scholarly journals High Variability in Cellular Proliferation, Gene Expression, and Cytokine Production in the Nonneoplastic Colonic Epithelium of Young Apc+/Min-FCCC Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Alyssa A. Leystra ◽  
Kristen N. Harvey ◽  
Esther Kaunga ◽  
Harvey Hensley ◽  
Lisa A. Vanderveer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colonic Mucosa ◽  
Cellular Proliferation ◽  
Preventive Intervention ◽  
Fold Change ◽  
Time Interval ◽  
Egfr Signaling ◽  
Wild Type ◽  
Colon Adenoma ◽  
Tumor Bearing

An urgent need exists to identify efficacious therapeutic preventive interventions for individuals who are at high risk of developing colorectal cancer. To maximize the benefits of preventive intervention, it is vital to identify the time interval during which the initiation of a preventive intervention will lead to an optimal outcome. The goal of the present study was to determine if oncogenic events can be detected in the nonneoplastic colonic mucosa of Apc+/Min-FCCC mice prior to formation of the first adenoma, thus defining an earlier point of intervention along the cancer continuum. Tissues taken at three potential points of intervention were characterized: prior to Apc mutation (wild type Apc+/+-FCCC mice); after initiation but prior to colon adenoma formation (tumor-free Apc+/Min-FCCC mice); and after formation of the first colon adenoma (tumor-bearing Apc+/Min-FCCC mice). Experimentation focused on molecular processes that are dysregulated in early colon lesions: 1) cellular proliferation (proliferative index and size of the proliferative zone); 2) cellular stemness (expression of Ascl2, Grem1, Lgr5 and Muc2); 3) EGFR signaling (expression of Ereg); and 4) inflammation (expression of Mmp9, Ptsg2, and Reg4, as well as secretion of 18 cytokines involved in immune activation and response). Interestingly, the nonneoplastic colonic mucosa of wild type, tumor-free Apc+/Min-FCCC, and tumor-bearing Apc+/Min-FCCC mice did not display significant differences in average epithelial cell proliferation (fold change 0.8–1.3, p≥0.11), mucosal gene expression (fold change 0.8–1.4, p≥0.22), or secretion of specific cytokines from colonic mucosa (fold change 0.2–1.5, p≥0.06). However, the level of cytokine secretion was highly variable, with many (22% of wild type, 31% of tumor-free Apc+/Min-FCCC, and 31% of tumor-bearing Apc+/Min-FCCC) mice categorized as outliers (> 1.5 x interquartile ranges below the first quartile or above the third quartile) due to elevated expression of at least one cytokine. In summary, no differences were observed in proliferation, stemness, and EGFR signaling in the colonic mucosa of wild type vs Apc+/Min-FCCC mice, with low baseline cytokine expression, prior to the formation of the first colon adenoma. The results of this study provide valuable baseline data to inform the design of future cancer prevention studies.

Association of microRNA-21 with efficacy of cetuximab in RAS wild-type patients in the FIRE-3 study (AIO KRK-0306) and microRNA-21’s influence on gene expression in the EGFR signaling pathway.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3593-3593
Author(s):  
Lisa Miller-Phillips ◽  
Volker Heinemann ◽  
Arndt Stahler ◽  
Ludwig Fischer von Weikersthal ◽  
Florian Kaiser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microarray Data ◽  
Multiple Testing ◽  
Predictive Biomarker ◽  
Cancer Gene ◽  
Egfr Signaling ◽  
Wild Type ◽  
Egfr Signaling Pathway ◽  
Gene Sets ◽  
Mrna Microarray

3593 Background: FIRE-3 compared first-line therapy with FOLFIRI plus cetuximab (cet) or bevacizumab (bev) in KRAS exon 2 wild-type (wt) patients with metastatic colorectal cancer. Recent analyses showed mircoRNA-21 (miR-21) expression level may be a predictive biomarker for anti-EGFR-therapy raising the question whether miR-21 influences gene expression in the EGFR signaling pathway. Methods: Reverse-transcription quantitative polymerase chain reaction assay identified quantitative miR-21 expression. Median expression was defined as a threshold value to discriminate FIRE-3 population into miR-21 low and high groups. Differential gene expression based on additional mRNA microarray data (Almac Inc, Xcel Array) was calculated by linear models adjusted for multiple testing followed by single sample gene set enrichment analysis (ssGSEA) to compare differentially enriched hallmarks of cancer gene sets. Overall response rate (ORR) was compared using Fisher´s exact test. Median progression-free (PFS) and overall survival (OS) were analyzed using Kaplan-Meier estimation and log-rank test. Results: 333 RAS wt patients provided material for miR-21 expression analysis. In these patients, low miR-21 expression was associated with higher ORR (80.0% vs. 57.9%; p = 0.005) and longer OS (35.8 months (mo) vs. 25.9 mo; p = 0.005) when cet vs bev was added to FOLFIRI. High miR-21 expression was associated with comparable ORR (74.6% vs. 64.0%; p = 0.21) and OS (24.5 mo vs. 23.8 mo; p = 0.4). There was no significant difference in PFS in either group. By comparing miR-21 low and high groups using normalized mRNA microarray data, 538 genes were found to be significantly differentially expressed in RAS wt patients after adjustment for multiple testing. Including data from the two groups into ssGSEA yielded 23 hallmark of cancer gene sets that were significantly differentially enriched; among them, KRAS-signaling showed higher enrichment in the miR-21 high group (adjusted p = 2.09 E-13). Conclusions: MiR-21 expression level might be a predictive biomarker for anti-EGFR-therapy by modulating KRAS signaling in FIRE-3 patients.

scholarly journals Voluntary Wheel Running Did Not Alter Gene Expression in 5xfad Mice, but in Wild-Type Animals Exclusively after One-Day of Physical Activity

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 693
Author(s):  
Anna Wierczeiko ◽  
Lena Gammel ◽  
Konstantin Radyushkin ◽  
Vu Thu Thuy Nguyen ◽  
Hristo Todorov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Physical Activity ◽  
Preventive Intervention ◽  
Wheel Running ◽  
Wild Type ◽  
Voluntary Wheel Running ◽  
5Xfad Mice ◽  
Disease Stages ◽  
The Impact ◽  
Voluntary Wheel

Physical activity is considered a promising preventive intervention to reduce the risk of developing Alzheimer’s disease (AD). However, the positive effect of therapeutic administration of physical activity has not been proven conclusively yet, likely due to confounding factors such as varying activity regimens and life or disease stages. To examine the impact of different routines of physical activity in the early disease stages, we subjected young 5xFAD and wild-type mice to 1-day (acute) and 30-day (chronic) voluntary wheel running and compared them with age-matched sedentary controls. We observed a significant increase in brain lactate levels in acutely trained 5xFAD mice relative to all other experimental groups. Subsequent brain RNA-seq analysis did not reveal major differences in transcriptomic regulation between training durations in 5xFAD mice. In contrast, acute training yielded substantial gene expression changes in wild-type animals relative to their chronically trained and sedentary counterparts. The comparison of 5xFAD and wild-type mice showed the highest transcriptional differences in the chronic and sedentary groups, whereas acute training was associated with much fewer differentially expressed genes. In conclusion, our results suggest that different training durations did not affect the global transcriptome of 3-month-old 5xFAD mice, whereas acute running seemed to induce a similar transcriptional stress state in wild-type animals as already known for 5xFAD mice.

scholarly journals Voluntary Wheel Running Did Not Alter Gene Expression in 5xFAD Mice, but in Wild-Type Animals Exclusively After One-Day Exercise Bout

2021 ◽  
Author(s):  
Anna Wierczeiko ◽  
Lena Gammel ◽  
Konstantin Radyushkin ◽  
Vu Thu Thuy Nguyen ◽  
Hristo Todorov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Preventive Intervention ◽  
Wheel Running ◽  
Exercise Bout ◽  
Wild Type ◽  
Voluntary Wheel Running ◽  
5Xfad Mice ◽  
Disease Stages ◽  
The Impact ◽  
Voluntary Wheel

Physical activity is considered a promising preventive intervention to reduce the risk of developing Alzheimer’s disease (AD). However, the positive effect of exercise therapy has not been proven conclusively yet, likely due to confounding factors such as varying activity regimens and life or disease stages. To examine the impact of different routines of physical exercise in the early disease stages, we subjected young 5xFAD and wild-type mice to 1-day (acute) and 30-day (chronic) voluntary wheel running and compared them with age-matched sedentary controls. We observed a significant increase in brain lactate levels in acutely trained 5xFAD mice relative to all other experimental groups. Subsequent brain RNA-seq analysis did not reveal major differences in transcriptomic regulation between training durations in 5xFAD mice. In contrast, acute training yielded substantial gene expression changes in wild-type animals relative to their chronically trained and sedentary counterparts. The comparison of 5xFAD and wild-type mice showed the highest transcriptional differences in the chronic and sedentary groups, whereas acute training was associated with much fewer differentially expressed genes. In conclusion, our results suggest that different training durations did not affect the global transcriptome of 3-month-old 5xFAD mice, whereas acute running seemed to induce a similar transcriptional stress state in wild-type animals as already known for 5xFAD mice.

scholarly journals The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ian Edward Gentle ◽  
Isabel Moelter ◽  
Mohamed Tarek Badr ◽  
Konstanze Döhner ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Wild Type ◽  
Elevated Expression ◽  
Factor C ◽  
Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

scholarly journals Differential gene expression analysis of dasatinib-induced colitis in a patient with chronic myeloid leukemia followed for 3 years: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Naoki Oshima ◽  
Yoshiyuki Mishima ◽  
Kotaro Shibagaki ◽  
Kousaku Kawashima ◽  
Norihisa Ishimura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Differential Gene Expression ◽  
Myeloid Leukemia ◽  
Colonic Mucosa ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Multikinase Inhibitor ◽  
Differential Gene

Abstract Background Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) developed for treatment of patients with chronic myeloid leukemia (CML). The drug has been shown to act as a potent multikinase inhibitor by blocking not only the BCR-ABL1 gene sequence but also the SRC kinase family, though unexpected adverse events such as pleural effusion have recently been reported in patients undergoing treatment with dasatinib. Hemorrhagic colitis is a unique gastrointestinal adverse events associated with dasatinib and its pathogenesis remains poorly understood. Case presentation We report here a case of dasatinib-induced asymptomatic colitis in a patient with CML, who showed no exacerbation in careful observations and maintained deep molecular response (DMR) during a 3-year period. In addition, we performed transcriptome analysis of inflamed colonic mucosa specimens to clarify the possible mechanism of colitis that develops in association with dasatinib administration. Our results demonstrated that differential gene expression, especially lymphocyte-associated genes and chemokines, is substantially involved in inflammation of colonic mucosa in affected patients. Conclusion Dasatinib induces immune-mediated colitis following lymphocyte infiltration.

scholarly journals Species diversity and spatial distribution of CL/VL vectors: assessing bioclimatic effect on expression plasticity of genes possessing vaccine properties isolated from wild-collected sand flies in endemic areas of Iran

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ali Bordbar ◽  
Parviz Parvizi
Keyword(s):  
Gene Expression ◽  
Spatial Distribution ◽  
Interpolation Method ◽  
Diversity Index ◽  
Fold Change ◽  
Control Measures ◽  
Pcr Analysis ◽  
Physiological Status ◽  
Sand Flies ◽  
Risk Maps

Abstract Background Leishmaniasis is one of the ten most important neglected tropical diseases worldwide. Understanding the distribution of vectors of visceral and cutaneous leishmaniasis (VL/CL) is one of the significant strategic frameworks to control leishmaniasis. In this study, the extent of the bioclimatic variability was investigated to recognize a rigorous cartographic of the spatial distribution of VL/CL vectors as risk-maps using ArcGIS modeling system. Moreover, the effect of bioclimatic diversity on the fold change expression of genes possessing vaccine traits (SP15 and LeIF) was evaluated in each bioclimatic region using real-time PCR analysis. Methods The Inverse Distance Weighting interpolation method was used to obtain accurate geography map in closely-related distances. Bioclimatic indices were computed and vectors spatial distribution was analyzed in ArcGIS10.3.1 system. Species biodiversity was calculated based on Shannon diversity index using Rv.3.5.3. Expression fold change of SP15 and LeIF genes was evaluated using cDNA synthesis and RT-qPCR analysis. Results Frequency of Phlebotomus papatasi was predominant in plains areas of Mountainous bioclimate covering the CL hot spots. Mediterranean region was recognized as an important bioclimate harboring prevalent patterns of VL vectors. Semi-arid bioclimate was identified as a major contributing factor to up-regulate salivary-SP15 gene expression (P = 0.0050, P < 0.05). Also, Mediterranean bioclimate had considerable effect on up-regulation of Leishmania-LeIF gene in gravid and semi-gravid P. papatasi population (P = 0.0109, P < 0.05). Conclusions The diversity and spatial distribution of CL/VL vectors associated with bioclimatic regionalization obtained in our research provide epidemiological risk maps and establish more effectively control measures against leishmaniasis. Oscillations in gene expression indicate that each gene has its own features, which are profoundly affected by bioclimatic characteristics and physiological status of sand flies. Given the efficacy of species-specific antigens for vaccine production, it is essential to consider bioclimatic factors that have a fundamental role in affecting the regulatory regions of environmentally responsive loci for genes used in vaccine design.

scholarly journals Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice

2008 ◽  
Vol 295 (1) ◽  
pp. G45-G53 ◽  
Author(s):  
Bin Hu ◽  
Lisa M. Colletti
Keyword(s):  
Stem Cell ◽  
Liver Injury ◽  
Stem Cell Factor ◽  
Cellular Proliferation ◽  
Hepatocyte Proliferation ◽  
Mrna Levels ◽  
Wild Type ◽  
Hepatocyte Apoptosis ◽  
Large Reservoir ◽  
A Cell

Stem cell factor (SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. c-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF, and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen (APAP)-induced liver injury in C57BL/6J mice or SCF-deficient sl-sld mice and their appropriate wild-type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 h postinjury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 h post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild-type mice; furthermore, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. Bromodeoxyuridine incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 h in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bcl-xL expression, suggesting that this decrease in hepatocyte apoptosis is mediated through Bcl-2 and Bcl-xL. In summary, SCF and c-kit expression was increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation, and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries.

scholarly journals Effects of the domestic thyroid stimulating hormone receptor (TSHR) variant on the hypothalamic-pituitary-thyroid axis and behavior in chicken

Genetics ◽  
2021 ◽  
Vol 217 (1) ◽  
Author(s):  
Amir Fallahshahroudi ◽  
Martin Johnsson ◽  
Enrico Sorato ◽  
S J Kumari A Ubhayasekera ◽  
Jonas Bergquist ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hormone Receptor ◽  
Thyroid Stimulating Hormone ◽  
Phenotypic Traits ◽  
Wild Type ◽  
Data Set ◽  
Red Junglefowl ◽  
Pituitary Thyroid Axis ◽  
And Behavior ◽  
Stimulating Hormone

Abstract Domestic chickens are less fearful, have a faster sexual development, grow bigger, and lay more eggs than their primary ancestor, the red junglefowl. Several candidate genetic variants selected during domestication have been identified, but only a few studies have directly linked them with distinct phenotypic traits. Notably, a variant of the thyroid stimulating hormone receptor (TSHR) gene has been under strong positive selection over the past millennium, but it’s function and mechanisms of action are still largely unresolved. We therefore assessed the abundance of the domestic TSHR variant and possible genomic selection signatures in an extensive data set comprising multiple commercial and village chicken populations as well as wild-living extant members of the genus Gallus. Furthermore, by mean of extensive backcrossing we introgressed the wild-type TSHR variant from red junglefowl into domestic White Leghorn chickens and investigated gene expression, hormone levels, cold adaptation, and behavior in chickens possessing either the wild-type or domestic TSHR variant. While the domestic TSHR was the most common variant in all studied domestic populations and in one of two red junglefowl population, it was not detected in the other Gallus species. Functionally, the individuals with the domestic TSHR variant had a lower expression of the TSHR in the hypothalamus and marginally higher in the thyroid gland than wild-type TSHR individuals. Expression of TSHB and DIO2, two regulators of sexual maturity and reproduction in birds, was higher in the pituitary gland of the domestic-variant chickens. Furthermore, the domestic variant was associated with higher activity in the open field test. Our findings confirm that the spread of the domestic TSHR variant is limited to domesticated chickens, and to a lesser extent, their wild counterpart, the red junglefowl. Furthermore, we showed that effects of genetic variability in TSHR mirror key differences in gene expression and behavior previously described between the red junglefowl and domestic chicken.

scholarly journals The nucleoplasmic interactions among Lamin A/C-pRB-LAP2α-E2F1 are modulated by dexamethasone

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anastasia Ricci ◽  
Sara Orazi ◽  
Federica Biancucci ◽  
Mauro Magnani ◽  
Michele Menotta
Keyword(s):  
Gene Expression ◽  
Cell Cycle Progression ◽  
Regulation Of Gene Expression ◽  
Lamin A ◽  
Wild Type ◽  
Cycle Progression ◽  
C Dynamics ◽  
E2f Transcription Factor ◽  
Transcription Factor 1

AbstractAtaxia telangiectasia (AT) is a rare genetic neurodegenerative disease. To date, there is no available cure for the illness, but the use of glucocorticoids has been shown to alleviate the neurological symptoms associated with AT. While studying the effects of dexamethasone (dex) in AT fibroblasts, by chance we observed that the nucleoplasmic Lamin A/C was affected by the drug. In addition to the structural roles of A-type lamins, Lamin A/C has been shown to play a role in the regulation of gene expression and cell cycle progression, and alterations in the LMNA gene is cause of human diseases called laminopathies. Dex was found to improve the nucleoplasmic accumulation of soluble Lamin A/C and was capable of managing the large chromatin Lamin A/C scaffolds contained complex, thus regulating epigenetics in treated cells. In addition, dex modified the interactions of Lamin A/C with its direct partners lamin associated polypeptide (LAP) 2a, Retinoblastoma 1 (pRB) and E2F Transcription Factor 1 (E2F1), regulating local gene expression dependent on E2F1. These effects were differentially observed in both AT and wild type (WT) cells. To our knowledge, this is the first reported evidence of the role of dex in Lamin A/C dynamics in AT cells, and may represent a new area of research regarding the effects of glucocorticoids on AT. Moreover, future investigations could also be extended to healthy subjects or to other pathologies such as laminopathies since glucocorticoids may have other important effects in these contexts as well.

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