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1.  Associations Between Abnormal Rod-Mediated Dark Adaptation and Health and Functioning in Older Adults With Normal Macular Health 
Delayed rod-mediated dark adaptation (DA) is characteristic of early age-related macular degeneration (AMD) and also can be observed in some older adults in normal macular health. We examine cross-sectional associations between rod-mediated DA and risk factors for AMD in older adults in normal macular health.
The sample consisted of adults aged ≥60 years old in normal macular health per grading of fundus photos using an established disease classification system. Rod-mediated DA was measured psychophysically following a photobleach using a computer-automated dark adaptometer with targets centered at 5° on the inferior vertical meridian. The speed of DA was characterized by the rod-intercept value, with abnormal DA defined as rod-intercept ≥ 12.3 minutes. We assessed several health and functional characteristics that the literature has suggested increase AMD risk (e.g., smoking, alcohol use, inflammatory markers, apolipoproteins, low luminance visual acuity, chronic medical conditions, body mass, family history).
Among 381 participants (mean age, 68.5 years; SD, 5.5), 78% had normal and 22% had abnormal DA, with the prevalence of abnormal DA increasing with age. After age-adjustment, abnormal DA was associated with increased odds of elevated C-reactive protein (CRP), heavy use of or abstention from alcohol, high blood pressure, and drop in visual acuity under mesopic conditions.
Despite having normal macular health according to accepted definitions of AMD presence, approximately one-quarter of older adults recruited from primary eye care clinics had abnormal DA, which was associated with known risk factors for AMD, including elevated CRP.
Abnormal rod-mediated dark adaptation in older adults in normal macular health is associated with elevated plasma C-reactive protein levels.
PMCID: PMC4122017  PMID: 24854857
aging; dark adaptation; rod function; age-related macular degeneration
2.  HER2-Positive Breast Cancer: Current Management of Early, Advanced, and Recurrent Disease 
Purpose of review
This review describes the current treatment of human epidermal growth factor receptor-2 (HER2) positive breast cancer with a focus on recently reported clinical trials. Treatment of resistant disease and central nervous system metastases will be reviewed as will new agents that are being developed to target HER2 amplified breast cancers.
Recent Findings
Recent studies evaluating trastuzumab-resistant breast cancer have shown a benefit of continuing trastuzumab with chemotherapy or with another HER2-targeted agent. Targeting the vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and PI3 kinase pathways in addition to HER2 may enhance efficacy compared with individual agents. Several novel anti-HER2 compounds are being evaluated with promising early data.
HER2-positive breast cancer has traditionally been associated with poor prognosis. However, treatment with HER2-targeted therapies has changed the natural history of this disease. Greater success depends on elucidating mechanisms of resistance and exploring new methods of blocking signal transduction via HER2 and related pathways.
PMCID: PMC4307801  PMID: 21500375
Breast cancer; HER2; trastuzumab; lapatinib; brain metastases
3.  Complete Genome Sequence of Pseudoalteromonas sp. Strain OCN003, Isolated from Kāne’ohe Bay, O’ahu, Hawaii 
Genome Announcements  2015;3(1):e01396-14.
Pseudoalteromonas sp. strain OCN003 is a marine gammaproteobacterium that was isolated from a diseased colony of the common Hawaiian reef coral, Montipora capitata, found on a reef surrounding Moku o Lo’e in Kāne’ohe Bay, Hawaii. Here, we report the complete genome of Pseudoalteromonas sp. strain OCN003.
PMCID: PMC4299895  PMID: 25593253
4.  Identifying Zn-bound histidine residues in metalloproteins using hydrogen deuterium exchange mass spectrometry 
Analytical chemistry  2013;86(1):766-773.
In this work we have developed a method that uses hydrogen deuterium exchange (HDX) of C2-hydrogens of histidines coupled with mass spectrometry (MS) to identify Zn-bound histidines in metalloproteins. This method relies on differences in HDX reaction rates of Zn-bound and Zn-free His residues. Using several model peptides and proteins, we find that all Zn-bound His residues have substantially lower HDX reaction rates in the presence of the metal. The vast majority of non-Zn-binding His residues undergo no significant changes in HDX reaction rates when their reactivity is compared in the presence and absence of Zn. Using this new approach, we then determined the Zn binding site of β-2-microglobulin, a protein associated with metal-induced amyloidosis. Together these results suggest that HDX-MS of His C2-hydrogens is a promising new method for identifying Zn-bound histidines in metalloproteins.
PMCID: PMC3912567  PMID: 24313328
5.  Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor 
Cancer immunology research  2013;2(1):10.1158/2326-6066.CIR-13-0160.
RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.
PMCID: PMC3883307  PMID: 24416731
Melanoma; BRAF; RAF inhibitors; CTLA-4; immunotherapy; T cell
6.  Depressive Symptom Clusters as Predictors of Incident Coronary Artery Disease Events: A 15-Year Prospective Study of Older Adults 
Psychosomatic medicine  2013;76(1):38-43.
Because it is not known whether particular clusters of depressive symptoms are more cardiotoxic than others, we compared the utility of four clusters in predicting incident coronary artery disease (CAD) events over 15 years in large cohort of older primary care patients.
Participants were 2,537 primary care patients aged ≥ 60 years who were screened for depression between 1991–1993 and had no existing CAD diagnosis. Depressive symptoms clusters scores (depressed affect, somatic symptoms, interpersonal distress, and positive affect) were computed from responses on the Center for Epidemiologic Studies Depression Scale administered at baseline. CAD events, defined as the occurrence of a nonfatal acute myocardial infarction or CAD death during the follow-up period, were identified using electronic medical record and National Death Index data.
There were 678 CAD events. In separate fully-adjusted Cox proportional hazard models (controlling for demographics and cardiovascular risk factors), the depressed affect (HR = 1.11, 95% CI: 1.04–1.20), somatic (HR = 1.17, 95% CI: 1.08–1.26), and positive affect (HR = 0.88, 95% CI: 0.82–0.95) clusters each predicted CAD events. When the depressive symptom clusters were entered simultaneously into the fully-adjusted model, however, only the somatic cluster remained predictive of CAD events (HR = 1.13, 95% CI: 1.03–1.23).
Our findings suggest that the longitudinal relationship between overall depressive symptom severity and incident CAD events may be driven primarily by the somatic cluster.
PMCID: PMC3891500  PMID: 24367122
Coronary artery disease; depression; depressive symptoms clusters; elderly; primary care; prospective study
7.  Effect of Collaborative Care for Depression on Risk of Cardiovascular Events: Data from the IMPACT Randomized Controlled Trial 
Psychosomatic medicine  2013;76(1):29-37.
Although depression is a risk and prognostic factor for cardiovascular disease (CVD), depression trials involving cardiac patients have not observed the anticipated cardiovascular benefits. To test our hypothesis that depression treatment delivered before clinical CVD onset reduces risk of CVD events, we conducted an 8-year follow-up study of the Indiana sites of the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) randomized controlled trial.
Participants were 235 primary care patients aged ≥60 years with major depression or dysthymia who were randomized to a 12-month collaborative care program involving antidepressants and psychotherapy (85 without and 35 with baseline CVD) or usual care (83 without and 32 with baseline CVD). Hard CVD events (fatal/nonfatal) were identified using electronic medical record and Medicare/Medicaid data.
119 patients (51%) had a hard CVD event. As hypothesized, the Treatment x Baseline CVD interaction was significant (p = .021). IMPACT patients without baseline CVD had a 48% lower risk of an event than Usual Care patients (28% vs. 47%, HR = 0.52, 95% CI: 0.31–0.86). The number needed to treat to prevent one event over five years was 6.1. The likelihood of an event did not differ between IMPACT and Usual Care patients with baseline CVD (86% vs. 81%, HR = 1.19, 95% CI: 0.70–2.03).
Collaborative depression care delivered before CVD onset halved the excess risk of hard CVD events among older, depressed patients. Our findings raise the possibility that the IMPACT intervention could be used as a CVD primary prevention strategy.
Trial Registration Identifier: NCT01561105 (
PMCID: PMC3899245  PMID: 24367124
depression; coronary disease; cerebrovascular disorders; follow-up studies; prevention
8.  Comparisons of Body Image Perceptions of a Sample of Black and White Women with Rheumatoid Arthritis and Fibromyalgia in the US 
Objective :
To explore the disease-related, body image (BI) perceptions of women diagnosed with, rheumatoid arthritis (RA) and fibromyalgia (FM).
Methods :
A purposive sample of twenty-seven females participated in individual semi-structured phone interviews to elicit BI perceptions relative to pain, activity limitations and coping measures. Sessions were digitally recorded, transcribed verbatim, and content analyzed.
Results :
Body image perceptions relative to 5 major themes emerged in the analysis. They focused on Pain, Disease Impact on Physical and Mental Function, Weight, Diseased-Induced Fears and, Coping measures. Pain was a common experience of all participants. Other troubling factors verbalized by participants included dislike and shame of visibly affected body parts, and disease-induced social, psychological and physical limitations. RA participants thought that manifested joint changes, such as swelling and redness, undergirded their prompt diagnosis and receipt of health care. Contrarily, women with fibromyalgia perceived that the lack of visible, disease-related, physical signs led to a discounting of their disease, which led to delayed health care and subsequent frustrations and anger. All but one participant used prayer and meditation as a coping measure.
Conclusion :
The body image perceptions evidenced by the majority of participants were generally negative and included specific focus on their disease-affected body parts (e.g. joints), mental function, self-identity, health care experiences, activity limitations and overall quality of life. Given the global effect of RA and FM, assessment and integration of findings about the BI perceptions of individuals with FM and RA may help define suitable interdisciplinary strategies for managing these conditions and improving participants’ quality of life.
PMCID: PMC4319189
Black women; body image; fibromyalgia; perceptions; rheumatoid arthritis; white women.
9.  Complete Genome Sequence of Vibrio coralliilyticus Strain OCN014, Isolated from a Diseased Coral at Palmyra Atoll 
Genome Announcements  2014;2(6):e01318-14.
Vibrio coralliilyticus is a marine gammaproteobacterium that has been implicated as an etiological agent of disease for multiple coral genera on reefs worldwide. We report the complete genome of V. coralliilyticus strain OCN014, isolated from a diseased Acropora cytherea colony off the western reef terrace of Palmyra Atoll.
PMCID: PMC4271164  PMID: 25523774
10.  Geographic miss of lung tumours due to respiratory motion: a comparison of 3D vs 4D PET/CT defined target volumes 
PET/CT scans acquired in the radiotherapy treatment position are typically performed without compensating for respiratory motion. The purpose of this study was to investigate geographic miss of lung tumours due to respiratory motion for target volumes defined on a standard 3D-PET/CT.
29 patients staged for pulmonary malignancy who completed both a 3D-PET/CT and 4D-PET/CT were included. A 3D-Gross Tumour Volume (GTV) was defined on the standard whole body PET/CT scan. Subsequently a 4D-GTV was defined on a 4D-PET/CT MIP. A 5 mm, 10 mm, 15 mm symmetrical and 15×10 mm asymmetrical Planning Target Volume (PTV) was created by expanding the 3D-GTV and 4D-GTV’s. A 3D conformal plan was generated and calculated to cover the 3D-PTV. The 3D plan was transferred to the 4D-PTV and analysed for geographic miss. Three types of miss were measured. Type 1: any part of the 4D-GTV outside the 3D-PTV. Type 2: any part of the 4D-PTV outside the 3D-PTV. Type 3: any part of the 4D-PTV receiving less than 95% of the prescribed dose. The lesion motion was measured to look at the association between lesion motion and geographic miss.
When a standard 15 mm or asymmetrical PTV margin was used there were 1/29 (3%) Type 1 misses. This increased 7/29 (24%) for the 10 mm margin and 23/29 (79%) for a 5 mm margin. All patients for all margins had a Type 2 geographic miss. There was a Type 3 miss in 25 out of 29 cases in the 5, 10, and 15 mm PTV margin groups. The asymmetrical margin had one additional Type 3 miss. Pearson analysis showed a correlation (p < 0.01) between lesion motion and the severity of the different types of geographic miss.
Without any form of motion suppression, the current standard of a 3D- PET/CT and 15 mm PTV margin employed for lung lesions has an increasing risk of significant geographic miss when tumour motion increases. Use of smaller asymmetric margins in the cranio-caudal direction does not comprise tumour coverage. Reducing PTV margins for volumes defined on 3D-PET/CT will greatly increase the chance and severity of a geometric miss due to respiratory motion. 4D-imaging reduces the risk of geographic miss across the population of tumour sizes and magnitude of motion investigated in the study.
PMCID: PMC4278238  PMID: 25511904
4D-PET/CT; Geographic miss; Lung cancer; Margins; Radiotherapy
11.  Comorbidity Profile and Health Care Utilization in Elderly Patients with Serious Mental Illnesses 
Patients with serious mental illness are living longer. Yet there remain few studies that focus on health care utilization and its relationship to comorbidities in these elderly mentally ill patients.
Comparative study. Information on demographics, comorbidities and health care utilization were taken from an electronic medical record system.
Wishard Health Services senior care and community mental health clinics.
Patients age 65 years and over-255 patients with serious mental illness (schizophrenia, major recurrent depression and bipolar illness) attending a mental health clinic and a representative sample of 533 non-demented patients without serious mental illness attending primary care clinics.
Patients having serious mental illness had significantly higher rates of medical emergency room visits (p=0.0027) and significantly longer lengths of medical hospitalizations (p<0.0001) than did the primary care control group. The frequency of medical comorbidities such as diabetes, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, thyroid disease, and cancer were not significantly different between the groups. Hypertension was lower in the mentally ill group (p<0.0001). Reported falls (p<0.0001), diagnoses of substance abuse (p=0.02), and alcoholism (p=0.0016) were higher in the seriously mentally ill. The differences in health care utilization between the groups remained significant after adjusting for comorbidity levels, lifestyle factors, and attending primary care.
Our findings of higher rates of emergency care, longer hospitalizations, and increased frequency of falls, substance abuse, and alcoholism suggest the elderly seriously mentally ill remain a vulnerable population requiring an integrated model of health care.
PMCID: PMC3572246  PMID: 24206938
serious mental illness; comorbidity; health care utilization; elderly patients
12.  Chlorpyrifos Exposure and Respiratory Health among Adolescent Agricultural Workers 
Chlorpyrifos (CPF) is a commonly used organophosphate insecticide (OP). In adults, exposure to OPs has been inconsistently associated with reduced lung function. OP exposure and lung function has not been assessed in adolescents. The objective of this study was to assess CPF exposure and lung function among Egyptian adolescents. We conducted a 10-month study of male adolescent pesticide applicators (n = 38) and non-applicators of similar age (n = 24). Urinary 3,5,6-trichloro-2-pyridinol (TPCy), a CPF-specific metabolite, was analyzed in specimens collected throughout the study. Spirometry was performed twice after pesticide application: day 146, when TCPy levels were elevated and day 269, when TCPy levels were near baseline. Applicators had higher levels of TCPy (mean cumulative TCPy day 146 = 33,217.6; standard deviation (SD) = 49,179.3) than non-applicators (mean cumulative TCPy day 146 = 3290.8; SD = 3994.9). Compared with non-applicators, applicators had higher odds of reporting wheeze, odds ratio = 3.41 (95% CI: 0.70; 17.41). Cumulative urinary TCPy was inversely associated with spirometric measurements at day 146, but not at day 269. Although generally non-significant, results were consistent with an inverse association between exposure to CPF and lung function.
PMCID: PMC4276666  PMID: 25522051
chlorpyrifos; lung function; adolescents
Pain  2013;154(12):10.1016/j.pain.2013.08.024.
Pain behaviors that are maintained beyond the acute stage post-injury can contribute to subsequent psychosocial and physical disability. Critical to the study of pain behaviors is the availability of psychometrically sound pain behavior measures. In this study we developed a self-report measure of pain behaviors, the Pain Behaviors Self Report (PaB-SR). PaB-SR scores were developed using item response theory and evaluated using a rigorous, multiple-witness approach to validity testing. Participants included: a) 661 survey participants with chronic pain and with multiple sclerosis (MS), back pain, or arthritis; b) 618 survey participants who were significant others of a chronic pain participant; and c) 86 participants in a videotaped pain behavior observation protocol. Scores on the PaB-SR were found to be measurement invariant with respect to clinical condition. PaB-SR scores, observer-reports, and the video-taped protocol yielded distinct, but convergent views of pain behavior, supporting the validity of the new measure. The PaB-SR is expected to be of substantial utility to researchers wishing to explore the relationship between pain behaviors and constructs such as pain intensity, pain interference, and disability.
PMCID: PMC3875313  PMID: 23994451
Chronic pain; assessment; psychometrics
15.  Short communication: timeline of radiation-induced kidney function loss after stereotactic ablative body radiotherapy of renal cell carcinoma as evaluated by serial 99mTc-DMSA SPECT/CT 
Stereotactic ablative body radiotherapy (SABR) has been proposed as a definitive treatment for patients with inoperable primary renal cell carcinoma. However, there is little documentation detailing the radiobiological effects of hypofractionated radiation on healthy renal tissue.
In this study we describe a methodology for assessment of regional change in renal function in response to single fraction SABR of 26 Gy. In a patient with a solitary kidney, detailed follow-up of kidney function post-treatment was determined through 3-dimensional SPECT/CT imaging and 51Cr-EDTA measurements. Based on measurements of glomerular filtration rate, renal function declined rapidly by 34% at 3 months, plateaued at 43% loss at 12 months, with minimal further decrease to 49% of baseline by 18 months.
The pattern of renal functional change in 99mTc-DMSA uptake on SPECT/CT imaging correlates with dose delivered. This study demonstrates a dose effect relationship of SABR with loss of kidney function.
PMCID: PMC4251855  PMID: 25424613
Stereotactic radiation; Renal cell carcinoma; Primary kidney cancer; Functional imaging; Single photon emission tomography
16.  Microfluidic continuous-flow radiosynthesis of [18F]FPEB suitable for human PET imaging 
MedChemComm  2013;5(4):432-435.
The synthesis of fluorine-18 labeled 3-fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([18F]FPEB) for imaging metabotropic glutamate receptor subtype type 5 (mGluR5) was achieved with a commercial continuous-flow microfluidics device. This work represents the first positron emission tomography (PET) radiopharmaceutical that is suitable for human use with this technology. We also describe a validated synthesis of [18F]FPEB with a commercial reactor-based system.
PMCID: PMC4243709  PMID: 25431646
17.  Academic achievement and course taking among language minority youth in U.S. schools: Effects of ESL placement 
The 1974 Lau decision requires that U.S. public schools ensure a meaningful education for students learning English. English as a Second Language (ESL) placement is an institutional response to the linguistic needs of these students; however, its academic implications remain largely unexplored. Using nationally representative data from the Educational Longitudinal Study (ELS), the effects of ESL placement on college preparatory course enrollment and academic achievement of language minority students are estimated, first with fixed effects regression models and then with multi-level propensity score matching techniques. While numerous school and individual level factors beyond language proficiency predict ESL placement, a significant negative estimated effect of ESL placement on science enrollment and cumulative GPA is consistently found. Perhaps more important, however, no positive effects of ESL placement on the achievement of language minority youth are found when accounting for English proficiency and other potential covariates.
PMCID: PMC4244003  PMID: 25431506
ESL; immigrant; language minority; policy; school context
18.  Effects of Dietary Fat and Saturated Fat Content on Liver Fat and Markers of Oxidative Stress in Overweight/Obese Men and Women under Weight-Stable Conditions 
Nutrients  2014;6(11):4678-4690.
Dietary fat and oxidative stress are hypothesized to contribute to non-alcoholic fatty liver disease and progression to steatohepatitis. To determine the effects of dietary fat content on hepatic triglyceride, body fat distribution and markers of inflammation and oxidative stress, overweight/obese subjects with normal glucose tolerance consumed a control diet (CONT: 35% fat/12% saturated fat/47% carbohydrate) for ten days, followed by four weeks on a low fat (LFD (n = 10): 20% fat/8% saturated fat/62% carbohydrate) or high fat diet (HFD (n = 10): 55% fat/25% saturated fat/27% carbohydrate). Hepatic triglyceride content was quantified by MRS and abdominal fat distribution by MRI. Fasting biomarkers of inflammation (plasma hsCRP, IL-6, IL-12, TNFα, IFN-γ) and oxidative stress (urinary F2-α isoprostanes) were measured. Body weight remained stable. Compared to the CONT, hepatic triglyceride decreased on the LFD (mean (95% CI): change −2.13% (−3.74%, −0.52%)), but did not change on the HFD and there was no significant difference between the LFD and HFD. Intra-abdominal fat did not change significantly on either diet, but subcutaneous abdominal fat increased on the HFD. There were no significant changes in fasting metabolic markers, inflammatory markers and urinary F2-α isoprostanes. We conclude that in otherwise healthy overweight/obese adults under weight-neutral conditions, a diet low in fat and saturated fat has modest effects to decrease liver fat and may be beneficial. On the other hand, a diet very high in fat and saturated fat had no effect on hepatic triglyceride or markers of metabolism, inflammation and oxidative stress.
PMCID: PMC4245556  PMID: 25353663
non-alcoholic fatty liver; dietary fat; saturated fat; oxidative stress
19.  Bridging Worlds in the Social Studies Classroom:Teachers' Practices and Latino Immigrant Youths' Civic and Political Development 
Prior research suggests that high school experiences shape young adult political behaviors, particularly among immigrant youth. The U.S. social studies classroom, focused on democratic citizenship education, proves an interesting socializing institution.
Through qualitative inquiry, we interviewed Latino immigrant young adults and their former teachers regarding their high school social studies experiences and evolving political and civic engagement.
indicate that armed with experience bridging the worlds of the school and home, immigrant students respond and relate to the content and pedagogy of the social studies classroom in such a way that they (1) participate in civic discourse and (2) nurture a disposition toward leadership through teachers' civic expectations of them and instructional emphasis on critical thinking skills.
Social Implications
The ability to engage in civic discourse and a disposition toward leadership are both necessary to foster America's democratic ideals, and to take on leadership roles during adulthood. With focused effort on the unique perspective of immigrant youth, high school social studies teachers can nurture in these students the ability to become leaders in young adulthood, broadening the potential leadership pool.
This study highlights how the social studies curriculum may be particularly salient to Latino immigrant youth as they transition from adolescence to young adulthood and develop their political and civic identities.
PMCID: PMC4215544  PMID: 25364306
immigrant; civic development; high school; adolescence; pedagogy
20.  Netrin-1 Can Affect Morphogenesis and Differentiation of the Mouse Mammary Gland 
Journal of cellular physiology  2008;216(3):824-834.
Netrin-1 has been shown to regulate the function of the EGF-like protein Cripto-1 (Cr-1) and affect mammary gland development. Since Cr-1 is a target gene of Nanog and Oct4, we investigated the relationship between Netrin-1 and Cr-1, Nanog and Oct4 during different stages of development in the mouse mammary gland. Results from histological analysis show that exogenous Netrin-1 was able to induce formation of alveolar-like structures within the mammary gland terminal end buds of virgin transgenic Cripto-1 mice and enhance mammary gland alveologenesis in early pregnant FVB/N mice. Results from immunostaining and Western blot analysis show that Netrin-1, Nanog and Oct4 are expressed in the mouse embryonic mammary anlage epithelium while Cripto-1 is predominantly expressed outside this structure in the surrounding mesenchyme. We find that in lactating mammary glands of postnatal FVB/N mice, Netrin-1 expression is highest while Cripto-1 and Nanog levels are lowest indicating that Netrin-1 may perform a role in the mammary gland during lactation. HC-11 mouse mammary epithelial cells stimulated with lactogenic hormones and exogenous soluble Netrin-1 showed increased beta-casein expression as compared to control thus supporting the potential role for Netrin-1 during functional differentiation of mouse mammary epithelial cells. Finally, mouse ES cells treated with exogenous soluble Netrin-1 showed reduced levels of Nanog and Cripto-1 and higher levels of beta-III tubulin during differentiation. These results suggest that Netrin-1 may facilitate functional differentiation of mammary epithelial cells and possibly affect the expression of Nanog and/or Cripto-1 in multipotent cells that may reside in the mammary gland.
PMCID: PMC4209409  PMID: 18425773
21.  Occurrence of Radiographic Osteoarthritis of the Knee and Hip Among African Americans and Whites: A Population-Based Prospective Cohort Study 
Arthritis care & research  2013;65(6):928-935.
To compare the incidence and progression of radiographic osteoarthritis (OA) in the knee and hip among African Americans and whites.
Using the joint as the unit of analysis, we analyzed data from the Johnston County Osteoarthritis Project, a population-based prospective cohort study in rural North Carolina. Baseline and followup assessments were 3–13 years apart. Assessments included standard knee and hip radiographs read for Kellgren/Lawrence (K/L) radiographic grade. Weighted analyses controlled for age, sex, body mass index, level of education, and baseline K/L grade; bootstrap methods adjusted for lack of independence between left and right joints. Time-to-event analysis was used to analyze the data.
For radiographic knee OA, being African American had no association with incidence (adjusted hazard ratio [HRadj] 0.80, 95% confidence interval [95% CI] 0.53–1.22), but had a positive association with progression (HRadj 1.67, 95% CI 1.05–2.67). For radiographic hip OA, African Americans had a significantly lower incidence (HRadj 0.44, 95% CI 0.27–0.71), whereas the association with progression was positive but nonsignificant (HRadj 1.46, 95% CI 0.53–4.01). In sensitivity analyses, the association with hip OA incidence was robust to a wide range of assumptions.
African Americans are protected against incident hip OA, but may be more susceptible to progressive knee OA.
PMCID: PMC4206562  PMID: 23281251
22.  A prospective observational study of Gallium-68 ventilation and perfusion PET/CT during and after radiotherapy in patients with non-small cell lung cancer 
BMC Cancer  2014;14(1):740.
Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers, and is the leading cause of cancer deaths. Radiation therapy (RT), alone or in combination with chemotherapy, is the standard of care for curative intent treatment of patients with locally advanced or inoperable NSCLC. The ability to intensify treatment to achieve a better chance for cure is limited by the risk of injury to the surrounding lung.
This is a prospective observational study of 60 patients with NSCLC receiving curative intent RT. Independent human ethics board approval was received from the Peter MacCallum Cancer Centre ethics committee. In this research, Galligas and Gallium-68 macroaggregated albumin (MAA) positron emission tomography (PET) imaging will be used to measure ventilation (V) and perfusion (Q) in the lungs. This is combined with computed tomography (CT) and both performed with a four dimensional (4D) technique that tracks respiratory motion. This state-of-the-art scan has superior resolution, accuracy and quantitative ability than previous techniques. The primary objective of this research is to observe changes in ventilation and perfusion secondary to RT as measured by 4D V/Q PET/CT. Additionally, we plan to model personalised RT plans based on an individual’s lung capacity. Increasing radiation delivery through areas of poorly functioning lung may enable delivery of larger, more effective doses to tumours without increasing toxicity. By performing a second 4D V/Q PET/CT scan during treatment, we plan to simulate biologically adapted RT depending on the individual’s accumulated radiation injury. Tertiary aims of the study are assess the prognostic significance of a novel combination of clinical, imaging and serum biomarkers in predicting for the risk of lung toxicity. These biomarkers include spirometry, 18 F-Fluorodeoxyglucose PET/CT, gamma-H2AX signals in hair and lymphocytes, as well as assessment of blood cytokines.
By correlating these biomarkers to toxicity outcomes, we aim to identify those patients early who will not tolerate RT intensification during treatment. This research is an essential step leading towards the design of future biologically adapted radiotherapy strategies to mitigate the risk of lung injury during dose escalation for patients with locally advanced lung cancer.
Trials registration
Universal Trial Number (UTN) U1111-1138-4421.
PMCID: PMC4192760  PMID: 25277150
Positron emission tomography; Definitive radiation; Lung cancer; 4D; Adaptive radiotherapy; Biological dose escalation; Biomarkers; Gamma-H2AX; Inflammatory cytokines
23.  Checkpoint Modulation in Melanoma: An Update on Ipilimumab and Future Directions 
Current oncology reports  2013;15(5):500-508.
Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, was the first therapy demonstrated to improve overall survival in melanoma. Since ipilimumab’s approval by the FDA in 2011, a wealth of data have amassed, helping clinicians to optimize its use. We have learned how to mitigate the adverse effects of ipilimumab, identified its effects in melanoma subpopulations such as those with brain metastases, uveal melanoma, and mucosal melanoma, discovered potential biomarkers of activity, and investigated its use in combination with other therapeutic modalities. These discoveries have paved the way for rapid development of second-generation immunomodulatory antibodies such as inhibitors of the programmed cell death 1 receptor axis. These new agents hold promise as monotherapy, but perhaps the greatest allure lies in the possibility of combining these agents in synergistic multidrug regimens.
PMCID: PMC3799873  PMID: 23933888
Ipilimumab; Checkpoint; Immunotherapy; Melanoma; Anti-programmed cell death 1
24.  Vibrio coralliilyticus Strain OCN008 Is an Etiological Agent of Acute Montipora White Syndrome 
Identification of a pathogen is a critical first step in the epidemiology and subsequent management of a disease. A limited number of pathogens have been identified for diseases contributing to the global decline of coral populations. Here we describe Vibrio coralliilyticus strain OCN008, which induces acute Montipora white syndrome (aMWS), a tissue loss disease responsible for substantial mortality of the coral Montipora capitata in Kāne‘ohe Bay, Hawai‘i. OCN008 was grown in pure culture, recreated signs of disease in experimentally infected corals, and could be recovered after infection. In addition, strains similar to OCN008 were isolated from diseased coral from the field but not from healthy M. capitata. OCN008 repeatedly induced the loss of healthy M. capitata tissue from fragments under laboratory conditions with a minimum infectious dose of between 107 and 108 CFU/ml of water. In contrast, Porites compressa was not infected by OCN008, indicating the host specificity of the pathogen. A decrease in water temperature from 27 to 23°C affected the time to disease onset, but the risk of infection was not significantly reduced. Temperature-dependent bleaching, which has been observed with the V. coralliilyticus type strain BAA-450, was not observed during infection with OCN008. A comparison of the OCN008 genome to the genomes of pathogenic V. coralliilyticus strains BAA-450 and P1 revealed similar virulence-associated genes and quorum-sensing systems. Despite this genetic similarity, infections of M. capitata by OCN008 do not follow the paradigm for V. coralliilyticus infections established by the type strain.
PMCID: PMC3993142  PMID: 24463971
25.  Hospital and Nursing Home Use from 2002 to 2008 among U.S. Older Adults with Cognitive Impairment, Not dementia in 2002 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e318276994e.
Little is known about health care use in the cognitive impairment, not dementia (CIND) subpopulation. Using a cohort of 7,130 persons aged 71 years or over from the Health and Retirement Survey we compared mean and total health care use from 2002–2008 for those with no cognitive impairment [CI], CIND, or dementia in 2002.
Cognitive status was determined using a validated method based on self or proxy interview measures. Health care use was also based on self or proxy reports.
Based on the HRS, the CIND subpopulation in 2002 was 5.3 million; or 23% of the total population 71 years of age or over. Mean hospital nights was similar and mean nursing home nights was less in persons with CIND compared to persons with dementia. The CIND subpopulation, however, had more total hospital and nursing home nights; 71,000 total hospital nights and 223,000 total nursing home nights versus 32,000 hospital nights and 138,000 nursing home nights in the dementia subpopulation.
A relatively large population and high health care use result in a large health care impact of the CIND subpopulation.
PMCID: PMC3607633  PMID: 23151595
Older Adults; Cognitive Impairment; Health Services Use

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