Publications by authors named "Jason Kost"

8 Publications

  • Page 1 of 1

RUNX1 and RUNX2 transcription factors function in opposing roles to regulate breast cancer stem cells.

J Cell Physiol 2020 10 17;235(10):7261-7272. Epub 2020 Mar 17.

Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont.

Breast cancer stem cells (BCSCs) are competent to initiate tumor formation and growth and refractory to conventional therapies. Consequently BCSCs are implicated in tumor recurrence. Many signaling cascades associated with BCSCs are critical for epithelial-to-mesenchymal transition (EMT). We developed a model system to mechanistically examine BCSCs in basal-like breast cancer using MCF10AT1 FACS sorted for CD24 (negative/low in BCSCs) and CD44 (positive/high in BCSCs). Ingenuity Pathway Analysis comparing RNA-seq on the CD24 versus CD24 MCF10AT1 indicates that the top activated upstream regulators include TWIST1, TGFβ1, OCT4, and other factors known to be increased in BCSCs and during EMT. The top inhibited upstream regulators include ESR1, TP63, and FAS. Consistent with our results, many genes previously demonstrated to be regulated by RUNX factors are altered in BCSCs. The RUNX2 interaction network is the top significant pathway altered between CD24 and CD24 MCF10AT1. RUNX1 is higher in expression at the RNA level than RUNX2. RUNX3 is not expressed. While, human-specific quantitative polymerase chain reaction primers demonstrate that RUNX1 and CDH1 decrease in human MCF10CA1a cells that have grown tumors within the murine mammary fat pad microenvironment, RUNX2 and VIM increase. Treatment with an inhibitor of RUNX binding to CBFβ for 5 days followed by a 7-day recovery period results in EMT suggesting that loss of RUNX1, rather than increase in RUNX2, is a driver of EMT in early stage breast cancer. Increased understanding of RUNX regulation on BCSCs and EMT will provide novel insight into therapeutic strategies to prevent recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.29625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415511PMC
October 2020

Association of Circulating YKL-40 Levels and CHI3L1 Variants with the Risk of Spinal Deformity Progression in Adolescent Idiopathic Scoliosis.

Sci Rep 2019 04 5;9(1):5712. Epub 2019 Apr 5.

Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Sainte-Justine University Hospital, Research Center, Montreal, QC, Canada.

The cellular and molecular mechanisms underlying spinal deformity progression in adolescent idiopathic scoliosis (AIS) remain poorly understood. In this study, 804 French-Canadian patients and 278 age- and sex-matched controls were enrolled and genotyped for 12 single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene or its promoter. The plasma YKL-40 levels were determined by ELISA. We showed that elevation of circulating YKL-40 levels was correlated with a reduction of spinal deformity progression risk. We further identified significant associations of multiple CHI3L1 SNPs and their haplotypes with plasma YKL-40 levels and scoliosis severity as a function of their classification in a specific endophenotype. In the endophenotype FG3 group, we found that patients harboring the haplotype G-G-A-G-G-A (rs880633|rs1538372|rs4950881|rs10399805|rs6691378|rs946261), which presented in 48% of the cases, showed a positive correlation with the plasma YKL-40 levels (P = 7.6 × 10 and coefficient = 36). Conversely, the haplotype A-A-G-G-G-G, which presented in 15% of the analyzed subjects, showed a strong negative association with the plasma YKL-40 levels (P = 2 × 10 and coefficient = -9.56). We found that this haplotype showed the strongest association with AIS patients in endophenotype FG2 (P = 9.9 × 10 and coefficient = -13.53), who more often develop severe scoliosis compared to those classified in the other two endophenotypes. Of note, it showed stronger association in females (P = 1.6 × 10 and coefficient = -10.08) than males (P = 0.0021 and coefficient = -9.01). At the functional level, we showed that YKL-40 treatments rescued Gi-coupled receptor signalling dysfunction occurring in primary AIS osteoblasts. Collectively, our findings reveal a novel role for YKL-40 in AIS pathogenesis and a new molecular mechanism interfering with spinal deformity progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-41191-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450973PMC
April 2019

A virome-wide clonal integration analysis platform for discovering cancer viral etiology.

Genome Res 2019 05 14;29(5):819-830. Epub 2019 Mar 14.

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 05405, USA.

Oncoviral infection is responsible for 12%-15% of cancer in humans. Convergent evidence from epidemiology, pathology, and oncology suggests that new viral etiologies for cancers remain to be discovered. Oncoviral profiles can be obtained from cancer genome sequencing data; however, widespread viral sequence contamination and noncausal viruses complicate the process of identifying genuine oncoviruses. Here, we propose a novel strategy to address these challenges by performing virome-wide screening of early-stage clonal viral integrations. To implement this strategy, we developed VIcaller, a novel platform for identifying viral integrations that are derived from any characterized viruses and shared by a large proportion of tumor cells using whole-genome sequencing (WGS) data. The sensitivity and precision were confirmed with simulated and benchmark cancer data sets. By applying this platform to cancer WGS data sets with proven or speculated viral etiology, we newly identified or confirmed clonal integrations of hepatitis B virus (HBV), human papillomavirus (HPV), Epstein-Barr virus (EBV), and BK Virus (BKV), suggesting the involvement of these viruses in early stages of tumorigenesis in affected tumors, such as HBV in and (also known as ) gene loci in liver cancer, HPV and BKV in bladder cancer, and EBV in non-Hodgkin's lymphoma. We also showed the capacity of VIcaller to identify integrations from some uncharacterized viruses. This is the first study to systematically investigate the strategy and method of virome-wide screening of clonal integrations to identify oncoviruses. Searching clonal viral integrations with our platform has the capacity to identify virus-caused cancers and discover cancer viral etiologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gr.242529.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499315PMC
May 2019

Demonstration of a quasi-monostatic autonomous underwater vehicle based high duty cycle active sonar.

J Acoust Soc Am 2019 Jan;145(1):EL90

University of Massachusetts Dartmouth, Dartmouth, Massachusetts 02747,

The feasibility of resolving target returns within receive signals collected by a continuously transmitting quasi-monostatic, broadband, autonomous underwater vehicle (AUV) based sonar is explored. Theoretical studies supported by experimental results suggest that it is possible to capture the source-to-receiver coupling response and target scattering with sufficient fidelity during the continuous transmission to enable detection and (potentially) classification processing. Demonstrations focused upon the detection of a bottomed target object at sea using transmit signals with duty cycles of 60% and 100% indicate that such an approach is feasible for a representative AUV-based side looking sonar system operating in shallow water.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1121/1.5088029DOI Listing
January 2019

Comprehensive comparative analysis of methods and software for identifying viral integrations.

Brief Bioinform 2019 11;20(6):2088-2097

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 05405, USA.

Many viruses are capable of integrating in the human genome, particularly viruses involved in tumorigenesis. Viral integrations can be considered genetic markers for discovering virus-caused cancers and inferring cancer cell development. Next-generation sequencing (NGS) technologies have been widely used to screen for viral integrations in cancer genomes, and a number of bioinformatics tools have been developed to detect viral integrations using NGS data. However, there has been no systematic comparison of the methods or software. In this study, we performed a comprehensive comparative analysis of the designs, performance, functionality and limitations among the existing methods and software for detecting viral integrations. We further compared the sensitivity, precision and runtime of integration detection of four representative tools. Our analyses showed that each of the existing software had its own merits; however, none of them were sufficient for parallel or accurate virome-wide detection. After carefully evaluating the limitations shared by the existing methods, we proposed strategies and directions for developing virome-wide integration detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bib/bby070DOI Listing
November 2019

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

Nat Commun 2016 Apr 15;7:11253. Epub 2016 Apr 15.

Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms11253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835537PMC
April 2016

Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS.

Neuron 2014 Oct 22;84(2):324-31. Epub 2014 Oct 22.

Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, SERMAS, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), 28041 Madrid, Spain.

Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2014.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521390PMC
October 2014

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis.

Nature 2012 Aug;488(7412):499-503

Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature11280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575525PMC
August 2012
-->