tbuckley/cabot-search huggingface dataset:
Abstract 819: DNA methylation genome-wide analysis in remnant gastric cancer
Authors: Tomoaki Ito, Kiichi Sugimoto, Hajime Orita, Masahiro Maeda, Hiroshi Moro, Toshikazu Ushijima, Hitoshi Katai, Ryo Wada, Kazuhiro Sakamoto, Koichi Sato, Malcolm V. Brock
Journal: Cancer Research (2019)

Abstract Purpose: Although primary gastric cancers (PGC) and remnant gastric cancers (RGC) both originate from the same gastrointestinal organ, they have very distinct clinicopathological behaviors. Due to the importance of chronic inflammation in the carcinogenesis of gastric malignancies, we hypothesized that DNA promoter hypermethylation would play a critical role in the carcinogenesis of RGC as well as PGC. Methods: We investigated the genome-wide DNA methylation patterns of PGC and RGC tissues from 48 patients from an academic medical center in Japan using the Infinium HumanMethylation450 BeadChip assay. The results were validated by quantitative methylation-specific PCR (qMSP) in separate, independent cohorts. Results: We found that in our training cohort of 48 patients, genes from the gastric cancer tissues identified by the Infinium HumanMethylation 450 Beadchip clustered into high and low methylation groups on multivariate analysis (p=0.004, OR=12.33). PGCs contributed significantly to the high methylation group suggesting that the DNA promoter methylation status in PGC is higher than that in RGC. Supporting this conclusion was the finding that in a separate qMSP analysis in a test cohort, the gene A had significantly higher DNA promoter methylation in cancer tissues in the validation PGC tissues than in RGC. Conclusion: This study demonstrated that DNA promoter methylation status in PGC is higher than in RGC. This result may reflect the effects of Helicobacter pylori on the induction of DNA methylation in the remnant stomach. Citation Format: Tomoaki Ito, Kiichi Sugimoto, Hajime Orita, Masahiro Maeda, Hiroshi Moro, Toshikazu Ushijima, Hitoshi Katai, Ryo Wada, Kazuhiro Sakamoto, Koichi Sato, Malcolm V. Brock. DNA methylation genome-wide analysis in remnant gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 819.
Impact of HS on work loss, indirect costs and income
Authors: T. Tzellos, H. Yang, F. Mu, B. Calimlim, J. Signorovitch
Journal: British Journal of Dermatology (2019)

Hidradenitis suppurativa (HS) is a rare, long‐term skin disease that causes painful lumps under the skin. HS affects between 0.1% and 4% of the population of the U.S., where this study took place, and the symptoms can interfere with daily life and ability to work. HS often begins between puberty and the age of 40, so many people with HS are in their prime working years. This study aimed to find out how the work life of people with HS was impacted compared to similar people without HS. The authors used a database of insurance claims to find employed people with HS and without HS (controls) who were between 18 and 64 years old. The authors found that people with HS had lower annual income, more missed days at work, and higher costs related to missed work days and disability than people without HS. In addition, people with newly diagnosed HS had a slower increase in income and were more likely to leave their job than those without it, over 5 years following the diagnosis. In conclusion, HS can negatively affect a person's work life and income earning, suggesting that better therapies are needed to help manage the disease symptoms and improve the lives of people with HS.
Abstract 708: Targeting fatty acid synthase induces apoptosis and senescence
Authors: Travis Van der Steen, George Kemble, Ruth Lupu
Journal: Cancer Research (2019)

Abstract Fatty acid synthase (FASN) is a novel therapeutic target for cancer as it has increased expression in many different types of cancers. There has been significant understanding that cancer cells can hijack and modify tightly regulated metabolic pathway for its own survival. FASN is the enzyme that synthesizes palmitate from malonyl-CoA for energy storage, structure and biomolecules. FASN expression is low to undetectable in normal cells with the exception of liver and adipose tissue. In this study, we investigated the role of FASN in breast cancer cells. We observed that in highly expressing FASN breast cancer cells, TVB-3166, FASN inhibitor, results in a decrease in cellular proliferation and an increase in cellular death. FASN inhibition increased reactive oxygen species (ROS) and altered NADPH/NADP+ ratio. Increase in ROS and NADPH have been linked to the intrinsic apoptosis pathway. Additionally, there is an increase in expression of the BH3-only proteins Bim, Puma and Noxa, leading to the permeabilization of the mitochondria and the release of cytochrome c. Furthermore, after prolong exposure to TVB-3166 a number of cells enter into a senescent state. This was observed the in detection of β-galactosidase and confirmed by the expression of senescent markers including ARF, INK4A, and CIP. Additionally, when the cells were treated with a CDK4/6 inhibitor in combination with the FASN inhibitor TVB-3166, an increase in stress induced premature senescence was observed. Our data demonstrates that inhibition of FASN induces intrinsic apoptosis while it stimulates cellular senescence to the apoptotic resistant cells. Therefore, the ability for TVB-3166 to both eradicate and overturn cell growth makes it potential therapeutic modality. Citation Format: Travis Van der Steen, George Kemble, Ruth Lupu. Targeting fatty acid synthase induces apoptosis and senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 708.
Abstract 873: Molecular mechanisms of non-small cell lung cancer growth and drug resistance
Authors: SK Kayum Alam, Matteo Astone, Ping Liu, Li Wang, Abbygail M. Coyle, Erin N. Dankert, Dane K. Hoffman, Stephanie R. Hall, Wei Zhang, Rui Kuang, Anja C. Roden, Aaron S. Mansfield, Luke H. Hoeppner
Journal: Cancer Research (2019)

Abstract Lung cancer is the deadliest and most frequently diagnosed type of tumor worldwide, with 1.6 million deaths reported annually. Non-small cell lung cancer (NSCLC) represents 85% of all lung cancer cases and carries a poor 5-year survival rate below 15%. Prognoses remain dismal due to the large number of patients diagnosed with advanced stage disease and the development of resistance to current therapies. A better understanding of acquired drug resistance will help to circumvent the progression of lung cancer and make significant strides in improving NSCLC patient treatment. Our recent work demonstrates that dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) and its amino-terminally truncated splice variant (t-DARPP) promote lung tumor growth in orthotopic mouse models. IHC staining of 62 human lung adenocarcinoma tissues showed that t-DARPP expression is elevated with increasing tumor (T) staging score, which represents the size of the primary tumor and whether it has grown into nearby areas, as a metric of tumor progression and growth. Correspondingly, a computational biology analysis of 513 lung adenocarcinoma patients revealed upregulation of t-DARPP isoform expression correlates with advanced T stage and is associated with poor overall survival. We identified a novel physical interaction between DARPP-32 and inhibitory kappa B kinase-α (IKKα) that promotes NSCLC cell migration through activation of non-canonical NF-κB2 signaling. It has been shown that DARPP-32 overexpression inhibits gefitinib-induced apoptosis in gastric cancer and t-DARPP contributes to the trastuzumab resistance phenotype in breast cancer. Our recent findings suggest DARPP-32 and t-DARPP overexpression in NSCLC promotes resistance to specific molecular targeted inhibitors by enabling tumor cells to evade apoptosis via Akt- and Erk-dependent cell survival mechanisms. Current ongoing studies are focused on manipulating expression of DARPP-32 isoforms in lung tumor cells to prevent resistance to targeted therapies in NSCLC patients. Citation Format: SK Kayum Alam, Matteo Astone, Ping Liu, Li Wang, Abbygail M. Coyle, Erin N. Dankert, Dane K. Hoffman, Stephanie R. Hall, Wei Zhang, Rui Kuang, Anja C. Roden, Aaron S. Mansfield, Luke H. Hoeppner. Molecular mechanisms of non-small cell lung cancer growth and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 873.
Abstract 2683: Biomarkers of glucose homeostasis and inflammation and risk of prostate cancer: A case-cohort study
Authors: Ying Wang, Peter T. Campbell, Victoria L. Stevens, Christina C. Newton, Eric J. Jacobs, Michael Pollak, Susan M. Gapstur
Journal: Cancer Research (2019)

Abstract Background: Type 2 diabetes (T2DM) is associated with a lower risk of prostate cancer especially low-grade and localized prostate cancer. The association with aggressive prostate cancer is inconclusive. Few studies have directly examined the associations of diabetes biomarkers with prostate cancer risk. Methods: Among a cohort of 13,994 men who were on average 70.2 years (SD=5.5) and cancer free at blood draw between 1998 and 2001, 1,206 developed non-aggressive prostate cancer and 313 developed aggressive prostate cancer (AJCC stage 3-4 or Gleason score 8-10) during follow-up through June 2013. We conducted a case-cohort study including a random sub-cohort of 1,303 men, 391 non-aggressive cases and 313 aggressive cases to examine circulating hemoglobin A1c (HbA1c), c-peptide, and C-reactive protein (CRP) in relation to prostate cancer risk. Results: HbA1c, a biomarker of hyperglycemia, was inversely associated with non-aggressive prostate cancer after adjusting for age, race, family history of prostate cancer, prostate-specific antigen screening, smoking, alcohol intake, physical activity, and total energy intake (relative risk (RR) per unit increase: 0.89, 95% confidence interval (CI): 0.79-1.00, P=0.04). Further adjustment for body mass index (BMI) attenuated the association. In contrast, HbA1c was associated with a higher risk of aggressive prostate cancer after adjusting for the covariates including BMI (RR per unit increase: 1.11, 95% CI: 0.98-1.25, P=0.11). In an analysis combining self-reported T2DM and HbA1c, men with T2DM and poor blood glucose control (HbA1c ≥6.5%) had a lower risk of developing non-aggressive prostate cancer (RR: 0.53, 95% CI: 0.30-0.95) than men without T2DM and good blood glucose control (HbA1c &amp;lt;6.5%). After excluding men with self-reported T2DM, HbA1c was statistically significantly positively associated with risk of aggressive prostate cancer (RR per unit increase: 1.25, 95% CI: 1.04-1.51, P=0.02) but was not associated with non-aggressive prostate cancer. C-peptide and CRP were not associated with risk of either aggressive or non-aggressive prostate cancer.Conclusions: The present study suggests that men with hyperglycemia may have a lower risk of developing non-aggressive but a higher risk of developing aggressive prostate cancer. Further studies are needed to examine the role of hyperglycemia in the etiology of aggressive prostate cancer and in prostate cancer progression. Citation Format: Ying Wang, Peter T. Campbell, Victoria L. Stevens, Christina C. Newton, Eric J. Jacobs, Michael Pollak, Susan M. Gapstur. Biomarkers of glucose homeostasis and inflammation and risk of prostate cancer: A case-cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2683.
Abstract 4304: Anti-proliferative activity of nodosin is associated with the regulation of wnt signaling pathway in colon cancer cell
Authors: Eunseo Bae, Donghwa Kim, Woong sub Byun, Sang Kook Lee, Young-Won Chin
Journal: Cancer Research (2019)

Abstract Wnt signaling is a critical mechanism of biological processes, including cell proliferation, tissue homeostasis and development. The aberrant activity of Wnt signaling pathway is highly correlated with the colorectal carcinogenesis. Therefore, the effective compounds targeting Wnt signaling pathway could be applicable for colorectal cancer treatment. The bioactivity of nodosin, a component of Isodon serra, was evaluated in HCT116 colorectal cancer cells. Nodosin exhibited a potential growth inhibition of colon cancer cells. Nodosin also showed an effective inhibition upon wnt/β-catenin reporter gene assay in HEK293 and HCT116 cells. In addition, Wnt target genes such as β-catenin, Axin2, cyclin D1 and survivin were suppressed by nodosin in HCT116 cells. The inhibition of cell proliferation by nodosin was in part associated with the G2/M phase cell cycle arrest in colon cancer cell. These findings suggest that the anti-proliferative activity of nodosin against colorectal cancer cell should be associated with the regulation of Wnt/β-catenin signaling pathway. This work was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MEST) (NRF-2016M3A9B6903499). Citation Format: Eunseo Bae, Donghwa Kim, Woong sub Byun, Sang Kook Lee, Young-Won Chin. Anti-proliferative activity of nodosin is associated with the regulation of wnt signaling pathway in colon cancer cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4304.
The microbiology of pleural infection in adults: a systematic review
Authors: Maged Hassan, Tamsin Cargill, Elinor Harriss, Rachelle Asciak, Rachel M. Mercer, Eihab O. Bedawi, David J. McCracken, Ioannis Psallidas, John P. Corcoran, Najib M. Rahman
Journal: European Respiratory Journal (2019)

Pleural infection is a major cause of morbidity and mortality among adults. Identification of the offending organism is key to appropriate antimicrobial therapy. It is not known whether the microbiological pattern of pleural infection is variable temporally or geographically. This systematic review aimed to investigate available literature to understand the worldwide pattern of microbiology and the factors that might affect such pattern.Ovid MEDLINE and Embase were searched between 2000 and 2018 for publications that reported on the microbiology of pleural infection in adults. Both observational and interventional studies were included. Studies were excluded if the main focus of the report was paediatric population, tuberculous empyema or post-operative empyema.Studies of ≥20 patients with clear reporting of microbial isolates were included. The numbers of isolates of each specific organism/group were collated from the included studies. Besides the overall presentation of data, subgroup analyses by geographical distribution, infection setting (community versus hospital) and time of the report were performed.From 20 980 reports returned by the initial search, 75 articles reporting on 10 241 patients were included in the data synthesis. The most common organism reported worldwide was Staphylococcus aureus. Geographically, pneumococci and viridans streptococci were the most commonly reported isolates from tropical and temperate regions, respectively. The microbiological pattern was considerably different between community- and hospital-acquired infections, where more Gram-negative and drug-resistant isolates were reported in the hospital-acquired infections. The main limitations of this systematic review were the heterogeneity in the method of reporting of certain bacteria and the predominance of reports from Europe and South East Asia.In pleural infection, the geographical location and the setting of infection have considerable bearing on the expected causative organisms. This should be reflected in the choice of empirical antimicrobial treatment.
Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer
Authors: Sunil Acharya, Jun Yao, Ping Li, Chenyu Zhang, Frank J. Lowery, Qingling Zhang, Hua Guo, Jingkun Qu, Fei Yang, Ignacio I. Wistuba, Helen Piwnica-Worms, Aysegul A. Sahin, Dihua Yu
Journal: Cancer Research (2019)

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. To identify TNBC therapeutic targets, we performed integrative bioinformatics analysis of multiple breast cancer patient-derived gene expression datasets and focused on kinases with FDA-approved or in-pipeline inhibitors. Sphingosine kinase 1 (SPHK1) was identified as a top candidate. SPHK1 overexpression or downregulation in human TNBC cell lines increased or decreased spontaneous metastasis to lungs in nude mice, respectively. SPHK1 promoted metastasis by transcriptionally upregulating the expression of the metastasis-promoting gene FSCN1 via NFκB activation. Activation of the SPHK1/NFκB/FSCN1 signaling pathway was associated with distance metastasis and poor clinical outcome in patients with TNBC. Targeting SPHK1 and NFκB using clinically applicable inhibitors (safingol and bortezomib, respectively) significantly inhibited aggressive mammary tumor growth and spontaneous lung metastasis in orthotopic syngeneic TNBC mouse models. These findings highlight SPHK1 and its downstream target, NFκB, as promising therapeutic targets in TNBC. SIGNIFICANCE: SPHK1 is overexpressed in TNBC and promotes metastasis, targeting SPHK1 or its downstream target NFκB with clinically available inhibitors could be effective for inhibiting TNBC metastasis.
Abstract 937: Nr4a transcription factors limit CAR T-cell function in solid tumors
Authors: Joyce Chen, Isaac F. Lopez-Moyado, Hyungseok Seo, Chan-Wang J. Lio, Laura J. Hempleman, Takashi Sekiya, Akihiko Yoshimura, James P. Scott-Browne, Anjana Rao
Journal: Cancer Research (2019)

Abstract In cancer immunotherapy, CD19-targeted CAR T cells have exhibited impressive clinical efficacy against B cell leukemias and lymphomas; however, they have been less effective against solid tumors. This is in part because CAR T cells enter a hyporesponsive (“exhausted” or “dysfunctional”) state that is triggered by chronic antigen stimulation and characterized by upregulation of several inhibitory surface receptors and loss of effector function. To identify transcriptional regulators and other candidates contributing to the diminished CAR T cell function in solid tumors, we developed a CAR T cell model in which recipient mice bearing murine melanoma tumors expressing human CD19 were adoptively transferred with CD19-targeted CAR T cells. We demonstrate that in both CD8+ CAR T tumor-infiltrating lymphocytes (TILs) and endogenous CD8+ TILs expressing high levels of PD-1 and TIM3, the Nr4a proteins Nr4a1 (Nur77), Nr4a2 (Nurr1), and Nr4a3 (Nor1) are prominent effectors of the transcriptional program downstream of NFAT: they promote the expression of inhibitory receptors and genes associated with early hyporesponsive state, and limit effector function. Most importantly, treatment of tumor-bearing mice with CD8+ CAR T cells lacking all three Nr4a factors (Nr4aTKO) resulted in tumor regression and prolonged survival. Nr4aTKO CD8+ CAR T TILs displayed a transcriptomic profile characteristic of effector function, including upregulation of granzymes and cytokines, and many of these gene expression changes were associated with altered regulatory element accessibility near effector genes. Our data identify Nr4a transcription factors as major players in the cell-intrinsic program of T cell hyporesponsiveness and point to Nr4a inhibition as a promising strategy for cancer immunotherapy. Citation Format: Joyce Chen, Isaac F. Lopez-Moyado, Hyungseok Seo, Chan-Wang J. Lio, Laura J. Hempleman, Takashi Sekiya, Akihiko Yoshimura, James P. Scott-Browne, Anjana Rao. Nr4a transcription factors limit CAR T-cell function in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 937.
Rivaroxaban With or Without Aspirin in Patients With Heart Failure and Chronic Coronary or Peripheral Artery Disease
Authors: Kelley R. Branch, Jeffrey L. Probstfield, John W. Eikelboom, Jackie Bosch, Aldo P. Maggioni, Richard K. Cheng, Deepak L. Bhatt, Alvaro Avezum, Keith A.A. Fox, Stuart J. Connolly, Olga Shestakovska, Salim Yusuf
Journal: Circulation (2019)

Patients with chronic coronary artery disease or peripheral artery disease and history of heart failure (HF) are at high risk for major adverse cardiovascular events. We explored the effects of rivaroxaban with or without aspirin in these patients.The COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) randomized 27 395 participants with chronic coronary artery disease or peripheral artery disease to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg alone. Patients with New York Heart Association functional class III or IV HF or left ventricular ejection fraction (EF) <30% were excluded. The primary major adverse cardiovascular events outcome comprised cardiovascular death, stroke, or myocardial infarction, and the primary safety outcome was major bleeding using modified International Society of Thrombosis and Haemostasis criteria. Investigators recorded a history of HF and EF at baseline, if available. We examined the effects of rivaroxaban on major adverse cardiovascular events and major bleeding in patients with or without a history of HF and an EF <40% or ≥40% at baseline.Of the 5902 participants (22%) with a history of HF, 4971 (84%) had EF recorded at baseline, and 12% had EF <40%. Rivaroxaban and aspirin had similar relative reduction in major adverse cardiovascular events compared with aspirin in participants with HF (5.5% versus 7.9%; hazard ratio [HR], 0.68; 95% CI, 0.53-0.86) and those without HF (3.8% versus 4.7%; HR, 0.79; 95% CI, 0.68-0.93; P for interaction 0.28) but larger absolute risk reduction in those with HF (HF absolute risk reduction 2.4%, number needed to treat=42; no HF absolute risk reduction 1.0%, number needed to treat=103). The primary major adverse cardiovascular events outcome was not statistically different between those with EF <40% (HR, 0.88; 95% CI, 0.55-1.42) and ≥40% (HR, 0.81; 95% CI, 0.67-0.98; P for interaction 0.36). The excess hazard for major bleeding was not different in participants with HF (2.5% versus 1.8%; HR, 1.36; 95% CI, 0.88-2.09) than in those without HF (3.3% versus 1.9%; HR, 1.79; 95% CI, 1.45-2.21; P for interaction 0.26). There were no significant differences in the primary outcomes with rivaroxaban alone.In patients with chronic coronary artery disease or peripheral artery disease and a history of mild or moderate HF, combination rivaroxaban and aspirin compared with aspirin alone produces similar relative but larger absolute benefits than in those without HF.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.
RUNX1 Expression Characterizes the Endothelial Cells from the Spleen and Bone Marrow of Patients with Primary Myelofibrosis
Authors: Rita Campanelli, Margherita Massa, Laura Villani, Paolo Catarsi, Carlotta Abbà, Elisabetta Dejana, Monica Corada, Federica Pisati, Giovanni Barosi, Vittorio Rosti
Journal: Blood (2018)