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Majumder A, Bano S, Nayak KB. The Pivotal Role of One-Carbon Metabolism in Neoplastic Progression During the Aging Process. Biomolecules 2024; 14:1387. [PMID: 39595564 PMCID: PMC11591851 DOI: 10.3390/biom14111387] [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: 09/18/2024] [Revised: 10/29/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
One-carbon (1C) metabolism is a complex network of metabolic reactions closely related to producing 1C units (as methyl groups) and utilizing them for different anabolic processes, including nucleotide synthesis, methylation, protein synthesis, and reductive metabolism. These pathways support the high proliferative rate of cancer cells. While drugs that target 1C metabolism (like methotrexate) have been used for cancer treatment, they often have significant side effects. Therefore, developing new drugs with minimal side effects is necessary for effective cancer treatment. Methionine, glycine, and serine are the main three precursors of 1C metabolism. One-carbon metabolism is vital not only for proliferative cells but also for non-proliferative cells in regulating energy homeostasis and the aging process. Understanding the potential role of 1C metabolism in aging is crucial for advancing our knowledge of neoplastic progression. This review provides a comprehensive understanding of the molecular complexities of 1C metabolism in the context of cancer and aging, paving the way for researchers to explore new avenues for developing advanced therapeutic interventions for cancer.
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Affiliation(s)
- Avisek Majumder
- Department of Medicine, University of California, San Francisco, CA 94158, USA
| | - Shabana Bano
- Department of Medicine, University of California, San Francisco, CA 94158, USA
| | - Kasturi Bala Nayak
- Quantitative Biosciences Institute, Department of Medicine, University of California, San Francisco, CA 94158, USA
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Sivasubramanian M, Chu CH, Hsia Y, Chen NT, Cai MT, Tew LS, Chuang YC, Chen CT, Aydogan B, Liao LD, Lo LW. Illuminating and Radiosensitizing Tumors with 2DG-Bound Gold-Based Nanomedicine for Targeted CT Imaging and Therapy. NANOMATERIALS (BASEL, SWITZERLAND) 2023; 13:nano13111790. [PMID: 37299694 DOI: 10.3390/nano13111790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023]
Abstract
Although radiotherapy is one of the most important curative treatments for cancer, its clinical application is associated with undesired therapeutic effects on normal or healthy tissues. The use of targeted agents that can simultaneously achieve therapeutic and imaging functions could constitute a potential solution. Herein, we developed 2-deoxy-d-glucose (2DG)-labeled poly(ethylene glycol) (PEG) gold nanodots (2DG-PEG-AuD) as a tumor-targeted computed tomography (CT) contrast agent and radiosensitizer. The key advantages of the design are its biocompatibility and targeted AuD with excellent sensitivity in tumor detection via avid glucose metabolism. As a consequence, CT imaging with enhanced sensitivity and remarkable radiotherapeutic efficacy could be attained. Our synthesized AuD displayed linear enhancement of CT contrast as a function of its concentration. In addition, 2DG-PEG-AuD successfully demonstrated significant augmentation of CT contrast in both in vitro cell studies and in vivo tumor-bearing mouse models. In tumor-bearing mice, 2DG-PEG-AuD showed excellent radiosensitizing functions after intravenous injection. Results from this work indicate that 2DG-PEG-AuD could greatly potentiate theranostic capabilities by providing high-resolution anatomical and functional images in a single CT scan and therapeutic capability.
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Affiliation(s)
- Maharajan Sivasubramanian
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan
| | - Chia-Hui Chu
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan
| | - Yu Hsia
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan
| | - Nai-Tzu Chen
- Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan
- Department of Cosmoceutics, China Medical University, Taichung 40402, Taiwan
| | - Meng-Ting Cai
- Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan
- Department of Cosmoceutics, China Medical University, Taichung 40402, Taiwan
| | - Lih Shin Tew
- Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan
- Department of Cosmoceutics, China Medical University, Taichung 40402, Taiwan
| | - Yao-Chen Chuang
- Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 110301, Taiwan
| | - Chin-Tu Chen
- Department of Radiology, The University of Chicago, Chicago, IL 60637, USA
| | - Bulent Aydogan
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637, USA
| | - Lun-De Liao
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan
| | - Leu-Wei Lo
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan
- Department of Radiology, The University of Chicago, Chicago, IL 60637, USA
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Xia W, Singh N, Goel S, Shi S. Molecular Imaging of Innate Immunity and Immunotherapy. Adv Drug Deliv Rev 2023; 198:114865. [PMID: 37182699 DOI: 10.1016/j.addr.2023.114865] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/17/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023]
Abstract
The innate immune system plays a key role as the first line of defense in various human diseases including cancer, cardiovascular and inflammatory diseases. In contrast to tissue biopsies and blood biopsies, in vivo imaging of the innate immune system can provide whole body measurements of immune cell location and function and changes in response to disease progression and therapy. Rationally developed molecular imaging strategies can be used in evaluating the status and spatio-temporal distributions of the innate immune cells in near real-time, mapping the biodistribution of novel innate immunotherapies, monitoring their efficacy and potential toxicities, and eventually for stratifying patients that are likely to benefit from these immunotherapies. In this review, we will highlight the current state-of-the-art in noninvasive imaging techniques for preclinical imaging of the innate immune system particularly focusing on cell trafficking, biodistribution, as well as pharmacokinetics and dynamics of promising immunotherapies in cancer and other diseases; discuss the unmet needs and current challenges in integrating imaging modalities and immunology and suggest potential solutions to overcome these barriers.
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Affiliation(s)
- Wenxi Xia
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, United States
| | - Neetu Singh
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, United States
| | - Shreya Goel
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, United States; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, United States; Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84112, United States
| | - Sixiang Shi
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, United States; Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84112, United States.
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Dobre EG, Surcel M, Constantin C, Ilie MA, Caruntu A, Caruntu C, Neagu M. Skin Cancer Pathobiology at a Glance: A Focus on Imaging Techniques and Their Potential for Improved Diagnosis and Surveillance in Clinical Cohorts. Int J Mol Sci 2023; 24:1079. [PMID: 36674595 PMCID: PMC9866322 DOI: 10.3390/ijms24021079] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/02/2023] [Accepted: 01/03/2023] [Indexed: 01/08/2023] Open
Abstract
Early diagnosis is essential for completely eradicating skin cancer and maximizing patients' clinical benefits. Emerging optical imaging modalities such as reflectance confocal microscopy (RCM), optical coherence tomography (OCT), magnetic resonance imaging (MRI), near-infrared (NIR) bioimaging, positron emission tomography (PET), and their combinations provide non-invasive imaging data that may help in the early detection of cutaneous tumors and surgical planning. Hence, they seem appropriate for observing dynamic processes such as blood flow, immune cell activation, and tumor energy metabolism, which may be relevant for disease evolution. This review discusses the latest technological and methodological advances in imaging techniques that may be applied for skin cancer detection and monitoring. In the first instance, we will describe the principle and prospective clinical applications of the most commonly used imaging techniques, highlighting the challenges and opportunities of their implementation in the clinical setting. We will also highlight how imaging techniques may complement the molecular and histological approaches in sharpening the non-invasive skin characterization, laying the ground for more personalized approaches in skin cancer patients.
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Affiliation(s)
- Elena-Georgiana Dobre
- Faculty of Biology, University of Bucharest, Splaiul Independentei 91-95, 050095 Bucharest, Romania
| | - Mihaela Surcel
- Immunology Department, “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania
| | - Carolina Constantin
- Immunology Department, “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania
- Department of Pathology, Colentina University Hospital, 020125 Bucharest, Romania
| | | | - Ana Caruntu
- Department of Oral and Maxillofacial Surgery, “Carol Davila” Central Military Emergency Hospital, 010825 Bucharest, Romania
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, “Titu Maiorescu” University, 031593 Bucharest, Romania
| | - Constantin Caruntu
- Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Monica Neagu
- Faculty of Biology, University of Bucharest, Splaiul Independentei 91-95, 050095 Bucharest, Romania
- Immunology Department, “Victor Babes” National Institute of Pathology, 050096 Bucharest, Romania
- Department of Pathology, Colentina University Hospital, 020125 Bucharest, Romania
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Kilicoglu O, Sepay N, Ozgenc E, Gundogdu E, Kara U, Alomairy S, Al-Buriahi M. Evaluation of F-18 FDG radiopharmaceuticals through Molecular Docking and radiation effects. Appl Radiat Isot 2022; 191:110553. [DOI: 10.1016/j.apradiso.2022.110553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/23/2022] [Accepted: 11/02/2022] [Indexed: 11/08/2022]
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Suzuki M, Tezuka K, Handa T, Sato R, Takeuchi H, Takao M, Tano M, Uchida Y. Upregulation of ribosome complexes at the blood-brain barrier in Alzheimer's disease patients. J Cereb Blood Flow Metab 2022; 42:2134-2150. [PMID: 35766008 PMCID: PMC9580172 DOI: 10.1177/0271678x221111602] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The cerebrovascular-specific molecular mechanism in Alzheimer's disease (AD) was investigated by employing comprehensive and accurate quantitative proteomics. Highly purified brain capillaries were isolated from cerebral gray and white matter of four AD and three control donors, and examined by SWATH (sequential window acquisition of all theoretical fragment ion spectra) proteomics. Of the 29 ribosomal proteins that were quantified, 28 (RPLP0, RPL4, RPL6, RPL7A, RPL8, RPL10A, RPL11, RPL12, RPL14, RPL15, RPL18, RPL23, RPL27, RPL27A, RPL31, RPL35A, RPS2, RPS3, RPS3A, RPS4X, RPS7, RPS8, RPS14, RPS16, RPS20, RPS24, RPS25, and RPSA) were significantly upregulated in AD patients. This upregulation of ribosomal protein expression occurred only in brain capillaries and not in brain parenchyma. The protein expression of protein processing and N-glycosylation-related proteins in the endoplasmic reticulum (DDOST, STT3A, MOGS, GANAB, RPN1, RPN2, SEC61B, UGGT1, LMAN2, and SSR4) were also upregulated in AD brain capillaries and was correlated with the expression of ribosomal proteins. The findings reported herein indicate that the ribosome complex, the subsequent protein processing and N-glycosylation-related processes are significantly and specifically upregulated in the brain capillaries of AD patients.
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Affiliation(s)
- Masayoshi Suzuki
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Kenta Tezuka
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Takumi Handa
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Risa Sato
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Hina Takeuchi
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Masaki Takao
- Department of Neurology and Brain Bank, Mihara Memorial Hospital, Isesaki, Japan.,Department of Clinical Laboratory, National Center of Neurology and Psychiatry, National Center Hospital, Kodaira, Japan
| | - Mitsutoshi Tano
- Department of Neurology and Brain Bank, Mihara Memorial Hospital, Isesaki, Japan
| | - Yasuo Uchida
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
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Polvoy I, Qin H, Flavell RR, Gordon J, Viswanath P, Sriram R, Ohliger MA, Wilson DM. Deuterium Metabolic Imaging-Rediscovery of a Spectroscopic Tool. Metabolites 2021; 11:570. [PMID: 34564385 PMCID: PMC8470013 DOI: 10.3390/metabo11090570] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 08/18/2021] [Indexed: 01/31/2023] Open
Abstract
The growing demand for metabolism-specific imaging techniques has rekindled interest in Deuterium (2H) Metabolic Imaging (DMI), a robust method based on administration of a substrate (glucose, acetate, fumarate, etc.) labeled with the stable isotope of hydrogen and the observation of its metabolic fate in three-dimensions. This technique allows the investigation of multiple metabolic processes in both healthy and diseased states. Despite its low natural abundance, the short relaxation time of deuterium allows for rapid radiofrequency (RF) pulses without saturation and efficient image acquisition. In this review, we provide a comprehensive picture of the evolution of DMI over the course of recent decades, with a special focus on its potential clinical applications.
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Affiliation(s)
- Ilona Polvoy
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., San Francisco, CA 94158, USA; (I.P.); (H.Q.); (R.R.F.); (J.G.); (P.V.); (R.S.); (M.A.O.)
| | - Hecong Qin
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., San Francisco, CA 94158, USA; (I.P.); (H.Q.); (R.R.F.); (J.G.); (P.V.); (R.S.); (M.A.O.)
| | - Robert R. Flavell
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., San Francisco, CA 94158, USA; (I.P.); (H.Q.); (R.R.F.); (J.G.); (P.V.); (R.S.); (M.A.O.)
| | - Jeremy Gordon
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., San Francisco, CA 94158, USA; (I.P.); (H.Q.); (R.R.F.); (J.G.); (P.V.); (R.S.); (M.A.O.)
| | - Pavithra Viswanath
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., San Francisco, CA 94158, USA; (I.P.); (H.Q.); (R.R.F.); (J.G.); (P.V.); (R.S.); (M.A.O.)
| | - Renuka Sriram
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., San Francisco, CA 94158, USA; (I.P.); (H.Q.); (R.R.F.); (J.G.); (P.V.); (R.S.); (M.A.O.)
| | - Michael A. Ohliger
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., San Francisco, CA 94158, USA; (I.P.); (H.Q.); (R.R.F.); (J.G.); (P.V.); (R.S.); (M.A.O.)
- Department of Radiology, Zuckerberg San Francisco General Hospital, San Francisco, CA 94110, USA
| | - David M. Wilson
- Department of Radiology and Biomedical Imaging, University of California, 185 Berry St., San Francisco, CA 94158, USA; (I.P.); (H.Q.); (R.R.F.); (J.G.); (P.V.); (R.S.); (M.A.O.)
- Department of Radiology and Biomedical Imaging, University of California, 505 Parnassus Ave, San Francisco, CA 94143, USA
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Bochiński A, Sujenthiran A, Al-Hussini M, Fruhwirth GO, Shabbir M, Yap T. 18 F-FDG PET/CT use in functional assessment of the testes: A systematic review. Andrology 2021; 9:1410-1421. [PMID: 34019736 DOI: 10.1111/andr.13042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 04/29/2021] [Accepted: 05/18/2021] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Our study analysed previous studies employing positron emission tomography with co-registered computer tomography (PET/CT) in andrological patient evaluation and assessed the differences in 2-[18 F]F-fluoro-2'-deoxyglucose (FDG) uptake between three groups: healthy testes, benign and malignant testicular pathology. METHODS Medline and Embase were systematically searched for studies involving FDG-PET/CT imaging of testes with results expressed as mean standardised uptake value (SUVmean ). A one-way ANOVA was used to compare SUVmean between three groups. All papers assessing andrological parameters were pooled to compare fertility data. RESULTS Seventeen studies, including three relating to fertility diagnosis, with a total of 830 patients, were included in the review. One-way ANOVA showed a statistical difference between mean values of tracer SUVmean in healthy and malignant testes (Dif. = -2.77, 95% CI = -4.32 to 1.21, p < 0.01) as well as benign and malignant (Dif. = -2.95, 95% CI = -4.33 to -1.21, p < 0.01) but no difference between healthy and benign (Dif. = 0.19, 95% CI = -0.96 to 1.33, p = 0.90). There is some evidence to suggest that FDG uptake and testicular volume are positively correlated to total sperm count, sperm concentration and sperm motility and that germ cells are likely to account for the majority of testicular FDG accumulation. CONCLUSION Our findings indicate that malignant testicular lesions demonstrate a significantly higher FDG uptake than benign testicular lesions or healthy testes. Some evidence also suggests that FDG-PET could visualise metabolic activity and thus spermatogenesis; however more studies are required to determine whether FDG-PET could also be used to diagnose infertility. Further studies should focus on correlating both sex hormone-serum levels and semen analysis results with imaging data.
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Affiliation(s)
- Antoni Bochiński
- School of Bioscience Education, Guy's Campus, King's College London, London, UK
| | | | | | - Gilbert O Fruhwirth
- Imaging Therapies and Cancer Group, School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK
| | - Majed Shabbir
- Department of Urology, Guy's and St Thomas' NHS Trust, London, UK
| | - Tet Yap
- Department of Urology, Guy's and St Thomas' NHS Trust, London, UK
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Recent advances in iron oxide nanoparticles for brain cancer theranostics: from in vitro to clinical applications. Expert Opin Drug Deliv 2021; 18:949-977. [PMID: 33567919 DOI: 10.1080/17425247.2021.1888926] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Today, the development of multifunctional nanoplatforms is more seriously considered in the field of cancer theranostics.Areas covered: In this respect, nanoparticles provide several advantages over the routine, conventional diagnostic methods, and treatments. Due to the expedient properties of iron oxide nanoparticles, such as being readily modified, great payload potential, intrinsic magnetic qualification, considerable biocompatibility, and overwhelming response to targeting strategies, these nanoparticles can be considered good candidates for application as diagnostic contrast agents and drug/gene delivery vehicles, while also being incorporated into hyperthermia-based approaches. Interestingly, these agents are detectable with routine imaging modalities such as magnetic resonance imaging.Expert opinion: Therefore, combining the traditional diagnostics and therapies with nanotechnological approaches may leave a positive impact on the survival rate of patients with cancer. This review summarizes the application of magnetic iron oxide nanoparticles in both in vitro and in vivo models of brain tumors.
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Role of PET/CT in patients with unexplained rising alpha fetoprotein post HCC interventional management. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2020. [DOI: 10.1186/s43055-020-00158-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Positron emission tomography–computed tomography (PET/CT) is considered a powerful modality in the follow-up of hepatocellular carcinoma (HCC) patients. In this study, PET/CT was done in an evaluation of patients with unexplained rising alpha fetoprotein (AFP) post hepatocellular carcinoma (HCC) interventional management in 40 patients (16 females and 24 males); their age ranged from 25 to 82 years, had undergone interventional management for HCC and underwent PET/CT follow-up within an 8-month duration from their intervention. Whole-body PET/CT was performed after injection of (18)-FDG, and the results were read in a masked manner by two specialists, and diagnostic performance was assessed from the results of consensus masked reading. All the results were evaluated with the Barcelona criteria and biopsy correlation.
Results
During the follow-up PET/CT, 24 patients had complete response and 8 patients showed focal residual while the rest 8 patients showed newly developed lesions.
Conclusion
PET/CT is an excellent method for the evaluation of HCC patients with equivocal results after interventional management.
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Li Y, Tian H, Luo H, Fu J, Jiao Y, Li Y. Prognostic Significance and Related Mechanisms of Hexokinase 1 in Ovarian Cancer. Onco Targets Ther 2020; 13:11583-11594. [PMID: 33204111 PMCID: PMC7667154 DOI: 10.2147/ott.s270688] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/13/2020] [Indexed: 01/10/2023] Open
Abstract
PURPOSE Ovarian cancer (OC) has the highest mortality among gynecological malignancies. Therefore, it is urgent to explore prognostic biomarkers to improve the survival of OC patients. One of the most prominent metabolic characteristics of cancer is effective glycolysis. Hexokinase 1 (HK1), as the first rate-limiting enzyme in glycolysis, is closely related to cancer progression. However, the role of HK1 in OC remains unclear. MATERIALS AND METHODS The Cancer Genome Atlas (TCGA) database was used to detect the expression of HK1 in OC patients. The chi-squared test was performed to examine the correlations between HK1 and patients' clinical characteristics. Survival analyses were undertaken to determine the relationship between HK1 and patient survival, while the univariate/multivariate Cox model was used to evaluate the role of HK1 in patient prognosis. Gene Set Enrichment Analysis (GSEA) was performed to ascertain the related signaling pathways of HK1. RT-qPCR was implemented to validate the mRNA expression of HK1 in OC cells. MTT was used to detect cell viability after adding 2DG and knocking down HK1 in OC cells. HK1 protein expression was examined by Western blotting. Glucose uptake, lactate production, and ATP assays were undertaken following knockdown of HK1 in OC cells. Colony formation assays were performed to determine OC cell proliferation after HK1 knockdown. Transwell and wound healing assays were carried out to detect the invasion and migration of OC cells after HK1 knockdown. RESULTS We found that HK1 expression was increased in OC tissues and cells, and HK1 was related to the clinical characteristics of OC patients. Survival analysis revealed that OC patients in the HK1 overexpression group had poor survival. Moreover, univariant/multivariate analyses showed that HK1 may be an independent biomarker for the poor prognosis of OC patients. OC cell viability and proliferation decreased after knockdown of HK1. Consistently, glucose uptake, lactic acid production, ATP production, invasion, and migration were also decreased. Finally, GSEA enrichment analysis and Western blotting showed that HK1 was involved in MAPK/ERK signaling. CONCLUSION HK1 may be a biomarker for the poor prognosis of OC patients and a potential therapeutic target.
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Affiliation(s)
- Yanqing Li
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Huining Tian
- College of Translational Medicine, The First Affiliated Hospital of Jilin University, Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Haoge Luo
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Jiaying Fu
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, People’s Republic of China
| | - Yang Li
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin130021, People’s Republic of China
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Vasquez JH, Borniger JC. Neuroendocrine and Behavioral Consequences of Hyperglycemia in Cancer. Endocrinology 2020; 161:5810322. [PMID: 32193527 PMCID: PMC7174055 DOI: 10.1210/endocr/bqaa047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 03/16/2020] [Indexed: 12/20/2022]
Abstract
A hallmark of cancer is the disruption of cellular metabolism during the course of malignant growth. Major focus is now on how these cell-autonomous processes propagate to the tumor microenvironment and, more generally, to the entire host system. This chain of events can have major consequences for a patient's health and wellbeing. For example, metabolic "waste" produced by cancer cells activates systemic inflammatory responses, which can interfere with hepatic insulin receptor signaling and glucose homeostasis. Research is just now beginning to understand how these processes occur, and how they contribute to systemic symptoms prevalent across cancers, including hyperglycemia, fatigue, pain, and sleep disruption. Indeed, it is only recently that we have begun to appreciate that the brain does not play a passive role in responding to cancer-induced changes in physiology. In this review, we provide a brief discussion of how oncogene-directed metabolic reprogramming disrupts host metabolism, with a specific emphasis on cancer-induced hyperglycemia. We further discuss how the brain senses circulating glucose concentrations and how this process goes awry as a response to distant neoplastic growth. Finally, as glucose-sensing neurons control diverse aspects of physiology and behavior, we link cancer-induced changes in energy balance to neuroendocrine and behavioral consequences for the host organism.
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Affiliation(s)
- Juan H Vasquez
- Department of Biology, University of Texas – San Antonio, San Antonio, Texas
| | - Jeremy C Borniger
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
- Correspondence: Jeremy C. Borniger, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. E-mail:
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Belge G, Bilgin C, Ozkaya G, Kandemirli SG, Alper E. Prognostic value of pretreatment tumor-to-blood standardized uptake ratio (SUR) in rectal cancer. Ann Nucl Med 2020; 34:432-440. [PMID: 32297136 DOI: 10.1007/s12149-020-01465-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/02/2020] [Indexed: 12/22/2022]
Abstract
OBJECTIVES The prognostic value of SUV on pretreatment F-18 FDG PET/CT imaging in patients with rectal cancer is a matter of debate. SUR is of prognostic value for survival in different cancers. In this study, we aimed to examine the potential prognostic value of SUR and other parameters in pretreatment F-18 FDG PET/CT for non-metastatic rectal cancer. METHODS One hundred four non-metastatic rectal cancer patients who underwent pretreatment PET/CT between March 2012 and January 2018 were included in the study. Firstly, SUVmax, SUVmean, MTV, and TLG were calculated semi-automatically at the workstation. SUR was calculated as the ratio of tumor SUVmax to thoracic aorta blood SUVmean. Univariate Cox regression and Kaplan-Meier analysis were used to evaluate overall survival (OS), progression free survival (PFS), and local recurrence (LR). Then, multivariate Cox regression analysis, which included the parameters that were significant in the univariate analysis, was performed. RESULTS Multivariate Cox regression analysis revealed that SUR was a prognostic factor for PFS. Age and T stage were prognostic factors for both OS and PFS. MTV was found to be independent risk factors for OS. CONCLUSIONS In our study, SUR was the only F-18 FDG PET/CT parameter found to be significant for PFS. The development of new parameters can increase the prognostic value of F-18 FDG PET/CT.
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Affiliation(s)
- Gokce Belge
- Department of Nuclear Medicine, Uludag University School of Medicine, 16059, Bursa, Turkey.
| | - Cem Bilgin
- Department of Radiology, Uludag University School of Medicine, Bursa, Turkey
| | - Guven Ozkaya
- Department of Statistics, Uludag University School of Medicine, Bursa, Turkey
| | | | - Eray Alper
- Department of Nuclear Medicine, Uludag University School of Medicine, 16059, Bursa, Turkey
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14
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Fernando S, Lin M, Pham TT, Chong S, Ip E, Wong K, Chua W, Ng W, Lin P, Lim S. Prognostic utility of serial 18F-FDG-PET/CT in patients with locally advanced rectal cancer who underwent tri-modality treatment. Br J Radiol 2019; 93:20190455. [PMID: 31617737 DOI: 10.1259/bjr.20190455] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE This study explored the value of serial 18-fludeoxyglucose-positron emission tomography (18F-FDG-PET/CT) in predicting disease-free survival (DFS) in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NCRT) and surgery. METHODS We prospectively studied 46 patients with LARC who underwent NCRT and surgery. 18F-FDG-PET/CT scans were performed at three time-points before surgery (pre-NCRT-PET1, during NCRT-PET2 and following completion of NCRT-PET3). The following semi-quantitative PET parameters were analysed at each time point: maximum standardized uptake value (SUVmax), SUVmean, metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG). Absolute and percentage changes in these parameters were analysed between time points. Statistical analysis consisted of median tests, Cox regression and Kaplan-Meier analysis for DFS. RESULTS The median follow-up time was 24 months. A reduction in PET parameters showed statistically significant differences for patients with recurrence compared to those without; percentage changes in MTV between PET1 and PET3 (cut-off: 87%, p = 0.023), percentage changes in TLG between PET1 and PET3 (cut-off: 94%, p = 0.02) and absolute change in MTV PET1 and PET2 (cut-off: 10.25, p = 0.001).An absolute reduction in MTV between PET1 and PET3 (p=0.013), a percentage reduction in TLG between PET1 and PET2 (p=0.021), SUVmax and SUVmean at PET2 (p = 0.01, p = 0.027 respectively)were also prognostic indicators of recurrence.MTV percentage change between PET1 and PET2 and SUVmean percentage change between PET1 and PET3 were also trending towards significance (p = 0.052, p = 0.053 respectively). CONCLUSION Serial 18F-FDG-PET/CT is a potentially reliable non-invasive method to predict recurrence in patients with LARC. Volumetric parameters were the best predictors. This could allow risk-stratification in patients who may benefit from conservative management. ADVANCES IN KNOWLEDGE This paper will add to the literature in risk-stratifying patients with LARC based on prognosis, using 18F-FDG-PET/CT. This may improve patient outcomes by selecting suitable candidates for conservative management.
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Affiliation(s)
| | - Michael Lin
- University of New South Wales, Sydney, Australia.,Western Sydney University, Sydney, Australia.,Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, Australia
| | - Trang Thanh Pham
- University of New South Wales, Sydney, Australia.,Western Sydney University, Sydney, Australia.,Department of Radiation Oncology, Liverpool Hospital, Sydney, Australia.,Ingham Institute for Applied Medical Research, Sydney, Australia
| | - Shanley Chong
- University of New South Wales, Sydney, Australia.,Population Health Intelligence, Healthy People and Places Unit, South Western Sydney Local Health District, Sydney, Australia
| | - Emilia Ip
- Ingham Institute for Applied Medical Research, Sydney, Australia.,Department of Medical Oncology, Liverpool Hospital, Sydney, Australia
| | - Karen Wong
- University of New South Wales, Sydney, Australia.,Department of Radiation Oncology, Liverpool Hospital, Sydney, Australia.,Ingham Institute for Applied Medical Research, Sydney, Australia
| | - Wei Chua
- Ingham Institute for Applied Medical Research, Sydney, Australia.,Department of Medical Oncology, Liverpool Hospital, Sydney, Australia
| | - Weng Ng
- University of New South Wales, Sydney, Australia.,Ingham Institute for Applied Medical Research, Sydney, Australia.,Department of Medical Oncology, Liverpool Hospital, Sydney, Australia
| | - Peter Lin
- University of New South Wales, Sydney, Australia.,Western Sydney University, Sydney, Australia.,Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, Australia
| | - Stephanie Lim
- University of New South Wales, Sydney, Australia.,Ingham Institute for Applied Medical Research, Sydney, Australia
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15
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Scrotal Fibroepithelial Polyp With Acute and Chronic Inflammation Mimics Malignancy on 18F-FDG PET/CT Imaging. Clin Nucl Med 2019; 44:920-922. [PMID: 31524677 DOI: 10.1097/rlu.0000000000002771] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Computed tomography (CT) of a 68-year-old man showed multiple small nodules in the bilateral lungs (maximum 14 mm in the left upper lobe). CT-guided biopsy of left upper lobe lesion showed no tumor or granuloma. Fluorodeoxyglucose (FDG) PET/CT showed multiple nodules with background-to-mild FDG-avid activity, and an incidental left scrotal skin lesion with intensely increased accumulation of F-FDG (SUVmax, 11.7), suspected malignant. After urologist consultation, local dermatological findings suggested a huge wart. Excision was done, and pathology concluded nodular papillary fibroepithelial polyp with acute and chronic inflammation.
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16
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Berrino E, Supuran CT. Novel approaches for designing drugs that interfere with pH regulation. Expert Opin Drug Discov 2019; 14:231-248. [PMID: 30681011 DOI: 10.1080/17460441.2019.1567488] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION In all living species, pH regulation is a tightly controlled process, with a plethora of proteins involved in its regulation. These include sodium-proton exchangers, carbonic anhydrases, anion exchangers, bicarbonate transporters/cotransporters, H+-ATPases, and monocarboxylate transporters. All of them play crucial roles in acid-base balancing, both in eukaryotic as well as in prokaryotic organisms, making them interesting drug targets for the management of pathological events (in)directly involved in pH regulation. Areas covered: Interfering with pH regulation for the treatment of tumors and microbial infections is the main focus of this review, with particular attention paid to inhibitors targeting the above-mentioned proteins. The latest advances in each field id reviewed. Expert opinion: Interfering with the pH regulation of tumor cells is a validated approach to tackle primary tumors and metastases growth. Carbonic anhydrases are the most investigated proteins of those aforementioned, with several inhibitors in clinical development. Recent advances in the characterization of proteins involved in pH homeostasis of various pathogens evidenced their crucial role in the survival and virulence of bacterial, fungal, and protozoan microorganisms. Some encouraging results shed light on the possibility to target such proteins for obtaining new anti-infectives, overcoming the extensive drug resistance problems of clinically used drugs.
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Affiliation(s)
- Emanuela Berrino
- a NEUROFARBA Department, Sezione di Scienze Farmaceutiche , University of Florence , Sesto Fiorentino (Florence) , Italy
| | - Claudiu T Supuran
- a NEUROFARBA Department, Sezione di Scienze Farmaceutiche , University of Florence , Sesto Fiorentino (Florence) , Italy
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17
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Lee J, Lee M, Koom WS, Kim HJ, Kim WC. Metabolic positron emission tomography parameters predict failure patterns in early non-small-cell lung cancer treated with stereotactic body radiation therapy: a single institution experience. Jpn J Clin Oncol 2018; 48:920-926. [PMID: 30124920 DOI: 10.1093/jjco/hyy115] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 07/20/2018] [Indexed: 12/11/2022] Open
Abstract
Objective The prognostic value of metabolic parameters using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) has not been established for early non-small cell lung cancer (NSCLC). Accordingly, the authors investigated the prognostic value of metabolic parameters in terms of failure patterns in patients with early NSCLC who underwent stereotactic body radiation therapy (SBRT). Methods Data from 35 patients with Stage I NSCLC who underwent SBRT using CyberKnife and received pretreatment FDG PET/CT between 2008 and 2016 were retrospectively reviewed. Maximum standardized uptake value (SUVmax), metabolic tumor volume, and total lesion glycolysis were measured. The significance of these parameters with regard to failure patterns was assessed. Results The median follow-up was 23 months for all patients and 34 months for living patients. Ten patients experienced recurrence: three local failures, five regional failures (RF), and eight distant failures (DF). Three-year local, regional and distant control rates were 96.7%, 86.4% and 71.1%, respectively. High SUVmax (<9 vs. ≥9) was an independent predictive factor associated with increased RF (P = 0.027) and DF (P = 0.008). Furthermore, SUVmax was indicative of both progression-free (P = 0.015) and overall (P = 0.034) survival. Conclusions High SUVmax was a significant metabolic parameter associated with increased RF and DF in patients with early NSCLC who received SBRT, having a high propensity for dissemination. These results suggest that adjuvant treatment in conjunction with SBRT may be considered in patients with early NSCLC and high SUVmax.
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Affiliation(s)
- Jeongshim Lee
- Department of Radiation Oncology, Inha University Hospital, Inha University School of Medicine, Incheon.,Department of Radiation Oncology, Yonsei University College of Medicine, Seoul
| | - Minkyung Lee
- Department of Nuclear Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea
| | - Woong Sub Koom
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul
| | - Hun Jung Kim
- Department of Radiation Oncology, Inha University Hospital, Inha University School of Medicine, Incheon
| | - Woo Chul Kim
- Department of Radiation Oncology, Inha University Hospital, Inha University School of Medicine, Incheon
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18
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Marbaniang C, Kma L. Dysregulation of Glucose Metabolism by Oncogenes and Tumor Suppressors in Cancer Cells. Asian Pac J Cancer Prev 2018; 19:2377-2390. [PMID: 30255690 PMCID: PMC6249467 DOI: 10.22034/apjcp.2018.19.9.2377] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 08/20/2018] [Indexed: 02/07/2023] Open
Abstract
Cancers are complex diseases having several unique features, commonly described as ‘hallmarks of cancer’. Among them, altered signaling pathways are the common characteristic features that drive cancer progression; this is achieved due to mutations that lead to the activation of growth promoting(s) oncogenes and inactivation of tumor suppressors. As a result of which, cancer cells increase their glycolytic rate by consuming a large amount of glucose, and convert a majority of glucose to lactate even in the presence of oxygen known as the “Warburg effect”. Tumor cells like other cells are strictly dependent on energy for growth and survival; therefore, understanding energy metabolism will give us an idea to develop new effective anti-cancer therapies that target cancer energy production pathways. This review summarizes the roles of tumor suppressors and oncogenes and their products that provide metabolic advantages to cancer cells which in turn leads to the establishment of the “Warburg effect” and ultimately leads to cancer progression. Understanding cancer cell’s vulnerability will provide potential targets for its control.
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Affiliation(s)
- Casterland Marbaniang
- Department of Biochemistry, Cancer and Radiation Countermeasures Unit,North-Eastern Hill University, Shillong, Meghalaya, India.
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19
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Nakajima M, Muroi H, Yokoyama H, Kikuchi M, Yamaguchi S, Sasaki K, Kato H. 18 F-Fluorodeoxyglucose positron emission tomography can be used to determine the indication for endoscopic resection of superficial esophageal cancer. Cancer Med 2018; 7:3604-3610. [PMID: 29953743 PMCID: PMC6089148 DOI: 10.1002/cam4.1628] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/29/2018] [Accepted: 05/31/2018] [Indexed: 12/31/2022] Open
Abstract
18F‐Fluorodeoxyglucose positron emission tomography (FDG‐PET) is a useful imaging modality that reflects the tumor activity. However, FDG‐PET is mainly used for advanced cancer, not superficial cancer. In this study, we investigated the relationship between the superficial tumor depth of esophageal cancer and the FDG uptake to determine the indications for endoscopic resection (ER). From 2009 to 2017, 444 patients with esophageal cancer underwent esophagectomy or endoscopic submucosal dissection (ESD), and 195 patients were pathologically diagnosed with superficial cancer. Among them, 146 patients were examined by FDG‐PET before esophagectomy or ESD. In these 146 patients, the relationship between the pathological tumor depth and FDG uptake was analyzed. The mean maximum standardized uptake value in pT1a‐EP/LPM tumors was 1.362 ± 0.890, that in pT1a‐MM/pT1b‐SM1 tumors was 2.453 ± 1.872, and that in pT1b‐SM2/SM3 tumors was 4.265 ± 3.233 (P < .0001). Among 51 pT1a‐EP/LPM tumors, 10 (19.6%) showed positive detection of FDG. For pT1a‐MM/pT1b‐SM1 and pT1b‐SM2/SM3 tumors, the detection rate was 52.9% (18/34) and 82.0% (50/61), respectively. The detection rate of pT1a‐EP/LPM was significantly lower than in the other two groups (P < .0001). Among 10 FDG‐PET‐positive lesions, only 1 had no apparent reason for PET positivity; however, 9 of 10 had a suitable reason for detectability by PET and inadequacy for ER. Negative detection of superficial esophageal squamous cell carcinoma by FDG‐PET is useful to determine the indication for ER when the tumor depth cannot be diagnosed even after performing magnifying endoscopy with narrow band imaging and endoscopic ultrasonography. When FDG uptake is recognized, a therapeutic modality other than ER should be considered.
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Affiliation(s)
- Masanobu Nakajima
- First Department of Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Hiroto Muroi
- First Department of Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Haruka Yokoyama
- First Department of Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Maiko Kikuchi
- First Department of Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Satoru Yamaguchi
- First Department of Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Kinro Sasaki
- First Department of Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Hiroyuki Kato
- First Department of Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan
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20
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San-Millán I, Brooks GA. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. Carcinogenesis 2017; 38:119-133. [PMID: 27993896 PMCID: PMC5862360 DOI: 10.1093/carcin/bgw127] [Citation(s) in RCA: 256] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 12/08/2016] [Indexed: 12/15/2022] Open
Abstract
Herein, we use lessons learned in exercise physiology and metabolism to propose that augmented lactate production (‘lactagenesis’), initiated by gene mutations, is the reason and purpose of the Warburg Effect and that dysregulated lactate metabolism and signaling are the key elements in carcinogenesis. Lactate-producing (‘lactagenic’) cancer cells are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Otto Warburg 93 years ago, which still remains unexplained. After a hiatus of several decades, interest in lactate as a player in cancer has been renewed. In normal physiology, lactate, the obligatory product of glycolysis, is an important metabolic fuel energy source, the most important gluconeogenic precursor, and a signaling molecule (i.e. a ‘lactormone’) with major regulatory properties. In lactagenic cancers, oncogenes and tumor suppressor mutations behave in a highly orchestrated manner, apparently with the purpose of increasing glucose utilization for lactagenesis purposes and lactate exchange between, within and among cells. Five main steps are identified (i) increased glucose uptake, (ii) increased glycolytic enzyme expression and activity, (iii) decreased mitochondrial function, (iv) increased lactate production, accumulation and release and (v) upregulation of monocarboxylate transporters MTC1 and MCT4 for lactate exchange. Lactate is probably the only metabolic compound involved and necessary in all main sequela for carcinogenesis, specifically: angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism. We hypothesize that lactagenesis for carcinogenesis is the explanation and purpose of the Warburg Effect. Accordingly, therapies to limit lactate exchange and signaling within and among cancer cells should be priorities for discovery.
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Affiliation(s)
- Iñigo San-Millán
- Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine, Aurora, CO 80045, USA.,Physiology Laboratory, CU Sports Medicine and Performance Center, Boulder, CO 80309, USA and
| | - George A Brooks
- Department of Integrative Biology, University of California, Berkeley, CA 94720, USA
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21
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Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG. Int J Pharm 2017; 532:149-156. [PMID: 28844900 DOI: 10.1016/j.ijpharm.2017.08.095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/05/2017] [Accepted: 08/20/2017] [Indexed: 01/27/2023]
Abstract
Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti-cancer drug belonging to the PITenins class of PI3K-Akt inhibitors. Our analysis suggested that NCL-240 caused disruptions in mitochondrial oxidative phosphorylation and up-regulated glycolysis, as evidenced by the loss of NMR peaks for the amino acid products derived from the TCA cycle along with presence of only lactate peaks and the loss of glucose peaks. NCL-240 was combined with 2-deoxy-d-glucose (2-DG) in early proof-of-concept studies on multiple cell lines. 2-DG enhanced cell death response to NCL-240 administration, with cytotoxicity results similar to those under hypoglycemic conditions. In further studies, NCL-240 encapsulated in phosphatidylcholine/cholesterol liposomes was combined with freely dissolved 2-DG. Cell cycle analysis of sensitive and resistant strains of A2780 cells treated with combinations of NCL-240/2-DG pointed to a G0/G1 phase arrest for 80-90% of the total, indicating an inability to grow and divide. Cytotoxicity studies with in vitro cancer cell monolayer models confirmed the results of cell cycle analysis. Significant improvements in cytotoxicity with combination treatments over control and individual treatments were seen in multiple cell lines. NCI/ADR-RES cancer cell spheroids further demonstrated the effectiveness of a NCL-240/2-DG combination.
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22
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Elevated tumor-to-liver uptake ratio (TLR) from 18F-FDG-PET/CT predicts poor prognosis in stage IIA colorectal cancer following curative resection. Eur J Nucl Med Mol Imaging 2017; 44:1958-1968. [PMID: 28812134 PMCID: PMC5656694 DOI: 10.1007/s00259-017-3779-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 07/11/2017] [Indexed: 02/06/2023]
Abstract
Purpose The prognostic value of the tumor-to-liver uptake ratio (TLR) from 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F–FDG-PET/CT) in the early stage of colorectal cancer (CRC) is unclear. Notably, some stage IIA CRC patients experience early recurrence even after curative resection and might benefit from neoadjuvant or adjuvant chemotherapy. This study aims to evaluate whether elevated TLR from 18F–FDG-PET/CT can predict poor prognosis in stage IIA CRC patients undergoing curative resection. Methods From April 2010 to December 2013, 504 consecutive CRC patients with different TNM stages (I-IV) underwent 18F–FDG-PET/CT scans at the 6th Affiliated Hospital of Sun Yat-Sen University. Among the patients, 118 with stage IIA CRC who accepted preoperative 18F–FDG-PET/CT scanning and were treated with curative surgery alone were reviewed retrospectively. The maximum standardized uptake value (SUVmax) in the primary tumor, TLR, and demographic, clinical, histopathological, and laboratory data were analyzed. Receiver operating characteristic (ROC) curve, univariate and multivariate analyses were performed to identify prognostic factors associated with patient disease-free survival (DFS) and overall survival (OS). Results ROC curve analysis demonstrated that TLR was superior to primary tumor SUVmax in predicting the risk of recurrence in stage IIA CRC. The optimal TLR cutoff was 6.2. Univariate analysis indicated that elevated TLR, tumor size, and lymphovascular/neural invasion correlated with DFS (P = 0.001, P = 0.002, and P = 0.001, respectively) and OS (P = 0.001, P = 0.003, and P < 0.001, respectively). The 1-, 3-, and 5-year DFS rates were 98.4%, 96.9%, and 96.9% for stage IIA CRC patients with lower TLR (≤6.2) versus 77.8%, 60.6%, and 60.6% for those with elevated TLR (>6.2), respectively. The 1-, 3-, and 5-year OS rates were 100.0%, 100.0%, and 98.3% for the patients with lower TLR versus 98.1%, 83.3%, and 74.3% for those with elevated TLR. Cox regression analysis showed that elevated TLR [>6.2; hazard ratio (HR): 3.109–57.463; P < 0.001] and tumor size (>4.4 cm; HR: 1.636–19.155; P = 0.006) were independent risk factors for DFS. Meanwhile, elevated TLR (>6.2; HR: 1.398–84.945; P = 0.023) and lymphovascular/neural invasion (positive; HR: 1.278–12.777; P = 0.017) were independent risk factors for OS. Conclusion Elevated TLR predicted worse DFS and OS for stage IIA CRC patients and might serve as a potential radiological index to identify candidates for neoadjuvant or adjuvant chemotherapy. Stage IIA CRC patients with elevated TLR should be monitored carefully for early detection of possible recurrence.
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Garrigue P, Bodin-Hullin A, Balasse L, Fernandez S, Essamet W, Dignat-George F, Pacak K, Guillet B, Taïeb D. The Evolving Role of Succinate in Tumor Metabolism: An 18F-FDG-Based Study. J Nucl Med 2017; 58:1749-1755. [PMID: 28619735 DOI: 10.2967/jnumed.117.192674] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 05/24/2017] [Indexed: 12/27/2022] Open
Abstract
In recent years, inherited and acquired mutations in the tricarboxylic acid (TCA) cycle enzymes have been reported in diverse cancers. Pheochromocytomas and paragangliomas often exhibit dysregulation of glucose metabolism, which is also driven by mutations in genes encoding the TCA cycle enzymes or by activation of hypoxia signaling. Pheochromocytomas and paragangliomas associated with succinate dehydrogenase (SDH) deficiency are characterized by high 18F-FDG avidity. This association is currently only partially explained. Therefore, we hypothesized that accumulation of succinate due to the TCA cycle defect could be the major connecting hub between SDH-mutated tumors and the 18F-FDG uptake profile. Methods: To test whether succinate modifies the 18F-FDG metabolic profile of tumors, we performed in vitro and in vivo (small-animal PET/CT imaging and autoradiography) experiments in the presence of succinate, fumarate, and phosphate-buffered saline (PBS) in different cell models. As a control, we also evaluated the impact of succinate on 18F-fluorocholine uptake and retention. Glucose transporter 1 (GLUT1) immunohistochemistry was performed to assess whether 18F-FDG uptake correlates with GLUT1 staining. Results: Intratumoral injection of succinate significantly increased 18F-FDG uptake at 24 h on small-animal PET/CT imaging and autoradiography. No effect of succinate was observed on cancer cells in vitro, but interestingly, we found that succinate caused increased 18F-FDG uptake by human umbilical vein endothelial cells in a concentration-dependent manner. No significant effect was observed after intratumoral injection of fumarate or PBS. Succinate, fumarate, and PBS have no effect on cell viability, regardless of cell lineage. Intramuscular injection of succinate also significantly increases 18F-FDG uptake by muscle when compared with either PBS or fumarate, highlighting the effect of succinate on connective tissues. No difference was observed between PBS and succinate on 18F-fluorocholine uptake in the tumor and muscle and on hind limb blood flow. GLUT1 expression quantification did not significantly differ between the study groups. Conclusion: The present study shows that succinate stimulates 18F-FDG uptake by endothelial cells, a finding that partially explains the 18F-FDG metabotype observed in tumors with SDH deficiency. Although this study is an 18F-FDG-based approach, it provides an impetus to better characterize the determinants of 18F-FDG uptake in various tumors and their surrounding microenvironment, with a special emphasis on the role of tumor-specific oncometabolites.
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Affiliation(s)
- Philippe Garrigue
- Aix-Marseille University, INSERM, UMR-S 1076, Marseille, France.,Aix-Marseille University, CERIMED, Marseille, France.,Department of Nuclear Medicine, Aix-Marseille University, Marseille, France
| | | | - Laure Balasse
- Aix-Marseille University, INSERM, UMR-S 1076, Marseille, France.,Aix-Marseille University, CERIMED, Marseille, France
| | | | - Wassim Essamet
- Department of Neuropathology, APHM Timone, Marseille, France; and
| | | | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland
| | - Benjamin Guillet
- Aix-Marseille University, INSERM, UMR-S 1076, Marseille, France.,Aix-Marseille University, CERIMED, Marseille, France.,Department of Nuclear Medicine, Aix-Marseille University, Marseille, France
| | - David Taïeb
- Aix-Marseille University, CERIMED, Marseille, France .,Department of Nuclear Medicine, Aix-Marseille University, Marseille, France
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24
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Ertay T, Sencan Eren M, Karaman M, Oktay G, Durak H. 18F-FDG-PET/CT in Initiation and Progression of Inflammation and Infection. Mol Imaging Radionucl Ther 2017; 26:47-52. [PMID: 28613196 PMCID: PMC5472086 DOI: 10.4274/mirt.18291] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Objective: Detection/localization of infection and inflammation is important for the initiation of correct treatment as well as its maintenance. Nuclear medicine imaging methods play an important role in determining infection and inflammation. 18F-2’-deoxy-2-fluoro-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is highly sensitive in such cases when used with tomographic cross-sections. In this study, the development and progression of infection and inflammation were monitored on rats by using 18F-FDG via PET/CT. Methods: Sterile and infected abscesses were formed on rats using turpentine and S. aureus, respectively. For evaluation of the formation and progression of the abscess, 18F-FDG was injected into the rats and they were imaged by PET/CT at intervals of twenty-four hours for five days. Maximum standard uptake value (SUVmax) of 18F-FDG was calculated. Results: The highest activity involvement was seen on the first day of abscess formation. On the first day, SUVmax of the S. aureus abscess was 3.9±0.9 while in the sterile abscess SUVmax in the first day was 2.2±0.8. 18F-FDG uptake decreased day by day and it reached the background level on the fourth and fifth days. There were statistically significant differences between S. aureus and sterile abscess, and between sterile abscess and background activity in terms of SUVmax values during the first three days (p<0.05). On the fourth and fifth days, there was no statistically significant difference between S. aureus and sterile abscess, and between sterile abscess and background activity (p>0.05). Conclusion: The results demonstrated that the SUVmax value for 18F-FDG can be useful in the early differentiation of sterile and infected abscess. In addition, 18F-FDG-PET imaging has the advantage of local availability of equipment and labeled agents leading rapid diagnosis of differentiation of infection and inflammation.
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Affiliation(s)
- Türkan Ertay
- Dokuz Eylül University Faculty of Medicine, Department of Nuclear Medicine, İzmir, Turkey
| | - Mine Sencan Eren
- Dokuz Eylül University Faculty of Medicine, Department of Nuclear Medicine, İzmir, Turkey
| | - Meral Karaman
- Dokuz Eylül University Faculty of Medicine, Department of Clinical Microbiology, İzmir, Turkey
| | - Gülgün Oktay
- Dokuz Eylül University Faculty of Medicine, Department of Clinical Biochemistry, İzmir, Turkey
| | - Hatice Durak
- Dokuz Eylül University Faculty of Medicine, Department of Nuclear Medicine, İzmir, Turkey
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Kozlovski I, Siegfried Z, Amar-Schwartz A, Karni R. The role of RNA alternative splicing in regulating cancer metabolism. Hum Genet 2017; 136:1113-1127. [PMID: 28429085 DOI: 10.1007/s00439-017-1803-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 04/13/2017] [Indexed: 12/12/2022]
Abstract
Tumor cells alter their metabolism by a wide array of mechanisms to promote growth and proliferation. Dysregulated expression and/or somatic mutations of key components of the glycolytic pathway/TCA cycle as well as other metabolic pathways allow tumor cells to improve their ability to survive harsh conditions such as hypoxia and the presence of reactive oxygen species, as well as the ability to obtain nutrients to increase lipids, protein, and nucleic acids biogenesis. Approximately 95% of the human protein encoding genes undergo alternative splicing (AS), a regulated process of gene expression that greatly diversifies the proteome by creating multiple proteins from a single gene. In recent years, a growing body of evidence suggests that unbalanced AS, the formation of certain pro-tumorigenic isoforms and the reduction of anti-tumorigenic isoforms, is implicated in a variety of cancers. It is becoming increasingly clear that cancer-associated AS contributes to increased growth and proliferation, partially due to effects on metabolic reprogramming. Here, we summarize the known roles of AS in regulating cancer metabolism. We present evidence supporting the idea that AS, in many types of cancer, acts as a molecular switch that alters metabolism to drive tumorigenesis. We propose that the elucidation of misregulated AS and its downstream effects on cancer metabolism emphasizes the need for new therapeutic approaches aiming to modulate the splicing machinery to selectively target cancer cells.
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Affiliation(s)
- Itamar Kozlovski
- Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel
| | - Zahava Siegfried
- Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel
| | - Adi Amar-Schwartz
- Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel
| | - Rotem Karni
- Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Ein Karem, 91120, Jerusalem, Israel.
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Yang HJ, Xu WJ, Guan YH, Zhang HW, Ding WQ, Rong L, Qiu ZB, Zhong L. Expression of Glut-1 and HK-II in Pancreatic Cancer and Their Impact on Prognosis and FDG Accumulation. Transl Oncol 2016; 9:583-591. [PMID: 27916293 PMCID: PMC5143352 DOI: 10.1016/j.tranon.2016.08.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 08/09/2016] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE: The purpose of this article is to analyze the expression of Glut-1 and HK-II, the association between their expression and 18F-FDG accumulation in pancreatic cancer. METHODS: Fifty patients with histologically proven pancreatic cancer were included in this preliminary study, all of whom received 18F-FDG PET/CT performance before surgery. Immunohistochemical staining of tumor tissue and adjacent normal tissue was performed for Glut-1 and HK-II. By combining proportions and intensity of immunochemical staining, we obtained the modified immunohistological scores for Glut-1 and HK-II respectively. The relationship between expression of Glut-1, HK-II and series of parameters was analyzed, i.e. clinicopathological characteristics, prognosis of patients and SUVmax of PET-CT. RESULTS: Compared with normal tissue, the Glut-1 and HK-II expression in pancreatic cancer tissue was significantly increased (P < .001). There was no correlation between expression of Glut-1, HK-II and age, gender, tumor size, tumor location, tumor histological type, tumor differentiation, the nerve infiltration, vascular invasion, local infiltration, lymph node metastasis or tumor staging in pancreatic cancer (P > .05). During the follow-up period, the survival curves of low Glut-1 group and high Glut-1 group were statistically different (P = .049). Multivariate analysis (Cox regression) revealed that Glut-1 expression was not associated with mortality (P > .05). No statistical difference was found in the survival curves of negative HK-II group and positive HK-II group (P = .545). There was no correlation between 18F-FDG uptake and expression of Glut-1 and HK-II(P > .05). CONCLUSION: The Glut-1 and HK-II expression in pancreatic cancer tissue was significantly increased. There was no correlation between expression of Glut-1, HK-II and clinicopathological characteristics, prognosis and 18F-FDG uptake.
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Affiliation(s)
- Hai-Jing Yang
- Department of Gastroenterology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200040, China.
| | - Wei-Jia Xu
- Department of Gastroenterology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200040, China.
| | - Yi-Hui Guan
- PET Center of Huashan Hospital, Fudan University, 518 Wuzhong East Road, Shanghai 200235, China
| | - Hui-Wei Zhang
- PET Center of Huashan Hospital, Fudan University, 518 Wuzhong East Road, Shanghai 200235, China
| | - Wei-Qun Ding
- Department of Gastroenterology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200040, China
| | - Lan Rong
- Department of Gastroenterology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200040, China
| | - Zhi-Bing Qiu
- Department of Gastroenterology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200040, China
| | - Liang Zhong
- Department of Gastroenterology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai 200040, China.
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Initial Staging of Locally Advanced Rectal Cancer and Regional Lymph Nodes: Comparison of Diffusion-Weighted MRI With 18F-FDG-PET/CT. Clin Nucl Med 2016; 41:289-95. [PMID: 26828149 PMCID: PMC4851242 DOI: 10.1097/rlu.0000000000001172] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Purpose The aim of the study was to compare diffusion-weighted MRI (DW-MRI) parameters with 18F-FDG PET/CT in primary locally advanced rectal cancer (LARC). Methods From October 2012 to September 2014, 24 patients with histologically confirmed and untreated LARC (T3–T4) prospectively underwent a pelvic 1.5-T DW-MRI (b = 0 s/mm2, b = 600 s/mm2) and a whole-body 18F-FDG PET/CT, before neoadjuvant therapy. The 2 examinations were performed on the same day. Two readers measured 18F-FDG SUVmax and SUVmean of the rectal tumor and of the pathological regional lymph nodes on PET/CT and compared these with minimum and mean values of the ADC (ADCmin and ADCmean) on maps generated from DW-MRI. The diagnostic performance of ADC values in identifying pathological lymph nodes was also assessed. Results Regarding tumors (n = 24), we found a significant negative correlation between SUVmean and corresponding ADCmean values (ρ = −0.61, P = 0.0017) and between ADCmin and SUVmax (ρ = −0.66, P = 0.0005). Regarding the lymph nodes (n = 63), there was a significant negative correlation between ADCmean and SUVmean values (ρ = −0.38, P = 0.0021), but not between ADCmin and SUVmax values (ρ = −0.11, P = 0.41). Neither ADCmean nor ADCmin values helped distinguish pathological from benign lymph nodes (AUC of 0.24 [confidence interval, 0.10–0.38] and 0.41 [confidence interval, 0.22–0.60], respectively). Conclusions The correlations between ADCmean and SUVmean suggest an association between tumor cellularity and metabolic activity in untreated LARC and in regional lymph nodes. However, compared with 18F-FDG PET/CT, ADC values are not reliable for identifying pathological lymph nodes.
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Nascimento RAS, Özel RE, Mak WH, Mulato M, Singaram B, Pourmand N. Single Cell "Glucose Nanosensor" Verifies Elevated Glucose Levels in Individual Cancer Cells. NANO LETTERS 2016; 16:1194-200. [PMID: 26752097 PMCID: PMC4887140 DOI: 10.1021/acs.nanolett.5b04495] [Citation(s) in RCA: 128] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
Because the transition from oxidative phosphorylation to anaerobic glycolytic metabolism is a hallmark of cancer progression, approaches to identify single living cancer cells by their unique glucose metabolic signature would be useful. Here, we present nanopipettes specifically developed to measure glucose levels in single cells with temporal and spatial resolution, and we use this technology to verify the hypothesis that individual cancer cells can indeed display higher intracellular glucose levels. The nanopipettes were functionalized as glucose nanosensors by immobilizing glucose oxidase (GOx) covalently to the tip so that the interaction of glucose with GOx resulted in a catalytic oxidation of β-d-glucose to d-gluconic acid, which was measured as a change in impedance due to drop in pH of the medium at the nanopipette tip. Calibration studies showed a direct relationship between impedance changes at the tip and glucose concentration in solution. The glucose nanosensor quantified single cell intracellular glucose levels in human fibroblasts and the metastatic breast cancer lines MDA-MB-231 and MCF7 and revealed that the cancer cells expressed reproducible and reliable increases in glucose levels compared to the nonmalignant cells. Nanopipettes allow repeated sampling of the same cell, as cells remain viable during and after measurements. Therefore, nanopipette-based glucose sensors provide an approach to compare changes in glucose levels with changes in proliferative or metastatic state. The platform has great promise for mechanistic investigations, as a diagnostic tool to distinguish cancer cells from nonmalignant cells in heterogeneous tissue biopsies, as well as a tool for monitoring cancer progression in situ.
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Affiliation(s)
- Raphael A. S. Nascimento
- Biomolecular Engineering Department, University of California Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States
- Department of Physics, Faculty of Philosophy, Science and Letters at Ribeirão Preto, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, São Paulo 14040-401, Brazil
| | - Rıfat Emrah Özel
- Biomolecular Engineering Department, University of California Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States
- Corresponding Author: Tel.: +1-831-459-4382. Fax: +1-831-459-2891.
| | - Wai Han Mak
- Biomolecular Engineering Department, University of California Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States
| | - Marcelo Mulato
- Biomolecular Engineering Department, University of California Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States
- Department of Physics, Faculty of Philosophy, Science and Letters at Ribeirão Preto, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, São Paulo 14040-401, Brazil
| | - Bakthan Singaram
- Department of Chemistry and Biochemistry, University of California Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States
| | - Nader Pourmand
- Biomolecular Engineering Department, University of California Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States
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Exogenous normal mammary epithelial mitochondria suppress glycolytic metabolism and glucose uptake of human breast cancer cells. Breast Cancer Res Treat 2015; 153:519-29. [DOI: 10.1007/s10549-015-3583-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 09/21/2015] [Indexed: 10/23/2022]
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Kim D, Kim W, Lee J, Ki Y, Lee B, Cho K, Kim S, Nam J, Lee J, Kim D. Pretreatment maximum standardized uptake value of (18)F-fluorodeoxyglucose positron emission tomography as a predictor of distant metastasis in adenoid cystic carcinoma of the head and neck. Head Neck 2015; 38:755-61. [PMID: 25524466 DOI: 10.1002/hed.23953] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2014] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND The purpose of this study was to determine whether the maximum standardized uptake value (SUVmax) of the primary tumor on pretreatment (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) has prognostic significance in patients with adenoid cystic carcinoma (ACC) of the head and neck. METHODS A retrospective review was carried out on 34 patients with ACC of the head and neck who underwent pretreatment (18)F-FDG PET imaging from June 2005 through July 2009. All patients underwent surgery with curative intent, and 26 of them received adjuvant radiotherapy (RT). RESULTS When subjects were stratified into 2 groups according to a cutoff value for SUVmax of 4.15, the risk of distant metastasis was significantly high in patients with high SUVmax (p = .014). Multivariate analysis showed that high SUVmax and histologic grade 3 were independent poor prognostic factors for distant metastasis-free and disease-free survival. CONCLUSION Pretreatment SUVmax of the primary tumor is an independent prognostic factor in patients with ACC of the head and neck.
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Affiliation(s)
- Donghyun Kim
- Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Pusan National University, Busan, Korea
| | - Wontaek Kim
- Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Pusan National University, Busan, Korea
| | - Joohye Lee
- Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Pusan National University, Busan, Korea
| | - Yongkan Ki
- Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Pusan National University, Busan, Korea
| | - Byungjoo Lee
- Department of Otorhinolaryngology, Biomedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Pusan National University, Busan, Korea
| | - Kyusup Cho
- Department of Otorhinolaryngology, Biomedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Pusan National University, Busan, Korea
| | - Seongjang Kim
- Department of Nuclear Medicine, Biomedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Pusan National University, Busan, Korea
| | - Jiho Nam
- Department of Radiation Oncology, Yangsan Pusan National University Hospital, Yangsan, Korea
| | - Jinchoon Lee
- Department of Otorhinolaryngology, Yangsan Pusan National University Hospital, Yangsan, Korea
| | - Dongwon Kim
- Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Pusan National University, Busan, Korea
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Silvoniemi A, Silén J, Forsback S, Löyttyniemi E, Schrey AR, Solin O, Grénman R, Minn H, Grönroos TJ. Evaluation of repeated [(18)F]EF5 PET/CT scans and tumor growth rate in experimental head and neck carcinomas. EJNMMI Res 2014; 4:65. [PMID: 25977879 PMCID: PMC4412195 DOI: 10.1186/s13550-014-0065-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 11/11/2014] [Indexed: 01/07/2023] Open
Abstract
Background Tumor hypoxia is linked to invasion and metastasis but whether this associates with tumor growth rate is not well understood. We aimed to study the relationship between hypoxia evaluated with the positron emission tomography (PET) tracer [18F]EF5 and tumor growth. Our second goal was to assess the variability in the uptake of [18F]EF5 in tumor between two scans. Methods Four human head and neck squamous cell carcinoma (UT-SCC) cell lines were xenografted in flank or neck of nude mice, and tumor size was closely monitored over the study period. The tumors were clearly visible when the first [18F]EF5 scan was acquired. After an exponential growth phase, the tumors were imaged again with [18F]EF5 and also with 18F-fluorodeoxyglucose ([18F]FDG). Results There was a clear correlation between the percentage of tumor growth rate per day and the [18F]EF5 uptake in the latter scan (r = 0.766, p = 0.01). The uptake of [18F]EF5 in the first scan and the uptake of [18F]FDG did not significantly correlate with the tumor growth rate. We also observed considerable variations in the uptake of [18F]EF5 between the two scans. Conclusions The uptake of [18F]EF5 in the late phase of exponential tumor growth is associated with the tumor growth rate in mice bearing HNC xenografts.
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Affiliation(s)
- Antti Silvoniemi
- Turku PET Centre, Medicity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, FI-20520, Finland ; Department of Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital, Turku, FI-20521, Finland
| | - Jonna Silén
- Turku PET Centre, Medicity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, FI-20520, Finland
| | - Sarita Forsback
- Turku PET Centre, Medicity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, FI-20520, Finland
| | - Eliisa Löyttyniemi
- Department of Biostatistics, University of Turku, Lemminkäisenkatu 1, Turku, FI-20520, Finland
| | - Aleksi R Schrey
- Department of Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital, Turku, FI-20521, Finland
| | - Olof Solin
- Turku PET Centre, Medicity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, FI-20520, Finland
| | - Reidar Grénman
- Department of Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital, Turku, FI-20521, Finland
| | - Heikki Minn
- Turku PET Centre, Medicity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, FI-20520, Finland ; Department of Oncology and Radiotherapy, Turku University Hospital, Turku, FI-20521, Finland
| | - Tove J Grönroos
- Turku PET Centre, Medicity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, FI-20520, Finland ; Department of Oncology and Radiotherapy, Turku University Hospital, Turku, FI-20521, Finland
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Radisavljevic Z. AKT as Locus of Cancer Phenotype. J Cell Biochem 2014; 116:1-5. [DOI: 10.1002/jcb.24947] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 08/22/2014] [Indexed: 12/12/2022]
Affiliation(s)
- Ziv Radisavljevic
- Department of Surgery; Brigham and Women's Hospital; Harvard Medical School; Boston Massachusetts 02115
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Early treatment response monitoring using 2-deoxy-2-[ 18F]fluoro-D-glucose positron emission tomography imaging during fractionated radiotherapy of head neck cancer xenografts. BIOMED RESEARCH INTERNATIONAL 2014; 2014:598052. [PMID: 24877119 PMCID: PMC4022256 DOI: 10.1155/2014/598052] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 03/28/2014] [Indexed: 12/15/2022]
Abstract
Background. To determine the optimal timing and analytic method of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (PET) imaging during fractionated radiotherapy (RT) to predict tumor control. Methods. Ten head neck squamous cell carcinoma xenografts derived from the UT-14-SCC cell line were irradiated with 50 Gy at 2 Gy per day over 5 weeks. Dynamic PET scans were acquired over 70 minutes at baseline (week 0) and weekly for seven weeks. PET data were analyzed using standard uptake value (SUV), retention index (RI), sensitivity factor (SF), and kinetic index (Ki). Results. Four xenografts had local failure (LF) and 6 had local control. Eighty scans from week 0 to week 7 were analyzed. RI and SF after 10 Gy appeared to be the optimal predictors for LF. In contrast, SUV and Ki during RT were not significant predictors for LF. Conclusion. RI and SF of PET obtained after the first week of fractionated RT were the optimal methods and timing to predict tumor control.
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Pretreatment [18F]-fluoro-2-deoxy-glucose positron emission tomography maximum standardized uptake value as predictor of distant metastasis in early-stage non-small cell lung cancer treated with definitive radiation therapy: rethinking the role of positron emission tomography in personalizing treatment based on risk status. Int J Radiat Oncol Biol Phys 2014; 88:312-8. [PMID: 24411602 DOI: 10.1016/j.ijrobp.2013.10.029] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 10/07/2013] [Accepted: 10/22/2013] [Indexed: 11/20/2022]
Abstract
PURPOSE The aim of this study was to determine whether the preradiation maximum standardized uptake value (SUVmax) of the primary tumor for [(18)F]-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) has a prognostic significance in patients with Stage T1 or T2N0 non-small cell lung cancer (NSCLC) treated with curative radiation therapy, whether conventional or stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS Between January 2007 and December 2011, a total of 163 patients (180 tumors) with medically inoperable histologically proven Stage T1 or T2N0 NSCLC and treated with radiation therapy (both conventional and SBRT) were entered in a research ethics board approved database. All patients received pretreatment FDG-PET / computed tomography (CT) at 1 institution with consistent acquisition technique. The medical records and radiologic images of these patients were analyzed. RESULTS The overall survival at 2 years and 3 years for the whole group was 76% and 67%, respectively. The mean and median SUVmax were 8.1 and 7, respectively. Progression-free survival at 2 years with SUVmax <7 was better than that of the patients with tumor SUVmax ≥7 (67% vs 51%; P=.0096). Tumors with SUVmax ≥7 were associated with a worse regional recurrence-free survival and distant metastasis-free survival. In the multivariate analysis, SUVmax ≥7 was an independent prognostic factor for distant metastasis-free survival. CONCLUSION In early-stage NSCLC managed with radiation alone, patients with SUVmax ≥7 on FDG-PET / CT scan have poorer outcomes and high risk of progression, possibly because of aggressive biology. There is a potential role for adjuvant therapies for these high-risk patients with intent to improve outcomes.
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Preuss J, Richardson AD, Pinkerton A, Hedrick M, Sergienko E, Rahlfs S, Becker K, Bode L. Identification and characterization of novel human glucose-6-phosphate dehydrogenase inhibitors. JOURNAL OF BIOMOLECULAR SCREENING 2013; 18:286-97. [PMID: 23023104 DOI: 10.1177/1087057112462131] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Glucose-6-phosphate dehydrogenase (G6PD) is the key enzyme of the pentose phosphate pathway, converting glucose-6-phosphate to 6-phosphoglucono-δ-lactone with parallel reduction of NADP(+). Several human diseases, including cancer, are associated with increased G6PD activity. To date, only a few G6PD inhibitors have been available. However, adverse side effects and high IC(50) values hamper their use as therapeutics and basic research probes. In this study, we developed a high-throughput screening assay to identify novel human G6PD (hG6PD) inhibitors. Screening the LOPAC (Sigma-Aldrich; 1280 compounds), Spectrum (Microsource Discovery System; 1969 compounds), and DIVERSet (ChemBridge; 49 971 compounds) small-molecule compound collections revealed 139 compounds that presented ≥50% hG6PD inhibition. Hit compounds were further included in a secondary and orthogonal assay in order to identify false-positives and to determine IC(50) values. The most potent hG6PD inhibitors presented IC(50) values of <4 µM. Compared with the known hG6PD inhibitors dehydroepiandrosterone and 6-aminonicotinamide, the inhibitors identified in this study were 100- to 1000-fold more potent and showed different mechanisms of enzyme inhibition. One of the newly identified hG6PD inhibitors reduced viability of the mammary carcinoma cell line MCF10-AT1 (IC(50) ~25 µM) more strongly than that of normal MCF10-A cells (IC(50) >50 µM).
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Lee JE, Kim SW, Kim JS, Choi KY, Kang WK, Oh ST, Yoo IR, Kim SH. Prognostic value of 18-fluorodeoxyglucose positron emission tomography-computed tomography in resectable colorectal cancer. World J Gastroenterol 2012; 18:5072-7. [PMID: 23049216 PMCID: PMC3460334 DOI: 10.3748/wjg.v18.i36.5072] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Revised: 03/09/2012] [Accepted: 03/20/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the prognostic value of preoperative 18 fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) in patients with resectable colorectal cancer.
METHODS: One hundred sixty-three patients with resectable colorectal cancer who underwent FDG-PET/CT before surgery were included. Patient data including pathologic stage at presentation, histology, treatment, disease-free survival and the maximum standardized uptake value (SUVmax) of the primary tumor on FDG-PET/CT were retrospectively analyzed. Median follow up duration was 756 (range, 419-1355). The primary end point was disease-free survival.
RESULTS: Twenty-five of 163 patients (15.3%) had recurrences. The median SUVmax values of the recurrence and no-recurrence groups were 8.9 (range, 5-24) and 8.2 (range, 0-23, P = 0.998). Receiver operating characteristic (ROC) curve analysis showed no significant association between SUVmax and recurrence (area under the curve = 0.5, P = 0.998, 95% CI: 0.389-0.611). Because a statistically significant value was not found, SUVmax was dichotomized at its median of 8.6. The disease-free survival curve was analyzed using the median SUVmax (8.6) as the cut off. Univariate and multivariate analysis did not provide evidence that disease-free survival rates for the subgroups defined by the median SUVmax were significantly different (P = 0.52, P = 0.25).
CONCLUSION: Our study suggests that the high FDG uptake of primary mass in resectable colorectal cancer doesn’t have a significant relationship with tumor recurrence and disease-free survival.
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Huang J, Chunta JL, Amin M, Lee DY, Grills IS, Wong CYO, Yan D, Marples B, Martinez AA, Wilson GD. Detailed characterization of the early response of head-neck cancer xenografts to irradiation using (18)F-FDG-PET imaging. Int J Radiat Oncol Biol Phys 2012; 84:485-91. [PMID: 22331000 DOI: 10.1016/j.ijrobp.2011.11.053] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2011] [Indexed: 10/14/2022]
Abstract
PURPOSE To investigate the metabolic information provided by (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) during the early response of head-and-neck squamous cell carcinoma (HNSCC) xenografts to radiotherapy (RT). METHODS AND MATERIALS Low-passage HNSCC cells (UT14) were injected into the rear flanks of female nu/nu mice to generate xenografts. After tumors grew to 400-500 mm(3), they were treated with either 15 Gy in one fraction (n = 18) or sham RT (n = 12). At various time points after treatment, tumors were assessed with 2-h dynamic FDG-PET and immediately harvested for direct histological correlation. Different analytical parameters were used to process the dynamic PET data: kinetic index (Ki), standard uptake value (SUV), sensitivity factor (SF), and retention index (RI). Tumor growth was assessed using the specific growth rate (SGR) and correlated with PET parameters using the Pearson correlation coefficient (r). Receiver operating characteristic (ROC) and the area under the ROC curve (AUC) were used to test PET parameters for their ability to predict for radiation necrosis and radiation change. RESULTS Tumor growth was arrested for the first 20 days after RT and recovered thereafter. Histologically, radiation change was observed in the peripheral regions of tumors between days 7 and 23 after RT, and radiation necrosis were observed in the central regions of tumors between days 7 and 40. Ki provided the best correlation with SGR (r = 0.51) and was the optimal parameter to predict for early radiation necrosis (AUC = 0.804, p = 0.07). SUV(30 min) was the strongest predictor for late radiation necrosis (AUC = 0.959, p = 0.004). Both RI(30-60 min) and SF(12-70 min) were very accurate in predicting for radiation change (AUC = 0.891 and 0.875, p = 0.009 and 0.01, respectively). CONCLUSIONS Dynamic FDG-PET analysis (such as Ki or SF) may provide informative assessment of early radiation necrosis or radiation change of HNSCC xenografts after RT.
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Affiliation(s)
- Jiayi Huang
- Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA
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Relationship Between Dual-Time Point FDG PET and Immunohistochemical Parameters in Preoperative Colorectal Cancer: Preliminary Study. Nucl Med Mol Imaging 2012; 46:48-56. [PMID: 24900032 DOI: 10.1007/s13139-011-0120-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Revised: 10/11/2011] [Accepted: 11/18/2011] [Indexed: 12/25/2022] Open
Abstract
PURPOSE The clinical availability of 2-deoxy-2-[18F] fluoro-D-glucose (FDG) dual-time point positron emission tomography/computerized tomography (DTPP) has been investigated in diverse oncologic fields. The aim of this preliminary study was to evaluate the relationship between various immunohistopathologic markers reflecting disease progression of colorectal cancer and parameters extracted from FDG DTPP in colorectal cancer patients. MATERIALS AND METHODS Forty-seven patients with histologically confirmed colorectal cancer were analyzed in this preliminary study. FDG DTPP consisted of an early scan 1 h after FDG injection and a delayed scan 1.5 h after the early scan. Based on an analysis of FDG DTPP, we estimated the maximum standardized uptake value (SUV) of tumors on the early and delayed scans (SUVearly and SUVdelayed, respectively). The retention index (RI) was calculated as follows: (SUVdelayed - SUVearly) × 100/ SUVearly. The clinicopathological findings (size and T and N stages) and immunohistochemical factors [glucose transporter 1 (GLUT-1), hexokinase 2 (HK-2), p53, P504S, and β-catenin] were analyzed by visual analysis. RESULTS The RIs calculated from the SUVs ranged from -1.8 to 73.4 (31.8 ± 15.5). The RIs were significantly higher in patients with high T stages (T3 and T4) than with low T stages (T1 and T2; p < 0.05). Among the immunohistochemical analytic markers, GLUT-1 had the highest positive staining rate (93.6%) compared to other markers. Based on univariable analysis, it was shown that the RI of high-level GLUT-1 expression was significantly higher than low-level GLUT-1 expression (p = 0.01), and the RI of high-level p53 expression was slightly higher than low-level p53 expression (p = 0.08). Multivariate analysis to investigate a link between RI and clinicopathologic parameters of colorectal carcinoma showed that GLUT-1, p53, and T staging were independently connected with increased RIs (p < 0.05, total) using backward selection methods. There was no significant statistical relationship between SUVearly and SUVdelayed and clinicopathologic parameters in this study. CONCLUSION The RIs obtained from preoperative colorectal cancers had a significant relationship to tumor size, T staging, GLUT-1, and p53, in contrast to SUVearly or SUVdelayed. Compared with previous reports, our results showed that RI can better predict GLUT-1 expression than HK-2 and other immunohistochemical markers. This study demonstrated that the RI might have the potential to be applied as a prognostic marker in preoperative colorectal cancer.
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Lin M, Wong K, Ng WL, Shon IH, Morgan M. Positron emission tomography and colorectal cancer. Crit Rev Oncol Hematol 2011; 77:30-47. [PMID: 20619671 DOI: 10.1016/j.critrevonc.2010.04.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Revised: 04/30/2010] [Accepted: 04/30/2010] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality. Molecular imaging using positron emission tomography (PET) is now an integral part of multidisciplinary cancer care. In this review, we discuss the role of PET in CRC including well established indications in the assessment of recurrent disease and emerging applications such as initial staging, monitoring therapy efficacy and using PET for radiotherapy planning. With rapid advancement in imaging technology, we also discuss the future potential of combining PET and magnetic resonance imaging and the use of novel radiotracers.
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Affiliation(s)
- Michael Lin
- Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, Australia; University of New South Wales, Sydney, Australia.
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Strauss LG, Koczan D, Klippel S, Pan L, Cheng C, Haberkorn U, Willis S, Dimitrakopoulou-Strauss A. Impact of cell-proliferation-associated gene expression on 2-deoxy-2-[(18)f]fluoro-D-glucose (FDG) kinetics as measured by dynamic positron emission tomography (dPET) in colorectal tumors. Mol Imaging Biol 2010; 13:1290-300. [PMID: 21153447 DOI: 10.1007/s11307-010-0465-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2010] [Revised: 10/07/2010] [Accepted: 10/28/2010] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Glucose transporters and hexokinases determine the kinetics of 2-deoxy-2-[(18)F]fluoro-D: -glucose (FDG). However, the genes controlling these proteins are not independent and may be modulated from other biological processes, e.g., like angiogenesis and proliferation. The impact of cell-proliferation-related genes on the FDG kinetics was assessed in colorectal tumors in this study. METHODS Patients with primary colorectal tumors (n = 25) were examined with positron emission tomography and FDG within 2 days prior to surgery. Tissue specimens were obtained from the colorectal tumor and the normal colon by surgery and gene expression was assessed using gene arrays. RESULTS Overall, an increase of the expression of proliferation associated genes was observed by a factor of 2-5.3 for the colorectal tumors as compared with the normal colon. Correlation analysis revealed an impact of cdk2 on K1, thus directing to a modulation of the FDG uptake into the cells. The correlations were generally higher for the FDG influx as compared with the standardized uptake value (SUV). The influx was mainly correlated with proliferation inhibiting genes (cyclin G2, cdk inhibitor 1 C, cdk inhibitor 2B). It was possible to predict the expression of cyclin D2 using a multiple linear regression function and the parameters of the FDG kinetics with r = 0.67. Using a group based analysis it was possible to demonstrate, that tumors with an SUV >12 are associated with a high expression of cyclin D2 in the colorectal tumors. If the gene expression data for cyclin D1, cyclin G2, cdk2, cdk6 and cdk inhibtor 2B were used, the overall FDG uptake as measured by the SUV could be predicted with r = 0.75. CONCLUSIONS The results suggest that the FDG kinetics is modulated by proliferation associated genes. Especially K1, the parameter for the FDG transport into the cells, is modulated by cdk2. Tumors with a SUV exceeding 12 have usually a higher expression of cyclin D2. The parameters of the FDG kinetics can be used to predict the expression of proliferation associated genes individually.
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Affiliation(s)
- Ludwig G Strauss
- Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany.
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Neary CL, Pastorino JG. Nucleocytoplasmic shuttling of hexokinase II in a cancer cell. Biochem Biophys Res Commun 2010; 394:1075-81. [PMID: 20346347 PMCID: PMC2873843 DOI: 10.1016/j.bbrc.2010.03.129] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Accepted: 03/21/2010] [Indexed: 10/19/2022]
Abstract
In yeast, the hexokinase type II enzyme (HXKII) translocates to the nucleus in the presence of excess glucose, and participates in glucose repression. However, no evidence has suggested a nuclear function for HXKII in mammalian cells. Herein, we present data showing nuclear localization of HXKII in HeLa cells, both by immunocytochemistry and subcellular fractionation. HXKII is extruded from the nucleus, at least in part, by the activity of the exportin 1/CrmA system, as demonstrated by increased nuclear expression and decreased cytoplasmic expression after incubation with leptomycin B, a bacterially-derived exportin inhibitor. Furthermore, cytoplasmic localization of HXKII is dependent on its enzymatic activity, as inhibiting HXKII activity using 2-deoxy-D-glucose (2DG) increased nuclear localization. This effect was more significant in cells incubated in the absence of glucose for 24 h prior to addition of 2DG. Regulated translocation of HXKII to the nucleus of mammalian cells could represent a previously unknown glucose-sensing mechanism.
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Affiliation(s)
- Catherine L Neary
- Department of Molecular Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.
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Zhang W, Liu Y, Chen X, Bergmeier SC. Novel inhibitors of basal glucose transport as potential anticancer agents. Bioorg Med Chem Lett 2010; 20:2191-4. [PMID: 20194024 DOI: 10.1016/j.bmcl.2010.02.027] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2009] [Revised: 02/05/2010] [Accepted: 02/08/2010] [Indexed: 01/26/2023]
Abstract
Cancer cells commonly show increased levels of glucose uptake and dependence. A potential strategy for the treatment of cancer may be the inhibition of basal glucose transport. We report here the synthesis of a small library of polyphenolic esters that inhibit basal glucose transport in H1299 lung and other cancer cells. These basal glucose transport inhibitors also inhibit cancer cell growth in H1299 cells, and these two activities appear to be correlated.
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Affiliation(s)
- Weihe Zhang
- Department of Chemistry & Biochemistry, Ohio University, Athens, OH 45701, USA
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Murrey DA, Bahnson EE, Hall NC, Povoski SP, Mojzisik CM, Young DC, Sharif S, Johnson MA, Abdel-Misih S, Martin EW, Knopp MV. Perioperative (18)F-fluorodeoxyglucose-guided imaging using the becquerel as a quantitative measure for optimizing surgical resection in patients with advanced malignancy. Am J Surg 2010; 198:834-40. [PMID: 19969138 DOI: 10.1016/j.amjsurg.2009.08.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2009] [Revised: 08/17/2009] [Accepted: 08/17/2009] [Indexed: 11/18/2022]
Abstract
BACKGROUND (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) scanning is a widely accepted preoperative tumor imaging modality. Herein, we evaluate the becquerel (Bq) as a potential novel quantitative PET measure for application of surgical specimen imaging. METHODS Retrospectively, PET-avid lesions that could be followed from preoperative imaging, confidently identified in the operating room, imaged ex vivo, and correlated with histopathology were included in this study. Bq counts from both in vivo (preoperative) and ex vivo (surgical specimen) PET/CT images were measured and correlated with histopathology. RESULTS Fifty-five PET-avid lesions in 37 patients were included. Forty-six of 55 PET-avid lesions identified were found to contain malignancy on histopathology. Mean Bq counts for the PET-avid lesions were significantly higher that the adjacent PET-nonavid areas (background) within both in vivo and ex vivo imaging (P < .001 and P < .001, respectively). When analyzing all 55 lesions, we found significant increases in Bq levels. PET-avid lesions from in vivo to ex vivo images (P < .001) without significant increases in Bq levels in PET-nonavid lesions from in vivo to ex vivo images (P = .06). When comparing Bq levels between the 2 groups (malignant and benign), we found significantly higher Bq counts in the malignant group on in vivo imaging (P = .02) as well as significantly lower Bq counts in FDG-nonavid areas on ex vivo imaging (P = .04) within the malignant group. Significant differences in PET-avid to PET-nonavid Becquerels ratios within both in vivo and ex vivo images (P = .004, P = .002 respectively) were found, with ex vivo ratio being significantly higher (P < .001). CONCLUSIONS (18)F-FDG PET/CT imaging using Bqs is the potential to discern malignant lesions from benign tissues within both in vivo and ex vivo scans.
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Affiliation(s)
- Douglas A Murrey
- Department of Radiology, The Ohio State University, Columbus, OH, USA
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Jadvar H, Alavi A, Gambhir SS. 18F-FDG uptake in lung, breast, and colon cancers: molecular biology correlates and disease characterization. J Nucl Med 2009; 50:1820-7. [PMID: 19837767 DOI: 10.2967/jnumed.108.054098] [Citation(s) in RCA: 172] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
It is hoped that in the not too distant future, noninvasive imaging-based molecular interrogation and characterization of tumors can improve our fundamental understanding of the dynamic biologic behavior of cancer. For example, the new dimension of diagnostic information that is provided by (18)F-FDG PET has led to improved clinical decision making and management changes in a substantial number of patients with cancer. In this context, the aim of this review is to bring together and summarize the current data on the correlation between the underlying molecular biology and the clinical observations of tumor (18)F-FDG accumulation in 3 major human cancers: lung, breast, and colon.
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Affiliation(s)
- Hossein Jadvar
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
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Lee JH, Gulec SA, Kyshtoobayeva A, Sim MS, Morton DL. Biological factors, tumor growth kinetics, and survival after metastasectomy for pulmonary melanoma. Ann Surg Oncol 2009; 16:2834-9. [PMID: 19603235 DOI: 10.1245/s10434-009-0583-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2009] [Revised: 06/05/2009] [Accepted: 06/05/2009] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Approximately 23% of melanoma patients will eventually develop pulmonary metastases and have a median survival of only about 7-11 months. Because pulmonary metastasectomy can improve this statistic, we investigated clinicopathologic features and biological correlates that might be used to identify surgical candidates. METHODS Archived operative specimens and clinical records were retrieved for 20 melanoma patients who underwent resection of isolated pulmonary metastases at the John Wayne Cancer Institute, Saint John's Health Center. Five-year postmetastasectomy survival (PMS) rate was correlated with age, number of pulmonary metastases, tumor doubling time (TDT), tumor necrosis, and immunohistochemical expressions of four biological markers: Ki-67, glucose transporter-1 (Glut-1), caspase-3, and CD31. RESULTS Median TDT was 61 days. On multivariate analysis, TDT (P = 0.008), Glut-1 intensity (P = 0.04), and CD31 expression (P = 0.004) were the significant predictors of PMS. Age, number of pulmonary metastases, tumor necrosis, and expression of Ki-67 or caspase-3 did not significantly impact survival. Median TDT was 56 days with Glut-1 expression versus 165 days without Glut-1 expression (P = 0.002), and Glut-1 staining intensity independently affected TDT (P = 0.012). CONCLUSIONS Surgical resection may be preferable to toxic systemic therapies in melanoma patients whose isolated pulmonary metastases have a long TDT (> or = 61 days) and no biopsy evidence of Glut-1 expression.
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Affiliation(s)
- Jonathan H Lee
- Division of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA.
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Abstract
Up to 50% of cancer patients suffer from a progressive atrophy of adipose tissue and skeletal muscle, called cachexia, resulting in weight loss, a reduced quality of life, and a shortened survival time. Anorexia often accompanies cachexia, but appears not to be responsible for the tissue loss, particularly lean body mass. An increased resting energy expenditure is seen, possibly arising from an increased thermogenesis in skeletal muscle due to an increased expression of uncoupling protein, and increased operation of the Cori cycle. Loss of adipose tissue is due to an increased lipolysis by tumor or host products. Loss of skeletal muscle in cachexia results from a depression in protein synthesis combined with an increase in protein degradation. The increase in protein degradation may include both increased activity of the ubiquitin-proteasome pathway and lysosomes. The decrease in protein synthesis is due to a reduced level of the initiation factor 4F, decreased elongation, and decreased binding of methionyl-tRNA to the 40S ribosomal subunit through increased phosphorylation of eIF2 on the alpha-subunit by activation of the dsRNA-dependent protein kinase, which also increases expression of the ubiquitin-proteasome pathway through activation of NFkappaB. Tumor factors such as proteolysis-inducing factor and host factors such as tumor necrosis factor-alpha, angiotensin II, and glucocorticoids can all induce muscle atrophy. Knowledge of the mechanisms of tissue destruction in cachexia should improve methods of treatment.
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Affiliation(s)
- Michael J Tisdale
- Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, UK.
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Frezza C, Gottlieb E. Mitochondria in cancer: not just innocent bystanders. Semin Cancer Biol 2008; 19:4-11. [PMID: 19101633 DOI: 10.1016/j.semcancer.2008.11.008] [Citation(s) in RCA: 199] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Accepted: 11/25/2008] [Indexed: 12/12/2022]
Abstract
The first half of the 20th century produced substantial breakthroughs in bioenergetics and mitochondria research. During that time, Otto Warburg observed abnormally high glycolysis and lactate production in oxygenated cancer cells, leading him to suggest that defects in mitochondrial functions are at the heart of malignant cell transformation. Warburg's hypothesis profoundly influenced the present perception of cancer metabolism, positioning what is termed aerobic glycolysis in the mainstream of clinical oncology. While some of his ideas stood the test of time, they also frequently generated misconceptions regarding the biochemical mechanisms of cell transformation. This review examines experimental evidence which supports or refutes the Warburg effect and discusses the possible advantages conferred on cancer cells by 'metabolic transformation'.
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Affiliation(s)
- Christian Frezza
- Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland, United Kingdom
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Sarikaya I, Sarikaya A, Reba RC. Gamma probes and their use in tumor detection in colorectal cancer. ACTA ACUST UNITED AC 2008; 5:25. [PMID: 19019238 PMCID: PMC2596150 DOI: 10.1186/1477-7800-5-25] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Accepted: 11/19/2008] [Indexed: 11/17/2022]
Abstract
The purpose of this article is to summarize the role of gamma probes in intraoperative tumor detection in patients with colorectal cancer (CRC), as well as provide basic information about the physical and practical characteristics of the gamma probes, and the radiopharmaceuticals used in gamma probe tumor detection. In a significant portion of these studies, radiolabeled monoclonal antibodies (Mabs), particularly 125I labeled B72.3 Mab that binds to the TAG-72 antigen, have been used to target tumor. Studies have reported that intraoperative gamma probe radioimmunodetection helps surgeons to localize primary tumor, clearly delineate its resection margins and provide immediate intraoperative staging. Studies also have emphasized the value of intraoperative gamma probe radioimmunodetection in defining the extent of tumor recurrence and finding sub-clinical occult tumors which would assure the surgeons that they have completely removed the tumor burden. However, intraoperative gamma probe radioimmunodetection has not been widely adapted among surgeons because of some constraints associated with this technique. The main difficulty with this technique is the long period of waiting time between Mab injection and surgery. The technique is also laborious and costly. In recent years, Fluorine-18-2-fluoro-2-deoxy-D-glucose (18F-FDG) use in gamma probe tumor detection surgery has renewed interest among surgeons. Preliminary studies during surgery have demonstrated that use of FDG in gamma probe tumor detection during surgery is feasible and useful.
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Affiliation(s)
- Ismet Sarikaya
- Division of Nuclear Medicine, Georgetown University Hospital, Washington DC, 20007, USA.
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Affiliation(s)
- Yongjun Fan
- Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA
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50
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Abstract
Established tumors develop ways to elude destruction by the host immune system. Recent work has revealed that tumors can take advantage of the generation of metabolic dysregulation to inhibit immune responses. Effector T-cell functions are particularly sensitive to nutrient availability in the tumor microenvironment. In this review, we highlight experimental data supporting the importance of glucose, oxygen, tryptophan, and arginine for optimal T-cell function, and the mechanisms by which these nutrients may become depleted in the tumor microenvironment. These observations provide a conceptual framework for modulating metabolic features of the T cell-tumor interaction, toward the end of promoting more effective immune-mediated tumor destruction in vivo.
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Affiliation(s)
- Candace M Cham
- Department of Pathology, Department of Medicine, and the Ben May Institute, University of Chicago, Chicago, IL 60637, USA
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