Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells
(2024) Nature Genetics, . Cited 1 time.
Jang, H.J.a b c , Shah, N.M.a b , Maeng, J.H.a b , Liang, Y.a b , Basri, N.L.a b , Ge, J.a b , Qu, X.a b , Mahlokozera, T.d , Tzeng, S.-C.e , Williams, R.B.e , Moore, M.J.a b , Annamalai, D.d , Chen, J.Y.a b , Lee, H.J.a b , DeSouza, P.A.d , Li, D.a b , Xing, X.a b , Kim, A.H.d f , Wang, T.a b g
a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, United States
d Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
e Donald Danforth Plant Science Center, St. Louis, MO, United States
f The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
g McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy
(2024) Annals of Clinical and Translational Neurology, .
Mohan, S.a , McNulty, S.a , Thaxton, C.a , Elnagheeb, M.a , Owens, E.a , Flowers, M.a , Nunnery, T.a , Self, A.a , Palus, B.a , Gorokhova, S.b c , Kennedy, A.d , Niu, Z.e , Johari, M.f g , Maiga, A.B.h , Macalalad, K.i , Clause, A.R.i , Beckmann, J.S.j , Bronicki, L.k , Cooper, S.T.l m n , Ganesh, V.S.o p , Kang, P.B.q , Kesari, A.r , Lek, M.s , Levy, J.t , Rufibach, L.u , Savarese, M.g , Spencer, M.J.v , Straub, V.w , Tasca, G.w , Weihl, C.C.i
a Department of Genetics, University of North Carolina, Chapel Hill, NC, United States
b Aix Marseille Univ, INSERM, MMG, U 1251, Marseille, France
c Department of Medical Genetics, Timone Children’s Hospital, APHM, Marseille, France
d Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada
e Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
f Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
g Folkhälsan Research Center, Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
h Department of Medicine, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali
i Department of Neurology, Washington University School of Medicine in St. Louis, St Louis, MO, United States
j Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
k Department of clinical genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
l Kids Neuroscience Centre, Children’s Hospital at Westmead, Westmead, NSW, Australia
m School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
n Functional Neuromics, Children’s Medical Research Institute, Westmead, NSW, Australia
o Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
p Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
q Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology, University of Minnesota, Minneapolis, MN, United States
r Illumina Inc, San Diego, CA, United States
s Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
t Coalition to Cure Calpain 3, Westport, CT, United States
u Jain Foundation, Seattle, WA, United States
v Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
w John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle Upon Tyne, United Kingdom
Abstract
Objective: Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. Methods: The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene–disease relationships (GDR) using the ClinGen gene–disease clinical validity framework to evaluate 31 genes implicated in LGMD. Results: The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. Interpretation: The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations. © 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A single-center retrospective series of OCT and MRI findings in pediatric MOGAD optic neuritis patients
(2024) Canadian Journal of Ophthalmology, .
Guniganti, R.a , Rho, S.a , Morales-Leόn, J.F.b , Mar, S.c , Lee, A.a , Goyal, M.b , Reynolds, M.M.a , Van Stavern, G.P.a
a Department of Ophthalmology & Visual Sciences, Washington University in St Louis, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University in St Louis, St. Louis, MO, United States
c Division of Pediatric & Developmental Neurology, Department of Neurology, St Louis Children’s Hospital, St. Louis, MO, United States
Abstract
Background: Whether optical computed tomography (OCT) and magnetic resonance imaging (MRI) findings are associated with final visual acuity in children with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) optic neuritis is unclear. Methods: We retrospectively reviewed the charts of pediatric patients with MOGAD optic neuritis seen at St. Louis Children’s Hospital/Barnes Jewish Hospital since 2016. Results: In the 12 patients in this study, presenting visual acuity was worse in the optic neuritis-affected eyes but significantly improved from presentation to follow-up, such that, at last follow-up, there was no longer a statistical difference between the affected and unaffected eyes. The number of affected eyes with nerve enhancement and the amount of optic nerve affected, as well as thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and macula, decreased from presentation to follow-up. Ultimately, none of these variables were associated with final visual acuity. Conclusion: In this cohort, pediatric MOGAD optic neuritis patients had positive visual outcomes despite significant RNFL thinning and involvement of the optic nerve on MRI, leading to a lack of correlation between follow-up visual acuity and OCT and MRI measures of disease severity, respectively. © 2024 Canadian Ophthalmological Society
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Isoflurane conditioning improves functional outcomes after peripheral nerve injury in a sciatic cut repair murine model
(2024) Frontiers in Neurology, 15, art. no. 1406463, .
Xu, Y.a , Yan, Y.b , Zipfel, G.J.b c , MacEwan, M.b , Ray, W.Z.b d e , Athiraman, U.b f
a The Institute of Materials Science & Engineering, Washington University, St. Louis, MO, United States
b Department of Neurological Surgery, Washington University, St. Louis, MO, United States
c Department of Neurology, Washington University, St. Louis, MO, United States
d Department of Orthopedic Surgery, Washington University, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
f Department of Anesthesiology, Washington University, St. Louis, MO, United States
Abstract
Introduction: Anesthetic conditioning has been shown to provide neuroprotection in several neurological disorders. Whether anesthetic conditioning provides protection against peripheral nerve injuries remains unknown. The aim of our current study is to investigate the impact of isoflurane conditioning on the functional outcomes after peripheral nerve injury (PNI) in a rodent sciatic nerve injury model. Methods: Adult male Lewis rats underwent sciatic nerve cut and repair and exposed to none (Group 1, sham), single isoflurane exposure (Group 2), three-time isoflurane exposure (Group 3), and six-time isoflurane exposure (Group 4). Isoflurane conditioning was established by administration of 2% isoflurane for 1 hour, beginning 1-hour post sciatic nerve cut and repair. Groups 3 and 4 were exposed to isoflurane for 1 hour, 3 and 6 consecutive days respectively. Functional outcomes assessed included compound muscle action potential (CMAP), evoked muscle force (tetanic and specific tetanic force), wet muscle mass, and axonal counting. Results: We observed an increase in axons, myelin width and a decrease in G-ratio in the isoflurane conditioning groups (3- and 6-days). This correlated with a significant improvement in tetanic and specific tetanic forces, observed in both groups 3 and 4. Discussion: Isoflurane conditioning (3- and 6-day groups) resulted in improvement in functional outcomes at 12 weeks post peripheral nerve injury and repair in a murine model. Future experiments should be focused on identifying the therapeutic window of isoflurane conditioning and exploring the underlying molecular mechanisms responsible for isoflurane conditioning induced neuroprotection in PNI. Copyright © 2024 Xu, Yan, Zipfel, MacEwan, Ray and Athiraman.
Author Keywords
axonal regeneration; functional outcomes; isoflurane conditioning; myelin regeneration; neuroprotection; peripheral nerve injury
Document Type: Article
Publication Stage: Final
Source: Scopus
Body mass index is lower in asymptomatic C9orf72 expansion carriers but not in SOD1 pathogenic variant carriers compared to gene negatives
(2024) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, .
Lee, I.a , Garret, M.A.b , Wuu, J.c , Harrington, E.A.a , Berry, J.D.b , Miller, T.M.d , Harms, M.a , Benatar, M.c , Shneider, N.a
a Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
b Sean M. Healey & AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
c Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States
d Department of Neurology, Washington University, St. Louis, MO, United States
Abstract
Objective: To examine the relationship between body mass index (BMI) and genotype among pre-symptomatic carriers of different pathogenic variants associated with amyotrophic lateral sclerosis. Methods: C9orf72+ carriers, SOD1+ carriers, and pathogenic variant negative controls (Gene-Negatives) were included from 3 largely independent cohorts: ALS Families Project (ALS-Families); Dominantly inherited ALS (DIALS); and Pre-symptomatic Familial ALS (Pre-fALS). First reported (ALS-Families) or measured (DIALS and Pre-fALS) weight and height were used to calculate BMI. Age at weight measurement, self-reported sex (male vs. female), and highest education (high school or below vs. college education vs. graduate school or above) were extracted. The associations between BMI and genotype in each cohort were examined with multivariable linear regression models, adjusted for age, sex, and education. Results: A total of 223 C9orf72+ carriers, 135 SOD1+ carriers, and 191 Gene-Negatives were included, deriving from ALS-Families (n = 114, median age 46, 37% male), DIALS (n = 221, median age 46, 30% male), and Pre-fALS (n = 214, median age 44, 39% male). Adjusting for age, sex, and education, the mean BMI of C9orf72+ carriers was lower than Gene-Negatives by 2.4 units (95% confidence interval [CI] = 0.3–4.6, p = 0.02) in ALS-Families; 2.7 units (95% CI = 0.9–4.4, p = 0.003) in DIALS; and 1.9 units (95% CI = 0.5–4.2, p = 0.12) in Pre-fALS. There were no significant differences in BMI between SOD1+ carriers and Gene-Negatives in any of the 3 cohorts. Conclusions: Compared to Gene-Negatives, average BMI is lower in asymptomatic C9orf72+ carriers across 3 cohorts while no significant difference was found between Gene-Negatives and SOD1+ carriers. © 2024 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.
Author Keywords
Amyotrophic Lateral Sclerosis; Body mass index; C9orf72; Presymptomatic; SOD1
Funding details
Biogen
American Academy of NeurologyAAN
ALS Recovery Fund
Ionis Pharmaceuticals
ALS AssociationALSA
A. O. Smith Foundation
Muscular Dystrophy AssociationMDA
National Center for Advancing Translational SciencesNCATSU54NS092091
National Institute of Neurological Disorders and StrokeNINDSK23NS131586
American Brain FoundationABF2015, 172123, 4365
National Institutes of HealthNIHR01 NS105479
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Poor Sleep is Common in Treatment-Resistant Late-life Depression and Associated With Poorer Antidepressant Response: Findings From the OPTIMUM Clinical Trial
(2024) American Journal of Geriatric Psychiatry, .
Mak, M.S.B.a b , Gebara, M.A.c , Lenze, E.J.d , Blumberger, D.M.a b , Brown, P.J.e , Cristancho, P.d , Flint, A.J.a g , Karp, J.F.i , Lavretsky, H.f , Miller, J.P.h , Reynolds, C.F., IIIc , Roose, S.P.e , Mulsant, B.H.a b , Stahl, S.T.c
a Department of Psychiatry (MSBM, DMB, AJF, BHM), Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
b Centre for Addiction and Mental Health (MSBM, DMB, BHM), Toronto, Canada
c Department of Psychiatry (MAG, CFR, STS), University of Pittsburgh School of Medicine, Toronto, Canada
d Department of Psychiatry (EJL, PC), Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Department of Psychiatry (PJB, SPR), Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, United States
f Department of Psychiatry and Biobehavioral Sciences (HL), University of California, Los Angeles, United States
g Centre for Mental Health (AJF), University Health Network, Toronto, Canada
h Data Science and Biostatistics (JPM), Washington University School of Medicine in St. Louis, Institute for Informatics, St. Louis, MO, United States
i Department of Psychiatry (JFK), College of Medicine, University of Arizona, Tucson, AZ, United States
Abstract
Background: Adults with treatment-resistant late-life depression (TRLLD) have high rates of sleep problems; however, little is known about the occurrence and change in sleep during pharmacotherapy of TRLLD. This analysis examined: (1) the occurrence of insufficient sleep among adults with TRLLD; (2) how sleep changed during pharmacotherapy; and (3) whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep. Methods: Secondary analysis of data from 634 participants age 60+ years in the OPTIMUM clinical trial for TRLLD. Sleep was assessed using the sleep item from the Montgomery-Asberg Depression Rating Scale at the beginning (week-0) and end (week-10) of treatment. The analyses examined whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep during depression treatment. Results: About half (51%, n = 323) of participants reported insufficient sleep at baseline. Both persistent insufficient sleep (25%, n = 158) and worsened sleep (10%, n = 62) during treatment were associated with antidepressant nonresponse. Participants who maintained sufficient sleep (26%, n = 164) or who improved their sleep (n = 25%, n = 158) were three times more likely to experience a depression response than those with persistent insufficient sleep or worsened sleep. Conclusion: Insufficient sleep is common in TRLLD and it is associated with poorer treatment response to antidepressants. © 2024 The Authors
Author Keywords
Aging; geriatric mental health; sleep; sleep disturbance
Document Type: Article
Publication Stage: Article in Press
Source: Scopus