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Article ; Online: Dietary risk assessment of benzophenone derivatives using bread consumption estimates in a Taiwanese population.

Chen, Hsin-Chang / Tsai, Chung-Jung / Huang, Yu-Fang / Wu, Chen-Ting

Environmental science and pollution research international

2023 Volume 30, Issue 46, Page(s) 102323–102334

Abstract: Listed as endocrine-disrupting chemicals, benzophenone (BP) and its nine analogues (BPs) are an emerging group of contaminants. The migration of BPs from ultraviolet inks to food has been investigated in many studies; however, few studies have ... ...

Abstract	Listed as endocrine-disrupting chemicals, benzophenone (BP) and its nine analogues (BPs) are an emerging group of contaminants. The migration of BPs from ultraviolet inks to food has been investigated in many studies; however, few studies have investigated BPs in foods and the risks of human exposure to BPs. We validated a trace and multi-residue method for simultaneously determining 10 BPs, including BP, BP-1, BP-2, BP-3, BP-8, 4-MBP, 2-OHBP, 4-OHBP, M2BB, and PBZ. Eighty-one bread samples were analyzed using stable isotope labeling and ultrahigh-performance liquid chromatography-electrospray ionization tandem mass spectrometry with solid-liquid extraction. We determined the estimated daily intake of BPs, non-cancer risks, and lifetime cancer risks (LTCRs) from daily bread consumption for seven age groups using a Monte Carlo simulation. The method demonstrated robust linearity (R
MeSH term(s)	Humans ; Bread/analysis ; Chromatography, High Pressure Liquid ; Tandem Mass Spectrometry/methods ; Risk Assessment ; Benzophenones/analysis
Chemical Substances	benzophenone (701M4TTV9O) ; Benzophenones
Language	English
Publishing date	2023-09-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1178791-0
ISSN	1614-7499 ; 0944-1344
ISSN (online)	1614-7499
ISSN	0944-1344
DOI	10.1007/s11356-023-29493-7
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Article ; Online: Pan-cancer clinical impact of latent drivers from double mutations.

Yavuz, Bengi Ruken / Tsai, Chung-Jung / Nussinov, Ruth / Tuncbag, Nurcan

Communications biology

2023 Volume 6, Issue 1, Page(s) 202

Abstract: Here, we discover potential 'latent driver' mutations in cancer genomes. Latent drivers have low frequencies and minor observable translational potential. As such, to date they have escaped identification. Their discovery is important, since when paired ... ...

Abstract	Here, we discover potential 'latent driver' mutations in cancer genomes. Latent drivers have low frequencies and minor observable translational potential. As such, to date they have escaped identification. Their discovery is important, since when paired in cis, latent driver mutations can drive cancer. Our comprehensive statistical analysis of the pan-cancer mutation profiles of ~60,000 tumor sequences from the TCGA and AACR-GENIE cohorts identifies significantly co-occurring potential latent drivers. We observe 155 same gene double mutations of which 140 individual components are cataloged as latent drivers. Evaluation of cell lines and patient-derived xenograft response data to drug treatment indicate that in certain genes double mutations may have a prominent role in increasing oncogenic activity, hence obtaining a better drug response, as in PIK3CA. Taken together, our comprehensive analyses indicate that same-gene double mutations are exceedingly rare phenomena but are a signature for some cancer types, e.g., breast, and lung cancers. The relative rarity of doublets can be explained by the likelihood of strong signals resulting in oncogene-induced senescence, and by doublets consisting of non-identical single residue components populating the background mutational load, thus not identified.
MeSH term(s)	Humans ; Mutation ; Lung Neoplasms ; Proteomics
Language	English
Publishing date	2023-02-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-04519-5
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Article ; Online: Neurodevelopmental disorders, immunity, and cancer are connected.

Nussinov, Ruth / Tsai, Chung-Jung / Jang, Hyunbum

iScience

2022 Volume 25, Issue 6, Page(s) 104492

Abstract: Immunity could be viewed as the common factor in neurodevelopmental disorders and cancer. The immune and nervous systems coevolve as the embryo develops. Immunity can release cytokines that activate MAPK signaling in neural cells. In specific embryonic ... ...

Abstract	Immunity could be viewed as the common factor in neurodevelopmental disorders and cancer. The immune and nervous systems coevolve as the embryo develops. Immunity can release cytokines that activate MAPK signaling in neural cells. In specific embryonic brain cell types, dysregulated signaling that results from germline or embryonic mutations can promote changes in chromatin organization and gene accessibility, and thus expression levels of essential genes in neurodevelopment. In cancer, dysregulated signaling can emerge from sporadic somatic mutations during human life. Neurodevelopmental disorders and cancer share similarities. In neurodevelopmental disorders, immunity, and cancer, there appears an almost invariable involvement of small GTPases (e.g., Ras, RhoA, and Rac) and their pathways. TLRs, IL-1, GIT1, and FGFR signaling pathways, all can be dysregulated in neurodevelopmental disorders and cancer. Although there are signaling similarities, decisive differentiating factors are timing windows, and cell type specific perturbation levels, pointing to chromatin reorganization. Finally, we discuss drug discovery.
Language	English
Publishing date	2022-05-30
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.104492
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Article ; Online: A New View of Activating Mutations in Cancer.

Nussinov, Ruth / Tsai, Chung-Jung / Jang, Hyunbum

Cancer research

2022 Volume 82, Issue 22, Page(s) 4114–4123

Abstract: A vast effort has been invested in the identification of driver mutations of cancer. However, recent studies and observations call into question whether the activating mutations or the signal strength are the major determinant of tumor development. The ... ...

Abstract	A vast effort has been invested in the identification of driver mutations of cancer. However, recent studies and observations call into question whether the activating mutations or the signal strength are the major determinant of tumor development. The data argue that signal strength determines cell fate, not the mutation that initiated it. In addition to activating mutations, factors that can impact signaling strength include (i) homeostatic mechanisms that can block or enhance the signal, (ii) the types and locations of additional mutations, and (iii) the expression levels of specific isoforms of genes and regulators of proteins in the pathway. Because signal levels are largely decided by chromatin structure, they vary across cell types, states, and time windows. A strong activating mutation can be restricted by low expression, whereas a weaker mutation can be strengthened by high expression. Strong signals can be associated with cell proliferation, but too strong a signal may result in oncogene-induced senescence. Beyond cancer, moderate signal strength in embryonic neural cells may be associated with neurodevelopmental disorders, and moderate signals in aging may be associated with neurodegenerative diseases, like Alzheimer's disease. The challenge for improving patient outcomes therefore lies in determining signaling thresholds and predicting signal strength.
MeSH term(s)	Humans ; Mutation ; Neoplasms/genetics ; Signal Transduction/genetics ; Cell Proliferation ; Proteins/genetics
Chemical Substances	Proteins
Language	English
Publishing date	2022-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-22-2125
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Article ; Online: How can same-gene mutations promote both cancer and developmental disorders?

Nussinov, Ruth / Tsai, Chung-Jung / Jang, Hyunbum

Science advances

2022 Volume 8, Issue 2, Page(s) eabm2059

Abstract: The question of how same-gene mutations can drive both cancer and neurodevelopmental disorders has been puzzling. It has also been puzzling why those with neurodevelopmental disorders have a high risk of cancer. Ras, MEK, PI3K, PTEN, and SHP2 are among ... ...

Abstract	The question of how same-gene mutations can drive both cancer and neurodevelopmental disorders has been puzzling. It has also been puzzling why those with neurodevelopmental disorders have a high risk of cancer. Ras, MEK, PI3K, PTEN, and SHP2 are among the oncogenic proteins that can harbor mutations that encode diseases other than cancer. Understanding why some of their mutations can promote cancer, whereas others promote neurodevelopmental diseases, and why even the same mutations may promote both phenotypes, has important clinical ramifications. Here, we review the literature and address these tantalizing questions. We propose that cell type–specific expression of the mutant protein, and of other proteins in the respective pathway, timing of activation (during embryonic development or sporadic emergence), and the absolute number of molecules that the mutations activate, alone or in combination, are pivotal in determining the pathological phenotypes—cancer and (or) developmental disorders.
Language	English
Publishing date	2022-01-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abm2059
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Article ; Online: Allostery, and how to define and measure signal transduction.

Nussinov, Ruth / Tsai, Chung-Jung / Jang, Hyunbum

Biophysical chemistry

2022 Volume 283, Page(s) 106766

Abstract: Here we ask: What is productive signaling? How to define it, how to measure it, and most of all, what are the parameters that determine it? Further, what determines the strength of signaling from an upstream to a downstream node in a specific cell? These ...

Abstract	Here we ask: What is productive signaling? How to define it, how to measure it, and most of all, what are the parameters that determine it? Further, what determines the strength of signaling from an upstream to a downstream node in a specific cell? These questions have either not been considered or not entirely resolved. The requirements for the signal to propagate downstream to activate (repress) transcription have not been considered either. Yet, the questions are pivotal to clarify, especially in diseases such as cancer where determination of signal propagation can point to cell proliferation and to emerging drug resistance, and to neurodevelopmental disorders, such as RASopathy, autism, attention-deficit/hyperactivity disorder (ADHD), and cerebral palsy. Here we propose a framework for signal transduction from an upstream to a downstream node addressing these questions. Defining cellular processes, experimentally measuring them, and devising powerful computational AI-powered algorithms that exploit the measurements, are essential for quantitative science.
MeSH term(s)	Algorithms ; Attention Deficit Disorder with Hyperactivity ; Autism Spectrum Disorder ; Cell Proliferation ; Humans ; Signal Transduction
Language	English
Publishing date	2022-01-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	185052-0
ISSN	1873-4200 ; 0301-4622
ISSN (online)	1873-4200
ISSN	0301-4622
DOI	10.1016/j.bpc.2022.106766
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Article ; Online: Anticancer drug resistance: An update and perspective.

Nussinov, Ruth / Tsai, Chung-Jung / Jang, Hyunbum

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy

2021 Volume 59, Page(s) 100796

Abstract: Driver mutations promote initiation and progression of cancer. Pharmacological treatment can inhibit the action of the mutant protein; however, drug resistance almost invariably emerges. Multiple studies revealed that cancer drug resistance is based upon ...

Abstract	Driver mutations promote initiation and progression of cancer. Pharmacological treatment can inhibit the action of the mutant protein; however, drug resistance almost invariably emerges. Multiple studies revealed that cancer drug resistance is based upon a plethora of distinct mechanisms. Drug resistance mutations can occur in the same protein or in different proteins; as well as in the same pathway or in parallel pathways, bypassing the intercepted signaling. The dilemma that the clinical oncologist is facing is that not all the genomic alterations as well as alterations in the tumor microenvironment that facilitate cancer cell proliferation are known, and neither are the alterations that are likely to promote metastasis. For example, the common KRas
MeSH term(s)	Acetonitriles ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Artificial Intelligence ; Drug Resistance, Neoplasm/genetics ; Humans ; Lung Neoplasms/drug therapy ; Mutation ; Piperazines ; Pyrimidines ; Tumor Microenvironment
Chemical Substances	Acetonitriles ; Antineoplastic Agents ; Piperazines ; Pyrimidines ; adagrasib (8EOO6HQF8Y)
Language	English
Publishing date	2021-12-16
Publishing country	Scotland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	1474513-6
ISSN	1532-2084 ; 1368-7646
ISSN (online)	1532-2084
ISSN	1368-7646
DOI	10.1016/j.drup.2021.100796
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Article ; Online: Emerging Allosteric Mechanism of EGFR Activation in Physiological and Pathological Contexts.

Tsai, Chung-Jung / Nussinov, Ruth

Biophysical journal

2019 Volume 117, Issue 1, Page(s) 5–13

Abstract: Protein kinases are key players in signal transduction pathways where they are crafted into two functional states. In response to growth factor binding stimulus, epidermal growth factor receptor (EGFR), which is physiologically populated in an ... ...

Abstract	Protein kinases are key players in signal transduction pathways where they are crafted into two functional states. In response to growth factor binding stimulus, epidermal growth factor receptor (EGFR), which is physiologically populated in an autoinhibited inactive state, becomes active. Here, we outline a simple allostery scheme to clarify how an extracellular (ligand-dependent) binding event activates the intracellular EGFR kinase domain via (dimer-dependent) asymmetric dimerization, as well as how pathologically overexpressed EGFR or constitutively active mutants, leads to oncogenic pathway activation. Our underlying allosteric activation mechanism derives from a collection of inactive versus active EGFR structural, biochemical (negatively cooperative ligand binding), and biophysical (weak coupling between extracellular and intracellular kinase dimerization) data. The emerging structural insight reveals that ligand-dependent physiological activation is an outside-in allosteric activation with strong structural coupling across the membrane. In contrast, ligand-independent pathological activation is a weak inside-out activation mediated by intracellular kinase dimerization, which is structurally accommodated by additional extracellular dimers.
MeSH term(s)	Allosteric Regulation ; Allosteric Site ; Animals ; ErbB Receptors/chemistry ; ErbB Receptors/metabolism ; Humans ; Protein Multimerization ; Signal Transduction
Chemical Substances	ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2019-05-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2019.05.021
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Article ; Online: Signaling in the crowded cell.

Nussinov, Ruth / Tsai, Chung-Jung / Jang, Hyunbum

Current opinion in structural biology

2021 Volume 71, Page(s) 43–50

Abstract: High-resolution technologies have clarified some of the principles underlying cellular actions. However, understanding how cells receive, communicate, and respond to signals is still challenging. Questions include how efficient regulation of assemblies, ... ...

Abstract	High-resolution technologies have clarified some of the principles underlying cellular actions. However, understanding how cells receive, communicate, and respond to signals is still challenging. Questions include how efficient regulation of assemblies, which execute cell actions at the nanoscales, transmits productively at micrometer scales, especially considering the crowded environment, and how the cell organization makes it happen. Here, we describe how cells can navigate long-range diffusion-controlled signaling via association/dissociation of spatially proximal entities. Dynamic clusters can span the cell, engaging in most signaling steps. Effective local concentration, allostery, scaffolding, affinities, and the chemical and mechanical properties of the macromolecules and the environment play key roles. Signaling strength and duration matter, for example, deciding if a mutation promotes cancer or developmental syndromes.
MeSH term(s)	Diffusion ; Signal Transduction
Language	English
Publishing date	2021-07-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2021.05.009
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Zs.A 3206: Show issues

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Article ; Online: Allosteric activation of RAF in the MAPK signaling pathway.

Tsai, Chung-Jung / Nussinov, Ruth

Current opinion in structural biology

2018 Volume 53, Page(s) 100–106

Abstract: Protein kinases are evolutionarily crafted into two functional states. In response to stimuli, kinase, which is usually populated in an inactive state, becomes active. Here, we outline a unified scheme to explain how kinases are activated physiologically ...

Abstract	Protein kinases are evolutionarily crafted into two functional states. In response to stimuli, kinase, which is usually populated in an inactive state, becomes active. Here, we outline a unified scheme to explain how kinases are activated physiologically and pathologically, focusing on RAF allosteric activation. Key concepts include the population shift from the inactive to the active state is relative; the relative populations are altered additively via allosteric events; and the structural features of the active conformation are coupled with the regulatory and catalytic spines to align the catalytic sequence motifs. This structural insight clarifies why the prerequisite of RAF dimerization, how the V600E oncogenic mutation activates RAF, how a RAF inhibitor executes paradoxical activation, and provides pharmaceutical guidelines.
MeSH term(s)	Allosteric Regulation ; Enzyme Activation ; Humans ; MAP Kinase Signaling System ; Point Mutation ; Protein Domains ; Protein Kinase Inhibitors/metabolism ; Protein Multimerization ; Protein Structure, Quaternary ; Signal Transduction ; raf Kinases/chemistry ; raf Kinases/genetics ; raf Kinases/metabolism
Chemical Substances	Protein Kinase Inhibitors ; raf Kinases (EC 2.7.11.1)
Language	English
Publishing date	2018-07-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2018.07.007
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