65 results on '"Enrique Fuentes-Mattei"'
Search Results
2. Anti–miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response
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Mihnea P. Dragomir, Enrique Fuentes-Mattei, Melanie Winkle, Keishi Okubo, Recep Bayraktar, Erik Knutsen, Aiham Qdaisat, Meng Chen, Yongfeng Li, Masayoshi Shimizu, Lan Pang, Kevin Liu, Xiuping Liu, Simone Anfossi, Huanyu Zhang, Ines Koch, Anh M. Tran, Swati Mohapatra, Anh Ton, Mecit Kaplan, Matthew W. Anderson, Spencer J. Rothfuss, Robert Silasi, Ravi S. Keshari, Manuela Ferracin, Cristina Ivan, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Constantin Georgescu, Pinaki P. Banerjee, Rafet Basar, Ziyi Li, David Horst, Catalin Vasilescu, Maria Teresa S. Bertilaccio, Katayoun Rezvani, Florea Lupu, Sai-Ching Yeung, and George A. Calin
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Immunology ,Infectious disease ,Medicine - Abstract
Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture–induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and Gram– sepsis models. miR-93-5p met the criteria for a therapeutic target, as it was overexpressed in baboons that died early after induction of sepsis, was downregulated in patients who survived after sepsis, and correlated with negative clinical prognosticators for sepsis. Therapeutically, inhibition of miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in older mice. Mechanistically, anti–miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially the CD4+ subset. AGO2 IP in miR-93–KO T cells identified important regulatory receptors, such as CD28, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis through the regulation of both innate and adaptive immunity, with possibly a greater benefit for elderly patients than for young patients.
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- 2023
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3. Salutary effects of moderate but not high intensity aerobic exercise training on the frequency of peripheral T-cells associated with immunosenescence in older women at high risk of breast cancer: a randomized controlled trial
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Grace M Niemiro, Adriana M Coletta, Nadia H. Agha, Preteesh Leo Mylabathula, Forrest L. Baker, Abenaa M Brewster, Therese B Bevers, Enrique Fuentes-Mattei, Karen Basen-Engquist, Emmanuel Katsanis, Susan C Gilchrist, and Richard J. Simpson
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Physical activity ,Myokines ,Exercise immunology ,β2 adrenergic receptor ,Aging ,Maximal oxygen uptake ,Immunologic diseases. Allergy ,RC581-607 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background Immunosenescence is described as age-associated changes within the immune system that are responsible for decreased immunity and increased cancer risk. Physically active individuals have fewer ‘senescent’ and more naïve T-cells compared to their sedentary counterparts, but it is not known if exercise training can rejuvenate ‘older looking’ T-cell profiles. We determined the effects of 12-weeks supervised exercise training on the frequency of T-cell subtypes in peripheral blood and their relationships with circulating levels of the muscle-derived cytokines (i.e. ‘myokines’) IL-6, IL-7, IL-15 and osteonectin in older women at high risk of breast cancer. The intervention involved 3 sessions/week of either high intensity interval exercise (HIIT) or moderate intensity continuous exercise (MICT) and were compared to an untrained control (UC) group. Results HIIT decreased total granulocytes, CD4+ T-cells, CD4+ naïve T-cells, CD4+ recent thymic emigrants (RTE) and the CD4:CD8 ratio after training, whereas MICT increased total lymphocytes and CD8 effector memory (EM) T-cells. The change in total T-cells, CD4+ naïve T-cells, CD4+ central memory (CM) T-cells and CD4+ RTE was elevated after MICT compared to HIIT. Changes in V ̇ O 2 max $$ \dot{\mathrm{V}}{\mathrm{O}}_{2\max } $$ after training, regardless of exercise prescription, was inversely related to the change in highly differentiated CD8+ EMRA T-cells and positively related to changes in β2-adrenergic receptor (β2-AR) expression on CM CD4+ and CM CD8+ T-cells. Plasma myokine levels did not change significantly among the groups after training, but individual changes in IL-7 were positively related to changes in the number of β2-AR expressing CD4 naïve T cells in both exercise groups but not controls. Further, CD4 T-cells and CD4 naive T-cells were negatively related to changes in IL-6 and osteonectin after HIIT but not MICT, whereas CD8 EMRA T-cells were inversely related to changes in IL-15 after MICT but not HIIT. Conclusions Aerobic exercise training alters the frequency of peripheral T-cells associated with immunosenescence in middle aged/older women at high risk of breast cancer, with HIIT (pro-senescent) and MICT (anti-senescent) evoking divergent effects. Identifying the underlying mechanisms and establishing whether exercise-induced changes in peripheral T-cell numbers can alter the risk of developing breast cancer warrants investigation.
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- 2022
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4. Impact of diabetes on promoting the growth of breast cancer
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Ping‐Chieh Chou, Hyun Ho Choi, Yizhi Huang, Enrique Fuentes‐Mattei, Guermarie Velazquez‐Torres, Fanmao Zhang, Liem Phan, Jaehyuk Lee, Yanxia Shi, James A. Bankson, Yun Wu, Huamin Wang, Ruiying Zhao, Sai‐Ching Jim Yeung, and Mong‐Hong Lee
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diabetes ,human epidermal growth factor receptor 2 ,breast cancer ,metformin ,metabolism ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well‐established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression. Methods We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2+ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Leprdb/+) mice with MMTV‐ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism. Results Treatment with metformin/rosiglitazone in MMTV‐ErbB2/Leprdb/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti‐insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized 13C pyruvate‐to‐lactate reaction. The tumor cells from MMTV‐ErbB2/Leprdb/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles. Conclusions MMTV‐ErbB2/Leprdb/db mouse model was able to recapitulate diabetic HER2+ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti‐insulin resistance therapy.
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- 2021
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5. Correction: Salutary effects of moderate but not high intensity aerobic exercise training on the frequency of peripheral T-cells associated with immunosenescence in older women at high risk of breast cancer: a randomized controlled trial
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Grace M. Niemiro, Adriana M. Coletta, Nadia H. Agha, Preteesh Leo Mylabathula, Forrest L. Baker, Abenaa M. Brewster, Therese B. Bevers, Enrique Fuentes-Mattei, Karen Basen-Engquist, Emmanuel Katsanis, Susan C. Gilchrist, and Richard J. Simpson
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Immunologic diseases. Allergy ,RC581-607 ,Geriatrics ,RC952-954.6 - Published
- 2022
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6. A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression
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Guermarie Velazquez-Torres, Einav Shoshan, Cristina Ivan, Li Huang, Enrique Fuentes-Mattei, Harrison Paret, Sun Jin Kim, Cristian Rodriguez-Aguayo, Victoria Xie, Denise Brooks, Steven J. M. Jones, A. Gordon Robertson, George Calin, Gabriel Lopez-Berenstein, Anil Sood, and Menashe Bar-Eli
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Science - Abstract
In melanoma, reduced ADAR1 impairs A-to-I microRNA editing. Here, the authors show that miR-378a-3p undergoes this editing in non-metastatic cells and the edited form of miR-378a-3p binds to the PARVA oncogene, inhibiting its expression and preventing melanoma progression and metastasis.
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- 2018
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7. Plasma Viral miRNAs Indicate a High Prevalence of Occult Viral Infections
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Enrique Fuentes-Mattei, Dana Elena Giza, Masayoshi Shimizu, Cristina Ivan, John T. Manning, Stefan Tudor, Maria Ciccone, Osman Aykan Kargin, Xinna Zhang, Pilar Mur, Nayra Soares do Amaral, Meng Chen, Jeffrey J. Tarrand, Florea Lupu, Alessandra Ferrajoli, Michael J. Keating, Catalin Vasilescu, Sai-Ching Jim Yeung, and George A. Calin
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Viral miRNAs ,KSHV ,HHV8 ,EBV ,HHV4 ,Infection prevalence ,Medicine ,Medicine (General) ,R5-920 - Abstract
Prevalence of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) varies greatly in different populations. We hypothesized that the actual prevalence of KSHV/HHV8 infection in humans is underestimated by the currently available serological tests. We analyzed four independent patient cohorts with post-surgical or post-chemotherapy sepsis, chronic lymphocytic leukemia and post-surgical patients with abdominal surgical interventions. Levels of specific KSHV-encoded miRNAs were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and KSHV/HHV-8 IgG were measured by immunoassay. We also measured specific miRNAs from Epstein Barr Virus (EBV), a virus closely related to KSHV/HHV-8, and determined the EBV serological status by ELISA for Epstein-Barr nuclear antigen 1 (EBNA-1) IgG. Finally, we identified the viral miRNAs by in situ hybridization (ISH) in bone marrow cells. In training/validation settings using independent multi-institutional cohorts of 300 plasma samples, we identified in 78.50% of the samples detectable expression of at least one of the three tested KSHV-miRNAs by RT-qPCR, while only 27.57% of samples were found to be seropositive for KSHV/HHV-8 IgG (P
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- 2017
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8. Obesity-associated NLRC4 inflammasome activation drives breast cancer progression
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Ryan Kolb, Liem Phan, Nicholas Borcherding, Yinghong Liu, Fang Yuan, Ann M. Janowski, Qing Xie, Kathleen R. Markan, Wei Li, Matthew J. Potthoff, Enrique Fuentes-Mattei, Lesley G. Ellies, C. Michael Knudson, Mong-Hong Lee, Sai-Ching J. Yeung, Suzanne L. Cassel, Fayyaz S. Sutterwala, and Weizhou Zhang
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Science - Abstract
Obesity is associated with higher breast cancer risk and poor prognosis. Here, the authors show that obesity promotes breast cancer through the recruitment of macrophages with activated NLRC4 inflammasome, which activate IL-1β production, resulting in VEGFA expression in adipocytes and angiogenesis.
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- 2016
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9. Exenatide improves glucocorticoid-induced glucose intolerance in mice
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Ruiying Zhao, Enrique Fuentes-Mattei, Guermarie Velazquez-Torres, and et al
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Specialties of internal medicine ,RC581-951 - Abstract
Ruiying Zhao1,2*, Enrique Fuentes-Mattei1,2*, Guermarie Velazquez-Torres1,3, Chun-Hui Su1,2, Jian Chen1, Mong-Hong Lee1,2, Sai-Ching Jim Yeung4,51Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Program in Genes and Development, 3Program in Cancer Biology, Graduate School of Biomedical Sciences, University of Texas Health Science Center in Houston, Houston, TX, USA; 4Department of Endocrine Neoplasia and Hormonal Disorders, 5Department of Emergency Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA *Both authors contributed equally.Abstract: Exenatide is an incretin mimetic that is recently available in the US for the treatment of diabetes. There is a paucity of information on the effects of exenatide in glucocorticoid (GC)-induced diabetes. Although the effect of continuous intravenous infusion of exenatide on GC-induced glucose intolerance has been investigated before in healthy human males receiving oral prednisolone, we investigated the efficacy of a single subcutaneous dose of exenatide (3 µg/kg) in lowering blood glucose in GC-induced glucose intolerance in C57BL/6 mice. In a longitudinal experiment, the area under the curve (AUC) of oral glucose tolerance tests (OGTT) significantly increased after dexamethasone (P = 0.004), which was subsequently decreased by exenatide (P < 0.001). A cross-sectional experiment showed that exenatide improved glucose tolerance compared with placebo in a mouse model of dexamethasone-induced glucose intolerance. AUC of OGTT in the exenatide group were significantly (P < 0.001) lower than in the placebo group. Insulin tolerance tests (ITT) demonstrated that exenatide decreased the ability of the mice to tolerate insulin compared with placebo. The AUC of ITT in the exenatide group were also significantly (P = 0.006) lower than in the placebo group. In conclusion, a single dose of exenatide was able to decrease glucose intolerance and insulin resistance in these placebo-controlled experiments. Future clinical trials are justified to investigate the role of exenatide in the treatment of GC-induced glucose intolerance/diabetes.Keywords: exenatide, dexamethasone, glucocorticoid, insulin resistance, mouse model
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- 2011
10. Supplementary Figures 1-7 from Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin–Bound Paclitaxel in Pancreatic Ductal Adenocarcinoma
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Gabriel Lopez-Berestein, Craig Logsdon, Anil K. Sood, James M. Reuben, Bulent Ozpolat, Yolanda Gutierrez-Puente, Mumin Alper Erdogan, Burcu Aslan, Mohammed H. Rashed, Bincy Philip, Paloma del C. Monroig-Bosque, Guillermo N. Armaiz-Pena, Hui Gao, Evan Cohen, Raul Joshua Garza, Cristina Ivan, Huamin Wang, Rosa F. Hwang, Defeng Deng, Enrique Fuentes-Mattei, Zobeida Cruz-Monserrate, Thiruvengadam Arumugam, Cristian Rodriguez-Aguayo, and Vianey Gonzalez-Villasana
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Supplementary Figures 1-7. Supplementary Figure 1. (A) Capan-2 animal protocol. Supplementary Figure 2. Effects of the combination of ZA with nab-paclitaxel on the mRNA levels of alpha-SMA and Rap1A in vivo. Supplementary Figure 3. (A) Reduction of pancreatic tumor volume by Gem alone or ZA alone. Supplementary Figure 4. Cell viability assessed by MTS assay. Supplementary Figure 5. Isobologram analysis. Supplementary Figure 6. Combination of ZA with nab-paclitaxel decrease fibronectin levels in vitro and laminin levels in vivo. Supplementary Figure 7. Mechanistic association of ZA and nab-paclitaxel.
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- 2023
11. Supplementary Figure Legends, Materials and Methods, and Table 1 from Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin–Bound Paclitaxel in Pancreatic Ductal Adenocarcinoma
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Gabriel Lopez-Berestein, Craig Logsdon, Anil K. Sood, James M. Reuben, Bulent Ozpolat, Yolanda Gutierrez-Puente, Mumin Alper Erdogan, Burcu Aslan, Mohammed H. Rashed, Bincy Philip, Paloma del C. Monroig-Bosque, Guillermo N. Armaiz-Pena, Hui Gao, Evan Cohen, Raul Joshua Garza, Cristina Ivan, Huamin Wang, Rosa F. Hwang, Defeng Deng, Enrique Fuentes-Mattei, Zobeida Cruz-Monserrate, Thiruvengadam Arumugam, Cristian Rodriguez-Aguayo, and Vianey Gonzalez-Villasana
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Supplementary Figure Legends, Materials and Methods, and Table 1. Supplementary Figure Legends, Supplementary Material and Methods for RNA isolation, cDNA synthesis, and quantification of RNA species, Supplementary Table 1. Primer Sequences.
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- 2023
12. Supplementary Figure Legends (Figures 1-6) from Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer
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Gabriel Lopez-Berestein, Anil K. Sood, George Calin, Bulent Ozpolat, Pinar Kanlikilicer, Huamin Wang, Nermin Kahraman, Sunila Pradeep, Rebecca A. Previs, Guermarie Velazquez-Torres, Paloma del C. Monroig, Burcu Aslan, Ricardo J. Fernandez-de Thomas, Cristian Rodriguez-Aguayo, Heather J. Dalton, Cristina Ivan, Enrique Fuentes-Mattei, and Vianey Gonzalez-Villasana
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Supplementary Figure Legends (Figures 1-6)
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- 2023
13. Data from Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer
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Gabriel Lopez-Berestein, Anil K. Sood, George Calin, Bulent Ozpolat, Pinar Kanlikilicer, Huamin Wang, Nermin Kahraman, Sunila Pradeep, Rebecca A. Previs, Guermarie Velazquez-Torres, Paloma del C. Monroig, Burcu Aslan, Ricardo J. Fernandez-de Thomas, Cristian Rodriguez-Aguayo, Heather J. Dalton, Cristina Ivan, Enrique Fuentes-Mattei, and Vianey Gonzalez-Villasana
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Purpose: Zoledronic acid is being increasingly recognized for its antitumor properties, but the underlying functions are not well understood. In this study, we hypothesized that zoledronic acid inhibits ovarian cancer angiogenesis preventing Rac1 activation.Experimental Design: The biologic effects of zoledronic acid were examined using a series of in vitro [cell invasion, cytokine production, Rac1 activation, reverse-phase protein array, and in vivo (orthotopic mouse models)] experiments.Results: There was significant inhibition of ovarian cancer (HeyA8-MDR and OVCAR-5) cell invasion as well as reduced production of proangiogenic cytokines in response to zoledronic acid treatment. Furthermore, zoledronic acid inactivated Rac1 and decreased the levels of Pak1/p38/matrix metalloproteinase-2 in ovarian cancer cells. In vivo, zoledronic acid reduced tumor growth, angiogenesis, and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. These in vivo antitumor effects were enhanced in both models when zoledronic acid was combined with nab-paclitaxel.Conclusions: Zoledronic acid has robust antitumor and antiangiogenic activity and merits further clinical development as ovarian cancer treatment. Clin Cancer Res; 21(9); 2127–37. ©2015 AACR.
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- 2023
14. Supplemental Figure 1 from Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers
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George A. Calin, Muller Fabbri, Michael J. Keating, Gabriel Lopez-Berestein, Anil K. Sood, Hagop M. Kantarjian, Ignacio I. Wistuba, Massimo Negrini, Ioana Berindan-Neagoe, Ramana V. Davuluri, Tara M. Lichtenberg, William Plunkett, Robert Orlowski, Alessandra Ferrajoli, M. James You, Xuemei Wang, Steliana Calin, Lynne Abruzzo, Dino Amadori, Chad V. Pecot, Vivian R. Ruvolo, Peter P. Ruvolo, Antonino Neri, Fortunato Morabito, Manuela Ferracin, Rajesha Rupaimoole, Vianey Gonzalez-Villasana, Simona Rossi, Milena S. Nicoloso, Xinna Zhang, Lucilla D'Abundo, Roxana S. Redis, Ivan Vannini, Lianchun Xiao, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Cristina Ivan, Tetsuro Setoyama, Francesca Fanini, and Katrien Van Roosbroeck
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Dose-response curves for MEC1 and MEC2 cells treated with fludarabine.
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- 2023
15. Supplemental Figure 5 from Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers
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George A. Calin, Muller Fabbri, Michael J. Keating, Gabriel Lopez-Berestein, Anil K. Sood, Hagop M. Kantarjian, Ignacio I. Wistuba, Massimo Negrini, Ioana Berindan-Neagoe, Ramana V. Davuluri, Tara M. Lichtenberg, William Plunkett, Robert Orlowski, Alessandra Ferrajoli, M. James You, Xuemei Wang, Steliana Calin, Lynne Abruzzo, Dino Amadori, Chad V. Pecot, Vivian R. Ruvolo, Peter P. Ruvolo, Antonino Neri, Fortunato Morabito, Manuela Ferracin, Rajesha Rupaimoole, Vianey Gonzalez-Villasana, Simona Rossi, Milena S. Nicoloso, Xinna Zhang, Lucilla D'Abundo, Roxana S. Redis, Ivan Vannini, Lianchun Xiao, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Cristina Ivan, Tetsuro Setoyama, Francesca Fanini, and Katrien Van Roosbroeck
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Supplementary Table S1 Clinical characteristics of two chronic lymphocytic leukemia patient datasets; Supplementary Table S2 Clinical characteristics of two lung cancer patient datasets; Supplementary Table S3 Clinical characteristics of the ALL dataset; Supplementary Table S4 Integrated function and pathway analysis on 248 experimentally validated targets of miR-155; Supplementary Table S5 Univariate and multivariate analyses of survival with patient characteristics and miR-155 and TP53 expression as categorical and continuous variables in different patient cohorts; Supplementary Table S6 Estimate of Cox model and multivariate Cox model, as well as the HR estimated based on the model for miR-155 high and TP53 low vs. miR-155 low and TP53 high.
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- 2023
16. Data from Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers
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George A. Calin, Muller Fabbri, Michael J. Keating, Gabriel Lopez-Berestein, Anil K. Sood, Hagop M. Kantarjian, Ignacio I. Wistuba, Massimo Negrini, Ioana Berindan-Neagoe, Ramana V. Davuluri, Tara M. Lichtenberg, William Plunkett, Robert Orlowski, Alessandra Ferrajoli, M. James You, Xuemei Wang, Steliana Calin, Lynne Abruzzo, Dino Amadori, Chad V. Pecot, Vivian R. Ruvolo, Peter P. Ruvolo, Antonino Neri, Fortunato Morabito, Manuela Ferracin, Rajesha Rupaimoole, Vianey Gonzalez-Villasana, Simona Rossi, Milena S. Nicoloso, Xinna Zhang, Lucilla D'Abundo, Roxana S. Redis, Ivan Vannini, Lianchun Xiao, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Cristina Ivan, Tetsuro Setoyama, Francesca Fanini, and Katrien Van Roosbroeck
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Purpose: The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors.Experimental Design: We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.Results: We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer.Conclusions: Our findings support the existence of an miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death. Clin Cancer Res; 23(11); 2891–904. ©2016 AACR.
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- 2023
17. Supplemental Figure 3 from Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers
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George A. Calin, Muller Fabbri, Michael J. Keating, Gabriel Lopez-Berestein, Anil K. Sood, Hagop M. Kantarjian, Ignacio I. Wistuba, Massimo Negrini, Ioana Berindan-Neagoe, Ramana V. Davuluri, Tara M. Lichtenberg, William Plunkett, Robert Orlowski, Alessandra Ferrajoli, M. James You, Xuemei Wang, Steliana Calin, Lynne Abruzzo, Dino Amadori, Chad V. Pecot, Vivian R. Ruvolo, Peter P. Ruvolo, Antonino Neri, Fortunato Morabito, Manuela Ferracin, Rajesha Rupaimoole, Vianey Gonzalez-Villasana, Simona Rossi, Milena S. Nicoloso, Xinna Zhang, Lucilla D'Abundo, Roxana S. Redis, Ivan Vannini, Lianchun Xiao, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Cristina Ivan, Tetsuro Setoyama, Francesca Fanini, and Katrien Van Roosbroeck
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Clinical correlation of miR-155 expression with survival in leukemia. Kaplan-Meier survival analysis for patients expressing high levels of miR-155 vs. low levels of miR-155 in two CLL cohorts, CLL - NEJM (A) and CLL - Italy (B), and in one ALL cohort, ALL - MDACC (C).
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- 2023
18. Supplementary Figures 1-6 from Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer
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Gabriel Lopez-Berestein, Anil K. Sood, George Calin, Bulent Ozpolat, Pinar Kanlikilicer, Huamin Wang, Nermin Kahraman, Sunila Pradeep, Rebecca A. Previs, Guermarie Velazquez-Torres, Paloma del C. Monroig, Burcu Aslan, Ricardo J. Fernandez-de Thomas, Cristian Rodriguez-Aguayo, Heather J. Dalton, Cristina Ivan, Enrique Fuentes-Mattei, and Vianey Gonzalez-Villasana
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Supplementary Figures 1-6. Supplementary Figure S1: In vivo and in vitro effects of ZA on apoptosis. Supplementary Figure S2: Nab-paclitaxel inhibits tube formation.Supplementary Figure S3: RPPA analysis in HeyA8 MDR treated with ZA. Supplementary Figure S4: Functional changes induced by ZA in HeyA8 MDR. Supplementary Figure S5: ZA decreases angiogenic factors. Supplementary Figure S6: ZA inhibits cell invasion
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- 2023
19. Supplemental Figure 2 from Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers
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George A. Calin, Muller Fabbri, Michael J. Keating, Gabriel Lopez-Berestein, Anil K. Sood, Hagop M. Kantarjian, Ignacio I. Wistuba, Massimo Negrini, Ioana Berindan-Neagoe, Ramana V. Davuluri, Tara M. Lichtenberg, William Plunkett, Robert Orlowski, Alessandra Ferrajoli, M. James You, Xuemei Wang, Steliana Calin, Lynne Abruzzo, Dino Amadori, Chad V. Pecot, Vivian R. Ruvolo, Peter P. Ruvolo, Antonino Neri, Fortunato Morabito, Manuela Ferracin, Rajesha Rupaimoole, Vianey Gonzalez-Villasana, Simona Rossi, Milena S. Nicoloso, Xinna Zhang, Lucilla D'Abundo, Roxana S. Redis, Ivan Vannini, Lianchun Xiao, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Cristina Ivan, Tetsuro Setoyama, Francesca Fanini, and Katrien Van Roosbroeck
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In vivo orthotopic lung cancer model for the role of miR-155 in chemoresistance. (A) Injection and treatment schedule for CDDP (green arrows) and anti-miR negative control (NC) or anti-miR-155 liposomal nanoparticles (red stars) for four different treatment groups: mice that were injected with A549-LVEV cells and untreated (group 1), injected with A549-LVEV cells and treated with anti-miR-NC and CDDP (group 2), injected with A549-155LV cells and treated with anti-miR-NC and CDDP (group 3), and injected with A549-155LV cells and treated with anti-miR-155 and CDDP (group 4). (B) Representative pictures of dissected mice belonging to each of the treatment groups described in panel A of this Figure. Tumor nodules are marked by dotted white circles. (C-D) Graphs of the primary tumor size (C) and aggregate mass of nodules in mediastinum (D) of the four treatment groups mentioned above. (E) In situ hybridization for miR-155 for each of the four treatment groups mentioned above. (F) Immunohistochemical analysis for Ki-67 (proliferation) and CD31 (angiogenesis), as well as the TUNEL assay (apoptosis) and TP53 immunostaining for each of the four treatment groups mentioned above.
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- 2023
20. Supplemental Figure 4 from Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers
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George A. Calin, Muller Fabbri, Michael J. Keating, Gabriel Lopez-Berestein, Anil K. Sood, Hagop M. Kantarjian, Ignacio I. Wistuba, Massimo Negrini, Ioana Berindan-Neagoe, Ramana V. Davuluri, Tara M. Lichtenberg, William Plunkett, Robert Orlowski, Alessandra Ferrajoli, M. James You, Xuemei Wang, Steliana Calin, Lynne Abruzzo, Dino Amadori, Chad V. Pecot, Vivian R. Ruvolo, Peter P. Ruvolo, Antonino Neri, Fortunato Morabito, Manuela Ferracin, Rajesha Rupaimoole, Vianey Gonzalez-Villasana, Simona Rossi, Milena S. Nicoloso, Xinna Zhang, Lucilla D'Abundo, Roxana S. Redis, Ivan Vannini, Lianchun Xiao, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Cristina Ivan, Tetsuro Setoyama, Francesca Fanini, and Katrien Van Roosbroeck
- Abstract
Clinical correlation of miR-155 and TP53 expression with survival in the lung adenocarcinoma - TCGA dataset when distinguishing between TP53 wild-type and TP53 mutated samples. (A-B) Kaplan-Meier survival analysis for patients expressing high levels of miR-155 vs. low levels of miR-155 in samples that express wild-typeTP53 or harbor TP53 mutations that do not affect TP53 function (A), and in samples expressing mutated TP53 that affects TP53 function (B). (C-D) Kaplan-Meier survival analysis for patients expressing high levels of miR-155 and low levels of TP53 vs. low levels of miR-155 and high levels of TP53 in samples that express wild-type TP53 or harbor TP53 mutations that do not affect TP53 function (C), and in samples expressing mutated TP53 that affects TP53 function (D).
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- 2023
21. Supplementary Table Legend from Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma
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Mouhammed Amir Habra, Sai-Ching J. Yeung, Mong-Hong Lee, Maria Angelica Cortez, Lance Pagliaro, Roeland Verhaak, Siyuan Zheng, Marie-Claude Hofmann, Levent Ozsari, Gilbert J. Cote, Camilo Jimenez, Tao Hai, Christopher G. Wood, Kanishka Sircar, Guermarie Velazquez-Torres, Weixin Wu, Enrique Fuentes-Mattei, and Liem M. Phan
- Abstract
Supplementary Table Legend from Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma
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- 2023
22. Supplementary Figures S1-S6 from Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma
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Mouhammed Amir Habra, Sai-Ching J. Yeung, Mong-Hong Lee, Maria Angelica Cortez, Lance Pagliaro, Roeland Verhaak, Siyuan Zheng, Marie-Claude Hofmann, Levent Ozsari, Gilbert J. Cote, Camilo Jimenez, Tao Hai, Christopher G. Wood, Kanishka Sircar, Guermarie Velazquez-Torres, Weixin Wu, Enrique Fuentes-Mattei, and Liem M. Phan
- Abstract
High MET expression in ACC patients (S1); High MET mRNA expression levels in ACC (S2); cMET signaling is activated in ACC (S3); Increased HGF/cMET signaling is associated with enhanced proliferation and reduced apoptosis in tumors from ACC patients (S4); HGF stimulates NCI-H295R ACC cell proliferation (S5); HGF/cMET signaling is important for ACC cell energy metabolism (S6).
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- 2023
23. Supplementary Tables S1-S12 from Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma
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Mouhammed Amir Habra, Sai-Ching J. Yeung, Mong-Hong Lee, Maria Angelica Cortez, Lance Pagliaro, Roeland Verhaak, Siyuan Zheng, Marie-Claude Hofmann, Levent Ozsari, Gilbert J. Cote, Camilo Jimenez, Tao Hai, Christopher G. Wood, Kanishka Sircar, Guermarie Velazquez-Torres, Weixin Wu, Enrique Fuentes-Mattei, and Liem M. Phan
- Abstract
Basic patients characteristics of the cohort used for serum HGF measurements ; Patients characteristics of second TMA ; Genes with significantly (P {less than or equal to} 0.05, absolute value of log ratio > 0.1) changed expression in tumors from ACC patients (dataset GSE10927) relative to expression in normal adrenocortical tissues ; Biological processes Significantly (P 0.1) changed in tumors from ACC patients with high MET expression compared to those with low MET expression (dataset GSE10927) ; Gene set enrichment analysis of ACC patients' cohort for genes related to cell proliferation (dataset GSE10927) ; Gene set enrichment analysis of ACC patients' cohort for genes related to the negative regulation of cell apoptosis (dataset GSE10927) ; Gene set enrichment analysis of ACC patients' cohort for genes related to cell proliferation (dataset GSEA49278) ; Gene set enrichment analysis of ACC patients' cohort for genes related to the negative regulation of cell apoptosis (dataset GSEA49278) ; Drug metabolism-related genes with significantly (P {less than or equal to} 0.05, absolute value of log ratio > 0.1) changed expression in tumors from ACC patients (dataset GSE10927) with high MET expression relative to those with low MET expression ; Gene set enrichment analysis detail of ACC patients' cohort for genes associated with resistance and metabolism of cisplatin, etoposide and doxorubicin (dataset GSEA10927) ; Gene set enrichment analysis detail of ACC patients' cohort for genes associated with resistance and metabolism of cisplatin, etoposide and doxorubicin (dataset GSEA49278) .
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- 2023
24. The impact of high-intensity interval exercise training on NK-cell function and circulating myokines for breast cancer prevention among women at high risk for breast cancer
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Enrique Fuentes-Mattei, Nadia H. Agha, Grace M. Niemiro, Forrest L. Baker, Karen Basen-Engquist, Therese B. Bevers, Abenaa M. Brewster, Susan C. Gilchrist, Richard J. Simpson, Preteesh L. Mylabathula, and Adriana M. Coletta
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Breast Neoplasms ,High-Intensity Interval Training ,Interval training ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Myokine ,Breast cancer prevention ,medicine ,Humans ,Exercise ,Aerobic capacity ,Exercise immunology ,business.industry ,Cardiorespiratory fitness ,medicine.disease ,Clinical Trial ,Exercise Therapy ,Clinical trial ,030104 developmental biology ,Cardiorespiratory Fitness ,030220 oncology & carcinogenesis ,Exercise intensity ,Cytokines ,Female ,Analysis of variance ,business - Abstract
Purpose Preclinical evidence suggests that natural killer cell (NK-cell) function and myokines facilitate the protective effects of exercise for breast cancer prevention. Since higher-intensity exercise acutely promotes greater mobilization and larger changes in NK-cell cytotoxicity than lower-intensity, high-intensity interval training (HIIT) might offer increased immune protection compared to moderate-intensity continuous-training (MICT). This study compared a 12-week HIIT program to a 12-week MICT program and usual care on changes in resting NK-cell function and circulating myokines among women at high risk for breast cancer. Methods Thirty-three women were randomized to HIIT, MICT, or usual care, for a supervised exercise intervention. Blood was collected at baseline and end-of-study. The cytotoxic activity of CD3−/CD56+ NK-cells against the K562 target cell line in vitro was determined by flow cytometry. Circulating myokines (IL-15, IL-6, irisin, OSM, osteonectin, IL-7) were assessed with luminex multiplex assays and ELISA. One-way ANOVA and paired sample t-tests assessed between- and within-group differences, respectively. Pearson correlation coefficients determined relationships between baseline fitness and change variables. Results Significant differences were not observed between groups for change in NK-cell function or circulating myokines (p > 0.05). Significant correlations were only observed for baseline peak aerobic capacity (ml/kg/min) and change in NK-cell-specific lysis (r = − 0.43, p = 0.02) and hemacytotoxicity for the total sample (r = − 0.46, p = 0.01). Conclusion Our findings suggest that exercise intensity may not significantly impact change in resting NK-cell function and circulating myokines among women at high risk for breast cancer. Structured exercise training may have a larger impact on NK-cell function in those with lower levels of cardiorespiratory fitness. Clinical trial registration: NCT02923401; Registered on October 4, 2016
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- 2021
25. Impact of diabetes on promoting the growth of breast cancer
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Mong Hong Lee, Yun Wu, Jaehyuk Lee, Enrique Fuentes-Mattei, Fanmao Zhang, Huamin Wang, Ping Chieh Chou, Ruiying Zhao, Guermarie Velazquez-Torres, Yizhi Huang, Sai Ching J. Yeung, James A. Bankson, Yanxia Shi, Hyun Ho Choi, and Liem Phan
- Subjects
0301 basic medicine ,Genetically modified mouse ,Cancer Research ,Breast Neoplasms ,Mice, Transgenic ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Breast cancer ,breast cancer ,Medicine ,Animals ,Humans ,skin and connective tissue diseases ,PI3K/AKT/mTOR pathway ,RC254-282 ,diabetes ,business.industry ,Akt/PKB signaling pathway ,human epidermal growth factor receptor 2 ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Original Articles ,medicine.disease ,Metformin ,Disease Models, Animal ,030104 developmental biology ,Oncology ,Diabetes Mellitus, Type 2 ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Original Article ,Female ,business ,Rosiglitazone ,metformin ,metabolism ,medicine.drug ,Signal Transduction - Abstract
Background Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well‐established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression. Methods We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2+ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Leprdb/+) mice with MMTV‐ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism. Results Treatment with metformin/rosiglitazone in MMTV‐ErbB2/Leprdb/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti‐insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized 13C pyruvate‐to‐lactate reaction. The tumor cells from MMTV‐ErbB2/Leprdb/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles. Conclusions MMTV‐ErbB2/Leprdb/db mouse model was able to recapitulate diabetic HER2+ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti‐insulin resistance therapy., Our results define the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti‐insulin resistance therapy.
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- 2021
26. Inhibition of G protein-coupled receptor kinase 2 promotes unbiased downregulation of IGF-1 receptor and restrains malignant cell growth
- Author
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Caitrin Crudden, Julianna Serly, Ada Girnita, Daniela Nedelcu, George A. Calin, Dawei Song, Sonia Cismas, Takashi Shibano, Enrique Fuentes-Mattei, Mihnea P. Dragomir, Andrei Adrian Tica, Leonard Girnita, Pathology, CCA - Cancer biology and immunology, Medicinal chemistry, and AIMMS
- Subjects
0301 basic medicine ,Male ,Cancer Research ,G-Protein-Coupled Receptor Kinase 2 ,Mice, Nude ,Apoptosis ,Bone Neoplasms ,Sarcoma, Ewing ,Receptor tyrosine kinase ,Receptor, IGF Type 1 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Gene silencing ,Animals ,Humans ,Insulin-Like Growth Factor I ,Phosphorylation ,Receptor ,Insulin-like growth factor 1 receptor ,G protein-coupled receptor ,Cell Proliferation ,G protein-coupled receptor kinase ,biology ,Chemistry ,Beta adrenergic receptor kinase ,Ubiquitination ,G-Protein-Coupled Receptor Kinases ,Xenograft Model Antitumor Assays ,Cell biology ,Gene Expression Regulation, Neoplastic ,body regions ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein - Abstract
The ability of a receptor to preferentially activate only a subset of available downstream signal cascades is termed biased signaling. Although comprehensively recognized for the G protein–coupled receptors (GPCR), this process is scarcely explored downstream of receptor tyrosine kinases (RTK), including the cancer-relevant insulin-like growth factor-1 receptor (IGF1R). Successful IGF1R targeting requires receptor downregulation, yet therapy-mediated removal from the cell surface activates cancer-protective β-arrestin–biased signaling (β-arr-BS). As these overlapping processes are initiated by the β-arr/IGF1R interaction and controlled by GPCR-kinases (GRK), we explored GRKs as potential anticancer therapeutic targets to disconnect IGF1R downregulation and β-arr-BS. Transgenic modulation demonstrated that GRK2 inhibition or GRK6 overexpression enhanced degradation of IGF1R, but both scenarios sustained IGF1–induced β-arr-BS. Pharmacologic inhibition of GRK2 by the clinically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated the effects of GRK2 silencing with dose- and time-dependent IGF1R downregulation without associated β-arr-BS. In vivo, PX treatment caused substantial downregulation of IGF1R, suppressing the growth of Ewing's sarcoma xenografts. Functional studies reveal that PX exploits the antagonism between β-arrestin isoforms; in low ligand conditions, PX favored β-arrestin1/Mdm2-mediated ubiquitination/degradation of IGF1R, a scenario usually exclusive to ligand abundancy, making PX more effective than antibody-mediated IGF1R downregulation. This study provides the rationale, molecular mechanism, and validation of a clinically feasible concept for “system bias” targeting of the IGF1R to uncouple downregulation from signaling. Demonstrating system bias as an effective anticancer approach, our study reveals a novel strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF1R or other RTK. Significance: This work provides insight into the molecular and biological roles of biased signaling downstream RTK and provides a novel “system bias” strategy to increase the efficacy of anti–IGF1R-targeted therapy in cancer.
- Published
- 2021
27. Salutary effects of moderate but not high intensity aerobic exercise training on the frequency of peripheral T-cells associated with immunosenescence in older women at high risk of breast cancer: a randomized controlled trial
- Author
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Karen Basen-Engquist, Nadia H. Agha, Forrest L. Baker, Richard J. Simpson, Adriana M. Coletta, Grace M. Niemiro, Therese B. Bevers, Preteesh L. Mylabathula, Abenaa M. Brewster, Enrique Fuentes-Mattei, Susan C. Gilchrist, and Emmanuel Katsanis
- Subjects
medicine.medical_specialty ,Aging ,business.industry ,High intensity ,Immunology ,Immunosenescence ,medicine.disease ,Peripheral ,law.invention ,Breast cancer ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Aerobic exercise ,business - Abstract
Background Immunosenescence is described as age-associated changes within the immune system that are responsible for decreased immunity and increased cancer risk. Physically active individuals have fewer ‘senescent’ and more naïve T-cells compared to their sedentary counterparts, but it is not known if exercise training can rejuvenate ‘older looking’ T-cell profiles. We determined the effects of 12-weeks supervised exercise training on the frequency of T-cell subtypes in peripheral blood and their relationships with circulating levels of the muscle-derived cytokines (i.e. ‘myokines’) IL-6, IL-7, IL-15 and osteonectin in older women at high risk of breast cancer. The intervention involved 3 sessions/week of either high intensity interval exercise (HIIT) or moderate intensity continuous exercise (MICT) and were compared to an untrained control (UC) group. Results HIIT decreased total granulocytes, CD4+ T-cells, CD4+ naïve T-cells, CD4+ recent thymic emigrants (RTE) and the CD4:CD8 ratio after training, whereas MICT increased total lymphocytes and CD8 effector memory (EM) T-cells. The change in total T-cells, CD4+ naïve T-cells, CD4+ central memory (CM) T-cells and CD4+ RTE was elevated after MICT compared to HIIT. Changes in $$ \dot{\mathrm{V}}{\mathrm{O}}_{2\max } $$ V ̇ O 2 max after training, regardless of exercise prescription, was inversely related to the change in highly differentiated CD8+ EMRA T-cells and positively related to changes in β2-adrenergic receptor (β2-AR) expression on CM CD4+ and CM CD8+ T-cells. Plasma myokine levels did not change significantly among the groups after training, but individual changes in IL-7 were positively related to changes in the number of β2-AR expressing CD4 naïve T cells in both exercise groups but not controls. Further, CD4 T-cells and CD4 naive T-cells were negatively related to changes in IL-6 and osteonectin after HIIT but not MICT, whereas CD8 EMRA T-cells were inversely related to changes in IL-15 after MICT but not HIIT. Conclusions Aerobic exercise training alters the frequency of peripheral T-cells associated with immunosenescence in middle aged/older women at high risk of breast cancer, with HIIT (pro-senescent) and MICT (anti-senescent) evoking divergent effects. Identifying the underlying mechanisms and establishing whether exercise-induced changes in peripheral T-cell numbers can alter the risk of developing breast cancer warrants investigation.
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- 2022
28. Salutary effects of moderate but not high intensity aerobic exercise training on the frequency of peripheral T-cells associated with immunosenescence in older women at high risk of breast cancer: a randomized controlled trial
- Author
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Grace M, Niemiro, Adriana M, Coletta, Nadia H, Agha, Preteesh Leo, Mylabathula, Forrest L, Baker, Abenaa M, Brewster, Therese B, Bevers, Enrique, Fuentes-Mattei, Karen, Basen-Engquist, Emmanuel, Katsanis, Susan C, Gilchrist, and Richard J, Simpson
- Abstract
Immunosenescence is described as age-associated changes within the immune system that are responsible for decreased immunity and increased cancer risk. Physically active individuals have fewer 'senescent' and more naïve T-cells compared to their sedentary counterparts, but it is not known if exercise training can rejuvenate 'older looking' T-cell profiles. We determined the effects of 12-weeks supervised exercise training on the frequency of T-cell subtypes in peripheral blood and their relationships with circulating levels of the muscle-derived cytokines (i.e. 'myokines') IL-6, IL-7, IL-15 and osteonectin in older women at high risk of breast cancer. The intervention involved 3 sessions/week of either high intensity interval exercise (HIIT) or moderate intensity continuous exercise (MICT) and were compared to an untrained control (UC) group.HIIT decreased total granulocytes, CD4+ T-cells, CD4+ naïve T-cells, CD4+ recent thymic emigrants (RTE) and the CD4:CD8 ratio after training, whereas MICT increased total lymphocytes and CD8 effector memory (EM) T-cells. The change in total T-cells, CD4+ naïve T-cells, CD4+ central memory (CM) T-cells and CD4+ RTE was elevated after MICT compared to HIIT. Changes in [Formula: see text] after training, regardless of exercise prescription, was inversely related to the change in highly differentiated CD8+ EMRA T-cells and positively related to changes in β2-adrenergic receptor (β2-AR) expression on CM CD4+ and CM CD8+ T-cells. Plasma myokine levels did not change significantly among the groups after training, but individual changes in IL-7 were positively related to changes in the number of β2-AR expressing CD4 naïve T cells in both exercise groups but not controls. Further, CD4 T-cells and CD4 naive T-cells were negatively related to changes in IL-6 and osteonectin after HIIT but not MICT, whereas CD8 EMRA T-cells were inversely related to changes in IL-15 after MICT but not HIIT.Aerobic exercise training alters the frequency of peripheral T-cells associated with immunosenescence in middle aged/older women at high risk of breast cancer, with HIIT (pro-senescent) and MICT (anti-senescent) evoking divergent effects. Identifying the underlying mechanisms and establishing whether exercise-induced changes in peripheral T-cell numbers can alter the risk of developing breast cancer warrants investigation.
- Published
- 2021
29. MiR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2
- Author
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Wanting Tina Ho, Linda Fabris, Elizabeth Torres-Claudio, Roxana S. Redis, Xinna Zhang, Srdan Verstovsek, Cristina Ivan, Taghi Manshouri, Pranav Narayanan, Nayra Soares do Amaral, Masayoshi Shimizu, Zhizhuang Joe Zhao, Geoffrey Bartholomeusz, Cristina Perez, Enrique Fuentes-Mattei, Leonard Golfman, Pilar Mur, Adriana Badillo-Perez, Mihnea P. Dragomir, Erik Knutsen, Patrick A. Zweidler-McKay, Zeev Estrov, Andreia M. Silva, Marcos Roberto Estecio, Ioana Berindan-Neagoe, Ciprian Tomuleasa, Diana Gulei, Recep Bayraktar, Wanke Zhao, George A. Calin, and Instituto de Investigação e Inovação em Saúde
- Subjects
0301 basic medicine ,Ruxolitinib ,DNA-Binding Proteins / genetics ,Myelofibrosis ,Epigenesis, Genetic ,DNA-Binding Proteins / drug effects ,Mixed Function Oxygenases ,Histones ,Mice ,0302 clinical medicine ,Janus Kinase Inhibitors / therapeutic use ,Janus Kinases / metabolism ,Primary Myelofibrosis / genetics ,Hematology ,Primary Myelofibrosis / drug therapy ,General Medicine ,MicroRNAs / metabolism ,Extramedullary hematopoiesis ,DNA-Binding Proteins ,MicroRNAs / pharmacology ,030220 oncology & carcinogenesis ,Cytokines ,medicine.drug ,Research Article ,STAT3 Transcription Factor ,medicine.medical_specialty ,Proto-Oncogene Proteins / drug effects ,Dioxygenases ,03 medical and health sciences ,Downregulation and upregulation ,Internal medicine ,Proto-Oncogene Proteins ,Hematopoesi ,Nitriles ,medicine ,Janus Kinase Inhibitors ,Animals ,Humans ,Epigenetics ,Proto-Oncogene Proteins / genetics ,Protein Kinase Inhibitors ,Myeloproliferative neoplasm ,Janus Kinases ,Cytopenia ,Myeloproliferative Disorders ,Mielofibrosi ,business.industry ,Protein Kinase Inhibitors / pharmacology ,Pyrazoles / therapeutic use ,medicine.disease ,United States ,Hematopoiesis ,MicroRNAs ,Disease Models, Animal ,Epigenesis, Genetic / drug effects ,030104 developmental biology ,Cytokines / metabolism ,MicroRNAs / genetics ,Pyrimidines ,Primary Myelofibrosis ,Mutation ,Cancer research ,Pyrazoles ,business ,Transcriptome - Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAKV617F mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK2V617F inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-543 was significantly upregulated in nonresponders. We validated these findings by reverse transcription–quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2V617F mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options The work in GAC’s laboratory was partly supported by NIH/National Center for Advancing Translational Sciences grant UH3TR00943-01, the NIH/National Cancer Institute (NCI) grant 1 R01 CA182905-01, U54 grant UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, Team Department of Defense grant CA160445P1, a Ladies Leukemia League grant, a Chronic Lymphocytic Leukemia Moonshot Flagship project, a Sister Institution Network Fund 2017 grant, and the Estate of C. G. Johnson, Jr. EFM was supported in part by award number P50 CA140388 from the NCI and by the NIH Clinical Research Loan Repayment Program. AMS was supported by Fundação para a Ciência e a Tecnologia through fellowship SFRH/BD/85968/2012. ZJZ’s work was supported by grants from the MPN Foundation and the Oklahoma Center for the Advancement of Science and Technology. DG, MPD, and IBN were supported in part by a Programul Opera¿ional Competitivitate grant nr35/01.09.2016, ID 37_796, titled “Clinical and economical impact of personalized targeted anti-mi-croRNA therapies in reconverting lung cancer chemoresistance” (CANTEMIR). NSDA was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo, BEPE 2016/09349-4.
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- 2020
30. Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer
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Mihnea P. Dragomir, Menashe Bar-Eli, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Ayumu Taguchi, Tina Catela Ivkovic, Diana L. Bonilla, Zhihui Wang, Xinna Zhang, Isidore Rigoutsos, Giovanni Lanza, Erik Knutsen, Hiroyuki Katayama, Cristina Ivan, Sanja Kapitanović, Emine Bayraktar, Martin Pichler, Anh M. Tran, Li Huang, Recep Bayraktar, Rajat Bhattacharya, Ondrej Slaby, Yoshinaga Okugawa, Bozo Loncar, George A. Calin, Simone Anfossi, Ajay Goel, Paola Amero, William Ruixian He, Samir M. Hanash, Sang Kil Lee, Guoliang Huang, Roberta Gafà, Su Youn Nam, Gabriel Lopez-Berestein, Vittorio Cristini, Hui Ling, Christiane Klec, and Petra Vychytilova-Faltejskova
- Subjects
0301 basic medicine ,Genetic Markers ,STAT3 Transcription Factor ,Vascular Endothelial Growth Factor A ,Small interfering RNA ,Colorectal cancer ,Angiogenesis ,Carcinogenesis ,oncogenes ,Genetic enhancement ,colorectal cancer ,Biology ,Article ,NO ,angiogenesis ,gene therapy ,molecular genetics ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Drug Discovery ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Cell Proliferation ,Neovascularization, Pathologic ,Gastroenterology ,Genetic Therapy ,medicine.disease ,Long non-coding RNA ,3. Good health ,Pharmacogenomic Testing ,Gene Expression Regulation, Neoplastic ,Vascular endothelial growth factor A ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,RNA, Long Noncoding ,Colorectal Neoplasms ,angiogenesis, colorectal cancer, gene therapy, molecular genetics, oncogenes - Abstract
ObjectiveTo investigate the function of a novel primate-specific long non-coding RNA (lncRNA), named FLANC, based on its genomic location (co-localised with a pyknon motif), and to characterise its potential as a biomarker and therapeutic target.DesignFLANC expression was analysed in 349 tumours from four cohorts and correlated to clinical data. In a series of multiple in vitro and in vivo models and molecular analyses, we characterised the fundamental biological roles of this lncRNA. We further explored the therapeutic potential of targeting FLANC in a mouse model of colorectal cancer (CRC) metastases.ResultsFLANC, a primate-specific lncRNA feebly expressed in normal colon cells, was significantly upregulated in cancer cells compared with normal colon samples in two independent cohorts. High levels of FLANC were associated with poor survival in two additional independent CRC patient cohorts. Both in vitro and in vivo experiments demonstrated that the modulation of FLANC expression influenced cellular growth, apoptosis, migration, angiogenesis and metastases formation ability of CRC cells. In vivo pharmacological targeting of FLANC by administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with a specific small interfering RNA, induced significant decrease in metastases, without evident tissue toxicity or pro-inflammatory effects. Mechanistically, FLANC upregulated and prolonged the half-life of phosphorylated STAT3, inducing the overexpression of VEGFA, a key regulator of angiogenesis.ConclusionsBased on our findings, we discovered, FLANC as a novel primate-specific lncRNA that is highly upregulated in CRC cells and regulates metastases formation. Targeting primate-specific transcripts such as FLANC may represent a novel and low toxic therapeutic strategy for the treatment of patients.
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- 2020
31. Diabetes mellitus type 2 drives metabolic reprogramming to promote pancreatic cancer growth
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Xiangqi Meng, Hyun Ho Choi, Enrique Fuentes-Mattei, Guermarie Velazquez-Torres, Sai Ching J. Yeung, and Mong-Hong Lee
- Subjects
business.industry ,type 2 diabetes mellitus ,pancreatic cancer ,Gastroenterology ,Type 2 Diabetes Mellitus ,Cancer ,cancer metabolism ,Original Articles ,medicine.disease ,Metformin ,Pancreatic tumor ,Tumor progression ,Pancreatic cancer ,medicine ,Cancer research ,Rosiglitazone ,business ,PI3K/AKT/mTOR pathway ,medicine.drug ,AcademicSubjects/MED00260 - Abstract
BackgroundDiabetes mellitus type 2 (DM2) is a modifiable risk factor associated with pancreatic carcinogenesis and tumor progression on the basis of epidemiology studies, but the biological mechanisms are not completely understood. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic phenomena. Our hypothesis is that DM2 accelerates pancreatic cancer growth and that metformin treatment has a beneficial impact.MethodsTo determine the effect of glucose and insulin in pancreatic cancer proliferation, we used conditioned media to mimic DM2 conditions. Also, we studied the effect of anti-diabetic drugs, particularly metformin and rosiglitazone on pancreatic cancer growth. We established orthotopic/syngeneic (Leprdb/db) mouse cancer models to evaluate the effect of diabetes on pancreatic tumor growth and aggressiveness.ResultsOur results showed that diabetes promotes pancreatic tumor growth. Furthermore, enhanced tumor growth and aggressiveness (e.g. epithelial–mesenchymal transition) can be explained by functional transcriptomic and metabolomic changes in the mice with diabetes, namely via activation of the AKT/mTOR pathway. Metformin treatment suppressed the diabetes-induced AKT/mTOR pathway activation and tumor growth. The metabolic profile determined by mass spectrum showed important changes of metabolites in the pancreatic cancer derived from diabetic mice treated with metformin.ConclusionsDiabetes mellitus type 2 has critical effects that promote pancreatic cancer progression via transcriptomic and metabolomic changes. Our animal models provide strong evidence for the causal relationship between diabetes and accelerated pancreatic cancers. This study sheds a new insight into the effects of metformin and its potential as part of therapeutic interventions for pancreatic cancer in diabetic patients.
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- 2019
32. Plasma Viral miRNAs Indicate a High Prevalence of Occult Viral Infections
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Stefan Tudor, Meng Chen, Jeffrey J. Tarrand, Dana Elena Giza, Cristina Ivan, Maria Ciccone, Enrique Fuentes-Mattei, Michael J. Keating, Xinna Zhang, Osman Aykan Kargin, Florea Lupu, Nayra Soares do Amaral, George A. Calin, Catalin Vasilescu, Alessandra Ferrajoli, Masayoshi Shimizu, Pilar Mur, Sai Ching J. Yeung, John T. Manning, and Halk Sağlığı
- Subjects
0301 basic medicine ,Micro RNAs ,Chronic lymphocytic leukemia ,viruses ,lcsh:Medicine ,Antibodies, Viral ,medicine.disease_cause ,Immunoglobulin G ,Serology ,Cohort Studies ,Leukocyte Count ,HHV4 ,Prevalence ,HHV8 ,In Situ Hybridization ,lcsh:R5-920 ,virus diseases ,General Medicine ,Viral Load ,3. Good health ,Real-time polymerase chain reaction ,Virus Diseases ,Herpesvirus 8, Human ,RNA, Viral ,lcsh:Medicine (General) ,Viral load ,Research Paper ,Herpesviruses ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,Enzyme-Linked Immunosorbent Assay ,KSHV ,Biology ,Real-Time Polymerase Chain Reaction ,Viral miRNAs ,General Biochemistry, Genetics and Molecular Biology ,Virus ,03 medical and health sciences ,Antigen ,EBV ,medicine ,Humans ,Lymphocyte Count ,ComputingMethodologies_COMPUTERGRAPHICS ,Infection prevalence ,lcsh:R ,Reproducibility of Results ,Herpesvirus ,medicine.disease ,Epstein–Barr virus ,Virology ,MicroRNAs ,030104 developmental biology ,Immunology ,biology.protein - Abstract
Graphical abstract Image 1, Prevalence of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) varies greatly in different populations. We hypothesized that the actual prevalence of KSHV/HHV8 infection in humans is underestimated by the currently available serological tests. We analyzed four independent patient cohorts with post-surgical or post-chemotherapy sepsis, chronic lymphocytic leukemia and post-surgical patients with abdominal surgical interventions. Levels of specific KSHV-encoded miRNAs were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and KSHV/HHV-8 IgG were measured by immunoassay. We also measured specific miRNAs from Epstein Barr Virus (EBV), a virus closely related to KSHV/HHV-8, and determined the EBV serological status by ELISA for Epstein-Barr nuclear antigen 1 (EBNA-1) IgG. Finally, we identified the viral miRNAs by in situ hybridization (ISH) in bone marrow cells. In training/validation settings using independent multi-institutional cohorts of 300 plasma samples, we identified in 78.50% of the samples detectable expression of at least one of the three tested KSHV-miRNAs by RT-qPCR, while only 27.57% of samples were found to be seropositive for KSHV/HHV-8 IgG (P, Highlights • There is no agreement on a standard assay to detect the true prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) infection. • Measurement of the viral miRNAs in plasma by RT-qPCR allows a direct and accurate assessment of viral infection. • Measurement of the viral miRNAs in plasma by RT-qPCR shows prevalence of KSHV infection in immuno-depressed patients. • Measurement of plasma viral miRNAs for viral infection assessment has the potential to become a “gold” standard method in the clinical practice. Chronic viral infections represent risk factors for diseases and development of infection-related complications. There is no agreement on a standard assay to detect the true prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) infection. The current method used in the clinical practice (ELISA-test) identifies a great geographic variation in KSHV seroprevalence and may underestimate the true-prevalence of KSHV infection. Here we showed that detection of plasma viral miRNAs levels for the identification of viral infection (e.g., KSHV, Epstein-Bar virus or EBV) is more accurate than the current method for detection of virus-derived antigen, especially in patients with low number of immune cells.
- Published
- 2017
33. Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers
- Author
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Alessandra Ferrajoli, Katrien Van Roosbroeck, Massimo Negrini, Ioana Berindan-Neagoe, Dino Amadori, Hagop M. Kantarjian, Peter P. Ruvolo, Manuela Ferracin, Roxana S. Redis, Lianchun Xiao, Xuemei Wang, George A. Calin, Simona Rossi, Ivan Vannini, Antonino Neri, Robert Z. Orlowski, Steliana Calin, Vivian Ruvolo, Fortunato Morabito, Vianey Gonzalez-Villasana, Tara M. Lichtenberg, Gabriel Lopez-Berestein, Lynne V. Abruzzo, Ramana V. Davuluri, Michael J. Keating, Anil K. Sood, Rajesha Rupaimoole, M. James You, William Plunkett, Francesca Fanini, Chad V. Pecot, Tetsuro Setoyama, Xinna Zhang, Ignacio I. Wistuba, Muller Fabbri, Lucilla D’Abundo, Milena S. Nicoloso, Cristina Ivan, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Van Roosbroeck, Katrien, Fanini, Francesca, Setoyama, Tetsuro, Ivan, Cristina, Rodriguez-Aguayo, Cristian, Fuentes-Mattei, Enrique, Xiao, Lianchun, Vannini, Ivan, Redis, Roxana S., D'Abundo, Lucilla, Zhang, Xinna, Nicoloso, Milena S., Rossi, Simona, Gonzalez-Villasana, Vianey, Rupaimoole, Rajesha, Ferracin, Manuela, Morabito, Fortunato, Neri, Antonino, Ruvolo, Peter P., Ruvolo, Vivian R., Pecot, Chad V., Amadori, Dino, Abruzzo, Lynne, Calin, Steliana, Wang, Xuemei, You, M. Jame, Ferrajoli, Alessandra, Orlowski, Robert, Plunkett, William, Lichtenberg, Tara M., Davuluri, Ramana V., Berindan-Neagoe, Ioana, Negrini, Massimo, Wistuba, Ignacio I., Kantarjian, Hagop M., Sood, Anil K., Lopez-Berestein, Gabriel, Keating, Michael J., Fabbri, Muller, and Calin, George A.
- Subjects
0301 basic medicine ,Cancer Research ,therapy resistance ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,chemotherapy, therapy resistance, miR-155 ,Socio-culturale ,Drug resistance ,Gene mutation ,chemotherapy ,miR-155 ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,medicine ,Doxorubicin ,Lung cancer ,Chemotherapy ,microRNA ,business.industry ,Cancer ,medicine.disease ,3. Good health ,lung cancer ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,business ,medicine.drug - Abstract
Purpose: The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design: We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia. Results: We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions: Our findings support the existence of an miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death. Clin Cancer Res; 23(11); 2891–904. ©2016 AACR.
- Published
- 2017
34. Interplay between epigenetic abnormalities and deregulated expression of microRNAs in cancer
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Sundas Fayyaz, Matthew Goblirsch, Enrique Fuentes-Mattei, Ammad Ahmad Farooqi, Priyank Raj, George A. Calin, and Palmiro Poltronieri
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Epigenomics ,0301 basic medicine ,Cancer Research ,RNA, Untranslated ,Carcinogenesis ,Biology ,epigenetic regulation ,Epigenesis, Genetic ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Mirna expression ,law ,Neoplasms ,microRNA ,Gene expression ,medicine ,Animals ,Humans ,Epigenetics ,Cancer ,Oncogenes ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Expression (architecture) ,030220 oncology & carcinogenesis ,Cancer cell ,miRNAs ,Cancer research ,Suppressor ,non-coding RNAs - Abstract
It is becoming apparent that spatio-temporally controlled patterns of DNA methylation and histone modifications ensure that each cell in the body gets differentiated into its required cell fate during normal development. It is a well-coordinated and tightly synchronized unidirectional process that involves stepwise gene silencing associated with developmental stages, as well as the activation of tissue-specific programming of genes. However, dysregulations in epigenetic modifications can severely disturb normal developmental pathways, thus leading to cancer development and progression. Furthermore, increasing lists of research publications are examining tumor suppressor and oncogenic miRNAs, which are epigenetically modified in different cancers, as well as upregulated long non-coding RNAs acting as miRNA sponges.
- Published
- 2019
35. S-MiRAGE: A Quantitative, Secreted RNA-Based Reporter of Gene Expression and Cell Persistence
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Enrique Fuentes-Mattei, Maria Inês Almeida, Aryeh Warmflash, William N. Feist, Jean J. Kim, Kinshuk Mitra, George A. Calin, and Simone Anfossi
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Cell ,Biomedical Engineering ,Gene Expression ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Persistence (computer science) ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,Genes, Reporter ,Gene expression ,medicine ,Animals ,Humans ,Tumor growth ,030304 developmental biology ,0303 health sciences ,Reverse Transcriptase Polymerase Chain Reaction ,RNA ,Cell Differentiation ,General Medicine ,Cellular Reprogramming ,Embryonic stem cell ,In vitro ,Cell biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Research studies - Abstract
Nondestructive measurements of cell persistence and gene expression are crucial for longitudinal research studies and for prognostic assessment of cell therapies. Here we describe S-MiRAGE, a platform that utilizes small secreted RNA molecules as sensitive and quantitatively accurate reporters of cellular processes. S-MiRAGE allows cellular numbers or gene expression to be measured from culture media or from biofluids. We show that multiple S-MiRAGE reporters can be multiplexed, and demonstrate the utility of S-MiRAGE by monitoring the differentiation status of human embryonic stem cells in vitro and tumor growth in a mouse model in vivo.
- Published
- 2018
36. Gene Expression Profile of the Clinically Aggressive Micropapillary Variant of Bladder Cancer
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Shizhen Zhang, David J. McConkey, Woonyoung Choi, Weronika Wronowska, Vipulkumar Dadhania, Tadeusz Majewski, Maciej Sykulski, Enrique Fuentes-Mattei, Ashish M. Kamat, Colin P.N. Dinney, Li Zhang, Arlene O. Siefker-Radtke, Yan Wang, Keith A. Baggerly, John N. Weinstein, Bogdan Czerniak, Charles C. Guo, Jolanta Bondaruk, and Anna Gambin
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Bladder cancer ,Tissue microarray ,business.industry ,Proportional hazards model ,Urology ,medicine.disease ,Metastasis ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,microRNA ,Cancer research ,medicine ,Immunohistochemistry ,business ,Survival rate - Abstract
Background Progression of conventional urothelial carcinoma of the bladder to a tumor with unique microscopic features referred to as micropapillary carcinoma is coupled with aggressive clinical behavior signified by a high propensity for metastasis to regional lymph nodes and distant organs resulting in shorter survival. Objective To analyze the expression profile of micropapillary cancer and define its molecular features relevant to clinical behavior. Design, setting, and participants We retrospectively identified 43 patients with micropapillary bladder cancers and a reference set of 89 patients with conventional urothelial carcinomas and performed whole-genome expression messenger RNA profiling. Outcome measurements and statistical analysis The tumors were segregated into distinct groups according to hierarchical clustering analyses. They were also classified according to luminal, p53-like, and basal categories using a previously described algorithm. We applied Ingenuity Pathway Analysis software (Qiagen, Redwood City, CA, USA) and gene set enrichment analysis for pathway analyses. Cox proportional hazards models and Kaplan-Meier methods were used to assess the relationship between survival and molecular subtypes. The expression profile of micropapillary cancer was validated for selected markers by immunohistochemistry on parallel tissue microarrays. Results and limitations We show that the striking features of micropapillary cancer are downregulation of miR-296 and activation of chromatin-remodeling complex RUVBL1. In contrast to conventional urothelial carcinomas that based on their expression can be equally divided into luminal and basal subtypes, micropapillary cancer is almost exclusively luminal, displaying enrichment of active peroxisome proliferator-activated receptor γ and suppression of p63 target genes. As with conventional luminal urothelial carcinomas, a subset of micropapillary cancers exhibit activation of wild-type p53 downstream genes and represent the most aggressive molecular subtype of the disease with the shortest survival. The involvement of miR-296 and RUVBL1 in the development of micropapillary bladder cancer was identified by the analyses of correlative associations of genome expression profiles and requires mechanistic validation. Conclusions Micropapillary cancer evolves through the luminal pathway and is characterized by the activation of miR-296 and RUVBL1 target genes. Patient summary Our observations have important implications for prognosis and for possible future development of more effective therapies for micropapillary bladder cancer.
- Published
- 2016
37. OncomiR-10b hijacks the small molecule inhibitor linifanib in human cancers
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Hui Ling, Ana Carolina P. Mafra, Calin Dan Dumitru, Nazila Nouraee, Michael Lehrer, Maria del Mar Monroig-Bosque, Valentina Pileczki, Roxana S. Redis, Edward P. Nikonowicz, Eun-Jung Jung, Xiao Fu, Enrique Fuentes-Mattei, Cristina Ivan, Rahul Nagvekar, Carlos A Rivera, Xinna Zhang, Shuxing Zhang, Beibei Huang, Maitri Y. Shah, Ioana Berindan-Neagoe, Paloma del C. Monroig-Bosque, George A. Calin, Lu Chen, and Alexandra Iulia Irimie
- Subjects
Male ,0301 basic medicine ,Indazoles ,lcsh:Medicine ,Breast Neoplasms ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,microRNA ,Humans ,Medicine ,RNA, Neoplasm ,Neoplasm Metastasis ,lcsh:Science ,Multidisciplinary ,business.industry ,Kinase ,Phenylurea Compounds ,lcsh:R ,Liver Neoplasms ,Cancer ,Hep G2 Cells ,Oncomir ,medicine.disease ,Small molecule ,3. Good health ,MicroRNAs ,Linifanib ,030104 developmental biology ,chemistry ,Drug development ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Cancer research ,lcsh:Q ,Female ,business ,Tyrosine kinase - Abstract
The pervasive role of microRNAs (miRNAs) in cancer pathobiology drives the introduction of new drug development approaches such as miRNA inhibition. In order to advance miRNA-therapeutics, meticulous screening strategies addressing specific tumor targets are needed. Small molecule inhibitors represent an attractive goal for these strategies. In this study, we devised a strategy to screen for small molecule inhibitors that specifically inhibit, directly or indirectly, miR-10b (SMIRs) which is overexpressed in metastatic tumors. We found that the multi-tyrosine kinase inhibitor linifanib could significantly inhibit miR-10b and reverse its oncogenic function in breast cancer and liver cancer both in vitro and in vivo. In addition, we showed that the efficacy of linifanib to inhibit tyrosine kinases was reduced by high miR-10b levels. When the level of miR-10b is high, it can “hijack” the linifanib and reduce its kinase inhibitory effects in cancer resulting in reduced anti-tumor efficacy. In conclusion, our study describes an effective strategy to screen for small molecule inhibitors of miRNAs. We further propose that miR-10b expression levels, due to the newly described “hijacking” effect, may be used as a biomarker to select patients for linifanib treatment.
- Published
- 2018
38. Implications of dietary ω‑3 and ω‑6 polyunsaturated fatty acids in breast cancer (Review)
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Cornelia Braicu, Roxana Cojocneanu Petric, Enrique Fuentes‑Mattei, Lajos Raduly, Ancuta Jurj, Claudia Gherman, Oana Zanoaga, Ioana Berindan Neagoe, and Oscar Wu
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,microRNA expression ,signal transduction pathways ,Review ,Biology ,medicine.disease_cause ,ω-3 and ω-6 polyunsaturated fatty acids ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Breast cancer ,Immunology and Microbiology (miscellaneous) ,Internal medicine ,microRNA ,medicine ,chemistry.chemical_classification ,Oncogene ,Cancer ,General Medicine ,medicine.disease ,Molecular medicine ,diet and health effects ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Signal transduction ,Carcinogenesis ,Polyunsaturated fatty acid - Abstract
Breast cancer represents one of the most common forms of cancer in women worldwide, with an increase in the number of newly diagnosed patients in the last decade. The role of fatty acids, particularly of a diet rich in ω-3 and ω-6 polyunsaturated fatty acids (PUFAs), in breast cancer development is not fully understood and remains controversial due to their complex mechanism of action. However, a large number of animal models and cell culture studies have demonstrated that high levels of ω-3 PUFAs have an inhibitory role in the development and progression of breast cancer, compared to ω-6 PUFAs. The present review focused on recent studies regarding the correlation between dietary PUFAs and breast cancer development, and aimed to emphasize the main molecular mechanisms involved in the modification of cell membrane structure and function, modulation of signal transduction pathways, gene expression regulation, and antiangiogenic and antimetastatic effects. Furthermore, the anticancer role of ω-3 PUFAs through the modulation of microRNA expression levels was also reviewed.
- Published
- 2017
39. Regulation of hnRNPA1 by microRNAs controls the miR-18a–K-RAS axis in chemotherapy-resistant ovarian cancer
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Anil K. Sood, Mohammed H. Rashed, George A. Calin, Emine Bayraktar, Cristina Ivan, Gabriel Lopez-Berestein, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Roxana S. Redis, Rahul Mitra, Maria Inês Almeida, Bulent Ozpolat, Paloma Monroig, and Arturo Chavez-Reyes
- Subjects
0301 basic medicine ,chemotherapy resistance ,hnRNPA1 ,RNA-binding proteins ,RNA-binding protein ,Biology ,medicine.disease_cause ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,RNA interference ,microRNA ,Genetics ,medicine ,Molecular Biology ,Oncogene ,RNA ,Cell Biology ,medicine.disease ,microRNAs ,ovarian cancer ,030104 developmental biology ,Docetaxel ,030220 oncology & carcinogenesis ,Cancer research ,KRAS ,Ovarian cancer ,K-RAS ,medicine.drug - Abstract
The regulation of microRNA (miRNA) biogenesis, function and degradation involves a range of mechanisms, including interactions with RNA-binding proteins. The potential contribution of regulatory miRNAs to the expression of these RNA interactor proteins that could control other miRNAs expression is still unclear. Here we demonstrate a regulatory circuit involving oncogenic and tumor-suppressor miRNAs and an RNA-binding protein in a chemotherapy-resistant ovarian cancer model. We identified and characterized miR-15a-5p and miR-25-3p as negative regulators of hnRNPA1 expression, which is required for the processing of miR-18a-3p, an inhibitor of the K-RAS oncogene. The inhibition of miR-25-3p and miR-15a-5p decreased the proliferation, motility, invasiveness and angiogenic potential and increased apoptosis when combined with docetaxel. Alteration of this regulatory circuit causes poor overall survival outcome in ovarian cancer patients. These results highlight miR-15a-5p and miR-25-3p as key regulators of miR-18a-3p expression and its downstream target K-RAS, through direct modulation of hnRNPA1 expression. Our results demonstrate the therapeutic potential of inhibiting miR-25-3p and miR-15a-5p and the use of miR-18a-3p/KRAS ratio as a prominent outcome prognostic factor.
- Published
- 2017
40. A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression
- Author
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Cristina Ivan, A. Gordon Robertson, Victoria K. Xie, Gabriel Lopez-Berenstein, Guermarie Velazquez-Torres, Li Huang, Einav Shoshan, Anil K. Sood, Harrison Paret, George A. Calin, Menashe Bar-Eli, Sun Jin Kim, Steven J.M. Jones, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, and Denise Brooks
- Subjects
0301 basic medicine ,Adenosine ,Skin Neoplasms ,Science ,General Physics and Astronomy ,Mice, Nude ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Metastasis ,Epigenesis, Genetic ,03 medical and health sciences ,Mice ,Cell Line, Tumor ,microRNA ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Cancer epigenetics ,Neoplasm Metastasis ,lcsh:Science ,3' Untranslated Regions ,Melanoma ,Cell Proliferation ,Regulation of gene expression ,Multidisciplinary ,Oncogene ,Three prime untranslated region ,Microfilament Proteins ,General Chemistry ,Oncogenes ,medicine.disease ,Inosine ,3. Good health ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,RNA editing ,Cancer research ,Disease Progression ,lcsh:Q ,Female ,RNA Editing - Abstract
Previously we have reported that metastatic melanoma cell lines and tumor specimens have reduced expression of ADAR1 and consequently are impaired in their ability to perform A-to-I microRNA (miRNA) editing. The effects of A-to-I miRNAs editing on melanoma growth and metastasis are yet to be determined. Here we report that miR-378a–3p is undergoing A-to-I editing only in the non-metastatic but not in metastatic melanoma cells. The function of the edited form is different from its wild-type counterpart. The edited form of miR-378a-3p preferentially binds to the 3′-UTR of the PARVA oncogene and inhibits its expression, thus preventing the progression of melanoma towards the malignant phenotype. Indeed, edited miR-378a-3p but not its WT form inhibits melanoma metastasis in vivo. These results further emphasize the role of RNA editing in melanoma progression., In melanoma, reduced ADAR1 impairs A-to-I microRNA editing. Here, the authors show that miR-378a-3p undergoes this editing in non-metastatic cells and the edited form of miR-378a-3p binds to the PARVA oncogene, inhibiting its expression and preventing melanoma progression and metastasis.
- Published
- 2017
41. Regulation of hnRNPA1 by microRNAs controls the miR-18a–K-RAS axis in chemotherapy-resistant ovarian cancer
- Author
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Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Anil K. Sood, Gabriel Lopez-Berestein, Cristina Ivan, Rahul Mitra, Emine Bayraktar, Bulent Ozpolat, and George A. Calin
- Subjects
Oncology ,business.industry ,microRNA ,medicine ,Cancer research ,Chemotherapy resistant ,Hematology ,Ovarian cancer ,medicine.disease ,business - Published
- 2018
42. Cellular and viral microRNAs in sepsis: mechanisms of action and clinical applications
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George A. Calin, Muller Fabbri, Marc D. Bullock, Florea Lupu, Stefan Tudor, Matthew Goblirsch, Catalin Vasilescu, Sai Ching J. Yeung, Dana Elena Giza, and Enrique Fuentes-Mattei
- Subjects
0301 basic medicine ,Review ,Biology ,Bioinformatics ,medicine.disease_cause ,Regulatory molecules ,Sepsis ,03 medical and health sciences ,Immune system ,Antibiotic therapy ,microRNA ,medicine ,Animals ,Humans ,Molecular Biology ,Clinical Trials as Topic ,Septic shock ,Molecular Mimicry ,Cell Biology ,medicine.disease ,Molecular mimicry ,MicroRNAs ,030104 developmental biology ,Immunology ,Viruses ,Biomarker (medicine) ,Biomarkers - Abstract
Regardless of its etiology, once septic shock is established, survival rates drop by 7.6% for every hour antibiotic therapy is delayed. The early identification of the cause of infection and prognostic stratification of patients with sepsis are therefore important clinical priorities. Biomarkers are potentially valuable clinical tools in this context, but to date, no single biomarker has been shown to perform adequately. Hence, in an effort to discover novel diagnostic and prognostic markers in sepsis, new genomic approaches have been employed. As a result, a number of small regulatory molecules called microRNAs (miRNAs) have been identified as key regulators of the inflammatory response. Although deregulated miRNA expression is increasingly well described, the pathophysiological roles of these molecules in sepsis have yet to be fully defined. Moreover, non-human miRNAs, including two Kaposi Sarcoma herpesvirus-encoded miRNAs, are implicated in sepsis and may drive enhanced secretion of pro-inflammatory and anti-inflammatory cytokines exacerbating sepsis. A better understanding of the mechanism of action of both cellular and viral miRNAs, and their interactions with immune and inflammatory cascades, may therefore identify novel therapeutic targets in sepsis and make biomarker-guided therapy a realistic prospect.
- Published
- 2016
43. Obesity-associated NLRC4 inflammasome activation drives breast cancer progression
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Kathleen R. Markan, Suzanne L. Cassel, Fayyaz S. Sutterwala, Qing Xie, Wei Li, Nicholas Borcherding, Weizhou Zhang, Sai Ching J. Yeung, Yinghong Liu, Fang Yuan, Enrique Fuentes-Mattei, Ryan Kolb, C. Michael Knudson, Lesley G. Ellies, Matthew J. Potthoff, Mong Hong Lee, Ann M. Janowski, and Liem Phan
- Subjects
Vascular Endothelial Growth Factor A ,0301 basic medicine ,Inflammasomes ,Angiogenesis ,Interleukin-1beta ,General Physics and Astronomy ,Inbred C57BL ,Cardiovascular ,Mice ,NLRC4 ,2.1 Biological and endogenous factors ,Myeloid Cells ,Lymphocytes ,Breast ,Aetiology ,skin and connective tissue diseases ,Cancer ,Tumor ,Multidisciplinary ,Interleukin ,Inflammasome ,3. Good health ,Metformin ,Vascular endothelial growth factor A ,5.1 Pharmaceuticals ,Disease Progression ,Female ,Development of treatments and therapeutic interventions ,Signal transduction ,Signal Transduction ,medicine.drug ,Science ,Breast Neoplasms ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Experimental ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,Breast cancer ,Cell Line, Tumor ,Breast Cancer ,medicine ,Animals ,Humans ,Tumor-Infiltrating ,Obesity ,Nutrition ,business.industry ,Mammary Neoplasms ,Calcium-Binding Proteins ,Mammary Neoplasms, Experimental ,General Chemistry ,medicine.disease ,CARD Signaling Adaptor Proteins ,Mice, Inbred C57BL ,030104 developmental biology ,Cancer research ,Apoptosis Regulatory Proteins ,business ,Neoplasm Transplantation - Abstract
Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1β, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Further studies show that treatment of mice with metformin inhibits obesity-associated tumour progression associated with a marked decrease in angiogenesis. This report provides a causal mechanism by which obesity promotes breast cancer progression and lays out a foundation to block NLRC4 inflammasome activation or IL-1β signalling transduction that may be useful for the treatment of obese cancer patients., Obesity is associated with higher breast cancer risk and poor prognosis. Here, the authors show that obesity promotes breast cancer through the recruitment of macrophages with activated NLRC4 inflammasome, which activate IL-1β production, resulting in VEGFA expression in adipocytes and angiogenesis.
- Published
- 2016
44. Differential impact of structurally different anti-diabetic drugs on proliferation and chemosensitivity of acute lymphoblastic leukemia cells
- Author
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Juliana Benito, Yanli Jin, Enrique Fuentes-Mattei, Sai Ching J. Yeung, Michael Andreeff, Guermarie Velazquez-Tores, Mong Hong Lee, Jingxuan Pan, Chun Chen, and Marina Konopleva
- Subjects
Male ,Adolescent ,endocrine system diseases ,Anthracycline ,Daunorubicin ,medicine.medical_treatment ,Insulin Glargine ,Apoptosis ,Biology ,Pharmacology ,Rosiglitazone ,Insulin aspart ,Cell Line, Tumor ,Report ,medicine ,Humans ,Hypoglycemic Agents ,Insulin ,Child ,Molecular Biology ,Protein kinase B ,Insulin Aspart ,Cell Proliferation ,Insulin glargine ,TOR Serine-Threonine Kinases ,nutritional and metabolic diseases ,Cell Biology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Metformin ,Insulin, Long-Acting ,Child, Preschool ,Female ,Thiazolidinediones ,Proto-Oncogene Proteins c-akt ,Developmental Biology ,medicine.drug - Abstract
Hyperglycemia during hyper-CVAD chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL) (Cancer 2004; 100: 1179-85). The optimal clinical strategy to manage hyperglycemia during hyper-CVAD is unclear. To examine whether anti-diabetic pharmacotherapy can influence chemosensitivity of ALL cells, we examined the impacts of different anti-diabetic agents on ALL cell lines and patient samples. Pharmacologically achievable concentrations of insulin, aspart and glargine significantly increased the number of ALL cells, and aspart and glargine did so at lower concentrations than human insulin. In contrast, metformin and rosiglitazone significantly decreased the cell number. Human insulin and analogs activated AKT/mTOR signaling and stimulated ALL cell proliferation (as measured by flow cytometric methods), but metformin and rosiglitazone blocked AKT/mTOR signaling and inhibited proliferation. Metformin 500 μM and rosiglitazone 10 μM were found to sensitize Reh cells to daunorubicin, while aspart, glargine and human insulin (all at 1.25 mIU/L) enhanced chemoresistance. Metformin and rosiglitazone enhanced daunorubicin-induced apoptosis, while insulin, aspart and glargine antagonized daunorubicin-induced apoptosis. In addition, metformin increased etoposide-induced and L-asparaginase-induced apoptosis; rosiglitazone increased etoposide-induced and vincristine-induced apoptosis. In conclusion, our results suggest that use of insulins to control hyperglycemia in ALL patients may contribute to anthracycline chemoresistance, while metformin and thiazolidinediones may improve chemosensitivity to anthracycline as well as other chemotherapy drugs through their different impacts on AKT/mTOR signaling in leukemic cells. Our data suggest that the choice of anti-diabetic pharmacotherapy during chemotherapy may influence clinical outcomes in ALL.
- Published
- 2012
45. Abstract LB-384: A-to-I miR-378a-3p editing prevents melanoma progression via regulation ofPARVA expression
- Author
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Guermarie Velazquez-Torres, Einav Shoshan, Menashe Bar-Eli, Enrique Fuentes-Mattei, and Cristina Ivan
- Subjects
Cancer Research ,Oncology ,Expression (architecture) ,Melanoma ,medicine ,Cancer research ,Biology ,medicine.disease - Abstract
Although recent studies have shown that adenosine-to-inosine (A-to-I) RNA editing occurs in microRNAs (miRNAs), the effects of A-to-I miRNAs editing on melanoma growth and metastasis are yet to be determined. Previously we have reported that metastatic melanoma cell lines and tumor specimens have reduced expression of ADAR1 and consequently are impaired in their ability to perform A-to-I microRNA (miRNA) editing. Here we report that miR-378a-3p is undergoing A-to-I editing only in the non-metastatic but not in metastatic melanoma cells. The function of the edited form is different from its wild-type counterpart. The edited form of miR-378a-3p preferentially binds to the 3'UTR of the PARVA oncogene and inhibits its expression, thus preventing the progression of melanoma towards the malignant phenotype. Indeed, edited miR- 378a-3p but not its WT form inhibits melanoma metastasis in vivo. These results further emphasize the role of RNA editing in melanoma progression. Citation Format: Einav Shoshan, Guermarie Velazquez-Torres, Enrique Fuentes-Mattei, Cristina Ivan, Menashe Bar-Eli. A-to-I miR-378a-3p editing prevents melanoma progression via regulation ofPARVA expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-384.
- Published
- 2018
46. Use of human bronchial epithelial cells (BEAS-2B) to study immunological markers resulting from exposure to PM2.5 organic extract from Puerto Rico
- Author
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Felix R. Roman-Velazquez, Enrique Fuentes-Mattei, Diana Sánchez-Rivera, Evasomary Rivera, Adriana Gioda, and Braulio Jiménez-Vélez
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Transcriptional Activation ,Receptors, Steroid ,medicine.medical_treatment ,Genes, MHC Class II ,Bronchi ,Inflammation ,Air Pollutants, Occupational ,Biology ,Toxicology ,Article ,Cell Line ,Microbiology ,Suppression, Genetic ,medicine ,Cytochrome P-450 CYP3A ,Humans ,HLA-DR2 Antigen ,RNA, Messenger ,Cytotoxicity ,Pharmacology ,Reverse Transcriptase Polymerase Chain Reaction ,Puerto Rico ,Pregnane X Receptor ,Lymphokine ,Epithelial Cells ,Biological activity ,In vitro ,Trace Elements ,Cytokine ,medicine.anatomical_structure ,Immunology ,Toxicity ,Cytokines ,Particulate Matter ,medicine.symptom ,Biomarkers ,Environmental Monitoring ,Respiratory tract - Abstract
Fine particulate air pollutants, mainly their organic fraction, have been demonstrated to be associated with cardiovascular and respiratory health problems. Puerto Rico has been reported to have the highest prevalence of pulmonary diseases (e.g., asthma) in the United States. The aim of this study was to assess, for the first time, the immunological response of human bronchial epithelial cells (BEAS-2B) to organic extracts isolated from airborne particulate matter (PM 2.5 ) in Puerto Rico. Organic extracts from PM 2.5 collected throughout an 8-month period (2000–2001) were pooled (composite) in order to perform chemical analysis and biological activity testing. BEAS-2B cells were exposed to PM 2.5 organic extract to assess cytotoxicity, levels of cytokines and relative gene expression of MHC-II, hPXR and CYP3A5. Our findings show that organic PM 2.5 consist of toxic as well as bioactive components that can regulate the secretion of cytokines in BEAS-2B, which could modulate inflammatory response in the lung. Trace element analyses confirmed the presence of metals in organic extracts highlighting the relative high abundance of Cu and Zn in polar organic extracts. Polar organic extracts exhibited dose-dependant toxicity and were found to significantly induce the release of interleukin 6 (IL-6), IL-1β and IL-7 while significantly inhibiting the secretion of IL-8, G-CSF and MCP-1. Moreover, MHC-II transcriptional activity was up-regulated after 24 h of exposure, whereas PXR and CYP3A5 were down-regulated. This research provides a new insight into the effects of PM 2.5 organic fractions on specific effectors and their possible role in the development of respiratory inflammatory diseases in Puerto Rico.
- Published
- 2010
47. Hepatocyte growth factor/cMET pathway activation enhances cancer hallmarks in adrenocortical carcinoma
- Author
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Christopher G. Wood, Gilbert J. Cote, Camilo Jimenez, Levent Ozsari, Siyuan Zheng, Guermarie Velazquez-Torres, Weixin Wu, Mouhammed Amir Habra, Maria Angelica Cortez, Liem Phan, Mong Hong Lee, Lance C. Pagliaro, Enrique Fuentes-Mattei, Kanishka Sircar, Tao Hai, Roeland Verhaak, Marie Claude Hofmann, and Sai Ching J. Yeung
- Subjects
Male ,Cancer Research ,Angiogenesis ,Pyridines ,Mice ,Adrenocortical carcinoma ,Mitotane ,Anilides ,Molecular Targeted Therapy ,RNA, Small Interfering ,Aged, 80 and over ,Neovascularization, Pathologic ,Hepatocyte Growth Factor ,Middle Aged ,Proto-Oncogene Proteins c-met ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Oncology ,Hepatocyte growth factor ,Female ,RNA Interference ,Cell Division ,medicine.drug ,Signal Transduction ,Adenoma ,Adult ,medicine.medical_specialty ,Mice, Nude ,Antineoplastic Agents ,Biology ,Article ,Internal medicine ,Cell Line, Tumor ,medicine ,Carcinoma ,Animals ,Humans ,Aged ,Cisplatin ,Cell growth ,Gene Expression Profiling ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Adrenal Cortex Neoplasms ,Endocrinology ,Drug Resistance, Neoplasm ,Cancer research ,Transcriptome - Abstract
Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA–mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer. Cancer Res; 75(19); 4131–42. ©2015 AACR.
- Published
- 2015
48. ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development
- Author
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Chwan-Deng Hsiao, David G. Menter, Jung Yu Tung, Hyun Ho Choi, Jianping Wang, Lei Wang, Chuangqi Chen, Sai Ching J. Yeung, Mong Hong Lee, Weisi Lu, Enrique Fuentes-Mattei, and Lekun Fang
- Subjects
Male ,Cancer Research ,Beta-catenin ,Colorectal cancer ,Blotting, Western ,Cetuximab ,Mice, Nude ,Antineoplastic Agents ,Article ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,COP9 signalosome ,Phosphorylation ,neoplasms ,beta Catenin ,Adaptor Proteins, Signal Transducing ,Oligonucleotide Array Sequence Analysis ,Mitogen-Activated Protein Kinase 1 ,Mice, Inbred BALB C ,biology ,COP9 Signalosome Complex ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Ubiquitination ,Cell Biology ,Middle Aged ,medicine.disease ,HCT116 Cells ,Xenograft Model Antitumor Assays ,digestive system diseases ,3. Good health ,Tumor Burden ,Gene expression profiling ,Oncology ,Cancer research ,biology.protein ,Female ,RNA Interference ,Signal transduction ,Colorectal Neoplasms ,medicine.drug ,Signal Transduction - Abstract
SummaryBiomarkers for predicting prognosis are critical to treating colorectal cancer (CRC) patients. We found that CSN6, a subunit of COP9 signalosome, is overexpressed in CRC samples and that CSN6 overexpression is correlated with poor patient survival. Mechanistic studies revealed that CSN6 is deregulated by epidermal growth factor receptor (EGFR) signaling, in which ERK2 binds directly to CSN6 Leu163/Val165 and phosphorylates CSN6 at Ser148. Furthermore, CSN6 regulated β-Trcp and stabilized β-catenin expression by blocking the ubiquitin-proteasome pathway, thereby promoting CRC development. High CSN6 expression was positively correlated with ERK2 activation and β-catenin overexpression in CRC samples, and inhibiting CSN6 stability with cetuximab reduced colon cancer growth. Taken together, our study’s findings indicate that the deregulation of β-catenin by ERK2-activated CSN6 is important for CRC development.
- Published
- 2015
49. The cell cycle regulator 14-3-3σ opposes and reverses cancer metabolic reprogramming
- Author
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Shaofan Weng, Hyun Ho Choi, Douglas Webb, Ismael Samudio, Nibal Rizk, John D. Hazle, Enrique Fuentes-Mattei, Mouhammed Amir Habra, Lajos Pusztai, Sai Ching J. Yeung, Stephen Skerl, Wei Tse Yang, Marc S. Ramirez, Jaehyuk Lee, Yaling Huang, Huamin Wang, Xin Lin, Ping Chieh Chou, Yu Ye Wen, James A. Bankson, Chun Hui Su, Dianna D. Cody, Charles V. Kingsley, Kenneth Parreno, Marzenna Blonska, Yun Wu, Guermarie Velazquez-Torres, Andrew Elliott, Jian Chen, Colin Carlock, Jorge Delacerda, Christine Y. Shiang, Hua Wang, Mong Hong Lee, Thuy M. Vu, Brian C. Grabiner, Lei Li, Christopher Gully, Xuefeng Xia, Yiping Shao, Liem Phan, Ji-Hyun Shin, Zhongguo Zhou, Yun Chih Hsieh, Aijun Zhang, Chieh Tseng, Yongxing Wang, and Edward Wang
- Subjects
Adult ,Glutamine ,Regulator ,General Physics and Astronomy ,Breast Neoplasms ,Biology ,Article ,Disease-Free Survival ,General Biochemistry, Genetics and Molecular Biology ,Proto-Oncogene Proteins c-myc ,Gene Knockout Techniques ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Humans ,Aged ,030304 developmental biology ,Aged, 80 and over ,Regulation of gene expression ,0303 health sciences ,Organelle Biogenesis ,Multidisciplinary ,Glutaminolysis ,Ubiquitination ,Cancer ,General Chemistry ,Middle Aged ,Cell cycle ,HCT116 Cells ,Prognosis ,medicine.disease ,3. Good health ,Gene Expression Regulation, Neoplastic ,14-3-3 Proteins ,Mitochondrial biogenesis ,Biochemistry ,030220 oncology & carcinogenesis ,Exoribonucleases ,Proteolysis ,Cancer research ,Female ,Organelle biogenesis ,Energy Metabolism ,Glycolysis ,Reprogramming - Abstract
Summary Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumourigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programs by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anti-cancer metabolism therapy development in future.
- Published
- 2015
50. Obesity and Cancer: Jet Fuel Accelerating Cancer Hallmarks and Increasing the Economic Burden of Cancer
- Author
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Enrique Fuentes-Mattei
- Subjects
General Medicine - Published
- 2015
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