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Article: The crosstalk between non-coding RNAs and cell-cycle events: A new frontier in cancer therapy.

Pathania, Anup S / Chava, Haritha / Balusu, Ramesh / Pasupulati, Anil K / Coulter, Don W / Challagundla, Kishore B

Molecular therapy. Oncology

2024 Volume 32, Issue 2, Page(s) 200785

Abstract: The cell cycle comprises sequential events during which a cell duplicates its genome and divides it into two daughter cells. This process is tightly regulated to ensure that the daughter cell receives identical copied chromosomal DNA and that any errors ... ...

Abstract	The cell cycle comprises sequential events during which a cell duplicates its genome and divides it into two daughter cells. This process is tightly regulated to ensure that the daughter cell receives identical copied chromosomal DNA and that any errors in the DNA during replication are correctly repaired. Cyclins and their enzyme partners, cyclin-dependent kinases (CDKs), are critical regulators of G- to M-phase transitions during the cell cycle. Mitogenic signals induce the formation of the cyclin/CDK complexes, resulting in phosphorylation and activation of the CDKs. Once activated, cyclin/CDK complexes phosphorylate specific substrates that drive the cell cycle forward. The sequential activation and inactivation of cyclin-CDK complexes are tightly controlled by activating and inactivating phosphorylation events induced by cell-cycle proteins. The non-coding RNAs (ncRNAs), which do not code for proteins, regulate cell-cycle proteins at the transcriptional and translational levels, thereby controlling their expression at different cell-cycle phases. Deregulation of ncRNAs can cause abnormal expression patterns of cell-cycle-regulating proteins, resulting in abnormalities in cell-cycle regulation and cancer development. This review explores how ncRNA dysregulation can disrupt cell division balance and discusses potential therapeutic approaches targeting these ncRNAs to control cell-cycle events in cancer treatment.
Language	English
Publishing date	2024-02-29
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2950-3299
ISSN	2950-3299
DOI	10.1016/j.omton.2024.200785
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Article: Low Motor Dexterity and Significant Behaviors Following Hospitalized Isolation in Children.

Fraser, Kaitlin / Kuhn, Miriam / Swanson, Rebecca / Coulter, Don W / Copeland, Christopher / Zuniga, Jorge M

Children (Basel, Switzerland)

2023 Volume 10, Issue 8

Abstract: The main objective of this study was to describe the cortical patterns of brain activity during a gross dexterity task and develop a behavioral profile of children experiencing isolation. A cross-sectional assessment was conducted during one visit. ... ...

Abstract	The main objective of this study was to describe the cortical patterns of brain activity during a gross dexterity task and develop a behavioral profile of children experiencing isolation. A cross-sectional assessment was conducted during one visit. Sample: Four pediatric patients who had undergone isolation within a hospital comprised the full data collection. During the collection, participants completed the Box and Blocks Test of gross manual dexterity while undergoing imaging of the motor cortex using functional near-infrared spectroscopy. Participants also completed a Behavioral Assessment System for Children, Third Edition (BASC-3) self-report, which was analyzed along with a parent report to quantify their emotional and social behaviors. All participants displayed lower gross dexterity levels than normative data. Furthermore, three out of the four participants displayed ipsilateral dominance of the motor cortex during the dexterity task. Three of the participants displayed behavioral measures reported within clinically significant or at-risk scores. Clinically significant behavioral scores coupled with lower than expected manual dexterity values and ipsilateral hemispheric dominance indicate that neuroplastic changes can occur in populations undergoing hospitalized isolation. While the impacts of the treatments and isolation in this case cannot be separated, further studies should be conducted to understand these impacts of isolation.
Language	English
Publishing date	2023-07-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2732685-8
ISSN	2227-9067
ISSN	2227-9067
DOI	10.3390/children10081287
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Article: PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma.

Kumar, Devendra / Jain, Stuti / Coulter, Don W / Joshi, Shantaram S / Chaturvedi, Nagendra K

Cancers

2023 Volume 15, Issue 24

Abstract: MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes. Recently, protein arginine methyltransferase 5 (PRMT5) overexpression has been shown to be associated with ... ...

Abstract	MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes. Recently, protein arginine methyltransferase 5 (PRMT5) overexpression has been shown to be associated with tumorigenic MYC functions in cancers, particularly in brain cancers such as glioblastoma and medulloblastoma. PRMT5 regulates oncogenes, including MYC, that are often deregulated in medulloblastomas. However, the role of PRMT5-mediated post-translational modification in the stabilization of these oncoproteins remains poorly understood. The potential impact of PRMT5 inhibition on MYC makes it an attractive target in various cancers. PRMT5 inhibitors are a promising class of anti-cancer drugs demonstrating preclinical and preliminary clinical efficacies. Here, we review the publicly available preclinical and clinical studies on PRMT5 targeting using small molecule inhibitors and discuss the prospects of using them in medulloblastoma therapy.
Language	English
Publishing date	2023-12-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15245855
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Article ; Online: Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma.

Coulter, Don W / Chhonker, Yashpal S / Kumar, Devendra / Kesherwani, Varun / Aldhafiri, Wafaa N / McIntyre, Erin M / Alexander, Gracey / Ray, Sutapa / Joshi, Shantaram S / Li, Rongshi / Murry, Daryl J / Chaturvedi, Nagendra K

Journal of experimental & clinical cancer research : CR

2024 Volume 43, Issue 1, Page(s) 18

Abstract: Background: Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor prognoses and therapy resistance. However, MYC itself has been one of the most challenging targets for cancer treatment. Here, we identify ...

Abstract	Background: Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor prognoses and therapy resistance. However, MYC itself has been one of the most challenging targets for cancer treatment. Here, we identify a novel marinopyrrole natural derivative, MP1, that shows desirable anti-MYC and anti-cancer activities in MB. Methods: In this study, using MYC-amplified (Group 3) and non-MYC amplified MB cell lines in vitro and in vivo, we evaluated anti-cancer efficacies and molecular mechanism(s) of MP1. Results: MP1 significantly suppressed MB cell growth and sphere counts and induced G2 cell cycle arrest and apoptosis in a MYC-dependent manner. Mechanistically, MP1 strongly downregulated the expression of MYC protein. Our results with RNA-seq revealed that MP1 significantly modulated global gene expression and inhibited MYC-associated transcriptional targets including translation/mTOR targets. In addition, MP1 inhibited MYC-target metabolism, leading to declined energy levels. The combination of MP1 with an FDA-approved mTOR inhibitor temsirolimus synergistically inhibited MB cell growth/survival by downregulating the expression of MYC and mTOR signaling components. Our results further showed that as single agents, both MP1 and temsirolimus, were able to significantly inhibit tumor growth and MYC expression in subcutaneously or orthotopically MYC-amplified MB bearing mice. In combination, there were further anti-MB effects on the tumor growth and MYC expression in mice. Conclusion: These preclinical findings highlight the promise of marinopyrrole MP1 as a novel MYC inhibition approach for MYC-amplified MB.
MeSH term(s)	Humans ; Animals ; Mice ; Medulloblastoma/drug therapy ; Medulloblastoma/genetics ; G2 Phase Cell Cycle Checkpoints ; Cerebellar Neoplasms/drug therapy ; Cerebellar Neoplasms/genetics ; TOR Serine-Threonine Kinases ; Sirolimus/analogs & derivatives
Chemical Substances	temsirolimus (624KN6GM2T) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2024-01-11
Publishing country	England
Document type	Journal Article
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-024-02944-w
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Article ; Online: Biological Evaluation of a Potential Anticancer Agent Methyl

Kortylewicz, Zbigniew P / Coulter, Don W / Baranowska-Kortylewicz, Janina

Cancer biotherapy & radiopharmaceuticals

2019 Volume 35, Issue 1, Page(s) 16–25

Abstract: Background: ...

Abstract	Background:
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Carbamates/pharmacology ; Carbamates/therapeutic use ; Cell Line, Tumor ; Humans ; Mice ; Structure-Activity Relationship
Chemical Substances	Antineoplastic Agents ; Carbamates
Language	English
Publishing date	2019-11-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1315649-4
ISSN	1557-8852 ; 1084-9785
ISSN (online)	1557-8852
ISSN	1084-9785
DOI	10.1089/cbr.2019.2988
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Article ; Online: In vitro and in vivo evaluation of radiolabeled methyl N-[5-(3'-halobenzoyl)-1H-benzimidazol-2-yl]carbamate for cancer radiotherapy.

Kortylewicz, Zbigniew P / Coulter, Don W / Baranowska-Kortylewicz, Janina

Drug development research

2019 Volume 81, Issue 1, Page(s) 62–69

Abstract: The role of theranostics in cancer management is growing so is the selection of vectors used to deliver these modalities to cancer cells. We describe biological evaluation of a novel theranostic agent targeted to microtubules. Methyl N-[5-(3'-[ ...

Abstract	The role of theranostics in cancer management is growing so is the selection of vectors used to deliver these modalities to cancer cells. We describe biological evaluation of a novel theranostic agent targeted to microtubules. Methyl N-[5-(3'-[
MeSH term(s)	Animals ; Brain Neoplasms/radiotherapy ; Carbamates/administration & dosage ; Carbamates/chemistry ; Carbamates/pharmacokinetics ; Cell Line, Tumor ; Cell Proliferation/radiation effects ; Cell Survival/radiation effects ; Glioblastoma/radiotherapy ; Humans ; Injections, Intraperitoneal ; Iodine Radioisotopes/chemistry ; Mice ; Theranostic Nanomedicine ; Tissue Distribution ; Treatment Outcome ; Xenograft Model Antitumor Assays
Chemical Substances	Carbamates ; Iodine Radioisotopes ; Iodine-131
Language	English
Publishing date	2019-10-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604587-x
ISSN	1098-2299 ; 0272-4391
ISSN (online)	1098-2299
ISSN	0272-4391
DOI	10.1002/ddr.21604
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Zs.B 2542: Show issues

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Article ; Online: Radiolabeled (R)-(-)-5-iodo-3'-O-[2-(ε-guanidinohexanoyl)-2-phenylacetyl]-2'-deoxyuridine: A new theranostic for neuroblastoma.

Kortylewicz, Zbigniew P / Coulter, Don W / Han, Guang / Baranowska-Kortylewicz, Janina

Journal of labelled compounds & radiopharmaceuticals

2020

Abstract: Neuroblastoma, the most common extracranial solid tumor in children, accounts for nearly 8% of childhood cancers in the United States. It is a disease with pronounced clinical and biological heterogeneities. The amplification of MYCN, whose key ... ...

Abstract	Neuroblastoma, the most common extracranial solid tumor in children, accounts for nearly 8% of childhood cancers in the United States. It is a disease with pronounced clinical and biological heterogeneities. The amplification of MYCN, whose key tumorigenic functions include the promotion of proliferation, facilitation of the cell's entry into the S phase, and prevention of cells from leaving the cell cycle, correlates with poor prognosis. Patients with a high proliferation index disease have low survival rates. Neuroblastoma is one of the most radioresponsive of all human tumors. To exploit this radiosensitivity, radioactive guanidine (R)-(-)-5-[
Language	English
Publishing date	2020-03-09
Publishing country	England
Document type	Journal Article
ZDB-ID	196095-7
ISSN	1099-1344 ; 0362-4803 ; 0022-2135
ISSN (online)	1099-1344
ISSN	0362-4803 ; 0022-2135
DOI	10.1002/jlcr.3836
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Zs.A 1332: Show issues

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Article ; Online: Multifarious Functions of Butyrylcholinesterase in Neuroblastoma: Impact of BCHE Deletion on the Neuroblastoma Growth In Vitro and In Vivo.

Baranowska-Kortylewicz, Janina / Kortylewicz, Zbigniew P / McIntyre, Erin M / Sharp, John G / Coulter, Don W

Journal of pediatric hematology/oncology

2021 Volume 44, Issue 6, Page(s) 293–304

Abstract: The physiological functions of butyrylcholinesterase (BChE) and its role in malignancy remain unexplained. Our studies in children newly diagnosed with neuroblastoma indicated that BChE expressions is proportional to MYCN amplification suggesting that ... ...

Abstract	The physiological functions of butyrylcholinesterase (BChE) and its role in malignancy remain unexplained. Our studies in children newly diagnosed with neuroblastoma indicated that BChE expressions is proportional to MYCN amplification suggesting that pathogenesis of high-risk disease may be related to the persistent expression of abnormally high levels of tumor-associated BChE. BChE-deficient neuroblastoma cells (KO [knockout]) were produced from MYCN -amplified BE(2)-C cells (WT [wild-type]) by the CRISPR-Cas9 targeted disruption of the BCHE locus. KO cells have no detectable BChE activity. The compensatory acetylcholinesterase activity was not detected. The average population doubling time of KO cells is 47.0±2.4 hours, >2× longer than WT cells. Reduced proliferation rates of KO cells were accompanied by the loss of N-Myc protein and a significant deactivation of tyrosine kinase receptors associated with the aggressive neuroblastoma phenotype including Ros1, TrkB, and Ltk. Tumorigenicity of WT and KO cells in male mice was essentially identical. In contrast, KO xenografts in female mice were very small (0.37±0.10 g), ~3× smaller compared with WT xenografts (1.11±0.30 g). Unexpectedly, KO xenografts produced changes in plasma BChE similarly to WT tumors but lesser in magnitude. The disruption of BCHE locus in MYCN -amplified neuroblastoma cells decelerates proliferation and produces neuroblastoma cells that are less aggressive in female mice.
MeSH term(s)	Acetylcholinesterase/genetics ; Animals ; Butyrylcholinesterase/genetics ; Female ; Humans ; Male ; Mice ; N-Myc Proto-Oncogene Protein/genetics ; Neuroblastoma/genetics ; Neuroblastoma/pathology ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins
Chemical Substances	N-Myc Proto-Oncogene Protein ; Proto-Oncogene Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Acetylcholinesterase (EC 3.1.1.7) ; Butyrylcholinesterase (EC 3.1.1.8)
Language	English
Publishing date	2021-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1231152-2
ISSN	1536-3678 ; 1077-4114 ; 0192-8562
ISSN (online)	1536-3678
ISSN	1077-4114 ; 0192-8562
DOI	10.1097/MPH.0000000000002285
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Article ; Online: Long non-coding RNA profiling of pediatric Medulloblastoma.

Kesherwani, Varun / Shukla, Mamta / Coulter, Don W / Sharp, J Graham / Joshi, Shantaram S / Chaturvedi, Nagendra K

BMC medical genomics

2020 Volume 13, Issue 1, Page(s) 87

Abstract: Background: Medulloblastoma (MB) is one of the most common malignant cancers in children. MB is primarily classified into four subgroups based on molecular and clinical characteristics as (1) WNT (2) Sonic-hedgehog (SHH) (3) Group 3 (4) Group 4. ... ...

Abstract	Background: Medulloblastoma (MB) is one of the most common malignant cancers in children. MB is primarily classified into four subgroups based on molecular and clinical characteristics as (1) WNT (2) Sonic-hedgehog (SHH) (3) Group 3 (4) Group 4. Molecular characteristics used for MB classification are based on genomic and mRNAs profiles. MB subgroups share genomic and mRNA profiles and require multiple molecular markers for differentiation from each other. Long non-coding RNAs (lncRNAs) are more than 200 nucleotide long RNAs and primarily involve in gene regulation at epigenetic and post-transcriptional levels. LncRNAs have been recognized as diagnostic and prognostic markers in several cancers. However, the lncRNA expression profile of MB is unknown. Methods: We used the publicly available gene expression datasets for the profiling of lncRNA expression across MB subgroups. Functional analysis of differentially expressed lncRNAs was accomplished by Ingenuity pathway analysis (IPA). Results: In the current study, we have identified and validated the lncRNA expression profile across pediatric MB subgroups and associated molecular pathways. We have also identified the prognostic significance of lncRNAs and unique lncRNAs associated with each MB subgroup. Conclusions: Identified lncRNAs can be used as single biomarkers for molecular identification of MB subgroups that warrant further investigation and functional validation.
MeSH term(s)	Adolescent ; Biomarkers, Tumor/genetics ; Cerebellar Neoplasms/genetics ; Cerebellar Neoplasms/pathology ; Child ; Child, Preschool ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Humans ; Infant ; Infant, Newborn ; Male ; Medulloblastoma/genetics ; Medulloblastoma/pathology ; Prognosis ; RNA, Long Noncoding/genetics ; Survival Rate
Chemical Substances	Biomarkers, Tumor ; RNA, Long Noncoding
Language	English
Publishing date	2020-06-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1755-8794
ISSN (online)	1755-8794
DOI	10.1186/s12920-020-00744-7
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Article ; Online: Alpha-Particle Therapy for Multifocal Osteosarcoma: A Hypothesis.

Baranowska-Kortylewicz, Janina / Sharp, John G / McGuire, Timothy R / Joshi, Shantharam / Coulter, Don W

Cancer biotherapy & radiopharmaceuticals

2020 Volume 35, Issue 6, Page(s) 418–424

Abstract: Osteosarcoma (OST) is the most common bone tumor in children and adolescents with a second peak of incidence in elderly adults usually diagnosed as secondary tumors in Paget's disease or irradiated bone. Subjects with metastatic disease or whose disease ... ...

Abstract	Osteosarcoma (OST) is the most common bone tumor in children and adolescents with a second peak of incidence in elderly adults usually diagnosed as secondary tumors in Paget's disease or irradiated bone. Subjects with metastatic disease or whose disease relapses after the initial therapy have a poor prognosis. Moreover, multifocal OST contains tumor-initiating cells that are resistant to chemotherapy. The use of aggressive therapies in an attempt to eradicate these cells can have long-term negative consequences in these vulnerable patient populations.
MeSH term(s)	Adolescent ; Alpha Particles/therapeutic use ; Antigens, Surface ; Bone Neoplasms/mortality ; Bone Neoplasms/pathology ; Bone Neoplasms/radiotherapy ; Child ; Dose-Response Relationship, Radiation ; Drug Carriers/chemistry ; Glutamate Carboxypeptidase II/antagonists & inhibitors ; Humans ; Molecular Targeted Therapy/adverse effects ; Molecular Targeted Therapy/methods ; Nanoparticles/chemistry ; Osteosarcoma/mortality ; Osteosarcoma/pathology ; Osteosarcoma/radiotherapy ; Prognosis ; Radiopharmaceuticals/administration & dosage ; Radiopharmaceuticals/adverse effects ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, IGF Type 1/antagonists & inhibitors ; Theranostic Nanomedicine/methods ; Thorium/administration & dosage ; Thorium/adverse effects
Chemical Substances	Antigens, Surface ; Drug Carriers ; IGF1R protein, human ; Radiopharmaceuticals ; Thorium-227 ; Thorium (60YU5MIG9W) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Receptor, IGF Type 1 (EC 2.7.10.1) ; FOLH1 protein, human (EC 3.4.17.21) ; Glutamate Carboxypeptidase II (EC 3.4.17.21)
Language	English
Publishing date	2020-02-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1315649-4
ISSN	1557-8852 ; 1084-9785
ISSN (online)	1557-8852
ISSN	1084-9785
DOI	10.1089/cbr.2019.3112
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