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Article ; Online: Evaluation of the effects of the T-type calcium channel enhancer SAK3 in a rat model of TAF1 deficiency.

Dhanalakshmi, Chinnasamy / Janakiraman, Udaiyappan / Moutal, Aubin / Fukunaga, Kohji / Khanna, Rajesh / Nelson, Mark A

2020 Volume 149, Page(s) 105224

Abstract: The TATA-box binding protein associated factor 1 (TAF1) is part of the TFIID complex that plays a key role during the initiation of transcription. Variants of TAF1 are associated with neurodevelopmental disorders. Previously, we found that CRISPR/Cas9 ... ...

Abstract	The TATA-box binding protein associated factor 1 (TAF1) is part of the TFIID complex that plays a key role during the initiation of transcription. Variants of TAF1 are associated with neurodevelopmental disorders. Previously, we found that CRISPR/Cas9 based editing of the TAF1 gene disrupts the morphology of the cerebral cortex and blunts the expression as well as the function of the CaV3.1 (T-type) voltage gated calcium channel. Here, we tested the efficacy of SAK3 (ethyl 8'-methyl-2', 4-dioxo-2-(piperidin-1-yl)-2'H-spiro [cyclopentane-1, 3'-imidazo [1, 2-a] pyridine]-2-ene-3-carboxylate), a T-type calcium channel enhancer, in an animal model of TAF1 intellectual disability (ID) syndrome. At post-natal day 3, rat pups were subjected to intracerebroventricular (ICV) injection of either gRNA-control or gRNA-TAF1 CRISPR/Cas9 viruses. At post-natal day 21, the rat pups were given SAK3 (0.25 mg/kg, p.o.) or vehicle for 14 days (i.e. till post-natal day 35) and then subjected to behavioral, morphological, and molecular studies. Oral administration of SAK3 (0.25 mg/kg, p.o.) significantly rescued locomotion abnormalities associated with TAF1 gene editing. SAK3 treatment prevented the loss of cortical neurons and GFAP-positive astrocytes observed after TAF1 gene editing. In addition, SAK3 protected cells from apoptosis. SAK3 also restored the Brain-derived neurotrophic factor/protein kinase B/Glycogen Synthase Kinase 3 Beta (BDNF/AKT/GSK3β) signaling axis in TAF1 edited animals. Finally, SAK3 normalized the levels of three GSK3β substrates - CaV3.1, FOXP2, and CRMP2. We conclude that the T-type calcium channel enhancer SAK3 is beneficial against the deleterious effects of TAF1 gene-editing, in part, by stimulating the BDNF/AKT/GSK3β signaling pathway.
MeSH term(s)	Animals ; Animals, Newborn ; Calcium Channels, T-Type/metabolism ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Female ; Histone Acetyltransferases/deficiency ; Histone Acetyltransferases/genetics ; Imidazoles/administration & dosage ; Injections, Intraventricular ; Intellectual Disability/drug therapy ; Intellectual Disability/genetics ; Intellectual Disability/metabolism ; Locomotion/drug effects ; Locomotion/physiology ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Spiro Compounds/administration & dosage ; TATA-Binding Protein Associated Factors/deficiency ; TATA-Binding Protein Associated Factors/genetics ; Transcription Factor TFIID/deficiency ; Transcription Factor TFIID/genetics
Chemical Substances	Cacna1g protein, rat ; Calcium Channels, T-Type ; Imidazoles ; SAK3 compound ; Spiro Compounds ; TATA-Binding Protein Associated Factors ; Transcription Factor TFIID ; Histone Acetyltransferases (EC 2.3.1.48) ; TATA-binding protein associated factor 250 kDa (EC 2.7.11.1)
Language	English
Publishing date	2020-12-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2020.105224
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Book ; Online: Comparison of Optical and Electrical Links for Highly-Interconnected Systems

Kruchowski, James / Sokolov, Vladimir / Harff, Nathan E. / Nelson, Mark A. / Liou, KY / Cameron, Graham / Gilbert, Barry K. / Daniel, Erik S.

2023

Abstract: As data rates for multi-gigabit serial interfaces within multi-node compute systems approach and exceed 10 Gigabits per second (Gbps), board-to-board and chip-to-chip optical signaling solutions become more attractive, particularly for longer (e.g. 50- ... ...

Abstract	As data rates for multi-gigabit serial interfaces within multi-node compute systems approach and exceed 10 Gigabits per second (Gbps), board-to-board and chip-to-chip optical signaling solutions become more attractive, particularly for longer (e.g. 50-100 cm) links. The transition to optical signaling will potentially allow new high performance compute (HPC) system architectures that benefit from characteristics unique to optical links. To examine these characteristics, we built and tested several optical demonstration vehicles; one based on dense wavelength division multiplexing (DWDM), and others based on multiple point-to-point links carried across multimode fibers. All test vehicles were constructed to evaluate applicability to a multi-node compute system. Test results, combined with data from recent research efforts are summarized and compared to equivalent electrical links and the advantages and design characteristics unique to optical signaling are identified. Comment: 25 pages, 18 figures, DesignCon 2011
Keywords	Electrical Engineering and Systems Science - Signal Processing
Publishing date	2023-01-17
Publishing country	us
Document type	Book ; Online
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Article: Inhibition of lipoxygenase activity: implications for the treatment and chemoprevention of prostate cancer.

Nelson, Mark A

Cancer biology & therapy

2007 Volume 6, Issue 2, Page(s) 237

MeSH term(s)	Antineoplastic Agents/therapeutic use ; Humans ; Lipoxygenase/metabolism ; Lipoxygenase Inhibitors/therapeutic use ; Male ; Plant Extracts/pharmacology ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/metabolism
Chemical Substances	Antineoplastic Agents ; Lipoxygenase Inhibitors ; Plant Extracts ; Zyflamend ; Lipoxygenase (EC 1.13.11.12)
Language	English
Publishing date	2007-02-08
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	2146305-0
ISSN	1538-4047
ISSN	1538-4047
DOI	10.4161/cbt.6.2.4120
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Zs.A 5887: Show issues

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Article ; Online: Cell-free DNA methylation analysis as a marker of malignancy in pleural fluid.

Bixby, Billie / Vrba, Lukas / Lenka, Jyoti / Oshiro, Marc M / Watts, George S / Hughes, Trina / Erickson, Heidi / Chopra, Madhav / Knepler, James L / Knox, Kenneth S / Jarnagin, Lisa / Alalawi, Raed / Kala, Mrinalini / Bernert, Richard / Routh, Joshua / Roe, Denise J / Garland, Linda L / Futscher, Bernard W / Nelson, Mark A

Scientific reports

2024 Volume 14, Issue 1, Page(s) 2939

Abstract: Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is ... ...

Abstract	Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology for the diagnosis of malignant pleural effusion is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), indeterminate pleural effusion in subjects with known malignancy or IPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p < 0.0001) and the same tendency was observed relative to IPE (p = 0.004). We also noted that the methylation signal was significantly higher in IPE relative to BPE (p < 0.001). We also assessed the diagnostic efficiency of the Sentinel-MPE test by performing receiver operating characteristic analysis (ROC). For the ROC analysis we combined the malignant and indeterminate pleural effusion groups (n = 76) and compared against the benign group (n = 28). The detection sensitivity and specificity of the Sentinel-MPE test was high (AUC = 0.912). The Sentinel-MPE appears to have better performance characteristics than cytology analysis. However, combining Sentinel-MPE with cytology analysis could be an even more effective approach for the diagnosis of MPE. The Sentinel-MPE test can discriminate between BPE and MPE. The Sentinel-MPE liquid biopsy test can detect aberrant DNA in several different tumor types. The Sentinel-MPE test can be a complementary tool to cytology in the diagnosis of MPE.
MeSH term(s)	Humans ; Pleural Effusion, Malignant/diagnosis ; Pleural Effusion, Malignant/genetics ; Pleural Effusion, Malignant/pathology ; Cell-Free Nucleic Acids ; DNA Methylation ; Biomarkers, Tumor/metabolism ; Pleural Effusion/diagnosis ; Pleural Effusion/pathology
Chemical Substances	Cell-Free Nucleic Acids ; Biomarkers, Tumor
Language	English
Publishing date	2024-02-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-53132-x
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Article: Cell-Free DNA Methylation Analysis as a Marker of Malignancy in Pleural Fluid.

Bixby, Billie / Vrba, Lukas / Lenka, Jyoti / Oshiro, Marc / Watts, George S / Hughes, Trina / Erickson, Heidi / Chopra, Madhav / Knepler, James L / Knox, Kenneth S / Jarnagin, Lisa / Alalawi, Raed / Kala, Mrinalini / Bernert, Richard / Routh, Joshua / Roe, Denise J / Garland, Linda L / Futscher, Bernard W / Nelson, Mark A

Research square

2023

Abstract: Background: Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of ... ...

Abstract	Background: Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology malignant pleural effusion diagnosis is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. Results: This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), PPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p < 0.0001) and the same tendency was observed relative to PPE (p = 0.004). We also noted that the methylation signal was significantly higher in PPE relative to BPE (p < 0.001). We also assessed the diagnostic efficiency of the Sentinel-MPE test by performing receiver operating characteristic analysis (ROC). For the ROC analysis we combined the malignant and paramalignant groups (n = 76) and compared against the benign group (n = 28). The detection sensitivity and specificity of the Sentinel-MPE test was high (AUC = 0.912). The Sentinel-MPE appears to have better performance characteristics than cytology analysis. However, combining Sentinel-MPE with cytology analysis could be an even more effective approach for the diagnosis of MPE. Conclusions: The Sentinel-MPE test can discriminate between BPE and MPE. The Sentinel-MPE liquid biopsy test can detect aberrant DNA in several different tumor types. The Sentinel-MPE test can be a complementary tool to cytology in the diagnosis of MPE.
Language	English
Publishing date	2023-10-09
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3390107/v1
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Article ; Online: Liquid biopsy, using a novel DNA methylation signature, distinguishes pancreatic adenocarcinoma from benign pancreatic disease.

Vrba, Lukas / Futscher, Bernard W / Oshiro, Marc / Watts, George S / Menashi, Emmanuel / Hu, Charles / Hammad, Hytham / Pennington, Daniel R / Golconda, Umamaheshwari / Gavini, Hemanth / Roe, Denise J / Shroff, Rachna T / Nelson, Mark A

Clinical epigenetics

2022 Volume 14, Issue 1, Page(s) 28

Abstract: We tested the ability of a novel DNA methylation biomarker set to distinguish metastatic pancreatic cancer cases from benign pancreatic cyst patients and to monitor tumor dynamics using quantitative DNA methylation analysis of cell-free DNA (cfDNA) from ... ...

Abstract	We tested the ability of a novel DNA methylation biomarker set to distinguish metastatic pancreatic cancer cases from benign pancreatic cyst patients and to monitor tumor dynamics using quantitative DNA methylation analysis of cell-free DNA (cfDNA) from blood samples. The biomarkers were able to distinguish malignant cases from benign disease with high sensitivity and specificity (AUC = 0.999). Furthermore, the biomarkers detected a consistent decline in tumor-derived cfDNA in samples from patients undergoing chemotherapy. The study indicates that our liquid biopsy assay could be useful for management of pancreatic cancer patients.
MeSH term(s)	Adenocarcinoma/diagnosis ; Adenocarcinoma/genetics ; Biomarkers, Tumor/genetics ; DNA Methylation ; Humans ; Liquid Biopsy ; Pancreatic Diseases/genetics ; Pancreatic Neoplasms/diagnosis ; Pancreatic Neoplasms/genetics
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2022-02-22
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-022-01246-2
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Article ; Online: The investigation of the T-type calcium channel enhancer SAK3 in an animal model of TAF1 intellectual disability syndrome.

Janakiraman, Udaiyappan / Dhanalakshmi, Chinnasamy / Yu, Jie / Moutal, Aubin / Boinon, Lisa / Fukunaga, Kohji / Khanna, Rajesh / Nelson, Mark A

Neurobiology of disease

2020 Volume 143, Page(s) 105006

Abstract: T-type calcium channels, in the central nervous system, are involved in the pathogenesis of many neurodegenerative diseases, including TAF1 intellectual disability syndrome (TAF1 ID syndrome). Here, we evaluated the efficacy of a novel T-type ... ...

Abstract	T-type calcium channels, in the central nervous system, are involved in the pathogenesis of many neurodegenerative diseases, including TAF1 intellectual disability syndrome (TAF1 ID syndrome). Here, we evaluated the efficacy of a novel T-type Ca
MeSH term(s)	Animals ; Calcium Channels, T-Type/drug effects ; Calcium Channels, T-Type/metabolism ; Cerebellum/drug effects ; Disease Models, Animal ; Histone Acetyltransferases/genetics ; Imidazoles/pharmacology ; Intellectual Disability/genetics ; Intellectual Disability/physiopathology ; Neurons/drug effects ; Rats ; Rats, Sprague-Dawley ; Spiro Compounds/pharmacology ; Syndrome ; TATA-Binding Protein Associated Factors/genetics ; Transcription Factor TFIID/genetics
Chemical Substances	Calcium Channels, T-Type ; Imidazoles ; SAK3 compound ; Spiro Compounds ; TATA-Binding Protein Associated Factors ; Transcription Factor TFIID ; Histone Acetyltransferases (EC 2.3.1.48) ; TATA-binding protein associated factor 250 kDa (EC 2.7.11.1)
Language	English
Publishing date	2020-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2020.105006
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Article ; Online: Oxaliplatin-induced neuropathy: a tale of two electrolytes.

Babiker, Hani M / Green, Myke R / Nelson, Mark A / Elquza, Emad

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer

2015 Volume 23, Issue 6, Page(s) 1483–1485

MeSH term(s)	Antineoplastic Agents/adverse effects ; Calcium/metabolism ; Colorectal Neoplasms/drug therapy ; Electrolytes/metabolism ; Humans ; Magnesium/metabolism ; Neurotoxicity Syndromes/etiology ; Neurotoxicity Syndromes/metabolism ; Organoplatinum Compounds/adverse effects ; Peripheral Nervous System Diseases/chemically induced ; Peripheral Nervous System Diseases/metabolism
Chemical Substances	Antineoplastic Agents ; Electrolytes ; Organoplatinum Compounds ; oxaliplatin (04ZR38536J) ; Magnesium (I38ZP9992A) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2015-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1134446-5
ISSN	1433-7339 ; 0941-4355
ISSN (online)	1433-7339
ISSN	0941-4355
DOI	10.1007/s00520-015-2702-0
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Zs.A 3697: Show issues

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Article ; Online: DNA methylation biomarkers discovered

Vrba, Lukas / Oshiro, Marc M / Kim, Samuel S / Garland, Linda L / Placencia, Crystal / Mahadevan, Daruka / Nelson, Mark A / Futscher, Bernard W

Epigenetics

2019 Volume 15, Issue 4, Page(s) 419–430

Abstract: Identification of cancer-specific methylation of DNA released by tumours can be used for non-invasive diagnostics and monitoring. We previously ... ...

Abstract	Identification of cancer-specific methylation of DNA released by tumours can be used for non-invasive diagnostics and monitoring. We previously reported
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/blood ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/standards ; Carcinoma, Non-Small-Cell Lung/blood ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell-Free Nucleic Acids/blood ; Cell-Free Nucleic Acids/genetics ; Cell-Free Nucleic Acids/standards ; DNA Methylation ; Female ; Humans ; Liquid Biopsy ; Lung Neoplasms/blood ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Sensitivity and Specificity
Chemical Substances	Biomarkers, Tumor ; Cell-Free Nucleic Acids
Language	English
Publishing date	2019-11-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1559-2308
ISSN (online)	1559-2308
DOI	10.1080/15592294.2019.1695333
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Article ; Online: TAF1-gene editing alters the morphology and function of the cerebellum and cerebral cortex.

Janakiraman, Udaiyappan / Yu, Jie / Moutal, Aubin / Chinnasamy, Dhanalakshmi / Boinon, Lisa / Batchelor, Shelby N / Anandhan, Annaduri / Khanna, Rajesh / Nelson, Mark A

Neurobiology of disease

2019 Volume 132, Page(s) 104539

Abstract: TAF1/MRSX33 intellectual disability syndrome is an X-linked disorder caused by loss-of-function mutations in the TAF1 gene. How these mutations cause dysmorphology, hypotonia, intellectual and motor defects is unknown. Mouse models which have ... ...

Abstract	TAF1/MRSX33 intellectual disability syndrome is an X-linked disorder caused by loss-of-function mutations in the TAF1 gene. How these mutations cause dysmorphology, hypotonia, intellectual and motor defects is unknown. Mouse models which have embryonically targeted TAF1 have failed, possibly due to TAF1 being essential for viability, preferentially expressed in early brain development, and intolerant of mutation. Novel animal models are valuable tools for understanding neuronal pathology. Here, we report the development and characterization of a novel animal model for TAF1 ID syndrome in which the TAF1 gene is deleted in embryonic rats using clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) technology and somatic brain transgenesis mediated by lentiviral transduction. Rat pups, post-natal day 3, were subjected to intracerebroventricular (ICV) injection of either gRNA-control or gRNA-TAF1 vectors. Rats were subjected to a battery of behavioral tests followed by histopathological analyses of brains at post-natal day 14 and day 35. TAF1-edited rats exhibited behavioral deficits at both the neonatal and juvenile stages of development. Deletion of TAF1 lead to a hypoplasia and loss of the Purkinje cells. We also observed a decreased in GFAP positive astrocytes and an increase in Iba1 positive microglia within the granular layer of the cerebellum in TAF1-edited animals. Immunostaining revealed a reduction in the expression of the CaV3.1 T-type calcium channel. Abnormal motor symptoms in TAF1-edited rats were associated with irregular cerebellar output caused by changes in the intrinsic activity of the Purkinje cells due to loss of pre-synaptic CaV3.1. This animal model provides a powerful new tool for studies of neuronal dysfunction in conditions associated with TAF1 abnormalities and should prove useful for developing therapeutic strategies to treat TAF1 ID syndrome.
MeSH term(s)	Animals ; Animals, Newborn ; CRISPR-Cas Systems/genetics ; Cerebellum/abnormalities ; Cerebellum/pathology ; Cerebellum/physiology ; Cerebral Cortex/abnormalities ; Cerebral Cortex/pathology ; Cerebral Cortex/physiology ; Female ; Gene Editing/methods ; Histone Acetyltransferases/genetics ; Injections, Intraventricular ; Locomotion/physiology ; Organ Culture Techniques ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; TATA-Binding Protein Associated Factors/genetics ; Transcription Factor TFIID/genetics
Chemical Substances	TATA-Binding Protein Associated Factors ; Transcription Factor TFIID ; Histone Acetyltransferases (EC 2.3.1.48) ; TATA-binding protein associated factor 250 kDa (EC 2.7.11.1)
Language	English
Publishing date	2019-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2019.104539
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