Development of adaptive anoikis resistance promotes metastasis that can be overcome by CDK8/19 Mediator kinase inhibition.

Anoikis resistance or evasion of cell death triggered by cell detachment into suspension is a hallmark of cancer that is concurrent with cell survival and metastasis. The effects of frequent matrix detachment encounters on the development of anoikis resistance in cancer remains poorly defined. Here we show using a panel of ovarian cancer models, that repeated exposure to suspension stress in vitro followed by attached recovery growth leads to the development of anoikis resistance paralleling in vivo development of anoikis resistance in ovarian cancer ascites. This resistance is concurrent with enhanced invasion, chemoresistance and the ability of anoikis adapted cells to metastasize to distant sites. Adapted anoikis resistant cells show a heightened dependency on oxidative phosphorylation and can also evade immune surveillance. We find that such acquired anoikis resistance is not genetic, as acquired resistance persists for a finite duration in the absence of suspension stress. Transcriptional reprogramming is however essential to this process, as acquisition of adaptive anoikis resistance in vitro and in vivo is exquisitely sensitive to inhibition of CDK8/19 Mediator kinase, a pleiotropic regulator of transcriptional reprogramming. Our data demonstrate that growth after recovery from repeated exposure to suspension stress is a direct contributor to metastasis and that inhibition of CDK8/19 Mediator kinase during such adaptation provides a therapeutic opportunity to prevent both local and distant metastasis in cancer.

Examination of the COVID-19 Pandemic's Impact on Mental Health From Three Perspectives: Global, Social, and Individual.

The extent of the deleterious effects of the COVID-19 pandemic on mental health is recognized ubiquitously. However, these effects are subject to many modulatory factors from a plethora of domains of examination. It is important to understand the intersection of societal and individual levels for global stressors compared with local phenomena and physical-health outcomes. Here, we consider three perspectives: international/cultural, social, and individual. Both the enduring threat of COVID-19 infection and the protective measures to contain contagion have important consequences on individual mental health. These consequences, together with possible remedial interventions, are the focus of this article. We hope this work will stimulate more research and will suggest factors that need to be considered in the coordination of responses to a global threat, allowing for better preparation in the future.

Webinar and survey on quality management principles within the Australian and New Zealand ACPSEM Workforce.

Healthcare relies upon the accurate and safe delivery of patient care. This is only achievable when systems are developed to ensure high quality, robust outcomes, for instance quality management systems. The concept of quality management can take on a different meaning depending on the context in which it is found. To add complication, the amount of education required for quality management will vary depending on one's exposure to the implementation of quality systems. In part to address these issues, the Australasian College of Physical Scientists and Engineers in Medicine (ACPSEM) Queensland Branch held a quality management webinar for members and non-members across Australia and New Zealand. The purpose of the webinar was to educate and facilitate discussion regarding the application of quality management principles for the ACPSEM profession. In conjunction, a pre- and post-webinar survey was conducted to gain an insight into existing knowledge and attitudes within the professions governed by the ACPSEM and students undertaking related studies. This paper authored by the webinar speakers reintroduces the quality management principles that were discussed in webinar, exemplifies the importance of quality management skills within the ACPSEM professions and presents the results of the surveys, promoting the need for more educational resources on quality management tools.

Commissioning measurements on an Elekta Unity MR-Linac.

Magnetic resonance-guided radiotherapy technology is relatively new and commissioning publications, quality assurance (QA) protocols and commercial products are limited. This work provides guidance for implementation measurements that may be performed on the Elekta Unity MR-Linac (Elekta, Stockholm, Sweden). Adaptations of vendor supplied phantoms facilitated determination of gantry angle accuracy and linac isocentre, whereas in-house developed phantoms were used for end-to-end testing and anterior coil attenuation measurements. Third-party devices were used for measuring beam quality, reference dosimetry and during treatment plan commissioning; however, due to several challenges, variations on standard techniques were required. Gantry angle accuracy was within 0.1°, confirmed with pixel intensity profiles, and MV isocentre diameter was < 0.5 mm. Anterior coil attenuation was approximately 0.6%. Beam quality as determined by TPR20,10 was 0.705 ± 0.001, in agreement with treatment planning system (TPS) calculations, and gamma comparison against the TPS for a 22.0 × 22.0 cm2 field was above 95.0% (2.0%, 2.0 mm). Machine output was 1.000 ± 0.002 Gy per 100 MU, depth 5.0 cm. During treatment plan commissioning, sub-standard results indicated issues with machine behaviour. Once rectified, gamma comparisons were above 95.0% (2.0%, 2.0 mm). Centres which may not have access to specialized equipment can use in-house developed phantoms, or adapt those supplied by the vendor, to perform commissioning work and confirm operation of the MRL within published tolerances. The plan QA techniques used in this work can highlight issues with machine behaviour when appropriate gamma criteria are set.

Medical Symptom Validity Test (MSVT) profiles in individuals being evaluated for Alzheimer's disease.

Objective:Our purpose was to determine whether Medical Symptom Validity Test (MSVT) profiles could differentiate performance invalidity from true impairment in patients with varying levels of memory impairment and functional ability being evaluated for Alzheimer's disease (AD). Method: Seventy-three older adults (13 healthy controls, 25 mild cognitive impairment [MCI], 16 mild AD, 19 moderate AD) were evaluated with a neuropsychological battery including the MSVT and activities of daily living (ADL) measures. Using MSVT classification guidelines, examinees' MSVT profiles were categorized as: 1) valid, 2) invalid, 3) weak memory, or 4) genuine memory impairment (GMIP). Results: Eighty-four percent of moderate AD examinees produced a GMIP. Among MCI and mild AD examinees, who had only modestly affected ADLs, a substantial proportion manifested a GMIP (40% and 62.5%, respectively). An invalid profile was uncommon across patient groups (12.5% in mild AD, 5.3% in moderate AD, and 0% in MCI). Conclusions: The MSVT functions reasonably well in a dementia sample to determine if an examinee has an invalid profile, although for mild AD examinees, the false positive rate is slightly above the recommended 10% cut-off. However, even individuals with MCI, mild AD and relative preservation of ADLs may manifest a GMIP, demonstrating that such profile is found across patients with lower and higher degrees of functional impairment. Given this finding, the usefulness of the GMIP in differentiating performance invalidity from true impairment in patients being evaluated for AD appears limited.

Evaluation of optical 3D scanning system for radiotherapy use.

INTRODUCTION: Optical three-dimensional scanning devices can produce geometrically accurate, high-resolution models of patients suitable for clinical use. This article describes the use of a metrology-grade structured light scanner for the design and production of radiotherapy medical devices and synthetic water-equivalent computer tomography images. METHODS: Following commissioning of the device by scanning objects of known properties, 173 scans were performed on 26 volunteers, with observations of subjects and operators collected. RESULTS: The fit of devices produced using these scans was assessed, and a workflow for the design of complex devices using a treatment planning system was identified. CONCLUSIONS: Recommendations are provided on the use of the device within a radiation oncology department.

3D printed brachytherapy jig for Reference Air Kerma Rate calibration.

3D printing in modern radiotherapy allows users the ability to create custom devices which can be a valuable tool for use in brachytherapy source calibration. Radiotherapy centres may verify their brachytherapy source activity with a calibrated Farmer chamber. For this purpose, a jig was designed, 3D printed and commissioned for in-air source strength calibration. Measurements on four afterloaders with varied equipment and environments were completed. A full uncertainty budget was developed and measurements with the in-air jig were consistently within 3% of the certificate source strength, and within the 4.1% combined uncertainty for comparing a well chamber measurement (1.7%) with the in air jig (3.75%). By creating a jig that is able to be customised to multiple catheter sizes and cylindrical chamber designs, centres can be provided with the option of independently checking their source strength with ease and for little cost.

The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study.

RATIONALE: Arginine vasopressin (AVP) is a neuropeptide that modulates both physiological and emotional responses to threat. Until recently, drugs that target vasopressin receptors (V1a) in the human central nervous system were unavailable. The development of a novel V1a receptor antagonist, SRX246, permits the experimental validation of vasopressin's role in the regulation of anxiety and fear in humans. OBJECTIVES: Here, we examined the effects of SRX246 in a proof-of-concept translational paradigm of fear (phasic response to imminent threat) and anxiety (prolonged response to potential threat). METHODS: Healthy volunteers received both SRX246 and placebo in a randomized, double-blind, counter-balanced order separated by a 5-7-day wash-out period. Threat consisted of unpleasant electric shocks. The "NPU" threat test probed startle reactivity during predictable threat (i.e., fear-potentiated startle) and unpredictable threat (i.e., anxiety-potentiated startle). RESULTS: As predicted, SRX246 decreased anxiety-potentiated startle independent of fear-potentiated startle. CONCLUSIONS: As anxiety-potentiated startle is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as SSRIs and benzodiazepines, the V1a receptor is a promising novel treatment target.

Correction: Work-Related and Personal Factors Associated With Mental Well-Being During the COVID-19 Response: Survey of Health Care and Other Workers.

[This corrects the article DOI: 10.2196/21366.].

Work-Related and Personal Factors Associated With Mental Well-Being During the COVID-19 Response: Survey of Health Care and Other Workers.

BACKGROUND: The response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created an unprecedented disruption in work conditions. This study describes the mental health and well-being of workers both with and without clinical exposure to patients with coronavirus disease (COVID-19). OBJECTIVE: The aim of this study is to measure the prevalence of stress, anxiety, depression, work exhaustion, burnout, and decreased well-being among faculty and staff at a university and academic medical center during the SARS-CoV-2 pandemic and describe work-related and personal factors associated with their mental health and well-being. METHODS: All faculty, staff, and postdoctoral fellows of a university, including its medical school, were invited in April 2020 to complete an online questionnaire measuring stress, anxiety, depression, work exhaustion, burnout, and decreased well-being. We examined associations between these outcomes and factors including work in high-risk clinical settings and family/home stressors. RESULTS: There were 5550 respondents (overall response rate of 34.3%). Overall, 34% of faculty and 14% of staff (n=915) were providing clinical care, while 61% of faculty and 77% of staff were working from home. Among all workers, anxiety (prevalence ratio 1.37, 95% CI 1.09-1.73), depression (prevalence ratio 1.28, 95% CI 1.03-1.59), and high work exhaustion (prevalence ratio 1.24, 95% CI 1.13-1.36) were independently associated with community or clinical exposure to COVID-19. Poor family-supportive behaviors by supervisors were also associated with these outcomes (prevalence ratio 1.40, 95% CI 1.21-1.62; prevalence ratio 1.69, 95% CI 1.48-1.92; and prevalence ratio 1.54, 95% CI 1.44-1.64, respectively). Age <40 years and a greater number of family/home stressors were also associated with these poorer outcomes. Among the subset of clinicians, caring for patients with COVID-19 and working in high-risk clinical settings were additional risk factors. CONCLUSIONS: Our findings suggest that the pandemic has had negative effects on the mental health and well-being of both clinical and nonclinical employees. Mitigating exposure to COVID-19 and increasing supervisor support are modifiable risk factors that may protect mental health and well-being for all workers.

Distinct patterns of increased translocator protein in posterior cortical atrophy and amnestic Alzheimer's disease.

We sought to determine whether patients with posterior cortical atrophy (PCA) demonstrate a pattern of binding to translocator protein 18 kDa, a marker of microglial activation, that is distinct from that in patients with amnestic presentation of Alzheimer's disease (AD). Eleven PCA patients, 11 amnestic AD patients, and 15 age-matched controls underwent positron emission tomography with 11C-PBR28 to measure translocator protein 18 kDa. PCA patients showed greater 11C-PBR28 binding than controls in occipital, posterior parietal, and temporal regions. In contrast, amnestic AD patients showed greater 11C-PBR28 binding in inferior and medial temporal cortex. Increased 11C-PBR28 binding overlapped with reduced cortical volume for both PCA and amnestic AD patients, and with areas of reduced glucose metabolism in PCA patients. While both patient groups showed diffuse amyloid binding, PCA patients showed greater binding than amnestic AD patients in bilateral occipital cortex. These results suggest that microglial activation is closely associated with neurodegeneration across different subtypes of AD.

(11)C-PBR28 binding to translocator protein increases with progression of Alzheimer's disease.

This longitudinal study sought to determine whether the 18 kDa translocator protein (TSPO), a marker of neuroinflammation, increases over time in Alzheimer's disease. Positron emission tomography imaging with the TSPO radioligand (11)C-PBR28 was performed at baseline and after a median follow-up of 2.7 years in 14 amyloid-positive patients and 8 amyloid-negative controls. Patients had a greater increase in TSPO binding than controls in inferior parietal lobule, precuneus, occipital cortex, hippocampus, entorhinal cortex, and combined middle and inferior temporal cortex. TSPO binding in temporoparietal regions increased from 3.9% to 6.3% per annum in patients, but ranged from -0.5% to 1% per annum in controls. The change in TSPO binding correlated with cognitive worsening on clinical dementia rating scale-sum of boxes and reduced cortical volume. The annual rate of increased TSPO binding in temporoparietal regions was about 5-fold higher in patients with clinical progression (n = 9) compared with those who did not progress (n = 5). TSPO may serve as a biomarker of Alzheimer's progression and response to anti-inflammatory therapies.

(18)F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier.

Efflux transporters at the blood-brain barrier can decrease the entry of drugs and increase the removal of those molecules able to bypass the transporter. We previously hypothesized that (18)F-FCWAY, a radioligand for the serotonin 5-HT1A receptor, is a weak substrate for permeability glycoprotein (P-gp) based on its very early peak and rapid washout from human brain. To determine whether (18)F-FCWAY is a substrate for P-gp, breast cancer resistance protein (BCRP), and multidrug resistance protein (MRP1) - the three most prevalent efflux transporters at the blood-brain barrier - we performed three sets of experiments. In vitro, we conducted fluorescence-activated cell sorting (FACS) flow cytometry studies in cells over-expressing P-gp, BCRP, and MRP1 treated with inhibitors specific to each transporter and with FCWAY. Ex vivo, we measured (18)F-FCWAY concentration in plasma and brain homogenate of transporter knockout mice using γ-counter and radio-HPLC. In vivo, we conducted positron emission tomography (PET) studies to assess changes in humans who received (18)F-FCWAY during an infusion of tariquidar (2-4mg/kg iv), a potent and selective P-gp inhibitor. In vitro studies showed that FCWAY allowed fluorescent substrates to get into the cell by competitive inhibition of all three transporters at the cell membrane. Ex vivo measurements in knockout mice indicate that (18)F-FCWAY is a substrate only for P-gp and not BCRP. In vivo, tariquidar increased (18)F-FCWAY brain uptake in seven of eight subjects by 60-100% compared to each person's baseline. Tariquidar did not increase brain uptake via some peripheral mechanism, given that it did not significantly alter concentrations in plasma of the parent radioligand (18)F-FCWAY or its brain-penetrant radiometabolite (18)F-FC. These results show that (18)F-FCWAY is a weak substrate for efflux transport at the blood-brain barrier; some radioligand can enter brain, but its removal is hastened by P-gp. Although (18)F-FCWAY is not ideal for measuring 5-HT1A receptors, it demonstrates that weak substrate radioligands can be useful for measuring both increased and decreased function of efflux transporters, which is not possible with currently available radioligands such as (11)C-loperamide and (11)C-verapamil that are avid substrates for transporters.