tbuckley/cabot-search huggingface dataset:
Abstract 4556: Activation of sonic hedgehog signaling is essential for non-alcoholic steatohepatitis induced by liver-specific disruption of Nrf1
Authors: Mingnan Cao, Limei Guo, Juan Li, Chun Liu, Yiguo Zhang, Siwang Yu, Tony A-N. Kong
Journal: Cancer Research (2016)

Abstract Liver-specific inactivation of NF-E2 p45-related factor 1 (Nrf1) results in sequential development of non-alcoholic steatohepatitis (NASH), fibrosis, and finally hepatocellular carcinoma (HCC). However, the detailed mechanisms responsible for this phenotype remain uncertain. In the present study, a β-naphthoflavone (β-NF)-inducible liver-specific Nrf1 knockout mouse line which harbors an Nrf1flox/flox allele and a rat CYP1A1-Cre transgene was employed to investigate potential mechanism underlying Nrf1 deficiency-induced NASH. β-NF-induced liver-specific knockout Nrf1 resulted in a reversible typical NASH and mild fibrosis phenotype. β-NF treatment almost abolished Nrf1 expression after 2 weeks, and induced dramatic elevation of serum transaminase, inflammation, necrosis, ballooning degeneration and HSC activation, but these phenotype diminished after 16 weeks, accompanied by restoration of Nrf1 expression. These observations clearly demonstrated the dependency of NASH and fibrosis on loss of Nrf1, and provide a novel model of reversible non-alcoholic liver diseases. Notably, disruption of Nrf1 caused a sustained activation of sonic hedgehog (shh) signaling pathway accompanied by pronounced endoplasmic reticulum (ER) stress. More importantly, vismodegib, a hedgehog signaling inhibitor, dramatically reversed the deleterious effects caused by loss of Nrf1, such as elevation of serum transaminase activities, inflammatory cells infiltration and hepatocyte necrosis. It has been reported that hepatocytes undergoing endoplasmic reticulum stress and showed elevated expression of hedgehog ligands. However, the mRNA level of hedgehog ligand was not changed in Nrf1 deficiency mice, while the protein levels of both shh and Gli2 were significantly increased. Furthermore, chemical chaperone 4-PBA which can promote protein degradation partially reversed the effects of Nrf1 deficiency on shh signaling. Collectively, these data demonstrate that activation of sonic hedgehog signaling is essential for non-alcoholic steatohepatitis induced by liver-specific disruption of Nrf1, possibly through post-translational modification/procession of shh, and hedgehog signaling could be targeted to treat non-alcoholic liver diseases. The present works were supported by the National Natural Science Foundation of China (No. 91429305, 81272468, and 81372266) Citation Format: Mingnan Cao, Limei Guo, Juan Li, Chun Liu, Yiguo Zhang, Siwang Yu, Tony A-N. Kong. Activation of sonic hedgehog signaling is essential for non-alcoholic steatohepatitis induced by liver-specific disruption of Nrf1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4556.
Abstract 2979: Dual targeting of HER3 and PIK3CA has potent anti-tumor effects in pre-clinical models of HNSCC
Authors: Nayel Khan, Kara S. Davis, Neal Godse, Carolyn Kemp, Sucheta Kulkarni, Diego Alvarado, Theresa LaVallee, Jennifer R. Grandis, Umamaheswar Duvvuri
Journal: Cancer Research (2016)

Abstract Background: The phosphoinositide 3-kinase (PI3K) pathway is a frequently mutated oncogenic pathway in head and neck squamous cell carcinoma (HNSCC). This pathway is often further activated by dysregulation of receptor tyrosine kinases, such as the epidermal growth factor receptor family. HER3 has a direct phosphorylation site with the regulatory subunit of PIK3CA, and is being investigated as a potential co-target to increase anti-tumor effects of PI3K inhibition. In this study, we use the human monoclonal antibody KTN3379, which blocks HER3 in the autoinhibited configuration and thus inhibits ligand-independent and ligand, neuregulin β-1,-dependent HER3 activation, and an inhibitor of PIK3CA (BYL719) to determine if HER3 and PIK3CA can be inhibited in a synergistic fashion. KTN3379 and BYL719 are clinical stage compounds and are being evaluated in HNSCC clinical trials. Methods and Results: Treatment with neuregulin β-1 significantly increased phosphorylation of HER3, AKT, and S6 across HNSCC cell lines, regardless of baseline level of HER3 expression. HER3 inhibition (KTN3379) consistently abrogated these effects and decreased baseline phosphorylation of HER3. Combined blockade of HER3 (KTN3379) and PI3K (BYL719) inhibited the growth of HNSCC cell lines in a synergistic fashion (CI range 0.1-0.5), in both cell proliferation and colony formation assays. This synergy appeared to be less pronounced in HPV-associated cancer cell lines. Combined treatment decreased tumor growth in xenograft models of HNSCC. Furthermore, treatment of some HNSCC cell lines with BYL719 led to upregulation of the HER3 protein in HNSCC cell lines by Western blotting analysis, suggesting a possible role of HER3 in PI3K pathway inhibitor resistance. Conclusion: HER3 interacts with PI3KCA, and the PI3K pathway in multiple HNSCC cell lines, and combined blockade has synergistic effects in pre-clinical HNSCC models. These findings suggest that HER3 and PI3K dual inhibition may be more effective in tumors that are resistant to mono-therapy with either HER3 or PI3K inhibition alone. Citation Format: Nayel Khan, Kara S. Davis, Neal Godse, Carolyn Kemp, Sucheta Kulkarni, Diego Alvarado, Theresa LaVallee, Jennifer R. Grandis, Umamaheswar Duvvuri. Dual targeting of HER3 and PIK3CA has potent anti-tumor effects in pre-clinical models of HNSCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2979.
Everolimus in ER + /HER-2 negative metastatic breast cancer (MBC): what we have learned from two years of clinical practice. A single Institution experience
Authors: A. Della Mora, M. Pistelli, N. Battelli, Z. Ballatore, A. Pagliacci, R. Berardi, M. De Lisa, E. Maccaroni, R. Bracci, A. Santinelli, T. Biscotti, S. Cascinu
Journal: Annals of Oncology (2015)
Implementation of a Community Hospital-Based Fast Track Pathway for the Treatment of Acute Pain Episodes in Adults with Sickle Cell Disease
Authors: Richard Lottenberg, Robert Krywicki, Gurinder Doad, Witemba Kabange, Monisola Modupe, Gregory Steele, Zerettia K McGriff, James A Sirleaf, Abdullah Kutlar, Robert Gibson, Betsy Clair, Matthew L Lyon
Journal: Blood (2014)
Abstract 484: Pre-treatment platelet counts as a prognostic factor in stage II and III rectal adenocarcinoma
Authors: Ioannis Voutsadakis, Morgan Steele
Journal: Cancer Research (2016)

Abstract Background. Thrombocytosis is often associated with malignancies and has been confirmed as an adverse prognostic factor in various cancers. We investigated if pre-treatment elevated platelet counts could provide prognostic information in patients with stage II and III rectal adenocarcinoma that received neo-adjuvant treatment before surgery. Patients and Methods. Platelet number on diagnosis of stage II and III rectal cancer was evaluated in 51 patients receiving neo-adjuvant treatment and for whom there were complete follow-up data on progression and survival, as well as pathologic outcome at time of surgery. Pathologic response after neo-adjuvant treatment of patients with lower platelet counts (150-300× 109/L) was compared with that of patients with higher platelet counts (&amp;gt;300× 109/L) by the χ2 test. Overall and progression free survival Kaplan-Meier curves of the two groups were constructed and compared with the LogRank test. Results. A significant difference was present between the two groups in regards to pathologic response with patients with lower platelet counts being more likely to exhibit a good or complete response to neo-adjuvant treatment than patients with higher platelet counts (P = 0.015). There was also a significant difference between the CEA at presentation of patients that exhibited a good or complete response and those that had no response or a minimal to moderate response. Patients with a good or complete response were more likely to present with a CEA of less than 5 (P = 0.00066). There was no significant difference in overall and progression free survival between the two groups (LogRank tests p = 0.42 and p = 0.35, respectively). Conclusion. In this retrospective analysis of stage II and III rectal cancer patients, platelet counts at the time of diagnosis had prognostic value for neo-adjuvant treatment pathologic effect. Pre-treatment CEA also held prognostic value in regards to treatment effect. Citation Format: Ioannis Voutsadakis, Morgan Steele. Pre-treatment platelet counts as a prognostic factor in stage II and III rectal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 484.
Abstract 4119: Inhibition of PORCN prolongs metastasis free survival in a mouse model of Ewing sarcoma
Authors: Masanori Hayashi, Alissa C. Baker, Seth D. Goldstein, Catherine M. Albert, Kyle W. Jackson, David M. Loeb
Journal: Cancer Research (2016)

Abstract Metastatic disease is the most important factor in determining the survival of patients with Ewing sarcoma (ES). Although intensive cytotoxic chemotherapy has improved the survival of patients with localized disease, the survival rate for patients with metastatic disease remains dismal, and the most pressing unmet need in ES is to prevent and treat metastasis better. The Wnt signaling pathway is a key regulator of a number of cellular functions associated with metastasis, including proliferation, motility, and stem cell self-renewal. A single enzyme, Porcupine (Porcn), mediates post-translational palmitoylation of Wnt ligands, and it's activity is required for secretion of all 17 Wnt ligands, making it an attractive target for a pan-Wnt inhibitor. We have studied the effect of LGK974, a potent, selective, Porcn inhibitor, on Ewing sarcoma metastasis. In vitro, we have observed that LGK974 does not affect proliferation or sarcosphere formation, but inhibits migration of ES cell lines through the suppression of expression of multiple transcriptional regulators of Epithelial-Mesenchymal Transition (EMT). In our orthotopic implantation/amputation mouse model, single agent LGK974 treatment leads to significant delay in formation of lung metastasis following amputation of the affected leg, without a significant effect on primary tumor growth. This delay leads to a significant post-amputation survival benefit in multiple xenografts. In LGK974 treated xenografts, the expression of multiple EMT related transcription factors were observed to be suppressed. Furthermore, in tail vein injection models, LGK974 did not produce a survival benefit, suggesting that LGK974 effects Ewing sarcoma metastasis by inhibiting early steps in the metastatic cascade, such as migration and invasion. Our findings strongly implicate Wnt signaling in the early steps of ES metastasis and demonstrate that LGK974 has the potential to significantly improve the survival of ES patients through the specific inhibition of metastasis. Citation Format: Masanori Hayashi, Alissa C. Baker, Seth D. Goldstein, Catherine M. Albert, Kyle W. Jackson, David M. Loeb. Inhibition of PORCN prolongs metastasis free survival in a mouse model of Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4119.
Abstract 4350: Human oral microbiome and prospective risk for pancreatic cancer: a population based, nested case control study
Authors: Xiaozhou Fan, Alexander V. Alekseyenko, Jing Wu, Eric J. Jacobs, Susan M. Gapstur, Mark P. Purdue, Christian C. Abnet, Rachael Stolzenberg-Solomon, George Miller, Jacque Ravel, Richard B. Hayes, Jiyoung Ahn
Journal: Cancer Research (2016)

Abstract Background: A history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer in prospective studies; however, relationships of oral microbes with pancreatic cancer have not been directly evaluated. We conducted a prospective study to examine the relationship of oral microbiota with subsequent risk of pancreatic cancer. Methods: We selected 361 incident pancreatic cancer cases and 371 matched controls from two prospective cohort studies, the ACS Cancer Prevention Study (CPS) II and the NCI Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). From pre-diagnostic oral wash samples, we characterized the composition of the oral microbiota using bacterial 16S rRNA gene amplification and sequencing. Logistic regression analysis was used to examine the association between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, age, race, sex, smoking status, alcohol consumption, body mass index, and history of diabetes. Findings: Carriage of oral pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were associated with higher risk of pancreatic cancer (adjusted Odds Ratio [OR]p.g = 1·59 and 95% confidence interval [CI] = 1·15-2·20; ORa.a = 2·19 and 95%CI = 1·15-4·15, respectively). Greater relative abundance of phylum Fusobacteria was associated with decreased pancreatic cancer risk (OR per percent increase of abundance = 0·92, 95%CI = 0·87-0·98). Risks related to these phylotypes remained after exclusion of cases that developed within two years of sample collection, reducing the likelihood of reverse causation in this prospective study. Interpretation: The study provides evidence that the oral mcirobiota plays a role in the etiology of pancreatic cancer and may point to accessible means for prevention of this disease. Citation Format: Xiaozhou Fan, Alexander V. Alekseyenko, Jing Wu, Eric J. Jacobs, Susan M. Gapstur, Mark P. Purdue, Christian C. Abnet, Rachael Stolzenberg-Solomon, George Miller, Jacque Ravel, Richard B. Hayes, Jiyoung Ahn. Human oral microbiome and prospective risk for pancreatic cancer: a population based, nested case control study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4350.
Update: Interim Guidance for Prevention of Sexual Transmission of Zika Virus — United States, July 2016
Authors: John T. Brooks, Allison Friedman, Rachel E. Kachur, Michael LaFlam, Philip J. Peters, Denise J. Jamieson
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Zika virus has been identified as a cause of congenital microcephaly and other serious brain defects (1). CDC issued interim guidance for the prevention of sexual transmission of Zika virus on February 5, 2016, with an initial update on April 1, 2016 (2). The following recommendations apply to all men and women who have traveled to or reside in areas with active Zika virus transmission* and their sex partners. The recommendations in this report replace those previously issued and are now updated to reduce the risk for sexual transmission of Zika virus from both men and women to their sex partners. This guidance defines potential sexual exposure to Zika virus as having had sex with a person who has traveled to or lives in an area with active Zika virus transmission when the sexual contact did not include a barrier to protect against infection. Such barriers include male or female condoms for vaginal or anal sex and other barriers for oral sex.(†) Sexual exposure includes vaginal sex, anal sex, oral sex, or other activities that might expose a sex partner to genital secretions.(§) This guidance will be updated as more information becomes available.
Abstract 4911: SOCS-1 inhibits tumor growth by enhancing T cell mediated antitumor immunity related to PD-L1
Authors: Satoshi Nakagawa, Satoshi Serada, Satoko Matsuzaki, Yutaka Ueda, Kiyoshi Yoshino, Minoru Fujimoto, Tadashi Kimura, Tetsuji Naka
Journal: Cancer Research (2016)

Abstract [Background] In many solid cancers, constitutive activation of JAK/ signal transducers and activators of transcription (STAT) signaling pathway is associated with poor prognosis. Constitutive JAK/STAT signaling enhances the expression of cyclins and anti-apoptosis proteins, leads to the increased tumor cell proliferation and survival. Furthermore, one of the immune checkpoint molecules programmed cell death 1 ligand 1 (PD-L1), which is involved in the suppression of T cell mediated antitumor immunity, is induced by STATs. Suppressor of cytokine signaling (SOCS)-1 is a negative feedback molecule, which is induced by JAK/STAT signaling and inhibits the JAK activity, resulted in the suppression of JAK/STAT signaling. This study aimed to reveal the antitumor effects by SOCS-1 in vitro and in vivo. [METHODS] Five human OC cell lines (OVCAR-3, SKOV-3, RMG-1, A2780, ES-2) and 4 murine cancer cell lines (B16F10, LLC, 4T1, CT26) were assessed. SOCS-1 or LacZ were overexpressed by adenoviral vector. Anti-proliferative effect was assessed by WST-8 assay. Female BALB/c mice were injected with CT26 for subcutaneous xenograft experiments. AdSOCS-1 or AdLacZ was intra-tumorally administered every other day and PD-L1 expression in tumor cells and activation levels of tumor infiltrated T cells were analyzed by flow cytometry. [RESULT] Overexpression of SOCS-1 inhibited proliferation of all cancer cell lines. Three OC (OVCAR-3, SKOV-3, ES2) and all murine cancer constitutively expressed PD-L1. Expression levels of PD-L1 in OVCAR-3 and CT26 cells were downregulated about 30% compared with control by overexpressed SOCS-1 in vitro. In CT26 allografted model, SOCS-1 treatment significantly inhibited tumor growth (62.2±5.2%, P&amp;lt;0.01)and suppressed expression of PD-L1 on CT26 cells in the tumor (65.2±8.4%, P&amp;lt;0.05). Granzyme B and CD107a expression of intratumorally infiltrated CD8 T cells were increased more than 50% (P&amp;lt;0.05) in the AdSOCS-1 injected group compared with AdLacZ injected group. PD-L1 Fc fusion protein significantly inhibited antitumor effect of SOCS-1. [Conclusion] SOCS-1 mediated inhibition of JAK/STAT signaling shows not only direct antitumor effect against tumor cells but also enhances T cell mediated anti-tumor immunity in vivo by downregulating the expression of PD-L1 on tumor cells and preventing the interaction of PD-1/ PD-L1. Citation Format: Satoshi Nakagawa, Satoshi Serada, Satoko Matsuzaki, Yutaka Ueda, Kiyoshi Yoshino, Minoru Fujimoto, Tadashi Kimura, Tetsuji Naka. SOCS-1 inhibits tumor growth by enhancing T cell mediated antitumor immunity related to PD-L1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4911.
Abstract LB-024: PIM kinase inhibitors selectively kill hypoxic cancer cells by reducing Nrf2 activity and increasing reactive oxygen species
Authors: Alva G. Sainz, Jin H. Song, Andrew S. Kraft, Noel A. Warfel
Journal: Cancer Research (2016)

Abstract Prostate cancer (PCa) is the leading cause of cancer death in men worldwide. Patients diagnosed with metastatic prostate cancer initially respond to androgen deprivation therapy, but this response is not durable, and all patients develop hormone-refractory disease that ultimately leads to death. Current treatment options for metastatic PCa patients are limited (e.g., cytotoxic chemotherapy or radiation), and the response to these agents is invariably temporary and does not improve survival. A significant obstacle to the successful treatment of advanced PCa is tumor hypoxia. While hypoxia is toxic to normal cells, cancer cells take particular advantage of their ability to adapt to these harsh conditions by increasing the expression of proteins that promote angiogenesis and survival. Therefore, elucidating the molecular mechanisms controlling survival in hypoxia is important for the development of effective therapeutic strategies to selectively kill hypoxic tumor cells. The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases represent a pro-survival pathawy that is upregulated in response to hypoxia in a HIF-1 independent manner. We demonstrate that pharmacological or genetic inhibition of PIM kinases is significantly more toxic toward cancer cells in hypoxia versus normoxia. Xenograft studies confirm that PIM kinase inhibitors impede tumor growth and selectively kill hypoxic tumor cells in vivo. Experiments show that PIM kinases enhance the ability of tumor cells to adapt to hypoxia-induced oxidative stress by increasing the nuclear localization and activity of Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which functions to increase the expression of antioxidant genes. Small molecule PIM kinase inhibitors reduce the ability of Nrf2 to enter the nucleus and block the transcrption of cytoprotective genes, leading to the accumulation of intracellular reactive oxygen species (ROS) to toxic levels in hypoxic tumor cells. This toxic effect of PIM inhibitors can be succesfully blocked by ROS scavengers, including N-acetyl cystine and superoxide dismutase. Thus, inhibition of PIM kinases has the potential to oppose hypoxia-mediate therapeutic resistance and induce cell death in the hypoxic tumor microenvironment. Citation Format: Alva G. Sainz, Jin H. Song, Andrew S. Kraft, Noel A. Warfel. PIM kinase inhibitors selectively kill hypoxic cancer cells by reducing Nrf2 activity and increasing reactive oxygen species. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-024.
Clinical Characteristics and Outcomes In Patients With Acute Promyelocytic Leukemia (APL) and Hyperleukocytosis
Authors: Naval Daver, Hagop M. Kantarjian, Stefan H. Faderl, Guillermo Garcia-Manero, Susan O'Brien, Alessandra Ferrajoli, Srdan Verstovsek, Uday Popat, Chitra M Hosing, Tapan M. Kadia, Jorge E. Cortes, Farhad Ravandi, Paolo Anderlini
Journal: Blood (2013)