Medicine (Austin & Northern Health) - Research Publications

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    BECLIN1 is essential for intestinal homeostasis involving autophagy-independent mechanisms through its function in endocytic trafficking
    Tran, S ; Juliani, J ; Harris, TJ ; Evangelista, M ; Ratcliffe, J ; Ellis, SL ; Baloyan, D ; Reehorst, CM ; Nightingale, R ; Luk, IY ; Jenkins, LJ ; Ghilas, S ; Yakou, MH ; Inguanti, C ; Johnson, C ; Buchert, M ; Lee, JC ; De Cruz, P ; Duszyc, K ; Gleeson, PA ; Kile, BT ; Mielke, LA ; Yap, AS ; Mariadason, JM ; Douglas Fairlie, W ; Lee, EF (NATURE PORTFOLIO, 2024-02-20)
    Autophagy-related genes have been closely associated with intestinal homeostasis. BECLIN1 is a component of Class III phosphatidylinositol 3-kinase complexes that orchestrate autophagy initiation and endocytic trafficking. Here we show intestinal epithelium-specific BECLIN1 deletion in adult mice leads to rapid fatal enteritis with compromised gut barrier integrity, highlighting its intrinsic critical role in gut maintenance. BECLIN1-deficient intestinal epithelial cells exhibit extensive apoptosis, impaired autophagy, and stressed endoplasmic reticulum and mitochondria. Remaining absorptive enterocytes and secretory cells display morphological abnormalities. Deletion of the autophagy regulator, ATG7, fails to elicit similar effects, suggesting additional novel autophagy-independent functions of BECLIN1 distinct from ATG7. Indeed, organoids derived from BECLIN1 KO mice show E-CADHERIN mislocalisation associated with abnormalities in the endocytic trafficking pathway. This provides a mechanism linking endocytic trafficking mediated by BECLIN1 and loss of intestinal barrier integrity. Our findings establish an indispensable role of BECLIN1 in maintaining mammalian intestinal homeostasis and uncover its involvement in endocytic trafficking in this process. Hence, this study has important implications for our understanding of intestinal pathophysiology.
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    FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy
    Chan, JD ; Scheffler, CM ; Munoz, I ; Sek, K ; Lee, JN ; Huang, Y-K ; Yap, KM ; Saw, NYL ; Li, J ; Chen, AXY ; Chan, CW ; Derrick, EB ; Todd, KL ; Tong, J ; Dunbar, PA ; Li, J ; Hoang, TX ; de Menezes, MN ; Petley, EV ; Kim, JS ; Nguyen, D ; Leung, PSK ; So, J ; Deguit, C ; Zhu, J ; House, IG ; Kats, LM ; Scott, AM ; Solomon, BJ ; Harrison, SJ ; Oliaro, J ; Parish, IA ; Quinn, KM ; Neeson, PJ ; Slaney, CY ; Lai, J ; Beavis, PA ; Darcy, PK (NATURE PORTFOLIO, 2024-05)
    Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.
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    Amygdala enlargement in temporal lobe epilepsy: Histopathology and surgical outcomes
    Shakhatreh, L ; Sinclair, B ; McLean, C ; Lui, E ; Morokoff, AP ; King, JA ; Chen, Z ; Perucca, P ; O'Brien, TJ ; Kwan, P (WILEY, 2024-06)
    OBJECTIVES: Amygdala enlargement is detected on magnetic resonance imaging (MRI) in some patients with drug-resistant temporal lobe epilepsy (TLE), but its clinical significance remains uncertain We aimed to assess if the presence of amygdala enlargement (1) predicted seizure outcome following anterior temporal lobectomy with amygdalohippocampectomy (ATL-AH) and (2) was associated with specific histopathological changes. METHODS: This was a case-control study. We included patients with drug-resistant TLE who underwent ATL-AH with and without amygdala enlargement detected on pre-operative MRI. Amygdala volumetry was done using FreeSurfer for patients who had high-resolution T1-weighted images. Mann-Whitney U test was used to compare pre-operative clinical characteristics between the two groups. The amygdala volume on the epileptogenic side was compared to the amygdala volume on the contralateral side among cases and controls. Then, we used a two-sample, independent t test to compare the means of amygdala volume differences between cases and controls. The chi-square test was used to assess the correlation of amygdala enlargement with (1) post-surgical seizure outcomes and (2) histopathological changes. RESULTS: Nineteen patients with and 19 patients without amygdala enlargement were studied. Their median age at surgery was 38 years for cases and 39 years for controls, and 52.6% were male. There were no statistically significant differences between the two groups in their pre-operative clinical characteristics. There were significant differences in the means of volume difference between cases and controls (Diff = 457.2 mm3, 95% confidence interval [CI] 289.6-624.8; p < .001) and in the means of percentage difference (p < .001). However, there was no significant association between amygdala enlargement and surgical outcome (p = .72) or histopathological changes (p = .63). SIGNIFICANCE: The presence of amygdala enlargement on the pre-operative brain MRI in patients with TLE does not affect the surgical outcome following ATL-AH, and it does not necessarily suggest abnormal histopathology. These findings suggest that amygdala enlargement might reflect a secondary reactive process to seizures in the epileptogenic temporal lobe.
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    Lacosamide and pregnancy: Data from spontaneous and solicited reports
    Perucca, P ; Bourikas, D ; Voinescu, PE ; Vadlamudi, L ; Chellun, D ; Kumke, T ; Werhahn, KJ ; Schmitz, B (WILEY, 2024-05)
    OBJECTIVE: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. METHODS: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. RESULTS: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. SIGNIFICANCE: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.
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    Effect of Feminizing Hormone Therapy on QTc Interval A Secondary Analysis of a Randomized Clinical Trial
    Angus, LM ; Lin, T ; Leemaqz, SY ; Cheung, AS (AMER MEDICAL ASSOC, 2024-03-28)
    This secondary analysis of a randomized clinical trial investigates the effect of spironolactone and cyproterone acetate hormone therapy on the QT interval corrected for heart rate among transgender women and nonbinary or transfeminine individuals.
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    The effect of estradiol add-back: a longitudinal MRI study in prostate cancer patients.
    Dandash, O ; Allebone, J ; Mirabelli, A ; Russell, N ; Grossmann, M ; Gogos, A ; Kanaan, RA (Bioscientifica, 2024-03-01)
    We investigated the effect of estradiol add-back therapy (EAT) on brain activation related to cognitive function and affect in addition to putative changes in gray and white matter volume in testosterone depleted participants with prostate cancer. We conducted a randomized controlled, double-blinded trial in which 40 patients received 0.9 mg of transdermal estradiol per day for 6 months or matched placebo. Anatomical MRI and three functional MRI (fMRI) scans were obtained for the emotion recognition task, verbal memory task, and visuospatial memory task. Activation in corresponding cognitive and affective brain networks was demonstrated for all tasks. Longitudinally, there was no difference in brain activation, reaction time, or accuracy in response to the fMRI tasks between the EAT group and placebo group at 6 months. In addition, there was no detectable change in whole-brain gray or white matter volume or in hippocampal volume between the two groups after 6 months. This study supports earlier findings that EAT does not improve verbal memory or affect and has no immediate effect on hippocampal volume in testosterone depleted patients with prostate cancer.
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    Response to Letter to the Editor From Kirk & Stebbings: The Impact of Gender-Affirming Hormone Therapy on Physical Performance
    Cheung, AS ; Zwickl, S ; Miller, K ; Nolan, BJ ; Wong, AFQ ; Jones, P ; Eynon, N (ENDOCRINE SOC, 2024-03-19)
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    Testosterone Treatment, Weight Loss, and Health-related Quality of Life and Psychosocial Function in Men: A 2-year Randomized Controlled Trial
    Grossmann, M ; Robledo, KP ; Daniel, M ; Handelsman, DJ ; Inder, WJ ; Stuckey, BGA ; Yeap, BB ; Fui, MNT ; Bracken, K ; Allan, CA ; Jesudason, D ; Zajac, JD ; Wittert, GA (ENDOCRINE SOC, 2024-02-09)
    OBJECTIVE: To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of a 2-year, randomised controlled, testosterone therapy trial for prevention, or reversal of newly diagnosed, type 2 diabetes, enrolling men > 50 years at high risk for type 2 diabetes from six Australian centers. INTERVENTIONS: Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES: Self-reported measures of HR-QOL/psychosocial function. RESULTS: Of 1007 participants randomised into T4DM, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and two years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and less depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSIONS: In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.
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    Four-week inhibition of the renin-angiotensin system in spontaneously hypertensive rats results in persistently lower blood pressure with reduced kidney renin and changes in expression of relevant gene networks
    Byars, SG ; Prestes, PR ; Suphapimol, V ; Takeuchi, F ; De Vries, N ; Maier, MC ; Melo, M ; Balding, D ; Samani, N ; Allen, AM ; Kato, N ; Wilkinson-Berka, JL ; Charchar, F ; Harrap, SB (OXFORD UNIV PRESS, 2024-05-29)
    AIMS: Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown. METHODS AND RESULTS: In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme inhibitor, perindopril [with controls for non-specific effects of lowering blood pressure (BP)], on differential RNA expression, DNA methylation, and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a six-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 × 10-6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs, and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4), the miRNA miR-145-3p, and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS, and the kidneys. CONCLUSION: Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks.
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    Comparing Video-Based, Telehealth-Delivered Exercise and Weight Loss Programs With Online Education on Outcomes of Knee Osteoarthritis : A Randomized Trial
    Bennell, KL ; Lawford, BJ ; Keating, C ; Brown, C ; Kasza, J ; Mackenzie, D ; Metcalf, B ; Kimp, AJ ; Egerton, T ; Spiers, L ; Proietto, J ; Sumithran, P ; Harris, A ; Quicke, JG ; Hinman, RS (American College of Physicians, 2022-02)
    Background: Scalable knee osteoarthritis (OA) programs are needed to deliver recommended education, exercise and weight loss interventions. Objective: Evaluate two 6-month telehealth-delivered exercise programs, with and without dietary intervention. Design: Three-arm parallel randomized (5:5:2) trial. Setting: Australian private health insurance members. Participants: 415 people with symptomatic knee OA, body mass index 28-40 kg/m2, aged 45-80. Interventions: All groups received access to electronic OA information (Control). The Exercise program comprised six videoconferencing physiotherapist consultations for exercise, self-management advice and behavioral counselling plus exercise equipment and resources. The Diet+Exercise program included an additional six dietitian consultations for a ketogenic very low-calorie diet (two formulated meal replacements and low carbohydrate meal daily) then transition to healthy eating, and nutrition and behavioral resources. Measurements: Primary outcomes were changes in knee pain (0-10 numeric rating scale, higher worse) and physical function (0-68 WOMAC, higher worse) at 6- (primary time-point) and 12-months. Secondary outcomes were weight, physical activity, quality-of-life, mental health, global change, satisfaction, willingness for surgery, orthopaedic appointments, and knee surgery. Results: 379 (91%) and 372 (90%) participants provided 6- and 12-month primary outcomes respectively. At 6-months, both programs were superior to Control for pain (between-group mean differences: Diet+Exercise, -1.5 [95% CI, -2.1 to -0.8]; Exercise, -0.8 [CI, -1.5 to -0.2]) and function (Diet+Exercise, -9.8 [CI, -12.5 to -7.0]; Exercise, -7.0 [CI -9.7 to -4.2]) while Diet+Exercise was superior to Exercise (pain, -0.6 [CI, -1.1 to -0.2]; function, -2.8 [CI -4.7 to -0.8]). Similar findings occurred at 12-months. Limitations: Unblinded participants and clinicians. Conclusion: Telehealth-delivered exercise and diet programs improved pain and function in people with knee OA and overweight/obesity. Dietary intervention conferred modest additional pain and function benefits to exercise.