Project description:Transcriptomic profiling of normal mouse thyroid tissue following 211At irradiation Introduction The cellular response to stimuli can be studied on different molecular levels, including gene expression regulation. RNA microarray is a high-throughput technique that enables comparison of genome-wide transcriptional status between samples. 211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. Metabolically released 211At accumulates in the thyroid gland, which is one of the main critical organs for such therapy. The aim of this study was to determine the effect of absorbed dose, dose-rate, and time after 211At exposure on transcriptional expression in mouse thyroid gland. Method BALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq were killed after 1, 6, or 168 h with mean absorbed doses to thyroid of 0.023, 0.32, and 1.4 Gy, respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively, resulting in mean absorbed doses to thyroid of 1.4 Gy. Animals were killed through cardiac puncture under anesthesia, and thyroids were removed and snap-frozen. Total RNA was extracted from pooled thyroid tissue samples and mRNA levels were determined with the Illumina RNA microarray platform. Nexus Expression 3.0 was used to identify differentially expressed transcripts (adjusted p-value <0.01, fold change >1.5) and enriched GO terms (p-value <0.05) between irradiated groups and controls. Results In total, 1232 differentially expressed transcripts were detected after 211At administration, demonstrating a profound effect on gene regulation. The number of regulated transcripts increased with higher initial dose-rate/absorbed dose when the exposure time was 1 or 6 h. However, the number of regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. This suggests that initial dose-rate (thus injected activity) is an important parameter in radiation-induced responses. Furthermore, the regulation profiles of groups administered 1.7 kBq were similar. Few previously proposed radiation responsive genes were identified in the present study, but, e.g. Gadd45g and Cdkn1a were among the regulated genes identified in the present study. A response involving immunological processes was identified especially at 1, 6, and 168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy). Conclusion The present study allowed a comprehensive assessment of how variations in exposure parameters affect transcriptional regulation. The regulation profiles were dependent on both absorbed dose and time after exposure, but, initial dose-rate was the most influential parameter. Functional annotation of regulated genes revealed exposure-specific effects on biological processes. Additionally, we have identified several recurrently regulated genes after 211At exposure that may play a role in how mouse thyroid tissue responds to 211At exposure. Introduction The cellular response to stimuli can be studied on different molecular levels, including gene expression regulation. RNA microarray is a high-throughput technique that enables comparison of genome-wide transcriptional status between samples. 211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. Metabolically released 211At accumulates in the thyroid gland, which is one of the main critical organs for such therapy. The aim of this study was to determine the effect of absorbed dose, dose-rate, and time after 211At exposure on transcriptional expression in mouse thyroid gland. Method BALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq were killed after 1, 6, or 168 h with mean absorbed doses to thyroid of 0.023, 0.32, and 1.4 Gy, respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively, resulting in mean absorbed doses to thyroid of 1.4 Gy. Animals were killed through cardiac puncture under anesthesia, and thyroids were removed and snap-frozen. Total RNA was extracted from pooled thyroid tissue samples and mRNA levels were determined with the Illumina RNA microarray platform. Nexus Expression 3.0 was used to identify differentially expressed transcripts (adjusted p-value <0.01, fold change >1.5) and enriched GO terms (p-value <0.05) between irradiated groups and controls. Results In total, 1232 differentially expressed transcripts were detected after 211At administration, demonstrating a profound effect on gene regulation. The number of regulated transcripts increased with higher initial dose-rate/absorbed dose when the exposure time was 1 or 6 h. However, the number of regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. This suggests that initial dose-rate (thus injected activity) is an important parameter in radiation-induced responses. Furthermore, the regulation profiles of groups administered 1.7 kBq were similar. Few previously proposed radiation responsive genes were identified in the present study, but, e.g. Gadd45g and Cdkn1a were among the regulated genes identified in the present study. A response involving immunological processes was identified especially at 1, 6, and 168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy). Conclusion The present study allowed a comprehensive assessment of how variations in exposure parameters affect transcriptional regulation. The regulation profiles were dependent on both absorbed dose and time after exposure, but, initial dose-rate was the most influential parameter. Functional annotation of regulated genes revealed exposure-specific effects on biological processes. Additionally, we have identified several recurrently regulated genes after 211At exposure that may play a role in how mouse thyroid tissue responds to 211At exposure. Total RNA was isolated from fresh-frozen tissue samples (Normal balb/c mouse thyroids)

Project description:Transcriptomic profiling of normal mouse thyroid tissue following 211At irradiation Introduction The cellular response to stimuli can be studied on different molecular levels, including gene expression regulation. RNA microarray is a high-throughput technique that enables comparison of genome-wide transcriptional status between samples. 211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. Metabolically released 211At accumulates in the thyroid gland, which is one of the main critical organs for such therapy. The aim of this study was to determine the effect of absorbed dose, dose-rate, and time after 211At exposure on transcriptional expression in mouse thyroid gland. Method BALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq were killed after 1, 6, or 168 h with mean absorbed doses to thyroid of 0.023, 0.32, and 1.4 Gy, respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively, resulting in mean absorbed doses to thyroid of 1.4 Gy. Animals were killed through cardiac puncture under anesthesia, and thyroids were removed and snap-frozen. Total RNA was extracted from pooled thyroid tissue samples and mRNA levels were determined with the Illumina RNA microarray platform. Nexus Expression 3.0 was used to identify differentially expressed transcripts (adjusted p-value <0.01, fold change >1.5) and enriched GO terms (p-value <0.05) between irradiated groups and controls. Results In total, 1232 differentially expressed transcripts were detected after 211At administration, demonstrating a profound effect on gene regulation. The number of regulated transcripts increased with higher initial dose-rate/absorbed dose when the exposure time was 1 or 6 h. However, the number of regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. This suggests that initial dose-rate (thus injected activity) is an important parameter in radiation-induced responses. Furthermore, the regulation profiles of groups administered 1.7 kBq were similar. Few previously proposed radiation responsive genes were identified in the present study, but, e.g. Gadd45g and Cdkn1a were among the regulated genes identified in the present study. A response involving immunological processes was identified especially at 1, 6, and 168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy). Conclusion The present study allowed a comprehensive assessment of how variations in exposure parameters affect transcriptional regulation. The regulation profiles were dependent on both absorbed dose and time after exposure, but, initial dose-rate was the most influential parameter. Functional annotation of regulated genes revealed exposure-specific effects on biological processes. Additionally, we have identified several recurrently regulated genes after 211At exposure that may play a role in how mouse thyroid tissue responds to 211At exposure. Introduction The cellular response to stimuli can be studied on different molecular levels, including gene expression regulation. RNA microarray is a high-throughput technique that enables comparison of genome-wide transcriptional status between samples. 211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. Metabolically released 211At accumulates in the thyroid gland, which is one of the main critical organs for such therapy. The aim of this study was to determine the effect of absorbed dose, dose-rate, and time after 211At exposure on transcriptional expression in mouse thyroid gland. Method BALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq were killed after 1, 6, or 168 h with mean absorbed doses to thyroid of 0.023, 0.32, and 1.4 Gy, respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively, resulting in mean absorbed doses to thyroid of 1.4 Gy. Animals were killed through cardiac puncture under anesthesia, and thyroids were removed and snap-frozen. Total RNA was extracted from pooled thyroid tissue samples and mRNA levels were determined with the Illumina RNA microarray platform. Nexus Expression 3.0 was used to identify differentially expressed transcripts (adjusted p-value <0.01, fold change >1.5) and enriched GO terms (p-value <0.05) between irradiated groups and controls. Results In total, 1232 differentially expressed transcripts were detected after 211At administration, demonstrating a profound effect on gene regulation. The number of regulated transcripts increased with higher initial dose-rate/absorbed dose when the exposure time was 1 or 6 h. However, the number of regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. This suggests that initial dose-rate (thus injected activity) is an important parameter in radiation-induced responses. Furthermore, the regulation profiles of groups administered 1.7 kBq were similar. Few previously proposed radiation responsive genes were identified in the present study, but, e.g. Gadd45g and Cdkn1a were among the regulated genes identified in the present study. A response involving immunological processes was identified especially at 1, 6, and 168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy). Conclusion The present study allowed a comprehensive assessment of how variations in exposure parameters affect transcriptional regulation. The regulation profiles were dependent on both absorbed dose and time after exposure, but, initial dose-rate was the most influential parameter. Functional annotation of regulated genes revealed exposure-specific effects on biological processes. Additionally, we have identified several recurrently regulated genes after 211At exposure that may play a role in how mouse thyroid tissue responds to 211At exposure.

Project description:Pappalardo2016 - PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer This model is described in the article: Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer. Pappalardo F, Russo G, Candido S, Pennisi M, Cavalieri S, Motta S, McCubrey JA, Nicoletti F, Libra M. PLoS ONE 2016; 11(3): e0152104 Abstract: Malignant melanoma is an aggressive tumor of the skin and seems to be resistant to current therapeutic approaches. Melanocytic transformation is thought to occur by sequential accumulation of genetic and molecular alterations able to activate the Ras/Raf/MEK/ERK (MAPK) and/or the PI3K/AKT (AKT) signalling pathways. Specifically, mutations of B-RAF activate MAPK pathway resulting in cell cycle progression and apoptosis prevention. According to these findings, MAPK and AKT pathways may represent promising therapeutic targets for an otherwise devastating disease.Here we show a computational model able to simulate the main biochemical and metabolic interactions in the PI3K/AKT and MAPK pathways potentially involved in melanoma development. Overall, this computational approach may accelerate the drug discovery process and encourages the identification of novel pathway activators with consequent development of novel antioncogenic compounds to overcome tumor cell resistance to conventional therapeutic agents. The source code of the various versions of the model are available as S1 Archive. This model is hosted on BioModels Database and identified by: MODEL1609190000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Hyperactivation of the PI3K/AKT pathway is observed in most NSCLCs, promoting proliferation, migration and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of the positive regulator phosphatydil-inositol-3â phosphate kinase (PIK3CA) and/or mutations of AKT1 itself. However, whereas the effects of AKT activation on mRNAs and proteins in the cell are fairly clear, the role of miRNAs as downstream targets of activated PI3K/AKT signalling is still poorly defined so far. To identify miRNAs that are targets of constitutive signalling of PI3K/AKT in lung cancer cells, we performed miRNA profiling of human lung epithelial cells expressing active mutant AKT1 (E17K), active mutant PI3KCA (E545K) or that are silenced for PTEN. We identified 28 differentially expressed miRNAs (8 up-regulated, 20 down-regulated) that were common to BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells. Among the 8 up-regulated miRNAs that were common to all the alterations, the miRNA most consistently up-regulated by activation of the PI3K/AKT pathway in BEAS-2B cells was miR-196a. The results reported here demonstrate that miR-196a acts as oncogene downstream the PI3K/AKT pathway, mediating the proliferative, pro-migratory and tumorigenic activity of this pathway in NSCLC cells by targeting FoxO1 and p27 expression. By adoptive expression of miR-196a in BEAS-2B cells, we demonstrated that miR-196a stimulates anchorage-dependent and -independent proliferation, migration and tumorigenicity in BEAS-2B cells. On the other hand, by use of antimir-196a in NCI-H460 cells to silence the endogenous expression of miR-196a, we demonstrate that miR-196a plays a pivotal role in mediating the stimulation of proliferation, migration and tumorigenicity induced by aberrant activation of PI3K/AKT signalling. Accordingly, we found that miR-196a was significantly overexpressed in human NSCLC-derived cell lines (n=6) and primary lung cancer samples (n=28). Finally, based on predicted binding sites for miR-196a by microRNA analysis software, we found that miR-196a affects protein levels of FoxO1 and p27 in NSCLC cells.

			Action	DRS
	a_MTBLS15015_LC-MS_alternating_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS15015_LC-MS_alternating_reverse-phase_v2_maf.tsv	Tabular
	s_MTBLS15015.txt	Txt

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Xiaoyukang Capsules Promote Hematoma Absorption and Alleviate Neuronal Apoptosis via the Sema3A/NRP1-PI3K/AKT Signaling Axis in Rats with Intracerebral Hemorrhage

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