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1.  Analysis of expressed sequence tags from Actinidia: applications of a cross species EST database for gene discovery in the areas of flavor, health, color and ripening 
BMC Genomics  2008;9:351.
Kiwifruit (Actinidia spp.) are a relatively new, but economically important crop grown in many different parts of the world. Commercial success is driven by the development of new cultivars with novel consumer traits including flavor, appearance, healthful components and convenience. To increase our understanding of the genetic diversity and gene-based control of these key traits in Actinidia, we have produced a collection of 132,577 expressed sequence tags (ESTs).
The ESTs were derived mainly from four Actinidia species (A. chinensis, A. deliciosa, A. arguta and A. eriantha) and fell into 41,858 non redundant clusters (18,070 tentative consensus sequences and 23,788 EST singletons). Analysis of flavor and fragrance-related gene families (acyltransferases and carboxylesterases) and pathways (terpenoid biosynthesis) is presented in comparison with a chemical analysis of the compounds present in Actinidia including esters, acids, alcohols and terpenes. ESTs are identified for most genes in color pathways controlling chlorophyll degradation and carotenoid biosynthesis. In the health area, data are presented on the ESTs involved in ascorbic acid and quinic acid biosynthesis showing not only that genes for many of the steps in these pathways are represented in the database, but that genes encoding some critical steps are absent. In the convenience area, genes related to different stages of fruit softening are identified.
This large EST resource will allow researchers to undertake the tremendous challenge of understanding the molecular basis of genetic diversity in the Actinidia genus as well as provide an EST resource for comparative fruit genomics. The various bioinformatics analyses we have undertaken demonstrates the extent of coverage of ESTs for genes encoding different biochemical pathways in Actinidia.
PMCID: PMC2515324  PMID: 18655731
2.  Calretinin expression in high-grade invasive ductal carcinoma of the breast is associated with basal-like subtype and unfavorable prognosis 
Human pathology  2013;44(12):10.1016/j.humpath.2013.07.021.
Calretinin, a calcium-binding protein, is a widely utilized marker for mesothelial differentiation. There is accumulating evidence of calretinin expression in epithelial and mesenchymal malignancies as well. The objectives of this study were 1) further delineate the expression of calretinin in grade 3 breast carcinomas in the context of molecular subtypes and 2) identify the impact of calretinin expression on overall- and disease-free survival. On the basis of immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), CK5/6 and epidermal growth factor receptor (EGFR), 214 grade 3 invasive ductal carcinomas were stratified into 36 luminal A, 63 luminal B, 24 HER2-positive, 81 basal-like (including 13 metaplastic carcinomas), and 10 unclassified. Tissue microarrays were analyzed for immunohistochemical expression of calretinin. High-level calretinin expression was identified in a significant proportion of basal-like (54.3%), HER2 (33.3%) and unclassified (30%) tumors. In contrast, luminal A and B subtypes demonstrated high-level calretinin expression in only 11.1% and 12.7%, respectively (P<0.0001). Within the basal-like group, 38.5% of the metaplastic carcinomas demonstrated high-level expression, associated predominantly with the epithelial component and squamous metaplasia. High-level calretinin expression was strongly associated with decreased overall survival in the entire cohort of grade 3 cancer (P=0.0096) and in the basal-like group (P=0.039). Multivariate analysis revealed that both tumor stage and high-level calretinin expression were independent predictors of overall survival (P=0.0002 and P=0.0023, respectively). In conclusion, high-level calretinin expression is most common in grade 3 tumors with a basal-like phenotype and is associated with poor overall survival.
PMCID: PMC3838787  PMID: 24262018
Breast; Carcinoma; Basal-like; Immunohistochemisty; Calretinin
3.  Dynamic evolution of clonal epialleles revealed by methclone 
Genome Biology  2014;15(9):472.
We describe methclone, a novel method to identify epigenetic loci that harbor large changes in the clonality of their epialleles (epigenetic alleles). Methclone efficiently analyzes genome-wide DNA methylation sequencing data. We quantify the changes using a composition entropy difference calculation and also introduce a new measure of global clonality shift, loci with epiallele shift per million loci covered, which enables comparisons between different samples to gauge overall epiallelic dynamics. Finally, we demonstrate the utility of methclone in capturing functional epiallele shifts in leukemia patients from diagnosis to relapse. Methclone is open-source and freely available at
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0472-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4242486  PMID: 25260792
4.  Rebuilding TRUST: A Community, Multi-Agency, State, and University Partnership to Improve Behavioral Health Care for American Indian Youth, their Families, and Communities 
Journal of community psychology  2011;39(4):452-477.
American Indian/Alaska Native youth represent the strength and survival of many Nations and Tribes. However, the aftermath of colonialism has resulted in numerous health disparities and challenges for Native youth, including the highest rate of suicide in the United States. With the aims of elucidating the causes of behavioral health disparities, eliminating them, and improving behavioral health care for Native youth, a partnership of providers, community members, and university faculty and staff completed a comprehensive literature review; conducted advisory meetings with 71 American Indian youth, parents, and elders; surveyed 25 service providers; and engaged in ongoing consultation with traditional practitioners. Results from the multiple sources were synthesized and are reported with 20 policy, provider, and research recommendations that recognize the importance of moving beyond exclusive reliance on western models of care and that seek to foster transformation of individuals, families, communities, behavioral health service systems of care, and social structures.
PMCID: PMC4112470  PMID: 25076801
5.  The sleeping brain regulates to the edge of chaos 
BMC Neuroscience  2014;15(Suppl 1):O19.
PMCID: PMC4124958
6.  SYK Regulates mTOR Signaling in AML 
Leukemia  2013;27(11):2118-2128.
Spleen Tyrosine Kinase (SYK) was recently identified as a new target in acute myeloid leukemia (AML); however, its mechanistic role in this disease is poorly understood. Based on the known interaction between SYK and mTOR signaling in lymphoma, we hypothesized that SYK may regulate mTOR signaling in AML. Both small-molecule inhibition of SYK and SYK-directed shRNA suppressed mTOR and its downstream signaling effectors, as well as its upstream activator, AKT. Moreover, the inhibition of multiple nodes of the PI3K signaling pathway enhanced the effects of SYK suppression on AML cell viability and differentiation. Evaluation of the collateral MAPK pathway revealed a heterogeneous response to SYK inhibition in AML with down-regulation of MEK and ERK phosphorylation in some AML cell lines but a paradoxical increase in MEK/ERK phosphorylation in RAS-mutated AML. These studies reveal SYK as a regulator of mTOR and MAPK signaling in AML and demonstrate that inhibition of PI3K pathway activity enhances the effects of SYK inhibition on AML cell viability and differentiation.
PMCID: PMC4028963  PMID: 23535559
AML; SYK; mTOR; differentiation therapy; RPS6; 4E-BP1; MAPK
7.  Association Between Antiretroviral Exposure and Renal Impairment Among HIV-Positive Persons With Normal Baseline Renal Function: the D:A:D Studya 
The Journal of Infectious Diseases  2013;207(9):1359-1369.
Background. Several antiretroviral agents (ARVs) are associated with chronic renal impairment, but the extent of such adverse events among human immunodeficiency virus (HIV)–positive persons with initially normal renal function is unknown.
Methods. D:A:D study participants with an estimated glomerular filtration rate (eGFR) of ≥90 mL/min after 1 January 2004 were followed until they had a confirmed eGFR of ≤70 mL/min (the threshold below which we hypothesized that renal interventions may begin to occur) or ≤60 mL/min (a value indicative of moderately severe chronic kidney disease [CKD]) or until the last eGFR measurement during follow-up. An eGFR was considered confirmed if it was detected at 2 consecutive measurements ≥3 months apart. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression.
Results. Of 22 603 persons, 468 (2.1%) experienced a confirmed eGFR of ≤70 mL/min (incidence rate, 4.78 cases/1000 person-years of follow-up [95% confidence interval {CI}, 4.35–5.22]) and 131 (0.6%) experienced CKD (incidence rate, 1.33 cases/1000 person-years of follow-up [95% CI, 1.10–1.56]) during a median follow-up duration of 4.5 years (interquartile range [IQR], 2.7–6.1 years). A current eGFR of 60–70 mL/min caused significantly higher rates of discontinuation of tenofovir (adjusted incidence rate ratio [aIRR], 1.72 [95% CI, 1.38–2.14]) but not other ARVs compared with a current eGFR of ≥90 mL/min. Cumulative tenofovir use (aIRR, 1.18/year [95% CI, 1.12–1.25]) and ritonavir-boosted atazanavir use (aIRR, 1.19/year [95% CI, 1.09–1.32]) were independent predictors of a confirmed eGFR of ≤70 but were not significant predictors of CKD whereas ritonavir-boosted lopinavir use was a significant predictor for both end points (aIRR, 1.11/year [95% CI, 1.05–1.17] and 1.22/year [95% CI, 1.16–1.28], respectively). Associations were unaffected by censoring for concomitant ARV use but diminished after discontinuation of these ARVs.
Conclusions. Tenofovir, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir use were independent predictors of chronic renal impairment in HIV-positive persons without preexisting renal impairment. Increased tenofovir discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation, the ARV-associated incidence rates decreased.
PMCID: PMC3610424  PMID: 23382571
HIV; eGFR; ART; tenofovir; atazanavir; lopinavir; chronic kidney disease; nephrotoxicity
8.  Protein Thermodynamics Can Be Predicted Directly from Biological Growth Rates 
PLoS ONE  2014;9(5):e96100.
Life on Earth is capable of growing from temperatures well below freezing to above the boiling point of water, with some organisms preferring cooler and others hotter conditions. The growth rate of each organism ultimately depends on its intracellular chemical reactions. Here we show that a thermodynamic model based on a single, rate-limiting, enzyme-catalysed reaction accurately describes population growth rates in 230 diverse strains of unicellular and multicellular organisms. Collectively these represent all three domains of life, ranging from psychrophilic to hyperthermophilic, and including the highest temperature so far observed for growth (122°C). The results provide credible estimates of thermodynamic properties of proteins and obtain, purely from organism intrinsic growth rate data, relationships between parameters previously identified experimentally, thus bridging a gap between biochemistry and whole organism biology. We find that growth rates of both unicellular and multicellular life forms can be described by the same temperature dependence model. The model results provide strong support for a single highly-conserved reaction present in the last universal common ancestor (LUCA). This is remarkable in that it means that the growth rate dependence on temperature of unicellular and multicellular life forms that evolved over geological time spans can be explained by the same model.
PMCID: PMC4006894  PMID: 24787650
9.  Simulations of pattern dynamics for reaction-diffusion systems via SIMULINK 
BMC Systems Biology  2014;8:45.
Investigation of the nonlinear pattern dynamics of a reaction-diffusion system almost always requires numerical solution of the system’s set of defining differential equations. Traditionally, this would be done by selecting an appropriate differential equation solver from a library of such solvers, then writing computer codes (in a programming language such as C or Matlab) to access the selected solver and display the integrated results as a function of space and time. This “code-based” approach is flexible and powerful, but requires a certain level of programming sophistication. A modern alternative is to use a graphical programming interface such as Simulink to construct a data-flow diagram by assembling and linking appropriate code blocks drawn from a library. The result is a visual representation of the inter-relationships between the state variables whose output can be made completely equivalent to the code-based solution.
As a tutorial introduction, we first demonstrate application of the Simulink data-flow technique to the classical van der Pol nonlinear oscillator, and compare Matlab and Simulink coding approaches to solving the van der Pol ordinary differential equations. We then show how to introduce space (in one and two dimensions) by solving numerically the partial differential equations for two different reaction-diffusion systems: the well-known Brusselator chemical reactor, and a continuum model for a two-dimensional sheet of human cortex whose neurons are linked by both chemical and electrical (diffusive) synapses. We compare the relative performances of the Matlab and Simulink implementations.
The pattern simulations by Simulink are in good agreement with theoretical predictions. Compared with traditional coding approaches, the Simulink block-diagram paradigm reduces the time and programming burden required to implement a solution for reaction-diffusion systems of equations. Construction of the block-diagram does not require high-level programming skills, and the graphical interface lends itself to easy modification and use by non-experts.
PMCID: PMC4006638  PMID: 24725437
Simulink modelling; Brusselator model; Cortical model; Turing–Hopf pattern
10.  Cyclodextrin-Crosslinked Poly(Acrylic Acid): Adhesion and Controlled Release of Diflunisal and Fluconazole from Solid Dosage Forms 
AAPS PharmSciTech  2013;14(1):301-311.
The controlled release of diflunisal and fluconazole from tablets made of novel polymers, poly(acrylic acid) (PAA) crosslinked with either β-cyclodextrin (βCD) or hydroxypropyl-βCD (HPβCD), was investigated and Carbopol 934P (Carbopol) was used as a highly crosslinked PAA for comparison. Diflunisal strongly associates with βCD-PAA and HPβCD-PAA polymers (Ka of 486 and 6,055 M−1 respectively); thus, it was physically mixed into the conjugates and also precomplexed to identify whether decomplexation has any influence on release kinetics. Fluconazole has poor complexing ability (Ka of 34 M−1 with HPβCD-PAA); thus, it was only tested as a physical mixture. Swelling and adhesion studies were conducted on all tablet combinations and adhesivity of the CD-PAA polymer tablets was maintained. Diflunisal release was much slower from HPβCD-PAA tablets than from βCD-PAA, suggesting that a higher degree of complexation retards release. The precomplexed diflunisal release was also slower than the physically mixed diflunisal of the corresponding conjugate. The release closely followed zero-order kinetics for HPβCD-PAA, but was more sigmoidal for βCD-PAA and especially Carbopol. Conversely, poorly associating fluconazole released in almost exactly the same way across both polymers and Carbopol, indicating that the release kinetics of poorly associating drugs are not influenced by the presence of cyclodextrins. In view of the varying profiles and release rates shown with diflunisal for the different polymers, the fluconazole data support the concept that adequate complexation can indeed modulate the release kinetics of drugs.
Electronic supplementary material
The online version of this article (doi:10.1208/s12249-012-9903-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3581673  PMID: 23307066
controlled release; cyclodextrin; diflunisal; fluconazole; poly(acrylic acid)
11.  EEG slow-wave coherence changes in propofol-induced general anesthesia: experiment and theory 
The electroencephalogram (EEG) patterns recorded during general anesthetic-induced coma are closely similar to those seen during slow-wave sleep, the deepest stage of natural sleep; both states show patterns dominated by large amplitude slow waves. Slow oscillations are believed to be important for memory consolidation during natural sleep. Tracking the emergence of slow-wave oscillations during transition to unconsciousness may help us to identify drug-induced alterations of the underlying brain state, and provide insight into the mechanisms of general anesthesia. Although cellular-based mechanisms have been proposed, the origin of the slow oscillation has not yet been unambiguously established. A recent theoretical study by Steyn-Ross et al. (2013) proposes that the slow oscillation is a network, rather than cellular phenomenon. Modeling anesthesia as a moderate reduction in gap-junction interneuronal coupling, they predict an unconscious state signposted by emergent low-frequency oscillations with chaotic dynamics in space and time. They suggest that anesthetic slow-waves arise from a competitive interaction between symmetry-breaking instabilities in space (Turing) and time (Hopf), modulated by gap-junction coupling strength. A significant prediction of their model is that EEG phase coherence will decrease as the cortex transits from Turing–Hopf balance (wake) to Hopf-dominated chaotic slow-waves (unconsciousness). Here, we investigate changes in phase coherence during induction of general anesthesia. After examining 128-channel EEG traces recorded from five volunteers undergoing propofol anesthesia, we report a significant drop in sub-delta band (0.05–1.5 Hz) slow-wave coherence between frontal, occipital, and frontal–occipital electrode pairs, with the most pronounced wake-vs.-unconscious coherence changes occurring at the frontal cortex.
PMCID: PMC4212622  PMID: 25400558
slow-wave sleep; phase-coherence measure; mean-field cortical model; gap-junction; Turing–Hopf instabilities
12.  P50 Sensory Gating in Infants 
Attentional deficits are common in a variety of neuropsychiatric disorders including attention deficit-hyperactivity disorder, autism, bipolar mood disorder, and schizophrenia. There has been increasing interest in the neurodevelopmental components of these attentional deficits; neurodevelopmental meaning that while the deficits become clinically prominent in childhood or adulthood, the deficits are the results of problems in brain development that begin in infancy or even prenatally. Despite this interest, there are few methods for assessing attention very early in infancy. This report focuses on one method, infant auditory P50 sensory gating.
Attention has several components. One of the earliest components of attention, termed sensory gating, allows the brain to tune out repetitive, noninformative sensory information. Auditory P50 sensory gating refers to one task designed to measure sensory gating using changes in EEG. When identical auditory stimuli are presented 500 ms apart, the evoked response (change in the EEG associated with the processing of the click) to the second stimulus is generally reduced relative to the response to the first stimulus (i.e. the response is "gated"). When response to the second stimulus is not reduced, this is considered a poor sensory gating, is reflective of impaired cerebral inhibition, and is correlated with attentional deficits.
Because the auditory P50 sensory gating task is passive, it is of potential utility in the study of young infants and may provide a window into the developmental time course of attentional deficits in a variety of neuropsychiatric disorders. The goal of this presentation is to describe the methodology for assessing infant auditory P50 sensory gating, a methodology adapted from those used in studies of adult populations.
PMCID: PMC4108026  PMID: 24430259
Behavior; Issue 82; Child Development; Psychophysiology; Attention Deficit and Disruptive Behavior Disorders; Evoked Potentials; Auditory; auditory evoked potential; sensory gating; infant; attention; electrophysiology; infants; sensory gating; endophenotype; attention; P50
13.  Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors 
Cell Reports  2013;5(4):1047-1059.
To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.
Graphical Abstract
•Bcl-2 and Bcl-xL are the key survival factors downstream of oncogenic JAK2•Combined targeting of JAK2 and Bcl-2/Bcl-xL is highly efficacious in vivo•Combination therapy is well tolerated in preclinical models of JAK2-driven ALL•Combination therapy can overcome and circumvent resistance to JAK2 inhibitors
Better therapeutic options are required for mutant JAK2-driven hemopoietic malignancies to overcome intrinsic and acquired therapy resistance. Johnstone and colleagues functionally dissect signaling pathways downstream of hyperactive JAK2 and define the STAT5-Bcl-2/Bcl-xL axis as crucial for tumor cell survival and development of acquired JAK inhibitor resistance. Combined inhibition of this oncogenic JAK2 signaling network at two critical points—JAK2 and Bcl-2/Bcl-xL—proved highly efficacious in vivo and was able to circumvent and overcome acquired resistance to single-agent JAK inhibitors.
PMCID: PMC3898474  PMID: 24268771
14.  Mapping In Vivo Tumor Oxygenation within Viable Tumor by 19F-MRI and Multispectral Analysis1 
Neoplasia (New York, N.Y.)  2013;15(11):1241-1250.
Quantifying oxygenation in viable tumor remains a major obstacle toward a better understanding of the tumor micro-environment and improving treatment strategies. Current techniques are often complicated by tumor heterogeneity. Herein, a novel in vivo approach that combines 19F magnetic resonance imaging (19F-MRI) R1 mapping with diffusion-based multispectral (MS) analysis is introduced. This approach restricts the partial pressure of oxygen (pO2) measurements to viable tumor, the tissue of therapeutic interest. The technique exhibited sufficient sensitivity to detect a breathing gas challenge in a xenograft tumor model, and the hypoxic region measured by MS 19F-MRI was strongly correlated with histologic estimates of hypoxia. This approach was then applied to address the effects of antivascular agents on tumor oxygenation, which is a research question that is still under debate. The technique was used to monitor longitudinal pO2 changes in response to an antibody to vascular endothelial growth factor (B20.4.1.1) and a selective dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor (GDC-0980). GDC-0980 reduced viable tumor pO2 during a 3-day treatment period, and a significant reduction was also produced by B20.4.1.1. Overall, this method provides an unprecedented view of viable tumor pO2 and contributes to a greater understanding of the effects of antivascular therapies on the tumor's microenvironment.
PMCID: PMC3858898  PMID: 24339736
15.  Dimeric naphthoquinones, a novel class of compounds with prostate cancer cytotoxicity 
BJU international  2010;108(3):447-454.
To evaluate the cytotoxicity of dimeric naphthoquinones (BiQs) in prostate cancer cells.To assess the interaction of dimeric naphthoquinones with common therapies including radiation and docetaxel.
The cytotoxicity of 12 different dimeric naphthoquinones was assessed in androgen-independent (PC-3, DU-145) and androgen-responsive (LNCaP, 22RV1) prostate cancer cell lines and in prostate epithelial cells (PrECs).BiQ2 and BiQ11 were selected for determination of dose response, effects on colony formation and initial exploration into mechanism of action.Synergistic effects with radiation and docetaxel were explored using colony-forming and MTT assays.
At concentrations of 15μM, BiQ2, BiQ3, BiQ11, BiQ12, and BiQ15 demonstrated cytotoxicity in all prostate cancer cell lines.Treatment with BiQs limited the ability of prostate cancer cells to form colonies in clonogenic assays.Exposure of prostate cancer to BiQs increased cellular reactive oxygen species (ROS), decreased ATP production, and promoted apoptosis.BiQ cytotoxicity was independent of NADP(H):quinone oxidoreductase 1 (NQO1) activity in PrECs, PC-3 and 22RV1, but not DU-145 cells.Exposure of prostate cancer cells to radiation before treatment with BiQs increased their activity allowing for inhibitory effects well below the IC50s of these compounds in PrECs.Co-administration of BiQs with docetaxel had minimal additive effects.
Dimeric naphthoquinones represent a new class of compounds with prostate cancer cytotoxicity and synergistic effects with radiation. The cytotoxic effect of these agents is probably contributed to by the accumulation of ROS and mitochondrial dysfunction.Further studies are warranted to better characterize this class of potential chemotherapeutics.
PMCID: PMC3700341  PMID: 21176082
dimeric naphthoquinones; oxidative stress; cytotoxicity; prostate cancer; radiation synergy
16.  Gap junctions modulate seizures in a mean-field model of general anesthesia for the cortex 
Cognitive Neurodynamics  2012;6(3):215-225.
During slow-wave sleep, general anesthesia, and generalized seizures, there is an absence of consciousness. These states are characterized by low-frequency large-amplitude traveling waves in scalp electroencephalogram. Therefore the oscillatory state might be an indication of failure to form coherent neuronal assemblies necessary for consciousness. A generalized seizure event is a pathological brain state that is the clearest manifestation of waves of synchronized neuronal activity. Since gap junctions provide a direct electrical connection between adjoining neurons, thus enhancing synchronous behavior, reducing gap-junction conductance should suppress seizures; however there is no clear experimental evidence for this. Here we report theoretical predictions for a physiologically-based cortical model that describes the general anesthetic phase transition from consciousness to coma, and includes both chemical synaptic and direct electrotonic synapses. The model dynamics exhibits both Hopf (temporal) and Turing (spatial) instabilities; the Hopf instability corresponds to the slow (≲8 Hz) oscillatory states similar to those seen in slow-wave sleep, general anesthesia, and seizures. We argue that a delicately balanced interplay between Hopf and Turing modes provides a canonical mechanism for the default non-cognitive rest state of the brain. We show that the Turing mode, set by gap-junction diffusion, is generally protective against entering oscillatory modes; and that weakening the Turing mode by reducing gap conduction can release an uncontrolled Hopf oscillation and hence an increased propensity for seizure and simultaneously an increased sensitivity to GABAergic anesthesia.
PMCID: PMC3368060  PMID: 23730353
Seizure; Gap junctions; Mean-field cortical model; Hopf oscillations; Turing patterns; Nonlinear interactions; Phase coherence
17.  High-grade Angiosarcoma Associated with Ruptured Breast Implants 
Since the serendipitous discovery that implanted polymers cause sarcomas in rats, much research has been conducted to prove or disprove a link between silicone breast implants and/or polymer-based materials and breast cancer. In light of an initial report that 35% of rats implanted with a variety of polymers developed fibrosarcomas, we report a case of primary angiosarcoma found in a patient presenting with bilateral rupture of gel-filled breast implants.
PMCID: PMC4174177  PMID: 25289205
18.  Large-scale replication and heterogeneity in Parkinson disease genetic loci 
Sharma, Manu | Ioannidis, John P.A. | Aasly, Jan O. | Annesi, Grazia | Brice, Alexis | Van Broeckhoven, Christine | Bertram, Lars | Bozi, Maria | Crosiers, David | Clarke, Carl | Facheris, Maurizio | Farrer, Matthew | Garraux, Gaetan | Gispert, Suzana | Auburger, Georg | Vilariño-Güell, Carles | Hadjigeorgiou, Georgios M. | Hicks, Andrew A. | Hattori, Nobutaka | Jeon, Beom | Lesage, Suzanne | Lill, Christina M. | Lin, Juei-Jueng | Lynch, Timothy | Lichtner, Peter | Lang, Anthony E. | Mok, Vincent | Jasinska-Myga, Barbara | Mellick, George D. | Morrison, Karen E. | Opala, Grzegorz | Pramstaller, Peter P. | Pichler, Irene | Park, Sung Sup | Quattrone, Aldo | Rogaeva, Ekaterina | Ross, Owen A. | Stefanis, Leonidas | Stockton, Joanne D. | Satake, Wataru | Silburn, Peter A. | Theuns, Jessie | Tan, Eng-King | Toda, Tatsushi | Tomiyama, Hiroyuki | Uitti, Ryan J. | Wirdefeldt, Karin | Wszolek, Zbigniew | Xiromerisiou, Georgia | Yueh, Kuo-Chu | Zhao, Yi | Gasser, Thomas | Maraganore, Demetrius | Krüger, Rejko | Boyle, R.S | Sellbach, A | O'Sullivan, J.D. | Sutherland, G.T. | Siebert, G.A | Dissanayaka, N.N.W | Van Broeckhoven, Christine | Theuns, Jessie | Crosiers, David | Pickut, Barbara | Engelborghs, Sebastiaan | Meeus, Bram | De Deyn, Peter P. | Cras, Patrick | Rogaeva, Ekaterina | Lang, Anthony E | Agid, Y | Anheim, M | Bonnet, A-M | Borg, M | Brice, A | Broussolle, E | Corvol, JC | Damier, P | Destée, A | Dürr, A | Durif, F | Lesage, S | Lohmann, E | Pollak, P | Rascol, O | Tison, F | Tranchant, C | Viallet, F | Vidailhet, M | Tzourio, Christophe | Amouyel, Philippe | Loriot, Marie-Anne | Mutez, Eugénie | Duflot, Aurélie | Legendre, Jean-Philippe | Waucquier, Nawal | Gasser, Thomas | Riess, Olaf | Berg, Daniela | Schulte, Claudia | Klein, Christine | Djarmati, Ana | Hagenah, Johann | Lohmann, Katja | Auburger, Georg | Hilker, Rüdiger | van de Loo, Simone | Dardiotis, Efthimios | Tsimourtou, Vaia | Ralli, Styliani | Kountra, Persa | Patramani, Gianna | Vogiatzi, Cristina | Hattori, Nobutaka | Tomiyama, Hiroyuki | Funayama, Manabu | Yoshino, Hiroyo | Li, Yuanzhe | Imamichi, Yoko | Toda, Tatsushi | Satake, Wataru | Lynch, Tim | Gibson, J. Mark | Valente, Enza Maria | Ferraris, Alessandro | Dallapiccola, Bruno | Ialongo, Tamara | Brighina, Laura | Corradi, Barbara | Piolti, Roberto | Tarantino, Patrizia | Annesi, Ferdinanda | Jeon, Beom S. | Park, Sung-Sup | Aasly, J | Opala, Grzegorz | Jasinska-Myga, Barbara | Klodowska-Duda, Gabriela | Boczarska-Jedynak, Magdalena | Tan, Eng King | Belin, Andrea Carmine | Olson, Lars | Galter, Dagmar | Westerlund, Marie | Sydow, Olof | Nilsson, Christer | Puschmann, Andreas | Lin, JJ | Maraganore, Demetrius M. | Ahlskog, J, Eric | de Andrade, Mariza | Lesnick, Timothy G. | Rocca, Walter A. | Checkoway, Harvey | Ross, Owen A | Wszolek, Zbigniew K. | Uitti, Ryan J.
Neurology  2012;79(7):659-667.
Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.
Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.
In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14–1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.
Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology® 2012;79:659–667
PMCID: PMC3414661  PMID: 22786590
19.  Analysis of Fluorouracil-Based Adjuvant Chemotherapy and Radiation After Pancreaticoduodenectomy for Ductal Adenocarcinoma of the Pancreas: Results of a Large, Prospectively Collected Database at the Johns Hopkins Hospital 
To examine the efficacy of adjuvant chemoradiotherapy after pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PC) in patients undergoing resection at Johns Hopkins Hospital (JHH; Baltimore, MD).
Patients and Methods
Between August 30, 1993, and February 28, 2005, a total of 908 patients underwent PD for PC at JHH. A prospective database was reviewed to determine which patients received fluorouracil (FU) -based CRT. Excluded patients had metastatic disease, died 60 or fewer days after PD, received preoperative therapy, an experimental vaccine, adjuvant chemotherapy or radiation alone. The final cohort includes 616 patients.
The median follow-up was 17.8 months (interquartile range, 9.7 to 33.5 months). Overall median survival was 17.9 months (95% CI, 16.3 to 19.5 months). Groups were similar with respect to tumor size, nodal status, and margin status, but the CRT group was younger (P < .001), and less likely to present with a severe comorbid disease (P = .001). Patients with carcinomas larger than 3 cm (P = .001), grade 3 and 4 (P < .001), margin-positive resection (P = .001), and complications after surgery (P = .017) had poor long-term survival. Patients receiving CRT experienced an improved median (21.2 v 14.4 months; P < .001), 2-year (43.9% v 31.9%), and 5-year (20.1% v 15.4%) survival compared with no CRT. After controlling for high-risk features, CRT was still associated with improved survival (relative risk = 0.74; 95% CI, 0.62 to 0.89).
These data suggest that adjuvant concurrent FU-based CRT significantly improves survival after PD for PC when compared with patients not receiving CRT. These data support the use of combined adjuvant CRT for PC.
PMCID: PMC3558690  PMID: 18640931
20.  Metabolic and Electrochemical Mechanisms of Dimeric Naphthoquinones Cytotoxicity in Breast Cancer Cells 
Bioorganic & medicinal chemistry  2011;19(23):7057-7062.
Cancer cells reprogram their metabolism due to genetic alteration to compensate for increased energy demand and enhanced anabolism, cell proliferation, and protection from oxidative damage. Here, we assessed the cytotoxicity of three dimeric naphthoquinones against the glycolytic MCF-7 versus the oxidative MDA-453 breast carcinoma cell lines. Dimeric naphthoquinones 1 and 2 impaired MDA-453, but not MCF-7, cell growth at IC50 = 15 μM. Significant increase in reactive oxygen species, decrease in oxygen consumption and ATP production were observed in MDA-453 cells but not in MCF-7 cell. These findings suggest that oxidative stress and mitochondrial dysfunction are mechanisms by which these agents exert their cytotoxic effects. Cyclic voltammetry and semi-empirical molecular orbital calculations further characterized the electrochemical behavior of these compounds. These results also suggest that dimeric naphthoquinones may be used to selectively target cancer cells that depend on oxidative phosphorylation for energy production and macromolecular synthesis.
PMCID: PMC3216315  PMID: 22036210
Dimeric Naphthoquinones; Anticancer Agents; Cytotoxicity; Oxidative Stress; Tumor Metabolism
21.  An Update on Female Sexual Function and Dysfunction in Old Age and Its Relevance to Old Age Psychiatry 
Aging and Disease  2012;3(5):373-384.
Numerous studies have now demonstrated that many older women retain an interest in their sexual lives. Yet, how many old age psychiatrists commonly check with older women about whether the depression they are treating, or the SSRIs (Selective Serotonin Re-uptake Inhibitors) they have prescribed, have adversely affected their patient’s sexual lives? We consider the latest evidence regarding cultural, social and medical influences on older women’s sexual lives and some specific issues which affect lesbian and transsexual people. We examine how mental illness and psychotropic medication in particular can adversely affect older women’s sexual functioning and at how difficult it often proves to be for women to seek help. We also focus on why doctors and in particular psychiatrists may not take a sexual history, look for sexual side effects or refer for appropriate treatment, especially when interviewing older women patients. Most published information about psychiatric training and sexual issues focuses on the younger male patient. We therefore aimed to provide a broad-ranging review of the literature regarding female sexual functioning in old age, the difficulties that can arise and the role that old age psychiatrists have an opportunity to fulfil, in this often neglected aspect of their patients’ treatment. From our review it was clear that, in the light of the increasing cultural acceptability of discussions regarding sexuality and older women, the training of student doctors and trainee psychiatrists needs to reflect this change so that old age psychiatrists can enhance the quality of their patient care.
PMCID: PMC3501393  PMID: 23185718
Female; old age; sexuality; chronic disease; help-seeking; psychiatry
23.  The Parametric Response Map: An Imaging Biomarker for Early Cancer Treatment Outcome 
Nature Medicine  2009;15(5):572-576.
Here we describe the Parametric Response Map (PRM), a voxel-wise approach for image analysis and quantification of hemodynamic alterations during treatment for 44 patients with high-grade glioma. Relative cerebral blood volume (rCBV) and flow (rCBF) maps were acquired before treatment and after 1 and 3 weeks of therapy. We compared the standard approach using region-of-interest analysis for change in rCBV or rCBF to the change in perfusion parameters on the basis of PRM (PRMrCBV and PRMrCBF) for their accuracy in predicting overall survival. Neither the percentage change of rCBV or rCBF predicted survival, whereas the regional response evaluations based upon PRM were highly predictive of survival. Even when accounting for baseline rCBV, which is prognostic, PRMrCBV proved more predictive of overall survival.
PMCID: PMC3307223  PMID: 19377487
24.  Universality of Thermodynamic Constants Governing Biological Growth Rates 
PLoS ONE  2012;7(2):e32003.
Mathematical models exist that quantify the effect of temperature on poikilotherm growth rate. One family of such models assumes a single rate-limiting ‘master reaction’ using terms describing the temperature-dependent denaturation of the reaction's enzyme. We consider whether such a model can describe growth in each domain of life.
Methodology/Principal Findings
A new model based on this assumption and using a hierarchical Bayesian approach fits simultaneously 95 data sets for temperature-related growth rates of diverse microorganisms from all three domains of life, Bacteria, Archaea and Eukarya. Remarkably, the model produces credible estimates of fundamental thermodynamic parameters describing protein thermal stability predicted over 20 years ago.
The analysis lends support to the concept of universal thermodynamic limits to microbial growth rate dictated by protein thermal stability that in turn govern biological rates. This suggests that the thermal stability of proteins is a unifying property in the evolution and adaptation of life on earth. The fundamental nature of this conclusion has importance for many fields of study including microbiology, protein chemistry, thermal biology, and ecological theory including, for example, the influence of the vast microbial biomass and activity in the biosphere that is poorly described in current climate models.
PMCID: PMC3279425  PMID: 22348140
25.  The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia 
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3α (GSK-3α) in AML by performing 2 independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes, including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3α induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3α–specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3β has been well studied in cancer development, these studies support a role for GSK-3α in AML.
PMCID: PMC3287215  PMID: 22326953

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