Gary S. Jacob

Inhibition of HIV replication by amino-sugar derivatives

The plant alkaloids castanospermine, dihydroxymethyldihydroxypyrrolidine and deoxynojirimycin have recently been shown to have potential anti‐HIV activity [(1987) Proc. Natl. Acad. Sci. USA 84, 8120–8124; (1987) Nature 330, 74–77; (1987) Lancet i, 1025–1026]. They are thought to act by inhibiting α‐glucosidase I, an enzyme involved in the processing of N‐linked oligosaccharides on glycoproteins. We report here the relative efficacy of a spectrum of amino‐sugar derivatives as inhibition of HIV cytopathicity. Several α‐glucosidase inhibitors and α‐fucosidase inhibitors were found to be active at concentrations which were non‐cytotoxic.

A shape-space-based approach to tracking myocardial borders and quantifying regional left-ventricular function applied in echocardiography

Presents a new semi-automatic method for quantifying regional heart function from two-dimensional echocardiography. In the approach, we first track the endocardial and epicardial boundaries using a new variant of the dynamic snake approach. The tracked borders are then decomposed into clinically meaningful regional parameters, using a novel interpretational shape-space motivated by the 16-segment model used in clinical practice for qualitative assessment of heart function. We show how a quantitative and automatic scoring scheme for the endocardial excursion and myocardial thickening can be derived from this. Results illustrating our approach on apical long-axis two-chamber-view data from a patient with a myocardial infarct in the apical anterior/inferior region of the heart are presented. In a case study (five patients, nine data sets) the performance of the tracking and interpretation techniques are compared with manual delineations of borders using a number of quantitative measures of regional comparison.

Evaluating a robust contour tracker on echocardiographic sequences

In this paper we present an evaluation of a robust visual image tracker on echocardiographic image sequences. We show how the tracking framework can be customized to define an appropriate shape space that describes heart shape deformations that can be learnt from a training data set. We also investigate energy-based temporal boundary enhancement methods to improve image feature measurement. Results are presented demonstrating real-time tracking on real normal heart motion data sequences and abnormal synthesized and real heart motion data sequences. We conclude by discussing some of our current research efforts.

Robust contour tracking in echocardiographic sequences

In this paper we present an evaluation of a robust visual image tracker on echocardiographic image sequences. We show how the tracking framework can be customised to define an appropriate shape-space that describes heart shape deformations that can be learnt from a training data set. We also investigate an energy-based temporal boundary enhancement method to improve image feature measurement. Preliminary results are presented demonstrating tracking on real normal heart motion data sequences and synthesised and real abnormal heart motion data sequences. We conclude by discussing some of our current research efforts.

Quantitative regional analysis of myocardial wall motion.

This paper presents a new technique for semiautomatic quantification of regional heart function from 2-D echocardiography. It uses a novel left ventricular border tracking algorithm based on shape-space ideas that we have recently described. In this paper, we show how to decompose the tracked output into clinically meaningful segmental parameters (wall excursion and thickening), using what we call a computational interpretational space (CIS). This leads to a quantitative and automatic scoring scheme for endocardial excursion and myocardial thickening. The method is illustrated on data from a patient with a myocardial infarct in the apical anterior/inferior region of the heart and is also assessed in a small retrospective dobutamine stress echocardiography clinical case study.

Biological pathways and in vivo antitumor activity induced by Atiprimod in myeloma.

Atiprimod (Atip) is a novel oral agent with anti-inflammatory properties. Although its in vitro activity and effects on signaling in multiple myeloma (MM) have been previously reported, here we investigated its molecular and in vivo effects in MM. Gene expression analysis of MM cells identified downregulation of genes involved in adhesion, cell-signaling, cell cycle and bone morphogenetic protein (BMP) pathways and upregulation of genes implicated in apoptosis and bone development, following Atip treatment. The pathway analysis identified integrin, TGF-β and FGF signaling as well as Wnt/β-catenin, IGF1 and cell-cycle regulation networks as being most modulated by Atip treatment. We further evaluated its in vivo activity in three mouse models. The subcutaneous model confirmed its in vivo activity and established its dose; the SCID-hu model using INA-6 cells, confirmed its ability to overcome the protective effects of BM milieu; and the SCID-hu model using primary MM cells reconfirmed its activity in a model closest to human disease. Finally, we observed reduced number of osteoclasts and modulation of genes related to BMP pathways. Taken together, these data demonstrate the in vitro and in vivo antitumor activity of Atip, delineate potential molecular targets triggered by this agent, and provide a preclinical rational for its clinical evaluation in MM.

Glucosidase/protein folding inhibitors as possible mutation-proof, anti-hepatitis B & C agents

Publisher Summary Hepatitis B virus (HBV) and hepatitis C virus (HCV) are completely different viruses with similar natural histories of infection. Both target the liver and cause chronic, probably immunopathological diseases. The morphogenesis of HBV and bovine viral diarrhea virus (BVDV) is more dependent on the glucosidase step of glycoprocessing than most host functions. Because BVDV is similar with respect to its morphogenesis to HCV, it is speculated that inhibitors of glucosidases will have broad therapeutic value. Glucosidases mediate the first step of glycoprocessing that is necessary for the proper folding and trafficking of some glycoproteins. Viruses that acquire their lipid envelopes and glycoproteins from intracellular membranes—such as the ER and Golgi—are extremely dependent on the ER glucosidase. It is less conventional to propose targeting a host enzyme for the treatment of a viral infection. The ultimate usefulness of these compounds as therapeutics depends on their safety profiles.