Neuroanatomical distribution of fluorophores within adult RXFP3 Cre-tdTomato/YFP mouse brain.

Relaxin-family peptide 3 receptor (RXFP3) is activated by relaxin-3 in the brain to influence arousal and related functions, such as feeding and stress responses. Two transgenic mouse lines have recently been developed that co-express different fluorophores within RXFP3-expressing neurons: either yellow fluorescent protein (YFP; RXFP3-Cre/YFP mice) or tdTomato (RXFP3-Cre/tdTomato mice). To date, the characteristics of neurons that express RXFP3-associated fluorophores in these mice have only been investigated in the bed nucleus of the stria terminalis and the hypothalamic arcuate nucleus. To better determine the utility of these fluorophore-expressing mice for further research, we characterised the neuroanatomical distribution of fluorophores throughout the brain of these mice and compared this to the published distribution of Rxfp3 mRNA (detected by in situ hybridisation) in wildtype mice. Coronal sections of RXFP3-Cre/YFP (n = 8) and RXFP3-Cre/tdTomato (n = 8) mouse brains were imaged, and the density of fluorophore-expressing cells within various brain regions/nuclei was qualitatively assessed. Comparisons with our previously reported RXFP3 mRNA distribution revealed that of 212 brain regions that contained either fluorophore or RXFP3 mRNA, approximately half recorded densities that were within two qualitative measurements of each other (on a 9-point scale), including hippocampal dentate gyrus and amygdala subregions. However, many brain areas with likely non-authentic, false-positive, or false-negative fluorophore expression were also detected, including the cerebellum. Therefore, this study provides a guide to which brain regions should be prioritized for future study of RXFP3 in these mice, to better understand the neuroanatomy and function of this intriguing, neuronal peptide receptor.

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma.

Paediatric and adult astrocytomas are notably different, where clinical treatments used for adults are not as effective on children with the same form of cancer and these treatments lead to adverse long-term health concerns. Integrative omics-based studies have shown the pathology and fundamental molecular characteristics differ significantly and cannot be extrapolated from the more widely studied adult disease. Recent clinical advances in our understanding of paediatric astrocytomas, with the aid of next-generation sequencing and epigenome-wide profiling, have led to the identification of key canonical mutations that vary based on the tumour location and age of onset. These driver mutations, in particular the identification of the recurrent histone H3 mutations in high-grade tumours, have confirmed the important role epigenetic dysregulations play in cancer progression. This review summarises the current updates of the classification, epidemiology, pathogenesis and clinical management of paediatric astrocytoma based on their grades and the ongoing clinical trials. It also provides novel insights on genetic and epigenetic alterations as diagnostic biomarkers, highlighting the potential of targeting these pathways as therapeutics for this devastating childhood cancer.

Lithium use and bone health in women with bipolar disorder: A cross-sectional study.

INTRODUCTION: Several psychiatric disorders and medications used to treat them appear to be independently associated with skeletal deficits. As there is increasing evidence that lithium possesses skeletal protective properties, we aimed to investigate the association between lithium use and bone health in a group of women with bipolar disorder. METHOD: Women with bipolar disorder (n = 117, 20+ years) were recruited from south-eastern Australia. Bipolar disorder was confirmed using a clinical interview (SCID-I/NP). Bone mineral density (BMD; g/cm2 ) was measured at the spine, hip and total body using dual-energy x-ray absorptiometry and low bone mass determined by BMD T-score of <-1.0. Weight and height were measured, socioeconomic status (SES) determined and information on medication use and lifestyle factors self-reported. Linear and logistic regression were used to test associations between lithium and (i) BMD and (ii) low bone mass, respectively. RESULTS: Thirty-five (29.9%) women reported current lithium use. Lithium users and non-users differed in regard to SES and BMD; otherwise, groups were similar. After adjustments, mean BMD among lithium users was 5.1% greater at the spine (1.275 [95% CI 1.229-1.321] vs. 1.214 [1.183-1.244] g/cm2 , p = 0.03), 4.2% greater at the total hip (0.979 [0.942-1.016] vs. 0.938 [0.910-0.966] g/cm2 , p = 0.03) and 2.2% greater at the total body (1.176 [1.148-1.205] vs. 1.150 [1.129-1.171] g/cm2 , p = 0.08) compared to participants not receiving lithium. Lithium users were also less likely to have low bone mass (22.9% vs. 43.9%, p = 0.031). Associations persisted after adjustment for confounders. CONCLUSION: These data suggest lithium is associated with greater BMD and reduced risk of low bone mass in women with bipolar disorder. Research into the underlying mechanisms is warranted.

Unravelling the Glioblastoma Tumour Microenvironment: Can Aptamer Targeted Delivery Become Successful in Treating Brain Cancers?

The key challenges to treating glioblastoma multiforme (GBM) are the heterogeneous and complex nature of the GBM tumour microenvironment (TME) and difficulty of drug delivery across the blood-brain barrier (BBB). The TME is composed of various neuronal and immune cells, as well as non-cellular components, including metabolic products, cellular interactions, and chemical compositions, all of which play a critical role in GBM development and therapeutic resistance. In this review, we aim to unravel the complexity of the GBM TME, evaluate current therapeutics targeting this microenvironment, and lastly identify potential targets and therapeutic delivery vehicles for the treatment of GBM. Specifically, we explore the potential of aptamer-targeted delivery as a successful approach to treating brain cancers. Aptamers have emerged as promising therapeutic drug delivery vehicles with the potential to cross the BBB and deliver payloads to GBM and brain metastases. By targeting specific ligands within the TME, aptamers could potentially improve treatment outcomes and overcome the challenges associated with larger therapies such as antibodies.

Biofabrication of functional bone tissue: defining tissue-engineered scaffolds from nature.

Damage to bone leads to pain and loss of movement in the musculoskeletal system. Although bone can regenerate, sometimes it is damaged beyond its innate capacity. Research interest is increasingly turning to tissue engineering (TE) processes to provide a clinical solution for bone defects. Despite the increasing biomimicry of tissue-engineered scaffolds, significant gaps remain in creating the complex bone substitutes, which include the biochemical and physical conditions required to recapitulate bone cells' natural growth, differentiation and maturation. Combining advanced biomaterials with new additive manufacturing technologies allows the development of 3D tissue, capable of forming cell aggregates and organoids based on natural and stimulated cues. Here, we provide an overview of the structure and mechanical properties of natural bone, the role of bone cells, the remodelling process, cytokines and signalling pathways, causes of bone defects and typical treatments and new TE strategies. We highlight processes of selecting biomaterials, cells and growth factors. Finally, we discuss innovative tissue-engineered models that have physiological and anatomical relevance for cancer treatments, injectable stimuli gels, and other therapeutic drug delivery systems. We also review current challenges and prospects of bone TE. Overall, this review serves as guide to understand and develop better tissue-engineered bone designs.

Antipsychotic medication use and fracture: a case-control study.

It has been reported that antipsychotic use is associated with lower bone mineral density and bone quality. We aimed to determine whether antipsychotic use is associated with fracture risk in a population-based sample of adults living in the Barwon Statistical Division, south-eastern Australia. In this case-control study, 1458 participants (51.8% women) with radiologically confirmed fracture between June 1st 2012 and May 31st 2013 (cases) were compared with 1795 participants (46.5% women) without fracture (controls) for the same time period. Medication use, medical history and lifestyle factors were documented by self-report. Multivariable binary logistic regression was used to explore associations between antipsychotic use and fracture following adjustment for possible confounders. In women, antipsychotic use was identified for 20 of 755 (2.6%) cases and 10 of 834 (1.2%) controls (p = 0.034) and in men, antipsychotic use was identified for 13 of 703 (1.8%) cases and 5 of 961 (0.5%) controls (p = 0.010). Following adjustments, antipsychotic use was associated with a 3.0-fold increased risk of fracture in men and a 2.3-fold increased risk of fracture in women. Patterns persisted after exclusion of participants with non-fragility fractures and self-reported schizophrenia. While future research exploring underlying mechanisms is needed, regular monitoring of bone health in antipsychotic users is suggested.

Antipsychotic medication use in association with quantitative heel ultrasound (QUS).

Purpose: Antipsychotic medication use has been associated with decreased bone mineral density; however, less is known whether antipsychotics affect other parameters of bone health. Therefore, the aim of this study was to investigate the association between antipsychotic medication use and quantitative heel ultrasound (QUS) in a population based sample of men and women. Methods: Thirty-one antipsychotic users and 155 non-users matched for age and sex were drawn from the Geelong Osteoporosis Study. QUS was undertaken and included the parameters: Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI). Current medication use, lifestyle factors, anthropometry and socio-economic status were collected. Generalized Estimation Equation models were conducted to determine associations between antipsychotic medication use and each of the QUS parameters, adjusting for covariates. Results: Antipsychotic users were less active, consumed less alcohol, were more likely to smoke and take antidepressants; otherwise, the groups were similar. After adjusting for age, sex and weight, antipsychotic users had a 7.7 % lower mean BUA [108.70 (95 % CI 104.26-113.14) vs. 116.42 (95 % CI 115.48-117.37) dB/MHz, p = 0.005] and 7.4 % lower mean SI [89.92 (95 % CI 86.89-92.95) vs. 97.30 (95 % CI 96.48-98.12) %, p < 0.001] compared to non-users. Differences in mean SOS between antipsychotic users and non-users failed to reach statistical significance (p = 0.07). Conclusion: Antipsychotic use was associated with lower QUS parameters. The risk of bone deterioration should be considered when antipsychotics are prescribed.

Antipsychotic-induced bone loss: the role of dopamine, serotonin and adrenergic receptor signalling.

Antipsychotics are commonly used in treating psychiatric disorders. These medications primarily target dopamine the serotonin receptors, they have some affinity to adrenergic, histamine, glutamate and muscarinic receptors. There is clinical evidence that antipsychotic use decreases BMD and increases fracture risk, with dopamine, serotonin and adrenergic receptor-signalling becoming an increasing area of focus where the presence of these receptors in osteoclasts and osteoblasts have been demonstrated. Osteoclasts and osteoblasts are the most important cells in the bone remodelling and the bone regeneration process where the activity of these cells determine the bone resorption and formation process in order to maintain healthy bone. However, an imbalance in osteoclast and osteoblast activity can lead to decreased BMD and increased fracture risk, which is also believed to be exacerbated by antipsychotics use. Therefore, the aim of this review is to provide an overview of the mechanisms of action of first, second and third generation antipsychotics and the expression profiles of dopamine, serotonin and adrenergic receptors during osteoclastogenesis and osteoblastogenesis.

Lipopolysaccharide-binding protein and bone health: data from a population-based sample of men.

We aimed to investigate the association between serum lipopolysaccharide-binding protein (LBP) and bone health in men. LBP was associated with lower bone density at the mid-forearm and the quantitative heel ultrasound measure, broadband ultrasound attenuation, for heavier participants. Data do not support clear associations between serum LBP and bone health. INTRODUCTION: The objective of this study was to investigate the association between serum lipopolysaccharide-binding protein (LBP) and potential downstream effects on skeletal density, quality, and turnover in a population-based sample of men. METHODS: This cross-sectional study utilised data from 1149 men (aged 20-96 year) enrolled in the Geelong Osteoporosis Study. Blood samples were obtained and lipopolysaccharide-binding protein (LBP), bone resorption marker, C-telopeptide (CTx), and formation marker, type 1 procollagen amino-terminal-propeptide (P1NP), were measured. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Stiffness Index (SI), broadband ultrasound attenuation (BUA), and speed of sound (SOS) were derived from quantitative heel ultrasound (QUS). Linear regression models were developed to test associations between log-transformed LBP (ln-LBP), BMD, QUS, and bone turnover, after adjusting for potential covariates. RESULTS: Serum LBP ranged from 1.07-208.53 ng/mL (median 16.53 ng/mL). Those with higher levels were older, less mobile, and had lower BMD at the mid-forearm, otherwise, groups were similar. Before and after adjustment for age, ln-LBP was associated with lower BMD at the spine, total body, and mid-forearm. Further adjustment for weight attenuated associations at the spine and total body, yet the relationship at the mid-forearm was sustained (ß - 0.014 ± 0.004, p = 0.001). SOS and SI were not associated with ln-LBP either before or after adjustment for age; however, weight was identified as an effect modifier in the relationship between ln-LBP and BUA. An association was observed for those weighing greater than 82.7 kg (ß 3.366 ± 0.929, p < 0.001), after adjustment for potential covariates. Neither bone turnover marker was associated with ln-LBP. CONCLUSION: Our data do not support a clear association between serum LBP and measures of bone health in this sample of men.

Zebrafish Models of Paediatric Brain Tumours.

Paediatric brain cancer is the second most common childhood cancer and is the leading cause of cancer-related deaths in children. Despite significant advancements in the treatment modalities and improvements in the 5-year survival rate, it leaves long-term therapy-associated side effects in paediatric patients. Addressing these impairments demands further understanding of the molecularity and heterogeneity of these brain tumours, which can be demonstrated using different animal models of paediatric brain cancer. Here we review the use of zebrafish as potential in vivo models for paediatric brain tumour modelling, as well as catalogue the currently available zebrafish models used to study paediatric brain cancer pathophysiology, and discuss key findings, the unique attributes that these models add, current challenges and therapeutic significance.

Self-Assembled Peptide Habitats to Model Tumor Metastasis.

Metastatic tumours are complex ecosystems; a community of multiple cell types, including cancerous cells, fibroblasts, and immune cells that exist within a supportive and specific microenvironment. The interplay of these cells, together with tissue specific chemical, structural and temporal signals within a three-dimensional (3D) habitat, direct tumour cell behavior, a subtlety that can be easily lost in 2D tissue culture. Here, we investigate a significantly improved tool, consisting of a novel matrix of functionally programmed peptide sequences, self-assembled into a scaffold to enable the growth and the migration of multicellular lung tumour spheroids, as proof-of-concept. This 3D functional model aims to mimic the biological, chemical, and contextual cues of an in vivo tumor more closely than a typically used, unstructured hydrogel, allowing spatial and temporal activity modelling. This approach shows promise as a cancer model, enhancing current understandings of how tumours progress and spread over time within their microenvironment.

Triple-negative breast cancer brain metastasis: An update on druggable targets, current clinical trials, and future treatment options.

The key challenges with the treatment of triple-negative breast cancer brain metastasis (TNBC-BM) are the lack of any targeted therapy and difficulties associated with drug delivery to the brain. These add to the high toxicity profile of existing treatments and the poor outcomes for patient. In this review, we introduce current drugs based on their molecular targets and look to improve brain drug delivery using more efficient and promising drug delivery systems. We describe ongoing clinical trials on druggable targets in TNBC-BM for a more targeted treatment and introduce the obstacles hindering drug delivery to the brain, bringing strategies and advancing knowledge for future steps in the treatment of patients with TNBC-BM.

Use of antipsychotic medication and its relationship with bone mineral density: A population-based study of men and women.

Background: Schizophrenia has been shown to be associated with reduced bone mineral density (BMD) and higher fracture risk. However, less is known whether antipsychotic treatment is associated with reduced BMD. Thus, we aimed to examine associations between antipsychotic use and BMD among men and women drawn from the general population. Methods: This cross-sectional study involved 793 women and 587 men enrolled in the Geelong Osteoporosis Study (GOS). BMD was determined using dual-energy X-ray absorptiometry at the spine and hip. Information regarding socio-economic status (SES), current medication and/or supplementation use, lifestyle factors, and anthropometry was collected. Association between antipsychotic use and BMD was determined using linear regression after adjusting for potential confounders. Results: Of the group, 33 women (4.2%) and 16 men (2.7%) currently used antipsychotics. Age was identified as an effect modifier in the association between antipsychotic use and BMD for women. Amongst women aged < 60 years, adjusted mean BMD was 11.1% lower at the spine [1.139 (95%CI 1.063-1.216) vs. 1.250 (95%CI 1.223-1.277) g/cm2, p = 0.005] for antipsychotic users compared to non-users. At the hip, age, weight, and smoking adjusted mean BMD was 9.9% lower [0.893 (95%CI 0.837-0.950) vs. 0.992 (95%CI 0.976-1.007) g/cm2, p < 0.001] for antipsychotic users in comparison with non-users. The pattern persisted following further adjustments. There was no association detected between antipsychotic use and BMD for women aged 60 years and over and for men. Conclusion: Our data suggest that antipsychotic medication use is associated with reduced BMD in younger women but not older women or men.

Anticonvulsant use and fracture: a case-control study.

OBJECTIVES: We aimed to investigate fracture risk associated with anticonvulsant use in a population-based sample of men and women. METHODS: Data from 1,458 participants (51.8% women) with a radiologically confirmed incident fracture (cases) were compared to 1,796 participants (46.5% women) without fracture (controls). Lifestyle factors, medication use and medical history were self-reported. Associations between anticonvulsant use and fracture were explored using binary logistic regression following adjustment for confounders. RESULTS: In men, fracture cases and controls differed in age, smoking history, education, alcohol use, and gonadal hormone supplementation. In women, fracture cases and controls differed by previous fracture history, alcohol use, physical activity levels and use of anti-fracture agents. After adjustment for age, pooled anticonvulsant use was associated with a 3.4-fold higher risk of fracture in men and a 1.8-fold higher risk in women. Following further adjustments for confounders these patterns persisted; a 2.8-fold higher fracture risk in men and a 1.8-fold higher fracture risk in women. CONCLUSIONS: Anticonvulsant use was associated with increased fracture risk, independent of demographic, lifestyle, medical and medication related factors. While further studies exploring potential underlying mechanisms are warranted, regular monitoring of bone health in anticonvulsant users with risk factors may be useful.

Augmented reality in medical education: students' experiences and learning outcomes.

Augmented reality (AR) is a relatively new technology that allows for digitally generated three-dimensional representations to be integrated with real environmental stimuli. AR can make use of smart phones, tablets, or other devices to achieve a highly stimulating learning environment and hands-on immersive experience. The use of AR in industry is becoming widespread with applications being developed for use not just for entertainment and gaming but also healthcare, retail and marketing, education, military, travel and tourism, automotive industry, manufacturing, architecture, and engineering. Due to the distinct learning advantages that AR offers, such as remote learning and interactive simulations, AR-based teaching programs are also increasingly being adopted within medical schools across the world. These advantages are further highlighted by the current COVID-19 pandemic, which has caused an even greater shift towards online learning. In this review, we investigate the use of AR in medical training/education and its effect on students' experiences and learning outcomes. This includes the main goals of AR-based learning, such as to simplify the delivery and enhance the comprehension of complex information. We also describe how AR can enhance the experiences of medical students, by improving knowledge and understanding, practical skills and social skills. These concepts are discussed within the context of specific AR medical training programs, such as HoloHuman, OculAR SIM, and HoloPatient. Finally, we discuss the challenges of AR in learning and teaching and propose future directions for the use of this technology in medical education.

Anticonvulsant use and bone health in a population-based study of men and women: cross-sectional data from the Geelong Osteoporosis Study.

BACKGROUND: Anticonvulsant use has been linked to bone deficits in specific patient populations. We studied the association between anticonvulsant use and bone health in a population-based sample of men and women. METHODS: Data from 926 men (24-73 yr) and 1070 women (21-94 yr) participating in the Geelong Osteoporosis Study were included. Bone mineral density (BMD, g/cm2) of the PA-spine and total hip was measured using dual-energy X-ray absorptiometry (Lunar). Bone quality was determined using quantitative heel ultrasound (QUS). Anthropometry was conducted and socioeconomic status was determined. Medication and lifestyle information was obtained via questionnaire. Linear regression was used to test associations between anticonvulsant use and bone health before and after adjustment for potential confounders. RESULTS: Seventeen (1.8%) men and 20 (1.9%) women reported anticonvulsant use. In men, anticonvulsant users had 9.1% lower adjusted mean BMD at the spine and hip compared to non-users. Body mass index was an effect modifier at the spine. Anticonvulsant users also had 1.8% lower speed of sound (SOS), 10.6% lower broadband ultrasound attenuation (BUA) and 13.7% lower stiffness index (SI) compared to non-users. In women, BMD tended to be lower at the hip compared to non-users as with the bone quality measure, BUA. No significant associations were observed at the spine or the other bone quality measures, SOS and SI. CONCLUSION: Our data suggest that bone quantity and quality, assessed using BMD and QUS, are lower for men and possibly women who use anticonvulsants. While further exploration into potential mechanisms is needed, our findings suggest that monitoring bone health among users of anticonvulsants is warranted.

Dietary tryptophan and bone health: a cross-sectional, population-based study.

Tryptophan metabolites influence bone. We aimed to investigate the relationship between dietary tryptophan and bone health in a population-based sample of men and women. Following adjustment for age, dietary tryptophan was not associated with bone quantity or quality, suggesting a non-critical role of superfluous tryptophan on the skeleton. PURPOSE: Tryptophan metabolites, such as serotonin, influence bone. We sought to determine the relationship between dietary intake of tryptophan and bone health in a population-based study of men and women. METHODS: Participants (1033 women and 900 men, aged 20-98 years) enrolled in the Geelong Osteoporosis Study (GOS) were investigated. Dietary information was collected using a validated questionnaire. Tryptophan levels were calculated (mg/day) in accordance with Food Standards Australia and New Zealand and dichotomised according to the median. Bone mineral density (BMD; g/cm2) was measured at the spine (postero-anterior projection) and total hip using dual-energy X-ray absorptiometry. Stiffness index (SI), broadband ultrasound attenuation (BUA) and speed of sound (SOS) were derived from quantitative heel ultrasound. Linear regression models were used to test associations between dietary tryptophan and bone health, after adjustment for potential confounders. RESULTS: Tryptophan intakes ranged from 112 to 3796 mg/day (median 1035) in men and 115-2869 mg/day (median 885) in women. In men older than 45 years and women, a high tryptophan intake was associated with greater hip BMD compared to participants with a low tryptophan intake (p = 0.002 and p = 0.04, respectively); however, these relationships were attenuated by age (all p > 0.05). Participants with high tryptophan intake had greater BUA and SI compared to participants with low tryptophan intake (men; BUA, p = 0.02 and SI, p = 0.02, and women; BUA, p = 0.03 and SI, p = 0.08), yet also attenuated by age (all p > 0.05). CONCLUSION: No association was found between tryptophan intake and bone health in this population, which suggests a non-critical role of superfluous tryptophan consumption on the skeleton.

Non-Invasive Delivery of Therapeutics into the Brain: The Potential of Aptamers for Targeted Delivery.

The blood-brain barrier (BBB) is a highly specialised network of blood vessels that effectively separates the brain environment from the circulatory system. While there are benefits, in terms of keeping pathogens from entering the brain, the BBB also complicates treatments of brain pathologies by preventing efficient delivery of macromolecular drugs to diseased brain tissue. Although current non-invasive strategies of therapeutics delivery into the brain, such as focused ultrasound and nanoparticle-mediated delivery have shown various levels of successes, they still come with risks and limitations. This review discusses the current approaches of therapeutic delivery into the brain, with a specific focus on non-invasive methods. It also discusses the potential for aptamers as alternative delivery systems and several reported aptamers with promising preliminary results.

Antibodies, Nanobodies, or Aptamers-Which Is Best for Deciphering the Proteomes of Non-Model Species?

This planet is home to countless species, some more well-known than the others. While we have developed many techniques to be able to interrogate some of the "omics", proteomics is becoming recognized as a very important part of the puzzle, given how important the protein is as a functional part of the cell. Within human health, the proteome is fairly well-established, with numerous reagents being available to decipher cellular pathways. Recent research advancements have assisted in characterizing the proteomes of some model (non-human) species, however, in many other species, we are only just touching the surface. This review considers three main reagent classes-antibodies, aptamers, and nanobodies-as a means of continuing to investigate the proteomes of non-model species without the complications of understanding the full protein signature of a species. Considerations of ease of production, potential applications, and the necessity for producing a new reagent depending on homology are presented.

Multimodal Nanomedicine Strategies for Targeting Cancer Cells as well as Cancer Stem Cell Signalling Mechanisms.

Increasing evidence suggests that stem cells, a small population of cells with unique selfrenewable and tumour regenerative capacity, are aiding tumour re-growth and multidrug resistance. Conventional therapies are highly ineffective at eliminating these cells leading to relapse of disease and formation of chemoresistance tumours. Cancer and stem cells targeted therapies that utilizes nanotherapeutics to delivery anti-cancer drugs to specific sites are continuously investigated. This review focuses on recent research using nanomedicine and targeting entities to eliminate cancer cells and cancer stem cells. Current nanotherapeutics in clinical trials along with more recent publications on targeted therapies are addressed.