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1.  Excess smoking in malignant-phase hypertension 
British Medical Journal  1979;1(6163):579-581.
The smoking habits of 82 patients with malignant-phase hypertension were compared with those of subjects in three control groups matched for age and sex. Sixty-seven (82%) of the patients with malignant-phase hypertension were smokers compared with 41 (50%) and 71 (43%) of the patients in two control groups with non-malignant hypertension, and 43 people (52%) in a general population survey. The excess of smokers in the malignant-phase group was significant for men and women, together and separately, for cigarette smoking alone, and for all forms of smoking. There were no significant differences between the control groups. The chance of a hypertensive patient who smoked having the malignant phase was five times that of a hypertensive patient who did not. Twelve patients in the malignant-phase group had never smoked. All were alive three and a half years on average after presentation (range 11 months to seven years). Twenty-four (36%) of the smokers with malignant-phase hypertension died during the same period. The mortality rate was significantly higher among patients with renal failure, as was the prevalence of smoking. Eighteen patients with malignant-phase hypertension had a serum creatinine concentration higher than 250 μmol/l (2·8 mg/100 ml); 17 were smokers and one an ex-smoker. Eleven of these 18 patients died.
It is concluded that hypertensive patients who smoke are much more likely to develop the malignant phase than those who do not, and that once the condition has developed it follows a particularly lethal course in smokers.
PMCID: PMC1598399  PMID: 427450
2.  Prognostic and predictive value of VEGF, sVEGFR-2 and CEA in mCRC studies comparing cediranib, bevacizumab and chemotherapy 
British Journal of Cancer  2013;108(6):1316-1323.
The prognostic/predictive value of potential vascular endothelial growth factor (VEGF) signalling biomarkers was evaluated retrospectively using samples from two randomized Phase III studies (HORIZON II and III) investigating cediranib in metastatic colorectal cancer (mCRC).
Baseline levels of VEGF, soluble VEGF receptor-2 (sVEGFR-2) and carcinoembryonic antigen (CEA) were measured in plasma/serum samples collected from patients participating in HORIZON II (n=860; FOLFOX/XELOX plus cediranib 20 mg (n=502) or placebo (n=358)) and HORIZON III (n=1422; mFOLFOX6 plus cediranib 20 mg (n=709) or bevacizumab (n=713)). Median biomarker baseline levels determined cutoff values for the patient subgroups.
Baseline data were available for 88–97% of patients/study (>2000 patients). In both the studies, high baseline VEGF and CEA were associated with worse outcomes for progression-free survival (PFS) and overall survival (OS) independent of treatment (HORIZON II OS: VEGF, hazard ratio (HR)=1.35 (95% confidence interval (CI): 1.12–1.63); CEA, HR=1.63 (1.36–1.96); HORIZON III OS: VEGF, HR=1.32 (1.12–1.54); CEA, HR=1.50 (1.29–1.76)). sVEGFR-2 was not prognostic for PFS/OS. Baseline VEGF and CEA were not predictive for PFS/OS outcome to cediranib treatment; low sVEGFR-2 was associated with a trend towards improved cediranib effect in HORIZON II.
Baseline VEGF and CEA levels were treatment-independent prognostic biomarkers for PFS and OS in both the studies.
PMCID: PMC3619270  PMID: 23449351
colorectal; cediranib; bevacizumab; VEGF; biomarkers
3.  Cediranib with mFOLFOX6 vs bevacizumab with mFOLFOX6 in previously treated metastatic colorectal cancer 
British Journal of Cancer  2013;108(3):493-502.
Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signalling with activity against all three VEGF receptors. Bevacizumab is an anti-VEGF-A monoclonal antibody with clinical benefit in previously treated metastatic colorectal cancer (mCRC).
Patients with mCRC who had progressed following first-line therapy were randomised 1 : 1 : 1 to modified (m)FOLFOX6 plus cediranib (20 or 30 mg day−1) or bevacizumab (10 mg kg−1 every 2 weeks). The primary objective was to compare progression-free survival (PFS) between treatment arms.
A total of 210 patients were included in the intent-to-treat (ITT) analysis (cediranib 20 mg, n=71; cediranib 30 mg, n=73; bevacizumab, n=66). Median PFS in the cediranib 20 mg, cediranib 30 mg and bevacizumab groups was 5.8, 7.2 and 7.8 months, respectively. There were no statistically significant differences between treatment arms for PFS (cediranib 20 mg vs bevacizumab: HR=1.28 (95% CI, 0.85–1.95; P=0.29); cediranib 30 mg vs bevacizumab: HR=1.17 (95% CI, 0.77–1.76; P=0.79)) or overall survival (OS). Grade ⩾3 adverse events were more common with cediranib 30 mg (91.8%) vs cediranib 20 mg (81.4%) or bevacizumab (84.8%).
There were no statistically significant differences between treatment arms for PFS or OS. When combined with mFOLFOX6, the 20 mg day−1 dose of cediranib was better tolerated than the 30 mg day−1 dose.
PMCID: PMC3593537  PMID: 23299530
cediranib; mFOLFOX6; bevacizumab; metastatic; colorectal cancer
4.  Chicken or the leg: Sigmoid colon perforation by ingested poultry fibula proximal to an occult malignancy☆ 
Colonic perforation by ingested foreign bodies is exceedingly rare, with the diagnosis made more challenging by patients infrequently recalling any inadvertent ingestion and the poor sensitivity of plain radiography.
The presented case demonstrates that bony perforation of the large bowel might occur immediately proximal to an otherwise occult colonic malignancy.
Ingestion of foreign bodies is common and rarely results in colonic perforation. However, bony ingestion is not usually remembered and can be missed even with cross-sectional imaging. If present, consideration should be given to the presence of an adjacent concealed colon cancer.
The co-existence of separate pathology should be carefully assessed in these patients, since this has important implications for relevant investigations and appropriate surgical management.
PMCID: PMC3825972  PMID: 24060703
Bone perforation; Colon cancer; Radiology surgery
5.  Alternative Immunomodulatory Strategies for Xenotransplantation: CD40/154 Pathway-sparing Regimens Promote Xenograft Survival 
American Journal of Transplantation  2012;12(7):1765-1775.
Immunosuppressive therapies that block the CD40/CD154 costimulatory pathway have proven to be uniquely effective in preclinical xenotransplant models. Given the challenges facing clinical translation of CD40/CD154 pathway blockade, we examined the efficacy and tolerability of CD40/CD154 pathway-sparing immunomodulatory strategies in a pig-to-nonhuman primate islet xenotransplant model. Rhesus macaques were rendered diabetic with streptozocin and given an intraportal infusion of ~50,000 IEQ/kg wild-type neonatal porcine islets. Base immunosuppression for all recipients included maintenance therapy with belatacept and mycophenolate mofetil plus induction with basiliximab and LFA-1 blockade. Cohort 1 recipients (n=3) were treated with the base regimen alone; cohort 2 recipients (n=5) were additionally treated with tacrolimus induction, and cohort 3 recipients (n=5) were treated with alefacept in place of basiliximab, and more intense LFA-1 blockade. Three of 5 recipients in both cohorts 2 and 3 achieved sustained insulin-independent normoglycemia (median rejection-free survivals 60 and 111 days, respectively), compared to 0 of 3 recipients in cohort 1. These data show that CD40/CD154 pathway-sparing regimens can promote xenoislet survival. Further optimization of these strategies is warranted to aid the clinical translation of islet xenotransplantation.
PMCID: PMC3387302  PMID: 22458586
Xenotransplantation; costimulation blockade; type 1 diabetes; islets; LFA-1; LFA-3; tacrolimus; T cell memory
6.  ttm-1 Encodes CDF Transporters That Excrete Zinc from Intestinal Cells of C. elegans and Act in a Parallel Negative Feedback Circuit That Promotes Homeostasis 
PLoS Genetics  2013;9(5):e1003522.
Zinc is an essential metal involved in a wide range of biological processes, and aberrant zinc metabolism is implicated in human diseases. The gastrointestinal tract of animals is a critical site of zinc metabolism that is responsible for dietary zinc uptake and distribution to the body. However, the role of the gastrointestinal tract in zinc excretion remains unclear. Zinc transporters are key regulators of zinc metabolism that mediate the movement of zinc ions across membranes. Here, we identified a comprehensive list of 14 predicted Cation Diffusion Facilitator (CDF) family zinc transporters in Caenorhabditis elegans and demonstrated that zinc is excreted from intestinal cells by one of these CDF proteins, TTM-1B. The ttm-1 locus encodes two transcripts, ttm-1a and ttm-1b, that use different transcription start sites. ttm-1b expression was induced by high levels of zinc specifically in intestinal cells, whereas ttm-1a was not induced by zinc. TTM-1B was localized to the apical plasma membrane of intestinal cells, and analyses of loss-of-function mutant animals indicated that TTM-1B promotes zinc excretion into the intestinal lumen. Zinc excretion mediated by TTM-1B contributes to zinc detoxification. These observations indicate that ttm-1 is a component of a negative feedback circuit, since high levels of cytoplasmic zinc increase ttm-1b transcript levels and TTM-1B protein functions to reduce the level of cytoplasmic zinc. We showed that TTM-1 isoforms function in tandem with CDF-2, which is also induced by high levels of cytoplasmic zinc and reduces cytoplasmic zinc levels by sequestering zinc in lysosome-related organelles. These findings define a parallel negative feedback circuit that promotes zinc homeostasis and advance the understanding of the physiological roles of the gastrointestinal tract in zinc metabolism in animals.
Author Summary
Zinc is an essential mineral nutrient involved in many physiological processes, and it plays a critical role in human health. Insufficient dietary zinc causes a wide range of health problems, and excess dietary zinc causes toxicity. Furthermore, genetic mutations affecting zinc metabolism have been implicated in a variety of human diseases. Therefore, animals require homeostatic mechanisms that effectively regulate zinc metabolism in response to dietary fluctuations. The gastrointestinal tract is a major tissue that orchestrates zinc metabolism in animals, and zinc transporters are key molecular regulators involved in this process. To understand these regulatory mechanisms, we used bioinformatic techniques to identify 14 genes that encode predicted Cation Diffusion Facilitator (CDF) family zinc transporters in the C. elegans genome. We demonstrated that one of these, ttm-1, functions in intestinal cells to promote zinc excretion, and this activity protects animals from zinc toxicity. Genetic analysis revealed that zinc excretion mediated by TTM-1B is coordinated with zinc storage mediated by CDF-2, and these transporters function in a parallel negative feedback circuit to maintain zinc homeostasis in intestinal cells. These findings provide molecular and physiological insight into the regulatory mechanisms of zinc metabolism in animals.
PMCID: PMC3662639  PMID: 23717214
7.  Inhibiting the Growth of Pancreatic Adenocarcinoma In Vitro and In Vivo through Targeted Treatment with Designer Gold Nanotherapeutics 
PLoS ONE  2013;8(3):e57522.
Pancreatic cancer is one of the deadliest of all human malignancies with limited options for therapy. Here, we report the development of an optimized targeted drug delivery system to inhibit advanced stage pancreatic tumor growth in an orthotopic mouse model.
Method/Principal Findings
Targeting specificity in vitro was confirmed by preincubation of the pancreatic cancer cells with C225 as well as Nitrobenzylthioinosine (NBMPR - nucleoside transporter (NT) inhibitor). Upon nanoconjugation functional activity of gemcitabine was retained as tested using a thymidine incorporation assay. Significant stability of the nanoconjugates was maintained, with only 12% release of gemcitabine over a 24-hour period in mouse plasma. Finally, an in vivo study demonstrated the inhibition of tumor growth through targeted delivery of a low dose of gemcitabine in an orthotopic model of pancreatic cancer, mimicking an advanced stage of the disease.
We demonstrated in this study that the gold nanoparticle-based therapeutic containing gemcitabine inhibited tumor growth in an advanced stage of the disease in an orthotopic model of pancreatic cancer. Future work would focus on understanding the pharmacokinetics and combining active targeting with passive targeting to further improve the therapeutic efficacy and increase survival.
PMCID: PMC3590245  PMID: 23483913
8.  Switching Targeting Pathways of Therapeutic Antibody by Nanodesign 
PMCID: PMC3324088  PMID: 22135077
Targeting; Epidermal Growth Factor Receptor (EGFR); Gold Nanoparticles; Pathway Switching; Lipid Microdomain; GTPases
9.  Gold Coated Lanthanide Phosphate Nanoparticles for Targeted Alpha Generator Radiotherapy 
PLoS ONE  2013;8(1):e54531.
Targeted radiotherapies maximize cytotoxicty to cancer cells. In vivo α-generator targeted radiotherapies can deliver multiple α particles to a receptor site dramatically amplifying the radiation dose delivered to the target. The major challenge with α-generator radiotherapies is that traditional chelating moieties are unable to sequester the radioactive daughters in the bioconjugate which is critical to minimize toxicity to healthy, non-target tissue. The recoil energy of the 225Ac daughters following α decay will sever any metal-ligand bond used to form the bioconjugate. This work demonstrates that an engineered multilayered nanoparticle-antibody conjugate can deliver multiple α radiations and contain the decay daughters of 225Ac while targeting biologically relevant receptors in a female BALB/c mouse model. These multi-shell nanoparticles combine the radiation resistance of lanthanide phosphate to contain 225Ac and its radioactive decay daughters, the magnetic properties of gadolinium phosphate for easy separation, and established gold chemistry for attachment of targeting moieties.
PMCID: PMC3548790  PMID: 23349921
10.  Luminescence as a Continuous Real-Time Reporter of Promoter Activity in Yeast Undergoing Respiratory Oscillations or Cell Division Rhythms 
This chapter describes a method for generating yeast respiratory oscillations in continuous culture and monitoring rhythmic promoter activity of the culture by automated real-time recording of luminescence. These techniques chiefly require the use of a strain of Saccharomyces cerevisiae that has been genetically modified to express firefly luciferase under the control of a promoter of interest and a continuous culture bioreactor that incorporates a photomultiplier apparatus for detecting light emission. Additionally, this chapter describes a method for observing rhythmic (cell cycle-related) promoter activity in small batch cultures of yeast through luminescence monitoring.
PMCID: PMC3433746  PMID: 21468985
Saccharomyces cerevisiae; Luciferase; Bioluminescence; Continuous culture; Bioreactor; Yeast respiratory oscillation
11.  A simple synthesis of a targeted drug delivery system with enhanced cytotoxicity 
In this communication we describe a simple one step synthesis of a targeted drug delivery system with enhanced cytotoxicity to EGFR+cancer cells. The delivery system comprises of carboplatin as a chemotherapeutic, anti-EGFR antibody cetuximab as a targeting agent and gold nanoparticle as a delivery vehicle. Nanoconjugates were characterized using ICP-MS, TEM, INAA and by stability studies in mouse plasma. Stability study indicates that the nanoconjugates prepared using this simple mixing procedure is significantly stable as more than 50 % of carboplatin remains in gold bound form even after incubation in mouse plasma for 24 h. Targeting efficacy of the nanoconjugates determined by gold-content of EGFR+ lung and ovarian cancer cells demonstrated enhanced uptake of gold nanoconjugates when delivered in a targeted fashion as compared to its non-targeted counterpart. Cytoxicity of the Nano conjugates were tested by 3H-thymidine incorporation assay against EGFR+ lung and ovarian cancer cell lines. Cytoxicity data demonstrates that carboplatin is more effective to inhibit the proliferation of EGFR+ lung and ovarian cancer cells when delivered in a targeted fashion. Such strategies may be utilized in future for targeted delivery of cytotoxic drugs to cancer with enhanced efficacy and reduced side effects.
PMCID: PMC3324332  PMID: 21717027
12.  pHlash: A New Genetically Encoded and Ratiometric Luminescence Sensor of Intracellular pH 
PLoS ONE  2012;7(8):e43072.
We report the development of a genetically encodable and ratiometic pH probe named “pHlash” that utilizes Bioluminescence Resonance Energy Transfer (BRET) rather than fluorescence excitation. The pHlash sensor–composed of a donor luciferase that is genetically fused to a Venus fluorophore–exhibits pH dependence of its spectral emission in vitro. When expressed in either yeast or mammalian cells, pHlash reports basal pH and cytosolic acidification in vivo. Its spectral ratio response is H+ specific; neither Ca++, Mg++, Na+, nor K+ changes the spectral form of its luminescence emission. Moreover, it can be used to image pH in single cells. This is the first BRET-based sensor of H+ ions, and it should allow the approximation of pH in cytosolic and organellar compartments in applications where current pH probes are inadequate.
PMCID: PMC3419163  PMID: 22905204
13.  Polyethylenimine-conjugated gold nanoparticles: Gene transfer potential and low toxicity in the cornea 
This study examined the gene transfer efficiency and toxicity of 2-kDa polyethylenimine conjugated to gold nanoparticles (PEI2-GNP) in the human cornea in vitro and rabbit cornea in vivo. PEI2-GNP with nitrogen-to-phosphorus (N/P) ratios of up to 180 exhibited significant transgene delivery in the human cornea without altering the viability or phenotype of these cells. Similarly, PEI2-GNP applied to corneal tissues collected after 12 h, 72 h, or 7 days exhibited appreciable gold uptake throughout the rabbit stroma with gradual clearance of GNP over time. Transmission electron microscopy detected GNP in the keratocytes and the extracellular matrix of the rabbit corneas. Additionally, slitlamp biomicroscopy in live animals even 7 days after topical PEI2-GNP application to the cornea detected no inflammation, redness, or edema in rabbit eyes in vivo, with only moderate cell death and immune reactions. These results suggest that PEI2-GNP are safe for the cornea and can be potentially useful for corneal gene therapy in vivo.
PMCID: PMC3094737  PMID: 21272669
gold nanoparticles; polyethylenimine; cornea; gene transfer; toxicity
14.  Ecological release in White Sands lizards 
Ecology and Evolution  2011;1(4):571-578.
Ecological opportunity is any change that allows populations to escape selection from competition and predation. After encountering ecological opportunity, populations may experience ecological release: enlarged population size, broadened resource use, and/or increased morphological variation. We identified ecological opportunity and tested for ecological release in three lizard colonists of White Sands, New Mexico (Sceloporus undulatus, Holbrookia maculata, and Aspidoscelis inornata). First, we provide evidence for ecological opportunity by demonstrating reduced species richness and abundance of potential competitors and predators at White Sands relative to nearby dark soils habitats. Second, we characterize ecological release at White Sands by demonstrating density compensation in the three White Sands lizard species and expanded resource use in White Sands S. undulatus. Contrary to predictions from ecological release models, we observed directional trait change but not increased trait variation in S. undulatus. Our results suggest that ecological opportunity and ecological release can be identified in natural populations, especially those that have recently colonized isolated ecosystems.
PMCID: PMC3287326  PMID: 22393523
Adaptation; colonization; density compensation; ecological opportunity; ecological release; natural selection; reptiles; selection; speciation; White Sands
15.  Modulating Pharmacokinetics, Tumor Uptake and Biodistribution by Engineered Nanoparticles 
PLoS ONE  2011;6(9):e24374.
Inorganic nanoparticles provide promising tools for biomedical applications including detection, diagnosis and therapy. While surface properties such as charge are expected to play an important role in their in vivo behavior, very little is known how the surface chemistry of nanoparticles influences their pharmacokinetics, tumor uptake, and biodistribution.
Method/Principal Findings
Using a family of structurally homologous nanoparticles we have investigated how pharmacological properties including tumor uptake and biodistribution are influenced by surface charge using neutral (TEGOH), zwitterionic (Tzwit), negative (TCOOH) and positive (TTMA) nanoparticles. Nanoparticles were injected into mice (normal and athymic) either in the tail vein or into the peritoneum.
Neutral and zwitterionic nanoparticles demonstrated longer circulation time via both IP and IV administration, whereas negatively and positively charged nanoparticles possessed relatively short half-lives. These pharmacological characteristics were reflected on the tumor uptake and biodistribution of the respective nanoparticles, with enhanced tumor uptake by neutral and zwitterionic nanoparticles via passive targeting.
PMCID: PMC3172229  PMID: 21931696
16.  Developmental Dysplasia of the Hip: Open Reduction as a Risk Factor for Substantial Osteonecrosis 
Kalamchi and MacEwen (K&M) described a four-group scheme for classifying osteonecrosis (ON) following treatment for developmental dysplasia of the hip (DDH). However, the four groups can overlap in radiographic appearance, making assessment difficult.
We (1) describe a simplified K&M classification; (2) determined whether the simplified classification was reliable; and (3) assessed whether differences in the type of reduction or age at reduction resulted in different degrees of ON.
Patients and Methods
We retrospectively reviewed 300 patients with DDH treated with either open or closed reduction. We included 101 of these patients (133 involved hips). Intraobserver and interobserver reliability testing of the original and our simplified classification was performed. ON occurred in 64 hips (48%). Of these, 22 had original K&M Group I disease (classified as simplified Group A), and 42 had original K&M Groups II, III, or IV disease (classified as simplified Group B). The mean age of the patients at final followup was 12.4 years (range, 6–26.3 years).
The interobserver reliability of the simplified classification was greater than that of the K&M classification (0.51 vs 0.33, respectively). Closed reduction after skin traction resulted in a lower incidence of Group B ON than open reduction, regardless of age at reduction.
We propose a simplified and more reliable classification of ON after DDH. With the new classification we found type of reduction (closed with traction versus open without femoral shortening) but not age influenced the risk of ON.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2919866  PMID: 20532719
17.  Effect of nanoparticle surface charge at the plasma membrane and beyond 
Nano letters  2010;10(7):2543-2548.
Herein, we demonstrate that the surface charge of gold nanoparticles (AuNPs) plays a critical role in modulating membrane potential of different malignant and non-malignant cell types and subsequent downstream intracellular events. The findings presented here describe a novel mechanism for cell-nanoparticle interactions and AuNP uptake: modulation of membrane potential and its effect on intracellular events. These studies will help understand the biology of cell-nanoparticle interactions and facilitate the engineering of nanoparticles for specific intracellular targets.
PMCID: PMC2925219  PMID: 20533851
Gold nanoparticles; surface properties; cancer; lung; ovary; plasma membrane; membrane potential; calcium; apoptosis; proliferation
18.  Designing Nanoconjugates to Effectively Target Pancreatic Cancer Cells In Vitro and In Vivo 
PLoS ONE  2011;6(6):e20347.
Pancreatic cancer is the fourth leading cause of cancer related deaths in America. Monoclonal antibodies are a viable treatment option for inhibiting cancer growth. Tumor specific drug delivery could be achieved utilizing these monoclonal antibodies as targeting agents. This type of designer therapeutic is evolving and with the use of gold nanoparticles it is a promising approach to selectively deliver chemotherapeutics to malignant cells.
Gold nanoparticles (GNPs) are showing extreme promise in current medicinal research. GNPs have been shown to non-invasively kill tumor cells by hyperthermia using radiofrequency. They have also been implemented as early detection agents due to their unique X-ray contrast properties; success was revealed with clear delineation of blood capillaries in a preclinical model by CT (computer tomography). The fundamental parameters for intelligent design of nanoconjugates are on the forefront. The goal of this study is to define the necessary design parameters to successfully target pancreatic cancer cells.
Methodology/Principal Findings
The nanoconjugates described in this study were characterized with various physico-chemical techniques. We demonstrate that the number of cetuximab molecules (targeting agent) on a GNP, the hydrodynamic size of the nanoconjugates, available reactive surface area and the ability of the nanoconjugates to sequester EGFR (epidermal growth factor receptor), all play critical roles in effectively targeting tumor cells in vitro and in vivo in an orthotopic model of pancreatic cancer.
Our results suggest the specific targeting of tumor cells depends on a number of crucial components 1) targeting agent to nanoparticle ratio 2) availability of reactive surface area on the nanoparticle 3) ability of the nanoconjugate to bind the target and 4) hydrodynamic diameter of the nanoconjugate. We believe this study will help define the design parameters for formulating better strategies for specifically targeting tumors with nanoparticle conjugates.
PMCID: PMC3124468  PMID: 21738572
Pediatric transplantation  2010;14(3):431-436.
To evaluate the epidemiology and to investigate the impact of respiratory viral infections (RVI) on chronic allograft rejection after pediatric lung transplantation, a retrospective study of pediatric lung transplant recipients from 2002 to 2007 was conducted. Association between RVI and continuous and categorical risk factors was assessed using Wilcoxon rank-sum tests and Fisher’s exact tests, respectively. Association between risk factors and outcomes were assessed using Cox proportional hazards models.
Fifty-five subjects were followed for a mean of 674 days (range 14–1790). Twenty-eight (51%) developed 51 RVI at a median of 144 days posttransplant (mean 246; range 1–1276); 41% of infections were diagnosed within 90 days. 25 subjects developed 39 lower respiratory infections, and eight subjects had 11 upper respiratory infections (URI). Organisms recovered included rhinovirus(n=14), adenovirus(n=10), parainfluenza(n=10), influenza(n=5) and RSV(n=4). Three subjects expired secondary to their RVI (2 adenovirus, 1 RSV). Younger age and prior CMV infection were risks for RVI (HR 2.4 95% CI 1.1–5.3 and 17.0; 3.0–96.2, respectively). RVI was not associated with the development of chronic allograft rejection (P=0.25) or death during the study period.
RVI occur in the majority of pediatric lung transplant recipients, but were not associated with mortality or chronic allograft rejection.
PMCID: PMC2893330  PMID: 20214745
Lung transplantation; Respiratory virus infection; Pediatrics
20.  Histidine Protects Against Zinc and Nickel Toxicity in Caenorhabditis elegans 
PLoS Genetics  2011;7(3):e1002013.
Zinc is an essential trace element involved in a wide range of biological processes and human diseases. Zinc excess is deleterious, and animals require mechanisms to protect against zinc toxicity. To identify genes that modulate zinc tolerance, we performed a forward genetic screen for Caenorhabditis elegans mutants that were resistant to zinc toxicity. Here we demonstrate that mutations of the C. elegans histidine ammonia lyase (haly-1) gene promote zinc tolerance. C. elegans haly-1 encodes a protein that is homologous to vertebrate HAL, an enzyme that converts histidine to urocanic acid. haly-1 mutant animals displayed elevated levels of histidine, indicating that C. elegans HALY-1 protein is an enzyme involved in histidine catabolism. These results suggest the model that elevated histidine chelates zinc and thereby reduces zinc toxicity. Supporting this hypothesis, we demonstrated that dietary histidine promotes zinc tolerance. Nickel is another metal that binds histidine with high affinity. We demonstrated that haly-1 mutant animals are resistant to nickel toxicity and dietary histidine promotes nickel tolerance in wild-type animals. These studies identify a novel role for haly-1 and histidine in zinc metabolism and may be relevant for other animals.
Author Summary
Zinc is an essential nutrient that is critical for human health. However, excess zinc can cause toxicity, indicating that regulatory mechanisms are necessary to maintain homeostasis. The analysis of mechanisms that promote zinc homeostasis can elucidate fundamental regulatory processes and suggest new approaches for treating disorders of zinc metabolism. To discover genes that modulate zinc tolerance, we screened for C. elegans mutants that were resistant to zinc toxicity. Here we demonstrate that mutations of the histidine ammonia lyase (haly-1) gene promote zinc tolerance. haly-1 encodes a protein that is similar to vertebrate HAL, an enzyme that converts histidine to urocanic acid. Mutations in the human HAL gene cause elevated levels of serum histidine and abnormal zinc metabolism. Mutations in C. elegans haly-1 cause elevated levels of histidine, suggesting that histidine causes resistance to excess zinc. Consistent with this hypothesis, we demonstrated that dietary histidine promoted tolerance to excess zinc in wild-type worms. Mutations in haly-1 and supplemental dietary histidine also caused resistance to nickel, another metal that can bind histidine. A likely mechanism of protection is chelation of zinc and nickel by histidine. These studies suggest that histidine plays a physiological role in zinc metabolism.
PMCID: PMC3063764  PMID: 21455490
21.  Avian Use of Perennial Biomass Feedstocks as Post-Breeding and Migratory Stopover Habitat 
PLoS ONE  2011;6(3):e16941.
Increased production of biomass crops in North America will require new agricultural land, intensify the cultivation of land already under production and introduce new types of biomass crops. Assessing the potential biodiversity impacts of novel agricultural systems is fundamental to the maintenance of biodiversity in agricultural landscapes, yet the consequences of expanded biomass production remain unclear. We evaluate the ability of two candidate second generation biomass feedstocks (switchgrass, Panicum virgatum, and mixed-grass prairie) not currently managed as crops to act as post-breeding and fall migratory stopover habitat for birds. In total, we detected 41 bird species, including grassland specialists and species of state and national conservation concern (e.g. Henslow's Sparrow, Ammodramus henslowii). Avian species richness was generally comparable in switchgrass and prairie and increased with patch size in both patch types. Grassland specialists were less abundant and less likely to occur in patches within highly forested landscapes and were more common and likely to occur in larger patches, indicating that this group is also area-sensitive outside of the breeding season. Variation in the biomass and richness of arthropod food within patches was generally unrelated to richness and abundance metrics. Total bird abundance and that of grassland specialists was higher in patches with greater vegetation structural heterogeneity. Collectively, we find that perennial biomass feedstocks have potential to provide post-breeding and migratory stopover habitat for birds, but that the placement and management of crops will be critical factors in determining their suitability for species of conservation concern. Industrialization of cellulosic bioenergy production that results in reduced crop structural heterogeneity is likely to dramatically reduce the suitability of perennial biomass crops for birds.
PMCID: PMC3048387  PMID: 21390274
22.  Protein tyrosine and serine–threonine phosphatases in the sea urchin, Strongylocentrotus purpuratus: Identification and potential functions 
Developmental biology  2006;300(1):194-218.
Protein phosphatases, in coordination with protein kinases, play crucial roles in regulation of signaling pathways. To identify protein tyrosine phosphatases (PTPs) and serine–threonine (ser–thr) phosphatases in the Strongylocentrotus purpuratus genome, 179 annotated sequences were studied (122 PTPs, 57 ser–thr phosphatases). Sequence analysis identified 91 phosphatases (33 conventional PTPs, 31 dual specificity phosphatases, 1 Class III Cysteine-based PTP, 1 Asp-based PTP, and 25 ser–thr phosphatases). Using catalytic sites, levels of conservation and constraint in amino acid sequence were examined. Nine of 25 receptor PTPs (RPTPs) corresponded to human, nematode, or fly homologues. Domain structure revealed that sea urchin-specific RPTPs including two, PTPRLec and PTPRscav, may act in immune defense. Embryonic transcription of each phosphatase was recorded from a high-density oligonucleotide tiling microarray experiment. Most RPTPs are expressed at very low levels, whereas nonreceptor PTPs (NRPTPs) are generally expressed at moderate levels. High expression was detected in MAP kinase phosphatases (MKPs) and numerous ser–thr phosphatases. For several expressed NRPTPs, MKPs, and ser–thr phosphatases, morpholino antisense-mediated knockdowns were performed and phenotypes obtained. Finally, to assess roles of annotated phosphatases in endomesoderm formation, a literature review of phosphatase functions in model organisms was superimposed on sea urchin developmental pathways to predict areas of functional activity.
PMCID: PMC3045532  PMID: 17087928
Phosphatase; PTP; DSP; MKP; Serine-threonine phosphatase; PPP; PPM; Genome; Strongylocentrotus; Urchin
23.  Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer 
Journal of Clinical Pathology  2007;60(11):1216-1221.
Although in vitro breast cancer models have demonstrated a role for protein kinase C (PKC) α and δ isoforms in endocrine insensitivity and resistance respectively, there is currently little clinical evidence to support these observations.
To define the pattern of PKC α and δ expression using breast cancer cell lines, with and without endocrine resistance, and also breast cancer samples, where expression can be correlated with clinicopathological and endocrine therapy outcome data.
PKC isoform expression was examined in tamoxifen responsive, oestrogen receptor positive (ER+), ER+ acquired tamoxifen resistant (TAM‐R) and oestrogen receptor negative (ER−) cell lines by western blotting and immunocytochemical analysis. PKC isoform expression was then examined by immunohistochemistry in archival breast cancer specimens from primary breast cancer patients with known clinical outcome in relation to endocrine response and survival on therapy.
ER+ breast cancer cell lines expressed considerable PKC‐δ but barely detectable levels of PKC‐α, whereas ER− cell lines expressed PKC‐α but little PKC‐δ. ER+ acquired TAM‐R cell lines expressed substantial levels of both PKC‐α and δ. In clinical samples, high PKC‐δ expression correlated to endocrine responsiveness whereas PKC‐α expression correlated to ER negativity. PKC‐δ was an independent predictor of duration of response to therapy. Patients showing a PKC‐δ+/PKC‐α− phenotype had a six times longer endocrine response than patients with the PKC‐δ+/ PKC‐α+ phenotype (equating to tamoxifen resistance in vitro).
Levels of PKC‐α and δ expression appear to be indicative of response to anti‐oestrogen therapy and could be useful in predicting a patient's suitability for endocrine therapy.
PMCID: PMC2095478  PMID: 17965220
To evaluate the epidemiology and investigate the impact of colonization and pulmonary fungal infections (PFI), we performed a retrospective analysis of 55 pediatric lung transplant recipients from 2002–2007 at a single institution. While 29 had positive pretransplant colonization, thirty-three (60%) were colonized post-transplant and 20% (11 subjects) developed proven or probable PFI. In a multivariable model, posttransplant fungal colonization was associated with older age (HR 2.9; 95% CI 1.1–7.6), CMV prophylaxis (5.6; 1.3–24.6) and respiratory viral infection prior to fungal colonization (2.9; 1.0–8.3). Neither fungal colonization nor PFI were associated with the development of chronic allograft rejection or death.
PMCID: PMC2782648  PMID: 19782585
Lung transplantation; Fungal infection; Pediatrics; Aspergillus
25.  Light Emitting Diode Flashlights as Effective and Inexpensive Light Sources for Fluorescence Microscopy 
Journal of microscopy  2009;236(1):1-4.
Light-emitting diodes (LEDs) are becoming more commonly used as light sources for fluorescence microscopy. We describe the adaptation of a commercially available LED flashlight for use as a source for fluorescence excitation. This light source is long-lived, inexpensive, and is effective for excitation in the range of 440–600 nm.
PMCID: PMC2751867  PMID: 19772530
fluorescence microscopy; light-emitting diode; LED; flashlight

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