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Montoya Mira JL, Quentel A, Patel RK, Keith D, Sousa M, Minnier J, Kingston BR, David L, Esener SC, Sears RC, Lopez CD, Sheppard BC, Demirci U, Wong MH, Fischer JM. Early detection of pancreatic cancer by a high-throughput protease-activated nanosensor assay. Sci Transl Med 2025; 17:eadq3110. [PMID: 39937880 DOI: 10.1126/scitranslmed.adq3110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 10/11/2024] [Accepted: 01/23/2025] [Indexed: 02/14/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the top causes of cancer-related death. Patients are frequently diagnosed in the more advanced stages when effective treatment options are limited; however, earlier detection of PDAC by liquid biopsy may expand treatment options and improve survival outcomes. Here, we developed a noninvasive detection assay for PDAC based on serum protease activity to leverage the increase in cancer-associated protease activity in the peripheral blood of patients with PDAC. We screened a series of protease-cleavable peptide probes for the discrimination of PDAC samples versus healthy controls and noncancerous pancreatic disease. We identified a single MMP-sensitive probe, which could distinguish PDAC from controls with 79 ± 6% accuracy. We further developed this probe into a rapid magnetic nanosensor assay, termed PAC-MANN, that measures serum protease cleavage of a target-probe nanosensor with a simple fluorescent readout. In a longitudinal cohort of patients undergoing surgical removal of the primary tumor, the probe cleavage signal was reduced by 16 ± 24% after surgery. In a separate blinded retrospective study, the PAC-MANN assay identified PDAC samples with 98% specificity and 73% sensitivity across all stages and distinguished 100% of patients with noncancer pancreatic disease relative to patients with PDAC. The PAC-MANN assay combined with the clinical biomarker CA 19-9 was 85% sensitive for detection of stage I PDAC with 96% specificity. Therefore, the PAC-MANN assay is a rapid, high-throughput method that uses small blood volumes with the potential to enhance early PDAC detection, specifically among individuals at high risk of developing PDAC.
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Affiliation(s)
- Jose L Montoya Mira
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University (OHSU), Portland, OR 97201, USA
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
| | - Arnaud Quentel
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University (OHSU), Portland, OR 97201, USA
| | | | - Dove Keith
- Brenden-Colson Center for Pancreatic Care, OHSU, Portland, OR 97201, USA
| | - Megan Sousa
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University (OHSU), Portland, OR 97201, USA
| | - Jessica Minnier
- Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Biostatistics, OHSU, Portland, OR 97239, USA
| | - Benjamin R Kingston
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University (OHSU), Portland, OR 97201, USA
| | - Larry David
- Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Chemical Physiology and Biochemistry, OHSU, Portland, OR 97239, USA
| | - Sadik C Esener
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University (OHSU), Portland, OR 97201, USA
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Rosalie C Sears
- Brenden-Colson Center for Pancreatic Care, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Molecular and Medical Genetics, OHSU, Portland, OR 97239, USA
| | - Charles D Lopez
- Brenden-Colson Center for Pancreatic Care, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Cell, Development and Cancer Biology, OHSU, Portland, OR 97239, USA
| | - Brett C Sheppard
- Department of Surgery, OHSU, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Utkan Demirci
- Bio-Acoustic MEMS in Medicine Lab, Canary Center, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
- Electrical Engineering Department (by courtesy), Stanford University School of Engineering, Palo Alto, CA 94305, USA
| | - Melissa H Wong
- Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Cell, Development and Cancer Biology, OHSU, Portland, OR 97239, USA
| | - Jared M Fischer
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University (OHSU), Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Department of Molecular and Medical Genetics, OHSU, Portland, OR 97239, USA
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Duarte CA, Cabrales A, Echevarría R, Paneque T, Ramírez AC, Casillas D, Sobrino-Iglesias X, Garay H, Besada V, Fernández-Ortega C. Stability in human serum and plasma of the HIV peptide drug candidate CIGB-210 and improved variants. Biotechnol Appl Biochem 2025; 72:187-195. [PMID: 39219226 DOI: 10.1002/bab.2655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 08/05/2024] [Indexed: 09/04/2024]
Abstract
The peptide CIGB-210 inhibits HIV replication, inducing a rearrangement of vimentin intermediate filaments. The assessment of the in vitro serum and plasma stability of this peptide is important to develop an optimal pharmacological formulation. A half-life of 17.68 ± 0.59 min was calculated for CIGB-210 in human serum by reverse-phase high-performance liquid chromatography (HPLC) and mass spectrometry (MS). Eight metabolites of CIGB-210 were identified with this methodology, all of them lacking the N-terminal moiety. A previously developed CIGB-210 in-house competitive ELISA was used to compare the stability of CIGB-210 derivatives containing either D-amino acids, acetylation at the N-terminus, or both modifications. The half-life of CIGB-210 in serum was five times higher when measured by ELISA than by HPLC/MS, and twice higher in plasma as compared to serum. The substitution of D-asparagine on position 6 doubled the half-life, while D-amino acids on positions 8 and 9 did not improve the stability. The acetylation of the N-terminus resulted in a 24-fold more stable peptide in plasma. The positive effect of N-terminal acetylation on CIGB-210 serum stability was confirmed by the HPLC/MS method, as the half-life of the peptide was not reached after 2 h of incubation, which represents more than a 6.8-fold increase in the half-life with respect to the original peptide.
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Affiliation(s)
- Carlos A Duarte
- Departamento de Farmacéuticos, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
| | - Ania Cabrales
- Departamento de Química-Física, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
| | - Reina Echevarría
- Departamento de Farmacéuticos, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
| | - Taimí Paneque
- Departamento de Farmacéuticos, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
| | - Anna C Ramírez
- Departamento de Farmacéuticos, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
| | - Dionne Casillas
- Departamento de Farmacéuticos, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
| | - Xeila Sobrino-Iglesias
- Departamento de Química-Física, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
| | - Hilda Garay
- Departamento de Química-Física, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
| | - Vladimir Besada
- Departamento de Química-Física, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
| | - Celia Fernández-Ortega
- Departamento de Farmacéuticos, Centro de Ingeniería Genética y Biotecnología, La Habana, Cuba
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González-Turén F, Lobos-González L, Riquelme-Herrera A, Ibacache A, Meza Ulloa L, Droguett A, Alveal C, Carrillo B, Gutiérrez J, Ehrenfeld P, Cárdenas-Oyarzo A. Kinin Receptors B1 and B2 Mediate Breast Cancer Cell Migration and Invasion by Activating the FAK-Src Axis. Int J Mol Sci 2024; 25:11709. [PMID: 39519260 PMCID: PMC11546324 DOI: 10.3390/ijms252111709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/27/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Kinin receptors B1 and B2 are involved in migration and invasion in gastric, glioma, and cervical cancer cells, among others. However, the role of kinin receptors in breast cancer cells has been poorly studied. We aimed to reveal the impact of B1 and B2 receptors on migration and invasion in breast cancer cells and demonstrate their capacity to modulate in vivo tumor growth. MDA-MB-231, MCF-7, and T47D cells treated with Lys-des[Arg9]bradykinin (LDBK) or bradykinin (BK) were used to evaluate migration and invasion. Des-[Arg9]-Leu8-BK and HOE-140 were used as antagonists for the B1 and B2 receptors. MDA-MB-231 cells incubated or not with antagonists were subcutaneously inoculated in BALBc NOD/SCID mice to evaluate tumor growth. LDBK and BK treatment significantly increased migration and invasion in breast cancer cells, effects that were negated when antagonists were used. The use of antagonists in vivo inhibited tumor growth. Moreover, the migration and invasion induced by kinins in breast cancer cells were inhibited when focal adhesion kinase (FAK) and Src inhibitors were used. The novelty revealed in our work is that B1 and B2 receptors activated by LDBK and BK induce migration and invasion in breast cancer cells via a mechanism that involves the FAK-Src signaling pathway, and the antagonism of both receptors in vivo impairs breast tumor growth.
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Affiliation(s)
- Felipe González-Turén
- School of Nursing, Faculty of Health Sciences, Universidad Bernardo O’Higgins, Santiago 8370854, Chile
| | - Lorena Lobos-González
- Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8370854, Chile
- Center for Regenerative Medicine, Institute for Sciences and Innovation in Medicine, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
| | - Alexander Riquelme-Herrera
- Centro Integrativo de Biología y Química Aplicada (CIBQA), Faculty of Health Sciences, Universidad Bernardo O’Higgins, Santiago 8370854, Chile
| | - Andrés Ibacache
- Laboratory of Molecular Design, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8370854, Chile
| | - Luis Meza Ulloa
- School of Medical Technology, Faculty of Health Sciences, Universidad Bernardo O’Higgins, Santiago 8370854, Chile
| | - Alexandra Droguett
- School of Medical Technology, Faculty of Health Sciences, Universidad Bernardo O’Higgins, Santiago 8370854, Chile
| | - Camila Alveal
- School of Medical Technology, Faculty of Health Sciences, Universidad Bernardo O’Higgins, Santiago 8370854, Chile
| | - Bastián Carrillo
- School of Medical Technology, Faculty of Health Sciences, Universidad Bernardo O’Higgins, Santiago 8370854, Chile
| | - Javiera Gutiérrez
- School of Medical Technology, Faculty of Health Sciences, Universidad Bernardo O’Higgins, Santiago 8370854, Chile
| | - Pamela Ehrenfeld
- Laboratory of Cellular Pathology, Institute of Anatomy, Histology & Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia 5110566, Chile
- Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia 5110566, Chile
| | - Areli Cárdenas-Oyarzo
- School of Obstetrics and Puericulture, Faculty of Medical Sciences, Universidad Bernardo O’Higgins, Santiago 8370854, Chile
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Puchalski M, Tretiakow D, Skorek A, Szydłowski K, Stodulski D, Mikaszewski B, Odroniec A, Musiał N, Thiel M, Czaplewska P, Ołdziej S. Comparison of Peptidomes Extracted from Healthy Tissue and Tumor Tissue of the Parotid Glands and Saliva Samples. Int J Mol Sci 2024; 25:8799. [PMID: 39201484 PMCID: PMC11354857 DOI: 10.3390/ijms25168799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/04/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Salivary gland tumors are highly variable in clinical presentation and histology. The World Health Organization (WHO) classifies 22 types of malignant and 11 types of benign tumors of the salivary glands. Diagnosis of salivary gland tumors is based on imaging (ultrasound, magnetic resonance imaging) and fine-needle aspiration biopsy, but the final diagnosis is based on histopathological examination of the removed tumor tissue. In this pilot study, we are testing a new approach to identifying peptide biomarkers in saliva that can be used to diagnose salivary gland tumors. The research material for the peptidomic studies was extracts from washings of neoplastic tissues and healthy tissues (control samples). At the same time, saliva samples from patients and healthy individuals were analyzed. The comparison of the peptidome composition of tissue extracts and saliva samples may allow the identification of potential peptide markers of salivary gland tumors in patients' saliva. The peptidome compositions extracted from 18 tumor and 18 healthy tissue samples, patients' saliva samples (11 samples), and healthy saliva samples (8 samples) were analyzed by LC-MS tandem mass spectrometry. A group of 109 peptides was identified that were present only in the tumor tissue extracts and in the patients' saliva samples. Some of the identified peptides were derived from proteins previously suggested as potential biomarkers of salivary gland tumors (ANXA1, BPIFA2, FGB, GAPDH, HSPB1, IGHG1, VIM) or tumors of other tissues or organs (SERPINA1, APOA2, CSTB, GSTP1, S100A8, S100A9, TPI1). Unfortunately, none of the identified peptides were present in all samples analyzed. This may be due to the high heterogeneity of this type of cancer. The surprising result was that extracts from tumor tissue did not contain peptides derived from salivary gland-specific proteins (STATH, SMR3B, HTN1, HTN3). These results could suggest that the developing tumor suppresses the production of proteins that are essential components of saliva.
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Affiliation(s)
- Michał Puchalski
- Intercollegiate Faculty of Biotechnology UG&MUG, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.P.); (A.O.); (N.M.); (M.T.); (P.C.)
| | - Dmitry Tretiakow
- Department of Otolaryngology, the Nicolaus Copernicus Hospital in Gdansk, Copernicus Healthcare Entity, Powstańców Warszawskich 1/2, 80-152 Gdansk, Poland; (A.S.); (K.S.)
- Department of Otolaryngology, Faculty of Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland; (D.S.); (B.M.)
| | - Andrzej Skorek
- Department of Otolaryngology, the Nicolaus Copernicus Hospital in Gdansk, Copernicus Healthcare Entity, Powstańców Warszawskich 1/2, 80-152 Gdansk, Poland; (A.S.); (K.S.)
- Department of Otolaryngology, Faculty of Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland; (D.S.); (B.M.)
| | - Konrad Szydłowski
- Department of Otolaryngology, the Nicolaus Copernicus Hospital in Gdansk, Copernicus Healthcare Entity, Powstańców Warszawskich 1/2, 80-152 Gdansk, Poland; (A.S.); (K.S.)
| | - Dominik Stodulski
- Department of Otolaryngology, Faculty of Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland; (D.S.); (B.M.)
| | - Bogusław Mikaszewski
- Department of Otolaryngology, Faculty of Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland; (D.S.); (B.M.)
| | - Amadeusz Odroniec
- Intercollegiate Faculty of Biotechnology UG&MUG, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.P.); (A.O.); (N.M.); (M.T.); (P.C.)
| | - Natalia Musiał
- Intercollegiate Faculty of Biotechnology UG&MUG, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.P.); (A.O.); (N.M.); (M.T.); (P.C.)
| | - Marcel Thiel
- Intercollegiate Faculty of Biotechnology UG&MUG, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.P.); (A.O.); (N.M.); (M.T.); (P.C.)
| | - Paulina Czaplewska
- Intercollegiate Faculty of Biotechnology UG&MUG, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.P.); (A.O.); (N.M.); (M.T.); (P.C.)
| | - Stanisław Ołdziej
- Intercollegiate Faculty of Biotechnology UG&MUG, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.P.); (A.O.); (N.M.); (M.T.); (P.C.)
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Zhao Y, Shen H, Wu J, Yu J, Yuan Y, Zhong C. Discovery, identification and mechanism of chemosensitivity-relate biomarker inter-α-trypsin inhibitor heavy chain 4 in metastatic colorectal cancer. Heliyon 2024; 10:e33571. [PMID: 39040328 PMCID: PMC11260961 DOI: 10.1016/j.heliyon.2024.e33571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/24/2024] Open
Abstract
Predictive biomarkers of response to chemotherapy in patients with metastatic colorectal cancer (mCRC) are needed to better characterize tumors and enable more tailored therapies. Here we used serum proteomics to screen for chemotherapy predictive markers. We found that higher baseline serum inter-α-trypsin inhibitor Heavy Chain 4 (ITIH4) expression in newly diagnosed mCRC patients was associated with poorer response to standard first-line chemotherapy. In addition, the higher expression of ITIH4 in CRC tissue also suggested poorer prognosis mCRC patients. Moreover, the overexpression of ITIH4 could promote the proliferation of CRC cells and reduce the sensitivity of CRC cells to 5-fluorouracil (5-FU) by inhibiting apoptosis in vivo and vitro. Through RNA-seq combined with bioinformatics analysis, we speculated that ITIH4 may activate phosphatidyl 3-kinase-protein kinase B (PI3K-AKT) pathway to inhibit apoptosis, thereby reducing the sensitivity of CRC cells to 5-FU. In conclusion, our findings unveil that ITIH4 is associated with CRC resistance to 5-FU, and may serve as a potential predictive biomarker for the sensitivity of advanced CRC patients to standard first-line chemotherapy regimens, and also provide a potential therapeutic target to render 5-FU resistance in CRC patients.
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Affiliation(s)
- Yingxin Zhao
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Hong Shen
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Jianmin Wu
- Institute of Microanalytical System Department of Chemistry, Zhejiang University Hangzhou, Zhejiang, 310058, China
| | - Jiekai Yu
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Ying Yuan
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China
- Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang, 310009, China
| | - Chenhan Zhong
- Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
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Li Z, Chen J, Xu B, Zhao W, Zha H, Han Y, Shen W, Dong Y, Zhao N, Zhang M, He K, Li Z, Liu X. Correlation between small-cell lung cancer serum protein/peptides determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and chemotherapy efficacy. Clin Proteomics 2024; 21:35. [PMID: 38764042 PMCID: PMC11103996 DOI: 10.1186/s12014-024-09483-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 04/22/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Currently, no effective measures are available to predict the curative efficacy of small-cell lung cancer (SCLC) chemotherapy. We expect to develop a method for effectively predicting the SCLC chemotherapy efficacy and prognosis in clinical practice in order to offer more pertinent therapeutic protocols for individual patients. METHODS We adopted matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinPro Tools system to detect serum samples from 154 SCLC patients with different curative efficacy of standard chemotherapy and analyze the different peptides/proteins of SCLC patients to discover predictive tumor markers related to chemotherapy efficacy. Ten peptide/protein peaks were significantly different in the two groups. RESULTS A genetic algorithm model consisting of four peptides/proteins was developed from the training group to separate patients with different chemotherapy efficacies. Among them, three peptides/proteins (m/z 3323.35, 6649.03 and 6451.08) showed high expression in the disease progression group, whereas the peptide/protein at m/z 4283.18 was highly expressed in the disease response group. The classifier exhibited an accuracy of 91.4% (53/58) in the validation group. The survival analysis showed that the median progression-free survival (PFS) of 30 SCLC patients in disease response group was 9.0 months; in 28 cases in disease progression group, the median PFS was 3.0 months, a statistically significant difference (χ2 = 46.98, P < 0.001). The median overall survival (OS) of the two groups was 13.0 months and 7.0 months, a statistically significant difference (χ2 = 40.64, P < 0.001). CONCLUSIONS These peptides/proteins may be used as potential biological markers for prediction of the curative efficacy and prognosis for SCLC patients treated with standard regimen chemotherapy.
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Affiliation(s)
- Zhihua Li
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Junnan Chen
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Bin Xu
- National Center of Biomedical Analysis, Beijing, 100850, China
| | - Wei Zhao
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Haoran Zha
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Yalin Han
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Wennan Shen
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Yuemei Dong
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Nan Zhao
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Manze Zhang
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China
| | - Kun He
- National Center of Biomedical Analysis, Beijing, 100850, China
| | - Zhaoxia Li
- Department of Oncology, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China.
| | - Xiaoqing Liu
- Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, 100071, China.
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Dempsey PW, Sandu CM, Gonzalezirias R, Hantula S, Covarrubias-Zambrano O, Bossmann SH, Nagji AS, Veeramachaneni NK, Ermerak NO, Kocakaya D, Lacin T, Yildizeli B, Lilley P, Wen SWC, Nederby L, Hansen TF, Hilberg O. Description of an activity-based enzyme biosensor for lung cancer detection. COMMUNICATIONS MEDICINE 2024; 4:37. [PMID: 38443590 PMCID: PMC10914759 DOI: 10.1038/s43856-024-00461-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 02/14/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND Lung cancer is associated with the greatest cancer mortality as it typically presents with incurable distributed disease. Biomarkers relevant to risk assessment for the detection of lung cancer continue to be a challenge because they are often not detectable during the asymptomatic curable stage of the disease. A solution to population-scale testing for lung cancer will require a combination of performance, scalability, cost-effectiveness, and simplicity. METHODS One solution is to measure the activity of serum available enzymes that contribute to the transformation process rather than counting biomarkers. Protease enzymes modify the environment during tumor growth and present an attractive target for detection. An activity based sensor platform sensitive to active protease enzymes is presented. A panel of 18 sensors was used to measure 750 sera samples from participants at increased risk for lung cancer with or without the disease. RESULTS A machine learning approach is applied to generate algorithms that detect 90% of cancer patients overall with a specificity of 82% including 90% sensitivity in Stage I when disease intervention is most effective and detection more challenging. CONCLUSION This approach is promising as a scalable, clinically useful platform to help detect patients who have lung cancer using a simple blood sample. The performance and cost profile is being pursued in studies as a platform for population wide screening.
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Affiliation(s)
| | | | | | | | | | | | - Alykhan S Nagji
- University of Kansas Medical Center (KUMC), Kansas City, KS, USA
| | | | | | | | | | | | | | - Sara W C Wen
- Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Line Nederby
- Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Torben F Hansen
- Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Ole Hilberg
- Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark
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8
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Greive SJ, Bacri L, Cressiot B, Pelta J. Identification of Conformational Variants for Bradykinin Biomarker Peptides from a Biofluid Using a Nanopore and Machine Learning. ACS NANO 2024; 18:539-550. [PMID: 38134312 DOI: 10.1021/acsnano.3c08433] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2023]
Abstract
There is a current need to develop methods for the sensitive detection of peptide biomarkers in complex mixtures of molecules, such as biofluids, to enable early disease detection. Moreover, to our knowledge, there is currently no detection method capable of identifying the different conformations of a peptide biomarker differing by a single amino acid. Single-molecule nanopore sensing promises to provide this level of resolution. In order to be able to identify these differences in a biofluid such as serum, it is necessary to carefully characterize electrical parameters to obtain specific signatures of each biomarker population observed. We are interested here in a family of peptide biomarkers, kinins such as bradykinin and des-Arg9 bradykinin, that are involved in many disabling pathologies (allergy, asthma, angioedema, sepsis, or cancer). We show the proof of concept for direct identification of these biomarkers in serum at the single-molecule level using a protein nanopore. Each peptide exhibits two unique electrical signatures attributed to specific conformations in bulk. The same signatures are found in serum, allowing their discrimination and identification in a complex mixture such as biofluid. To extend the utility of our experimental results, we developed a principal component analysis approach to define the most relevant electrical parameters for their identification. Finally, we used semisupervised classification to assign each event type to a specific biomarker at physiological serum concentration. In the future, single-molecule scale analysis of peptide biomarkers using a powerful nanopore coupled with machine learning will facilitate the identification and quantification of other clinically relevant biomarkers from biofluids.
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Affiliation(s)
| | - Laurent Bacri
- Université Paris-Saclay, Univ Evry, CY Cergy Paris Université, CNRS, LAMBE, 91025 Evry-Courcouronnes, France
| | - Benjamin Cressiot
- Université Paris-Saclay, Univ Evry, CY Cergy Paris Université, CNRS, LAMBE, F-95000 Cergy, France
| | - Juan Pelta
- Université Paris-Saclay, Univ Evry, CY Cergy Paris Université, CNRS, LAMBE, 91025 Evry-Courcouronnes, France
- Université Paris-Saclay, Univ Evry, CY Cergy Paris Université, CNRS, LAMBE, F-95000 Cergy, France
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9
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Whitham D, Bruno P, Haaker N, Arcaro KF, Pentecost BT, Darie CC. Deciphering a proteomic signature for the early detection of breast cancer from breast milk: the role of quantitative proteomics. Expert Rev Proteomics 2024; 21:81-98. [PMID: 38376826 PMCID: PMC11694492 DOI: 10.1080/14789450.2024.2320158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 12/26/2023] [Indexed: 02/21/2024]
Abstract
INTRODUCTION Breast cancer is one of the most prevalent cancers among women in the United States. Current research regarding breast milk has been focused on the composition and its role in infant growth and development. There is little information about the proteins, immune cells, and epithelial cells present in breast milk which can be indicative of the emergence of BC cells and tumors. AREAS COVERED We summarize all breast milk studies previously done in our group using proteomics. These studies include 1D-PAGE and 2D-PAGE analysis of breast milk samples, which include within woman and across woman comparisons to identify dysregulated proteins in breast milk and the roles of these proteins in both the development of BC and its diagnosis. Our projected outlook for the use of milk for cancer detection is also discussed. EXPERT OPINION Analyzing the samples by multiple methods allows one to interrogate a set of samples with various biochemical methods that complement each other, thus providing a more comprehensive proteome. Complementing methods like 1D-PAGE, 2D-PAGE, in-solution digestion and proteomics analysis with PTM-omics, peptidomics, degradomics, or interactomics will provide a better understanding of the dysregulated proteins, but also the modifications or interactions between these proteins.
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Affiliation(s)
- Danielle Whitham
- Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY, USA
| | - Pathea Bruno
- Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY, USA
| | - Norman Haaker
- Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY, USA
| | - Kathleen F. Arcaro
- Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, MA, USA
| | - Brian T. Pentecost
- Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY, USA
- Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, MA, USA
| | - Costel C. Darie
- Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY, USA
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10
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Bose S, Saha S, Goswami H, Shanmugam G, Sarkar K. Involvement of CCCTC-binding factor in epigenetic regulation of cancer. Mol Biol Rep 2023; 50:10383-10398. [PMID: 37840067 DOI: 10.1007/s11033-023-08879-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 10/03/2023] [Indexed: 10/17/2023]
Abstract
A major global health burden continues to be borne by the complex and multifaceted disease of cancer. Epigenetic changes, which are essential for the emergence and spread of cancer, have drawn a huge amount of attention recently. The CCCTC-binding factor (CTCF), which takes part in a wide range of cellular processes including genomic imprinting, X chromosome inactivation, 3D chromatin architecture, local modifications of histone, and RNA polymerase II-mediated gene transcription, stands out among the diverse array of epigenetic regulators. CTCF not only functions as an architectural protein but also modulates DNA methylation and histone modifications. Epigenetic regulation of cancer has already been the focus of plenty of studies. Understanding the role of CTCF in the cancer epigenetic landscape may lead to the development of novel targeted therapeutic strategies for cancer. CTCF has already earned its status as a tumor suppressor gene by acting like a homeostatic regulator of genome integrity and function. Moreover, CTCF has a direct effect on many important transcriptional regulators that control the cell cycle, apoptosis, senescence, and differentiation. As we learn more about CTCF-mediated epigenetic modifications and transcriptional regulations, the possibility of utilizing CTCF as a diagnostic marker and therapeutic target for cancer will also increase. Thus, the current review intends to promote personalized and precision-based therapeutics for cancer patients by shedding light on the complex interplay between CTCF and epigenetic processes.
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Affiliation(s)
- Sayani Bose
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Srawsta Saha
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Harsita Goswami
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Geetha Shanmugam
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
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11
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Rungkamoltip P, Roytrakul S, Navakanitworakul R. MALDI-TOF MS Analysis of Serum Peptidome Patterns in Cervical Cancer. Biomedicines 2023; 11:2327. [PMID: 37626823 PMCID: PMC10452062 DOI: 10.3390/biomedicines11082327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Cervical cancer is the fourth most common cancer among females worldwide. Identifying peptide patterns discriminating healthy individuals from those with diseases has gained interest in the early detection of cancers. Our study aimed to determine signature peptide patterns for cervical cancer screening. METHODS Our study focused on the serum peptidome analysis of 83 healthy women and 139 patients with cervical cancer. All spectra derived from matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were analyzed using FlexAnalysis 3.0 and ClinProTools 2.2 software. RESULTS In the mass range of 1000-10,000 Da, the total average spectra were represented as the signature pattern. Principal component analysis showed that all the groups were separately distributed. Furthermore, the peaks at m/z 1466.91, 1898.01, 3159.09, and 4299.40 significantly differed among the investigated groups (Wilcoxon/Kruskal-Wallis test and ANOVA, p < 0.001). CONCLUSIONS Laboratory-based rapid mass spectrometry showed that serum peptidome patterns could serve as diagnostic tools for diagnosing cervical cancer; however, verification through larger cohorts and association with clinical data are required, and the use of externally validated samples, such as patients with other types of cancers, should be investigated to validate the specific peptide patterns.
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Affiliation(s)
- Phetploy Rungkamoltip
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand;
| | - Sittiruk Roytrakul
- Proteomic Research Laboratory, National Center for Genetic Engineering and Biotechnology, Thailand Science Park, Pathum Thani 12120, Thailand;
| | - Raphatphorn Navakanitworakul
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand;
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12
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Gallo A, Massaro MG, Camilli S, Verrecchia E, Montalto M. Chronic cough in very old patients on long-term therapy with angiotensin converting enzyme inhibitors and new-onset cancer. Eur J Intern Med 2023; 114:141-142. [PMID: 37164886 DOI: 10.1016/j.ejim.2023.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/28/2023] [Accepted: 05/04/2023] [Indexed: 05/12/2023]
Affiliation(s)
- Antonella Gallo
- Department of Geriatric Medicine, Fondazione Policlinico Universitario A. Gemelli, IRCSS, Rome, Italy.
| | - Maria Grazia Massaro
- Department of Geriatric Medicine, Fondazione Policlinico Universitario A. Gemelli, IRCSS, Rome, Italy
| | - Sara Camilli
- Department of Geriatric Medicine, Fondazione Policlinico Universitario A. Gemelli, IRCSS, Rome, Italy
| | - Elena Verrecchia
- Department of Geriatric Medicine, Fondazione Policlinico Universitario A. Gemelli, IRCSS, Rome, Italy
| | - Massimo Montalto
- Department of Geriatric Medicine, Fondazione Policlinico Universitario A. Gemelli, IRCSS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy
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13
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Jordaens S, Oeyen E, Willems H, Ameye F, De Wachter S, Pauwels P, Mertens I. Protein Biomarker Discovery Studies on Urinary sEV Fractions Separated with UF-SEC for the First Diagnosis and Detection of Recurrence in Bladder Cancer Patients. Biomolecules 2023; 13:932. [PMID: 37371512 DOI: 10.3390/biom13060932] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/26/2023] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
Urinary extracellular vesicles (EVs) are an attractive source of bladder cancer biomarkers. Here, a protein biomarker discovery study was performed on the protein content of small urinary EVs (sEVs) to identify possible biomarkers for the primary diagnosis and recurrence of non-muscle-invasive bladder cancer (NMIBC). The sEVs were isolated by ultrafiltration (UF) in combination with size-exclusion chromatography (SEC). The first part of the study compared healthy individuals with NMIBC patients with a primary diagnosis. The second part compared tumor-free patients with patients with a recurrent NMIBC diagnosis. The separated sEVs were in the size range of 40 to 200 nm. Based on manually curated high quality mass spectrometry (MS) data, the statistical analysis revealed 69 proteins that were differentially expressed in these sEV fractions of patients with a first bladder cancer tumor vs. an age- and gender-matched healthy control group. When the discriminating power between healthy individuals and first diagnosis patients is taken into account, the biomarkers with the most potential are MASP2, C3, A2M, CHMP2A and NHE-RF1. Additionally, two proteins (HBB and HBA1) were differentially expressed between bladder cancer patients with a recurrent diagnosis vs. tumor-free samples of bladder cancer patients, but their biological relevance is very limited.
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Affiliation(s)
- Stephanie Jordaens
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, 2610 Wilrijk, Belgium
| | - Eline Oeyen
- Health Unit, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
- Centre for Proteomics (CfP), University of Antwerp, 2020 Antwerp, Belgium
| | - Hanny Willems
- Health Unit, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
| | - Filip Ameye
- Department of Urology, AZ Maria Middelares, 9000 Ghent, Belgium
| | - Stefan De Wachter
- Department of Urology, Antwerp University Hospital (UZA), 2650 Edegem, Belgium
| | - Patrick Pauwels
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, 2610 Wilrijk, Belgium
- Laboratory of Pathological Anatomy, Antwerp University Hospital (UZA), 2650 Edegem, Belgium
| | - Inge Mertens
- Health Unit, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
- Centre for Proteomics (CfP), University of Antwerp, 2020 Antwerp, Belgium
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Brusco I, Becker G, Palma TV, Pillat MM, Scussel R, Steiner BT, Sampaio TB, Ardisson-Araújo DMP, de Andrade CM, Oliveira MS, Machado-De-Avila RA, Oliveira SM. Kinin B 1 and B 2 receptors mediate cancer pain associated with both the tumor and oncology therapy using aromatase inhibitors. Sci Rep 2023; 13:4418. [PMID: 36932156 PMCID: PMC10023805 DOI: 10.1038/s41598-023-31535-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
Pain caused by the tumor or aromatase inhibitors (AIs) is a disabling symptom in breast cancer survivors. Their mechanisms are unclear, but pro-algesic and inflammatory mediators seem to be involved. Kinins are endogenous algogenic mediators associated with various painful conditions via B1 and B2 receptor activation, including chemotherapy-induced pain and breast cancer proliferation. We investigate the involvement of the kinin B1 and B2 receptors in metastatic breast tumor (4T1 breast cancer cells)-caused pain and in aromatase inhibitors (anastrozole or letrozole) therapy-associated pain. A protocol associating the tumor and antineoplastic therapy was also performed. Kinin receptors' role was investigated via pharmacological antagonism, receptors protein expression, and kinin levels. Mechanical and cold allodynia and muscle strength were evaluated. AIs and breast tumor increased kinin receptors expression, and tumor also increased kinin levels. AIs caused mechanical allodynia and reduced the muscle strength of mice. Kinin B1 (DALBk) and B2 (Icatibant) receptor antagonists attenuated these effects and reduced breast tumor-induced mechanical and cold allodynia. AIs or paclitaxel enhanced breast tumor-induced mechanical hypersensitivity, while DALBk and Icatibant prevented this increase. Antagonists did not interfere with paclitaxel's cytotoxic action in vitro. Thus, kinin B1 or B2 receptors can be a potential target for treating the pain caused by metastatic breast tumor and their antineoplastic therapy.
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Affiliation(s)
- Indiara Brusco
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.
| | - Gabriela Becker
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil
| | - Tais Vidal Palma
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil
| | - Micheli Mainardi Pillat
- Department of Microbiology and Parasitology, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Rahisa Scussel
- Graduate Program in Health Sciences, University of Extreme South Catarinense, Criciuma, SC, Brazil
| | - Bethina Trevisol Steiner
- Graduate Program in Health Sciences, University of Extreme South Catarinense, Criciuma, SC, Brazil
| | - Tuane Bazanella Sampaio
- Graduate Program in Pharmacology, Department of Physiology and Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Daniel Mendes Pereira Ardisson-Araújo
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil
- Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasilia, DF, Brazil
| | - Cinthia Melazzo de Andrade
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil
| | - Mauro Schneider Oliveira
- Graduate Program in Pharmacology, Department of Physiology and Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | | | - Sara Marchesan Oliveira
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.
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15
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He B, Huang Z, Huang C, Nice EC. Clinical applications of plasma proteomics and peptidomics: Towards precision medicine. Proteomics Clin Appl 2022; 16:e2100097. [PMID: 35490333 DOI: 10.1002/prca.202100097] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/16/2022] [Accepted: 04/28/2022] [Indexed: 02/05/2023]
Abstract
In the context of precision medicine, disease treatment requires individualized strategies based on the underlying molecular characteristics to overcome therapeutic challenges posed by heterogeneity. For this purpose, it is essential to develop new biomarkers to diagnose, stratify, or possibly prevent diseases. Plasma is an available source of biomarkers that greatly reflects the physiological and pathological conditions of the body. An increasing number of studies are focusing on proteins and peptides, including many involving the Human Proteome Project (HPP) of the Human Proteome Organization (HUPO), and proteomics and peptidomics techniques are emerging as critical tools for developing novel precision medicine preventative measures. Excitingly, the emerging plasma proteomics and peptidomics toolbox exhibits a huge potential for studying pathogenesis of diseases (e.g., COVID-19 and cancer), identifying valuable biomarkers and improving clinical management. However, the enormous complexity and wide dynamic range of plasma proteins makes plasma proteome profiling challenging. Herein, we summarize the recent advances in plasma proteomics and peptidomics with a focus on their emerging roles in COVID-19 and cancer research, aiming to emphasize the significance of plasma proteomics and peptidomics in clinical applications and precision medicine.
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Affiliation(s)
- Bo He
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China.,Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
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16
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Wang F, Wang ZR, Ding XS, Yang H, Guo Y, Su H, Wan XR, Wang LJ, Jiang XY, Xu YH, Chen F, Cui W, Feng FZ. Combining serum peptide signatures with International Federation of Gynecology and Obstetrics (FIGO) risk score to predict the outcomes of patients with gestational trophoblastic neoplasia (GTN) after first-line chemotherapy. Front Oncol 2022; 12:982806. [PMID: 36338720 PMCID: PMC9634134 DOI: 10.3389/fonc.2022.982806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/06/2022] [Indexed: 11/21/2022] Open
Abstract
Background Gestational trophoblastic neoplasia (GTN) is a group of clinically rare tumors that develop in the uterus from placental tissue. Currently, its satisfactory curability derives from the timely and accurately classification and refined management for patients. This study aimed to discover biomarkers that could predict the outcomes of GTN patients after first-line chemotherapy. Methods A total of 65 GTN patients were included in the study. Patients were divided into the good or poor outcome group and the clinical characteristics of the patients in the two groups were compared. Furthermore, the serum peptide profiles of all patients were uncovered by using weak cation exchange magnetic beads and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Feature peaks were identified by three machine learning algorithms and then models were constructed and compared using five machine learning methods. Additionally, liquid chromatography mass spectrometry was used to identify the feature peptides. Results Multivariate logistic regression analysis showed that the International Federation of Gynecology and Obstetrics (FIGO) risk score was associated with poor outcomes. Eight feature peaks (m/z =1287, 2042, 2862, 2932, 2950, 3240, 3277 and 6626) were selected for model construction and validation by the three algorithms. Based on the panel combining FIGO risk score and peptide serum signatures, the neural network (nnet) model showed promising performance in both the training (AUC=0.9635) and validation (AUC=0.8788) cohorts. Peaks at m/z 2042, 2862, 2932, 3240 were identified as the partial sequences of transthyretin, fibrinogen alpha chain (FGA), beta-globin and FGA, respectively. Conclusion We combined FIGO risk score and serum peptide signatures using the nnet method to construct the model which can accurately predict outcome of GTN patients after first-line chemotherapy. With this model, patients can be further classified and managed, and those with poor predicted outcomes can be given more attention for developing treatment failure.
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Affiliation(s)
- Fei Wang
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zi-ran Wang
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xue-song Ding
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hua Yang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ye Guo
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hao Su
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xi-run Wan
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Li-juan Wang
- Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiang-yang Jiang
- Department of Obstetrics and Gynecology, Shanxi Provincial People’s Hospital, Xian, China
| | - Yan-hua Xu
- Department of Obstetrics and Gynecology, Jinan Maternity and Child Health Care Hospital, Jinan, China
| | - Feng Chen
- Department of Clinical Laboratory, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Cui
- Department of Clinical Laboratory, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Wei Cui, ; Feng-zhi Feng,
| | - Feng-zhi Feng
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- *Correspondence: Wei Cui, ; Feng-zhi Feng,
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Kreimer S, Haghani A, Binek A, Hauspurg A, Seyedmohammad S, Rivas A, Momenzadeh A, Meyer JG, Raedschelders K, Van Eyk JE. Parallelization with Dual-Trap Single-Column Configuration Maximizes Throughput of Proteomic Analysis. Anal Chem 2022; 94:12452-12460. [PMID: 36044770 PMCID: PMC9900495 DOI: 10.1021/acs.analchem.2c02609] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Proteomic analysis on the scale that captures population and biological heterogeneity over hundreds to thousands of samples requires rapid mass spectrometry methods, which maximize instrument utilization (IU) and proteome coverage while maintaining precise and reproducible quantification. To achieve this, a short liquid chromatography gradient paired to rapid mass spectrometry data acquisition can be used to reproducibly quantify a moderate set of analytes. High-throughput profiling at a limited depth is becoming an increasingly utilized strategy for tackling large sample sets but the time spent on loading the sample, flushing the column(s), and re-equilibrating the system reduces the ratio of meaningful data acquired to total operation time and IU. The dual-trap single-column configuration (DTSC) presented here maximizes IU in rapid analysis (15 min per sample) of blood and cell lysates by parallelizing trap column cleaning and sample loading and desalting with the analysis of the previous sample. We achieved 90% IU in low microflow (9.5 μL/min) analysis of blood while reproducibly quantifying 300-400 proteins and over 6000 precursor ions. The same IU was achieved for cell lysates and over 4000 proteins (3000 at CV below 20%) and 40,000 precursor ions were quantified at a rate of 15 min/sample. Thus, DTSC enables high-throughput epidemiological blood-based biomarker cohort studies and cell-based perturbation screening.
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Affiliation(s)
- Simion Kreimer
- Cedars-Sinai Medical Center, 121 N San Vicente, Beverly Hills, California 90211, United States
| | - Ali Haghani
- Cedars-Sinai Medical Center, 121 N San Vicente, Beverly Hills, California 90211, United States
| | - Aleksandra Binek
- Cedars-Sinai Medical Center, 121 N San Vicente, Beverly Hills, California 90211, United States
| | - Alisse Hauspurg
- University of Pittsburgh School of Medicine, 300 Halket Street, Pittsburgh, Pennsylvania 15213, United States
| | - Saeed Seyedmohammad
- Cedars-Sinai Medical Center, 121 N San Vicente, Beverly Hills, California 90211, United States
| | - Alejandro Rivas
- Cedars-Sinai Medical Center, 121 N San Vicente, Beverly Hills, California 90211, United States
| | - Amanda Momenzadeh
- Cedars-Sinai Medical Center, 121 N San Vicente, Beverly Hills, California 90211, United States
| | - Jesse G Meyer
- Cedars-Sinai Medical Center, 121 N San Vicente, Beverly Hills, California 90211, United States
| | - Koen Raedschelders
- Cedars-Sinai Medical Center, 121 N San Vicente, Beverly Hills, California 90211, United States
| | - Jennifer E Van Eyk
- Cedars-Sinai Medical Center, 121 N San Vicente, Beverly Hills, California 90211, United States
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Xu Z, Chen H, Chu H, Shen X, Deng C, Sun N, Wu H. Diagnosis and subtype classification on serum peptide fingerprints by mesoporous polydopamine with built-in metal-organic framework. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.107829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Jayasinghe R, Jayarajah U, Seneviratne S. Circulating Biomarkers in Predicting Pathological Response to Neoadjuvant Therapy for Colorectal Cancer. Biomark Med 2022. [DOI: 10.2174/9789815040463122010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Circulating biomarkers show promise in the management of many cancers.
They have become the novel non-invasive approach to complement the current
strategies in colorectal cancer (CRC) management. Their ability in guiding diagnosis,
evaluating response to treatment, screening and prognosis is phenomenal, especially
when it comes to their minimally invasive nature. These “liquid biopsies,” which show
potential for replacing invasive surgical biopsies, provide useful information on the
primary and metastatic disease by providing an insight into cancer biology. Analysis of
blood and body fluids for circulating tumour DNA (ctDNA), carcinoembryonic antigen
(CEA), circulating tumour cells (CTC), or circulating micro RNA (miRNA) shows
potential for improving CRC management. Recognizing a predictive model to assess
response to neoadjuvant chemotherapy would help in better patient selection. This
review was conducted with the aim of outlining the use of circulatory biomarkers in
current practice and their effectiveness in the management of patients having CRC with
a focus on response to neoadjuvant therapy.
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Affiliation(s)
- Ravindri Jayasinghe
- Department of Surgery, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Umesh Jayarajah
- Department of Surgery, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Sanjeewa Seneviratne
- Department of Surgery, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
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20
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Zhai G, Yang L, Luo Q, Wu K, Zhao Y, Wang F. Serum phosphopeptide profiling for colorectal cancer diagnosis using liquid chromatography-mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2022; 36:e9316. [PMID: 35416361 DOI: 10.1002/rcm.9316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/10/2022] [Accepted: 04/11/2022] [Indexed: 06/14/2023]
Abstract
RATIONALE The identification and evaluation of novel biomarkers are essential to clinical diagnosis and prognosis of colorectal cancer (CRC). Serum phosphopeptides have been recognized as a potential signature pool for cancers; therefore, we aim to profile the expression of serum phosphopeptides and to evaluate their feasibility in CRC diagnosis. METHODS We conducted the characterization and absolute quantification of endogenous phosphopeptides in sera using liquid chromatography-mass spectrometry analysis in combination with enrichment of phosphopeptides by ZrAs-Fe3 O4 @SiO2 nanoparticles and use of deuterium-labeled standards. Differentially expressed analysis of four phosphopeptides was performed, generating a two-phosphopeptide-based biomarker, LF3-4 , by logistic regression analysis, where LF3-4 is equal to (5.85 - 5.13 × [F3] - 3.57 × [F4]), and [F3] and [F4] are the concentration of phosphopeptides DpSGEGDFLAEGGGVR and ADpSGEGDFLAEGGGVR in sera, respectively. RESULTS The LF3-4 values showed significant difference in CRC cases compared with controls, and yielded a specificity of 100%, leading to correct classification of 56 (93%) out of 60 CRC patients, including 12 (92.3%) of 13 CRC cases in stage I. Double-blind validation showed that 97.5% of CRC cases were discriminated accurately. CONCLUSIONS The LF3-4 value was firstly verified to be a potential biomarker for CRC diagnosis, and may expand our view in underlying mechanisms for CRC.
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Affiliation(s)
- Guijin Zhai
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- Department of Biochemistry and Molecular Biology; Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China
| | - Liping Yang
- Cancer Research Centre, Tumour Hospital Affiliated to Nantong University, Nantong, Jiangsu, China
| | - Qun Luo
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Science, Beijing, China
| | - Kui Wu
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Yao Zhao
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Fuyi Wang
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Science, Beijing, China
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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21
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Circulating SOD2 Is a Candidate Response Biomarker for Neoadjuvant Therapy in Breast Cancer. Cancers (Basel) 2022; 14:cancers14163858. [PMID: 36010852 PMCID: PMC9405919 DOI: 10.3390/cancers14163858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/28/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
There is a great need for non-invasive tools that inform of an early molecular response to cancer therapeutic treatment. Here, we tested the hypothesis that proteolytically resistant proteins could be candidate circulating tumor biomarkers for cancer therapy. Proteins resistant to proteolysis are drastically under-sampled by current proteomic workflows. These proteins could be reliable sensors for the response to therapy since they are likely to stay longer in circulation. We selected manganese superoxide dismutase (SOD2), a mitochondrial redox enzyme, from a screening of proteolytic resistant proteins in breast cancer (BC). First, we confirmed the robustness of SOD2 and determined that its proteolytic resistance is mediated by its quaternary protein structure. We also proved that the release of SOD2 upon chemotherapy treatment correlates with cell death in BC cells. Then, after confirming that SOD2 is very stable in human serum, we sought to measure its circulating levels in a cohort of BC patients undergoing neoadjuvant therapy. The results showed that circulating levels of SOD2 increased when patients responded to the treatment according to the tumor shrinkage during neoadjuvant chemotherapy. Therefore, the measurement of SOD2 levels in plasma could improve the non-invasive monitoring of the therapeutic treatment in breast cancer patients. The identification of circulating biomarkers linked to the tumor cell death induced by treatment could be useful for monitoring the action of the large number of cancer drugs currently used in clinics. We envision that our approach could help uncover candidate tumor biomarkers to measure a tumor’s response to cancer therapy in real time by sampling the tumor throughout the course of treatment.
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22
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Marconi S, Croce M, Chiorino G, Rossi G, Guana F, Profumo A, Ostano P, Alama A, Longo L, De Luca G, Dono M, Dal Bello MG, Ponassi M, Rosano C, Romano P, Cavalieri Z, Grassi M, Tagliamento M, Zullo L, Venturi C, Dellepiane C, Mastracci L, Bennicelli E, Pronzato P, Genova C, Coco S. A Circulating Risk Score, Based on Combined Expression of Exo-miR-130a-3p and Fibrinopeptide A, as Predictive Biomarker of Relapse in Resectable Non-Small Cell Lung Cancer Patients. Cancers (Basel) 2022; 14:3412. [PMID: 35884472 PMCID: PMC9317031 DOI: 10.3390/cancers14143412] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/30/2022] [Accepted: 07/11/2022] [Indexed: 02/01/2023] Open
Abstract
To date, the 5-year overall survival rate of 60% for early-stage non-small cell lung cancer (NSCLC) is still unsatisfactory. Therefore, reliable prognostic factors are needed. Growing evidence shows that cancer progression may depend on an interconnection between cancer cells and the surrounding tumor microenvironment; hence, circulating molecules may represent promising markers of cancer recurrence. In order to identify a prognostic score, we performed in-depth high-throughput analyses of plasma circulating markers, including exosomal microRNAs (Exo-miR) and peptides, in 67 radically resected NSCLCs. The miRnome profile selected the Exo-miR-130a-3p as the most overexpressed in relapsed patients. Peptidome analysis identified four progressively more degraded forms of fibrinopeptide A (FpA), which were depleted in progressing patients. Notably, stepwise Cox regression analysis selected Exo-miR-130a-3p and the greatest FpA (2-16) to build a score predictive of recurrence, where high-risk patients had 18 months of median disease-free survival. Moreover, in vitro transfections showed that higher levels of miR-130a-3p lead to a deregulation of pathways involved in metastasis and angiogenesis, including the coagulation process and metalloprotease increase which might be linked to FpA reduction. In conclusion, by integrating circulating markers, the identified risk score may help clinicians predict early-stage NSCLC patients who are more likely to relapse after primary surgery.
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Affiliation(s)
- Silvia Marconi
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
| | - Michela Croce
- Biotherapies Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
| | - Giovanna Chiorino
- Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, 13900 Biella, Italy; (F.G.); (P.O.)
| | - Giovanni Rossi
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, 07100 Sassari, Italy
| | - Francesca Guana
- Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, 13900 Biella, Italy; (F.G.); (P.O.)
| | - Aldo Profumo
- Proteomics and Mass Spectrometry Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (A.P.); (M.P.); (C.R.); (P.R.)
| | - Paola Ostano
- Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, 13900 Biella, Italy; (F.G.); (P.O.)
| | - Angela Alama
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
| | - Luca Longo
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
| | - Giuseppa De Luca
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (G.D.L.); (M.D.)
| | - Mariella Dono
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (G.D.L.); (M.D.)
| | - Maria Giovanna Dal Bello
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
| | - Marco Ponassi
- Proteomics and Mass Spectrometry Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (A.P.); (M.P.); (C.R.); (P.R.)
| | - Camillo Rosano
- Proteomics and Mass Spectrometry Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (A.P.); (M.P.); (C.R.); (P.R.)
| | - Paolo Romano
- Proteomics and Mass Spectrometry Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (A.P.); (M.P.); (C.R.); (P.R.)
| | - Zita Cavalieri
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
| | - Massimiliano Grassi
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
| | - Marco Tagliamento
- Department of Internal Medicine and Medical Specialties, University of Genova, 16132 Genova, Italy; (M.T.); (C.G.)
| | - Lodovica Zullo
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
| | - Consuelo Venturi
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (C.V.); (L.M.)
| | - Chiara Dellepiane
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
| | - Luca Mastracci
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (C.V.); (L.M.)
- Department of Surgical Sciences and Integrated Diagnostic, University of Genova, 16132 Genova, Italy
| | - Elisa Bennicelli
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
| | - Paolo Pronzato
- Medical Oncology 2 Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
| | - Carlo Genova
- Department of Internal Medicine and Medical Specialties, University of Genova, 16132 Genova, Italy; (M.T.); (C.G.)
- Academic Medical Oncology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Simona Coco
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (S.M.); (G.R.); (A.A.); (L.L.); (M.G.D.B.); (Z.C.); (L.Z.); (C.D.); (E.B.)
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23
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Chen R, Hu B, Jiang M, Deng W, Zheng P, Fu B. Bioinformatic Analysis of the Expression and Clinical Significance of the DNA Replication Regulator MCM Complex in Bladder Cancer. Int J Gen Med 2022; 15:5465-5485. [PMID: 35698656 PMCID: PMC9188401 DOI: 10.2147/ijgm.s368573] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/26/2022] [Indexed: 12/04/2022] Open
Abstract
Objective The minichromosome maintenance (MCM) complex (MCM2, MCM3, MCM4, MCM5, MCM6, and MCM7), which regulates DNA replication and cell cycle progression, is essential for the development and progression of multiple tumors, but their role in bladder cancer development remains unclear. In the present study, the biological role and clinical significance of the MCM complex in bladder cancer were systematically elucidated. Materials and Methods We analyzed DNA mutations, mRNA expression and protein levels, protein–protein interaction (PPI) networks, functional enrichment, prognostic value of MCM2/3/4/5/6/7 in bladder urothelial carcinoma (BLC) and the connections between the immune cell infiltration and the overall survival of BLC patients with the MCM expression levels using Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), the Cancer Genome Atlas database (TCGA), Human Protein Atlas, UALCAN, STRING, cBioPortal, TIMER and GSCALite databases. Results The outcomes showed that the mRNA expression level of each member of the MCM complex was significantly correlated with histologic grade and tumor histology in BLC patients. Moreover, survival analysis showed that MCM/2/3/4/5/6/7 mRNA expressions were significantly associated with prognosis in patients with bladder cancer. Moreover, we experimentally validated the overexpression of the MCM2-7 complex in the BLC. Based on functional enrichment and PPI network analysis, the MCM complex might promote the progression of bladder cancer by activating DNA replication and accelerating cell cycle progression. In addition, MCM2/3/4/5/6/7 genes were also significantly associated with tumor immune cells infiltration and the drug sensitivity in BLC. Conclusion Our study suggests that the MCM complex especially MCM2/4/6/7 might be potential molecular therapeutic targets for BLC treatment and might be useful biomarkers for diagnosis and prognosis.
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Affiliation(s)
- Ru Chen
- Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
- Department of Urology, The First Hospital of Putian City, Putian, Fujian, People’s Republic of China
| | - Bing Hu
- Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
| | - Ming Jiang
- Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
| | - Wen Deng
- Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
| | - Ping Zheng
- Department of Urology, Shangrao municipal Hospital, Shangrao, 334000, Jiangxi Province, People’s Republic of China
| | - Bin Fu
- Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
- Jiangxi Institute of Urology, Nanchang City, Jiangxi Province, People’s Republic of China
- Correspondence: Bin Fu, Email
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24
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Ghose A, Gullapalli SVN, Chohan N, Bolina A, Moschetta M, Rassy E, Boussios S. Applications of Proteomics in Ovarian Cancer: Dawn of a New Era. Proteomes 2022; 10:proteomes10020016. [PMID: 35645374 PMCID: PMC9150001 DOI: 10.3390/proteomes10020016] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/01/2022] [Accepted: 05/06/2022] [Indexed: 12/11/2022] Open
Abstract
The ability to identify ovarian cancer (OC) at its earliest stages remains a challenge. The patients present an advanced stage at diagnosis. This heterogeneous disease has distinguishable etiology and molecular biology. Next-generation sequencing changed clinical diagnostic testing, allowing assessment of multiple genes, simultaneously, in a faster and cheaper manner than sequential single gene analysis. Technologies of proteomics, such as mass spectrometry (MS) and protein array analysis, have advanced the dissection of the underlying molecular signaling events and the proteomic characterization of OC. Proteomics analysis of OC, as well as their adaptive responses to therapy, can uncover new therapeutic choices, which can reduce the emergence of drug resistance and potentially improve patient outcomes. There is an urgent need to better understand how the genomic and epigenomic heterogeneity intrinsic to OC is reflected at the protein level, and how this information could potentially lead to prolonged survival.
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Affiliation(s)
- Aruni Ghose
- Department of Medical Oncology, Barts Cancer Centre, St. Bartholomew’s Hospital, Barts Health NHS Trust, London EC1A 7BE, UK; (A.G.); (N.C.)
- Department of Medical Oncology, Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, Northwood HA6 2RN, UK
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK
- Division of Research, Academics and Cancer Control, Saroj Gupta Cancer Centre and Research Institute, Kolkata 700063, India
| | | | - Naila Chohan
- Department of Medical Oncology, Barts Cancer Centre, St. Bartholomew’s Hospital, Barts Health NHS Trust, London EC1A 7BE, UK; (A.G.); (N.C.)
| | - Anita Bolina
- Department of Haematology, Clatterbridge Cancer Centre Liverpool, The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool L7 8YA, UK;
| | - Michele Moschetta
- Novartis Institutes for BioMedical Research, 4033 Basel, Switzerland;
| | - Elie Rassy
- Department of Medical Oncology, Gustave Roussy Institut, 94805 Villejuif, France;
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK
- School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King’s College London, London WC2R 2LS, UK
- AELIA Organization, 9th Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
- Correspondence: or or
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25
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Mac QD, Sivakumar A, Phuengkham H, Xu C, Bowen JR, Su FY, Stentz SZ, Sim H, Harris AM, Li TT, Qiu P, Kwong GA. Urinary detection of early responses to checkpoint blockade and of resistance to it via protease-cleaved antibody-conjugated sensors. Nat Biomed Eng 2022; 6:310-324. [PMID: 35241815 DOI: 10.1038/s41551-022-00852-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 01/28/2022] [Indexed: 12/15/2022]
Abstract
Immune checkpoint blockade (ICB) therapy does not benefit the majority of treated patients, and those who respond to the therapy can become resistant to it. Here we report the design and performance of systemically administered protease activity sensors conjugated to anti-programmed cell death protein 1 (αPD1) antibodies for the monitoring of antitumour responses to ICB therapy. The sensors consist of a library of mass-barcoded protease substrates that, when cleaved by tumour proteases and immune proteases, are released into urine, where they can be detected by mass spectrometry. By using syngeneic mouse models of colorectal cancer, we show that random forest classifiers trained on mass spectrometry signatures from a library of αPD1-conjugated mass-barcoded activity sensors for differentially expressed tumour proteases and immune proteases can be used to detect early antitumour responses and discriminate resistance to ICB therapy driven by loss-of-function mutations in either the B2m or Jak1 genes. Biomarkers of protease activity may facilitate the assessment of early responses to ICB therapy and the classification of refractory tumours based on resistance mechanisms.
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Affiliation(s)
- Quoc D Mac
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - Anirudh Sivakumar
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - Hathaichanok Phuengkham
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - Congmin Xu
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - James R Bowen
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - Fang-Yi Su
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - Samuel Z Stentz
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - Hyoungjun Sim
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - Adrian M Harris
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - Tonia T Li
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA
| | - Peng Qiu
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA.,Parker H. Petit Institute for Bioengineering and Bioscience, Atlanta, GA, USA.,The Georgia Immunoengineering Consortium, Emory University and Georgia Tech, Atlanta, GA, USA.,Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Gabriel A Kwong
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA. .,Parker H. Petit Institute for Bioengineering and Bioscience, Atlanta, GA, USA. .,The Georgia Immunoengineering Consortium, Emory University and Georgia Tech, Atlanta, GA, USA. .,Winship Cancer Institute, Emory University, Atlanta, GA, USA. .,Institute for Electronics and Nanotechnology, Georgia Tech, Atlanta, GA, USA. .,Integrated Cancer Research Center, Georgia Tech, Atlanta, GA, USA.
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26
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Wang B, Yan Y, Ding CF. Metal-organic framework-based sample preparation in proteomics. J Chromatogr A 2022; 1671:462971. [DOI: 10.1016/j.chroma.2022.462971] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 03/12/2022] [Indexed: 01/05/2023]
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27
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Zafar M, Mirza MR, Awan FR, Tahir M, Sultan R, Hussain M, Bilal A, Abbas S, Larsen MR, Choudhary MI, Malik IR. Effect of APOB polymorphism rs562338 (G/A) on serum proteome of coronary artery disease patients: a "proteogenomic" approach. Sci Rep 2021; 11:22766. [PMID: 34815491 PMCID: PMC8610978 DOI: 10.1038/s41598-021-02211-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 11/09/2021] [Indexed: 11/08/2022] Open
Abstract
In the current study, APOB (rs1052031) genotype-guided proteomic analysis was performed in a cohort of Pakistani population. A total of 700 study subjects, including Coronary Artery Disease (CAD) patients (n = 480) and healthy individuals (n = 220) as a control group were included in the study. Genotyping was carried out by using tetra primer-amplification refractory mutation system-based polymerase chain reaction (T-ARMS-PCR) whereas mass spectrometry (Orbitrap MS) was used for label free quantification of serum samples. Genotypic frequency of GG genotype was found to be 90.1%, while 6.4% was for GA genotype and 3.5% was for AA genotypes in CAD patients. In the control group, 87.2% healthy subjects were found to have GG genotype, 11.8% had GA genotype, and 0.9% were with AA genotypes. Significant (p = 0.007) difference was observed between genotypic frequencies in the patients and the control group. The rare allele AA was found to be strongly associated with the CAD [OR: 4 (1.9-16.7)], as compared to the control group in recessive genetic model (p = 0.04). Using label free proteomics, altered expression of 60 significant proteins was observed. Enrichment analysis of these protein showed higher number of up-regulated pathways, including phosphatidylcholine-sterol O-acyltransferase activator activity, cholesterol transfer activity, and sterol transfer activity in AA genotype of rs562338 (G>A) as compared to the wild type GG genotype. This study provides a deeper insight into CAD pathobiology with reference to proteogenomics, and proving this approach as a good platform for identifying the novel proteins and signaling pathways in relation to cardiovascular diseases.
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Affiliation(s)
- Muneeza Zafar
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences ICCBS), University of Karachi, Karachi, 75270, Pakistan
- Department of Biotechnology, University of Sargodha, Sargodha, Pakistan
- Diabetes and Cardio-Metabolic Disorders Lab, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Jhang Road, P.O. Box. 577, Faisalabad, Pakistan
| | - Munazza Raza Mirza
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences ICCBS), University of Karachi, Karachi, 75270, Pakistan.
| | - Fazli Rabbi Awan
- Diabetes and Cardio-Metabolic Disorders Lab, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Jhang Road, P.O. Box. 577, Faisalabad, Pakistan.
| | - Muhammad Tahir
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Rabia Sultan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Misbah Hussain
- Department of Biotechnology, University of Sargodha, Sargodha, Pakistan
- Diabetes and Cardio-Metabolic Disorders Lab, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Jhang Road, P.O. Box. 577, Faisalabad, Pakistan
| | - Ahmed Bilal
- Allied Hospital, Faisalabad Medical University, Faisalabad, Pakistan
| | - Shahid Abbas
- Faisalabad Institute of Cardiology (FIC), Faisalabad, Pakistan
| | - Martin R Larsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Muhammad Iqbal Choudhary
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences ICCBS), University of Karachi, Karachi, 75270, Pakistan
| | - Imran Riaz Malik
- Department of Biotechnology, University of Sargodha, Sargodha, Pakistan.
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Masaki T, Kodera Y, Terasaki M, Fujimoto K, Hirano T, Shichiri M. GIP_HUMAN[22-51] is a new proatherogenic peptide identified by native plasma peptidomics. Sci Rep 2021; 11:14470. [PMID: 34262109 PMCID: PMC8280211 DOI: 10.1038/s41598-021-93862-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 07/01/2021] [Indexed: 12/25/2022] Open
Abstract
We recently established a new plasma peptidomic technique and comprehensively identified a large number of low-molecular weight and low-abundance native peptides using a single drop of human plasma. To discover a novel polypeptide that potently modulates the cardiovascular system, we performed a bioinformatics analysis of the large-scale identification results, sequentially synthesized the selected peptide sequences, tested their biological activities, and identified a 30-amino-acid proatherogenic peptide, GIP_HUMAN[22-51], as a potent proatherosclerotic peptide hormone. GIP_HUMAN[22-51] has a common precursor with the glucose-dependent insulinotropic polypeptide (GIP) and is located immediately N-terminal to GIP. Chronic infusion of GIP_HUMAN[22-51] into ApoE-/- mice accelerated the development of aortic atherosclerotic lesions, which were inhibited by co-infusions with an anti-GIP_HUMAN[22-51] antibody. GIP_HUMAN[22-51] increased the serum concentrations of many inflammatory and proatherogenic proteins, whereas neutralising antibodies reduced their levels. GIP_HUMAN[22-51] induced IκB-α degradation and nuclear translocation of NF-κB in human vascular endothelial cells and macrophages. Immunoreactive GIP_HUMAN[22-51] was detected in human tissues but there was no colocalization with the GIP. The plasma GIP_HUMAN[22-51] concentration in healthy humans determined using a stable-isotope tagged peptide was approximately 0.6 nM. This study discovered a novel endogenous proatherogenic peptide by using a human plasma native peptidomic resource.
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Affiliation(s)
- Tsuguto Masaki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yoshio Kodera
- Department of Physics, Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Michishige Terasaki
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
| | - Kazumi Fujimoto
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
- Department of Physics, Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Tsutomu Hirano
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
| | - Masayoshi Shichiri
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
- Tokyo Kyosai Hospital, 2-3-8 Nakameguro, Meguro-ku, Tokyo, 153-8934, Japan.
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29
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Yan L, Yi J, Huang C, Zhang J, Fu S, Li Z, Lyu Q, Xu Y, Wang K, Yang H, Ma Q, Cui X, Qiao L, Sun W, Liao P. Rapid Detection of COVID-19 Using MALDI-TOF-Based Serum Peptidome Profiling. Anal Chem 2021; 93:4782-4787. [PMID: 33656857 PMCID: PMC7945584 DOI: 10.1021/acs.analchem.0c04590] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 02/22/2021] [Indexed: 01/08/2023]
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) caused by SARS CoV-2 is ongoing and a serious threat to global public health. It is essential to detect the disease quickly and immediately to isolate the infected individuals. Nevertheless, the current widely used PCR and immunoassay-based methods suffer from false negative results and delays in diagnosis. Herein, a high-throughput serum peptidome profiling method based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is developed for efficient detection of COVID-19. We analyzed the serum samples from 146 COVID-19 patients and 152 control cases (including 73 non-COVID-19 patients with similar clinical symptoms, 33 tuberculosis patients, and 46 healthy individuals). After MS data processing and feature selection, eight machine learning methods were used to build classification models. A logistic regression machine learning model with 25 feature peaks achieved the highest accuracy (99%), with sensitivity of 98% and specificity of 100%, for the detection of COVID-19. This result demonstrated a great potential of the method for screening, routine surveillance, and diagnosis of COVID-19 in large populations, which is an important part of the pandemic control.
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Affiliation(s)
- Ling Yan
- Department of Clinical Laboratory,
Chongqing General Hospital, Chongqing 400014,
China
| | - Jia Yi
- Department of Chemistry, Fudan
University, Shanghai 200438, China
| | - Changwu Huang
- Department of Clinical Laboratory, Renji Hospital,
University of Chinese Academy of Sciences, Chongqing,
China
| | - Jian Zhang
- State Key Laboratory of Proteomics, Beijing Proteome
Research Center, National Center for Protein Sciences (Beijing), Beijing
Institute of Lifeomics, Beijing 102206, China
| | - Shuhui Fu
- Bioyong Technologics, Inc.,
Beijing 100176, China
| | - Zhijie Li
- Department of Clinical Laboratory,
Chongqing General Hospital, Chongqing 400014,
China
| | - Qian Lyu
- Bioyong Technologics, Inc.,
Beijing 100176, China
| | - Yuan Xu
- Department of Clinical Laboratory,
Chongqing General Hospital, Chongqing 400014,
China
| | - Kun Wang
- Department of Clinical Laboratory,
Chongqing General Hospital, Chongqing 400014,
China
| | - Huan Yang
- Department of Clinical Laboratory,
Chongqing General Hospital, Chongqing 400014,
China
| | - Qingwei Ma
- Bioyong Technologics, Inc.,
Beijing 100176, China
| | - Xiaoping Cui
- Department of Clinical Laboratory, Sanxia
Hospital Affiliated to Chongqing University, Chongqing 404000,
China
| | - Liang Qiao
- Department of Chemistry, Fudan
University, Shanghai 200438, China
| | - Wei Sun
- State Key Laboratory of Proteomics, Beijing Proteome
Research Center, National Center for Protein Sciences (Beijing), Beijing
Institute of Lifeomics, Beijing 102206, China
| | - Pu Liao
- Department of Clinical Laboratory,
Chongqing General Hospital, Chongqing 400014,
China
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30
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Zhong H, Li Y, Huang Y, Zhao R. Metal-organic frameworks as advanced materials for sample preparation of bioactive peptides. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2021; 13:862-873. [PMID: 33543184 DOI: 10.1039/d0ay02193h] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Development of novel affinity materials and separation techniques is crucial for the progress of modern proteomics and peptidomics. Detection of peptides and proteins from complex matrices still remains a challenging task due to the highly complicated biological composition, low abundance of target molecules, and large dynamic range of proteins. As an emerging area of analytical science, metal-organic framework (MOF)-based separation of proteins and peptides is attracting growing interest. This minireview summarizes the recent advances in MOF-based affinity materials for the sample preparation of proteins and peptides. Some newly emerging MOF nanoreactors for the degradation of peptides and proteins are introduced. An update of MOF-based affinity materials for the isolation of glycopeptides, phosphopeptides and low-abundance endogenous peptides in the last two years is focused on. The separation mechanism is discussed along with the chemical structures of MOFs. Finally, the remaining challenges and future development of MOFs in analyzing peptides and proteins in complicated biological samples are discussed.
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Affiliation(s)
- Huifei Zhong
- Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
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31
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Taguchi T, Kodera Y, Oba K, Saito T, Nakagawa Y, Kawashima Y, Shichiri M. Suprabasin-derived bioactive peptides identified by plasma peptidomics. Sci Rep 2021; 11:1047. [PMID: 33441610 PMCID: PMC7806982 DOI: 10.1038/s41598-020-79353-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/08/2020] [Indexed: 01/29/2023] Open
Abstract
Identification of low-abundance, low-molecular-weight native peptides using non-tryptic plasma has long remained an unmet challenge, leaving potential bioactive/biomarker peptides undiscovered. We have succeeded in efficiently removing high-abundance plasma proteins to enrich and comprehensively identify low-molecular-weight native peptides using mass spectrometry. Native peptide sequences were chemically synthesized and subsequent functional analyses resulted in the discovery of three novel bioactive polypeptides derived from an epidermal differentiation marker protein, suprabasin. SBSN_HUMAN[279-295] potently suppressed food/water intake and induced locomotor activity when injected intraperitoneally, while SBSN_HUMAN[225-237] and SBSN_HUMAN[243-259] stimulated the expression of proinflammatory cytokines via activation of NF-κB signaling in vascular cells. SBSN_HUMAN[225-237] and SBSN_HUMAN[279-295] immunoreactivities were present in almost all human organs analyzed, while immunoreactive SBSN_HUMAN[243-259] was abundant in the liver and pancreas. Human macrophages expressed the three suprabasin-derived peptides. This study illustrates a new approach for discovering unknown bioactive peptides in plasma via the generation of peptide libraries using a novel peptidomic strategy.
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Affiliation(s)
- Tomomi Taguchi
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Yoshio Kodera
- grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan ,grid.410786.c0000 0000 9206 2938Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Kazuhito Oba
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Tatsuya Saito
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan ,grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Yuzuru Nakagawa
- grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Yusuke Kawashima
- grid.410786.c0000 0000 9206 2938Department of Physics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373 Japan
| | - Masayoshi Shichiri
- grid.410786.c0000 0000 9206 2938Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
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32
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Hoang AT, Vizio B, Chiusa L, Cimino A, Solerio D, Do NH, Pileci S, Camandona M, Bellone G. Impact of Tissue Enolase 1 Protein Overexpression in Esophageal Cancer Progression. Int J Med Sci 2021; 18:1406-1414. [PMID: 33628097 PMCID: PMC7893569 DOI: 10.7150/ijms.52688] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/18/2020] [Indexed: 12/31/2022] Open
Abstract
Enolase (ENO) 1 is a key glycolytic enzyme and important player in tumorigenesis. ENO1 overexpression has been correlated with tumor progression and/or worse prognosis in several solid malignancies. However, data concerning the impact of ENO1 in cancer conflict. The study correlated local and circulating ENO1 protein levels in esophageal cancer (EC) with clinicopathological data, to assess its potential clinical value. ENO1 expression was analyzed by immunohistochemistry in paired tumor and non-tumor tissue samples from 40 EC cases and mucosal biopsies from 45 Barrett's esophagus (BE) cases, plus in plasma from these patients and 25 matched healthy controls. ENO1 was abnormally elevated in cancer-cell cytoplasm in both EC types, in esophageal squamous cell carcinoma and in adenocarcinoma (EAC), increasing significantly with tumor stage progression and the transition from BE to EAC. EAC patients exhibited significantly lower ENO1 plasma concentrations than normal subjects. Neither local nor systemic ENO1 expression levels were significantly associated with overall survival. These results indicate ENO1 as potential biomarker, delineating a population of patients with Barrett's esophagus at high risk of cancer, and as new therapeutic opportunity in EC patient management. However, further confirmation might be necessary.
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Affiliation(s)
- Anh Tuan Hoang
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | - Barbara Vizio
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | - Luigi Chiusa
- Pathology Unit, AOU City of Health and Science of Turin, 10126 Turin, Italy
| | - Antonio Cimino
- Pathology Unit, AOU City of Health and Science of Turin, 10126 Turin, Italy
| | - Dino Solerio
- Department of Surgical Sciences, University of Turin, Unit of Digestive and Oncological Surgery 1U, AOU City of Health and Science of Turin, 10126 Turin, Italy
| | - Nhu Hon Do
- Vietnam National Institute of Ophthalmology, Hanoi, Vietnam
| | - Stefano Pileci
- Department of Surgical Sciences, University of Turin, Unit of Digestive and Oncological Surgery 1U, AOU City of Health and Science of Turin, 10126 Turin, Italy
| | - Michele Camandona
- Department of Surgical Sciences, University of Turin, Unit of Digestive and Oncological Surgery 1U, AOU City of Health and Science of Turin, 10126 Turin, Italy
| | - Graziella Bellone
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
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33
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The Activation of Prothrombin Seems to Play an Earlier Role than the Complement System in the Progression of Colorectal Cancer: A Mass Spectrometry Evaluation. Diagnostics (Basel) 2020; 10:diagnostics10121077. [PMID: 33322644 PMCID: PMC7763171 DOI: 10.3390/diagnostics10121077] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 01/13/2023] Open
Abstract
Colorectal cancer (CRC) is the second cause of death in men and the third in women. This work deals with the study of the low molecular weight protein fraction of sera from patients who underwent surgery for CRC and who were followed for several years thereafter. MALDI-TOF MS was used to identify serum peptidome profiles of healthy controls, non-metastatic CRC patients and metastatic CRC patients. A multiple regression model was applied to signals preliminarily selected by SAM analysis to take into account the age and gender differences between the groups. We found that, while a signal m/z 2021.08, corresponding to the C3f fragment of the complement system, appears significantly increased only in serum from metastatic CRC patients, a m/z 1561.72 signal, identified as a prothrombin fragment, has a significantly increased abundance in serum from non-metastatic patients as well. The findings were also validated by a bootstrap resampling procedure. The present results provide the basis for further studies on large cohorts of patients in order to confirm C3f and prothrombin as potential serum biomarkers. Thus, new and non-invasive tests might be developed to improve the classification of colorectal cancer.
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34
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Li W, Zhang Y, Li Y, Cao Y, Zhou J, Sun Z, Wu W, Tan X, Shao Y, Xie K, Yan X. Profiling Analysis Reveals the Crucial Role of the Endogenous Peptides in Bladder Cancer Progression. Onco Targets Ther 2020; 13:12443-12455. [PMID: 33311987 PMCID: PMC7725083 DOI: 10.2147/ott.s281713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 11/07/2020] [Indexed: 11/25/2022] Open
Abstract
Background Peptide drugs provide promising regimes in bladder cancer. In order to identify potential bioactive peptides involved in bladder cancer, we performed the present study. Methods Liquid chromatography/mass spectrometry assay was used to compare the endogenous peptides between bladder cancer and normal control. The potential biological functions of these dysregulated peptides are assessed by GO analysis and KEGG pathway analysis of their precursors. The SMART and UniProt databases are used to identify the sequences of the dysregulated peptides located in the functional domains. The Open Targets Platform database was used to investigate the precursors related to metabolic diseases. Results A total of 9 up-regulated peptides and 110 down-regulated peptides in bladder cancer compared with normal control were identified (fold change > 1.2, P < 0.05). The MW of these dysregulated peptides ranged from 500 Da to 2500 Da and the MW of all identified peptides was below 3500 Da. The GO and KEGG pathway analysis indicated that these dysregulated peptides could play an important role in bladder cancer. Our further analysis revealed that 45HFNPRFNAHGDAN 57 derived from LGALS1 and those peptides derived from P4HB and SERPINA1 might be the promising diagnostic biomarkers and therapeutic targets of bladder cancer. Conclusion In the present study, we have identified the profile of the peptides significantly dysregulated in bladder cancer. Moreover, using bioinformatic analysis, we found the peptides derived from LGALS1, P4HB and SERPINA1 could be the promising diagnostic biomarkers and therapeutic targets of bladder cancer.
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Affiliation(s)
- Weijian Li
- Department of Nephrology and Urology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People's Republic of China
| | - Yang Zhang
- Department of Nephrology and Urology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People's Republic of China.,Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, People's Republic of China
| | - Youjian Li
- Department of Nephrology and Urology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People's Republic of China.,Department of Urology Surgery, The People's Hospital of Xuancheng City, Xuancheng, People's Republic of China
| | - Yuepeng Cao
- Department of Critical Care Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, People's Republic of China
| | - Jun Zhou
- Department of Nephrology and Urology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People's Republic of China
| | - Zhongxu Sun
- Department of Nephrology and Urology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People's Republic of China
| | - Wanke Wu
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, The Affiliated Obstetrics and Gynaecology Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiaofang Tan
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, The Affiliated Obstetrics and Gynaecology Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Yang Shao
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, The Affiliated Obstetrics and Gynaecology Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Kaipeng Xie
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, The Affiliated Obstetrics and Gynaecology Hospital of Nanjing Medical University, Nanjing, People's Republic of China.,Department of Women's Health Care, The Affiliated Obstetrics and Gynaecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, People's Republic of China
| | - Xiang Yan
- Department of Nephrology and Urology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People's Republic of China.,Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, People's Republic of China
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35
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Soleimany AP, Kirkpatrick JD, Su S, Dudani JS, Zhong Q, Bekdemir A, Bhatia SN. Activatable Zymography Probes Enable In Situ Localization of Protease Dysregulation in Cancer. Cancer Res 2020; 81:213-224. [PMID: 33106334 DOI: 10.1158/0008-5472.can-20-2410] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/16/2020] [Accepted: 10/21/2020] [Indexed: 12/25/2022]
Abstract
Recent years have seen the emergence of conditionally activated diagnostics and therapeutics that leverage protease-cleavable peptide linkers to enhance their specificity for cancer. However, due to a lack of methods to measure and localize protease activity directly within the tissue microenvironment, the design of protease-activated agents has been necessarily empirical, yielding suboptimal results when translated to patients. To address the need for spatially resolved protease activity profiling in cancer, we developed a new class of in situ probes that can be applied to fresh-frozen tissue sections in a manner analogous to immunofluorescence staining. These activatable zymography probes (AZP) detected dysregulated protease activity in human prostate cancer biopsy samples, enabling disease classification. AZPs were leveraged within a generalizable framework to design conditional cancer diagnostics and therapeutics and showcased in the Hi-Myc mouse model of prostate cancer, which models features of early pathogenesis. Multiplexed screening against barcoded substrates yielded a peptide, S16, that was robustly and specifically cleaved by tumor-associated metalloproteinases in the Hi-Myc model. In situ labeling with an AZP incorporating S16 revealed a potential role of metalloproteinase dysregulation in proliferative, premalignant Hi-Myc prostatic glands. Systemic administration of an in vivo imaging probe incorporating S16 perfectly classified diseased and healthy prostates, supporting the relevance of ex vivo activity assays to in vivo translation. We envision AZPs will enable new insights into the biology of protease dysregulation in cancer and accelerate the development of conditional diagnostics and therapeutics for multiple cancer types. SIGNIFICANCE: Visualization of protease activity within the native tissue context using AZPs provides new biological insights into protease dysregulation in cancer and guides the design of conditional diagnostics and therapeutics.
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Affiliation(s)
- Ava P Soleimany
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Harvard Graduate Program in Biophysics, Harvard University, Boston, Massachusetts
| | - Jesse D Kirkpatrick
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Susan Su
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Jaideep S Dudani
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Qian Zhong
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Ahmet Bekdemir
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Sangeeta N Bhatia
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. .,Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Howard Hughes Medical Institute, Cambridge, Massachusetts.,Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.,Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.,Wyss Institute at Harvard, Boston, Massachusetts.,Ludwig Center at the MIT Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts
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36
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Huang J, Ling Z, Zhong H, Yin Y, Qian Y, Gao M, Ding H, Cheng Q, Jia R. Distinct expression profiles of peptides in placentae from preeclampsia and normal pregnancies. Sci Rep 2020; 10:17558. [PMID: 33067549 PMCID: PMC7567870 DOI: 10.1038/s41598-020-74840-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 10/06/2020] [Indexed: 01/03/2023] Open
Abstract
This study sought to identify potential bioactive peptides from the placenta that are involved in preeclampsia (PE) to obtain information about the prediction, diagnosis and treatment of PE. The liquid chromatography/mass spectrometry was used to perform a comparative analysis of placental peptides in normal and PE pregnancies. Gene ontology (GO), pathway analysis and ingenuity pathway analysis (IPA) were used to evaluate the underlying biological function of the differential peptides based on their protein precursors. Transwell assays and qPCR were used to study the effect of the identified bioactive peptides on the function of HTR-8/SVneo cells. A total of 392 upregulated peptides and 420 downregulated peptides were identified (absolute fold change ≥ 2 and adjusted P value < 0.05). The GO analysis, pathway analysis, and IPA revealed that these differentially expressed peptides play a role in PE. In addition, the up-regulated peptide “DQSATALHFLGRVANPLSTA” derived from Angiotensinogen exhibited effect on the invasiveness of HTR-8/SVneo cells. The current preliminary research not only provides a new research direction for studying the pathogenesis of PE, but also brings new insights for the prediction, diagnosis and treatment of PE.
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Affiliation(s)
- Jin Huang
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, Jiangsu, China.,Yixing People's Hospital, YiXing, 214200, Jiangsu, China
| | - Zhonghui Ling
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, Jiangsu, China
| | - Hong Zhong
- Fourth Clinical Medicine College, Nanjing Medical University, Nanjing, 210000, Jiangsu, China
| | - Yadong Yin
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, Jiangsu, China
| | - Yating Qian
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, Jiangsu, China
| | - Mingming Gao
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, Jiangsu, China.,Fourth Clinical Medicine College, Nanjing Medical University, Nanjing, 210000, Jiangsu, China
| | - Hongjuan Ding
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, Jiangsu, China
| | - Qing Cheng
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, Jiangsu, China.
| | - Ruizhe Jia
- Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, Jiangsu, China.
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Molina L, Bustamante F, Ortloff A, Ramos I, Ehrenfeld P, Figueroa CD. Continuous Exposure of Breast Cancer Cells to Tamoxifen Upregulates GPER-1 and Increases Cell Proliferation. Front Endocrinol (Lausanne) 2020; 11:563165. [PMID: 33117280 PMCID: PMC7561417 DOI: 10.3389/fendo.2020.563165] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 09/08/2020] [Indexed: 12/13/2022] Open
Abstract
GPER-1 is a novel membrane sited G protein-coupled estrogen receptor. Clinical studies have shown that patients suffering an estrogen receptor α (ERα)/GPER-1 positive, breast cancer have a lower survival rate than those who have developed ERα-positive/GPER-1 negative tumors. Moreover, absence of GPER-1 improves the prognosis of patients treated with tamoxifen, the most used selective estrogen receptor modulator to treat ERα-positive breast cancer. MCF-7 breast cancer cells were continuously treated with 1,000 nM tamoxifen for 7 days to investigate its effect on GPER-1 protein expression, cell proliferation and intracellular [Ca2+]i mobilization, a key signaling pathway. Breast cancer cells continuously treated with tamoxifen, exhibited a robust [Ca2+]i mobilization after stimulation with 1,000 nM tamoxifen, a response that was blunted by preincubation of cells with G15, a commercial GPER-1 antagonist. Continuously treated cells also displayed a high [Ca2+]i mobilization in response to a commercial GPER-1 agonist (G1) and to estrogen, in a magnitude that doubled the response observed in untreated cells and was almost completely abolished by G15. Proliferation of cells continuously treated with tamoxifen and stimulated with 2,000 nM tamoxifen, was also higher than that observed in untreated cells in a degree that was approximately 90% attributable to GPER-1. Finally, prolonged tamoxifen treatment did not increase ERα expression, but did overexpress the kinin B1 receptor, another GPCR, which we have previously shown is highly expressed in breast tumors and increases proliferation of breast cancer cells. Although we cannot fully extrapolate the results obtained in vitro to the patients, our results shed some light on the occurrence of drug resistance in breast cancer patients who are ERα/GPER-1 positive, have been treated with tamoxifen and display low survival rate. Overexpression of kinin B1 receptor may explain the increased proliferative response observed in breast tumors under continuous treatment with tamoxifen.
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Affiliation(s)
- Luis Molina
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Puerto Montt, Chile
| | - Felipe Bustamante
- Laboratory of Cellular Pathology, Institute of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia, Chile
- Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile
| | - Alexander Ortloff
- Departamento de Ciencias Veterinarias y Salud Pública, Facultad de Recursos Naturales, Universidad Católica de Temuco, Temuco, Chile
| | - Iraidi Ramos
- Laboratory of Cellular Pathology, Institute of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia, Chile
- Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile
| | - Pamela Ehrenfeld
- Laboratory of Cellular Pathology, Institute of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia, Chile
- Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile
| | - Carlos D. Figueroa
- Laboratory of Cellular Pathology, Institute of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia, Chile
- Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile
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Fiala C, Diamandis EP. The Outcomes of Scientific Debates Should Be Published: The Arivale Story. J Appl Lab Med 2020; 5:1070-1075. [PMID: 32830260 DOI: 10.1093/jalm/jfaa110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/20/2020] [Indexed: 12/19/2022]
Abstract
There is an ongoing scientific debate regarding the merits and shortcomings of P4 Medicine (predictive, preventive, personalized, and participatory) and O4 Medicine (overtesting, overdiagnosis, overtreatment, and overcharging). P4 Medicine promises to revolutionize scientific wellness through longitudinal big data collection, denoted as "dense phenotyping," which could uncover early, actionable signs of disease, thus allowing earlier interventions and possible disease reversal. On the other hand, O4 Medicine draws attention to the potential side effects of P4 Medicine: overtesting, overdiagnosis, overtreatment, and overcharging fees. Preliminary data from the P4 Medicine concept have been recently published. A novel biotechnology company, Arivale, provided customers with services based on P4 Medicine principles; however it could not sustain its operations and closed its doors in April 2019. In this report, we provide our own insights as to why Arivale failed. While we do not discount that in the future, improved testing strategies may provide a path to better health, we suggest that until the evidence is provided, selling of such products to the public, especially through the "direct to consumer" approach, should be discouraged. We hope that our analysis will provide useful information for the burgeoning fields of personalized medicine, preventive medicine, and direct to consumer health testing.
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Affiliation(s)
- Clare Fiala
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Eleftherios P Diamandis
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
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Hanas JS, Hocker JRS, Evangeline B, Prabhakaran V, Oommen A, Rajshekhar V, Drevets DA, Carabin H. Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform. PLoS One 2020; 15:e0237064. [PMID: 32823271 PMCID: PMC7527271 DOI: 10.1371/journal.pone.0237064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 06/24/2020] [Indexed: 11/19/2022] Open
Abstract
A major source of epilepsy is Neurocysticercosis (NCC), caused by Taenia solium infection. Solitary cysticercus granuloma (SCG), a sub-group of NCC induced epilepsy, is the most common form of NCC in India. Current diagnostic criteria for SCG epilepsy require brain imaging which may not be available in communities where the disease is endemic. Identification of serum changes and potential biomolecules that could distinguish SCG epilepsy from idiopathic generalized epilepsy (IE), without the initial need for imaging, could assist in disease identification, understanding, and treatment. The objective here was to investigate, using mass spectrometry (MS), sera biomolecule differences between patients with SCG epilepsy or IE to help distinguish these disorders based on physiological differences, to understand underlying phenotypes and mechanisms, and to lay ground work for future therapeutic and biomarker analyses. Sera were obtained from patients with SCG or IE (N = 29 each group). Serum mass peak profiling was performed with electrospray ionization (ESI) MS, and mass peak area means in the two groups were compared using leave one [serum sample] out cross validation (LOOCV). Serum LOOCV analysis identified significant differences between SCG and IE patient groups (p = 10-20), which became non-significant (p = 0.074) when the samples were randomly allocated to the groups and reanalyzed. Tandem MS/MS peptide analysis of serum mass peaks from SCG or IE patients was performed to help identify potential peptide/protein biochemical and phenotypic changes involving these two forms of epilepsy. Bioinformatic analysis of these peptide/protein changes suggested neurological, inflammatory, seizure, blood brain barrier, cognition, ion channel, cell death, and behavior related biochemical systems were being altered in these disease states. This study provides groundwork for aiding in distinguishing SCG and IE patients in minimally invasive, lower-cost manners, for improving understanding of underlying epilepsy mechanisms, and for further identifying discriminatory biomarkers and potential therapeutic targets.
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Affiliation(s)
- Jay S. Hanas
- Department of Biochemistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - James Randolph Sanders Hocker
- Department of Biochemistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Betcy Evangeline
- Department of Neurological Sciences, Christian Medical College, Vellore, India
| | | | - Anna Oommen
- Department of Neurological Sciences, Christian Medical College, Vellore, India
| | - Vedantam Rajshekhar
- Department of Neurological Sciences, Christian Medical College, Vellore, India
| | - Douglas A. Drevets
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, and the Veterans Administration Medical Center, Oklahoma City, OK, United States of America
| | - Hélène Carabin
- Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
- Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Université de Montréal, Saint-Hyacinthe, Canada
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Hocker JR, Lerner M, Lightfoot SA, Peyton MD, Thompson JL, Deb S, Reinersman M, Hanas RJ, Postier RG, Edil BH, Burkhart HM, Hanas JS. Serum discrimination and phenotype assessment of coronary artery disease patents with and without type 2 diabetes prior to coronary artery bypass graft surgery. PLoS One 2020; 15:e0234539. [PMID: 32756554 PMCID: PMC7527241 DOI: 10.1371/journal.pone.0234539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 05/12/2020] [Indexed: 11/18/2022] Open
Abstract
Diabetes Mellitus (DM) accelerates coronary artery disease (CAD) and atherosclerosis, the causes of most heart attacks. The biomolecules involved in these inter-related disease processes are not well understood. This study analyzes biomolecules in the sera of patients with CAD, with and without type (T) 2DM, who are about to undergo coronary artery bypass graft (CABG) surgery. The goal is to develop methodology to help identify and monitor CAD patients with and without T2DM, in order to better understand these phenotypes and to glean relationships through analysis of serum biomolecules. Aorta, fat, muscle, and vein tissues from CAD T2DM patients display diabetic-related histologic changes (e.g., lipid accumulation, fibrosis, loss of cellularity) when compared to non-diabetic CAD patients. The patient discriminatory methodology utilized is serum biomolecule mass profiling. This mass spectrometry (MS) approach is able to distinguish the sera of a group of CAD patients from controls (p value 10−15), with the CAD group containing both T2DM and non-diabetic patients. This result indicates the T2DM phenotype does not interfere appreciably with the CAD determination versus control individuals. Sera from a group of T2DM CAD patients however are distinguishable from non-T2DM CAD patients (p value 10−8), indicating it may be possible to examine the T2DM phenotype within the CAD disease state with this MS methodology. The same serum samples used in the CAD T2DM versus non-T2DM binary group comparison were subjected to MS/MS peptide structure analysis to help identify potential biochemical and phenotypic changes associated with CAD and T2DM. Such peptide/protein identifications could lead to improved understanding of underlying mechanisms, additional biomarkers for discriminating and monitoring these disease conditions, and potential therapeutic targets. Bioinformatics/systems biology analysis of the peptide/protein changes associated with CAD and T2DM suggested cell pathways/systems affected include atherosclerosis, DM, fibrosis, lipogenesis, loss of cellularity (apoptosis), and inflammation.
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Affiliation(s)
- James R. Hocker
- Department of Biochemistry and Molecular Biology The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Megan Lerner
- Department of Surgery The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Stan A. Lightfoot
- Department of Medicine The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Marvin D. Peyton
- Department of Surgery The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Jess L. Thompson
- Department of Surgery The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Subrato Deb
- Department of Surgery The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Mathew Reinersman
- Department of Surgery The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - R. Jane Hanas
- Department of Biochemistry and Molecular Biology The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Russel G. Postier
- Department of Surgery The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Barish H. Edil
- Department of Surgery The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Harold M. Burkhart
- Department of Surgery The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Jay S. Hanas
- Department of Biochemistry and Molecular Biology The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
- * E-mail:
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Kessler JL, Li Y, Fornetti J, Welm AL, Yu SM. Enrichment of Collagen Fragments Using Dimeric Collagen Hybridizing Peptide for Urinary Collagenomics. J Proteome Res 2020; 19:2926-2932. [PMID: 32500704 DOI: 10.1021/acs.jproteome.0c00055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Collagen remodeling in normal and pathologic conditions releases numerous collagen fragments into biological fluids. Although a few collagen fragments have been tested as biomarkers for disease indication, most occur at trace levels, making them nearly impossible to detect even with modern analytical tools. Here we report a new way to enrich collagen fragments that allows complete peptidomic analysis of collagen fragments in urine. Enrichment is made possible by dimeric collagen hybridizing peptides (CHPs) that bind collagen fragments originating from the triple helical regions of all collagen types with minimal sequence bias. LC-MS/MS analysis of enriched mouse urine revealed an average of 383 collagenous peptide fragments per sample (compared to 34 for unenriched sample), which could be mapped to all types of mouse collagens in the SwissProt database including FACITs and MACITs. Hierarchical clustering of a selected panel of the detected fragments separated osteopenic mice from healthy mice. The results demonstrate dimeric CHP's ability to enrich collagen fragments from biological fluid and its potential to aid peptidomics-based disease detection and biomarker discovery.
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Affiliation(s)
- Julian L Kessler
- Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah 84112, United States
| | - Yang Li
- Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah 84112, United States
| | - Jaime Fornetti
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, United States
| | - Alana L Welm
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, United States
| | - S Michael Yu
- Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah 84112, United States.,Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, United States
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Hanas JS, Hocker JRS, Vannarath C, Evangeline B, Prabhakaran V, Oommen A, Couch J, Anderson M, Rajshekhar V, Carabin H, Drevets D. Distinguishing and Biochemical Phenotype Analysis of Epilepsy Patients Using a Novel Serum Profiling Platform. Brain Sci 2020; 10:brainsci10080504. [PMID: 32751954 PMCID: PMC7464346 DOI: 10.3390/brainsci10080504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 07/19/2020] [Accepted: 07/29/2020] [Indexed: 11/19/2022] Open
Abstract
Diagnosis of non-symptomatic epilepsy includes a history of two or more seizures and brain imaging to rule out structural changes like trauma, tumor, infection. Such analysis can be problematic. It is important to develop capabilities to help identify non-symptomatic epilepsy in order to better monitor and understand the condition. This understanding could lead to improved diagnostics and therapeutics. Serum mass peak profiling was performed using electrospray ionization mass spectrometry (ESI-MS). A comparison of sera mass peaks between epilepsy and control groups was performed via leave one [serum sample] out cross-validation (LOOCV). MS/MS peptide analysis was performed on serum mass peaks to compare epilepsy patient and control groups. LOOCV identified significant differences between the epilepsy patient group and control group (p = 10−22). This value became non-significant (p = 0.10) when the samples were randomly allocated between the groups and reanalyzed by LOOCV. LOOCV was thus able to distinguish a non-symptomatic epilepsy patient group from a control group based on physiological differences and underlying phenotype. MS/MS was able to identify potential peptide/protein changes involved in this epilepsy versus control comparison, with 70% of the top 100 proteins indicating overall neurologic function. Specifically, peptide/protein sera changes suggested neuro-inflammatory, seizure, ion-channel, synapse, and autoimmune pathways changing between epilepsy patients and controls.
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Affiliation(s)
- Jay S. Hanas
- Department of Biochemistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (J.R.S.H.); (C.V.)
- Correspondence:
| | - James R. S. Hocker
- Department of Biochemistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (J.R.S.H.); (C.V.)
| | - Christian Vannarath
- Department of Biochemistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (J.R.S.H.); (C.V.)
| | - Betcy Evangeline
- Department of Neurological Sciences, Christian Medical College, Vellore 632004, India; (B.E.); (V.P.); (A.O.); (V.R.)
| | - Vasudevan Prabhakaran
- Department of Neurological Sciences, Christian Medical College, Vellore 632004, India; (B.E.); (V.P.); (A.O.); (V.R.)
| | - Anna Oommen
- Department of Neurological Sciences, Christian Medical College, Vellore 632004, India; (B.E.); (V.P.); (A.O.); (V.R.)
| | - James Couch
- Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Michael Anderson
- Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (M.A.); (H.C.)
| | - Vedantam Rajshekhar
- Department of Neurological Sciences, Christian Medical College, Vellore 632004, India; (B.E.); (V.P.); (A.O.); (V.R.)
| | - Hélène Carabin
- Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (M.A.); (H.C.)
- Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Université de Montréal, Saint-Hyacinthe, QC H3T 1J4, Canada
| | - Douglas Drevets
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
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Zhu C, Yuan C, Wei FQ, Sun XY, Zheng SG. Comparative evaluation of peptidome and microbiota in different types of saliva samples. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:686. [PMID: 32617306 PMCID: PMC7327340 DOI: 10.21037/atm-20-393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background Clinical and research interest in salivary peptidome and microbiota is ever-growing owing to its great value for diagnosis, risk assessment and prediction of prognosis in oral and systemic diseases. Saliva can be stimulated for the purpose of rapid collection, but currently there are no studies systematically addressing the similarities and differences of salivary peptidome and microbiota in different types of samples. The purpose of this study was to investigate the variations of salivary peptidome and microbial profiles in response to different stimulating conditions. Methods Unstimulated saliva and three types of stimulated saliva samples (olfaction, gustation, and mastication stimulated saliva) were collected from 10 systematically and orally healthy donors. The peptidome profiles were detected by weak cation exchange magnetic beads and analyzed through matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF MS), while their microbial profiles were analyzed by 16S rDNA V3-V4 hypervariable region amplicon sequencing utilizing the Illumina MiSeq PE300 platform. The distance matrixes of salivary peptidome and microbial profiles were generated and the intra-individual distances were extracted, then the variations brought by different sampling conditions and repeated collections were compared. Results By comparisons of the overall salivary peptidome and microbial profiles, olfactory stimulation led to minimal variations comparing with that of unstimulated saliva, but appreciable variations were observed between saliva samples collected with gustatory/masticatory stimulation and unstimulated saliva. The three types of stimulated saliva exhibited significantly different peptidome and microbial profiles. Conclusions Stimulated saliva collected in response to olfactory stimulation is an appropriate alternative to unstimulated saliva, whereas gustatory/masticatory stimulation introduced appreciable variations. It is suggested that only one type of stimulating method should be used throughout one peptidome/microbiome research, which provides comprehensive insight into the optimization of sampling methods for salivaomic studies in the future.
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Affiliation(s)
- Ce Zhu
- Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Chao Yuan
- Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Fang-Qiao Wei
- Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Xiang-Yu Sun
- Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Shu-Guo Zheng
- Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
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Li N, Zhou Y, Wang J, Niu L, Zhang Q, Sun L, Ding X, Guo X, Xie Z, Zhu N, Zhang M, Chen X, Cai T, Yang F. Sequential Precipitation and Delipidation Enables Efficient Enrichment of Low-Molecular Weight Proteins and Peptides from Human Plasma. J Proteome Res 2020; 19:3340-3351. [DOI: 10.1021/acs.jproteome.0c00232] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Na Li
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yue Zhou
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- Thermo Fisher Scientific, Shanghai 200000, China
| | - Jifeng Wang
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Lili Niu
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Qing Zhang
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lang Sun
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiang Ding
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiaojing Guo
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhensheng Xie
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Nali Zhu
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Mengmeng Zhang
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiulan Chen
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tanxi Cai
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fuquan Yang
- Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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45
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Thavarajah T, Dos Santos CC, Slutsky AS, Marshall JC, Bowden P, Romaschin A, Marshall JG. The plasma peptides of sepsis. Clin Proteomics 2020; 17:26. [PMID: 32636717 PMCID: PMC7331219 DOI: 10.1186/s12014-020-09288-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 06/15/2020] [Indexed: 12/28/2022] Open
Abstract
Background A practical strategy to discover sepsis specific proteins may be to compare the plasma peptides and proteins from patients in the intensive care unit with and without sepsis. The aim was to discover proteins and/or peptides that show greater observation frequency and/or precursor intensity in sepsis. The endogenous tryptic peptides of ICU-Sepsis were compared to ICU Control, ovarian cancer, breast cancer, female normal, sepsis, heart attack, Alzheimer’s and multiple sclerosis along with their institution-matched controls, female normals and normal samples collected directly onto ice. Methods Endogenous tryptic peptides were extracted from individual sepsis and control EDTA plasma samples in a step gradient of acetonitrile for random and independent sampling by LC–ESI–MS/MS with a set of robust and sensitive linear quadrupole ion traps. The MS/MS spectra were fit to fully tryptic peptides within proteins using the X!TANDEM algorithm. The protein observation frequency was counted using the SEQUEST algorithm after selecting the single best charge state and peptide sequence for each MS/MS spectra. The protein observation frequency of ICU-sepsis versus ICU Control was subsequently tested by Chi square analysis. The average protein or peptide log10 precursor intensity was compared across disease and control treatments by ANOVA in the R statistical system. Results Peptides and/or phosphopeptides of common plasma proteins such as ITIH3, SAA2, SAA1, and FN1 showed increased observation frequency by Chi square (χ2 > 9, p < 0.003) and/or precursor intensity in sepsis. Cellular gene symbols with large Chi square values from tryptic peptides included POTEB, CTNNA1, U2SURP, KIF24, NLGN2, KSR1, GTF2H1, KIT, RPS6KL1, VAV2, HSPA7, SMC2, TCEB3B, ZNF300, SUPV3L1, ADAMTS20, LAMB4, MCCC1, SUPT6H, SCN9A, SBNO1, EPHA1, ABLIM2, cB5E3.2, EPHA10, GRIN2B, HIVEP2, CCL16, TKT, LRP2 and TMF1 amongst others showed increased observation frequency. Similarly, increased frequency of tryptic phosphopeptides were observed from POM121C, SCN8A, TMED8, NSUN7, SLX4, MADD, DNLZ, PDE3B, UTY, DEPDC7, MTX1, MYO1E, RXRB, SYDE1, FN1, PUS7L, FYCO1, USP26, ACAP2, AHI1, KSR2, LMAN1, ZNF280D and SLC8A2 amongst others. Increases in mean precursor intensity in peptides from common plasma proteins such as ITIH3, SAA2, SAA1, and FN1 as well as cellular proteins such as COL24A1, POTEB, KANK1, SDCBP2, DNAH11, ADAMTS7, MLLT1, TTC21A, TSHR, SLX4, MTCH1, and PUS7L among others were associated with sepsis. The processing of SAA1 included the cleavage of the terminal peptide D/PNHFRPAGLPEKY from the most hydrophilic point of SAA1 on the COOH side of the cystatin C binding that was most apparent in ICU-Sepsis patients compared to all other diseases and controls. Additional cleavage of SAA1 on the NH2 terminus side of the cystatin binding site were observed in ICU-Sepsis. Thus there was disease associated variation in the processing of SAA1 in ICU-Sepsis versus ICU controls or other diseases and controls. Conclusion Specific proteins and peptides that vary between diseases might be discovered by the random and independent sampling of multiple disease and control plasma from different hospital and clinics by LC–ESI–MS/MS for storage in a relational SQL Server database and analysis with the R statistical system that will be a powerful tool for clinical research. The processing of SAA1 may play an unappreciated role in the inflammatory response to Sepsis.
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Affiliation(s)
- Thanusi Thavarajah
- Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Claudia C Dos Santos
- St. Michael's Hospital, Keenan Research Centre for Biomedical Science, Toronto, Canada
| | - Arthur S Slutsky
- St. Michael's Hospital, Keenan Chair in Medicine, University of Toronto, Toronto, Canada
| | - John C Marshall
- International Biobank of Luxembourg (IBBL), Institute of Health (formerly CRP Sante Luxembourg), Dudelange, Luxembourg
| | - Pete Bowden
- Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Alexander Romaschin
- St. Michael's Hospital, Keenan Research Centre for Biomedical Science, Toronto, Canada
| | - John G Marshall
- Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada.,International Biobank of Luxembourg (IBBL), Institute of Health (formerly CRP Sante Luxembourg), Dudelange, Luxembourg
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Adem S, Jain S, Sveiven M, Zhou X, O'Donoghue AJ, Hall DA. Giant magnetoresistive biosensors for real-time quantitative detection of protease activity. Sci Rep 2020; 10:7941. [PMID: 32409675 PMCID: PMC7224196 DOI: 10.1038/s41598-020-62910-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 03/18/2020] [Indexed: 12/19/2022] Open
Abstract
Proteases are enzymes that cleave proteins and are crucial to physiological processes such as digestion, blood clotting, and wound healing. Unregulated protease activity is a biomarker of several human diseases. Synthetic peptides that are selectively hydrolyzed by a protease of interest can be used as reporter substrates of unregulated protease activity. We developed an activity-based protease sensor by immobilizing magnetic nanoparticles (MNPs) to the surface of a giant magnetoresistive spin-valve (GMR SV) sensor using peptides. Cleavage of these peptides by a protease releases the magnetic nanoparticles resulting in a time-dependent change in the local magnetic field. Using this approach, we detected a significant release of MNPs after 3.5 minutes incubation using just 4 nM of the cysteine protease, papain. In addition, we show that proteases in healthy human urine do not release the MNPs, however addition of 20 nM of papain to the urine samples resulted in a time-dependent change in magnetoresistance. This study lays the foundation for using GMR SV sensors as a platform for real-time, quantitative detection of protease activity in biological fluids.
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Affiliation(s)
- Sandeep Adem
- University of California - San Diego, Department of Bioengineering, La Jolla, CA, 92093, USA
| | - Sonal Jain
- University of California - San Diego, Department of Bioengineering, La Jolla, CA, 92093, USA
| | - Michael Sveiven
- University of California - San Diego, Department of Bioengineering, La Jolla, CA, 92093, USA
| | - Xiahan Zhou
- University of California - San Diego, Department of Electrical and Computer Engineering, La Jolla, CA, 92093, USA
| | - Anthony J O'Donoghue
- University of California - San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, 92093, USA.
| | - Drew A Hall
- University of California - San Diego, Department of Bioengineering, La Jolla, CA, 92093, USA.
- University of California - San Diego, Department of Electrical and Computer Engineering, La Jolla, CA, 92093, USA.
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Ren AH, Fiala CA, Diamandis EP, Kulasingam V. Pitfalls in Cancer Biomarker Discovery and Validation with Emphasis on Circulating Tumor DNA. Cancer Epidemiol Biomarkers Prev 2020; 29:2568-2574. [PMID: 32277003 DOI: 10.1158/1055-9965.epi-20-0074] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/19/2020] [Accepted: 04/03/2020] [Indexed: 11/16/2022] Open
Abstract
Despite significant investment of funds and resources, few new cancer biomarkers have been introduced to the clinic in the last few decades. Although many candidates produce promising results in the laboratory, deficiencies in sensitivity, specificity, and predictive value make them less than desirable in a patient setting. This review will analyze these challenges in detail as well as discuss false discovery, problems with reproducibility, and tumor heterogeneity. Circulating tumor DNA (ctDNA), an emerging cancer biomarker, is also analyzed, particularly in the contexts of assay specificity, sensitivity, fragmentation, lead time, mutant allele fraction, and clinical relevance. Emerging artificial intelligence technologies will likely be valuable tools in maximizing the clinical utility of ctDNA which is often found in very small quantities in patients with early-stage tumors. Finally, the implications of challenging false discoveries are examined and some insights about improving cancer biomarker discovery are provided.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."
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Affiliation(s)
- Annie H Ren
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Clare A Fiala
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Eleftherios P Diamandis
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada
| | - Vathany Kulasingam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. .,Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada
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Peng J, Zhang H, Niu H, Wu R. Peptidomic analyses: The progress in enrichment and identification of endogenous peptides. Trends Analyt Chem 2020. [DOI: 10.1016/j.trac.2020.115835] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Lv P, Liu Z, Xu B, Tang C, Li X, Qin H, Yang S, Gao H, He K, Liu X. Exploratory study on application of MALDI‑TOF‑MS to detect serum and urine peptides related to small cell lung carcinoma. Mol Med Rep 2020; 21:51-60. [PMID: 31746355 PMCID: PMC6896340 DOI: 10.3892/mmr.2019.10794] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 06/25/2019] [Indexed: 02/06/2023] Open
Abstract
Matrix‑assisted laser desorption/ionization time‑of‑flight mass spectrometry (MALDI‑TOF‑MS) was employed to analyze differential serum and urine peptides in patients with small cell lung cancer (SCLC) and healthy individuals, and SCLC diagnostic classification models were constructed. Serum and urine samples from 72 patients with SCLC, age‑ and gender‑matched with 72 healthy individuals, were divided into training and testing sets in a 3:1 ratio. Serum and urine peptides were extracted using copper ion‑chelating nanomagnetic beads, and mass spectra were obtained using MALDI‑TOF‑MS. Peptide spectra for the training set were analyzed, and the classification model was constructed using ClinProTools (CPT). The testing set was used for blinded model validation. For training‑set sera, 122 differential peptide signal peaks with a mass of 0.8‑10 kDa were observed, and 19 peptides showed significantly different expression [P<0.0005; area under curve (AUC) ≥0.80]. CPT screened 5 peptide peaks (0.8114, 0.83425, 1.86655, 4.11133 and 5.81192 kDa) to construct the classification model. The testing set was used for the blinded validation, which had 95.0% sensitivity and 90.0% specificity. For the training‑set urine, 132 differential peptide signal peaks with m/z ratios of 0.8‑10 kDa were observed, and 8 peptides had significantly different expression (P<0.0005; AUC ≥0.80). Then, 5 peaks (1.0724, 2.37692, 2.7554, 4.75475 and 4.7949 kDa) were used for classification model construction. The testing set was used for 36 blinded validation, which had 85.0% sensitivity and 80.0% specificity. Among the differential peptides, 3 had the same significant peaks at 2.3764, 0.8778 and 0.8616 kDa, identified as fibrinogen α, glucose‑6‑phosphate isomerase and cyclin‑dependent kinase‑1, respectively. The present study highlighted the differences that exist in serum and urine peptides between patients with SCLC and healthy individuals. Serum and urine peptide diagnostic classification models could be constructed using MALDI‑TOF‑MS, and showed high sensitivity and specificity.
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Affiliation(s)
- Panpan Lv
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, P.R. China
- Academy of Military Medical Science, Beijing 100069, P.R. China
| | - Zeyuan Liu
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, P.R. China
| | - Bin Xu
- National Center of Biomedical Analysis, Beijing 100069, P.R. China
| | - Chuanhao Tang
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, P.R. China
| | - Xiaoyan Li
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, P.R. China
| | - Haifeng Qin
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, P.R. China
| | - Shaoxing Yang
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, P.R. China
| | - Hongjun Gao
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, P.R. China
| | - Kun He
- National Center of Biomedical Analysis, Beijing 100069, P.R. China
| | - Xiaoqing Liu
- Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, P.R. China
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50
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Dufresne J, Bowden P, Thavarajah T, Florentinus-Mefailoski A, Chen ZZ, Tucholska M, Norzin T, Ho MT, Phan M, Mohamed N, Ravandi A, Stanton E, Slutsky AS, Dos Santos CC, Romaschin A, Marshall JC, Addison C, Malone S, Heyland D, Scheltens P, Killestein J, Teunissen C, Diamandis EP, Siu KWM, Marshall JG. The plasma peptides of breast versus ovarian cancer. Clin Proteomics 2019; 16:43. [PMID: 31889940 PMCID: PMC6927194 DOI: 10.1186/s12014-019-9262-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023] Open
Abstract
Background There is a need to demonstrate a proof of principle that proteomics has the capacity to analyze plasma from breast cancer versus other diseases and controls in a multisite clinical trial design. The peptides or proteins that show a high observation frequency, and/or precursor intensity, specific to breast cancer plasma might be discovered by comparison to other diseases and matched controls. The endogenous tryptic peptides of breast cancer plasma were compared to ovarian cancer, female normal, sepsis, heart attack, Alzheimer's and multiple sclerosis along with the institution-matched normal and control samples collected directly onto ice. Methods Endogenous tryptic peptides were extracted from individual breast cancer and control EDTA plasma samples in a step gradient of acetonitrile, and collected over preparative C18 for LC-ESI-MS/MS with a set of LTQ XL linear quadrupole ion traps working together in parallel to randomly and independently sample clinical populations. The MS/MS spectra were fit to fully tryptic peptides or phosphopeptides within proteins using the X!TANDEM algorithm. The protein observation frequency was counted using the SEQUEST algorithm after selecting the single best charge state and peptide sequence for each MS/MS spectra. The observation frequency was subsequently tested by Chi Square analysis. The log10 precursor intensity was compared by ANOVA in the R statistical system. Results Peptides and/or phosphopeptides of common plasma proteins such as APOE, C4A, C4B, C3, APOA1, APOC2, APOC4, ITIH3 and ITIH4 showed increased observation frequency and/or precursor intensity in breast cancer. Many cellular proteins also showed large changes in frequency by Chi Square (χ2 > 100, p < 0.0001) in the breast cancer samples such as CPEB1, LTBP4, HIF-1A, IGHE, RAB44, NEFM, C19orf82, SLC35B1, 1D12A, C8orf34, HIF1A, OCLN, EYA1, HLA-DRB1, LARS, PTPDC1, WWC1, ZNF562, PTMA, MGAT1, NDUFA1, NOGOC, OR1E1, OR1E2, CFI, HSA12, GCSH, ELTD1, TBX15, NR2C2, FLJ00045, PDLIM1, GALNT9, ASH2L, PPFIBP1, LRRC4B, SLCO3A1, BHMT2, CS, FAM188B2, LGALS7, SAT2, SFRS8, SLC22A12, WNT9B, SLC2A4, ZNF101, WT1, CCDC47, ERLIN1, SPFH1, EID2, THOC1, DDX47, MREG, PTPRE, EMILIN1, DKFZp779G1236 and MAP3K8 among others. The protein gene symbols with large Chi Square values were significantly enriched in proteins that showed a complex set of previously established functional and structural relationships by STRING analysis. An increase in mean precursor intensity of peptides was observed for QSER1 as well as SLC35B1, IQCJ-SCHIP1, MREG, BHMT2, LGALS7, THOC1, ANXA4, DHDDS, SAT2, PTMA and FYCO1 among others. In contrast, the QSER1 peptide QPKVKAEPPPK was apparently specific to ovarian cancer. Conclusion There was striking agreement between the breast cancer plasma peptides and proteins discovered by LC-ESI-MS/MS with previous biomarkers from tumors, cells lines or body fluids by genetic or biochemical methods. The results indicate that variation in plasma peptides from breast cancer versus ovarian cancer may be directly discovered by LC-ESI-MS/MS that will be a powerful tool for clinical research. It may be possible to use a battery of sensitive and robust linear quadrupole ion traps for random and independent sampling of plasma from a multisite clinical trial.
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Affiliation(s)
- Jaimie Dufresne
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Pete Bowden
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Thanusi Thavarajah
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Angelique Florentinus-Mefailoski
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Zhuo Zhen Chen
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Monika Tucholska
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Tenzin Norzin
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Margaret Truc Ho
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Morla Phan
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Nargiz Mohamed
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada
| | - Amir Ravandi
- 2Institute of Cardiovascular Sciences, St. Boniface Hospital Research Center, University of Manitoba, Winnipeg, Canada
| | - Eric Stanton
- 3Division of Cardiology, Department of Medicine, McMaster University, Hamilton, Canada
| | - Arthur S Slutsky
- 4St. Michael's Hospital, Keenan Chair in Medicine, Professor of Medicine, Surgery & Biomedical Engineering, University of Toronto, Toronto, Canada
| | - Claudia C Dos Santos
- 5St. Michael's Hospital, Keenan Research Centre for Biomedical Science, Toronto, Canada
| | - Alexander Romaschin
- 5St. Michael's Hospital, Keenan Research Centre for Biomedical Science, Toronto, Canada
| | - John C Marshall
- 5St. Michael's Hospital, Keenan Research Centre for Biomedical Science, Toronto, Canada
| | - Christina Addison
- 6Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Shawn Malone
- 6Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Daren Heyland
- 7Clinical Evaluation Research Unit, Kingston General Hospital, Kingston, Canada
| | - Philip Scheltens
- 8Alzheimer Center, Dept of Neurology, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Joep Killestein
- 9MS Center, Dept of Neurology, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Charlotte Teunissen
- 10Neurochemistry Lab and Biobank, Dept of Clinical Chemsitry, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | | | - K W M Siu
- 12University of Windsor, Windsor, Canada
| | - John G Marshall
- 1Ryerson Analytical Biochemistry Laboratory (RABL), Department of Chemistry and Biology, Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON Canada.,13International Biobank of Luxembourg (IBBL), Luxembourg Institute of Health (formerly CRP Sante Luxembourg), Strassen, Luxembourg
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