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Book ; Online ; E-Book: Molecular basis of resilience

Iversen, Patrick L.

adapting to a changing environment

2018

Author's details	Patrick L. Iversen
Keywords	Toxicology ; Medicine
Subject code	615
Language	English
Size	1 Online-Ressource (xix, 312 Seiten), Illustrationen
Publisher	Springer
Publishing place	Cham
Publishing country	Switzerland
Document type	Book ; Online ; E-Book
Remark	Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
HBZ-ID	HT019861116
ISBN	978-3-319-98164-2 ; 9783319981635 ; 3-319-98164-1 ; 3319981633
DOI	10.1007/978-3-319-98164-2
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Is there space for a three-dose vaccine to fight the spread of SARS-CoV-2?

Iversen, Patrick L / Bavari, Sina

The Lancet. Infectious diseases

2021 Volume 21, Issue 8, Page(s) 1054–1055

MeSH term(s)	COVID-19 ; Humans ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Viral Vaccines
Chemical Substances	Spike Glycoprotein, Coronavirus ; Viral Vaccines
Language	English
Publishing date	2021-03-24
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(21)00149-3
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Article ; Online: Inactivated COVID-19 vaccines to make a global impact.

Iversen, Patrick L / Bavari, Sina

The Lancet. Infectious diseases

2021 Volume 21, Issue 6, Page(s) 746–748

MeSH term(s)	Adult ; Aged ; COVID-19 ; COVID-19 Vaccines ; Double-Blind Method ; Humans ; Middle Aged ; SARS-CoV-2 ; Vaccines, Inactivated
Chemical Substances	COVID-19 Vaccines ; Vaccines, Inactivated
Language	English
Publishing date	2021-02-03
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(21)00020-7
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Article ; Online: Extending the interval of COVID-19 vaccine regimens in individuals aged 80 years or older.

Iversen, Patrick L / Bavari, Sina

The Lancet. Healthy longevity

2021 Volume 2, Issue 9, Page(s) e529–e530

MeSH term(s)	BNT162 Vaccine ; COVID-19/prevention & control ; COVID-19 Vaccines ; ChAdOx1 nCoV-19 ; Humans ; Vaccination ; Vaccines
Chemical Substances	COVID-19 Vaccines ; Vaccines ; ChAdOx1 nCoV-19 (B5S3K2V0G8) ; BNT162 Vaccine (N38TVC63NU)
Language	English
Publishing date	2021-08-19
Publishing country	England
Document type	Journal Article ; Comment
ISSN	2666-7568
ISSN (online)	2666-7568
DOI	10.1016/S2666-7568(21)00205-1
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Chimpanzee adenovirus type 3 vectored Ebola vaccine: expanding the field.

Bavari, Sina / Iversen, Patrick L

The Lancet. Infectious diseases

2020 Volume 20, Issue 6, Page(s) 636–637

MeSH term(s)	Africa ; Animals ; Ebola Vaccines ; Ebolavirus/immunology ; Hemorrhagic Fever, Ebola ; Pan troglodytes
Chemical Substances	Ebola Vaccines
Language	English
Publishing date	2020-03-19
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(20)30065-7
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Article ; Online: The Threat from Viruses

Iversen, Patrick L.

Molecular Basis of Resilience

Abstract: Infectious disease represent the most significant threat to human health. Significant geologic cataclysmic events have caused the extinction of countless species, but these “Wrath of God” events predate the emergence of Homo sapiens. Pandemic infections ... ...

Abstract	Infectious disease represent the most significant threat to human health. Significant geologic cataclysmic events have caused the extinction of countless species, but these “Wrath of God” events predate the emergence of Homo sapiens. Pandemic infections have accompanied the rise of human civilization frequently re-occurring leaving a lasting imprint on human history punctuated by profound loss of life. Emerging infections become endemic and are here to stay marking their presence with an annual death toll. Each decade brings a new onslaught of emerging infectious agents. We are surprised again and again but are never prepared. The long-term consequences often remain unrecognized and are always inconvenient including cancer, cardiovascular disease and immune associated diseases that threaten our health. Reliance on clusters of clinical symptoms in the face of diverse and non-descriptive viral infection symptoms is a foolhardy form of crisis management. Viral success is based on rapid replication resulting in large numbers. Single-stranded RNA viruses with their high replication error rate represent a paradigm for resilience.
Keywords	covid19
Publisher	PMC
Document type	Article ; Online
DOI	10.1007/978-3-319-98164-2_3
Database	COVID19

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Article ; Online: Prologue

Iversen, Patrick L.

Molecular Basis of Resilience

Abstract: All living things are associated with a boundary defined ecological niche. Steady state conditions are rarely constant but evolutionary adaptation is too slow to adapt to daily threats so a surrogate variation mechanism is necessary. The genome defines ... ...

Abstract	All living things are associated with a boundary defined ecological niche. Steady state conditions are rarely constant but evolutionary adaptation is too slow to adapt to daily threats so a surrogate variation mechanism is necessary. The genome defines the most basic instructions for life so that a molecular biology perspective provides the foundation for understanding resilience. Variations in the expression of RNA offers rapid variation and this book proposes this is the basis of resilience. This book attempts to illuminate mechanisms of resilience beginning with elaborating threats leading to disruption in steady state conditions. Recognition of threats and defense systems are described followed by adaptive changes in gene expression that refine responses. Finally, environmental conditions are discussed that serve to dampen the adaptive response oscillator to disruptive threats at the level of RNA expression. This prologue is intended to acquaint the reader with my background and the genesis of optimism for an idea that the benefit of transcriptome plasticity is resilience. I grew up in several National Parks, remote regions of the United States that are set aside to preserve natural environments. I attended 12 schools by the time I graduated from high school, a fact that forced me to develop personal resilience. My career path as a scientist followed a path from ecologist to pharmacologist to molecular biologist. I was a professor that transitioned to biotechnology ensuring research subjects involving very diverse in subject matter so I appreciate the value of plasticity.
Keywords	covid19
Publisher	PMC
Document type	Article ; Online
DOI	10.1007/978-3-319-98164-2_1
Database	COVID19

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Article ; Online: The development of broad-spectrum antiviral medical countermeasures to treat viral hemorrhagic fevers caused by natural or weaponized virus infections.

Hickman, Mark R / Saunders, David L / Bigger, Catherine A / Kane, Christopher D / Iversen, Patrick L

PLoS neglected tropical diseases

2022 Volume 16, Issue 3, Page(s) e0010220

Abstract: The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. ...

Abstract	The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir's clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule. The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA's established Animal Rule (21 CFR 314.600-650 for drugs; 21 CFR 601.90-95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Animals ; Antiviral Agents/pharmacology ; Drug Development ; Hemorrhagic Fevers, Viral/drug therapy ; Humans ; Medical Countermeasures ; Models, Animal ; Primates ; RNA Virus Infections/drug therapy ; United States ; United States Food and Drug Administration/legislation & jurisprudence
Chemical Substances	Antiviral Agents ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2022-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2735
ISSN (online)	1935-2735
ISSN	1935-2735
DOI	10.1371/journal.pntd.0010220
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Alternative Splicing in the Nuclear Receptor Superfamily Expands Gene Function to Refine Endo-Xenobiotic Metabolism.

Annalora, Andrew J / Marcus, Craig B / Iversen, Patrick L

Drug metabolism and disposition: the biological fate of chemicals

2020 Volume 48, Issue 4, Page(s) 272–287

Abstract: The human genome encodes 48 nuclear receptor (NR) genes, whose translated products transform chemical signals from endo-xenobiotics into pleotropic RNA transcriptional profiles that refine drug metabolism. This review describes the remarkable ... ...

Abstract	The human genome encodes 48 nuclear receptor (NR) genes, whose translated products transform chemical signals from endo-xenobiotics into pleotropic RNA transcriptional profiles that refine drug metabolism. This review describes the remarkable diversification of the 48 human NR genes, which are potentially processed into over 1000 distinct mRNA transcripts by alternative splicing (AS). The average human NR expresses ∼21 transcripts per gene and is associated with ∼7000 single nucleotide polymorphisms (SNPs). However, the rate of SNP accumulation does not appear to drive the AS process, highlighting the resilience of NR genes to mutation. Here we summarize the altered tissue distribution/function of well characterized NR splice variants associated with human disease. We also describe a cassette exon visualization pictograph methodology for illustrating the location of modular, cassette exons in genes, which can be skipped in-frame, to facilitate the study of their functional relevance to both drug metabolism and NR evolution. We find cassette exons associated with all of the functional domains of NR genes including the DNA and ligand binding domains. The matrix of inclusion or exclusion for functional domain-encoding cassette exons is extensive and capable of significant alterations in cellular phenotypes that modulate endo-xenobiotic metabolism. Exon inclusion options are differentially distributed across NR subfamilies, suggesting group-specific conservation of resilient functionalities. A deeper understanding of this transcriptional plasticity expands our understanding of how chemical signals are refined and mediated by NR genes. This expanded view of the NR transcriptome informs new models of chemical toxicity, disease diagnostics, and precision-based approaches to personalized medicine. SIGNIFICANCE STATEMENT: This review explores the impact of alternative splicing (AS) on the human nuclear receptor (NR) superfamily and highlights the dramatic expansion of more than 1000 potential transcript variants from 48 individual genes. Xenobiotics are increasingly recognized for their ability to perturb gene splicing events, and here we explore the differential sensitivity of NR genes to AS and chemical exposure. Using the cassette exon visualization pictograph methodology, we have documented the conservation of splice-sensitive, modular, cassette exon domains among the 48 human NR genes, and we discuss how their differential expression profiles may augment cellular resilience to oxidative stress and fine-tune adaptive, metabolic responses to endo-xenobiotic exposure.
MeSH term(s)	Alternative Splicing ; Exons/genetics ; Humans ; Oxidative Stress/drug effects ; Oxidative Stress/genetics ; Polymorphism, Single Nucleotide ; Precision Medicine/methods ; RNA, Messenger/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; Transcriptome/genetics ; Xenobiotics/metabolism ; Xenobiotics/pharmacology
Chemical Substances	RNA, Messenger ; Receptors, Cytoplasmic and Nuclear ; Xenobiotics
Language	English
Publishing date	2020-01-24
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.119.089102
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Article: A novel therapeutic vaccine targeting the soluble TNFα receptor II to limit the progression of cardiovascular disease: AtheroVax™.

Iversen, Patrick L / Kipshidze, Nicholas / Kipshidze, Nodar / Dangas, George / Ramacciotti, Eduardo / Kakabadze, Zurab / Fareed, Jawed

Frontiers in cardiovascular medicine

2023 Volume 10, Page(s) 1206541

Abstract: The burden of atherosclerotic cardiovascular disease contributes to a large proportion of morbidity and mortality, globally. Vaccination against atherosclerosis has been proposed for over 20 years targeting different mediators of atherothrombosis; ... ...

Abstract	The burden of atherosclerotic cardiovascular disease contributes to a large proportion of morbidity and mortality, globally. Vaccination against atherosclerosis has been proposed for over 20 years targeting different mediators of atherothrombosis; however, these have not been adequately evaluated in human clinical trials to assess safety and efficacy. Inflammation is a driver of atherosclerosis, but inflammatory mediators are essential components of the immune response. Only pathogenic forms of sTNFR2 are acted upon while preserving the membrane-bound (wild-type) TNFR2 contributions to a non-pathogenic immune response. We hypothesize that the inhibition of sTNRF2 will be more specific and offer long-term treatment options. Here we describe pre-clinical findings of an sTNFR2-targeting peptide vaccine (AtheroVax™) in a mouse model. The multiple pathways to synthesis of the soluble TNFRII receptor (sTNFRII) were identified as sTNFRII(PC), sTNFRII(Δ7), and sTNFRII(Δ7,9). The sTNFRII(Δ7) peptide, NH2-DFALPVEKPLCLQR-COOH is specific to sTNFR2 based on an mRNA splice-variant in which exon 6 is joined to exon 8. The role of sTNFRII(Δ7) as a mediator of prolonged TNFα activity by preventing degradation and clearance was investigated. Inflammation is a critical driver of onset, progression and expansion of atherosclerosis. The TNFα ligand represents a driver of inflammation that is mediated by a splice variant of TNFR2, referred to as sTNFRII(Δ7). The multiple forms of TNFRII, both membrane bound and soluble, are associated with distinctly different phenotypes. sTNFRII(PC) and sTNFRII(Δ7) are not equivalent to etanercept because they lack a clearance mechanism. The unique peptide associated with sTNFRII(Δ7) contains a linear B-cell epitope with amino acids from both exon 6 and exon 8 supporting the vaccine design. Animal studies to evaluate the vaccine are ongoing, and results will be forthcoming. We describe a peptide vaccine targeting sTNFR2 in limiting the progression of atherosclerosis. A therapeutic vaccine limiting the progression of atherosclerosis will greatly contribute to the reduction in morbidity and mortality from cardiovascular disease. It is likely the vaccine will be used in combination with the current standards of care and lifestyle modifications.
Language	English
Publishing date	2023-07-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2023.1206541
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