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Article ; Online: Current views on inducing synthetic lethal RNAi responses in the treatment of cancer.

Kacsinta, Apollo D / Dowdy, Steven F

2016 Volume 16, Issue 2, Page(s) 161–172

Abstract: Introduction: Cancer cells arise from normal cells that have incurred mutations in oncogenes and tumor suppressor genes. The mutations are often unique and not readily found in normal cells, giving rise to the opportunity of exploiting these mutations ... ...

Abstract	Introduction: Cancer cells arise from normal cells that have incurred mutations in oncogenes and tumor suppressor genes. The mutations are often unique and not readily found in normal cells, giving rise to the opportunity of exploiting these mutations to induce synthetic lethality. Synthetic lethality occurs when inhibition or mutation in two or more separate genes leads to cell death while inhibition or mutations of either gene alone has no lethal effect on the cell. Using RNA interference (RNAi) to identify synthetic lethality has become a growingly popular screening approach. Areas covered: In this review, we cover the use of RNAi therapeutics to induce synthetic lethality in cancer. Additionally, we discuss several select small molecule inhibitors that were identified or verified by RNAi that induce synthetic lethality in specific cancers. We also discuss the identification of novel synthetic lethal combinations and the cancer model that the combination was validated in. Lastly, we discuss RNAi delivery vehicles. Expert opinion: While RNAi therapeutics have great potential to treat cancer, due to the siRNA delivery problem, RNAi remains more commonly used as a tool, rather than a therapeutic. However, with emerging technological advances in the field of RNAi therapeutics, it is only a matter of time before RNAi-induced synthetic lethal clinical studies are initiated in cancer patients.
MeSH term(s)	Animals ; Gene Transfer Techniques/trends ; Genes, Synthetic/genetics ; Humans ; Mutation/genetics ; Neoplasms/genetics ; Neoplasms/therapy ; Oncogenes/genetics ; RNA Interference/physiology ; RNA, Small Interfering/administration & dosage ; RNA, Small Interfering/genetics ; Treatment Outcome
Chemical Substances	RNA, Small Interfering
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2052501-1
ISSN	1744-7682 ; 1471-2598
ISSN (online)	1744-7682
ISSN	1471-2598
DOI	10.1517/14712598.2016.1110141
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Inhibition of Allograft Inflammatory Factor-1 in Dendritic Cells Restrains CD4

Elizondo, Diana M / Andargie, Temesgen E / Yang, Dazhi / Kacsinta, Apollo D / Lipscomb, Michael W

Frontiers in immunology

2017 Volume 8, Page(s) 1502

Abstract: Allograft inflammatory factor-1 (AIF1) is a cytoplasmic scaffold protein shown to influence immune responses in macrophages and microglial cells. The protein contains ... ...

Abstract	Allograft inflammatory factor-1 (AIF1) is a cytoplasmic scaffold protein shown to influence immune responses in macrophages and microglial cells. The protein contains Ca
Language	English
Publishing date	2017-11-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2017.01502
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Article ; Online: Allograft Inflammatory Factor-1 Governs Hematopoietic Stem Cell Differentiation Into cDC1 and Monocyte-Derived Dendritic Cells Through IRF8 and RelB

Elizondo, Diana M / Brandy, Nailah Z D / da Silva, Ricardo L L / Haddock, Naomi L / Kacsinta, Apollo D / de Moura, Tatiana R / Lipscomb, Michael W

Frontiers in immunology

2019 Volume 10, Page(s) 173

Abstract: The multistep differentiation process from hematopoietic stem cells through common myeloid progenitors into committed dendritic cell (DC) subsets remains to be fully addressed. These studies now show that Allograft Inflammatory Factor-1 (AIF1) is ... ...

Abstract	The multistep differentiation process from hematopoietic stem cells through common myeloid progenitors into committed dendritic cell (DC) subsets remains to be fully addressed. These studies now show that Allograft Inflammatory Factor-1 (AIF1) is required for differentiation of classical DC type 1 (cDC1) subsets and monocyte-derived DC (Mo-DC). Phenotypic studies found that AIF1 expression increased in committed subsets differentiating from common myeloid progenitors (CMP). However, silencing AIF1 expression in hematopoietic stem progenitors restrained the capacity to differentiate into Mo-DC and cDC1 cell subsets under GM-CSF or Flt3-L stimuli conditions, respectively. This was further marked by restrained expression of IRF8, which is critical for development of Mo-DC and cDC1 subsets. As a result, absence of AIF1 restrained the cells at the Lin
MeSH term(s)	Animals ; Bone Marrow Cells/cytology ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/metabolism ; Cell Differentiation/drug effects ; Cell Differentiation/physiology ; Cells, Cultured ; Dendritic Cells/cytology ; Female ; Gene Knockdown Techniques ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Hematopoiesis/drug effects ; Hematopoietic Stem Cells/physiology ; Interferon Regulatory Factors/metabolism ; Male ; Membrane Proteins/pharmacology ; Mice ; Mice, Inbred C57BL ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Monocytes/cytology ; NF-kappa B p50 Subunit/metabolism ; Protein Kinase C/metabolism ; RNA, Small Interfering/genetics ; Transcription Factor RelB/metabolism ; Transfection ; p38 Mitogen-Activated Protein Kinases/metabolism
Chemical Substances	Aif1 protein, mouse ; Calcium-Binding Proteins ; Interferon Regulatory Factors ; Membrane Proteins ; Microfilament Proteins ; NF-kappa B p50 Subunit ; RNA, Small Interfering ; Relb protein, mouse ; flt3 ligand protein ; interferon regulatory factor-8 ; Nfkb1 protein, mouse (147257-52-1) ; Transcription Factor RelB (147337-75-5) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1) ; Protein Kinase C (EC 2.7.11.13) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2019-02-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.00173
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Enhancing Endosomal Escape for Intracellular Delivery of Macromolecular Biologic Therapeutics.

Lönn, Peter / Kacsinta, Apollo D / Cui, Xian-Shu / Hamil, Alexander S / Kaulich, Manuel / Gogoi, Khirud / Dowdy, Steven F

Scientific reports

2016 Volume 6, Page(s) 32301

Abstract: Bioactive macromolecular peptides and oligonucleotides have significant therapeutic potential. However, due to their size, they have no ability to enter the cytoplasm of cells. Peptide/Protein transduction domains (PTDs), also called cell-penetrating ... ...

Abstract	Bioactive macromolecular peptides and oligonucleotides have significant therapeutic potential. However, due to their size, they have no ability to enter the cytoplasm of cells. Peptide/Protein transduction domains (PTDs), also called cell-penetrating peptides (CPPs), can promote uptake of macromolecules via endocytosis. However, overcoming the rate-limiting step of endosomal escape into the cytoplasm remains a major challenge. Hydrophobic amino acid R groups are known to play a vital role in viral escape from endosomes. Here we utilize a real-time, quantitative live cell split-GFP fluorescence complementation phenotypic assay to systematically analyze and optimize a series of synthetic endosomal escape domains (EEDs). By conjugating EEDs to a TAT-PTD/CPP spilt-GFP peptide complementation assay, we were able to quantitatively measure endosomal escape into the cytoplasm of live cells via restoration of GFP fluorescence by intracellular molecular complementation. We found that EEDs containing two aromatic indole rings or one indole ring and two aromatic phenyl groups at a fixed distance of six polyethylene glycol (PEG) units from the TAT-PTD-cargo significantly enhanced cytoplasmic delivery in the absence of cytotoxicity. EEDs address the critical rate-limiting step of endosomal escape in delivery of macromolecular biologic peptide, protein and siRNA therapeutics into cells.
Language	English
Publishing date	2016-09-08
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/srep32301
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Article ; Online: Intracellular modifiers of integrin alpha 6p production in aggressive prostate and breast cancer cell lines.

Kacsinta, Apollo D / Rubenstein, Cynthia S / Sroka, Isis C / Pawar, Sangita / Gard, Jaime M / Nagle, Raymond B / Cress, Anne E

Biochemical and biophysical research communications

2014 Volume 454, Issue 2, Page(s) 335–340

Abstract: Cancer metastasis is a multi-step process in which tumor cells gain the ability to invade beyond the primary tumor and colonize distant sites. The mechanisms regulating the metastatic process confer changes to cell adhesion receptors including the ... ...

Abstract	Cancer metastasis is a multi-step process in which tumor cells gain the ability to invade beyond the primary tumor and colonize distant sites. The mechanisms regulating the metastatic process confer changes to cell adhesion receptors including the integrin family of receptors. Our group previously discovered that the α6 integrin (ITGA6/CD49f) is post translationally modified by urokinase plasminogen activator (uPA) and its receptor, urokinase plasminogen activator receptor (uPAR), to form the variant ITGA6p. This variant of ITGA6 is a cleaved form of the receptor that lacks the ligand-binding domain. Although it is established that the uPA/uPAR axis drives ITGA6 cleavage, the mechanisms regulating cleavage have not been defined. Intracellular integrin dependent "inside-out" signaling is a major regulator of integrin function and the uPA/uPAR axis. We hypothesized that intracellular signaling molecules play a role in formation of ITGA6p to promote cell migration during cancer metastasis. In order to test our hypothesis, DU145 and PC3B1 prostate cancer and MDA-MB-231 breast cancer cell lines were treated with small interfering RNA targeting actin and the intracellular signaling regulators focal adhesion kinase (FAK), integrin linked kinase (ILK), and paxillin. The results demonstrated that inhibition of actin, FAK, and ILK expression resulted in significantly increased uPAR expression and ITGA6p production. Inhibition of actin increased ITGA6p, although inhibition of paxillin did not affect ITGA6p formation. Taken together, these results suggest that FAK and ILK dependent "inside-out" signaling, and actin dynamics regulate extracellular production of ITGA6p and the aggressive phenotype.
MeSH term(s)	Actins/genetics ; Actins/metabolism ; Breast/metabolism ; Breast/pathology ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Movement ; Female ; Focal Adhesion Protein-Tyrosine Kinases/genetics ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Gene Expression Regulation, Neoplastic ; Genetic Variation ; Humans ; Integrin alpha6/analysis ; Integrin alpha6/genetics ; Integrin alpha6/metabolism ; Male ; Neoplasm Invasiveness/genetics ; Neoplasm Invasiveness/pathology ; Prostate/metabolism ; Prostate/pathology ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Receptors, Urokinase Plasminogen Activator/genetics ; Up-Regulation
Chemical Substances	Actins ; ITGA6 protein, human ; Integrin alpha6 ; RNA, Small Interfering ; Receptors, Urokinase Plasminogen Activator ; integrin-linked kinase (EC 2.7.1.-) ; Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2014-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2014.10.073
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Intracellular modifiers of integrin alpha 6p production in aggressive prostate and breast cancer cell lines

Kacsinta, Apollo D / Rubenstein, Cynthia S / Sroka, Isis C / Pawar, Sangita / Gard, Jaime M / Nagle, Raymond B / Cress, Anne E

Biochemical and biophysical research communications. 2014 Nov. 14, v. 454

2014

Abstract	Cancer metastasis is a multi-step process in which tumor cells gain the ability to invade beyond the primary tumor and colonize distant sites. The mechanisms regulating the metastatic process confer changes to cell adhesion receptors including the integrin family of receptors. Our group previously discovered that the α6 integrin (ITGA6/CD49f) is post translationally modified by urokinase plasminogen activator (uPA) and its receptor, urokinase plasminogen activator receptor (uPAR), to form the variant ITGA6p. This variant of ITGA6 is a cleaved form of the receptor that lacks the ligand-binding domain. Although it is established that the uPA/uPAR axis drives ITGA6 cleavage, the mechanisms regulating cleavage have not been defined. Intracellular integrin dependent “inside-out” signaling is a major regulator of integrin function and the uPA/uPAR axis. We hypothesized that intracellular signaling molecules play a role in formation of ITGA6p to promote cell migration during cancer metastasis. In order to test our hypothesis, DU145 and PC3B1 prostate cancer and MDA-MB-231 breast cancer cell lines were treated with small interfering RNA targeting actin and the intracellular signaling regulators focal adhesion kinase (FAK), integrin linked kinase (ILK), and paxillin. The results demonstrated that inhibition of actin, FAK, and ILK expression resulted in significantly increased uPAR expression and ITGA6p production. Inhibition of actin increased ITGA6p, although inhibition of paxillin did not affect ITGA6p formation. Taken together, these results suggest that FAK and ILK dependent “inside-out” signaling, and actin dynamics regulate extracellular production of ITGA6p and the aggressive phenotype.
Keywords	actin ; breast neoplasms ; cell adhesion ; cell movement ; integrins ; metastasis ; neoplasm cells ; non-specific protein-tyrosine kinase ; phenotype ; prostatic neoplasms ; receptors ; small interfering RNA ; translation (genetics) ; u-plasminogen activator
Language	English
Dates of publication	2014-1114
Size	p. 335-340.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2014.10.073
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications.

Meade, Bryan R / Gogoi, Khirud / Hamil, Alexander S / Palm-Apergi, Caroline / van den Berg, Arjen / Hagopian, Jonathan C / Springer, Aaron D / Eguchi, Akiko / Kacsinta, Apollo D / Dowdy, Connor F / Presente, Asaf / Lönn, Peter / Kaulich, Manuel / Yoshioka, Naohisa / Gros, Edwige / Cui, Xian-Shu / Dowdy, Steven F

Nature biotechnology

2014 Volume 32, Issue 12, Page(s) 1256–1261

Abstract: RNA interference (RNAi) has great potential to treat human disease. However, in vivo delivery of short interfering RNAs (siRNAs), which are negatively charged double-stranded RNA macromolecules, remains a major hurdle. Current siRNA delivery has begun to ...

Abstract	RNA interference (RNAi) has great potential to treat human disease. However, in vivo delivery of short interfering RNAs (siRNAs), which are negatively charged double-stranded RNA macromolecules, remains a major hurdle. Current siRNA delivery has begun to move away from large lipid and synthetic nanoparticles to more defined molecular conjugates. Here we address this issue by synthesis of short interfering ribonucleic neutrals (siRNNs) whose phosphate backbone contains neutral phosphotriester groups, allowing for delivery into cells. Once inside cells, siRNNs are converted by cytoplasmic thioesterases into native, charged phosphodiester-backbone siRNAs, which induce robust RNAi responses. siRNNs have favorable drug-like properties, including high synthetic yields, serum stability and absence of innate immune responses. Unlike siRNAs, siRNNs avidly bind serum albumin to positively influence pharmacokinetic properties. Systemic delivery of siRNNs conjugated to a hepatocyte-specific targeting domain induced extended dose-dependent in vivo RNAi responses in mice. We believe that siRNNs represent a technology that will open new avenues for development of RNAi therapeutics.
MeSH term(s)	Animals ; Drug Delivery Systems ; Humans ; Mice ; Nanoparticles/chemistry ; Nanoparticles/therapeutic use ; Prodrugs/chemistry ; Prodrugs/therapeutic use ; RNA, Small Interfering/chemistry ; RNA, Small Interfering/genetics ; RNA, Small Interfering/therapeutic use ; Serum Albumin/chemistry
Chemical Substances	Prodrugs ; RNA, Small Interfering ; Serum Albumin
Language	English
Publishing date	2014-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/nbt.3078
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Article: Intracellular modifiers of integrin alpha 6p production in aggressive prostate and breast cancer cell lines

Language	English
Document type	Article
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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