Alex K. Shalek, PhD
Pfizer-Laubach Career Development Associate Professor
Institute for Medical Engineering & Science
Department of Chemistry and Koch Institute
Massachusetts Institute of Technology
Abstract: While several methods exist for sampling tissues in clinical contexts, without high-fidelity tools for comprehensively profiling them, we are both limited in our capacity to understand how constituent cells and their interactions impact prognosis, and to select and develop precision therapeutics. Recent years have witnessed transformative and intersecting advances in nanofabrication and molecular biology that now enable deep profiling of low-input samples. Collectively, these afford new and exciting opportunities to study cellular heterogeneity, starting from the level of the single cell, and may unlock the diagnostic, prognostic, and discovery potential of clinical isolates. Illustratively, I will introduce how we can leverage single-cell genomic approaches – and, in particular, single-cell RNA-Seq – to explore the extensive functional diversity between cells, uncovering, from the “bottom-up,” distinct cell states and their molecular drivers. Moreover, I will discuss high-throughput experimental strategies and demonstrate, in the context of Acute Lymphoblastic Leukemia, how they can be leveraged to achieve the statistical power necessary to reconstruct intracellular circuits, enumerate and redefine cell states and types, and transform our understanding of cellular decision-making in health and disease on a genomic scale.
Bio: Alex K. Shalek is currently the Pfizer-Laubach Career Development Associate Professor at MIT, as well as a Core Member of the Institute for Medical Engineering and Science (IMES), an Associate Professor of Chemistry, and an Extramural Member of The Koch Institute for Integrative Cancer Research. He is also an Institute Member of the Broad Institute, an Associate Member of the Ragon Institute, an Assistant in Immunology at MGH, and an Instructor in Health Sciences and Technology at HMS. His research is directed towards the development and application of new technologies that facilitate understanding of how cells collectively perform systems-level functions in healthy and diseased states. Dr. Shalek received his bachelor’s degree summa cum laude from Columbia University and his Ph.D. from Harvard University in chemical physics under the guidance of Hongkun Park, and performed postdoctoral training under Hongkun Park and Aviv Regev (Broad/MIT). To date, his interdisciplinary research has focused on realizing and utilizing nanoscale manipulation and measurement technologies to examine how small components (molecules, cells) drive systems of vast complexity (cellular responses, population behaviors).
Muna Aryal Rizal, PhD
Mentor: Jeremy Dahl, PhD and Raag Airan, MD, PhD
Noninvasive Focused Ultrasound Accelerates Glymphatic Transport to Bypass the Blood-Brain Barrier
Recent advancement in neuroscience revealed that the Central Nervous System (CNS) comprise glial-cell driven lymphatic system and coined the term called “Glymphatic pathway” by Neuroscientist, Maiden Nedergaard. Furthermore, it has been proven in rodent and non-human primate studies that the glymphatic exchange efficacy can decay in healthy aging, alzheimer’s disease models, traumatic brain injury, cerebral hemorrhage, and stroke. Studies in rodents have also shown that the glymphatic function can accelerate by doing easily-implemented, interventions like physical exercise, changes in body posture during sleep, intake of omega-3 polyunsaturated fatty acids, and low dose alcohol (0.5 g/kg). Here, we proposed for the first time to accelerate the glymphatic function by manipulating the whole-brain ultrasonically using focused ultrasound, an emerging clinical technology that can noninvasively reach virtually throughout the brain. During this SCIT seminar, I will introduce the new ultrasonic approach to accelerates glymphatic transport and will share some preliminary findings.
Eduardo Somoza, MD
Mentor: Sandy Napel, PhD
Prediction of Clinical Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) Utilizing Radiomic Features Derived from Pretreatment Positron Emission Tomography (PET) Scan
Diffuse Large B-Cell lymphoma (DLBCL) is the most common type of lymphoma, accounting for a third of cases worldwide. Despite advancements in treatment, the five-year percent survival for this patient population is around sixty percent. This indicates a clinical need for being able to predict outcomes before the initiation of standard treatment. The approach we will be employing to address this need is the creation of a prognostic model from pretreatment clinical data of DLBCL patients seen at Stanford University Medical Center. In particular, there will be a focus on the derivation of radiomic features from pretreatment positron emission tomography (PET) scans as this has not been thoroughly investigated in similar published research efforts. We will layout the framework for our approach, with an emphasis on the aspects of our design that will allow for the translation of our efforts to multiple clinical settings. More importantly, we will discuss the importance and challenges of assembling a quality clinical database for this type of research. Ultimately, we hope our efforts will lead to the development of a prognostic model that can be utilized to guide treatment in DLBCL patients with refractory disease and/or high risk of relapse after completion of standard treatment.
“Tumor-Immune Interactions in TNBC Brain Metastases”
Maxine Umeh Garcia, PhD
ABSTRACT: It is estimated that metastasis is responsible for 90% of cancer deaths, with 1 in every 2 advanced staged triple-negative breast cancer patients developing brain metastases – surviving as little as 4.9 months after metastatic diagnosis. My project hypothesizes that the spatial architecture of the tumor microenvironment reflects distinct tumor-immune interactions that are driven by receptor-ligand pairing; and that these interactions not only impact tumor progression in the brain, but also prime the immune system (early on) to be tolerant of disseminated cancer cells permitting brain metastases. The main goal of my project is to build a model that recapitulates tumor-immune interactions in brain-metastatic triple-negative breast cancer, and use this model to identify novel druggable targets to improve survival outcomes in patients with devastating brain metastases.
“Classification of Malignant and Benign Peripheral Nerve Sheath Tumors With An Open Source Feature Selection Platform”
Michael Zhang, MD
ABSTRACT: Radiographic differentiation of malignant peripheral nerve sheath tumors (MPNSTs) from benign PNSTs is a diagnostic challenge. The former is associated with a five-year survival rate of 30-50%, and definitive management requires gross total surgical with wide negative margins in areas of sensitive neurologic function. This presentation describes a radiomics approach to pre-operatively identifying a diagnosis, thereby possibly avoiding surgical complexity and debilitating symptoms. Using an open-source, feature extraction platform and machine learning, we produce a radiographic signature for MPNSTs based on routine MRI.
ZOOM LINK HERE
“High Resolution Breast Diffusion Weighted Imaging”
Jessica McKay, PhD
ABSTRACT: Diffusion-weighted imaging (DWI) is a quantitative MRI method that measures the apparent diffusion coefficient (ADC) of water molecules, which reflects cell density and serves as an indication of malignancy. Unfortunately, however, the clinical value of DWI is severely limited by the undesirable features in images that common clinical methods produce, including large geometric distortions, ghosting and chemical shift artifacts, and insufficient spatial resolution. Thus, in order to exploit information encoded in diffusion characteristics and fully assess the clinical value of ADC measurements, it is first imperative to achieve technical advancements of DWI.
In this talk, I will largely focus on the background of breast DWI, providing the clinical motivation for this work and explaining the current standard in breast DWI and alternatives proposed throughout the literature. I will also present my PhD dissertation work in which a novel strategy for high resolution breast DWI was developed. The purpose of this work is to improve DWI methods for breast imaging at 3 Tesla to robustly provide diffusion-weighted images and ADC maps with anatomical quality and resolution. This project has two major parts: Nyquist ghost correction and the use of simultaneous multislice imaging (SMS) to achieve high resolution. Exploratory work was completed to characterize the Nyquist ghost in breast DWI, showing that, although the ghost is mostly linear, the three-line navigator is unreliable, especially in the presence of fat. A novel referenceless ghost correction, Ghost/Object minimization was developed that reduced the ghost in standard SE-EPI and advanced SMS. An advanced SMS method with axial reformatting (AR) is presented for high resolution breast DWI. In a reader study, AR-SMS was preferred by three breast radiologists compared to the standard SE-EPI and readout-segmented-EPI.
“Machine-learning Approach to Differentiation of Benign and Malignant Peripheral Nerve Sheath Tumors: A Multicenter Study”
Michael Zhang, MD
ABSTRACT: Clinicoradiologic differentiation between benign and malignant peripheral nerve sheath tumors (PNSTs) is a diagnostic challenge with important management implications. We sought to develop a radiomics classifier based on 900 features extracted from gadolinium-enhanced, T1-weighted MRI, using the Quantitative Imaging Feature Pipeline and the PyRadiomics package. Additional patient-specific clinical variables were recorded. A radiomic signature was derived from least absolute shrinkage and selection operator, followed by gradient boost machine learning. A training and test set were selected randomly in a 70:30 ratio. We further evaluated the performance of radiomics-based classifier models against human readers of varying medical-training backgrounds. Following image pre-processing, 95 malignant and 171 benign PNSTs were available. The final classifier included 21 features and achieved a sensitivity 0.676, specificity 0.882, and area under the curve (AUC) 0.845. Collectively, human readers achieved sensitivity 0.684, specificity 0.742, and AUC 0.704. We concluded that radiomics using routine gadolinium enhanced, T1-weighted MRI sequences and clinical features can aid in the evaluation of PNSTs, particularly by increasing specificity for diagnosing malignancy. Further improvement may be achieved with incorporation of additional imaging sequences.