• Automated analysis of interactional synchrony using robust facial tracking and expression recognition

      Yu, Xiang; Zhang, Shaoting; Yu, Yang; Dunbar, Norah; Jensen, Matthew; Burgoon, Judee K.; Metaxas, Dimitris N. (IEEE, 2013-04)
      In this paper, we propose an automated, data-driven and unobtrusive framework to analyze interactional synchrony. We use this information to determine whether interpersonal synchrony can be an indicator of deceit. Our framework includes a robust facial tracking module, an effective expression recognition method, synchrony feature extraction and feature selection methods. These synchrony features are used to learn classification models for the deception recognition. To evaluate our proposed framework, we have conducted extensive experiments on a database of 242 video samples. We validate the performance of each technical module in our framework, and also show that these synchrony features are very effective at detecting deception.
    • Automated annotation of learner English

      Picoral, Adriana; Staples, Shelley; Reppen, Randi; University of Arizona (John Benjamins Publishing Company, 2021-03-01)
      This paper explores the use of natural language processing (NLP) tools and their utility for learner language analyses through a comparison of automatic linguistic annotation against a gold standard produced by humans. While there are a number of automated annotation tools for English currently available, little research is available on the accuracy of these tools when annotating learner data. We compare the performance of three linguistic annotation tools (a tagger and two parsers) on academic writing in English produced by learners (both L1 and L2 English speakers). We focus on lexico-grammatical patterns, including both phrasal and clausal features, since these are frequently investigated in applied linguistics studies. Our results report both precision and recall of annotation output for argumentative texts in English across four L1s: Arabic, Chinese, English, and Korean. We close with a discussion of the benefits and drawbacks of using automatic tools to annotate learner language.
    • Automated bug localization in JIT compilers

      Lim, HeuiChan; Debray, Saumya; Department of Computer Science, University of Arizona (ACM, 2021-04-07)
      Many widely-deployed modern programming systems use just-in-Time (JIT) compilers to improve performance. The size and complexity of JIT-based systems, combined with the dynamic nature of JIT-compiler optimizations, make it challenging to locate and fix JIT compiler bugs quickly. At the same time, JIT compiler bugs can result in exploitable security vulnerabilities, making rapid bug localization important. Existing work on automated bug localization focuses on static code, i.e., code that is not generated at runtime, and so cannot handle bugs in JIT compilers that generate incorrect code during optimization. This paper describes an approach to automated bug localization in JIT compilers, down to the level of distinct optimization phases, starting with a single initial Proof-of-Concept (PoC) input that demonstrates the bug. Experiments using a prototype implementation of our ideas on Google's V8 JavaScript interpreter and TurboFan JIT compiler demonstrates that it can successfully identify buggy optimization phases. © 2021 ACM.
    • Automated data processing architecture for the Gemini Planet Imager Exoplanet Survey

      Wang, Jason J.; Perrin, Marshall; Savransky, Dmitry; Arriaga, Pauline; Chilcote, Jeffrey; De Rosa, Robert J.; Millar-Blanchaer, Maxwell A.; Marois, Christian; Rameau, Julien; Wolff, Schuyler; et al. (SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS, 2018-01)
      The Gemini Planet Imager Exoplanet Survey (GPIES) is a multiyear direct imaging survey of 600 stars to discover and characterize young Jovian exoplanets and their environments. We have developed an automated data architecture to process and index all data related to the survey uniformly. An automated and flexible data processing framework, which we term the Data Cruncher, combines multiple data reduction pipelines (DRPs) together to process all spectroscopic, polarimetric, and calibration data taken with GPIES. With no human intervention, fully reduced and calibrated data products are available less than an hour after the data are taken to expedite follow up on potential objects of interest. The Data Cruncher can run on a supercomputer to reprocess all GPIES data in a single day as improvements are made to our DRPs. A backend MySQL database indexes all files, which are synced to the cloud, and a front-end web server allows for easy browsing of all files associated with GPIES. To help observers, quicklook displays show reduced data as they are processed in real time, and chatbots on Slack post observing information as well as reduced data products. Together, the GPIES automated data processing architecture reduces our workload, provides real-time data reduction, optimizes our observing strategy, and maintains a homogeneously reduced dataset to study planet occurrence and instrument performance. (c) 2018 Society of Photo-Optical Instrumentation Engineers (SPIE)
    • Automated Design of CubeSats using Evolutionary Algorithm for Trade Space Selection

      Kalita, Himangshu; Thangavelautham, Jekan; Univ Arizona, Aerosp & Mech Engn Dept, Space & Terr Robot Explorat SpaceTREx Lab (MDPI, 2020-09-28)
      The miniaturization of electronics, sensors, and actuators has enabled the growing use of nanosatellites for earth observation, astrophysics, and even interplanetary missions. This rise of nanosatellites has led to the development of an inventory of modular, interchangeable commercially-off-the-shelf (COTS) components by a multitude of commercial vendors. As a result, the capability of combining subsystems in a compact platform has considerably advanced in the last decade. However, to ascertain these spacecraft's maximum capabilities in terms of mass, volume, and power, there is an important need to optimize their design. Current spacecraft design methods need engineering experience and judgements made by of a team of experts, which can be labor intensive and might lead to a sub-optimal design. In this work we present a compelling alternative approach using machine learning to identify near-optimal solutions to extend the capabilities of a design team. The approach enables automated design of a spacecraft that requires developing a virtual warehouse of components and specifying quantitative goals to produce a candidate design. The near-optimal solutions found through this approach would be a credible starting point for the design team that will need further study to determine their implementation feasibility.
    • Automated digital TIL analysis (ADTA) adds prognostic value to standard assessment of depth and ulceration in primary melanoma

      Moore, Michael R.; Friesner, Isabel D.; Rizk, Emanuelle M.; Fullerton, Benjamin T.; Mondal, Manas; Trager, Megan H.; Mendelson, Karen; Chikeka, Ijeuru; Kurc, Tahsin; Gupta, Rajarsi; et al. (Nature Research, 2021-02-02)
      Accurate prognostic biomarkers in early-stage melanoma are urgently needed to stratify patients for clinical trials of adjuvant therapy. We applied a previously developed open source deep learning algorithm to detect tumor-infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) images of early-stage melanomas. We tested whether automated digital (TIL) analysis (ADTA) improved accuracy of prediction of disease specific survival (DSS) based on current pathology standards. ADTA was applied to a training cohort (n = 80) and a cutoff value was defined based on a Receiver Operating Curve. ADTA was then applied to a validation cohort (n = 145) and the previously determined cutoff value was used to stratify high and low risk patients, as demonstrated by Kaplan–Meier analysis (p ≤ 0.001). Multivariable Cox proportional hazards analysis was performed using ADTA, depth, and ulceration as co-variables and showed that ADTA contributed to DSS prediction (HR: 4.18, CI 1.51–11.58, p = 0.006). ADTA provides an effective and attainable assessment of TILs and should be further evaluated in larger studies for inclusion in staging algorithms. © 2021, The Author(s).
    • An automated imaging BRDF polarimeter for fruit quality inspection

      Boyer, Jacob; Keresztes, Janos C.; Saeys, Wouter; Koshel, John; Univ Arizona, Coll Opt Sci; College of Optical Sciences, The Univ. of Arizona (United States); KU Leuven (Belgium); KU Leuven (Belgium); College of Optical Sciences, The Univ. of Arizona (United States) (SPIE-INT SOC OPTICAL ENGINEERING, 2016-10-17)
      The purpose of this project was to test and implement recent research of polarization and scatter properties that suggest using a cross polarization imaging system to reduce glare artifacts. In particular, the use of this research is to improve the machine vision of apple quality detection in the food industry. The automated measurement system was implemented by acquiring pictures at different angles and different polarization states of apples. The opto-mechanics, system integration, synchronization and data collection are controlled with LabVIEW.
    • Automated Laboratory Growth Assessment and Maintenance of Azotobacter vinelandii

      Carruthers, B.M.; Garcia, A.K.; Rivier, A.; Kacar, B.; Department of Molecular and Cellular Biology, University of Arizona; Department of Astronomy and Steward Observatory, University of Arizona; Lunar and Planetary Laboratory, University of Arizona (Blackwell Publishing Inc., 2021)
      Azotobacter vinelandii (A. vinelandii) is a commonly used model organism for the study of aerobic respiration, the bacterial production of several industrially relevant compounds, and, perhaps most significantly, the genetics and biochemistry of biological nitrogen fixation. Laboratory growth assessments of A. vinelandii are useful for evaluating the impact of environmental and genetic modifications on physiological properties, including diazotrophy. However, researchers typically rely on manual growth methods that are oftentimes laborious and inefficient. We present a protocol for the automated growth assessment of A. vinelandii on a microplate reader, particularly well-suited for studies of diazotrophic growth. We discuss common pitfalls and strategies for protocol optimization, and demonstrate the protocol's application toward growth evaluation of strains carrying modifications to nitrogen-fixation genes. © 2021 The Authors. Basic Protocol 1: Preparation of A. vinelandii plate cultures from frozen stock. Basic Protocol 2: Preparation of A. vinelandii liquid precultures. Basic Protocol 3: Automated growth rate experiment of A. vinelandii on a microplate reader. © 2021 The Authors.
    • Automated microscope-independent fluorescence-guided micropipette

      Miranda, C.; Howell, M.R.; Lusk, J.F.; Marschall, E.; Eshima, J.; Anderson, T.; Smith, B.S.; University of Arizona, College of Medicine – Phoenix (The Optical Society, 2021)
      Glass micropipette electrodes are commonly used to provide high resolution recordings of neurons. Although it is the gold standard for single cell recordings, it is highly dependent on the skill of the electrophysiologist. Here, we demonstrate a method of guiding micropipette electrodes to neurons by collecting fluorescence at the aperture, using an intra-electrode tapered optical fiber. The use of a tapered fiber for excitation and collection of fluorescence at the micropipette tip couples the feedback mechanism directly to the distance between the target and electrode. In this study, intra-electrode tapered optical fibers provide a targeted robotic approach to labeled neurons that is independent of microscopy. © 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement
    • Automated thalamic nuclei segmentation using multi-planar cascaded convolutional neural networks

      Majdi, Mohammad S; Keerthivasan, Mahesh B; Rutt, Brian K; Zahr, Natalie M; Rodriguez, Jeffrey J; Saranathan, Manojkumar; Univ Arizona, Dept Elect & Comp Engn; Univ Arizona, Dept Med Imaging (ELSEVIER SCIENCE INC, 2020-08-21)
      Purpose: To develop a fast and accurate convolutional neural network based method for segmentation of thalamic nuclei. Methods: A cascaded multi-planar scheme with a modified residual U-Net architecture was used to segment thalamic nuclei on conventional and white-matter-nulled (WMn) magnetization prepared rapid gradient echo (MPRAGE) data. A single network was optimized to work with images from healthy controls and patients with multiple sclerosis (MS) and essential tremor (ET), acquired at both 3 T and 7 T field strengths. WMn-MPRAGE images were manually delineated by a trained neuroradiologist using the Morel histological atlas as a guide to generate reference ground truth labels. Dice similarity coefficient and volume similarity index (VSI) were used to evaluate performance. Clinical utility was demonstrated by applying this method to study the effect of MS on thalamic nuclei atrophy. Results: Segmentation of each thalamus into twelve nuclei was achieved in under a minute. For 7 T WMn-MPRAGE, the proposed method outperforms current state-of-the-art on patients with ET with statistically significant improvements in Dice for five nuclei (increase in the range of 0.05-0.18) and VSI for four nuclei (increase in the range of 0.05-0.19), while performing comparably for healthy and MS subjects. Dice and VSI achieved using 7 T WMn-MPRAGE data are comparable to those using 3 T WMn-MPRAGE data. For conventional MPRAGE, the proposed method shows a statistically significant Dice improvement in the range of 0.14-0.63 over FreeSurfer for all nuclei and disease types. Effect of noise on network performance shows robustness to images with SNR as low as half the baseline SNR. Atrophy of four thalamic nuclei and whole thalamus was observed for MS patients compared to healthy control subjects, after controlling for the effect of parallel imaging, intracranial volume, gender, and age (p < 0.004). Conclusion: The proposed segmentation method is fast, accurate, performs well across disease types and field strengths, and shows great potential for improving our understanding of thalamic nuclei involvement in neurological diseases.
    • Automatic Detection of Everyday Social Behaviours and Environments from Verbatim Transcripts of Daily Conversations

      Yordanova, Kristina Y.; Demiray, Burcu; Mehl, Matthias R.; Martin, Mike; Univ Arizona, Dept Psychol (IEEE, 2019-03)
      Coding in social sciences is a process that involves the categorisation of qualitative or quantitative data in order to facilitate further analysis. Coding is usually a manual process that involves a lot of effort and time to produce codes with high validity and interrater reliability. Although automated methods for quantitative data analysis are largely used in social sciences, there are only a few attempts at automatically or semi-automatically coding the data collected in qualitative studies. To address this problem, in this work we propose an approach for automated coding of social behaviours and environments based on verbatim transcriptions of everyday conversations. To evaluate the approach, we analysed the transcripts from three datasets containing recordings of everyday conversations from: (1) young healthy adults (German transcriptions), (2) elderly healthy adults (German transcriptions), and (3) young healthy adults (English transcriptions). The results show that it is possible to automatically code the social behaviours and environments based on verbatim transcripts of the recorded conversations. This could reduce the time and effort researchers need to assign accurate codes to transcribed conversations.
    • An automatic holographic adaptive phoropter

      Peyman, Gholam A.; Schwiegerling, Jim; Amirsolaimani, Babak; Bablumyan, Arkady; Savidis, Nickolaos; Peyghambarian, Nasser N.; Univ Arizona, Coll Opt Sci (SPIE-INT SOC OPTICAL ENGINEERING, 2017-08-29)
      Phoropters are the most common instrument used to detect refractive errors. During a refractive exam, lenses are flipped in front of the patient who looks at the eye chart and tries to read the symbols. The procedure is fully dependent on the cooperation of the patient to read the eye chart, provides only a subjective measurement of visual acuity, and can at best provide a rough estimate of the patient's vision. Phoropters are difficult to use for mass screenings requiring a skilled examiner, and it is hard to screen young children and the elderly etc. We have developed a simplified, lightweight automatic phoropter that can measure the optical error of the eye objectively without requiring the patient's input. The automatic holographic adaptive phoropter is based on a Shack-Hartmann wave front sensor and three computer-controlled fluidic lenses. The fluidic lens system is designed to be able to provide power and astigmatic corrections over a large range of corrections without the need for verbal feedback from the patient in less than 20 seconds.
    • Automatic segmentation, feature extraction and comparison of healthy and stroke cerebral vasculature

      Deshpande, Aditi; Jamilpour, Nima; Jiang, Bin; Michel, Patrik; Eskandari, Ashraf; Kidwell, Chelsea; Wintermark, Max; Laksari, Kaveh; Department of Bioengineering, University of Arizona; Department of Neurology, University of Arizona; et al. (Elsevier Inc., 2021-01-26)
      Accurate segmentation of cerebral vasculature and a quantitative assessment of its morphology is critical to various diagnostic and therapeutic purposes and is pertinent to studying brain health and disease. However, this is still a challenging task due to the complexity of the vascular imaging data. We propose an automated method for cerebral vascular segmentation without the need of any manual intervention as well as a method to skeletonize the binary segmented map to extract vascular geometric features and characterize vessel structure. We combine a Hessian-based probabilistic vessel-enhancing filtering with an active-contour-based technique to segment magnetic resonance and computed tomography angiograms (MRA and CTA) and subsequently extract the vessel centerlines and diameters to calculate the geometrical properties of the vasculature. Our method was validated using a 3D phantom of the Circle-of-Willis region, demonstrating 84% mean Dice similarity coefficient (DSC) and 85% mean Pearson's correlation coefficient (PCC) with minimal modified Hausdorff distance (MHD) error (3 surface pixels at most), and showed superior performance compared to existing segmentation algorithms upon quantitative comparison using DSC, PCC and MHD. We subsequently applied our algorithm to a dataset of 40 subjects, including 1) MRA scans of healthy subjects (n = 10, age = 30 ± 9), 2) MRA scans of stroke patients (n = 10, age = 51 ± 15), 3) CTA scans of healthy subjects (n = 10, age = 62 ± 12), and 4) CTA scans of stroke patients (n = 10, age = 68 ± 11), and obtained a quantitative comparison between the stroke and normal vasculature for both imaging modalities. The vascular network in stroke patients compared to age-adjusted healthy subjects was found to have a significantly (p < 0.05) higher tortuosity (3.24 ± 0.88 rad/cm vs. 7.17 ± 1.61 rad/cm for MRA, and 4.36 ± 1.32 rad/cm vs. 7.80 ± 0.92 rad/cm for CTA), higher fractal dimension (1.36 ± 0.28 vs. 1.71 ± 0.14 for MRA, and 1.56 ± 0.05 vs. 1.69 ± 0.20 for CTA), lower total length (3.46 ± 0.99 m vs. 2.20 ± 0.67 m for CTA), lower total volume (61.80 ± 18.79 ml vs. 34.43 ± 22.9 ml for CTA), lower average diameter (2.4 ± 0.21 mm vs. 2.18 ± 0.07 mm for CTA), and lower average branch length (4.81 ± 1.97 mm vs. 8.68 ± 2.03 mm for MRA), respectively. We additionally studied the change in vascular features with respect to aging and imaging modality. While we observed differences between features as a result of aging, statistical analysis did not show any significant differences, whereas we found that the number of branches were significantly different (p < 0.05) between the two imaging modalities (201 ± 73 for MRA vs. 189 ± 69 for CTA). Our segmentation and feature extraction algorithm can be applied on any imaging modality and can be used in the future to automatically obtain the 3D segmented vasculature for diagnosis and treatment planning as well as to study morphological changes due to stroke and other cerebrovascular diseases (CVD) in the clinic.
    • Automating Wavefront Parallelization for Sparse Matrix Computations

      Venkat, Anand; Mohammadi, Mahdi Soltan; Park, Jongsoo; Rong, Hongbo; Barik, Rajkishore; Strout, Michelle Mills; Hall, Mary; Univ Arizona, Dept Comp Sci (IEEE, 2016)
      This paper presents a compiler and runtime framework for parallelizing sparse matrix computations that have loop-carried dependences. Our approach automatically generates a runtime inspector to collect data dependence information and achieves wavefront parallelization of the computation, where iterations within a wavefront execute in parallel, and synchronization is required across wavefronts. A key contribution of this paper involves dependence simplification, which reduces the time and space overhead of the inspector. This is implemented within a polyhedral compiler framework, extended for sparse matrix codes. Results demonstrate the feasibility of using automatically-generated inspectors and executors to optimize ILU factorization and symmetric Gauss-Seidel relaxations, which are part of the Preconditioned Conjugate Gradient (PCG) computation. Our implementation achieves a median speedup of 2.97x on 12 cores over the reference sequential PCG implementation, significantly outperforms PCG parallelized using Intel's Math Kernel Library (MKL), and is within 6% of the median performance of manually-parallelized PCG.
    • Automation and control of the MMT thermal system

      Gibson, J. D.; Porter, Dallan; Goble, William; Univ Arizona, MMT Observ; MMT Observatory (United States); MMT Observatory (United States); MMT Observatory (United States) (SPIE-INT SOC OPTICAL ENGINEERING, 2016-07-26)
      This study investigates the software automation and control framework for the MMT thermal system. Thermal-related effects on observing and telescope behavior have been considered during the entire software development process. Regression analysis of telescope and observatory subsystem data is used to characterize and model these thermal-related effects. The regression models help predict expected changes in focus and overall astronomical seeing that result from temperature variations within the telescope structure, within the primary mirror glass, and between the primary mirror glass and adjacent air (i.e., mirror seeing). This discussion is followed by a description of ongoing upgrades to the heating, ventilation and air conditioning (HVAC) system and the associated software controls. The improvements of the MMT thermal system have two objectives: 1) to provide air conditioning capabilities for the MMT facilities, and 2) to modernize and enhance the primary mirror (M1) ventilation system. The HVAC upgrade necessitates changes to the automation and control of the M1 ventilation system. The revised control system must factor in the additional requirements of the HVAC system, while still optimizing performance of the M1 ventilation system and the M1's optical behavior. An industry-standard HVAC communication and networking protocol, BACnet (Building Automation and Control network), has been adopted. Integration of the BACnet protocol into the existing software framework at the MMT is discussed. Performance of the existing automated system is evaluated and a preliminary upgraded automated control system is presented. Finally, user interfaces to the new HVAC system are discussed.
    • Autonomous Detection of Particles and Tracks in Optical Images

      Liounis, Andrew J.; Small, Jeffrey L.; Swenson, Jason C.; Lyzhoft, Joshua R.; Ashman, Benjamin W.; Getzandanner, Kenneth M.; Moreau, Michael C.; Adam, Coralie D.; Leonard, Jason M.; Nelson, Derek S.; et al. (AMER GEOPHYSICAL UNION, 2020-08)
      When optical navigation images acquired by the OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) mission revealed the periodic ejection of particles from asteroid (101955) Bennu, it became a mission priority to quickly identify and track these objects for both spacecraft safety and scientific purposes. The large number of particles and the mission criticality rendered time-intensive manual inspection impractical. We present autonomous techniques for particle detection and tracking that were developed in response to the Bennu phenomenon but that have the capacity for general application to particles in motion about a celestial body. In an example OSIRIS-REx data set, our autonomous techniques identified 93.6% of real particle tracks and nearly doubled the number of tracks detected versus manual inspection alone.
    • Autophagic/lysosomal dysfunction in Alzheimer's disease

      Orr, Miranda; Oddo, Salvatore; Department of Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Banner Sun Health Research Institute and Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, 10515 W. Santa Fe Drive, Sun City, AZ 85351, USA (BioMed Central, 2013)
      Autophagy serves as the sole catabolic mechanism for degrading organelles and protein aggregates. Increasing evidence implicates autophagic dysfunction in Alzheimer's disease (AD) and other neurodegenerative diseases associated with protein misprocessing and accumulation. Under physiologic conditions, the autophagic/lysosomal system efficiently recycles organelles and substrate proteins. However, reduced autophagy function leads to the accumulation of proteins and autophagic and lysosomal vesicles. These vesicles contain toxic lysosomal hydrolases as well as the proper cellular machinery to generate amyloid-beta, the major component of AD plaques. Here, we provide an overview of current research focused on the relevance of autophagic/lysosomal dysfunction in AD pathogenesis as well as potential therapeutic targets aimed at restoring autophagic/lysosomal pathway function.
    • Autophagy and chloroplast-associated ubiquitination cooperate to manage oxidative damage and starvation responses

      Kikuchi, Yuta; Nakamura, Sakuya; Woodson, Jesse; Ishida, Hiroyuki; Ling, Qihua; Hidema, Jun; Jarvis, Paul; Hagihara, Shinya; Izumi, Masanori; Univ Arizona, Sch Plant Sci (American Society of Plant Biologists, 2020-08)
      Autophagy and the ubiquitin-proteasome system are the major degradation processes for intracellular components in eukaryotes. Although ubiquitination acts as a signal inducing organelle-targeting autophagy, the interaction between ubiquitination and autophagy in chloroplast turnover has not been addressed. In this study, we found that two chloroplast-associated E3 enzymes, SUPPRESSOR OF PPI1 LOCUS1 and PLANT U-BOX4 (PUB4), are not necessary for the induction of either piecemeal autophagy of chloroplast stroma or chlorophagy of whole damaged chloroplasts in Arabidopsis (Arabidopsis thaliana). Double mutations of an autophagy gene and PUB4 caused synergistic phenotypes relative to single mutations. The double mutants developed accelerated leaf chlorosis linked to the overaccumulation of reactive oxygen species during senescence and had reduced seed production. Biochemical detection of ubiquitinated proteins indicated that both autophagy and PUB4-associated ubiquitination contributed to protein degradation in the senescing leaves. Furthermore, the double mutants had enhanced susceptibility to carbon or nitrogen starvation relative to single mutants. Together, these results indicate that autophagy and chloroplast-associated E3s cooperate for protein turnover, management of reactive oxygen species accumulation, and adaptation to starvation.
    • Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma

      Haas, Naomi B; Appleman, Leonard J; Stein, Mark; Redlinger, Maryann; Wilks, Melissa; Xu, Xiaowei; Onorati, Angelique; Kalavacharla, Anusha; Kim, Taehyong; Zhen, Chao Jie; et al. (AMER ASSOC CANCER RESEARCH, 2019-04-01)
      Purpose: Everolimus inhibits the mTOR, activating cytoprotective autophagy. Hydroxychloroquine inhibits autophagy. On the basis of preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and hydroxychloroquine, to determine its safety and activity in patients with clear-cell renal cell carcinoma (ccRCC). Patients and Methods: Three centers conducted a phase I/II trial of everolimus 10 mg daily and hydroxychloroquine in patients with advanced ccRCC. The objectives were to determine the MTD of hydroxychloroquine with daily everolimus, and to estimate the rate of 6-month progression-free survival (PFS) in patients with ccRCC receiving everolimus/hydroxychloroquine after 1-3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy, and next-generation tumor sequencing. Results: No dose-limiting toxicity was observed in the phase I trial. The recommended phase II dose of hydroxychloroquine 600 mg twice daily with everolimus was identified. Disease control [stable disease thorn partial response (PR)] occurred in 22 of 33 (67%) evaluable patients. PR was observed in 2 of 33 patients (6%). PFS >= 6 months was achieved in 15 of 33 (45%) of patients who achieved disease control. Conclusions: Combined hydroxychloroquine 600 mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6-month PFS rate was met. Hydroxychloroquine is a tolerable autophagy inhibitor in future RCC or other trials.
    • An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

      Ferdinandusse, Sacha; McWalter, Kirsty; te Brinke, Heleen; IJlst, Lodewijk; Mooijer, Petra M.; Ruiter, Jos P. N.; van Lint, Alida E. M.; Pras-Raves, Mia; Wever, Eric; Millan, Francisca; et al. (Springer Science and Business Media LLC, 2020-11-26)
      Purpose: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). Methods: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients’ fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. Results: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients’ fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. Conclusion: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts. © 2020, The Author(s).