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Article ; Online: Global impact of somatic structural variation on the cancer proteome.

Chen, Fengju / Zhang, Yiqun / Chandrashekar, Darshan S / Varambally, Sooryanarayana / Creighton, Chad J

2023 Volume 14, Issue 1, Page(s) 5637

Abstract: Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to ... ...

Abstract	Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to determine the extent somatic structural variant (SV) breakpoint patterns impact protein expression of nearby genes. We find that about 25% of the hundreds of genes with SV-associated cis-regulatory alterations at the mRNA level are similarly associated at the protein level. SVs associated with enhancer hijacking, retrotransposon translocation, altered DNA methylation, or fusion transcripts are implicated in protein over-expression. SVs combined with altered protein levels considerably extend the numbers of patients with tumors somatically altered for critical pathways. We catalog both SV breakpoint patterns involving patient survival and genes with nearby SV breakpoints associated with increased cell dependency in cancer cell lines. Pan-cancer proteogenomics identifies targetable non-coding alterations, by virtue of the associated deregulated genes.
MeSH term(s)	Humans ; Proteome/genetics ; Neoplasms/genetics ; Cell Line ; DNA Methylation/genetics ; Mass Spectrometry
Chemical Substances	Proteome
Language	English
Publishing date	2023-09-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41374-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Author Correction: Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways.

Zhang, Yiqun / Chen, Fengju / Chandrashekar, Darshan S / Varambally, Sooryanarayana / Creighton, Chad J

Nature communications

2022 Volume 13, Issue 1, Page(s) 4688

Language	English
Publishing date	2022-08-10
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-32539-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Using cancer proteomics data to identify gene candidates for therapeutic targeting.

Monsivais, Diana / Parks, Sydney E / Chandrashekar, Darshan S / Varambally, Sooryanarayana / Creighton, Chad J

Oncotarget

2023 Volume 14, Page(s) 399–412

Abstract: Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, ...

Abstract	Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer cell lines, CRISPR loss of function and drug sensitivity scoring can be readily integrated with protein data to predict any gene's functional impact before bench experiments are carried out. Public data portals make cancer proteomics data more accessible to the research community. Drug discovery platforms can screen hundreds of millions of small molecule inhibitors for those that target a gene or pathway of interest. Here, we discuss some of the available public genomic and proteomic resources while considering approaches to how these could be leveraged for molecular biology insights or drug discovery. We also demonstrate the inhibitory effect of BAY1217389, a TTK inhibitor recently tested in a Phase I clinical trial for the treatment of solid tumors, on uterine cancer cell line viability.
MeSH term(s)	Humans ; Proteomics ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Genomics ; Protein Kinases
Chemical Substances	Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2023-05-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.28420
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Article ; Online: Author Correction

Yiqun Zhang / Fengju Chen / Darshan S. Chandrashekar / Sooryanarayana Varambally / Chad J. Creighton

Nature Communications, Vol 13, Iss 1, Pp 1-

Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways

2022 Volume 1

Keywords	Science ; Q
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A comparative cross-reactivity and paraspecific neutralization study on Hypnale hypnale, Echis carinatus, and Daboia russelii monovalent and therapeutic polyvalent anti-venoms.

Sandesha, Vaddaragudisalu D / Darshan, Bhaskar / Tejas, Chandrashekar / Girish, Kesturu S / Kempaiah, Kemparaju

PLoS neglected tropical diseases

2022 Volume 16, Issue 3, Page(s) e0010292

Abstract: Envenoming by the hump-nosed pit viper (Hypnale hypnale) raises concern as it inflicts significant debilitation and death in the Western Ghats of India and in the adjacent island nation of Sri Lanka. In India, its medical significance was realized only ... ...

Abstract	Envenoming by the hump-nosed pit viper (Hypnale hypnale) raises concern as it inflicts significant debilitation and death in the Western Ghats of India and in the adjacent island nation of Sri Lanka. In India, its medical significance was realized only during 2007 due to its misidentification as Echis carinatus and sometimes as Daboia russelii. Of late, several case reports have underlined the ineptness of the existing polyvalent anti-venom therapy against H. hypnale envenoming. Currently, H. hypnale bite has remained dreadful in India due to the lack of neutralizing anti-venom therapy. Hence, this study was undertaken to establish a systematic comparative, biochemical, pathological, and immunological properties of Sri Lankan H. hypnale venom alongside Indian E. carinatus, and D. russelii venoms. All three venoms differed markedly in the extent of biochemical activities including proteolytic, deoxyribonuclease, L-amino acid oxidase, 5'-nucleotidase, hyaluronidase, and indirect hemolytic activities. The venoms also differed markedly in their pathological properties such as edema, hemorrhage, myotoxic, cardiotoxic, and coagulant activities. The venoms showed stark differences in their protein banding pattern. Strikingly, the affinity-purified rabbit monovalent anti-venoms prepared against H. hypnale, E. carinatus, and D. russelii venoms readily reacted and neutralized the biochemical and pathological properties of their respective venoms, but they insignificantly cross-reacted with, and thus failed to show paraspecific neutralization of any of the effects of the other two venoms, demonstrating the large degree of variations between these venoms. Further, the Indian therapeutic polyvalent anti-venoms from VINS Bioproducts, and Bharath Serums and Vaccines failed to protect H. hypnale venom-induced lethal effects in mice.
MeSH term(s)	Animals ; Antivenins/pharmacology ; Antivenins/therapeutic use ; Crotalinae ; Humans ; Mice ; Rabbits ; Daboia ; Viper Venoms ; Viperidae
Chemical Substances	Antivenins ; Viper Venoms
Language	English
Publishing date	2022-03-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2735
ISSN (online)	1935-2735
ISSN	1935-2735
DOI	10.1371/journal.pntd.0010292
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways

Yiqun Zhang / Fengju Chen / Darshan S. Chandrashekar / Sooryanarayana Varambally / Chad J. Creighton

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 19

Abstract: Pan-cancer proteomics analysis enables the analysis of protein expression across multiple cancer types. Here, the authors compare proteomics from 14 cancer types and show 11 distinct subtypes across multiple cancer types. Proteome data could link higher ... ...

Abstract	Pan-cancer proteomics analysis enables the analysis of protein expression across multiple cancer types. Here, the authors compare proteomics from 14 cancer types and show 11 distinct subtypes across multiple cancer types. Proteome data could link higher pathway activity levels with somatic alteration of specific genes in the pathway.
Keywords	Science ; Q
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparative transcriptome analyses reveal genes associated with SARS-CoV-2 infection of human lung epithelial cells.

Chandrashekar, Darshan S / Athar, Mohammad / Manne, Upender / Varambally, Sooryanarayana

Scientific reports

2021 Volume 11, Issue 1, Page(s) 16212

Abstract: During 2020, understanding the molecular mechanism of SARS-CoV-2 infection (the cause of COVID-19) became a scientific priority due to the devastating effects of the COVID-19. Many researchers have studied the effect of this viral infection on lung ... ...

Abstract	During 2020, understanding the molecular mechanism of SARS-CoV-2 infection (the cause of COVID-19) became a scientific priority due to the devastating effects of the COVID-19. Many researchers have studied the effect of this viral infection on lung epithelial transcriptomes and deposited data in public repositories. Comprehensive analysis of such data could pave the way for development of efficient vaccines and effective drugs. In the current study, we obtained high-throughput gene expression data associated with human lung epithelial cells infected with respiratory viruses such as SARS-CoV-2, SARS, H1N1, avian influenza, rhinovirus and Dhori, then performed comparative transcriptome analysis to identify SARS-CoV-2 exclusive genes. The analysis yielded seven SARS-CoV-2 specific genes including CSF2 [GM-CSF] (colony-stimulating factor 2) and calcium-binding proteins (such as S100A8 and S100A9), which are known to be involved in respiratory diseases. The analyses showed that genes involved in inflammation are commonly altered by infection of SARS-CoV-2 and influenza viruses. Furthermore, results of protein-protein interaction analyses were consistent with a functional role of CSF2 and S100A9 in COVID-19 disease. In conclusion, our analysis revealed cellular genes associated with SARS-CoV-2 infection of the human lung epithelium; these are potential therapeutic targets.
MeSH term(s)	Alveolar Epithelial Cells/metabolism ; Alveolar Epithelial Cells/virology ; COVID-19/genetics ; COVID-19/metabolism ; COVID-19/virology ; Calgranulin A/genetics ; Calgranulin A/metabolism ; Calgranulin B/genetics ; Calgranulin B/metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Humans ; SARS-CoV-2/pathogenicity ; Transcriptome
Chemical Substances	CSF2 protein, human ; Calgranulin A ; Calgranulin B ; S100A8 protein, human ; S100A9 protein, human ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
Language	English
Publishing date	2021-08-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-95733-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways.

Zhang, Yiqun / Chen, Fengju / Chandrashekar, Darshan S / Varambally, Sooryanarayana / Creighton, Chad J

Nature communications

2022 Volume 13, Issue 1, Page(s) 2669

Abstract: Mass-spectrometry-based proteomic data on human tumors-combined with corresponding multi-omics data-present opportunities for systematic and pan-cancer proteogenomic analyses. Here, we assemble a compendium dataset of proteomics data of 2002 primary ... ...

Abstract	Mass-spectrometry-based proteomic data on human tumors-combined with corresponding multi-omics data-present opportunities for systematic and pan-cancer proteogenomic analyses. Here, we assemble a compendium dataset of proteomics data of 2002 primary tumors from 14 cancer types and 17 studies. Protein expression of genes broadly correlates with corresponding mRNA levels or copy number alterations (CNAs) across tumors, but with notable exceptions. Based on unsupervised clustering, tumors separate into 11 distinct proteome-based subtypes spanning multiple tissue-based cancer types. Two subtypes are enriched for brain tumors, one subtype associating with MYC, Wnt, and Hippo pathways and high CNA burden, and another subtype associating with metabolic pathways and low CNA burden. Somatic alteration of genes in a pathway associates with higher pathway activity as inferred by proteome or transcriptome data. A substantial fraction of cancers shows high MYC pathway activity without MYC copy gain but with mutations in genes with noncanonical roles in MYC. Our proteogenomics survey reveals the interplay between genome and proteome across tumor lineages.
MeSH term(s)	DNA Copy Number Variations ; Humans ; Neoplasms/genetics ; Proteogenomics ; Proteome/genetics ; Proteomics
Chemical Substances	Proteome
Language	English
Publishing date	2022-05-13
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-30342-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells.

Moore, Kyle H / Boitet, Laurence M / Chandrashekar, Darshan S / Traylor, Amie M / Esman, Stephanie K / Erman, Elise N / Srivastava, Ritesh K / Khan, Jasim / Athar, Mohammad / Agarwal, Anupam / George, James F

The Journal of pharmacology and experimental therapeutics

2024 Volume 388, Issue 2, Page(s) 605–612

Abstract: Arsenicals are deadly chemical warfare agents that primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated ... ...

Abstract	Arsenicals are deadly chemical warfare agents that primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced understanding of how arsenical exposure can lead to kidney injury is needed. We used a nontargeted transcriptional approach to evaluate the effects of cutaneous exposure to phenylarsine oxide, a common arsenical, in a murine model. Here we identified an upregulation of metabolic pathways such as fatty acid oxidation, fatty acid biosynthesis, and peroxisome proliferator-activated receptor (PPAR)-
MeSH term(s)	Mice ; Humans ; Animals ; Endothelial Cells/metabolism ; Kidney/metabolism ; Acute Kidney Injury/chemically induced ; Acute Kidney Injury/genetics ; Acute Kidney Injury/metabolism ; Epithelial Cells/metabolism ; Fatty Acids/metabolism ; Arsenicals/adverse effects ; Arsenicals/metabolism
Chemical Substances	Fatty Acids ; Arsenicals
Language	English
Publishing date	2024-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.123.001742
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Comparative transcriptome analyses reveal genes associated with SARS-CoV-2 infection of human lung epithelial cells

Darshan S. Chandrashekar / Mohammad Athar / Upender Manne / Sooryanarayana Varambally

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 11

Abstract: Abstract During 2020, understanding the molecular mechanism of SARS-CoV-2 infection (the cause of COVID-19) became a scientific priority due to the devastating effects of the COVID-19. Many researchers have studied the effect of this viral infection on ... ...

Abstract	Abstract During 2020, understanding the molecular mechanism of SARS-CoV-2 infection (the cause of COVID-19) became a scientific priority due to the devastating effects of the COVID-19. Many researchers have studied the effect of this viral infection on lung epithelial transcriptomes and deposited data in public repositories. Comprehensive analysis of such data could pave the way for development of efficient vaccines and effective drugs. In the current study, we obtained high-throughput gene expression data associated with human lung epithelial cells infected with respiratory viruses such as SARS-CoV-2, SARS, H1N1, avian influenza, rhinovirus and Dhori, then performed comparative transcriptome analysis to identify SARS-CoV-2 exclusive genes. The analysis yielded seven SARS-CoV-2 specific genes including CSF2 [GM-CSF] (colony-stimulating factor 2) and calcium-binding proteins (such as S100A8 and S100A9), which are known to be involved in respiratory diseases. The analyses showed that genes involved in inflammation are commonly altered by infection of SARS-CoV-2 and influenza viruses. Furthermore, results of protein–protein interaction analyses were consistent with a functional role of CSF2 and S100A9 in COVID-19 disease. In conclusion, our analysis revealed cellular genes associated with SARS-CoV-2 infection of the human lung epithelium; these are potential therapeutic targets.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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