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- Glycolaldehyde and maleyl conjugated human serum albumin as potential macrophage-targeting carriers for molecular imaging purposes. [JOURNAL ARTICLE]
- Contrast Media Mol Imaging 2014 Apr 22.
Maleylated bovine serum albumin is a known ligand for targeting macrophages and has potential as a carrier for molecular imaging purposes. We present a novel synthesis of glycolaldehyde-conjugated human serum albumin (GA-HSA) and maleylated human serum albumin (Mal-HSA). Seventeen modifications of fluorescently tagged GA-HSA and Mal-HSA molecules with different degrees of conjugation were prepared. The comparative uptake studies, using 12 of these modifications, were done in vitro on mouse monocytes/macrophages (RAW264.7), and evaluated qualitatively by confocal microscopy and quantitatively by flow cytometry. The GA modifications are taken up by the macrophages approximately 40% better than the maleyl modifications at low concentrations (≤3 μm), while at higher concentrations it appears that the maleyl modifications are taken up around 25-44% better than the GA-modified HSA. However, high uptake at low concentrations will be beneficial for in vivo localizing inflammation in areas with low penetration of the probe as in an atherosclerotic plaque. Further, another advantage of GA-HSA is that GA competes less than the maleyl group for the free reactive amine sites that are to be used for conjugation of metal chelating ligands (e.g. tetraazacyclododecanetetraacetic acid and triazacyclononanetriacetic acid). Metal ions such as Gd(3+) and Mn(2+) can be chelated for positive Magnetic Resonance (MR) contrast and positron emitting ions such as (64) Cu(2+) and (68) Ga(3+) for Positron Emission Tomography (PET) imaging. These are important properties, especially, when considering the MR contrast possibilities owing to the low sensitivity of the technique, and would motivate the use of GA-HSA before Mal-HSA. © 2014 The Authors. Contrast Media & Molecular Imaging published by John Wiley & Sons, Ltd.
- Sub-second proton imaging of (13) C hyperpolarized contrast agents in water. [JOURNAL ARTICLE]
- Contrast Media Mol Imaging 2014 Apr 21.
Indirect proton detection of (13) C hyperpolarized contrast agents potentially enables greater sensitivity. Presented here is a study of sub-second projection imaging of hyperpolarized (13) C contrast agent addressing the obstacle posed by water suppression for indirect detection in vivo. Sodium acetate phantoms were used to develop and test water suppression and sub-second imaging with frequency-selective RF pulses using spectroscopic and imaging indirect proton detection. A 9.8 mm aqueous solution of (13) C PHIP hyperpolarized 2-hydroxyethyl-(13) C-propionate-d2,3,3 (HEP), <P > ~25% was used for demonstration of indirect proton sub-second imaging detection. Balanced 2D FSSFP (fast steady-state free precession) allowed the recording of proton images with a field of view of 64 × 64 mm(2) and spatial resolution 2 × 2 mm(2) with total acquisition time of less than 0.2 s. In thermally polarized sodium 1-(13) C-acetate, (13) C to (1) H polarization transfer efficiency of 45.1% of the theoretically predicted values was observed in imaging detection corresponding to an 11-fold overall sensitivity improvement compared with direct (13) C FSSFP imaging. (13) C to (1) H polarization transfer efficiency of 27% was observed in imaging detection, corresponding to a 3.25-fold sensitivity improvement compared with direct (13) C FSSFP imaging with hyperpolarized HEP. The range of potential applications and limitations of this sub-second and ultra-sensitive imaging approach are discussed. Copyright © 2014 John Wiley & Sons, Ltd.
- Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. [JOURNAL ARTICLE]
- Pediatr Blood Cancer 2014 Apr 22.
Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN.Patients (3-21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m(2) orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as ≥20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated.Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed.Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
- Machine learning in preoperative glioma MRI: Survival associations by perfusion-based support vector machine outperforms traditional MRI. [JOURNAL ARTICLE]
- J Magn Reson Imaging 2013 Nov 13.
To retrospectively evaluate the performance of an automatic support vector machine (SVM) routine in combination with perfusion-based dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) for preoperative survival associations in patients with gliomas and compare our results to traditional MRI.The study was approved by the Ethics Committee and informed consent was signed. Structural, diffusion- and perfusion-weighted MRI was performed at 1.5-T preoperatively in 94 adult patients (49 males, 45 females, 23-82 years; mean 51 years) later diagnosed with a primary glioma. Patients were randomly assigned in training and test datasets and the resulting DSC-based survival associations by SVM were compared to traditional MRI features including contrast-agent enhancement, perfusion- and diffusion-weighted imaging, tumor size, and location. The results were adjusted for age, neurological status, and postoperative factors associated with survival, including surgery and adjuvant therapy.For 1- (26/33 alive, 11/14 deceased), 2- (15/21, 21/26), 3- (12/16, 27/31) and 4- (12/15, 28/32) year survival associations in the test dataset (47 patients), the SVM routine was the only biomarker to consistently associate with survival (Cox; P < 0.001).The automatic machine learning routine presented in our study may provide the operator with a reliable instrument for assessing survival in patients with glioma. J. Magn. Reson. Imaging 2013;. © 2013 Wiley Periodicals, Inc.
- Crystal structure of the Campylobacter jejuni CmeC outer membrane channel. [JOURNAL ARTICLE]
- Protein Sci 2014 Apr 19.
As one of the world's most prevalent enteric pathogens, Campylobaceter jejuni is a major causative agent of human enterocolitis and is responsible for more than 400 million cases of diarrhea each year. The impact of this pathogen on children is of particular significance. Campylobacter has developed resistance to many antimicrobial agents via multidrug efflux machinery. The CmeABC tripartite multidrug efflux pump, belonging to the resistance-nodulation-cell division (RND) superfamily, plays a major role in drug resistant phenotypes of C. jejuni. This efflux complex spans the entire cell envelop of C. jejuni and mediates resistance to various antibiotics and toxic compounds. We here report the crystal structure of C. jejuni CmeC, the outer membrane component of the CmeABC tripartite multidrug efflux system. The structure reveals a possible mechanism for substrate export.
- Multifunctional Yolk-in-Shell Nanoparticles for pH-triggered Drug Release and Imaging. [JOURNAL ARTICLE]
- Small 2014 Apr 19.
Multifunctional nanoparticles are synthesized for both pH-triggered drug release and imaging with radioluminescence, upconversion luminescent, and magnetic resonance imaging (MRI). The particles have a yolk-in-shell morphology, with a radioluminescent core, an upconverting shell, and a hollow region between the core and shell for loading drugs. They are synthesized by controlled encapsulation of a radioluminescent nanophosphor yolk in a silica shell, partial etching of the yolk in acid, and encapsulation of the silica with an upconverting luminescent shell. Metroxantrone, a chemotherapy drug, was loaded into the hollow space between X-ray phosphor yolk and up-conversion phosphor shell through pores in the shell. To encapsulate the drug and control the release rate, the nanoparticles are coated with pH-responsive biocompatible polyelectrolyte layers of charged hyaluronic acid sodium salt and chitosan. The nanophosphors display bright luminescence under X-ray, blue light (480 nm), and near infrared light (980 nm). They also served as T1 and T2 MRI contrast agents with relaxivities of 3.5 mM(-1) s(-1) (r1 ) and 64 mM(-1) s(-1) (r2 ). These multifunctional nanocapsules have applications in controlled drug delivery and multimodal imaging.
- Patterns of Antibacterial Use and Impact of Age, Race/Ethnicity, and Geographic Region on Antibacterial Use in an Outpatient Medicaid Cohort. [JOURNAL ARTICLE]
- Pharmacotherapy 2014 Apr 19.
To describe patterns of outpatient antibacterial use among California Medicaid (Medi-Cal) fee-for-service system beneficiaries, and to investigate the influence of demographic factors-age, race/ethnicity, state county, and population density-on those patterns.Retrospective analysis of administrative claims data.Medi-Cal fee-for-service system claims database.All outpatient Medi-Cal fee-for-service system beneficiaries enrolled between 2006 and 2011 who had at least one systemic antibacterial claim.Rates of antibacterial prescribing and the proportion of broad-spectrum antibacterial use were measured over the study period and among age, racial/ethnic, and geographic (county) groups. Of the 10,018,066 systemic antibacterial claims selected for analysis, antibacterial prescribing rates decreased from 542 claims/1000 beneficiaries in 2006 to 461 claims/1000 beneficiaries in 2011 (r = -0.971, p=0.0012; τ-b = -1.00, p=0.009). Among age groups, children had the highest rate of use (605 claims/1000 beneficiaries, χ(2) (2) = 320,000, p<0.001); among racial/ethnic groups, Alaskan Natives and Native Americans had the highest rate of use (1086/1000 beneficiaries, χ(2) (5) = 197,000, p<0.001). Broad-spectrum antibacterial prescribing increased from 28.1% (95% confidence interval [CI] 28.1-28.2%) to 32.7% (95% CI 32.6-32.8%) over the study period. Senior age groups and whites received the highest proportions of broad-spectrum agents (53.4% [95% CI 52.5-54.3%] and 36.6% [95% CI 36.6-36.7%], respectively). Population density was inversely related to both overall antibacterial use (ρ = -0.432, p=0.0018) and broad-spectrum antibacterial prescribing (ρ = -0.359, p<0.001). The rate of prescribing decreased over the study period for all antibacterial classes with the exception of macrolides and sulfonamides. Amoxicillin was the most frequently prescribed agent.Overall and broad-spectrum antibacterial use in the Medi-Cal fee-for-service program are less than that observed nationally. Significant variations in prescribing exist between age and racial/ethnic groups, and heavily populated areas are associated with both less antibacterial use and less broad-spectrum antibacterial prescribing. Studies are needed to determine the reasons for the observed differences in antibacterial use among demographic groups.
- Optimized saturation pulse train for human first-pass myocardial perfusion imaging at 7T. [JOURNAL ARTICLE]
- Magn Reson Med 2014 Apr 18.
To investigate whether saturation using existing methods developed for 3T imaging is feasible for clinical perfusion imaging at 7T, and to propose a new design of saturation pulse train for first-pass myocardial perfusion imaging at 7T.The new design of saturation pulse train consists of four hyperbolic-secant (HS8) radiofrequency pulses, whose peak amplitudes are optimized for a target range of static and transmit field variations and radiofrequency power deposition restrictions measured in the myocardium at 7T. The proposed method and existing methods were compared in simulation, phantom, and in vivo experiments.In healthy volunteer experiments without contrast agent, average saturation efficiency with the proposed method was 97.8%. This is superior to results from the three previously published methods at 86/95/90.8%. The first series of human first-pass myocardial perfusion images at 7T have been successfully acquired with the proposed method.Existing saturation methods developed for 3T imaging are not optimal for perfusion imaging at 7T. The proposed new design of saturation pulse train can saturate effectively, and with this method first-pass myocardial perfusion imaging is feasible in humans at 7T. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.
- Coffee, alcohol and other beverages in relation to cirrhosis mortality: the Singapore Chinese Health Study. [JOURNAL ARTICLE]
- Hepatology 2014 Feb 6.
Limited experimental and epidemiologic data suggest that coffee may reduce hepatic damage in chronic liver disease. The association between consumption of coffee and other beverages, and risk of cirrhosis mortality was evaluated in The Singapore Chinese Health Study. This is a prospective population-based cohort of 63,275 middle-aged and older Chinese subjects who provided data on diet, lifestyle and medical histories through in-person interviews using structured questionnaire at enrollment between 1993 and 1998. Mortality from cirrhosis in the cohort was ascertained through linkage analysis with nationwide death registry. After a mean follow-up of 14.7 years, 114 subjects died from cirrhosis; 33 of them from viral hepatitis B (29%), two from hepatitis C (2%), and 14 from alcohol-related cirrhosis (12%). Compared to non-drinkers, daily alcohol drinkers had a strong dose-dependent positive association between amount of alcohol and risk of cirrhosis mortality. Conversely, there was a strong dose-dependent inverse association between coffee intake and risk of non-viral hepatitis related cirrhosis mortality (p for trend=0.013). Compared to non-daily coffee drinkers, those who drank two or more cups per day had 66% reduction in mortality risk (HR=0.34, 95% CI=0.14-0.80). However, coffee intake was not associated with hepatitis B related cirrhosis mortality. The inverse relationship between caffeine intake and hepatitis B related cirrhosis mortality became null after adjustment for coffee drinking. The consumption of black tea, green tea, fruit juices or soft drinks was not associated with risk of cirrhosis death. Conclusion: This study demonstrates the protective effect of coffee on non-viral hepatitis related cirrhosis mortality, and provides further impetus to evaluate coffee as a potential therapeutic agent in patients with cirrhosis. (Hepatology 2014;).
- Redox-Switchable Supramolecular Graft Polymer Formation via Ferrocene-Cyclodextrin Assembly. [JOURNAL ARTICLE]
- Macromol Rapid Commun 2014 Apr 22.
The redox switchable formation of very well-defined supramolecular graft polymers in aqueous solution driven by host-guest interactions between ferrocene (Fc) and cyclodextrin (CD) is presented. The Fc-containing acrylic backbone copolymer (PDMA-stat-Fc) is prepared via reversible addition-fragmentation chain transfer (RAFT) copolymerization of N,N-dimethyl-acrylamide (DMA) and the novel monomer N-(ferrocenoylmethyl)acrylamide (NFMA). Via the RAFT process, copolymers containing variable Fc ratios (5-10 mol%) are prepared, affording polymers of molecular masses of close to 11 000 g mol(-1) and molar mass dispersities (Đ) of 1.2. The β-cyclodextrin (β-CD) containing building block is synthesized via RAFT-polymerization, too, in order to afford a polymer with well-defined molecular mass and low dispersity (M¯n = 10 300 g mol(-1) , Đ = 1.1), employing a propargyl-functionalized chain transfer agent for the polymerization of N,N-diethylacrylamide (DEA). The polymerization product is subsequently terminated with β-CD via the regiospecific copper (I)-catalyzed 1,3-cycloaddition (PDEA-βCD). Host-guest interactions between Fc and CD lead to the formation of supramolecular graft-polymers, verified via nuclear Overhauser enhancement spectroscopy (NOESY). Importantly, their redox-responsive character is clearly confirmed via cyclic voltammetry (CV). The self-assembly of the statistical Fc-containing lateral polymer chain in aqueous solution leads to mono- and multi-core micelle-aggregates evidenced via TEM. Only diffused cloud-like, non-spherical nanostructures are observed after addition of PDEA-βCD (TEM).