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1.  Barriers reported among patients with breast and cervical abnormalities in the patient navigation research program: impact on timely care 
Patient navigation (PN) is a system-level strategy to decrease cancer mortality rates by reducing barriers to cancer care. Barriers to resolution among participants in the PN intervention arm with a breast or cervical abnormality in the Patient Navigation Research Program (PNRP) and navigators’ actions to address those barriers were examined.
Data were from seven institutions (2005 to 2010) included 1,995 breast and 1,194 cervical patients. A stratified Cox proportional hazards regression model was used to examine the effects of barriers on time to resolution of an abnormal screening test or clinical finding.
The range of unique barriers was 0 to 12 and 0 to 7 among participants with breast and cervical abnormalities, respectively. About two-thirds of breast and half of cervical participants had at least one barrier resulting in longer time to diagnostic resolution among breast (adjusted HR=0.744; p<0.001) and cervical (adjusted HR=0.792; p<0.001) participants. Patient-level and system-level barriers were most common. Frequent navigator actions were: making arrangements, scheduling appointments, referrals, and education.
Having a barrier resulted in a delay in diagnostic resolution of an abnormal screening test or clinical finding. Health care systems can use these findings to improve existing PN programs or when developing new programs.
PMCID: PMC3896921  PMID: 24439942
patient navigation; patient navigators; patient-centered care; cancer
2.  Clinimetric properties of the Tinetti Mobility Test, Four Square Step Test, Activities-specific Balance Confidence Scale, and spatiotemporal gait measures in individuals with Huntington's disease 
Gait & posture  2014;40(4):647-651.
Background and purpose
Individuals with Huntington's disease (HD) experience balance and gait problems that lead to falls. Clinicians currently have very little information about the reliability and validity of outcome measures to determine the efficacy of interventions that aim to reduce balance and gait impairments in HD. This study examined the reliability and concurrent validity of spatiotemporal gait measures, the Tinetti Mobility Test (TMT), Four Square Step Test (FSST), and Activities-specific Balance Confidence (ABC) Scale in individuals with HD.
Participants with HD [n = 20; mean age ± SD = 50.9 ± 13.7; 7 male] were tested on spatiotemporal gait measures the TMT, FSST, and ABC Scale before and after a six week period to determine test–retest reliability and minimal detectable change (MDC) values. Linear relationships between gait and clinical measures were estimated using Pearson's correlation coefficients.
Spatiotemporal gait measures, the TMT total and the FSST showed good to excellent test–retest reliability (ICC > 0.75). MDC values were 0.30 m/s and 0.17 m/s for velocity in forward and backward walking respectively, four points for the TMT, and 3 s for the FSST. The TMT and FSST were highly correlated with most spatiotemporal measures. The ABC Scale demonstrated lower reliability and less concurrent validity than other measures.
The high test–retest reliability over a six week period and concurrent validity between the TMT, FSST, and spatiotemporal gait measures suggest that the TMT and FSST may be useful outcome measures for future intervention studies in ambulatory individuals with HD.
PMCID: PMC4230319  PMID: 25128156
Balance; Gait; Test–retest reliability; Validity; Huntington's disease
3.  Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder 
Brain  2013;136(9):2825-2835.
Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6–9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6–9, 12–15, and 18–24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 ‘high-risk’ infants having an older sibling with autism spectrum disorder and 22 ‘low-risk’ infants having no relatives with autism spectrum disorder) were imaged at 6–9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12–15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18–24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6–9 months, which persisted and remained elevated at 12–15 and 18–24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12–15 and 18–24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.
PMCID: PMC3754460  PMID: 23838695
autism; magnetic resonance imaging; infant brain development; cerebrospinal fluid; external hydrocephalus
4.  Ambulatory Subspecialty Visits in a Large Pediatric Primary Care Network 
Health Services Research  2012;47(4):1755-1769.
To determine patterns of subspecialty utilization within a pediatric primary care network.
Data Sources/Study Setting
Paid claims from a large not-for-profit health plan for patients of The Pediatric Physicians' Organization at Children's, a network of private pediatric practices affiliated with Children's Hospital Boston.
Principal Findings
The subspecialty visit rate was 1.01 visits per subject-year. In 2007, 56.8 percent of subjects had no subspecialty visits, whereas 4.2 percent had ≥5 visits; the corresponding figures in 2008 were 54.1 and 4.5 percent, respectively. The most frequently visited subspecialties were Ophthalmology, Orthopedics, Dermatology, Otorhinolaryngology, and Allergy/Immunology. Visit rates varied sevenfold by practice.
Wide practice variability in pediatric subspecialty utilization suggests an opportunity for reducing unnecessary visits. Better integration between primary care and the most commonly used subspecialties will be needed to meaningfully reduce unnecessary visits and enhance value.
PMCID: PMC3401409  PMID: 22375886
Specialty care; utilization; pediatrics
5.  Correlates of colorectal cancer screening among residents of Ohio Appalachia 
Journal of community health  2013;38(4):609-618.
There is an excess burden of colorectal cancer (CRC) in the Appalachian region of the U.S., which could be reduced by increased uptake of CRC screening tests. Thus, we examined correlates of screening among Appalachian residents at average-risk for CRC. Using a population-based sample, we conducted interviews with and obtained medical records of Appalachian Ohio residents 50–75 years between September 2009 and April 2010. Using multivariable logistic regression, we identified correlates of being within CRC screening guidelines by medical records. About half of participants were within CRC screening guidelines. Participants who were older (OR=1.04, 95% CI: 1.01, 1.07), had higher income ($30,000–$60,000, OR=1.92, 95% CI: 1.29, 2.86; ≥$60,000, OR=1.80, 95% CI: 1.19, 2.72), a primary care provider (OR=4.22, 95% CI: 1.33, 13.39), a recent check-up (OR=2.37, 95% CI: 1.12, 4.99), had been encouraged to be screened (OR=1.57, 95% CI: 1.11, 2.22), had been recommended by their doctor to be screened (OR=6.68, 95% CI: 3.87, 11.52), or asked their doctor to order a screening test (OR=2.24, 95% CI: 1.36, 3.69) had higher odds of being screened within guidelines in multivariable analysis. Findings suggest that access to and utilization of healthcare services, social influence, and patient-provider communication were the major factors associated with CRC screening. Researchers and healthcare providers should develop and implement strategies targeting these barriers/facilitators to improve CRC screening rates and reduce the CRC burden among residents of Appalachia.
PMCID: PMC3706501  PMID: 23529450
colorectal cancer; screening; Appalachia; health disparities
6.  Novel Small Molecule XPO1/CRM1 Inhibitors Induce Nuclear Accumulation of TP53, Phosphorylated MAPK and Apoptosis in Human Melanoma Cells 
PLoS ONE  2014;9(7):e102983.
XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI)], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.
PMCID: PMC4109950  PMID: 25057921
7.  Validation of Self-Reported Colorectal Cancer Screening Behaviors among Appalachian Residents 
Public health nursing (Boston, Mass.)  2013;30(4):10.1111/phn.12038.
We determined the validity of self-reported colorectal cancer (CRC) screening data provided by Appalachian Ohio residents and identified correlates of providing accurate data.
We conducted cross-sectional telephone interviews between September 2009 and April 2010.
Our study included Appalachian Ohio residents (n=721) ages 51–75.
We compared self-reported CRC screening data to medical records to determine validity. Multivariable logistic regression was used to identify correlates of providing accurate self-reported screening data.
About 68% of participants self-reported having any CRC screening test within recommended guidelines, while medical records indicated that only 49% were within guidelines (concordance=0.76). Concordance was higher for flexible sigmoidoscopy and FOBT compared to colonoscopy, though sensitivity and positive predictive value were much higher for colonoscopy. Participants overreported CRC screening behaviors for all tests. Participants who had a regular check-up in the last two years (OR=2.78, 95% CI: 1.15-6.73) or self-rated their health as good or better (OR=1.88, 95% CI: 1.12-3.16) were more likely to provide accurate screening data.
Many participants failed to provide accurate CRC screening data, and validity varied greatly across individual CRC screening tests. Future CRC screening studies among Appalachian residents should use medical records, if possible, to determine screening histories.
PMCID: PMC3809100  PMID: 23808856
Colorectal cancer; Cancer screening; Validity; Appalachia
8.  Avocado Consumption Enhances Human Postprandial Provitamin A Absorption and Conversion from a Novel High–β-Carotene Tomato Sauce and from Carrots12 
The Journal of Nutrition  2014;144(8):1158-1166.
Dietary lipids have been shown to increase bioavailability of provitamin A carotenoids from a single meal, but the effects of dietary lipids on conversion to vitamin A during absorption are essentially unknown. Based on previous animal studies, we hypothesized that the consumption of provitamin A carotenoids with dietary lipid would enhance conversion to vitamin A during absorption compared with the consumption of provitamin A carotenoids alone. Two separate sets of 12 healthy men and women were recruited for 2 randomized, 2-way crossover studies. One meal was served with fresh avocado (Persea americana Mill), cultivated variety Hass (delivering 23 g of lipid), and a second meal was served without avocado. In study 1, the source of provitamin A carotenoids was a tomato sauce made from a novel, high–β-carotene variety of tomatoes (delivering 33.7 mg of β-carotene). In study 2, the source of provitamin A carotenoids was raw carrots (delivering 27.3 mg of β-carotene and 18.7 mg of α-carotene). Postprandial blood samples were taken over 12 h, and provitamin A carotenoids and vitamin A were quantified in triglyceride-rich lipoprotein fractions to determine baseline-corrected area under the concentration-vs.-time curve. Consumption of lipid-rich avocado enhanced the absorption of β-carotene from study 1 by 2.4-fold (P < 0.0001). In study 2, the absorption of β-carotene and α-carotene increased by 6.6- and 4.8-fold, respectively (P < 0.0001 for both). Most notably, consumption of avocado enhanced the efficiency of conversion to vitamin A (as measured by retinyl esters) by 4.6-fold in study 1 (P < 0.0001) and 12.6-fold in study 2 (P = 0.0013). These observations highlight the importance of provitamin A carotenoid consumption with a lipid-rich food such as avocado for maximum absorption and conversion to vitamin A, especially in populations in which vitamin A deficiency is prevalent. This trial was registered at as NCT01432210.
PMCID: PMC4093981  PMID: 24899156
9.  Behavior and Sleep Problems in Children with a Family History of Autism 
The present study explores behavioral and sleep outcomes in preschool age siblings of children with autism spectrum disorders (ASD). This study focuses on behavior problems that are common in children with ASD, such as emotional reactivity, anxiety, inattention, aggression, and sleep problems. Infant siblings were recruited from families with at least one older child with ASD (high-risk group, n = 104) or families with no history of ASD (low-risk group, n = 76). As part of a longitudinal prospective study, children completed the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, and parents completed the Child Behavior Checklist (CBCL) and the Social Communication Questionnaire at 36 months of age. This study focuses on developmental concerns outside of ASD; therefore, only siblings who did not develop an ASD were included in analyses. Negative binomial regression analyses revealed that children in the high-risk group were more likely to have elevated behavior problems on the CBCL Anxious/Depressed and Aggression subscales. To explore sleep problems as a correlate of these behavior problems, a second series of models was specified. For both groups of children, sleep problems were associated with elevated behavior problems in each of the areas assessed (reactivity, anxiety, somatic complaints, withdrawal, attention, and aggression). These findings support close monitoring of children with a family history of ASD for both behavioral and sleep issues.
PMCID: PMC3947924  PMID: 23436793
autism; siblings; behavior problems; sleep
10.  Pancreatic Cancer-Associated Stellate Cells Promote Differentiation of Myeloid-Derived Suppressor Cells in a STAT3-Dependent Manner 
Cancer research  2013;73(10):3007-3018.
Pancreatic stellate cells (PSC) are a subset of pancreatic cancer-associated fibroblasts. These cells provide prosurvival signals to tumors; however, little is known regarding their interactions with immune cells within the tumor microenvironment. We hypothesized that factors produced by human PSC could enhance myeloid-derived suppressor cell (MDSC) differentiation and function, which promotes an immunosuppressive microenvironment. Primary PSC cell lines (n = 7) were generated from human specimens and phenotypically confirmed via expression of vimentin, α-smooth muscle actin (α-SMA), and glial fibrillary acidic protein (GFAP). Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF)] and chemokines (SDF-1, MCP-1). Culture of peripheral blood mononuclear cells [peripheral blood mononuclear cell (PBMC), n = 3 donors] with PSC supernatants or IL-6/granulocyte macrophage colony-stimulating factor (GM-CSF; positive control) for 7 days promoted PBMC differentiation into an MDSC (CD11b+CD33+) phenotype and a subpopulation of polymorphonuclear CD11b+CD33+CD15+ cells. The resulting CD11b+CD33+ cells functionally suppressed autologous T-lymphocyte proliferation. In contrast, supernatants from HPF did not induce an MDSC phenotype in PBMCs. Culture of normal PBMCs with PSC supernatants led to STAT3 but not STAT1 or STAT5 phosphorylation. IL-6 was an important mediator as its neutralization inhibited PSC supernatant-mediated STAT3 phosphorylation and MDSC differentiation. Finally, the FLLL32 STAT3 inhibitor abrogated PSC supernatant-mediated MDSC differentiation, PSC viability, and reduced autocrine IL-6 production indicating these processes are STAT3 dependent. These results identify a novel role for PSC in driving immune escape in pancreatic cancer and extend the evidence that STAT3 acts as a driver of stromal immunosuppression to enhance its interest as a therapeutic target.
PMCID: PMC3785672  PMID: 23514705
11.  Enhancing Cancer Screening in Primary Care: Rationale, Design, Analysis Plan, and Recruitment Results 
Contemporary clinical trials  2013;34(2):356-363.
Colorectal cancer (CRC) is the third leading type of cancer and the third leading cause of cancer death in the United States. National policy-making organizations recognize and support a variety of CRC screening strategies among average-risk adults aged 50 and older based on strong evidence showing that screening decreases mortality from CRC and can also reduce the incidence of the disease. The goal of this study was to test a multi-level stepped intervention to increase CRC screening rates. We used a group-randomized trial design where the units of assignment were clinics and the units of observation were eligible patients receiving care at those clinics, with stratified random assignment of clinics to study conditions. The primary analysis was planned as a mixed-model logistic regression to account for the expected positive intraclass correlation associated with clinics. Our recruitment experience reflected the difficulties of conducting research in the real world where changes in economic conditions, staff turnover/layoff, inadequate medical records, and poor acceptance of research can significantly impact study plans. It demonstrated the problems that can emerge when procedures used in the study depart from those used in the pilot work to generate parameter estimates for power analysis. It also demonstrated the importance of allowing for attrition at the group and patient levels so that if recruitment falls short, it is possible to maintain adequate power with only a slight increase in the detectable difference. This experience should assist others planning group-randomized trials, whether in cancer screening or in other areas.
PMCID: PMC3601898  PMID: 23357561
colorectal cancer; screening; group-randomized trial
12.  Beyond Autism: A Baby Siblings Research Consortium Study of High-Risk Children at Three Years of Age 
First-degree relatives of persons with an autism spectrum disorder (ASD) are at increased risk for ASD-related characteristics. As little is known about the early expression of these characteristics, this study characterizes the non-ASD outcomes of 3-year-old high-risk (HR) siblings of children with ASD.
Two groups of children without ASD participated: 507 HR siblings and 324 low-risk (LR) control subjects (no known relatives with ASD). Children were enrolled at a mean age of 8 months, and outcomes were assessed at 3 years. Outcome measures were Autism Diagnostic Observation Schedule (ADOS) calibrated severity scores, and Mullen Verbal and Non-Verbal Developmental Quotients (DQ).
At 3 years, HR siblings without an ASD outcome exhibited higher mean ADOS severity scores and lower verbal and non-verbal DQs than LR controls. HR siblings were over-represented (21% HR versus 7% LR) in latent classes characterized by elevated ADOS severity and/or low to low-average DQs. The remaining HR siblings without ASD outcomes (79%) belonged to classes in which they were not differentially represented with respect to LR siblings.
Having removed a previously identified 18.7% of HR siblings with ASD outcomes from all analyses, HR siblings nevertheless exhibited higher mean levels of ASD severity and lower levels of developmental functioning than LR children. However, the latent class membership of four-fifths of the HR siblings was not significantly different from that of LR control subjects. One-fifth of HR siblings belonged to classes characterized by higher ASD severity and/or lower levels of developmental functioning. This empirically derived characterization of an early-emerging pattern of difficulties in a minority of 3-year-old HR siblings suggests the importance of developmental surveillance and early intervention for these children.
PMCID: PMC3625370  PMID: 23452686
ASD; high-risk siblings; outcome; broad autism phenotype
13.  Effect of Oxygen Concentration on Viability and Metabolism in a Fluidized-Bed Bioartificial Liver Using 31P and 13C NMR Spectroscopy 
Many oxygen mass-transfer modeling studies have been performed for various bioartificial liver (BAL) encapsulation types; yet, to our knowledge, there is no experimental study that directly and noninvasively measures viability and metabolism as a function of time and oxygen concentration. We report the effect of oxygen concentration on viability and metabolism in a fluidized-bed NMR-compatible BAL using in vivo 31P and 13C NMR spectroscopy, respectively, by monitoring nucleotide triphosphate (NTP) and 13C-labeled nutrient metabolites, respectively. Fluidized-bed bioreactors eliminate the potential channeling that occurs with packed-bed bioreactors and serve as an ideal experimental model for homogeneous oxygen distribution. Hepatocytes were electrostatically encapsulated in alginate (avg. diameter, 500 μm; 3.5×107 cells/mL) and perfused at 3 mL/min in a 9-cm (inner diameter) cylindrical glass NMR tube. Four oxygen treatments were tested and validated by an in-line oxygen electrode: (1) 95:5 oxygen:carbon dioxide (carbogen), (2) 75:20:5 nitrogen:oxygen:carbon dioxide, (3) 60:35:5 nitrogen:oxygen:carbon dioxide, and (4) 45:50:5 nitrogen:oxygen:carbon dioxide. With 20% oxygen, β-NTP steadily decreased until it was no longer detected at 11 h. The 35%, 50%, and 95% oxygen treatments resulted in steady β-NTP levels throughout the 28-h experimental period. For the 50% and 95% oxygen treatment, a 13C NMR time course (∼5 h) revealed 2-13C-glycine and 2-13C-glucose to be incorporated into [2-13C-glycyl]glutathione (GSH) and 2-13C-lactate, respectively, with 95% having a lower rate of lactate formation. 31P and 13C NMR spectroscopy is a noninvasive method for determining viability and metabolic rates. Modifying tissue-engineered devices to be NMR compatible is a relatively easy and inexpensive process depending on the bioreactor shape.
PMCID: PMC3540897  PMID: 22835003
14.  Preventative topical diclofenac treatment differentially decreases tumor burden in male and female Skh-1 mice in a model of UVB-induced cutaneous squamous cell carcinoma 
Carcinogenesis  2012;34(2):370-377.
Ultraviolet B (UVB) light is the major environmental carcinogen contributing to non-melanoma skin cancer (NMSC) development. There are over 3.5 million NMSC diagnoses in two million patients annually, with men having a 3-fold greater incidence of squamous cell carcinoma (SCC) compared with women. Chronic inflammation has been linked to tumorigenesis, with a key role for the cyclooxygenase-2 (COX-2) enzyme. Diclofenac, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, currently is prescribed to patients as a short-term therapeutic agent to induce SCC precursor lesion regression. However, its efficacy as a preventative agent in patients without evidence of precursor lesions but with significant UVB-induced cutaneous damage has not been explored. We previously demonstrated in a murine model of UVB-induced skin carcinogenesis that when exposed to equivalent UVB doses, male mice had lower levels of inflammation but developed increased tumor multiplicity, burden and grade compared with female mice. Because of the discrepancy in the degree of inflammation between male and female skin, we sought to determine if topical treatment of previously damaged skin with an anti-inflammatory COX-2 inhibitor would decrease tumor burden and if it would be equally effective in the sexes. Our results demonstrated that despite observed sex differences in the inflammatory response, prolonged topical diclofenac treatment of chronically UVB-damaged skin effectively reduced tumor multiplicity in both sexes. Unexpectedly, tumor burden was significantly decreased only in male mice. Our data suggest a new therapeutic use for currently available topical diclofenac as a preventative intervention for patients predisposed to cutaneous SCC development before lesions appear.
PMCID: PMC3564442  PMID: 23125227
15.  Levels of Soluble Adhesion Molecules PECAM-1 and P-Selectin are Decreased in Children with Autism Spectrum Disorder 
Biological psychiatry  2012;72(12):1020-1025.
Although the etiopathology of Autism Spectrum Disorder (ASD) is not clear there is increasing evidence that dysfunction in the immune system affects many children with ASD. Findings of immune dysfunction in ASD include increases in inflammatory cytokines, chemokines and microglial activity in brain tissue and CSF, as well as abnormal peripheral immune cell function.
Adhesion molecules, such as platelet endothelial adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), P-Selectin, and L-Selectin, function to facilitate leukocyte transendothelial migration. We assessed concentrations of soluble adhesion molecules, sPECAM-1, sICAM-1, sVCAM-1, sP-Selectin, and sL-Selectin in the plasma of 49 participants with ASD, and 31 typically developing controls of the same age, all of whom were enrolled as part of the Autism Phenome Project (APP). Behavioral assessment, the levels of soluble adhesion molecules, head circumference and MRI measurements of brain volume were compared in the same subjects.
Levels of sPECAM-1 and sP-Selectin were significantly reduced in the ASD group compared to typically developing controls (p < 0.02). Soluble PECAM-1 levels were negatively associated with repetitive behavior and abnormal brain growth in children with ASD (p=0.03).
As adhesion molecules modulate the permeability and signaling at the blood brain barrier as well as leukocyte infiltration into the CNS, current data suggests a role for these molecules in the complex pathophysiology of ASD.
PMCID: PMC3496806  PMID: 22717029
Autism; PECAM-1; P-Selectin; CD31; CD62-P; Adhesion
17.  Extended UVB Exposures Alter Tumorigenesis and Treatment Efficacy in a Murine Model of Cutaneous Squamous Cell Carcinoma 
Journal of Skin Cancer  2013;2013:246848.
Epidemiological studies support a link between cumulative sun exposure and cutaneous squamous cell carcinoma (SCC) development. However, the presumed effects of extended ultraviolet light B (UVB) exposure on tumorigenesis in the sexes have not been formally investigated. We examined differences in ultimate tumorigenesis at 25 weeks in mice exposed to UVB for either 10 or 25 weeks. Additionally, we investigated the effect of continued UVB exposure on the efficacy of topical treatment with anti-inflammatory (diclofenac) or antioxidant (C E Ferulic or vitamin E) compounds on modulating tumorigenesis. Vehicle-treated mice in the 25-week UVB exposure model exhibited an increased tumor burden and a higher percentage of malignant tumors compared to mice in the 10-week exposure model, which correlated with increases in total and mutant p53-positive epidermal cells. Only topical diclofenac decreased tumor number and burden in both sexes regardless of UVB exposure length. These data support the commonly assumed but not previously demonstrated fact that increased cumulative UVB exposure increases the risk of UVB-induced SCC development and can also affect therapeutic efficacies. Our study suggests that cessation of UVB exposure by at-risk patients may decrease tumor development and that topical NSAIDs such as diclofenac may be chemopreventive.
PMCID: PMC3826430  PMID: 24286011
18.  PRMT5 Is Upregulated in Malignant and Metastatic Melanoma and Regulates Expression of MITF and p27Kip1 
PLoS ONE  2013;8(9):e74710.
Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte-lineage specific oncogene, and increased expression of the cell cycle regulator p27Kip1. These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27Kip1 expression in human melanoma cells.
PMCID: PMC3786975  PMID: 24098663
19.  The Ohio Patient Navigation Research Program (OPNRP): Does the American Cancer Society patient navigation model improve time to resolution among patients with abnormal screening tests? 
Patient navigation (PN) has been suggested as a way to reduce cancer health disparities; however, many models of PN exist and most have not been carefully evaluated. The goal of this study was to test the Ohio American Cancer Society model of PN as it relates to reducing time to diagnostic resolution among persons with abnormal breast, cervical, or colorectal cancer screening tests or symptoms.
862 patients from 18 clinics participated in this group-randomized trial. Chart review documented the date of the abnormality and the date of resolution. The primary analysis used shared frailty models to test for the effect of PN on time to resolution. Crude Hazard Ratios (HR)were used since there was no evidence of confounding. Costs were tracked with a 52-item instrument that recorded fixed costs of running a PN program and operational costs of navigating patients.
HRs became significant at 6 months; conditional on the random clinic effect, the resolution rate at 15 months was 65% higher in the PN arm (p=0.012 for difference in risk across arms; p=0.009) for an increase in relative risk over time. The cost of navigating to diagnostic resolution averaged $150 per participant.
Participants with abnormal cancer screening tests or symptoms resolved faster if assigned to PN compared to those not assigned to PN. The effect of PN became apparent beginning six months after detection of the abnormality.
PN may help address health disparities by reducing time to resolution after an abnormal cancer screening test.
PMCID: PMC3785236  PMID: 23045536
cancer; patient navigation; abnormal screening tests; disparities
20.  Imitation from 12 to 24 months in autism and typical development: A longitudinal Rasch analysis 
Developmental psychology  2011;47(6):1565-1578.
The development of imitation during the second year of life plays an important role in domains of socio-cognitive development such as language and social learning. Deficits in imitation ability in persons with autism spectrum disorder (ASD) have also been repeatedly documented from toddlerhood into adulthood, raising the possibility that early disruptions in imitation contribute to the onset of ASD and the deficits in language and social interaction that define the disorder. This study prospectively examined the development of imitation between 12 and 24 months of age in 154 infants at familial risk for ASD and 78 typically developing infants who were all later assessed at 36 months for ASD or other developmental delays. The study established a developmental measure of imitation ability, and examined group differences over time, using an analytic Rasch measurement model. Results revealed a unidimensional latent construct of imitation and verified a reliable sequence of imitation skills that was invariant over time for all outcome groups. Results also showed that all groups displayed similar significant linear increases in imitation ability between 12 and 24 months and that these increases were related to individual growth in both expressive language and ratings of social engagement, but not fine motor development. The group of children who developed ASD by age 3 years exhibited delayed imitation development compared to the low-risk typical outcome group across all time-points, but were indistinguishable from other high-risk infants who showed other cognitive delays not related to ASD.
PMCID: PMC3712626  PMID: 21910524
imitation; autism; Rasch analysis; early identification; HGLM
21.  Onset patterns in autism: Correspondence between home video and parent report 
The onset of autism is usually conceptualized as occurring in one of two patterns, an early onset and a regressive pattern. This study examined the number and shape of trajectories of symptom onset evident in coded home movies of children with autism and examined their correspondence with parent report of onset.
Four social-communicative behaviors were coded from the home video of children with autism (n = 52) or typical development (n = 23). All home video from 6 through 24 months of age was coded (3199 segments). Latent class modeling was used to characterize trajectories and determine the optimal number needed to describe the coded home video. These trajectories were then compared to parent report of onset patterns, as defined by the Autism Diagnostic Interview-Revised.
A three trajectory model best fit the data from the participants with autism. One trajectory displayed low levels of social-communication across time. A second trajectory displayed high levels of social-communication early in life, followed by a significant decline over time. A third trajectory displayed initial levels of behavior that were similar to the typically developing group, but little progress in social-communication with age. There was poor correspondence between home video-based trajectories and parent report of onset.
More than two onset categories may be needed to describe the ways in which symptoms emerge in children with autism. There is low agreement between parent report and home video, suggesting that methods for improving parent report of early development must be developed.
PMCID: PMC3668453  PMID: 21784299
Autism; regression; onset; parent report
22.  Differential Effects of Topical Vitamin E and C E Ferulic® Treatments on Ultraviolet Light B-Induced Cutaneous Tumor Development in Skh-1 Mice 
PLoS ONE  2013;8(5):e63809.
Because of the ever-increasing incidence of ultraviolet light B (UVB)-induced skin cancer, considerable attention is being paid to prevention through the use of both sunscreens and after sun treatments, many of which contain antioxidants. Vitamin E is included as an antioxidant in many sunscreens and lotions currently on the market. Studies examining the efficacy of vitamin E as a topical preventative agent for UVB-induced skin cancer have yielded conflicting results. A likely contributor to differences in study outcome is the stability of vitamin E in the particular formulation being tested. In the current study we examined the effects of topical vitamin E alone as well as vitamin E combined with vitamin C and ferulic acid in a more stable topical formula (C E Ferulic®). Mice were exposed to UVB for 10 weeks in order to induce skin damage. Then, before the appearance of any cutaneous lesions, mice were treated for 15 weeks with a topical antioxidant, without any further UVB exposure. We found that topical C E Ferulic decreased tumor number and tumor burden and prevented the development of malignant skin tumors in female mice with chronically UVB-damaged skin. In contrast, female mice chronically exposed to UVB and treated topically with vitamin E alone showed a trend towards increased tumor growth rate and exhibited increased levels of overall DNA damage, cutaneous proliferation, and angiogenesis compared to vehicle-treated mice. Thus, we have demonstrated that topical 5% alpha tocopherol may actually promote carcinogenesis when applied on chronically UVB-damaged skin while treating with a more stable antioxidant compound may offer therapeutic benefits.
PMCID: PMC3653797  PMID: 23691100
23.  The “fossilized” mitochondrial genome of Liriodendron tulipifera: ancestral gene content and order, ancestral editing sites, and extraordinarily low mutation rate 
BMC Biology  2013;11:29.
The mitochondrial genomes of flowering plants vary greatly in size, gene content, gene order, mutation rate and level of RNA editing. However, the narrow phylogenetic breadth of available genomic data has limited our ability to reconstruct these traits in the ancestral flowering plant and, therefore, to infer subsequent patterns of evolution across angiosperms.
We sequenced the mitochondrial genome of Liriodendron tulipifera, the first from outside the monocots or eudicots. This 553,721 bp mitochondrial genome has evolved remarkably slowly in virtually all respects, with an extraordinarily low genome-wide silent substitution rate, retention of genes frequently lost in other angiosperm lineages, and conservation of ancestral gene clusters. The mitochondrial protein genes in Liriodendron are the most heavily edited of any angiosperm characterized to date. Most of these sites are also edited in various other lineages, which allowed us to polarize losses of editing sites in other parts of the angiosperm phylogeny. Finally, we added comprehensive gene sequence data for two other magnoliids, Magnolia stellata and the more distantly related Calycanthus floridus, to measure rates of sequence evolution in Liriodendron with greater accuracy. The Magnolia genome has evolved at an even lower rate, revealing a roughly 5,000-fold range of synonymous-site divergence among angiosperms whose mitochondrial gene space has been comprehensively sequenced.
Using Liriodendron as a guide, we estimate that the ancestral flowering plant mitochondrial genome contained 41 protein genes, 14 tRNA genes of mitochondrial origin, as many as 7 tRNA genes of chloroplast origin, >700 sites of RNA editing, and some 14 colinear gene clusters. Many of these gene clusters, genes and RNA editing sites have been variously lost in different lineages over the course of the ensuing ∽200 million years of angiosperm evolution.
PMCID: PMC3646698  PMID: 23587068
Angiosperm; RNA editing; Molecular evolution; Substitution rate; Intracellular gene transfer; Mitochondrial genome
24.  CYP2D6 genotypes, endoxifen levels, and disease recurrence in 224 Filipino and Vietnamese women receiving adjuvant tamoxifen for operable breast cancer 
SpringerPlus  2013;2:52.
While tamoxifen activity is mainly due to endoxifen and the concentration of this active metabolite is, in part, controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results.
In an exploratory study, we determined the CYP2D6 metabolic status and plasma concentrations of endoxifen among 224 Filipino and Vietnamese women participating in a clinical trial of adjuvant hormonal therapy for operable breast cancer. We further conducted a nested-case–control study among 48 women (half with recurrent disease, half without) investigating the relationship of endoxifen concentrations and recurrence of disease.
We found a significant association of reduced endoxifen plasma concentrations with functionally important CYP2D6 genotypes. High endoxifen concentrations were associated with higher risk of recurrence; with a quadratic trend fitted to a stratified Cox proportional hazards regression model, the likelihood ratio p-value was 0.002. The trend also showed that in 8 out of 9 pairs with low endoxifen concentrations, the recurrent case had lower endoxifen levels than the matched control.
This exploratory analysis suggests that there is an optimal range for endoxifen concentrations to achieve favorable effects as adjuvant therapy. In particular, at higher concentrations (>70, endoxifen may promote recurrence.
PMCID: PMC3584248  PMID: 23476897
25.  Cytoplasmic Estrogen Receptor in breast cancer 
Clinical Cancer Research  2011;18(1):118-126.
In addition to genomic signaling, it is accepted that ERα has non-nuclear signaling functions, which correlate with tamoxifen resistance in preclinical models. However, evidence for cytoplasmic ER localization in human breast tumors is less established. We sought to determine the presence and implications of non-nuclear ER in clinical specimens.
Experimental Design
A panel of ERα-specific antibodies (SP1, MC20, F10, 60c, 1D5) were validated by western blot and quantitative immunofluorescent (QIF) analysis of cell lines and patient controls. Then eight retrospective cohorts collected on tissue microarrays were assessed for cytoplasmic ER. Four cohorts were from Yale (YTMA 49, 107, 130, 128) and four others (NCI YTMA 99, South Swedish Breast Cancer Group SBII, NSABP B14, and a Vietnamese Cohort) from other sites around the world.
Four of the antibodies specifically recognized ER by western and QIF, showed linear increases in amounts of ER in cell line series with progressively increasing ER, and the antibodies were reproducible on YTMA 49 with pearson’s correlations (r2 values)ranging from 0.87-0.94. One antibody with striking cytoplasmic staining (MC20) failed validation. We found evidence for specific cytoplasmic staining with the other 4 antibodies across eight cohorts. The average incidence was 1.5%, ranging from 0 to 3.2%.
Our data shows ERα present in the cytoplasm in a number of cases using multiple antibodies, while reinforcing the importance of antibody validation. In nearly 3,200 cases, cytoplasmic ER is present at very low incidence, suggesting its measurement is unlikely to be of routine clinical value.
PMCID: PMC3263348  PMID: 21980134
non-nuclear; Estrogen Receptor; cytoplasmic; breast cancer

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