Natalie Thomas

ABC transporters do not contribute to extracellular translocation of hyaluronan in human breast cancer in vitro.

Extracellular translocation of the polysaccharide, hyaluronan (HA) has been thought to be mediated via its transmembrane synthetic enzyme, hyaluronan synthase (HAS) but recent studies have indicated that the ATP-Binding-Cassette (ABC) transporter, MRP5 contributes to this process. Liberated and cell-associated HA contributes to breast cancer initiation and progression, and therefore the inhibition of ABC transporters and consequently HA transport could provide therapeutic benefit in the treatment of breast cancer. Quantitation of ABC transporter genes, MRP1-5, BCRP and MDR1 were determined in six breast cancer cell lines selected for their differential HA synthetic rates. Low endogenous expression of transporters was detected but no significant correlation existed between ABC transporter and HAS gene expression or HA production. A dose titration of up to ten times the IC(50) of ten small molecule ABC transporter inhibitors did not significantly inhibit HA export in four breast cancer cell lines. Unlike the changes observed after inhibition of HA synthesis by the characterised inhibitor 4-MU, inhibition of ABC transporters did not alter the cell morphology, HA glycocalyx or the intracellular quantity or localisation of HA. Collectively these data indicate that ABC transporters do not contribute to the extracellular transport of HA in breast cancer, supporting a role for the hyaluronan synthase in translocation.

Menstrual cycle irregularity and menopause status influence cognition in women with schizophrenia

Cognitive impairments are a core feature of schizophrenia and contribute significantly to functional complications. Current pharmacological treatments do not ameliorate cognitive dysfunction and the aetiology of cognitive impairments are poorly understood. Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain and have been suggested to also influence cognition. The aim of the current study was to investigate how HPG axis hormones effect cognition, specifically exploring the influence of menopause status and menstrual cycle irregularity on cognitive performance in women with schizophrenia. The data for the present study represents pooled baseline data from three clinical trials. Two hundred and forty female participants with a diagnosis of schizophrenia or schizoaffective disorder were included in the analysis. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Hormone assays for serum sex steroids and pituitary hormones (including estradiol, progesterone, luteinising hormone and follicle-stimulating hormone) were conducted and women were classified as postmenopausal; perimenopausal; premenopausal/reproductive, further classified into regular and irregular menstrual cycles. To model a comparison of cognitive performance for i) perimenopausal; ii) post-menopausal women and iii) reproductive aged women with irregular cycles to reproductive aged women with regular cycles a semiparametric regression model (generalised additive mode) was fitted. The results revealed that in females with schizophrenia, menstrual cycle irregularity predicted significantly poorer cognitive performance in the areas of psychomotor speed, verbal fluency and verbal memory. Perimenopause was not associated with cognitive changes and the post-menopausal period was associated with poorer visuospatial performance. This study provides evidence to associate reproductive hormones with cognitive dysfunction in schizophrenia.

Role of Hyaluronan Metabolism in the Initiation, Invasion, and Metastasis of Breast Cancer

Publisher Summary The evolutionary process of breast cancer involves progression through defined pathological and clinical stages, initiating with ductal hyperproliferation, subsequent development into in situ and invasive carcinomas, and finally metastatic disease. This chapter focuses on the intratumoral metabolism of the extracellular matrix (ECM) glycosaminoglycan, hyaluronan (HA), and the role that anabolic and catabolic products play in the initiation, progression, and invasion of breast cancer. The dynamic balance between HA synthesis and degradation within the tumor microenvironment plays an integral role in the complex, multistep process of carcinogenesis. Substantial preclinical work has elegantly elucidated the potential participation of both the synthetic and degradative enzymes in the metabolic processes of breast cancer. Tumor initiation, progression, and maintenance appear to be highly dependent on the accumulation of high MW HA within the breast cancer stroma, where it provides a hydrated growth matrix for tumor cells, promotes tumor survival by prevention of apoptosis, camouflages cancer cells from cytotoxic attack by host immunocompetent cells, and ultimately stimulates invasion. The specific signaling events induce neovascularization, lymphangiogenesis, and ECM degradation via the enhanced expression of matrix metalloproteinases. Numerous cellular ligands and molecules have been shown to participate in the process of HA metabolism and carcinogenesis of the breast, but a complete understanding of the significance with translation into clinical benefit requires substantially more work and elucidation.

Raloxifene as a treatment for cognition in women with schizophrenia: the influence of menopause status

Cognitive impairments cause significant functional issues for people with schizophrenia, often emerging before the onset of hallucinations, delusions and other psychosis symptoms. Current pharmacological treatments do not target cognitive dysfunction. Several lines of evidence support the beneficial effects of estrogens on cognition. Raloxifene hydrochloride, a selective estrogen receptor modulator, has been associated with cognitive improvements in healthy postmenopausal women and in schizophrenia, although findings are inconsistent. Using pooled data from two clinical trials, the aim of the current study was to compare the efficacy of 120 mg/day adjunctive raloxifene to placebo for 12 weeks on cognitive performance in women with schizophrenia who were stratified by menopause status (pre-menopausal; peri-menopausal or post-menopausal). A total of sixty-nine participants with a diagnosis of schizophrenia or schizoaffective disorder were included. Cognition was assessed at baseline and study end using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results indicated that after stratifying for menopause status (strata) and adjusting for endogenous hormone levels (estrogen, progesterone, follicle stimulating hormone and luteinising hormone), semantic fluency, picture naming and list recognition change from baseline scores for the raloxifene group differed significantly from the placebo group. The findings from the current study highlight the importance of considering menopause status when interpreting the effects of hormonal treatments.

Ondansetron – a promising adjunctive treatment for persistent schizophrenia

Background: Ondansetron is a serotonin 3 receptor antagonist widely used to prevent nausea and vomiting in pregnancy and in patients receiving chemotherapy. There is growing evidence that adjunctive ondansetron treatment improves symptomatology associated with schizophrenia, particularly with respect to the positive, negative and cognitive symptoms. Further studies that are applicable to real world practice are required to assess the efficacy and effectiveness of this treatment, which could be readily and rapidly translated into clinical practice. Aims: This randomized control trial compared adjunctive (8 mg/daily) ondansetron or placebo to commonly prescribed atypical antipsychotics for people suffering with chronic schizophrenia (ClinicalTrials.gov NCT01121042). Methods: The study involved 85 outpatients aged 18–65 years with a diagnosis of schizophrenia or schizoaffective disorder who participated in a two-arm randomized control trial. Results: Longitudinal analyses revealed adjunctive ondansetron provided significant improvement in the cognitive domain (p<0.05) as measured by the Positive and Negative Syndrome Scale between baseline and week 12. The analysis of “Combination” showed ondansetron effect on Total Positive and Negative Syndrome Scale, approaching significance by week 12 (p=0.06). No group differences were obtained in the Montgomery-Asberg Depression Rating Scale or Positive and Negative Syndrome Scale subscales. Conclusion: This treatment trial provides some support for adjunctive ondansetron medication as a treatment for the cognitive disorganization symptoms of schizophrenia.

Sex Differences and the Influence of Sex Hormones on Cognition through Adulthood and the Aging Process

Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain. Sex differences in cognitive functioning have been reported in both health and disease, which may be partly attributed to sex hormones. The aim of the current paper was to provide a theoretical review of how sex hormones influence cognitive functioning across the lifespan as well as provide an overview of the literature on sex differences and the role of sex hormones in cognitive decline, specifically in relation to Alzheimer’s disease (AD). A summary of current hormone and sex-based interventions for enhancing cognitive functioning and/or reducing the risk of Alzheimer’s disease is also provided.