tbuckley/cabot-search huggingface dataset:
Abstract 4982: BNC105 induces tumor micro-environment changes which enhance the efficacy of checkpoint inhibitor therapy in preclinical models
Authors: Daniel J. Inglis, Donna M. Beaumont, Annabell F. Leske, Michaela A. Scherer, Tina C. Lavranos
Journal: Cancer Research (2016)

Abstract BNC105 is a Phase II stage drug that specifically targets tubulin causing rapid depolymerisation. The therapeutic window of BNC105 has been shown to be superior compared to similar compounds in its class with highly specific action on tumor vasculature and minimal off target activity. BNC105 shows evidence of strong anti-cancer efficacy in vitro and in animal models not only through destruction of tumour microvasculature but also through strong suppression of cancer cell proliferation. Complementary studies in models of chronic lymphocytic leukaemia have shown that BNC105 also activates pro-apoptotic proteins, which mediate cancer cell death. Recent studies have been conducted to assess changes in the tumour microenvironment that make BNC105 amenable to combination with immune checkpoint inhibitors. Strong synergy with BNC105 has been seen with anti-PD-1 (97%TGI in combination compared to 40% with BNC105 and 74% with anti-PD-1 as monotherapies) and anti-CTLA-4 (70%TGI in combination compared to 27% with BNC105 and 14% with anti-CTLA-4 as monotherapies) using syngeneic MC38 and CT26 colorectal murine tumor models respectively. We hypothesised that the rapid BNC105 induced tumor microvasculature destruction and onset of tumor hypoxia and necrosis leads to an efflux of tumor antigens being presented to the immune system. This has the potential to elicit an immune response against tumors with a lower mutational load than those that would otherwise activate the immune system using checkpoint inhibitors alone. An increase in tumoral IFNgamma can be associated with the presence of antigen-stimulated lymphocytes within the tumor. IFNgamma levels, CD3+ and CD8+ cells were assessed in tumors treated with BNC105 to elucidate the changes in the recruitment of T cell populations within the tumor microenvironment. A more rapid rate of maturation of dendritic cells upon presentation of antigen is also a potential mechanism associated with changes in the tubulin content of the dendritic cell. The elucidation of the mechanism whereby the disruption of micro-vasculature caused by BNC105 further validates the complementary functional role of BNC105 in immune activation with checkpoint inhibitors. These findings support the investigation of combining BNC105 with immune checkpoint inhibitors with the view of progressing such combinations to clinical evaluation. Citation Format: Daniel J. Inglis, Donna M. Beaumont, Annabell F. Leske, Michaela A. Scherer, Tina C. Lavranos. BNC105 induces tumor micro-environment changes which enhance the efficacy of checkpoint inhibitor therapy in preclinical models. [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 4982.
Abstract 3518: Flow cytometry as a single platform tool to evaluate multiple mechanisms of actions of therapeutic antibodies
Authors: Antony R. Chadderton, Shane Harvey, Brandy Strake, Jill Giles-Komar, Renold J. Capocasale, T. Shantha Raju
Journal: Cancer Research (2016)

Abstract The unique ability of flow cytometry to simultaneously examine intricate details of multiple cell subsets is unparalleled and the platform is now a dominant tool for measuring antibody mediated effector functions on cancer cells. The objective of this study is to illustrate the utility of flow cytometry as a single platform for concurrently measuring the multiple mechanisms of actions of therapeutic antibodies such as ADCC, ADCP, Apoptosis, CDC and Trogocytosis on human cancer cells and immune functioning cells. Rituximab® was tested with the Burkett's Lymphoma cell line (Daudi) for all assays between the ranges of 0.01 and 100ug/mL. Apoptosis was evaluated by measuring Caspase 3/7 staining. ADCC assays were established with Rituximab®/CFSE labeled Daudi cells and human PBMC’s. ADCP was assessed with Rituximab®/ CFSE labeled Daudi cells and CD14+/CD11b+ in vitro generated phagocytes using a 4 hour exposure. CDC assays were established with Daudi cells/ 10% pooled human serum using 7-AAD as the cytotoxic indicator in a 4 hour assay. Trogocytosis was measured up to 4 hours with Rituximab®/ Daudi and PBMC's and CD19/20 and CD14. All assays were analyzed using a FACS ARIA III flow cytometer and replicates of 3 were evaluated for statistical relevance. Results demonstrated that Rituximab® induced effects were observed in all 5 assays using flow cytometry. Apoptosis was induced when 0.01ug/mL Rituximab® was present. ADCP occurred at levels as low as 0.01ug/mL Rituximab®. ADCC and CDC occurred at levels as low as 0.1ug/mL Rituximab®. Trogocytosis, indicated by the transfer of CD19+ B cells to CD14+ monocytes, occurred at 0.1ug/ml Rituximab®. In summary, we demonstrated the clinical applicability of flow cytometry as a single platform to simultaneously evaluate five different mechanisms of actions that can occur when therapeutic antibodies are used to treat cancer cells. Citation Format: Antony R. Chadderton, Shane Harvey, Brandy Strake, Jill Giles-Komar, Renold J. Capocasale, T. Shantha Raju. Flow cytometry as a single platform tool to evaluate multiple mechanisms of actions of therapeutic antibodies. [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 3518.
Abstract 5029: The clinical prognostic factors of 889 patients with non-small cell lung cancer
Authors: Yiping Han
Journal: Cancer Research (2016)

Abstract Abstract Objective:To analyse the clinical characteristics and investigate the prognostic factors of the patients with non-small cell lung cancer. Method: We analysed the clinical characteristics of 889 cases with non-small cell lung cancer including age, gender, smoking history, TNM stage, Pathologic grade, the expression of Ki67 and p53, chemotherapy, radiotherapy and targeted therapy. Then, we identified the prognosis through the follow-up. The prognostic factors of the non-small cell lung cancer patients were analysed through survival analysis.We chose the Kaplan-Meier method for the univariate analysis and the Cox proportional hazard regression model for multivariate analysis.Results:The overall median survival time of the patients were 12.87 months,and 1-year,2-year,3-year survival rates were 49%, 26% and 12% respectively. Conclusion: Smoking history,TNM stage,Performance Status score, Pathologic grade, treatment and the expression of Ki67 were independent prognostic factors. Citation Format: Yiping Han. The clinical prognostic factors of 889 patients with non-small cell lung cancer. [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 5029.
PKM2 and CD44 tumoral expression to predict the effectiveness of front-line paclitaxel and carboplatin chemotherapy in epithelial ovarian cancer.
Authors: Chara Papadaki, Spyros Pontikakis, Eleni Lagoudaki, Maria Trypaki, Filippos Koinis, Maria Tzardi, Linda Giannikaki, Maria Sfakianaki, Antonia Kalykaki, Dimitrios Mavroudis, Vassilis Georgoulias, Ioannis Souglakos
Journal: Journal of Clinical Oncology (2015)

e16564 Background: CD44, a surface marker for cancer stem cells interacts with PKM2, a key regulator of aerobic glycolysis and enhances the glycolytic phenotype of cancer cells that, subsequently, leads to increased glutathione levels and decreased ROS accumulation. To explore the clinical importance of this interaction as a mechanism of drug resistance, we assessed the expression of PKM2 and CD44 in cancer cells of patients with epithelial ovarian cancer (EOC) treated with front-line paclitaxel and carboplatin. Methods: FFPE from primary tumors of 172 patients with EOC were evaluated for PKM2 mRNA expression by qRT-PCR and evaluated for PKM2 and CD44 protein by immunohistochemistry. Results: PKM2 mRNA and protein were detectable in the majority (97%) of patients while CD44 protein expression in 83% of patients. There was a linear correlation between PKM2 and CD44 protein expression (Spearman’s test: 0.229; p = 0.001). High PKM2 mRNA and protein levels were significantly associated with lower progression-free survival (PFS; p =0.001 and p =0.008, respectively) and shorter overall survival (OS; p =0.005 and p =0.001, respectively). Also, high CD44 protein expression but not PFS was significantly correlated with shorter OS (p =0.004 and p =0.118, respectively). Patients with high PKM2 and CD44 protein levels experienced shorter PFS and OS (p =0.005 and p =0.001, respectively). Multivariate analysis revealed high mRNA expression of PKM2 as independent prognostic factor for decreased mPFS (p= 0.041) and mOS (p= 0.038). Conclusions: PKM2 expression is a negative prognostic factor for PFS and OS in EOC patients. These data further confirm that CD44 and PKM2 interaction may contribute to platinum resistance, a finding which has to be confirmed in future studies.
Use of leucine-rich and immunoglobulin-like domains germ-line polymorphisms to predict clinical outcome in metastatic colorectal cancer.
Authors: David Páez, Melissa Janae Labonte, Laia Paré, Dongyun Yang, Pierre Oliver Bohanes, Armin Gerger, Wu Zhang, Leonor Benhaim, Yan Ning, Takeru Wakatsuki, Fotios Loupakis, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2012)

e14052 Background: Leucine-rich and immunoglobulin-like domains (LRIG) 1, 2, and 3 are integral membrane proteins recently discovered as regulators of the epidermal growth factor signalling. LRIG1 negatively regulates growth factor signaling and increasing evidence indicates that LRIG1 is a tumor suppressor in certain cancer types. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some colorectal tumors.We postulate that polymorphisms located in the LRIG1 gene could influence the EGFR signalling pathway and be related with the clinical outcome in metastatic colorectal cancer (mCRC). Methods: This study included 318 patients with mCRC treated between 1992 and 2003 at the University of Southern California/Norris Comprehensive Cancer Center or Los Angeles County/University of Southern California Medical Center. Common and putatively functional polymorphisms in the LRIG genes were selected using public literature resources and databases (NCBI, PubMed, db SNP, Ensembl and GeneCards). Whole blood samples were analyzed for germline polymorphisms by direct DNA-sequencing. Overall survival (OS) was evaluated according to each genotype. Furthermore, polymorphisms with suggestive statistical significance were replicated in an independent validation cohort of 126 Spanish mCRC. Results: In a preliminary analysis, two non-synonymous (c3158A&gt;C and c1843A&gt;G) and two synonymous (c2221T&gt;C and c1317C&gt;T) polymorphisms in the LRIG1 gene were selected. There were significant interactions between LRIG1 c1317C&gt;T polymorphisms and clinical outcome. OS was lower for patients harboring T/T genotype (median=11.9 months, 95% C.I (3.5-16 months) than for patients with the C/C or C/T genotypes (median=14.5 months; 95% C.I (12.2-18.3 months); p= 0.04, log-rank test) and the association was also significant in the validation cohort (p=0.01). Conclusions: In this study, we identified common germline variants in LRIG1 gene predicting clinical outcome in patients with mCRC. Although, no functionality has been documented for these SNPs to date, our clinical data suggest that these polymorphisms may affect the mRNA stability and/or translation efficiency of the gene.
Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration
Authors: Markus Wallner, Jason M. Duran, Sadia Mohsin, Constantine D. Troupes, Davy Vanhoutte, Giulia Borghetti, Ronald J. Vagnozzi, Polina Gross, Daohai Yu, Danielle M. Trappanese, Hajime Kubo, Amir Toib, Thomas E. Sharp, Shavonn C. Harper, Michael A. Volkert, Timothy Starosta, Eric A. Feldsott, Remus M. Berretta, Tao Wang, Mary F. Barbe, Jeffrey D. Molkentin, Steven R. Houser
Journal: Circulation Research (2016)

Catecholamines increase cardiac contractility, but exposure to high concentrations or prolonged exposures can cause cardiac injury. A recent study demonstrated that a single subcutaneous injection of isoproterenol (ISO; 200 mg/kg) in mice causes acute myocyte death (8%-10%) with complete cardiac repair within a month. Cardiac regeneration was via endogenous cKit(+) cardiac stem cell-mediated new myocyte formation.Our goal was to validate this simple injury/regeneration system and use it to study the biology of newly forming adult cardiac myocytes.C57BL/6 mice (n=173) were treated with single injections of vehicle, 200 or 300 mg/kg ISO, or 2 daily doses of 200 mg/kg ISO for 6 days. Echocardiography revealed transiently increased systolic function and unaltered diastolic function 1 day after single ISO injection. Single ISO injections also caused membrane injury in ≈10% of myocytes, but few of these myocytes appeared to be necrotic. Circulating troponin I levels after ISO were elevated, further documenting myocyte damage. However, myocyte apoptosis was not increased after ISO injury. Heart weight to body weight ratio and fibrosis were also not altered 28 days after ISO injection. Single- or multiple-dose ISO injury was not associated with an increase in the percentage of 5-ethynyl-2'-deoxyuridine-labeled myocytes. Furthermore, ISO injections did not increase new myocytes in cKit(+/Cre)×R-GFP transgenic mice.A single dose of ISO causes injury in ≈10% of the cardiomyocytes. However, most of these myocytes seem to recover and do not elicit cKit(+) cardiac stem cell-derived myocyte regeneration.
Vitamin D-Dependent Induction of Cathelicidin in Human Macrophages Results in Cytotoxicity Against High Grade B-Cell Lymphoma
Authors: Heiko Bruns, Maike Büttner, Mario Fabri, Dimitrios Mougiakakos, Joerg Thomas Bittenbring, Shirin Pasemann, Frank Neumann, Anna Maurberger, Bettina Kempkes, Andreas Mackensen, Armin Gerbitz
Journal: Blood (2014)
Abstract 2992: Propranolol induces G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway
Authors: Chengfang Zhou, Xiang Chen, Howard L McLeod, Todd C Knepper, Yijing He
Journal: Cancer Research (2016)

Abstract Both preclinical and clinical studies implied that β-adrenoceptor-blockers (β-blockers) could inhibit the growth of melanoma. However, the underline mechanism is still unclear, especially in acral melanoma. MAPK and AKT pathway is involved in tumor survival and apoptosis. Therefore, we investigated the effect of propranolol on melanoma in the A375, two primary acral melanoma cell lines and mice model. In this study, propranolol significantly reduced cell viability and induced apoptosis by activating intrinsic mitochondrial pathway and inhibiting MAPK and AKT pathway in vitro. Meanwhile, we further highlighted that low dose propranolol could slow down the growth of tumor in immunodeficient mice engrafted with human melanoma cells. Thus, our data firstly showed that propranolol may inhibit melanoma by activating intrinsic mitochondrial pathway and regulating MAPK pathway and AKT pathway. Citation Format: Chengfang Zhou, Xiang Chen, Howard L McLeod, Todd C Knepper, Yijing He. Propranolol induces G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway. [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 2992.
Abstract 3246: Phytotherapy boosts innate immunity to maximize cancer survival
Authors: Benjamin H. Lau
Journal: Cancer Research (2016)

Abstract We studied surgery, radiation, and chemotherapy in animals and found all these modalities suppressed cancer growth but they also impaired the immune functions of the animal host. We also studied phytotherapy (use of plant chemicals) and found it to have no side effects and with more lasting benefits. Using in vitro cell culture system with both malignant and non-malignant cells, and immune cells (macrophages and natural killer cells), we compared crude extract of Pacific yew and the chemotherapeutic drug Paclitaxel derived from Pacific yew. The crude extract or the drug was incubated separately with: human malignant ovarian cells, nonmalignant ovarian cells, macrophages, and natural killer cells. Cell viability was determined by MTT (methylthiazol tetrazolium) assay. Results show the drug damaged all these four types of cells while the crude plant extract only damaged the cancer cells showing its selective toxicity for cancer cells. Study with other phytochemicals also shows selective toxicity for cancer cells while enhancing the activities of immune cells. Phytotherapy is thus a non-toxic chemotherapy and immunotherapy. In our clinical observation, 160 men and women diagnosed with five types of cancer (72 with breast cancer, 28 with prostate cancer, 18 with colon cancer, 14 with lung cancer, 28 with ovarian cancer) chose to use phytotherapy (a plant-based diet) plus lifestyle modification. The five year survival of these patients were 90%, 89%, 83%, 86%, and 82%, respectively. Compared with five year survival data from National Cancer Institute (www.seer.cancer.gov) for these five types of cancer: 82%, 50%, 62%, 15%, and 45%, respectively, the phytotherapy group exhibits greater cancer survival. Since numerous studies have now revealed that cancer is attributable to our lifestyle habits – the way we eat, and the way we live, our data suggest that regardless of treatment choices, a change in diet and lifestyle is likely to improve cancer survival. Citation Format: Benjamin H. Lau. Phytotherapy boosts innate immunity to maximize cancer survival. [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 3246.
Abstract 2433: Loss of chd5-mediated gene repression synergizes with MYCN to accelerate neuroblastoma tumorigenesis in zebrafish
Authors: Mark W. Zimmerman, Shuning He, Jimann Shin, Shizhen Zhu, Feng Guo, Marc Mansour, Deepak Reyon, J Keith Joung, Jinhua Quan, Timur Yusufzai, A Thomas Look
Journal: Cancer Research (2016)

Abstract Neuroblastoma is a malignancy of the peripheral sympathetic nervous system (PSNS) and accounts for 10-15% of cancer deaths among children. For the 40% of patients presenting with high-risk disease, current therapeutic approaches are insufficient and long-term survival is less than 50%. Along with genomic amplification of the MYCN oncogene, hemizygous loss of the 1p36 chromosomal region is a major risk factor in neuroblastoma. The human CHD5 gene is a neuronal specific chromatin remodeling helicase that maps to 1p36, and is thus frequently lost in high-risk neuroblastoma. Our laboratory has previously generated a faithful model of pediatric neuroblastoma in the zebrafish driven by overexpression of the MYCN oncogene in the PSNS (dbh:MYCN). Additionally, zebrafish chd5 mutant alleles were created using the newly developed gene editing technologies TALEN and CRISPR-Cas9. The resulting chd5 mutant fish exhibit abnormal development of the PSNS in the form of expansion of the superior cervical ganglia and enlargement of the interrenal gland (adrenal medulla). Haploinsufficiency for Chd5 combined with dbh:MYCN expression accelerates the onset and increases the penetrance of neuroblastoma tumorigenesis in zebrafish, indicating a tumor suppressive function. Elevated p-ERK and PCNA+ cells in tumor tissue indicates that loss of Chd5, cooperates with MYCN overexpression to accelerate neuroblast proliferation in vivo. Chd5 (in addition to Chd3 and Chd4) is a core member of the epigenetic regulatory NuRD complex, which also contains HDAC1-2, MTA1-3, MBD2-3, GATAD2A/B and RBBP4/7. The conserved biological function of Chd5 is to silence gene expression through the maintenance of a repressed chromatin state. Tumors deficient for Chd5 expression exhibit reduced levels of the H3K27me3 histone modification, a marker of facultatively repressed genes. Future studies will further explore the mechanism and function of Chd5 so that the pathways mediating tumor suppression can be elucidated and that essential proteins in these pathways can be targeted in ways that exploit the synthetic lethal relationships that are established. Citation Format: Mark W. Zimmerman, Shuning He, Jimann Shin, Shizhen Zhu, Feng Guo, Marc Mansour, Deepak Reyon, J Keith Joung, Jinhua Quan, Timur Yusufzai, A Thomas Look. Loss of chd5-mediated gene repression synergizes with MYCN to accelerate neuroblastoma tumorigenesis in zebrafish. [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 2433.
Bromodomain Inhibition By OTX015 Regulates c-MYC and HEXIM1 in a Panel of Human Acute Leukemia Cell Lines
Authors: Marie-Magdelaine Coudé, Thorsten Braun, Jeannig Berrou, Mélanie Dupont, Raphael Itzykson, Aline Masse, Emmanuel Raffoux, Maria Eugenia Riveiro, Patrice Herait, Andre Baruchel, Hervé Dombret, Claude Gardin
Journal: Blood (2014)
Extended Molecular and Clinical Phenotype of Human G6PC3 Deficiency.
Authors: Kaan Boztug, Philip S. Rosenberg, Marie Böhm, Thomas Moulton, Julie Curtin, Nima Rezaei, John Corns, Jeffrey Innis, Zekai Avci, Hung Chi Tran, Isabelle Pellier, Simona Gatti, Rachel Fruge, Nima Parvaneh, Phil Darbyshire, George R. Buchanan, Blanche P Alter, Larry Boxer, Jean Donadieu, Karl Welte, Christoph Klein
Journal: Blood (2010)
Tropheryma whipplei DNA in bronchoalveolar lavage samples: a case control study
Authors: J.-C. Lagier, L. Papazian, F. Fenollar, S. Edouard, C. Melenotte, S. Laroumagne, G. Michel, C. Martin, M. Gainnier, C. Lions, P. Carrieri, A. Stein, P. Brouqui, D. Raoult
Journal: Clinical Microbiology and Infection (2016)
Case 33-1981
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Edwin P. Maynard, Christos A. Athanasoulis
Journal: New England Journal of Medicine (1981)

Presentation of Case First admission. A 54-year-old woman was admitted to the hospital because of abdominal pain.She was well until seven months earlier, when periumbilical pain developed and was ascribed to nephrolithiasis. The pain soon subsided but recurred four months before admission and was particularly evident 20 to 30 minutes after eating. Diarrhea and back pain developed. The patient was admitted to another hospital. The erythrocyte sedimentation rate was 76 mm per hour. Serum immunoelectrophoresis showed that IgM was 485 mg per 100 ml, and the complement 320 U. A culture of urine yielded Escherichia coli. A . . .