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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/predictive value of 207 serum factors in colorectal cancer treated with cediranib and/or chemotherapy 
British Journal of Cancer  2013;109(11):2765-2773.
The prognostic and predictive value of multiple serum biomarkers was evaluated using samples from a randomised phase III study (HORIZON II) investigating chemotherapy with or without cediranib in metastatic colorectal cancer (mCRC).
Baseline levels of 207 protein markers were measured in serum samples from 582 HORIZON II (FOLFOX/XELOX plus cediranib 20 mg (n=330) or placebo (n=252)) patients. Median baseline values of each biomarker were used to categorise patients as high or low. Markers were then assessed for their association with efficacy, defined by progression-free survival (PFS) and overall survival (OS). A generalised boosted regression model identified markers of particular interest.
Correlation of protein levels with PFS and OS suggested that multiple factors had a prognostic value, independent of treatment arm, including IL-6, IL-8, C-reactive protein (CRP), ICAM-1 and carcinoembryonic antigen (CEA). Among the angiogenesis regulators, low levels of vascular endothelial growth factor (VEGF), VEGF-D, VEGFR-1, VEGFR-3, NRP1 and Tie-2 correlated with better outcome.
This large data set generated using serum samples from mCRC patients treated with chemotherapy and VEGF inhibitors, defines baseline characteristics for 207 serum proteins. Multiple prognostic factors were identified that could be disease related or predict which patients derive most benefit from 5-fluorouracil (5-FU)-based chemotherapy, meriting further exploration in prospective studies.
PMCID: PMC3844909  PMID: 24149180
cediranib; biomarker; prognostic/predictive marker; colorectal cancer; FOLFOX/XELOX
3.  The DAF-16 FOXO Transcription Factor Regulates natc-1 to Modulate Stress Resistance in Caenorhabditis elegans, Linking Insulin/IGF-1 Signaling to Protein N-Terminal Acetylation 
PLoS Genetics  2014;10(10):e1004703.
The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance.
Author Summary
What are the mechanisms used by animals to cope with stressful environments that inflict damage or restrict essential processes such as growth, development, and reproduction? One strategy is changes in physiology that increase stress resistance, and an extreme version of this strategy is diapause, an alternative developmental state that is enduring and stress resistant. In the nematode C. elegans, stress tolerance and entry into a diapause state called dauer larvae are mediated by the conserved insulin/IGF-1 pathway. Specifically, the FOXO transcription factor DAF-16 promotes stress tolerance and dauer larvae development. However, the targets of DAF-16 that mediate these processes remain largely elusive. Using an unbiased forward genetic screen to discover new mediators of stress tolerance, we identified natc-1, a novel target of DAF-16 and the insulin/IGF-1 pathway. natc-1 encodes a conserved subunit of the N-terminal acetyltransferase C (NAT) complex. The NatC complex modifies target proteins by acetylating the N-terminus. We demonstrated that natc-1 mediates diapause entry and stress tolerance. Furthermore, we elucidated regulation of NatC by demonstrating that natc-1 is a direct transcriptional target that is repressed by DAF-16. These findings may be relevant to other animals because both the insulin/IGF-1 signaling pathway and the NAT system are conserved during evolution.
PMCID: PMC4199503  PMID: 25330323
4.  Tuning Pharmacokinetics and Biodistribution of a Targeted Drug Delivery System Through Incorporation of a Passive Targeting Component 
Scientific Reports  2014;4:5669.
Major challenges in the development of drug delivery systems (DDSs) have been the short half-life, poor bioavailability, insufficient accumulation and penetration of the DDSs into the tumor tissue. Understanding the pharmacokinetic (PK) parameters of the DDS is essential to overcome these challenges. Herein we investigate how surface chemistry affects the PK profile and organ distribution of a gold nanoparticle-based DDS containing both a passive and active targeting moiety via two common routes of administration: intravenous and intraperitoneal injections. Using LC/MS/MS, ELISA and INAA we report the half-life, peak plasma concentrations, area under the curve, ability to cross the peritoneal barrier and biodistribution of the nanoconjugates. The results highlight the design criteria for fine-tuning the PK parameters of a targeted drug delivery system that exploits the benefits of both active and passive targeting.
PMCID: PMC4092331  PMID: 25011609
5.  Fungal Planet description sheets: 214–280 
Novel species of microfungi described in the present study include the following from South Africa: Cercosporella dolichandrae from Dolichandra unguiscati, Seiridium podocarpi from Podocarpus latifolius, Pseudocercospora parapseudarthriae from Pseudarthria hookeri, Neodevriesia coryneliae from Corynelia uberata on leaves of Afrocarpus falcatus, Ramichloridium eucleae from Euclea undulata and Stachybotrys aloeticola from Aloe sp. (South Africa), as novel member of the Stachybotriaceae fam. nov. Several species were also described from Zambia, and these include Chaetomella zambiensis on unknown Fabaceae, Schizoparme pseudogranati from Terminalia stuhlmannii, Diaporthe isoberliniae from Isoberlinia angolensis, Peyronellaea combreti from Combretum mossambiciensis, Zasmidium rothmanniae and Phaeococcomyces rothmanniae from Rothmannia engleriana, Diaporthe vangueriae from Vangueria infausta and Diaporthe parapterocarpi from Pterocarpus brenanii. Novel species from the Netherlands include: Stagonospora trichophoricola, Keissleriella trichophoricola and Dinemasporium trichophoricola from Trichophorum cespitosum, Phaeosphaeria poae, Keissleriella poagena, Phaeosphaeria poagena, Parastagonospora poagena and Pyrenochaetopsis poae from Poa sp., Septoriella oudemansii from Phragmites australis and Dendryphion europaeum from Hedera helix (Germany) and Heracleum sphondylium (the Netherlands). Novel species from Australia include: Anungitea eucalyptorum from Eucalyptus leaf litter, Beltraniopsis neolitseae and Acrodontium neolitseae from Neolitsea australiensis, Beltraniella endiandrae from Endiandra introrsa, Phaeophleospora parsoniae from Parsonia straminea, Penicillifer martinii from Cynodon dactylon, Ochroconis macrozamiae from Macrozamia leaf litter, Triposporium cycadicola, Circinotrichum cycadis, Cladosporium cycadicola and Acrocalymma cycadis from Cycas spp. Furthermore, Vermiculariopsiella dichapetali is described from Dichapetalum rhodesicum (Botswana), Ophiognomonia acadiensis from Picea rubens (Canada), Setophoma vernoniae from Vernonia polyanthes and Penicillium restingae from soil (Brazil), Pseudolachnella guaviyunis from Myrcianthes pungens (Uruguay) and Pseudocercospora neriicola from Nerium oleander (Italy). Novelties from Spain include: Dendryphiella eucalyptorum from Eucalyptus globulus, Conioscypha minutispora from dead wood, Diplogelasinospora moalensis and Pseudoneurospora canariensis from soil and Inocybe lanatopurpurea from reforested woodland of Pinus spp. Novelties from France include: Kellermania triseptata from Agave angustifolia, Zetiasplozna acaciae from Acacia melanoxylon, Pyrenochaeta pinicola from Pinus sp. and Pseudonectria rusci from Ruscus aculeatus. New species from China include: Dematiocladium celtidicola from Celtis bungeana, Beltrania pseudorhombica, Chaetopsina beijingensis and Toxicocladosporium pini from Pinus spp. and Setophaeosphaeria badalingensis from Hemerocallis fulva. Novel genera of Ascomycetes include Alfaria from Cyperus esculentus (Spain), Rinaldiella from a contaminated human lesion (Georgia), Hyalocladosporiella from Tectona grandis (Brazil), Pseudoacremonium from Saccharum spontaneum and Melnikomyces from leaf litter (Vietnam), Annellosympodiella from Juniperus procera (Ethiopia), Neoceratosperma from Eucalyptus leaves (Thailand), Ramopenidiella from Cycas calcicola (Australia), Cephalotrichiella from air in the Netherlands, Neocamarosporium from Mesembryanthemum sp. and Acervuloseptoria from Ziziphus mucronata (South Africa) and Setophaeosphaeria from Hemerocallis fulva (China). Several novel combinations are also introduced, namely for Phaeosphaeria setosa as Setophaeosphaeria setosa, Phoma heteroderae as Peyronellaea heteroderae and Phyllosticta maydis as Peyronellaea maydis. Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa.
PMCID: PMC4150077  PMID: 25264390
ITS DNA barcodes; LSU; novel fungal genera; novel fungal species; systematics
6.  Pharmacokinetics, clearance, and biosafety of polyethylene glycol-coated hollow gold nanospheres 
Gold nanoparticles have attracted enormous interest as potential theranostic agents. However, little is known about the long-term elimination and systemic toxicity of gold nanoparticles in the literature. Hollow gold nanospheres (HAuNS) is a class of photothermal conducting agent that have shown promises in photoacoustic imaging, photothermal ablation therapy, and drug delivery. It’s very necessary to make clear the biosafety of HAuNS for its further application.
We investigated the cytotoxicity, complement activation, and platelet aggregation of polyethylene glycol (PEG)-coated HAuNS (PEG-HAuNS, average diameter of 63 nm) in vitro and their pharmacokinetics, biodistribution, organ elimination, hematology, clinical chemistry, acute toxicity, and chronic toxicity in mice.
PEG-HAuNS did not induce detectable activation of the complement system and did not induce detectable platelet aggregation. The blood half-life of PEG-HAuNS in mice was 8.19 ± 1.4 hr. The single effective dose of PEG-HAuNS in photothermal ablation therapy was determined to be 12.5 mg/kg. PEG-HAuNS caused no adverse effects after 10 daily intravenous injections over a 2-week period at a dose of 12.5 mg/kg per injection (accumulated dose: 125 mg/kg). Quantitative analysis of the muscle, liver, spleen, and kidney revealed that the levels of Au decreased 45.2%, 28.6%, 41.7%, and 40.8%, respectively, from day 14 to day 90 after the first intravenous injection, indicating that PEG-HAuNS was slowly cleared from these organs in mice.
Our data support the use of PEG-HAuNS as a promising photothermal conducting agent.
PMCID: PMC4082425  PMID: 24886070
Hollow gold nanospheres; Toxicity; Photothermal ablation therapy
7.  Lysosome-Related Organelles in Intestinal Cells Are a Zinc Storage Site in C. elegans 
Cell metabolism  2012;15(1):88-99.
Zinc is an essential trace element involved in many biological processes and human diseases. Because zinc deficiency and excess are deleterious, animals require homeostatic mechanisms to maintain zinc levels in response to dietary fluctuations. Here we demonstrate that lysosome-related organelles in intestinal cells of C. elegans, called gut granules, function as the major site of zinc storage. Zinc storage in gut granules promotes detoxification and subsequent mobilization, linking cellular and organismal zinc metabolism. The cation diffusion facilitator protein CDF-2 plays a critical role in this process by transporting zinc into gut granules. In response to high dietary zinc, gut granules displayed structural changes characterized by a bilobed morphology with asymmetric distributions of zinc and molecular markers. We defined a genetic pathway that mediates the formation of bilobed morphology. These findings elucidate mechanisms of zinc storage, detoxification and mobilization in C. elegans and may be relevant to other animals.
PMCID: PMC4026189  PMID: 22225878
8.  A Microfluidic-Enabled Mechanical Microcompressor for the Immobilization of Live Single- and Multi-Cellular Specimens 
A microcompressor is a precision mechanical device that flattens and immobilizes living cells and small organisms for optical microscopy, allowing enhanced visualization of sub-cellular structures and organelles. We have developed an easily fabricated device, which can be equipped with microfluidics, permitting the addition of media or chemicals during observation. This device can be used on both upright and inverted microscopes. The apparatus permits micrometer precision flattening for nondestructive immobilization of specimens as small as a bacterium, while also accommodating larger specimens, such as Caenorhabditis elegans, for long-term observations. The compressor mount is removable and allows easy specimen addition and recovery for later observation. Several customized specimen beds can be incorporated into the base. To demonstrate the capabilities of the device, we have imaged numerous cellular events in several protozoan species, in yeast cells, and in Drosophila melanogaster embryos. We have been able to document previously unreported events, and also perform photobleaching experiments, in conjugating Tetrahymena thermophila.
PMCID: PMC4026272  PMID: 24444078
microcompression; microfluidics; laser machining; pyramidal wells; Paramecium tetraurelia; Saccharomyces cerevisiae; polydimethylsiloxane
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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