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1.  Effect of Right Ventricular Function and Venous Congestion on Cardio-Renal Interactions during the Treatment of Decompensated Heart Failure 
The American journal of cardiology  2010;105(4):511-516.
Recent reports have demonstrated the adverse effects of venous congestion on renal function and challenged the assumption that worsening renal function (RF) is driven by diminished cardiac output (CO). We hypothesized that diuresis in patients with right ventricular (RV) dysfunction, despite diminished CO, would lead to a reduction in venous congestion and resultant improvement in renal function. We reviewed consecutive admissions with a discharge diagnosis of heart failure (HF). RV function was assessed by multiple echocardiographic methods and those with ≥2 measures of RV dysfunction were considered to have significant RV dysfunction. Worsening RF was defined as an increase in creatinine of ≥0.3 mg/dL and improved RF as improvement in glomerular filtration rate ≥25%. A total of 141 admissions met eligibility criteria, 34% developed worsening RF. Venous congestion was more common in those with RV dysfunction (OR=3.3, p=0.009). All measures of RV dysfunction excluding RV dilation correlated with CO (p<0.05). Significant RV dysfunction predicted a lower incidence of worsening RF (OR=0.21, p<0.001) and higher incidence of improved RF (OR=6.4, p<0.001). CO emerged as a significant predictor of change in glomerular filtration rate during hospitalization in those without significant RV dysfunction (r=0.38, p<0.001). In conclusion, RV dysfunction is a strong predictor of improved renal outcomes in patients with acute decompensated HF, an effect likely mediated by relief of venous congestion.
PMCID: PMC2995805  PMID: 20152246
Cardio-renal syndrome; worsening renal function; RV dysfunction; improved renal function
2.  Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration, and cognitive impairment 
Cell Cycle  2014;13(15):2446-2458.
Cognitive dysfunction has been reported in patients with spinal cord injury (SCI), but it has been questioned whether such changes may reflect concurrent head injury, and the issue has not been addressed mechanistically or in a well-controlled experimental model. Our recent rodent studies examining SCI-induced hyperesthesia revealed neuroinflammatory changes not only in supratentorial pain-regulatory sites, but also in other brain regions, suggesting that additional brain functions may be impacted following SCI. Here we examined effects of isolated thoracic SCI in rats on cognition, brain inflammation, and neurodegeneration. We show for the first time that SCI causes widespread microglial activation in the brain, with increased expression of markers for activated microglia/macrophages, including translocator protein and chemokine ligand 21 (C–C motif). Stereological analysis demonstrated significant neuronal loss in the cortex, thalamus, and hippocampus. SCI caused chronic impairment in spatial, retention, contextual, and fear-related emotional memory—evidenced by poor performance in the Morris water maze, novel objective recognition, and passive avoidance tests. Based on our prior work implicating cell cycle activation (CCA) in chronic neuroinflammation after SCI or traumatic brain injury, we evaluated whether CCA contributed to the observed changes. Increased expression of cell cycle-related genes and proteins was found in hippocampus and cortex after SCI. Posttraumatic brain inflammation, neuronal loss, and cognitive changes were attenuated by systemic post-injury administration of a selective cyclin-dependent kinase inhibitor. These studies demonstrate that chronic brain neurodegeneration occurs after isolated SCI, likely related to sustained microglial activation mediated by cell cycle activation.
PMCID: PMC4128888  PMID: 25483194
spinal cord injury; brain; inflammation; cognitive impairment; neurodegeneration; cell cycle activation
3.  Connecting leptin signaling to biological function 
The Journal of endocrinology  2014;223(1):T25-T35.
Hypothalamic leptin action promotes negative energy balance and modulates glucose homeostasis, as well as serving as a permissive signal to the neuroendocrine axes that control growth and reproduction. Since the initial discovery of leptin 20 years ago, we have learned a great deal about the molecular mechanisms of leptin action. An important aspect of this has been the dissection of the cellular mechanisms of leptin signaling, and how specific leptin signals influence physiology. Leptin acts via the long form of the leptin receptor, LepRb. LepRb activation and subsequent tyrosine phosphorylation recruits and activates multiple signaling pathways, including STAT transcription factors, SHP2 and ERK signaling, the IRS-protein/PI3Kinase pathway, and SH2B1. Each of these pathways controls specific aspects of leptin action and physiology. Important inhibitory pathways mediated by suppressor of cytokine signaling (SOCS) proteins and protein tyrosine phosphatases (PTPases) also limit physiologic leptin action. This review summarizes the signaling pathways engaged by LepRb and their effects on energy balance, glucose homeostasis, and reproduction. Particular emphasis is given to the multiple mouse models which have been used to elucidate these functions in vivo.
PMCID: PMC4170570  PMID: 25232147
4.  Forward and backward wave morphology and central pressure augmentation in men and women in the Framingham Heart Study 
Hypertension  2014;64(2):259-265.
Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) from 19 to 90 years of age (mean age 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated non-linear relations with age (age: βx00302; =4.6±0.1%, P<0.001; age2: βx00302;=−4.2±0.1%, P<0.001) and higher augmentation in women (βx00302; =4.5±0.4%, P<0.001, model R2=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R2=0.62) and reduced the age coefficients: age (βx00302; =2.3±0.1%, P<0.001) and age2 (βx00302; =−2.2±0.1%, P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke and forward wave amplitude further improved model fit (R2=0.75) and attenuated the sex coefficient (βx00302;=1.9±0.2%, P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex-difference in augmentation index may be explained by forward and backward wave morphology.
PMCID: PMC4184952  PMID: 24866142
augmentation index; wave reflection; pulse pressure; aortic stiffness; left ventricular contraction
5.  Gamma delta (γδ) T-cells regulate wound myeloid cell activity after burn 
Shock (Augusta, Ga.)  2014;42(2):133-141.
Major burns induce immune complications, which are associated with myeloid cell activation by ill-defined mechanisms. While γδ T-cells have been shown to be important in post-injury inflammation and wound healing, their role in the regulation of myeloid cells remains unknown. To study this wildtype (WT) and γδ T-cell deficient (δTCR−/−) mice were subjected to major burn (25% TBSA, 3rd degree) or sham treatment. At 3 days thereafter, skin samples were assayed for cytokine content or used to isolate single cells that were used for myeloid cell characterization by flow cytometry. The number of CD11b+ myeloid cells increased by ~75% in the wound skin of WT mice. This influx was due to increased myeloid-derived suppressor cells (MDSC; CD11b+ GR1+), who’s numbers increased 19-fold compared to sham skin. In contrast, macrophage (MØ; CD11b+ F4/80+) numbers decreased by ~50% after burn. In δTCR−/− mice, burn increased the myeloid cell numbers ~5-fold. The increase in myeloid cells at the injury site of δTCR−/− mice was due to both a MDSC (50-fold) and a MØ (2-fold) influx. Burn increased skin cytokine levels for a number of prototypic inflammatory cytokines (IL-1β, IL-6, TNF-α, MIP-1β etc). TNF-α, MIP-1 α and MIP-1β levels were further elevated (2–3 fold) in the injured skin of δTCR−/− mice, as compared with WT mice. In conclusion these data show that γδ T-cells regulate myeloid cell infiltration of the wound site and act to quell inflammation, thereby promoting the transition to the proliferative phase of wound healing.
PMCID: PMC4101017  PMID: 24667623
Injury; Inflammation; Macrophage; MDSC; Cytokines
6.  Bridged Cyclams as Imaging Agents for Chemokine Receptor 4 (CXCR4) 
Nuclear medicine and biology  2014;41(7):552-561.
Over-expression of chemokine receptor 4 (CXCR4) is present in a majority of cancers, has been linked to an aggressive phenotype, and may indicate the metastatic potential of primary tumor. Several CXCR4 targeted therapeutics are in clinical trials and the development of the corresponding imaging agents is an area of active interest. Previously, 64Cu-labeled imaging agents for CXCR4 have provided clear images of CXCR4-bearing tissues in relevant experimental models but demonstrated fast washout from tissues harboring receptor. Addition of stabilizing bridges is known to provide more robust chelator-Cu(II) complexes. In addition, bridged cyclam-based CXCR4 binding agents demonstrated increased receptor residence times relative to existing agents. Based on that knowledge we synthesized several bridged cyclam analogs of AMD3465, a monocyclam-based CXCR4 imaging agent, to increase the retention time of the tracer bound to the receptor to allow for protracted imaging and improved target-to-non-target ratios. Specific accumulation of two radiolabeled, cross-bridged analogs ([64Cu] RAD1–24 and [64Cu]RAD1–52) was observed in U87-stb-CXCR4 tumors in both PET/CT imaging and biodistribution studies. At 90 min post-injection of radiotracer, tumor-to-muscle and tumor-to-blood ratios reached 106.05 ± 17.19 and 28.08 ± 4.78, respectively, for cross-bridged pyrimidine analog [64Cu]RAD1–52. Receptor blockade performed in vivo denoted target binding specificity. The biodistribution and PET/CT imaging studies with the radiolabeled bridged cyclams demonstrated longer tumor retention and comparable uptake to [64Cu]AMD3465, though [64Cu]AMD3465 demonstrated superior overall pharmacokinetics.
PMCID: PMC4104431  PMID: 25038987
7.  Pleiotropic genes for metabolic syndrome and inflammation 
Molecular genetics and metabolism  2014;112(4):317-338.
Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.
PMCID: PMC4122618  PMID: 24981077
8.  Usability evaluation and adaptation of the e-health Personal Patient Profile-Prostate decision aid for Spanish-speaking Latino men 
The Personal Patient Profile-Prostate (P3P), a web-based decision aid, was demonstrated to reduce decisional conflict in English-speaking men with localized prostate cancer early after initial diagnosis. The purpose of this study was to explore and enhance usability and cultural appropriateness of a Spanish P3P by Latino men with a diagnosis of prostate cancer.
P3P was translated to Spanish and back-translated by three native Spanish-speaking translators working independently. Spanish-speaking Latino men with a diagnosis of localized prostate cancer, who had made treatment decisions in the past 24 months, were recruited from two urban clinical care sites. Individual cognitive interviews were conducted by two bilingual research assistants as each participant used the Spanish P3P. Notes of user behavior, feedback, and answers to direct questions about comprehension, usability and perceived usefulness were analyzed and categorized.
Seven participants with a range of education levels identified 25 unique usability issues in navigation, content comprehension and completeness, sociocultural appropriateness, and methodology. Revisions were prioritized to refine the usability and cultural and linguistic appropriateness of the decision aid.
Usability issues were discovered that are potential barriers to effective decision support. Successful use of decision aids requires adaptation and testing beyond translation. Our findings led to revisions further refining the usability and linguistic and cultural appropriateness of Spanish P3P.
PMCID: PMC4513952  PMID: 26204920
Usability; Adaptation; Spanish; Localized prostate cancer; Disparities; Decision aid
9.  Tailorable Plasmonic Circular Dichroism Properties of Helical Nanoparticle Superstructures 
Nano letters  2013;13(7):3256-3261.
We utilize a peptide-based methodology to prepare a diverse collection of double-helical gold nanoparticle superstructures having controllable handedness and structural metrics. These materials exhibit well-defined circular dichroism signatures at visible wavelengths owing to the collective dipole–dipole interactions between the nanoparticles. We couple theory and experiment to show how tuning the metrics and structure of the helices results in predictable and tailorable chirooptical properties. Finally, we experimentally and theoretically demonstrate that the intensity, position, and nature of the chirooptical activity can be carefully adjusted via silver overgrowth. These studies illustrate the utility of peptide-based nanoparticle assembly platforms for designing and preparing complex plasmonic materials with tailorable optical properties.
PMCID: PMC4506777  PMID: 23777529
Chiral nanostructures; circular dichroism; nanoparticle assembly; chirality; surface plasmon
10.  Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition 
Kool, Marcel | Jones, David T.W. | Jäger, Natalie | Northcott, Paul A. | Pugh, Trevor J. | Hovestadt, Volker | Piro, Rosario M. | Esparza, L. Adriana | Markant, Shirley L. | Remke, Marc | Milde, Till | Bourdeaut, Franck | Ryzhova, Marina | Sturm, Dominik | Pfaff, Elke | Stark, Sebastian | Hutter, Sonja | Şeker-Cin, Huriye | Johann, Pascal | Bender, Sebastian | Schmidt, Christin | Rausch, Tobias | Shih, David | Reimand, Jüri | Sieber, Laura | Wittmann, Andrea | Linke, Linda | Witt, Hendrik | Weber, Ursula D. | Zapatka, Marc | König, Rainer | Beroukhim, Rameen | Bergthold, Guillaume | van Sluis, Peter | Volckmann, Richard | Koster, Jan | Versteeg, Rogier | Schmidt, Sabine | Wolf, Stephan | Lawerenz, Chris | Bartholomae, Cynthia C. | von Kalle, Christof | Unterberg, Andreas | Herold-Mende, Christel | Hofer, Silvia | Kulozik, Andreas E. | von Deimling, Andreas | Scheurlen, Wolfram | Felsberg, Jörg | Reifenberger, Guido | Hasselblatt, Martin | Crawford, John R. | Grant, Gerald A. | Jabado, Nada | Perry, Arie | Cowdrey, Cynthia | Croul, Sydney | Zadeh, Gelareh | Korbel, Jan O. | Doz, Francois | Delattre, Olivier | Bader, Gary D. | McCabe, Martin G. | Collins, V. Peter | Kieran, Mark W. | Cho, Yoon-Jae | Pomeroy, Scott L. | Witt, Olaf | Brors, Benedikt | Taylor, Michael D. | Schüller, Ulrich | Korshunov, Andrey | Eils, Roland | Wechsler-Reya, Robert J. | Lichter, Peter | Pfister, Stefan M.
Cancer cell  2014;25(3):393-405.
Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
PMCID: PMC4493053  PMID: 24651015
Hypertension  2014;64(1):103-110.
Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease (CKD). We investigated the association between serum aldosterone and death and end-stage renal disease (ESRD) in 3,866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure (CHF) and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and RAAS inhibitors. Over a median follow-up period of 5.4 years, 587 participants died, 743 developed ESRD, 187 developed CHF, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per standard deviation of the log transformed aldosterone) were not an independent risk factor for death (adjusted HR 1.00, 95% CI [0.93–1.12]), ESRD (adjusted HR 1.07, 95% CI [0.99–1.17]), or atherosclerotic events (adjusted HR 1.04, 95% CI [0.85–1.18]). Aldosterone was associated with CHF (adjusted HR 1.21, 95% CI [1.02–1.35]). Among participants with CKD, higher aldosterone concentrations were independently associated with the development of CHF, but not for death, ESRD, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with CKD since elevated cortisol levels may activate the mineralocorticoid receptor.
PMCID: PMC4089190  PMID: 24752431
Aldosterone; Chronic kidney disease; Outcomes; Death; Congestive Heart Failure
12.  Recommended Patient-Reported Core Set of Symptoms to Measure in Prostate Cancer Treatment Trials 
The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee convened four working groups to recommend core sets of patient-reported outcomes to be routinely incorporated in clinical trials. The Prostate Cancer Working Group included physicians, researchers, and a patient advocate. The group’s process included 1) a systematic literature review to determine the prevalence and severity of symptoms, 2) a multistakeholder meeting sponsored by the NCI to review the evidence and build consensus, and 3) a postmeeting expert panel synthesis of findings to finalize recommendations. Five domains were recommended for localized prostate cancer: urinary incontinence, urinary obstruction and irritation, bowel-related symptoms, sexual dysfunction, and hormonal symptoms. Four domains were recommended for advanced prostate cancer: pain, fatigue, mental well-being, and physical well-being. Additional domains for consideration include decisional regret, satisfaction with care, and anxiety related to prostate cancer. These recommendations have been endorsed by the NCI for implementation.
PMCID: PMC4192044  PMID: 25006192
13.  Radioiodinated DPA-713 Imaging Correlates with Bactericidal Activity of Tuberculosis Treatments in Mice 
Current tools for monitoring response to tuberculosis treatments have several limitations. Noninvasive biomarkers could accelerate tuberculosis drug development and clinical studies, but to date little progress has been made in developing new imaging technologies for this application. In this study, we developed pulmonary single-photon emission computed tomography (SPECT) using radioiodinated DPA-713 to serially monitor the activity of tuberculosis treatments in live mice, which develop necrotic granulomas and cavitary lesions. C3HeB/FeJ mice were aerosol infected with Mycobacterium tuberculosis and administered either a standard or a highly active bedaquiline-containing drug regimen. Serial 125I-DPA-713 SPECT imaging was compared with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and standard microbiology. Ex vivo studies were performed to characterize and correlate DPA-713 imaging with cellular and cytokine responses. Pulmonary 125I-DPA-713 SPECT, but not 18F-FDG PET, was able to correctly identify the bactericidal activities of the two tuberculosis treatments as early as 4 weeks after the start of treatment (P < 0.03). DPA-713 readily penetrated the fibrotic rims of necrotic and cavitary lesions. A time-dependent decrease in both tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels was observed with treatments, with 125I-DPA-713 SPECT correlating best with tissue TNF-α levels (ρ = 0.94; P < 0.01). 124I-DPA-713 was also evaluated as a PET probe and demonstrated a 4.0-fold-higher signal intensity in the infected tuberculous lesions than uninfected controls (P = 0.03). These studies provide proof of concept for application of a novel noninvasive imaging biomarker to monitor tuberculosis treatments, with the potential for application for humans.
PMCID: PMC4291409  PMID: 25403669
14.  Evidence for the embodiment of space perception: concurrent hand but not arm action moderates reachability and egocentric distance perception 
The perception of reachability (i.e., whether an object is within reach) relies on body representations and action simulation. Similarly, egocentric distance estimation (i.e., the perception of the distance an object is from the self) is thought to be partly derived from embodied action simulation. Although motor simulation is important for both, it is unclear whether the cognitive processes underlying these behaviors rely on the same motor processes. To investigate this, we measured the impact of a motor interference dual-task paradigm on reachability judgment and egocentric distance estimation, while allocentric length estimation (i.e., how distant two stimuli are from each other independent from the self) was used as a control task. Participants were required to make concurrent actions with either hand actions of foam ball grip squeezing or arm actions of weight lifting, or no concurrent actions. Results showed that concurrent squeeze actions significantly slowed response speed in the reachability judgment and egocentric distance estimation tasks, but that there was no impact of the concurrent actions on allocentric length estimation. Together, these results suggest that reachability and distance perception, both egocentric perspective tasks, and in contrast to the allocentric perspective task, involve action simulation cognitive processes. The results are discussed in terms of the implication of action simulation when evaluating the position of a target relative to the observer’s body, supporting an embodied view of spatial cognition.
PMCID: PMC4481150  PMID: 26167153
reachability judgment; distance estimation; action simulation; dual-task; space perception
15.  In-vivo detection of binary PKA network interactions upon activation of endogenous GPCRs 
Scientific Reports  2015;5:11133.
Membrane receptor-sensed input signals affect and modulate intracellular protein-protein interactions (PPIs). Consequent changes occur to the compositions of protein complexes, protein localization and intermolecular binding affinities. Alterations of compartmentalized PPIs emanating from certain deregulated kinases are implicated in the manifestation of diseases such as cancer. Here we describe the application of a genetically encoded Protein-fragment Complementation Assay (PCA) based on the Renilla Luciferase (Rluc) enzyme to compare binary PPIs of the spatially and temporally controlled protein kinase A (PKA) network in diverse eukaryotic model systems. The simplicity and sensitivity of this cell-based reporter allows for real-time recordings of mutually exclusive PPIs of PKA upon activation of selected endogenous G protein-coupled receptors (GPCRs) in cancer cells, xenografts of mice, budding yeast, and zebrafish embryos. This extends the application spectrum of Rluc PCA for the quantification of PPI-based receptor-effector relationships in physiological and pathological model systems.
PMCID: PMC4477410  PMID: 26099953
16.  Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation 
PLoS ONE  2015;10(6):e0129618.
In Alzheimer’s disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1ΔE9 mice were used in small animal PET with a CB2-targeting radiotracer, [11C]A836339. These studies revealed increased binding of [11C]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with Aβ plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that Aβ amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.
PMCID: PMC4472959  PMID: 26086915
17.  Draft Genome Sequence of the Moderately Halophilic Methanotroph Methylohalobius crimeensis Strain 10Ki 
Genome Announcements  2015;3(3):e00644-15.
Methylohalobius crimeensis strain 10Ki is a moderately halophilic aerobic methanotroph isolated from a hypersaline lake in the Crimean Peninsula, Ukraine. This organism has the highest salt tolerance of any cultured methanotroph. Here, we present a draft genome sequence of this bacterium.
PMCID: PMC4463540  PMID: 26067976
18.  Influence of solar variability on the infrared radiative cooling of the thermosphere from 2002 to 2014 
Geophysical Research Letters  2014;41(7):2508-2513.
Infrared radiative cooling of the thermosphere by carbon dioxide (CO2, 15 µm) and by nitric oxide (NO, 5.3 µm) has been observed for 12 years by the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) instrument on the Thermosphere-Ionosphere-Mesosphere Energetics and Dynamics satellite. For the first time we present a record of the two most important thermospheric infrared cooling agents over a complete solar cycle. SABER has documented dramatic variability in the radiative cooling on time scales ranging from days to the 11 year solar cycle. Deep minima in global mean vertical profiles of radiative cooling are observed in 2008–2009. Current solar maximum conditions, evidenced in the rates of radiative cooling, are substantially weaker than prior maximum conditions in 2002–2003. The observed changes in thermospheric cooling correlate well with changes in solar ultraviolet irradiance and geomagnetic activity during the prior maximum conditions. NO and CO2 combine to emit 7 × 1018 more Joules annually at solar maximum than at solar minimum.
Key Points
First record of thermospheric IR cooling rates over a complete solar cycleIR cooling in current solar maximum conditions much weaker than prior maximumVariability in thermospheric IR cooling observed on scale of days to 11 years
PMCID: PMC4459182  PMID: 26074647
thermosphere; radiative cooling; solar cycle; carbon dioxide; nitric oxide
19.  Draft Genomes of Gammaproteobacterial Methanotrophs Isolated from Terrestrial Ecosystems 
Genome Announcements  2015;3(3):e00515-15.
Genome sequences of Methylobacter luteus, Methylobacter whittenburyi, Methylosarcina fibrata, Methylomicrobium agile, and Methylovulum miyakonense were generated. The strains represent aerobic methanotrophs typically isolated from various terrestrial ecosystems.
PMCID: PMC4457054  PMID: 26044417
Urology  2014;83(6):1362-1368.
To modify the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) to predict low- versus high-grade (Gleason grade ≥ 7) prostate cancer and incorporate percent free PSA.
Data from 6664 PCPT placebo arm biopsies [5826 individuals] where prostate-specific antigen (PSA) and digital rectal examination (DRE) results were available within one year prior to the biopsy and PSA was ≤ 10 ng/mL were used to develop a nominal logistic regression model to predict the risk of no versus low-grade (Gleason grade < 7) versus high-grade (Gleason grade ≥ 7) cancer. Percent free PSA was incorporated into the model based on likelihood ratio (LR) analysis of a San Antonio Biomarkers of Risk cohort. Models were externally validated on ten Prostate Biopsy Collaborative Group cohorts and one Early Detection Research Network (EDRN) reference set.
5468 (82.1%) of the PCPT biopsies were negative for prostate cancer, 942 (14.1%) detected low-grade and 254 (3.8%) high-grade disease. Significant predictors were (log-base-2) PSA (OR for low-grade versus no cancer: 1.29*, high-grade versus no cancer: 2.02*, high-grade versus low-grade cancer: 1.57*), DRE (0.96, 1.49*, 1.55*, respectively), age (1.02*, 1.05*, 1.03*), African American race (1.13, 2.83*, 2.51*), prior biopsy (0.63*, 0.81, 1.27), and family history (1.31*, 1.25, 0.95), where * indicates p-value < 0.05. The new PCPTRC 2.0 either with or without percent free PSA (also significant by the LR method) validated well externally.
By differentiating risk of low- versus high-grade disease on biopsy, PCPTRC 2.0 better enables physician-patient counseling concerning whether to proceed to biopsy.
PMCID: PMC4035700  PMID: 24862395
Low-grade prostate Cancer; High-grade prostate Cancer; Prostate-specific Antigen; Percent free PSA; Prostate Cancer Prevention Trial; Risk prediction
21.  Leptin-inhibited PBN neurons enhance counter-regulatory responses to hypoglycemia in negative energy balance 
Nature neuroscience  2014;17(12):1744-1750.
Hypoglycemia initiates the counter regulatory response (CRR), in which the sympathetic nervous system, glucagon, and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin restrains energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here, we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates leptin receptor (LepRb) and cholecystokinin (CCK)-expressing neurons of the parabrachial nucleus (PBN), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells and Cckcre-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, while their activation mimics the CRR in a CCK-dependent manner. PBN LepRbCCK neurons represent a crucial component of the CRR system, and may represent a therapeutic target in hypoglycemia.
PMCID: PMC4255234  PMID: 25383904
22.  Phosphorus-32, a Clinically Available Drug, Inhibits Cancer Growth by Inducing DNA Double-Strand Breakage 
PLoS ONE  2015;10(6):e0128152.
Radioisotopes that emit electrons (beta particles), such as radioiodine, can effectively kill target cells, including cancer cells. Aqueous 32P[PO4] is a pure beta-emitter that has been used for several decades to treat non-malignant human myeloproliferative diseases. 32P[PO4] was directly compared to a more powerful pure beta-emitter, the clinically important 90Y isotope. In vitro, 32P[PO4] was more effective at killing cells than was the more powerful isotope 90Y (P ≤ 0.001) and also caused substantially more double-stranded DNA breaks than did 90Y. In vivo, a single low-dose intravenous dose of aqueous elemental 32P significantly inhibited tumor growth in the syngeneic murine cancer model (P ≤ 0.001). This effect is exerted by direct incorporation into nascent DNA chains, resulting in double-stranded breakage, a unique mechanism not duplicatable by other, more powerful electron-emitting radioisotopes. 32P[PO4] should be considered for human clinical trials as a potential novel anti-cancer drug.
PMCID: PMC4450878  PMID: 26030880
25.  Angiographic detection of cerebral cavernous malformations with C-arm cone beam CT imaging in three patients 
BMJ Case Reports  2013;2013:bcr2013010650.
Cerebral cavernous malformations (CMs) are typically not seen during conventional digital subtraction angiography (DSA) and are therefore classically referred to as angiographically occult malformations. We present three cases in which DSA with selective intra-arterial contrast injection in the common carotid artery and C-arm cone beam CT imaging was able to demonstrate a CM. In addition, an associated developmental venous anomaly (DVA) was present in all three cases, although detected by MRI in only one of them. In light of this finding, we suspect that the incidence of DVA associated with CM is probably higher than previously reported.
PMCID: PMC3670038  PMID: 23704473
Technique; CT; Vascular Malformation

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