المؤلفون: Christian K. Ramsoomair, Michele Ceccarelli, John D. Heiss, Ashish H. Shah

المصدر: Journal of Translational Medicine, Vol 21, Iss 1, Pp 1-14 (2023)

مصطلحات موضوعية: Glioblastoma, Epitranscriptomics, RNA modifications, Endogenous retrovirus, Microenvironment, Medicine

الوصف: Abstract Glioblastoma (GBM) comprises 45.6% of all primary malignant brain cancers and is one of the most common and aggressive intracranial tumors in adults. Intratumoral heterogeneity with a wide range of proteomic, genetic, and epigenetic dysregulation contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. To date, numerous clinical trials have been developed to target the proteome and epigenome of high-grade gliomas with promising results. However, studying RNA modifications, or RNA epitranscriptomics, is a new frontier within neuro-oncology. RNA epitranscriptomics was discovered in the 1970s, but in the last decade, the extent of modification of mRNA and various non-coding RNAs has emerged and been implicated in transposable element activation and many other oncogenic processes within the tumor microenvironment. This review provides background information and discusses the therapeutic potential of agents modulating epitranscriptomics in high-grade gliomas. A particular emphasis will be placed on how combination therapies that include immune agents targeting hERV-mediated viral mimicry could improve the treatment of GBM.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1479-5876Test

الوصول الحر: https://doaj.org/article/add735e8d2144017b4517284089db22cTest

المؤلفون: Sarah R. Rivas, Mynor J. Mendez Valdez, Jay S. Chandar, Jelisah F. Desgraves, Victor M. Lu, Leo Ampie, Eric B. Singh, Deepa Seetharam, Christian K. Ramsoomair, Anna Hudson, Shreya M. Ingle, Vaidya Govindarajan, Tara T. Doucet-O’Hare, Catherine DeMarino, John D. Heiss, Avindra Nath, Ashish H. Shah

المصدر: Cancers, Vol 16, Iss 9, p 1754 (2024)

مصطلحات موضوعية: abacavir, antiretroviral, drug repurposing, glioblastoma, lamivudine, reverse transcriptase inhibitors, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Outcomes for glioblastoma (GBM) remain poor despite standard-of-care treatments including surgical resection, radiation, and chemotherapy. Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear. To better understand the pleiotropic anticancer effects of ART on GBM, we conducted a comprehensive drug repurposing analysis of ART in GBM to highlight its utility in translational neuro-oncology. To uncover the anticancer role of ART in GBM, we conducted a comprehensive bioinformatic and in vitro screen of antiretrovirals against glioblastoma. Using the DepMap repository and reversal of gene expression score, we conducted an unbiased screen of 16 antiretrovirals in 40 glioma cell lines to identify promising candidates for GBM drug repositioning. We utilized patient-derived neurospheres and glioma cell lines to assess neurosphere viability, proliferation, and stemness. Our in silico screen revealed that several ART drugs including reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) demonstrated marked anti-glioma activity with the capability of reversing the GBM disease signature. RTIs effectively decreased cell viability, GBM stem cell markers, and proliferation. Our study provides mechanistic and functional insight into the utility of ART repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, ARTs may be a promising adjuvant treatment for GBM.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/16/9/1754Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/84becb1793e6493e936299f35f6baecfTest

المؤلفون: Smit P. Shah, John D. Heiss

المصدر: Brain Sciences, Vol 14, Iss 3, p 228 (2024)

مصطلحات موضوعية: artificial, intelligence, neurology, stroke, epilepsy, neuroimaging, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Neurology is a quickly evolving specialty that requires clinicians to make precise and prompt diagnoses and clinical decisions based on the latest evidence-based medicine practices. In all Neurology subspecialties—Stroke and Epilepsy in particular—clinical decisions affecting patient outcomes depend on neurologists accurately assessing patient disability. Artificial intelligence [AI] can predict the expected neurological impairment from an AIS [Acute Ischemic Stroke], the possibility of ICH [IntraCranial Hemorrhage] expansion, and the clinical outcomes of comatose patients. This review article informs readers of artificial intelligence principles and methods. The article introduces the basic terminology of artificial intelligence before reviewing current and developing AI applications in neurology practice. AI holds promise as a tool to ease a neurologist’s daily workflow and supply unique diagnostic insights by analyzing data simultaneously from several sources, including neurological history and examination, blood and CSF laboratory testing, CNS electrophysiologic evaluations, and CNS imaging studies. AI-based methods are poised to complement the other tools neurologists use to make prompt and precise decisions that lead to favorable patient outcomes.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2076-3425/14/3/228Test; https://doaj.org/toc/2076-3425Test

الوصول الحر: https://doaj.org/article/5c9cd6250e744a6c866efb35b11fa4a8Test

المؤلفون: Danielle D. Dang, Vikram Chandrashekhar, Vibhu Chandrashekhar, Nagela Ghabdanzanluqui, Russell H. Knutsen, Matthew A. Nazari, Likitha Nimmagadda, Danielle R. Donahue, Dorian B. McGavern, Beth A. Kozel, John D. Heiss, Karel Pacak, Zhengping Zhuang, Jared S. Rosenblum

المصدر: STAR Protocols, Vol 4, Iss 3, Pp 102367- (2023)

مصطلحات موضوعية: Model Organisms, Neuroscience, Systems biology, Science (General), Q1-390

الوصف: Summary: Mapping cranial vasculature and adjacent neurovascular interfaces in their entirety will enhance our understanding of central nervous system function in any physiologic state. We present a workflow to visualize in situ murine vasculature and surrounding cranial structures using terminal polymer casting of vessels, iterative sample processing and image acquisition, and automated image registration and processing. While this method does not obtain dynamic imaging due to mouse sacrifice, these studies can be performed before sacrifice and processed with other acquired images.For complete details on the use and execution of this protocol, please refer to Rosenblum et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2666166723003349Test; https://doaj.org/toc/2666-1667Test

الوصول الحر: https://doaj.org/article/ae9471c45db847b68da91dbec8d63a83Test

المؤلفون: Aimee L. Dowling, Stuart Walbridge, Celine Ertekin, Sriya Namagiri, Krystal Camacho, Ashis Chowdhury, Jean-Paul Bryant, Eric Kohut, John D. Heiss, Desmond A. Brown, Sangamesh G. Kumbar, Yeshavanth Kumar Banasavadi-Siddegowda

المصدر: Cells, Vol 12, Iss 21, p 2562 (2023)

مصطلحات موضوعية: FKBP38, apoptosis, autophagy, self-renewal, glioblastoma, PTEN, Cytology, QH573-671

الوصف: Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway. FKBP38, a member of the immunophilin family of proteins, is a multidomain protein that plays an important role in the regulation of cellular functions, including apoptosis and autophagy. In this study, we tested the role of FKBP38 in glioblastoma tumor biology. Expression of FKBP38 was upregulated in the patient-derived primary glioblastoma neurospheres (GBMNS), compared to normal human astrocytes. Attenuation of FKBP38 expression decreased the viability of GBMNSs and increased the caspase 3/7 activity, indicating that FKBP38 is required for the survival of GBMNSs. Further, the depletion of FKBP38 significantly reduced the number of neurospheres that were formed, implying that FKBP38 regulates the self-renewal of GBMNSs. Additionally, the transient knockdown of FKBP38 increased the LC3-II/I ratio, suggesting the induction of autophagy with the depletion of FKBP38. Further investigation showed that the negative regulation of autophagy by FKBP38 in GBMNSs is mediated through the JNK/C-Jun–PTEN–AKT pathway. In vivo, FKBP38 depletion significantly extended the survival of tumor-bearing mice. Overall, our results suggest that targeting FKBP38 imparts an anti-glioblastoma effect by inducing apoptosis and autophagy and thus can be a potential therapeutic target for glioblastoma therapy.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2073-4409/12/21/2562Test; https://doaj.org/toc/2073-4409Test

الوصول الحر: https://doaj.org/article/a2a25bc8c4914f2f9d2697c28c7973a6Test

المؤلفون: Ashish H. Shah, Sarah R. Rivas, Tara T. Doucet-O’Hare, Vaidya Govindarajan, Catherine DeMarino, Tongguang Wang, Leonel Ampie, Yong Zhang, Yeshavanth Kumar Banasavadi-Siddegowda, Stuart Walbridge, Dragan Maric, Marta Garcia-Montojo, Robert K. Suter, Myoung-Hwa Lee, Kareem A. Zaghloul, Joseph Steiner, Abdel G. Elkahloun, Jay Chandar, Deepa Seetharam, Jelisah Desgraves, Wenxue Li, Kory Johnson, Michael E. Ivan, Ricardo J. Komotar, Mark R. Gilbert, John D. Heiss, Avindra Nath

المصدر: The Journal of Clinical Investigation, Vol 133, Iss 13 (2023)

مصطلحات موضوعية: Stem cells, Virology, Medicine

الوصف: Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype and poor outcomes. Using single-cell RNA-Seq, we identified glioblastoma cellular populations with elevated HML-2 transcripts in neural progenitor–like cells (NPC-like) that drive cellular plasticity. Using CRISPR interference, we demonstrate that HML-2 critically maintained glioblastoma stemness and tumorigenesis in both glioblastoma neurospheres and intracranial orthotopic murine models. Additionally, we demonstrate that HML-2 critically regulated embryonic stem cell programs in NPC-derived astroglia and altered their 3D cellular morphology by activating the nuclear transcription factor OCT4, which binds to an HML-2–specific long-terminal repeat (LTR5Hs). Moreover, we discovered that some glioblastoma cells formed immature retroviral virions, and inhibiting HML-2 expression with antiretroviral drugs reduced reverse transcriptase activity in the extracellular compartment, tumor viability, and pluripotency. Our results suggest that HML-2 fundamentally contributes to the glioblastoma stem cell niche. Because persistence of glioblastoma stem cells is considered responsible for treatment resistance and recurrence, HML-2 may serve as a unique therapeutic target.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1558-8238Test

الوصول الحر: https://doaj.org/article/b841f1b345c0461faf2a96f0d318229bTest

المؤلفون: Clare I. Grady, Lisa M. Walsh, John D. Heiss

المصدر: Frontiers in Neurology, Vol 14 (2023)

مصطلحات موضوعية: mitoepigenetics, epigenetics, glioma, mitochondria, glioblastoma, mtDNA, Neurology. Diseases of the nervous system, RC346-429

الوصف: Epigenetic mechanisms allow cells to fine-tune gene expression in response to environmental stimuli. For decades, it has been known that mitochondria have genetic material. Still, only recently have studies shown that epigenetic factors regulate mitochondrial DNA (mtDNA) gene expression. Mitochondria regulate cellular proliferation, apoptosis, and energy metabolism, all critical areas of dysfunction in gliomas. Methylation of mtDNA, alterations in mtDNA packaging via mitochondrial transcription factor A (TFAM), and regulation of mtDNA transcription via the micro-RNAs (mir 23-b) and long noncoding RNAs [RNA mitochondrial RNA processing (RMRP)] have all been identified as contributing to glioma pathogenicity. Developing new interventions interfering with these pathways may improve glioma therapy.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fneur.2023.1154753/fullTest; https://doaj.org/toc/1664-2295Test

الوصول الحر: https://doaj.org/article/a1f9e856d9014ccf8f6b7f9079814d86Test

المؤلفون: Eric A. Kohut, Shantelle A. Graff, Samuel H. Wakelin, Martin Arhin, Govind Nair, John D. Heiss

المصدر: Journal of Clinical Medicine, Vol 12, Iss 21, p 6725 (2023)

مصطلحات موضوعية: syringomyelia, Chiari malformation Type 1, spinal cord, surgical outcomes, quantitative magnetic resonance imaging, Medicine

الوصف: Neurosurgeons evaluate MRI scans to document whether surgical treatment has reduced syrinx size. Manual measurement of syrinx volume is time-consuming and potentially introduces operator error and bias. Developing convenient semiautomated volumetric analysis methods may encourage their clinical implementation and improve syringomyelia monitoring. We analyzed 30 SPGR axial MRI scans from 15 pre- and postoperative Chiari I and syringomyelia patients using two semiautomated (SCAT and 3DQI) methods and a manual Cavalieri (CAV) method. Patients’ spinal cord and syrinx volumes pre- and postoperatively were compared by paired t-test. A decrease in syrinx volume (mm3) after surgery was detected across all methods. Mean syrinx volume (± SD) measured by CAV (n = 30) was, preoperatively, 4515 mm3 ± 3720, postoperatively 1109 ± 1469; (p = 0.0004). SCAT was, pre, 4584 ± 3826, post, 1064 ± 1465; (p = 0.0007) and 3DQI was, pre, 4027 ± 3805, post, 819 ± 1242; (p = 0.001). 3DQI and CAV detected similar mean spinal cord volumes before (p = 0.53) and after surgery (p = 0.23), but SCAT volumes differed significantly (p = 0.005, p = 0.0001). The SCAT and 3DQI semiautomated methods recorded surgically related syrinx volume changes efficiently and with enough accuracy for clinical decision-making and research studies.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2077-0383/12/21/6725Test; https://doaj.org/toc/2077-0383Test

الوصول الحر: https://doaj.org/article/ada2127fe6574424819112a517f78daeTest

المؤلفون: Ashish H. Shah, Vaidya Govindarajan, Tara T. Doucet-O’Hare, Sarah Rivas, Leo Ampie, Catherine DeMarino, Yeshavanth Kumar Banasavadi-Siddegowda, Yong Zhang, Kory R. Johnson, Fahad Almsned, Mark R. Gilbert, John D. Heiss, Avindra Nath

المصدر: Scientific Reports, Vol 12, Iss 1, Pp 1-11 (2022)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Comprising approximately 8% of our genome, Human Endogenous RetroViruses (HERVs) represent a class of germline retroviral infections that are regulated through epigenetic modifications. In cancer cells, which often have epigenetic dysregulation, HERVs have been implicated as potential oncogenic drivers. However, their role in gliomas is not known. Given the link between HERV expression in cancer cell lines and the distinct epigenetic dysregulation in gliomas, we utilized a tailored bioinformatic pipeline to characterize and validate the glioma retrotranscriptome and correlate HERV expression with locus-specific epigenetic modifications. We identified robust overexpression of multiple HERVs in our cell lines, including a retroviral transcript, HML-6, at 19q13.43b in glioblastoma cells. HERV expression inversely correlated with loci-specific DNA methylation. HML-6 contains an intact open reading frame encoding a small envelope protein, ERVK3-1. Increased expression of ERVK3-1 in GBM patients is associated with a poor prognosis independent of IDH-mutational status. Our results suggest that not only is HML-6 uniquely overexpressed in highly invasive cell lines and tissue samples, but also its gene product, ERVK3-1, may be associated with reduced survival in GBM patients. These results may have implications for both the tumor biology of GBM and the role of ERVK3-1 as a potential therapeutic target.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/881d38f1fc7640198c8a35126450c536Test

المؤلفون: Hannah P. Famili, Christopher K. Zalewski, Alaaddin Ibrahimy, Jessica Mack, Fredric Cantor, John D. Heiss, Carmen C. Brewer

المصدر: Journal of Clinical Medicine; Volume 12; Issue 8; Pages: 2767

مصطلحات موضوعية: Chiari, Chiari Malformation Type I, vestibular, dizziness, balance, somatosensory, posturography, VEMP, SHA, rotational

الوصف: Chiari Malformation Type I (CM1) is a neurological condition in which the cerebellar tonsils extend past the foramen magnum. While many studies have reported dizziness symptoms in patients with CM1, the prevalence of peripheral labyrinthine lesions is largely unknown. This study aimed to comprehensively describe the audiovestibular phenotype in a cohort of patients with CM1 expressly referred for dizziness. Twenty-four patients with CM1 and a complaint of dizziness/vertigo were evaluated. Hearing and auditory brainstem tract function were essentially normal. While vestibular abnormalities were most prevalent during rotational testing (33%), abnormal functional balance was the most common finding (40%). Patients with CM1 had a greater likelihood of exhibiting an abnormal sensory organization test (SOT) postural stability score for fixed platform conditions, and for the somatosensory analysis score. While no significant associations were identified between tonsillar ectopia extent and any vestibular/balance outcome measure, a significant negative association was identified between neck pain and the somatosensory sensory analysis score. Abnormal functional balance in the somatosensory domain was remarkable, with poorer scores associated with neck pain. An isolated peripheral vestibulopathy was present in only 8% of patients. Despite the low prevalence of vestibulopathy, vestibular/balance assessment is warranted to identify patients who may benefit from referral to specialized medical disciplines.

وصف الملف: application/pdf

العلاقة: Clinical Neurology; https://dx.doi.org/10.3390/jcm12082767Test

الإتاحة: https://doi.org/10.3390/jcm12082767Test