tbuckley/cabot-search huggingface dataset:
Abstract 5542: Flaxseed and its lignan component protect from asbestos-induced inflammation in mice
Authors: Steven M. Albelda, Ralph A. Pietrofesa, Craig W. Menges, Joseph R. Testa, Melpo Christofidou-Solomidou
Journal: Cancer Research (2015)

Abstract Introduction/Background: Malignant mesothelioma (MM) is a highly lethal form of thoracic cancer with high mortality and poor treatment options. Development of MM has been linked directly to exposure to asbestos fibers, but with a long latency period. Recent studies have indicated that the pathogenesis of asbestos-induced cancers is due, in part, to chronic inflammation and oxidative tissue damage caused by persistent asbestos fibers. Whole grain flaxseed (FS) has known antioxidant, anti-inflammatory and cancer chemopreventive properties. Rationale: As a prelude to future chemoprevention studies, we tested the ability of oral FS and its lignan component, FLC which is enriched in the lignan secoisolariciresinol diglucoside (SDG), to prevent acute asbestos-induced inflammation and inflammatory cytokine release in MM-prone Nf2+/mut;Cdkn2a+/mut mice. Methods: Mice were given a single ip bolus of 400 mM of crocidolite asbestos. They were then placed on 10% FS or 10% FLC supplemented diets 1 day prior (-1) to or after (+1) asbestos instillation. All mice were evaluated 3 days after injection of asbestos for abdominal inflammation and proinflammatory cytokine release. The Nf2+/mut;Cdkn2a+/mut model was selected as it develops an accelerated form of MM when exposed to asbestos. Results: Using liquid chromatography and tandem mass spectrometry (LC/MS/MS), we showed that systemic levels (plasma) of flaxseed lignan metabolites (such as the mammalian lignans Enterolactone (EL) and Enterodiol (ED)) were comparable to those in other mouse models where FS was shown to be an effective chemopreventive agent. The numbers of macrophages (MF) and neutrophils (PMN) in peritoneal lavage fluid indicated that both FS and FLC blunted acute abdominal inflammation induced by asbestos. In addition, the levels of pro-inflammatory cytokines TNF alpha and IL-1 beta in lavage fluid were also decreased by the dietary agents. Conclusions: Our findings suggest that the known chemopreventive properties of FS and its lignan component appear to reduce short-term asbestos-induced inflammation and may thus prove to be a promising dietary agent in the chemoprevention of MM. Funding: This study was supported in part by Penn's SRP Center Grant (P42 ES027320), “Asbestos fate, exposure, remediation and adverse health effects” from the National Institute of Environmental Health (NIEHS) and 1R03CA180548-02 (MCS). Citation Format: Steven M. Albelda, Ralph A. Pietrofesa, Craig W. Menges, Joseph R. Testa, Melpo Christofidou-Solomidou. Flaxseed and its lignan component protect from asbestos-induced inflammation in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5542. doi:10.1158/1538-7445.AM2015-5542
Inhibition of Pulmonary Coagulopathy by Nebulized Natural Anticoagulants during Streptococcus Pneumoniae Pneumonia in Rats
Authors: J. J. Hofstra, F. E. van den Boogaard, A. D. Cornet, A. P.J. Vlaar, T. van der Poll, M. Levi, M. J. Schultz
Journal: Blood (2008)
Abstract 4281: Determination of the Relative Potency of a Selective Agonist of the Intermediate-Affinity IL-2 Receptor on Lymphocytes from Human, Cynomolgus Monkey and Mouse
Authors: Emily E. Rosentrater, Heather Flick, Jared E. Lopes, Heather C. Losey, Chunhua Wang, Juan C. Alvarez
Journal: Cancer Research (2015)

Abstract RDB 1450 is an engineered fusion protein designed to selectively activate the intermediate-affinity IL-2 receptor versus the high-affinity IL-2 receptor. The potencies of RDB 1450 and IL-2 for activation of distinct subsets of effector and regulatory lymphocytes from murine, non-human primate and human donors were determined. Splenocytes isolated from mice or leukocytes isolated from human or cyno blood were stimulated with either RDB 1450 or IL-2. Multicolor flow cytometry was used to identify distinct subpopulations and the extent of phosphorylation of STAT5 was measured. Whereas IL-2 is 2-3 orders of magnitude more potent on immunosuppressive Tregs relative to NK cells and memory CD8 T cells, RDB 1450 induces activation of NK cells, memory CD8 T cells and Tregs at comparable concentrations within each species. The non-differentiated potency of RDB 1450 on the lymphocyte subpopulations examined suggests that its effects are mediated through the intermediate affinity receptors even on CD25-expressing Tregs. The preferential activation of Tregs by IL-2 may lead to immunosuppression and limit its antitumor efficacy. In contrast, RDB 1450 does not exhibit the same preference for Treg activation and is expected to be more effective in driving antitumor immune responses. These results highlight the differentiated immunological profile of RDB 1450 and support its potential as a novel human immunotherapy. Citation Format: Emily E. Rosentrater, Heather Flick, Jared E. Lopes, Heather C. Losey, Chunhua Wang, Juan C. Alvarez. Determination of the Relative Potency of a Selective Agonist of the Intermediate-Affinity IL-2 Receptor on Lymphocytes from Human, Cynomolgus Monkey and Mouse. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4281. doi:10.1158/1538-7445.AM2015-4281
Genomic Imbalances Are Associated with Outcome of Helicobacter pylori Eradication in t(11;18)(q21;q21)-Negative Gastric MALT Lymphomas.
Authors: Noriko Fukuhara, Hiroyuki Tagawa, Tsuneya Nakamura, Hiroshi Inagaki, Yasuo Morishima, Shigeo Nakamura, Masao Seto
Journal: Blood (2006)
CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer
Authors: Raghvendra M. Srivastava, Sumita Trivedi, Fernando Concha-Benavente, Sandra P. Gibson, Carly Reeder, Soldano Ferrone, Robert L. Ferris
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell–based immunity. Experimental design: CD137 expression on tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells. Results: CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcγRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab. Conclusions: These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. Clin Cancer Res; 23(3); 707–16. ©2016 AACR.
Impact of Prior Therapy with Imatinib Mesylate on the Outcome of Hematopoietic Cell Transplantation (HCT) for Chronic Myeloiod Leukemia (CML).
Authors: Stephanie Lee, Richard Maziarz, Manisha Kukreja, Tao Wang, Sergio Giralt, Jeffrey Szer, Ann Woolfrey, Mukta Arora
Journal: Blood (2007)
High impact of methylation accumulation on metachronous gastric cancer: 5-year follow-up of a multicentre prospective cohort study
Authors: Masahiro Maeda, Takeshi Nakajima, Ichiro Oda, Taichi Shimazu, Nobutake Yamamichi, Takao Maekita, Kiyoshi Asada, Chizu Yokoi, Takayuki Ando, Takeichi Yoshida, Sohachi Nanjo, Mitsuhiro Fujishiro, Takuji Gotoda, Masao Ichinose, Toshikazu Ushijima
Journal: Gut (2016)

We recently published in your journal a 3-year multicentre prospective cohort study demonstrating the usefulness of an epigenetic cancer risk marker for gastric metachronous cancers.1 This study achieved the first proof of concept of epigenetic cancer risk diagnosis in any type of cancer but, due to the short follow-up period, a relatively small number of events were observed, resulting in a marginally significant difference (p=0.042). It was anticipated that a longer follow-up could lead to a clearer difference and HR with a smaller 95% CI. We now report the 5-year follow-up data, which show highly significant results.

Among the 826 enrolled patients, 795 patients received annual follow-ups by endoscopy for a median period of 5.46 years (IQR: 3.95–6.09). By the end, 133 patients had developed a metachronous gastric cancer. Among them, 116 patients developed a metachronous gastric cancer detected 1 year after the enrolment (authentic metachronous cancer).

Statistical analyses were conducted in the same manner as previously …
P0745 : EQ-5D utility index in French patients with chronic hepatits C (CHC) infection: severe comorbidities and perceived progression of CHC infection matter more than actual liver disease stage
Authors: M. Schwarzinger, S. Cossais, S. Deuffic-Burban, S. Pol, H. Fontaine, D. Larrey, G.-P. Pageaux, V. Canva, P. Mathurin, Y. Yazdanpanah
Journal: Journal of Hepatology (2015)
Changing prognosis of glioblastoma multiforme (GBM) in the 21st century: The influence of age and regional income.
Authors: M. V. Mishra, A. Dicker, M. Werner-Wasik, D. W. Andrews, X. Shen, T. N. Showalter, J. Glass, Z. Symon, Y. R. Lawrence
Journal: Journal of Clinical Oncology (2011)

6089 Background: The addition of concurrent/adjuvant temozolomide (TMZ) to post-operative radiation therapy (RT) has been shown to improve overall survival (OS) of GBM patients in a randomized trial testing the benefit of this treatment in patients <70 years. It is unknown if this benefit has been reflected at the population-based level. We therefore performed a population-based survival analysis of newly diagnosed GBM patients covering the period before and after the introduction of TMZ. We further analyzed the impact of mean regional income on any improvements in OS during this time period. Methods: Survival statistics and pertinent clinical and demographic variables were extracted from the Survival, Epidemiology and End Results (SEER) Database for GBM patients diagnosed from 2001-2007. Patients were divided into income quartiles based on mean household income in their county of residence. Survival was analyzed using the Kaplan-Meier method. A multivariate analysis (MVA) was performed to determine independent prognostic factors associated with OS using proportional hazard models. A p-value <0.05 was considered statistically significant. Results: We identified 13,303 adult patients diagnosed with a GBM from 2001-2007. One and 2-year estimated OS rates were 37% and 14% respectively. Favorable prognostic variables identified on MVA included age <70 years, use of RT, gross total resection (GTR), later year of diagnosis, and residence in a high-income district (HI) (p <0.001). From 2001-2007, the median survival time increased from 7 to 9 months for the entire population. One-year survival rate increased from 29% to 39%. Outcomes in patients >70 years did not improve over this period, even amongst patients who had GTR and RT. Over the study period, the absolute disparity in one-year survival between economically poor-and-affluent areas increased from 6.6% to 10.1%. Conclusions: Prognosis of GBM patients has continuously improved from 2001-2007. This improvement has been confined to patients <70 years and has been most prominent amongst patients living in HI districts. Future efforts should be made to identify and mitigate factors contributing to the widening economic disparities gap.
391. Increased Levels of Amyloid β Peptides in RPE via AAV-Mediated Gene Transfer Mimics AMD-Like Pathology in Mice
Authors: Tuhina Prasad, Ping Zhu, Amrisha Verma, Paramita Chakrabarty, Awilda M. Rosario, Todd E. Golde, Qiuhong Li
Journal: Molecular Therapy (2015)

Age-related macular degeneration (AMD) is a progressive retinal neurodegenerative disorder and shares several common characteristics of Alzheimer's disease (AD). Recent studies have provided evidence that amyloid β, a major extracellular deposit in the senile plaques of the AD brain, is also found in drusen, the extracellular deposits characteristic of AMD patients. The goal of this study is to investigate the effects of selective increase of human Aβ42 and Aβ40 in adult mouse retina and to examine the contribution of each to retinal pathophysiology via AAV mediated gene delivery. AAV1 vectors encoding BRI-Aβ cDNAs, fusions between human Aβ peptides and the BRI protein involved in amyloid deposition in British and Danish familial dementia were used to achieve high-level subretinal expression and secretion of the specific encoded Aβ peptide. C57Bl6J mice were randomly divided into following groups based on the vector injected subretinally: (1) AAV1-Bri-Aβ40, (2) AAV1-Bri-Aβ42, (3) Combination of AAV1-Bri-Aβ40 and Aβ42, (4) Control vector AAV1-Bri-Delta KR and (5) Uninjected control. In vivo retinal morphology was assessed by fundus and OCT imaging. Visual function was evaluated by ERG six weeks after injection. Retinal histology was evaluated from paraffin-embedded H&E stained sections. Immunofluorescence was performed to examine Aβ peptides, gliosis, and cell death using specific markers. The large drusen-like extracellular deposits were present in the subretinal space in AAV1-Bri-Aβ40 or Aβ42 injected eyes, absent in control vector injected or uninjected eyes. Immunofluorescence study showed that these deposits were positive for Aβ. Besides the subretinal deposits, the thickness of photoreceptor outer nuclear layer is normal and the ERG responses were only slightly affected in eyes with single vector injection of AAV1-Bri-Aβ40 or Aβ42. Combination of both vectors resulted in more drusen-like deposits, correlated with more severe reduction in ERG responses and photoreceptor cell loss. Our results show that overexpression of either Aβ40 or Aβ42 peptide in the retina is sufficient to initiate Aβ deposition, combination of both caused more severe retinal pathophysiology and that AAV-mediated gene transfer of Aβ peptides is a valuable tool to model aspects of AMD.
475. Effects of HSV-Tk Mediated Suicide Gene Therapy on Normal Brain Cells
Authors: Jubayer Al Hossain, Lars Romø Ystaas, Jelena Mrdalj, Kristjan Vaelk, Kristoffer Riecken, Boris Fehse, Rolf Bjerkvig, Janne Grønli, Hrvoje Miletic
Journal: Molecular Therapy (2016)

Malignant gliomas, the largest group of primary intracerebral tumours, are one of the most difficult-to-cure cancers. For glioblastoma, the most malignant form of glioma, the median survival time is generally less than one year. Lentiviral vector mediated suicide gene therapy has been reported to be a potential therapeutic option for glioma and has been validated in clinically relevant animal models. At this end, specific targeting of tumor cells sparing normal brain tissue is a significant concern. Although several studies may suggest that HSV-Tk mediated suicide gene therapy is not likely to be toxic for normal brain cells, it has never been investigated which effect lentiviral vector mediated HSV-Tk suicide gene therapy exerts on the normal brain in a non-tumor setting. We addressed this important question by delivering the suicide gene HSV-Tk. 007 to the brain of healthy, immunocompetent rats using lentiviral vectors pseudotyped with VSV-G. First, we studied behavior patterns and assessed any potential neurological symptoms in treatment and the control groups, during prodrug treatment with Ganciclovir. We did not observe any significant changes in their physical and behavioral patterns. Then, we carried detailed histological/immunohistochemical analyses of the brains to analyze potential differences in the number of transduced brain cells between control and treatment groups. There was no significant difference in numbers of neurons, astrocytes and oligodendrocyte progenitor cells among the groups, indicating successful survival of these cells after pro-drug treatment. Furthermore, potential inflammation and apoptosis of brain cells were also investigated. No significant infiltration of immune cells was detected across the groups. We could not detect any sign of apoptosis or necrosis across all groups. In conclusion, our study which suggests that lentiviral suicide gene therapy mediated by HSV-Tk. 007 is not toxic for normal brain cells.
Abstract 4124: Potent anti-tumor and metastatic breast cancer efficacy of bevacizumab with CRLX101, an investigational chemotherapy nanoparticle-drug conjugate that secondarily suppresses HIF-1α
Authors: Elizabeth Pham, Christina R. Lee, Ping Xu, Shan Man, Melissa Yin, F. Stuart Foster, Christian G. Peters, Douglas Lazarus, Scott Eliasof, Robert S. Kerbel
Journal: Cancer Research (2015)

Abstract Despite the approval of seven different VEGF-pathway targeting agents, such as bevacizumab, for ten different cancer types, VEGF inhibition has shown only modest survival benefits - especially in breast cancer. One hypothesis for this is the adaptive resistance that emerges, such as increased tumor hypoxia and elevated hypoxia-inducible factor 1α (HIF-1α), which up-regulates genes causing tumor angiogenesis, resistance and metastasis. Here we evaluated bevacizumab paired with a potent cytotoxic investigational drug called CRLX101, a nanoparticle-drug conjugate containing the payload camptothecin that secondarily suppresses HIF-1α. In a preclinical mouse model of primary human breast tumor xenografts grown in the mammary fat pad after cell-line implantation, CRLX101 monotherapy was highly efficacious. More importantly, CRLX101 with bevacizumab resulted in dramatic primary tumor shrinkages and greatly improved mice survival, despite bevacizumab alone having no activity in this model. This potent anti-tumor efficacy was further confirmed in a patient-derived xenograft (PDX) model, where again CRLX101 and bevacizumab led to obvious shrinkage of established primary tumors. HIF-1α suppression was confirmed by immunohistochemistry while changes in tumor hypoxia and perfusion were evaluated using photoacoustic imaging and contrast-enhanced ultrasound, respectively. To better reflect the clinical treatment setting, the combination was next evaluated in our preclinical model of post-surgical, overt metastatic disease. Both CRLX101 monotherapy and CRLX101 in combination with bevacizumab showed shrinkage of existing metastatic masses and prevented the emergence of new metastases. In conclusion, we showed that pairing an anti-angiogenic agent with a potent chemotherapy backbone that is able to suppress HIF-1α up-regulation induced by anti-angiogenic therapy greatly improve efficacy in both primary and metastatic breast cancer models. The data from these preclinical experiments demonstrate that further research of the combination of bevacizumab and other anti-angiogenic drugs with CRLX101 is warranted in solid tumors. Citation Format: Elizabeth Pham, Christina R. Lee, Ping Xu, Shan Man, Melissa Yin, F. Stuart Foster, Christian G. Peters, Douglas Lazarus, Scott Eliasof, Robert S. Kerbel. Potent anti-tumor and metastatic breast cancer efficacy of bevacizumab with CRLX101, an investigational chemotherapy nanoparticle-drug conjugate that secondarily suppresses HIF-1α. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4124. doi:10.1158/1538-7445.AM2015-4124
Abstract LB-239: The Hippo effector YAP promotes resistance to RAF and MEK targeted therapies
Authors: Luping Lin, Amit Sabnis, Elton Chan, Victor Olivas, Lindsay Cade, Evangelos Pazarentzos, Saurabh Asthana, Dana Neel, Jenny Jiacheng Yan, Xinyuan Lu, Luu Pham, Mingxue Wang, Niki Karachaliou, Maria G. Cao, Jose L. Manzano, Jose L. Ramirez, Jose M. Torres, Fiamma Buttitta, Charles M. Rudin, Eric A. Collisson, Alain Algazi, Eric Robinson, Iman Osman, Eva Munoz-Couselo, Javier Cortes, Dennie T. Frederick, Zachary A. Cooper, Martin McMahon, Antonio Marchetti, Rafael Rosell, Keith T. Flaherty, Jennifer A. Wargo, Trever G. Bivona
Journal: Cancer Research (2015)

Abstract Resistance to RAF-MEK targeted therapy is a major clinical challenge. RAF-MEK inhibitors are initially but only transiently effective in some but not all BRAF mutant patients, and largely ineffective in RAS mutant patients because of resistance. Through a genetic screen in BRAF mutant tumor cells, we show that the Hippo pathway effector YAP acts as a parallel survival input to promote resistance to RAF-MEK inhibitor therapy. Combined YAP and RAF-MEK inhibition was synthetically lethal not only in several BRAF mutant tumor types but also in RAS mutant tumors. Increased YAP in BRAFV600E patient tumors was a biomarker of worse initial response to RAF inhibition in patients, establishing the clinical relevance of our findings. Our data uncover YAP as a novel mechanism of resistance to RAF-MEK targeted therapy. The findings unveil the synthetic lethality of YAP and RAF-MEK co-suppression as a promising strategy to enhance response and patient survival. Citation Format: Luping Lin, Amit Sabnis, Elton Chan, Victor Olivas, Lindsay Cade, Evangelos Pazarentzos, Saurabh Asthana, Dana Neel, Jenny Jiacheng Yan, Xinyuan Lu, Luu Pham, Mingxue Wang, Niki Karachaliou, Maria G. Cao, Jose L. Manzano, Jose L. Ramirez, Jose M. Torres, Fiamma Buttitta, Charles M. Rudin, Eric A. Collisson, Alain Algazi, Eric Robinson, Iman Osman, Eva Munoz-Couselo, Javier Cortes, Dennie T. Frederick, Zachary A. Cooper, Martin McMahon, Antonio Marchetti, Rafael Rosell, Keith T. Flaherty, Jennifer A. Wargo, Trever G. Bivona. The Hippo effector YAP promotes resistance to RAF and MEK targeted therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-239. doi:10.1158/1538-7445.AM2015-LB-239
Does An Anthracycline Make a Difference for Follicular Lymphoma (FL) Grade 3? Patterns of Care and Treatment Outcomes of Grade 3 FL From the National LymphoCare Study (NLCS)
Authors: Christopher R Flowers, Michael Taylor, Michelle Byrtek, Jamie H. Hirata, James Cerhan, John Hainsworth, Brian Link, Thomas P. Miller, Hildy Dillon, Jonathan W. Friedberg
Journal: Blood (2010)