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1.  New Connections Between Old Pathways: PDK1 Signaling Promotes Cellular Transformation through PLK1-Dependent MYC Stabilization 
Cancer discovery  2013;3(10):10.1158/2159-8290.CD-13-0581.
Limited understanding of the functional link between multiple oncogenic pathways is a major barrier in the ongoing effort of cancer biology to design an effective therapeutic approach to treat malignancies characterized by driver oncogenic network signals. In this issue of Cancer Discovery, Tan and colleagues elucidate a novel PDK1-PLK1-MYC signaling pathway connecting two fundamental oncogenic programs, PI3K and MYC. They define the functional role for PDK1-PLK1-MYC signaling in cancer cell survival and tumor formation to demonstrate the therapeutic benefit of inhibiting PDK1 and PLK1 pharmacologically in cancer, tackling the most undruggable tumors defined by elevated levels of the MYC oncoprotein.
PMCID: PMC3857155  PMID: 24124229
2.  A Novel Method for Curvefitting the Stretched Exponential Function to Experimental Data 
Biomedical engineering research  2013;2(4):153-158.
The stretched exponential function has many applications in modeling numerous types of experimental relaxation data. However, problems arise when using standard algorithms to fit this function: we have observed that different initializations result in distinct fitted parameters. To avoid this problem, we developed a novel algorithm for fitting the stretched exponential model to relaxation data. This method is advantageous both because it requires only a single adjustable parameter and because it does not require initialization in the solution space. We tested this method on simulated data and experimental stress-relaxation data from bone and cartilage and found favorable results compared to a commonly-used Quasi-Newton method. For the simulated data, strong correlations were found between the simulated and fitted parameters suggesting that this method can accurately determine stretched exponential parameters. When this method was tested on experimental data, high quality fits were observed for both bone and cartilage stress-relaxation data that were significantly better than those determined with the Quasi-Newton algorithm.
PMCID: PMC3966632
Cartilage Biomechanics; Osteoarthritis; Curvefitting; Optimization; Polymer Dynamics
3.  Evaluating a Brief, Internet-Based Intervention for Co-Occurring Depression and Problematic Alcohol Use in Young People: Protocol for a Randomized Controlled Trial 
JMIR Research Protocols  2014;3(1):e6.
Depression and alcohol misuse represent two of the major causes of disease burden in young adults. These conditions frequently co-occur and this co-occurrence is associated with increased risks and poorer outcomes than either disorder in isolation. Integrated treatments have been shown to be effective, however, there remains a significant gap between those in need of treatment and those receiving it, particularly in young people. The increased availability of Internet-based programs to complement health care presents a unique opportunity in the treatment of these conditions.
The objective of our study was to evaluate whether a brief, Internet-based, self-help intervention (the DEAL [DEpression-ALcohol] Project) can be effective in treating co-occurring depression and problematic alcohol use in young people (18-25 years old).
The evaluation will take the form of a randomized controlled trial (RCT), comparing the DEAL Project with an attention-control condition (HealthWatch). The RCT will consist of a four-week intervention phase and a 24-week follow-up. It will be entirely Internet-based and open Australia-wide to young people 18 to 25 years old. The primary outcomes will be change in depression symptoms and alcohol use at 5, 12, and 24 weeks post baseline. Secondary outcomes include change in general functioning and quality of life, anxiety/stress symptomatology, and a number of other depression/alcohol related outcomes. Process analysis will also measure engagement across the conditions.
This study is currently ongoing with preliminary results expected in late 2014.
This study, to our knowledge, will be the first RCT of a Internet-based treatment for comorbid depression and problematic alcohol use in any age group. If successful, the program represents a novel and innovative approach to addressing the significant harms associated with these conditions and will be an invaluable resource to those not receiving help elsewhere.
Trial Registration
Australian New Zealand Clinical Trials Registry; ACTRN12613000033741; (Archived by WebCite at
PMCID: PMC3961749  PMID: 24583824
depression; alcohol; young people; Internet-based; comorbidity
4.  A Prospective Natural History Study of Quitting or Reducing Gambling With or Without Treatment: Protocol 
JMIR Research Protocols  2013;2(2):e51.
Only a small percentage of gamblers ever seek treatment, often due to stigma, embarrassment, or a desire to handle their problems on their own. While the majority of pathological gamblers who achieve remittance do so without accessing formal treatment, factors related to successful resolution have not been thoroughly explored.
Employing a prospective natural history design, the study will therefore undertake an investigation to explore life events, motivating factors, and strategies used by problem gamblers to quit or reduce their gambling without formal treatment.
Prospective participants (19 years or older) currently gambling at problematic levels with strong intentions toward quitting gambling will be directed to fill out a Web-based survey. Eligible participants will subsequently complete a survey that will assess: (1) types, frequency, and amount of money spent on gambling, (2) life events experienced in the past 12 months, (3) level of autonomous motivation for change, and (4) use of treatment services. Every 3 months for the duration of one year following the completion of their baseline survey, participants will be sent an email notification requesting them to complete a follow-up survey similar in content to the baseline survey. The four surveys will assess whether participants have experienced changes in their gambling behaviors along with positive or negative life events and motivations for change since the last survey. Individuals who are in the action and maintenance stages of quitting gambling at follow-up will be also asked about their techniques and strategies used to quit or reduce gambling. At 18 months post baseline, participants will be asked to complete a fifth and final follow-up survey that will also assess whether participants have experienced any barriers to change and whether they resolved their gambling to low risk levels.
The study has commenced in May 2013 and is currently in the recruitment stage. The study is scheduled to conclude in 2016.
As this study will examine the active ingredients in natural recovery from gambling problems, the results will inform ways of promoting change among the large number of problem gamblers who do not seek treatment as well as improve treatment for those who do seek help. The information gained will also be useful in identifying effective self-help strategies for those who face challenges in accessing treatment, may be incorporated in standard treatment, provide brief intervention techniques, as well as inform relapse prevention strategies.
PMCID: PMC3868981  PMID: 24297873
gambling; treatment; life events; motivational factors; natural recovery; prospective natural history study; longitudinal study
5.  Disruption of Growth Factor Receptor–Binding Protein 10 in the Pancreas Enhances β-Cell Proliferation and Protects Mice From Streptozotocin-Induced β-Cell Apoptosis 
Diabetes  2012;61(12):3189-3198.
Defects in insulin secretion and reduction in β-cell mass are associated with type 2 diabetes in humans, and understanding the basis for these dysfunctions may reveal strategies for diabetes therapy. In this study, we show that pancreas-specific knockout of growth factor receptor–binding protein 10 (Grb10), which is highly expressed in pancreas and islets, leads to elevated insulin/IGF-1 signaling in islets, enhanced β-cell mass and insulin content, and increased insulin secretion in mice. Pancreas-specific disruption of Grb10 expression also improved glucose tolerance in mice fed with a high-fat diet and protected mice from streptozotocin-induced β-cell apoptosis and body weight loss. Our study has identified Grb10 as an important regulator of β-cell proliferation and demonstrated that reducing the expression level of Grb10 could provide a novel means to increase β-cell mass and reduce β-cell apoptosis. This is critical for effective therapeutic treatment of both type 1 and 2 diabetes.
PMCID: PMC3501856  PMID: 22923474
6.  Effect of remote ischaemic conditioning on contrast-induced nephropathy in patients undergoing elective coronary angiography (ERICCIN): rationale and study design of a randomised single-centre, double-blind placebo-controlled trial 
Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is an important cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for an effective intervention. Remote ischaemic conditioning (RIC), where non-injurious ischaemia is applied to an arm prior to the administration of contrast, has shown promise in attenuating CIN but its effectiveness in preserving long-term renal function is unknown, which will be studied as part of the effect of remote ischaemic conditioning against contrast-induced nephropathy (ERICCIN) trial. ( Identifier: ISRCTN49645414.)
The ERICCIN trial is a single-centre, randomised double-blinded placebo-controlled trial which plans to recruit 362 patients who are at risk of CIN, defined by pre-existent renal impairment (estimated glomerular filtration rate <60 ml/min/1.73 m2), over a period of 2 years. Patients will be randomised to either control or RIC consisting of 4, 5 min 200 mmHg balloon-cuff inflation/deflations, to the upper arm. The primary endpoint will be the development of CIN (>25 % of eGFR, or rise of creatinine of >44 μmol/l) at 48 h. A key secondary endpoint will be whether RIC impacts upon persistent renal impairment over the 3-month follow-up period. Additional secondary endpoints include the measurement of serum neutrophil gelatinase-associated lipocalin and urinary albumin at 6, 48 h and 3 months following administration of contrast.
Findings from ERICCIN trial will potentially demonstrate that RIC attenuates contrast-induced acute and chronic kidney injury and influence future clinical practice guidelines in at-risk patients undergoing coronary angiographic procedures.
PMCID: PMC3937541  PMID: 24292557
Remote ischaemic conditioning; Preconditioning; Contrast-induced nephropathy; Acute kidney injury; Clinical trial; Coronary angiography; Percutaneous intervention
7.  Testing models of dental development in the earliest bony vertebrates, Andreolepis and Lophosteus 
Biology Letters  2012;8(5):833-837.
Theories on the development and evolution of teeth have long been biased by the fallacy that chondrichthyans reflect the ancestral condition for jawed vertebrates. However, correctly resolving the nature of the primitive vertebrate dentition is challenged by a dearth of evidence on dental development in primitive osteichthyans. Jaw elements from the Silurian–Devonian stem-osteichthyans Lophosteus and Andreolepis have been described to bear a dentition arranged in longitudinal rows and vertical files, reminiscent of a pattern of successional development. We tested this inference, using synchrotron radiation X-ray tomographic microscopy (SRXTM) to reveal the pattern of skeletal development preserved in the sclerochronology of the mineralized tissues. The tooth-like tubercles represent focal elaborations of dentine within otherwise continuous sheets of the dermal skeleton, present in at least three stacked generations. Thus, the tubercles are not discrete modular teeth and their arrangement into rows and files is a feature of the dermal ornamentation that does not reflect a polarity of development or linear succession. These fossil remains have no bearing on the nature of the dentition in osteichthyans and, indeed, our results raise questions concerning the homologies of these bones and the phylogenetic classification of Andreolepis and Lophosteus.
PMCID: PMC3440983  PMID: 22628098
Osteichthyes; Andreolepis; Lophosteus; tooth; development; evolution
8.  Claiming Positive Results From Negative Trials: A Cause for Concern in Randomized Controlled Trial Research 
PMCID: PMC3758039  PMID: 23958686
research methods; randomised controlled trials; alcohol; Internet; brief intervention
9.  The Effectiveness of a Web-Based Personalized Feedback and Social Norms Alcohol Intervention on United Kingdom University Students: Randomized Controlled Trial 
Alcohol consumption in the student population continues to be cause for concern. Building on the established evidence base for traditional brief interventions, interventions using the Internet as a mode of delivery are being developed. Published evidence of replication of initial findings and ongoing development and modification of Web-based personalized feedback interventions for student alcohol use is relatively rare. The current paper reports on the replication of the initial Unitcheck feasibility trial.
To evaluate the effectiveness of Unitcheck, a Web-based intervention that provides instant personalized feedback on alcohol consumption. It was hypothesized that use of Unitcheck would be associated with a reduction in alcohol consumption.
A randomized control trial with two arms (control=assessment only; intervention=fully automated personalized feedback delivered using a Web-based intervention). The intervention was available week 1 through to week 15. Students at a UK university who were completing a university-wide annual student union electronic survey were invited to participate in the current study. Participants (n=1618) were stratified by sex, age group, year of study, self-reported alcohol consumption, then randomly assigned to one of the two arms, and invited to participate in the current trial. Participants were not blind to allocation. In total, n=1478 (n=723 intervention, n=755 control) participants accepted the invitation. Of these, 70% were female, the age ranged from 17-50 years old, and 88% were white/white British. Data were collected electronically via two websites: one for each treatment arm. Participants completed assessments at weeks 1, 16, and 34. Assessment included CAGE, a 7-day retrospective drinking diary, and drinks consumed per drinking occasion.
The regression model predicted a monitoring effect, with participants who completed assessments reducing alcohol consumption over the final week. Further reductions were predicted for those allocated to receive the intervention, and additional reductions were predicted as the number of visits to the intervention website increased.
Unitcheck can reduce the amount of alcohol consumed, and the reduction can be sustained in the medium term (ie, 19 weeks after intervention was withdrawn). The findings suggest self-monitoring is an active ingredient to Web-based personalized feedback.
PMCID: PMC3742391  PMID: 23883616
personalized feedback; Web-based intervention; student alcohol consumption
10.  Use of mobile devices to answer online surveys: implications for research 
BMC Research Notes  2013;6:258.
There is a growing use of mobile devices to access the Internet. We examined whether participants who used a mobile device to access a brief online survey were quicker to respond to the survey but also, less likely to complete it than participants using a traditional web browser.
Using data from a recently completed online intervention trial, we found that participants using mobile devices were quicker to access the survey but less likely to complete it compared to participants using a traditional web browser. More concerning, mobile device users were also less likely to respond to a request to complete a six week follow-up survey compared to those using traditional web browsers.
With roughly a third of participants using mobile devices to answer an online survey in this study, the impact of mobile device usage on survey completion rates is a concern.
Trial registration NCT01521078
PMCID: PMC3708744  PMID: 23834999
Internet; Brief intervention; Alcohol; College; University; Mobile device
11.  The Systematic Removal of Participants Post-Randomization Can Lead to Alternate Explanations of the Results 
PMCID: PMC3713941  PMID: 23796473
research methods; randomized controlled trial; confound; alternate explanation
12.  Distinguishing geology from biology in the Ediacaran Doushantuo biota relaxes constraints on the timing of the origin of bilaterians 
The Ediacaran Doushantuo biota has yielded fossils that include the oldest widely accepted record of the animal evolutionary lineage, as well as specimens with alleged bilaterian affinity. However, these systematic interpretations are contingent on the presence of key biological structures that have been reinterpreted by some workers as artefacts of diagenetic mineralization. On the basis of chemistry and crystallographic fabric, we characterize and discriminate phases of mineralization that reflect: (i) replication of original biological structure, and (ii) void-filling diagenetic mineralization. The results indicate that all fossils from the Doushantuo assemblage preserve a complex mélange of mineral phases, even where subcellular anatomy appears to be preserved. The findings allow these phases to be distinguished in more controversial fossils, facilitating a critical re-evaluation of the Doushantuo fossil assemblage and its implications as an archive of Ediacaran animal diversity. We find that putative subcellular structures exhibit fabrics consistent with preservation of original morphology. Cells in later developmental stages are not in original configuration and are therefore uninformative concerning gastrulation. Key structures used to identify Doushantuo bilaterians can be dismissed as late diagenetic artefacts. Therefore, when diagenetic mineralization is considered, there is no convincing evidence for bilaterians in the Doushantuo assemblage.
PMCID: PMC3350665  PMID: 22319125
Ediacaran; Doushantuo; Bilateria; fossilization; diagenesis
13.  A High-Performance Neural Prosthesis Enabled by Control Algorithm Design 
Nature neuroscience  2012;15(12):1752-1757.
Neural prostheses translate neural activity from the brain into control signals for guiding prosthetic devices, such as computer cursors and robotic limbs, and thus offer disabled patients greater interaction with the world. However, relatively low performance remains a critical barrier to successful clinical translation; current neural prostheses are considerably slower with less accurate control than the native arm. Here we present a new control algorithm, the recalibrated feedback intention-trained Kalman filter (ReFIT-KF), that incorporates assumptions about the nature of closed loop neural prosthetic control. When tested with rhesus monkeys implanted with motor cortical electrode arrays, the ReFIT-KF algorithm outperforms existing neural prostheses in all measured domains and halves acquisition time. This control algorithm permits sustained uninterrupted use for hours and generalizes to more challenging tasks without retraining. Using this algorithm, we demonstrate repeatable high performance for years after implantation across two monkeys, thereby increasing the clinical viability of neural prostheses.
PMCID: PMC3638087  PMID: 23160043
14.  p19Arf Represses Platelet-Derived Growth Factor Receptor β by Transcriptional and Posttranscriptional Mechanisms 
Molecular and Cellular Biology  2012;32(21):4270-4282.
In addition to cancer surveillance, p19Arf plays an essential role in blocking signals stemming from platelet-derived growth factor receptor β (Pdgfrβ) during eye development, but the underlying mechanisms have not been clear. We now show that without Arf, pericyte hyperplasia in the eye results from enhanced Pdgfrβ-dependent proliferation from embryonic day 13.5 (E13.5) of mouse development. Loss of Arf in the eye increases Pdgfrβ expression. In cultured fibroblasts and pericyte-like cells, ectopic p19Arf represses and Arf knockdown enhances the expression of Pdgfrβ mRNA and protein. Ectopic Arf also represses primary Pdgfrβ transcripts and a plasmid driven by a minimal promoter, including one missing the CCAAT element required for high-level expression. p19Arf uses both p53-dependent and -independent mechanisms to control Pdgfrβ. In vivo, without p53, Pdgfrβ mRNA is elevated and eye development abnormalities resemble the Arf −/− phenotype. However, effects of p53 on Pdgfrβ mRNA do not appear to be due to direct p53 or RNA polymerase II recruitment to the promoter. Although p19Arf controls Pdgfrβ mRNA in a p53-dependent manner, it also blunts Pdgfrβ protein expression by blocking new protein synthesis in the absence of p53. Thus, our findings demonstrate a novel capacity for p19Arf to control Pdgfrβ expression by p53-dependent and -independent mechanisms involving RNA transcription and protein synthesis, respectively, to promote the vascular remodeling needed for normal vision.
PMCID: PMC3486135  PMID: 22907756
15.  Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling 
Cell Metabolism  2012;15(4):505-517.
Rapamycin and derivatives are mTOR inhibitors used in tissue transplantation and cancer therapy. A percentage of patients treated with these inhibitors develop diabetic-like symptoms but the molecular mechanisms are unknown. We show here that chronic rapamycin treatment in mice leads to insulin resistance with suppression of insulin/IGF signaling and genes associated within this pathway, such as IGFs, IRS1/2 and AKTs. Importantly, skeletal muscle-specific YY1 knockout mice were protected from rapamycin-induced diabetic-like symptoms. This protection was caused by hyperactivation of insulin/IGF signaling with increases in genes in this cascade that, in contrast to wild-type mice, were not suppressed by rapamycin. Mechanistically, rapamycin induced YY1 dephosphorylation and recruitment to promoters of insulin/IGF genes, which promoted interaction with the polycomb protein-2 corepressor. This was associated with H3K27 tri-methylation leading to decreases in gene expression and insulin signaling. These results have implications for rapamycin action in human diseases and biological processes, such as longevity.
PMCID: PMC3324784  PMID: 22482732
16.  Bridging Cancer Biology with the Clinic: Relative Expression of a GRHL2-Mediated Gene-Set Pair Predicts Breast Cancer Metastasis 
PLoS ONE  2013;8(2):e56195.
Identification and characterization of crucial gene target(s) that will allow focused therapeutics development remains a challenge. We have interrogated the putative therapeutic targets associated with the transcription factor Grainy head-like 2 (GRHL2), a critical epithelial regulatory factor. We demonstrate the possibility to define the molecular functions of critical genes in terms of their personalized expression profiles, allowing appropriate functional conclusions to be derived. A novel methodology, relative expression analysis with gene-set pairs (RXA-GSP), is designed to explore the potential clinical utility of cancer-biology discovery. Observing that Grhl2-overexpression leads to increased metastatic potential in vitro, we established a model assuming Grhl2-induced or -inhibited genes confer poor or favorable prognosis respectively for cancer metastasis. Training on public gene expression profiles of 995 breast cancer patients, this method prioritized one gene-set pair (GRHL2, CDH2, FN1, CITED2, MKI67 versus CTNNB1 and CTNNA3) from all 2717 possible gene-set pairs (GSPs). The identified GSP significantly dichotomized 295 independent patients for metastasis-free survival (log-rank tested p = 0.002; severe empirical p = 0.035). It also showed evidence of clinical prognostication in another independent 388 patients collected from three studies (log-rank tested p = 3.3e–6). This GSP is independent of most traditional prognostic indicators, and is only significantly associated with the histological grade of breast cancer (p = 0.0017), a GRHL2-associated clinical character (p = 6.8e–6, Spearman correlation), suggesting that this GSP is reflective of GRHL2-mediated events. Furthermore, a literature review indicates the therapeutic potential of the identified genes. This research demonstrates a novel strategy to integrate both biological experiments and clinical gene expression profiles for extracting and elucidating the genomic impact of a novel factor, GRHL2, and its associated gene-sets on the breast cancer prognosis. Importantly, the RXA-GSP method helps to individualize breast cancer treatment. It also has the potential to contribute considerably to basic biological investigation, clinical tools, and potential therapeutic targets.
PMCID: PMC3575392  PMID: 23441166
17.  Defective Mitochondrial Morphology and Bioenergetic Function in Mice Lacking the Transcription Factor Yin Yang 1 in Skeletal Muscle 
Molecular and Cellular Biology  2012;32(16):3333-3346.
The formation, distribution, and maintenance of functional mitochondria are achieved through dynamic processes that depend strictly on the transcription of nuclear genes encoding mitochondrial proteins. A large number of these mitochondrial genes contain binding sites for the transcription factor Yin Yang 1 (YY1) in their proximal promoters, but the physiological relevance is unknown. We report here that skeletal-muscle-specific YY1 knockout (YY1mKO) mice have severely defective mitochondrial morphology and oxidative function associated with exercise intolerance, signs of mitochondrial myopathy, and short stature. Gene set enrichment analysis (GSEA) revealed that the top pathways downregulated in YY1mKO mice were assigned to key metabolic and regulatory mitochondrial genes. This analysis was consistent with a profound decrease in the level of mitochondrial proteins and oxidative phosphorylation (OXPHOS) bioenergetic function in these mice. In contrast to the finding for wild-type mice, inactivation of the mammalian target of rapamycin (mTOR) did not suppress mitochondrial genes in YY1mKO mice. Mechanistically, mTOR-dependent phosphorylation of YY1 resulted in a strong interaction between YY1 and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), a major regulator of mitochondrial function. These results underscore the important role of YY1 in the maintenance of mitochondrial function and explain how its inactivation might contribute to exercise intolerance and mitochondrial myopathies.
PMCID: PMC3434543  PMID: 22711985
18.  Internet-based interventions for disordered gamblers: study protocol for a randomized controlled trial of online self-directed cognitive-behavioural motivational therapy 
BMC Public Health  2013;13:10.
Gambling disorders affect about one percent of adults. Effective treatments are available but only a small proportion of affected individuals will choose to attend formal treatment. As a result, self-directed treatments have also been developed and found effective. Self-directed treatments provide individuals with information and support to initiate a recovery program without attending formal treatment. In previous research we developed an telephone-based intervention package that helps people to be motivated to tackle their gambling problem and to use basic behavioral and cognitive change strategies. The present study will investigate the efficacy of this self-directed intervention offered as a free online resource. The Internet is an excellent modality in which to offer self-directed treatment for gambling problems. The Internet is increasingly accessible to members of the public and is frequently used to access health-related information. Online gambling sites are also becoming more popular gambling platforms.
A randomized clinical trial (N=180) will be conducted in which individuals with gambling problems who are not interested in attending formal treatment are randomly assigned to have access to an online self-directed intervention or to a comparison condition. The comparison condition will be an alternative website that offers a self-assessment of gambling involvement and gambling-related problems. The participant’s use of the resources and their gambling involvement (days of gambling, dollars loss) and their gambling problems will be tracked for a twelve month follow-up period.
The results of this research will be important for informing policy-makers who are developing treatment systems.
Trial registration
PMCID: PMC3545736  PMID: 23294668
Clinical trial; Brief intervention; Gambling disorders; Online intervention; Trial protocol
20.  ER stress–mediated autophagy promotes Myc-dependent transformation and tumor growth 
The Journal of Clinical Investigation  2012;122(12):4621-4634.
The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc–induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/–) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc–induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.
PMCID: PMC3533536  PMID: 23143306
21.  Ultra-Brief Intervention for Problem Drinkers: Results from a Randomized Controlled Trial 
PLoS ONE  2012;7(10):e48003.
There are a number of evidence-based, in-person clinical inteventions for problem drinkers, but most problem drinkers will never seek such treatments. Reaching the population of non-treatment seeking problem drinkers will require a different approach. Accordingly, this randomized clinical trial evaluated an intervention that has been validated in clinical settings and then modified into an ultra-brief format suitable for use as an indicated public health intervention (i.e., targeting the population of non-treatment seeking problem drinkers).
Methodology/Principal Findings
Problem drinkers (N = 1767) completed a baseline population telephone survey and then were randomized to one of three conditions – a personalized feedback pamphlet condition, a control pamphlet condition, or a no intervention control condition. In the week after the baseline survey, households in the two pamphlet conditions were sent their respective interventions by postal mail addressed to ‘Check Your Drinking.’ Changes in drinking were assessed post intervention at three-month and six-month follow-ups. The follow-up rate was 86% at three-months and 76% at six-months. There was a small effect (p = .04) in one of three outcome variables (reduction in AUDIT-C, a composite measure of quantity and frequency of drinking) observed for the personalized feedback pamphlet compared to the no intervention control. No significant differences (p>.05) between groups were observed for the other two outcome variables – number of drinks consumed in the past seven days and highest number of drinks on one occasion.
Based on the results of this study, we tentatively conclude that a brief intervention, modified to an ultra-brief, public health format can have a meaningful impact.
Trial Registration NCT00688584.
PMCID: PMC3480504  PMID: 23110157
22.  Regulation of Delta-Aminolevulinic Acid Dehydratase by Krüppel-Like Factor 1 
PLoS ONE  2012;7(10):e46482.
Krüppel-like factor 1(KLF1) is a hematopoietic-specific zinc finger transcription factor essential for erythroid gene expression. In concert with the transacting factor GATA1, KLF1 modulates the coordinate expression of the genes encoding the multi-enzyme heme biosynthetic pathway during erythroid differentiation. To explore the mechanisms underpinning KLF1 action at the gene loci regulating the first 3 steps in this process, we have exploited the K1-ERp erythroid cell line, in which KLF1 translocates rapidly to the nucleus in response to treatment with 4-OH-Tamoxifen (4-OHT). KLF1 acts as a differentiation-independent transcriptional co-regulator of delta-aminolevulinic acid dehydratase (Alad), but not 5-aminolevulinate synthase gene (Alas2) or porphobilinogen deaminase (Pbgd). Similar to its role at the β-globin promoter, KLF1 induces factor recruitment and chromatin changes at the Alad1b promoter in a temporally-specific manner. In contrast to these changes, we observed a distinct mechanism of histone eviction at the Alad1b promoter. Furthermore, KLF1-dependent events were not modulated by GATA1 factor promoter co-occupancy alone. These results not only enhance our understanding of erythroid-specific modulation of heme biosynthetic regulation by KLF1, but provide a model that will facilitate the elucidation of novel KLF1-dependent events at erythroid gene loci that are independent of GATA1 activity.
PMCID: PMC3463598  PMID: 23056320
23.  Who uses online interventions for problem drinkers? 
The goal of this research was to understand why some people use online interventions for drinking problems while others with comparable access to the interventions do not. As part of a randomized controlled trial, 92 participants in the experimental condition were provided access to a password protected version of a web-based personalized feedback intervention (the Check Your Drinking screener; CYD; Information collected at baseline was compared between those who accessed the website and those who did not. Those who accessed the website tended to be more frequent users of the Internet, to drink less, and to perceive that others of the same age and sex drank less as compared to those who did not access the intervention. Some of these results are troubling as the preferred target of this type of intervention would be those who drink more and perceive that others are also heavy alcohol consumers.
PMCID: PMC3166539  PMID: 21632197
Alcohol; Internet; brief intervention; adherence
24.  Comparison of Two Internet-Based Interventions for Problem Drinkers: Randomized Controlled Trial 
Alcohol problems are a serious public health concern, and few problem drinkers ever seek treatment. The Internet is one means of promoting access to care, but more research is needed to test the best types of interventions to employ. Evaluation of Internet-based interventions that contain a variety of research-validated cognitive-behavioral tools, which have been shown to be helpful to those with more severe alcohol concerns, should be a priority.
To evaluate whether providing access to an extended Internet intervention for alcohol problems offers additional benefits in promoting reductions in alcohol consumption compared with a brief Internet intervention. The hypothesis for the current trial was that respondents who were provided with access to an extended Internet intervention (the Alcohol Help Center [AHC]) would display significantly improved drinking outcomes at 6-month follow-up, compared with respondents who were provided with access to a brief Internet intervention (the Check Your Drinking [CYD] screener).
A single-blinded randomized controlled trial with a 6-month follow-up. A general population sample of problem drinkers was recruited through newspaper advertisements in a large metropolitan city. Baseline and follow-up data were collected by postal mail.
A volunteer sample of problem drinkers of legal drinking age with home access to the Internet were recruited for the trial. Of 239 potential respondents recruited in 2010, 170 met inclusion criteria (average age 45 years; 101/170, 59.4% male; average Alcohol Use Disorders Identification Test [AUDIT] score of 22). Follow-up rates were 90.0% (153/170) with no adverse effects of the interventions reported. A repeated-measures multivariate analysis of variance of the outcome measures using an intent-to-treat approach found a significantly greater reduction in amount of drinking among participants provided access to the AHC than among participants provided access to the CYD (P = .046).
The provision of the AHC gave additional benefit in the short term to problem drinkers over that seen from the research-validated CYD, indicating the benefits of promoting access to these interventions as one means of helping people with problem drinking concerns.
Trial Registration NCT01114919; (Archived by WebCite at
PMCID: PMC3799611  PMID: 22954459
Randomized controlled trial; problem drinking; alcohol abuse; Internet-based intervention; eHealth; brief intervention
25.  Internet-Based Brief Personalized Feedback Intervention in a Non-Treatment-Seeking Population of Adult Heavy Drinkers: A Randomized Controlled Trial 
Internet-based interventions for heavy drinkers show promising results, but existing research is characterized by few studies in nonstudent adult populations and few comparisons with appropriate control groups.
To test whether a fully automated Internet-based brief personalized feedback intervention and a fully automated Internet-based personalized brief advice intervention in a non-treatment-seeking population of heavy drinkers would result in a reduced alcohol intake.
We conducted a 3-arm parallel randomized controlled trial in a general population-based sample of heavy drinkers. The 54,157 participants (median age of 58 years) were screened for heavy drinking. Of the 3418 participants who had a weekly alcohol consumption above 14 drinks for women and 21 drinks for men, 1380 (619 women) consented to take part in the trial and were randomly assigned to an Internet-based brief personalized feedback intervention group (normative feedback, n = 476), an Internet-based personalized brief advice intervention group (n = 450), or a nonintervention control group (n = 454). Follow-up after 6 and 12 months included 871 and 1064 participants, respectively, of all groups combined. The outcome measure was self-reported weekly alcohol consumption. We analyzed the data according to the intention-to-treat principle. To examine changes over time and to account for the multiple time measurements, we used a multilevel linear mixed model. To take attrition into account, we used multiple imputation to address missing data.
The intervention effect of the Internet-based brief personalized feedback intervention, determined as the mean additional difference in changes in alcohol consumption in the Internet-based brief personalized feedback intervention compared with the control group, was –1.8 drinks/week after 6 months and –1.4 drinks/week after 12 months; these effects were nonsignificant (95% confidence interval –4.0 to 0.3 at 6 months, –3.4 to 0.6 at 12 months). The intervention effect of the Internet-based personalized brief advice intervention was –0.5 drinks/week after 6 months and –1.2 drinks/week after 12 months; these effects were nonsignificant (95% confidence interval –2.7 to 1.6 at 6 months, –3.3 to 0.9 at 12 months).
In this randomized controlled trial we found no evidence that an Internet-based brief personalized feedback intervention was effective in reducing drinking in an adult population of heavy drinkers.
Trial registration NCT00751985; (Archived by WebCite at
PMCID: PMC3409578  PMID: 22846542
Internet-based personalized feedback; normative feedback; alcohol; heavy drinking; adult; Internet-based personalized brief advice, brief intervention

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