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Head & neck  2011;33(12):1666-1674.
Cellular immune suppression is observed in head and neck squamous cell cancer (HNSCC) and contributes to poor prognosis. Restoration of immune homeostasis may require primary cell-derived cytokines at physiologic doses. An immunotherapy regimen containing a biologic, with multiple-active cytokine components, and administered with cytoxan, zinc, and indomethacin was developed to modulate cellular immunity.
Study methods were designed to determine the safety and efficacy of a 21-day neoadjuvant immunotherapy regimen in a phase 2 trial that enrolled 27 therapy-naïve patients with stage II to IVa HNSCC. Methods included safety, clinical and radiologic tumor response, disease-free survival (DFS), overall survival (OS), and tumor lymphocytic infiltrate (LI) data collection.
Acute toxicity was minimal. Patients completed neoadjuvant treatment without surgical delay. By independent radiographic review, 83% had stable disease during treatment. OS was 92%, 73%, and 69% at 12, 24, and 36 months, respectively. Histologic analysis suggested correlation between survival and tumor LI.
Immunotherapy regimen was tolerated. Survival results are encouraging.
PMCID: PMC4062188  PMID: 21284052
cytokine; head and neck squamous cell carcinoma; immune response; IRX-2; phase 2
2.  Exploring the Frontier of Electronic Health Record Surveillance: The Case of Post-Operative Complications 
Medical care  2013;51(6):509-516.
The aim of this study was to build electronic algorithms using a combination of structured data and natural language processing (NLP) of text notes for potential safety surveillance of nine post-operative complications.
Post-operative complications from six medical centers in the Southeastern United States were obtained from the Veterans Affairs Surgical Quality Improvement Program (VASQIP) registry. Development and test datasets were constructed using stratification by facility and date of procedure for patients with and without complication. Algorithms were developed from VASQIP outcome definitions using NLP coded concepts, regular expressions, and structured data. The VASQIP nurse reviewer served as the reference standard for evaluating sensitivity and specificity. The algorithms were designed in the development and evaluated in the test dataset.
Sensitivity and specificity in the test set were 85% and 92% for acute renal failure, 80% and 93% for sepsis, 56% and 94% for deep vein thrombosis, 80% and 97% for pulmonary embolism, 88% and 89% for acute myocardial infarction, 88% and 92% for cardiac arrest, 80% and 90% for pneumonia, 95% and 80% for urinary tract infection, and 80% and 93% for wound infection, respectively. A third of the complications occurred outside of the hospital setting.
Computer algorithms on data extracted from the electronic health record produced respectable sensitivity and specificity across a large sample of patients seen in six different medical centers. This study demonstrates the utility of combining natural language processing with structured data for mining the information contained within the electronic health record.
PMCID: PMC3658153  PMID: 23673394
surgical complications; adverse events; patient safety; electronic surveillance; natural language processing; text mining
3.  Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action 
This report provides a summary of deliberations conducted under the charge for members of Module C Panel participating in the Naphthalene State-of-the-Science Symposium (NS3), Monterey, CA, October 9–12, 2006. The panel was charged with reviewing the current state of knowledge and uncertainty about naphthalene metabolism in relation to anatomy, physiology and cytotoxicity in tissues observed to have elevated tumor incidence in these rodent bioassays. Major conclusions reached concerning scientific claims of high confidence were that: (1) rat nasal tumor occurrence was greatly enhanced, if not enabled, by adjacent, histologically related focal cellular proliferation; (2) elevated incidence of mouse lung tumors occurred at a concentration (30 ppm) cytotoxic to the same lung region at which tumors occurred, but not at a lower and less cytotoxic concentration (tumorigenesis NOAEL = 10 ppm); (3) naphthalene cytotoxicity requires metabolic activation (unmetabolized naphthalene is not a proximate cause of observed toxicity or tumors); (4) there are clear regional and species differences in naphthalene bioactivation; and (5) target tissue anatomy and physiology is sufficiently well understood for rodents, non-human primates and humans to parameterize species-specific physiologically based pharmacokinetic (PBPK) models for nasal and lung effects. Critical areas of uncertainty requiring resolution to enable improved human cancer risk assessment were considered to be that: (1) cytotoxic naphthalene metabolites, their modes of cytotoxic action, and detailed low-dose dose–response need to be clarified, including in primate and human tissues, and neonatal tissues; (2) mouse, rat, and monkey inhalation studies are needed to better define in vivo naphthalene uptake and metabolism in the upper respiratory tract; (3) in vivo validation studies are needed for a PBPK model for monkeys exposed to naphthalene by inhalation, coupled to cytotoxicity studies referred to above; and (4) in vivo studies are needed to validate a human PBPK model for naphthalene. To address these uncertainties, the Panel proposed specific research studies that should be feasible to complete relatively promptly. Concerning residual uncertainty far less easy to resolve, the Panel concluded that environmental, non-cytotoxic exposure levels of naphthalene do not induce tumors at rates that can be predicted meaningfully by simple linear extrapolation from those observed in rodents chronically exposed to far greater, cytotoxic naphthalene concentrations.
PMCID: PMC4030291  PMID: 18191315
Naphthalene; Cancer; Carcinogenicity; Tumorigenesis; Mode-of-action; Mechanism of action; Cytotoxicity; Olfactory epithelial neuroblastoma; Respiratory epithelial adenoma; Inflammation; Metabolism; Cytochrome P450; 1,2-Naphthoquinone; 1,4-Naphthoquinone; 1,2-Epoxide; Glutathione depletion; Species differences; Age-dependent differences; Gender differences; PBPK modeling
4.  NSF Workshop Report: Discovering General Principles of Nervous System Organization by Comparing Brain Maps across Species 
Efforts to understand nervous system structure and function have received new impetus from the federal Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Comparative analyses can contribute to this effort by leading to the discovery of general principles of neural circuit design, information processing, and gene-structure-function relationships that are not apparent from studies on single species. We here propose to extend the comparative approach to nervous system ‘maps’ comprising molecular, anatomical, and physiological data. This research will identify which neural features are likely to generalize across species, and which are unlikely to be broadly conserved. It will also suggest causal relationships between genes, development, adult anatomy, physiology, and, ultimately, behavior. These causal hypotheses can then be tested experimentally. Finally, insights from comparative research can inspire and guide technological development. To promote this research agenda, we recommend that teams of investigators coalesce around specific research questions and select a set of ‘reference species’ to anchor their comparative analyses. These reference species should be chosen not just for practical advantages, but also with regard for their phylogenetic position, behavioral repertoire, well-annotated genome, or other strategic reasons. We envision that the nervous systems of these reference species will be mapped in more detail than those of other species. The collected data may range from the molecular to the behavioral, depending on the research question. To integrate across levels of analysis and across species, standards for data collection, annotation, archiving, and distribution must be developed and respected. To that end, it will help to form networks or consortia of researchers and centers for science, technology, and education that focus on organized data collection, distribution, and training. These activities could be supported, at least in part, through existing mechanisms at NSF, NIH, and other agencies. It will also be important to develop new integrated software and database systems for cross-species data analyses. Multidisciplinary efforts to develop such analytical tools should be supported financially. Finally, training opportunities should be created to stimulate multidisciplinary, integrative research into brain structure, function, and evolution.
PMCID: PMC4028317  PMID: 24603302
5.  Differential Expression of Placental Glucocorticoid Receptors and Growth Arrest-Specific Transcript 5 in Term and Preterm Pregnancies: Evidence for Involvement of Maternal Stress 
Pregnancy-specific stress predicts birth outcomes. We hypothesized that there is a maternal stress-GR interaction that can influence fetal birth weight. This study examined the relationship between mothers' stress and attitude towards their pregnancies, placental glucocorticoid receptors (GRs) and growth arrest-specific transcript 5 (GAS5) expression, and the status of GR polymorphism, with their infants' birth weights. GAS5 and GRα were the predominant transcripts in both term and preterm placentas, with GAS5 being primarily localized in the syncytiotrophoblasts. In an attempt to mimic moderate and high stress environment in vitro, BeWo and JEG-3 cytotrophoblast cell lines were treated with 10 nM–1000 nM cortisol. Only expression of GAS5 was significantly upregulated by cortisol in all treatments compared with basal levels, but none of the GRs changed expression significantly. In an attempt to assess a stress versus gene interaction, we studied four GR polymorphisms. In the homozygous group for Tth111I polymorphism, mothers with negative attitudes towards the pregnancy gave birth to infants with significantly lower birth weights compared to women with positive/neutral attitudes. None of the GR splice variants were associated with maternal stress. However, placental GAS5 levels were inversely correlated with maternal stress. This study points towards a potential gene-environment interaction that could be of predictive value for fetal weight.
PMCID: PMC4037583  PMID: 24899900
6.  Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling 
Biological psychiatry  2012;73(9):915-923.
The stomach-derived hormone ghrelin drives higher-order feeding processes related to food reward and food seeking via CNS signaling at its receptor (GHSR1A). The specific nuclei mediating these effects are only partially understood. Here, we use a rat model to examine whether ghrelin signaling in the ventral subregion of the hippocampus (VHPC), a brain substrate of recent interest in energy balance control, affects learned and motivational aspects of feeding behavior.
The effects of VHPC ghrelin administration were examined on feeding-relevant behavioral paradigms, including meal pattern analysis, operant lever pressing for sucrose, and conditioned stimulus-induced feeding. The intracellular signaling and downstream neuronal pathways stimulated by VHPC GHSR1A activation were assessed using immunoblot analysis and behavioral pharmacology.
Ghrelin delivery to the VHPC, but not the dorsal hippocampus, increased food intake primarily by increasing meal frequency. Intra-VHPC ghrelin delivery also increased willingness to work for sucrose and increased spontaneous meal initiation in nondeprived rats following the presentation of a conditioned stimulus that previously signaled meal access when the rats were food restricted. The food intake enhancing effects of VHPC ghrelin were blocked by co-administration of a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). Immunoblot analyses provided complementary support for ghrelin activated PI3K-Akt signaling in the VHPC and revealed that this activation is blunted with high fat diet consumption. Other immunoblot results show that VHPC GHSR1A signaling activates downstream dopaminergic activity in the nucleus accumbens.
These findings illuminate novel neuronal and behavioral mechanisms mediating ghrelin's modulation of cognitive aspects of feeding control.
PMCID: PMC3498600  PMID: 22884970
GHSR; learning; memory; nucleus accumbens; reward; obesity; dopamine
7.  Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse 
Environmental Health Perspectives  2014;122(5):456-463.
Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, interindividual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data.
Objectives: We evaluated the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study.
Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and 1 hybrid mouse strains to calibrate and extend existing physiologically based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). We used a Bayesian population analysis of interstrain variability to quantify variability in TCE metabolism.
Results: Concentration–time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation were less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production were less variable (2-fold range) than DCA production (5-fold range), although the uncertainty bounds for DCA exceeded the predicted variability.
Conclusions: Population PBPK modeling of genetically diverse mouse strains can provide useful quantitative estimates of toxicokinetic population variability. When extrapolated to lower doses more relevant to environmental exposures, mouse population-derived variability estimates for TCE metabolism closely matched population variability estimates previously derived from human toxicokinetic studies with TCE, highlighting the utility of mouse interstrain metabolism studies for addressing toxicokinetic variability.
Citation: Chiu WA, Campbell JL Jr, Clewell HJ III, Zhou YH, Wright FA, Guyton KZ, Rusyn I. 2014. Physiologically based pharmacokinetic (PBPK) modeling of interstrain variability in trichloroethylene metabolism in the mouse. Environ Health Perspect 122:456–463;
PMCID: PMC4014769  PMID: 24518055
9.  The Modulation of Hepatitis C Virus 1a Replication by PKR is Dependent on NF-kB Mediated Interferon Beta Response in Huh7.5.1 Cells 
Virology  2013;438(1):28-36.
Protein kinase R (PKR), a sensor of double-stranded RNA, plays an important role in the host response to viral infection. Hepatitis C genotype 2a virus (HCV 2a) has been shown to induce PKR activation to suppress the translation of antiviral interferon stimulated genes (ISGs), suggesting that PKR inhibitor can be beneficial for treating chronically HCV-infected patients in conjunction with interferon alpha and ribavirin. However, in this study, we found that PKR inhibition using siRNA PKR, shRNA PKR or PKR inhibitor enhanced HCV 1a replication and rendered Huh7.5.1 cells more susceptible to HCV1a infection. Additionally, PKR silencing suppressed NF-kB activation and NF-kB mediated STAT1 phosphorylation in Huh7.5.1 cells and HCV1a persistently-infected Huh7.5.1 cells (2HDD4). These effects were accompanied by a reduction of interferon beta response and thereby enhanced HCV1a replication in Huh7.5.1 cells. We conclude that host cells can employ PKR activation to restrict HCV1a replication through regulation of NF-kB expression.
PMCID: PMC3594529  PMID: 23399035
PKR silencing; NF-kB activation; IFN-β; HCV1a replication
10.  Postinduction Dexamethasone and Individualized Dosing of Escherichia Coli L-Asparaginase Each Improve Outcome of Children and Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia: Results From a Randomized Study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 
Journal of Clinical Oncology  2013;31(9):1202-1210.
We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL).
Patients and Methods
Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m2 fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m2, adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations.
Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS.
There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.
PMCID: PMC3595424  PMID: 23358966
11.  Case Study Approaches for Implementing the 2007 NRC Report “Toxicity Testing in the 21st Century: A Vision and A Strategy” 
ALTEX  2011;28(3):175-182.
The 2007 report “Toxicity Testing in the 21st Century: A Vision and A Strategy” argued for a change in toxicity testing for environmental agents and discussed federal funding mechanisms that could be used to support this transformation within the USA. The new approach would test for in vitro perturbations of toxicity pathways using human cells with high throughput testing platforms. The NRC report proposed a deliberate timeline, spanning about 20 years, to implement a wholesale replacement of current in-life toxicity test approaches focused on apical responses with in vitro assays. One approach to accelerating implementation is to focus on well-studied prototype compounds with known toxicity pathway targets. Through a series of carefully executed case studies with four or five pathway prototypes, the various steps required for implementation of an in vitro toxicity pathway approach to risk assessment could be developed and refined. In this article, we discuss alternative approaches for implementation and also outline advantages of a case study approach and the manner in which the cases studies could be pursued using current methodologies. A case study approach would be complementary to recently proposed efforts to map the human toxome, while representing a significant extension toward more formal risk assessment compared to the profiling and prioritization approaches offered by programs such as the EPA’s ToxCast effort.
PMCID: PMC3943477  PMID: 21993955
12.  Preoperative Cetuximab, Irinotecan, Cisplatin, and Radiation Therapy for Patients With Locally Advanced Esophageal Cancer 
The Oncologist  2013;18(3):281-287.
The efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer were evaluated. This schedule was toxic and did not achieve a sufficient pathologic complete response rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.
To determine the efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer.
Methods and Materials.
Patients with stage IIA–IVA esophageal or gastroesophageal junction cancer were enrolled in a Simon's two-stage phase II study. Patients received weekly cetuximab on weeks 0–8 and irinotecan and cisplatin on weeks 1, 2, 4, and 5, with concurrent radiotherapy (50.4 Gy on weeks 1–6), followed by surgical resection.
In the first stage, 17 patients were enrolled, 16 of whom had adenocarcinoma. Because of a low pathologic complete response (pCR) rate in this cohort, the trial was discontinued for patients with adenocarcinoma but squamous cell carcinoma patients continued to be enrolled; two additional patients were enrolled before the study was closed as a result of poor accrual. Of the 19 patients enrolled, 18 patients proceeded to surgery, and 16 patients underwent an R0 resection. Three patients (16%) had a pCR. The median progression-free survival interval was 10 months, and the median overall survival duration was 31 months. Severe neutropenia occurred in 47% of patients, and severe diarrhea occurred in 47% of patients. One patient died preoperatively from sepsis, and one patient died prior to hospital discharge following surgical resection.
This schedule of cetuximab in combination with irinotecan, cisplatin, and radiation therapy was toxic and did not achieve a sufficient pCR rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.
PMCID: PMC3607524  PMID: 23429739
Cetuximab; Esophageal cancer; EGFR; Chemoradiation
13.  The accuracy of chromosomal microarray testing for identification of embryonic mosaicism in human blastocysts 
Most previous studies of chromosomal mosaicism in IVF embryos were performed by fluorescence in situ hybridization (FISH) methods. While there are reports implicating chromosome aneuploidy in implantation failure following transfer and pregnancy loss by spontaneous miscarriage, the significance of mosaicism for the developmental potential of growing embryos is unknown. However, the low prevalence of chromosomal mosaicism in chorionic villus sampling and amniotic fluid specimens suggests the presence of selection against mosaic embryos for implantation and early pregnancy. The absence of evidence for selective allocation of abnormal cells to the trophectoderm (TE) of mosaic blastocysts permits these cells to be a good proxy for embryonic mosaicism detection by chromosomal microarrays (CMA). The purpose of this study was to establish the limits of detection and the prevalence of chromosome mosaicism in day 5/6 human embryos using CMA with TE biopsies.
From reconstitution experiments we established log2 ratio thresholds for mosaicism detection. These studies indicated that chromosomal mosaicism at levels as low as between 25-37% can be consistently identified. Follow-up studies by FISH on non-transferred abnormal embryos confirmed the diagnostic accuracy of CMA testing. The number of cells in a TE biopsy can influence mosaicism detection.
Chromosomal microarrays can detect mosaicism in TE biopsies when present at levels as low as between 25-37% and the prevalence of day 5/6 blastocysts which were mosaic and had no other abnormalities reached 15% among a cohort of 551 embryos examined. Validated protocols for establishing detection thresholds for mosaicism are important to reduce the likelihood of transferring abnormal embryos.
PMCID: PMC3944884  PMID: 24581286
14.  A planned, prospective comparison of short-term quality of life outcomes among older breast cancer patients treated with standard chemotherapy in a randomized clinical trial vs. an observational study: CALGB #49907 and #369901✰ 
Journal of geriatric oncology  2013;4(4):353-361.
Patients ≥65 years old (“older”) are often not included in randomized clinical trials (RCT), but when they are, care in an RCT might improve quality of life (QoL). We conducted a prospective comparison of QoL among older women receiving standard chemotherapy from the same cooperative group physicians in an RCT vs. an observational study (“off-trial”).
Older women with invasive, non-metastatic breast cancer (n = 150 RCT; 530 off-trial) were included. Linear mixed-effects models tested associations between chemotherapy on- vs. off-trial and changes in EORTC (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) QoL scores over 24 months, controlling for pre-treatment QoL, age, education, tumor factors, comorbidity, and other covariates.
Anthracycline regimens were used by 58% of women treated on-trial vs. 54% of those treated off-trial. Women in the RCT reported an adjusted mean increase of 13.7 points (95% CI 10.2, 17.1) in global QoL at 24 months (vs. mid-treatment), while women treated off-trial had only an adjusted improvement of 7.0 points (95% CI 3.5, 10.4; p = .007 for difference in mean changes). Women in the RCT had significantly greater improvement in emotional function than those treated off-trial, controlling for baseline; they also had greater reductions in therapy side effects and fatigue at 24 months than women off-trial, controlling for covariates.
There may be different QoL trajectories for older women undergoing breast cancer chemotherapy on- vs. off-trial. If confirmed, the results suggest that the extra monitoring and communication within an RCT could provide the infrastructure for interventions to address symptoms and improve QoL for the growing older cancer population.
PMCID: PMC3910230  PMID: 24472479
Older patients; Breast cancer; Chemotherapy; Quality of Life; Randomized clinical trials; Observational studies
15.  Development of PBPK Models for PFOA and PFOS for Human Pregnancy and Lactation Life Stages 
Perfluoroalkyl acid carboxylates and sulfonates (PFAAs) have many consumer and industrial applications. Developmental toxicity studies in animals have raised concern about potential reproductive/developmental effects of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS); however, in humans conflicting results have been reported for associations between maternal PFAA levels and these outcomes. Risk assessments and interpretation of available human data during gestation and lactation are hindered due to lack of a framework for understanding and estimating maternal, fetal, and neonatal pharmacokinetics (PK). Physiologically-based pharmacokinetic (PBPK) models were developed for PFOA & PFOS for the gestation and lactation life stages in humans to understand how the physiological changes associated with development affect pharmacokinetics of these compounds in the mother, fetus, and infant. These models were derived from PBPK models for PFOA/PFOS that were previously developed for adult humans and rats during gestation and lactation and from existing human pregnancy and lactation models developed for other chemicals. The models simulated PFOA and PFOS concentrations in fetal, infant, and maternal plasma and milk, were compared to available data in humans, and also used to estimate maternal exposure. The models reported here identified several research needs, which include: 1) the identification of transporters involved in renal resorption to explain the multi-year half-lives of these compounds in humans, 2) factors affecting clearance of PFOA/PFOS during gestation and lactation, and 3) data to estimate clearance of PFOA/PFOS in infants. These models may help address concerns regarding possible adverse health effects due to PFOA/PFOS exposure in the fetus and infant and may be useful in comparing pharmacokinetics across life stages.
PMCID: PMC3502013  PMID: 23151209
PFOA; PFOS; perfluoroalkyls; gestation; lactation; physiologically based pharmacokinetic model; PBPK
16.  Current challenges in photosynthesis: from natural to artificial 
PMCID: PMC4035565  PMID: 24904626
photosynthesis; artificial photosynthesis; water oxidation; thylakoid; chlorophyll f
17.  Does Nocturnality Drive Binocular Vision? Octodontine Rodents as a Case Study 
PLoS ONE  2013;8(12):e84199.
Binocular vision is a visual property that allows fine discrimination of in-depth distance (stereopsis), as well as enhanced light and contrast sensitivity. In mammals enhanced binocular vision is structurally associated with a large degree of frontal binocular overlap, the presence of a corresponding retinal specialization containing a fovea or an area centralis, and well-developed ipsilateral retinal projections to the lateral thalamus (GLd). We compared these visual traits in two visually active species of the genus Octodon that exhibit contrasting visual habits: the diurnal Octodon degus, and the nocturnal Octodon lunatus. The O. lunatus visual field has a prominent 100° frontal binocular overlap, much larger than the 50° of overlap found in O. degus. Cells in the retinal ganglion cell layer were 40% fewer in O. lunatus (180,000) than in O. degus (300,000). O. lunatus has a poorly developed visual streak, but a well developed area centralis, located centrally near the optic disk (peak density of 4,352 cells/mm2). O. degus has a highly developed visual streak, and an area centralis located more temporally (peak density of 6,384 cells/mm2). The volumes of the contralateral GLd and superior colliculus (SC) are 15% larger in O. degus compared to O. lunatus. However, the ipsilateral projections to GLd and SC are 500% larger in O. lunatus than in O. degus. Other retinorecipient structures related to ocular movements and circadian activity showed no statistical differences between species. Our findings strongly suggest that nocturnal visual behavior leads to an enhancement of the structures associated with binocular vision, at least in the case of these rodents. Expansion of the binocular visual field in nocturnal species may have a beneficial effect in light and contrast sensitivity, but not necessarily in stereopsis. We discuss whether these conclusions can be extended to other mammalian and non-mammalian amniotes.
PMCID: PMC3877236  PMID: 24391911
18.  Memory Deficit is Associated with Worse Functional Trajectories Among Older Adults in Low Vision Rehabilitation for Macular Disease 
Older adults with macular disease are at increased risk of memory decline and incident dementia. Low vision rehabilitation (LVR) aims to preserve independence in people with irreversible vision loss, but comorbid memory problems could limit the success of rehabilitation. This study examined whether performance on a brief memory test is related to functional outcomes among older patients undergoing LVR for macular disease.
Observational cohort study of patients receiving outpatient LVR
Academic center
91 seniors (average age 80.1 years) with macular disease
Memory was assessed at baseline with a 10-word list; memory deficit was defined as immediate recall of ≤ two words. Vision-related function was measured with the 25-item Visual Function Questionnaire (VFQ-25)administered at baseline and during subsequent interviews (mean length of follow up = 115 days). Linear mixed models (LMMs) were constructed to compare average trajectories of four VFQ-25 subscales: near activities, distance activities, dependency, and role difficulty.
The 29.7% of patients with memory deficit tended to decline in ability to accomplish activities that involve near vision. Controlling for age, sex, and education, the functional trajectory of participants with memory deficit differed significantly from that of participants with better memory (p=0.002), who tended to report improvements in ability to accomplish near activities.
Among older adults receiving LVR for macular disease, those with memory deficit experienced worse functional trajectories in their ability to perform specific visually mediated tasks. A brief memory screen may help explain variability in rehabilitation outcomes and identify patients who might require special accommodations.
PMCID: PMC3498592  PMID: 23126548
age-related macular degeneration; comorbidity; disability; cognitive impairment
19.  Results and patterns of failure in patients treated with adjuvant combined chemo-radiation therapy for resected pancreatic adenocarcinoma 
Cancer  2009;115(16):10.1002/cncr.24410.
While adjuvant chemoradiation is commonly used in the United States for treatment of resected pancreatic cancer, there is no consensus on the benefit of this therapy as results from randomized trials are conflicting. We reviewed our experience in a consecutive, unselected series of patients treated with adjuvant 5-FU and radiation therapy for resected pancreatic adenocarcinoma.
86 patients with resected pancreatic adenocarcinoma who underwent adjuvant therapy from 1998–2005 were identified. Medical records were reviewed. 93% of patients were treated with external beam RT to ≥ 50.4 Gy and 91% of patients received concurrent 5-FU by continuous infusion. 45% of patients went on to receive adjuvant gemcitabine.
Median follow-up was 31 months (range 21–62) among the 20 patients still alive. Fewer than half of patients had positive (33%) or close (<1mm, 15%) resection margins. 81% of the tumors were T3; 66% had involved lymph nodes. The median overall survival (OS) for all patients was 22 months; negative lymph node status (p=0.016) was a significant prognostic factor for improved OS, while treatment with gemcitabine trended towards improved OS (p=0.080). Median disease-free survival (DFS) for all patients was 10 months, and treatment with gemcitabine (p=0.044) or any chemotherapy (p=0.047) were significant predictors of DFS. 75 patients (87%) had disease recurrence, the majority of whom recurred with peritoneal (55%) or liver (53%) metastases. Negative lymph nodes trended towards a lower rate of distant failure (p=0.060).
The median survival of this cohort is greater than that of the chemoradiation arms of the EORTC and ESPAC-1 trials, and comparable to the survival observed on the GITSG chemoradiation arm. Lymph node status and treatment with adjuvant chemotherapy were significant predictors of OS and DFS, respectively. Future survival improvements should be directed at reducing peritoneal and liver metastases. Further randomized trials are required to define the role of adjuvant therapy for pancreatic adenocarcinoma.
PMCID: PMC3808178  PMID: 19514088
pancreatic cancer; adjuvant therapy; chemoradiation; gemcitabine; patterns of failure
20.  Role of Pain Medications, Consultants, and Other Services in Improved Pain Control of Elderly Adults with Cancer in Geriatric Evaluation and Management Units 
To determine whether pain medication use and inpatient consultations and services were associated with significantly better pain control.
Secondary data analysis from a randomized two-by-two factorial trial. Hospitalized, frail individuals aged 65 and older were randomized to receive care in a geriatric inpatient unit, a geriatric outpatient clinic, both, or neither.
Eleven Veterans Affairs Medical Centers.
Ninety-nine individuals with a diagnosis of cancer, excluding nonmelanoma skin cancer; 44 received geriatric evaluation and management unit (GEMU) care and 55 usual care.
Pain medications were measured at baseline and discharge; consultations and other services were quantified for the entire admission.
Participants receiving GEMU care had a significantly higher number of consultations than those in usual care. Participants in GEMU care received psychiatry, endocrinology, and psychology consultations 12.7% (P = .004), 9.1% (P = .04), and 21.8% (P = .05) times more, respectively, and occupational and physical therapy 27.3% (P = .004) and 18.2% (P = .04) more, respectively. There were no significant differences in pain medication use between intervention and usual care.
Significantly greater use of psychology, psychiatry, physical and occupational therapy in the GEMU participants may have improved the effectiveness of pain management in individuals in inpatient GEMUs. Although analgesic use was not significantly different between the GEMU and usual care groups, small sample size may have limited the ability to detect these differences.
PMCID: PMC3645305  PMID: 23036028
cancer; pain control; geriatric units
21.  A study of prostaglandin pathway genes and interactions with current non-steroidal anti-inflammatory drug use in colorectal adenoma 
Colorectal cancer (CRC) is the second leading cause of cancer-related death, and usually arises from colorectal polyps. Screening and removal of polyps reduce mortality from CRC. Colorectal polyps are known to aggregate in families; however the genetic determinants for risk of polyps are unknown. Additionally, it has been shown that nonsteroidal anti-inflammatory drug (NSAID) use decreases the risk of CRC and the incidence and size of polyps. In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to evaluate selected genes from the prostaglandin metabolism and signaling pathways for association with risk of polyps and for interactions with NSAIDs. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian polyp cases and 3,285 Caucasian controls. We performed multivariable logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. We detected association signals in the genes prostaglandin E receptor 3 (PTGER3) and 15-hydroxyprostaglandin dehydrogenase (HPGD), both strong biological candidates for influence on polyp risk. We did not observe the previously reported effects and effect modification in prostaglandin-endoperoxide synthase 2 (PTGS2), prostaglandin E receptor 2 (PTGER2), or prostaglandin E receptor 4 (PTGER4), although we did observe a single nucleotide polymorphism in PTGER2 associated with risk of multiple adenomas. We also observed effect modification of the HPGD signal by NSAID exposure.
PMCID: PMC3789595  PMID: 22551900
Colorectal adenoma; genetic association; prostaglandin signaling; prostaglandin metabolism; NSAIDs
22.  Is the Relationship between Prenatal Exposure to PCB-153 and Decreased Birth Weight Attributable to Pharmacokinetics? 
Environmental Health Perspectives  2013;121(10):1219-1224.
Background: A recent meta-analysis based on data from > 7,000 pregnancies reported an association between prenatal polychlorinated biphenyl (PCB)–153 exposure and reduced birth weight. Gestational weight gain, which is associated negatively with PCB levels in maternal and cord blood, and positively with birth weight, could substantially confound this association.
Objective: We sought to estimate the influence of gestational weight gain on the association between PCB-153 exposure and birth weight using a pharmacokinetic model.
Methods: We modified a recently published pharmacokinetic model and ran Monte Carlo simulations accounting for variability in physiologic parameters and their correlations. We evaluated the pharmacokinetic model by comparing simulated plasma PCB-153 levels during pregnancy to serial measurements in 10 pregnant women from another study population. We estimated the association between simulated plasma PCB-153 levels and birth weight using linear regression models.
Results: The plasma PCB-153 level profiles generated with the pharmacokinetic model were comparable to measured levels in 10 pregnant women. We estimated a 118-g decrease in birth weight (95% CI: –129, –106 g) for each 1-μg/L increase in simulated cord plasma PCB-153, compared with the 150-g decrease estimated based on the previous meta-analysis. The estimated decrease in birth weight was reduced to –6 g (95% CI: –18, 6 g) when adjusted for simulated gestational weight gain.
Conclusion: Our findings suggest that associations previously noted between PCB levels and birth weight may be attributable to confounding by maternal weight gain during pregnancy.
Citation: Verner MA, McDougall R, Glynn A, Andersen ME, Clewell HJ III, Longnecker MP. 2013. Is the relationship between prenatal exposure to PCB-153 and decreased birth weight attributable to pharmacokinetics? Environ Health Perspect 121:1219–1224;
PMCID: PMC3801461  PMID: 23934733
23.  Identifying technical aliases in SELDI mass spectra of complex mixtures of proteins 
BMC Research Notes  2013;6:358.
Biomarker discovery datasets created using mass spectrum protein profiling of complex mixtures of proteins contain many peaks that represent the same protein with different charge states. Correlated variables such as these can confound the statistical analyses of proteomic data. Previously we developed an algorithm that clustered mass spectrum peaks that were biologically or technically correlated. Here we demonstrate an algorithm that clusters correlated technical aliases only.
In this paper, we propose a preprocessing algorithm that can be used for grouping technical aliases in mass spectrometry protein profiling data. The stringency of the variance allowed for clustering is customizable, thereby affecting the number of peaks that are clustered. Subsequent analysis of the clusters, instead of individual peaks, helps reduce difficulties associated with technically-correlated data, and can aid more efficient biomarker identification.
This software can be used to pre-process and thereby decrease the complexity of protein profiling proteomics data, thus simplifying the subsequent analysis of biomarkers by decreasing the number of tests. The software is also a practical tool for identifying which features to investigate further by purification, identification and confirmation.
PMCID: PMC3847147  PMID: 24010718
24.  Reweighted Mahalanobis Distance Matching for Cluster Randomized Trials with Missing Data 
Pharmacoepidemiology and drug safety  2012;21(0 2):148-154.
This paper introduces an improved tool for designing matched-pairs randomized trials. The tool allows the incorporation of clinical and other knowledge regarding the relative importance of variables used in matching and allows for multiple types of missing data. The method is illustrated in the context of a cluster-randomized trial. A web application and R package are introduced to implement the method and incorporate recent advances in the area.
Reweighted Mahalanobis Distance (RMD) matching incorporates user-specified weights and imputed values for missing data. Weight may be assigned to missingness indicators to match on missingness patterns. Three examples are presented, using real data from a cohort of 90 Veterans Health Administration sites that had at least 100 incident metformin users in 2007. Matching is utilized to balance seven factors aggregated at the site level. Covariate balance is assessed for 10,000 randomizations under each strategy: simple randomization, matched randomization using the Mahalanobis distance, and matched randomization using the RMD.
The RMD matching achieved better balance than simple randomization or MD randomization. In the first example, simple and MD randomization resulted in a 10% chance of seeing an absolute mean difference of greater than 26% in the percent of nonwhite patients per site; the RMD dramatically reduced that to 6%. The RMD achieved significant improvement over simple randomization even with as much as 20% of the data missing.
RMD matching provides an easy-to-use tool that incorporates user knowledge and missing data.
PMCID: PMC3760213  PMID: 22552990
25.  FGF-23 Regulates CYP27B1 Transcription in the Kidney and in Extra-Renal Tissues 
PLoS ONE  2013;8(9):e72816.
The mitochondrial enzyme 25-hydroxyvitamin D 1α-hydroxylase, which is encoded by the CYP27B1 gene, converts 25OHD to the biological active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). Renal 1α-hydroxylase activity is the principal determinant of the circulating 1,25(OH)2D concentration and enzyme activity is tightly regulated by several factors. Fibroblast growth factor-23 (FGF-23) decreases serum 1,25(OH)2D concentrations by suppressing CYP27B1 mRNA abundance in mice. In extra-renal tissues, 1α-hydroxylase is responsible for local 1,25(OH)2D synthesis, which has important paracrine actions, but whether FGF-23 regulates CYP27B1 gene expression in extra-renal tissues is unknown. We sought to determine whether FGF-23 regulates CYP27B1 transcription in the kidney and whether extra-renal tissues are target sites for FGF-23-induced suppression of CYP27B1. In HEK293 cells transfected with the human CYP27B1 promoter, FGF-23 suppressed promoter activity by 70%, and the suppressive effect was blocked by CI-1040, a specific inhibitor of extracellular signal regulated kinase 1/2. To examine CYP27B1 transcriptional activity in vivo, we crossed fgf-23 null mice with mice bearing the CYP27B1 promoter-driven luciferase transgene (1α-Luc). In the kidney of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity was increased by 3-fold compared to that in wild-type/1α-Luc mice. Intraperitoneal injection of FGF-23 suppressed renal CYP27B1 promoter activity and protein expression by 26% and 60% respectively, and the suppressive effect was blocked by PD0325901, an ERK1/2 inhibitor. These findings provide evidence that FGF-23 suppresses CYP27B1 transcription in the kidney. Furthermore, we demonstrate that in FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA abundance are increased in several extra-renal sites. In the heart of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA were 2- and 5-fold higher, respectively, than in control mice. We also observed a 3- to 10-fold increase in CYP27B1 mRNA abundance in the lung, spleen, aorta and testis of FGF-23 null/1α-Luc mice. Thus, we have identified novel extra-renal target sites for FGF-23-mediated regulation of CYP27B1.
PMCID: PMC3760837  PMID: 24019880

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