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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.  A prudent path forward for genomic engineering and germline gene modification 
Science (New York, N.Y.)  2015;348(6230):36-38.
A framework for open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome is urgently needed
PMCID: PMC4394183  PMID: 25791083
3.  B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies 
Europace  2014;16(10):1426-1433.
B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
Methods and results
We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56–1.76], P < 0.0001 and 1.18 (95% CI, 1.11–1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ2 = 17.0; CRP, χ2 = 10.5; BNP and CRP, χ2 = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022–0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322–0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
PMCID: PMC4197895  PMID: 25037055
Atrial fibrillation; Risk prediction; Epidemiology; Biomarker; B-type natriuretic peptide; C-reactive protein
4.  Stromal Cell-Derived Factor 1 (SDF-1) as a Biomarker of Heart Failure and Mortality Risk 
CXCL12 encodes stromal cell-derived factor 1 alpha (SDF-1), which binds to the receptor encoded by CXCR4. Variation at the CXCL12 locus is associated with coronary artery disease (CAD) and endothelial progenitor cell (EPC) numbers, while variation at the CXCR4 locus is associated with leukocyte telomere length (LTL), which has been shown to be associated with CAD. We therefore examined the relations of plasma SDF-1 levels to cardiovascular disease (CVD)-related outcomes, risk factors, LTL, and EPCs.
Approach and Results
SDF-1 was measured in 3359 Framingham Heart Study participants. We used Cox regression to examine relations of SDF-1 to new-onset CVD, myocardial infarction (MI), heart failure (HF), and all-cause mortality; we used linear regression to evaluate associations of SDF-1 with risk factors, LTL, and CD34+ cell phenotypes. In multivariable models, higher SDF-1 levels were associated with older age, lower levels of HDL cholesterol, and cigarette smoking. Higher SDF-1 levels were associated with lower CD34+ cell frequency (p=0.02), but not with LTL. During follow-up (median 9.3 years), there were 263 new-onset CVD events, 160 MIs, 200 HF events, and 385 deaths. After adjusting for clinical risk factors, SDF-1 levels were associated with HF (p=0.04) and all-cause mortality (p=0.003), but not with CVD (p=0.39) or MI (p=0.10). The association of SDF-1 levels with MI was attenuated after adjustment for HDL cholesterol.
After adjusting for traditional CVD risk factors, SDF-1 is associated with HF and all-cause mortality risk. Further studies are needed to determine whether measurement of SDF-1 levels has clinical utility.
PMCID: PMC4142677  PMID: 25060794
Cardiovascular disease; epidemiology; myocardial infarction; heart failure; mortality; stromal cell-derived factor 1; progenitor cells
5.  Initial Evaluation of [18F]DCFPyL for Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer 
Prostate-specific membrane antigen (PSMA) is a recognized target for imaging prostate cancer. Here we present initial safety, biodistribution, and radiation dosimetry results with [18F]DCFPyL, a second-generation fluorine-18-labeled small-molecule PSMA inhibitor, in patients with prostate cancer.
Biodistribution was evaluated using sequential positron-emission tomography (PET) scans in nine patients with prostate cancer. Time-activity curves from the most avid tumor foci were determined. The radiation dose to selected organs was estimated using OLINDA/EXM.
No major radiotracer-specific adverse events were observed. Physiologic accumulation was observed in known sites of PSMA expression. Accumulation in putative sites of prostate cancer was observed (SUVmax up to >100, and tumor-to-blood ratios up to >50). The effective radiation dose from [18F]DCFPyL was 0.0139 mGy/MBq or 5 mGy (0.5 rem) from an injected dose of 370 MBq (10 mCi).
[18F]DCFPyL is safe with biodistribution as expected, and its accumulation is high in presumed primary and metastatic foci. The radiation dose from [18F]DCFPyL is similar to that from other PET radiotracers.
PMCID: PMC4531836  PMID: 25896814
PSMA; PET; Prostate cancer; Molecular imaging; Fluorine-18
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  The contribution of opiate analgesics to the development of infectious complications in trauma patients 
Trauma-related pain is a natural consequence of injury and its surgical management; however, the relationship between opiates and complications in trauma patients is unknown. To study this a retrospective chart review of selected subjects following traumatic injury with admission to the SICU for > 3 days was performed, and opiate administration data was collected for the first 3 days of admission. Associated data from each subject’s chart was also collected. Analysis of the data revealed that increased opiate intake after admission to the SICU was associated with significantly increased SICU and hospital LOS independent of injury severity. This increase in LOS was independent of mechanical ventilation in the moderate ISS group. Infectious complications were also more prevalent in the moderate ISS group with higher opiate use. These findings suggest that increased doses of opiate analgesics in trauma patients may contribute to an increased overall LOS and associated infectious complications. Analgesic regimes that minimize opiate intake, while still providing adequate pain relief, may be advantageous in reducing LOS, complications and reduce hospitalization costs.
PMCID: PMC4539093  PMID: 26309777
Pain; mechanical ventilation; analgesia; LOS; infection; ICU
13.  Multiple synchronous sites of origin of vestibular schwannomas in neurofibromatosis Type 2 
Journal of Medical Genetics  2015;52(8):557-562.
Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour syndrome with a phenotype which includes bilateral vestibular (eighth cranial nerve) schwannomas. Conventional thinking suggests that these tumours originate at a single point along the superior division of the eighth nerve.
High resolution MRI was performed in children genetically proven to have NF2. The superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) were visualised along their course with points of tumour origin calculated as a percentage relative to the length of the nerve.
Out of 41 patients assessed, 7 patients had no identifiable eighth cranial nerve disease. In 16 patients there was complete filling of the internal auditory meatus by a tumour mass such that its specific neural origin could not be determined. In the remaining 18 cases, 86 discrete separate foci of tumour origin on the SVN or IVN could be identified including 23 tumours on the right SVN, 26 tumours on the right IVN, 18 tumours on the left SVN and 19 tumours on the left IVN.
This study, examining the origins of vestibular schwannomas in NF2, refutes their origin as being from a single site on the transition zone of the superior division of the vestibular nerve. We hypothesise a relationship between the number of tumour foci, tumour biology and aggressiveness of disease. The development of targeted drug therapies in addition to bevacizumab are therefore essential to improve prognosis and quality of life in patients with NF2 given the shortcomings of surgery and radiation treatments when dealing with the multifocality of the disease.
PMCID: PMC4518745  PMID: 26104281
Cancer: CNS; Cancer: head and neck; Clinical genetics; Diagnostics; Neurology
14.  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
15.  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
16.  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
17.  Adaptive shut-down of EEG activity predicts critical acidemia in the near-term ovine fetus 
Physiological Reports  2015;3(7):e12435.
In fetal sheep, the electrocorticogram (ECOG) recorded directly from the cortex during repetitive heart rate (FHR) decelerations induced by umbilical cord occlusions (UCO) predictably correlates with worsening hypoxic-acidemia. In human fetal monitoring during labor, the equivalent electroencephalogram (EEG) can be recorded noninvasively from the scalp. We tested the hypothesis that combined fetal EEG – FHR monitoring allows for early detection of worsening hypoxic-acidemia similar to that shown for ECOG-FHR monitoring. Near-term fetal sheep (n = 9) were chronically instrumented with arterial and venous catheters, ECG, ECOG, and EEG electrodes and umbilical cord occluder, followed by 4 days of recovery. Repetitive UCOs of 1 min duration and increasing strength (with regard to the degree of reduction in umbilical blood flow) were induced each 2.5 min until pH dropped to <7.00. Repetitive UCOs led to marked acidosis (arterial pH 7.35 ± 0.01 to 7.00 ± 0.03). At pH of 7.22 ± 0.03 (range 7.32–7.07), and 45 ± 9 min (range 1 h 33 min–20 min) prior to attaining pH < 7.00, both ECOG and EEG amplitudes began to decrease ∼fourfold during each FHR deceleration in a synchronized manner. Confirming our hypothesis, these findings support fetal EEG as a useful adjunct to FHR monitoring during human labor for early detection of incipient fetal acidemia.
PMCID: PMC4552521  PMID: 26149280
Acidosis; asphyxia; ECOG; EEG; Fetus; FHR; hypoxia; monitoring
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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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