Jason Chiang

Bio: Jason Chiang is an academic researcher from St. Jude Children's Research Hospital. The author has contributed to research in topics: Medicine & Pilocytic astrocytoma. The author has an hindex of 11, co-authored 32 publications receiving 397 citations. Previous affiliations of Jason Chiang include University of Pittsburgh.

Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features.

Abstract: Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p < 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively—laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT.

Inflammatory Reaction in Neurological Diseases

Abstract: Inflammatory reaction in the central nervous system (CNS) is now recognized to be a feature of all neurological disorders. In neurological degenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), there is prominent infiltration of various leukocyte subsets into the CNS or there is intense activation of microglia with resultant elevation of many inflammatory mediators within the CNS. In acute critical CNS diseases, such as delayed deterioration associated with vasospasm after subarachnoid hemorrhage (SAH), ischemic stroke, spontaneous intracerebral hemorrhage (ICH), and traumatic brain injury (TBI), recent evidences show that inflammation may be a potential target for therapy. Inflammation has become a promising area of research for new treatments. To accelerate the process of translating this information to clinical applications, a number of important issues must be addressed such as their ability to consistently detect characteristic cerebral deficits in individuals with neurological degenerative diseases, the relationships of cerebral injuries to clinical symptoms and genetic characteristics, and the degree to which these injuries respond to different therapies. In this special issue, several research groups report findings that address some of these issues. In neurological degenerative diseases, the paper by C. Millington et al. reviewed the role of chronic neuroinflammation in the pathogenesis of Alzheimer's disease (AD). With the glial fibrillary acidic protein-interleukin 6 (GFAP-IL6) transgenic mice model, the authors found that this animal model, in which chronic neuroinflammation triggered constitutive expression of the cytokine interleukin-6 (IL-6) in astrocytes, could serve as an excellent tool for drug discovery and validation in vivo. The paper by X. Su and H. J. Federoff reviewed the role of inflammation in Parkinson's disease (PD) neuropathology. They provide an overview of current knowledge on the temporal profile of central and peripheral immune responses in PD and discuss the potential synergistic effects of the central and peripheral inflammation in disease development. The study by W.-C. Lin et al. used TRODAT-1 SPECT to evaluate leukocyte apoptosis in PD patients and its association with central dopamine neuron loss. The leukocyte apoptosis and striatal dopamine transporter uptake ratios were further associated with increased severity and longer duration of disease. The interaction between brain and systemic inflammation may be responsible for the neurodegenerative disease progression. The paper by K. Lu et al. used the Longitudinal Health Insurance Database 2000 (LHID2000) to investigate and compare the risk of dementia between patients clinically diagnosed with autoimmune rheumatic diseases (ARD) and non-ARD patients during a 5-year follow-up period. Their findings suggest that patients with and without ARD were found to have similar risks of developing dementia. In acute critical CNS diseases, the study by K.-W. Wang et al. used traumatic brain injury (TBI) model to determine whether simvastatin combined with an antioxidant could attenuate cerebral vascular endothelial inflammatory response after traumatic brain injury in rat. Their findings support that simvastatin combined with an antioxidant could provide neuroprotection and it may be attributed to a dampening of cerebral vascular endothelial inflammatory response. The study by W. Winardi et al. used a structural equation modeling to evaluate the predictive value of admission Glasgow Coma Scale (GCS) scores, duration of unconsciousness, neurosurgical intervention, and countercoup lesion on the impairment of memory and processing speed functions six months after a TBI. The study demonstrated that admission GCS score is a robust predictor of memory/processing speed dysfunctions after TBI. The study by N.-W. Tsai et al. investigated serum thiobarbituric acid-reactive substances (TBARS) and free thiol levels in different subtypes of acute ischemic stroke (AIS) and evaluated their association with clinical outcomes. They found that patients with large-vessel disease have higher oxidative stress but lower antioxidant defense compared to those with small-vessel disease after AIS. Serum TBARS level at the acute phase of stroke is a potential predictor for three-month outcome. And the paper by C.-M. Su et al. aimed to determine whether serum adhesion molecules are associated with septic encephalopathy (SE). Their findings demonstrate that SE implies higher mortality in nontraumatic, nonsurgical patients with severe sepsis. Serum vascular cell adhesion molecule-1 (VCAM-1) level on presentation is a more powerful predictor of SE in these patients than lactate concentration and other adhesion molecules on admission. In the CNS malignancy, the study by D. Winardi et al. investigated the relationship between protein expressions of two autophagy markers, LC3B and Beclin-1, with clinical parameters in astrocytoma patients. Their results suggest that astrocytoma cancer stem-like cells together with enhanced autophagy may cause resistance to radiation therapy/chemotherapy and that targeting the cancer stem-like cell in astrocytoma may offer a viable therapeutic approach. And the study by C.-L. Chung et al. investigated DAPK protein expression and promoter hypermethylation in central neurocytoma and oligodendroglioma. Their results show that DAPK promoter hypermethylation and repressed expression of DAPK protein were more common in central neurocytoma than in oligodendroglioma. Thus, DAPK promoter hypermethylation could be useful for differential diagnosis between these two types of tumors. In summary, the papers in this series highlight several important research strategies that are making it increasingly evident that the neuroinflammation is of translational value for different types of neurological diseases. The results from these studies not only help us to understand the pathogenesis of these disorders but also show great potential to provide urgently needed objective biomarkers for clinical diagnosis and evaluation. Knowledge and understanding of these conditions have led to the development of animal models, successful therapies, and novel tools to characterize these clinical conditions and provide better care to patients. Hung-Chen Wang Cheng-Hsien Lu Kuang-I Cheng Jason Cheng-Hsuan Chiang

Structure and evolution of double minutes in diagnosis and relapse brain tumors

Abstract: Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric patient, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were present in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only. For the EGFR-carrying double minutes, we found a secondary somatic deletion in all copies at relapse, after erlotinib treatment. However, the somatic mutation was present at very low frequency at diagnosis, suggesting potential resistance to the EGFR inhibitor. This mutation caused an in-frame RNA transcript to skip exon 16, a novel transcript isoform absent in EST database, as well as about 700 RNA-seq of normal brains that we reviewed. We observed similar patterns involving longitudinal copy number shift of double minutes in another four pairs (diagnosis/relapse) of adult glioblastoma. Overall, in three of five paired tumor samples, we found that although the same oncogenes were amplified at diagnosis and relapse, they were amplified on different double minutes. Our results suggest that double minutes readily evolve, increasing tumor heterogeneity rapidly. Understanding patterns of double minute evolution can shed light on future therapeutic solutions to brain tumors carrying such variants.

Molecular pathology of paediatric central nervous system tumours.

Abstract: Advances in our understanding of the biology of paediatric central nervous system (CNS) tumours have encouraged pathologists to use molecular markers alongside histopathological analysis for disease classification or prognostication and treatment stratification. In this article, we review molecular genetic alterations in paediatric CNS tumours, including those in low-grade and high-grade gliomas, ependymomas, and embryonal tumours. Some of these molecular changes with clinicopathological utility have been used for the first time in the most recent edition of the World Health Organization (WHO) classification of CNS tumours to define entities like ependymoma, RELA fusion-positive or diffuse midline glioma, H3 K27M-mutant. The classification of paediatric CNS tumours is entering a new era when histopathologists must work with molecular genetic data and their molecular pathology colleagues to provide an optimal diagnostic evaluation for their patients and clinical colleagues. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery.

Abstract: Background Immunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class I expression is unknown, which is critical for tumor recognition by conventional αβTCR T cells. Methods We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of 5 CAR targets (B7-H3, GD2, IL-13Rα2, EphA2, and HER2), and HLA class I. In addition, we generated B7-H3-CAR T cells and evaluated their antitumor activity in vitro and in vivo. Results We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL-13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage. Conclusions Our study highlights the importance of studying target antigen and HLA class I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.

Evaluation of Training.

Abstract: The main purpose of this paper is to draw attention to some facts and ideas that perhaps can help to identify problems or fields for development and research within the evaluation of training. Topics for group discussion are preceded by material on some basic concepts of evaluation and educational measurement. The ratio scale, the interval scale, the ordinal scale, and the nominal scale are given as examples of kinds of scales used in educational measurement; the problem of norms is discussed; potential purposes of evaluation or educational measurement are outlined; and some characteristics of a good measuring instrument are explained. The author also defends the inclusion of evaluation as an Integral part of a model for planning and carrying out educational programs. (BW) *********************************************************************** Documents acquired by ERIC include many informal unpublished * materials not available from other sources. ERIC makes every effort * * to obtain the best copy available. Nevertheless, items of marginal * * reproducibility are often encountered and this affects the quality * of the microfiche and hardcopy reproductions ERIC makes available * * via the ERIC Document Reproduction Service (EDRS). EDRS is not * responsible for the quality of the original document. Reproductions * * supplied by EDRS are the best that can be made from the original. *********************************************************************** U S DEPARTMENT OF HEALTH, EDUCATION &WELFARE NATIONAL INSTITUTE OF EDUCATION EVALUATION OF TRAINING

cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading.

Abstract: cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.

Circular ecDNA promotes accessible chromatin and high oncogene expression

Abstract: Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer1,2, but our understanding of the structure of ecDNA and its effect on gene regulation is limited. Here, by integrating ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing, we demonstrate the structure of circular ecDNA. Pan-cancer analyses reveal that oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of the tumours, linking increased copy number with high transcription levels. Quantitative assessment of the chromatin state reveals that although ecDNA is packaged into chromatin with intact domain structure, it lacks higher-order compaction that is typical of chromosomes and displays significantly enhanced chromatin accessibility. Furthermore, ecDNA is shown to have a significantly greater number of ultra-long-range interactions with active chromatin, which provides insight into how the structure of circular ecDNA affects oncogene function, and connects ecDNA biology with modern cancer genomics and epigenetics.

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

Abstract: Recently, we described a machine learning approach for classification of central nervous system tumors based on the analysis of genome-wide DNA methylation patterns [6]. Here, we report on DNA methylation-based central nervous system (CNS) tumor diagnostics conducted in our institution between the years 2015 and 2018. In this period, more than 1000 tumors from the neurosurgical departments in Heidelberg and Mannheim and more than 1000 tumors referred from external institutions were subjected to DNA methylation analysis for diagnostic purposes. We describe our current approach to the integrated diagnosis of CNS tumors with a focus on constellations with conflicts between morphological and molecular genetic findings. We further describe the benefit of integrating DNA copy-number alterations into diagnostic considerations and provide a catalog of copy-number changes for individual DNA methylation classes. We also point to several pitfalls accompanying the diagnostic implementation of DNA methylation profiling and give practical suggestions for recurring diagnostic scenarios.