Michael J. Welch

Bio: Michael J. Welch is an academic researcher from Washington University in St. Louis. The author has contributed to research in topics: Biodistribution & In vivo. The author has an hindex of 97, co-authored 692 publications receiving 35647 citations. Previous affiliations of Michael J. Welch include Tel Aviv University & Texas A&M University.

A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography.

Abstract: We propose an in vivo method for use with positron emission tomography (PET) that results in a quantitative characterization of neuroleptic binding sites using radiolabeled spiperone. The data are analyzed using a mathematical model that describes transport, nonspecific binding, and specific binding in the brain. The model demonstrates that the receptor quantities Bmax (i.e., the number of binding sites) and KD-1 (i.e., the binding affinity) are not separably ascertainable with tracer methodology in human subjects. We have, therefore, introduced a new term, the binding potential, equivalent to the product BmaxKD-1, which reflects the capacity of a given tissue, or region of a tissue, for ligand-binding site interaction. The procedure for obtaining these measurements is illustrated with data from sequential PET scans of baboons after intravenous injection of carrier-added (18F)spiperone. From these data we estimate the brain tissue nonspecific binding of spiperone to be in the range of 94.2 to 95.3%, and the regional brain spiperone permeability (measured as the permeability-surface area product) to be in the range of 0.025 to 0.036 cm3/(s X ml). The binding potential of the striatum ranged from 17.4 to 21.6; these in vivo estimates compare favorably to in vitro values in the literature. To ourmore » knowledge this represents the first direct evidence that PET can be used to characterize quantitatively, locally and in vivo, drug binding sites in brain. The ability to make such measurements with PET should permit the detailed investigation of diseases thought to result from disorders of receptor function.« less

The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus

Abstract: Recent evidence has defined an important role for PPARα in the transcriptional control of cardiac energy metabolism. To investigate the role of PPARα in the genesis of the metabolic and functional derangements of diabetic cardiomyopathy, mice with cardiac-restricted overexpression of PPARα (MHC-PPAR) were produced and characterized. The expression of PPARα target genes involved in cardiac fatty acid uptake and oxidation pathways was increased in MHC-PPAR mice. Surprisingly, the expression of genes involved in glucose transport and utilization was reciprocally repressed in MHC-PPAR hearts. Consistent with the gene expression profile, myocardial fatty acid oxidation rates were increased and glucose uptake and oxidation decreased in MHC-PPAR mice, a metabolic phenotype strikingly similar to that of the diabetic heart. MHC-PPAR hearts exhibited signatures of diabetic cardiomyopathy including ventricular hypertrophy, activation of gene markers of pathologic hypertrophic growth, and transgene expression–dependent alteration in systolic ventricular dysfunction. These results demonstrate that (a) PPARα is a critical regulator of myocardial fatty acid uptake and utilization, (b) activation of cardiac PPARα regulatory pathways results in a reciprocal repression of glucose uptake and utilization pathways, and (c) derangements in myocardial energy metabolism typical of the diabetic heart can become maladaptive, leading to cardiomyopathy.

Gold nanocages as photothermal transducers for cancer treatment.

Abstract: Gold nanocages represent a new class of nanomaterials with compact size and tunable optical properties for biomedical applications. They exhibit strong light absorption in the near-infrared region in which light can penetrate deeply into soft tissue. After PEGylation, the Au nanocages can be passively delivered to tumors in animals. Analysis of tissue distribution for the PEGylated Au nanocages showed that the tumor uptake was 5.7 %ID/g at 96 h post injection. The Au nanocages were found not only on the surface, but also in the core of the tumor. By exposing tumors to a near-infrared diode laser (0.7 W/cm2, CW, λ=808 nm) for 10 min, the photothermal effect of the Au nanocages could selectively destroy tumor tissue with minimum damage to the surrounding healthy tissue. Data from functional [18F]fluorodexoyglucose positron emission tomography revealed a decrease in tumor metabolic activity upon the photothermal treatment. Histological examination identified extensive damage to the nuclei of tumor cells and tumor interstitium.

Hypoxia — a key regulatory factor in tumour growth

Abstract: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.

Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation.

Abstract: Neuronal activity causes local changes in cerebral blood flow, blood volume, and blood oxygenation. Magnetic resonance imaging (MRI) techniques sensitive to changes in cerebral blood flow and blood oxygenation were developed by high-speed echo planar imaging. These techniques were used to obtain completely noninvasive tomographic maps of human brain activity, by using visual and motor stimulus paradigms. Changes in blood oxygenation were detected by using a gradient echo (GE) imaging sequence sensitive to the paramagnetic state of deoxygenated hemoglobin. Blood flow changes were evaluated by a spin-echo inversion recovery (IR), tissue relaxation parameter T1-sensitive pulse sequence. A series of images were acquired continuously with the same imaging pulse sequence (either GE or IR) during task activation. Cine display of subtraction images (activated minus baseline) directly demonstrates activity-induced changes in brain MR signal observed at a temporal resolution of seconds. During 8-Hz patterned-flash photic stimulation, a significant increase in signal intensity (paired t test; P less than 0.001) of 1.8% +/- 0.8% (GE) and 1.8% +/- 0.9% (IR) was observed in the primary visual cortex (V1) of seven normal volunteers. The mean rise-time constant of the signal change was 4.4 +/- 2.2 s for the GE images and 8.9 +/- 2.8 s for the IR images. The stimulation frequency dependence of visual activation agrees with previous positron emission tomography observations, with the largest MR signal response occurring at 8 Hz. Similar signal changes were observed within the human primary motor cortex (M1) during a hand squeezing task and in animal models of increased blood flow by hypercapnia. By using intrinsic blood-tissue contrast, functional MRI opens a spatial-temporal window onto individual brain physiology.

Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications

Abstract: A. Water Exchange 2326 B. Proton Exchange 2327 C. Electronic Relaxation 2327 D. Relaxivity 2331 E. Outerand Second-Sphere Relaxivity 2334 F. Methods of Improving Relaxivity 2336 V. Macromolecular Conjugates 2336 A. Introduction 2336 B. General Conjugation Methods 2336 C. Synthetic Linear Polymers 2336 D. Synthetic Dendrimer-Based Agents 2338 E. Naturally Occurring Polymers (Proteins, Polysaccharides, and Nucleic Acids) 2339

Analysis of nanoparticle delivery to tumours

Abstract: This Perspective explores and explains the fundamental dogma of nanoparticle delivery to tumours and answers two central questions: ‘how many nanoparticles accumulate in a tumour?’ and ‘how does this number affect the clinical translation of nanomedicines?’

From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors

Abstract: The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with 18 F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0. Methods: PubMed searches, including searches for the terms RECIST, positron, WHO, FDG, cancer (including specific types), treatment response, region of interest, and derivative references, were performed. Abstracts and articles judged most relevant to the goals of this report were reviewed with emphasis on limitations and strengths of the anatomic and PET approaches to treatment response assessment. On the basis of these data and the authors’ experience, draft criteria were formulated for PET tumor response to treatment. Results: Approximately 3,000 potentially relevant references were screened. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria is widely applied but still has