2010 MIPS Molecular Imaging Seminar Series
Seminar 4:30 − 5:15 pm
Discussion 5:15 − 5:30 pm
Non-linear optical microscopy in vivo
Recent developments in the use of non-linear optical techniques have provided the unique ability to image the molecular structure and function of cells in vivo. This technology is on the verge of bringing together cell biology, physiology and medicine in intact systems where sub-cellular events can be observed in the context of the intact body. The basic use of two-photon excitation fluorescence microscopy essentially permits the delivery of visible photons deep into tissues using infrared light making intra-vital fluorescence microscopy feasible and practical. New optical excitation and detection schemes along with dynamic motion compensation are resulting in several fold improvements in the signal to noise characteristics providing the most sensitive method of imaging any optical fluorescence probe. These approaches permit sub-cellular micrometer fluorescence resolution in intact tissues, in vivo. Other information that can be collected using non-linear excitation approaches include anti-Stokes Raman imaging of water and deuterium, providing microscopic MRI, and coherent scattering generated harmonics in macromolecules that allow the imaging of macromolecular structures and orientation. I will review two examples using non linear optical techniques:
- Imaging the macromolecular structure (i.e. collagen and elastin) of the arterial wall to examine the earliest events associated with LDL deposition and atherosclerosis using second harmonic and fluorescence imaging.
- Application of this approach to study the structure and dynamics of skeletal muscle microvasculature and intra-cellular regional metabolism, in vivo.
These studies reveal that the sub-cellular topology of mitochondria in the muscle may be playing a role in modulating the distribution of oxygen in the tissue. The application of these non-linear optical techniques to the study of cell biology, in vivo, will provide a power tool in bringing the fields of cell biology and physiology together on a common platform and level of complexity.
February 1, 2010
Hamid Mirzaei, PhD
Res Sci, Inst for Sys Bio Targeted Mass Spectrometry (SRM): a new approach to quantitative proteomics
Systems biology depends intimately on the ability to make quantitative measurements of transcriptome, proteome and metabolome. To answer this need, quantitative proteomics has grown in the last 6-7 years, to become a major source of information for systems biology studies where iterative measurements of reproducible sets of proteins from differentially perturbed biological states are essential. A more recent development in the field of quantitative proteomics is Selected Reaction Monitoring (SRM). This mass spectrometry based technology is aimed at fast, sensitive and reproducible screening of large sets of known targets and is ideal for building biological assays in which the presence and quantity of specific analytes is being determined in multiple samples. We applied this technology to study gene regulation in yeast by developing SRM assays for the entire yeast transcription machinery that includes more than 400 proteins. We used this assay to dissect the most complicated gene promoter in yeast (FLO11) in order to understand how it is regulated. We also applied this technology to study protein ubiquitination. We developed a set of SRM assays to determine the frequency of different types of inter-ubiquitin linkages in polyubiquitin chains relative to total ubiquitin concentration. We used this assay to explore changes in poly-ubiquitination of single proteins and the whole proteome under various stress conditions. We demonstrated that SRM is a highly sensitive and quantitative technology that can be used to measure proteins rapidly and reproducibly.
February 8, 2010
A pluripotency signature predicts transformation and survival in follicular lymphoma patients
Andrew J Gentles, PhD
Research Associate, Stanford School of Medicine
Transformation of follicular lymphoma (FL) to diffuse large B cell lymphoma is associated with accelerated disease course and drastically worse outcome, yet the underlying mechanisms are poorly understood. Our computational analysis of expression data suggests that a network of gene transcriptional modules underlies transformation. Central to the network hierarchy is a signature that is strikingly enriched for pluripotency - related genes. These genes are typically expressed in embryonic stem cells (ESC), including MYC and its direct targets. The ESC program is correlated with transcriptional programs maintaining tumor phenotype in transgenic MYC - driven mouse models of lymphoma. A model based on ESC/differentiation programs stratifies patient outcomes in the training dataset as well as in an independent validation set, and is predictive of propensity of FL tumors to transform. Transformation is associated with an expression signature combining high expression of ESC transcriptional programs in combination with reduced stromal signaling. Together, these findings suggest a central role for an ESC - like signature in the mechanism of transformation and provide new clues for potential therapeutic targets. I will also describe how the approach can generalize to other cancers, leveraging large cancer datasets to identify key processes and molecules involved in early stages of the disease.
February 22, 2010
Alway Bldg, Rm M114
Samuel A. Wickline, M.D.
Prof. of Med, Biomed Eng, Phys, & Cell Bio
Perfluorocarbon nanosystems for quantitative molecular imaging and therapy
The goal of Nanomedicine is to develop new diagnostic and therapeutic agents derived from fundamental discoveries in nanotechnology that can be applied safely and efficaciously in the treatment of human diseases. We have developed a number of platforms that meet these goals that have now progressed to clinical trials. In particular, emulsion based nanoparticle comprising perfluorocarbon cores and lipid-surfactant shells can be functionalized with imaging agents, drugs, genes, and targeting moieties to bind to specific molecular epitopes for both sensitive image-based detection and drug delivery at high local concentrations. Novel methods for the use of MRI, ultrasound, CT, optical and nuclear diagnostics have been developed. Drug delivery through unique mechanistic pathways involving fusional complexation of soft nanoparticles with cell membranes transports drugs (small molecules, cytolytic peptides, oligonucleotides, etc.) to cytoplasm for immediate effect. Novel pharmacokinetic approaches allow quantification of local drug delivery based on noninvasive imaging readouts. These and other innovations promise to alter the traditional paradigm for delivery and monitoring of therapeutic agents by taking advantage of targeted delivery at low serum concentrations that should reduce side effects while improving selective deposition of agents at greater concentrations than can be achieved by traditional diffusional mechanisms.
March 22, 2010
Jens Hasseroot, PhD
Professor, Chemistry Laboratory, University of Lyon, France
Designing Molecular Probes for MRI and Fluorescence Imaging that Detect Enzyme Activity
March 29, 2010
Minal Vasanawala, MD
Stanford Nuclear Medicine Clinic, VA
April 5, 2010
A New Therapeutic Approach for Treating Receptor Negative Breast Cancers
Ramasamy Paulmurugan, PhD
Assistant Professor, Stanford University
April 12, 2010
Jason S. Lewis, PhD
Vice Chair, Basic Research
Sloan-Kettering Cancer Ctr
Targeted Radiopharmaceuticals: New Insights into Cancer
The use of Positron Emission Tomography (PET) for cancer imaging is a well-established and widely used molecular imaging modality both in clinical and research settings. PET offers the ability to quantitatively measure biological and receptor-based processes using a wide spectrum of specifically designed radiopharmaceuticals. The use of PET is expanding and the inclusion of longer-lived radiometal positron-emitters is broadening the application and appeal of this imaging modality.
Dr. Lewis' research interests are focused on the development of new PET radiopharmaceuticals for the diagnosis and treatment of cancer. His work incorporates F-18, C-11, and nonstandard nuclide radiopharmaceutical development, with an emphasis on cancer detection and therapy. The Lewis Lab works on the development of small molecules, radiolabeled peptides and antibodies that target the overexpression of receptors and antigens on tumors as well as imaging changes in the tumor microenvironment associated with malignancy.
This presentation will review the current state-of-the-art in non-standard PET nuclide application with an emphasis on the use of radiometals with peptide and antibody constructs. In addition, since the effective use of a radiometal nuclide often relies on their attachment to the targeting probe via a bifunctional chelator, this talk will focus on novel strategies for using click chemistry methodology for attachment of the radiometals to active biomolecules.
April 19, 2010
Time-of-flight positron emission tomography (ToF-PET): study of detector attributes for sub-nanosecond timing
Virginia Spanoudaki, PhD Levin Lab
April 26, 2010
Molecular Correlates of Dynamic Contrast-Enhanced MRI in Locally Advanced Breast Cancer
Nick Hughes Gambhir Lab
May 10, 2010
Badri Roysam, PhD
Prof, Rensselaer Polytechnic Inst
Quantifying Structures and Phenomena in Complex and Dynamic Biological Microenvironments from 4D/5D Optical Microscopy Data
Many tissue microenvironments that play critical roles in health and disease are complex and dynamic, e.g., tumors, stem-cell niches, brain tissue surrounding neuroprosthetic devices, retinal tissue, cancer stem-cell niches, glands, and immune system tissues. Progress in these areas is much too slow compared to the need. Knowledge is pieced together from large numbers of experiments, each of which yields a small amount of information. Much of the knowledge still remains qualitative. There is a compelling need to accelerate progress towards a quantitative understanding. I will describe strategies based on multi-dimensional optical microscopy and computational image analysis.
Modern optical microscopy has grown into a multi-dimensional imaging tool. It is now possible to record dynamic processes in living specimens in their spatial context and temporal order, yielding information-rich 5-D images (3-D space, time, spectra). The task of analyzing these images exceeds human ability. There is a need for automated systems to map the tissue anatomy, quantify structural associations, identify critical events, map event locations and timing, identify and quantify spatial and temporal dependencies, produce meaningful summaries of multivariate measurement data, and compare 4-D/5-D datasets for testing hypotheses, exploration, and systems modeling. Importantly, there is a need for "computational sensing" methods capable of exceeding human ability.
In this talk, I will use examples from neuroscience, cancer histopathology, immunology, and retinal stem-cell biology to show the practicality of multi-dimensional image analysis and computational sensing.
May 17, 2010
Imaging changes in stem cell fate
Helen Blau, PhD
The Donald E. and Delia B. Baxter Professor of Pharmacology and Professor of Chemical and Systems Biology
June 7, 2010
Imaging and Therapy of the Vessel Wall
Mike McConnell, MD, MSEE
Cardiovascular Medicine, Stanford
June 14, 2010
Viking Treasure: Digging through the Recent ISMRM Meeting in Stockholm.
Michael E Moseley, PhD
Professor of Radiology, Stanford
June 28, 2010
Dual Axis Microscopes for Point of Care Microscopy
Christopher Contag, PhD
Associate Professor of Pediatrics and of Microbiology and Immunology and, by courtesy, of Radiology,
July 12, 2010
Immobilization Bed for pre-clinical CT/PET/Optical imaging
Graduate Student, Graves Laboratory
July 19, 2010
Zahi A Fayad, MD
Prof of Radiology
Dir, Translational and Molecular Imaging Institute
Mt. Sinai Med Sch
Whole-body MR-PET, Multimodal Imaging and Drug Delivery in Atherosclerosis
Atherosclerosis is an inflammatory disease, where the degree of inflammation, not the plaque size, determines risk of rupture and therefore likelihood of a clinical event. Magnetic Resonance Imaging (MRI) can image atherosclerotic plaque with high resolution, and several MRI parameters of disease extent in the carotid arteries and aorta have been shown to correlate with atherosclerotic risk factors. Dynamic-contrast-enhanced MRI (DCE-MRI) is a new technique for the study of plaque composition. In this study, the extent of plaque inflammation determined by FDG uptake was correlated with DCE-MRI. By providing a metabolic image of macrophage activity, F18-Fluorodeoxuglucose (FDG) positron emission tomography (PET) can image atherosclerotic plaque inflammation in patients and in animal models of disease, with a strong correlation between FDG uptake and plaque macrophage content. In addition, autoradiography has confirmed that the FDG signal originates from activated macrophages within the lipid core and fibrous cap of the plaque. This has led to the suggestion that FDG-PET might have a role in identifying high risk plaques and monitoring their response to therapy. Computed tomography (CT) can be used in conjunction with PET to help co-register the PET images and for attenuation corrections. Moreover, CT with its exquisite coronary imaging has the potential to address atherosclerosis in the vessel wall of the coronary arteries. We review in this talk to use of multimodality imaging (MR, PET, and CT), the emergence of combined MR/PET scanners and the use of nanotechnology to improve molecular imaging and drug delivery in atherosclerosis.
July 26, 2010-4:00pm
Osman Ratib, MD, PhD
Prof & Chair of Radiology
Dept of Med Imaging & Info Sci
University Hospital of Geneva, Switzerland
Whole Body PET-MRI: First Clinical Experience
This presentation reports our initial experience with a first whole-body PET-MR imaging prototype unit at the University Hospital of Geneva. A prototype whole-body scanner combining a 3T MR and a time-of-flight PET scanner sharing a single bed allowing sequential acquisition of co-registered MR and PET images was implemented and tested. This device consists of the two separate scanners linked through a single patient table allowing sequential imaging of the patient moving from one device to another.
The presentation will report our initial clinical experience and will focus on the performance and clinical applicability of combined imaging protocols on hybrid PET-MR scanner for oncology. It will also report our first clinical experience in patients and our preliminary observation and attempted efforts on the optimization of imaging protocols and acquisition of diagnostic quality whole body images in clinically acceptable time frame.
Optimized imaging protocols combining whole body MR attenuation correction data set with standard MR diagnostic protocols of both modalities while reducing the total time of the study were developed. Clinical results from this hybrid imaging technique applied to oncology investigations were evaluated and compared to findings of corresponding standard PET-CT studies. Initial studies included lymphomas, head and neck tumors, prostate and breast tumors as well as lung and colon cancers. Diagnostic quality of fused PET-MR images were compared to corresponding PET-CT studies.
August 2, 2010
High Field and Molecular MRI
Brian Rutt, PhD
Professor of Radiology
August 9, 2010
Ralph P Mason, PhD
Professor, UT Southwestern Medical Center
Tumor hypoxia-assessing and exploiting oxygen dynamics in cancer therapy
Hypoxia has long been recognized to influence solid tumor response to therapy. Increasingly, hypoxia has also been implicated in tumor aggressiveness, including growth, development and metastatic potential. Thus, there is a fundamental, as well as a clinical interest, in assessing in situ tumor hypoxia and Dr. Mason's Laboratory for Prognostic Radiology is developing MRI methods for assessing tumor oxygen dynamics. A primary focus has been 19F MRI oximetry, which reveals not only hypoxia in vivo, but more significantly, dynamics of spatial distribution of pO2 quantitatively, with a precision relevant to radiation therapy. In addition recent studies suggest that non-invasive BOLD (blood oxygen level dependant) and TOLD (tissue oxygen level dependant) measurements may provide predictive biomarkers suitable for use in patients, where measurements should be non-invasive. Dr. Mason will discuss recent translation to clinical studies in breast, cervix, lung and prostate at UT Southwestern.
Aug 16, 2010
Nan Ma, Rao Laboratory
Aug 23, 2010
Pradeep K. Garg, Ph.D.
Wake Forest University
PET probes for pre-clinical research at WFU- A brief overview
A rationale approach to design PET imaging agent for improved imaging characteristics would be presented. Examples would include the development of probe to image prostate cancer via targeting androgen receptors (AR). While the Ligand Lab at WFU is engaged in developing numerous ligands for different applications, this presentation will focus on development of F-18 fluoromethyl dihydro-testosterone (F-18 FMDHT), a PET probe to image prostate cancer, a second generation F-18 labeled androgen that show high specificity and selectivity to AR rich tissues. The design of this ligand incorporates the placement of functional groups to improve in vivo metabolic stability and kinetics of this ligand while retaining affinity towards the AR. Specific localization of this tracer in AR expressing tumors and improved imaging characteristics when compared F-18 FDG and F-18 Choline reflect its merits. Studies in non-human primates showed favorable distribution kinetics of this tracer with little urinary bladder accumulation for over 50 minutes, a property useful to image prostate bed lesions. The Ligand Lab research facilities at WFU engaged in translational research activities including the development of PET probe to image melanoma will also be presented.
Aug 30, 2010
September 13, 2010
Venu Raman, PhD
Associate Professor, Radiaiton & Oncology
Johns Hopkins School of Medicine
RNA Helicases: The Next Generation of Targets for Cancer Treatment
Effective treatment of cancers is a major challenge to the medical community. A majority of the current chemotherapeutic agents damage DNA or target the mitotic pathway. This approach has been successful to a degree but also induces chemo-resistance and systemic toxicity. One way to circumvent development of resistant disease is to develop novel drugs that target normal cellular functions, which are over-expressed in the transformed phenotype. In our quest to characterize altered cellular pathways that are essential for the transformed phenotype, we have identified a member of a RNA helicase family, DDX3, which is dysregulated in many cancer types such as breast, brain, lung and leukemia. Although the biological functions of DDX3 are still under investigation, we have demonstrated that over-expression of DDX3 promotes epithelial-mesenchymal transition and down-regulates E-cadherin expression. In our efforts to abrogate DDX3 functions in vivo, we have designed a novel small molecule, RK-33 (diimidazodiazepine) that decreased DDX3 expression under both normoxic and hypoxic conditions. Functional analysis revealed that RK-33 was able to reduce lung tumor load in a transgenic mouse model of lung cancer. Moreover, in combination with radiation, there was a synergistic effect with respect to lung tumor reduction in the preclinical model. Similar results were obtained using a preclinical model of breast cancer. Importantly, RK-33 showed no toxicity in animals and thus we anticipate an expeditious translation of the preclinical data into the clinical setting.
Sept 20, 2010
History of FLT: The Long Path to PET
David Dick, PhD
October 4, 2010
October 25, 2010
November 1, 2010
November 15, 2010
LUCAS LEARNING CENTER/P083 PET
November 29, 2010
Hypoxia in Models of Lung Cancer. Implications for Therapeutics Studies
Marta Vilalta Colomer, PhD, Graves Lab
Strategies for Potent and Specific Therapeutic Gene Therapy of Hepatocellular Carcinoma
John Ronald, PhD, Gambhir Lab
December 6, 2010
The State of Hypoxia PET Imaging at Stanford
Ted Graves, PhD
Assistant Professor, Department of Radiation Oncology