Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.

Supraphysiological androgen (SPA) treatment can paradoxically restrict growth of castration-resistant prostate cancer with high androgen receptor (AR) activity, which is the basis for use of Bipolar Androgen Therapy (BAT) for patients with this disease. While androgens are widely appreciated to enhance anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. Here, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models.

Cognitive heterogeneity in Attention Deficit Hyperactivity Disorder: Implications for maths.

This study investigated whether cognitive function better predicted maths test performance than a clinical diagnosis of attention deficit hyperactivity disorder (ADHD). Forty-four drug naïve children (M = 101.34 months, SD = 19.

Co-production of the 'EPIC' multidimensional tool-kit to support neurodivergent children and young people at home and school: a feasibility and pilot study.

Background: Interventions focused on cognitive function in neurodivergent children typically focus on single functions, e.g. working memory training.

The Synergistic Benefit of Combination Strategies Targeting Tumor Cell Polyamine Homeostasis.

Mammalian polyamines, including putrescine, spermidine, and spermine, are positively charged amines that are essential for all living cells including neoplastic cells. An increasing understanding of polyamine metabolism, its molecular functions, and its role in cancer has led to the interest in targeting polyamine metabolism as an anticancer strategy, as the metabolism of polyamines is frequently dysregulated in neoplastic disease. In addition, due to compensatory mechanisms, combination therapies are clinically more promising, as agents can work synergistically to achieve an effect beyond that of each strategy as a single agent.

Polyamine Depletion by D, L-alpha-difluoromethylornithine Inhibits Ewing Sarcoma Metastasis by Inducing Ferroptosis.

Polyamine metabolism and signaling play important roles in multiple cancers but have not previously been studied in Ewing sarcoma. Here, we show that blocking polyamine synthesis with D, L-alpha-difluoromethylornithine (DFMO) causes a G1 cell cycle arrest, dose-dependent decreases in sarcosphere formation from Ewing sarcoma cell lines growing in non-adherent conditions and a decrease in clonogenic growth in soft agar. Further, we utilized our orthotopic implantation/amputation model of Ewing sarcoma metastasis to demonstrate that DFMO slowed primary tumor growth in addition to limiting metastasis.

The Polyamine Analogue Ivospemin Increases Chemotherapeutic Efficacy in Murine Ovarian Cancer.

Polyamines are small polycationic alkylamines that are absolutely required for the continual growth and proliferation of cancer cells. The polyamine analogue ivospemin, also known as SBP-101, has shown efficacy in slowing pancreatic and ovarian tumor progression in vitro and in vivo and has demonstrated encouraging results in early pancreatic cancer clinical trials. We sought to determine if ivospemin was a viable treatment option for the under-served platinum-resistant ovarian cancer patient population by testing its efficacy in combination with commonly used chemotherapeutics.

Cognitive Profiles are Better Predictors of Literacy Attainment Than Diagnostic Outcomes in Children with High ADHD Symptoms.

We examined whether cognitive profiles or diagnostic outcomes are better predictors of literacy performance for children being considered for an ADHD diagnosis. Fifty-five drug naïve children (M = 103.13 months, SD = 18.

Snyder-Robinson syndrome presenting with learning disability, epilepsy, and osteoporosis: a novel gene variant.

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder characterized by a collection of clinical features including mild to severe intellectual disability, hypertonia, marfanoid habitus, facial asymmetry, osteoporosis, developmental delay and seizures. Whole genome sequencing (WGS) identified a mutation in the spermine synthase () gene (c.746 A>G, p.

Polyamines: the pivotal amines in influencing the tumor microenvironment.

Cellular proliferation, function and survival is reliant upon maintaining appropriate intracellular polyamine levels. Due to increased metabolic needs, cancer cells elevate their polyamine pools through coordinated metabolism and uptake. High levels of polyamines have been linked to more immunosuppressive tumor microenvironments (TME) as polyamines support the growth and function of many immunosuppressive cell types such as MDSCs, macrophages and regulatory T-cells.

Reduction of spermine synthase enhances autophagy to suppress Tau accumulation.

Precise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder-Robinson intellectual disability syndrome (SRS), characterized by significant spermidine accumulation and autophagy blockage in the nervous system. Emerging evidence connects polyamine metabolism with other autophagy-related diseases, such as Tauopathy, however, the functional intersection between polyamine metabolism and autophagy in the context of these diseases remains unclear.

Polyamine Catabolism and Its Role in Renal Injury and Fibrosis in Mice Subjected to Repeated Low-Dose Cisplatin Treatment.

Cisplatin, a chemotherapeutic agent, can cause nephrotoxic and ototoxic injuries. Using a mouse model of repeated low dose cisplatin (RLDC), we compared the kidneys of cisplatin- and vehicle-treated mice on days 3 (early injury phase) and 35 (late injury/recovery phase) after the final treatment. RNA-seq analyses revealed increases in the expression of markers of kidney injury (e.

Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome.

Snyder-Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment.

Editorial to the Special Issue on "Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention".

To introduce this Special Issue, I refer the reader to the timely review by Zahedi and colleagues [...

Polyamine transport inhibition and cisplatin synergistically enhance tumor control through oxidative stress in murine head and neck cancer models.

Background: Surgery and/or platinum-based chemoradiation remain standard of care for patients with head and neck squamous cell carcinoma (HNSCC). While these therapies are effective in a subset of patients, a substantial proportion experience recurrence or treatment resistance. As cisplatin mediates cytotoxicity through oxidative stress while polyamines play a role in redox regulation, we posited that combining cisplatin with polyamine transport inhibitor, AMXT-1501, would increase oxidative stress and tumor cell death in HNSCC cells.

Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.

DHPS deficiency is a rare genetic disease caused by biallelic hypomorphic variants in the () gene. The DHPS enzyme functions in mRNA translation by catalyzing the post-translational modification, and therefore activation, of eukaryotic initiation factor 5A (eIF5A). The observed clinical outcomes associated with human mutations in include developmental delay, intellectual disability, and seizures.

Lived experiences of depression in autistic children and adolescents: A qualitative study on child and parent perspectives.

Background: Depression is highly prevalent in autistic children and adolescents. Despite this, little is known about the nature of the autistic child's subjective experience of depression and the impact of depression on their lives.

Methods: We therefore conducted a qualitative study using thematic analysis with 7 autistic children and adolescents and their parents to identify common themes and individual differences.

Reduction of Spermine Synthase Suppresses Tau Accumulation Through Autophagy Modulation in Tauopathy.

Tauopathy, including Alzheimer Disease (AD), is characterized by Tau protein accumulation and autophagy dysregulation. Emerging evidence connects polyamine metabolism with the autophagy pathway, however the role of polyamines in Tauopathy remains unclear. In the present study we investigated the role of spermine synthase (SMS) in autophagy regulation and tau protein processing in and human cellular models of Tauopathy.

Cognition and maths in children with Attention-Deficit/Hyperactivity disorder with and without co-occurring movement difficulties.

Background: Movement difficulties are common in ADHD, however, the implications of their co-occurrences on cognitive and maths performance is unknown.

Aims: This study set out to examine whether cognitive and maths performance of children with high ADHD symptoms differs depending on the co-occurrence of movement difficulties given evidence that weaker visuospatial processing, known to be important for maths performance, differentiates ADHD and DCD. We also aimed to examine whether relationships between cognition and maths in ADHD differs depending on co-occurring movement difficulties.

Adolescent Mental Health Priorities During the Covid-19 Pandemic.

Increasing evidence has shown that the Covid-19 outbreak has impacted adolescents' mental health. Utilising a mixed-method design, the current study examined a total of 518 adolescent perspectives (60% female), in Scotland, on what and help their mental health in the context of Covid-19. A reflexive thematic analysis revealed three themes in relation to what helped adolescents' mental health since the Covid-19 outbreak.

Short Report: Exploring the extent to which Intellectual Disability is undiagnosed within children attending developmental paediatric clinics.

Intellectual Disability is under-ascertained worldwide and is associated with greater physical and mental health difficulties. This research aimed to identify clinical features and characteristics of children with Intellectual Disability in a population of 126 6-18 year olds in mainstream school, attending paediatric developmental clinics. Intellectual Disability was defined according to the DSM-5 (deficits in intellectual and adaptive functioning, present during childhood).

Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout.

We report the first well-characterized selective chemical probe for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group ("aza-scan") into the hexyl linker moiety of the approved drug Vorinostat (SAHA).

Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth.

Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine N-acetylspermidine (N-AcSpd). Although intracellular concentrations of N-AcSpd are low, extracellular sources can be abundant, particularly in the colonic lumen. Extracellular polyamines, including those from the diet and microbiota, can support tumor growth both locally and at distant sites.

Helping the helpers: polyamines help maintain helper T-cell lineage fidelity.

The awareness that polyamines play a critical role in immune system regulation and function is coming into focus as the biological systems and analytical tools necessary to evaluate their roles have become available. Puleston et al have recently demonstrated that polyamine metabolism plays a central role in helper T-cell lineage determination through the production of the translational cofactor hypusinated eIF5A and faithful epigenetic regulation through proper histone acetylation. Their findings add to the rapidly growing body of data implicating properly controlled polyamine metabolism as essential for a normally functioning immune system.

Hyaluronate-coated perfluoroalkyl polyamine prodrugs as bioactive siRNA delivery systems for the treatment of peritoneal cancers.

RNA interference (RNAi) is an emerging therapeutic modality for cancer, which remains in critical need of effective delivery vectors due to the unfavorable biopharmaceutical properties of small RNAs. Polyamines are essential for functioning of mammalian cells. Dysregulated polyamine metabolism is found in many cancers and has been an attractive therapeutic target in combination therapies.