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A 10‐year‐old female spayed mixed breed dog was evaluated for diarrhea and vomiting. Diagnostic imaging demonstrated the presence of an intracardiac mass. A modified Seldinger technique was used to access the right jugular vein, and an endomyocardial biopsy forceps was introduced through a sheath to obtain several biopsies. Histopathology and immunohistochemistry demonstrated a paraganglioma. The dog underwent 1 fraction of radiotherapy and l‐asparaginase chemotherapy and was discharged. The dog developed a pulmonary thromboembolism 2 days after radiotherapy and chemotherapy, and the owner elected humane euthanasia. Although long‐term assessment of treatment response was unable to be performed, this novel diagnostic option could be considered for similar cases due to success in obtaining a histopathologic diagnosis, which is essential in developing a disease‐specific treatment plan. This report also describes the use of radiotherapy for primary treatment of an intracardiac neoplasm, which can be a consideration in the future.

Background Natural killer (NK) cells are key effectors of the innate immune system, but major differences between human and murine NK cells impede translation. Outbred dogs offer an important link for NK-based cancer immunotherapy studies. We compared gene expression profiles of dog NK signatures in vitro and from a phase I clinical trial of inhaled IL-15, and analyzed dog, mouse and human NK cells using a novel orthologous transcriptome. Methods We performed differential gene expression (DGE) using resting healthy donor CD5dim NK populations and following ex vivo activation using recombinant human (rh)IL-15 or co-culture with irradiated feeder cells. Eight dogs with naturally-occurring pulmonary metastases were enrolled on a Phase I clinical trial of inhaled rhIL-15 using a 3+3 cohort design with escalating doses of inhaled rhIL-15. Blood was collected from study dogs before, during, and after therapy. We compared DGE among healthy and cancer-bearing dogs and then across mouse, dog and human NK cells in resting and activated states using ~7000 1:1 orthologous genes. Results DGE revealed distinct transcriptional profiles between the ex vivo resting, IL-15 and co-cultured canine NK cells. Among treated patients, hierarchical clustering revealed that in vivo NK cell transcriptional signatures grouped by individual dog, and not amount of time exposed to treatment. PCA showed in vivo profiles of the clinical responders were distinctly separate from the non-responding patients (PC1 38%, PC2 12%). Patient in vivo NK cell transcription profiles most closely resembled those of ex vivo resting NK cells and not IL-15 treated or co-culture activated (PC1 43%, PC2 19%), likely reflecting key differences in activation. In cross-species analysis, PCA showed within-species spatial clustering of resting NK cells. After activation, variance between dog and human NK cells decreased, while variance between human and mouse NK cells increased (PC1 40%, PC2 28%). Conclusions In this first transcriptomic sequencing of dog NK cells, we demonstrate distinct gene profiles of ex vivo activated NK cells from healthy donors compared to circulating NK cells from dogs receiving inhaled rhIL-15 on a clinical trial. Baseline in vivo NK cell profiles appear to predict response to therapy more than changes over time. We also show distinct gene profiles of NK cells across the most commonly used mouse, dog, and human NK populations, with convergence of dog and human NK cells after activation. By defining the canine NK cell DGE signatures, these data fill a gap in translational NK studies. Ethics Approval The canine clinical trial study was approved by IACUC and Clinical Trials Review Board (Inhaled IL-15 Immunotherapy for Treatment of Lung Metastases, Protocol #20179).

A 12 yr old 13.5 kg male castrated Pembroke Welsh corgi was presented for evaluation of a suspected renal cyst following multiple episodes of lethargy and abdominal pain. Abdominal imaging revealed a large, thin-walled, hypoechoic cystic lesion associated with the cranial pole of the left kidney and a second smaller cystic lesion on the caudal pole. The larger cystic lesion was repeatedly drained percutaneously, but the lesion returned to initial size and clinical signs returned within weeks. Percutaneous ethanol sclerotherapy achieved only transient improvement in lesion size and abdominal discomfort. Laparoscopic deroofing and omentalization of the larger left renal cystic lesion was performed. The resected cystic wall was histopathologically consistent with a renal adenoma. Abdominal ultrasonography performed 1 mo postoperatively found no recurrence of the cystic renal adenoma. Repeated ultrasonography at 3 mo postoperatively detected a small cystic lesion at the cranial pole of the left kidney, which remained static in appearance at 11 and 18 mo postoperatively. During all follow-up visits, the dog was reported to be doing well with no recurrence of clinical signs. Renal cysts causing clinical signs and renal adenomas are rare in veterinary medicine; laparoscopic deroofing and omentalization provides a minimally invasive treatment approach.

Introduction: Natural killer (NK) cells are key effectors of the innate immune system, but major differences between human and murine NK cells have been a barrier to translation. Outbred dogs are an important link for NK-based cancer immunotherapy studies, so better characterization of canine NK cells is needed. We used RNAseq to compare gene expression profiles of ex vivo dog NK cells to in vivo NK signatures from dogs with pulmonary metastases receiving inhaled recombinant human (rh) IL-15 in a phase I clinical trial. Methods: Eight dogs with spontaneous pulmonary metastases were enrolled on an IACUC and clinical trials review board-approved Phase I clinical trial of inhaled rhIL-15 using a 3+3 cohort design with escalating doses of inhaled rhIL-15. Blood was collected from study subjects immediately pre-treatment and on days 7, 14 and 21 after treatment initiation for isolation of NK cells (CD5dim) and RNAseq. We performed differential gene expression (DGE) comparing trial patients to healthy beagle CD5dim NK populations (resting) and ex vivo activated beagle NK cells using IL-15 and feeder line co-culture. We assessed global transcriptional profile, specific activating and inhibitory receptors of NK function, and principal component analysis (PCA) for variation between treatment groups (FDR Results: Of 8 dogs, 2 demonstrated > 100-day survival with 1 stable disease and 1 partial response based on RECIST criteria. DGE revealed distinct transcriptional profiles between the ex vivo resting, IL-15 and co-cultured canine NK cells. Among treated patients, hierarchical clustering revealed that in vivo NK cell transcriptional signatures grouped by individual dog, and not amount of time exposed to treatment. PCA showed in vivo profiles of the long term survivors were distinctly separate from the non-responding patients (PC1 38%, PC2 12%). This suggests response to therapy could be determined by baseline NK cell characteristics rather than changes over time following treatment. Patient in vivo NK cell transcription profiles most closely resembled those of ex vivo resting NK cells and not IL-15 or co-culture activated (PC1 43%, PC2 19%), likely reflecting key differences in activation ex vivo vs in vivo. Key genes induced in vivo (>20X) post inhalation of rhIL-15 include DLA-DRA, B2M, and thymosin beta 4, while key genes induced ex vivo post rhIL-15 exposure include CD96, KLRB1, and SPP1/OPN. Conclusion: In this first transcriptomic sequencing of dog NK cells, we demonstrate distinct gene profiles of ex vivo activated NK cells from healthy donors compared to circulating NK cells from dogs receiving inhaled rhIL-15 on clinical trial. Baseline NK cell profiles appear to predict response more than changes over time. These data highlight the strength of the outbred dog model in speeding novel immunotherapy and biomarker studies. Citation Format: Alicia A. Gingrich, Taylor Reiter, Sean Judge, Daniel York, Mio Yanagisawa, Ian Sturgill, Rachel Brady, Kevin Stoffel, Arta Monjazeb, C. Titus Brown, Robert Rebhun, Robert J. Canter. Transcriptomic profiles improve characterization natural killer cells and predict response to cytokine therapy in clinical trial for dogs with pulmonary metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1339.

INTRODUCTION The purpose of this study was to determine how short- and long-duration spaceflight affects astronauts' performance on functional tests that challenge the balance control system (Seated Egress and Walk; Object Translation; Recovery from Fall/Stand; and Jump Down) and on clinical tests of balance function (Computerized Dynamic Posturography and Tandem Walk). In addition, we examined how exercise affects functional performance after long-term axial body unloading during 70 d of bed rest at 6° head-down tilt. METHODS Data were collected twice during the 2-mo period before spaceflight or during the 2-wk period before bed rest, and four times after flight or bed rest: on the day of landing or the day bed rest ended, 1 d and 6 d later, and a final session 12 d after bed rest or 30 d after spaceflight. RESULTS For bed rest subjects, long-term axial unloading alone caused functional performance deficits immediately after bed rest. However, the addition of an exercise regimen did not significantly improve median functional performance immediately after this axial unloading. For spaceflight subjects, the length of the space mission was directly related to the severity of functional performance deficits within 1 d of landing and during the subsequent recovery period after flight. DISCUSSION The performance data suggest that an additional sensorimotor-based countermeasure may be necessary to maintain functional performance at preflight levels immediately after spaceflight.Miller CA, Kofman IS, Brady RR, May-Phillips TR, Batson CD, Lawrence EL, Taylor LC, Peters BT, Mulavara AP, Feiveson AH, Reschke MF, Bloomberg JJ. Functional task and balance performance in bed rest subjects and astronauts. Aerosp Med Hum Perform. 2018; 89(9):805-815.

The IGF pathway has been implicated in the regulation of neuroendocrine tumor (NET) growth, and preliminary studies suggested that ganitumab (AMG 479), a human MAB against IGF1R, may have antitumor activity in this setting. We performed a two-cohort phase II study of ganitumab in patients with metastatic progressive carcinoid or pancreatic NETs (pNETs). This open-label study enrolled patients (≥18 years) with metastatic low- and intermediate-grade carcinoid or pNETs. Inclusion criteria included evidence of progressive disease (by Response Evaluation Criteria in Solid Tumors (RECIST)) within 12 months of enrollment, ECOG PS 0–2, and fasting blood sugar

Space flight causes astronauts to be exposed to adaptation in both the vestibular and body load-sensing somatosensory systems. The goal of these studies was to examine the contributions of vestibular and body load-sensing somatosensory influences on vestibular mediated head movement control during locomotion after long-duration space flight. Subjects walked on a motor driven treadmill while performing a gaze stabilization task. Data were collected from three independent subject groups that included bilateral labyrinthine deficient (LD) patients, normal subjects before and after 30 minutes of 40% bodyweight unloaded treadmill walking, and astronauts before and after long-duration space flight. Motion data from the head and trunk segments were used to calculate the amplitude of angular head pitch and trunk vertical translation movement while subjects performed a gaze stabilization task, to estimate the contributions of vestibular reflexive mechanisms in head pitch movements. Exposure to unloaded locomotion caused a significant increase in head pitch movements in normal subjects, whereas the head pitch movements of LD patients were significantly decreased. This is the first evidence of adaptation of vestibular mediated head movement responses to unloaded treadmill walking. Astronaut subjects showed a heterogeneous response of both increases and decreases in the amplitude of head pitch movement. We infer that body load-sensing somatosensory input centrally modulates vestibular input and can adaptively modify vestibularly mediated head-movement control during locomotion. Thus, space flight may cause central adaptation of the converging vestibular and body load-sensing somatosensory systems leading to alterations in head movement control.

Astronauts returning from space flight and performing Earth-bound activities must rapidly transition from the microgravity-adapted sensorimotor state to that of Earth’s gravity. The goal of the current study was to assess locomotor dysfunction and recovery of function after long-duration space flight using a test of functional mobility. Eighteen International Space Station crewmembers experiencing an average flight duration of 185 days performed the functional mobility test (FMT) pre-flight and post-flight. To perform the FMT, subjects walked at a self selected pace through an obstacle course consisting of several pylons and obstacles set up on a base of 10-cm-thick, medium-density foam for a total of six trials per test session. The primary outcome measure was the time to complete the course (TCC, in seconds). To assess the long-term recovery trend of locomotor function after return from space flight, a multilevel exponential recovery model was fitted to the log-transformed TCC data. All crewmembers exhibited altered locomotor function after space flight, with a median 48% increase in the TCC. From the fitted model we calculated that a typical subject would recover to 95% of his/her pre-flight level at approximately 15 days post-flight. In addition, to assess the early motor learning responses after returning from space flight, we modeled performance over the six trials during the first post-flight session by a similar multilevel exponential relation. We found a significant positive correlation between measures of long-term recovery and early motor learning (P < 0.001) obtained from the respective models. We concluded that two types of recovery processes influence an astronaut’s ability to re-adapt to Earth’s gravity environment. Early motor learning helps astronauts make rapid modifications in their motor control strategies during the first hours after landing. Further, this early motor learning appears to reinforce the adaptive realignment, facilitating re-adaptation to Earth’s 1-g environment on return from space flight.

Falls are the leading cause of injury and death in older adults in the United States. People with developmental disabilities experience accelerated physiologic and degenerative changes associated with aging and are at risk for falls sooner than the general population. There is little information specifically regarding the evaluation and prevention of falls for individuals with developmental disabilities. This article examines how the strategies used to evaluate and prevent falls in the general population translate to use in adults with developmental disabilities and highlights the research that indicates how risk factors, evaluation, interventions, and prevention strategies may differ for people with developmental disabilities.

The goal of the current study was to investigate the effects of different virtual environment (VE) technologies on emotional arousal and task performance in a modified Stroop task presented under low- and high-stress conditions. Fifty-three participants were recruited from a college population. Reactivity to stressful VEs was examined in three representative VE systems from desktop to high-end fully immersive systems. The experiment was a 3 (desktop system, head mounted display (HMD), and six wall system) × 2 (high- and low-stressful VE) within subject design, with self-reported emotional arousal and valence, skin conductance, task performance, presence, and simulator sickness. Replicating previous studies, the fully immersive system induced the highest sense of presence and the HMD system elicited the highest amount of simulator sickness. Extending previous studies, the results showed that different technological platforms evoked unique response patterns. Our findings suggest that different VE systems may be appropriate for different scientific purposes when studying stress reactivity using emotionally evocative tasks.

Introduction: Astronauts exhibit sensorimotor changes upon return from long-duration spaceflight that can result in altered gait kinematics and possibly an increased risk of tripping. Toe trajectory during locomotion is a precise motor control task involving both legs, thus providing a composite metric of locomotor control. The purpose of this study was to determine whether astronauts are at an increased risk of tripping after their return from long-duration spaceflight. This was accomplished by assessing the pre- to postflight changes in toe clearance during treadmill walking. Methods: Ten crewmembers walked on a treadmill while performing a visual-acuity task pre- and postflight. Results: In the three subjects on whom landing day data were available, each exhibited a characteristic of increased tripping risk on landing day: either a decreased median toe clearance or an increased interquartile range (a measure of variance). For all crewmembers, toe clearance median and interquartile range were not significantly different from preflight for the other postflight sessions (the earliest being 1 d after landing). A follow-up analysis showed that changes in foot pitch, ankle dorsiflexion, and pelvis roll angles were significant predictors of changes in toe clearance. Discussion: The landing-day observations indicated an increased risk of tripping, which may pose a hazard during locomotion immediately upon return to Earth, especially in an emergency scenario. However, tripping risk on subsequent days was not different than preflight. The joint angle analysis suggested that the crewmembers tried to reestablish their normal walking pattern postflight, instead of developing a new motor control strategy.

Assistive technology (AT) and AT services enable children and youth with disabilities and special health care needs to participate in society and are increasingly a part of service provider practice. It is not clear how professional preparation programs are meeting the challenge of preparing service providers to provide AT/AT services. An electronic survey was sent to the program directors for occupational therapy, physical therapy, special education, and speech-language pathology programs in the United States (n = 959) to determine the extent to which AT/AT services were included in the curriculum. The results (n = 153) showed that nearly all of the programs that responded covered AT/AT services in their curriculum, used similar types of faculty and teaching method patterns, and were generally satisfied with the amount of time they spent on the subject. The programs differed, however, in terms of the time spent and emphasis of content specific to their program type. Gaps existed in the extent to which programs covered the influence of culture on the use of AT and addressing the requirement to discuss AT/AT services at every Individualized Education Program meeting. These gaps and emphasis on specific topics within program types indicate that service providers may leave programs with a narrow scope of knowledge about AT/AT services. Information from this survey suggests that to promote contemporary practice in the areas of AT/AT services, entry-level curricula should be enriched or expanded to comprehensively present AT information instruction in this growing service area.

4125 Background: The IGF pathway is thought play an important role in neuroendocrine tumor progression. We therefore investigated AMG 479, a human monocolonal antibody against IGF1-R, in patients with metastatic progressive carcinoid and pancreatic neuroendocrine tumors (NETS). Methods: This open-label phase II study enrolled patients (≥18 yrs) with metastatic low and intermediate-grade carcinoid and pancreatic NETs. Key inclusion criteria included evidence of progressive disease (by RECIST) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar

Resume Saint Alphonse de Liguori (1686-1797) est le patron des moralistes catholiques, mais on en tient peu compte aujourd’hui. Cet article presente en trois temps l’argument en faveur de son actualite permanente. D’abord, il propose un status quaestionis. Ensuite, dans la section la plus etendue, il expose, textes d’Alphonse a l’appui, les elements qui suggerent son actualite : la conscience, la liberte, l’argumentation intrinseque, la prudence pastorale, une theologie de la conversion. L’article conclut en indiquant le type de theologie morale que prone Gaudium et Spes : bien que le contexte soit different de celui de l’epoque de saint Alphonse, l’auteur propose quelques lignes de convergence qui pourraient faciliter l’integration de son systeme a celui utilise aujourd’hui.