scholarly journals Transformed Canine and Murine Mesenchymal Stem Cells as a Model for Sarcoma with Complex Genomics

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1126
Author(s):  
Natasja Franceschini ◽  
Bas Verbruggen ◽  
Marianna A. Tryfonidou ◽  
Alwine B. Kruisselbrink ◽  
Hans Baelde ◽  
...  
Keyword(s):  
Copy Number ◽  
Point Mutations ◽  
Comparative Approach ◽  
Cell Of Origin ◽  
Mesenchymal Tumors ◽  
Spontaneous Transformation ◽  
Exon 2 ◽  
Species Analysis ◽  
Gains And Losses

Sarcomas are rare mesenchymal tumors with a broad histological spectrum, but they can be divided into two groups based on molecular pathology: sarcomas with simple or complex genomics. Tumors with complex genomics can have aneuploidy and copy number gains and losses, which hampers the detection of early, initiating events in tumorigenesis. Often, no benign precursors are known, which is why good models are essential. The mesenchymal stem cell (MSC) is the presumed cell of origin of sarcoma. In this study, MSCs of murine and canine origin are used as a model to identify driver events for sarcomas with complex genomic alterations as they transform spontaneously after long-term culture. All transformed murine but not canine MSCs formed sarcomas after subcutaneous injection in mice. Using whole genome sequencing, spontaneously transformed murine and canine MSCs displayed a complex karyotype with aneuploidy, point mutations, structural variants, inter-chromosomal translocations, and copy number gains and losses. Cross-species analysis revealed that point mutations in Tp53/Trp53 are common in transformed murine and canine MSCs. Murine MSCs with a cre-recombinase induced deletion of exon 2-10 of Trp53 transformed earlier compared to wild-type murine MSCs, confirming the contribution of loss of p53 to spontaneous transformation. Our comparative approach using transformed murine and canine MSCs points to a crucial role for p53 loss in the formation of sarcomas with complex genomics.

Determinants of Corporate Long-Term Capital Policy. Poland vs. France, Germany, and Great Britain: Comparative Approach and Panel Analysis

2005 ◽  
Author(s):  
Waldemar Frackowiak ◽  
Sebastian Gryglewicz ◽  
Piotr Stobiecki ◽  
Maciej Stradomski ◽  
Adam Szyszka
Keyword(s):  
Great Britain ◽  
Comparative Approach ◽  
Panel Analysis

CBIO-23. ANTIAPOPTOTIC Bcl-xL RESTRICTS APOPTOSIS IN SHH MEDULLOBLASTOMA AND PROMOTES PROGRESSION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi31-vi32
Author(s):  
Abigail Cleveland ◽  
Katherine Veleta ◽  
Timothy Gershon
Keyword(s):  
Therapeutic Potential ◽  
Radiation Sensitivity ◽  
Genetically Engineered ◽  
Translation Regulation ◽  
Spontaneous Apoptosis ◽  
Cell Of Origin ◽  
Tumor Resistance ◽  
Cerebellar Granule Neuron ◽  
Apoptotic Pathway

Abstract Medulloblastomas in most patients are distinctively sensitive to radiation therapy, but the mechanisms that mediate this sensitivity are unclear. Current treatments still fail 20%-60% of patients with SHH medulloblastoma and can leave survivors with long-term neurocognitive and social deficits. Understanding the mechanisms driving the typical radiation-sensitivity may identify less-toxic therapeutic strategies and provide insight into treatment failure. We previously showed that radiation sensitivity depends on the intrinsic apoptotic pathway, mediated by pro-apoptotic BAX. In cerebellar granule neuron progenitors (CGNPs), the cell of origin for SHH medulloblastoma, BAX activity is directly inhibited by anti-apoptotic BCL-xL; Bcl-xL-deleted CGNPs undergo spontaneous apoptosis. To test the therapeutic potential of disrupting BCL-xL in medulloblastoma, we conditionally deleted Bcl-xL in mice genetically engineered to develop SHH medulloblastoma. Here, I show that Bcl-xL deletion slows SHH medulloblastoma growth and prolongs survival of medulloblastoma-bearing mice. Bcl-xL-deleted tumors initially showed increased rates of spontaneous apoptosis, but this effect waned over time, suggesting the emergence of BCL-xL-independent survival mechanisms. We also noted increased microglial infiltration in Bcl-xL-deleted medulloblastomas. We hypothesize that IGF1 produced by microglia in the tumor microenvironment may be contributing to tumor resistance by upregulating translation of MCL-1, an anti-apoptotic BCL-xL homolog. IGF1 is known to upregulate translation through the mTOR pathway, while anti-apoptotic MCL-1 protein abundance is dependent upon translation regulation. Our on-going studies are testing the efficacy of pharmacologically targeting BCL-xL in mice with medulloblastoma, in combination with targeting IGF1 signaling using mTORC1 inhibitors.

scholarly journals Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease

Blood ◽  
2014 ◽  
Vol 123 (16) ◽  
pp. 2504-2512 ◽  
Author(s):  
Jeffrey R. Sawyer ◽  
Erming Tian ◽  
Christoph J. Heuck ◽  
Joshua Epstein ◽  
Donald J. Johann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Copy Number ◽  
High Risk Disease ◽  
Key Points ◽  
Gains And Losses

Key Points Jumping translocations of 1q12 (JT1q12) provide a mechanism for the deletion of 17p in cytogenetically defined high-risk myeloma. Sequential JT1q12s introduce unexpected copy number gains and losses in receptor chromosomes during subclonal evolution.

Analysis of point mutations and copy number variation in Grade II and III meningioma

2018 ◽  
Vol 105 (3) ◽  
pp. 328-333 ◽  
Author(s):  
Samantha N. McNulty ◽  
Katherine Schwetye ◽  
Michael Goldstein ◽  
Jamal Carter ◽  
Robert E. Schmidt ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Copy Number ◽  
Point Mutations ◽  
Number Variation ◽  
Grade Ii

scholarly journals A genetic-algorithm approach to simulating human immunodeficiency virus evolution reveals the strong impact of multiply infected cells and recombination

2005 ◽  
Vol 86 (11) ◽  
pp. 3109-3118 ◽  
Author(s):  
Gennady Bocharov ◽  
Neville J. Ford ◽  
John Edwards ◽  
Tanja Breinig ◽  
Simon Wain-Hobson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Copy Number ◽  
Hamming Distance ◽  
Point Mutations ◽  
Strong Impact ◽  
Hiv Replication ◽  
Immunodeficiency Virus ◽  
Genetic Algorithm Approach ◽  
Infected Cells

It has been previously shown that the majority of human immunodeficiency virus type 1 (HIV-1)-infected splenocytes can harbour multiple, divergent proviruses with a copy number ranging from one to eight. This implies that, besides point mutations, recombination should be considered as an important mechanism in the evolution of HIV within an infected host. To explore in detail the possible contributions of multi-infection and recombination to HIV evolution, the effects of major microscopic parameters of HIV replication (i.e. the point-mutation rate, the crossover number, the recombination rate and the provirus copy number) on macroscopic characteristics (such as the Hamming distance and the abundance of n-point mutants) have been simulated in silico. Simulations predict that multiple provirus copies per infected cell and recombination act in synergy to speed up the development of sequence diversity. Point mutations can be fixed for some time without fitness selection. The time needed for the selection of multiple mutations with increased fitness is highly variable, supporting the view that stochastic processes may contribute substantially to the kinetics of HIV variation in vivo.

scholarly journals What has happened and what has not happened due to the coronavirus disease pandemic: a systemic perspective on policy change

2022 ◽  
Author(s):  
Christoph Knill ◽  
Yves Steinebach
Keyword(s):  
Policy Change ◽  
Comprehensive Analysis ◽  
Policy Agenda ◽  
Economic Crises ◽  
Policy Area ◽  
Catching Up ◽  
Policy Transformations ◽  
Gains And Losses ◽  
Academic Debate

Abstract The societal and policy transformations associated with the coronavirus disease pandemic are currently subject of intense academic debate. In this paper, we contribute to this debate by adopting a systemic perspective on policy change, shedding light on the hidden and indirect crisis effects. Based on a comprehensive analysis of policy agenda developments in Germany, we find that the pandemic led to profound shifts in political attention across policy areas. We demonstrate that these agenda gains and losses per policy area vary by the extent to which the respective areas can be presented as relevant in managing the coronavirus disease crisis and its repercussions. Moreover, relying on the analysis of past four economic crises, we also find that there is limited potential for catching up dynamics after the crisis is over. Policy areas that lost agenda share during crisis are unlikely to make up for these losses by strong attention gains once the crisis is over. Crises have hence substantial, long-term and so far, neglected effects on policymaking in modern democracies.

scholarly journals Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma

2016 ◽  
Vol 54 (3) ◽  
pp. 278-286
Author(s):  
J. Perez-Escuredo ◽  
A. Lopez-Hernandez ◽  
M. Costales ◽  
F. Lopez ◽  
S.P. Ares ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Copy Number ◽  
Genetic Alterations ◽  
Intestinal Type ◽  
Dust Exposure ◽  
Copy Number Alterations ◽  
A Genome ◽  
Sinonasal Adenocarcinoma ◽  
Gains And Losses ◽  
Microarray Cgh

Background: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. Material and methods: Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. Results: Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. Conclusion: ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.

scholarly journals Effect of EPSPS Gene Copy Number and Glyphosate Selection on Fitness of Glyphosate-Resistant Bassia Scoparia in The Field

2021 ◽  
Author(s):  
Charlemagne Ajoc Lim ◽  
Prashant Jha ◽  
Vipan Kumar ◽  
Alan T. Dyer
Keyword(s):  
Sugar Beet ◽  
Seed Production ◽  
Great Plains ◽  
Copy Number ◽  
Gene Copy Number ◽  
Reproductive Traits ◽  
Gene Copy ◽  
Epsps Gene ◽  
Gene Copies

Abstract The widespread evolution of glyphosate-resistant (GR) Bassia scoparia in the U.S. Great Plains poses a serious threat to the long-term sustainability of GR sugar beet. Glyphosate resistance in B. scoparia is due to an increase in the EPSPS (5-enolpyruvyl-shikimate-3-phosphate) gene copy number. The variation in EPSPS gene copies among individuals from within a single GR B. scoparia population indicated a differential response to glyphosate selection. We tested the hypothesis of reduced GR B. scoparia fitness (reproductive traits) to increasing glyphosate rates (applied as single or sequential applications) potentially experienced within a GR sugar beet field. The variation in EPSPS gene copy number and total glyphosate rate (single or sequential applications) did not influence any of the reproductive traits of GR B. scoparia, except seed production. Sequential applications of glyphosate with a total rate of 2,214 g ae ha− 1 or higher prevented seed production in B. scoparia plants with 2–4 (low levels of resistance) and 5–6 (moderate levels of resistance) EPSPS gene copies. Timely sequential applications of glyphosate (full recommended rates) can potentially slow down the evolution of GR B. scoparia with low to moderate levels of resistance (2–6 EPSPS gene copies), but any survivors (highly-resistant individuals with ≥ 8 EPSPS gene copies) need to be mechanically removed before flowering from GR sugar beet fields. This research warrants the need to adopt ecologically based, multi-tactic strategies to reduce exposure of B. scoparia to glyphosate in GR sugar beet.

scholarly journals The phasmid as a tool for plasmid genetics: II. Isolation of point mutations that affect replication of a ColE1-related plasmid

1982 ◽  
Vol 40 (3) ◽  
pp. 233-247 ◽  
Author(s):  
Gianni Cesareni ◽  
Luisa Castagnoli ◽  
Sydney Brenner
Keyword(s):  
Copy Number ◽  
Point Mutations ◽  
Plasmid Replication ◽  
Single Base ◽  
Lambdoid Phage ◽  
Copy Number Plasmid ◽  
High Copy Number Plasmid ◽  
Single Base Pair ◽  
Related Plasmid ◽  
Single Base Pair Change

SUMMARYThe insertion of a high-copy-number plasmid into a lambdoid phage chromosome which lacks a functional repressor gene confers on the hybrid ‘phasmid’ the capacity to grow on an immune lysogen. This was found to be due to titration of repressor because of plasmid replication. We have exploited this property in order to isolate mutants that affect plasmid replication. These mutants have been mapped in a region that was previously characterized as necessary for plasmid replication and incompatibility properties. Some of the mutations could revert at frequencies characteristic of single-base-pair change mutations.

scholarly journals DNA Amplifications and Aneuploidy, High Proliferative Activity and Impaired Cell Cycle Control Characterize Breast Carcinomas with Poor Prognosis

2003 ◽  
Vol 25 (3) ◽  
pp. 103-114 ◽  
Author(s):  
Harald Blegen ◽  
John S. Will ◽  
B. Michael Ghadimi ◽  
Hesed‐Padilla Nash ◽  
Anders Zetterberg ◽  
...  
Keyword(s):  
Copy Number ◽  
Proliferative Activity ◽  
Distant Metastases ◽  
Comparative Genomic ◽  
Short Term ◽  
Ki 67 ◽  
Chromosomal Copy ◽  
Copy Number Changes ◽  
Long Term Survivors

In order to explore whether specific cytogenetic abnormalities can be used to stratify tumors with a distinctly different clinical course, we performed comparative genomic hybridization (CGH) of tumors from patients who were diagnosed with metastatic disease after an interval of less than 2 years or who remained free from distant metastases for more than 10 years. All patients presented with distant metastases after mastectomy indicating that none of the patients in this study was cured and free of remaining tumor cells. Tumors in the group of short‐term survivors showed a higher average number of chromosomal copy alterations compared to the long‐term survivors. Of note, the number of sub‐chromosomal high‐level copy number increases (amplifications) was significantly increased in the group of short‐term survivors. In both short‐ and long‐term survivors recurrent chromosomal gains were mapped to chromosomes 1q, 4q, 8q, and 5p. Copy number changes that were more frequent in the group of short‐term survivors included gains of chromosome 3q, 9p, 11p and 11q and loss of 17p. Our results indicate that low‐ and high grade malignant breast adenocarcinomas are characterized by a specific pattern of chromosomal copy number changes. Furthermore, immunohistochemical evaluation of the expression levels of Ki‐67, p27KIP1, p21WAF1, p53, cyclin A and cyclin E revealed a correlation between increased proliferative activity and poor outcome.

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