1,772 results on '"L. Dawson"'
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2. Productivity measurement in psychology and neuropsychology: existing standards and alternative suggestions
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Erica L. Dawson and Claire Speelman
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Psychiatry and Mental health ,Clinical Psychology ,Neuropsychology and Physiological Psychology ,Arts and Humanities (miscellaneous) ,Developmental and Educational Psychology - Published
- 2023
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3. DNA Methylation Signature of Aging: Potential Impact on the Pathogenesis of Parkinson’s Disease
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Volkan Yazar, Valina L. Dawson, Ted M. Dawson, and Sung-Ung Kang
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Cellular and Molecular Neuroscience ,Neurology (clinical) - Abstract
Regulation of gene expression by epigenetic modifications means lasting and heritable changes in the function of genes without alterations in the DNA sequence. Of all epigenetic mechanisms identified thus far, DNA methylation has been of particular interest in both aging and age-related disease research over the last decade given the consistency of site-specific DNA methylation changes during aging that can predict future health and lifespan. An increasing line of evidence has implied the dynamic nature of DNA (de)methylation events that occur throughout the lifespan has a role in the pathophysiology of aging and age-associated neurodegenerative conditions, including Parkinson’s disease (PD). In this regard, PD methylome shows, to some extent, similar genome-wide changes observed in the methylome of healthy individuals of matching age. In this review, we start by providing a brief overview of studies outlining global patterns of DNA methylation, then its mechanisms and regulation, within the context of aging and PD. Considering diverging lines of evidence from different experimental and animal models of neurodegeneration and how they combine to shape our current understanding of tissue-specific changes in DNA methylome in health and disease, we report a high-level comparison of the genomic methylation landscapes of brain, with an emphasis on dopaminergic neurons in PD and in natural aging. We believe this will be particularly useful for systematically dissecting overlapping genome-wide alterations in DNA methylation during PD and healthy aging, and for improving our knowledge of PD-specific changes in methylation patterns independent of aging process.
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- 2023
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4. Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly
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Margaux Serey-Gaut, Marisol Cortes, Periklis Makrythanasis, Mohnish Suri, Alexander M.R. Taylor, Jennifer A. Sullivan, Ayat N. Asleh, Jaba Mitra, Mohamad A. Dar, Amy McNamara, Vandana Shashi, Sarah Dugan, Xiaofei Song, Jill A. Rosenfeld, Christelle Cabrol, Justyna Iwaszkiewicz, Vincent Zoete, Davut Pehlivan, Zeynep Coban Akdemir, Elizabeth R. Roeder, Rebecca Okashah Littlejohn, Harpreet K. Dibra, Philip J. Byrd, Grant S. Stewart, Bilgen B. Geckinli, Jennifer Posey, Rachel Westman, Chelsy Jungbluth, Jacqueline Eason, Rani Sachdev, Carey-Anne Evans, Gabrielle Lemire, Grace E. VanNoy, Anne O’Donnell-Luria, Frédéric Tran Mau-Them, Aurélien Juven, Juliette Piard, Cheng Yee Nixon, Ying Zhu, Taekjip Ha, Michael F. Buckley, Christel Thauvin, George K. Essien Umanah, Lionel Van Maldergem, James R. Lupski, Tony Roscioli, Valina L. Dawson, Ted M. Dawson, and Stylianos E. Antonarakis
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Genetics ,Genetics (clinical) - Published
- 2023
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5. Community-Based Hospitals Benefit From Restrictive Transfusion Practices
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James L. Hill, Jennifer L. Dawson, Meghan Ramic, Julia Manzo, and Peter J. Pronovost
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Health Policy ,Public Health, Environmental and Occupational Health - Published
- 2023
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6. The Impact of a Group Telemedicine Program for Chronic Disease: A Retrospective Cohort Survey Study on Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder
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Dacre R.T. Knight, Katelyn A. Bruno, Jessica M. Gehin, Kristin A. Lothman, John Leschitz, Amanda L. Lazo, Lisa Mejia, Lesley S. Motherwell, Andrea M. Seymour-Sonnier, Nancy L. Dawson, and DeLisa Fairweather
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Health Information Management ,Health Informatics ,General Medicine - Published
- 2023
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7. Age as a predictor of clinical outcomes and determinant of therapeutic measures for emergency medical services treated cardiogenic shock
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X. Xiao, J. Bloom, E. Andrew, L. Dawson, Z. Nehme, M. Stephenson, D. Anderson, H. Fernando, S. Noaman, S. Cox, W. Chan, D. Kaye, K. Smith, and D. Stub
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Pulmonary and Respiratory Medicine ,Geriatrics and Gerontology ,Cardiology and Cardiovascular Medicine ,Research Article - Abstract
BACKGROUND: The impact of age on outcomes in cardiogenic shock (CS) is poorly described in the pre-hospital setting. We assessed the impact of age on outcomes of patients treated by emergency medical services (EMS). METHODS: This population-based cohort study included consecutive adult patients with CS transported to hospital by EMS. Successfully linked patients were stratified into tertiles by age (18-63, 64-77, and > 77 years). Predictors of 30-day mortality were assessed through regression analyses. The primary outcome was 30-day all-cause mortality. RESULTS: A total of 3523 patients with CS were successfully linked to state health records. The average age was 68 ± 16 years and 1398 (40%) were female. Older patients were more likely to have comorbidities including pre-existing coronary artery disease, hypertension, dyslipidemia, diabetes mellitus, and cerebrovascular disease. The incidence of CS was significantly greater with increasing age (incidence rate per 100,000 person years 6.47 [95% CI: 6.1-6.8] in age 18-63 years, 34.34 [32.4-36.4] in age 64-77 years, 74.87 [70.6-79.3] in age > 77 years, P < 0.001). There was a step-wise increase in the rate of 30-day mortality with increasing age tertile. After adjustment, compared to the lowest age tertile, patients aged > 77 years had increased risk of 30-day mortality (adjusted hazard ratio = 2.26 [95% CI: 1.96-2.60]). Older patients were less likely to receive inpatient coronary angiography. CONCLUSION: Older patients with EMS-treated CS have significantly higher rates of short-term mortality. The reduced rates of invasive interventions in older patients underscore the need for further development of systems of care to improve outcomes for this patient group.
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- 2023
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8. Environmental Legal Research is Changing: Alternating Tenor/Terror of Scholarship, Despair and Self-Care
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Duncan French, David L Dawson, and Nima Golijani-Moghaddam
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Management, Monitoring, Policy and Law ,Law - Abstract
No one can tell us—as individuals—how we should feel about environmental harm, be it upset at individual species loss, distress at systemic level change, or deeper existential angst. That universal truism applies as much to us, as scholars, as it does to us as world-citizens. Recognising that environmental harm is increasingly impacting lived experiences, this commentary both argues that we should not only reflect consciously on how this might affect our scholarship, but that we should proactively take steps to improve our mental health and self-care. Written collaboratively by an environmental lawyer and research clinical psychologists, the commentary concludes that acceptance of the challenges confronting us, and that it is all right to be anxious about them in our own lives, will not necessarily make our scholarship any better but it might allow us to avoid unhelpful, artificial, and potentially painful deep-seated, divisions within ourselves.
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- 2022
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9. Chronic total occlusion percutaneous coronary intervention in heart transplant patients
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Lorenzo Azzalini, Francesco Moroni, Kathryn L. Dawson, and Kathleen E. Kearney
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Radiology, Nuclear Medicine and imaging ,General Medicine ,Cardiology and Cardiovascular Medicine - Published
- 2022
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10. CYFIP1 Dosages Exhibit Divergent Behavioral Impact via Diametric Regulation of NMDA Receptor Complex Translation in Mouse Models of Psychiatric Disorders
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Valina L. Dawson, Guo Li Ming, Kimberly M. Christian, Stephanie J. Temme, Weidong Li, Stephen M. Eacker, Kuei Sen Hsu, Stefan Canzar, Ki Jun Yoon, Francisca Rojas Ringeling, Ted M. Dawson, Ha Nam Nguyen, Bo Xiao, Paul F. Worley, Yu Ting Lin, Namshik Kim, Hongjun Song, and Ying Zhou
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0301 basic medicine ,N-Methylaspartate ,DNA Copy Number Variations ,Autism Spectrum Disorder ,RNA-binding protein ,Biology ,Receptors, N-Methyl-D-Aspartate ,Gene dosage ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Postsynaptic potential ,mental disorders ,medicine ,Animals ,RNA, Messenger ,Copy-number variation ,Biological Psychiatry ,Adaptor Proteins, Signal Transducing ,Messenger RNA ,Mental Disorders ,Translation (biology) ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Schizophrenia ,RNA ,NMDA receptor ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Background Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear. Methods We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo. Results Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities. Conclusions CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.
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- 2022
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11. The Absence of Parkin Does Not Promote Dopamine or Mitochondrial Dysfunction in PolgAD257A/D257AMitochondrial Mutator Mice
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Laura Scott, Senthilkumar S. Karuppagounder, Stewart Neifert, Bong Gu Kang, Hu Wang, Valina L. Dawson, and Ted M. Dawson
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General Neuroscience - Abstract
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, we generated a transgenic model by crossing germline Parkin–/–mice with PolgAD257Amice, an established model of premature aging and mitochondrial stress. We hypothesized that loss of Parkin–/–in PolgAD257A/D257Amice would exacerbate mitochondrial dysfunction, leading to loss of dopamine neurons and nigral-striatal specific neurobehavioral motor dysfunction. We found that aged Parkin–/–/PolgAD257A/D257Amale and female mice exhibited severe behavioral deficits, nonspecific to the nigral-striatal pathway, with neither dopaminergic neurodegeneration nor reductions in striatal dopamine. We saw no difference in expression levels of nuclear-encoded subunits of mitochondrial markers and mitochondrial Complex I and IV activities, although we did observe substantial reductions in mitochondrial-encoded COX41I, indicating mitochondrial dysfunction as a result of PolgAD257A/D257AmtDNA mutations. Expression levels of mitophagy markers LC3I/LC3II remained unchanged between cohorts, suggesting no overt mitophagy defects. Expression levels of the parkin substrates, VDAC, NLRP3, and AIMP2 remained unchanged, suggesting no parkin dysfunction. In summary, we were unable to observe dopaminergic neurodegeneration with corresponding nigral-striatal neurobehavioral deficits, nor Parkin or mitochondrial dysfunction in Parkin–/–/PolgAD257A/D257Amice. These findings support a lack of synergism of Parkin loss on mitochondrial dysfunction in mouse models of mitochondrial deficits.SIGNIFICANCE STATEMENTProducing a mouse model of Parkinson's disease (PD) that is etiologically relevant, recapitulates clinical hallmarks, and exhibits reproducible results is crucial to understanding the underlying pathology and in developing disease-modifying therapies. Here, we show that Parkin–/–/PolgAD257A/D257Amice, a previously reported PD mouse model, fails to reproduce a Parkinsonian phenotype. We show that these mice do not display dopaminergic neurodegeneration nor nigral-striatal-dependent motor deficits. Furthermore, we report that Parkin loss does not synergize with mitochondrial dysfunction. Our results demonstrate that Parkin–/–/PolgAD257A/D257Amice are not a reliable model for PD and adds to a growing body of work demonstrating that Parkin loss does not synergize with mitochondrial dysfunction in mouse models of mitochondrial deficits.
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- 2022
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12. The Effectiveness of EMDR for Medically Unexplained Symptoms: A Systematic Literature Review
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Amelia Staton, Sarah Wilde, and David L Dawson
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Psychiatry and Mental health ,Neuropsychology and Physiological Psychology ,Cognitive Neuroscience ,Experimental and Cognitive Psychology ,Biological Psychiatry - Abstract
Introduction: It has been hypothesized that certain persistent physical symptoms (PPS) may be linked to unresolved traumatic or distressing somatic-symptom related memories. EMDR intervention targets and reintegrates distressing memories, thus reducing the re-experiencing of physical sensations. The primary aim of this review was to examine effectiveness of EMDR for PPS. Secondary aims were to investigate effectiveness of EMDR on secondary outcomes (post-traumatic stress, anxiety, and depression), and to evaluate the acceptability of EMDR for this client group.Method: Six electronic databases (PsycInfo, PsycArticles, CINAHL, MEDLINE, Web of Science and SCOPUS) were searched for peer-reviewed literature, with no restrictions on publication dates. Twenty-eight studies met inclusion criteria. Studies were included if the primary aim of EMDR intervention was to reduce intensity, frequency or reported distress associated with PPS. Studies were quality appraised using the MMAT tool prior to narrative synthesis of key findings.Results: Studies varied in design and included RCT, UCT, case study and case series. EMDR treatment length varied between studies; 1–20 sessions. All studies reported significant improvement in PPS at post-test. Effect sizes were available to report in five studies and ranged from moderate to large. Improvement in secondary outcomes were reported in all repeated measure studies. Where available, large effect sizes were reported for reduction in anxiety and depression. Overall drop-out rates in studies with representative samples was low (10.6%). Quality of research varied; low (42.8%), medium (21.4%), and high (35.7%).Conclusions: There is promising emerging evidence for effectiveness and acceptability of EMDR for a range of PPS. However, firm conclusions on efficacy cannot be made. While comparisons between PPS presentations cannot be drawn due to methodological differences, the findings for pain and tinnitus are the most compelling due to methodological quality. High-quality sufficiently powered RCTs are recommended to determine efficacy.
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- 2022
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13. Association of Vitamin B12, Vitamin D, and Thyroid-Stimulating Hormone With Fatigue and Neurologic Symptoms in Patients With Fibromyalgia
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Bala Munipalli, Shelby Strothers, Fernando Rivera, Pedro Malavet, Ghada Mitri, Abd Moain Abu Dabrh, and Nancy L. Dawson
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To assess the association between vitamin B12 (B12) deficiency and the prevalence of fatigue and prespecified neurologic symptoms in patients with fibromyalgia.A retrospective chart analysis of patients diagnosed with fibromyalgia in the years 2015-2020 was performed. The values of B12 were collected. The chart reviews assessed reported fatigue and neurologic symptoms, including brain fog, memory loss, cognitive impairment, paresthesias, numbness, and tingling, to assess their correlation with B12 levels. Concurrent vitamin D and thyroid-stimulating hormone levels were reviewed to assess their association with fibromyalgia.A total of 2142 patients with fibromyalgia with documented levels of B12 and vitamin D were included. Of them, 42.4% had B12 deficiency (400 ng/L). Fatigue and memory loss were more common in the B12 deficiency group. After adjusting for vitamin D levels, B12 deficiency remained statistically significantly associated with the presence of fatigue (odds ratio, 1.39; 95% confidence interval, 1.11-1.75;This is the first study to report the association of B12 in patients with fibromyalgia complaining of fatigue. This symptom was prevalent in our group of patients with fibromyalgia with B12 deficiency, regardless of whether the cutoff point was 400 or 350 ng/L.
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- 2022
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14. Poly(ADP-ribose) mediates bioenergetic defects and redox imbalance in neurons following oxygen and glucose deprivation
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M Iqbal Hossain, Jun Hee Lee, Jean-Philippe Gagne, Junaid Khan, Guy G Poirier, Valina L Dawson, Ted M Dawson, and Shaida A Anadrabi
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PARP-1 over-activation results in cell death via excessive PAR generation in different cell types, including neurons following brain ischemia. Glycolysis, mitochondrial function, and redox balance are key cellular processes altered in brain ischemia. Studies show that PAR generated after PARP-1 over-activation can bind hexokinase-1 (HK-1) and result in glycolytic defects and subsequent mitochondrial dysfunction. HK-1 is the neuronal hexokinase and catalyzes the first reaction of glycolysis, converting glucose to glucose-6-phosphate (G6P), a common substrate for glycolysis, and the pentose phosphate pathway (PPP) (Wilson, 2003). PPP is critical in maintaining NADPH and GSH levels via G6P dehydrogenase activity. Therefore, defects in HK-1 will not only decrease cellular bioenergetics but will also cause redox imbalance due to the depletion of GSH. In brain ischemia, whether PAR-mediated inhibition of HK-1 results in bioenergetics defects and redox imbalance is not known. We used oxygen-glucose deprivation (OGD) in mouse cortical neurons to mimic brain ischemia in neuronal cultures and observed that PARP-1 activation via PAR formation alters glycolysis, mitochondrial function, and redox homeostasis in neurons. We used pharmacological inhibition of PARP and adenoviral-mediated overexpression of wild-type HK-1 (wtHK-1) and PAR-binding mutant HK-1 (pbmHK-1). Our data show that PAR inhibition or overexpression of HK-1 significantly improves glycolysis, mitochondrial function, redox homeostasis, and cell survival in mouse cortical neurons exposed to OGD. These results suggest that PAR binding and inhibition of HK-1 during OGD drives bioenergetic defects in neurons due to inhibition of glycolysis and impairment of mitochondrial function. Significance: Brain ischemia is a leading cause of death and disability. Bioenergetic collapse, mitochondrial defects, and oxidative stress are early pathological pathways elicited after PARP-1 activation in brain ischemia. This study revealed a critical finding that PAR generated by oxygen-glucose deprivation inhibits HK-1 and results in glycolytic defects, mitochondrial dysfunction, and oxidative stress in neurons. This study suggests that PAR binding to HK-1 is a pathological process and that strategies targeted to block PAR interaction with HK-1 may be beneficial in limiting neuronal injury after ischemia.
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- 2023
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15. Pathological Tau transmission initiated by binding lymphocyte-activation gene 3
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Chan Chen, Ramhari Kumbhar, Hu Wang, Xiuli Yang, Kundlik Gadhave, Cyrus Rastegar, Yasuyoshi Kimura, Adam Behensky, Sruthi Katakam, Deok Jeong, Liang Wang, Anthony Wang, Rong Chen, Shu Zhang, Lingtao Jin, Creg J. Workman, Dario A.A. Vignali, Olga Pletinkova, David W. Nauen, Philip C. Wong, Juan C. Troncoso, Mingyao Ying, Valina L. Dawson, Ted M. Dawson, and Xiaobo Mao
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Article - Abstract
The spread of prion-like protein aggregates is believed to be a common driver of pathogenesis in many neurodegenerative diseases. Accumulated tangles of filamentous Tau protein are considered pathogenic lesions of Alzheimer’s disease (AD) and related Tauopathies, including progressive supranuclear palsy, and corticobasal degeneration. Tau pathologies in these illnesses exhibits a clear progressive and hierarchical spreading pattern that correlates with disease severity1, 2. Clinical observation combined with complementary experimental studies3, 4have shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remains poorly understood. Here, we show that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF, but not monomer, of Tau. Deletion ofLag3or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lackingLag3selectively in neurons. Our results identify neuronal Lag3 as a receptor of pathologic Tau in the brain, and for AD and related Tauopathies a therapeutic target.One Sentence SummaryLag3 is a neuronal receptor specific for Tau PFF, and is required for uptake, propagation and transmission of Tau pathology.
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- 2023
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16. Hematological and Other Cancers in People Using Clozapine
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Jessica L. Dawson, Janet K. Sluggett, Nicholas G. Procter, Nicholas Myles, J. Simon Bell, Dawson, Jessica, Slugget, Janet, Procter, Nicholas Gerard, Myles, Nicholas, and Bell, Simon J
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Psychiatry and Mental health ,Pharmacology (medical) - Abstract
Background: Recent observational study evidence suggests that clozapine, unlike other antipsychotics, may be associated with a small increased risk of hematological malignancy. This study described characteristics of hematological and other cancers in those taking clozapine reported to the Australian Therapeutic Goods Administration. Methods: We analyzed public case reports for “clozapine,” “Clozaril,” or “Clopine” from January 1995 to December 2020 classified as “neoplasm benign, malignant and unspecified” by the Australian Therapeutic Goods Administration. Data on age, sex, dose, clozapine start and cessation dates, Medical Dictionary for Regulatory Activities reaction terms, and date of cancer were extracted. Results: Overall, 384 spontaneous reports of cancers in people taking clozapine were analyzed. The mean age of patients was 53.9 years (SD, 11.4 years), and 224 (58.3%) were male. The most frequent cancers were hematological (n = 104 [27.1%]), lung (n = 50 [13.0%]), breast (n = 37 [9.6%]), and colorectal (n = 28 [7.3%]). The outcome was fatal for 33.9% of cancer reports. Lymphoma comprised 72.1% of all hematological cancers (mean patient age, 52.1 years; SD, 11.6 years). The median daily dose of clozapine at the time of hematological cancer report was 400 mg (interquartile range, 300–543.8 mg), and the median duration of clozapine use before hematological cancer diagnosis was 7.0 years (interquartile range, 2.8–13.2 years). Conclusions: Lymphoma and other hematological cancers are overrepresented in spontaneous adverse event reports compared with other cancer types. Clinicians should be aware of the possible association with hematological cancers and monitor for and report any hematological cancers identified. Future studies should examine histology of lymphomas in people using clozapine and corresponding blood level of clozapine. Refereed/Peer-reviewed
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- 2023
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17. The prevalence and classification of mandibular third molar impactions and associated second molar pathology in a Gauteng population group. A retrospective study
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L Dawson, TC Postma, and Leanne Sykes
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An impacted tooth is one that has not erupted or is unlikely to erupt into its functional position within the dental arch1, and which has remained embedded in the jawbone or mucosa for more than 2 years following its physiological eruption time2 . It may be visible, not visible but palpable, or neither visible nor palpable but evident on a radiograph.1,3 Third molars are the most commonly impacted teeth followed by maxillary canines, with reported variations in prevalence amongst different population groups2,4. In 2000 The National Institute for Health and Clinical Excellence (NICE) issued guidelines stating that third molars should only be removed if there is evidence of pathology, and advocated that the practice of prophylactic removal be discontinued.1
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- 2022
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18. The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results
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Patrick D. Lyden, Francesca Bosetti, Márcio A. Diniz, André Rogatko, James I. Koenig, Jessica Lamb, Karisma A. Nagarkatti, Ryan P. Cabeen, David C. Hess, Pradip K. Kamat, Mohammad B. Khan, Kristofer Wood, Krishnan Dhandapani, Ali S. Arbab, Enrique C. Leira, Anil K. Chauhan, Nirav Dhanesha, Rakesh B. Patel, Mariia Kumskova, Daniel Thedens, Andreia Morais, Takahiko Imai, Tao Qin, Cenk Ayata, Ligia S.B. Boisserand, Alison L. Herman, Hannah E. Beatty, Sofia E. Velazquez, Sebastian Diaz-Perez, Basavaraju G. Sanganahalli, Jelena M. Mihailovic, Fahmeed Hyder, Lauren H. Sansing, Raymond C. Koehler, Steven Lannon, Yanrong Shi, Senthilkumar S. Karuppagounder, Adnan Bibic, Kazi Akhter, Jaroslaw Aronowski, Louise D. McCullough, Anjali Chauhan, Andrew Goh, Shahneela Siddiqui, Kevin Sheth, Charles Matouk, Charles Dela Cruz, Jiangbing Zhou, Valina L. Dawson, Ted M. Dawson, Jian Liang, Peter C.M. van Zijl, Steven R. Zeiler, W. Taylor Kimberly, Taylan Erdogan, Lili Yu, Joseph Mandeville, and Jonah Patrick Weigand Whittier
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Male ,Advanced and Specialized Nursing ,Brain ,Infarction, Middle Cerebral Artery ,Article ,Brain Ischemia ,Stroke ,Mice ,Animals ,Feasibility Studies ,Humans ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,Aged - Abstract
Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues—such as incomplete mechanistic knowledge and faulty clinical trial design—a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.
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- 2022
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19. A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia
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A. J. McGuinness, J. A. Davis, S. L. Dawson, A. Loughman, F. Collier, M. O’Hely, C. A. Simpson, J. Green, W. Marx, C. Hair, G. Guest, M. Mohebbi, M. Berk, D. Stupart, D. Watters, and F. N. Jacka
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Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,digestive system ,Molecular Biology - Abstract
The emerging understanding of gut microbiota as ‘metabolic machinery’ influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to ‘healthy’ controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (β-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.
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- 2022
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20. Supporting Maternal and Child Mental Health Through Dietary Changes Focused on the Gut Microbiota
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Samantha L. Dawson, Amy Finlay-Jones, Lauren Ball, Tetyana Rocks, and Felice Jacka
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Psychiatry and Mental health - Abstract
Growing evidence from preclinical studies, epidemiology, and randomized controlled trials supports a causal role for diet quality in mental disorder risk, and clinical psychiatric guidelines now place diet, along with other lifestyle behaviors, as foundational treatment targets for mood disorders. Diet quality in the perinatal period is related to both mothers' mental health and children's emotional and neurodevelopment outcomes. The human gut microbiota composition is influenced by diet, and emerging evidence suggests that disturbances in gut microbiota, at least in part, mediate these relationships. Thus, optimizing maternal diet should be prioritized as part of a multidisciplinary approach for promoting physical and mental health in mothers and their off spring. This paper addresses the current evidence base and discusses its application in perinatal health care. [ Psychiatr Ann . 2022;52(2):51–55.]
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- 2022
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21. An analysis of the relationships between religious orientation, authoritarianism, cross‐cultural interactions, and political views
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Joshua A. Cuevas, Bryan L. Dawson, and Ashley C. Grant
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General Social Sciences ,Management, Monitoring, Policy and Law - Published
- 2022
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22. Diverse experiences and approaches to tele neuropsychology: Commentary and reflections over the past year of COVID-19
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Kelsey C. Hewitt, Cady Block, John A. Bellone, Erica L. Dawson, Patricia Garcia, Adam Gerstenecker, Jonathan M. Grabyan, Christopher Howard, Vidyulata Kamath, Brittany C. LeMonda, Seth A. Margolis, Willie F. McBride, Christine M. Salinas, Danny M. Tam, Keenan A. Walker, and Victor A. Del Bene
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Adult ,COVID-19 ,Neuropsychological Tests ,Telemedicine ,United States ,Psychiatry and Mental health ,Clinical Psychology ,Neuropsychology and Physiological Psychology ,Arts and Humanities (miscellaneous) ,Neuropsychology ,Surveys and Questionnaires ,Developmental and Educational Psychology ,Humans ,Child ,Pandemics ,Aged - Published
- 2022
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23. Waiting for PARIS—A Biological Target in Search of a Drug
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Valina L. Dawson, Ted M. Dawson, Richard K. Wyse, Simon R.W. Stott, Helen Matthews, and Leah Mursaleen
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Cognitive science ,Drug ,media_common.quotation_subject ,Translational medicine ,Parkin ,Cellular and Molecular Neuroscience ,Therapeutic approach ,Drug class ,Biological target ,Intervention (counseling) ,In patient ,Neurology (clinical) ,Psychology ,media_common - Abstract
A recent breakthrough paper published in Science Translational Medicine has provided compelling evidence that inhibition of Parkin Interacting Substrate (PARIS) may offer clinical researchers an important new therapeutic approach since it shows considerable promise as an important biological target potentially capable of pharmaceutical intervention to slow long term neurodegeneration in patients with Parkinson’s disease (PD). We present several PD-relevant perspectives on this paper that were not discussed in that otherwise entirely scientific narrative. We also outline the some of the work leading up to it, including the massive drug screen that proved necessary to discover a clinically suitable inhibitor of PARIS (Farnesol), as well as relevant PD research within the wider drug class, issues surrounding its future formulation, and next steps in translating this new knowledge into the clinic to evaluate possible long-term PD patient benefits.
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- 2022
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24. A Comparative Analysis of Australian and Canadian Foreign Fighters Traveling to Syria and Iraq
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Shandon Harris-Hogan, Amarnath Amarasingam, and Lorne L. Dawson
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Sociology and Political Science ,Political Science and International Relations ,Safety, Risk, Reliability and Quality ,Safety Research - Published
- 2022
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25. Supplementary Methods and Table 1 from Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with Autologous Stem Cell Transplant in Refractory Cancer: Pharmacokinetic and Pharmacodynamic Correlates
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Daniel M. Sullivan, Richard M. Lush, Anthony M. Neuger, Christine E. Simonelli, Beth L. Maddox, Karen K. Fields, James S. Partyka, Teresa L. Field, Jongphil Kim, Jana L. Dawson, Steven C. Goldstein, and Janelle B. Perkins
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PDF file - 64K
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- 2023
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26. Data from Melphalan and Exportin 1 Inhibitors Exert Synergistic Antitumor Effects in Preclinical Models of Human Multiple Myeloma
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Daniel M. Sullivan, William S. Dalton, Taiga Nishihori, Christopher L. Cubitt, Jongphil Kim, Juan A. Gomez, Jana L. Dawson, Alexis A. Bauer, Yan Cui, and Joel G. Turner
- Abstract
High-dose chemotherapy with melphalan followed by autologous transplantation is a first-line treatment for multiple myeloma. Here, we present preclinical evidence that this treatment may be significantly improved by the addition of exportin 1 inhibitors (XPO1i). The XPO1i selinexor, eltanexor, and KOS-2464 sensitized human multiple myeloma cells to melphalan. Human 8226 and U266 multiple myeloma cell lines and melphalan-resistant cell lines (8226-LR5 and U266-LR6) were highly sensitized to melphalan by XPO1i. Multiple myeloma cells from newly diagnosed and relapsed/refractory multiple myeloma patients were also sensitized by XPO1i to melphalan. In NOD/SCIDγ mice challenged with either parental 8226 or U266 multiple myeloma and melphalan-resistant multiple myeloma tumors, XPO1i/melphalan combination treatments demonstrated stronger synergistic antitumor effects than single-agent melphalan with minimal toxicity. Synergistic cell death resulted from increased XPO1i/melphalan-induced DNA damage in a dose-dependent manner and decreased DNA repair. In addition, repair of melphalan-induced DNA damage was inhibited by selinexor, which decreased melphalan-induced monoubiquitination of FANCD2 in multiple myeloma cells. Knockdown of FANCD2 was found to replicate the effect of selinexor when used with melphalan, increasing DNA damage (γH2AX) by inhibiting DNA repair. Thus, combination therapies that include selinexor or eltanexor with melphalan may have the potential to improve treatment outcomes of multiple myeloma in melphalan-resistant and newly diagnosed patients. The combination of selinexor and melphalan is currently being investigated in the context of high-dose chemotherapy and autologous transplant (NCT02780609).Significance:Inhibition of exportin 1 with selinexor synergistically sensitizes human multiple myeloma to melphalan by inhibiting Fanconi anemia pathway-mediated DNA repair.
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- 2023
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27. Data from Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with Autologous Stem Cell Transplant in Refractory Cancer: Pharmacokinetic and Pharmacodynamic Correlates
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Daniel M. Sullivan, Richard M. Lush, Anthony M. Neuger, Christine E. Simonelli, Beth L. Maddox, Karen K. Fields, James S. Partyka, Teresa L. Field, Jongphil Kim, Jana L. Dawson, Steven C. Goldstein, and Janelle B. Perkins
- Abstract
Purpose: To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with chemotherapy-refractory malignancies.Experimental Design: Patients were treated with (in mg/m2/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days −8 through −6 and etoposide 500 (days −5 through −3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured.Results: The topotecan MTD in this regimen was 64 mg/m2 (21.3 mg/m2/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose.Conclusion: Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy. Clin Cancer Res; 17(24); 7743–53. ©2011 AACR.
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- 2023
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28. Supplementary Data from Phase I Clinical Trial of Selinexor in Combination with Daunorubicin and Cytarabine in Previously Untreated Poor-Risk Acute Myeloid Leukemia
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Jeffrey E. Lancet, Bijal D. Shah, Julio Chavez, Daniel M. Sullivan, Jana L. Dawson, David A. Sallman, Alan F. List, Junmin Zhou, Joel G. Turner, Christopher L. Cubitt, Eric Padron, Rami Komrokji, and Kendra Sweet
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Supplementary table and figures.
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- 2023
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29. Data from Phase I Clinical Trial of Selinexor in Combination with Daunorubicin and Cytarabine in Previously Untreated Poor-Risk Acute Myeloid Leukemia
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Jeffrey E. Lancet, Bijal D. Shah, Julio Chavez, Daniel M. Sullivan, Jana L. Dawson, David A. Sallman, Alan F. List, Junmin Zhou, Joel G. Turner, Christopher L. Cubitt, Eric Padron, Rami Komrokji, and Kendra Sweet
- Abstract
Purpose:Induction chemotherapy results in complete remission (CR) rates of 20% to 50% among patients with poor-risk AML. Selinexor is an oral selective inhibitor of nuclear export with promising single-agent activity. By inhibiting the primary export protein, XPO1, selinexor localizes and activates tumor suppressor proteins in the nucleus and inhibits DNA damage repair, rationalizing combination with DNA-damaging agents.Patients and Methods:This was a single-arm phase I clinical trial of selinexor combined with cytarabine and daunorubicin (7+3). Dose escalation was selinexor alone (3+3) with an expansion at the MTD. Cohorts 1 and 2 received 60 and 80 mg orally, respectively, twice weekly during induction. Consolidation cycles (≤ 2) with selinexor at induction dose plus 5+2 were allowed for patients who achieved CR. MTD and recommended phase II dose of selinexor were the primary endpoints.Results:Twenty-one patients with poor-risk AML were enrolled. All 21 patients were included in the safety evaluations and survival analyses (4 in each of 2 cohorts; 13 in the expansion); 8 (53%) of the 19 patients evaluable for response achieved CR/CRi. MTD was not reached. Selinexor 80 mg (orally, twice weekly) was used in the expansion phase. The most common grade 3/4 nonhematologic treatment-emergent adverse events were febrile neutropenia (67%), diarrhea (29%), hyponatremia (29%), and sepsis (14%). At median follow-up (28.9 months), 38% of patients were alive. Median overall survival was 10.3 months.Conclusions:Selinexor plus 7+3 is a safe regimen for patients with newly diagnosed poor-risk AML and warrants further investigation in a larger clinical trial.
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- 2023
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30. Supplementary Data from Melphalan and Exportin 1 Inhibitors Exert Synergistic Antitumor Effects in Preclinical Models of Human Multiple Myeloma
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Daniel M. Sullivan, William S. Dalton, Taiga Nishihori, Christopher L. Cubitt, Jongphil Kim, Juan A. Gomez, Jana L. Dawson, Alexis A. Bauer, Yan Cui, and Joel G. Turner
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Supplemental figures
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- 2023
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31. A 3D-printed transepidermal microprojection array for human skin microbiome sampling
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Kun Liang, Cheryl Leong, Jia Min Loh, Nathania Chan, Larissa Lim, Yuen In Lam, Thomas L. Dawson, Hong Liang Tey, Lee Kong Chian School of Medicine (LKCMedicine), National University of Singapore, and National Skin Centre
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Multidisciplinary ,Microprojection Array ,Tissue Array Analysis ,Microbiota ,Printing, Three-Dimensional ,Humans ,Medicine [Science] ,Skin Microbiome Sampling ,Epidermis ,Specimen Handling - Abstract
Skin microbiome sampling is currently performed with tools such as swabs and tape strips to collect microbes from the skin surface. However, these conventional approaches may be unable to detect microbes deeper in the epidermis or in epidermal invaginations. We describe a sampling tool with a depth component, a transepidermal microprojection array (MPA), which captures microbial biomass from both the epidermal surface and deeper skin layers. We leveraged the rapid customizability of 3D printing to enable systematic optimization of MPA for human skin sampling. Evaluation of sampling efficacy on human scalp revealed the optimized MPA was comparable in sensitivity to swab and superior to tape strip, especially for nonstandard skin surfaces. We observed differences in species diversity, with the MPA detecting clinically relevant fungi more often than other approaches. This work delivers a tool in the complex field of skin microbiome sampling to potentially address gaps in our understanding of its role in health and disease. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) Published version This work was supported by the National Additive Manufacturing Innovation Cluster@NTUitive (NAMIC@NTUitive) , Singapore, grants 2018255 and 2019060. Authors were supported by funding from A*STAR and A*STAR BMRC EDB IAF-PP grants H17/01/a0/004 "Skin Research Institute of Singapore" (K.L. and T.L.D.J.) and H18/01a0/016 "Asian Skin Micro-biome Program" (C.L., N.C., Y.I.L., and T.L.D.J.) . H.L.T. was supported by Singa-pore Ministry of Health's National Medical Research Council under its Clinician Scientist Award (CSAINV20nov-0003).
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- 2023
32. The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson’s disease
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Senthilkumar S. Karuppagounder, Hu Wang, Terence Kelly, Roger Rush, Richard Nguyen, Shivani Bisen, Yoko Yamashita, Nicholas Sloan, Brianna Dang, Alexander Sigmon, Hyeun Woo Lee, Shirley Marino Lee, Leslie Watkins, Erica Kim, Saurav Brahmachari, Manoj Kumar, Milton H. Werner, Ted M. Dawson, and Valina L. Dawson
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General Medicine - Abstract
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein–dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.
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- 2023
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33. Parkinson Disease: Translating Insights from Molecular Mechanisms to Neuroprotection
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Sheila K. Pirooznia, Liana S. Rosenthal, Ted M. Dawson, and Valina L. Dawson
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Pharmacology ,Motor dysfunction ,business.industry ,Neurodegeneration ,Parkinson Disease ,Disease ,medicine.disease ,Neuroprotection ,Penetrance ,Mutation ,Research based ,Humans ,Molecular Medicine ,Medicine ,Functional studies ,business ,Neuroscience - Abstract
Parkinson disease (PD) used to be considered a nongenetic condition. However, the identification of several autosomal dominant and recessive mutations linked to monogenic PD has changed this view. Clinically manifest PD is then thought to occur through a complex interplay between genetic mutations, many of which have incomplete penetrance, and environmental factors, both neuroprotective and increasing susceptibility, which variably interact to reach a threshold over which PD becomes clinically manifested. Functional studies of PD gene products have identified many cellular and molecular pathways, providing crucial insights into the nature and causes of PD. PD originates from multiple causes and a range of pathogenic processes at play, ultimately culminating in nigral dopaminergic loss and motor dysfunction. An in-depth understanding of these complex and possibly convergent pathways will pave the way for therapeutic approaches to alleviate the disease symptoms and neuroprotective strategies to prevent disease manifestations. This review is aimed at providing a comprehensive understanding of advances made in PD research based on leveraging genetic insights into the pathogenesis of PD. It further discusses novel perspectives to facilitate identification of critical molecular pathways that are central to neurodegeneration that hold the potential to develop neuroprotective and/or neurorestorative therapeutic strategies for PD. SIGNIFICANCE STATEMENT: A comprehensive review of PD pathophysiology is provided on the complex interplay of genetic and environmental factors and biologic processes that contribute to PD pathogenesis. This knowledge identifies new targets that could be leveraged into disease-modifying therapies to prevent or slow neurodegeneration in PD.
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- 2021
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34. Chapter 5 Dancing with an Angel
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Elsa L. Dawson
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- 2022
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35. The human pathobiont
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Joleen P Z, Goh, Fiorella, Ruchti, Si En, Poh, Winston L C, Koh, Kiat Yi, Tan, Yan Ting, Lim, Steven T G, Thng, Radoslaw M, Sobota, Shawn S, Hoon, Chenxi, Liu, Anthony J, O'Donoghue, Salomé, LeibundGut-Landmann, Hazel H, Oon, Hao, Li, and Thomas L, Dawson
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Inflammation ,Mice ,Malassezia ,Aspartic Acid Proteases ,Humans ,Animals ,Aspartic Acid Endopeptidases ,Peptide Hydrolases ,Dermatitis, Atopic - Published
- 2022
36. Poly ADP-Ribose Signaling is Dysregulated in Huntington’s Disease Patients
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Tamara Maiuri, Carlos Barba Bazan, Rachel J. Harding, Nola Begeja, Tae-In Kam, Lauren M. Byrne, Filipe B. Rodrigues, Monica M. Warner, Kaitlyn Neuman, Muqtasid Mansoor, Mohsen Badiee, Morgan Dasovich, Anthony K. L. Leung, Sara N. Andres, Edward J. Wild, Ted M. Dawson, Valina L. Dawson, Cheryl H. Arrowsmith, and Ray Truant
- Abstract
Huntington’s disease (HD) is an autosomal dominant genetic neurodegenerative disease caused by a CAG expansion in theHuntingtin (HTT)gene, translating to an expanded polyglutamine tract in the huntingtin (HTT) protein. Age at disease onset is correlated to CAG repeat length, but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Recent clinical studies show elevated DNA damage in HD, even at the premanifest stage of disease. One of the major DNA repair nodes influencing neurodegenerative disease is the PARP pathway. Accumulation of poly ADP-ribose (PAR), produced by PARP1 and PARP2, has been implicated in the pathology of Alzheimer’s and Parkinson’s diseases, as well as autosomal recessive cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Patient-derived fibroblasts have reduced PARP1/2 activity and elevated DNA damage, while elevated PAR levels are only revealed upon inhibition of PAR degradation. These phenotypes are rescued by moderate huntingtin level reduction via the huntingtin-lowering splice modulator drug, LMI070 (Branaplam). As a direct mechanism, we have defined a PAR-binding motif in huntingtin, detected huntingtin complexed with PARylated proteins in human cells during stress, and localized huntingtin to mitotic chromosomes upon inhibition of PAR degradation. Direct huntingtin PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy. These results provide insight into a very early molecular mechanism of HD, suggesting possible targets in HD to design early preventive therapies.
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- 2022
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37. Cell Biology of Parkin: Clues to the Development of New Therapeutics for Parkinson's Disease
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Jaimin Patel, Nikhil Panicker, Valina L. Dawson, and Ted M. Dawson
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Psychiatry and Mental health ,Ubiquitin-Protein Ligases ,Humans ,Pharmacology (medical) ,Parkinson Disease ,Neurodegenerative Diseases ,Neurology (clinical) ,Mitochondria - Abstract
Parkinson's disease is the second most prevalent neurodegenerative disease and contributes significantly to morbidity globally. Currently, no disease-modifying therapies exist to combat this disorder. Insights from the molecular and cellular pathobiology of the disease seems to indicate promising therapeutic targets. The parkin protein has been extensively studied for its role in autosomal recessive Parkinson's disease and, more recently, its role in sporadic Parkinson's disease. Parkin is an E3 ubiquitin ligase that plays a prominent role in mitochondrial quality control, mitochondrial-dependent cell death pathways, and other diverse functions. Understanding the numerous roles of parkin has introduced many new possibilities for therapeutic modalities in treating both autosomal recessive Parkinson's disease and sporadic Parkinson's disease. In this article, we review parkin biology with an emphasis on mitochondrial-related functions and propose novel, potentially disease-modifying therapeutic approaches for treating this debilitating condition.
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- 2022
38. Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis
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Mohammed Repon Khan, Xiling Yin, Sung-Ung Kang, Jaba Mitra, Hu Wang, Saurav Brahmachari, Senthilkumar S. Karuppagounder, Yasuyoshi Kimura, Aanishaa Jhaldiyal, Hyun Hee Kim, Hao Gu, Rong Chen, Javier Redding-Ochoa, Juan Troncoso, Taekjip Ha, Valina L. Dawson, and Ted M. Dawson
- Abstract
Pathologic α-syn destabilizes the TSC 1 and 2 complex leading to mTORC1 activation, enhanced protein translation and neurodegeneration in PD.Abstract:Pathological α-synuclein (α-syn) plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson’s disease (PD). Disruption of protein homeostasis is thought be central to PD pathogenesis, however the molecular mechanism of this deregulation is poorly understood. Here we report that pathologic α-syn binds to tuberous sclerosis protein (TSC) 2 and destabilizes the TSC1-TSC2 complex leading to activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and enhanced mRNA translation. Dopamine neuron loss, behavioral deficits and aberrant biochemical signaling in the α-syn preformed fibril (PFF) and Drosophila α-syn transgenic models of pathologic α-syn induced degeneration were attenuated by genetic and pharmacologic inhibition of mTOR and protein translation. Our findings establish a potential molecular mechanism by which pathologic α-syn activates mTORC1 leading to enhanced protein translation and concomitant neurodegeneration in PD.
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- 2022
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39. Impact of ambulance off-load delays on mortality in patients with chest pain
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L. Dawson, E. Andrew, M. Stephenson, Z. Nehme, J. Bloom, S. Cox, D. Anderson, J. Lefkovits, A. Taylor, D. Kaye, K. Smith, and D. Stub
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Pulmonary and Respiratory Medicine ,Cardiology and Cardiovascular Medicine - Abstract
Background Ambulance off-load delays in transferring patient care to emergency departments (EDs) are increasingly common, but it is unclear whether clinical outcomes are impacted. Methods Population-based cohort study of ambulance attendances for non-traumatic chest pain transported to ED in Victoria, Australia (1/1/2015–30/6/2019) excluding patients transported to hospital with “lights and sirens” or triaged as ED category 1. Multivariable models were used to assess the relationship between ambulance off-load times and 30-day mortality and ambulance re-attendance for chest pain. Results The study included 213,544 ambulance attendances for chest pain (mean age 62 [SD 18] years; 51% female). Median ambulance off-load times increased across the study period from 21 minutes (interquartile range [IQR] 15–30) in 2015 to 24 minutes (IQR 17–37) in 2019. Patients were divided into tertiles according to off-load times with 69,247 patients included in tertile 1 (0–17 minutes), 73,109 patients in tertile 2 (18–28 minutes), and 71,188 patients in tertile 3 (>28 minutes). In multivariable models, ambulance off-load delays were associated with higher unadjusted and adjusted rates of 30-day mortality (1.57% tertile 3 vs. 1.29% tertile 1, adjusted risk difference 0.28% [95% CI 0.16% - 0.42%], p Conclusions Delays in ambulance off-load times appear to be associated with increased mortality and ambulance re-attendance risk among chest pain cohorts. This study has important policy implications given the increasing frequency of off-load delays in many healthcare settings. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Alfred health
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- 2022
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40. Variation in health-care quality and outcomes according to time of chest pain presentation: a state-wide prospective cohort study
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R. Navani, L. Dawson, E. Andrew, Z. Nehme, J. Bloom, S. Cox, D. Anderson, M. Stephenson, J. Lefkovits, A. Taylor, D. Kaye, K. Smith, and D. Stub
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Pulmonary and Respiratory Medicine ,Cardiology and Cardiovascular Medicine - Abstract
Background Previous studies examining temporal variation in cardiovascular care have largely been limited to assessing weekend and after-hours effects whereby those presenting on the weekend or after-hours have a poorer outcome. However, emerging evidence suggests more complex patterns in patterns and outcomes may exist. Purpose We aimed to determine patterns of temporal variation in chest pain presentations and subsequent health-care quality and outcomes. Methods This was an observational, prospective-cohort study of adult patients aged 18 and over who were attended by emergency medical services for non-traumatic chest pain between 1 January 2015 and 30 June 2019 in Victoria, Australia. Major exclusion criteria included pre-hospital diagnosis of ST elevation myocardial infarction or an out of hospital cardiac arrest. The exposure variable was time of day and day of week stratified into 168 hourly time periods. The primary outcome measure was 30-day mortality. Results The study cohort comprised 196,365 ambulance attendances for acute non-traumatic chest pain; mean age 62.4 years (SD 18.3) and 99,497 (50.7%) females. Three temporal patterns were observed for chest pain presentations (Figure 1): (1) a diurnal pattern with a sharp increase in presentations from 8 am, peaking around midday, before decreasing into late evening with a nadir between 3–4 am, (2) a weekend effect where Saturday and Sunday had a relatively lower rate of presentations compared to during the week, and (3) a Monday – Sunday gradient where more presentations were likely earlier in the week, than later. Six patterns were identified across pre-hospital and hospital key performance indicators (KPI) (diurnal, in/after-hours, weekend effect, Monday – Sunday gradient, a peak period and morning vs afternoon/evening effect. Risk of 30-day mortality was associated with weekend presentation (OR 1.15, 95% CI 1.06–1.24, p=0.001) and morning presentation between midnight and midday (OR 1.17, 95% CI 1.09–1.25, p Conclusion Chest pain presentations, care quality and outcomes demonstrate complex temporal variation beyond the already established weekend and after-hours effect. Such relationships should be considered during resource allocation and quality improvement programs in order to improve treatment quality across all days and times of the week. Funding Acknowledgement Type of funding sources: None.
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- 2022
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41. Differences in the gut microbiome across typical ageing and in Parkinson's disease
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Nathan D. Nuzum, Ewa A. Szymlek-Gay, Stella Loke, Samantha L. Dawson, Wei-Peng Teo, Ashlee M. Hendy, Amy Loughman, and Helen Macpherson
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Pharmacology ,Cellular and Molecular Neuroscience - Published
- 2023
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42. Safe food through better labelling; a robust method for the rapid determination of caprine and bovine milk allergens
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Joost L.D. Nelis, Amanda L. Dawson, Utpal Bose, Alisha Anderson, Michelle L. Colgrave, and James A. Broadbent
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General Medicine ,Food Science ,Analytical Chemistry - Published
- 2023
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43. A Review of Oral Therapies for the Treatment of Skin Hyperpigmentation
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Nancy L. Dawson, Leila M. Tolaymat, Maria Cooper, Serena J E Shimshak, Jason C. Sluzevich, Mingyuan Yin, Brandon Kirsch, Claire B. Haga, and Mindy S Gillis
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medicine.medical_specialty ,Blinding ,business.industry ,Melasma ,Administration, Oral ,Dermatology ,Administration, Cutaneous ,medicine.disease ,Hyperpigmentation ,Melanosis ,Review article ,Tranexamic Acid ,Skin hyperpigmentation ,medicine ,Humans ,Surgery ,medicine.symptom ,business ,Isotretinoin ,Tranexamic acid ,medicine.drug - Abstract
This review article examines evidence supporting the use of oral therapies in treating idiopathic, actinic, and metabolically induced skin hyperpigmentation. A thorough review of the literature regarding oral treatments for hyperpigmentation was systematically conducted through PubMed. Keywords used in the primary search include “Hyperpigmentation,” “Melanosis” or “Melasma,” “Lightening,” “Oral,” and “Therapeutics.” The search was limited to the English language, and no timeframe restrictions were implemented. Numerous orally administered therapies have been proposed for the treatment of skin hyperpigmentation. There is an abundant body of literature demonstrating the efficacy of orally administered tranexamic acid, glutathione, isotretinoin, and proanthocyanidin. It is reasonable to expect that the most effective oral therapies will address known underlying causes of hyperpigmentation such as thyroid disease, diabetes, and hormonal imbalance. Improvement due to oral therapy of otherwise unresponsive skin hyperpigmentation or hyperpigmentation of unknown cause is less predictable. This review is limited by the strength of evidence contained within the available studies. Clinical studies investigating the treatments discussed within this article are limited in number, at times lack blinding in the study design, and are based on small sample sizes. Based on existing research, the most promising oral remedies for hyperpigmentation appear to be tranexamic acid, glutathione, isotretinoin, and proanthocyanidin. Additional studies to better establish safety and efficacy are necessary.
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- 2021
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44. Review of the top 5 cardiology studies of 2019-20
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Chloe L. McMillan, Hazal E. Babadagli, Mohamed A. Omar, Arden R. Barry, Ellen L. Dawson, Jian Song Zhou, June W. Chen, David G. Lopaschuk, Binh V. Nguyen, Dylan M. Pollmann, Margaret L. Ackman, and Rosaleen Boswell
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Clinical Review ,2019-20 coronavirus outbreak ,Research and Clinical ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pharmaceutical Science ,Medicine ,Pharmacy ,business ,Virology - Published
- 2021
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45. Therapeutic Potential of a Novel Glucagon-like Peptide-1 Receptor Agonist, NLY01, in Experimental Autoimmune Encephalomyelitis
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Matthew D. Smith, Elias S. Sotirchos, Valina L. Dawson, Peter A. Calabresi, Seulki Lee, Marjan Gharagozloo, Ted M. Dawson, Hannah-Noelle Lord, Jing Jin, Keya Meyers, Thomas Garton, Riley Bannon, and Michelle Taylor
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Agonist ,Encephalomyelitis, Autoimmune, Experimental ,medicine.drug_class ,T-Lymphocytes ,Central nervous system ,Neuroprotection ,Glucagon-Like Peptide-1 Receptor ,Mice ,medicine ,Animals ,Glucose homeostasis ,Pharmacology (medical) ,Pharmacology ,business.industry ,Multiple sclerosis ,Neurodegeneration ,Experimental autoimmune encephalomyelitis ,medicine.disease ,Mice, Inbred C57BL ,Neuroprotective Agents ,medicine.anatomical_structure ,Gliosis ,Immunology ,Female ,Original Article ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by demyelination, gliosis, and neurodegeneration. While the currently available disease-modifying therapies effectively suppress the immune attack on the CNS, there are no therapies to date that directly mitigate neurodegeneration. Glucagon-like peptide-1 (GLP-1) is a small peptide hormone that maintains glucose homeostasis. A novel GLP-1 receptor (GLP-1R) agonist, NLY01, was recently shown to have neuroprotective effects in the animal models of Parkinson’s disease and is now in a phase 2 clinical trial. In this study, we investigated the therapeutic potential of NLY01 in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Our data show that NLY01 delays the onset and attenuates the severity of EAE in a prevention paradigm, when given before disease onset. NLY01 inhibits the activation of immune cells in the spleen and reduces their trafficking into the CNS. In addition, we show that NLY01 suppresses the production of chemokines that are involved in leukocyte recruitment to the site of inflammation. The anti-inflammatory effect of NLY01 at the early stage of EAE may block the expression of the genes associated with neurotoxic astrocytes in the optic nerves, thereby preventing retinal ganglion cell (RGC) loss in the progressive stage of EAE. In the therapeutic paradigm, NLY01 significantly decreases the clinical score and second attack in a model of relapsing–remitting EAE. GLP-1R agonists may have dual efficacy in MS by suppressing peripheral and CNS inflammation, thereby limiting neuronal loss. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01088-5.
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- 2021
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46. Poly(ADP-ribose) promotes toxicity of
- Author
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Junli, Gao, Quinlan T, Mewborne, Amandeep, Girdhar, Udit, Sheth, Alyssa N, Coyne, Ritika, Punathil, Bong Gu, Kang, Morgan, Dasovich, Austin, Veire, Mariely, DeJesus Hernandez, Shuaichen, Liu, Zheng, Shi, Ruxandra, Dafinca, Elise, Fouquerel, Kevin, Talbot, Tae-In, Kam, Yong-Jie, Zhang, Dennis, Dickson, Leonard, Petrucelli, Marka, van Blitterswijk, Lin, Guo, Ted M, Dawson, Valina L, Dawson, Anthony K L, Leung, Thomas E, Lloyd, Tania F, Gendron, Jeffrey D, Rothstein, and Ke, Zhang
- Subjects
DNA-Binding Proteins ,Poly Adenosine Diphosphate Ribose ,C9orf72 Protein ,Frontotemporal Dementia ,Humans ,Dipeptides ,Arginine - Abstract
Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in
- Published
- 2022
47. CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy
- Author
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Sumit Verma, Kelsey Perry, Raj Razdan, J. Christina Howell, Alice L. Dawson, and William T. Hu
- Subjects
Pharmacology ,Pharmacology (medical) ,Neurology (clinical) - Abstract
Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders.
- Published
- 2022
48. Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins
- Author
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Junli Gao, Quinlan T. Mewborne, Amandeep Girdhar, Udit Sheth, Alyssa N. Coyne, Ritika Punathil, Bong Gu Kang, Morgan Dasovich, Austin Veire, Mariely DeJesus Hernandez, Shuaichen Liu, Zheng Shi, Ruxandra Dafinca, Elise Fouquerel, Kevin Talbot, Tae-In Kam, Yong-Jie Zhang, Dennis Dickson, Leonard Petrucelli, Marka van Blitterswijk, Lin Guo, Ted M. Dawson, Valina L. Dawson, Anthony K. L. Leung, Thomas E. Lloyd, Tania F. Gendron, Jeffrey D. Rothstein, and Ke Zhang
- Subjects
General Medicine - Abstract
Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72 , play a critical role in C9ORF72 -related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR–induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.
- Published
- 2022
- Full Text
- View/download PDF
49. Taking control of microplastics data: A comparison of control and blank data correction methods
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Amanda L. Dawson, Marina F.M Santana, Joost L.D Nelis, and Cherie A. Motti
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Environmental Engineering ,Health, Toxicology and Mutagenesis ,Microplastics ,Environmental Chemistry ,Pollution ,Waste Management and Disposal ,Plastics ,Water Pollutants, Chemical ,Environmental Monitoring - Abstract
Although significant headway has been achieved regarding method harmonisation for the analysis of microplastics, analysis and interpretation of control data has largely been overlooked. There is currently no consensus on the best method to utilise data generated from controls, and consequently many methods are arbitrarily employed. This study identified 6 commonly implemented strategies: a) No correction; b) Subtraction; c) Mean Subtraction; d) Spectral Similarity; e) Limits of detection/ limits of quantification (LOD/LOQ) or f) Statistical analysis, of which many variations are possible. Here, the 6 core methods and 45 variant methods (n = 51) thereof were used to correct a dummy dataset using control data. Most of the methods tested were too inflexible to account for the inherent variation present in microplastic data. Only 7 of the 51 methods tested (six LOD/LOQ methods and one statistical method) showed promise, removing between 96.3 % and 100 % of the contamination data from the dummy set. The remaining 44 methods resulted in deficient corrections for background contamination due to the heterogeneity of microplastics. These methods should be avoided in the future to avoid skewed results, especially in low abundance samples. Overall, LOD/LOQ methods or statistical analysis comparing means are recommended for future use in microplastic studies.
- Published
- 2022
50. Pharmacologic inhibition of MIF nuclease: A new treatment paradigm to treat cell death
- Author
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Devanik Biswas, Valina L. Dawson, and Ted M. Dawson
- Subjects
Cell Death ,Molecular Medicine ,Medicine (miscellaneous) ,Endonucleases ,Macrophage Migration-Inhibitory Factors - Published
- 2022
- Full Text
- View/download PDF
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