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Article: Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives.

Hafezi, Shirin / Rahmani, Mohamed

2021 Volume 13, Issue 6

Abstract: The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the ... ...

Abstract	The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer.
Language	English
Publishing date	2021-03-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13061292
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Article: PROTACs: Walking through hematological malignancies.

Bou Malhab, Lara J / Alsafar, Habiba / Ibrahim, Saleh / Rahmani, Mohamed

Frontiers in pharmacology

2023 Volume 14, Page(s) 1086946

Abstract: Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that uses the proteasome ubiquitin system to target proteins of interest and promote their degradation with remarkable selectivity. Importantly, unlike conventional small ... ...

Abstract	Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that uses the proteasome ubiquitin system to target proteins of interest and promote their degradation with remarkable selectivity. Importantly, unlike conventional small molecule inhibitors, PROTACs have proven highly effective in targeting undruggable proteins and those bearing mutations. Because of these considerations, PROTACs have increasingly become an emerging technology for the development of novel targeted anticancer therapeutics. Interestingly, many PROTACs have demonstrated a great potency and specificity in degrading several oncogenic drivers. Many of these, following extensive preclinical evaluation, have reached advanced stages of clinical testing in various cancers including hematologic malignancies. In this review, we provide a comprehensive summary of the recent advances in the development of PROTACs as therapeutic strategies in diverse hematological malignancies. A particular attention has been given to clinically relevant PROTACs and those targeting oncogenic mutants that drive resistance to therapies. We also discus limitations, and various considerations to optimize the design for effective PROTACs.
Language	English
Publishing date	2023-02-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1086946
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Article ; Online: Interaction between mitochondria and microbiota modulating cellular metabolism in inflammatory bowel disease.

Hirose, Misa / Sekar, Priyadharshini / Eladham, Mariam Wed Abdelaziz / Albataineh, Mohammad T / Rahmani, Mohamed / Ibrahim, Saleh Mohamed

Journal of molecular medicine (Berlin, Germany)

2023 Volume 101, Issue 12, Page(s) 1513–1526

Abstract: Inflammatory bowel disease (IBD) is a prototypic complex disease in the gastrointestinal tract that has been increasing in incidence and prevalence in recent decades. Although the precise pathophysiology of IBD remains to be elucidated, a large body of ... ...

Abstract	Inflammatory bowel disease (IBD) is a prototypic complex disease in the gastrointestinal tract that has been increasing in incidence and prevalence in recent decades. Although the precise pathophysiology of IBD remains to be elucidated, a large body of evidence suggests the critical roles of mitochondria and intestinal microbiota in the pathogenesis of IBD. In addition to their contributions to the disease, both mitochondria and gut microbes may interact with each other and modulate disease-causing cell activities. Therefore, we hypothesize that dissecting this unique interaction may help to identify novel pathways involved in IBD, which will further contribute to discovering new therapeutic approaches to the disease. As poorly treated IBD significantly affects the quality of life of patients and is associated with risks and complications, successful treatment is crucial. In this review, we stratify previously reported experimental and clinical observations of the role of mitochondria and intestinal microbiota in IBD. Additionally, we review the intercommunication between mitochondria, and the intestinal microbiome in patients with IBD is reviewed along with the potential mediators for these interactions. We specifically focus on their roles in cellular metabolism in intestinal epithelial cells and immune cells. To this end, we propose a potential therapeutic intervention strategy for IBD.
MeSH term(s)	Humans ; Quality of Life ; Inflammatory Bowel Diseases/metabolism ; Microbiota ; Mitochondria/metabolism
Language	English
Publishing date	2023-10-11
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1223802-8
ISSN	1432-1440 ; 0946-2716
ISSN (online)	1432-1440
ISSN	0946-2716
DOI	10.1007/s00109-023-02381-w
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Article ; Online: The 14-Kilodalton Human Growth Hormone Fragment a Potent Inhibitor of Angiogenesis and Tumor Metastasis.

Shaker, Baraah Tariq / Ismail, Asmaa Anwar / Salih, Rawan / Hadj Kacem, Hassen / Rahmani, Mohamed / Struman, Ingrid / Bajou, Khalid

International journal of molecular sciences

2023 Volume 24, Issue 10

Abstract: The 14-kilodalton human growth hormone (14 kDa hGH) N-terminal fragment derived from the proteolytic cleavage of its full-length counterpart has been shown to sustain antiangiogenic potentials. This study investigated the antitumoral and antimetastatic ... ...

Abstract	The 14-kilodalton human growth hormone (14 kDa hGH) N-terminal fragment derived from the proteolytic cleavage of its full-length counterpart has been shown to sustain antiangiogenic potentials. This study investigated the antitumoral and antimetastatic effects of 14 kDa hGH on B16-F10 murine melanoma cells. B16-F10 murine melanoma cells transfected with 14 kDa hGH expression vectors showed a significant reduction in cellular proliferation and migration associated with an increase in cell apoptosis in vitro. In vivo, 14 kDa hGH mitigated tumor growth and metastasis of B16-F10 cells and was associated with a significant reduction in tumor angiogenesis. Similarly, 14 kDa hGH expression reduced human brain microvascular endothelial (HBME) cell proliferation, migration, and tube formation abilities and triggered apoptosis in vitro. The antiangiogenic effects of 14 kDa hGH on HBME cells were abolished when we stably downregulated plasminogen activator inhibitor-1 (PAI-1) expression in vitro. In this study, we showed the potential anticancer role of 14 kDa hGH, its ability to inhibit primary tumor growth and metastasis establishment, and the possible involvement of PAI-1 in promoting its antiangiogenic effects. Therefore, these results suggest that the 14 kDa hGH fragment can be used as a therapeutic molecule to inhibit angiogenesis and cancer progression.
MeSH term(s)	Mice ; Humans ; Animals ; Human Growth Hormone/metabolism ; Plasminogen Activator Inhibitor 1 ; Cell Proliferation ; Melanoma
Chemical Substances	Human Growth Hormone (12629-01-5) ; Plasminogen Activator Inhibitor 1
Language	English
Publishing date	2023-05-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24108877
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Article ; Online: 1

Shakartalla, Sarra B / Ashmawy, Naglaa S / Semreen, Mohammad H / Fayed, Bahgat / Al Shareef, Zainab M / Jayakumar, Manju N / Ibrahim, Saleh / Rahmani, Mohamed / Hamdy, Rania / Soliman, Sameh S M

Scientific reports

2024 Volume 14, Issue 1, Page(s) 253

Abstract: Breast cancer is one of the leading causes of death in females, mainly because of metastasis. Oncometabolites, produced via metabolic reprogramming, can influence metastatic signaling cascades. Accordingly, and based on our previous results, we propose ... ...

Abstract	Breast cancer is one of the leading causes of death in females, mainly because of metastasis. Oncometabolites, produced via metabolic reprogramming, can influence metastatic signaling cascades. Accordingly, and based on our previous results, we propose that metabolites from highly metastatic breast cancer cells behave differently from less-metastatic cells and may play a significant role in metastasis. For instance, we aim to identify these metabolites and their role in breast cancer metastasis. Less metastatic cells (MCF-7) were treated with metabolites secreted from highly metastatic cells (MDA-MB-231) and the gene expression of three epithelial-to-mesenchymal transition (EMT) markers including E-cadherin, N-cadherin and vimentin were examined. Some metabolites secreted from MDA-MB-231 cells significantly induced EMT activity. Specifically, hypoxanthine demonstrated a significant EMT effect and increased the migration and invasion effects of MCF-7 cells through a hypoxia-associated mechanism. Hypoxanthine exhibited pro-angiogenic effects via increasing the VEGF and PDGF gene expression and affected lipid metabolism by increasing the gene expression of PCSK-9. Notably, knockdown of purine nucleoside phosphorylase, a gene encoding for an important enzyme in the biosynthesis of hypoxanthine, and inhibition of hypoxanthine uptake caused a significant decrease in hypoxanthine-associated EMT effects. Collectively for the first time, hypoxanthine was identified as a novel metastasis-associated metabolite in breast cancer cells and represents a promising target for diagnosis and therapy.
MeSH term(s)	Female ; Humans ; Breast Neoplasms/pathology ; Proton Magnetic Resonance Spectroscopy ; MCF-7 Cells ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition/genetics ; Cell Movement ; Hypoxanthines/pharmacology
Chemical Substances	Hypoxanthines
Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-50866-y
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Article: Techno-economic assessment of quinoa production and transformation in Morocco

Rafik, Sifeddine / Rahmani, Mohamed / Choukr-Allah, Redouane / El Gharous, Mohamed / Calle, Juan Pablo Rodriguez / Filali, Kaoutar / Hirich, Abdelaziz

Environmental science and pollution research. 2021 Sept., v. 28, no. 34

2021

Abstract: Agriculture is facing many challenges as climate change, drought, and salinity which call for urgent interventions to fast adaptation and diversification such as the introduction of new climate smart and stress tolerant crops such as quinoa. This study ... ...

Abstract	Agriculture is facing many challenges as climate change, drought, and salinity which call for urgent interventions to fast adaptation and diversification such as the introduction of new climate smart and stress tolerant crops such as quinoa. This study aims to introduce new high yielding quinoa cultivars conducted under several agronomic practices (rainfed, irrigation, and organic amendment) and to assess the technical and economic aspects related to quinoa seed production, transformation, and quality. Results obtained from agronomic trials clearly showed that International Center for Biosaline Agriculture cultivars recorded higher yields than locally cultivated seeds. Irrigation and organic amendment had a tremendous effect on quinoa productivity as it increased most of cultivar’s yield by more than three times compared with rainfed conditions. Production cost analysis showed that using mechanized production and processing practices combined with irrigation and organic amendment can reduce seed production and processing cost from 2.8 to 1.2 USD kg⁻¹ compared with manual production system under rainfed conditions. The diagnosis of the quinoa transformation pathways revealed different transformation levels, and the production cost increased with the level of transformation due to high cost of labor and raw material. Analysis of quinoa seeds showed that macronutrient content is mostly not affected by pearling process, while micronutrients content was significantly decreased in processed seeds. In addition, total saponin content was reduced to an acceptable level after using mechanical pearling compared with manual abrasion.
Keywords	climate ; climate change ; cost analysis ; cultivars ; drought ; irrigation ; labor ; mechanization ; pollution ; raw materials ; research ; salinity ; saponins ; Morocco
Language	English
Dates of publication	2021-09
Size	p. 46781-46796.
Publishing place	Springer Berlin Heidelberg
Document type	Article
ZDB-ID	1178791-0
ISSN	1614-7499 ; 0944-1344
ISSN (online)	1614-7499
ISSN	0944-1344
DOI	10.1007/s11356-021-12665-8
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Article: Enriched transcriptome analysis of laser capture microdissected populations of single cells to investigate intracellular heterogeneity in immunostained FFPE sections

Hammoudeh, Sarah M. / Hammoudeh, Arabella M. / Venkatachalam, Thenmozhi / Rawat, Surendra / Jayakumar, Manju N. / Rahmani, Mohamed / Hamoudi, Rifat

Computational and Structural Biotechnology Journal. 2021, v. 19

2021

Abstract: To investigate intracellular heterogeneity, cell capture of particular cell populations followed by transcriptome analysis has been highly effective in freshly isolated tissues. However, this approach has been quite challenging in immunostained formalin- ... ...

Abstract	To investigate intracellular heterogeneity, cell capture of particular cell populations followed by transcriptome analysis has been highly effective in freshly isolated tissues. However, this approach has been quite challenging in immunostained formalin-fixed paraffin-embedded (FFPE) sections. This study aimed at combining the standard pathology techniques, immunostaining and laser capture microdissection, with whole RNA-sequencing and bioinformatics analysis to characterize FFPE breast cancer cell populations with heterogeneous expression of progesterone receptor (PR). Immunocytochemical analysis revealed that 60% of MCF-7 cells admixture highly express PR. Immunocytochemistry-based targeted RNA-seq (ICC-RNAseq) and in silico functional analysis revealed that the PR-high cell population is associated with upregulation in transcripts implicated in immunomodulatory and inflammatory pathways (e.g. NF-κB and interferon signaling). In contrast, the PR-low cell population is associated with upregulation of genes involved in metabolism and mitochondrial processes as well as EGFR and MAPK signaling. These findings were cross-validated and confirmed in FACS-sorted PR high and PR-low MCF-7 cells and in MDA-MB-231 cells ectopically overexpressing PR. Significantly, ICC-RNAseq could be extended to analyze samples captured at specific spatio-temporal states to investigate gene expression profiles using diverse biomarkers. This would also facilitate our understanding of cell population-specific molecular events driving cancer and potentially other diseases.
Keywords	bioinformatics ; biomarkers ; biotechnology ; breast neoplasms ; computer simulation ; interferons ; laser capture microdissection ; metabolism ; mitochondria ; neoplasm cells ; progesterone receptors ; sequence analysis ; transcriptomics
Language	English
Size	p. 5198-5209.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2021.09.010
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Article ; Online: Dual mTORC1/2 Inhibition Synergistically Enhances AML Cell Death in Combination with the BCL2 Antagonist Venetoclax.

Satta, Toshihisa / Li, Lin / Chalasani, Sri Lakshmi / Hu, Xiaoyan / Nkwocha, Jewel / Sharma, Kanika / Kmieciak, Maciej / Rahmani, Mohamed / Zhou, Liang / Grant, Steven

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 7, Page(s) 1332–1343

Abstract: Purpose: Acute myelogenous leukemia (AML) is an aggressive disease with a poor outcome. We investigated mechanisms by which the anti-AML activity of ABT-199 (venetoclax) could be potentiated by dual mTORC1/TORC2 inhibition.: Experimental design: ... ...

Abstract	Purpose: Acute myelogenous leukemia (AML) is an aggressive disease with a poor outcome. We investigated mechanisms by which the anti-AML activity of ABT-199 (venetoclax) could be potentiated by dual mTORC1/TORC2 inhibition. Experimental design: Venetoclax/INK128 synergism was assessed in various AML cell lines and primary patient AML samples in vitro. AML cells overexpressing MCL-1, constitutively active AKT, BAK, and/or BAX knockout, and acquired venetoclax resistance were investigated to define mechanisms underlying interactions. The antileukemic efficacy of this regimen was also examined in xenograft and patient-derived xenograft (PDX) models. Results: Combination treatment with venetoclax and INK128 (but not the mTORC1 inhibitor rapamycin) dramatically enhanced cell death in AML cell lines. Synergism was associated with p-AKT and p-4EBP1 downregulation and dependent upon MCL-1 downregulation and BAK/BAX upregulation as MCL-1 overexpression and BAX/BAK knockout abrogated cell death. Constitutive AKT activation opposed synergism between venetoclax and PI3K or AKT inhibitors, but not INK128. Combination treatment also synergistically induced cell death in venetoclax-resistant AML cells. Similar events occurred in primary patient-derived leukemia samples but not normal CD34+ cells. Finally, venetoclax and INK128 co-treatment displayed increased antileukemia effects in in vivo xenograft and PDX models. Conclusions: The venetoclax/INK128 regimen exerts significant antileukemic activity in various preclinical models through mechanisms involving MCL-1 downregulation and BAK/BAX activation, and offers potential advantages over PI3K or AKT inhibitors in cells with constitutive AKT activation. This regimen is active against primary and venetoclax-resistant AML cells, and in in vivo AML models. Further investigation of this strategy appears warranted.
MeSH term(s)	Humans ; Proto-Oncogene Proteins c-bcl-2 ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism ; Proto-Oncogene Proteins c-akt ; Cell Line, Tumor ; Apoptosis ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Cell Death ; Phosphatidylinositol 3-Kinases/metabolism
Chemical Substances	Proto-Oncogene Proteins c-bcl-2 ; venetoclax (N54AIC43PW) ; Myeloid Cell Leukemia Sequence 1 Protein ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; bcl-2-Associated X Protein ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Bridged Bicyclo Compounds, Heterocyclic ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; BCL2 protein, human
Language	English
Publishing date	2023-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-2729
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Article: Studying the ShcD and ERK interaction under acute oxidative stress conditions in melanoma cells

Ahmed, Samrein B.M / Amer, Sara / Emad, Mira / Rahmani, Mohamed / Prigent, Sally A

international journal of biochemistry & cell biology. 2019 July, v. 112

2019

Abstract: The newly identified melanoma-associated adaptor ShcD was found to translocate to the nucleus upon hydrogen peroxide treatment. Therefore, the aim of this study was to identify the ShcD network in melanoma cells under oxidative stress. LC–MS/MS and GFP- ... ...

Abstract	The newly identified melanoma-associated adaptor ShcD was found to translocate to the nucleus upon hydrogen peroxide treatment. Therefore, the aim of this study was to identify the ShcD network in melanoma cells under oxidative stress. LC–MS/MS and GFP-trap were performed to study the ShcD phosphorylation status during acute severe oxidative stress. ShcD was found to be phosphorylated at threonine-159 (Thr159) in response to 5 mM H2O2 treatment. The GPS 2.1 phosphorylation prediction program predicted that the Thr159Pro motif, housed in the N-terminus of the ShcD-CH2 domain, is a potential phosphorylation site for MAPKs (ERK, JNK or p38). Co-immunoprecipitation experiments revealed that ShcD mainly interacts with ERK in B16 and MM138 melanoma cells under both hydrogen peroxide-untreated and -treated conditions. Moreover, ShcD interacts with both phosphorylated and un-phosphorylated ERK, although the interaction between ShcD and phospho-ERK was primarily observed after H2O2 treatment. A MEK inhibitor (U0126) enhanced the interaction between ShcD and unphosphorylated ERK under oxidative stress conditions. Furthermore, Thr159 was mutated to either alanine (A) or glutamic acid (E) to study whether the threonine phosphorylation state influences the ShcD/ERK interaction. Introducing the T159E mutation obliterated the ShcD/ERK interaction. To identify the functional impact of the ShcD/ERK interaction on cell survival signalling under oxidative stress conditions, caspase 3/7 assays and 7AAD cell death assays were used. The ShcD/ERK interaction promoted anti-survival signalling upon exposure to hydrogen peroxide, while U0126 treatment reduced death signalling. Our data also showed that the death signalling initiated by the ShcD/ERK interaction was accompanied by p21 phosphorylation. In summary, these data identified ShcD, via its interaction with ERK, as a proapoptotic protein under oxidative stress conditions.
Keywords	alanine ; apoptosis ; caspases ; cell viability ; death ; global positioning systems ; glutamic acid ; hydrogen ; hydrogen peroxide ; liquid chromatography ; melanoma ; mitogen-activated protein kinase ; mutation ; oxidative stress ; phosphorylation ; precipitin tests ; prediction ; tandem mass spectrometry ; threonine
Language	English
Dates of publication	2019-07
Size	p. 123-133.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2019.05.009
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Article: Enriched transcriptome analysis of laser capture microdissected populations of single cells to investigate intracellular heterogeneity in immunostained FFPE sections.

Hammoudeh, Sarah M / Hammoudeh, Arabella M / Venkatachalam, Thenmozhi / Rawat, Surendra / Jayakumar, Manju N / Rahmani, Mohamed / Hamoudi, Rifat

Computational and structural biotechnology journal

2021 Volume 19, Page(s) 5198–5209

Abstract	To investigate intracellular heterogeneity, cell capture of particular cell populations followed by transcriptome analysis has been highly effective in freshly isolated tissues. However, this approach has been quite challenging in immunostained formalin-fixed paraffin-embedded (FFPE) sections. This study aimed at combining the standard pathology techniques, immunostaining and laser capture microdissection, with whole RNA-sequencing and bioinformatics analysis to characterize FFPE breast cancer cell populations with heterogeneous expression of progesterone receptor (PR). Immunocytochemical analysis revealed that 60% of MCF-7 cells admixture highly express PR. Immunocytochemistry-based targeted RNA-seq (ICC-RNAseq) and in silico functional analysis revealed that the PR-high cell population is associated with upregulation in transcripts implicated in immunomodulatory and inflammatory pathways (e.g. NF-κB and interferon signaling). In contrast, the PR-low cell population is associated with upregulation of genes involved in metabolism and mitochondrial processes as well as EGFR and MAPK signaling. These findings were cross-validated and confirmed in FACS-sorted PR high and PR-low MCF-7 cells and in MDA-MB-231 cells ectopically overexpressing PR. Significantly, ICC-RNAseq could be extended to analyze samples captured at specific spatio-temporal states to investigate gene expression profiles using diverse biomarkers. This would also facilitate our understanding of cell population-specific molecular events driving cancer and potentially other diseases.
Language	English
Publishing date	2021-09-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2021.09.010
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