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Duffy, Elizabeth

Publications and source records attributed to Duffy, Elizabeth.

Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.

CPTAC↗

Simulating Mars: Enabling Testing of the Perseverance Rover Sampling and Caching Subsystem on Earth

The development of the Sampling and Caching Subsystem (SCS) on the JPL Perseverance Rover lies at the intersection of testing, robotics, and geology. The SCS team established three primary system test campaigns and venues to aid in the development of SCS through verification and validation testing – Qualification Model Dirty Testing (QMDT) to provide a venue for testing in a Martian environment, Vehicle System Testbed (VSTB) for testing while integrated with the mobility subsystem on Martian-like terrain, and the Flight Software Testbed (FSWTB) for conducting tests using the flight motor controllers and software system on a hexapod which had the ability to simulate rover tilt. Each venue contributed a vital piece to the SCS building blocks. However, the QMDT venue operating within a 10-ft diameter Thermal Vacuum chamber to simulate Martian environment provided a sui generis opportunity to fine tune the entire sampling and caching process while building the team’s knowledge base about rock drillability, system life, and target selection. On Earth, because Martian rocks are not readily available, the development team must utilize geoanalogs to the rocks and regolith on Mars. Geologists on the team helped establish a set of standard rock types to use for Mars missions, like Basalt, Sandstone, Mudstone, Gypsum, and other related geoanalogs. These geoanalogs are characterized with a standard suite of tests for density, compressibility, and other characteristics to categorize potential drillability. This concept of drillability is what links the geoanalogs on Earth to the samples we collect on Mars. With the simulant characteristics defined, these geoanalog rocks are ready to be drilled into as we do on the Martian surface. A key aspect of interacting with the surface on Mars is rock target identification and selection. The Perseverance robotic system uses the on-board cameras, instrumentation, and software to collect enough information to identify potential scientific targets. With the targets identified, SCS can place the Corer and abrade the surface or collect a sample. For a ground test activity like QMDT, the test team did not have all of the camera and instrumentation systems that the rover does, so the team developed ground test equivalents to process a rock, build a target map, and define the target. The team constructed a Rock Scanning Station to build a 3D point cloud of the rock. This point cloud was then processed and evaluated with predefined and programmed criteria in a Target Downselect Tool. A primary output of the Target Downselect Tool is a defined target that can be uploaded directly to the robotic software system to simulate and build the robotic sequences used in tests. With these insights and programmatic definition of targets, the QMDT test team was able to make the same decisions that the Perseverance surface operations team does. In addition, valuable lessons learned from developing the target selection ground tools and using them were implemented into the tools used for surface operations.

Kim, Junggon↗

Mars 2020 Perseverance Rover SHERLOC Instrument Isolation System

The NASA Jet Propulsion Laboratory (JPL) successfully landed the Mars 2020 Perseverance Rover at Jezero Crater on the Martian surface. Perseverance’s main mission objective is to cache Martian rock and regolith samples in hermetically sealed tubes to be brought back to Earth by future missions. To achieve this goal the rover is equipped with a 2-meter-long Robotic Arm (RA) which manipulates the Turret to interact with the surface. The Turret is comprised of science instruments and tools that enable surface sampling and science. The backbone of the Turret hardware is the Rotary Percussive Coring Drill. The science instruments, which are directly mounted to the structural housing of this drill, must be able to withstand not only the launch and entry, descent and landing (EDL) loads of the vehicle but also the dynamic percussive environment, induced by the drill throughout surface operations. This paper discusses the technical hardware design, development and testing of a vibration isolation system to protect the Scanning Habitable Environments with Raman and Luminescence for Organics and Chemicals (SHERLOC) Instrument from these dynamic environments. The hardware design aspect of this problem was limited by both size and mass constraints. The Turret is tightly configured and the physical space in which hardware can reside is restricted due to multiple axes of surface interaction points. Another driving requirement is the extreme range of thermal non-operational environment from -135C to +90C. This, in addition to SHERLOC being a heavier instrument than previously integrated on a turret, made the use of isolation systems employed on previous rover missions problematic. The final design incorporates custom wire mesh springs preloaded within titanium hexapod struts equipped with flexure ends. Custom versions of commercially available wire mesh springs were designed and tested. These custom springs differed in dimension, density and stiffness from the off the shelf options. The newly designed springs went through various stages of flight acceptance testing. Detailed physics-based modeling to understand what loads the isolation system would experience was used to define the test conditions for the springs and entire isolation subsystem. The testing program developed around this was extensive to fully characterize the isolation performance over cleanliness levels, temperature and life. Another major aspect of this work was developing a method of replicating the drill’s percussive environment for performance and life testing of Turret mounted hardware. Attaching the instrument to an operating drill for testing was not a viable option. A method of using a Highly Accelerated Life Test (HALT) table was developed and applied across the project as the most representative and tunable option to physically simulate this new environment. This method, along with launch environment random vibration testing, was used to build an entire dynamic qualification and flight hardware test program. The results of the design, modeling, testing and analysis of the SHERLOC Isolation System is described throughout the following paper.

Krafchak, Todd↗

A proteogenomic portrait of lung squamous cell carcinoma

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

60 APPLIED LIFE SCIENCES↗

A sub-arcsecond Pointing stability fine stage for a high altitude balloon platform

High-altitude balloons (HABs) are platforms for collecting astrophysical and planetary science data that offer a number of advantages compared to conventional groundbased or space-based systems. However, they also pose a set of new environmental challenges that must be addressed in order to offer a viable alternative to ground- or space- based assets. In particular, maintaining science-quality pointing stability is a critical challenge for HAB platforms. For these missions, dynamic errors must be limited to a fraction of the observation wavelength, so as the wavelength becomes smaller, it becomes more difficult to meet the needed performance. As a result, there are very few existing pointing stabilization solutions that use visible-spectrum guide stars, despite their relatively wide distribution across the sky. This paper describes the results achieved with the STABLE (Subarcsecond Telescope And BaLloon Experiment) project whose goal is to provide the fine pointing stage for a balloonborne platform observing in the visible wavelength.

Porter, Michael↗