tbuckley/cabot-search huggingface dataset:
Abstract LB-190: CDC25A suppression of apoptosis in cutaneous squamous cell carcinoma depends on 14-3-3ε
Authors: Thomas R. Holmes, Jenan Al-Matouq, Brianna Hammiller, Yawah T. Nicholson, Matti J. Holmes, Laura A. Hansen
Journal: Cancer Research (2018)

Abstract Cytoplasmic relocalization of the dual-specificity phosphatase, CDC25A, occurs during nonmelanoma skin cancer development and progression, leading to suppression of cell death. Cytoplasmic CDC25A is phosphorylated at Ser178, which allows for its association with 14-3-3ϵ. 14-3-3ϵ is a member of the 14-3-3 family of proteins that bind phosphoserine/threonine-containing proteins and are involved in various processes including scaffolding, nuclear transport, protein degradation, cell cycle regulation, apoptosis and cell signaling. We hypothesized that CDC25A's antiapoptotic function depends upon 14-3-3ϵ binding to trigger activation of prosurvival signaling pathways in SCC cells. Co-immunoprecipitation of CDC25A from the SCC cell line SCC12B.2 followed by immunoblotting for 14-3-3ϵ confirmed an association between CDC25A and14-3-3ϵ. CDC25A over-expression in SCC12B.2 cells reduced apoptosis by approximately 50%, as assessed by a caspase 3/7 glo assay. However, inhibition of 14-3-3ϵ with the peptide R18, or silencing of 14-3-3ϵ, blocked the anti-apoptotic effect of CDC25A in SCC cells. Treatment with serial dilutions of R18 increased cell death with an IC50 of 8.9 μM in SCC12B.2 cells. Interestingly, over-expression of CDC25A significantly increased P-Akt (p=0.011), P-BAD (p=0.034) and Survivin (p=0.036) when compared to control. Consistent with our hypothesis that 14-3-3ϵ facilitates CDC25A's antiapoptotic activity, silencing of 14-3-3ϵ decreased P-Akt (p=0.044), P-BAD (p=0.034) and Survivin (p=0.008). Taken together, these results indicate that cytoplasmic CDC25A and 14-3-3ϵ interact in skin carcinomas to suppress apoptosis through a mechanism involving activation of Akt/BAD/Survivin signaling, rendering SCC cells sensitive to 14-3-3ϵ or CDC25A inhibition, a mechanism that requires further study. Citation Format: Thomas R. Holmes, Jenan Al-Matouq, Brianna Hammiller, Yawah T. Nicholson, Matti J. Holmes, Laura A. Hansen. CDC25A suppression of apoptosis in cutaneous squamous cell carcinoma depends on 14-3-3ϵ [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-190.
An Atypical Figurate Erythema With Seasonal Recurrences
Authors: Enrique Rodríguez-Lomba, Irene Molina-López, Ofelia Baniandrés-Rodríguez
Journal: JAMA Dermatology (2018)

A woman had a large annular erythematous plaque on her back that had centrifugally expanded. She had mild pruritus that had not responded to antihistamine therapy or topical steroids and reported a 20-year history of the plaques recurring every summer and resolving by autumn. What is your diagnosis?
Abstract P185: Novel Loci for Blood Pressure Using Gene-alcohol Interactions and 1000g Imputed Data
Authors: Mary F Feitosa, Thomas W Winkler, Amy R Bentley, Michael R Brown, Traci M Bartz, Daniel I Chasman, Rajkumar Dorajoo, Myriam Fornage, Nora Franceschini, Xiuqing Guo, Stella Aslibekyan, Caroline Hayward, Sharon L Kardia, Kurt Lohman, Ruth J Loos, Jonathan Marten, Bamidele Tayo, Dina Vojinovic, Wang Xu, Alanna Morrison, Dabeeru C Rao, Ingrid B Borecki, Michael A Province, Aldi T Kraja, L A Cupples
Journal: Circulation (2016)

Alcohol consumption has a complex relationship with blood pressure (BP). Whereas heavy alcohol consumption is associated with high BP, moderate alcohol consumption is associated with unchanged or modestly lower BP. We performed genome-wide meta-analysis of single SNP x alcohol drinking status interaction on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) blood pressure using 1000G imputed data. Our preliminary results comprise 23 European ancestry studies, including 87,098 individuals with known drinking status. Interaction associations were preformed using linear regression with main and interaction effects and accounting for family structure as needed. Meta-analyses were performed with METAL, for a 2 degrees of freedom joint test, after applying study- and meta-based genomic control adjustments. Results were further filtered if the meta-analysis N &lt; 5,000 individuals or if the number of cohorts contributing to meta-analysis were &lt; 3 for each SNP. For DBP, six novel loci (TRAF3IP1, ANKRD36, NLGN1, UBE3D, OFCC1 and C1orf167) were identified (p &lt; 5E-08). Known BP loci were found to be significant using the same interaction model, including MTHFR, CLCN6, NPPB, MECOM, NOS3, CACNB2, SH2B3, ATXN2, ALDH2, ATP2B1, CSK, FURIN and ZNF831. The significant DBP genes are enriched for hypertension (p-FDR=8.5E-08) and cardiac arrhythmias (p-FDR=5.3E-07) disease loci. MAP analyses identified similar loci as for DBP, while for SBP, ANKRD36 SNPs yielded the most significant associations. For PP, MYPN variants were most significant. In general for the joint test, known BP gene variants showed non-significant levels of meta-heterogeneity and common allele frequency (≥5%), whereas the novel loci often presented meta-heterogeneity and low allele frequency (≈1-5%). TRAF3IP1 interacts among others with TRAF3, reported in mice involved in a new pathway TRAF3-TBK1-AKT for cardiac hypertrophy and heart failure. ANKRD36 interacts with PHLPP2, involved in rats in FKBP51-PHLPP2-AKT signaling during cerebral ischemia/reperfusion injury. NLGN1 has been reported to associate with BP in ASCOT study (N=3,802), while in our meta-analysis out of 6 contributing studies, the joint test significance originates only from the GS_SFHS (N=6,504). Another significant result was C1orf167- rs12561919, a missense SNP considered cis-eQTL for neighboring BP known genes CLCN6 and MTHFR. Employing SNP x drinking status interaction for BP traits, we identified both novel and previously known BP genes. Our findings may provide insights into mechanisms underlying BP and inform lifestyle and therapeutic BP interventions.
Abstract LB-325: New synergistic mTOR-based combinations for the treatment of Ewing sarcoma
Authors: Brian A. Menegaz, Branko Cuglievan, Prasad S. Admane, Feng Yang, Dimitrov Dimiter, Yosef Landesman, Salah-Eddine Lamhamedi Cherradi, Joseph A. Ludwig
Journal: Cancer Research (2018)

Abstract Ewing sarcoma (ES), an aggressive bone cancer in children and young adults, is dependent upon the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) cell-signaling axis for malignancy, survival, and metastasis. Individual targeting of mTOR has negligible anti-tumor activity in ES, and single-agent IGF-1R targeting leads to only transient effects that benefit only 10-14% of patients. Co-targeting strategies using IGF-1R Abs combined with mTOR inhibitors were shown in 2012 to increase response rates to 29% but the high toxicity profile limited subsequent clinical development. While an ongoing COG protocol combines IGF-1R Abs with standard-of-care cytotoxic chemotherapy in newly diagnosed ES patients harboring metastatic disease, this combination is unlikely to benefit those who have recurred or developed chemoresistant disease. Herein, we present several highly synergistic drug combinations using novel biologically-targeted therapies aimed at the IGF-1R/mTOR pathway. A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody (m708.5), which binds human IGF-1 and IGF-2 with high pico-molar affinity, potently inhibited phosphorylation of the IGF-1R and the insulin receptor (IR) in an EW5 xenograft animal model of ES. In concert with mTOR inhibitors (e.g., everolimus or ridaforolimus), m708.5 demonstrated striking tumor regression and prolonged mouse survival. Additionally, we expand upon the synergistic role of CRM1 (XPO1) in combating ES tumor growth. A small molecule inhibitor of this protein (KPT-330) was previously shown to attenuate IGF-1-induced activation of IGF-1R when combined with a small-molecule inhibitor of IGF-1R and IR (Linsitinib, OSI906). Our results indicate superior preclinical anti-tumor activity when it is combined with everolimus in our xenograft ES models. Though these combinations have not yet been assessed in the clinical setting, early-phase clinical trials have begun testing KPT-330 in select sarcoma subtypes, and a host of mTOR inhibitors are FDA-approved and widely available. Our data supports several novel drug combinations that could rapidly be explored in the clinic to improve survival of ES patients. SELC &amp; JAL: Co-senior Authors Citation Format: Brian A. Menegaz, Branko Cuglievan, Prasad S. Admane, Feng Yang, Dimitrov Dimiter, Yosef Landesman, Salah-Eddine Lamhamedi Cherradi, Joseph A. Ludwig. New synergistic mTOR-based combinations for the treatment of Ewing sarcoma [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-325.
Why do breast cancer programs fail to refer patients to genetic counseling upon obtaining family history?
Authors: Julia R. Trosman, Christine B. Weldon, Danielle Dupuy, Betty Roggenkamp, Pamela Ganschow, Julian C. Schink, Anne Marie Murphy
Journal: Journal of Clinical Oncology (2012)

1553 Background: Women with personal or family history suggestive of susceptibility to hereditary breast or ovarian cancer should be referred to genetic counseling (US Preventive Services Task Force, Ann Intern Med. 2005). Our goal is to examine whether this guideline is followed by breast cancer programs providing screening and treatment in a large urban area; and if not followed, why. Funded by Susan G. Komen for the Cure. Methods: Using the framework approach of qualitative research, we conducted interviews with 130 providers of breast cancer screening and treatment at 26 institutions in Chicago (18 community, 4 academic and 4 public hospitals). We interviewed radiologists, mammography technologists, nurses, surgeons, oncologists, internists, and patient navigators. Interviews were transcribed and coded; theme analysis was conducted; simple frequencies and Fisher's exact test were calculated. Results: While all 26 programs collect patient personal and family history, only one program has both a protocol for referral to genetic counseling and a genetic counseling service. All six interviewees from that program (6/130, 5%) report referring appropriate patients to genetic counseling, compared to none from other programs (p&lt;0.0001). 90% of interviewees (118/130) did not perceive any role in raising patient awareness or referring them to genetic counseling. Among the 124 interviewees not referring to genetic counseling, 51 (41%) have genetic counseling available, but only 12% (6/51) of them view referring or making patients aware of genetic services as their responsibility; while none of the interviewees without genetic counseling services view this their responsibility (p&lt;0.0001). None of the interviewees noted reimbursement of genetic counseling as a barrier to referral. Conclusions: The lack of accountability by care providers is a barrier to referring patients with personal or family history of breast or ovarian cancer to genetic counseling, even when the service is available. A comprehensive approach addressing access to genetic counseling, adoption of referral protocols and clear assignment of referral responsibilities is needed to ensure that women appropriately receive genetic assessment.
Abstract 4864: Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype
Authors: Nicholas Schaum, Christopher Wiley, Fatouma Almirah, Jose A. Lopez-Dominguez, Gary Scott, Christopher Benz, Judith Campisi, Albert R. Davalos
Journal: Cancer Research (2018)

Abstract Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous cytokines, growth factors and proteases, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells. Upon treatment with the MDM2 inhibitors nutlin-3a or MI-63, human cells acquired a senescence-like growth arrest, but the arrest was reversible. Importantly, the inhibitors reduced expression of the signature SASP factors IL-6 and IL-1A by cells made senescent by genotoxic stimuli, and suppressed the ability of senescent fibroblasts to stimulate breast cancer cell aggressiveness. Our findings suggest that MDM2 inhibitors could reduce cancer progression in part by reducing the pro-inflammatory environment created by senescent cells. Citation Format: Nicholas Schaum, Christopher Wiley, Fatouma Almirah, Jose A. Lopez-Dominguez, Gary Scott, Christopher Benz, Judith Campisi, Albert R. Davalos. Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype [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 4864.
Abstract 14427: The Effect of Age and Gender on Endoleak and Reintervention After EVAR
Authors: Trissa Babrowski, Ross Milner
Journal: Circulation (2016)

Introduction: Endovascular aneurysm repair (EVAR) is an effective treatment strategy for abdominal aortic aneurysm (AAA). The late morbidity associated with repair is often due to the development o...
Abstract LB-253: Suppression of clear cell ovarian carcinoma growth by glutaminase-1 inhibitor as single agent and in combination with PARP-1 inhibitor
Authors: Tianjin Yi, Danos Christodoulou, Arimichi Okazaki, Michael Birrer, Othon Iliopoulos
Journal: Cancer Research (2018)

Abstract Tumor hypoxia and cancer-associated mutations reprogram central carbon metabolism and enhance the dependence of cancer cells on glutamine for growth. Clear cell ovarian cancer (CCOC) is a unique epithelial ovarian cancer histotype that is less responsive to chemotherapy and has poorer prognosis than serous histotype. Whole genomic analysis identified major pathways activated in clear cell involving in hypoxic cell growth and carbohydrate metabolism, which were driven by hypoxia-inducible factors HIF1a and/or 2a. We demonstrated before that treatment of HIF-expressing cancer cells with glutaminase 1 (GLS1) inhibitor CB-839, restricts nucleotide synthesis and causes DNA replication stress, which sensitizes cells to the PARP-1 inhibitor. Herein, we observed a range of sensitivities to CB-839 treatment in vitro in CCOC cell lines, from which we selected 4 most sensitive cell lines (ES2, SMOV2, TOV21G and RMG1) and 4 most resistant cell lines (OVSAYO, KK, HAC2 and OVISE) for further study. The synergistic effect of combination treatment of CB-839 and olaparib was achieved in all eight cell lines in vitro. To identify more molecular and metabolic biomarkers of CCOC sensitivity to GLS1 inhibitors, we are currently profiling the gene expression signatures of the most sensitive and resistant CCOC cell lines by RNAseq as well as and the metabolic profile of the CCOC lines. To test the sensitivity of the ES2 cells in vivo to a GLS1 as a single agent or in combination with PARP-1 inhibitors we injected them orthotopically in nude mice. Thirty mice bearing growing ES2 derived tumors were randomly assigned into four groups: vehicle control (n=8), treatment with CB-839 (200mg/kg, gavage, twice daily, n=7), olaparib (75mg/kg, gavage, once daily, n=7) or their combination (n=8). We monitored tumor growth by serial bioluminescence imaging, animal body weight as well as animal survival. To date, after 15-day treatment, we detected a synergistic effect between the 2 agents CB-839 and olaparib in controlling ovarian tumor growth in vivo. Our work discovered a range of sensitivities of CCOC cell lines to GLS1 inhibitor and supports the therapeutic strategies of combining GLS1 inhibitor and PARP inhibitor for targeting HIF-driven CCOC. Citation Format: Tianjin Yi, Danos Christodoulou, Arimichi Okazaki, Michael Birrer, Othon Iliopoulos. Suppression of clear cell ovarian carcinoma growth by glutaminase-1 inhibitor as single agent and in combination with PARP-1 inhibitor [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-253.
Predicting Graft Loss by 1 Year in Pediatric Heart Transplantation Candidates
Authors: Kurt R. Schumacher, Christopher Almond, Tajinder P. Singh, Richard Kirk, Robert Spicer, Timothy M. Hoffman, Daphne Hsu, David C. Naftel, Elizabeth Pruitt, Mary Zamberlan, Charles E. Canter, Robert J. Gajarski
Journal: Circulation (2015)

Background— Pediatric data on the impact of pre–heart transplantation (HTx) risk factors on early post-HTx outcomes remain inconclusive. Thus, among patients with previous congenital heart disease or cardiomyopathy, disease-specific risk models for graft loss were developed with the use pre-HTx recipient and donor characteristics. Methods and Results— Patients enrolled in the Pediatric Heart Transplant Study (PHTS) from 1996 to 2006 were stratified by pre-HTx diagnosis into cardiomyopathy and congenital heart disease cohorts. Logistic regression identified independent, pre-HTx risk factors. Risk models were constructed for 1-year post-HTx graft loss. Donor factors were added for model refinement. The models were validated with the use of patients transplanted from 2007 to 2009. Risk factors for graft loss were identified in patients with cardiomyopathy (n=896) and congenital heart disease (n=965). For cardiomyopathy, independent risk factors were earlier year of transplantation, nonwhite race, female sex, diagnosis other than dilated cardiomyopathy, higher blood urea nitrogen, and panel reactive antibody &gt;10%. The recipient characteristic risk model had good accuracy in the validation cohort, with predicted versus actual survival of 97.5% versus 95.3% (C statistic, 0.73). For patients with congenital heart disease, independent risk factors were nonwhite race, history of Fontan, ventilator dependence, higher blood urea nitrogen, panel reactive antibody &gt;10%, and lower body surface area. The risk model was less accurate, with 86.6% predicted versus 92.4% actual survival, in the validation cohort (C statistic, 0.63). Donor characteristics did not enhance model precision. Conclusions— Risk factors for 1-year post-HTx graft loss differ on the basis of pre-HTx cardiac diagnosis. Modeling effectively stratifies the risk of graft loss in patients with cardiomyopathy and may be an adjunctive tool in allocation policies and center performance metrics.
Abstract 13521: Augmented Inflammation in Pericoronary Adipose Tissue in Patients with Advanced Coronary Artery Disease
Authors: KokiNakanishi, ShotaFukuda, AtsushiTanaka, TakeshiIkuta, KenichiroOtsuka, KenjiMatsumoto, JunichiYoshikawa, KeneiShimada, MinoruYoshiyama
Journal: Circulation (2014)

Introduction: Epicardial adipose tissue (EAT), a visceral adipose tissue surrounding the heart, is associated with coronary atherosclerosis. However, the spatial distribution of inflammation within EAT has not been investigated. Multidetector computed tomography (MDCT) is useful for the assessment of tissue characteristics in vivo. This study aimed to investigate the inflammatory status of pericoronary EAT and its association with the radiodensity of contrast-enhanced MDCT in patients with coronary artery disease (CAD). Methods: Fifteen patients who underwent contrast-enhanced MDCT examination before elective coronary artery bypass grafting (CABG) were recruited. Four fat samples were obtained at surgery including pericoronary EAT, non-pericoronary EAT, extrapericardial fat, and subcutaneous fat (Figure left). MDCT assessment included CT radiodensity at 4 sites of fat depots. Five patients who underwent valvular surgery without CAD were also enrolled. Results: In 15 patients who underwent CABG, monocyte c...
Abstract 154: Inhibition of WEE1 expression reduces lipid metabolism and stemness in hepatocellular carcinoma
Authors: Keon Uk Park, Min Ji Ko, Ilseon Hwang, Hun-Mo Ryoo, Yun-Han Lee
Journal: Cancer Research (2018)

Abstract Background: Classical therapeutic regimens predominantly target proliferating cells, which are unlikely to be cancer stem cells (CSCs). Similarly, new generation therapies, e.g. sorafenib for hepatocellular carcinoma (HCC), do not seem to target CSCs as evidenced by frequent tumor relapse and resistance after therapy. Thus, identification and characterization of signaling pathways and biomarkers associated with CSC biology are therefore priorities for developing new paradigms of molecular cancer therapeutics. Increase of WEE1 kinase activity through an epigenetic regulation plays an important role in the development of HCC. However, the functional role of WEE1 in HCC progression remains to be clarified. Methods: Human HCC cell lines were transfected with WEE1 siRNA and tested for growth inhibition, apoptotic induction, molecular changes in both RNA and protein levels, and changes in CSC phenotype using various methods such as MTS, FACS, microscopic analysis, Real-time PCR, Western blotting, sphere forming assay. To obtain insights into the molecular changes in response to WEE1 knockdown, global changes in gene expression were examined using RNA sequencing. Results: Here we demonstrated that WEE1 siRNA silencing caused inhibition of HCC cell growth through blockade of cell cycle progression and induction of apoptosis. The anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of cdk inhibitor p21 and the downregulation of AKT1, CDK2, cyclin B1 (CCNB1), PARP1 and GPAM which are functionally involved in control of cell cycle, apoptosis and lipid metabolism. Wee1 silencing in tumor cells also resulted in a strong inhibition of lipogenesis (SREBP1C, FAS) and caused a marked decrease in fat accumulation. Of importance, knockdown of WEE1 dramatically reduced the portion of liver CSC population through co-downregulation of cancer stemness genes and weakened the capacity of sphere formation and the ability of cancer cell migration. Systemic delivery of a modified WEE1 siRNA encapsulated in lipid nanoparticles significantly inhibited human HCC growth in murine xenograft models, and increased mice survival. Our findings suggest that the epigenetic modifier WEE1 functionally involve to HCC lipid metabolism and CSC-like phenotype maintenance and that molecular targeting of WEE1 may be an effective systemic therapy for prevention of tumor recurrence via elimination of CSCs in liver tumor microenvironment. Citation Format: Keon Uk Park, Min Ji Ko, Ilseon Hwang, Hun-Mo Ryoo, Yun-Han Lee. Inhibition of WEE1 expression reduces lipid metabolism and stemness in hepatocellular carcinoma [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 154.