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Artikel ; Online: Network-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis.

Rosenberger, George / Li, Wenxue / Turunen, Mikko / He, Jing / Subramaniam, Prem S / Pampou, Sergey / Griffin, Aaron T / Karan, Charles / Kerwin, Patrick / Murray, Diana / Honig, Barry / Liu, Yansheng / Califano, Andrea

Nature communications

2024 Band 15, Heft 1, Seite(n) 3909

Abstract: Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific signaling network rewiring, continue ...

Abstract	Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific signaling network rewiring, continue to challenge therapeutic efficacy. Leveraging progress in proteomic technologies and network-based methodologies, we introduce Virtual Enrichment-based Signaling Protein-activity Analysis (VESPA)-an algorithm designed to elucidate mechanisms of cell response and adaptation to drug perturbations-and use it to analyze 7-point phosphoproteomic time series from colorectal cancer cells treated with clinically-relevant inhibitors and control media. Interrogating tumor-specific enzyme/substrate interactions accurately infers kinase and phosphatase activity, based on their substrate phosphorylation state, effectively accounting for signal crosstalk and sparse phosphoproteome coverage. The analysis elucidates time-dependent signaling pathway response to each drug perturbation and, more importantly, cell adaptive response and rewiring, experimentally confirmed by CRISPR knock-out assays, suggesting broad applicability to cancer and other diseases.
Mesh-Begriff(e)	Humans ; Drug Resistance, Neoplasm/genetics ; Drug Resistance, Neoplasm/drug effects ; Proteomics/methods ; Phosphoproteins/metabolism ; Signal Transduction/drug effects ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/genetics ; Cell Line, Tumor ; Phosphorylation ; Algorithms ; Proteome/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use
Chemische Substanzen	Phosphoproteins ; Proteome ; Antineoplastic Agents
Sprache	Englisch
Erscheinungsdatum	2024-05-09
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47957-3
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: The use of a centrifuge-free RABiT-II system for high-throughput micronucleus analysis.

Repin, Mikhail / Pampou, Sergey / Brenner, David J / Garty, Guy

Journal of radiation research

2019 Band 61, Heft 1, Seite(n) 68–72

Abstract: The cytokinesis-block micronucleus (CBMN) assay is considered to be the most suitable biodosimetry method for automation. Previously, we automated this assay on a commercial robotic biotech high-throughput system (RABiT-II) adopting both a traditional ... ...

Abstract	The cytokinesis-block micronucleus (CBMN) assay is considered to be the most suitable biodosimetry method for automation. Previously, we automated this assay on a commercial robotic biotech high-throughput system (RABiT-II) adopting both a traditional and an accelerated micronucleus protocol, using centrifugation steps for both lymphocyte harvesting and washing, after whole blood culturing. Here we describe further development of our accelerated CBMN assay protocol for use on high-throughput/high content screening (HTS/HCS) robotic systems without a centrifuge. This opens the way for implementation of the CBMN assay on a wider range of commercial automated HTS/HCS systems and thus increases the potential capacity for dose estimates following a mass-casualty radiological event.
Mesh-Begriff(e)	Biotechnology ; Blood Donors ; Centrifugation/instrumentation ; High-Throughput Screening Assays/methods ; Humans ; Image Processing, Computer-Assisted ; Micronucleus Tests/methods ; Robotics
Sprache	Englisch
Erscheinungsdatum	2019-12-22
Erscheinungsland	England
Dokumenttyp	Journal Article
ZDB-ID	603983-2
ISSN	1349-9157 ; 0449-3060
ISSN (online)	1349-9157
ISSN	0449-3060
DOI	10.1093/jrr/rrz074
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: RABiT-II: A Fully-Automated Micronucleus Assay System with Shortened Time to Result.

Repin, Mikhail / Pampou, Sergey / Garty, Guy / Brenner, David J

Radiation research

2019 Band 191, Heft 3, Seite(n) 232–236

Abstract: In this work, we describe a fully automated cytokinesis-block micronucleus (CBMN) assay with a significantly shortened time to result, motivated by the need for rapid high-throughput biodosimetric estimation of radiation doses from small-volume human ... ...

Abstract	In this work, we describe a fully automated cytokinesis-block micronucleus (CBMN) assay with a significantly shortened time to result, motivated by the need for rapid high-throughput biodosimetric estimation of radiation doses from small-volume human blood samples. The Rapid Automated Biodosimetry Tool (RABiT-II) currently consists of two commercial automated systems: a PerkinElmer cell::explorer Workstation and a GE Healthcare IN Cell Analyzer 2000 Imager. Blood samples (30 μl) from eight healthy volunteers were gamma-ray irradiated ex vivo with 0 (control), 0.5, 1.5, 2.5, 3.5 or 4.5 Gy and processed with full automation in 96-well plates on the RABiT-II system. The total cell culture time was 54 h and total assay time was 3 days. DAPI-stained fixed samples were imaged on an IN Cell Analyzer 2000 with fully-automated image analysis using the GE Healthcare IN Cell Developer Toolbox version 1.9. A CBMN dose-response calibration curve was established, after which the capability of the system to predict known doses was assessed. Various radiation doses for irradiated samples from two donors were estimated within 20% of the true dose (±0.5 Gy below 2 Gy) in 97% of the samples, with the doses in some 5 Gy irradiated samples being underestimated by up to 25%. In summary, the findings from this work demonstrate that the accelerated CBMN assay can be automated in a high-throughput format, using commercial biotech robotic systems, in 96-well plates, providing a rapid and reliable bioassay for radiation exposure.
Mesh-Begriff(e)	Automation ; Humans ; Micronucleus Tests/instrumentation ; Micronucleus Tests/methods ; Time Factors
Sprache	Englisch
Erscheinungsdatum	2019-01-18
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80322-4
ISSN	1938-5404 ; 0033-7587
ISSN (online)	1938-5404
ISSN	0033-7587
DOI	10.1667/RR15215.1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Elucidating Compound Mechanism of Action and Polypharmacology with a Large-scale Perturbational Profile Compendium.

Hu, Lucas ZhongMing / Douglass, Eugene / Turunen, Mikko / Pampou, Sergey / Grunn, Adina / Realubit, Ron / Antolin, Albert A / Wang, Alexander L E / Li, Hai / Subramaniam, Prem / Karan, Charles / Alvarez, Mariano / Califano, Andrea

bioRxiv : the preprint server for biology

2023

Abstract: The Mechanism of Action (MoA) of a drug is generally represented as a small, non-tissue-specific repertoire of high-affinity binding targets. Yet, drug activity and polypharmacology are increasingly associated with a broad range of off-target and tissue- ... ...

Abstract	The Mechanism of Action (MoA) of a drug is generally represented as a small, non-tissue-specific repertoire of high-affinity binding targets. Yet, drug activity and polypharmacology are increasingly associated with a broad range of off-target and tissue-specific effector proteins. To address this challenge, we have implemented an efficient integrative experimental and computational framework leveraging the systematic generation and analysis of drug perturbational profiles representing >700 FDA-approved and experimental oncology drugs, in cell lines selected as high-fidelity models of 23 aggressive tumor subtypes. Protein activity-based analyses revealed highly reproducible, drug-mediated modulation of tissue-specific targets, leading to generation of a proteome-wide polypharmacology map, characterization of MoA-related drug clusters and off-target effects, and identification and experimental validation of novel, tissue-specific inhibitors of undruggable oncoproteins. The proposed framework, which is easily extended to elucidating the MoA of novel small-molecule libraries, could help support more systematic and quantitative approaches to precision oncology.
Sprache	Englisch
Erscheinungsdatum	2023-10-10
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2023.10.08.561457
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Network-based elucidation of colon cancer drug resistance by phosphoproteomic time-series analysis.

bioRxiv : the preprint server for biology

2023

Abstract	Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific signaling network rewiring, continue to challenge therapeutic efficacy. By leveraging progress in proteomic technologies and network-based methodologies, over the past decade, we developed VESPA-an algorithm designed to elucidate mechanisms of cell response and adaptation to drug perturbations-and used it to analyze 7-point phosphoproteomic time series from colorectal cancer cells treated with clinically-relevant inhibitors and control media. Interrogation of tumor-specific enzyme/substrate interactions accurately inferred kinase and phosphatase activity, based on their inferred substrate phosphorylation state, effectively accounting for signal cross-talk and sparse phosphoproteome coverage. The analysis elucidated time-dependent signaling pathway response to each drug perturbation and, more importantly, cell adaptive response and rewiring that was experimentally confirmed by CRISPRko assays, suggesting broad applicability to cancer and other diseases.
Sprache	Englisch
Erscheinungsdatum	2023-02-16
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2023.02.15.528736
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: RABiT-II-DCA: A Fully-automated Dicentric Chromosome Assay in Multiwell Plates.

Royba, Ekaterina / Repin, Mikhail / Pampou, Sergey / Karan, Charles / Brenner, David J / Garty, Guy

Radiation research

2019 Band 192, Heft 3, Seite(n) 311–323

Abstract: We developed a fully-automated dicentric chromosome assay (DCA) in multiwell plates. All operations, from sample loading to chromosome scoring, are performed, without human intervention, by the second-generation Rapid Automated Biodosimetry Tool II ( ... ...

Abstract	We developed a fully-automated dicentric chromosome assay (DCA) in multiwell plates. All operations, from sample loading to chromosome scoring, are performed, without human intervention, by the second-generation Rapid Automated Biodosimetry Tool II (RABiT-II) robotic system, a plate imager and custom software, FluorQuantDic. The system requires small volumes of blood (30 µl per individual) to determine radiation dose received as a result of a radiation accident or terrorist attack. To visualize dicentrics in multiwell plates, we implemented a non-classical protocol for centromere FISH staining at 37°C. The RABiT-II performs rapid analysis of chromosomes after extracting them from metaphase cells. With the use of multiwell plates, many samples can be screened at the same time. Thus, the RABiT-II DCA provides an advantage during triage when risk-based stratification and medical management are required for a large population exposed to unknown levels of ionizing radiation.
Mesh-Begriff(e)	Automation ; Chromosome Aberrations/radiation effects ; Healthy Volunteers ; Humans ; In Situ Hybridization, Fluorescence ; Radioactive Hazard Release ; Radiometry/methods ; Robotics
Sprache	Englisch
Erscheinungsdatum	2019-07-11
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80322-4
ISSN	1938-5404 ; 0033-7587
ISSN (online)	1938-5404
ISSN	0033-7587
DOI	10.1667/RR15266.1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Validation of a High-Throughput Dicentric Chromosome Assay Using Complex Radiation Exposures.

Royba, Ekaterina / Repin, Mikhail / Balajee, Adayabalam S / Shuryak, Igor / Pampou, Sergey / Karan, Charles / Wang, Yi-Fang / Lemus, Olga Dona / Obaid, Razib / Deoli, Naresh / Wuu, Cheng-Shie / Brenner, David J / Garty, Guy

Radiation research

2022 Band 199, Heft 1, Seite(n) 1–16

Abstract: Validation of biodosimetry assays is routinely performed using primarily orthovoltage irradiators at a conventional dose rate of approximately 1 Gy/min. However, incidental/ accidental exposures caused by nuclear weapons can be more complex. The aim of ... ...

Abstract	Validation of biodosimetry assays is routinely performed using primarily orthovoltage irradiators at a conventional dose rate of approximately 1 Gy/min. However, incidental/ accidental exposures caused by nuclear weapons can be more complex. The aim of this work was to simulate the DNA damage effects mimicking those caused by the detonation of a several kilotons improvised nuclear device (IND). For this, we modeled complex exposures to: 1. a mixed (photons + IND-neutrons) field and 2. different dose rates that may come from the blast, nuclear fallout, or ground deposition of radionuclides (ground shine). Additionally, we assessed whether myeloid cytokines affect the precision of radiation dose estimation by modulating the frequency of dicentric chromosomes. To mimic different exposure scenarios, several irradiation systems were used. In a mixed field study, human blood samples were exposed to a photon field enriched with neutrons (ranging from 10% to 37%) from a source that mimics Hiroshima's A-bomb's energy spectrum (0.2-9 MeV). Using statistical analysis, we assessed whether photons and neutrons act in an additive or synergistic way to form dicentrics. For the dose rates study, human blood was exposed to photons or electrons at dose rates ranging from low (where the dose was spread over 32 h) to extremely high (where the dose was delivered in a fraction of a microsecond). Potential effects of cytokine treatment on biodosimetry dose predictions were analyzed in irradiated blood subjected to Neupogen or Neulasta for 24 or 48 h at the concentration recommended to forestall manifestation of an acute radiation syndrome in bomb survivors. All measurements were performed using a robotic station, the Rapid Automated Biodosimetry Tool II, programmed to culture lymphocytes and score dicentrics in multiwell plates (the RABiT-II DCA). In agreement with classical concepts of radiation biology, the RABiT-II DCA calibration curves suggested that the frequency of dicentrics depends on the type of radiation and is modulated by changes in the dose rate. The resulting dose-response curves suggested an intermediate dicentric yields and additive effects of photons and IND-neutrons in the mixed field. At ultra-high dose rate (600 Gy/s), affected lymphocytes exhibited significantly fewer dicentrics (P < 0.004, t test). In contrast, we did not find the dose-response modification effects of radiomitigators on the yields of dicentrics (Bonferroni corrected P > 0.006, ANOVA test). This result suggests no bias in the dose predictions should be expected after emergency cytokine treatment initiated up to 48 h prior to blood collection for dicentric analysis.
Mesh-Begriff(e)	Humans ; Dose-Response Relationship, Radiation ; Chromosome Aberrations ; Lymphocytes/radiation effects ; Radiation Exposure ; Chromosomes ; Radiometry/methods
Sprache	Englisch
Erscheinungsdatum	2022-08-19
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80322-4
ISSN	1938-5404 ; 0033-7587
ISSN (online)	1938-5404
ISSN	0033-7587
DOI	10.1667/RADE-22-00007.1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: The RABiT-II DCA in the Rhesus Macaque Model.

Royba, Ekaterina / Repin, Mikhail / Balajee, Adayabalam S / Shuryak, Igor / Pampou, Sergey / Karan, Charles / Brenner, David J / Garty, Guy

Radiation research

2020 Band 196, Heft 5, Seite(n) 501–509

Abstract: An automated platform for cytogenetic biodosimetry, the "Rapid Automated Biodosimetry Tool II (RABiT-II)," adapts the dicentric chromosome assay (DCA) for high-throughput mass-screening of the population after a large-scale radiological event. To ... ...

Abstract	An automated platform for cytogenetic biodosimetry, the "Rapid Automated Biodosimetry Tool II (RABiT-II)," adapts the dicentric chromosome assay (DCA) for high-throughput mass-screening of the population after a large-scale radiological event. To validate this test, the U.S. Federal Drug Administration (FDA) recommends demonstrating that the high-throughput biodosimetric assay in question correctly reports the dose in an in vivo model. Here we describe the use of rhesus macaques (Macaca mulatta) to augment human studies and validate the accuracy of the high-throughput version of the DCA. To perform analysis, we developed the 17/22-mer peptide nucleic acid (PNA) probes that bind to the rhesus macaque's centromeres. To our knowledge, these are the first custom PNA probes with high specificity that can be used for chromosome analysis in M. mulatta. The accuracy of fully-automated chromosome analysis was improved by optimizing a low-temperature telomere PNA FISH staining in multiwell plates and adding the telomere detection feature to our custom chromosome detection software, FluorQuantDic V4. The dicentric frequencies estimated from in vitro irradiated rhesus macaque samples were compared to human blood samples of individuals subjected to the same ex vivo irradiation conditions. The results of the RABiT-II DCA analysis suggest that, in the lymphocyte system, the dose responses to gamma radiation in the rhesus macaques were similar to those in humans, with small but statistically significant differences between these two model systems.
Mesh-Begriff(e)	Animals ; Biological Assay ; Macaca mulatta ; Radiometry
Sprache	Englisch
Erscheinungsdatum	2020-10-06
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80322-4
ISSN	1938-5404 ; 0033-7587
ISSN (online)	1938-5404
ISSN	0033-7587
DOI	10.1667/RR15547.1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: RABiT-II: Implementation of a High-Throughput Micronucleus Biodosimetry Assay on Commercial Biotech Robotic Systems.

Repin, Mikhail / Pampou, Sergey / Karan, Charles / Brenner, David J / Garty, Guy

Radiation research

2017 Band 187, Heft 4, Seite(n) 492–498

Abstract: We demonstrate the use of high-throughput biodosimetry platforms based on commercial high-throughput/high-content screening robotic systems. The cytokinesis-block micronucleus (CBMN) assay, using only 20 μl whole blood from a fingerstick, was implemented ...

Abstract	We demonstrate the use of high-throughput biodosimetry platforms based on commercial high-throughput/high-content screening robotic systems. The cytokinesis-block micronucleus (CBMN) assay, using only 20 μl whole blood from a fingerstick, was implemented on a PerkinElmer cell::explorer and General Electric IN Cell Analyzer 2000. On average 500 binucleated cells per sample were detected by our FluorQuantMN software. A calibration curve was generated in the radiation dose range up to 5.0 Gy using the data from 8 donors and 48,083 binucleated cells in total. The study described here demonstrates that high-throughput radiation biodosimetry is practical using current commercial high-throughput/high-content screening robotic systems, which can be readily programmed to perform and analyze robotics-optimized cytogenetic assays. Application to other commercial high-throughput/high-content screening systems beyond the ones used in this study is clearly practical. This approach will allow much wider access to high-throughput biodosimetric screening for large-scale radiological incidents than is currently available.
Mesh-Begriff(e)	Adult ; Blood Cells/radiation effects ; Blood Cells/ultrastructure ; Calibration ; Female ; High-Throughput Screening Assays/instrumentation ; High-Throughput Screening Assays/methods ; Humans ; Male ; Micronucleus Tests/instrumentation ; Micronucleus Tests/methods ; Middle Aged ; Radiometry/instrumentation ; Radiometry/methods ; Robotics/instrumentation ; Robotics/methods ; Young Adult
Sprache	Englisch
Erscheinungsdatum	2017-04
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	80322-4
ISSN	1938-5404 ; 0033-7587
ISSN (online)	1938-5404
ISSN	0033-7587
DOI	10.1667/RR011CC.1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection.

Laise, Pasquale / Stanifer, Megan L / Bosker, Gideon / Sun, Xiaoyun / Triana, Sergio / Doldan, Patricio / La Manna, Federico / De Menna, Marta / Realubit, Ronald B / Pampou, Sergey / Karan, Charles / Alexandrov, Theodore / Kruithof-de Julio, Marianna / Califano, Andrea / Boulant, Steeve / Alvarez, Mariano J

Communications biology

2022 Band 5, Heft 1, Seite(n) 714

Abstract: SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable to its replication. Here we show that analysis of Master Regulator proteins representing mechanistic determinants of the gene expression signature induced by ...

Abstract	SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable to its replication. Here we show that analysis of Master Regulator proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2 in infected cells revealed coordinated inactivation of Master Regulators enriched in physical interactions with SARS-CoV-2 proteins, suggesting their mechanistic role in maintaining a host cell state refractory to virus replication. To test their functional relevance, we measured SARS-CoV-2 replication in epithelial cells treated with drugs predicted to activate the entire repertoire of repressed Master Regulators, based on their experimentally elucidated, context-specific mechanism of action. Overall, 15 of the 18 drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 replication, without affecting cell viability. This model for host-directed pharmacological therapy is fully generalizable and can be deployed to identify drugs targeting host cell-based Master Regulator signatures induced by virtually any pathogen.
Mesh-Begriff(e)	COVID-19/drug therapy ; Humans ; SARS-CoV-2 ; Transcriptome ; Virus Diseases ; Virus Replication
Sprache	Englisch
Erscheinungsdatum	2022-07-19
Erscheinungsland	England
Dokumenttyp	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/s42003-022-03663-8
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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