Medicine (RMH) - Research Publications

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    Signaling pathways underlying TGF-β mediated suppression of IL-12A gene expression in monocytes.
    Hourani, T ; Eivazitork, M ; Balendran, T ; Mc Lee, K ; Hamilton, JA ; Zhu, H-J ; Iaria, J ; Morokoff, AP ; Luwor, RB ; Achuthan, AA (Elsevier BV, 2024-02)
    Transforming growth factor-β (TGF-β) is a pleiotropic cytokine essential for multiple biological processes, including the regulation of inflammatory and immune responses. One of the important functions of TGF-β is the suppression of the proinflammatory cytokine interleukin-12 (IL-12), which is crucial for mounting an anti-tumorigenic response. Although the regulation of the IL-12p40 subunit (encoded by the IL-12B gene) of IL-12 has been extensively investigated, the knowledge of IL-12p35 (encoded by IL-12A gene) subunit regulation is relatively limited. This study investigates the molecular regulation of IL-12A by TGF-β-activated signaling pathways in THP-1 monocytes. Our study identifies a complex regulation of IL-12A gene expression by TGF-β, which involves multiple cellular signaling pathways, such as Smad2/3, NF-κB, p38 and JNK1/2. Pharmacological inhibition of NF-κB signaling decreased IL-12A expression, while blocking the Smad2/3 signaling pathway by overexpression of Smad7 and inhibiting JNK1/2 signaling with a pharmacological inhibitor, SP600125, increased its expression. The elucidated signaling pathways that regulate IL-12A gene expression potentially provide new therapeutic targets to increase IL-12 levels in the tumor microenvironment.
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    Three-dimensional genome architecture coordinates key regulators of lineage specification in mammary epithelial cells
    Milevskiy, MJG ; Coughlan, HD ; Kane, SR ; Johanson, TM ; Kordafshari, S ; Chan, WF ; Tsai, M ; Surgenor, E ; Wilcox, S ; Allan, RS ; Chen, Y ; Lindeman, GJ ; Smyth, GK ; Visvader, JE (ELSEVIER, 2023-11-08)
    Although lineage-specific genes have been identified in the mammary gland, little is known about the contribution of the 3D genome organization to gene regulation in the epithelium. Here, we describe the chromatin landscape of the three major epithelial subsets through integration of long- and short-range chromatin interactions, accessibility, histone modifications, and gene expression. While basal genes display exquisite lineage specificity via distal enhancers, luminal-specific genes show widespread promoter priming in basal cells. Cell specificity in luminal progenitors is largely mediated through extensive chromatin interactions with super-enhancers in gene-body regions in addition to interactions with polycomb silencer elements. Moreover, lineage-specific transcription factors appear to be controlled through cell-specific chromatin interactivity. Finally, chromatin accessibility rather than interactivity emerged as a defining feature of the activation of quiescent basal stem cells. This work provides a comprehensive resource for understanding the role of higher-order chromatin interactions in cell-fate specification and differentiation in the adult mouse mammary gland.
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    Standardized measurement of balance and mobility post-stroke: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable
    Van Criekinge, T ; Heremans, C ; Burridge, J ; Deutsch, JE ; Hammerbeck, U ; Hollands, K ; Karthikbabu, S ; Mehrholz, J ; Moore, JL ; Salbach, NM ; Schroder, J ; Veerbeek, JM ; Weerdesteyn, V ; Borschmann, K ; Churilov, L ; Verheyden, G ; Kwakkel, G (SAGE PUBLICATIONS LTD, 2024-02)
    BACKGROUND: Mobility is a key priority for stroke survivors. Worldwide consensus of standardized outcome instruments for measuring mobility recovery after stroke is an essential milestone to optimize the quality of stroke rehabilitation and recovery studies and to enable data synthesis across trials. METHODS: Using a standardized methodology, which involved convening of 13 worldwide experts in the field of mobility rehabilitation, consensus was established through an a priori defined survey-based approach followed by group discussions. The group agreed on balance- and mobility-related definitions and recommended a core set of outcome measure instruments for lower extremity motor function, balance and mobility, biomechanical metrics, and technologies for measuring quality of movement. RESULTS: Selected measures included the Fugl-Meyer Motor Assessment lower extremity subscale for motor function, the Trunk Impairment Scale for sitting balance, and the Mini Balance Evaluation System Test (Mini-BESTest) and Berg Balance Scale (BBS) for standing balance. The group recommended the Functional Ambulation Category (FAC, 0-5) for walking independence, the 10-meter Walk Test (10 mWT) for walking speed, the 6-Minute Walk Test (6 MWT) for walking endurance, and the Dynamic Gait Index (DGI) for complex walking. An FAC score of less than three should be used to determine the need for an additional standing test (FAC < 3, add BBS to Mini-BESTest) or the feasibility to assess walking (FAC < 3, 10 mWT, 6 MWT, and DGI are "not testable"). In addition, recommendations are given for prioritized kinetic and kinematic metrics to be investigated that measure recovery of movement quality of standing balance and walking, as well as for assessment protocols and preferred equipment to be used. CONCLUSIONS: The present recommendations of measures, metrics, technology, and protocols build on previous consensus meetings of the International Stroke Recovery and Rehabilitation Alliance to guide the research community to improve the validity and comparability between stroke recovery and rehabilitation studies as a prerequisite for building high-quality, standardized "big data" sets. Ultimately, these recommendations could lead to high-quality, participant-specific data sets to aid the progress toward precision medicine in stroke rehabilitation.
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    Prevalence of Arm Weakness, Pre-Stroke Outcomes and Other Post-Stroke Impairments Using Routinely Collected Clinical Data on an Acute Stroke Unit
    Dalton, EJ ; Jamwal, R ; Augoustakis, L ; Hill, E ; Johns, H ; Thijs, V ; Hayward, KS (SAGE PUBLICATIONS INC, 2024-02)
    INTRODUCTION: The prevalence of upper limb motor weakness early post-stroke may be changing, which can have clinical and research implications. Our primary aim was to describe the prevalence of upper limb motor weakness early post-stroke, with a secondary aim to contextualize this prevalence by describing pre-stroke outcomes, other post-stroke impairments, functional activities, and discharge destination. METHODS: This cross-sectional observational study extracted clinical data from confirmed stroke patients admitted to a metropolitan stroke unit over 15-months. The primary upper limb weakness measure was Shoulder Abduction and Finger Extension (SAFE) score. Demographics (eg, age), clinical characteristics (eg, stroke severity), pre-stroke outcomes (eg, clinical frailty), other post-stroke impairments (eg, command following), functional activities (eg, ambulation), and discharge destination were also extracted. RESULTS: A total of 463 participants had a confirmed stroke and SAFE score. One-third of patients received ≥1 acute medical intervention(s). Nearly one-quarter of patients were classified as frail pre-stroke. Upper limb weakness (SAFE≤8) was present in 35% [95% CI: 30%-39%] at a median of 1-day post-stroke, with 22% presenting with mild-moderate weakness (SAFE5-8). The most common other impairments were upper limb coordination (46%), delayed recall (41%), and upper limb sensation (26%). After a median 3-day acute stroke stay, 52% of the sample were discharged home. CONCLUSION: Upper limb weakness was present in just over a third (35%) of the sample early post-stroke. Data on pre-stroke outcomes and the prevalence of other post-stroke impairments highlights the complexity and heterogeneity of stroke recovery. Further research is required to tease out meaningful recovery phenotypes and their implications.
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    Background and Breakthrough Opioid Choice May Determine Different Pain Outcomes
    Wong, AK ; Vogrin, S ; Le, B ; Klepstad, P ; Rubio, JP ; Somogyi, AA ; Philip, J (ELSEVIER SCIENCE INC, 2024-03)
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    The teratogenesis risk associated with antiseizure medication duotherapy in women with epilepsy.
    Vajda, FJE ; O'Brien, TJ ; Graham, JE ; Hitchcock, AA ; Perucca, P ; Lander, CM ; Eadie, MJ (Elsevier BV, 2024-02)
    PURPOSE: To investigate rates of occurrence of pregnancies associated with a foetal malformation (FM pregnancy rates) following simultaneous intrauterine exposure to two antiseizure medications in 524 pregnancies in women with epilepsy from the Australian Pregnancy Register who were treated simultaneously with various combinations and dosages of two antiseizure medications (duotherapy). RESULTS: FM pregnancy rates tended to be higher in those exposed simultaneously to two antiseizure medications, each of which was a statistically significant teratogen (valproate, topiramate, or carbamazepine), than when there was exposure to only one such teratogen. When there was exposure to only one such teratogen together with clonazepam or levetiracetam, for neither of which there was statistically significant evidence of heightened teratogenicity, the FM pregnancy rates also tended to be higher, but less so. When lamotrigine was the other component of the duotherapy with an established teratogen, FM pregnancy rates tended to be lower than that for the teratogen used as monotherapy. CONCLUSION: Leaving aside issues in relation to seizure control, our data suggest that it would be best to avoid using established teratogenic antiseizure medications (carbamazepine, valproate and topiramate) in combination with each other due to the increased FM risks. When combining an established teratogenic medication with a less teratogenic one, i.e. lamotrigine, levetiracetam or clonazepam, lamotrigine appears to be the safer option.
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    Mice with an autism-associated R451C mutation in neuroligin-3 show intact attention orienting but atypical responses to methylphenidate and atomoxetine in the mouse-Posner task
    Li, S ; May, C ; Pang, TY ; Churilov, L ; Hannan, AJ ; Johnson, KA ; Burrows, EL (SPRINGER, 2024-03)
    RATIONALE: Atypical attention orienting has been associated with some autistic symptoms, but the neural mechanisms remain unclear. The human Posner task, a classic attention orienting paradigm, was recently adapted for use with mice, supporting the investigation of the neurobiological underpinnings of atypical attention orienting in preclinical mouse models. OBJECTIVE: The current study tested mice expressing the autism-associated R451C gene mutation in neuroligin-3 (NL3) on the mouse-Posner (mPosner) task. METHODS: NL3R451C and wild-type (WT) mice were trained to respond to a validly or invalidly cued target on a touchscreen. The cue was a peripheral non-predictive flash in the exogenous task and a central spatially predictive image in the endogenous task. The effects of dopaminergic- and noradrenergic-modulating drugs, methylphenidate and atomoxetine, on task performance were assessed. RESULTS: In both tasks, mice were quicker and more accurate in the validly versus invalidly cued trials, consistent with results in the human Posner task. NL3R451C and WT mice showed similar response times and accuracy but responded differently when treated with methylphenidate and atomoxetine. Methylphenidate impaired exogenous attention disengagement in NL3R451C mice but did not significantly affect WT mice. Atomoxetine impaired endogenous orienting in WT mice but did not significantly affect NL3R451C mice. CONCLUSIONS: NL3R451C mice demonstrated intact attention orienting but altered responses to the pharmacological manipulation of the dopaminergic and noradrenergic networks. These findings expand our understanding of the NL3R451C mutation by suggesting that this mutation may lead to selective alterations in attentional processes.
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    Observational studies of treatment effectiveness in neurology
    Kalincik, T ; Roos, I ; Sharmin, S (OXFORD UNIV PRESS, 2023-12-01)
    The capacity and power of data from cohorts, registries and randomized trials to provide answers to contemporary clinical questions in neurology has increased considerably over the past two decades. Novel sophisticated statistical methods are enabling us to harness these data to guide treatment decisions, but their complexity is making appraisal of clinical evidence increasingly demanding. In this review, we discuss several methodological aspects of contemporary research of treatment effectiveness in observational data in neurology, aimed at academic neurologists and analysts specializing in outcomes research. The review discusses specifics of the sources of observational data and their key features. It focuses on the limitations of observational data and study design, as well as statistical approaches aimed to overcome these limitations. Among the examples of leading clinical themes typically studied with analyses of observational data, the review discusses methodological approaches to comparative treatment effectiveness, development of diagnostic criteria and definitions of clinical outcomes. Finally, this review provides a brief summary of key points that will help clinical audience critically evaluate design and analytical aspects of studies of disease outcomes using observational data.
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    Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis
    Kalincik, T ; Sharmin, S ; Massey, J ; Sutton, I ; Withers, B ; Freedman, MS ; Atkins, H ; Krasulova, E ; Havrdova, EK ; Trneny, M ; Kozak, T ; Burman, J ; MacDonell, R ; Torkildsen, Ø ; Bø, L ; Lehmann, AK ; Sharrack, B ; Snowden, J (BMJ Publishing Group, 2024)
    Background: Natalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous hematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive MS. Methods: Patients with primary/secondary progressive MS from 7 AHSCT MS centres and the MSBase registry, treated with AHSCT or natalizumab were matched on a propensity score derived from sex, age, Expanded Disability Status Scale (EDSS), number of relapses 12/24 months before baseline, time from MS onset, the most effective prior therapy and country. The pairwise- censored groups were compared on hazards of 6-month confirmed EDSS worsening and improvement, relapses and annualised relapse rates (ARR), using Andersen-Gill proportional hazards models and conditional negative binomial model. Findings: 39 patients treated with AHSCT (37 with secondary progressive MS, mean age 37 years, EDSS 5.7, 28% with recent disability progression, ARR 0.54 during the preceding year) were matched with 65 patients treated with natalizumab. The study found no evidence for difference in hazards of confirmed EDSS worsening (hazard ratio 1.49, 95% confidence interval [95%CI] 0.70-3.14) and improvement (hazard ratio 1.50, 95%CI 0.22-10.29) between AHSCT and natalizumab over up to 4 years. The relapse activity was also similar while treated with AHSCT and natalizumab (ARR: mean±standard deviation 0.08±0.28 vs. 0.08±0.25; hazard ratio 1.05, 95%CI 0.39-2.82). In the AHSCT group, 3 patients experienced febrile neutropenia during mobilisation, 9 patients experienced serum sickness, 6 patients required ICU admission, and 36 patients experienced complications after discharge. No treatment-related deaths were reported. Conclusion: This study does not support the use of AHSCT to control disability in progressive MS with advanced disability and low relapse activity.
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    Effect of gene variants on opioid dose, pain and adverse effect outcomes in advanced cancer: an explorative study
    Wong, AK ; Klepstad, P ; Somogyi, AA ; Vogrin, S ; Le, B ; Philip, J ; Rubio, JP (FUTURE MEDICINE LTD, 2023-12)
    Aim: Associations between gene variants and opioid net effect are unclear. We conducted an exploratory pharmacogenetic analysis of 35 gene variants and opioid response in advanced cancer. Patients & methods: This multi-center prospective cohort study included clinical data, questionnaires (pain and adverse effects) and DNA (blood). Negative binomial regression and logistic regression were used. Results: Within 54 participants, eight statistically significant associations (p = 0.002-0.038) were observed between gene variants and opioid dose, pain scores or adverse effects, the majority being within the neuroimmune TLR4 pathway (IL1B [rs1143634], IL2 [rs2069762], IL6 [rs1800795], BDNF [rs6265]) and ARRB2 pathway (ARRB2 [rs3786047], DRD2 [rs6275]). Conclusion: Neuroimmune pathway genes may contribute to differences in opioid response in cancer and may be included in future similar studies.