 3 respiration, succinate was added together with PC. In liver mitochondria, this resulted in an ∼50% smaller respiratory increase in the GK6 group compared with control and no respiratory increase at all in the GK16 animals. Yet no difference between groups was seen in muscle mitochondria. RCR and P/O ratio was increased ( P < 0.05) in liver but unchanged in muscle in both GK groups. We observed increased lipid peroxidation and decreased Akt phosphorylation in liver with the progression of T2DM but no change in muscle. We conclude that, during the progression of T2DM in GK rats, liver mitochondria are affected earlier and/or more severely than muscle mitochondria. Succinate dehydrogenase flux in the presence of fatty acids was reduced severely in liver but not in muscle mitochondria during manifest T2DM. The observations support the notion that T2DM pathogenesis is initiated in the liver and that only later are muscle mitochondria affected.
A short-term diet and exercise intervention ameliorates inflammation and markers of metabolic health in overweight/obese children
Authors: Izadpanah Ali , Barnard R. James , Almeda Anna Jane E. , Baldwin Gayle C. , Bridges Sydney A. , Shellman Erin R. , Burant Charles F. , Roberts Christian K.
Published: June 2012

The present study was designed to examine the effects of short-term diet and exercise on markers of metabolic health, serum-stimulated production of inflammatory biomarkers from cultured monocytes and adipocytes, and serum lipomics. Twenty-one overweight/obese children (9 boys and 12 girls, age 13.0 ± 0.5 yr, BMI 33.0 ± 1.8 kg/m2) were placed on a 2-wk ad libitum, high-fiber, low-fat diet and daily exercise regimen. Fasting serum samples were taken pre- and postintervention for determination of cytokines, metabolic risk markers, and lipomics. Monocytes and adipocytes were incubated with pre- and postintervention serum to investigate changes in cytokine secretion. Correlative associations were calculated, followed by hierarchical clustering to determine relationships between fatty acid (FA) species and clinical biomarkers. Despite remaining overweight/obese, interleukin (IL)-6, IL-8, TNFα, PAI-1, resistin, amylin, leptin, insulin, and IL-1ra decreased and adiponectin increased. Culture studies indicated decreases in monocyte secretion of IL-6, TNFα, and IL-1β and adipocyte secretion of IL-6. Lipomic analysis revealed a decrease in total lipids and decreases in saturated FAs and an increase in 18:1/18:0. In general, Pearson's correlations revealed that inflammatory markers are negatively associated with a cluster of polyunsaturated FAs and positively correlated with several saturated FAs. These results indicate significant modification of multiple indices of metabolic health with short-term rigorous lifestyle modification in overweight/obese children prior to obesity reversal.
Neuroanatomical phenotyping of the mouse brain with three-dimensional autofluorescence imaging
Authors: Gleave Jacqueline A. , Wong Michael D. , Dazai Jun , Altaf Maliha , Mark Henkelman R. , Lerch Jason P. , Nieman Brian J.
Published: June 2012

The structural organization of the brain is important for normal brain function and is critical to understand in order to evaluate changes that occur during disease processes. Three-dimensional (3D) imaging of the mouse brain is necessary to appreciate the spatial context of structures within the brain. In addition, the small scale of many brain structures necessitates resolution at the ∼10 μm scale. 3D optical imaging techniques, such as optical projection tomography (OPT), have the ability to image intact large specimens (1 cm3) with ∼5 μm resolution. In this work we assessed the potential of autofluorescence optical imaging methods, and specifically OPT, for phenotyping the mouse brain. We found that both specimen size and fixation methods affected the quality of the OPT image. Based on these findings we developed a specimen preparation method to improve the images. Using this method we assessed the potential of optical imaging for phenotyping. Phenotypic differences between wild-type male and female mice were quantified using computer-automated methods. We found that optical imaging of the endogenous autofluorescence in the mouse brain allows for 3D characterization of neuroanatomy and detailed analysis of brain phenotypes. This will be a powerful tool for understanding mouse models of disease and development and is a technology that fits easily within the workflow of biology and neuroscience labs.
Nanobody-Based Targeting of the Macrophage Mannose Receptor for EffectiveIn VivoImaging of Tumor-Associated Macrophages
Authors: Movahedi Kiavash , Schoonooghe Steve , Laoui Damya , Houbracken Isabelle , Waelput Wim , Breckpot Karine , Bouwens Luc , Lahoutte Tony , De Baetselier Patrick , Raes Geert , Devoogdt Nick , Van Ginderachter Jo A.
Published: June 2012

Tumor-associated macrophages (TAM) are an important component of the tumor stroma and exert several tumor-promoting activities. Strongly pro-angiogenic TAMs that reside in hypoxic tumor areas highly express macrophage mannose receptor (MMR, CD206). In this study, we targeted MMR+ TAMs using nanobodies, which are single-domain antigen-binding fragments derived from Camelidae heavy-chain antibodies. MMR-specific nanobodies stained TAMs in lung and breast tumor single-cell suspensions in vitro, and intravenous injection of 99mTc-labeled anti-MMR nanobodies successfully targeted tumor in vivo. Retention of the nanobody was receptor-specific and absent in MMR-deficient mice. Importantly, co-injection of excess unlabeled, bivalent anti-MMR nanobodies reduced nanobody accumulation in extratumoral organs to background levels, without compromising tumor uptake. Within tumors, the 99mTc-labeled nanobodies specifically labeled MMR+ TAMs, as CCR2-deficient mice that contain fewer TAMs showed significantly reduced tumor uptake. Further, anti-MMR nanobodies accumulated in hypoxic regions, thus targeting pro-angiogenic MMR+ TAMs. Taken together, our findings provide preclinical proof of concept that anti-MMR nanobodies can be used to selectively target and image TAM subpopulations in vivo. Cancer Res; 72(16); 4165–77. ©2012 AACR.
Distinct microRNA Expression Profiles in Prostate Cancer Stem/Progenitor Cells and Tumor-Suppressive Functions of let-7
Authors: Liu Can , Kelnar Kevin , Vlassov Alexander V. , Brown David , Wang Junchen , Tang Dean G.
Published: June 2012

MiRNAs regulate cancer cells, but their potential effects on cancer stem/progenitor cells are still being explored. In this study, we used quantitative real-time-PCR to define miRNA expression patterns in various stem/progenitor cell populations in prostate cancer, including CD44+, CD133+, integrin α2β1+, and side population cells. We identified distinct and common patterns in these different tumorigenic cell subsets. Multiple tumor-suppressive miRNAs were downregulated coordinately in several prostate cancer stem/progenitor cell populations, namely, miR-34a, let-7b, miR-106a, and miR-141, whereas miR-301 and miR-452 were commonly overexpressed. The let-7 overexpression inhibited prostate cancer cell proliferation and clonal expansion in vitro and tumor regeneration in vivo. In addition, let-7 and miR-34a exerted differential inhibitory effects in prostate cancer cells, with miR-34a inducing G1 phase cell-cycle arrest accompanied by cell senescence and let-7 inducing G2–M phase cell-cycle arrest without senescence. Taken together, our findings define distinct miRNA expression patterns that coordinately regulate the tumorigenicity of prostate cancer cells. Cancer Res; 72(13); 3393–404. ©2012 AACR.
Chronic Autophagy Is a Cellular Adaptation to Tumor Acidic pH Microenvironments
Authors: Wojtkowiak Jonathan W. , Rothberg Jennifer M. , Kumar Virendra , Schramm Karla J. , Haller Edward , Proemsey Joshua B. , Lloyd Mark C. , Sloane Bonnie F. , Gillies Robert J.
Published: June 2012

Tumor cell survival relies upon adaptation to the acidic conditions of the tumor microenvironment. To investigate potential acidosis survival mechanisms, we examined the effect of low pH (6.7) on human breast carcinoma cells. Acute low pH exposure reduced proliferation rate, induced a G1 cell cycle arrest, and increased cytoplasmic vacuolization. Gene expression analysis revealed elevated levels of ATG5 and BNIP3 in acid-conditioned cells, suggesting cells exposed to low pH may utilize autophagy as a survival mechanism. In support of this hypothesis, we found that acute low pH stimulated autophagy as defined by an increase in LC3-positive punctate vesicles, double-membrane vacuoles, and decreased phosphorylation of AKT and ribosomal protein S6. Notably, cells exposed to low pH for approximately 3 months restored their proliferative capacity while maintaining the cytoplasmic vacuolated phenotype. Although autophagy is typically transient, elevated autophagy markers were maintained chronically in low pH conditioned cells as visualized by increased protein expression of LC3-II and double-membrane vacuoles. Furthermore, these cells exhibited elevated sensitivity to PI3K-class III inhibition by 3-methyladenine. In mouse tumors, LC3 expression was reduced by systemic treatment with sodium bicarbonate, which raises intratumoral pH. Taken together, these results argue that acidic conditions in the tumor microenvironment promote autophagy, and that chronic autophagy occurs as a survival adaptation in this setting. Cancer Res; 72(16); 3938–47. ©2012 AACR.
Critical Function for Nuclear Envelope Protein TMEM209 in Human Pulmonary Carcinogenesis
Authors: Fujitomo Takashi , Daigo Yataro , Matsuda Koichi , Ueda Koji , Nakamura Yusuke
Published: June 2012

Therapeutic targets for more effective and less toxic treatments of lung cancer remain important. Here we report the identification of the integral nuclear envelope protein TMEM209 as a critical driver of human lung cancer growth and survival. TMEM209 expression was normally limited to testis, but we found that it was widely expressed in lung cancer, in which it localized to the nuclear envelope, Golgi apparatus, and the cytoplasm of lung cancer cells. Ectopic overexpression of TMEM209 promoted cell growth, whereas TMEM209 attenuation was sufficient to block growth. Mass spectrometric analysis identified the nucleoporin protein NUP205 as a TMEM209-interacting protein, stabilizing NUP205 and increasing the level of c-Myc in the nucleus. Taken together, our findings indicate that TMEM209 overexpression and TMEM209–NUP205 interaction are critical drivers of lung cancer proliferation, suggesting a promising new target for lung cancer therapy. Cancer Res; 72(16); 4110–8. ©2012 AACR.
Epithelial Plasticity, Cancer Stem Cells, and the Tumor-Supportive Stroma in Bladder Carcinoma
Authors: van der Horst Geertje , Bos Lieke , van der Pluijm Gabri
Published: June 2012

High recurrence rates and poor survival rates of metastatic bladder cancer emphasize the need for a drug that can prevent and/or treat bladder cancer progression and metastasis formation. Accumulating evidence suggests that cancer stem/progenitor cells are involved in tumor relapse and therapy resistance in urothelial carcinoma. These cells seem less affected by the antiproliferative therapies, as they are largely quiescent, have an increased DNA damage response, reside in difficult-to-reach, protective cancer stem cell niches and express ABC transporters that can efflux drugs from the cells. Recent studies have shown that epithelial-to-mesenchymal transition (EMT), a process in which sessile, epithelial cells switch to a motile, mesenchymal phenotype may render cancer cells with cancer stem cells properties and/or stimulate the expansion of this malignant cellular subpopulation. As cancer cells undergo EMT, invasiveness, drug resistance, angiogenesis, and metastatic ability seem to increase in parallel, thus giving rise to a more aggressive tumor type. Furthermore, the tumor microenvironment (tumor-associated stromal cells, extracellular matrix) plays a key role in tumorigenesis, tumor progression, and metastasis formation. Taken together, the secret for more effective cancer therapies might lie in developing and combining therapeutic strategies that also target cancer stem/progenitor cells and create an inhospitable microenvironment for highly malignant bladder cancer cells. This review will focus on the current concepts about the role of cancer stem cells, epithelial plasticity, and the supportive stroma in bladder carcinoma. The potential implications for the development of novel bladder cancer therapy will be discussed. Mol Cancer Res; 10(8); 995–1009. ©2012 AACR.
The HIF-1α Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy
Authors: Palazón Asís , Martínez-Forero Iván , Teijeira Alvaro , Morales-Kastresana Aizea , Alfaro Carlos , Sanmamed Miguel F. , Perez-Gracia Jose Luis , Peñuelas Iván , Hervás-Stubbs Sandra , Rouzaut Ana , Landázuri Manuel Ortiz de , Jure-Kunkel Maria , Aragonés Julian , Melero Ignacio
Published: June 2012

The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confirmed by positron emission tomographic (PET) imaging. CD8 and CD4 tumor-infiltrating T lymphocytes (TIL) of transplanted colon carcinomas, melanomas, and spontaneous breast adenocarcinomas are CD137 (4-1BB)-positive, as opposed to their counterparts in tumor-draining lymph nodes and spleen. Expression of CD137 on activated T lymphocytes is markedly enhanced by hypoxia and the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Importantly, hypoxia does not upregulate CD137 in hypoxia-inducible factor (HIF)-1α–knockout T cells, and such HIF-1α–deficient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infiltrating and co-transferred HIF-1α–sufficient T lymphocytes. The fact that CD137 is selectively expressed on TILs was exploited to confine the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue. As a result, low-dose intratumoral injections avoid liver inflammation, achieve antitumor systemic effects, and permit synergistic therapeutic effects with PD-L1/B7-H1 blockade.

Significance: CD137 (4-1BB) is an important molecular target to augment antitumor immunity. Hypoxia in the tumor microenvironment as sensed by the HIF-1α system increases expression of CD137 on tumor-infiltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials. Cancer Discov; 2(7); 608–23. ©2012 AACR.

Read the Commentary on this article by Melief, p. 586.

This article is highlighted in the In This Issue feature, p. 569.
Chimeric Transcript Generated by cis-Splicing of Adjacent Genes Regulates Prostate Cancer Cell Proliferation
Authors: Zhang Yanmei , Gong Mei , Yuan Huiling , Park Hong G. , Frierson Henry F. , Li Hui
Published: June 2012

Gene fusion is a common event in cancer. The fusion RNA and protein products often play causal roles in tumorigenesis and therefore represent ideal diagnostic and therapeutic targets. Formerly, fusion chimeric products in cancer were thought to be produced solely by chromosomal translocation. Here, we show that a chimeric SLC45A3-ELK4 RNA is generated in the absence of chromosomal rearrangement. We showed that it is not a product of RNA trans-splicing, but formed by cis-splicing of adjacent genes/read-through. The binding of CCCTC-binding factor (CTCF) to the insulator sequences inversely correlates with the expression of the chimera transcript. The SLC45A3-ELK4 fusion, but not wild-type, ELK4 plays important roles in regulating cell growth in both androgen-dependent and -independent prostate cancer cells. The level of the chimeric transcript correlates with disease progression, with the highest levels in prostate cancer metastases. Our results suggest that gene fusions can arise from cis-splicing of adjacent genes without corresponding DNA changes.

Significance: With the absence of corresponding DNA rearrangement, chimeric fusion SLC45A3-ELK4 transcript in prostate cancer cells is generated by cis-splicing of adjacent genes/gene read-through instead of trans-splicing. SLC45A3-ELK4 controls prostate cancer cell proliferation, and the chimera level correlates with prostate cancer disease progression. Cancer Discov; 2(7); 598–607. ©2012 AACR.

Read the Commentary on this article by Kumar-Sinha et al., p. 582.

This article is highlighted in the In This Issue feature, p. 569.
Consent and Research Governance in Biobanks: Evidence from Focus Groups with Medical Researchers
Authors: Whitley E.A. , Kanellopoulou N. , Kaye J.
Published: June 2012

Much is known about patient attitudes to ethical and legal questions in the context of biobanking, particularly regarding privacy protection and consent. However, little is known about the attitudes of medical researchers who use biobanks for research to these issues. Four focus groups with medical researchers in the UK were conducted in 2010–2011. The study highlights a range of issues associated with the research oversight and consent process (including obtaining ethical approval to use biobank samples and particular concerns for international studies), the benefits and limitations of broad consent and the possibilities of revoking consent. Many of these issues originate in the relatively static consent processes that currently govern the biobanking process. However, it is now possible to develop reliable, dynamic processes using information technology that can resolve many of these ethical and legal concerns. The ‘dynamic consent’ approach therefore offers the opportunity to fundamentally transform the process of medical research in a manner that addresses the concerns of both patients and medical researchers.
Using Genomic Data to Make Indirect (and Unauthorized) Estimates of Disease Risk
Authors: Nyholt D.R.
Published: June 2012

The number of genetic factors associated with common human traits and disease is increasing rapidly, and the general public is utilizing affordable, direct-to-consumer genetic tests. The results of these tests are often in the public domain. A combination of factors has increased the potential for the indirect estimation of an individual’s risk for a particular trait. Here we explain the basic principals underlying risk estimation which allowed us to test the ability to make an indirect risk estimation from genetic data by imputing Dr. James Watson’s redacted apolipoprotein E gene (APOE) information. The principles underlying risk prediction from genetic data have been well known and applied for many decades, however, the recent increase in genomic knowledge, and advances in mathematical and statistical techniques and computational power, make it relatively easy to make an accurate but indirect estimation of risk. There is a current hazard for indirect risk estimation that is relevant not only to the subject but also to individuals related to the subject; this risk will likely increase as more detailed genomic data and better computational tools become available.
The Necessity of Broad Consent and Complementary Regulations for the Protection of Personal Data in Biobanks: What Can We Learn from the German Case?
Authors: Taupitz J. , Weigel J.
Published: June 2012

In order to follow population-based approaches for certain causes and risks of illnesses, more and more biobanks have been set up during the last years. Here, samples and personal data of the donors are collected and saved, whereby concrete research aims, at the time of storage of the bio-probes and the related data, are mostly undetermined. Biobanks, therefore, have the character of a collection of material and data that can be used for initially undetermined research projects. Under legal aspects the question arises whether the data subjects can consent only to an already determined use of their samples and data or can consent to a general use for research. In this article, we discuss the validity of broad consent and in how far the arising deficits in data protection need to be and can be compensated. Broad consent is, in our opinion, generally legally valid. It leads, however, to an encroachment of the ruling basic principles of data protection law. The 5-pillar concept of the German Ethics Council therefore suggests additional regulations to compensate the lacks of broad consent. While other recommendations and opinions – as far as can be seen – do only describe in vague terms the conditions for statutory regulations, the opinion of the German Ethics Council comprises very concrete statements. It, therefore, might serve as a model in the international debate on privacy and biobanks. As a result of the current debate, we identify this as a paradigm shift in data protection in biobanks.
IT Solutions for Privacy Protection in Biobanking
Authors: Eder J. , Gottweis H. , Zatloukal K.
Published: June 2012

Biobanks containing human biological samples and associated data are key resources for the advancement of medical research. Efficient access to samples and data increases competitiveness in medical research, reduces effort and time for achieving scientific results and promotes scientific progress. In order to address upcoming health challenges, there is increasing need for transnational collaboration. This requires innovative solutions improving interoperability of biobanks in fields such as sample and data management as well as governance including ethical and legal frameworks. In this context, rights and expectations of donors to determine the usage of their biological material and data and to ensure their privacy have to be observed. We discuss the benefits of biobanks, the needs to support medical research and the societal demands and regulations, in particular, securing the rights of donors and present IT solutions that allow both to maintain the security of personal data and to increase the efficiency of access to data in biobanks. Disclosure filters are discussed as a strategy to combine European public expectations concerning informed consent with the requirements of biobank research.
The Privacy-Reciprocity Connection in Biobanking: Comparing German with UK Strategies
Authors: Hobbs A. , Starkbaum J. , Gottweis U. , Wichmann H.E. , Gottweis H.
Published: June 2012

In recent years, the adequacy of the ‘gift’ model of research participation has been increasingly questioned. This study used focus groups to explore how potential and actual participants of biobanks in the UK and Germany negotiate the relationship between concerns over privacy protection, reciprocity and benefit sharing. In Germany, 15 focus groups (n = 151) were conducted: 11 general public groups (n = 116) and 4 with former cohort study participants including the KORA and the Popgen cohort study (n = 35). In the UK, 9 focus groups (n = 61) were conducted: 4 general public groups (n = 33) and 5 with UK Biobank and European Huntington’s Disease (Euro-HD) Registry biorepository participants (n = 28). Forms of reciprocity were found to partially mitigate potential and actual biobank participants’ concerns over personal privacy risks and future unintended consequences of biobank in both Germany and the UK. Specifically, notions of individual reciprocity were at the forefront in the context of personal disadvantages to participation, while communal reciprocity was prominent when potential and actual participants were discussing the uncertainty of the long-term nature of biobanking. The research indicates that reciprocity can be viewed as a mode to deal with individuals’ concerns about participating in a biobank, both by acting as a return ‘favor’ or ‘gift,’ and through establishing an ongoing relationship between participants, researchers and society. It is suggested that future biobanking projects will need to flexibly combine individual and communal forms of reciprocity if they are to recruit and maintain sufficient numbers of participants.
Securing the Data Economy: Translating Privacy and Enacting Security in the Development of DataSHIELD
Authors: Murtagh M.J. , Demir I. , Jenkings K.N. , Wallace S.E. , Murtagh B. , Boniol M. , Bota M. , Laflamme P. , Boffetta P. , Ferretti V. , Burton P.R.
Published: June 2012

Contemporary bioscience is seeing the emergence of a new data economy: with data as its fundamental unit of exchange. While sharing data within this new ‘economy’ provides many potential advantages, the sharing of individual data raises important social and ethical concerns. We examine ongoing development of one technology, DataSHIELD, which appears to elide privacy concerns about sharing data by enabling shared analysis while not actually sharing any individual-level data. We combine presentation of the development of DataSHIELD with presentation of an ethnographic study of a workshop to test the technology. DataSHIELD produced an application of the norm of privacy that was practical, flexible and operationalizable in researchers’ everyday activities, and one which fulfilled the requirements of ethics committees. We demonstrated that an analysis run via DataSHIELD could precisely replicate results produced by a standard analysis where all data are physically pooled and analyzed together. In developing DataSHIELD, the ethical concept of privacy was transformed into an issue of security. Development of DataSHIELD was based on social practices as well as scientific and ethical motivations. Therefore, the ‘success’ of DataSHIELD would, likewise, be dependent on more than just the mathematics and the security of the technology.
Differentiating and Evaluating Common Good and Public Good: Making Implicit Assumptions Explicit in the Contexts of Consent and Duty to Participate
Authors: Bialobrzeski A. , Ried J. , Dabrock P.
Published: June 2012

The notions ‘common good’ and ‘public good’ are mostly used as synonyms in bioethical discussion of biobanks, but have different origins. As a consequence, they should be applied differently. In this article, the respective characteristics are worked out and then subsequently examined which consent models emerge from them. Distinguishing normative and descriptive traits of both concepts, it turns out that one concept is unjustly used, and that the other one fits better to the context of a plural society. A reflected use of these differing concepts may help to choose an appropriate form of consent and allows public trust in biobank research to deepen.
Cof a 1: Identification, Expression and Immunoreactivity of the First Coffee Allergen
Authors: Manavski Nikolay , Peters Ulrike , Brettschneider Reinhold , Oldenburg Marcus , Baur Xaver , Bittner Cordula
Published: June 2012

Background: Over the past years, dust of green coffee beans has become known to be a relevant cause for occupational type I allergies. Up to now, allergy diagnostics is based on native green coffee bean extract which exhibits insufficient specificity due to interfering substances as well as batch-to-batch variations. No coffee allergen has been described on the molecular level so far. The aim of this study was to identify the first allergen of green coffee. Methods: The allergenicity of native green coffee bean extracts was analyzed by means of ImmunoCAP in sera of 17 symptomatic coffee workers. A Coffea arabica pJuFo cDNA phage display library was constructed and screened for IgE binding to coffee proteins with 2 sera from allergic coffee workers. By sequence analysis, a new coffee allergen (Cof a 1) was identified, expressed in Escherichia coli, and evaluated by Western blots. The frequency of sensitization was investigated by ELISA screening. Results: The Cof a 1 cDNA encoded a 32-kDa C. arabica class III chitinase. Serum IgE antibodies to the recombinant allergen were found in 3 out of 17 symptomatic coffee workers (18%), whereas only 2 of them reacted to the commercial allergy test. Conclusions: A class III chitinase of C. arabica was identified to be the first known coffee allergen Cof a 1. It may have a relevant potential for the specific diagnosis of coffee sensitization.
Effects of Midazolam and Nitrous Oxide on Endocrine and Metabolic Measurements in Children
Authors: Ekbom Kerstin , Kalman Sigridur , Jakobsson Jan , Marcus Claude
Published: June 2012

Objective: Pain, stress as well as drugs may affect metabolic and endocrine measurements, especially in stressed children. The aim was to study how release of glucose and stress hormones are affected when procedural sedation with nitrous oxide or midazolam are used for establishing intravenous access in obese and lean children. Methods: In a prospective, double-blind, randomized study 90 children, 60 obese and 30 growth-retarded (GR), aged 5–18 years, with reported anxiety or difficulties connected with i.v. access, were randomized to 1 of 3 groups: oral midazolam (0.3 mg/kg, max. 15 mg), 50% nitrous oxide (N2O), and 10% N2O. In addition, all children received anesthesia cream (EMLA®) locally 1 h before i.v. access. Blood samples were drawn at 4 time points during 30 min after establishing venous access and, when feasible, after 24 h. The 24-hour sample was regarded as obtained during unstressed condition. The effect of procedural sedation was analyzed. Children’s evaluations of pain (Numeric Rating Scale) and procedure (Likert Scale) were correlated with mean values of cortisol and glucose after i.v. access. For the metabolic and hormone control measurements, 60 children aged 4–18 years (40 obese and 20 GR) served as controls. These children underwent a 24-hour blood sampling and did not receive sedation. The control samples were drawn 10–12 h after i.v. access. Results: After midazolam, significantly lower cortisol levels were found compared to both 50% N2O and 10% N2O and to unstressed controls. The growth hormone levels decreased with time in the midazolam group compared to 50 and 10% N2O, where the effect of time was reversed. Glucose levels among GR children increased from 0 to 30 min, whereas the opposite was found in obese children regardless of treatment. A post hoc analysis demonstrated significant correlations between children’s evaluations of the procedure and mean values of cortisol (r = –0.53), growth hormone (r = –0.52), and norepinephrine (r = –0.5) in children treated with a very low dose of N2O (10%). Conclusions: When sedation is insufficient during i.v. access, and blood sampling pain and stress affect hormone values, treatment with N2O or midazolam influence the glucose and stress hormone levels differently. These differences need to be accounted for when results are used for diagnosis and clinical decisions.
An Unusually Low Prevalence of Huntington’s Disease in Iceland
Authors: Sveinsson Ólafur , Halldórsson Sigurður , Olafsson Elias
Published: June 2012

Objectives: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary movements and psychiatric disturbances, found worldwide, with a variable prevalence. The purpose of this study was to determine the history of HD in Iceland and determine the prevalence and incidence of HD. Materials and Methods: Clinical information was obtained from general, neurologic, and psychiatric hospitals, practicing neurologists, general practitioners, and family members of affected individuals. Results: Twenty-seven individuals were identified with typical symptoms of HD from the 1850s to 2007. All but one sporadic case are descendants of a husband and wife living in the early and mid-19th century. The point prevalence of HD in Iceland is 1.0 per 100,000 individuals. Conclusions: The prevalence of HD in Iceland is markedly lower than in the neighboring countries (Norway and the British Isles), where Icelanders originate from.
Breastfeeding and Determinants of Adult Body Composition: A Prospective Study from Birth to Young Adulthood
Authors: Pirilä Satu , Saarinen-Pihkala Ulla M. , Viljakainen Heli , Turanlahti Maila , Kajosaari Merja , Mäkitie Outi , Taskinen Mervi
Published: June 2012

Background: The impact of breastfeeding on adult body composition is controversial. We evaluated effects of lifestyle and childhood-related factors, including infant feeding, on adult body composition. Methods: We determined total body and trunk fat and lean mass by densitometry in 158 adults who were born full-term and prospectively followed from birth to the age of 32 years. Data on various factors, extending from infancy to adulthood, with potential effect on body composition, were recorded. Results: Scapular skinfold thickness at 12 months correlated with adult trunk (R = 0.22, p = 0.005) and body fat percentage (R = 0.18, p = 0.023). In linear regression analysis, current physical activity (R = –0.33, p < 0.001) and maternal BMI (R = 0.28, p = 0.002) were associated with adult body fat percentage. Gender (R = 0.78, p < 0.001) and weight gain during infancy (R = 0.147, p = 0.008) were associated with adult lean mass. In the analysis of covariance, prolonged breastfeeding tended to lead to lower fat percentage in adulthood, but no direct association with the duration of breastfeeding and adult body composition was confirmed. Conclusions: Current physical activity, growth in infancy, gender and maternal BMI influence adult body composition. Breastfeeding has an indirect influence on adult body fat accumulation by affecting growth and body adiposity in infancy.
Adrenocortical Hormonal Activity in 20-Year-Old Subjects Born Small or Appropriate for Gestational Age
Authors: Todorova Boryana , Salonen Maria , Jääskeläinen Jarmo , Tapio Alise , Jääskeläinen Tiina , Palvimo Jorma , Turpeinen Ursula , Hämäläinen Esa , Räsänen Marita , Tenhola Sirpa , Voutilainen Raimo
Published: June 2012

Background: Altered adrenocortical activity is one suggested mechanism relating small birth size with the metabolic syndrome in adulthood. Adrenal androgen concentrations are higher in children born small (SGA) than appropriate for gestational age (AGA). Aim: To compare adrenocortical hormonal activity between 20-year-old subjects born SGA or AGA. Methods: Seventy 20-year-old subjects (35 SGA and 35 age- and gender-matched AGA controls) were studied. Serum cortisol, cortisone, corticosteroid-binding globulin (CBG), glucocorticoid bioactivity (GBA), aldosterone, dehydroepiandrosterone sulfate (DHEAS) and androstenedione were measured, and the free cortisol index (FCI) was calculated. Results: The mean levels of glucocorticoid parameters, aldosterone, DHEAS or androstenedione did not differ between the SGA and AGA groups. In both groups, the males had lower cortisol (p < 0.05) and CBG levels (p < 0.01) and higher DHEAS (p < 0.01) concentrations than the females. Females who used hormonal contraceptives had higher cortisol and CBG levels (p < 0.01) but similar FCI, GBA and DHEAS levels than females who did not use contraceptives. Conclusion: No differences in adrenocortical activity were found between 20-year-old SGA and AGA subjects. Enhanced peripubertal adrenal androgen secretion seems to disappear by early adulthood in full-term born SGA subjects. FCI and GBA are useful parameters in the evaluation of the glucocorticoid milieu during hormonal contraceptive use.
Genetic Analysis of Short Children with Apparent Growth Hormone Insensitivity
Authors: Wit J.M. , van Duyvenvoorde H.A. , Scheltinga S.A. , de Bruin S. , Hafkenscheid L. , Kant S.G. , Ruivenkamp C.A.L. , Gijsbers A.C.J. , van Doorn J. , Feigerlova E. , Noordam C. , Walenkamp M.J. , Claahsen-van de Grinten H. , Stouthart P. , Bonapart I.E. , Pereira A.M. , Gosen J. , Delemarre-van de Waal H.A. , Hwa V. , Breuning M.H. , Domené H.M. , Oostdijk W. , Losekoot M.
Published: June 2012

Background/Aims: In short children, a low IGF-I and normal GH secretion may be associated with various monogenic causes, but their prevalence is unknown. We aimed at testing GH1, GHR, STAT5B, IGF1, and IGFALS in children with GH insensitivity. Subjects and Methods: Patients were divided into three groups: group 1 (height SDS <–2.5, IGF-I <–2 SDS, n = 9), group 2 (height SDS –2.5 to –1.9, IGF-I <–2 SDS, n = 6) and group 3 (height SDS <–1.9, IGF-I –2 to 0 SDS, n = 21). An IGF-I generation test was performed in 11 patients. Genomic DNA was used for direct sequencing, multiplex ligation-dependent probe amplification and whole-genome SNP array analysis. Results: Three patients in group 1 had two novel heterozygous STAT5B mutations, in two combined with novel IGFALS variants. In groups 2 and 3 the association between genetic variants and short stature was uncertain. The IGF-I generation test was not predictive for the growth response to GH treatment. Conclusion: In severely short children with IGF-I deficiency, genetic assessment is advised. Heterozygous STAT5B mutations, with or without heterozygous IGFALS defects, may be associated with GH insensitivity. In children with less severe short stature or IGF-I deficiency, functional variants are rare.
Phylloquinone and Vitamin D Status: Associations with Incident Chronic Kidney Disease in the Framingham Offspring Cohort
Authors: O’Seaghdha Conall M. , Hwang Shih-Jen , Holden Rachel , Booth Sarah L. , Fox Caroline S.
Published: June 2012

Background: Cardiovascular risk factors are associated with the development of chronic kidney disease (CKD), and CKD and vascular disease are etiologically linked. Evidence suggests deficiencies of vitamins D and K may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. We hypothesized that deficiencies of vitamins D and K may be associated with incident CKD and/or incident albuminuria amongst members of the general population. Methods: We analyzed 1,442 Framingham Heart Study participants (mean age 58 years; 50.5% women), free of CKD (eGFR <60 ml/min/1.73 m2), with a mean follow-up of 7.8 years in 2005–2008. Incident albuminuria was defined using sex-specific cut-offs of urine albumin-to-creatinine ratio (≥17 mg/g men and ≥25 mg/g women). Baseline log plasma phylloquinone (vitamin K1) and 25(OH)D levels, analyzed as continuous variables and by quartile, were related to risk of incident CKD (n = 108) and incident albuminuria (n = 106) using logistic regression models adjusted for standard risk factors. Results: Participants in the highest phylloquinone quartile (≥1.78 nmol/l) had an increased risk of CKD (multivariable-adjusted OR Q4 vs. Q1 2.39; p = 0.006) and albuminuria at follow-up (multivariable-adjusted OR Q4 vs. Q1 1.95; p = 0.05), whereas no association was observed with continuous phylloquinone levels for either endpoint. Deficiency of 25(OH)D was not associated with incident CKD or albuminuria in either analysis. Conclusions: Contrary to our hypothesis, higher plasma phylloquinone levels are associated with an increased risk of incident CKD. Whether plasma phylloquinone is a marker for another unmeasured risk factor requires further study. External validation is necessary given the unexpected nature of these results.