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26.  Ecohydrodynamics of Cold-Water Coral Reefs: A Case Study of the Mingulay Reef Complex (Western Scotland) 
PLoS ONE  2014;9(5):e98218.
Ecohydrodynamics investigates the hydrodynamic constraints on ecosystems across different temporal and spatial scales. Ecohydrodynamics play a pivotal role in the structure and functioning of marine ecosystems, however the lack of integrated complex flow models for deep-water ecosystems beyond the coastal zone prevents further synthesis in these settings. We present a hydrodynamic model for one of Earth's most biologically diverse deep-water ecosystems, cold-water coral reefs. The Mingulay Reef Complex (western Scotland) is an inshore seascape of cold-water coral reefs formed by the scleractinian coral Lophelia pertusa. We applied single-image edge detection and composite front maps using satellite remote sensing, to detect oceanographic fronts and peaks of chlorophyll a values that likely affect food supply to corals and other suspension-feeding fauna. We also present a high resolution 3D ocean model to incorporate salient aspects of the regional and local oceanography. Model validation using in situ current speed, direction and sea elevation data confirmed the model's realistic representation of spatial and temporal aspects of circulation at the reef complex including a tidally driven current regime, eddies, and downwelling phenomena. This novel combination of 3D hydrodynamic modelling and remote sensing in deep-water ecosystems improves our understanding of the temporal and spatial scales of ecological processes occurring in marine systems. The modelled information has been integrated into a 3D GIS, providing a user interface for visualization and interrogation of results that allows wider ecological application of the model and that can provide valuable input for marine biodiversity and conservation applications.
doi:10.1371/journal.pone.0098218
PMCID: PMC4038632  PMID: 24873971
27.  Mapping calcium phosphate activated gene networks as a strategy for targeted osteoinduction of human progenitors in vitro and in vivo 
Biomaterials  2013;34(19):4612-4621.
Although calcium phosphate-containing biomaterials are promising scaffolds for bone regenerative strategies, the osteoinductive capacity of such materials is poorly understood. In this study, we investigated whether endogenous mechanisms of in vivo calcium phosphate-driven, ectopic bone formation could be identified and used to induce enhanced differentiation in vitro of the same progenitor population. To accomplish this, human periosteum derived cells (hPDCs) were seeded on hydroxyapatite/collagen scaffolds (calcium phosphate rich matrix or CPRM), or on decalcified scaffolds (calcium phosphate depleted matrix or CPDM), followed by subcutaneous implantation in nude mice to trigger ectopic bone formation. In this system, osteoblast differentiation occurred in CPRM scaffolds, but not in CPDM scaffolds. Gene expression was assessed by human full-genome microarray at 20 hours after seeding, and 2, 8 and 18 days after implantation. In both matrices, implantation of the cell constructs triggered a similar gene expression cascade, however, gene expression dynamics progressed faster in CPRM scaffolds than in CPDM scaffolds. The difference in gene expression dynamics was associated with differential activation of hub genes and molecular signaling pathways related to calcium signaling (CREB), inflammation (TNFα, NFkB, and IL6) and bone development (TGFβ, β-catenin, BMP, EGF, and ERK signaling). Starting from this set of pathways, a growth factor cocktail was developed that robustly enhanced osteogenesis in vitro and in vivo. Taken together, our data demonstrate that through the identification and subsequent stimulation of genes, proteins and signaling pathways associated with calcium phosphate mediated osteoinduction, a focused approach to develop targeted differentiation protocols in adult progenitor cells can be achieved.
doi:10.1016/j.biomaterials.2013.03.011
PMCID: PMC4037407  PMID: 23537666
Calcium phosphate; bone tissue engineering; gene expression; osteogenesis; progenitor cell
28.  Strong Phylogeographic Structure in a Millipede Indicates Pleistocene Vicariance between Populations on Banded Iron Formations in Semi-Arid Australia 
PLoS ONE  2014;9(3):e93038.
The Yilgarn Banded Iron Formations of Western Australia are topographical features that behave as terrestrial islands within the otherwise flat, semi-arid landscape. The formations are characterised by a high number of endemic species, some of which are distributed across multiple formations without inhabiting the intervening landscape. These species provide an ideal context for phylogeographic analysis, to investigate patterns of genetic variation at both spatial and temporal scales. We examined genetic variation in the spirostreptid millipede, Atelomastix bamfordi, found on five of these Banded Iron Formations at two mitochondrial loci and 11 microsatellite loci. Strong phylogeographic structuring indicated the five populations became isolated during the Pleistocene, a period of intensifying aridity in this landscape, when it appears populations have been restricted to pockets of moist habitat provided by the formations. The pattern of reciprocal monophyly identified within the mtDNA and strong differentiation within the nuclear microsatellite data highlight the evolutionary significance of these divergent populations and we suggest the degree of differentiation warrants designation of each as a conservation unit.
doi:10.1371/journal.pone.0093038
PMCID: PMC3963978  PMID: 24663390
29.  The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine 
Trials  2014;15:85.
Background
Whole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care.
Methods/Design
This pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients’ genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes, behaviors and outcomes of physician and patient participants at multiple time points before and after the disclosure of these results.
Discussion
The impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine will evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies.
Trial registration
ClinicalTrials.gov identifier NCT01736566
doi:10.1186/1745-6215-15-85
PMCID: PMC4113228  PMID: 24645908
Whole genome sequencing; Genome report; Genomic medicine; Translational genomics; Primary care; Cardiomyopathy genetics
30.  Counting whales in a challenging, changing environment 
Scientific Reports  2014;4:4170.
Estimating abundance of Antarctic minke whales is central to the International Whaling Commission's conservation and management work and understanding impacts of climate change on polar marine ecosystems. Detecting abundance trends is problematic, in part because minke whales are frequently sighted within Antarctic sea ice where navigational safety concerns prevent ships from surveying. Using icebreaker-supported helicopters, we conducted aerial surveys across a gradient of ice conditions to estimate minke whale density in the Weddell Sea. The surveys revealed substantial numbers of whales inside the sea ice. The Antarctic summer sea ice is undergoing rapid regional change in annual extent, distribution, and length of ice-covered season. These trends, along with substantial interannual variability in ice conditions, affect the proportion of whales available to be counted by traditional shipboard surveys. The strong association between whales and the dynamic, changing sea ice requires reexamination of the power to detect trends in whale abundance or predict ecosystem responses to climate change.
doi:10.1038/srep04170
PMCID: PMC3952195  PMID: 24622821
31.  Fine-scale nutrient and carbonate system dynamics around cold-water coral reefs in the northeast Atlantic 
Scientific Reports  2014;4:3671.
Ocean acidification has been suggested as a serious threat to the future existence of cold-water corals (CWC). However, there are few fine-scale temporal and spatial datasets of carbonate and nutrients conditions available for these reefs, which can provide a baseline definition of extant conditions. Here we provide observational data from four different sites in the northeast Atlantic that are known habitats for CWC. These habitats differ by depth and by the nature of the coral habitat. At depths where CWC are known to occur across these sites the dissolved inorganic carbon ranged from 2088 to 2186 μmol kg−1, alkalinity ranged from 2299 to 2346 μmol kg−1, and aragonite Ω ranged from 1.35 to 2.44. At two sites fine-scale hydrodynamics caused increased variability in the carbonate and nutrient conditions over daily time-scales. The observed high level of variability must be taken into account when assessing CWC sensitivities to future environmental change.
doi:10.1038/srep03671
PMCID: PMC3895924  PMID: 24441283
32.  Disclosing Individual CDKN2A Research Results to Melanoma Survivors: Interest, Impact, and Demands on Researchers 
Background
Whether to return individual research results from cancer genetics studies is widely debated, but little is known about how participants respond to results disclosure or about its time and cost burdens on investigators.
Methods
We recontacted participants at one site of a multicenter genetic epidemiologic study regarding their CDKN2A gene test results and implications for melanoma risk. Interested participants were disclosed their results by telephone and followed for 3 months.
Results
Among 39 patients approached, 27 were successfully contacted, and 19 (70% uptake) sought results, including three with mutations. Prior to disclosure, participants endorsed numerous benefits of receiving results (mean = 7.7 of 9 posed), including gaining information relevant to their children’s disease risk. Mean psychological well-being scores did not change from baseline, and no decreases to melanoma prevention behaviors were noted. Fifty-nine percent of participants reported that disclosure made participation in future research more likely. Preparation for disclosure required 40 minutes and $611 per recontact attempt. An additional 78 minutes and $68 was needed to disclose results.
Conclusion
Cancer epidemiology research participants who received their individual genetic research results showed no evidence of psychological harm or false reassurance from disclosure and expressed strong trust in the accuracy of results. Burdens to our investigators were high, but protocols may differ in their demands and disclosure may increase participants’ willingness to enroll in future studies.
Impact
Providing individual study results to cancer genetics research participants poses potential challenges for investigators, but many participants desire and respond positively to this information.
doi:10.1158/1055-9965.EPI-10-1045
PMCID: PMC3833711  PMID: 21307304
33.  Direct-to-consumer genetic testing: an assessment of genetic counselors' knowledge and beliefs 
Purpose
Direct-to-consumer genetic testing is a new means of obtaining genetic testing outside of a traditional clinical setting. This study assesses genetic counselors’ experience, knowledge, and beliefs regarding direct-to-consumer genetic testing for tests that would currently be offered in genetics clinics.
Methods
Members of the National Society of Genetic Counselors completed a web-administered survey in February 2008.
Results
Response rate was 36%; the final data analysis included 312 respondents. Eighty-three percent of respondents had two or fewer inquiries about direct-to-consumer genetic testing, and 14% had received requests for test interpretation or discussion. Respondents believed that genetic counselors have a professional obligation to be knowledgeable about direct-to-consumer genetic testing (55%) and interpret results (48%). Fifty-one percent of respondents thought genetic testing should be limited to a clinical setting; 56% agreed direct-to-consumer genetic testing is acceptable if genetic counseling is provided. More than 70% of respondents would definitely or possibly consider direct-to-consumer testing for patients who (1) have concerns about genetic discrimination, (2) want anonymous testing, or (3) have geographic constraints.
Conclusions
Results indicate that genetic counselors have limited patient experiences with direct-to-consumer genetic testing and are cautiously considering if and under what circumstances this approach should be used
doi:10.1097/GIM.0b013e3182011636
PMCID: PMC3804135  PMID: 21233722
34.  On Averages and Peaks: How Do People Integrate Attitudes about Multiple Diseases to Reach a Decision about Multiplex Genetic Testing? 
Background
The aim of the current study was to learn how people integrate attitudes about multiple health conditions to make a decision about genetic testing uptake.
Methods
This study recruited 294 healthy young adults from a parent research project, the Multiplex Initiative, conducted in a large health care system in Detroit, Michigan. All participants were offered a multiplex genetic test that assessed risk for 8 common health conditions (e.g., type 2 diabetes). Data were collected from a baseline survey, a web-based survey, and at the time of testing.
Results
Averaging attitudes across diseases predicted test uptake but did not contribute beyond peak attitudes, the highest attitude toward testing for a single disease in the set. Peak attitudes were found sufficient to predict test uptake.
Limitations
The effects of set size and mode of presentation could not be examined because these factors were constant in the multiplex test offered.
Conclusions
These findings support theories suggesting that people use representative evaluations in attitude formation. The implication of these findings for further developments in genetic testing is that the communication and impact of multiplex testing may need to be considered in the light of a bias toward peak attitudes.
doi:10.1177/0272989X12464432
PMCID: PMC3799841  PMID: 23128581
cognitive psychology; judgment and decision psychology; patient choice modeling; social judgment theory
35.  Navigating a research partnership between academia and industry to assess the impact of personalized genetic testing 
Purpose
To describe the process of structuring a partnership between academic researchers and two personalized genetic testing companies that would manage conflicts of interest while allowing researchers to study the impact of this nascent industry.
Methods
We developed a transparent process of ongoing communication about the interests of all research partners to address challenges in establishing study goals, survey development, data collection, analysis, and manuscript preparation. Using the existing literature on conflicts of interest and our experience, we created a checklist for academic and industry researchers seeking to structure research partnerships.
Results
Our checklist includes questions about the risk to research participants, sponsorship of the study, control of data analysis, freedom to publish results, the impact of the research on industry customers, openness to input from all partners, sharing results before publication, and publication of industry-specific data. Transparency is critical to building trust between partners. Involving all partners in the research development enhanced the quality of our research and provided an opportunity to manage conflicts early in the research process.
Conclusion
Navigating relationships between academia and industry is complex and requires strategies that are transparent and responsive to the concerns of all. Employing a checklist of questions prior to beginning a research partnership may help to manage conflicts of interest.
doi:10.1038/gim.2011.59
PMCID: PMC3763722  PMID: 22241103
conflicts of interest; direct-to-consumer; partnership; personalized genetic testing; personalized medicine
36.  Effectiveness of a condensed protocol for disclosing APOE genotype and providing risk education for Alzheimer disease 
Purpose
Brief, effective models of patient genetic education are needed for common, complex diseases. Using Alzheimer disease as a model, we compared participants’ risk knowledge and recall in extended versus condensed education protocols.
Methods
A four-site randomized clinical trial enrolled 280 first-degree relatives of individuals with Alzheimer disease (mean age = 58 years, 71% female); each received lifetime Alzheimer disease risk information (range: 13–74%) that incorporated apolipoprotein E genotype. In the condensed protocol, participants received an educational brochure in place of an in-person education session. Outcomes were assessed at 6 weeks and 6 months following risk disclosure.
Results
The condensed protocol required less clinician time than the extended protocol (mean = 34 min vs. 77 min). The groups did not differ on recall of apolipoprotein E genotype or lifetime risk, and most participants in both groups recalled and retained this information over time. Both groups showed improvement from baseline in Alzheimer disease risk knowledge (e.g., understanding the magnitude of apolipoprotein E genotype effect on risk).
Conclusion
A condensed protocol for communicating genetic risk for Alzheimer disease achieved similar educational results as an extended protocol in this study. Further research should explore the efficacy of brief genetic education protocols for complex diseases in diverse populations.
doi:10.1038/gim.2012.37
PMCID: PMC3718049  PMID: 22498844
Alzheimer disease; APOE; genetic counseling; health education; risk communication
37.  Inhibition of transforming growth factor-β-activated kinase-1 blocks cancer cell adhesion, invasion, and metastasis 
British Journal of Cancer  2012;107(1):129-136.
Background:
Tumour cell metastasis involves cell adhesion and invasion, processes that depend on signal transduction, which can be influenced by the tumour microenvironment. N-6 polyunsaturated fatty acids, found both in the diet and in response to inflammatory responses, are important components of this microenvironment.
Methods:
We used short hairpin RNA (shRNA) knockdown of TGF-β-activated kinase-1 (TAK1) in human tumour cells to examine its involvement in fatty acid-stimulated cell adhesion and invasion in vitro. An in vivo model of metastasis was developed in which cells, stably expressing firefly luciferase and either a control shRNA or a TAK1-specific shRNA, were injected into the mammary fat pads of mice fed diets, rich in n-6 polyunsaturated fatty acids. Tumour growth and spontaneous metastasis were monitored with in vivo and in situ imaging of bioluminescence.
Results:
Arachidonic acid activated TAK1 and downstream kinases in MDA-MB-435 breast cancer cells and led to increased adhesion and invasion. Knockdown of TAK1 blocked this activation and inhibited both cell adhesion and invasion in vitro. Tumour growth at the site of injection was not affected by TAK1 knockdown, but both the incidence and extent of metastasis to the lung were significantly reduced in mice injected with TAK1 knockdown cells compared with mice carrying control tumour cells.
Conclusion:
These data demonstrate the importance of TAK1 signalling in tumour metastasis in vivo and suggest an opportunity for antimetastatic therapies.
doi:10.1038/bjc.2012.214
PMCID: PMC3389413  PMID: 22644295
adhesion; invasion; metastasis; fatty acid; TGF-β-activated kinase-1; breast cancer
38.  Eavesdropping and signal matching in visual courtship displays of spiders 
Biology Letters  2012;8(3):375-378.
Eavesdropping on communication is widespread among animals, e.g. bystanders observing male–male contests, female mate choice copying and predator detection of prey cues. Some animals also exhibit signal matching, e.g. overlapping of competitors' acoustic signals in aggressive interactions. Fewer studies have examined male eavesdropping on conspecific courtship, although males could increase mating success by attending to others' behaviour and displaying whenever courtship is detected. In this study, we show that field-experienced male Schizocosa ocreata wolf spiders exhibit eavesdropping and signal matching when exposed to video playback of courting male conspecifics. Male spiders had longer bouts of interaction with a courting male stimulus, and more bouts of courtship signalling during and after the presence of a male on the video screen. Rates of courtship (leg tapping) displayed by individual focal males were correlated with the rates of the video exemplar to which they were exposed. These findings suggest male wolf spiders might gain information by eavesdropping on conspecific courtship and adjust performance to match that of rivals. This represents a novel finding, as these behaviours have previously been seen primarily among vertebrates.
doi:10.1098/rsbl.2011.1096
PMCID: PMC3367748  PMID: 22219390
communication; eavesdropping; signal matching; spiders; Lycosidae
39.  Patient, Center and Geographic Characteristics of Nationally Placed Livers 
Once a liver offer has been refused locally and regionally, it is offered nationally. We characterized nationally (n = 1567) versus locally (n = 19 893) placed grafts from adult, nonfulminant, deceased donor liver transplants (LT) from 2/1/05 to 1/31/10. Donors of nationally versus locally placed livers differed by age (50 vs. 42 years), positive HCV antibody (11 vs. 2%) and death from stroke (51 vs. 42%) (p < 0.001 for all). Recipients of nationally versus locally placed livers differed by LT-MELD (20 vs. 24), rates of ascites (35 vs. 37%), encephalopathy (12 vs. 15%), hepatocellular (17 vs. 24%) and nonhepatocellular exceptions (6 vs. 11%) (p ≤ 0.03 for all). Six (5%) centers utilized 64% of the nationally placed grafts while 43 (38%) centers accepted zero during the 5-year period; all high volume centers used ≥1. Compared to local distribution, transplantation with a nationally placed liver was associated with a similar adjusted risk of graft (HR, 0.99; 95% CI, 0.86–1.14) and patient (HR, 0.98; 95% CI, 0.84–1.14; p = 0.77) survival. In conclusion, utilization of nationally placed livers is highly concentrated in very few centers, with no increased adjusted risk of graft loss. These findings provide the foundation for a more informed discussion about changing our current liver allocation and distribution policies.
doi:10.1111/j.1600-6143.2011.03962.x
PMCID: PMC3689311  PMID: 22300591
Distribution; extended criteria donor; geographic-disparity
40.  PI3K/Akt signalling is required for the attachment and spreading, and growth in vivo of metastatic scirrhous gastric carcinoma 
British Journal of Cancer  2012;106(9):1535-1542.
Background:
PI3K/Akt (PKB) pathway has been shown in several cell types to be activated by ligands to cell surface integrins, leading to the metastasis of tumour cells. The signalling pathways involved in the metastatic spread of human scirrhous gastric carcinoma cells have not been defined.
Methods:
The role of the PI3K/Akt pathway in an extensive peritoneal-seeding cell line, OCUM-2MD3 and a parental cell line, OCUM-2M, was investigated by assessing in vitro adhesion and spreading assay, and in vivo peritoneal metastatic model. We also examined the correlation of PI3K/Akt pathway with integrin signals by immunoprecipitations, using cells by transfection with mutant p85 (Δp85).
Results:
Adhesiveness and spreading of OCUM-2MD3 cells on collagen type IV was significantly decreased by PI3K inhibitors and expression of mutant p85, but not by inhibitors of protein kinase C (PKC) or extracellular signal-regulated kinase (ERK). Immunoprecipitation studies indicated that the PI3K/Akt pathway was associated with integrin signalling through Src and vinculin. In an in vivo experimental metastasis model, p85 inhibition reduced peritoneal metastasis of OCUM-2MD3 cells.
Conclusion:
PI3K/Akt signalling may be required for integrin-dependent attachment and spreading of scirrhous gastric carcinoma cells, and would be translated into generating better strategies to optimise their use in cancer clinical trials.
doi:10.1038/bjc.2012.107
PMCID: PMC3341864  PMID: 22531720
PI3 kinase; gastric carcinoma; adhesion; spreading: metastasis; integrin signalling
41.  Risk perceptions and worry about common diseases: A between- and within-subjects examination 
Psychology & health  2012;28(4):434-449.
Objective
To test the relationships between worry and perceptions of likelihood and severity (two indicators of risk perception) across eight common diseases, and to examine contributions of individual and disease variability in worry and risk perceptions.
Methods
Participants were 294 people recruited through the Multiplex Initiative, in which a genetic susceptibility test for 8 common diseases was offered to healthy adults. Participants completed a baseline telephone survey and Web-based surveys measuring the variables for this ancillary study, without a commitment to be tested.
Results
Between- and within-subjects analyses yielded the following findings: 1) worry is more related to likelihood perceptions than to severity perceptions; 2) severity perceptions add significantly to explained worry variances above and beyond likelihood perceptions; 3) the likelihood × severity perception does not add to explained variance in worry above its components; 4) risk perceptions and worries form two identifiable clusters: cancer diseases and cardiovascular-metabolic diseases; 5) there are significant differences in risk perceptions and worry among diseases; 6) there are significant gender differences in risk perceptions and worry about common diseases; 7) variance in risk perception and worry is explained by a combination of between- and within-subjects variances, with the latter being more powerful.
Conclusions
Risk perception research should pay attention to severity perceptions, within-subjects variability and inter-disease differences should not be ignored, gender perspectives on illness perceptions should be acknowledged, and health psychologists must prepare for considering groups of illnesses in addition to single diseases.
doi:10.1080/08870446.2012.737464
PMCID: PMC3566271  PMID: 23121110
risk perception; worry; severity; likelihood; within-subjects
42.  Willingness to Pay for Genetic Testing for Alzheimer's Disease: A Measure of Personal Utility 
Background: The increased availability of genetic tests for common, complex diseases, such as Alzheimer's disease (AD), raises questions about what people are willing to pay for these services. Methods: We studied willingness-to-pay for genetic testing in a study of AD risk assessment that included APOE genotype disclosure among 276 first-degree relatives of persons with AD. Results: Seventy-one percent reported that they would ask for such testing from their doctor if it were covered by health insurance, and 60% would ask for it even if it required self-pay. Forty-one percent were willing to pay more than $100 for testing, and more than half would have been willing to pay for the test out of pocket. Participants who learned that they were APOE ɛ4 positive and those who had higher education were less likely to want testing if covered by insurance, possibly to avoid discrimination. Conclusion: This is the first report to examine willingness to pay for susceptibility genetic testing in a sample of participants who had actually undergone such testing. These findings reveal that some participants find valuable personal utility in genetic risk information even when such information does not have proven clinical utility.
doi:10.1089/gtmb.2011.0028
PMCID: PMC3241735  PMID: 21749214
43.  Interneurons hyperpolarize pyramidal cells along their entire somatodendritic axis 
Nature neuroscience  2008;12(1):21-23.
Although GABAergic interneurons are the main source of synaptic inhibition in the cortex, activation of GABAA receptors has been shown to depolarize specific neuronal compartments, resulting in excitation. By using a noninvasive approach to monitor the effect of individual interneurons on the pyramidal cell population, we found that rat hippocampal interneurons hyperpolarized pyramidal cells irrespective of the location of their synapses along the somato-dendritic axis.
doi:10.1038/nn.2230
PMCID: PMC3505023  PMID: 19029887
44.  Linoleic acid enhances angiogenesis through suppression of angiostatin induced by plasminogen activator inhibitor 1 
British Journal of Cancer  2011;105(11):1750-1758.
Background:
The intake of dietary fatty acids is highly correlated with the risk of various cancers. Linoleic acid (LA) is the most abundant polyunsaturated fat in the western diet, but the mechanism(s) by fatty acids such as LA modulate cancer cells is unclear. In this study, we examined the role of LA in various steps in gastric cancer progression.
Methods:
The difference in gene expression between LA-treated and untreated OCUM-2MD3 gastric carcinoma cells was examined by mRNA differential display. The involvement of candidate genes was examined by oligo- and plasmid-mediated RNA interference. Biological functions of several of these genes were examined using in vitro assays for invasion, angiogenesis, apoptosis, cell viability, and matrix digestion. Angiogenesis in vivo was measured by CD-31 immunohistochemistry and microvessel density scoring.
Results:
LA enhanced the plasminogen activator inhibitor 1 (PAI-1) mRNA and protein expression, which are controlled by PAI-1 mRNA-binding protein. LA-stimulated invasion depended on PAI-1. LA also enhanced angiogenesis by suppression of angiostatin, also through PAI-1. LA did not alter cell growth in culture, but increased dietary LA-enhanced tumour growth in an animal model.
Conclusion:
Our findings suggest that dietary LA impacts multiple steps in cancer invasion and angiogenesis, and that reducing LA in the diet may help slow cancer progression.
doi:10.1038/bjc.2011.434
PMCID: PMC3242595  PMID: 22015554
gastric carcinoma; linoleic acid; plasminogen activator inhibitor 1; angiostatin; invasion
45.  Using Alzheimer’s disease as a model for genetic risk disclosure: Implications for personal genomics 
Clinical Genetics  2011;80(5):407-414.
Susceptibility testing for common, complex adult-onset diseases is projected to become more commonplace as the rapid pace of genomic discoveries continues, and evidence regarding the potential benefits and harms of such testing is needed to inform medical practice and health policy. Apolipoprotein E (APOE) testing for risk of Alzheimer’s disease (AD) provides a paradigm in which to examine the process and impact of disclosing genetic susceptibility for a prevalent, severe and incurable neurological condition. This review summarizes findings from a series of multi-site randomized clinical trials examining psychological and behavioral responses to various methods of genetic risk assessment for AD using APOE disclosure. We discuss challenges involved in disease risk estimation and communication and the extent to which participants comprehend and perceive utility in their genetic risk information. Findings on the psychological impact of test results are presented (e.g., distress), along with data on participants’ health behavior and insurance purchasing responses (e.g., long term care). Finally, we report comparisons of the safety and efficacy of intensive genetic counseling approaches to briefer models that emphasize streamlined processes and educational materials. The implications of these findings for the emerging field of personal genomics are discussed, with directions identified for future research.
doi:10.1111/j.1399-0004.2011.01739.x
PMCID: PMC3191239  PMID: 21696382
46.  Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study 
Science translational medicine  2011;3(111):111ra121.
Individual cancers harbor a set of genetic aberrations that can be informative for identifying rational therapies currently available or in clinical trials. We implemented a pilot study to explore the practical challenges of applying high-throughput sequencing in clinical oncology. We enrolled patients with advanced or refractory cancer who were eligible for clinical trials. For each patient, we performed whole-genome sequencing of the tumor, targeted whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing (RNA-Seq) of the tumor to identify potentially informative mutations in a clinically relevant time frame of 3 to 4 weeks. With this approach, we detected several classes of cancer mutations including structural rearrangements, copy number alterations, point mutations, and gene expression alterations. A multidisciplinary Sequencing Tumor Board (STB) deliberated on the clinical interpretation of the sequencing results obtained. We tested our sequencing strategy on human prostate cancer xenografts. Next, we enrolled two patients into the clinical protocol and were able to review the results at our STB within 24 days of biopsy. The first patient had metastatic colorectal cancer in which we identified somatic point mutations in NRAS, TP53, AURKA, FAS, and MYH11, plus amplification and overexpression of cyclin-dependent kinase 8 (CDK8). The second patient had malignant melanoma, in which we identified a somatic point mutation in HRAS and a structural rearrangement affecting CDKN2C. The STB identified the CDK8 amplification and Ras mutation as providing a rationale for clinical trials with CDK inhibitors or MEK (mitogenactivated or extracellular signal–regulated protein kinase kinase) and PI3K (phosphatidylinositol 3-kinase) inhibitors, respectively. Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive, individual mutational landscape to facilitate biomarker-driven clinical trials in oncology.
doi:10.1126/scitranslmed.3003161
PMCID: PMC3476478  PMID: 22133722
47.  Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence 
British Journal of Cancer  2011;105(6):796-806.
Background:
We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer.
Methods:
We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo.
Results:
Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours.
Conclusion:
Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.
doi:10.1038/bjc.2011.321
PMCID: PMC3171020  PMID: 21847123
ErbB-2; trastuzumab; Notch-1; GSI; recurrence; resistance
48.  Recruitment and retention monitoring: facilitating the mission of the National Institute of Neurological Disorders and Stroke (NINDS) 
It is commonly accepted that inefficient recruitment and inadequate retention continue to threaten the completion of clinical trials intended to reduce the public health burden of neurological disease. This article will discuss the scientific, economic, and ethical implications of failure to recruit and retain adequate samples in clinical trials, including the consequences of failing to recruit adequately diverse samples. We will also discuss the more common challenges and barriers to efficient and effective recruitment and retention, and the impact these have on successful clinical trial planning. We will explain the newly established efforts within National Institute of Neurological Disorders and Stroke (NINDS) to monitor recruitment and retention with well-defined metrics and implementation of grant awards that include feasibility milestones for continued funding. Finally, we will describe our efforts to address some of the common challenges to recruitment and retention through assistance to investigators and coordinators with evidence-based support, tools, and resources for planning and strategizing recruitment and retention as well as a trans-NIH effort to improve awareness of clinical research in the general public.
PMCID: PMC3517027  PMID: 23230460
49.  Differences Between African American and White Research Volunteers in Their Attitudes, Beliefs and Knowledge Regarding Genetic Testing for Alzheimer’s Disease 
Journal of genetic counseling  2011;20(6):650-659.
Genetic susceptibility testing for common diseases is expanding, but little is known about race group differences in test perceptions. The purpose of this study was to examine differences between African Americans and Whites in knowledge, attitudes, and motivations regarding genetic susceptibility testing for Alzheimer’s disease (AD). Before enrolling in an AD genetic testing research trial, 313 first-degree relatives of AD patients (20% African American; 71% female; mean age = 58 years) were surveyed regarding: (1) knowledge about genetics and AD risk; (2) concerns about developing AD; and (3) reasons for seeking testing. In comparison to Whites, African Americans were less knowledgeable about genetics and AD risk (p<.01) and less concerned about developing AD (p<.05), with lower levels of perceived disease risk (p=.04). The results suggest that African Americans and Whites differ notably in their knowledge, beliefs, and attitudes regarding genetic testing for AD. Additional research with more representative samples is needed to better understand these differences.
doi:10.1007/s10897-011-9377-6
PMCID: PMC3223287  PMID: 21656311
Genetic testing; African Americans; Alzheimer’s disease; APOE; Risk assessment; Susceptibility testing; Health beliefs; Health literacy; Health disparities
50.  Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors 
Genetics in Medicine  2011;13(6):597-605.
Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10–12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apoli-poprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD.
doi:10.1097/GIM.0b013e31821d69b8
PMCID: PMC3326653  PMID: 21577118
Alzheimer disease; dementia; guideline; genetic testing; genetic counseling

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