Inhibition of hepatitis C virus replicon RNA synthesis by PSI-352938, a cyclic phosphate prodrug of β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methylguanosine.

PSI-352938 is a novel cyclic phosphate prodrug of β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methylguanosine 5'-monophosphate that has potent activity against hepatitis C virus (HCV) in vitro. The studies described here characterize the in vitro anti-HCV activity of PSI-352938, alone and in combination with other inhibitors of HCV, and the cross-resistance profile of PSI-352938. The effective concentration required to achieve 50% inhibition for PSI-352938, determined using genotype 1a-, 1b-, and 2a-derived replicons stably expressed in the Lunet cell line, were 0.

Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection.

Hepatitis C virus afflicts approximately 180 million people worldwide, and the development of direct acting antivirals may offer substantial benefit compared to the current standard of care. Accordingly, prodrugs of 2'-deoxy-2'-fluoro-2'-C-methylguanosine monophosphate analogues were prepared and evaluated for their anti-HCV efficacy and tolerability. These prodrugs demonstrated >1000 fold greater potency than the parent nucleoside in a cell-based replicon assay as a result of higher intracellular triphosphate levels.

2'-deoxy-2'-α-fluoro-2'-β-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs as inhibitors of HCV NS5B polymerase: discovery of PSI-352938.

A series of novel 2'-deoxy-2'-α-fluoro-2'-β-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs were synthesized and evaluated for their in vitro anti-HCV activity and safety. These prodrugs demonstrated a 10-100-fold greater potency than the parent nucleoside in a cell-based replicon assay due to higher cellular triphosphate levels. Our structure-activity relationship (SAR) studies provided compounds that gave high levels of active triphosphate in rat liver when administered orally to rats.

Image-based respiratory motion compensation for fluoroscopic coronary roadmapping.

We present a new image-based respiratory motion compensation method for coronary roadmapping in fluoroscopic images. A temporal analysis scheme is proposed to identify static structures in the image gradient domain. An extended Lucas-Kanade algorithm involving a weighted sum-of-squared-difference (WSSD) measure is proposed to estimate the soft tissue motion in the presence of static structures.

Graph based interactive detection of curve structures in 2D fluoroscopy.

An accurate and robust method to detect curve structures, such as a vessel branch or a guidewire, is essential for many medical imaging applications. A fully automatic method, although highly desired, is prone to detection errors that are caused by image noise and curve-like artifacts. In this paper, we present a novel method to interactively detect a curve structure in a 2D fluoroscopy image with a minimum requirement of human corrections.

Discovery of a β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus.

Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2'-Deoxy-2'-α-fluoro-2'-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic.

Upregulation of coronary endothelial P-selectin in a monkey heart ischemia reperfusion model.

The design of targeted ultrasound contrast agents for molecular imaging of myocardial ischemia-reperfusion (IR) requires the availability of an adequate in vivo model in a species in which cross reactivity with the target occurs. P-selectin (Psel) is an activation-dependent endothelial receptor that supports rapid and reversible cell adhesion in a flowing system. Together with E- and L-selectins it constitutes the selectin family of adhesion molecules.

Automated synthesis, characterization and biological evaluation of [(68)Ga]Ga-AMBA, and the synthesis and characterization of (nat)Ga-AMBA and [(67)Ga]Ga-AMBA.

Ga-AMBA (Ga-DO3A-CH(2)CO-G-[4-aminobenzoyl]-QWAVGHLM-NH(2)) is a bombesin-like agonist with high affinity for gastrin releasing peptide receptors (GRP-R). Syntheses for (nat)Ga-AMBA, [(67)Ga]Ga-AMBA and [(68)Ga]Ga-AMBA were developed. The preparation of HPLC-purified and Sep-Pak purified [(68)Ga]Ga-AMBA were fully automated, using the built-in radiodetector of the Tracerlab FX F-N synthesizer to monitor fractionated (68)Ge/(68)Ga generator elution and purification.

PSI-7851, a pronucleotide of beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication.

The hepatitis C virus (HCV) NS5B RNA polymerase facilitates the RNA synthesis step during the HCV replication cycle. Nucleoside analogs targeting the NS5B provide an attractive approach to treating HCV infections because of their high barrier to resistance and pan-genotype activity. PSI-7851, a pronucleotide of beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine-5'-monophosphate, is a highly active nucleotide analog inhibitor of HCV for which a phase 1b multiple ascending dose study of genotype 1-infected individuals was recently completed (M.

Shape regression machine and efficient segmentation of left ventricle endocardium from 2D B-mode echocardiogram.

We present a machine learning approach called shape regression machine (SRM) for efficient segmentation of an anatomic structure that exhibits a deformable shape in a medical image, e.g., left ventricle endocardial wall in an echocardiogram.

Two visual systems in monitoring of dynamic traffic: effects of visual disruption.

Studies from neurophysiology and neuropsychology provide support for two separate object- and location-based visual systems, ventral and dorsal. In the driving context, a study was conducted using a change detection paradigm to explore drivers' ability to monitor the dynamic traffic flow, and the effects of visual disruption on these two visual systems. While driving, a discrete change, such as vehicle location, color, or identity, was occasionally made in one of the vehicles on the road ahead of the driver.

A phospholipid-PEG2000 conjugate of a vascular endothelial growth factor receptor 2 (VEGFR2)-targeting heterodimer peptide for contrast-enhanced ultrasound imaging of angiogenesis.

The transition of a targeted ultrasound contrast agent from animal imaging to testing in clinical studies requires considerable chemical development. The nature of the construct changes from an agent that is chemically attached to microbubbles to one where the targeting group is coupled to a phospholipid, for direct incorporation to the bubble surface. We provide an efficient method to attach a heterodimeric peptide to a pegylated phospholipid and show that the resulting construct retains nanomolar affinity for its target, vascular endothelial growth factor receptor 2 (VEGFR2), for both the human (kinase insert domain-containing receptor - KDR) and the mouse (fetal liver kinase 1 - Flk-1) receptors.

Improving de novo sequence assembly using machine learning and comparative genomics for overlap correction.

Background: With the rapid expansion of DNA sequencing databases, it is now feasible to identify relevant information from prior sequencing projects and completed genomes and apply it to de novo sequencing of new organisms. As an example, this paper demonstrates how such extra information can be used to improve de novo assemblies by augmenting the overlapping step. Finding all pairs of overlapping reads is a key task in many genome assemblers, and to this end, highly efficient algorithms have been developed to find alignments in large collections of sequences.

In vitro and in vivo metabolism of Lu-AMBA, a GRP-receptor binding compound, and the synthesis and characterization of its metabolites.

The metabolism of (177)Lu-AMBA (AMBA = DO3A-CH(2)CO-G-(4-aminobenzoyl)-QWAVGHLM-NH(2)), a radiotherapeutic compound in clinical development that binds to GRP and NMB receptors, was studied in vitro (mouse, rat and human plasma, mouse kidney homogenate) and in vivo (by analysis of mouse and rat plasma and urine following IV injection of (177)Lu-AMBA). The primary metabolites were Lu-DO3A-CH(2)CO-G-Abz4-R, where R = -Q-OH (A), -QW-OH (B), and -QWAVGH-OH (C). Minor amounts of (D) where R = -QWAVGHLM-OH and (E) -QWAVGHL-OH were also observed.

The effect of reimbursement on medical decision making: do physicians alter treatment in response to a managed care incentive?

The empirical literature that explores whether physicians respond to financial incentives has not definitively answered the question of whether physicians alter their treatment behavior at the margin. Previous research has not been able to distinguish that part of a physician response that uniformly alters treatment of all patients under a physician's care from that which affects some, but not all of a physician's patients. To explore physicians' marginal responses to financial incentives while accounting for the selection of physicians into different financial arrangements where others could not, I use data from a survey of physician visits to isolate the effect that capitation, a form of reimbursement wherein physicians receive zero marginal revenue for a range of physician provided services, has on the care provided by a physician.

Isolation of a 177Hf complex formed by beta-decay of a 177Lu-labeled radiotherapeutic compound and NMR structural elucidation of the ligand and its Lu and Hf complexes.

(177)Lu-AMBA (AMBA = DO3A-CH(2)CO-G-[4-aminobenzoyl]-QWAVGHLM-NH(2)) is being developed for the radiotherapeutic treatment of tumors that express the gastrin-releasing peptide receptor (GRP-R). In this study we investigated the fate of the (177)hafnium ((177)Hf) that forms upon the decay of (177)Lu while the latter is complexed with AMBA. When decayed solutions of (177)Lu-AMBA were analyzed, it was found that (177)Hf is retained in the DO3A monoamide chelator, forming a pair of interconverting isomers.

Pharmacokinetics of CPX-351 (cytarabine/daunorubicin HCl) liposome injection in the mouse.

CPX-351 (cytarabine/daunorubicin liposome injection) is a liposomal formulation of a synergistic, fixed combination of the antineoplastic drugs cytarabine and daunorubicin for intravenous infusion. The two drugs are contained within the liposome in a 5:1 molar ratio, shown to be synergistic in vitro and in murine models of hematological malignancies. Mice were given a single intravenous dose of CPX-351 or conventional cytarabine and daunorubicin in saline and plasma and bone marrow were assayed for drug and lipid concentrations.

Localized priors for the precise segmentation of individual vertebras from CT volume data.

We present algorithms for the automatic and precise segmentation of individual vertebras in CT Volume data. When a local surface evolution method such as the level set is applied to such a complex structure, global shape priors will not be sufficient to avoid the leakage and local minima problems, particularly if precise object boundary is desired. We propose a prior knowledge base that contains localized priors--a group of high-level features whose detection will augment the surface model and be the key to success.

Automatic CT-ultrasound registration for diagnostic imaging and image-guided intervention.

The fusion of tracked ultrasound with CT has benefits for a variety of clinical applications, however extensive manual effort is usually required for correct registration. We developed new methods that allow one to simulate medical ultrasound from CT in real-time, reproducing the majority of ultrasonic imaging effects. They are combined with a robust similarity measure that assesses the correlation of a combination of signals extracted from CT with ultrasound, without knowing the influence of each signal.

An ontological knowledge framework for adaptive medical workflow.

As emerging technologies, semantic Web and SOA (Service-Oriented Architecture) allow BPMS (Business Process Management System) to automate business processes that can be described as services, which in turn can be used to wrap existing enterprise applications. BPMS provides tools and methodologies to compose Web services that can be executed as business processes and monitored by BPM (Business Process Management) consoles. Ontologies are a formal declarative knowledge representation model.

An Adaptable XML Based Approach for Scientific Data Management and Integration.

Increased complexity of scientific research poses new challenges to scientific data management. Meanwhile, scientific collaboration is becoming increasing important, which relies on integrating and sharing data from distributed institutions. We develop SciPort, a Web-based platform on supporting scientific data management and integration based on a central server based distributed architecture, where researchers can easily collect, publish, and share their complex scientific data across multi-institutions.

Indium-111 capromab pendetide in the management of recurrent prostate cancer.

The provision of accurate prognostic information is a long-standing goal for effective management of prostate adenocarcinoma. Nontargeted imaging modalities are less efficient at detecting slow-growing prostate cancers. Prostate-specific membrane antigen has emerged as a superior biomarker, especially for the evaluation of metastatic spread.