tbuckley/cabot-search huggingface dataset:
Abstract 965: Deleterious effects of MAPK pathway hyperactivation in BRAF-mutant melanoma
Authors: Grace P. Leung, Tianshu Feng, Matthew D. Shirley, Frederic D. Sigoillot, David A. Ruddy, Alyson K. Freeman, Mariela Jaskelioff, Darrin D. Stuart
Journal: Cancer Research (2018)

Abstract The most frequent genetic alterations in melanoma are gain-of-function mutations in BRAF, which result in addiction to RAF-MEK-ERK signaling. Given the centrality of this pathway in many cancers, inhibitors have been developed against various nodes in this signaling axis. Despite the success of these inhibitors in treating BRAFV600E mutant tumors, a major problem is the inevitable emergence of drug resistance. The mechanisms of acquired resistance often include reactivation of the MAPK pathway, thus efforts to combat resistance have used vertical combination strategies to inhibit multiple nodes of the pathway. Previous work from our group showed that vemurafenib-resistant melanoma tumors displayed increased levels of MAPK signaling as indicated by elevated phospho-ERK. Strikingly, cell lines derived from these resistant tumors were addicted to vemurafenib, and removal of drug caused loss in cell viability. Consistently, in vivo, the tumors regressed upon cessation of drug treatment, which was accompanied by elevated MAPK signaling. Recent studies have reported similar results for in vitro models of melanoma resistant to MAPK inhibitors, which are addicted to drug in an ERK2-dependent manner. Together these data suggest that extreme levels of MAPK signaling are not tolerated by tumor cells. To further characterize this phenomenon, we generated models of inducible MAPK hyperactivation in BRAFV600E melanoma cells. Using these model systems, we confirmed that increasing the levels of MAPK signaling can hinder tumor cell proliferation, and demonstrated that MAPK inhibitors can rescue this phenotype. Intriguingly, the effect of MAPK hyperactivation varied depending on the RAS/RAF mutation status of the tumor cells. Upon induction of MAPK hyperactivation in sensitive cells, there was no cell cycle arrest, but instead cell death occurred, which was accompanied by activation of caspases. On a global level, MAPK hyperactivation resulted in transcriptome changes that were opposite to those produced by treatment with an ERK inhibitor. This phenomenon of MAPK hyperactivation-induced cell death was also observed in vivo, where complete tumor regression was observed in a xenograft model. Ongoing studies seek to further define the mechanism of cell death, which could suggest potential avenues to leverage hyperactivation of MAPK signaling as a therapeutic approach. Citation Format: Grace P. Leung, Tianshu Feng, Matthew D. Shirley, Frederic D. Sigoillot, David A. Ruddy, Alyson K. Freeman, Mariela Jaskelioff, Darrin D. Stuart. Deleterious effects of MAPK pathway hyperactivation in BRAF-mutant melanoma [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 965.
Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall
Authors: HartmutHanke, ChristinaLenz, BeateHess, Klaus-DieterSpindler, WolfgangWeidemann
Journal: Circulation (2001)

Background—Recent studies have suggested that testosterone has a protective effect in the arterial vascular system. However, little is known about the molecular aspects of the mechanism(s) involved in these processes. The aim of the present study was to investigate the effect of testosterone on neointimal plaque development and on the expression of the vascular androgen receptor. Methods and Results—Neointimal plaque formation was induced by endothelial denudation in the aortas of male New Zealand White rabbits. Aortic ring segments were cultured for 21 days after endothelial denudation. Testosterone was applied to the culture medium in different doses. Compared with the non–hormone-treated control group, a significant inhibition of neointimal plaque development (expressed as the intima/media ratio) was found at testosterone concentrations of 10 ng/mL (P=0.037) and 100 ng/mL (P=0.012; intima/media ratios: median of controls, 0.25; median of 10 ng/mL testosterone group, 0.15; median of 100 ng/mL testostero...
Sirt7 Increases Stress Resistance of Cardiomyocytes and Prevents Apoptosis and Inflammatory Cardiomyopathy in Mice
Authors: OlesyaVakhrusheva, ChristianSmolka, PraveenGajawada, SawaKostin, ThomasBoettger, ThomasKubin, ThomasBraun, EvaBober
Journal: Circulation Research (2008)

Sirt7 is a member of the mammalian sirtuin family consisting of 7 genes, Sirt1 to Sirt7, which all share a homology to the founding family member, the yeast Sir2 gene. Most sirtuins are supposed to act as histone/protein deacetylases, which use oxidized NAD in a sirtuin-specific, 2-step deacetylation reaction. To begin to decipher the biological role of Sirt7, we inactivated the Sirt7 gene in mice. Sirt7-deficient animals undergo a reduction in mean and maximum lifespans and develop heart hypertrophy and inflammatory cardiomyopathy. Sirt7 mutant hearts are also characterized by an extensive fibrosis, which leads to a 3-fold increase in collagen III accumulation. We found that Sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo and an increased rate of apoptosis in the myocardium of mutant mice. Sirt7-deficient primary cardiomyocytes show a ≈200% increase in basal apoptosis and a significantly diminished resistance to oxidative and genoto...
Successful treatment of secondary poor graft function post allogeneic hematopoietic stem cell transplantation with eltrombopag
Authors: Cen Tang, Feng Chen, Danqing Kong, Qinfen Ma, Haiping Dai, Jia Yin, Zheng Li, Jia Chen, Xiaming Zhu, Xinliang Mao, Depei Wu, Xiaowen Tang
Journal: Journal of Hematology & Oncology (2018)

Poor graft function (PGF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Current treatment strategies include the use of growth factors, CD34+-selected stem cell boost, mesenchymal stem cell transfusion, and second allo-HSCT, but these treatments are not effective in all patients. Eltrombopag, an oral thrombopoietin receptor agonist, which showed promising results in severe aplasia anemia, may be an alternative choice for PGF patients. Therefore, we treated 12 patients who responded poorly to standard treatments for secondary PGF after allo-HSCT with eltrombopag. The median duration was 116 (35–1000) days from transplantation to PGF diagnosis and 59 (30–180) days from PGF diagnosis to eltrombopag treatment. Eltrombopag was started at a dose of 25 mg/d for 3 days and then increased to 50 or 75 mg/d. Median treatment duration was 8 (2–23) weeks. Ten patients (83.3%) responded to the treatment: 8 achieved complete response (CR), and the remaining 2 achieved partial response. In the 10 responding subjects, median platelet count was 18 (5–27) × 109/L vs 74 (30–117) × 109/L prior to and after treatment. Neutrophil count was 0.51 (0.28–0.69) × 109/L vs 1.84 (0.78–4.90) × 109/L. Hemoglobin was 88 (63–123) vs 101 (78–134) g/L. In the 8 patients who achieved CR, the time from eltrombopag initiation to achieving CR was 29 (10–49) days; the response lasted until the last follow-up in all 8 CR subjects (10–18 months). The 12-month overall survival rate was 83.3%. There was no treatment-related mortality and no evidence of cataract, thrombosis, or any other grade 3/4 toxicities.
Abstract 18523: Simultaneous Consideration of Imaging and Blood Markers for Prediction of Hemorrhagic Transformation in Acute Ischemic Stroke
Authors: Hye-YeonChoi
Journal: Circulation (2014)

Introduction: Prediction of hemorrhagic transformation (HT) may be helpful for the treatment decision in patients with acute ischemic stroke. Lower scores of Alberta Stroke program early CT score (ASPECTS), or high levels of plasma MMP-9 have been suggested to predict hemorrhage after thrombolytic treatment. Hypothesis: Combined measurements of baseline MMP-9 levels and ASPECTS can be surrogate markers of HT in acute ischemic stroke patients. Methods: Enrolled for this study were patients with acute cerebral infarction in the carotid artery territory who visited within 6 hours after symptom onset. Among them, those whose blood samples could be obtained before the thrombolytic treatment or before administration of any antithrombotic agent, and whose initial non-contrast CT of the brain was available were included. The baseline CT scans were scored by consensus approach of two neurologists. Plasma MMP-9 levels were measured by enzyme-linked immunosorbent assays. Severity of neurologic deficits was assessed ...
Homeostatic and Tissue Reparation Defaults in Mice Carrying Selective Genetic Invalidation of CXCL12/Proteoglycan Interactions
Authors: PatriciaRueda, AdèleRichart, AliceRécalde, PamelaGasse, JoséVilar, CoralieGuérin, HuguesLortat-Jacob, PauloVieira, Frano̧iseBaleux, FabriceChretien, FernandoArenzana-Seisdedos, Jean-SébastienSilvestre
Journal: Circulation (2012)

Background—Interaction with heparan sulfate proteoglycans is supposed to provide chemokines with the capacity to immobilize on cell surface and extracellular matrix for accomplishing both tissue homing and signaling of attracted cells. However, the consequences of the exclusive invalidation of such interaction on the roles played by endogenous chemokines in vivo remain unascertained. Methods and Results—We engineered a mouse carrying a Cxcl12 gene (Cxcl12Gagtm) mutation that precludes interactions with heparan sulfate structures while not affecting CXCR4-dependent cell signaling of CXCL12 isoforms (α, β, γ). Cxcl12Gagtm/Gagtm mice develop normally, express normal levels of total and isoform-specific Cxcl12 mRNA, and show increased counting of circulating CD34+ hematopoietic precursor cells. After induced acute ischemia, a marked impaired capacity to support revascularization was observed in Cxcl12Gagtm/Gagtm animals associated with a reduced number of infiltrating cells in the ischemic tissue despite the ...
Abstract 4218: Breast cancer survival by age and subtype (ER/PR/HER2) in a nationwide population-based cohort
Authors: Anna L. Johansson, Cassia B. Trewin, Kirsti V. Hjerkind, Merete Ellingjord-Dale, Tom B. Johannesen, Therese Sorlie, Giske Ursin
Journal: Cancer Research (2018)

Abstract Purpose: We assessed the effect of breast cancer subtype, as defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, on breast cancer survival among young (20-39y), middle-aged (40-49y), screen-aged (50-69y) and elderly (70-89y) women, to elucidate the role of tumor biology for differences in survival across age. Material and methods: A population-based cohort of 21,385 women with a breast cancer diagnosis at ages 20 to 89 between 2005 and 2015 was identified in the Cancer Register of Norway. Subtype was defined as luminal A-like (ER+ PR+ HER2-), luminal B-like HER2-negative (ER+ PR- HER2-), luminal B-like HER2-positive (ER+ PR+/PR- HER2+), HER2-positive (ER- PR- HER2+) and triple-negative (TRN) (ER- PR- HER2-). Cox regression models estimated hazard ratios (HR) for the association between age at diagnosis, subtype and breast cancer specific mortality, while adjusting for year, grade and TNM stage. Results: Young women had higher rates of HER2-positive and TRN tumors compared to middle-aged, screen-aged and elderly women who more often had luminal A-like tumors. Compared to women aged 50-59y, young women had doubled mortality rate (20-39y: HR=2.3 [95% CI 1.8-2.8]), while elderly had two to five times higher mortality rate (70-79y: HR=2.3 [1.9-2.7]; 80-89y: HR=5.2 [4.2-6.4]). After adjustment for subtype, grade and stage the association was reduced among young women (20-39y: HR=1.3 [1.1-1.6]) but less so among the elderly (70-79y: HR=2.1 [1.7-2.5]; 80-89y: HR=3.9 [3.2-4.9]). Among young women, luminal A-like and luminal B-like HER2-negative subtypes were still associated with increased mortality after adjustment for grade and stage. Among the elderly, all subtypes were associated with increased mortality after adjustment for grade and stage, with stronger effects for TRN, HER2-positive and luminal B-like HER2-positive subtypes. Conclusion: Tumor-associated factors, such as subtype, grade and stage, may explain a large part of the poorer survival among young patients, whereas comorbidities and less intensive treatment may explain the persisting poorer survival across subtypes among the elderly. Citation Format: Anna L. Johansson, Cassia B. Trewin, Kirsti V. Hjerkind, Merete Ellingjord-Dale, Tom B. Johannesen, Therese Sorlie, Giske Ursin. Breast cancer survival by age and subtype (ER/PR/HER2) in a nationwide population-based cohort [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 4218.
Abstract 4396: Targeting survivin to overcome docetaxel resistance in prostate cancer
Authors: Robert C. Peery
Journal: Cancer Research (2018)

Abstract Despite therapeutic advancements, castration-resistant prostate cancer (CRPC) remains the second most common cause of cancer-related mortality in men. Docetaxel is the first cytotoxic agent to show modest improvements in overall survival rate in patients with CRPC. Unfortunately, over half of these patients do not respond to treatment and ultimately all develop resistance. The mechanism mediating docetaxel resistance remains unknown. However, survivin, an inhibitor of apoptosis (IAP) family member, and known mediator of chemo-resistance has been previously associated with docetaxel resistance, as inhibition of survivin expression sensitized prostate cancer cells to docetaxel in vitro, and a small molecule inhibitor targeting survivin expression led to a significant regression in prostate cancer xenograft tumors when given in combination with docetaxel. However, how survivin may mediate docetaxel resistance in prostate cancer remains unknown. In this study, we tested the hypothesis that overexpression of nuclear survivin contributes to docetaxel resistance in prostate cancer cells. First, utilizing western blot to assess protein level and methylene blue assays to determine ability to proliferate under cytotoxic conditions, we found that survivin expression and docetaxel IC50 correlates strongly in five prostate cancer cell lines. Furthermore, using paired parental drug sensitive and stepwise selected docetaxel resistant cell lines, we determined that resistant cells overexpress survivin as compared to parental cells, and knockdown of survivin decreases resistance to docetaxel. Our studies suggest that survivin is likely implicated in CRPC and treatment with a direct survivin inhibitor may sensitize resistant cells to docetaxel. We are in the process of determining how this IAP may mechanistically mediate docetaxel resistance. Citation Format: Robert C. Peery. Targeting survivin to overcome docetaxel resistance in prostate cancer [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 4396.
Abstract 1144: Building Kras (G12D)/Trp53 null/Pdx1-cre (KPC) mouse allograft tumor model for efficacy evaluation of combinatory immunotherapies
Authors: Yanrui Song, Benqi Liu, Annie Xiaoyu An, Likun Zhang, Jie Cai, Qian Shi, Henry Qixiang Li, Davy Xuesong Ouyang
Journal: Cancer Research (2018)

Abstract Pancreas ductal adenocarcinoma (PDAC) has dreadful 5-year survival of 6% and remains one of the most difficult to treat cancers with very few standard-of-care options. Fueled by the clinical success of immune checkpoint inhibitors in other solid tumors, several clinical trials have been conducted in PDAC patients. Unfortunately, those attempts have achieved limited clinical benefits as single-agent treatment. Now investigators are eager to test combinatory therapies of chemotherapies, small-molecule immune modulators, and immune checkpoint antibodies. Highly relevant preclinical models are very much needed for proof-of-principle efficacy evaluation. KPC model, first described by Tuveson and colleagues as LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre, and later established in a variety of derivatives by several labs with Trp53 heterozygous or homozygous knockouts, recapitulates human PDAC tumors in many aspects including morphologic small ductal tumors with enriched stromal contents; key features of immune microenvironment of PDAC representing robust inflammatory reactions, like high levels of B cells and macrophages and exclusion of effector T cells; and most importantly, is nonresponsive to a series of chemotherapies and immune checkpoint inhibitors, including PD1 and CTLA4 antibodies. These features make KPC model an ideal model to test combinatory therapies for PDAC. However, parental KPC model is difficult to use for pharmacologic studies due to the spontaneous nature of tumor onset and progression. The compound mutant mice are also costly to breed. We have generated a transplantable KPC tumor model by passaging the primary tumor subcutaneously in the C57BL/6 mice. These KPC allografts retain morphologic similarity to human PDAC. Immune profiling of both subcutaneously and orthotopically grafted tumors demonstrated highly enriched CD45+ lymphocytes, particularly B cells and macrophages, in the tumor. The tumor is also nonresponsive to gemcitabine treatment, in line with the data from parental line. Orthotopically engrafted tumor leads to lethality of the host with the median survival time of 25 days. We are now testing a variety of combinatory therapies with chemotherapies, immune modulators and immune checkpoint antibodies. The results will be presented at the meeting. Citation Format: Yanrui Song, Benqi Liu, Annie Xiaoyu An, Likun Zhang, Jie Cai, Qian Shi, Henry Qixiang Li, Davy Xuesong Ouyang. Building Kras (G12D)/Trp53 null/Pdx1-cre (KPC) mouse allograft tumor model for efficacy evaluation of combinatory immunotherapies [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 1144.
A Plasma-Derived Protein-Metabolite Multiplexed Panel for Early-Stage Pancreatic Cancer
Authors: Johannes F Fahrmann, Leonidas E Bantis, Michela Capello, Ghislaine Scelo, Jennifer B Dennison, Nikul Patel, Eunice Murage, Jody Vykoukal, Deepali L Kundnani, Lenka Foretova, Eleonora Fabianova, Ivana Holcatova, Vladimir Janout, Ziding Feng, Michele Yip-Schneider, Jianjun Zhang, Randall Brand, Ayumu Taguchi, Anirban Maitra, Paul Brennan, C Max Schmidt, Samir Hanash
Journal: JNCI Journal of the National Cancer Institute (2018)

Abstract Background We applied a training and testing approach to develop and validate a plasma metabolite panel for the detection of early-stage pancreatic ductal adenocarcinoma (PDAC) alone and in combination with a previously validated protein panel for early-stage PDAC. Methods A comprehensive metabolomics platform was initially applied to plasmas collected from 20 PDAC cases and 80 controls. Candidate markers were filtered based on a second independent cohort that included nine invasive intraductal papillary mucinous neoplasm cases and 51 benign pancreatic cysts. Blinded validation of the resulting metabolite panel was performed in an independent test cohort consisting of 39 resectable PDAC cases and 82 matched healthy controls. The additive value of combining the metabolite panel with a previously validated protein panel was evaluated. Results Five metabolites (acetylspermidine, diacetylspermine, an indole-derivative, and two lysophosphatidylcholines) were selected as a panel based on filtering criteria. A combination rule was developed for distinguishing between PDAC and healthy controls using the Training Set. In the blinded validation study with early-stage PDAC samples and controls, the five metabolites yielded areas under the curve (AUCs) ranging from 0.726 to 0.842, and the combined metabolite model yielded an AUC of 0.892 (95% confidence interval [CI] = 0.828 to 0.956). Performance was further statistically significantly improved by combining the metabolite panel with a previously validated protein marker panel consisting of CA 19–9, LRG1, and TIMP1 (AUC = 0.924, 95% CI = 0.864 to 0.983, comparison DeLong test one-sided P= .02). Conclusions A metabolite panel in combination with CA19-9, TIMP1, and LRG1 exhibited substantially improved performance in the detection of early-stage PDAC compared with a protein panel alone.
Association of Interleukin 6 Receptor Variant With Cardiovascular Disease Effects of Interleukin 6 Receptor Blocking Therapy
Authors: Tianxi Cai, Yichi Zhang, Yuk-Lam Ho, Nicholas Link, Jiehuan Sun, Jie Huang, Tianrun A. Cai, Scott Damrauer, Yuri Ahuja, Jacqueline Honerlaw, Jie Huang, Lauren Costa, Petra Schubert, Chuan Hong, David Gagnon, Yan V. Sun, J. Michael Gaziano, Peter Wilson, Kelly Cho, Philip Tsao, Christopher J. O’Donnell, Katherine P. Liao
Journal: JAMA Cardiology (2018)

Electronic health record (EHR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform drug discovery. Individuals with interleukin 6 receptor (IL6R) single-nucleotide polymorphisms (SNPs) who are not receiving IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. This gene-drug pair provides an example to test whether associations of IL6R SNPs with a broad range of phenotypes can inform which diseases may benefit from treatment with IL6R blockade.To determine whether screening for clinical associations with the IL6R SNP in a phenome-wide association study (PheWAS) using EHR biobank data can identify drug effects from IL6R clinical trials.Diagnosis codes and routine laboratory measurements were extracted from the VA Million Veteran Program (MVP); diagnosis codes were mapped to phenotype groups using published PheWAS methods. A PheWAS was performed by fitting logistic regression models for testing associations of the IL6R SNPs with 1342 phenotype groups and by fitting linear regression models for testing associations of the IL6R SNP with 26 routine laboratory measurements. Significance was reported using a false discovery rate of 0.05 or less. Findings were replicated in 2 independent cohorts using UK Biobank and Vanderbilt University Biobank data. The Million Veteran Program included 332 799 US veterans; the UK Biobank, 408 455 individuals from the general population of the United Kingdom; and the Vanderbilt University Biobank, 13 835 patients from a tertiary care center.IL6R SNPs (rs2228145; rs4129267).Phenotypes defined by International Classification of Diseases, Ninth Revision codes.Of the 332 799 veterans included in the main cohort, 305 228 (91.7%) were men, and the mean (SD) age was 66.1 (13.6) years. The IL6R SNP was most strongly associated with a reduced risk of aortic aneurysm phenotypes (odds ratio, 0.87-0.90; 95% CI, 0.84-0.93) in the MVP. We observed known off-target effects of IL6R blockade from clinical trials (eg, higher hemoglobin level). The reduced risk for aortic aneurysms among those with the IL6R SNP in the MVP was replicated in the Vanderbilt University Biobank, and the reduced risk for coronary heart disease was replicated in the UK Biobank.In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.