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1.  Uncertainty and perception of danger among patients undergoing treatment for prostate cancer 
BJU international  2012;111(3 0 0):E84-E91.
To investigate patient uncertainty and perception of danger regarding prospects for clinical prostate cancer control.
To determine the impact of these factors on satisfaction with overall prostate cancer treatment outcome.
Men who had undergone primary treatment for early stage prostate cancer and who were participants in the Prostate Cancer Outcomes and Satisfaction with Treatment Quality Assessment (PROSTQA) prospective cohort study of prostate cancer outcomes (the parent study) were offered the opportunity to participate in the present study.
Centralized phone interviews were conducted to determine patient-reported uncertainty regarding cancer status (measured by the Mishel Uncertainty in Illness Scale-Community Form), perception of danger (measured by Folkman and Lazarus’ Appraisal Scale) and satisfaction with treatment outcome (measured by the Service Satisfaction Scale for Cancer Care). The study used the same centralized telephone interview centre as was used in the parent study.
Data were collected at 48, 60 or 72 months after the completion of prostate cancer treatment.
Relationships among measures were characterized by Spearman rank correlation coefficients (r).
A total of 338 agreed to participate, representing 76% of those who were invited.
Younger patients experienced less uncertainty (r = 0.20, P < 0.001), yet reported greater perception of danger (r = −0.12; P = 0.03) concerning their previously treated prostate cancer.
African-American patients showed greater uncertainty than other ethnic groups (P = 0.005) but did not have a greater perception of danger (P = 0.36).
Education played a major role in uncertainty; patients with lower levels of education tended to report higher degrees of uncertainty (r = −0.25; P < 0.001).
There was a mild to moderate general association between the three outcomes. A greater sense of uncertainty was associated with a greater perception of danger (r = 0.34, P < 0.001), and as danger and uncertainty increased, satisfaction with treatment outcome tended to decrease (r was between −0.30 and −0.34, P < 0.001).
Results suggest that possible disparities related to patient racial background and education may exist in the perception of cancer-related uncertainty.
Racial and educational disparities, coupled with a mild to moderate association of uncertainty or danger perception and overall outcome satisfaction, suggest an unmet need for healthcare and nursing services for men undergoing treatment for prostate cancer.
PMCID: PMC4075327  PMID: 22985348
2.  Respiratory treatment history predicts suck pattern stability in preterm infants 
Journal of neonatal nursing : JNN  2008;14(6):185-192.
Sensory deprivation and motor restriction associated with extensive oxygen therapy may lead to poor oromotor control in preterm infants. Non-nutritive suck is one of the first complex oromotor behaviors infants perform. This study determined the spatiotemporal variability of non-nutritive suck (NNS) pressure trajectories in three preterm groups with differing oxygen histories—one control group with minimal or no O2 therapy, and two Respiratory Distress Syndrome (RDS) groups with either a mild/moderate (RDS1) or moderate/severe (RDS2) O2 history. The Non-nutritive Suck Spatiotemporal Index (NNS STI) quantifies spatial and temporal variability across kinematic trajectories, and was calculated from digital representations of infants’ suck pressure signals. An ANCOVA revealed a significant effect for group (p < .001) on the NNS STI measure, with RDS2 infants showing highly variable NNS patterning, and thus relatively underdeveloped suck. Extensive oxygen therapy, which alters the oral sensory environment and reduces motor experiences, disrupts the development of coordinated NNS in preterm infants.
PMCID: PMC2614286  PMID: 19956344
Premature infant; Respiratory Distress Syndrome; Non-nutritive suck; Oromotor control; Spatiotemporal index; Suck variability; Suck central pattern generator; Oxygen therapy; Motor function
4.  Increased prevalence of seizures in boys who were probands with the FMR1 premutation and co-morbid autism spectrum disorder 
Human genetics  2011;131(4):581-589.
Seizures are a common co-occurring condition in those with fragile X syndrome (FXS), and in those with idiopathic autism spectrum disorder (ASD). Seizures are also associated with ASD in those with FXS. However, little is known about the rate of seizures and how commonly these problems co-occur with ASD in boys with the FMR1 premutation. We, therefore, determined the prevalence of seizures and ASD in boys with the FMR1 permutation compared with their sibling counterparts and population prevalence estimates. Fifty premutation boys who presented as clinical probands (N = 25), or non-probands (identified by cascade testing after the proband was found) (N = 25), and 32 non-carrier controls were enrolled. History of seizures was documented and ASD was diagnosed by standardized measures followed by a team consensus of ASD diagnosis. Seizures (28%) and ASD (68%) were more prevalent in probands compared with non-probands (0 and 28%), controls (0 and 0%), and population estimates (1 and 1.7%). Seizures occurred more frequently in those with the premutation and co-morbid ASD particularly in probands compared with those with the premutation alone (25 vs. 3.85%, p = 0.045). Although cognitive and adaptive functioning in non-probands were similar to controls, non-probands were more likely to meet the diagnosis of ASD than controls (28 vs. 0%, p < 0.0001). In conclusion, seizures were relatively more common in premutation carriers who presented clinically as probands of the family and seizures were commonly associated with ASD in these boys. Therefore, boys with the premutation, particularly if they are probands should be assessed carefully for both ASD and seizures.
PMCID: PMC4105134  PMID: 22001913
5.  The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia 
Oncogene  2012;32(7):930-938.
The Trithorax and Polycomb groups of chromatin regulators are critical for cell-lineage specification during normal development; functions that often become deregulated during tumorigenesis. As an example, oncogenic fusions of the Trithorax-related protein MLL can initiate aggressive leukemias by altering the transcriptional circuitry governing hematopoietic cell differentiation, a process that is known to require additional epigenetic pathways to implement. Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb Repressive Complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12, or Ezh1/Ezh2 led to proliferation-arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines. The requirement for PRC2 in leukemia is partly due to its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a. In addition to implicating a role for PRC2 in the pathogenesis of MLL-fusion leukemia, our results suggest, more generally, that Trithorax and Polycomb group proteins can cooperate with one another to maintain aberrant lineage programs in cancer.
PMCID: PMC4102143  PMID: 22469984
chromatin; leukemia; epigenetics; MLL; PRC2
6.  HIV and COPD: impact of risk behaviors and diseases on quality of life 
Smoking worsens quality of life among HIV-infected individuals, but it remains unclear if this association is related simply to smoking or to chronic obstructive pulmonary disease (COPD), the end-organ disease caused by smoking.
Using cross-sectional data from the AIDS Linked to the Intravenous Experience study, we determined the independent effects of smoking, HIV and COPD assessed using the Medical Outcome Studies-HIV questionnaire.
Of 973 participants, 287 (29.5%) were HIV infected and 151 (15.5%) had spirometry-defined obstruction. Eight hundred and thirty-four (85.7%) were current smokers with 23.3 mean pack-years history. HIV infection was independently associated with reduced physical and mental health. COPD was associated with a trend toward worse physical health (−1.48 units; 95%CI −3.33 to 0.38; p = 0.12) and was independently associated with worse mental health (−2.43 units; 95%CI −4.22 to −0.64; p < 0.01). After accounting for COPD and other covariates, smoking was not associated with changes in physical or mental health.
The presence of COPD, rather than smoking, is associated with worse quality of life independent of HIV infection. Diagnosis and management of COPD in former or current smokers with or at risk for HIV may further improve quality of life.
PMCID: PMC4097077  PMID: 20617387
Quality of life; Chronic obstructive pulmonary disease; Human immunodeficiency virus; Injection drug use; Smoking; Tobacco use
7.  Developing Safety Criteria for Introducing New Agents into Neoadjuvant Trials 
New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety.
PMCID: PMC4096560  PMID: 23470967
9.  Two-photon imaging of multiple fluorescent proteins by phase-shaping and linear unmixing with a single broadband laser 
Optics Express  2013;21(14):17256-17264.
Imaging multiple fluorescent proteins (FPs) by two-photon microscopy has numerous applications for studying biological processes in thick and live samples. Here we demonstrate a setup utilizing a single broadband laser and a phase-only pulse-shaper to achieve imaging of three FPs (mAmetrine, TagRFPt, and mKate2) in live mammalian cells. Phase-shaping to achieve selective excitation of the FPs in combination with post-imaging linear unmixing enables clean separation of the fluorescence signal of each FP. This setup also benefits from low overall cost and simple optical alignment, enabling easy adaptation in a regular biomedical research laboratory.
PMCID: PMC3724397  PMID: 23938572
(320.5540) Pulse shaping; (180.2520) Fluorescence microscopy; (190.4180) Multiphoton processes; (180.4315) Nonlinear microscopy
10.  In vivo mutation of pre-mRNA processing factor 8 (Prpf8) affects transcript splicing, cell survival and myeloid differentiation 
FEBS letters  2013;587(14):10.1016/j.febslet.2013.05.030.
Mutated spliceosome components are recurrently being associated with perturbed tissue development and disease pathogenesis. Cephalophŏnus (cph), is a zebrafish mutant carrying an early premature STOP codon in the spliceosome component Prpf8 (pre-mRNA processing factor 8). Cph initially develops normally, but then develops widespread cell death, especially in neurons, and is embryonic lethal. Cph mutants accumulate aberrantly spliced transcripts retaining both U2- and U12-type introns. Within early haematopoeisis, myeloid differentiation is impaired suggesting Prpf8 is required for haematopoietic development. Cph provides an animal model for zygotic PRPF8 dysfunction diseases and for evaluating therapeutic interventions.
PMCID: PMC3820954  PMID: 23714367
PRPF8; haematopoiesis; splicing; zebrafish; myelopoiesis; spliceosome; snRNP
11.  Retrospective reports of behavioral inhibition and young adults’ current symptoms of social anxiety, depression, and anxious arousal 
Journal of anxiety disorders  2009;23(7):884-890.
The primary goal of this study was to investigate the specificity of the social versus nonsocial components of self-reported behavioral inhibition during childhood with young adults’ current symptoms of anhedonic depression, social anxiety, and anxious arousal. As hypothesized, the social component of BI demonstrated some specificity for symptoms of social anxiety versus other internalizing disorders. Furthermore, results support the hypothesis that the relationship between BI and depressive symptoms is mediated by levels of social anxiety and anxious arousal.
PMCID: PMC4088955  PMID: 19592214
12.  Multimodal Intervention to Improve Osteoporosis Care in Home Health Settings: Results from a Cluster Randomized Trial 
To test an evidence-implementation intervention to improve the quality of care in the home health care setting for patients at high risk for fractures.
We conducted a cluster randomized trial of a multimodal intervention targeted at home care for high-risk patients (prior fracture or physician-diagnosed osteoporosis) receiving care in a statewide home health agency in Alabama. Offices throughout the state were randomized to receive the intervention or to usual care. The primary outcome was the proportion of high-risk home health patients treated with osteoporosis medications. A t-test of difference in proportions was conducted between intervention and control arms and constituted the primary analysis. Secondary analyses included logistic regression estimating the effect of individual patients being treated in an intervention arm office on the likelihood of a patient receiving osteoporosis medications. A follow-on analysis examined the effect of an automated alert built into the electronic medical record that prompted the home health care nurses to deploy the intervention for high risk patients using a pre-post design.
Among the offices in the intervention arm the average proportion of eligible patients receiving osteoporosis medications post-intervention was 19.1%, compared with 15.7% in the usual care arm (difference in proportions 3.4%, 95% CI: −2.6 −9.5%). The overall rates of osteoporosis medication use increased from 14.8% prior to activation of the automated alert to 17.6% afterward, a non-significant difference.
The home health intervention did not result in a significant improvement in use of osteoporosis medications in high risk patients.
PMCID: PMC4089895  PMID: 23536256
Osteoporosis; Home Care Services; Quality Improvement; Secondary Prevention
13.  Influence of Patient and Treatment Factors on Adherence to Adjuvant Endocrine Therapy in Breast Cancer 
Oncology nursing forum  2014;41(3):274-285.
To comprehensively assess the patient and illness or treatment factors that may predict nonadherence to adjuvant endocrine therapy and to explore whether an interaction occurs between these factors in women with breast cancer.
Repeated-measures design.
The Outpatient Services of the Women's Cancer Program at the University of Pittsburgh Cancer Institute and participants' homes.
91 women with early-stage breast cancer who received endocrine therapy.
Adherence was assessed continuously for the first 18 months of endocrine therapy. Patient and illness or treatment factors were assessed at four time points (Time 1 to Time 4). Time 1 (baseline) was within two weeks prior to the initiation of endocrine therapy. Times 2–4 occurred at six-month intervals, as many as 18 months after Time 1.
Main Research Variables
Adherence, patient factors, and illness or treatment factors.
Adherence to endocrine therapy declined significantly during the first 18 months of treatment in women with breast cancer. The presence of negative mood and symptoms before starting treatment predicted nonadherence to endocrine therapy over time. Perceptions of financial hardship, symptoms, disease stage, and more complex medication regimens intensified the effect of negative mood on adherence over time.
Women with breast cancer may be at risk for nonadherence to prescribed endocrine therapy if they experience depression or anxiety and symptoms prior to initiating therapy.
Implications for Nursing
Oncology nurses should be alert to women with breast cancer who are depressed or anxious or who are experiencing symptoms. Management of negative mood and symptoms may result in better adherence.
PMCID: PMC4090095  PMID: 24769592
breast cancer; adherence; symptoms; mood; financial hardship
14.  The use of the temporal scan statistic to detect methicillin-resistant Staphylococcus aureus clusters in a community hospital 
BMC Infectious Diseases  2014;14:375.
In healthcare facilities, conventional surveillance techniques using rule-based guidelines may result in under- or over-reporting of methicillin-resistant Staphylococcus aureus (MRSA) outbreaks, as these guidelines are generally unvalidated. The objectives of this study were to investigate the utility of the temporal scan statistic for detecting MRSA clusters, validate clusters using molecular techniques and hospital records, and determine significant differences in the rate of MRSA cases using regression models.
Patients admitted to a community hospital between August 2006 and February 2011, and identified with MRSA > 48 hours following hospital admission, were included in this study. Between March 2010 and February 2011, MRSA specimens were obtained for spa typing. MRSA clusters were investigated using a retrospective temporal scan statistic. Tests were conducted on a monthly scale and significant clusters were compared to MRSA outbreaks identified by hospital personnel. Associations between the rate of MRSA cases and the variables year, month, and season were investigated using a negative binomial regression model.
During the study period, 735 MRSA cases were identified and 167 MRSA isolates were spa typed. Nine different spa types were identified with spa type 2/t002 (88.6%) the most prevalent. The temporal scan statistic identified significant MRSA clusters at the hospital (n = 2), service (n = 16), and ward (n = 10) levels (P ≤ 0.05). Seven clusters were concordant with nine MRSA outbreaks identified by hospital staff. For the remaining clusters, seven events may have been equivalent to true outbreaks and six clusters demonstrated possible transmission events. The regression analysis indicated years 2009–2011, compared to 2006, and months March and April, compared to January, were associated with an increase in the rate of MRSA cases (P ≤ 0.05).
The application of the temporal scan statistic identified several MRSA clusters that were not detected by hospital personnel. The identification of specific years and months with increased MRSA rates may be attributable to several hospital level factors including the presence of other pathogens. Within hospitals, the incorporation of the temporal scan statistic to standard surveillance techniques is a valuable tool for healthcare workers to evaluate surveillance strategies and aid in the identification of MRSA clusters.
PMCID: PMC4097048  PMID: 25005247
Methicillin-resistant Staphylococcus aureus; Clusters; Temporal scan statistic; Community hospital; Epidemiology; Spa typing
15.  The Ubiquitin-Specific Protease USP15 Promotes RIG-I–Mediated Antiviral Signaling by Deubiquitylating TRIM25 
Science signaling  2014;7(307):ra3.
Ubiquitylation is an important mechanism for regulating innate immune responses to viral infections. Attachment of lysine 63 (Lys63)–linked ubiquitin chains to the RNA sensor retinoic acid–inducible gene-I (RIG-I) by the ubiquitin E3 ligase tripartite motif protein 25 (TRIM25) leads to the activation of RIG-I and stimulates production of the antiviral cytokines interferon-α (IFN-α) and IFN-β. Conversely, Lys48-linked ubiquitylation of TRIM25 by the linear ubiquitin assembly complex (LUBAC) stimulates the proteasomal degradation of TRIM25, thereby inhibiting the RIG-I signaling pathway. Here, we report that ubiquitin-specific protease 15 (USP15) deubiquitylates TRIM25, preventing the LUBAC-dependent degradation of TRIM25. Through protein purification and mass spectrometry analysis, we identified USP15 as an interaction partner of TRIM25 in human cells. Knockdown of endogenous USP15 by specific small interfering RNA markedly enhanced the ubiquitylation of TRIM25. In contrast, expression of wild-type USP15, but not its catalytically inactive mutant, reduced the Lys48-linked ubiquitylation of TRIM25, leading to its stabilization. Furthermore, ectopic expression of USP15 enhanced the TRIM25- and RIG-I–dependent production of type I IFN and suppressed RNA virus replication. In contrast, depletion of USP15 resulted in decreased IFN production and markedly enhanced viral replication. Together, these data identify USP15 as a critical regulator of the TRIM25- and RIG-I–mediated antiviral immune response, thereby highlighting the intricate regulation of innate immune signaling.
PMCID: PMC4008495  PMID: 24399297
16.  Perivascular Adipose Tissue Potentiates Contraction of Coronary Vascular Smooth Muscle: Influence of Obesity 
Circulation  2013;128(1):9-18.
This investigation examined the mechanisms by which coronary perivascular adipose tissue (PVAT)-derived factors influence vasomotor tone and the PVAT proteome in lean vs. obese swine.
Methods and Results
Coronary arteries from Ossabaw swine were isolated for isometric tension studies. We found that coronary (P=0.03) and mesenteric (P=0.04), but not subcutaneous adipose tissue, augmented coronary contractions to KCl (20 mM). Inhibition of CaV1.2 channels with nifedipine (0.1 μM) or diltiazem (10 μM) abolished this effect. Coronary PVAT increased baseline tension and potentiated constriction of isolated arteries to PGF2α in proportion to the amount of PVAT present (0.1–1.0 g). These effects were elevated in tissues obtained from obese swine and were observed in intact and endothelium denuded arteries. Coronary PVAT also diminished H2O2-mediated vasodilation in lean, and to a lesser extent in obese arteries. These effects were associated with alterations in the obese coronary PVAT proteome (detected 186 alterations) and elevated voltage-dependent increases in intracellular [Ca2+] in obese smooth muscle cells. Further studies revealed that a Rho-kinase inhibitor fasudil (1 μM) significantly blunted artery contractions to KCl and PVAT in lean, but not obese swine. Calpastatin (10 μM) also augmented contractions to levels similar to that observed in the presence of PVAT.
Vascular effects of PVAT vary according to anatomic location and are influenced by an obese phenotype. Augmented contractile effects of obese coronary PVAT are related to alterations in the PVAT proteome (e.g. calpastatin), Rho-dependent signaling, and the functional contribution of K+ and CaV1.2 channels to smooth muscle tone.
PMCID: PMC3755741  PMID: 23685742
smooth muscle; perivascular adipose; coronary disease; obesity; vasoconstriction
17.  Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma 
Neurology  2013;81(1):84-92.
To describe and correlate neurotoxicity indicators in long-term primary CNS lymphoma (PCNSL) survivors who were treated with high-dose methotrexate–based regimens with or without whole-brain radiotherapy (WBRT).
Eighty PCNSL survivors from 4 treatment groups (1 with WBRT and 3 without WBRT) who were a minimum of 2 years after diagnosis and in complete remission underwent prospective neuropsychological, quality-of-life (QOL), and brain MRI evaluation. Clinical characteristics were compared among treatments by using the χ2 test and analysis of variance. The association among neuroimaging, neuropsychological, and QOL outcomes was assessed by using the Pearson correlation coefficient.
The median interval from diagnosis to evaluation was 5.5 years (minimum, 2 years; maximum, 26 years). Survivors treated with WBRT had lower mean scores in attention/executive function (p = 0.0011), motor skills (p = 0.0023), and neuropsychological composite score (p = 0.0051) compared with those treated without WBRT. Verbal memory was better in survivors with longer intervals from diagnosis to evaluation (p = 0.0045). On brain imaging, mean areas of total T2 abnormalities were different among treatments (p = 0.0006). Total T2 abnormalities after WBRT were more than twice the mean of any non-WBRT group and were associated with poorer neuropsychological and QOL outcomes.
Our results suggest that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity. Verbal memory may improve over time.
Classification of evidence:
This study provides Class III evidence that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity.
PMCID: PMC3770201  PMID: 23685932
18.  Combining Urinary Detection of TMPRSS2:ERG and PCA3 with Serum PSA to Predict Diagnosis of Prostate Cancer 
Urologic oncology  2011;31(5):566-571.
We sought to develop a clinical algorithm combining serum PSA with detection of TMPRSS2:ERG fusion and PCA3 in urine collected after digital rectal exam (post-DRE urine) to predict prostate cancer on subsequent biopsy.
Materials and Methods
Post-DRE urine was collected in 48 consecutive patients before prostate biopsy at two centers; qRT-PCR was used to detect PCA3 and TMPRSS2:ERG fusion transcript expression. Serum PSA was measured by clinical assay. The performance of TMPRSS2:ERG fusion, PCA3, and serum PSA as biomarkers predicting prostate cancer at biopsy was measured; a clinically practical algorithm combining serum PSA with TMPRSS2:ERG and PCA3 in post-DRE urine to predict prostate cancer was developed.
Post-DRE urine sediment provided informative RNA in 45 patients; prostate cancer was present on subsequent biopsy in 15. TMPRSS2:ERG in post-DRE urine was associated with prostate cancer (OR = 12.02; p< 0.001). PCA3 had the highest sensitivity in predicting prostate cancer diagnosis (93%), whereas TMPRSS2:ERG had the highest specificity (87%). TMPRSS2:ERG had the greatest discriminatory value in predicting prostate cancer (AUC = 0.77 compared to 0.65 for PCA3 and 0.72 for serum PSA alone). Combining serum PSA, PCA3 and TMPRSS2:ERG in a multivariable algorithm optimized for clinical utility improved cancer prediction (AUC = 0.88; specificity = 90% at 80% sensitivity).
A clinical algorithm specifying biopsy for all patients with PSA ≥10ng/ml, while restricting biopsy among those with PSA <10ng/ml to only those with detectable PCA3 or TMPRSS2:ERG in post-DRE urine, performed better than the individual biomarkers alone in predicting prostate cancer.
PMCID: PMC3210917  PMID: 21600800
Screening; DRE; Biomarkers; Cancer Detection; Gene Fusion
19.  Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23 
Human Molecular Genetics  2013;22(13):2748-2753.
Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case–control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10−9). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10−3). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.
PMCID: PMC3674801  PMID: 23462292
20.  Impaired Cardiometabolic Responses to Glucagon-Like Peptide 1 in Obesity and Type 2 Diabetes Mellitus 
Basic research in cardiology  2013;108(4):365.
Glucagon-Like Peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7–36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1 mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.
PMCID: PMC3731771  PMID: 23764734
Obesity; diabetes; GLP-1; cardiac; glucose; metabolism
21.  Proton magnetic resonance spectroscopy of the substantia nigra in schizophrenia 
Schizophrenia research  2013;147(0):348-354.
Converging evidence in schizophrenia points to disruption of the dopamine and glutamate neurotransmitter systems in the pathophysiology of the disorder. Dopamine is produced in the substantia nigra, but few neuroimaging studies have specifically targeted this structure. In fact, no studies of the substantia nigra in schizophrenia have used proton magnetic resonance spectroscopy (MRS). We sought to demonstrate the feasibility of acquiring single-voxel MRS measurements at 3T from the substantia nigra and to determine which metabolites could be reliably quantified in schizophrenia patients and healthy controls.
We used a turbo spin echo sequence with magnetization transfer contrast to visualize the substantia nigra and single-voxel proton MRS to quantify levels of N-acetylaspartate, glutamate and glutamine (Glx), and choline in the left substantia nigra of 35 people with schizophrenia and 22 healthy controls.
We obtained spectra from the substantia nigra and quantified neurometabolites in both groups. We found no differences in levels of N-acetylaspartate/creatine, Glx/creatine, or choline/creatine between the groups. We found a significant correlation between Glx/creatine and overall cognitive performance, measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), in controls but not patients, a difference that was statistically significant.
Our study demonstrates the feasibility of obtaining single-voxel MRS data from the substantia nigra in schizophrenia. Such measurements may prove useful in understanding the biochemistry underlying cellular function in a region implicated in the pathophysiology of schizophrenia.
PMCID: PMC3760722  PMID: 23706412
schizophrenia; substantia nigra; magnetic resonance spectroscopy; glutamate; N-acetylaspartate; cognition
22.  Deficits in glycinergic inhibition within adult spinal nociceptive circuits after neonatal tissue damage 
Pain  2013;154(7):1129-1139.
Tissue injury during a critical period of early postnatal development can alter pain sensitivity throughout life. However, the degree to which neonatal tissue damage exerts prolonged effects on synaptic signaling within adult spinal nociceptive circuits remains unknown. Here we provide evidence that a transient surgical injury of the hind paw during the neonatal period compromises inhibitory transmission within the adult mouse superficial dorsal horn (SDH), while the same incision occurring during the third week of life failed to evoke these long-term modifications of the SDH synaptic network. The decrease in phasic inhibitory signaling after early tissue damage reflected a selective reduction in glycine receptor (GlyR)-mediated input onto both GABAergic and presumed glutamatergic neurons within lamina II of the adult SDH. Meanwhile, neonatal incision significantly decreased the density of tonic GlyR-mediated current only in the presumed glutamatergic population during adulthood. These persistent changes in synaptic function following early injury occurred in the absence of significant alterations in the transcription of genes known to be important for glycinergic transmission. These findings suggest that aberrant sensory input during early life has permanent consequences for the functional organization of nociceptive synaptic circuits within the adult spinal cord.
PMCID: PMC3795070  PMID: 23639821
Spinal cord; Superficial dorsal horn; Neonatal; Patch clamp; Synapse; Glycine; Development; Incision; Nociception
23.  Progression of GFR reduction determined in conscious Dahl S hypertensive rats 
Hypertension  2013;62(1):85-90.
Sequential changes in glomerular filtration rate (GFR) during development of hypertension in the conscious Dahl salt-sensitive (SS) rat were determined using a new method for measurement. Utilizing a miniaturized device, disappearance curves of fluorescein isothiocyanate (FITC)-sinistrin were measured by transcutaneous excitation and real time detection of the emitted light through the skin. Rats with implanted femoral venous catheters (dye injection and sampling) and carotid catheters (mean arterial pressure (MAP) by telemetry) were studied while maintained on a 0.4% NaCl diet and on days 2,5,7,14 and 21 after switching to 4.0% (HS) diet. A separate group of rats were maintained on 0.4% for 21 days as a time control. MAP rose progressively from the last day of 0.4% (130±2 mmHg) reaching significance by day 5 of HS and averaged 162±7 mmHg by day 21. Urine albumin excretion was significantly elevated (3×) by day 7 of HS in SS rats. GFR became reduced on day 14 of HS falling from 1.53±0.06 ml/min/100g bwgt to 1.27±0.04. By day 21, GFR had fallen 28% to 1.1±0.04 ml/min/100g bwgt (t1/2 28.4±1.1 min.) No significant reductions of creatinine clearance (Ccre) were observed throughout the study in response to HS demonstrating the insensitivity of Ccre measurements even with creatinine measured using mass spectrometry. We conclude that the observed reduction of GFR was a consequence and not a cause of the hypertension and that this non-invasive approach could be used in these conscious SS rats for a longitudinal assessment of renal function.
PMCID: PMC3806646  PMID: 23630946
GFR; Dahl S rat; salt-sensitive hypertension; creatinine clearance
24.  Identification of small molecules that inhibit the interaction of TEM8 with anthrax protective antigen using a FRET assay 
Journal of biomolecular screening  2013;18(6):10.1177/1087057113478655.
Tumor marker endothelial 8 (TEM8) is a receptor for the Protective Antigen (PA) component of anthrax toxin. TEM8 is upregulated on endothelial cells lining the blood vessels within tumors, compared to normal blood vessels. A number of studies have demonstrated a pivotal role for TEM8 in developmental and tumor angiogenesis. We have also shown that targeting the anthrax receptors with a mutated form of PA inhibits angiogenesis and tumor formation in vivo.
Here we describe the development and testing of a high-throughput fluorescence resonance energy transfer assay to identify molecules that strongly inhibit the interaction of PA and TEM8. The assay we describe is sensitive and robust, with a Z-prime value of 0.8. A preliminary screen of 2310 known bioactive library compounds identified ebselen and thimerosal as inhibitors of the TEM8-PA interaction. These molecules each contain a cysteine-reactive transition metal, and complimentary studies indicate that their inhibition of interaction is due to modification of a cysteine residue in the TEM8 extracellular domain. This is the first demonstration of a high-throughput screening assay that identifies inhibitors of TEM8, with potential application for anti-anthrax and anti-angiogenic diseases.
PMCID: PMC3859190  PMID: 23479355
High-throughput screening; FRET; anthrax; angiogenesis; Tumor endothelial marker 8
25.  Selective Actions of Novel Allosteric Modulators Reveal Functional Heteromers of Metabotropic Glutamate Receptors in the CNS 
The Journal of Neuroscience  2014;34(1):79-94.
Metabotropic glutamate (mGlu) receptors play important roles in regulating CNS function and are known to function as obligatory dimers. Although recent studies have suggested heterodimeric assembly of mGlu receptors in vitro, the demonstration that distinct mGlu receptor proteins can form heterodimers or hetero-complexes with other mGlu subunits in native tissues, such as neurons, has not been shown. Using biochemical and pharmacological approaches, we demonstrate here that mGlu2 and mGlu4 form a hetero-complex in native rat and mouse tissues which exhibits a distinct pharmacological profile. These data greatly extend our current understanding of mGlu receptor interaction and function and provide compelling evidence that mGlu receptors can function as heteromers in intact brain circuits.
PMCID: PMC3866496  PMID: 24381270

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