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1.  Chemical structure determines target organ carcinogenesis in rats 
SAR models were developed for 12 rat tumour sites using data derived from the Carcinogenic Potency Database. Essentially, the models fall into two categories: Target Site Carcinogen – Non-Carcinogen (TSC-NC) and Target Site Carcinogen – Non-Target Site Carcinogen (TSC-NTSC). The TSC-NC models were composed of active chemicals that were carcinogenic to a specific target site and inactive ones that were whole animal non-carcinogens. On the other hand, the TSC-NTSC models used an inactive category also composed of carcinogens but to any/all other sites but the target site. Leave one out validations produced an overall average concordance value for all 12 models of 0.77 for the TSC-NC models and 0.73 for the TSC-NTSC models.
Overall, these findings suggest that while the TSC-NC models are able to distinguish between carcinogens and non-carcinogens, the TSC-NTSC models are identifying structural attributes that associate carcinogens to specific tumour sites. Since the TSC-NTSC models are composed of active and inactive compounds that are genotoxic and non-genotoxic carcinogens, the TSC-NTSC models may be capable of deciphering non-genotoxic mechanisms of carcinogenesis. Together, models of this type may also prove useful in anticancer drug development since they essentially contain chemicals moieties that target specific tumour site.
PMCID: PMC3547634  PMID: 23066888
structure-activity relationship; cancer; organ-specific carcinogens; genotoxic carcinogens; non-genotoxic carcinogens
2.  Global structure–activity relationship model for nonmutagenic carcinogens using virtual ligand-protein interactions as model descriptors 
Carcinogenesis  2012;33(10):1940-1945.
Structure–activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe the use of a traditional fragment-based SAR approach along with a new virtual ligand-protein interaction-based approach for modeling of nonmutagenic carcinogens. The ligand-based SAR models used descriptors derived from computationally calculated ligand-binding affinities for learning set agents to 5495 proteins. Two learning sets were developed. One set was from the Carcinogenic Potency Database, where chemicals tested for rat carcinogenesis along with Salmonella mutagenicity data were provided. The second was from Malacarne et al. who developed a learning set of nonalerting compounds based on rodent cancer bioassay data and Ashby’s structural alerts. When the rat cancer models were categorized based on mutagenicity, the traditional fragment model outperformed the ligand-based model. However, when the learning sets were composed solely of nonmutagenic or nonalerting carcinogens and noncarcinogens, the fragment model demonstrated a concordance of near 50%, whereas the ligand-based models demonstrated a concordance of 71% for nonmutagenic carcinogens and 74% for nonalerting carcinogens. Overall, these findings suggest that expert system analysis of virtual chemical protein interactions may be useful for developing predictive SAR models for nonmutagenic carcinogens. Moreover, a more practical approach for developing SAR models for carcinogenesis may include fragment-based models for chemicals testing positive for mutagenicity and ligand-based models for chemicals devoid of DNA reactivity.
PMCID: PMC3463155  PMID: 22678118
3.  Mammary Carcinogen-Protein Binding Potentials: Novel and Biologically Relevant Structure-Activity Relationship Model Descriptors 
Previously, SAR models for carcinogenesis used descriptors that are essentially chemical descriptors. Herein we report the development of models with the cat-SAR expert system using biological descriptors (i.e., ligand-receptor interactions) rat mammary carcinogens. These new descriptors are derived from the virtual screening for ligand-receptor interactions of carcinogens, non-carcinogens, and mammary carcinogens to a set of 5494 target proteins. Leave-one-out validations of the ligand mammary carcinogen non-carcinogen model had a concordance between experimental and predicted results of 71% and the mammary carcinogen non-mammary carcinogen model was 72% concordant. The development of a hybrid fragment-ligand model improved the concordances to 85 and 83%, respectively. In a separate external validation exercise, hybrid fragment-ligand models had concordances of 81 and 76%. Analyses of example rat mammary carcinogens including the food mutagen and estrogenic compound PhIP, the herbicide atrazine, and the drug indomethacin, the ligand model identified a number of proteins associated with each compound that had previously been referenced in Medline in conjunction with the test chemical and separately with association to breast cancer. This new modelling approach can enhance model predictivity and help bridge the gap between chemical structure and carcinogenic activity by descriptors that are related to biological targets.
PMCID: PMC3383027  PMID: 20818582
4.  Circumcision and risk of sexually transmissible infections in a community-based cohort of HIV-negative homosexual men in Sydney, Australia 
The Journal of infectious diseases  2009;200(12):1813-1819.
Circumcision status was examined as an independent risk factor for STIs in the HIM cohort of homosexual men in Sydney.
From 2001–2004, 1,427 initially HIV-negative men were enrolled and followed to mid-2007. All participants were offered annual STI testing. Past history of STIs was collected at baseline and information on sexual risk behaviors, every 6 months. At annual face-to-face visits, participants reported STI diagnoses made in the previous year.
Circumcision was not associated with prevalent or incident HSV-1, HSV-2, or self-reported genital warts. There was also no independent association of circumcision with incident urethral gonorrhea or chlamydia. Being circumcised was associated with a significantly reduced risk of incident (HR 0.35, 95% CI 0.15–0.84), but not prevalent (OR 0.71, 95% CI 0.35–1.44) syphilis. The association was somewhat stronger among men who reported predominantly insertive unprotected anal intercourse (HR 0.10, 95% CI 0.01–0.82).
These are the first prospective data in homosexual men to assess circumcision status as a risk factor for STIs. Circumcised men were at reduced risk of incident syphilis but no other prevalent or incident STIs. Circumcision is unlikely to have a substantial public health impact in reducing acquisition of most STIs in homosexual men.
PMCID: PMC2784211  PMID: 19911990
circumcision; sexually transmitted diseases; homosexuality, male; prospective studies
5.  A methodology to establish a database to study gene environment interactions for childhood asthma 
Gene-environment interactions are likely to explain some of the heterogeneity in childhood asthma. Here, we describe the methodology and experiences in establishing a database for childhood asthma designed to study gene-environment interactions (PAGES - Paediatric Asthma Gene Environment Study).
Children with asthma and under the care of a respiratory paediatrician are being recruited from 15 hospitals between 2008 and 2011. An asthma questionnaire is completed and returned by post. At a routine clinic visit saliva is collected for DNA extraction. Detailed phenotyping in a proportion of children includes spirometry, bronchodilator response (BDR), skin prick reactivity, exhaled nitric oxide and salivary cotinine. Dietary and quality of life questionnaires are completed. Data are entered onto a purpose-built database.
To date 1045 children have been invited to participate and data collected in 501 (48%). The mean age (SD) of participants is 8.6 (3.9) years, 57% male. DNA has been collected in 436 children. Spirometry has been obtained in 172 children, mean % predicted (SD) FEV1 97% (15) and median (IQR) BDR is 5% (2, 9). There were differences in age, socioeconomic status, severity and %FEV1 between the different centres (p≤0.024). Reasons for non-participation included parents not having time to take part, children not attending clinics and, in a small proportion, refusal to take part.
It is feasible to establish a national database to study gene-environment interactions within an asthmatic paediatric population; there are barriers to participation and some different characteristics in individuals recruited from different centres. Recruitment to our study continues and is anticipated to extend current understanding of asthma heterogeneity.
PMCID: PMC3019209  PMID: 21134251
6.  Microglia and the urokinase plasminogen activator receptor/uPA system in innate brain inflammation 
Glia  2009;57(16):1802-1814.
The urokinase plasminogen activator (uPA) receptor (uPAR) is a GPI-linked cell surface protein that facilitates focused plasmin proteolytic activity at the cell surface. uPAR has been detected in macrophages infiltrating the central nervous system (CNS) and soluble uPAR has been detected in the cerebrospinal fluid during a number of CNS pathologies. However, its expression by resident microglial cells in vivo remains uncertain. In this work, we aimed to elucidate the murine CNS expression of uPAR and uPA as well as that of tissue plasminogen activator and plasminogen activator inhibitor 1 (PAI-1) during insults generating distinct and well-characterized inflammatory responses; acute intracerebral lipopolysaccharide (LPS), acute kainate-induced neurodegeneration, and chronic neurodegeneration induced by prion disease inoculation. All three insults induced marked expression of uPAR at both mRNA and protein level compared to controls (naïve, saline, or control inoculum-injected). uPAR expression was microglial in all cases. Conversely, uPA transcription and activity was only markedly increased during chronic neurodegeneration. Dissociation of uPA and uPAR levels in acute challenges is suggestive of additional proteolysis-independent roles for uPAR. PAI-1 was most highly expressed upon LPS challenge, whereas tissue plasminogen activator mRNA was constitutively present and less responsive to all insults studied. These data are novel and suggest much wider involvement of the uPAR/uPA system in CNS function and pathology than previously supposed. © 2009 Wiley-Liss, Inc.
PMCID: PMC2816357  PMID: 19459212
chronic neurodegeneration; neuroinflammation; plasminogen; proteolysis; activation
7.  The implantable cardioverter-defibrillator: postcode prescribing in the UK 1998–2002 
Heart  2005;91(10):1280-1283.
Objective: To determine the rate of implantable cardioverter-defibrillator (ICD) implantation across the UK during the period 1998 to 2002.
Design: Observational self reporting with cross checking.
Setting: All ICD implanting centres coordinated by the National Pacemaker and ICD Database.
Patients: Every patient receiving an ICD in the UK from 1998 to 2002.
Main outcome measures: Date of implantation and postcode of each ICD recipient during the study period.
Results: ICD implantation increased in the UK in the five year period studied but fell far short of the European average and national targets. Implantation rates varied greatly by region.
Conclusions: The low rate of ICD implantation in the UK and the disparity between regions require further study to determine the barriers to this evidence based treatment.
PMCID: PMC1769132  PMID: 15797937
ICD; implantable cardioverter-defibrillator
8.  Effects of improved home heating on asthma in community dwelling children: randomised controlled trial 
Objective To assess whether non-polluting, more effective home heating (heat pump, wood pellet burner, flued gas) has a positive effect on the health of children with asthma.
Design Randomised controlled trial.
Setting Households in five communities in New Zealand.
Participants 409 children aged 6-12 years with doctor diagnosed asthma.
Interventions Installation of a non-polluting, more effective home heater before winter. The control group received a replacement heater at the end of the trial.
Main outcome measures The primary outcome was change in lung function (peak expiratory flow rate and forced expiratory volume in one second, FEV1). Secondary outcomes were child reported respiratory tract symptoms and daily use of preventer and reliever drugs. At the end of winter 2005 (baseline) and winter 2006 (follow-up) parents reported their child’s general health, use of health services, overall respiratory health, and housing conditions. Nitrogen dioxide levels were measured monthly for four months and temperatures in the living room and child’s bedroom were recorded hourly.
Results Improvements in lung function were not significant (difference in mean FEV1 130.7 ml, 95% confidence interval −20.3 to 281.7). Compared with children in the control group, however, children in the intervention group had 1.80 fewer days off school (95% confidence interval 0.11 to 3.13), 0.40 fewer visits to a doctor for asthma (0.11 to 0.62), and 0.25 fewer visits to a pharmacist for asthma (0.09 to 0.32). Children in the intervention group also had fewer reports of poor health (adjusted odds ratio 0.48, 95% confidence interval 0.31 to 0.74), less sleep disturbed by wheezing (0.55, 0.35 to 0.85), less dry cough at night (0.52, 0.32 to 0.83), and reduced scores for lower respiratory tract symptoms (0.77, 0.73 to 0.81) than children in the control group. The intervention was associated with a mean temperature rise in the living room of 1.10°C (95% confidence interval 0.54°C to 1.64°C) and in the child’s bedroom of 0.57°C (0.05°C to 1.08°C). Lower levels of nitrogen dioxide were measured in the living rooms of the intervention households than in those of the control households (geometric mean 8.5 μg/m3 v 15.7 μg/m3, P<0.001). A similar effect was found in the children’s bedrooms (7.3 μg/m3 v 10.9 μg/m3, P<0.001).
Conclusion Installing non-polluting, more effective heating in the homes of children with asthma did not significantly improve lung function but did significantly reduce symptoms of asthma, days off school, healthcare utilisation, and visits to a pharmacist.
Trial registration Clinical Trials NCT00489762.
PMCID: PMC2658826  PMID: 18812366
9.  Effect of insulating existing houses on health inequality: cluster randomised study in the community 
BMJ : British Medical Journal  2007;334(7591):460.
Objective To determine whether insulating existing houses increases indoor temperatures and improves occupants' health and wellbeing.
Design Community based, cluster, single blinded randomised study.
Setting Seven low income communities in New Zealand.
Participants 1350 households containing 4407 participants.
Intervention Installation of a standard retrofit insulation package.
Main outcome measures Indoor temperature and relative humidity, energy consumption, self reported health, wheezing, days off school and work, visits to general practitioners, and admissions to hospital.
Results Insulation was associated with a small increase in bedroom temperatures during the winter (0.5°C) and decreased relative humidity (−2.3%), despite energy consumption in insulated houses being 81% of that in uninsulated houses. Bedroom temperatures were below 10°C for 1.7 fewer hours each day in insulated homes than in uninsulated ones. These changes were associated with reduced odds in the insulated homes of fair or poor self rated health (adjusted odds ratio 0.50, 95% confidence interval 0.38 to 0.68), self reports of wheezing in the past three months (0.57, 0.47 to 0.70), self reports of children taking a day off school (0.49, 0.31 to 0.80), and self reports of adults taking a day off work (0.62, 0.46 to 0.83). Visits to general practitioners were less often reported by occupants of insulated homes (0.73, 0.62 to 0.87). Hospital admissions for respiratory conditions were also reduced (0.53, 0.22 to 1.29), but this reduction was not statistically significant (P=0.16).
Conclusion Insulating existing houses led to a significantly warmer, drier indoor environment and resulted in improved self rated health, self reported wheezing, days off school and work, and visits to general practitioners as well as a trend for fewer hospital admissions for respiratory conditions.
PMCID: PMC1808149  PMID: 17324975
10.  Seroprevalence of hepatitis B and C in a Merseyside hospital for the mentally handicapped. 
Epidemiology and Infection  1994;112(1):195-200.
This study reports the prevalence of antibodies to hepatitis B virus (HBV) and C virus (HCV), and the frequency of potential exposure to these viruses among patients and staff in six long-stay wards of a hospital caring for mentally handicapped adults from the Mersey region. A retrospective survey of risk behaviour among 134 patients and questionnaire survey of 75 nursing staff was performed. Serum samples from both groups were tested for HBV markers and patient sera for antibodies to HCV by enzyme-linked immunosorbent assay (ELISA). None of the 102 patients tested had antibodies against HCV, although 17 had detectable antibody to HBV core (anti-HBc). Seven out of the 17 were positive for HBV surface antigen. None was positive for IgM antibody to HBV core. Only 1 out of 61 staff had anti-HBc and none was positive for surface antigen. Twenty-nine of 75 (39%) staff reported bites sufficient to break the skin and 52 (69%) significant other injuries from patients; 25 (31%) of staff had not received HBV vaccination. None of the patients had received HBV vaccine. We conclude that HCV does not appear to be a major hazard in this closed community but the prevalence of HBV markers indicating past exposure among patients is high, vaccine uptake is incomplete and incidents which may allow viral transmission are frequent.
PMCID: PMC2271497  PMID: 7509754
11.  TLR5-deficient mice lack basal inflammatory and metabolic defects but exhibit impaired CD4 T cell responses to a flagellated pathogen 
TLR5-deficient mice have been reported to develop spontaneous intestinal inflammation and metabolic abnormalities. However, we report that TLR5-deficient mice from two different animal colonies display no evidence of basal inflammatory disease, metabolic abnormalities, or enhanced resistance to Salmonella infection. In contrast, the absence of TLR5 hindered the initial activation and clonal expansion of intestinal flagellin-specific CD4 T cells following oral Salmonella infection. Together, these data demonstrate that a basal inflammatory phenotype is not a consistent feature of TLR5-deficient mice, and document a novel role for TLR5 in the rapid targeting of flagellin by intestinal pathogen-specific CD4 T cells.
PMCID: PMC4090138  PMID: 21451112
12.  A Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside 
Journal of clinical immunology  2013;33(6):1078-1087.
The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician’s observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way.We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.
PMCID: PMC4083684  PMID: 23657403
Primary immunodeficiency; classification; IUIS; diagnosis tool
13.  Phellinus tropicalis Abscesses in a Patient with Chronic Granulomatous Disease 
Journal of clinical immunology  2013;34(2):130-133.
Chronic Granulomatous Disease (CGD), caused by genetic defects in components of the phagocyte NADPH oxidase pathway, leads to recurrent life-threatening bacterial and invasive fungal infections. While a number of unique pathogens have been associated with this disease, the causative organisms may be difficult to identify. Here, we present a 24 year old male with known X-linked CGD who concurrently developed a cervical abscess and an abscess in the subcutaneous tissues of the right hip, both of which were surgically drained. Cultures failed to identify any organisms. He was treated empirically with ertapenem but the hip abscess recurred at the original site and in contiguous dependent areas in the posterior thigh and knee. A filamentous organism was observed microscopically, initially considered a contaminant, but on culture yielded a mold growth, identified as Phellinus tropicalis (synonym: Inonotus tropicalis) based on phenotypic and molecular methods. This is the third case report of human infection with P. tropicalis, all in subjects with CGD. The patient was treated with voriconazole with resolution of his symptoms.
PMCID: PMC4080424  PMID: 24310980
Chronic granulomatous disease; Phellinus tropicalis; abscess; voriconazole
14.  Androgenic anabolic steroid exposure during adolescence: Ramifications for brain development and behavior 
Hormones and behavior  2012;64(2):350-356.
Puberty is a critical period for brain maturation that is highly dependent on gonadal sex hormones. Modifications in the gonadal steroid environment, via the use of anabolic androgenic steroids (AAS), have been shown to affect brain development and behavior. Studies in both humans and animal models indicate that AAS exposure during adolescence alters normal brain remodeling, including structural changes and neurotransmitter function. The most commonly reported behavioral effect is an increase in aggression. Evidence has been presented to identify factors that influence the effect of AAS on the expression of aggression. The chemical composition of the AAS plays a major role in determining whether aggression is displayed, with testosterone being the most effective. The hormonal context, the environmental context, physical provocation and the perceived threat during the social encounter have all been found to influence the expression of aggression and sexual behavior. All of these factors point toward an altered behavioral state that includes an increased readiness to respond to a social encounter with heightened vigilance, and enhanced motivation. This AAS-induced state may be defined as emboldenment. The evidence suggests that the use of AAS during this critical period of development may increase the risk for maladaptive behaviors along with neurological disorders.
PMCID: PMC3633688  PMID: 23274699
Testosterone; adolescence; HPG; aggression; sex behavior; plasticity
15.  Buprenorphine Treatment Outcomes among Opioid-Dependent Cocaine Users and Non-users 
Background and Objectives
National treatment guidelines state that polysubstance users, including cocaine users, may not be appropriate candidates for office-based buprenorphine treatment. However, data to support this recommendation are sparse and conflicting, and the implications of this recommendation may include limiting the usefulness of buprenorphine treatment, as cocaine use is common among opioid-dependent individuals seeking buprenorphine treatment. We compared buprenorphine treatment outcomes (6-month treatment retention and self-reported opioid use over 6 months) in opioid-dependent cocaine users versus non-users who initiated buprenorphine treatment at an urban community health center.
We followed 87 participants over 6 months, collecting interview and medical record data. We used logistic regression models to test whether baseline cocaine use was associated with treatment retention and mixed effects non-linear models to test whether baseline cocaine use was associated with self-reported opioid use.
At baseline, 39.1% reported cocaine use. In all participants, self-reported opioid use decreased from 89.7% to 27.4% over 6 months, and 6-month treatment retention was 54.5%. We found no significant difference in 6-month treatment retention (AOR=1.56, 95%CI=0.58–4.17, p=0.38) or self-reported opioid use (AOR=0.89, 95%CI=0.26–3.07, p=0.85) between cocaine users and non-users.
Conclusions and Scientific Significance
This study demonstrates that buprenorphine treatment retention is not worse in cocaine users than non-users, with clinically meaningful improvements in self-reported opioid use. These findings suggest that opioid-dependent cocaine users attain considerable benefits from office-based buprenorphine treatment and argue for the inclusion of these patients in office-based buprenorphine treatment programs.
PMCID: PMC3694744  PMID: 23795874
16.  Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids 
Psychopharmacology  2013;228(2):321-333.
Receptor mechanisms underlying the behavioral effects of clinically used nicotinic acetylcholine receptor agonists have not been fully established.
Drug discrimination was used to compare receptor mechanisms underlying the effects of smoking cessation aids.
Separate groups of male C57BL/6J mice discriminated 0.56, 1, or 1.78 mg/kg of nicotine base. Nicotine, varenicline, and cytisine were administered alone, in combination with each other, and in combination with mecamylamine and dihydro-β-erythroidine (DHβE). Midazolam and morphine were tested to examine sensitivity to non-nicotinics.
The ED50 value of nicotine to produce discriminative stimulus effects systematically increased as training dose increased. Varenicline and cytisine did not fully substitute for nicotine and, as compared with nicotine, their ED50 values varied less systematically as a function of nicotine training dose. Morphine did not substitute for nicotine, whereas midazolam substituted for the low and not the higher training doses of nicotine. As training dose increased, the dose of mecamylamine needed to produce a significant rightward shift in the nicotine dose-effect function also increased. DHβE antagonized nicotine in animals discriminating the smallest dose of nicotine. Varenicline did not antagonize the effects of nicotine, whereas cytisine produced a modest though significant antagonism of nicotine.
These results suggest that differences in pharmacologic mechanism between nicotine, varenicline, and cytisine include not only differences in efficacy at a common subtype of nicotinic acetylcholine receptor, but also differential affinity and/or efficacy at multiple receptor subtypes.
PMCID: PMC3695008  PMID: 23494230
agonist; antagonist; cytisine; dihydro-β-erythroidine; drug discrimination; efficacy; mecamylamine; mouse; nicotine; varenicline
17.  Prevalence of Mycobacteremia among HIV-Infected Infants and Children in Northern Tanzania 
Mycobacterium tuberculosis is a common cause of bloodstream infections among HIV-infected adults in sub-Saharan Africa, and is associated with high morbidity and mortality. We found no cases of mycobacteremia among 93 ill, HIV-infected children in northern Tanzania, despite optimization of laboratory methods and selection of patients thought to be at highest risk for disseminated infection.
PMCID: PMC3696391  PMID: 23360831
mycobacteremia; children; Africa; Tanzania; tuberculosis
18.  A rapid, controlled-environment seedling root screen for wheat correlates well with rooting depths at vegetative, but not reproductive, stages at two field sites 
Annals of Botany  2013;112(2):447-455.
Background and Aims
Root length and depth determine capture of water and nutrients by plants, and are targets for crop improvement. Here we assess a controlled-environment wheat seedling screen to determine speed, repeatability and relatedness to performance of young and adult plants in the field.
Recombinant inbred lines (RILs) and diverse genotypes were grown in rolled, moist germination paper in growth cabinets, and primary root number and length were measured when leaf 1 or 2 were fully expanded. For comparison, plants were grown in the field and root systems were harvested at the two-leaf stage with either a shovel or a soil core. From about the four-leaf stage, roots were extracted with a steel coring tube only, placed directly over the plant and pushed to the required depth with a hydraulic ram attached to a tractor.
Key Results
In growth cabinets, repeatability was greatest (r = 0·8, P < 0·01) when the paper was maintained moist and seed weight, pathogens and germination times were controlled. Scanned total root length (slow) was strongly correlated (r = 0·7, P < 0·01) with length of the two longest seminal axile roots measured with a ruler (fast), such that 100–200 genotypes were measured per day. Correlation to field-grown roots at two sites at two leaves was positive and significant within the RILs and cultivars (r = 0·6, P = 0·01), and at one of the two sites at the five-leaf stage within the RILs (r = 0·8, P = 0·05). Measurements made in the field with a shovel or extracted soil cores were fast (5 min per core) and had significant positive correlations to scanner measurements after root washing and cleaning (>2 h per core). Field measurements at two- and five-leaf stages did not correlate with root depth at flowering.
The seedling screen was fast, repeatable and reliable for selecting lines with greater total root length in the young vegetative phase in the field. Lack of significant correlation with reproductive stage root system depth at the field sites used in this study reflected factors not captured in the screen such as time, soil properties, climate variation and plant phenology.
PMCID: PMC3698392  PMID: 23821620
Triticum aestivum; wheat; root architecture; branch; breeding; selection; elongation
19.  Identification of Novel Variants in Colorectal Cancer Families by High-Throughput Exome Sequencing 
Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants.
We completed exome sequencing on 40 affected cases from 16 multi-case pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single nucleotide variants (SNVs) predicted to be benign.
We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or non-coding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively.
Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in colorectal cancer susceptibility.
Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.
PMCID: PMC3704223  PMID: 23637064
colorectal cancer; familial and hereditary cancers; exome sequencing; rare variants; family study design
20.  Implicit chaining in cotton-top tamarins (Saguinus oedipus) with elements equated for probability of reinforcement 
Animal cognition  2013;16(4):611-625.
Three experiments examined the implicit learning of sequences under conditions in which the elements comprising a sequence were equated in terms of reinforcement probability. In Experiment 1 cotton-top tamarins (Saguinus oedipus) experienced a five-element sequence displayed serially on a touch screen in which reinforcement probability was equated across elements at .16 per element. Tamarins demonstrated learning of this sequence with higher latencies during a random test as compared to baseline sequence training. In Experiments 2 and 3, manipulations of the procedure used in the first experiment were undertaken to rule out a confound owing to the fact that the elements in Experiment 1 bore different temporal relations to the intertrial interval (ITI), an inhibitory period. The results of Experiments 2 and 3 indicated that the implicit learning observed in Experiment 1 was not due to temporal proximity between some elements and the inhibitory ITI. The results taken together support two conclusion: First that tamarins engaged in sequence learning whether or not there was contingent reinforcement for learning the sequence, and second that this learning was not due to subtle differences in associative strength between the elements of the sequence.
PMCID: PMC3665734  PMID: 23344718
Implicit learning; Chaining; Cotton-top tamarins; Finite state grammar
21.  MAPK/ERK Signaling Pathway Analysis in Primary Osteoblasts from Patients with Non-Syndromic Sagittal Craniosynostosis 
The MAPK/ERK signaling pathway has been implicated in several craniosynostosis syndromes and represents a plausible target for therapeutic management of craniosynostosis. The causes of sagittal non-syndromic craniosynostosis (sNSC) have not been well understood and the role that MAPK/ERK signaling cascade plays in this condition warrants an investigation. We hypothesized that MAPK-signaling is misregulated in calvarial osteoblasts derived from patients with sNSC.
In order to analyze if the MAPK/ERK pathway is perturbed in sNSC we established primary calvarial osteoblast cell lines from patients undergoing surgery for correction of this congenital anomaly. Appropriate negative and positive control cell lines were used for comparison and we examined the levels of phosphorylated ERK by immunoblotting.
Primary osteoblasts from patients with sNSC showed no difference in ERK1/2 phosphorylation with or without FGF2 stimulation as compared with control osteoblasts.
Under the described test conditions, we did not observe convincing evidence that MAP/ERK signaling contributes to the development of sNSC.
PMCID: PMC3708983  PMID: 23566293
FGF2; bFGF; FGFRs; sagittal craniosynostosis; non-syndromic; nonsyndromic; MAPK; ERK
22.  Selecting Patients With Locally Advanced Rectal Cancer for Neoadjuvant Treatment Strategies 
The Oncologist  2013;18(7):833-842.
Rectal cancer outcomes vary significantly according to the stage of disease and prognostic factors, including the distance of the tumor from the circumferential resection margin. Accurate staging allows stratification of patients into low-, moderate-, and high-risk disease, which can be used to inform multidisciplinary team decisions regarding the role of neoadjuvant therapy. This article reviews the management of locally advanced rectal cancer, with particular focus on the importance of appropriate patient selection.
Learning Objectives
Explain the use of MRI to stratify patients to undergo different neoadjuvant treatment strategies for locally advanced rectal cancer.Identify the benefits and risks of currently available neoadjuvant treatment strategies and appraise emerging treatment strategy.Identify tissue and imaging biomarkers that could predict tumor sensitivity to chemoradiation.
Rectal cancer remains a significant problem worldwide. Outcomes vary significantly according to the stage of disease and prognostic factors, including the distance of the tumor from the circumferential resection margin. Accurate staging, including high-resolution magnetic resonance imaging, allows stratification of patients into low-, moderate-, and high-risk disease; this information can be used to inform multidisciplinary team decisions regarding the role of neoadjuvant therapy. Both neoadjuvant short-course radiotherapy and long-course chemoradiation reduce the risk of local recurrence compared with surgery alone, but they have little impact on survival. Although there remains a need to reduce overtreatment of those patients at moderate risk, evaluation of intensified regimens for those with high-risk disease is still required to reduce distant failure rates and improve survival in these patients with an otherwise poor prognosis.
PMCID: PMC3720638  PMID: 23821325
Rectal cancer; Chemoradiation; Magnetic resonance imaging; Neoadjuvant treatment
23.  Prior buprenorphine experience is associated with office-based buprenorphine treatment outcomes 
Journal of addiction medicine  2013;7(4):287-293.
As buprenorphine treatment and illicit buprenorphine use increase, many patients seeking buprenorphine treatment will have had prior experience with buprenorphine. Little evidence is available to guide optimal treatment strategies for patients with prior buprenorphine experience. We examined whether prior buprenorphine experience was associated with treatment retention and opioid use. We also explored whether type of prior buprenorphine use (prescribed or illicit use) was associated with these treatment outcomes.
We analyzed interview and medical record data from a longitudinal cohort study of 87 individuals who initiated office-based buprenorphine treatment. We examined associations between prior buprenorphine experience and 6-month treatment retention using logistic regression models, and prior buprenorphine experience and any self-reported opioid use at 1, 3, and 6 months using non-linear mixed models.
Most (57.4%) participants reported prior buprenorphine experience; of these, 40% used prescribed buprenorphine and 60% illicit buprenorphine only. Compared to buprenorphine-naïve participants, those with prior buprenorphine experience had better treatment retention (AOR=2.65, 95% CI=1.05–6.70). Similar associations that did not reach significance were found when exploring prescribed and illicit buprenorphine use. There was no difference in opioid use when comparing participants with prior buprenorphine experience to those who were buprenorphine-naive (AOR=1.33, 95% CI=0.38–4.65). Although not significant, qualitatively different results were found when exploring opioid use by type of prior buprenorphine use (prescribed buprenorphine vs. buprenorphine-naïve, AOR=2.20, 95% CI=0.58–8.26; illicit buprenorphine vs. buprenorphine-naïve, AOR=0.47, 95% CI=0.07–3.46).
Prior buprenorphine experience was common and associated with better retention. Understanding how prior buprenorphine experience affects treatment outcomes has important clinical and public health implications.
PMCID: PMC3737355  PMID: 23722632
buprenorphine; opioid; opioid dependence; office-based treatment
24.  Laypersons’ ratings of appearance in children with and without single suture craniosynostosis 
The Journal of craniofacial surgery  2013;24(4):1331-1335.
Single suture craniosynostosis (SSC) results in head shape anomalies that likely affect social perceptions of appearance. The purpose of this study was to evaluate laypersons’ ratings of attractiveness in children with and without SSC. Among cases, we also examined differences by suture fused and age at surgery.
We collected photographs of 196 children with SSC and 186 children without SSC as infants (prior to surgery, for cases) and at ages 18 and 36 months. Photographs were rated by 8 raters, who were blinded to the population being studied. We used linear regression to compare appearance ratings for the two groups at each visit and to evaluate changes over time. Regression analyses were used to examine the association between age at surgery and appearance ratings.
Children with SSC received lower appearance ratings than unaffected controls at each visit (all p-values < .001). Appearance ratings decreased over time, with a similar trajectory for children with and without SSC. Among cases, those with unicoronal and lambdoid synostosis had the lowest ratings and those with sagittal synostosis had the highest. Age at surgery was inversely associated with appearance ratings.
Children with SSC received lower appearance ratings than unaffected controls, with minimal change following surgery. Better outcomes were associated with earlier surgery. These findings do not indicate that children with SSC failed to benefit from surgery, as without surgical intervention, asymmetrical head shape would likely have worsened over time. However, our data suggest that appearance does not fully ‘normalize’.
PMCID: PMC3758118  PMID: 23851801
Infant; Craniosynostosis; Appearance
25.  A Phase I Trial of Isolated Hepatic Perfusion (IHP) Using 5-FU and Oxaliplatin in Patients with Unresectable Isolated Liver Metastases from Colorectal Cancer 
Annals of surgical oncology  2013;20(7):10.1245/s10434-013-2960-3.
Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP.
Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined.
All 12 patients had received ≥1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m2, resulting in expansion of DL1 at 200 mg/m2 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0–60 min) were 10.9 ± 4.5 μgPt h/mL, 49.3 ± 30.7 μg h/mL 5-FU (DL1), and 70.5 ± 35.5 μg h/mL 5-FU (DL2). Systemic exposure (AUC0–inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %).
The MTD for IHP was 200 mg/m2 5-FU with 40 mg/m2 oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.
PMCID: PMC3808182  PMID: 23575907

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