Publications by authors named "Scott Wood"

135 Publications

Longitudinal MRI-visible perivascular space (PVS) changes with long-duration spaceflight.

Sci Rep 2022 May 5;12(1):7238. Epub 2022 May 5.

Division of Child Neurology, Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health and Science University, 707 SW Gaines St., CDRC-P, Portland, OR, 97239, USA.

Humans are exposed to extreme environmental stressors during spaceflight and return with alterations in brain structure and shifts in intracranial fluids. To date, no studies have evaluated the effects of spaceflight on perivascular spaces (PVSs) within the brain, which are believed to facilitate fluid drainage and brain homeostasis. Here, we examined how the number and morphology of magnetic resonance imaging (MRI)-visible PVSs are affected by spaceflight, including prior spaceflight experience. Fifteen astronauts underwent six T-weighted 3 T MRI scans, twice prior to launch and four times following their return to Earth after ~ 6-month missions to the International Space Station. White matter MRI-visible PVS number and morphology were calculated using an established, automated segmentation algorithm. We validated our automated segmentation algorithm by comparing algorithm PVS counts with those identified by two trained raters in 50 randomly selected slices from this cohort; the automated algorithm performed similarly to visual ratings (r(48) = 0.77, p < 0.001). In addition, we found high reliability for four of five PVS metrics across the two pre-flight time points and across the four control time points (ICC(3,k) > 0.50). Among the astronaut cohort, we found that novice astronauts showed an increase in total PVS volume from pre- to post-flight, whereas experienced crewmembers did not (p = 0.020), suggesting that experienced astronauts may exhibit holdover effects from prior spaceflight(s). Greater pre-flight PVS load was associated with more prior flight experience (r = 0.60-0.71), though these relationships did not reach statistical significance (p > 0.05). Pre- to post-flight changes in ventricular volume were not significantly associated with changes in PVS characteristics, and the presence of spaceflight associated neuro-ocular syndrome (SANS) was not associated with PVS number or morphology. Together, these findings demonstrate that PVSs can be consistently identified on T-weighted MRI scans, and that spaceflight is associated with PVS changes. Specifically, prior spaceflight experience may be an important factor in determining PVS characteristics.
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http://dx.doi.org/10.1038/s41598-022-11593-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072425PMC
May 2022

Cortical thickness of primary motor and vestibular brain regions predicts recovery from fall and balance directly after spaceflight.

Brain Struct Funct 2022 Apr 25. Epub 2022 Apr 25.

National Aeronautics and Space Administration Johnson Space Center, Houston, TX, USA.

Motor adaptations to the microgravity environment during spaceflight allow astronauts to perform adequately in this unique environment. Upon return to Earth, this adaptation is no longer appropriate and can be disruptive for mission critical tasks. Here, we measured if metrics derived from MRI scans collected from astronauts can predict motor performance post-flight. Structural and diffusion MRI scans from 14 astronauts collected before launch, and motor measures (balance performance, speed of recovery from fall, and tandem walk step accuracy) collected pre-flight and post-flight were analyzed. Regional measures of gray matter volume (motor cortex, paracentral lobule, cerebellum), myelin density (motor cortex, paracentral lobule, corticospinal tract), and white matter microstructure (corticospinal tract) were derived as a-priori predictors. Additional whole-brain analyses of cortical thickness, cerebellar gray matter, and cortical myelin were also tested for associations with post-flight and pre-to-post-flight motor performance. The pre-selected regional measures were not significantly associated with motor behavior. However, whole-brain analyses showed that paracentral and precentral gyri thickness significantly predicted recovery from fall post-spaceflight. Thickness of vestibular and sensorimotor regions, including the posterior insula and the superior temporal gyrus, predicted balance performance post-flight and pre-to-post-flight decrements. Greater cortical thickness pre-flight predicted better performance post-flight. Regional thickness of somatosensory, motor, and vestibular brain regions has some predictive value for post-flight motor performance in astronauts, which may be used for the identification of training and countermeasure strategies targeted for maintaining operational task performance.
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http://dx.doi.org/10.1007/s00429-022-02492-zDOI Listing
April 2022

The Effects of 30 Minutes of Artificial Gravity on Cognitive and Sensorimotor Performance in a Spaceflight Analog Environment.

Front Neural Circuits 2022 2;16:784280. Epub 2022 Mar 2.

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United States.

The altered vestibular signaling and somatosensory unloading of microgravity result in sensory reweighting and adaptation to conflicting sensory inputs. Aftereffects of these adaptive changes are evident postflight as impairments in behaviors such as balance and gait. Microgravity also induces fluid shifts toward the head and an upward shift of the brain within the skull; these changes are well-replicated in strict head-down tilt bed rest (HDBR), a spaceflight analog environment. Artificial gravity (AG) is a potential countermeasure to mitigate these effects of microgravity. A previous study demonstrated that intermittent (six, 5-mins bouts per day) daily AG sessions were more efficacious at counteracting orthostatic intolerance in a 5 day HDBR study than continuous daily AG. Here we examined whether intermittent daily AG was also more effective than continuous dosing for mitigating brain and behavioral changes in response to 60 days of HDBR. Participants ( = 24) were split evenly between three groups. The first received 30 mins of continuous AG daily (cAG). The second received 30 mins of intermittent AG daily (6 bouts of 5 mins; iAG). The third received no AG (Ctrl). We collected a broad range of sensorimotor, cognitive, and brain structural and functional assessments before, during, and after the 60 days of HDBR. We observed no significant differences between the three groups in terms of HDBR-associated changes in cognition, balance, and functional mobility. Interestingly, the intermittent AG group reported less severe motion sickness symptoms than the continuous group during centrifugation; iAG motion sickness levels were not elevated above those of controls who did not undergo AG. They also had a shorter duration of post-AG illusory motion than cAG. Moreover, the two AG groups performed the paced auditory serial addition test weekly while undergoing AG; their performance was more accurate than that of controls, who performed the test while in HDBR. Although AG did not counteract HDBR-induced gait and balance declines, iAG did not cause motion sickness and was associated with better self-motion perception during AG ramp-down. Additionally, both AG groups had superior cognitive performance while undergoing AG relative to controls; this may reflect attention or motivation differences between the groups.
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http://dx.doi.org/10.3389/fncir.2022.784280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924040PMC
April 2022

Public health primary prevention implemented by clinical high-risk services for psychosis.

Transl Psychiatry 2022 01 28;12(1):43. Epub 2022 Jan 28.

Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Clinical High Risk for Psychosis (CHR-P) services have been primarily developed to support young people with attenuated symptoms (indicated prevention). No evidence-based appraisal has systematically investigated to what extent these clinics may implement other preventive approaches. PRISMA 2020-compliant systematic review of Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO, from inception until 14th June 2021, identifying original studies describing public health strategies: (a) service characteristics (configuration of mental health service, outreach, pathways to care); (b) universal interventions (general population); (c) selective interventions targeting CHR-P service-users or family/carers. Public health preventive initiatives were systematically stratified according to core social determinants of mental disorders associated with the 2030 Sustainable Development Goals promoted by the United Nations Member States (UN 2030 SDG) and good mental health outcomes. A total of 66 publications were included, providing data on 13 standalone, 40 integrated, three networks, and six regional or international surveys of CHR-P services across Europe, Asia, Oceania, Africa, North and South America, providing care to >28 M people. CHR-P services implement numerous public health initiatives targeting social and cultural (16 initiatives), economic (seven initiatives), demographic (six initiatives), environmental events (four initiatives) and neighbourhood (three initiatives) UN 2030 SGD determinants of mental disorders. There is additional evidence for CHR-P services promoting good mental health. The main barriers were the lack of resources for expanding public health prevention at a large scale. CHR-P services implement numerous public health prevention initiatives and promotion of good mental health beyond indicated prevention of psychosis.
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http://dx.doi.org/10.1038/s41398-022-01805-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8799684PMC
January 2022

Effects of motion paradigm on human perception of tilt and translation.

Sci Rep 2022 01 26;12(1):1430. Epub 2022 Jan 26.

NASA Neuroscience Laboratory, Johnson Space Center, Houston, TX, USA.

The effect of varying sinusoidal linear acceleration on perception of human motion was examined using 4 motion paradigms: off-vertical axis rotation, variable radius centrifugation, linear lateral translation, and rotation about an earth-horizontal axis. The motion profiles for each paradigm included 6 frequencies (0.01-0.6 Hz) and 5 tilt amplitudes (5°-20°). Subjects verbally reported the perceived angle of their whole-body tilt and the peak-to-peak translation of their head in space and used a joystick capable of recording 2-axis motion in the sagittal and transversal planes to indicate the phase between the perceived and actual motions. The amplitudes of perceived tilt and translation were expressed in terms of gain, i.e., the ratio of perceived tilt to equivalent tilt angle, and the ratio of perceived translation to equivalent linear displacement. Tilt perception gain decreased, whereas translation perception gain increased, with increasing frequency. During off-vertical axis rotation, the phase of tilt perception and of translation perception did not vary across stimulus frequencies. These motion paradigms elicited similar responses in roll tilt and interaural perception of translation, with differences likely due to the influence of naso-occipital linear accelerations and input to the semicircular canals that varied across motion paradigms.
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http://dx.doi.org/10.1038/s41598-022-05483-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792002PMC
January 2022

Case Report: No Evidence of Intracranial Fluid Shifts in an Astronaut Following an Aborted Launch.

Front Neurol 2021 9;12:774805. Epub 2021 Dec 9.

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United States.

Spaceflight induces lasting enlargement of the brain's ventricles as well as intracranial fluid shifts. These intracranial fluid shifts have been attributed to prolonged microgravity exposure, however, the potential effects of hypergravity exposure during launch and landing have yet to be elucidated. Here we describe a case report of a Crewmember who experienced an Aborted Launch ("CAL"). CAL's launch and landing experience was dissociated from prolonged microgravity exposure. Using MRI, we show that hypergravity exposure during the aborted launch did not induce lasting ventricular enlargement or intracranial fluid shifts resembling those previously reported with spaceflight. This case study therefore rules out hypergravity during launch and landing as a contributing factor to previously reported long-lasting intracranial fluid changes following spaceflight.
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http://dx.doi.org/10.3389/fneur.2021.774805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8695608PMC
December 2021

Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance.

Cancer Cell 2022 01 23;40(1):88-102.e7. Epub 2021 Dec 23.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia; Mater Hospital, Sydney, NSW 2060, Australia. Electronic address:

We concurrently examine the whole genome, transcriptome, methylome, and immune cell infiltrates in baseline tumors from 77 patients with advanced cutaneous melanoma treated with anti-PD-1 with or without anti-CTLA-4. We show that high tumor mutation burden (TMB), neoantigen load, expression of IFNγ-related genes, programmed death ligand expression, low PSMB8 methylation (therefore high expression), and T cells in the tumor microenvironment are associated with response to immunotherapy. No specific mutation correlates with therapy response. A multivariable model combining the TMB and IFNγ-related gene expression robustly predicts response (89% sensitivity, 53% specificity, area under the curve [AUC], 0.84); tumors with high TMB and a high IFNγ signature show the best response to immunotherapy. This model validates in an independent cohort (80% sensitivity, 59% specificity, AUC, 0.79). Except for a JAK3 loss-of-function mutation, for patients who did not respond as predicted there is no obvious biological mechanism that clearly explained their outlier status, consistent with intratumor and intertumor heterogeneity in response to immunotherapy.
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http://dx.doi.org/10.1016/j.ccell.2021.11.012DOI Listing
January 2022

The Effects of Long Duration Spaceflight on Sensorimotor Control and Cognition.

Front Neural Circuits 2021 26;15:723504. Epub 2021 Oct 26.

Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, United States.

Astronauts returning from spaceflight typically show transient declines in mobility and balance. Other sensorimotor behaviors and cognitive function have not been investigated as much. Here, we tested whether spaceflight affects performance on various sensorimotor and cognitive tasks during and after missions to the International Space Station (ISS). We obtained mobility (Functional Mobility Test), balance (Sensory Organization Test-5), bimanual coordination (bimanual Purdue Pegboard), cognitive-motor dual-tasking and various other cognitive measures (Digit Symbol Substitution Test, Cube Rotation, Card Rotation, Rod and Frame Test) before, during and after 15 astronauts completed 6 month missions aboard the ISS. We used linear mixed effect models to analyze performance changes due to entering the microgravity environment, behavioral adaptations aboard the ISS and subsequent recovery from microgravity. We observed declines in mobility and balance from pre- to post-flight, suggesting disruption and/or down weighting of vestibular inputs; these behaviors recovered to baseline levels within 30 days post-flight. We also identified bimanual coordination declines from pre- to post-flight and recovery to baseline levels within 30 days post-flight. There were no changes in dual-task performance during or following spaceflight. Cube rotation response time significantly improved from pre- to post-flight, suggestive of practice effects. There was also a trend for better in-flight cube rotation performance on the ISS when crewmembers had their feet in foot loops on the "floor" throughout the task. This suggests that tactile inputs to the foot sole aided orientation. Overall, these results suggest that sensory reweighting due to the microgravity environment of spaceflight affected sensorimotor performance, while cognitive performance was maintained. A shift from exocentric (gravity) spatial references on Earth toward an egocentric spatial reference may also occur aboard the ISS. Upon return to Earth, microgravity adaptions become maladaptive for certain postural tasks, resulting in transient sensorimotor performance declines that recover within 30 days.
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http://dx.doi.org/10.3389/fncir.2021.723504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577506PMC
January 2022

Developing Proprioceptive Countermeasures to Mitigate Postural and Locomotor Control Deficits After Long-Duration Spaceflight.

Front Syst Neurosci 2021 27;15:658985. Epub 2021 Apr 27.

NASA Johnson Space Center, Houston, TX, United States.

Astronauts experience post-flight disturbances in postural and locomotor control due to sensorimotor adaptations during spaceflight. These alterations may have adverse consequences if a rapid egress is required after landing. Although current exercise protocols can effectively mitigate cardiovascular and muscular deconditioning, the benefits to post-flight sensorimotor dysfunction are limited. Furthermore, some exercise capabilities like treadmill running are currently not feasible on exploration spaceflight vehicles. Thus, new in-flight operational countermeasures are needed to mitigate postural and locomotor control deficits after exploration missions. Data from spaceflight and from analog studies collectively suggest that body unloading decreases the utilization of proprioceptive input, and this adaptation strongly contributes to balance dysfunction after spaceflight. For example, on return to Earth, an astronaut's vestibular input may be compromised by adaptation to microgravity, but their proprioceptive input is compromised by body unloading. Since proprioceptive and tactile input are important for maintaining postural control, keeping these systems tuned to respond to upright balance challenges during flight may improve functional task performance after flight through dynamic reweighting of sensory input. Novel approaches are needed to compensate for the challenges of balance training in microgravity and must be tested in a body unloading environment such as head down bed rest. Here, we review insights from the literature and provide observations from our laboratory that could inform the development of an in-flight proprioceptive countermeasure.
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http://dx.doi.org/10.3389/fnsys.2021.658985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111171PMC
April 2021

Deciphering the mechanisms of CC-122 resistance in DLBCL via a genome-wide CRISPR screen.

Blood Adv 2021 04;5(7):2027-2039

Bristol Myers Squibb, San Diego, CA.

CC-122 is a next-generation cereblon E3 ligase-modulating agent that has demonstrated promising clinical efficacy in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). Mechanistically, CC-122 induces the degradation of IKZF1/3, leading to T-cell activation and robust cell-autonomous killing in DLBCL. We report a genome-wide CRISPR/Cas9 screening for CC-122 in a DLBCL cell line SU-DHL-4 with follow-up mechanistic characterization in 6 DLBCL cell lines to identify genes regulating the response to CC-122. Top-ranked CC-122 resistance genes encode, not only well-defined members or regulators of the CUL4/DDB1/RBX1/CRBN E3 ubiquitin ligase complex, but also key components of signaling and transcriptional networks that have not been shown to modulate the response to cereblon modulators. Ablation of CYLD, NFKBIA, TRAF2, or TRAF3 induces hyperactivation of the canonical and/or noncanonical NF-κB pathways and subsequently diminishes CC-122-induced apoptosis in 5 of 6 DLBCL cell lines. Depletion of KCTD5, the substrate adaptor of the CUL3/RBX1/KCTD5 ubiquitin ligase complex, promotes the stabilization of its cognate substrate, GNG5, resulting in CC-122 resistance in HT, SU-DHL-4, and WSU-DLCL2. Furthermore, knockout of AMBRA1 renders resistance to CC-122 in SU-DHL-4 and U-2932, whereas knockout of RFX7 leads to resistance specifically in SU-DHL-4. The ubiquitous and cell line-specific mechanisms of CC-122 resistance in DLBCL cell lines revealed in this work pinpoint genetic alternations that are potentially associated with clinical resistance in patients and facilitate the development of biomarker strategies for patient stratification, which may improve clinical outcomes of patients with R/R DLBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020003431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045513PMC
April 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 02 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Age Differences in Vestibular Brain Connectivity Are Associated With Balance Performance.

Front Aging Neurosci 2020 16;12:566331. Epub 2020 Nov 16.

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United States.

Visual and auditory brain network connectivity decline with age, but less is known about age effects on vestibular functional connectivity and its association with behavior. We assessed age differences in the connectivity of the vestibular cortex with other sensory brain regions, both during rest and during vestibular stimulation. We then assessed the relationship between vestibular connectivity and postural stability. A sample of seventeen young and fifteen older adults participated in our study. We assessed the amount of body sway in performing the Romberg balance task, with degraded somatosensory and visual inputs. The results showed no significant difference in balance performance between age groups. However, functional connectivity analyses revealed a main effect of age and condition, suggesting that vestibular connectivity was higher in young adults than older adults, and vestibular connectivity increased from resting state to stimulation trials. Surprisingly, young adults who exhibited higher connectivity during stimulation also had greater body sway. This suggests that young adults who exhibit better balance are those who respond more selectively to vestibular inputs. This correlation is non-significant in older adults, suggesting that the relationship between vestibular functional connectivity and postural stability differs with age.
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http://dx.doi.org/10.3389/fnagi.2020.566331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703342PMC
November 2020

Exercise-Induced Abnormalities of Regional Myocardial Deformation in Anomalous Aortic Origin of the Right Coronary Artery.

World J Pediatr Congenit Heart Surg 2020 11;11(6):712-719

Division of Pediatric Cardiology, Department of Pediatrics, 1500Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Aims: Congenital coronary artery anomalies are uncommon and may result in sudden death. Management of asymptomatic patients with anomalous aortic origin of the right coronary artery (AAORCA) remains controversial with a lack of evidence to guide decision-making. We hypothesized that patients with AAORCA may have exercise-inducible ischemia detectable as abnormalities in regional myocardial deformation on exercise stress echocardiography (ESE).

Methods: We reviewed clinical data, computed tomography angiography, and treadmill ESE from 33 AAORCA patients (21 unoperated, 12 operated) and 11 controls. Regional wall motion on ESE was visually assessed. Doppler tissue imaging was done pre and post exercise to evaluate regional myocardial wall deformation. The post- to pre-exercise time to peak systolic strain corrected for heart rate ratio (TPScR) for the left ventricular inferior and anterior walls of AAORCA patients was compared to controls.

Results: No regional wall motion abnormalities were noted. The TPScR of the inferior wall was higher in unoperated (0.96 ± 0.41) but not operated (0.84 ± 0.28) AAORCA patients compared to controls (0.76 ± 0.18, = .03 vs .23, respectively). There was no significant difference in TPScR of the anterior wall between unoperated patients and controls ( = .08).

Conclusion: In some AAORCA patients undergoing ESE, TPScR of the left ventricular inferior wall is elevated, suggestive of ischemia induced by exercise in myocardium supplied by the right coronary artery. Further work is needed to understand the potential role of this finding in risk assessment.
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http://dx.doi.org/10.1177/2150135120947689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006085PMC
November 2020

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients.

Sci Rep 2020 10 19;10(1):17687. Epub 2020 Oct 19.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.

Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72-15.7). Stage IV (HR 2.5, 0.74-8.6) and low TMB (HR 2.3, 0.57-9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44-5.2).
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http://dx.doi.org/10.1038/s41598-020-74956-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572377PMC
October 2020

Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity.

Nat Commun 2020 10 16;11(1):5259. Epub 2020 Oct 16.

Center for Rare Melanomas, University of Colorado Cancer Center, Aurora, Colorado, USA.

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.
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http://dx.doi.org/10.1038/s41467-020-18988-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567804PMC
October 2020

Transcriptome dynamics of CD4 T cells during malaria maps gradual transit from effector to memory.

Nat Immunol 2020 12 12;21(12):1597-1610. Epub 2020 Oct 12.

QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.

The dynamics of CD4 T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4 T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (T1) and follicular helper T (T) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T1 and T trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between T and central memory were revealed, with antimalarials modulating these responses and boosting T1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4 T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations ( http://haquelab.mdhs.unimelb.edu.au/cd4_memory/ ).
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http://dx.doi.org/10.1038/s41590-020-0800-8DOI Listing
December 2020

The Impact of 6 and 12 Months in Space on Human Brain Structure and Intracranial Fluid Shifts.

Cereb Cortex Commun 2020 15;1(1):tgaa023. Epub 2020 Jun 15.

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32608, USA.

As plans develop for Mars missions, it is important to understand how long-duration spaceflight impacts brain health. Here we report how 12-month ( = 2 astronauts) versus 6-month ( = 10 astronauts) missions impact brain structure and fluid shifts. We collected MRI scans once before flight and four times after flight. Astronauts served as their own controls; we evaluated pre- to postflight changes and return toward preflight levels across the 4 postflight points. We also provide data to illustrate typical brain changes over 7 years in a reference dataset. Twelve months in space generally resulted in larger changes across multiple brain areas compared with 6-month missions and aging, particularly for fluid shifts. The majority of changes returned to preflight levels by 6 months after flight. Ventricular volume substantially increased for 1 of the 12-month astronauts (left: +25%, right: +23%) and the 6-month astronauts (left: 17 ± 12%, right: 24 ± 6%) and exhibited little recovery at 6 months. Several changes correlated with past flight experience; those with less time between subsequent missions had larger preflight ventricles and smaller ventricular volume increases with flight. This suggests that spaceflight-induced ventricular changes may endure for long periods after flight. These results provide insight into brain changes that occur with long-duration spaceflight and demonstrate the need for closer study of fluid shifts.
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http://dx.doi.org/10.1093/texcom/tgaa023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446230PMC
June 2020

Using whole-genome sequencing data to derive the homologous recombination deficiency scores.

NPJ Breast Cancer 2020 7;6:33. Epub 2020 Aug 7.

Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD Australia.

The homologous recombination deficiency (HRD) score was developed using whole-genome copy number data derived from arrays as a way to infer deficiency in the homologous recombination DNA damage repair pathway (in particular or deficiency) in breast cancer samples. The score has utility in understanding tumour biology and may be indicative of response to certain therapeutic strategies. Studies have used whole-exome sequencing to derive the HRD score, however, with increasing use of whole-genome sequencing (WGS) to characterise tumour genomes, there has yet to be a comprehensive comparison between HRD scores derived by array versus WGS. Here we demonstrate that there is both a high correlation and a good agreement between array- and WGS-derived HRD scores and between the scores derived from WGS and downsampled WGS to represent shallow WGS. For samples with an HRD score close to threshold for stratifying HR proficiency or deficiency there was however some disagreement in the HR status between array and WGS data, highlighting the importance of not relying on a single method of ascertaining the homologous recombination status of a tumour.
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http://dx.doi.org/10.1038/s41523-020-0172-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414867PMC
August 2020

Vestibular and Cardiovascular Responses After Long-Duration Spaceflight.

Aerosp Med Hum Perform 2020 Aug;91(8):621-627

The vestibulo-sympathetic reflex operates during orthostatically challenging movements to initiate cardiovascular responses in advance of a baroreceptor-mediated response. The objective of this study was to determine whether there was an association between changes in vestibular function and cardiovascular responses during a prone-to-stand movement in astronauts after return from long-duration spaceflight. Thirteen crewmembers who participated in International Space Station missions were tested before spaceflight and 1 d after landing. Vestibular function was evaluated by computerized dynamic posturography while their head was erect and while they performed dynamic head tilts. Heart rate and mean arterial blood pressure were measured while the subjects were in prone and standing positions. The 21.4% increase in the astronauts' heart rate during the prone to stand maneuver after spaceflight correlated significantly with their spaceflight-induced 48.7% decrease in postural stability during dynamic head tilts. The larger mean arterial pressure in the prone position after spaceflight compared to preflight (+7%) also correlated with the postflight decrease in postural stability during dynamic head tilts. These results indicate that an appropriate vestibular function is important to evoke optimum vestibulo-sympathetic response during orthostatically challenging voluntary movements performed after spaceflight. They also suggest that there may be a greater need to generate an anticipatory cardiovascular response after spaceflight.
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http://dx.doi.org/10.3357/AMHP.5502.2020DOI Listing
August 2020

User Experience Theories, Models, and Frameworks: A Focused Review of the Healthcare Literature.

Stud Health Technol Inform 2020 Jun;270:1076-1080

Office of Human Factors and Ergonomics, Veterans Health Affairs, USA.

User experience (UX) theories, models, and frameworks (TMFs) help scope user-centered design activities, aid in the selection of constructs and measures, and contextualize findings within a larger knowledge base. However, the fragmentation of literature across disciplines and the inconsistent use of TMFs makes integrating concepts and selecting UX tools challenging. Therefore, we conducted a focused review of the healthcare literature to identify a succinct list of UX-specific TMFs for academic UX researchers and industry practitioners alike.
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http://dx.doi.org/10.3233/SHTI200327DOI Listing
June 2020

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours.

Nat Commun 2020 05 15;11(1):2408. Epub 2020 May 15.

QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).
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http://dx.doi.org/10.1038/s41467-020-16276-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229209PMC
May 2020

Micropatterned Biphasic Nanocomposite Platform for Maintaining Chondrocyte Morphology.

ACS Appl Mater Interfaces 2020 Apr 23;12(13):14814-14824. Epub 2020 Mar 23.

Nanoscience and Nanoengineering, South Dakota School of Mines & Technology, 501 E St Joseph St, Rapid City, South Dakota 57701, United States.

One major limitation hindering the translation of in vitro osteoarthritis research into clinical disease-modifying therapies is that chondrocytes rapidly spread and dedifferentiate under standard monolayer conditions. Current strategies to maintain rounded morphologies of chondrocytes in culture either unnaturally restrict adhesion and place chondrocytes in an excessively stiff mechanical environment or are impractical for use in many applications. To address the limitations of current techniques, we have developed a unique composite thin-film cell culture platform, the CellWell, to model articular cartilage that utilizes micropatterned hemispheroidal wells, precisely sized to fit individual cells (12-18 μm diameters), to promote physiologically spheroidal chondrocyte morphologies while maintaining compatibility with standard cell culture and analytical techniques. CellWells were constructed of 15-μm-thick 5% agarose films embedded with electrospun poly(vinyl alcohol) (PVA) nanofibers. Transmission electron microscope (TEM) images of PVA nanofibers revealed a mean diameter of 60.9 ± 24 nm, closely matching the observed 53.8 ± 29 nm mean diameter of human ankle collagen II fibers. Using AFM nanoindentation, CellWells were found to have compressive moduli of 158 ± 0.60 kPa at 15 μm/s indentation, closely matching published stiffness values of the native pericellular matrix. Primary human articular chondrocytes taken from ankle cartilage were seeded in CellWells and assessed at 24 h. Chondrocytes maintained their rounded morphology in CellWells (mean aspect ratio of 0.87 ± 0.1 vs three-dimensional (3D) control [0.86 ± 0.1]) more effectively than those seeded under standard conditions (0.65 ± 0.3), with average viability of >85%. The CellWell's design, with open, hemispheroidal wells in a thin film substrate of physiological stiffness, combines the practical advantages of two-dimensional (2D) culture systems with the physiological advantages of 3D systems. Through its ease of use and ability to maintain the physiological morphology of chondrocytes, we expect that the CellWell will enhance the clinical translatability of future studies conducted using this culture platform.
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http://dx.doi.org/10.1021/acsami.9b22596DOI Listing
April 2020

kinase negatively regulates regenerative neurogenesis in planarians.

Elife 2020 01 20;9. Epub 2020 Jan 20.

Department of Molecular Biosciences, Northwestern University, Evanston, United States.

Negative regulators of adult neurogenesis are of particular interest as targets to enhance neuronal repair, but few have yet been identified. Planarians can regenerate their entire CNS using pluripotent adult stem cells, and this process is robustly regulated to ensure that new neurons are produced in proper abundance. Using a high-throughput pipeline to quantify brain chemosensory neurons, we identify the conserved tyrosine kinase as a negative regulator of planarian neuronal regeneration. RNAi increased the abundance of several CNS and PNS neuron subtypes regenerated or maintained through homeostasis, without affecting body patterning or non-neural cells. Experiments using TUNEL, BrdU, progenitor labeling, and stem cell elimination during regeneration indicate limits the survival of newly differentiated neurons. In vertebrates, the Tec kinase family has been studied extensively for roles in immune function, and our results identify a novel role for as negative regulator of planarian adult neurogenesis.
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http://dx.doi.org/10.7554/eLife.47293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970515PMC
January 2020

RELIABILITY of a MOVEMENT QUALITY ASSESSMENT TOOL to GUIDE EXERCISE PRESCRIPTION (MOVEMENTSCREEN).

Int J Sports Phys Ther 2019 Jun;14(3):424-435

Alliance for Research in Exercise, Nutrition and Activity, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.

Background/purpose: Movement quality is commonly assessed to identify movement limitations and guide exercise prescription. Rapid growth in the movement assessment landscape has led to the development and utilization of various movement quality assessments, many without reliability estimates. MovementSCREEN is a novel, tablet-based, video-recorded movement assessment tool, currently without published reliability information. Therefore, the purpose of this study was to determine the intra and inter-rater reliability of the MovementSCREEN, including the impact of rater experience, and provide estimates of measurement error and minimal detectable change.

Study Design: Cross-sectional design; reliability study.

Methods: Thirty healthy young adults (14M:16F, mean age 28.4 yrs, SD 9.1) were video recorded completing the nine MovementSCREEN assessment items on two occasions, two weeks apart. Each individual movement was assessed against objective scoring criteria (component items: yes/no) and using a 100-point sliding scale. To create an overall score for each movement, the scale score is weighted against the objective items to provide a score out of 100. At the completion of all nine individual movements, a mean composite score of movement quality is also established (0-100). The first recording was scored twice by two expert and two novice assessors to investigate inter- and intra-rater reliability. The second recording was scored by one expert assessor to investigate within-subject error. Inter- and intra-rater reliability was calculated using intraclass correlation coefficients (ICCs) and Kappa statistics. The standard error of measurement (SEM), and minimal detectable change (MDC) for the overall score for each movement, and the composite score of movement quality, were calculated.

Results: Intra-rater reliability for the component items ranged from κ = 0.619 - 1.000 (substantial to near perfect agreement) and 0.233 - 1.000 (slight to near perfect agreement) for expert and novice assessors, respectively. The ICCs for the overall movement quality scores for each individual movement ranged from 0.707 - 0.952 (fair to high) in expert and 0.502 - 0.958 (poor to high) in novice assessors. Inter-rater agreement for the component items between expert assessors ranged from κ = 0.242 - 1.000 (slight to almost perfect agreement), while for novice assessors ranged from 0.103 - 1.000 (less than chance to almost perfect agreement). ICCs for the overall scores for each individual movement from expert and novice assessors ranged from 0.294 - 0.851 (poor to good) and 0.249 - 0.775 (poor to fair), respectively. The SEM for the composite score was 2 points, while the MDC was 6 points, with an ICC 0.901.

Conclusions: The MovementSCREEN can assess movement quality with fair to high reliability on a test-retest basis when used by experienced assessors, although reliability scores decrease in novice assessors. Comparisons between assessors involve greater error. Therefore, the training of inexperienced assessors is recommended to improve reliability.

Level Of Evidence: 2b.
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http://dx.doi.org/10.26603/ijspt20190424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816299PMC
June 2019

Deactivation of somatosensory and visual cortices during vestibular stimulation is associated with older age and poorer balance.

PLoS One 2019 12;14(9):e0221954. Epub 2019 Sep 12.

Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, United States of America.

Aging is associated with peripheral and central declines in vestibular processing and postural control. Here we used functional MRI to investigate age differences in neural vestibular representations in response to pneumatic tap stimulation. We also measured the amount of body sway in multiple balance tasks outside of the MRI scanner to assess the relationship between individuals' balance ability and their vestibular neural response. We found a general pattern of activation in canonical vestibular cortex and deactivation in cross modal sensory regions in response to vestibular stimulation. We found that activation amplitude of the vestibular cortex was correlated with age, with younger individuals exhibiting higher activation. Deactivation of visual and somatosensory regions increased with age and was associated with poorer balance. The results demonstrate that brain activations and deactivations in response to vestibular stimuli are correlated with balance, and the pattern of these correlations varies with age. The findings also suggest that older adults exhibit less sensitivity to vestibular stimuli, and may compensate by differentially reweighting visual and somatosensory processes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221954PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742389PMC
March 2020

Running Genomic Analyses in the Cloud.

Stud Health Technol Inform 2019 Aug;266:149-155

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Genomic testing is rapidly moving into healthcare practice. However it comes with informatics challenges that the healthcare system has not previously faced - the raw data can be hundreds of gigabytes per test, the compute demands can be thousands of CPU hours, and the test can reveal deeply private health-srelated information that can have implications for anyone related to the person tested. While not a panacea, cloud computing has particular properties that can ameliorate some of these difficulties. This paper presents some of the key lessons learned while deploying a set of genomic analyses on cloud computing for Queensland Genomics.
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http://dx.doi.org/10.3233/SHTI190787DOI Listing
August 2019

Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.

Nat Commun 2019 07 18;10(1):3163. Epub 2019 Jul 18.

Department of Pathology, University of California, San Francisco, CA, 94143, USA.

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
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http://dx.doi.org/10.1038/s41467-019-11107-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639323PMC
July 2019

Changes in gain of horizontal vestibulo-ocular reflex during spaceflight.

J Vestib Res 2019 ;29(5):241-251

Neuroscience Laboratories, NASA Johnson Space Center, Houston, USA.

Background: The vestibulo-ocular reflex (VOR) is a basic function of the vestibular system that stabilizes gaze during head movement. Investigations on how spaceflight affects VOR gain and phase are few, and the magnitude of observed changes varies considerably and depends on the protocols used.

Objective: We investigated whether the gain and phase of the VOR in darkness and the visually assisted VOR were affected during and after spaceflight.

Methods: We measured the VOR gain and phase of 4 astronauts during and after a Space Shuttle spaceflight while the subjects voluntary oscillated their head around the yaw axis at 0.33 Hz or 1 Hz and fixed their gaze on a visual target (VVOR) or imagined this target when vision was occluded (DVOR). Eye position was recorded using electrooculography and angular velocity of the head was recorded with angular rate sensors.

Results: The VVOR gain at both oscillation frequencies remained near unity for all trials. DVOR gain was more variable inflight and postflight. Early inflight and immediately after the flight, DVOR gain was lower than before the flight. The phase between head and eye position was not altered by spaceflight.

Conclusion: The decrease in DVOR gain early in the flight and after the flight reflects adaptive changes in central integration of vestibular and proprioceptive sensory inputs during active head movements.
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http://dx.doi.org/10.3233/VES-190670DOI Listing
June 2020

Long-duration spaceflight adversely affects post-landing operator proficiency.

Sci Rep 2019 02 25;9(1):2677. Epub 2019 Feb 25.

NASA Neuroscience Laboratory, Johnson Space Center, Houston, TX, USA.

Performance of astronaut pilots during space shuttle landing was degraded after a few weeks of microgravity exposure, and longer-term exposure has the potential to impact operator proficiency during critical landing and post-landing operations for exploration-class missions. Full-motion simulations of operationally-relevant tasks were utilized to assess the impact of long-duration spaceflight on operator proficiency in a group of 8 astronauts assigned to the International Space Station, as well as a battery of cognitive/sensorimotor tests to determine the underlying cause of any post-flight performance decrements. A ground control group (N = 12) and a sleep restriction cohort (N = 9) were also tested to control for non-spaceflight factors such as lack of practice between pre- and post-flight testing and fatigue. On the day of return after 6 months aboard the space station, astronauts exhibited significant deficits in manual dexterity, dual-tasking and motion perception, and a striking degradation in the ability to operate a vehicle. These deficits were not primarily due to fatigue; performance on the same tasks was unaffected after a 30-h period of sleep restriction. Astronauts experienced a general post-flight malaise in motor function and motion perception, and a lack of cognitive reserve apparent only when faced with dual tasks, which had recovered to baseline by four days after landing.
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http://dx.doi.org/10.1038/s41598-019-39058-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389907PMC
February 2019

Complex structural rearrangements are present in high-grade dysplastic Barrett's oesophagus samples.

BMC Med Genomics 2019 02 4;12(1):31. Epub 2019 Feb 4.

Surgical Oncology Group, Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett's oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals.

Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples.

Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples.

Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC.
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http://dx.doi.org/10.1186/s12920-019-0476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360790PMC
February 2019
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