Quality assurance assessment of intra-acquisition diffusion-weighted and T2-weighted magnetic resonance imaging registration and contour propagation for head and neck cancer radiotherapy.

BACKGROUND/PURPOSE: Adequate image registration of anatomical and functional magnetic resonance imaging (MRI) scans is necessary for MR-guided head and neck cancer (HNC) adaptive radiotherapy planning. Despite the quantitative capabilities of diffusion-weighted imaging (DWI) MRI for treatment plan adaptation, geometric distortion remains a considerable limitation. Therefore, we systematically investigated various deformable image registration (DIR) methods to co-register DWI and T2-weighted (T2W) images. MATERIALS/METHODS: We compared three commercial (ADMIRE, Velocity, Raystation) and three open-source (Elastix with default settings [Elastix Default], Elastix with parameter set 23 [Elastix 23], Demons) post-acquisition DIR methods applied to T2W and DWI MRI images acquired during the same imaging session in twenty immobilized HNC patients. In addition, we used the non-registered images (None) as a control comparator. Ground-truth segmentations of radiotherapy structures (tumour and organs at risk) were generated by a physician expert on both image sequences. For each registration approach, structures were propagated from T2W to DWI images. These propagated structures were then compared with ground-truth DWI structures using the Dice similarity coefficient and mean surface distance. RESULTS: 19 left submandibular glands, 18 right submandibular glands, 20 left parotid glands, 20 right parotid glands, 20 spinal cords, and 12 tumours were delineated. Most DIR methods took <30 s to execute per case, with the exception of Elastix 23 which took ∼458 s to execute per case. ADMIRE and Elastix 23 demonstrated improved performance over None for all metrics and structures (Bonferroni-corrected p < 0.05), while the other methods did not. Moreover, ADMIRE and Elastix 23 significantly improved performance in individual and pooled analysis compared to all other methods. CONCLUSIONS: The ADMIRE DIR method offers improved geometric performance with reasonable execution time so should be favoured for registering T2W and DWI images acquired during the same scan session in HNC patients. These results are important to ensure the appropriate selection of registration strategies for MR-guided radiotherapy.

The Australian Temperament Project Generation 3 study: a population-based multigenerational prospective cohort study of socioemotional health and development.

PURPOSE: The Australian Temperament Project Generation 3 Study (ATPG3) was established to examine the extent to which offspring social and emotional development is shaped in the decades prior to conception, in parent and grandparent histories of psychosocial adjustment (eg, emotional regulation, relationship quality and prosociality) and maladjustment (eg, depressive symptoms, substance use and antisociality). PARTICIPANTS: The Australian Temperament Project (ATP) commenced in 1983 as a population representative survey of the social and emotional health of 2443 young Australians (Generation 2: 4-8 months old) and their parents (Generation 1). Since then, families have been followed from infancy to young adulthood (16 waves). Between 2012 and 2018, the cohort was screened biannually for pregnancies (Generation 3), with assessments conducted in the third trimester of pregnancy, and at 8 weeks and 1 year postpartum. FINDINGS TO DATE: A total of 1167 offspring (607 female) born to 703 Generation 2 parents (400 mothers) were recruited into the ATPG3 Study. Findings to date highlight: (1) strong continuities in depressive symptoms and substance use from adolescence through to becoming a parent; (2) a role for persistent preconception mental health problems in risk for parent-child bonding difficulties, as well as infant emotional reactivity and behaviour problems; (3) the importance of secure attachments in adolescence in reducing long-term risk for postpartum mental health problems; and (4) the protective nature of perceived social support, both preconception and postpartum, in strengthening relationship quality and social support during the COVID-19 pandemic. FUTURE PLANS: Assessments of ATPG3 families in preschool and middle childhood are currently funded and underway. We intend to maintain the offspring cohort through childhood, adolescence, young adulthood and into parenthood. Data will be used to map preconception determinants of emotional health, and enhance approaches to population monitoring and targeted intervention over the life course and across generations.

Dysregulation of Tweak and Fn14 in skeletal muscle of spinal muscular atrophy mice.

BACKGROUND: Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. METHODS: We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-; SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations. RESULTS: Here, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/-, and Fn14-/- mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models. CONCLUSIONS: Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.

Embryonic myosin is a regeneration marker to monitor utrophin-based therapies for DMD.

Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. Constitutive utrophin expression, a structural and functional paralogue of dystrophin, can successfully prevent the dystrophic pathology in the dystrophin-deficient mdx mouse model. In dystrophic muscles, utrophin is increased as part of the repair process and localized at the sarcolemma of regenerating myofibers. The presence of developmental myosin such as embryonic myosin (MyHC-emb) and neonatal represents a useful marker of muscle regeneration and a meaningful indicator of muscle damage, which correlates with the clinical severity of milder Becker muscular dystrophy and DMD patients. In the present study, we demonstrate that MyHC-emb is a robust marker of regeneration at different ages and in different skeletal muscles. We also evaluate the correlation between utrophin, dystrophin and MyHC-emb in wild-type (wt) and regenerating dystrophic muscles. Restoration of dystrophin significantly reduced MyHC-emb levels. Similarly, overexpression of utrophin in the transgenic mdx-Fiona mice reduced the number of MyHC-emb positive fibers to wt level, prevented the regenerative process and rescued the muscle function. In contrast, the absence of utrophin in the dystrophin-deficient double-knockout mice resulted in a higher MyHC-emb content and in a more severe dystrophic pathophysiology than in mdx mice. These data illustrate the importance of monitoring utrophin and MyHC-emb levels in the preclinical evaluation of therapies and provide translational support for the use of developmental myosin as a disease biomarker in DMD clinical trials.

Characterisation of ground motion recording stations in the Groningen gas field.

The seismic hazard and risk analysis for the onshore Groningen gas field requires information about local soil properties, in particular shear-wave velocity (VS). A fieldwork campaign was conducted at 18 surface accelerograph stations of the monitoring network. The subsurface in the region consists of unconsolidated sediments and is heterogeneous in composition and properties. A range of different methods was applied to acquire in situ VS values to a target depth of at least 30 m. The techniques include seismic cone penetration tests (SCPT) with varying source offsets, multichannel analysis of surface waves (MASW) on Rayleigh waves with different processing approaches, microtremor array, cross-hole tomography and suspension P-S logging. The offset SCPT, cross-hole tomography and common midpoint cross-correlation (CMPcc) processing of MASW data all revealed lateral variations on length scales of several to tens of metres in this geological setting. SCPTs resulted in very detailed VS profiles with depth, but represent point measurements in a heterogeneous environment. The MASW results represent VS information on a larger spatial scale and smooth some of the heterogeneity encountered at the sites. The combination of MASW and SCPT proved to be a powerful and cost-effective approach in determining representative VS profiles at the accelerograph station sites. The measured VS profiles correspond well with the modelled profiles and they significantly enhance the ground motion model derivation. The similarity between the theoretical transfer function from the VS profile and the observed amplification from vertical array stations is also excellent.

Extracellular Signal-Regulated Kinase Signaling in CD4-Expressing Cells Inhibits Osteochondromas.

Defects in cartilage homeostasis can give rise to various skeletal disorders including osteochondromas. Osteochondromas are benign bone tumors caused by excess accumulation of chondrocytes, the main cell type of cartilage. The extracellular signal-regulated kinase (ERK) pathway is a major signaling node that functions within chondrocytes to regulate their growth and differentiation. However, it is not known whether the ERK pathway in other cell types regulates cartilage homeostasis. We show here that mice with a germline deficiency of Erk1 and a conditional deletion of Erk2 in cells that express CD4, or expressed CD4 at one point in development, unexpectedly developed bone deformities. The bone lesions were due to neoplastic outgrowths of chondrocytes and disordered growth plates, similar to tumors observed in the human disease, osteochondromatosis. Chondrocyte accumulation was not due to deletion of Erk2 in the T cells. Rather, CD4cre was expressed in cell types other than T cells, including a small fraction of chondrocytes. Surprisingly, the removal of T cells accelerated osteochondroma formation and enhanced disease severity. These data show for the first time that T cells impact the growth of osteochondromas and describe a novel model to study cartilage homeostasis and osteochondroma formation.

Drak2 is not required for tumor surveillance and suppression.

Drak2 is a promising therapeutic target to treat organ-specific autoimmune diseases such as type 1 diabetes and multiple sclerosis without causing generalized immune suppression. Inhibition of Drak2 may also prevent graft rejection following organ transplantation. However, Drak2 may function as a critical tumor suppressor, which would challenge the prospect of targeting Drak2 for therapeutic treatment. Thus, we examined the susceptibility of Drak2 (-/-) mice in several tumor models. We show that Drak2 is not required to prevent tumor formation in a variety of settings. Therefore, Drak2 does not function as an essential tumor suppressor in in vivo tumor models. These data further validate Drak2 as a viable therapeutic target to treat autoimmune disease and graft rejection. Importantly, these data also indicate that while Drak2 may induce apoptosis when overexpressed in cell lines, it is not an essential tumor suppressor.

Oxr1 is essential for protection against oxidative stress-induced neurodegeneration.

Oxidative stress is a common etiological feature of neurological disorders, although the pathways that govern defence against reactive oxygen species (ROS) in neurodegeneration remain unclear. We have identified the role of oxidation resistance 1 (Oxr1) as a vital protein that controls the sensitivity of neuronal cells to oxidative stress; mice lacking Oxr1 display cerebellar neurodegeneration, and neurons are less susceptible to exogenous stress when the gene is over-expressed. A conserved short isoform of Oxr1 is also sufficient to confer this neuroprotective property both in vitro and in vivo. In addition, biochemical assays indicate that Oxr1 itself is susceptible to cysteine-mediated oxidation. Finally we show up-regulation of Oxr1 in both human and pre-symptomatic mouse models of amyotrophic lateral sclerosis, indicating that Oxr1 is potentially a novel neuroprotective factor in neurodegenerative disease.

Some chronobiological and physiological problems associated with long-distance journeys.

Long-distance travel is becoming increasingly common. Whatever the means of transport, any long journey will be associated with "travel fatigue". The symptoms associated with this phenomenon result from a changed routine (particularly sleep lost and meals) and the general disruption caused by travel. Planning any trip well in advance will minimise many of these problems, but some factors are less easy to guard against. These problems include sitting in cramped and uncomfortable conditions and, with flights, the hypoxic environment in the cabin. After arrival at the destination in another country, there can be problems coping with the local language, alterations in food and different customs. If the flight has crossed the equator, then there is likely to be a change in season and natural lighting and, if it has crossed several time zones, there will also be the problem of "jet lag", caused by a transient desynchrony between the "body clock" and the new local time. Moreover, the new environment might differ from the place of departure with regard to ambient temperature and humidity, altitude, natural lighting (including ultraviolet radiation) and pollution. The traveller needs to be aware of these changes before setting off, so that appropriate preparations (clothing, for example) can be made.

Syntheses and preliminary biological studies of four meso-Tetra[(nido-carboranylmethyl)phenyl]porphyrins.

Two meso-tetra[(nido-carboranylmethyl)phenyl]porphyrins (para- and meta-regioisomers) and their corresponding Zn(II) complexes have been synthesized with the aim of studying the effect of carborane distribution and metalation on the biological properties of this series of compounds. In vitro cell toxicity, uptake/efflux, and subcellular localization using rat 9L, mouse B16 and/or human U-373MG cells were evaluated. All four amphiphilic porphyrins display very low cytotoxicities and time- and concentration-dependent uptake by cells, which is influenced by serum proteins. Preliminary subcellular localization studies suggest that one of these compounds localizes in close proximity to the cell nucleus. All four nido-carboranylporphyrins show promise as boron-carriers for the boron neutron capture therapy of cancers, particularly the metal-free nido-carboranylporphyrins 5 and 12, which are able to deliver higher amount of boron to cells in vitro than the corresponding zinc complexes.