Photodynamic therapy (PDT) is a clinically approved, minimally invasive, and highly controllable therapeutic procedure, which has gained popularity as an alternative or additional approach to conventional cancer treatments, such as chemotherapy and surgery. Because PDT photosensitizers (PSs) only produce phototoxicity in the irradiated area, this approach avoids systemic toxicity. Despite recent efforts to develop tumor-targeted PDT PSs, complete eradication of tumor cells by PDT alone remains challenging due to the limited efficacy. As a way to improve PDT efficacy, we developed a new combinatory PDT therapy approach that specifically targets multilayers of cells. By introducing phototoxicity to distinct cellular layers simultaneously, various cellular pathways were activated, leading to desired synergistic effects. In addition, such a therapy approach offers minimal side effects due to use of localized light irradiation and multiple receptor targeting.

Cellular heterogeneity presents a significant challenge for cancer biology. Rare cell populations, such as cancer stem cells or tumor initiating cells, can resist therapy and metastasize to other organs. The ability to perturb and track rare cell behaviors present attractive translational strategies, yet, since rare cell behaviors do not reflect bulk population behavior, lysate-mixture-based experimental approaches are inadequate for characterizing rare cells from tissues. Here, I introduce single-cell experimental approaches, DISSECT-CyTOF and MultiOmyx microscopy, that assay signaling from epithelial cells isolated from intestinal tissue. Coupled with a graph-based computational approach we developed, we use multi-parameter analysis to define cell populations by their phenotypic behaviors. We present a case study using these approaches to illustrate the cellular signaling landscape of MSI vs. MSS colorectal cancer retrieved from FFPE tissue blocks.

Over the past two decades, molecular imaging tools have been aggressively developed and applied in cancer models and patients to study tumor biology while improving cancer detection and management. Despite many advances, one of the major challenges has been developing translational imaging tools that selectively measure the activity of important signaling pathways and/or drug targets within the cancer cell. To address this challenge, we have pioneered a workflow in which we apply ?omics? technologies to interrogate the biology downstream of an oncogene of interest to identify cell surface antigens that are compatible with PET imaging, and selectively regulated by the oncogene. Using this new approach, we have developed the first translational imaging tools to measure the activity of oncogenes like the androgen receptor, MYC, mTORC1, and RAS with PET, and we have begun to validate these imaging biomarkers in man at UCSF. Moving forward, we anticipate these radiotracers will significantly improve our understanding of human tumor biology, as well as empower more systematic decision making in the clinic.

CounterACTing Chemical Warfare with PET
The use of organophosphorus compounds (OP), such as sarin gas, as chemical weapons continues to be a significant threat to both military personnel and citizens. The lethality of these ?weapons of mass destruction? arises from OP potent inhibition of acetylcholinesterase (AChE), which, if not treated immediately (seconds to minutes), leads to paralysis and ultimately, death. To date, a single class of oxime compounds, such as 2PAM, is the only clinically approved treatment for OP toxicity and at physiological pH, the charged nature of these oximes renders them ineffective CNS penetrants. The main bottleneck for advancing countermeasures for the OP toxidrome is a lack of mechanism-based pharmacokinetic and pharmacodynamic (PK/PD) analyses that cannot efficiently quantitate and verify relative amounts of OP, OP-AChE adduct, and/or oxime antidote in peripheral circulation and the CNS. We have developed four positron-labeled OP nerve agents and a positron-labeled analogue of 2PAM and have used the agents to understand the OP toxidrome in vivo through dynamic PET imaging with concomitant arterial sampling. Moving forward, we aim to expand this methodology to allow external investigators to discern critical in vivo PK distribution, PD attributes and localization of the AChE target in appropriate animal models and ultimately, strengthen and/or develop new antidotes for OP toxicity.

GKX: A sugar substitute for cancer?
Lung cancer is responsible for the most cancer-related mortalities worldwide. Of the nearly 225,000 new cases of lung cancer in 2016, 85% will be classified as nonsmall cell lung cancer (NSCLC). Chemotherapy remains a major treatment modality and the only adjuvant therapy proven to prolong patient survival after surgical resection. Major advances in early-stage diagnostics have been made within the last 10 years, along with discoveries of novel biomarkers, which have formed the basis for targeted therapies based on oncogene/tumor suppressor status. However, to date, the 5-year survival rate for NSCLC remains marginal at 19%. The high mortality rate is due, in part, to the high molecular heterogeneity observed in NSCLC, which obfuscates correlating targetable driver mutations with chemotherapy response, leaving systemic chemotherapy as the frontline adjuvant therapy option. The lung cancer field would gain significantly by the availability of a non-invasive tool that could stratify early-stage NSCLC patients who are most likely to relapse after surgical resection; furthermore, guide the clinician on whether a systemic chemotherapy drug, such as cisplatin, will provide any relevant change in the patient?s 5-year survival rate and overall survival compared to a more targeted molecular therapy.

Objectives:
1) Understand the infrastructure and unique talent in the radiation department that may be leveraged for collaborative research
2) Review existing collaborations
3) Discuss key research questions in radiation oncology that require imaging endpoints

There will be a "Reception and Brainstorming Session" immediately following the seminar.

[18F] fluoride, a positron-emitting radiopharmaceutical widely used in medical imaging modality positron emission tomography(PET) due to its longer half-time of 110 minutes, is concentrated with a miniaturized anion exchange column located on PDMS microchip. Microfluidics has been applied to perform fluoride enrichment in small dimension and simultaneously obtains faster diffusion and reactive kinetics. This manuscript reported a simple and easy-controlling method for rapidly and efficiently radioactive isotope, here specifically [18F] fluoride, capture. Instead of relying on complicated flow control elements (e.g. valves), pillars, interval less than average diameter of anion exchange beads, are set inside microchannel for beads-trapping. In our own work, flow containing diluted [18F] fluoride was driven by syringe pump in proper loading rate through anion exchange column. The high flow resistance assisted elimination of air bubble inside channel, making simple control handling dependable. This device is further amended to trap exact amount of anion exchange beads, satisfying several human doses. We demonstrated the device by trapping [18F] fluoride rapidly and efficiently. Our device is composed of a main chamber (2.9 L) with microchannel (9mm long each) connecting to inlet and outlet. Direct laser writer was applied to create patterns on silicon wafer for simplifying fabrication procedures. Certain amount of anion exchange beads was trapped by double-row square pillars near the outlet of chamber, then following immediate beads activation. Diluted [18F] fluoride was concentrated by flowing through microchamber. The enriched product was then eluted to achieve fully released for further solvent exchange. Successful fluoride trapping was confirmed by actuating diluted radioactive solution (100 mCi/mL) through microchannel. We observed almost fully capture of radioactivity on our chips with fleeting time period (less than 10 minutes). Moreover elution with small volume(less than 200 L) of Kryptofix (K222) released nearly all fluoride. Thus, this device is capable of simply and efficiently trapping [18F] fluoride and being eluted to obtain high concentration product within small volume.

Healthy brain physiology is underpinned by dynamic patterns of fluid circulation and exchange. Recently, several novel anatomical and functional elements of brain fluid movement have been identified, such as the glymphatic system. This has led to a lively reappraisal of classical perspectives. In this talk, I will describe our recent efforts to develop new and non-invasive techniques to assess brain fluid movement using MRI. Such methods may lead to practical measurement in the human brain, working towards improved mechanistic understanding and early detection of pathology:

i) Non-invasive MRI of blood-CSF-barrier (BCSFB) function The BCSFB is a highly dynamic transport interface that serves brain homeostasis. Here, we introduce the first non-invasive technique for the quantitative assessment of BCSFB function. We describe a translational MRI method to quantify the rate of delivery of blood water across the BCSFB, into ventricular CSF. We then apply the technique to investigate the role of the BCSFB in ageing and ventriculomegaly, in the mouse brain.

ii) Non-invasive assessment of perivascular fluid movement using DTI MRI The perivascular (PV) space is a key conduit of CSF-interstitial fluid exchange. Here we use an ultra-long echo time diffusion tensor imaging (DTI) sequence to assess PV fluid movement and its modulation by vascular pulseatility in the rat brain.

iii) Non-invasive assessment of aquaporin-4 polarisation using multi-echo-time arterial spin labelling Aquaporin-4 (AQP4) channels are transmembrane proteins that facilitate rapid bi-directional flux of water and are critical to efficient glymphatic function. Here we employ a multi-echo-time arterial spin labelling (ASL) sequence to measures the rate of flux of labelled water across the blood brain barrier. By applying this technique to AQP4- mice, we examine sensitivity to AQP4 function.

Ultrasound has the ability to focus energy to a small point beyond the skull and is being widely explored by researchers as a tool for non-invasive neuromodulation. When combined with magnetic resonance imaging (MRI), focused ultrasound (FUS) can be precisely guided while the effects of FUS can be visualized at the network level using fMRI. In this talk, I will discuss our ongoing work in developing systems to apply image-guided FUS neuromodulation in the MRI environment while imaging functional activity. Specifically, I will cover the development of optical tracking as a method to guide FUS neuromodulation, the creation of transducer arrays for steerable FUS neuromodulation, and the development of MR acoustic radiation force imaging methods to visualize the acoustic focus. We have used these methods to modulate the somatosensory network in non-human primates, demonstrating that MRI-guided FUS is capable of exciting precise targets in somatosensory areas 3a/3b, causing downstream activations in off-target brain regions within the circuit which we can simultaneously detect with fMRI. Our observations are consistent with others' work in the field of FUS neuromodulation; however, questions remain about mechanisms underlying FUS neuromodulation and potential confounds. The talk will conclude by reporting on recent work at the cellular level where we are measuring calcium signaling in mouse brain slices with optical markers during FUS neuromodulation.

Cancer immunotherapy has shown great potential to treat cancers with limited treatment options. Despite its recent success in certain types of cancers, there have been major cases of non-responders, treatment-related side effects, and disease relapses. Molecular imaging can provide valuable information on infused therapeutic immune cells for their localization, amplification, and functional status. This information can be effectively used for patient selection, assessment of response, evaluation of potential toxicity, and further development of enhanced therapy. This talk will summarize the recent advancement of radionuclide imaging in cell-based immunotherapies. This talk will also discuss future directions of radionuclide imaging in immunotherapy for its potential roles.

Diffusion MRI fiber tractography has become a pillar of the neuroimaging community due to its ability to noninvasively map the structural connectivity of the brain. Despite widespread use in clinical and research domains, these methods suffer from several potential drawbacks or limitations. In this talk, we will discuss challenges in using tractography to study structural connectivity, and highlight our work (and others at the frontiers of the field) in overcoming these challenges with the goal to better map the connections and fiber pathways of the brain.

The field of medical ultrasound has undergone a significant evolution since the development of microbubbles as ultrasound contrast agents. Micron sized gas bubbles, or microbubbles, which are encapsulated by a lipid, protein or polymer shell, have become the building blocks of numerous diagnostic and therapeutic applications of ultrasound in the last decade. In ultrasound imaging, bubbles are used to enhance image quality and improve detection of diseases such as cancer. In therapeutic ultrasound, bubble oscillation and cavitation in the acoustic field is used to elicit various bioeffects. However, due to their size, microbubbles are intravascular contrast agents, and therefore cannot be used as robust molecular imaging agents. The question then becomes - how can we harness the mature, widely available, inexpensive ultrasound technologies to improve disease diagnosis and drive forward the field of molecular medicine? One possibility is through building a better - and smaller - bubble. Reducing the bubble size expands the applications of ultrasound contrast agents by allowing bubbles to extravasate from blood vessels - creating new opportunities. This has been the driving motivation for the development of NBs as contrast agents for ultrasound molecular imaging and as vehicles for ultrasound-mediated therapy. This presentation will provide an overview of the fundamentals of contrast enhanced ultrasound and will summarize recent and emerging research on the use of NBs as imaging agents and as therapeutic vehicles.

This talk will discuss two examples of successful academic-industrial collaborations in the areas of x-ray and computed tomography (CT) imaging. In the first, I will share my prior perspective from industry, collaborating with academia, and how tools developed in image-guided radiation therapy led to fast and accurate radiation dose reporting for CT imaging. In the second, I will share my perspective from academia, collaborating with industry on a novel dual-layer x-ray detector that provides simultaneous dual-energy x-ray images. With these dual-energy images, we can uniquely identify different materials such as soft tissue or bone for better image guidance. Lastly, I will present on our recent efforts to improve chest x-ray imaging of COVID patients using the dual-layer detector. Adam Wang, PhD is an Assistant Professor of Radiology and, by courtesy, Electrical Engineering at Stanford University. He completed his PhD at Stanford in 2012, on the topic of maximizing the information content of spectral x-ray imaging. He then completed a postdoctoral fellowship at Johns Hopkins University in 2014, on iterative reconstruction and image registration of cone-beam CT for image-guided surgery. Afterwards, Dr. Wang was a Senior Scientist at Varian Medical Systems, developing systems and algorithms for image-guided radiation therapy. He returned to Stanford in 2018, where he now leads a research group developing novel x-ray and CT systems and methods.

MRI has been widely used to probe the neuroanatomy of the mouse brain, directly correlating MRI findings to histology is still challenging due to the limited spatial resolution and various image contrasts derived from water relaxation or diffusion properties. Magnetic resonance histology has the potential to become an indispensable research tool to mitigate such challenges. In this talk, we will introduce the compressed sensing (CS) technique for 3D diffusion MRI and quantitative susceptibility mapping (QSM), which can reduce MRI acquisition times up to 8-fold. The saved scan time can be used to achieve much higher spatial resolution MR images. Our findings demonstrate that MRI at microscopic resolution delivers a three-dimensional, noninvasive and non-destructive platform for characterization of fine structural detail in both gray matter and white matter of the mouse brain. This acceleration enables high throughput genetic application of MRI technology to a wide range of mouse models, including Alzheimer's disease, Autism spectrum disorder, and multiple sclerosis.

In an effort to develop quantitative biomarkers for degenerative joint diseases and fill the void that exists for diagnosing, monitoring, and assessing the extent of whole joint degeneration, the past decade has been marked by a greatly increased role of noninvasive imaging. In addition to radiographs, Magnetic Resonance (MR) imaging has evolved over the last two decades to respond to this challenge. While MRI can exploit the complexity of the joint with capacity in imaging soft tissues from morphological and biochemical point of views, substantial challenges in image analysis and quantitative image biomarker extraction still hamper clinical translation of promising quantitative techniques widely used in research setting. Lack in standardization of image interpretation, tedious manual post processing pipelines, including image segmentation and registration, feature hand crafting for morphology and relaxometry analysis are just few of the issues related to high-throughput usage of imaging. However, coupled with advanced quantitative imaging techniques, novel computerized image post processing and more recently machine/deep learning techniques the quantitative characterization of early joint degeneration is now a tangible goal. Automation and advanced feature extraction techniques have applications on larger more heterogeneous samples. Analyses based on voxel based relaxometry have shown local patterns in relaxation time elevations and local correlations with outcome variables. Bone cartilage interactions are also enhanced by the analysis of three-dimensional bone morphology and the potential for the assessment of metabolic activity with simultaneous Positron Emission Tomography (PET)/MR systems. Novel techniques in image processing and deep learning are augmenting imaging to be a source of quantitative and reliable data and new multidimensional analytics allow us to exploit the interactions of data from various sources. In this seminar, I aim to summarize recent advances in quantitative imaging and the application of image processing and deep learning techniques to study degenerative joint diseases.

There are thousands of rare genetic diseases that impact human health. Many of these diseases have high mortality rates for both infants and children and, taken collectively, result in pathophysiologies for virtually all organs of the body. For many of these rare diseases, the specific disease prevalence is very low, which has historically limited drug development. With the advent of high throughput drug screening and next-generation sequencing technologies, the potential for developing therapies for these "orphan" diseases is now a reality. Looking forward, one major challenge for developing therapies for patients with rare genetic diseases is the lack of effective tools to be used as outcome measures in clinical trials, as many conventional clinical assessments lack the sensitivity to be used effectively for smaller-scale clinical trials. In this presentation, I will be discussing our preclinical and clinical work to develop safe, reproducible, and quantitative MRI assessments for patients with cystic fibrosis (CF) and autosomal recessive polycystic kidney disease (ARPKD).

Mild traumatic brain injury (mTBI) is the most common type of traumatic brain injury globally. Although its consequences may be short term, mTBI often leads to long-term neuropsychiatric and neurological impairments and has been estimated to increase the probability of later life dementia up to six-fold. It is presently not clear what neuropathological changes underlie these deficits. This talk will review our recent studies on the sustained neurogliovascular unit function changes in a murine model of repeated, mild traumatic brain injury. By leveraging two photon fluorescence microscopy, intracerebral electrophysiological recordings, optogenetics, and high field magnetic resonance imaging, we reveal pronounced, lasting, and diffuse changes in the neuronal and cerebrovascular functional signals in situ, accompanied by only subtle changes in histopathological readouts and no contrast on conventional neuroimaging. Our studies suggest the potential of disinhibitory interventions to ameliorate peri-contusional neuronal and cerebrovascular tone and reactivity. In light of known import of functional hyperemia for healthy brain functioning, normalization of the neurovascular unit function is likely key for decreasing the susceptibility of the concussed brain to subsequent pathologies. We expect sensitive in situ functional assays to be instrumental for development of such neurovascularly targeted interventions in the clinic.

There is a clear need to develop diagnostic and predictive imaging biomarkers to select patients who will benefit from therapy, assess durable outcomes and guide secondary interventions. Existing tools used in the clinic heavily rely on invasive biopsy procedures and non-standardized peripheral blood assays. These assays do not provide real time, in situ monitoring of the dynamic molecular events occurring within the tumor microenvironment. Molecular imaging through immunoPET can potentially bridge this gap. ImmunoPET detection of overly expressed antigens on the tumor can monitor drug response and select those that will respond to systemic targeted radiotherapy. The first part of my talk will present our work on the detection of cytokines, which are key hallmarks of an active immune system facilitating tumor clearance. The second part presents the development of theranostic agents targeting TRA-1-60, a pluripotent cancer stem cell marker.

ImmunoPET merges positron emission tomography (PET), a non-invasive imaging technique that employs positron-emitting radioisotopes, to an antibody's ability to bind to a specific target uniquely present or expressed in high levels in the tumor cells. This webinar will describe our studies showing the potential of antibody-PET to visualize the real-time heterogeneity and dynamics of membrane receptors during modulation of cell-surface target availability. The talk will summarize studies showing the potential of immunoPET in monitoring:
1) receptor tyrosine kinase activation during tyrosine kinase inhibition,
2) antibody-tumor binding in receptor "masked" tumors,
3) antibody-drug conjugates binding to tumors during temporal modulation of endocytosis.

Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease. The name is derived from the absence of three specific receptors that are commonly targeted in other subtypes of breast cancer. Until recently, patients with TNBC had no options for targeted treatments, relying on cytotoxic chemotherapy as standard of care with much lower rates of survival compared with those with the other subtypes. As new therapeutic targets emerge, monoclonal antibodies and antibody drug conjugates have played a significant role in improving treatment outcomes for patients with TNBC. In this talk, I will provide a brief overview of the changing landscape in the treatment of TNBC and potential role of PET imaging to select patients likely to respond to new antibody treatments. As an example, I will show how we develop 89Zr-labeled antibodies that predict response to corresponding antibody drug conjugate therapy in cell-derived and patient-derived xenograft models of TNBC.

The joint response to physiological loading plays a major role in joint health and degenerative arthropathies. Exercise and normal joint loading are beneficial for arthritic diseases as well as for preventing osteoporosis, skeletal fragility and osteopenia associated with aging and joint health. Excessive mechanical forces, due either to high loads or a breakdown in proper joint tissue function, can be pathologic and lead to joint degeneration. While many imaging methods have been developed to study tissue structure and microstructure, evaluation of whole-joint function and response to physiological loading remains a challenge. This seminar will discuss new PET and MRI imaging approaches for studying the response of the joint and musculoskeletal tissues to exercise and loading stresses. In particular, bone is an inherently dynamic and well-vascularized tissue that can quickly respond to external stimuli. Molecular information from [18F]sodium fluoride ([18F]NaF) PET uptake, interrogates areas of newly mineralizing bone and has been shown to detect changes in bone physiology from acute loading. In addition, MRI imaging of real-time motion as well as microstructural and tissue compositional changes after exercise can detect structural instabilities and deficiencies that are not present on conventional static scans.

Purpose: Amplified Magnetic Resonance Imaging (aMRI) has been introduced as a new method of detecting and visualizing pulsatile brain motion in 2D. Here, we improve aMRI by introducing a novel 3D aMRI approach.

Methods: 3D aMRI was developed and tested for its ability to amplify sub-voxel motion in all three directions. 3D aMRI was qualitatively compared to 2D aMRI on multi-slice and 3D (volumetric) data acquired on two healthy volunteers at 3T. Optical flow maps and 4D animations were produced from volumetric 3D aMRI data.

Results: 3D aMRI exhibits better image quality and fewer motion artifacts compared to 2D aMRI, in particular when it is applied to volumetric data. Optical flow maps capture the brain tissue motion and display the physical change in shape of the ventricles by the relative movement of the surrounding tissues. The 4D animations show the complete brain tissue and CSF motion, helping to highlight the 'piston-like' motion of the ventricles.

Conclusion: Here we introduce a novel 3D aMRI approach that enables one to visualize amplified cardiac- and CSF-induced brain motion in striking detail. Compared with the traditional multi-slice 2D aMRI approach, 3D aMRI coupled with isotropic volumetric data captures 3D brain motion with better image quality and supports a larger amplification factor. The optical flow maps and 4D animations of 3D aMRI may help to understand the dynamics of what drives the passage of CSF and extracellular fluids within the ventricular system and brain tissue, opening up exciting applications for neurological diseases that affect the biomechanics of the brain and brain fluids.

In this lecture I will discuss the development of purpose-built quantitative MR methods, informed by chemistry and biophysics, to probe the pathogenesis of type 2 diabetes. Recent studies have suggested that adipose tissue hypoxia, brought on by adipocyte hypertrophy, is a primary pathway to systemic insulin resistance. This "hypoxia-driven insulin resistance hypothesis" has been indirectly inferred from histologic data, yet adipose hypoxia and adipocyte hypertrophy have not been directly resolved in vivo. Rationally designed quantitative MR methods provide a means to these ends - adipose pO2 can be calculated from measures of triglyceride longitudinal relaxation and adipocyte size can be calculated from measures of triglyceride diffusion. These quantitative MR techniques provide completely new insight into adipose tissue structure and function and its key role in the pathogenesis of insulin resistance and type 2 diabetes.