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Artikel ; Online: Pharmacokinetic modeling reveals parameters that govern tumor targeting and delivery by a pH-Low Insertion Peptide (pHLIP).

Svoronos, Alexander A / Engelman, Donald M

Proceedings of the National Academy of Sciences of the United States of America

2020 Band 118, Heft 1

Abstract: A pH-Low Insertion Peptide (pHLIP) is a pH-sensitive peptide that undergoes membrane insertion, resulting in transmembrane helix formation, on exposure to acidity at a tumor cell surface. As a result, pHLIPs preferentially accumulate within tumors and ... ...

Abstract	A pH-Low Insertion Peptide (pHLIP) is a pH-sensitive peptide that undergoes membrane insertion, resulting in transmembrane helix formation, on exposure to acidity at a tumor cell surface. As a result, pHLIPs preferentially accumulate within tumors and can be used for tumor-targeted imaging and drug delivery. Here we explore the determinants of pHLIP insertion, targeting, and delivery through a computational modeling approach. We generate a simple mathematical model to describe the transmembrane insertion process and then integrate it into a pharmacokinetic model, which predicts the tumor vs. normal tissue biodistribution of the most studied pHLIP, "wild-type pHLIP," over time after a single intravenous injection. From these models, we gain insight into the various mechanisms behind pHLIP tumor targeting and delivery, as well as the various biological parameters that influence it. Furthermore, we analyze how changing the properties of pHLIP can influence the efficacy of tumor targeting and delivery, and we predict the properties for optimal pHLIP phenotypes that have superior tumor targeting and delivery capabilities compared with wild-type pHLIP.
Mesh-Begriff(e)	Cell Membrane/metabolism ; Computational Biology/methods ; Drug Delivery Systems/methods ; Hydrogen-Ion Concentration ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Membrane Proteins/pharmacokinetics ; Models, Theoretical ; Peptides/chemistry ; Peptides/pharmacokinetics ; Tissue Distribution ; Tumor Microenvironment/physiology
Chemische Substanzen	Membrane Proteins ; Peptides ; pHLIP protein
Sprache	Englisch
Erscheinungsdatum	2020-12-21
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2016605118
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: MicroRNA function can be reversed by altering target gene expression levels.

Svoronos, Alexander A / Campbell, Stuart G / Engelman, Donald M

iScience

2021 Band 24, Heft 10, Seite(n) 103208

Abstract: Paradoxically, many microRNAs appear to exhibit entirely opposite functions when placed in different contexts. For example, miR-125b has been shown to be pro-apoptotic in some studies, but anti-apoptotic in others. To investigate this phenomenon, we ... ...

Abstract	Paradoxically, many microRNAs appear to exhibit entirely opposite functions when placed in different contexts. For example, miR-125b has been shown to be pro-apoptotic in some studies, but anti-apoptotic in others. To investigate this phenomenon, we combine computational modeling with experimental approaches to examine how the function of miR-125b in apoptosis varies with respect to the expression levels of its pro-apoptotic and anti-apoptotic targets. In doing so, we elucidate a general trend that miR-125b is more pro-apoptotic when its anti-apoptotic targets are overexpressed, whereas it is more anti-apoptotic when its pro-apoptotic targets are overexpressed. We show that it is possible to completely reverse miR-125b's function in apoptosis by modifying the expression levels of its target genes. Furthermore, miR-125b's function may also be altered by the presence of anticancer drugs. These results suggest that the function of a microRNA can vary substantially and is dependent on its target gene expression levels.
Sprache	Englisch
Erscheinungsdatum	2021-10-02
Erscheinungsland	United States
Dokumenttyp	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.103208
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: MicroRNA function can be reversed by altering target gene expression levels

Alexander A. Svoronos / Stuart G. Campbell / Donald M. Engelman

iScience, Vol 24, Iss 10, Pp 103208- (2021)

2021

Abstract: Summary: Paradoxically, many microRNAs appear to exhibit entirely opposite functions when placed in different contexts. For example, miR-125b has been shown to be pro-apoptotic in some studies, but anti-apoptotic in others. To investigate this phenomenon, ...

Abstract	Summary: Paradoxically, many microRNAs appear to exhibit entirely opposite functions when placed in different contexts. For example, miR-125b has been shown to be pro-apoptotic in some studies, but anti-apoptotic in others. To investigate this phenomenon, we combine computational modeling with experimental approaches to examine how the function of miR-125b in apoptosis varies with respect to the expression levels of its pro-apoptotic and anti-apoptotic targets. In doing so, we elucidate a general trend that miR-125b is more pro-apoptotic when its anti-apoptotic targets are overexpressed, whereas it is more anti-apoptotic when its pro-apoptotic targets are overexpressed. We show that it is possible to completely reverse miR-125b′s function in apoptosis by modifying the expression levels of its target genes. Furthermore, miR-125b′s function may also be altered by the presence of anticancer drugs. These results suggest that the function of a microRNA can vary substantially and is dependent on its target gene expression levels.
Schlagwörter	Molecular biology ; Molecular mechanism of gene regulation ; Cell biology ; Computational bioinformatics ; Science ; Q
Thema/Rubrik (Code)	500
Sprache	Englisch
Erscheinungsdatum	2021-10-01T00:00:00Z
Verlag	Elsevier
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: OncomiR or Tumor Suppressor? The Duplicity of MicroRNAs in Cancer.

Svoronos, Alexander A / Engelman, Donald M / Slack, Frank J

Cancer research

2016 Band 76, Heft 13, Seite(n) 3666–3670

Abstract: MicroRNAs (miRNA) are short, noncoding RNAs whose dysregulation has been implicated in most, if not all, cancers. They regulate gene expression by suppressing mRNA translation and reducing mRNA stability. To this end, there is a great deal of interest in ...

Abstract	MicroRNAs (miRNA) are short, noncoding RNAs whose dysregulation has been implicated in most, if not all, cancers. They regulate gene expression by suppressing mRNA translation and reducing mRNA stability. To this end, there is a great deal of interest in modifying miRNA expression levels for the treatment of cancer. However, the literature is fraught with inconsistent accounts as to whether various miRNAs are oncogenic or tumor suppressive. In this review, we directly examine these inconsistencies and propose several mechanisms to explain them. These mechanisms include the possibility that specific miRNAs can simultaneously produce competing oncogenic and tumor suppressive effects by suppressing both tumor suppressive mRNAs and oncogenic mRNAs, respectively. In addition, miRNAs can modulate tumor-modifying extrinsic factors, such as cancer-immune system interactions, stromal cell interactions, oncoviruses, and sensitivity to therapy. Ultimately, it is the balance between these processes that determines whether a specific miRNA produces a net oncogenic or net tumor suppressive effect. A solid understanding of this phenomenon will likely prove valuable in evaluating miRNA targets for cancer therapy. Cancer Res; 76(13); 3666-70. ©2016 AACR.
Mesh-Begriff(e)	Animals ; Carcinogenesis/genetics ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor ; Humans ; MicroRNAs/genetics ; Neoplasms/genetics ; Neoplasms/pathology ; Oncogenes/genetics
Chemische Substanzen	MicroRNAs
Sprache	Englisch
Erscheinungsdatum	2016--01
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-16-0359
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: The Effect of Abuse and Mistreatment on Healthcare Providers (TEAM): A Survey Assessing the Prevalence of Aggression From Patients and Their Families and Its Impact.

Pinkhasov, Aaron / Filangieri, Carole / Rzeszut, Mary / Wilkenfeld, Marc / Akerman, Meredith / Divers, Jasmin / Oliveras, Jessica / Bostwick, J Michael / Svoronos, Alexander / Peltier, Morgan R

Journal of occupational and environmental medicine

2021 Band 64, Heft 3, Seite(n) e136–e144

Abstract: Objective: Aggression from patients and families on health care providers (HCP) is common yet understudied. We measured its prevalence and impact on HCPs in inpatient and outpatient settings.: Methods: Four thousand six hundred seven HCPs employed by ...

Abstract	Objective: Aggression from patients and families on health care providers (HCP) is common yet understudied. We measured its prevalence and impact on HCPs in inpatient and outpatient settings. Methods: Four thousand six hundred seven HCPs employed by a community teaching hospital received an anonymous survey with results analyzed. Results: Of 1609 HCPs (35%) completing the survey, 88% of inpatient staff reported experiencing different types of aggression compared to 82% in outpatient setting. Almost half did not report it to their supervisor. Younger staff were more likely to report abuse. Negative impacts on productivity and patient care were reported. A third of all responders' indicated negative effects on mental health. Conclusions: Despite negative impacts on staff wellbeing and productivity, patient/family aggression toward HCPs is highly prevalent and underreported. Our healthcare system needs measures to address staff security and wellness.
Mesh-Begriff(e)	Aggression ; Attitude of Health Personnel ; Health Personnel/education ; Humans ; Prevalence ; Surveys and Questionnaires
Sprache	Englisch
Erscheinungsdatum	2021-12-23
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	1223932-x
ISSN	1536-5948 ; 1076-2752
ISSN (online)	1536-5948
ISSN	1076-2752
DOI	10.1097/JOM.0000000000002467
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide.

Svoronos, Alexander A / Bahal, Raman / Pereira, Mohan C / Barrera, Francisco N / Deacon, John C / Bosenberg, Marcus / DiMaio, Daniel / Glazer, Peter M / Engelman, Donald M

Molecular pharmaceutics

2020 Band 17, Heft 2, Seite(n) 461–471

Abstract: Tumor-targeted drug delivery systems offer not only the advantage of an enhanced therapeutic index, but also the possibility of overcoming the limitations that have largely restricted drug design to small, hydrophobic, "drug-like" molecules. Here, we ... ...

Abstract	Tumor-targeted drug delivery systems offer not only the advantage of an enhanced therapeutic index, but also the possibility of overcoming the limitations that have largely restricted drug design to small, hydrophobic, "drug-like" molecules. Here, we explore the ability of a tumor-targeted delivery system centered on the use of a pH-low insertion peptide (pHLIP) to directly deliver moderately polar, multi-kDa molecules into tumor cells. A pHLIP is a short, pH-responsive peptide capable of inserting across a cell membrane to form a transmembrane helix at acidic pH. pHLIPs target the acidic tumor microenvironment with high specificity, and a drug attached to the inserting end of a pHLIP can be translocated across the cell membrane during the insertion process. We investigate the ability of wildtype pHLIP to deliver peptide nucleic acid (PNA) cargoes of varying sizes across lipid membranes. We find that pHLIP effectively delivers PNAs up to ∼7 kDa into cells in a pH-dependent manner. In addition, pHLIP retains its tumor-targeting capabilities when linked to cargoes of this size, although the amount delivered is reduced for PNA cargoes greater than ∼6 kDa. As drug-like molecules are traditionally restricted to sizes of ∼500 Da, this constitutes an order-of-magnitude expansion in the size range of deliverable drug candidates.
Mesh-Begriff(e)	A549 Cells ; Animals ; Cell Membrane/metabolism ; Cell Membrane Permeability/drug effects ; Cytoplasm/drug effects ; Disease Models, Animal ; Drug Delivery Systems/methods ; Humans ; Hydrogen-Ion Concentration ; Lipid Bilayers/metabolism ; Melanoma/drug therapy ; Melanoma/pathology ; Membrane Proteins/metabolism ; Membrane Proteins/pharmacology ; Mice ; Mice, Inbred C57BL ; Molecular Targeted Therapy/methods ; Peptide Nucleic Acids/administration & dosage ; Skin Neoplasms/drug therapy ; Skin Neoplasms/pathology ; Treatment Outcome ; Tumor Microenvironment/drug effects
Chemische Substanzen	Lipid Bilayers ; Membrane Proteins ; Peptide Nucleic Acids ; pHLIP protein
Sprache	Englisch
Erscheinungsdatum	2020-01-13
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.9b00883
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Imaging findings in encephalocraniocutaneous lipomatosis.

Svoronos, Alexandra / Hirsch, Lawrence J / Khandji, Alexander G

Neurology

2011 Band 77, Heft 7, Seite(n) 694

Mesh-Begriff(e)	Adult ; Brain/diagnostic imaging ; Brain Mapping ; Epilepsy/diagnostic imaging ; Eye Diseases/diagnostic imaging ; Humans ; Lipomatosis/diagnostic imaging ; Neurocutaneous Syndromes/diagnostic imaging ; Radiography
Sprache	Englisch
Erscheinungsdatum	2011-08-16
Erscheinungsland	United States
Dokumenttyp	Case Reports ; Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0b013e3182299fa9
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Micro-mold design controls the 3D morphological evolution of self-assembling multicellular microtissues.

Svoronos, Alexander A / Tejavibulya, Nalin / Schell, Jacquelyn Y / Shenoy, Vivek B / Morgan, Jeffrey R

Tissue engineering. Part A

2013 Band 20, Heft 7-8, Seite(n) 1134–1144

Abstract: When seeded into nonadhesive micro-molds, cells self-assemble three-dimensional (3D) multicellular microtissues via the action of cytoskeletal-mediated contraction and cell-cell adhesion. The size and shape of the tissue is a function of the cell type ... ...

Abstract	When seeded into nonadhesive micro-molds, cells self-assemble three-dimensional (3D) multicellular microtissues via the action of cytoskeletal-mediated contraction and cell-cell adhesion. The size and shape of the tissue is a function of the cell type and the size, shape, and obstacles of the micro-mold. In this article, we used human fibroblasts to investigate some of the elements of mold design and how they can be used to guide the morphological changes that occur as a 3D tissue self-organizes. In a loop-ended dogbone mold with two nonadhesive posts, fibroblasts formed a self-constrained tissue whose tension induced morphological changes that ultimately caused the tissue to thin and rupture. Increasing the width of the dogbone's connecting rod increased the stability, whereas increasing its length decreased the stability. Mapping the rupture points showed that the balance of cell volume between the toroid and connecting rod regions of the dogbone tissue controlled the point of rupture. When cells were treated with transforming growth factor-β1, dogbones ruptured sooner due to increased cell contraction. In mold designs to form tissues with more complex shapes such as three interconnected toroids or a honeycomb, obstacle design controlled tension and tissue morphology. When the vertical posts were changed to cones, they became tension modulators that dictated when and where tension was released in a large self-organizing tissue. By understanding how elements of mold design control morphology, we can produce better models to study organogenesis, examine 3D cell mechanics, and fabricate building parts for tissue engineering.
Mesh-Begriff(e)	Equipment Design ; Fibroblasts/drug effects ; Humans ; Tissue Engineering/instrumentation ; Tissue Engineering/methods ; Transforming Growth Factor beta1/pharmacology
Chemische Substanzen	Transforming Growth Factor beta1
Sprache	Englisch
Erscheinungsdatum	2013-12-14
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2420582-5
ISSN	1937-335X ; 1937-3341
ISSN (online)	1937-335X
ISSN	1937-3341
DOI	10.1089/ten.TEA.2013.0297
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: MicroRNA silencing for cancer therapy targeted to the tumour microenvironment.

Cheng, Christopher J / Bahal, Raman / Babar, Imran A / Pincus, Zachary / Barrera, Francisco / Liu, Connie / Svoronos, Alexander / Braddock, Demetrios T / Glazer, Peter M / Engelman, Donald M / Saltzman, W Mark / Slack, Frank J

Nature

2015 Band 518, Heft 7537, Seite(n) 107–110

Abstract: MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes, and dysregulated microRNA expression is correlated with ... ...

Abstract	MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes, and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction. Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells. Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.
Mesh-Begriff(e)	Acids ; Animals ; Cell Membrane/metabolism ; Cell Membrane Permeability ; Disease Models, Animal ; Drug Delivery Systems ; Female ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Hydrogen-Ion Concentration ; Lymphoma/genetics ; Lymphoma/pathology ; Lymphoma/therapy ; Male ; Mice ; MicroRNAs/antagonists & inhibitors ; MicroRNAs/genetics ; Molecular Targeted Therapy ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Oncogenes/genetics ; Peptide Nucleic Acids/administration & dosage ; Peptide Nucleic Acids/chemistry ; Peptide Nucleic Acids/therapeutic use ; Tumor Microenvironment/genetics
Chemische Substanzen	Acids ; MicroRNAs ; Mirn155 microRNA, mouse ; Peptide Nucleic Acids
Sprache	Englisch
Erscheinungsdatum	2015-02-05
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature13905
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Buch: Duality theory in infinite-horizon models

Svoronos, Alexander

(CORE discussion paper. Université catholique de Louvain ; 8807)

1988

Verfasserangabe	Alexander Svoronos
Serientitel	CORE discussion paper. Université catholique de Louvain ; 8807
Umfang	getr. Pag
Verlag	Center for Operations Research and Econometrics, Univ
Erscheinungsort	Louvain-la-Neuve
Dokumenttyp	Buch
Datenquelle	Katalog der Technische Informationsbibliothek Hannover

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