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This article examines the problem of bullying LGBT youth and gender minority students in school. Harassment and bullying toward LGBT and gender minority youth take place on an international level, engendering concerns of mental and physical well-being of LGBT youth and gender minority students due to heteronormative pressure and lack of inclusion. Solutions include community education, school support, and spaces of safety for youth. Educators and students can employ various strategies to make schools safe and accepting to LGBT students.

Background and purpose: Objective measurement of speech has shown promising results to monitor disease state in multiple sclerosis. In this study, we characterize the relationship between disease severity and speech metrics through perceptual (listener based) and objective acoustic analysis. We further look at deviations of acoustic metrics in people with no perceivable dysarthria. Methods: Correlations and regression were calculated between speech measurements and disability scores, brain volume, lesion load and quality of life. Speech measurements were further compared between three subgroups of increasing overall neurological disability: mild (as rated by the Expanded Disability Status Scale ≤2.5), moderate (≥3 and ≤5.5) and severe (≥6). Results: Clinical speech impairment occurred majorly in people with severe disability. An experimental acoustic composite score differentiated mild from moderate (P < 0.001) and moderate from severe subgroups (P = 0.003), and correlated with overall neurological disability (r = 0.6, P < 0.001), quality of life (r = 0.5, P < 0.001), white matter volume (r = 0.3, P = 0.007) and lesion load (r = 0.3, P = 0.008). Acoustic metrics also correlated with disability scores in people with no perceivable dysarthria. Conclusions: Acoustic analysis offers a valuable insight into the development of speech impairment in multiple sclerosis. These results highlight the potential of automated analysis of speech to assist in monitoring disease progression and treatment response. [ABSTRACT FROM AUTHOR]

In this paper, the adaptation of spectral kurtosis technology is proposed, demonstrated and experimentally validated. Raw data signals were collected from a single-stage gearbox run in different combinations of speed and load, after which time synchronous averaging was used to leave the classical residual signal once meshing harmonics were removed. Each data file is split into many individual realisations based on the time taken for the time synchronous average to converge on stable values, after which the short-time Fourier transform is used to calculate the spectral kurtosis for each realisation. The effects of adapting spectral kurtosis technology parameters such as the resolution and threshold used in creating a Wiener filter are evaluated, showing the effects on the consistent frequency bands identified throughout the realisations. Taking a baseline set of processing parameters, the probability of correct diagnosis was calculated using a three-stage decision-making technique incorporating the k-nearest neighbour and cluster analysis methods. Adaptation of the spectral kurtosis technology is then shown to dramatically improve the probability of correct diagnosis, highlighting that each speed and load case requires different resolution and threshold values to return the optimal results. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder typified by impaired social communication and restrictive and repetitive behaviors. Mice serve as an ideal candidate organism for studying the neuralmechanisms that subserve these symptoms. The Neuroligin-3 (NL3) mouse, expressing a R451C mutation discovered in two Swedish brothers with ASD, exhibits impaired social interactions and heightened aggressive behavior towards male mice. Social interactions with female mice have not been characterized and in the present study were assessed in male NL3R451C and WT mice. Mice were housed in social and isolation conditions to test for isolation-induced increases in social interaction. Tests were repeated to investigate potential differences in interaction in naïve and experienced mice. We identified heightened interest inmating and atypical aggressive behavior in NL3R451C mice. NL3R451C mice exhibited normal social interaction with WT females, indicating that abnormal aggressive behavior towards females is not due to alteredmotivation to engage. Social isolation rearing heightened interest in social behavior in all mice. Isolation housing selectively modulated the response to female pheromones in NL3R451C mice. This study is the first to show altered mating behavior in the NL3R451C mouse and has provided new insights into the aggressive phenotype in this model. [ABSTRACT FROM AUTHOR]

Background: The pathophysiology of multiple sclerosis (MS) tremor is uncertain with limited phenotypical studies available. Objective: To investigate whether dystonia contributes to MS tremor and its severity. Methods: MS patients (n = 54) with and without disabling uni- or bilateral upper limb tremor were recruited (39 limbs per group). We rated tremor severity, writing and Archimedes spiral drawing; cerebellar dysfunction (SARA score); the Global Dystonia Scale (GDS) for proximal and distal upper limbs, dystonic posturing, mirror movements, geste antagoniste, and writer's cramp. Results: Geste antagoniste, mirror dystonia, and dystonic posturing were more frequent and severe (p < 0.001) and dystonia scores were correlated with tremor severity in tremor compared to non-tremor patients. A 1-unit increase in distal dystonia predicted a 0.52-Bain unit (95% confidence interval (CI) 0.08-0.97), p = 0.022) increase in tremor severity and a 1-unit (95% CI 0.48-1.6,p = 0.001) increase in drawing scores. A 1-unit increase in proximal dystonia predicted 0.93-Bain unit increase (95% CI 0.45-1.41,p < 0.001) in tremor severity and 1.5-units (95% CI 0.62-2.41,p = 0.002) increase in the drawing score. Cerebellar function in the tremor limb and tremor severity was correlated (p < 0.001). Conclusions: Upper limb dystonia is common in MS tremor suggesting that MS tremor pathophysiology involves cerebello-pallido-thalamo-cortical network dysfunction. [ABSTRACT FROM AUTHOR]

• Scores on the SDMT represent deficits in sensorial, cognitive or motor processing. • There is a need to isolate and characterise cognitive IPS deficits in MS. • We demonstrated significant cognitive IPS deficits in early MS patients. • Cognitive IPS deficits were not associated with SDMT performance. The assessment of cognitive information processing speed (IPS) is complicated in MS, with altered performance on tests such as the Symbol Digit Modalities Test (SDMT) potentially representing changes not only within cognitive networks but in the initial sensorial transmission of information to cognitive networks, and/or efferent transmission of the motor response. We aimed to isolate and characterise cognitive IPS deficits in MS using ocular motor tasks; a prosaccade task (used to assess and control for sensorial and motor IPS) which was then used to adjust performance on the Simon task (cognitive IPS). All participants (22 MS patients with early disease, 22 healthy controls) completed the ocular motor tasks and the SDMT. The Simon task assessed cognitive IPS by manipulating the relationship between a stimulus location and its associated response direction. Two trial types were interleaved: (1) congruent, where stimulus location = response direction; or (2) incongruent, where stimulus location ≠ response direction. RESULTS MS patients did not perform differently to controls on the SDMT. For OM tasks, when sensorial and motor IPS was controlled, MS patients had significantly slower cognitive IPS (incongruent trials only) and poorer conflict resolution. SDMT performance did not correlate with slower cognitive IPS in MS patients, highlighting the limitation of using SDMT performance to interpret cognitive IPS changes in patients with MS. Cognitive IPS deficits in MS patients are dissociable from changes in other processing stages, manifesting as impaired conflict resolution between automatic and non-automatic processes. Importantly, these results raise concerns about the SDMT as an accurate measure of cognitive IPS in MS. [ABSTRACT FROM AUTHOR]

Study Objectives: Obstructive sleep apnea (OSA) may increase risk of dementia. A potential pathway for this risk is through cerebral small vessel disease (CSVD). In the context of an existing randomized trial of aspirin for primary prevention, we aimed to investigate OSA's impact on CSVD imaging measures and explore whether aspirin effects these measures over 3 years that differ in the presence or absence of OSA., Methods: A sub-study of the ASPirin in Reducing Events in the Elderly randomized placebo-controlled trial of low-dose aspirin. Community-dwelling participants aged 70 years and above, without cognitive impairment, cardiovascular disease or known OSA completed an unattended limited-channel sleep study that calculated the oxygen desaturation index and apnea-hypopnea index. At baseline and 3 years later, volumes of white matter hyperintensities (WMH) and silent brain infarctions (SBI) were measured on 1.5 Tesla brain magnetic resonance imaging, and retinal vessel calibers were calculated from retinal vascular imaging., Results: Mild and moderate/severe OSA was detected in 48.9% and 29.9%, respectively, of the 311 participants, who had a mean age of 73.7 years (SD 3.4 years), 38.6% female. OSA of any severity did not associate with WMH volumes, SBI, nor with retinal vessel calibers at baseline, nor with change in these measures in the 277 participants with repeated measures acquired after 3 years. OSA of any severity did not interact with aspirin on change in these measures over 3 years., Conclusion: In healthy older adults undiagnosed OSA was not associated with retinal vascular calibers and neuroimaging measures of CSVD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Introduction: Functional magnetic resonance imaging (fMRI) can improve our understanding of neural processes subserving motor speech function. Yet its reproducibility remains unclear. This study aimed to evaluate the reproducibility of fMRI using a word repetition task across two time points., Methods: Imaging data from 14 healthy controls were analysed using a multi-level general linear model., Results: Significant activation was observed during the task in the right hemispheric cerebellar lobules IV-V, right putamen, and bilateral sensorimotor cortices. Activation between timepoints was found to be moderately reproducible across time in the cerebellum but not in other brain regions., Discussion: Preliminary findings highlight the involvement of the cerebellum and connected cerebral regions during a motor speech task. More work is needed to determine the degree of reproducibility of speech fMRI before this could be used as a reliable marker of changes in brain activity., Competing Interests: GN and AdV were employed by Redenlab Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kenyon, Boonstra, Noffs, Morgan, Vogel, Kolbe and Van Der Walt.)

Purpose: Initially, prostate cancer responds to hormone therapy, but eventually resistance develops. Beta emitter-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs., Experimental Design: The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of 225Ac-macropa-pelgifatamab (225Ac-pelgi) and other TATs were investigated in cell line- and patient-derived prostate cancer xenograft models. The antitumor efficacy of 225Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide., Results: Actinium-225-labeling of 225Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both 225Ac-pelgi and 225Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, 225Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with 225Ac-DOTA-pelgi, 225Ac-DOTA-J591, and 227Th-HOPO-pelgifatamab (227Th-pelgi; all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. 225Ac-pelgi was less myelosuppressive than 227Th-pelgi. 225Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line- (22Rv1) and patient-derived (ST1273) xenograft models., Conclusions: These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase I study has been initiated (NCT06052306)., (©2024 American Association for Cancer Research.)

Up to half of all people with multiple sclerosis experience communication difficulties due to dysarthria, a disorder that impacts the motor aspects of speech production. Dysarthria in multiple sclerosis is linked to cerebellar dysfunction, disease severity and lesion load, but the neuroanatomical substrates of these symptoms remain unclear. In this study, 52 participants with multiple sclerosis and 14 age- and sex-matched healthy controls underwent structural and diffusion MRI, clinical assessment of disease severity and cerebellar dysfunction and a battery of motor speech tasks. Assessments of regional brain volume and white matter integrity, and their relationships with clinical and speech measures, were undertaken. White matter tracts of interest included the interhemispheric sensorimotor tract, cerebello-thalamo-cortical tract and arcuate fasciculus, based on their roles in motor and speech behaviours. Volumetric analyses were targeted to Broca's area, Wernicke's area, the corpus callosum, thalamus and cerebellum. Our results indicated that multiple sclerosis participants scored worse on all motor speech tasks. Fixel-based diffusion MRI analyses showed significant evidence of white matter tract atrophy in each tract of interest. Correlational analyses further indicated that higher speech naturalness-a perceptual measure of dysarthria-and lower reading rate were associated with axonal damage in the interhemispheric sensorimotor tract and left arcuate fasciculus in people with multiple sclerosis. Axonal damage in all tracts of interest also correlated with clinical scales sensitive to cerebellar dysfunction. Participants with multiple sclerosis had lower volumes of the thalamus and corpus callosum compared with controls, although no brain volumetrics correlated with measures of dysarthria. These findings indicate that axonal damage, particularly when measured using diffusion metrics, underpin dysarthria in multiple sclerosis., Competing Interests: K.H.K., F.M.C.B., M.S. and A.M. have nothing to disclose. A.v.d.W. served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche; has received speaker’s honoraria and travel support from Novartis, Roche and Merck; and receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. A.P.V. is the chief science officer of Redenlab Inc. G.N. works in the scientific development for Redenlab Inc. S.K. received unrestricted research grants from Biogen and grant support from MS Research Australia. I.H.H receives grants from the National Health and Medical Research Council and honoraria from Steminent Biotherapeutics and PTC therapeutics., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: PSMA (prostate-specific membrane antigen) is highly expressed on prostate cancer (PrCa) cells and extensively used as a homing target for PrCa treatment. Most prominently, PSMA-targeting conjugate PSMA-617, carrying a DOTA chelator and labeled with therapeutic radionuclides like beta-emitting lutetium-177 or alpha-emitting actinium-225, has shown clinical activity in PrCa patients. We sought to develop PSMA-targeting small molecule (SMOL) conjugates that show high uptake in PSMA-expressing tumors and fast clearance, and can easily be labeled with the alpha emitter thorium-227 (half-life 18.7 days)., Methods: A novel linker motif with improved competition against 3 H-PSMA-617 on PSMA-expressing LNCaP cells was identified. A 2,3-hydroxypyridinone chelator modified with carboxyl groups (carboxy-HOPO) with increased hydrophilicity and robust labeling with thorium-227 was developed and allowed the synthesis of mono-, di-, tri-, and tetrameric conjugates. The resulting monomeric and multimeric PSMA SMOL-TTCs (targeted thorium conjugate) were evaluated for cellular binding, internalization, and antiproliferative activity. The in vivo antitumor efficacy of the PSMA SMOL-TTCs was determined in ST1273 and KUCaP-1 PrCa models in mice, and their biodistribution was assessed in cynomolgus monkeys, minipigs, and mice., Results: The monomeric and multimeric PSMA SMOL conjugates were readily labeled with thorium-227 at room temperature and possessed high stability and good binding, internalization, and antiproliferative activity in vitro. In vivo, the monomeric, dimeric, and trimeric PSMA SMOL-TTCs showed fast clearance, potent antitumor efficacy, and high uptake and retention in prostate tumors in mice. No major uptake or retention in other organs was observed beyond kidneys. Low uptake of free thorium-227 into bone confirmed high complex stability in vivo. Salivary gland uptake remained inconclusive as mini pigs were devalidated as a relevant model and imaging controls failed in cynomolgus monkeys., Conclusion: Monomeric and multimeric PSMA SMOL-TTCs show high tumor uptake and fast clearance in preclinical models and warrant further therapeutic exploration., (© 2023. The Author(s).)

Targeted alpha therapies (TAT) are an innovative class of therapies for cancer treatment. The unique mode-of-action of TATs is the induction of deleterious DNA double-strand breaks. Difficult-to-treat cancers, such as gynecologic cancers upregulating the chemoresistance P-glycoprotein (p-gp) and overexpressing the membrane protein mesothelin (MSLN), are promising targets for TATs. Here, based on the previous encouraging findings with monotherapy, we investigated the efficacy of the mesothelin-targeted thorium-227 conjugate (MSLN-TTC) both as monotherapy and in combination with chemotherapies and antiangiogenic compounds in ovarian and cervical cancer models expressing p-gp. MSLN-TTC monotherapy showed equal cytotoxicity in vitro in p-gp-positive and -negative cancer cells, while chemotherapeutics dramatically lost activity on p-gp-positive cancer cells. In vivo, MSLN-TTC exhibited dose-dependent tumor growth inhibition with treatment/control ratios of 0.03-0.44 in various xenograft models irrespective of p-gp expression status. Furthermore, MSLN-TTC was more efficacious in p-gp-expressing tumors than chemotherapeutics. In the MSLN-expressing ST206B ovarian cancer patient-derived xenograft model, MSLN-TTC accumulated specifically in the tumor, which combined with pegylated liposomal doxorubicin (Doxil), docetaxel, bevacizumab, or regorafenib treatment induced additive-to-synergistic antitumor efficacy and substantially increased response rates compared with respective monotherapies. The combination treatments were well tolerated and only transient decreases in white and red blood cells were observed. In summary, we demonstrate that MSLN-TTC treatment shows efficacy in p-gp-expressing models of chemoresistance and has combination potential with chemo- and antiangiogenic therapies., (©2023 The Authors; Published by the American Association for Cancer Research.)

Multiple sclerosis (MS) is a progressive disease that often affects the cerebellum. It is characterised by demyelination, inflammation, and neurodegeneration within the central nervous system. Damage to the cerebellum in MS is associated with increased disability and decreased quality of life. Symptoms include gait and balance problems, motor speech disorder, upper limb dysfunction, and oculomotor difficulties. Monitoring symptoms is crucial for effective management of MS. A combination of clinical, neuroimaging, and task-based measures is generally used to diagnose and monitor MS. This paper reviews the present and new tools used by clinicians and researchers to assess cerebellar impairment in people with MS (pwMS). It also describes recent advances in digital and home-based monitoring for people with MS., (© 2022. The Author(s).)

Identifying when recovery from a sports-related concussion (SRC) has occurred remains a challenge in clinical practice. This study investigated the utility of ocular motor (OM) assessment to monitor recovery post-SRC between sexes and compared to common clinical measures. From 139 preseason baseline assessments (i.e. before they sustained an SRC), 18 (12 males, 6 females) consequent SRCs were sustained and the longitudinal follow-ups were collected at 2, 6, and 13 days post-SRC. Participants completed visually guided, antisaccade (AS), and memory-guided saccade tasks requiring a saccade toward, away from, and to a remembered target, respectively. Changes in latency (processing speed), visual-spatial accuracy, and errors were measured. Clinical measures included The Sports Concussion Assessment Tool, King-Devick test, Stroop task, and Digit span. AS latency was significantly longer at 2 days and returned to baseline by 13-days post-SRC in females only (P < 0.001). Symptom numbers recovered from 2 to 6 days and 13 days (P < 0.05). Persistently poorer AS visual-spatial accuracy was identified at 2, 6 and 13 days post-SRC (P < 0.05) in both males and females but with differing trajectories. Clinical measures demonstrated consistent improvement reminiscent of practice effects. OM saccade assessment may have improved utility in tracking recovery compared to conventional measures and between sexes., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We investigated choroid plexus (CP) volume in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs)., Methods: Three-dimensional (3D) T1, T2-FLAIR and diffusion-weighted sequences were acquired from 44 ON CIS patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 HCs were also included for comparison., Results: CP volumes was larger in both ON CIS and RRMS groups compared to HCs, but not significantly different between ON CIS and RRMS patients (analysis of covariance (ANCOVA) adjusted for multiple comparisons). Twenty-three ON CIS patients who converted to clinically definite MS (MS) demonstrated CP volume similar to RRMS patients, but significantly larger compared to HCs. In this sub-group, CP volume was not associated with the severity of optic nerve inflammation or long-term axonal loss, not with brain lesion load. A transient increase of CP volume was observed following an occurrence of new MS lesions on brain magnetic resonance imaging (MRI)., Interpretation: Enlarged CP can be observed very early in a disease. It transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.

Measuring tree response to wind loads is fundamental for the process-based analysis of wind-tree interactions. Comprehensive knowledge of wind-tree interactions enables the further development of decision support tools available for estimating the probability of wind damage to trees. The assessment of critical wind loads that lead to damage is particularly important. This paper describes the inexpensive Tree Strain Sensor (TSS) suitable for precisely measuring the response of tree parts to external loads such as pulling tests and natural wind loading. It is an addition to the recently developed Tree Motion Monitoring System (TreeMMoSys) but can also be used as a standalone device, allowing measurements necessary to estimate effective wind loads on trees., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Preclinical studies of remote degeneration have largely focused on brain changes over the first few days or weeks after stroke. Accumulating evidence suggests that neurodegeneration occurs in other brain regions remote to the site of infarction for months and even years following ischaemic stroke. Brain atrophy appears to be driven by both axonal degeneration and widespread brain inflammation. The evolution and duration of these changes are increasingly being described in human studies, using advanced brain imaging techniques. Here, we sought to investigate long-term structural brain changes in a model of mild focal ischaemic stroke following injection of endothlin-1 in adult Long-Evans rats ( n  = 14) compared with sham animals ( n  = 10), over a clinically relevant time-frame of 48 weeks. Serial structural and diffusion-weighted MRI data were used to assess dynamic volume and white matter trajectories. We observed dynamic regional brain volume changes over the 48 weeks, reflecting both normal changes with age in sham animals and neurodegeneration in regions connected to the infarct following ischaemia. Ipsilesional cortical volume loss peaked at 24 weeks but was less prominent at 36 and 48 weeks. We found significantly reduced fractional anisotropy in both ipsi- and contralesional motor cortex and cingulum bundle regions of infarcted rats ( P  < 0.05) from 4 to 36 weeks, suggesting ongoing white matter degeneration in tracts connected to but distant from the stroke. We conclude that there is evidence of significant cortical atrophy and white matter degeneration up to 48 weeks following infarct, consistent with enduring, pervasive stroke-related degeneration., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Black ash wetlands cover approximately 1.2 million ha of wetland forest in the western Great Lakes region, providing critical habitat for wildlife. The future of these wetlands is critically threatened by a variety of factors, including emerald ash borer (Agrilus planipennis; emerald ash borer [EAB]), which has been eliminating native populations of otherwise healthy ash throughout the Great Lakes region since it was discovered in 2002. To quantify the potential impacts of tree mortality from EAB on wildlife communities, we measured seasonal bird, mammal, and amphibian diversity in black ash wetlands using a dual approach: (1) documenting bird and amphibian species across 27 mature reference black ash wetlands in northern Minnesota, USA and (2) assessing how bird, mammal, and amphibian communities respond to experimental manipulations of black ash forests that emulate mortality and management strategies related to the potential impact of EAB. In total, 85 wildlife species were recorded for the entire study including 57 bird species, 5 amphibian species, and 23 mammal species. Results from the reference sites show that hydrologic regime, percentage of ash canopy cover, and understory cover were important habitat characteristics for bird and amphibian communities. Results from the experimental sites show there may be short-term increases in species richness for mammal and bird communities associated with changes in forest structure due to ash mortality; however, anticipated changes resulting from EAB-caused mortality, particularly the conversion of these sites to non-forested wetlands, will lead to significant shifts in bird and mammal community composition. Loss of ash may cause declines in forest-dependent species and increases in open-canopy and wetland-associated species. Additionally, whereas increased ponding extent and longer hydroperiods may be beneficial for some amphibian species, the loss of the forest canopy will result in an overall decrease in bird diversity and reduce forest connectivity for all species. Our results indicate the potential for significant large-scale impacts of black ash mortality on forest-associated wildlife. Management strategies that focus on establishing alternative trees species to maintain long-term forest cover and structural complexity in these wetlands will help to maintain and conserve wildlife diversity., (© 2022 The Ecological Society of America.)

Objective: To investigate the factors influencing enlarged perivascular space (EPVS) characteristics at the onset of acute ischemic stroke (AIS), and whether the PVS characteristics can predict later post-stroke epilepsy (PSE)., Methods: A total of 312 patients with AIS were identified, of whom 58/312 (18.6%) developed PSE. Twenty healthy participants were included as the control group. The number of PVS in the basal ganglia (BG), centrum semiovale (CS), and midbrain (MB) was manually calculated on T 2 -weighted MRI. The scores and asymmetry index (AI) of EPVS in each region were compared among the enrolled participants. Other potential risk factors for PSE were also analyzed, including NIHSS at admission and stroke etiologies., Results: The EPVS scores were significantly higher in the bilateral BG and CS of AIS patients compared to those of the control group (both p < 0.01). No statistical differences in EPVS scores in BG, CS, and MB were obtained between the PSE group and the nonepilepsy AIS group (all p > 0.01). However, markedly different AI scores in CS were found between the PSE group and the nonepilepsy AIS group (p = 0.004). Multivariable analysis showed that high asymmetry index of EPVS (AI≥0.2) in CS was an independent predictor for PSE (OR = 3.7, 95% confidence interval 1.5-9.1, p = 0.004)., Conclusions: Asymmetric distribution of EPVS in CS may be an independent risk factor and a novel imaging biomarker for the development of PSE. Further studies to understand the mechanisms of this association and confirmation with larger patient populations are warranted., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases., Methods: We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma., Results: Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth., Conclusions: These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Purpose: Perivascular spaces surround the blood vessels of the brain and are involved in neuroimmune functions and clearance of metabolites via the glymphatic system of the brain. Enlarged perivascular spaces could be a marker of dysfunction in these processes and, therefore, are highly relevant to monitoring disease activity in MS. This study aimed to compare the number of enlarged perivascular spaces in people with relapsing MS with MR imaging markers of inflammation and brain atrophy., Materials and Methods: Fifty-nine patients (18 with clinically isolated syndrome, 22 with early and 19 with late relapsing-remitting MS) were scanned longitudinally (mean follow-up duration = 19.6 [SD, 0.5] months) using T2-weighted, T1-weighted, and FLAIR MR imaging. Two expert raters identified and counted enlarged perivascular spaces on T2-weighted MR images from 3 ROIs (the centrum semiovale, basal ganglia, and midbrain). Baseline and change with time in the number of enlarged perivascular spaces were correlated with demographics and lesion and brain volumes., Results: Late relapsing-remitting MS had a greater average number of enlarged perivascular spaces at baseline at the level of the basal ganglia (72.3) compared with early relapsing-remitting MS (60.5) and clinically isolated syndrome (54.7) ( F  = 3.4, P  = .042), and this finding correlated with lesion volume ( R  = 0.44, P  = .0004) but not brain atrophy ( R = -0.16). Enlarged perivascular spaces increased in number with time in all regions, and the rate of increase did not differ among clinical groups., Conclusions: Enlarged perivascular spaces at the level of the basal ganglia are associated with greater neuroinflammatory burden, and the rate of enlargement appears constant in patients with relapsing-remitting disease phenotypes., (© 2022 by American Journal of Neuroradiology.)

Introduction: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP., Methods and Analysis: This will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures., Ethics and Dissemination: The study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12620001254987)., Competing Interests: Competing interests: All authors report a grant from the NHMRC to support this study. The authors report the following disclosures outside of this study: LV reports personal fees from Biogen Australia, and research funding from Biogen, Eisai and LMI. AHE reports honoraria for presentations from Merck, Allergan, Ipsen, Teva, UCB, Abbott, AbbVie, STADA, participation in scientific advisory board meetings with Allergan, AbbVie, Ipsen and STADA and shares in GKC and CSL. DD reports consultancy fees from Biogen, Novartis. KLB, CMalpas, CMarotta, IHH, SK, JF, MC, SJGL, ST, JDOS, TK, LC, ML, CMH and DV report no disclosures., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of this study was to investigate effects of high LET α-radiation in combination with inhibitors of DDR (DNA-PK and ATM) and to compare the effect with the radiosensitizing effect of low LET X-ray radiation. The various cell lines were irradiated with α-radiation and with X-ray. Clonogenic survival, the formation of micronuclei and cell cycle distribution were studied after combining of radiation with DDR inhibitors. The inhibitors sensitized different cancer cell lines to radiation. DNA-PKi affected survival rates in combination with α-radiation in selected cell lines. The sensitization enhancement ratios were in the range of 1.6-1.85 in cancer cells. ATMi sensitized H460 cells and significantly increased the micronucleus frequency for both radiation qualities. ATMi in combination with α-radiation reduced survival of HEK293. A significantly elicited cell cycle arrest in G 2 /M phase after co-treatment of ATMi with α-radiation and X-ray. The most prominent treatment effect was observed in the HEK293 by combining α-radiation and inhibitions. ATMi preferentially sensitized cancer cells and normal HEK293 cells to α-radiation. DNA-PKi and ATMi can sensitize cancer cells to X-ray, but the effectiveness was dependent on cancer cells itself. α-radiation reduced proliferation in primary fibroblast without G 2 /M arrest., (© 2021. The Author(s).)

Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organization. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "Fixel-Based Analysis" (FBA) framework, which implements bespoke solutions to this end. It has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to Fixel-Based Analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of all current FBA studies, categorized across a broad range of neuro-scientific domains, listing key design choices and summarizing their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the FBA framework, and outline some directions and future opportunities., (Copyright © 2021. Published by Elsevier Inc.)

Sports-related concussion (SRC) is a form of mild traumatic brain injury that has been linked to long-term neurological abnormalities. Australian rules football is a collision sport with wide national participation and is growing in popularity worldwide. However, the chronic neurological consequences of SRC in Australian footballers remain poorly understood. This study investigated the presence of brain abnormalities in Australian footballers with a history of sports-related concussion (HoC) using multimodal MRI. Male Australian footballers with HoC (n = 26), as well as noncollision sport athletes with no HoC (n = 27), were recruited to the study. None of the footballers had sustained a concussion in the preceding 6 months, and all players were asymptomatic. Data were acquired using a 3T MRI scanner. White matter integrity was assessed using diffusion tensor imaging. Cortical thickness, subcortical volumes, and cavum septum pellucidum (CSP) were analyzed using structural MRI. Australian footballers had evidence of widespread microstructural white matter damage and cortical thinning. No significant differences were found regarding subcortical volumes or CSP. These novel findings provide evidence of persisting white and gray matter abnormalities in Australian footballers with HoC, and raise concerns related to the long-term neurological health of these athletes., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

In this paper, two novel consistency vectors are proposed, which when combined with appropriate machine learning algorithms, can be used to adapt the Spectral Kurtosis technology for optimum gearbox damage diagnosis in varying operating conditions. Much of the existing research in the field is limited to test apparatus run in constant and carefully controlled operating conditions, and the authors have previously publicised that the Spectral Kurtosis technology requires adaptation to achieve the highest possible probabilities of correct diagnosis when a gearbox is run in non-stationary conditions of speed and load. However, the authors' previous adaptation has been computationally heavy using a brute-force approach unsuited to online use, and therefore, created the requirement to develop these two newly proposed vectors and allow computationally lighter techniques more suited to online condition monitoring. The new vectors are demonstrated and experimentally validated on vibration data collected from a gearbox run in multiple combinations of operating conditions; for the first time, the two consistency vectors are used to predict diagnosis effectiveness, with the comparison and proof of relative gains between the traditional and novel techniques discussed. Consistency calculations are computationally light and thus, many combinations of Spectral Kurtosis technology parameters can be evaluated on a dataset in a very short time. This study shows that machine learning can predict the total probability of correct diagnosis from the consistency values and this can quickly provide pre-adaptation/prediction of optimum Spectral Kurtosis technology parameters for a dataset. The full adaptation and damage evaluation process, which is computationally heavier, can then be undertaken on a much lower number of combinations of Spectral Kurtosis resolution and threshold.

Background: Targeted thorium-227 conjugates (TTCs) are an emerging class of targeted alpha therapies (TATs). Their unique mode of action (MoA) is the induction of difficult-to-repair clustered DNA double-strand breaks. However, thus far, their effects on the immune system are largely unknown. Here, we investigated the immunostimulatory effects of the mesothelin-targeted thorium-227 conjugate (MSLN-TTC) in vitro and in vivo in monotherapy and in combination with an inhibitor of the immune checkpoint programmed death receptor ligand 1 (PD-L1) in immunocompetent mice., Methods: The murine cell line MC38 was transfected with the human gene encoding for MSLN (hMSLN) to enable binding of the non-cross-reactive MSLN-TTC. The immunostimulatory effects of MSLN-TTC were studied in vitro on human cancer cell lines and MC38-hMSLN cells. The efficacy and MoA of MSLN-TTC were studied in vivo as monotherapy or in combination with anti-PD-L1 in MC38-hMSLN tumor-bearing immunocompetent C57BL/6 mice. Experiments were supported by RNA sequencing, flow cytometry, immunohistochemistry, mesoscale, and TaqMan PCR analyses to study the underlying immunostimulatory effects. In vivo depletion of CD8+ T cells and studies with Rag2/Il2Rg double knockout C57BL/6 mice were conducted to investigate the importance of immune cells to the efficacy of MSLN-TTC., Results: MSLN-TTC treatment induced upregulation of DNA sensing pathway transcripts ( IL-6 , CCL20 , CXCL10 , and stimulator of interferon genes ( STING )-related genes) in vitro as determined by RNASeq analysis. The results, including phospho-STING activation, were confirmed on the protein level. Danger-associated molecular pattern molecules were upregulated in parallel, leading to dendritic cell (DC) activation in vitro . MSLN-TTC showed strong antitumor activity (T:C 0.38, p<0.05) as a single agent in human MSLN-expressing MC38 tumor-bearing immunocompetent mice. Combining MSLN-TTC with anti-PD-L1 further enhanced the efficacy (T:C 0.08, p<0.001) as evidenced by the increased number of tumor-free surviving animals. MSLN-TTC monotherapy caused migration of CD103+ cDC1 DCs and infiltration of CD8+ T cells into tumors, which was enhanced on combination with anti-PD-L1. Intriguingly, CD8+ T-cell depletion decreased antitumor efficacy., Conclusions: These in vitro and in vivo data on MSLN-TTC demonstrate that the MoA of TTCs involves activation of the immune system. The findings are of relevance for other targeted radiotherapies and may guide clinical combination strategies., Competing Interests: Competing interests: PL, VC, ABL, AS, AM, LB, SB, SZK, CK, SS, SH, CS, HH, JK, AC, DM, and UH are employees of Bayer AG or Bayer AS. AS, SB, SH, CS, HH, and DM are shareholders of Bayer AG. PL, SH, JK, AC, and UH hold patents on targeted thorium-227 conjugates., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Eukaryotes have evolved two major pathways to repair potentially lethal DNA double-strand breaks. Homologous recombination represents a precise, DNA-template-based mechanism available during the S and G2 cell cycle phase, whereas non-homologous end joining, which requires DNA-dependent protein kinase (DNA-PK), allows for fast, cell cycle-independent but less accurate DNA repair. Here, we report the discovery of BAY-8400 , a novel selective inhibitor of DNA-PK. Starting from a triazoloquinoxaline, which had been identified as a hit from a screen for ataxia telangiectasia and Rad3-related protein (ATR) inhibitors with inhibitory activity against ATR, ATM, and DNA-PK, lead optimization efforts focusing on potency and selectivity led to the discovery of BAY-8400 . In in vitro studies, BAY-8400 showed synergistic activity of DNA-PK inhibition with DNA damage-inducing targeted alpha therapy. Combination of PSMA-targeted thorium-227 conjugate BAY 2315497 treatment of human prostate tumor-bearing mice with BAY-8400 oral treatment increased antitumor efficacy, as compared to PSMA-targeted thorium-227 conjugate monotherapy.

Purpose: Androgen receptor (AR) inhibitors are well established in the treatment of castration-resistant prostate cancer and have recently shown efficacy also in castration-sensitive prostate cancer. Although most patients respond well to initial therapy, resistance eventually develops, and thus, more effective therapeutic approaches are needed. Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and presents an attractive target for radionuclide therapy. Here, we evaluated the efficacy and explored the mode of action of the PSMA-targeted thorium-227 conjugate (PSMA-TTC) BAY 2315497, an antibody-based targeted alpha-therapy, in combination with the AR inhibitor darolutamide., Experimental Design: The in vitro and in vivo antitumor efficacy and mode of action of the combination treatment were investigated in preclinical cell line-derived and patient-derived prostate cancer xenograft models with different levels of PSMA expression., Results: Darolutamide induced the expression of PSMA in androgen-sensitive VCaP and LNCaP cells in vitro , and the efficacy of darolutamide in combination with PSMA-TTC was synergistic in these cells. In vivo , the combination treatment showed synergistic antitumor efficacy in the low PSMA-expressing VCaP and in the high PSMA-expressing ST1273 prostate cancer models, and enhanced efficacy in the enzalutamide-resistant KUCaP-1 model. The treatments were well tolerated. Mode-of-action studies revealed that darolutamide induced PSMA expression, resulting in higher tumor uptake of PSMA-TTC, and consequently, higher antitumor efficacy, and impaired PSMA-TTC-mediated induction of DNA damage repair genes, potentially contributing to increased DNA damage., Conclusions: These results provide a strong rationale to investigate PSMA-TTC in combination with AR inhibitors in patients with prostate cancer., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations., Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes., Results: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%., Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: Quantitative susceptibility mapping (QSM) is a novel MR technique that allows mapping of tissue susceptibility values from MR phase images. QSM is an ill-conditioned inverse problem, and although several methods have been proposed in the field, in the presence of a wide range of susceptibility sources, streaking artifacts appear around high susceptibility regions and contaminate the whole QSM map. QSMART is a post-processing pipeline that uses two-stage parallel inversion to reduce the streaking artifacts and remove banding artifact at the cortical surface and around the vasculature., Method: Tissue and vein susceptibility values were separately estimated by generating a mask of vasculature driven from the magnitude data using a Frangi filter. Spatially dependent filtering was used for the background field removal step and the two susceptibility estimates were combined in the final QSM map. QSMART was compared to RESHARP/iLSQR and V-SHARP/iLSQR inversion in a numerical phantom, 7T in vivo single and multiple-orientation scans, 9.4T ex vivo mouse data, and 4.7T in vivo rat brain with induced focal ischemia., Results: Spatially dependent filtering showed better suppression of phase artifacts near cortex compared to RESHARP and V-SHARP, while preserving voxels located within regions of interest without brain edge erosion. QSMART showed successful reduction of streaking artifacts as well as improved contrast between different brain tissues compared to the QSM maps obtained by RESHARP/iLSQR and V-SHARP/iLSQR., Conclusion: QSMART can reduce QSM artifacts to enable more robust estimation of susceptibility values in vivo and ex vivo., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Severe storms caused the largest amount of damaged timber in European forests in the past 70 years. Storm damage occurs when wind loads exceed the failure limits of trees. A decisive factor in assessing storm damage is comprehensive knowledge of interactions between the aerial parts of trees and the high-impact airflow. This paper describes the inexpensive multiple sensor system TreeMMoSys that can measure aerial tree parts' wind-induced reactions, including branches and the stem. The output of TreeMMoSys includes acceleration and angular rate data converted to tilt angles in the post-processing. The system consists of a scalable number of light-weight tree response sensors and ground receivers that communicate through a WLAN network. The weatherproofed system is highly portable, reusable, and allows for an efficient monitoring and a maximization of the number of study trees. Due to the stable measurement performance and accuracy of TreeMMoSys, it can be deployed in the field for long-term monitoring of single tree reactions or neighboring trees' reactions to wind excitation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Targeted α therapy (TAT) offers the potential for the targeted delivery of potent α-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 ( 223 Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 ( 227 Th), the progenitor nuclide of 223 Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.

Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody., Experimental Design: PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity in vitro . Biodistribution, pharmacokinetics, and antitumor efficacy were investigated in vivo using cell line and patient-derived xenograft (PDX) models of prostate cancer., Results: PSMA-TTC was selectively internalized into PSMA-positive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis in vitro . Decrease in cell viability was observed dependent on the cellular PSMA expression levels. In vivo, PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both in vitro and in vivo ., Conclusions: The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747)., (©2019 American Association for Cancer Research.)

Targeted alpha therapy is an emerging innovative approach for the treatment of advanced cancers, in which targeting agents deliver radionuclides directly to tumors and metastases. The biological effects of α-radiation are still not fully understood - partly due to the lack of sufficiently accurate research methods. The range of α-particles is <100 μm, and therefore, standard in vitro assays may underestimate α-radiation-specific radiation effects. In this report we focus on α-radiation-induced DNA lesions, DNA repair as well as cellular responses to DNA damage. Herein, we used Ra-223 to deliver α-particles to various tumor cells in a Transwell system. We evaluated the time and dose-dependent biological effects of α-radiation on several tumor cell lines by biological endpoints such as clonogenic survival, cell cycle distribution, comet assay, foci analysis for DNA damage, and calculated the absorbed dose by Monte-Carlo simulations. The radiobiological effects of Ra-223 in various tumor cell lines were evaluated using a novel in vitro assay designed to assess α-radiation-mediated effects. The α-radiation induced increasing levels of DNA double-strand breaks (DSBs) as detected by the formation of 53BP1 foci in a time- and dose-dependent manner in tumor cells. Short-term exposure (1-8 h) of different tumor cells to α-radiation was sufficient to double the number of cells in G 2 /M phase, reduced cell survival to 11-20% and also increased DNA fragmentation measured by tail intensity (from 1.4 to 3.9) dose-dependently. The α-particle component of Ra-223 radiation caused most of the Ra-223 radiation-induced biological effects such as DNA DSBs, cell cycle arrest and micronuclei formation, leading ultimately to cell death. The variable effects of α-radiation onto the different tumor cells demonstrated that tumor cells show diverse sensitivity towards damage caused by α-radiation. If these differences are caused by genetic alterations and if the sensitivity could be modulated by the use of DNA damage repair inhibitors remains a wide field for further investigations.

Background: Biomarkers are urgently required for predicting the likely progression of multiple sclerosis (MS) at the earliest stages of the disease to aid in personalised therapy., Objective: We aimed to examine early brain volumetric and microstructural changes and retinal nerve fibre layer thinning as predictors of longer term MS severity in patients with clinically isolated syndromes (CIS)., Methods: Lesion metrics, brain and regional atrophy, diffusion fractional anisotropy and retinal nerve fibre layer thickness were prospectively assessed in 36 patients with CIS over the first 12 months after presentation and compared with clinical outcomes at longer term follow-up [median (IQR) = 8.5 (7.8-8.9) years]., Results: In total, 25 (69%) patients converted to MS and had greater baseline lesion volume ( p  = 0.008) and number ( p  = 0.03)than CIS patients. Over the initial 12 months, new lesions ( p  = 0.0001), retinal nerve fibre layer thinning ( p  = 0.04) and ventricular enlargement ( p  = 0.03) were greater in MS than CIS patients. In MS patients, final Expanded Disability Status Scale score correlated with retinal nerve fibre layer thinning over the first 12 months (ρ = -0.67, p  = 0.001)., Conclusions: Additional to lesion metrics, early measurements of fractional anisotropy and retinal nerve fibre layer thinning are informative about longer term clinical outcomes in CIS.

Cognitive dysfunction can be identified in patients with clinically isolated syndromes suggestive of multiple sclerosis using ocular motor testing. This study aimed to identify the functional neural correlates of cognitive dysfunction in patients with clinically isolated syndrome using MRI. Eighteen patients with clinically isolated syndrome and 17 healthy controls were recruited. Subjects underwent standard neurological and neuropsychological testing. Subjects also underwent functional MRI (fMRI) during a cognitive ocular motor task, involving pro-saccade (direct gaze towards target) and anti-saccade (direct gaze away from target) trials. Ocular motor performance variables (averaged response time and error rate) were calculated for each subject. Patients showed a trend towards a greater rate of anti-saccade errors (p = 0.09) compared to controls. Compared to controls, patients exhibited increased activation in the right postcentral, right supramarginal gyrus, and the right parietal operculum during the anti-saccade>pro-saccade contrast. This study demonstrated that changes in functional organisation of cognitive brain networks is associated with subtle cognitive changes in patients with clinically isolated syndrome., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Parameter mapping in sodium MRI data is challenging due to inherently low SNR and spatial resolution, prompting the need to employ robust models and estimation techniques. This work aims to develop a continuum model of sodium T 2 * -decay to overcome the limitations of the commonly employed bi-exponential models. Estimates of mean T 2 * -decay and fast component fraction in tissue are emergent from the inferred continuum model., Methods: A closed-form continuum model was derived assuming a gamma distribution of T 2 * components. Sodium MRI was performed on four healthy human subjects and a phantom consisting of closely packed vials filled with an aqueous solution of varying sodium and agarose concentrations. The continuum model was applied to the phantom and in vivo human multi-echo 7T data. Parameter maps by voxelwise model-fitting were obtained., Results: The continuum model demonstrated comparable estimation performance to the bi-exponential model. The parameter maps provided improved contrast between tissue structures. The fast component fraction, an indicator of the heterogeneity of localised sodium motion regimes in tissue, was zero in CSF and high in WM structures., Conclusions: The continuum distribution model provides high quality, high contrast parameter maps, and informative voxelwise estimates of the relative weighting between fast and slow decay components., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: The catalytic function of BUB1 is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors and plays only a minor role in spindle assembly checkpoint activation. Here, we present the identification and preclinical pharmacologic profile of the first BUB1 kinase inhibitor with good bioavailability., Experimental Design: The Bayer compound library was screened for BUB1 kinase inhibitors and medicinal chemistry efforts to improve target affinity and physicochemical and pharmacokinetic parameters resulting in the identification of BAY 1816032 were performed. BAY 1816032 was characterized for kinase selectivity, inhibition of BUB1 signaling, and inhibition of tumor cell proliferation alone and in combination with taxanes, ATR, and PARP inhibitors. Effects on tumor growth in vivo were evaluated using human triple-negative breast xenograft models., Results: The highly selective compound BAY 1816032 showed long target residence time and induced chromosome mis-segregation upon combination with low concentrations of paclitaxel. It was synergistic or additive in combination with paclitaxel or docetaxel, as well as with ATR or PARP inhibitors in cellular assays. Tumor xenograft studies demonstrated a strong and statistically significant reduction of tumor size and excellent tolerability upon combination of BAY 1816032 with paclitaxel or olaparib as compared with the respective monotherapies., Conclusions: Our findings suggest clinical proof-of-concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors to enhance their efficacy and potentially overcome resistance., (©2018 American Association for Cancer Research.)

Despite the recent advances in the treatment of ovarian cancer, it remains an area of high unmet medical need. Epithelial ovarian cancer is associated with high levels of mesothelin expression, and therefore, mesothelin is an attractive candidate target for the treatment of this disease. Herein, we investigated the antitumor efficacy of the mesothelin-targeting antibody-drug conjugate (ADC) anetumab ravtansine as a novel treatment option for ovarian cancer in monotherapy and in combination with the antitumor agents pegylated liposomal doxorubicin (PLD), carboplatin, copanlisib and bevacizumab. Anetumab ravtansine showed potent antitumor activity as a monotherapy in ovarian cancer models with high mesothelin expression. No activity was seen in mesothelin-negative models. The combination of anetumab ravtansine with PLD showed additive anti-proliferative activity in vitro , which translated into improved therapeutic in vivo efficacy in ovarian cancer cell line- and patient-derived xenograft (PDX) models compared to either agents as a monotherapy. The combination of anetumab ravtansine with the PI3Kα/δ inhibitor copanlisib was additive in the OVCAR-3 and OVCAR-8 cell lines in vitro , showing increased apoptosis in response to the combination treatment. In vivo , the combination of anetumab ravtansine with copanlisib resulted in more potent antitumor activity than either of the treatments alone. Likewise, the combination of anetumab ravtansine with carboplatin or bevacizumab showed improved in vivo efficacy in the ST081 and OVCAR-3 models, respectively. All combinations were well-tolerated. Taken together, these data support the development of anetumab ravtansine for ovarian cancer treatment and highlight its suitability for combination therapy with PLD, carboplatin, copanlisib, or bevacizumab., Competing Interests: CONFLICTS OF INTEREST Conflicts of interest: Quanz, Hagemann, Zitzmann-Kolbe, Stelte-Ludwig, Golfier, Elbi, Mumberg, Ziegelbauer and Schatz are employees of Bayer AG, Cem Elbi is an employee of Bayer US LLS. Mumberg and Ziegelbauer have ownership interest as shares in Bayer AG.

Tremor in people with multiple sclerosis (MS) is a frequent and debilitating symptom with a relatively poorly understood pathophysiology. To determine the relationship between clinical tremor severity and structural magnetic resonance imaging parameters. Eleven patients with clinically definite MS and right-sided upper limb tremor were studied. Tremor severity was assessed using the Bain score (overall severity, writing, and Archimedes spiral drawing). Cerebellar dysfunction was assessed using the Scale for the Assessment and Rating of Ataxia. Dystonia was assessed using the Global Dystonia Scale adapted for upper limb. For all subjects, volume was calculated for the thalamus from T1-weighted volumetric scans using Freesurfer. Superior cerebellar peduncle (SCP) cross-sectional areas were measured manually. The presence of lesions was visually determined and the lesion volumes were calculated by the lesion growth algorithm as implemented in the Lesion Segmentation Toolbox. Right thalamic volume negatively correlated with Bain tremor severity score (ρ = - 0.65, p = 0.03). Left thalamic volume negatively correlated with general Bain tremor severity score (ρ = - 0.65, p = 0.03) and the Bain writing score (ρ = - 0.65, p = 0.03). Right SCP area negatively correlated with Bain writing score (ρ = - 0.69, p = 0.02). Finally, Bain Archimedes score was significantly higher in patients with lesions in the contralateral thalamus. Whole brain lesion load showed no relationship with tremor severity. These results implicate degeneration of key structures within the cerebello-thalamic pathway as pathological substrates for tremor in MS patients.

Long term irreversible disability in multiple sclerosis (MS) is thought to be primarily driven by axonal degeneration. Axonal degeneration leads to degenerative atrophy, therefore early markers of axonal degeneration are required to predict clinical disability and treatment efficacy. Given that additional pathologies such as inflammation, demyelination and oedema are also present in MS, it is essential to develop axonal markers that are not confounded by these processes. The present study investigated a novel method for measuring axonal degeneration in MS based on high angular resolution diffusion magnetic resonance imaging. Unlike standard methods, this novel method involved advanced acquisition and modelling for improved axonal sensitivity and specificity. Recent work has developed analytical methods, two novel axonal markers, fibre density and cross-section, that can be estimated for each fibre direction in each voxel (termed a "fixel"). This technique, termed fixel-based analysis, thus simultaneously estimates axonal density and white matter atrophy from specific white matter tracts. Diffusion-weighted imaging datasets were acquired for 17 patients with a history of acute unilateral optic neuritis (35.3 ± 10.2 years, 11 females) and 14 healthy controls (32.7 ± 4.8 years, 8 females) on a 3 T scanner. Fibre density values were compared to standard diffusion tensor imaging parameters (fractional anisotropy and mean diffusivity) in lesions and normal appearing white matter. Group comparisons were performed for each fixel to assess putative differences in fibre density and fibre cross-section. Fibre density was observed to have a comparable sensitivity to fractional anisotropy for detecting white matter pathology in MS, but was not affected by crossing axonal fibres. Whole brain fixel-based analysis revealed significant reductions in fibre density and fibre cross-section in the inferior fronto-occipital fasciculus (including the optic radiations) of patients compared to controls. We interpret this result to indicate that this fixel-based approach is able to detect early loss of fibre density and cross-section in the optic radiations in MS patients with a history of optic neuritis. Fibre-specific markers of axonal degeneration should be investigated further for use in early stage therapeutic trials, or to monitor axonal injury in early stage MS.

Objective: To examine the interrelationships between fragile X mental retardation 1 ( FMR1 ) mRNA and the FMR1 exon 1/intron 1 boundary methylation, white matter microstructure, and executive function, in women with a FMR1 premutation expansion (PM; 55-199 CGG repeats) and controls (CGG < 44)., Methods: Twenty women with PM without fragile X-associated tremor/ataxia syndrome (FXTAS) and 20 control women between 22 and 54 years of age completed this study. FMR1 mRNA and methylation levels for 9 CpG sites within the FMR1 exon 1/intron 1 boundary from peripheral blood samples were analyzed. To measure white matter microstructure, diffusion-weighted imaging was used, from which fractional anisotropy (FA) and mean diffusivity (MD) values from anatomic regions within the corpus callosum and cerebellar peduncles were extracted. Executive function was assessed across a range of tasks., Results: No differences were revealed in white matter microstructure between women with PM and controls. However, we reveal that for women with PM (but not controls), higher FMR1 mRNA correlated with lower MD values within the middle cerebellar peduncle and Paced Auditory Serial Addition Test scores, higher methylation of the FMR1 exon 1/intron 1 boundary correlated with lower MD within the inferior and middle cerebellar peduncles and longer prosaccade latencies, and higher FA values within the corpus callosum and cerebellar peduncle regions corresponded to superior executive function., Conclusions: We provide evidence linking white matter microstructure to executive dysfunction and elevated FMR1 mRNA and FMR1 exon 1/intron 1 boundary methylation in women with PM without FXTAS. This suggests that the FXTAS phenotype may not be distinct but may form part of a spectrum of PM involvement., (© 2017 American Academy of Neurology.)