Publications by authors named "Kesava Asam"

5 Publications

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The REASON score: an epigenetic and clinicopathologic score to predict risk of poor survival in patients with early stage oral squamous cell carcinoma.

Biomark Res 2021 Jun 5;9(1):42. Epub 2021 Jun 5.

New York University Rory Meyers College of Nursing, New York, NY, USA.

Background: Oral squamous cell carcinoma (OSCC) is a capricious cancer with poor survival rates, even for early-stage patients. There is a pressing need to develop more precise risk assessment methods to appropriately tailor clinical treatment. Genome-wide association studies have not produced a viable biomarker. However, these studies are limited by using heterogeneous cohorts, not focusing on methylation although OSCC is a heavily epigenetically-regulated cancer, and not combining molecular data with clinicopathologic data for risk prediction. In this study we focused on early-stage (I/II) OSCC and created a risk score called the REASON score, which combines clinicopathologic characteristics with a 12-gene methylation signature, to predict the risk of 5-year mortality.

Methods: We combined data from an internal cohort (n = 515) and The Cancer Genome Atlas (TCGA) cohort (n = 58). We collected clinicopathologic data from both cohorts to derive the non-molecular portion of the REASON score. We then analyzed the TCGA cohort DNA methylation data to derive the molecular portion of the risk score.

Results: 5-year disease specific survival was 63% for the internal cohort and 86% for the TCGA cohort. The clinicopathologic features with the highest predictive ability among the two the cohorts were age, race, sex, tobacco use, alcohol use, histologic grade, stage, perineural invasion (PNI), lymphovascular invasion (LVI), and margin status. This panel of 10 non-molecular features predicted 5-year mortality risk with a concordance (c)-index = 0.67. Our molecular panel consisted of a 12-gene methylation signature (i.e., HORMAD2, MYLK, GPR133, SOX8, TRPA1, ABCA2, HGFAC, MCPH1, WDR86, CACNA1H, RNF216, CCNJL), which had the most significant differential methylation between patients who survived vs. died by 5 years. All 12 genes have already been linked to survival in other cancers. Of the genes, only SOX8 was previously associated with OSCC; our study was the first to link the remaining 11 genes to OSCC survival. The combined molecular and non-molecular panel formed the REASON score, which predicted risk of death with a c-index = 0.915.

Conclusions: The REASON score is a promising biomarker to predict risk of mortality in early-stage OSCC patients. Validation of the REASON score in a larger independent cohort is warranted.
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http://dx.doi.org/10.1186/s40364-021-00292-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178935PMC
June 2021

Reduced Expression of the PP2A Methylesterase, PME-1, or the PP2A Methyltransferase, LCMT-1, Alters Sensitivity to Beta-Amyloid-Induced Cognitive and Electrophysiological Impairments in Mice.

J Neurosci 2020 06 27;40(23):4596-4608. Epub 2020 Apr 27.

Department of Pathology and Cell Biology, Columbia University, New York, New York 10032

Beta-amyloid (Aβ) is thought to play a critical role in Alzheimer's disease (AD), and application of soluble oligomeric forms of Aβ produces AD-like impairments in cognition and synaptic plasticity in experimental systems. We found previously that transgenic overexpression of the PP2A methylesterase, PME-1, or the PP2A methyltransferase, LCMT-1, altered the sensitivity of mice to Aβ-induced impairments, suggesting that PME-1 inhibition may be an effective approach for preventing or treating these impairments. To explore this possibility, we examined the behavioral and electrophysiological effects of acutely applied synthetic Aβ oligomers in male and female mice heterozygous for either a KO or an gene-trap mutation. We found that heterozygous KO mice were resistant to Aβ-induced impairments in cognition and synaptic plasticity, whereas gene-trap mice showed increased sensitivity to Aβ-induced impairments. The heterozygous KO mice produced normal levels of endogenous Aβ and exhibited normal electrophysiological responses to picomolar concentrations of Aβ, suggesting that reduced PME-1 expression in these animals protects against Aβ-induced impairments without impacting normal physiological Aβ functions. Together, these data provide additional support for roles for PME-1 and LCMT-1 in regulating sensitivity to Aβ-induced impairments, and suggest that inhibition of PME-1 may constitute a viable therapeutic approach for selectively protecting against the pathologic actions of Aβ in AD. Elevated levels of β-amyloid (Aβ) in the brain are thought to contribute to the cognitive impairments observed in Alzheimer's disease patients. Here we show that genetically reducing endogenous levels of the PP2A methylesterase, PME-1, prevents the cognitive and electrophysiological impairments caused by acute exposure to pathologic concentrations of Aβ without impairing normal physiological Aβ function or endogenous Aβ production. Conversely, reducing endogenous levels of the PP2A methyltransferase, LCMT-1, increases sensitivity to Aβ-induced impairments. These data offer additional insights into the molecular factors that control sensitivity to Aβ-induced impairments, and suggest that inhibiting PME-1 may constitute a viable therapeutic avenue for preventing Aβ-related impairments in Alzheimer's disease.
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http://dx.doi.org/10.1523/JNEUROSCI.2983-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275859PMC
June 2020

Molecular patterning of the embryonic cranial mesenchyme revealed by genome-wide transcriptional profiling.

Dev Biol 2019 11 24;455(2):434-448. Epub 2019 Jul 24.

Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, 10010, USA. Electronic address:

In the head of an embryo, a layer of mesenchyme surrounds the brain underneath the surface ectoderm. This cranial mesenchyme gives rise to the meninges, the calvaria (top part of the skull), and the dermis of the scalp. Abnormal development of these structures, especially the meninges and the calvaria, is linked to significant congenital defects in humans. It has been known that different areas of the cranial mesenchyme have different fates. For example, the calvarial bone develops from the cranial mesenchyme on the baso-lateral side of the head just above the eye (supraorbital mesenchyme, SOM), but not from the mesenchyme apical to SOM (early migrating mesenchyme, EMM). However, the molecular basis of this difference is not fully understood. To answer this question, we compared the transcriptomes of EMM and SOM using high-throughput sequencing (RNA-seq). This experiment identified a large number of genes that were differentially expressed in EMM and SOM, and gene ontology analyses found very different terms enriched in each region. We verified the expression of about 40 genes in the head by RNA in situ hybridization, and the expression patterns were annotated to make a map of molecular markers for 6 subdivisions of the cranial mesenchyme. Our data also provided insights into potential novel regulators of cranial mesenchyme development, including several axon guidance pathways, lectin complement pathway, cyclic-adenosine monophosphate (cAMP) signaling pathway, and ZIC family transcription factors. Together, information in this paper will serve as a unique resource to guide future research on cranial mesenchyme development.
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http://dx.doi.org/10.1016/j.ydbio.2019.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842427PMC
November 2019

Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria.

Dev Biol 2018 11 28;443(2):103-116. Epub 2018 May 28.

Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, United States. Electronic address:

The calvaria (upper part of the skull) is made of plates of bone and fibrous joints (sutures and fontanelles), and the proper balance and organization of these components are crucial to normal development of the calvaria. In a mouse embryo, the calvaria develops from a layer of head mesenchyme that surrounds the brain from shortly after mid-gestation. The mesenchyme just above the eye (supra-orbital mesenchyme, SOM) generates ossification centers for the bones, which then grow toward the apex gradually. In contrast, the mesenchyme apical to SOM (early migrating mesenchyme, EMM), including the area at the vertex, does not generate an ossification center. As a result, the dorsal midline of the head is occupied by sutures and fontanelles at birth. To date, the molecular basis for this regional difference in developmental programs is unknown. The current study provides vital insights into the genetic regulation of calvarial patterning. First, we showed that osteogenic signals were active in both EMM and SOM during normal development, which suggested the presence of an anti-osteogenic factor in EMM to counter the effect of these signals. Subsequently, we identified Lmx1b as an anti-osteogenic gene that was expressed in EMM but not in SOM. Furthermore, head mesenchyme-specific deletion of Lmx1b resulted in heterotopic ossification from EMM at the vertex, and craniosynostosis affecting multiple sutures. Conversely, forced expression of Lmx1b in SOM was sufficient to inhibit osteogenic specification. Therefore, we conclude that Lmx1b plays a key role as an anti-osteogenic factor in patterning the head mesenchyme into areas with different osteogenic competence. In turn, this patterning event is crucial to generating the proper organization of the bones and soft tissue joints of the calvaria.
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http://dx.doi.org/10.1016/j.ydbio.2018.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197925PMC
November 2018

Eicosanoyl-5-hydroxytryptamide (EHT) prevents Alzheimer's disease-related cognitive and electrophysiological impairments in mice exposed to elevated concentrations of oligomeric beta-amyloid.

PLoS One 2017 18;12(12):e0189413. Epub 2017 Dec 18.

Department of Pathology and Cell Biology, Columbia University, New York, NY, United States of America.

Soluble forms of oligomeric beta-amyloid (Aβ) are thought to play a central role in Alzheimer's disease (AD). Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Aβ. In addition, eicosanoyl-5-hydroxytryptamide (EHT), a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson's disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Aβ. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Aβ-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Aβ-induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Aβ-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734769PMC
January 2018
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