Claes Wahlestedt

Claes Wahlestedt
University of Miami Miller School of Medicine | UM · Center for Therapeutic Innovation

MD PhD

About

508
Publications
60,766
Reads
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39,496
Citations
Additional affiliations
July 2011 - present
University of Miami Miller School of Medicine
Position
  • Leonard M. Miller Professor and Associate Dean

Publications

Publications (508)
Article
Full-text available
Liver cancer ranks as the fourth leading cause of cancer-related deaths. Despite extensive research efforts aiming to evaluate the biological mechanisms underlying hepatocellular carcinoma (HCC) development, little has been translated towards new diagnostic and treatment options for HCC patients. Historically, the focus has been centered on coding...
Article
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The recent discovery of vast non-coding RNA-based regulatory networks that can be easily modulated by nucleic acid-based drugs has opened numerous new therapeutic possibilities. Long non-coding RNA, and natural antisense transcripts (NATs) in particular, play a significant role in networks that involve a wide variety of disease-relevant biological...
Article
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The use of inhibitors of epigenetic modifiers in the treatment of acute myeloid leukemia (AML) has become increasingly appealing due to the highly epigenetic nature of the disease. We evaluated a library of 164 epigenetic compounds in a cohort of 9 heterogeneous AML patients using an ex vivo drug screen. AML blasts were isolated from bone marrow bi...
Article
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Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer’s disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low...
Article
Purpose: While chemotherapies kill most cancer cells, stem cell-enriched survivors seed metastasis, particularly in triple negative breast cancers (TNBC). TNBC arise from and are enriched for tumor stem cells. Here, we tested if inhibition of DOT1L, an epigenetic regulator of normal tissue stem/progenitor populations, would target TNBC stem cells....
Article
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Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in...
Article
Background: Alzheimer's disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTRO...
Article
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Gastric cancer (GC) is frequently characterized by resistance to standard chemotherapeutic regimens and poor clinical outcomes. We aimed to identify a novel therapeutic approach using drug sensitivity testing (DST) and our computational SynerySeq pipeline. DST of GC cell lines was performed with a library of 215 Federal Drug Administration (FDA) ap...
Article
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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with available treatments only marginally slowing progression or improving survival. A hexanucleotide repeat expansion mutation in the C9ORF72 gene is the most commonly known genetic cause of both sporadic and familial cases of ALS and frontotemporal dementia (...
Article
Epigenetic mechanisms play important roles in the neurobiology of substance use disorder. In particular, bromodomain and extra-terminal domain (BET) proteins, a class of histone acetylation readers, have been found to regulate cocaine conditioned behaviors, but their role in the behavioral response to other drugs of abuse remains unclear. To addres...
Article
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Besides his vast contribution to the opioid receptor studies, Dr. G. W. Pasternak was among the early pioneers in the antisense oligonucleotide (ASO) field at the time when the crucial in vivo studies using ASO-mediated gene knockdown in the CNS were still impeded by the ASO’s inability to cross the blood–brain barrier. This changed at the start of...
Article
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Brain-derived neurotrophic factor (Bdnf) expression is tightly controlled at the transcriptional and post-transcriptional levels. Previously, we showed that inhibition of noncoding Bdnf antisense (Bdnf-AS) RNA upregulates Bdnf protein. Here, we generated a Bdnf-antisense knockout (Bdnf-AS KO) mouse model by deleting 6 kilobases upstream of Bdnf-AS....
Article
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The possibility of rational design and the resulting faster and more cost-efficient development cycles of nucleic acid-based therapeutics (NBTs), such as antisense oligonucleotides, siRNAs, and gene therapy vectors, have fueled increased activity in developing therapies for orphan diseases. Despite the difficulty of delivering NBTs beyond the blood...
Article
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Genome instability is associated with myriad human diseases and is a well-known feature of both cancer and neurodegenerative disease. Until recently, the ability to assess DNA damage—the principal driver of genome instability—was limited to relatively imprecise methods or restricted to studying predefined genomic regions. Recently, new techniques f...
Article
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Female sex is a leading risk factor for developing Alzheimer’s disease (AD). Sexual dimorphism in AD is gaining attention as clinical data show that women are not only more likely to develop AD but also to experience worse pathology and faster cognitive decline. Pre-clinical AD research in animal models often neglects to address sexual dimorphism i...
Article
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Alcohol use disorder (AUD) is a widespread disease leading to the deterioration of cognitive and other functions. Mechanisms by which alcohol affects the brain are not fully elucidated. Splicing constitutes a nuclear process of RNA maturation, which results in the formation of the transcriptome. We tested the hypothesis as to whether AUD impairs sp...
Article
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Background: The C9ORF72 hexanucleotide repeat expansion is the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two fatal age-related neurodegenerative diseases. The C9ORF72 expansion encodes five dipeptide repeat proteins (DPRs) that are produced through a non-canonical translation mechanis...
Article
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For most psychiatric diseases, pathogenetic concepts as well as paradigms underlying neuropsychopharmacologic approaches currently revolve around neurotransmitters such as dopamine, serotonin, and norepinephrine. However, despite the fact that several generations of neurotransmitter-based psychotropics including atypical antipsychotics, selective s...
Article
With the recent Alzheimer’s disease (AD) clinical trial shortcomings, we and colleagues agree that an epigenetic approach is needed to address the polygenicity of AD. Recently, a randomized clinical trial with the SIRT1 activator resveratrol (3,5,4’‐trihydroxy‐trans‐stilbene) has shown positive effects in AD patients (Turner et al., 2015; Moussa et...
Article
Drug screens leading to successful targeted therapies in cancer have been mainly based on cell viability assays identifying inhibitors of dominantly acting oncogenes. In contrast, there has been little success in discovering targeted therapies that reverse the effects of inactivating mutations in tumor-suppressor genes. BAP1 is one such tumor suppr...
Article
The Hedgehog/GLI (HH/GLI) signaling pathway plays a critical role in human oncogenesis. Unfortunately, the clinical use of HH inhibitor(s) has been associated with serious adverse effects and mutation-related drug resistance. Since the efficacy of SMO (Smoothened) and GLI inhibitors is limited in clinical trials, there remains a critical need for t...
Article
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Loading of skeletal muscle changes the tissue phenotype reflecting altered metabolic and functional demands. In humans, heterogeneous adaptation to loading complicates the identification of the underpinning molecular regulators. A within-person differential loading and analysis strategy reduces heterogeneity for changes in muscle mass by ~40% and u...
Preprint
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Single strand breaks (SSBs) represent the major form of DNA damage, yet no technique exists to map these lesions genome-wide with nucleotide-level precision. Herein, we present a method, termed SSiNGLe, and demonstrate its utility to explore the distribution and dynamic changes of genome-wide SSBs in response to different biological and environment...
Preprint
Full-text available
Single strand breaks (SSBs) represent the major form of DNA damage, yet no technique exists to map these lesions genome-wide with nucleotide-level precision. Herein, we present a method, termed SSiNGLe, and demonstrate its utility to explore the distribution and dynamic changes of genome-wide SSBs in response to different biological and environment...
Chapter
Neurological disorders, including Alzheimer’s and Parkinson’s diseases, Dravet syndrome, amyotrophic lateral sclerosis, Angelman syndrome, fragile X mental retardation, spinal muscular atrophy, and many others, affect a significant part of world population. The proportion of familial cases in many of these disorders is small, indicating a significa...
Article
Full-text available
Single-strand breaks (SSBs) represent the major form of DNA damage, yet techniques to map these lesions genome-wide with nucleotide-level precision are limited. Here, we present a method, termed SSiNGLe, and demonstrate its utility to explore the distribution and dynamic changes in genome-wide SSBs in response to different biological and environmen...
Article
Full-text available
Background: Treatment options for patients with platinum-resistant ovarian cancer are generally palliative in nature and rarely have realistic potential to be curative. Because many patients with recurrent ovarian cancer receive aggressive chemotherapy for prolonged periods, sometimes continuously, therapy-related toxicities are a major factor in...
Article
Full-text available
Epigenetic enzymes oversee long-term changes in gene expression by integrating genetic and environmental cues. While there are hundreds of enzymes that control histone and DNA modifications, their potential roles in substance abuse and alcohol dependence remain underexplored. A few recent studies have suggested that epigenetic processes could under...
Article
Full-text available
Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related live...
Article
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Emerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA)...
Article
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Different ChIP-seq peak callers often produce different output results from the same input. Since different peak callers are known to produce differentially enriched peaks with a large variance in peak length distribution and total peak count, accurately annotating peak lists with their nearest genes can be an arduous process. Functional genomic an...
Article
Full-text available
Background: Bromodomain and extra-terminal inhibitors (BETi) have shown efficacy for the treatment of aggressive triple negative breast cancer (TNBC). However, BETi are plagued by a narrow therapeutic window as manifested by severe toxicities at effective doses. Therefore, it is a limitation to their clinical implementation in patient care. Metho...
Article
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Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical factor in learning and memory. Due to the important role of BDNF in synaptic function and plasticity, an in-house epigenetic library was screened against human neural progenitor cel...
Article
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Targeting bromodomain and extra-terminal (BET) proteins has recently provided a useful approach for limiting production of pro-inflammatory cytokines. These epigenetic readers regulate transcription of genes involved in inflammation and cancer. Development of BET inhibitors (BETi) has generated significant interest for their therapeutic potential....
Chapter
In recent years, it has been shown that the central dogma of molecular biology with an underlying “one gene–one protein” concept is no longer viable. Instead, the transcriptome is dominated by non-coding RNA transcripts. Several classes of non-coding RNAs, including ribosomal RNAs, transport RNAs, microRNAs, small nuclear RNAs and a few others have...
Article
Full-text available
A recent approach for limiting production of pro-inflammatory cytokines has been to target bromodomain and extra-terminal (BET) proteins. These epigenetic readers of histone acetylation regulate transcription of genes involved in inflammation, cardiovascular disease, and cancer. Development of BET inhibitors (BETi) has generated enormous interest f...
Preprint
Full-text available
Motivation Different ChIP-seq peak callers often produce different output results from the same input. Since different peak callers are known to produce differentially enriched peaks with a large variance in peak length distribution and total peak count, accurately annotating peak lists with their nearest genes can be an arduous process. Functional...
Article
Recent advances in high throughput technologies have led to the generation of vast amounts of clinical data and the development of personalized medicine approaches in acute myeloid leukemia (AML). The ability to treat cancer patients based upon their individual molecular characteristics or drug sensitivity profiles is expected to significantly adva...
Article
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Glioblastoma (GBM) is the most common primary adult brain tumor. Despite extensive efforts, the median survival for GBM patients is approximately 14 months. GBM therapy could benefit greatly from patient-specific targeted therapies that maximize treatment efficacy. Here we report a platform termed SynergySeq to identify drug combinations for the tr...
Article
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Histone deacetylase (HDAC) inhibitors may have therapeutic utility in multiple neurological and psychiatric disorders, but the underlying mechanisms remain unclear. Here, we identify BRD4, a BET bromodomain reader of acetyl-lysine histones, as an essential component involved in potentiated expression of brain-derived neurotrophic factor (BDNF) and...
Article
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In all eukaryotic organisms, chromatin, the physiological template of all genetic information, is essential for heredity. Chromatin is subject to an array of diverse posttranslational modifications (PTMs) that mostly occur in the amino termini of histone proteins (i.e., histone tail) and regulate the accessibility and functional state of the underl...
Article
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Alzheimer’s disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of β-amyloid (Aβ) plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 an...
Article
Full-text available
Background Esophageal cancer remains one of the hardest cancers to treat with rising incidence rates, low overall survival and high levels of treatment resistance. The lack of clinically available biomarkers hinder diagnosis and treatment stratification. While large scale sequencing approaches have uncovered a number of molecular makers, little has...
Data
DSS and EC50 values for normal esophageal cells. (DOCX)
Data
Individual screening results. Bar graphs of clinically actionable drug responses for (A) Flo1 and (B) SK-GT2. (TIF)