bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosis-specific disability pension predicts suicidal behaviour and mortality in young adults: a nationwide prospective cohort study
Authors: Jonsson Ulf , Alexanderson Kristina , Kjeldgård Linnea , Westerlund Hugo , Mittendorfer-Rutz Ellenor
Published: February 2013

Objectives

Increasing rates of disability pension (DP), particularly owing to mental diagnoses, have been observed among young adults in Organisation for Economic Co-operation and Development (OECD) countries. There is a lack of knowledge about the health prognosis in this group. The aim of this study was to investigate whether DP in young adulthood owing to specific mental diagnoses or somatic diagnoses predicts suicidal behaviour and all-cause mortality.

Design

A nationwide prospective cohort study.

Setting

A register study of all young adults who in 2005 were 19–23 years old and lived in Sweden. Registers held by the National Board of Health and Welfare, Statistics Sweden and the National Social Insurance Agency were used.

Participants

525 276 young adults. Those who in 2005 had DP with mental diagnoses (n=8070) or somatic diagnoses (n=3975) were compared to all the other young adults in the same age group (n=513 231).

Outcome measures

HRs for suicide attempt, suicide and all-cause mortality in 2006–2010 were calculated by Cox proportionate hazard regression models, adjusted for sex, country of birth, parental education and parental and previous own suicidal behaviour.

Results

The adjusted HR for suicide attempt was 3.32 (95% CI 2.98 to 3.69) among those on DP with mental diagnoses and 1.78 (95% CI 1.41 to 2.26) among those on DP with somatic diagnoses. For the specific mental diagnoses, the unadjusted HRs ranged between 2.42 (mental retardation) and 22.94 (personality disorders), while the adjusted HRs ranged between 2.03 (mental retardation) and 6.00 (bipolar disorder). There was an increased risk of mortality for young adults on DP in general, but only those with mental DP diagnoses had a significantly elevated HR of completed suicide with an adjusted HR of 3.92 (95% CI 2.83 to 5.43).

Conclusions

Young adults on DP are at increased risk of suicidal behaviour and preterm death, which emphasises the need for improved treatment and follow-up.
Life-event stress induced by the Great East Japan Earthquake was associated with relapse in ulcerative colitis but not Crohn's disease: a retrospective cohort study
Authors: Shiga Hisashi , Miyazawa Teruko , Kinouchi Yoshitaka , Takahashi Seiichi , Tominaga Gen , Takahashi Hiroki , Takagi Sho , Obana Nobuya , Kikuchi Tatsuya , Oomori Shinya , Nomura Eiki , Shiraki Manabu , Sato Yuichirou , Takahashi Shuichiro , Umemura Ken , Yokoyama Hiroshi , Endo Katsuya , Kakuta Yoichi , Aizawa Hiroki , Matsuura Masaki , Kimura Tomoya , Kuroha Masatake , Shimosegawa Tooru
Published: February 2013

Objective

Stress is thought to be one of the triggers of relapses in patients with inflammatory bowel disease (IBD). We examined the rate of relapse in IBD patients before and after the Great East Japan Earthquake.

Design

A retrospective cohort study.

Settings

13 hospitals in Japan.

Participants

546 ulcerative colitis (UC) and 357 Crohn's disease (CD) patients who received outpatient and inpatient care at 13 hospitals located in the area that were seriously damaged by the earthquake. Data on patient's clinical characteristics, disease activity and deleterious effects of the earthquake were obtained from questionnaires and hospital records.

Primary outcome

We evaluated the relapse rate (from inactive to active) across two consecutive months before and two consecutive months after the earthquake. In this study, we defined ‘active’ as conditions with a partial Mayo score=2 or more (UC) or a Harvey-Bradshaw index=6 or more (CD).

Results

Among the UC patients, disease was active in 167 patients and inactive in 379 patients before the earthquake. After the earthquake, the activity scores increased significantly (p<0.0001). A total of 86 patients relapsed (relapse rate=15.8%). The relapse rate was about twice that of the corresponding period in the previous year. Among the CD patients, 86 patients had active disease and 271 had inactive disease before the earthquake. After the earthquake, the activity indices changed little. A total of 25 patients experienced a relapse (relapse rate=7%). The relapse rate did not differ from that of the corresponding period in the previous year. Multivariate analyses revealed that UC, changes in dietary oral intake and anxiety about family finances were associated with the relapse.

Conclusions

Life-event stress induced by the Great East Japan Earthquake was associated with relapse in UC but not CD.
Building collaborative teams in neonatal intensive care
Authors: Brodsky Dara , Gupta Munish , Quinn Mary , Smallcomb Jane , Mao Wenyang , Koyama Nina , May Virginia , Waldo Karen , Young Susan , Pursley DeWayne M
Published: February 2013

The complex multidisciplinary nature of neonatal intensive care combined with the numerous hand-offs occurring in this shift-based environment, requires efficient and clear communication and collaboration among staff to provide optimal care. However, the skills required to function as a team are not typically assessed, discussed, or even taught on a regular basis among neonatal personnel. We developed a multidisciplinary, small group, interactive workshop based on Team STEPPS to provide staff with formal teamwork skills, and to introduce new team-based practices; 129 (95%) of the eligible 136 staff were trained. We then compared the results of the pretraining survey (completed by 114 (84%) of staff) with the post-training survey (completed by 104 (81%) of participants) 2 years later. We found an improvement in the overall teamwork score from 7.37 to 8.08 (p=<0.0001) based on a range of poor (1) to excellent (9). Respondents provided higher ratings in 9 out of 15 team-based categories after the training. Specifically, staff found improvements in communication (p=0.037), placed greater importance on situation awareness (p=<0.00010), and reported that they supported each other more (p=<0.0001). Staff satisfaction was rated higher post-training, with responses showing that staff had greater job fulfilment (p=<0.0001), believed that their abilities were being utilised properly (p=0.003), and felt more respected (p=0.0037). 90% of staff found the new practice of team meetings to help increase awareness of unit acuity, and 77% of staff noted that they had asked for help or offered assistance because of information shared during these meetings. In addition to summarising the results of our training programme, this paper also provides practical tools that may be of use in developing team training programmes in other neonatal units.
Contextual information influences diagnosis accuracy and decision making in simulated emergency medicine emergencies
Authors: McRobert Allistair Paul , Causer Joe , Vassiliadis John , Watterson Leonie , Kwan James , Williams Mark A
Published: February 2013

Background

It is well documented that adaptations in cognitive processes with increasing skill levels support decision making in multiple domains. We examined skill-based differences in cognitive processes in emergency medicine physicians, and whether performance was significantly influenced by the removal of contextual information related to a patient's medical history.

Method

Skilled (n=9) and less skilled (n=9) emergency medicine physicians responded to high-fidelity simulated scenarios under high- and low-context information conditions.

Results

Skilled physicians demonstrated higher diagnostic accuracy irrespective of condition, and were less affected by the removal of context-specific information compared with less skilled physicians. The skilled physicians generated more options, and selected better quality options during diagnostic reasoning compared with less skilled counterparts. These cognitive processes were active irrespective of the level of context-specific information presented, although high-context information enhanced understanding of the patients’ symptoms resulting in higher diagnostic accuracy.

Conclusions

Our findings have implications for scenario design and the manipulation of contextual information during simulation training.
Homicides of law enforcement officers responding to domestic disturbance calls
Authors: Kercher Cassandra , Swedler David I , Pollack Keshia M , Webster Daniel W
Published: February 2013

Objective

To describe the law enforcement officer (LEO), encounter, perpetrator and victim characteristics of domestic disturbance-related LEO homicides in the USA from 1996 to 2010.

Methods

Narrative text analysis was conducted on the Federal Bureau of Investigation's annual report ‘Law Enforcement Officers Killed and Assaulted’. Potential cases were confirmed if the narrative included the term ‘domestic disturbance’ or a domestic disturbance situation was described.

Results

116 LEOs were killed while responding to domestic disturbance calls. Ninety-five per cent of these homicides were committed with a firearm. Sixty-seven per cent of LEOs were wearing body armour when killed; however, 52% received the fatal wound to the head/neck. Sixty-one per cent of suspects had a criminal history mentioned within the narratives and perpetrators of intimate partner violence (IPV) were more likely to be killed by LEOs than suspects involved in other forms of domestic violence. Victims of the domestic disturbance were killed in 21% of the IPV-related LEO homicide cases as opposed to only 5% of other domestic disturbance calls. A firearm was the most common weapon used in the murder of a domestic disturbance victim (86%).

Conclusions

This study describes domestic disturbance-related LEO homicides. Future research in this area should further examine the dangers unique to domestic disturbance calls. A longitudinal analysis could provide greater understanding of the injury and mortality risks faced by LEOs, in order to inform homicide prevention among law enforcement.
Sequence diversity of the leukotoxin (lktA) gene in caprine and ovine strains ofMannheimia haemolytica
Authors: Vougidou C. , Sandalakis V. , Psaroulaki A. , Petridou E. , Ekateriniadou L.
Published: February 2013

Mannheimia haemolyticais the aetiological agent of pneumonic pasteurellosis in small ruminants. The primary virulence factor of the bacterium is a leukotoxin (LktA), which induces apoptosis in susceptible cells via mitochondrial targeting. It has been previously shown that certainlktAalleles are associated either with cattle or sheep. The objective of the present study was to investigatelktAsequence variation among ovine and caprineM haemolyticastrains isolated from pneumonic lungs, revealing any potential adaptation for the caprine host, for which there is no available data. Furthermore, we investigated amino acid variation in the N‐terminal part of the sequences and its effect on targeting mitochondria. Data analysis showed that the prevalent caprine genotype differed at a single non‐synonymous site from a previously described uncommon bovine allele, whereas the ovine sequences represented new, distinct alleles. N‐terminal sequence differences did not affect the mitochondrial targeting ability of the isolates; interestingly enough in one case, mitochondrial matrix targeting was indicated rather than membrane association, suggesting an alternative LktA trafficking pattern.
Progress Toward Understanding Heterosis in Crop Plants
Authors: Schnable Patrick S. , Springer Nathan M.
Published: February 2013

Although heterosis, or hybrid vigor, is widely exploited in agriculture, a complete description of its molecular underpinnings has remained elusive despite extensive investigation. It appears that there is not a single, simple explanation for heterosis. Instead, it is likely that heterosis arises in crosses between genetically distinct individuals as a result of a diversity of mechanisms. Heterosis generally results from the action of multiple loci, and different loci affect heterosis for different traits and in different hybrids. Hence, multigene models are likely to prove most informative for understanding heterosis. Complementation of allelic variation, as well as complementation of variation in gene content and gene expression patterns, is likely to be an important contributor to heterosis. Epigenetic variation has the potential to interact in hybrid genotypes via novel mechanisms. Several other intriguing hypotheses are also under investigation. In crops, heterosis must be considered within the context of the genomic impacts of prior selection for agronomic traits.
Fruit Development and Ripening
Authors: Seymour Graham B. , Østergaard Lars , Chapman Natalie H. , Knapp Sandra , Martin Cathie
Published: February 2013

Fruiting structures in the angiosperms range from completely dry to highly fleshy organs and provide many of our major crop products, including grains. In the model plant Arabidopsis, which has dry fruits, a high-level regulatory network of transcription factors controlling fruit development has been revealed. Studies on rare nonripening mutations in tomato, a model for fleshy fruits, have provided new insights into the networks responsible for the control of ripening. It is apparent that there are strong similarities between dry and fleshy fruits in the molecular circuits governing development and maturation. Translation of information from tomato to other fleshy-fruited species indicates that regulatory networks are conserved across a wide spectrum of angiosperm fruit morphologies. Fruits are an essential part of the human diet, and recent developments in the sequencing of angiosperm genomes have provided the foundation for a step change in crop improvement through the understanding and harnessing of genome-wide genetic and epigenetic variation.
Intracellular Signaling from Plastid to Nucleus
Authors: Chi Wei , Sun Xuwu , Zhang Lixin
Published: February 2013

Intracellular signaling from plastids to the nucleus, called retrograde signaling, coordinates the expression of nuclear and plastid genes and is essential for plastid biogenesis and for maintaining plastid function at optimal levels. Recent identification of several components involved in plastid retrograde generation, transmission, and control of nuclear gene expression has provided significant insight into the regulatory network of plastid retrograde signaling. Here, we review the current knowledge of multiple plastid retrograde signaling pathways, which are derived from distinct sources, and of possible plastid signaling molecules. We describe the retrograde signaling–dependent regulation of nuclear gene expression, which involves multilayered transcriptional control, as well as the transcription factors involved. We also summarize recent advances in the identification of key components mediating signal transduction from plastids to the nucleus.
Integrative Data Analysis in Clinical Psychology Research
Authors: Hussong Andrea M. , Curran Patrick J. , Bauer Daniel J.
Published: February 2013

Integrative data analysis (IDA), a novel framework for conducting the simultaneous analysis of raw data pooled from multiple studies, offers many advantages including economy (i.e., reuse of extant data), power (i.e., large combined sample sizes), the potential to address new questions not answerable by a single contributing study (e.g., combining longitudinal studies to cover a broader swath of the lifespan), and the opportunity to build a more cumulative science (i.e., examining the similarity of effects across studies and potential reasons for dissimilarities). There are also methodological challenges associated with IDA, including the need to account for sampling heterogeneity across studies, to develop commensurate measures across studies, and to account for multiple sources of study differences as they impact hypothesis testing. In this review, we outline potential solutions to these challenges and describe future avenues for developing IDA as a framework for studies in clinical psychology.
Dissociative Disorders in DSM-5
Authors: Spiegel David , Lewis-Fernández Roberto , Lanius Ruth , Vermetten Eric , Simeon Daphne , Friedman Matthew
Published: February 2013

The rationale, research literature, and proposed changes to the dissociative disorders and conversion disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) are presented. Dissociative identity disorder will include reference to possession as well as identity fragmentation, to make the disorder more applicable to culturally diverse situations. Dissociative amnesia will include dissociative fugue as a subtype, since fugue is a rare disorder that always involves amnesia but does not always include confused wandering or loss of personality identity. Depersonalization disorder will include derealization as well, since the two often co-occur. A dissociative subtype of posttraumatic stress disorder (PTSD), defined by the presence of depersonalization or derealization in addition to other PTSD symptoms, is being recommended, based upon new epidemiological and neuroimaging evidence linking it to an early life history of adversity and a combination of frontal activation and limbic inhibition. Conversion disorder (functional neurological symptom disorder) will likely remain with the somatic symptom disorders, despite considerable dissociative comorbidity.
Postpartum Depression: Current Status and Future Directions
Authors: O'Hara Michael W. , McCabe Jennifer E.
Published: February 2013

Postpartum depression (PPD) is a common and serious mental health problem that is associated with maternal suffering and numerous negative consequences for offspring. The first six months after delivery may represent a high-risk time for depression. Estimates of prevalence range from 13% to 19%. Risk factors mirror those typically found with major depression, with the exception of postpartum-specific factors such as sensitivity to hormone changes. Controlled trials of psychological interventions have validated a variety of individual and group interventions. Medication often leads to depression improvement, but in controlled trials there are often no significant differences in outcomes between patients in the medication condition and those in placebo or active control conditions. Reviews converge on recommendations for particular antidepressant medications for use while breastfeeding. Prevention of PPD appears to be feasible and effective. Finally, there is a growing movement to integrate mental health screening into routine primary care for pregnant and postpartum women and to follow up this screening with treatment or referral and with follow-up care. Research and clinical recommendations are made throughout this review.
Prospects for Spin-Based Quantum Computing in Quantum Dots
Authors: Kloeffel Christoph , Loss Daniel
Published: February 2013

Experimental and theoretical progress toward quantum computation with spins in quantum dots (QDs) is reviewed, with particular focus on QDs formed in GaAs heterostructures, on nanowire-based QDs, and on self-assembled QDs. We report on a remarkable evolution of the field, where decoherence—one of the main challenges for realizing quantum computers—no longer seems to be the stumbling block it had originally been considered. General concepts, relevant quantities, and basic requirements for spin-based quantum computing are explained; opportunities and challenges of spin-orbit interaction and nuclear spins are reviewed. We discuss recent achievements, present current theoretical proposals, and make several suggestions for further experiments.
Phosphors for Solid-State White Lighting
Authors: George Nathan C. , Denault Kristin A. , Seshadri Ram
Published: February 2013

Since the mid-1990s, phosphors have played a key role in emerging solid-state white-lighting technologies that are based on combining a III-nitride-based near-UV or blue solid-state light source with downconversion to longer wavelengths. Almost all widely used phosphors comprise a crystalline oxide, nitride, or oxynitride host that is appropriately doped with either Ce3+ or Eu2+. These ions, with [Xe] 4fn5d0 configurations (n = 1 for Ce3+ and 7 for Eu2+) have proximal excited states that are [Xe] 4fn−15d1. Optical excitation into these states and concomitant reemission can be tuned into the appropriate regions of the visible spectrum by the crystal these ions are hosted in. In this article, we review the current needs and key aspects of the conversion process. We describe some currently used families of phosphors and consider why they are suitable for solid-state lighting. Finally, we describe some empirical rules for new and improved host materials.
Looking Back to See Ahead: Unanticipated Changes in Immigration from 1986 to the Present and Their Implications for American Politics Today
Authors: Jones-Correa Michael , de Graauw Els
Published: February 2013

This article explores how issues of immigration—and particularly undocumented immigration—have evolved since the enactment of the 1986 Immigration Reform and Control Act and how they have changed US politics in significant and often unexpected ways. In particular, our review explores five themes: (a) the failure of comprehensive immigration reform over the past quarter century; (b) the shift in immigration policy making toward state and local governments; (c) the identification of ethno-racial minorities around immigration status and immigrants as racialized groups; (d) the political mobilization of undocumented immigrants; and (e) the emergence of transnational political ties between the United States and sending countries. The article concludes by assessing possible blind spots within the contemporary discussion of immigration and how we might fail to anticipate possible changes or trends in the making.
Media and Political Polarization
Authors: Prior Markus
Published: February 2013

This article examines if the emergence of more partisan media has contributed to political polarization and led Americans to support more partisan policies and candidates. Congress and some newer media outlets have added more partisan messages to a continuing supply of mostly centrist news. Although political attitudes of most Americans have remained fairly moderate, evidence points to some polarization among the politically involved. Proliferation of media choices lowered the share of less interested, less partisan voters and thereby made elections more partisan. But evidence for a causal link between more partisan messages and changing attitudes or behaviors is mixed at best. Measurement problems hold back research on partisan selective exposure and its consequences. Ideologically one-sided news exposure may be largely confined to a small, but highly involved and influential, segment of the population. There is no firm evidence that partisan media are making ordinary Americans more partisan.
Pathogenic arterial remodeling: the good and bad of microRNAs
Authors: Wei Yuanyuan , Schober Andreas , Weber Christian
Published: February 2013

A number of cardiovascular diseases, such as restenosis, aneurysm, and atherosclerosis, lead to vascular remodeling associated with complex adaptive reactions of different cell populations. These reactions include growth of smooth muscle cells, proliferation of endothelial cells, and the inflammatory response of macrophages. MicroRNAs (miRNAs), a class of short RNAs, play key roles in various biological processes and in the development of human disease by post-transcriptional regulation of gene expression. Here, we review the molecular mechanisms of a subset of miRNAs involved in vascular remodeling, including miR-143/145, miR-221/222, miR-126, miR-21, and miR-155. Some of these miRNAs, such as miR-143/145 and miR-126, have been shown to be protective during vascular remodeling, whereas others, such as miR-21, may promote the cellular response that leads to neointima formation. The increasing knowledge regarding the roles of miRNAs in vascular remodeling opens novel avenues for the treatment of various cardiovascular diseases. However, more in vivo studies on the functional roles of these miRNAs are required in the future.
Sex differences in blood pressure control during 6° head-down tilt bed rest
Authors: Arzeno Natalia M. , Stenger Michael B. , Lee Stuart M. C. , Ploutz-Snyder Robert , Platts Steven H.
Published: February 2013

Spaceflight-induced orthostatic intolerance has been studied for decades. Although ∼22% of the astronaut corps are women, most mechanistic studies use mostly male subjects, despite known sex differences in autonomic control and postflight orthostatic intolerance. We studied adrenergic, baroreflex, and autonomic indexes during continuous infusions of vasoactive drugs in men and women during a 60-day head-down bed rest. Volunteers were tested before bed rest (20 men and 10 women) and around day 30 (20 men and 10 women) and day 60 (16 men and 8 women) of bed rest. Three increasing doses of phenylephrine (PE) and sodium nitroprusside were infused for 10 min after an infusion of normal saline. A 20-min rest period separated the phenylephrine and sodium nitroprusside infusions. Autonomic activity was approximated by spectral indexes of heart rate and blood pressure variability, and baroreflex sensitivity was measured by the spontaneous baroreflex slope. Parasympathetic modulation and baroreflex sensitivity decreased with bed rest, with women experiencing a larger decrease in baroreflex sensitivity by day 30 than men. The sympathetic activation of men and parasympathetic responsiveness of women in blood pressure control during physiological stress were preserved throughout bed rest. During PE infusions, women experienced saturation of the R-R interval at high frequency, whereas men did not, revealing a sex difference in the parabolic relationship between high-frequency R-R interval, a measurement of respiratory sinus arrhythmia, and R-R interval. These sex differences in blood pressure control during simulated microgravity reveal the need to study sex differences in long-duration spaceflight to ensure the health and safety of the entire astronaut corps.
Ketone body metabolism and cardiovascular disease
Authors: Cotter David G. , Schugar Rebecca C. , Crawford Peter A.
Published: February 2013

Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.
Targeted Cancer Therapy with a 2-Deoxyglucose–Based Adriamycin Complex
Authors: Cao Jie , Cui Sisi , Li Siwen , Du Changli , Tian Junmei , Wan Shunan , Qian Zhiyu , Gu Yueqing , Chen Wei R. , Wang Guangji
Published: February 2013

Adriamycin (ADM) has been effective against many types of solid tumors in clinical applications. However, its use is limited because of systemic toxicities, primarily cardiotoxicity, and multidrug resistance. In this study, a new active receptor-mediated complex, ADM conjugated with 2-amino-2-deoxy-d-glucose and succinic acid (2DG–SUC–ADM), was designed to target tumor cells through glucose transporter 1 (GLUT1). MTT assay and confocal images showed that the complex had better inhibition rate to tumor cells and low toxicity to normal cells. Most importantly, the complex displayed a potential to reverse overcome multidrug resistance in cancer cells, with more complex transported into the nucleus of tumor cells. Our in vivo experiments also showed that this new complex could significantly decrease organ toxicity and enhance the antitumor efficacy compared with free ADM, indicating a promising drug of 2DG–SUC–ADM for targeted cancer therapy. Cancer Res; 73(4); 1362–73. ©2012 AACR.
scFv-Based “Grababody” as a General Strategy to Improve Recruitment of Immune Effector Cells to Antibody-Targeted Tumors
Authors: Cai Zheng , Fu Ting , Nagai Yasuhiro , Lam Lian , Yee Marla , Zhu Zhiqiang , Zhang Hongtao
Published: February 2013

Recruitment of immune cells to tumor cells targeted by a therapeutic antibody can heighten the antitumor efficacy of the antibody. For example, p185her2/neu-targeting antibodies not only downregulate the p185her2/neu kinase (ERBB2) but also trigger complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) through the antibody Fc region. Here, we describe a generalized strategy to improve immune cell recruitment to targeted cancer cells, using a modified scFv antibody we call a “Grababody” that binds the target protein and endogenous immunoglobulins. The model system we used to illustrate the use of this platform recognizes p185her2/neu and includes an IgG binding domain. The recombinant scFv Grababody that was created recruited circulating human IgGs and attracted immune cells carrying Fc receptors to tumor cells that expressed p185her2/neu. The presence of the IgG binding domain significantly enhanced CDC and ADCC activity and improved antitumor activity in vivo. Our results illustrate a novel general approach to improve antibody-like proteins for therapeutic applications. Cancer Res; 73(8); 2619–27. ©2013 AACR.
Association of AMP-Activated Protein Kinase with Risk and Progression of Non–Hodgkin Lymphoma
Authors: Hoffman Aaron E. , Demanelis Kathryn , Fu Alan , Zheng Tongzhang , Zhu Yong
Published: February 2013

Background: Metabolic dysregulation has been identified as an “emerging hallmark” of cancer. The heterotrimeric AMP-activated protein kinase (AMPK) complex is a central regulator of the metabolic system and an important component of the mTOR pathway and the p53 axis, making it uniquely positioned to influence carcinogenesis through its canonical functions in the metabolic arena, as well as through more traditional mechanisms such as regulation of apoptosis and angiogenesis.

Methods: We conducted a population-based genetic association study to examine the impact of mutations in AMPK subunit genes on risk of non–Hodgkin lymphoma (NHL). We also analyzed public microarray data to determine the expression of AMPK in NHL cells and to assess the influence of AMPK expression on overall survival in patients with NHL.

Results: We identified an AMPK subunit haplotype, which was significantly associated with NHL [OR, 5.44, 95% confidence interval (CI), 2.15–13.75] in women with no family history of cancer. Haplotypes in two subunits, PRKAA2 and PRKAG3, were nominally associated with the follicular and diffuse large B-cell lymphoma histologic subtypes, respectively, although these associations did not retain statistical significance after correction for multiple comparisons. Further, both of these subunits were differentially expressed (P < 0.05) in one or more lymphoma cell type, and higher expression of two versions of the AMPK-β subunit was significantly associated with increased 5-year survival among patients with NHL (P = 0.001 and P = 0.021).

Conclusion: These results provide evidence for AMPK involvement in the pathogenesis and progression of NHL.

Impact: These findings may lead to a novel area of research into NHL treatment and chemoprevention. Cancer Epidemiol Biomarkers Prev; 22(4); 736–44. ©2013 AACR.
Metabolomics in Epidemiology: Sources of Variability in Metabolite Measurements and Implications
Authors: Sampson Joshua N. , Boca Simina M. , Shu Xiao Ou , Stolzenberg-Solomon Rachael Z. , Matthews Charles E. , Hsing Ann W. , Tan Yu Ting , Ji Bu-Tian , Chow Wong-Ho , Cai Qiuyin , Liu Da Ke , Yang Gong , Xiang Yong Bing , Zheng Wei , Sinha Rashmi , Cross Amanda J. , Moore Steven C.
Published: February 2013

Background: Metabolite levels within an individual vary over time. This within-individual variability, coupled with technical variability, reduces the power for epidemiologic studies to detect associations with disease. Here, the authors assess the variability of a large subset of metabolites and evaluate the implications for epidemiologic studies.

Methods: Using liquid chromatography/mass spectrometry (LC/MS) and gas chromatography-mass spectroscopy (GC/MS) platforms, 385 metabolites were measured in 60 women at baseline and year-one of the Shanghai Physical Activity Study, and observed patterns were confirmed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening study.

Results: Although the authors found high technical reliability (median intraclass correlation = 0.8), reliability over time within an individual was low. Taken together, variability in the assay and variability within the individual accounted for the majority of variability for 64% of metabolites. Given this, a metabolite would need, on average, a relative risk of 3 (comparing upper and lower quartiles of “usual” levels) or 2 (comparing quartiles of observed levels) to be detected in 38%, 74%, and 97% of studies including 500, 1,000, and 5,000 individuals. Age, gender, and fasting status factors, which are often of less interest in epidemiologic studies, were associated with 30%, 67%, and 34% of metabolites, respectively, but the associations were weak and explained only a small proportion of the total metabolite variability.

Conclusion: Metabolomics will require large, but feasible, sample sizes to detect the moderate effect sizes typical for epidemiologic studies.

Impact: We offer guidelines for determining the sample sizes needed to conduct metabolomic studies in epidemiology. Cancer Epidemiol Biomarkers Prev; 22(4); 631–40. ©2013 AACR.
HOXB13 Mutation and Prostate Cancer: Studies of Siblings and Aggressive Disease
Authors: Witte John S. , Mefford Joel , Plummer Sarah J. , Liu Jinghua , Cheng Iona , Klein Eric A. , Rybicki Benjamin A. , Casey Graham
Published: February 2013

Background: Recent work detected for the first time a high-risk prostate cancer mutation, in homeobox B13 (HOXB13) among European-Americans.

Methods: We further evaluated this G84E missense mutation (rs138213197) in two genetic association studies of prostate cancer: a family-based study of brothers and a case–control study of more aggressive disease (N = 2,665 total). We then calculated overall impact of this mutation by pooling all published studies of European-Americans.

Results: In our studies, the mutation was found exclusively among men with prostate cancer (carrier frequency = 1.48%) or unaffected brothers of cases carrying the mutation (frequency = 0.34%), and carrying the mutation gave an OR for disease = 4.79 (P = 0.01). The G84E mutation was more common among men with an earlier age of onset (≤55 years) or a family history of prostate cancer. We also observed for the first time an African-American case carrying the G84E mutation, although at HOXB13 both of his chromosomes were of European-American ancestry. The pooled analysis also indicated that carrying the G84E mutation results in an almost five-fold increase in risk of prostate cancer (P = 3.5 × 10−17), and this risk is even higher among cases with an early age of prostate cancer onset (≤55 years) or a family history of disease: a test of heterogeneity across these strata gives P < 1 × 10−5.

Conclusions: The HOXB13 mutation substantially increases risk of early onset, familial prostate cancer in European-American men.

Impact: Testing for the G84E mutation in men with a positive family history may help distinguish those who merit more regular screening for prostate cancer. Cancer Epidemiol Biomarkers Prev; 22(4); 675–80. ©2013 AACR.
Uncovering the Molecular Secrets of Inflammatory Breast Cancer Biology: An Integrated Analysis of Three Distinct Affymetrix Gene Expression Datasets
Authors: Van Laere Steven J. , Ueno Naoto T. , Finetti Pascal , Vermeulen Peter , Lucci Anthony , Robertson Fredika M. , Marsan Melike , Iwamoto Takayuki , Krishnamurthy Savitri , Masuda Hiroko , van Dam Peter , Woodward Wendy A. , Viens Patrice , Cristofanilli Massimo , Birnbaum Daniel , Dirix Luc , Reuben James M. , Bertucci François
Published: February 2013

Background: Inflammatory breast cancer (IBC) is a poorly characterized form of breast cancer. So far, the results of expression profiling in IBC are inconclusive due to various reasons including limited sample size. Here, we present the integration of three Affymetrix expression datasets collected through the World IBC Consortium allowing us to interrogate the molecular profile of IBC using the largest series of IBC samples ever reported.

Experimental Design: Affymetrix profiles (HGU133-series) from 137 patients with IBC and 252 patients with non-IBC (nIBC) were analyzed using unsupervised and supervised techniques. Samples were classified according to the molecular subtypes using the PAM50-algorithm. Regression models were used to delineate IBC-specific and molecular subtype-independent changes in gene expression, pathway, and transcription factor activation.

Results: Four robust IBC-sample clusters were identified, associated with the different molecular subtypes (P < 0.001), all of which were identified in IBC with a similar prevalence as in nIBC, except for the luminal A subtype (19% vs. 42%; P < 0.001) and the HER2-enriched subtype (22% vs. 9%; P < 0.001). Supervised analysis identified and validated an IBC-specific, molecular subtype-independent 79-gene signature, which held independent prognostic value in a series of 871 nIBCs. Functional analysis revealed attenuated TGF-β signaling in IBC.

Conclusion: We show that IBC is transcriptionally heterogeneous and that all molecular subtypes described in nIBC are detectable in IBC, albeit with a different frequency. The molecular profile of IBC, bearing molecular traits of aggressive breast tumor biology, shows attenuation of TGF-β signaling, potentially explaining the metastatic potential of IBC tumor cells in an unexpected manner. Clin Cancer Res; 19(17); 4685–96. ©2013 AACR.
Inhibition of HSP90 with AUY922 Induces Synergy in HER2-Amplified Trastuzumab-Resistant Breast and Gastric Cancer
Authors: Wainberg Zev A. , Anghel Adrian , Rogers Amy M. , Desai Amrita J. , Kalous Ondrej , Conklin Dylan , Ayala Raul , O'Brien Neil A. , Quadt Cornelia , Akimov Mikhail , Slamon Dennis J. , Finn Richard S.
Published: February 2013

HSP90 enables the activation of many client proteins of which the most clinically validated is HER2. NVP-AUY922, a potent HSP90 inhibitor, is currently in phase II clinical trials. To explore its potential clinical use in HER2-amplified breast and gastric cancers, we evaluated the effect of AUY922 alone and in combination with trastuzumab in both trastuzumab-sensitive and -resistant models. A panel of 16 human gastric and 45 breast cancer cell lines, including 16 HER2-amplified (3 and 13, respectively) cells, was treated with AUY922 over various concentrations. In both breast and gastric cancer, we used cell lines and xenograft models with conditioned trastuzumab-resistance to investigate the efficacy of AUY922 alongside trastuzumab. Effects of this combination on downstream markers were analyzed via Western blot analysis. AUY922 exhibited potent antiproliferative activity in the low nanomolar range (<40 nmol/L) for 59 of 61 cell lines. In both histologies, HER2-amplified cells expressed greater sensitivity to AUY than HER2-negative cells. In conditioned trastuzumab-resistant models, AUY922 showed a synergistic effect with trastuzumab. In vitro, the combination induced greater decreases in HER2, a G2 cell-cycle arrest, and increased apoptosis. In a trastuzumab-resistant gastric cancer xenograft model, the combination of AUY922 and trastuzumab showed greater antitumor efficacy than either drug alone. These data suggest that AUY922 in combination with trastuzumab has unique efficacy in trastuzumab-resistant models. The combination of HSP90 inhibition and direct HER2 blockade represents a novel approach to the treatment of HER2-amplified cancers and clinical trials based on the above data are ongoing. Mol Cancer Ther; 12(4); 509–19. ©2013 AACR.
GX15-070 (Obatoclax) Induces Apoptosis and Inhibits Cathepsin D- and L–Mediated Autophagosomal Lysis in Antiestrogen-Resistant Breast Cancer Cells
Authors: Schwartz-Roberts Jessica L. , Shajahan Ayesha N. , Cook Katherine L. , Wärri Anni , Abu-Asab Mones , Clarke Robert
Published: February 2013

In estrogen receptor–positive (ER+) breast cancer cells, BCL2 overexpression contributes to antiestrogen resistance. Direct targeting of the antiapoptotic BCL2 members with GX15-070 (obatoclax), a BH3-mimetic currently in clinical development, is an attractive strategy to overcome antiestrogen resistance in some breast cancers. Recently, GX15-070 has been shown to induce both apoptosis and autophagy, yet the underlying cell death mechanisms have yet to be elucidated. Here, we show that GX15-070 is more effective in reducing the cell density of antiestrogen-resistant breast cancer cells versus sensitive cells and that this increased sensitivity of resistant cells to GX15-070 correlates with an accumulation of autophagic vacuoles. Formation of autophagosomes in GX15-070-treated cells was verified by changes in expression of the lipidation of microtubule-associated protein-1 light chain-3 and both confocal and transmission electron microscopy. While GX15-070 treatment promotes autophagic vacuole and autolysosome formation, p62/SQSTM1, a marker for autophagic degradation, levels accumulate. Moreover, GX15-070 exposure leads to a reduction in cathepsin D (CTSD) and L (CTSL1) protein expression that would otherwise digest autolysosome cargo. Thus, GX15-070 has dual roles in promoting cell death: (i) directly inhibiting antiapoptotic BCL2 family members, thereby inducing apoptosis; and (ii) inhibiting downstream CTSD and CTSL1 protein expression to limit the ability of cells to use degraded material to fuel cellular metabolism and restore homeostasis. Our data highlight a new mechanism of GX15-070-induced cell death that could be used to design novel therapeutic interventions for antiestrogen resistant breast cancer. Mol Cancer Ther; 12(4); 448–59. ©2013 AACR.
Bidirectional Regulation of Nuclear Factor-κB and Mammalian Target of Rapamycin Signaling Functionally Links Bnip3 Gene Repression and Cell Survival of Ventricular Myocytes
Authors: Dhingra Rimpy , Gang Hongying , Wang Yan , Biala Agnieszka K. , Aviv Yaron , Margulets Victoria , Tee Andrew , Kirshenbaum Lorrie A.
Published: February 2013

Background—

Tumor necrosis factor-α and other proinflammatory cytokines activate the canonical Nuclear Factor (NF)-κB pathway through the kinase IKKβ. Previously, we established that IKKβ is also critical for Akt-mediated NF-κB activation in ventricular myocytes. Akt activates the kinase mammalian target of rapamycin (mTOR), which mediates important processes such as cardiac hypertrophy. However, whether mTOR regulates cardiac myocyte cell survival is unknown.

Methods and Results—

Herein, we demonstrate bidirectional regulation between NF-κB signaling and mTOR, the balance which determines ventricular myocyte survival. Overexpression of IKKβ resulted in mTOR activation and conversely overexpression of mTOR lead to NF-κB activation. Loss of function approaches demonstrated that endogenous levels of IKKβ and mTOR also signal through this pathway. NF-κB activation by mTOR was mediated by phosphorylation of the NF-κB p65 subunit increasing p65 nuclear translocation and activation of gene transcription. This circuit was also important for NF-κB activation by the canonical tumor necrosis factor-α pathway. Our previous work has shown that NF-κB signaling suppresses transcription of the death gene Bnip3 resulting in ventricular myocyte survival. Inhibition of mTOR with rapamycin decreased NF-κB activation resulting in increased Bnip3 expression and cell death. Conversely, mTOR overexpression suppressed Bnip3 levels and cell death of ventricular myocytes in response to hypoxia.

Conclusions—

To our knowledge, these data provide the first evidence for a bidirectional link between NF-κB signaling and mTOR that is critical in the regulation of Bnip3 expression and cardiac myocyte death. Hence, modulation of this axis may be cardioprotective during ischemia.
Prognostic Value of Changes in Galectin-3 Levels Over Time in Patients With Heart Failure
Authors: van der Velde A. Rogier , Gullestad Lars , Ueland Thor , Aukrust Pål , Guo Yu , Adourian Aram , Muntendam Pieter , van Veldhuisen Dirk J. , de Boer Rudolf A.
Published: February 2013

Background—

In several cross-sectional analyses, circulating baseline levels of galectin-3, a protein involved in myocardial fibrosis and remodeling, have been associated with increased risk for morbidity and mortality in patients with heart failure (HF). The importance and clinical use of repeated measurements of galectin-3 have not yet been reported.

Methods and Results—

Plasma galectin-3 was measured at baseline and at 3 months in patients enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trial (n=1329), and at baseline and at 6 months in patients enrolled in the Coordinating Study Evaluating Outcomes of Advising and Counseling Failure (COACH) trial (n=324). Patient results were analyzed by categorical and percentage changes in galectin-3 level. A threshold value of 17.8 ng/mL or 15% change from baseline was used to categorize patients. Increasing galectin-3 levels over time, from a low to high galectin-3 category, were associated with significantly more HF hospitalization and mortality compared with stable or decreasing galectin-3 levels (hazard ratio in CORONA, 1.60; 95% confidence interval, 1.13–2.25;
P
=0.007; hazard ratio in COACH, 2.38; 95% confidence interval, 1.02–5.55;
P
=0.046). In addition, patients whose galectin-3 increased by >15% between measurements had a 50% higher relative hazard of adverse event than those whose galectin-3 stayed within ±15% of the baseline value, independent of age, sex, diabetes mellitus, left ventricular ejection fraction, renal function, medication (β-blocker, angiotensin converting enzyme inhibitor, and angiotensin receptor blocker), and N-terminal probrain natriuretic peptide (hazard ratio in CORONA, 1.50; 95% confidence interval, 1.17–1.92;
P
=0.001). The impact of changing galectin-3 levels on other secondary end points was comparable.

Conclusions—

In 2 large cohorts of patients with chronic and acute decompensated HF, repeated measurements of galectin-3 level provided important and significant prognostic value in identifying patients with HF at elevated risk for subsequent HF morbidity and mortality.