Robert John Corona

Chronic traumatic encephalopathy – neuropathology in athletes and war veterans

Abstract Objective: The neuropathologic findings of chronic traumatic encephalopathy (CTE) were first described almost 40 years after the first clinical reports. We reviewed the literature and describe the neuropathological findings seen primarily in professional athletes and more recently, in war veterans. Methods: We reviewed the literature of CTE concentrating on references that focused on the correlation of clinical findings with the neuropathologic changes. The pathobiology and proposed mechanisms of injury are described. Diagnostic modalities and various diagnostic criteria of CTE are reviewed. Results: We are beginning to understand the neuropathologic basis of CTE, which appears to be a consequence of repetitive mild brain injuries. There appear to be reproducible criteria for the post-mortem diagnosis of CTE and the neuropathologic findings are becoming more widely accepted. More research is required to elucidate the risk factors that predispose athletes and war veterans to CTE. There is also a need for more diagnostic markers and a method to assess CTE in patients prior to death. The neuropathologic findings of a progressive tauopathy including the presence of numerous neurofibrillary tangles (NFTs), rare neuritic plaques, and widespread expression of TDP-43 (transactive response [TAR] DNA binding protein 43) also require further study. Discussion: The potential prevalence of CTE, as well as the vulnerable populations involved, makes research into this topic crucial. Currently, a comprehensive neurological exam, neuropsychiatric assessment, and standard radiographic techniques such as conventional MRI are the mainstay of diagnosis. There is a pressing need for the prevention of CTE and the development of non-invasive diagnostic tests in order to develop therapies that may be of clinical use to athletes and blast injury veterans during their lifetimes.

Genomic Characterization of Testicular Germ Cell Tumors Relapsing After Chemotherapy

BACKGROUNDnAlthough both seminomatous and nonseminomatous testicular germ cell tumors (TGCTs) have favorable outcomes with chemotherapy, a subset is chemorefractory, and novel therapeutic options are needed.nnnOBJECTIVEnTo molecularly characterize chemotherapy-refractory TGCTs.nnnDESIGN, SETTING, AND PARTICIPANTSnArchival tissues from 107 chemotherapy-treated and relapsed TGCT patients (23 seminomas; 84 nonseminomas) underwent hybrid-capture-based genomic profiling to evaluate four classes of genomic alterations (GAs). Tumor mutational burden (TMB) and microsatellite instability (MSI) were also measured.nnnINTERVENTIONnGenomic profiling on tumor samples from chemotherapy-refractory TGCTs.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnDescriptive analyses and differences between seminoma and nonseminoma subgroups were reported.nnnRESULTS AND LIMITATIONSnThe mean GA/tumor was 2.9 for seminomas and 4.0 for nonseminomas (p=0.04). KRAS alterations (mainly amplifications) were the most common GAs at the single-gene level (47.8% of seminomas and 51.2% of nonseminomas). RAS-RAF pathway (56.5% vs 52.3%) and cell-cycle pathway (52.2% vs 56.0%) were the most common GA classes in seminomas and nonseminomas, respectively. Receptor tyrosine kinase pathway and PI3K pathway GAs were more frequent in seminomas (p=0.02). Median TMB was 1.8 mutations/Mb for seminomas and 2.7 mutations/Mb for nonseminomas (p=0.098), and MSI-high status was found in one nonseminoma only (1.2%). A lack of clinical outcome correlation is a limitation of the present analyses.nnnCONCLUSIONSnIn chemotherapy-refractory TGCTs, trials with agents targeting the KRAS pathway may be pursued due to the high frequency of KRAS GAs. Overall, the GAs found in refractory seminomas and nonseminomas differ significantly. Considering the frequency of high TMB or MSI-high status, immunotherapy may benefit a small subset of nonseminomas.nnnPATIENT SUMMARYnTesticular cancers that are resistant to or relapse after standard chemotherapy may harbor genomic alterations that are potentially druggable, particularly in the clinical trial setting, and genomic profiling can guide clinical research and disclose therapeutic opportunities for these patients.

Chromatin run-on reveals nascent RNAs that differentiate normal and malignant brain tissue

Non-coding elements in our genomes that play critical roles in complex disease are frequently marked by highly unstable RNA species. Sequencing nascent RNAs attached to an actively transcribing RNA polymerase complex can identify unstable RNAs, including those templated from gene-distal enhancers (eRNAs). However, nascent RNA sequencing techniques remain challenging to apply in some cell lines and especially to intact tissues, limiting broad applications in fields such as cancer genomics and personalized medicine. Here we report the development of chromatin run-on and sequencing (ChRO-seq), a novel run-on technology that maps the location of RNA polymerase using virtually any frozen tissue sample, including samples with degraded RNA that are intractable to conventional RNA-seq. We used ChRO-seq to develop the first maps of nascent transcription in 23 human glioblastoma (GBM) brain tumors and patient derived xenografts. Remarkably, >90,000 distal enhancers discovered using the signature of eRNA biogenesis within primary GBMs closely resemble those found in the normal human brain, and diverge substantially from GBM cell models. Despite extensive overall similarity, 12% of enhancers in each GBM distinguish normal and malignant brain tissue. These enhancers drive regulatory programs similar to the developing nervous system and are enriched for transcription factor binding sites that specify a stem-like cell fate. These results demonstrate that GBMs largely retain the enhancer landscape associated with their tissue of origin, but selectively adopt regulatory programs that are responsible for driving stem-like cell properties.The human genome encodes a variety of poorly understood RNA species that remain challenging to identify using existing genomic tools. We developed chromatin run-on and sequencing (ChRO-seq) to map the location of RNA polymerase using virtually any input sample, including samples with degraded RNA that are intractable to conventional RNA-seq. We used ChRO-seq to develop the first maps of nascent transcription in primary human glioblastoma (GBM) brain tumors. Whereas enhancers discovered in primary GBMs resemble open chromatin in the normal human brain, rare enhancers activated in malignant tissue drive regulatory programs similar to the developing nervous system. We identified enhancers that regulate genes characteristic of each known GBM subtype, identified transcription factors that drive them, and discovered a core group of transcription factors that control the expression of genes associated with clinical outcomes. This study uncovers new insights into the molecular etiology of GBM and introduces ChRO-seq which can now be used to map regulatory programs contributing to a variety of complex diseases.

Chromatin run-on and sequencing maps the transcriptional regulatory landscape of glioblastoma multiforme

The human genome encodes a variety of poorly understood RNA species that remain challenging to identify using existing genomic tools. We developed chromatin run-on and sequencing (ChRO-seq) to map the location of RNA polymerase for almost any input sample, including samples with degraded RNA that are intractable to RNA sequencing. We used ChRO-seq to map nascent transcription in primary human glioblastoma (GBM) brain tumors. Enhancers identified in primary GBMs resemble open chromatin in the normal human brain. Rare enhancers that are activated in malignant tissue drive regulatory programs similar to the developing nervous system. We identified enhancers that regulate groups of genes that are characteristic of each known GBM subtype and transcription factors that drive them. Finally we discovered a core group of transcription factors that control the expression of genes associated with clinical outcomes. This study characterizes the transcriptional landscape of GBM and introduces ChRO-seq as a method to map regulatory programs that contribute to complex diseases.Chromatin run-on and sequencing (ChRO-seq) is a new method that maps the location of RNA polymerase using virtually any input sample. Here, ChRO-seq is used to study nascent transcription in human glioblastoma, and to identify regulators of tumor subtype.