tbuckley/cabot-search huggingface dataset:
Abstract 282: Increasing Cardiac Fatty Acid Oxidation Protects Against High Fat Diet Induced Mitochondria Dysfunction and Cardiomyopathy in Mice
Authors: Dan Shao, Stephen C. Kolwicz, Nathan Roe, Outi Villet, Rong Tian
Journal: Circulation Research (2018)

In the obese and diabetic heart, an imbalance between fatty acid uptake and fatty acid oxidation (FAO) promotes the development of cardiac lipotoxicity. In this study, we tested the hypothesis that enhancing FAO via ACC2 deletion in an adult heart would prevent the cardiac lipotoxic phenotype in a mouse model of diet-induced obesity. ACC2 flox/flox (CON) and ACC2 flox/flox-MerCreMer+ (iKO) were injected with tamoxifen and subjected to a high fat diet (HFD) for 24 weeks. In isolated Langendorff-perfused heart experiments, HFD feeding increased FAO 1.6-fold in CON mice which was further increased to 1.9-fold in iKO mice compared with CON on chow diet. HFD induced systolic and diastolic dysfunction was abolished in iKO mice compared with CON mice (Fractional shortening 32.8±2.8% (CON) vs. 39.2±3.2% (iKO), E’/A’ ratio 0.91±0.09 (CON) vs. 1.11±0.08 (iKO), p&lt; 0.05, n=5-6). Heart weight /Tibia length ratio was significantly higher in CON than iKO mice after HFD feeding (7.19±0.22 vs. 6.47±0.28, p&lt;0.05, n=6). These data indicate that enhancing myocardial FAO via ACC2 deletion prevents HFD induced cardiac dysfunction and attenuates pathological hypertrophy in obese mice. We then examined the mitochondrial respiration activity under chow and HFD fed conditions. HFD feeding significantly reduced mitochondria oxygen consumption rate in Con hearts but not in iKO mice (332 vs. 418 pmoles/min, p&lt;0.05, n=5), suggesting that enhancing FAO prevented HFD induced mitochondria dysfunction. In vitro, palmitate (PA) induced mitochondria fragmentation and increased reactive oxygen species production was partially attenuated in ACC2 knocked down cardiomyocyte. Knocking down of ACC2 also prevented PA induced cell death. Moreover, HFD treatment significantly reduced the expression of LC3 and p62 in mitochondria fraction, indicative of impaired mitophagy in obese mice, which was attenuated in iKO mice. Therefore, the beneficial effect for enhancing cardiac fatty oxidation in HFD induced obesity model is mediated, in part, by maintenance of mitochondrial function through regulating mitophagy activity. Taken together, our findings suggest that promoting cardiac FAO is an effective strategy to prevent the development of cardiac lipotoxicity during diet-induced obesity.
QUANTITATIVE ASSESSMENT OF LIPID COMPOSITION BY NIRS-IVUS IS HELPFUL FOR DIFFERENTIATING AMONG PLAQUE RUPTURE, PLAQUE EROSION, AND CALCIFIED NODULE IN THE CULPRIT LESION OF ACS
Authors: Kosei Terada, Takashi Kubo, Yoshiki Matsuo, Yasushi Ino, Hironori Kitabata, Kunihiro Shimamura, Yasutsugu Shiono, Atsushi Tanaka, Takeshi Hozumi, Takashi Akasaka
Journal: Journal of the American College of Cardiology (2019)
COMPARISON OF THE SAFETY OF CELECOXIB, IBUPROFEN, AND NAPROXEN IN PATIENTS WITHOUT ESTABLISHED CARDIOVASCULAR DISEASE
Authors: Grant W. Reed, Haris Riaz, Quiqing Wang, Kathy Wolski, Lisa Wisniewski, Venu Menon, A. Lincoff, Steven Nissen
Journal: Journal of the American College of Cardiology (2019)
IMPACT OF TREATMENT STRATEGY OF ACUTE MYOCARDIAL INFARCTION ON DISCHARGE MEDICATIONS
Authors: Grant Henderson, Mouin Abdallah, Michael Johnson, Moses Anabila, Kathleen Kravitz, Jeevanantham Rajeswaran, Venu Menon, Stephen Ellis, A. Lincoff, Eugene Blackstone, Samir Kapadia, Umesh Khot
Journal: Journal of the American College of Cardiology (2019)
Ibrutinib Treatment Mitigates Phenotypic Alterations of Non-Neoplastic Immune Cell Compartments in Chronic Lymphocytic Leukemia
Authors: Valentina Griggio, Candida Vitale, Chiara Salvetti, Francesca Romana Mauro, Daniela Pietrasanta, Iolanda Donatella Vincelli, Lydia Scarfo, Giovanni Del Poeta, Gianluca Gaidano, Valter Gattei, Robin Foà, Mario Boccadoro, Marta Coscia
Journal: Blood (2019)
Abstract 15729: Copper Transporter ATP7A Limits Vascular Inflammation and Aortic Aneurysm Development
Authors: Sudhahar Varadarajan, Archita Das, Seock-Won Youn, Takashi Kohno, Bayasgalan Surenkhuu, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation (2015)

Vascular inflammation and its-induced endothelial cell (EC) barrier dysfunction contribute to aortic aneurysm (AA) development. However, critical regulators of AA are poorly understood. Copper (Cu), an essential micronutrient, at excess level is shown to promote inflammatory diseases including AA with unknown mechanism. Cu transporting ATPase (ATP7A) functions to deliver Cu to the secretory extracellular matrix enzyme lysyl oxidase (LOX) via Cu chaperone Atox1, or exclude Cu. Here we show that ATP7A is a key regulator of vascular inflammation and AA formation using ATP7A mutant (ATP7Amut) mice with reduced Cu transport function. ATP7Amut/ApoE-/- mice fed with high fat diet (HFD) induced a robust AA formation (70%) with enhanced atherosclerotic lesion (3.9 fold), which was associated with increased macrophage recruitment and matrix metalloproteinase 2 &amp; 9 activity vs. ApoE-/-/HFD or Atox1-/-/ApoE-/-/HFD mice. Of note, both ATP7Amut and Atox1-/- mice showed similar extent of reduced LOX activity (54%) indicating that decrease in LOX activity was not sufficient to develop AA. However, EC permeability was markedly increased only in ATP7Amut/ApoE-/- mice. Mechanistically, ATP7A depletion or proinflammatory cytokine TNFα in HUVECs increased EC permeability (132%) and leukocyte transendothelial migration (TEM) (p&lt;0.05) in a Cu dependent manner. To determine the ATP7A dependent microRNAs (miRs), we performed miRs array and found that miR125b is highly upregulated (9 fold) miRs in ATP7A depleted ECs. Of note, miR125b is shown to suppress VE-Cadherin (VE-Cad) expression by inhibiting translation of 3’UTR of VE-cad mRNA. Consistent with this, ATP7A depletion upregulated miR125b and downregulated VE-Cad, thereby increasing EC permeability, which were rescued by anti-miR125b. Furthermore, ATP7A knockdown caused Rac1-mediated actin disassembly in Cu dependent manner, which also contributed to EC barrier dysfunction. In summary, endothelial ATP7A protects against AA formation by preventing inflammation-induced EC permeability and excess inflammatory recruitment via regulating actin reorganization, VE-Cad expression, and LOX activity in a Cu dependent manner. Thus, ATP7A is a potential therapeutic target for inflammatory vascular disease.
Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses
Authors: Shouping Xu, Shiyao Sui, Xianyu Zhang, Boran Pang, Lin Wan, Da Pang
Journal: Medicinal Research Reviews (2019)

Abstract Autophagy is central to the maintenance of intracellular homeostasis across species. Accordingly, autophagy disorders are linked to a variety of diseases from the embryonic stage until death, and the role of autophagy as a therapeutic target has been widely recognized. However, autophagy‐associated therapy for human diseases is still in its infancy and is supported by limited evidence. In this review, we summarize the landscape of autophagy‐associated diseases and current autophagy modulators. Furthermore, we investigate the existing autophagy‐associated clinical trials, analyze the obstacles that limit their progress, offer tactics that may allow barriers to be overcome along the way and then discuss the therapeutic potential of autophagy modulators in clinical applications.
TEMPORAL TRENDS IN RISK PROFILES OF ISOLATED SURGICAL AORTIC VALVE REPLACEMENT PATIENTS
Authors: Paige Craig, Toby Rogers, Quan Zou, Rebecca Torguson, Petros Okubagzi, Afshin Ehsan, John Goncalves, Chiwon Hahn, Thomas Bilfinger, Scott Buchanan, Robert Garrett, Vinod Thourani, Paul Corso, Ron Waksman
Journal: Journal of the American College of Cardiology (2019)
FEASIBILITY AND SAFETY OF ORBITAL ATHERECTOMY FOR THE TREATMENT OF IN-STENT RESTENOSIS
Authors: Saroj Neupane, Mir Basir, Christina Tan, Mishel Tabaku, Mohammad Alqarqaz, Akshay Khandelwal, William O'Neill, Creighton Don, Khaldoon Alaswad
Journal: Journal of the American College of Cardiology (2019)
LATE GADOLINIUM ENHANCEMENT IN PATIENTS WITH MYOCARDITIS FROM IMMUNE CHECKPOINT INHIBITORS
Authors: Lili Zhang, Magid Awadalla, Syed S. Mahmood, John D. Groarke, Anju Nohria, Shiying Liu, Malek Z.O. Hassan, Justine V. Cohen, Maeve Jones-O'Connor, Sean P.T. Murphy, Lucie M. Heinzerling, Gagan Sahni, Carol L. Chen, Dipti Gupta, Javid J. Moslehi, Sarju Ganatra, Stephane Ederhy, Franck Thuny, Alexander R. Lyon, Carlo G. Tocchetti, Muhammad A. Rizvi, Paaladinesh Thavendiranathan, Michael G. Fradley, Tomas G. Neilan
Journal: Journal of the American College of Cardiology (2019)
FRI0127 Atherosclerosis and arterial disease in systemic lupus erythematosus
Authors: J Frostegard, E Svenungsson, K Jensen-Urstad, M Heimburger, L Klareskog, A Hamsten, U De Faire, J Witztum
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Systemic lupus erythematosus (SLE) patients have increased morbidity and mortality in cardiovascular diseases. Whether this is caused by aggravated atherosclerosis has not been totally clarified. Since atherosclerosis recently has been shown to be an inflammatory disease it is important to study the inflammatory nature of SLE in this context. Furthermore the role of phospholipid antibodies and enhanced trombogenesis as well as the importance of other cardiovascular risk factors like LDL oxidation need to be studied in SLE patients. <h3>Objectives</h3> To determine the cause of the enhanced risk of cardiovascular disease present in systemic lupus erythematosus. <h3>Methods</h3> Twenty-six women (mean age 52 yrs) with SLE and a history of arterial disease (SLE cases) were compared with 26 age matched women with SLE but without manifest arterial disease (SLE controls) and 26 age matched population control women (population controls). Common carotid intima-media thickness (IMT) was measured by B-mode ultrasound as a surrogate measure of atherosclerosis. All were subject to clinical and laboratory evaluations with respect to known cardiovascular risk factors. A monoclonal antibody to oxLDL, EO6, was used to determine oxidation epitopes in LDL. <h3>Results</h3> SLE cases had increased IMT as compared to population controls (IMT 0.66 mm ± 0.15 vs 0.59 ± 0.12, p = 0.037) while the IMT of SLE controls (0.60 mm ± 0.14) did not differ from that of population controls. Raised plasma concentrations of oxLDL- (p = 0.033); dyslipidemia with raised triglycerides (p &lt; 0.001) and lipoprotein (a) (p = 0.002), and decreased HDL-cholesterol concentrations (p = 0.03); raised alfa-1-antitrypsin- (p = 0.002), antibodies to oxLDL (p &lt; 0.001), lupus anticoagulant (p = 0.007) and homocysteine-levels (p = 0.03) discriminated between SLE cases and SLE controls. SLE cases had been subject to significantly higher cumulative prednisone dose than SLE controls (p = 0.04). Disease duration, smoking, blood pressure, BMI or diabetes mellitus did not differ significantly between the groups. <h3>Conclusion</h3> We found that arterial disease in SLE is linked to aggravated atherosclerosis. However, unlike the situation in diabetes and hypertension, aggravated atherosclerosis was not present in SLE patients without signs of arterial disease. Dyslipidemia, systemic inflammation and raised concentrations of OxLDL, anti OxLDL antibodies, lupus anticoagulant and homocysteine distinguished women with SLE and arterial disease from both SLE controls and population controls.
Abstract 415: Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-mediated Enhancement of Anabolic Synthesis
Authors: Hong Ma, Shuo Yu, Xiaojing Liu, Yingao Zhang, Thomas Fakadej, Ziqing Liu, Chaoying Yin, Jason W Locasale, Joan M Taylor, Li Qian, Jiandong Liu
Journal: Circulation Research (2018)

During pathological hypertrophy, the heart undergoes extensive metabolic changes prior to the onset of structural remodeling, yet, it remains unknown whether and how this metabolic remodeling could contribute to cardiac hypertrophic growth. Here, we identified the RNA-binding protein Lin28a as a critical regulator of pathological cardiac hypertrophy and metabolic re-patterning. Cardiac specific deletion of Lin28a attenuated pressure overload-induced hypertrophy and cardiac dysfunction. Transcriptomics and metabolomic analysis highlighted roles for Lin28a in promoting cardiac glycolysis and anabolic biosynthesis. Mechanistically, Lin28a directly bound to mitochondrial phosphoenolpyruvate carboxykinase 2 ( Pck2 ) mRNA and positively modulated its transcript level. By utilizing the neonatal rat cardiomyocytes (NRCMs) hypertrophy model, we found that manipulation of Pck2 expression phenocopied the metabolic and hypertrophic phenotypes of manipulating Lin28a expression. Furthermore, epistatic analyses demonstrated that overexpression of Pck2 reversed the attenuation of norepinephrine-induced enhancement of cardiac glycolysis and cardiac hypertrophy by loss of Lin28a function, and knockdown of Pck2 suppressed Lin28a-induced increase in cardiac glycolysis and cardiomyocyte hypertrophic growth. Thus, our study revealed a critical role of Lin28a in the regulation of pathological cardiac hypertrophic growth through Pck2-mediated regulation of cardiac metabolism.
Abstract P4-08-26: Validation of different prognostic scores in breast cancer patients with brain metastases of the BMBC registry (GBG-79)
Authors: ID Witzel, K Riecke, E Laakmann, R Weide, T Neunhoeffer, T-W Park-Simon, M Schmidt, PA Fasching, T Hesse, A Polasik, S Mohrmann, F Würschmidt, C Schem, C Bechtner, R Würstlein, T Fehm, V Möbus, N Burchardi, S Loibl, V Müller
Journal: Cancer Research (2019)

Abstract Background The incidence of brain metastases from breast cancer is increasing and treatment is a major challenge. Different scores were developed to estimate the prognosis of patients with brain metastases by objective criteria. Sperduto et al. established the disease-specific breast-graded prognostic assessment (GPA) score in 400 breast cancer patients which includes age, performance status and tumor subtype. It has been described that the Breast- GPA best identifies patients with bad prognosis (Laakmann et al. 2016). Aim of this analysis was to validate the Breast-GPA in a large cohort of breast cancer patients with brain metastases. Materials and methods Data of 613 breast cancer patients from the Brain Metastases in Breast Cancer (BMBC) registry treated in 80 different clinical German institutions between 2000 and 2016 was analyzed. Results 135 patients (22%) had a triple-negative, 199 (32%) a luminal-like und 279 (46%) a HER2-positive primary breast cancer. At diagnosis of brain metastases most patients had a good Karnofsky performance status (100%: 14.4%, 80-90%: 44.7%, 60-70%: 28.9%, 40-50%: 9.0%, 10-30%: 3.1%). Median age of patients was 56 years (22-90 years). Median survival in the overall cohort was 7.1 months (95% CI 6.2-7.8 months). Distribution of GPA scores was: 0-1: 11.9% (n=73), 1,5-2: 22.3% (n=137), 2,5-3: 47.8% (n=293), 3,5-4: 18% (n=110). Median overall survival within the GPA-subgroups varied between 2.4 (CI95% 2.0 - 3.4); 4.8 (3.6 - 6.9); 9.2 (7.2 - 11.3) and 12.3 (8.9 - 18.0) months and, thus, was significantly shorter compared with the times published by Sperduto et al. (3.4; 7.7; 15.1 und 25.3 months). Conclusions The breast-GPA is easy to calculate in clinical routine, allows to assess patients` prognosis objectively and can facilitate making therapeutic decisions. However, absolute survival may differ from the originally published cohort in other settings. Citation Format: Witzel ID, Riecke K, Laakmann E, Weide R, Neunhoeffer T, Park-Simon T-W, Schmidt M, Fasching PA, Hesse T, Polasik A, Mohrmann S, Würschmidt F, Schem C, Bechtner C, Würstlein R, Fehm T, Möbus V, Burchardi N, Loibl S, Müller V. Validation of different prognostic scores in breast cancer patients with brain metastases of the BMBC registry (GBG-79) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-26.
Is an opt-out system likely to increase organ donation?
Authors: Veronica English, Emma Johnson, Blair L Sadler, Alfred M Sadler
Journal: BMJ (2019)

As England's presumed consent law for 2020 clears parliament, <b>Veronica English</b> and <b>Emma Johnson</b> say that evidence from Wales and other countries shows that it could increase transplantation rates. But <b>Blair L Sadler</b> and <b>Alfred M Sadler Jr</b> consider such legal changes a distraction lacking strong evidence: they say that public education and trained staff would have a proven impact
CONTRIBUTION OF UNDEREXPANDED/UNDERSIZED STENTING TO POST-PCI ISCHEMIA BY FRACTIONAL FLOW RESERVE AFTER ANGIOGRAPHIC OPTIMIZATION
Authors: Barry F. Uretsky, Srikanth Vallurupalli, Abdul Hakeem, Mohammed Eid Madmani, Mohamed Ayan, Malek Al-Hawwas, Rimsha Hasan, Shiv Kumar Agarwal
Journal: Journal of the American College of Cardiology (2019)
COMPLEX CORONARY INTERVENTION IN A PATIENT WITH VON WILLEBRAND DISEASE: NOVEL USE OF VWF/FVIII CONCENTRATES SUPPLEMENTATION PRIOR TO PROCEDURE
Authors: Ahmad Al Turk, Asaad Nakhle, Mehul Bhalja, Ahmad Jabbar, Gerard Chaaya, Cindy Leissinger, Charisse Ward
Journal: Journal of the American College of Cardiology (2019)
Global 3D-Epigenetic Dysregulation of Cyclin D1 and D2 Actively Controls Their Expression Pattern in Multiple Myeloma
Authors: Samrat Roy Choudhury, Cody Ashby, Ruslana G. Tytarenko, Yan Wang, Purvi Patel, Katie Rose Ryan, Judith A Dent, Faith E. Davies, Gareth Morgan, Brian A Walker
Journal: Blood (2018)
Abstract 19273: Association of Intraoperative Hypotension and Renal Replacement Therapy After Cardiac Surgery
Authors: Janet M Ngu, Amy M Chung, Michael Bourke, Louise Y Sun
Journal: Circulation (2017)

Introduction: Acute kidney injury (AKI) is a common and serious complication of cardiac surgery. AKI severe enough to necessitate renal replacement therapy (RRT) with hemodialysis or continuous ven...
Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL
Authors: Magdalena Klanova, Laurie H. Sehn, Isabelle Bence-Bruckler, Federica Cavallo, Jie Jin, Maurizio Martelli, Douglas Stewart, Umberto Vitolo, Francesco Zaja, Qingyuan Zhang, Federico Mattiello, Gila Sellam, Elizabeth A. Punnoose, Edith Szafer-Glusman, Christopher R. Bolen, Mikkel Z. Oestergaard, Guenter R. Fingerle-Rowson, Tina Nielsen, Marek Trneny
Journal: Blood (2019)
DOXORUBICIN DIRECTLY INDUCED FIBROTIC CHANGE OF CARDIAC FIBROBLASTS AND MATRIX METALLOPROTEINASE-1
Authors: Masatoshi Narikawa, Masanari Umemura, Ryo Tanaka, Tomoaki Ishigami, Koichi Tamura, Yoshihiro Ishikawa
Journal: Journal of the American College of Cardiology (2019)
Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling
Authors: Maja Kim Kuepper, Marlena Bütow, Oliver Herrmann, Janine Ziemons, Nicolas Chatain, Angela Maurer, Martin Kirschner, Tiago Maié, Ivan G. Costa, Jörg Eschweiler, Steffen Koschmieder, Tim H. Brümmendorf, Gerhard Müller-Newen, Mirle Schemionek
Journal: Leukemia (2019)
EFFECT OF DAPAGLIFLOZIN ON LEFT VENTRICULAR DIASTOLIC FUNCTION OF PATIENTS WITH TYPE 2 DIABETIC MELLITUS WITH CHRONIC HEART FAILURE
Authors: Fumitaka Soga, Hidekazu Tanaka, Kazuhiro Tatsumi, Yasuhide Mochizuki, Hiroyuki Sano, Hiromi Toki, Kensuke Matsumoto, Junya Shite, Hideyuki Takaoka, Tomofumi Doi, Ken-Ichi Hirata
Journal: Journal of the American College of Cardiology (2019)
EVALUATION OF A CLINICAL PRACTICE PATHWAY FOR THE MANAGEMENT OF ACUTE CATHETER-RELATED VENOUS THROMBOEMBOLISM IN PEDIATRIC CARDIOLOGY PATIENTS: YEAR FOUR REVIEW
Authors: Jarrett Linder, Whitney Petrosa, Rachel Keashen, Kelly Veneziale, Karen Murphy, Jungwon Min, Heather Griffis, Michele P. Lambert, Char Witmer, Leslie Raffini, Therese Giglia
Journal: Journal of the American College of Cardiology (2019)
<scp>IL</scp>‐4 receptor α blockade prevents sensitization and alters acute and long‐lasting effects of allergen‐specific immunotherapy of murine allergic asthma
Authors: D. Russkamp, A. Aguilar‐Pimentel, F. Alessandrini, V. Gailus‐Durner, H. Fuchs, C. Ohnmacht, A. Chaker, M. H. de Angelis, M. Ollert, C. B. Schmidt‐Weber, S. Blank
Journal: Allergy (2019)

Allergen-specific immunotherapy (AIT) is the only causal treatment for allergy. However, success rates vary depending on the type of allergy and disease background of the patient. Hence, strategies targeting an increased therapeutic efficacy are urgently needed. Here, the effects of blockade of IL-4 and IL-13 signaling on different phases of AIT were addressed.The impact of the recombinantly produced IL-4 and IL-13 antagonist IL-4 mutein (IL-4M) on allergic sensitization and AIT outcome in experimental allergic asthma were analyzed in a murine model. The effects of IL-4M administration were assessed prior/during sensitization, immediately after AIT under allergen challenge, and two weeks post-treatment.Intervention with IL-4M prior/during sensitization led to strong induction of IgG1, IgG2a, IgG2b, and IgG3, decrease of specific and total IgE, as well as of IL-5 in serum. Similar effects on the serum immunoglobulin levels were observed immediately after IL4M-supplemented AIT during allergen challenge. Additionally, IL4M markedly suppressed type-2 cytokine secretion of splenocytes beyond the effect of AIT alone. These effects were equaled to those of AIT alone two weeks post-treatment. Intriguingly, here, IL-4M induced a sustained decrease of Th2-biased Tregs (ST2+ FOXP3+ GATA3intermediate ).IL-4 and IL-13 blockade during experimental AIT demonstrates beneficial effects on immunological key parameters such as immunoglobulin and cytokine secretion immediately after AIT. Although two weeks later these effects were dropped to those of AIT alone, the number of potentially disease-triggering Th2-biased Tregs was further significantly decreased by IL-4M treatment. Hence, IL-4/IL13-targeting therapies prime the immune memory in therapy success-favoring manner.
Adenylate kinase 4 modulates oxidative stress and stabilizes HIF-1α to drive lung adenocarcinoma metastasis
Authors: Yi-Hua Jan, Tsung-Ching Lai, Chih-Jen Yang, Yuan-Feng Lin, Ming-Shyan Huang, Michael Hsiao
Journal: Journal of Hematology & Oncology (2019)

Adenylate kinase 4 (AK4) has been identified as a biomarker of metastasis in lung cancer. However, the impacts of AK4 on metabolic genes and its translational value for drug repositioning remain unclear. Ingenuity upstream analyses were used to identify potential transcription factors that regulate the AK4 metabolic gene signature. The expression of AK4 and its upstream regulators in lung cancer patients was examined via immunohistochemistry. Pharmacological and gene knockdown/overexpression approaches were used to investigate the interplay between AK4 and its upstream regulators during epithelial-to-mesenchymal transition (EMT). Drug candidates that reversed AK4-induced gene expression were identified by querying a connectivity map. Orthotopic xenograft mouse models were established to evaluate the therapeutic efficacy of drug candidates for metastatic lung cancer. We found that HIF-1α is activated in the AK4 metabolic gene signature. IHC analysis confirmed this positive correlation, and the combination of both predicts worse survival in lung cancer patients. Overexpression of AK4 exaggerates HIF-1α protein expression by increasing intracellular ROS levels and subsequently induces EMT under hypoxia. Attenuation of ROS production with N-acetylcysteine abolishes AK4-induced invasion potential under hypoxia. Pharmacogenomics analysis of the AK4 gene signature revealed that withaferin-A could suppress the AK4-HIF-1α signaling axis and serve as a potent anti-metastatic agent in lung cancer. Overexpression of AK4 promotes lung cancer metastasis by enhancing HIF-1α stability and EMT under hypoxia. Reversing the AK4 gene signature with withaferin-A may serve as a novel therapeutic strategy to treat metastatic lung cancer.