tbuckley/cabot-search huggingface dataset:
Abstract LB-217: PD-1 suppresses antibody responses to Tn+ tumors
Authors: Marcela A. Leyva, Karen M. Haas
Journal: Cancer Research (2015)

Abstract Cancer cells often have aberrant glycosylation of surface molecules leading to glycan antigens that are not typically found on normal cells. These antigens are referred to as tumor associated carbohydrate antigens (TACAs) and are a promising target for anti-cancer vaccines. One such TACA is the Thomsen-nouvelle (Tn) antigen, which is expressed by up to 90% of adenocarcinomas. The mechanisms regulating the B cell response to Tn and other TACAs are not well understood. This knowledge is essential for the development of vaccines to elicit protective immune responses to tumors bearing TACAs. PD-1 (programmed cell death 1) is a member of the B7:CD28 superfamily of receptors found on antigen-activated B and T cells. It negatively regulates antigen receptor signaling and thereby limits adaptive immune responses, including the anti-tumor T cell response. However, virtually nothing is known about the role of PD-1 in regulating B cell responses to tumors. In this study, we tested the hypothesis that PD-1 suppresses B cell production of Tn-specific antibodies and thereby suppresses protective humoral immunity against Tn+ tumors. Our results show that PD-1−/− mice immunized with a Tn-bearing mucin (desialyated bovine submaxillary mucin) have increased Tn+ tumor-reactive IgM and IgG antibodies, relative to wild type mice. PD-1−/− mice immunized with the Tn+ mucin had significantly increased survival relative to wild type mice following challenge with a Tn+ bearing mammary tumor (TA3-Ha). Survival in PD-1−/− mice was dependent on the presence of B cells. Therefore, our results show that PD-1 plays a critical role in suppressing the protective anti-tumor B cell response elicited by Tn-bearing antigen immunization. This work was supported by NIH/NCI F31 CA183567-01 fellowship to M.A.L. and an American Cancer Society Research Scholar Grant (RSG-12-170-01-LIB) to K.M.H. Citation Format: Marcela A. Leyva, Karen M. Haas. PD-1 suppresses antibody responses to Tn+ tumors. [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-217. doi:10.1158/1538-7445.AM2015-LB-217
Evaluation of notch and hypoxia signalling pathway in human renal cell carcinoma.
Authors: V. Medina Villaamil, G. Aparicio Gallego, I. Santamarina Caínzos, E. Grande Pulido, L. Antón Aparicio
Journal: Journal of Clinical Oncology (2011)

e21088 Background: Notch genes play a critical role in growth, development and tumorigenesis. HIF1-α can interact with the Notch intracellular domain to augment the Notch downstream response. Because the Notch signalling pathway is responsive to hypoxia we examined, in this study, the patterns of expression and clinical significance of Notch, Notch receptors and Hif1-α and β in human renal cell carcinoma paraffin-embedded tissues. Methods: Eighty cases of renal cell carcinoma (RCC) tissues were detected by immunohistochemistry. RNA of quality only was obtained in 60 samples (80% clear RCC, 10% papillary RCC and 10% chromophobe RCC) to carry out the study of gene expression through qPCR (quantitative real-time polymerase chain reaction). A pool of normal kidney-derived RNA samples (N=5) was used as healthy control. GAPDH and YWHAZ were used as reference genes. GenEx software was used for qPCR data processing and analysis. Results: Mann-Whitney's U test nonparametric statistical analysis showed: Hif1- α, Hif1- β, Notch1 and Notch3 were upregulated in chromophobe RCC (p=0.045, p=0.03, p=0.03 and p=0.02 respectively). Hif1- α and Notch3 were upregulated in clear RCC (p=0.034 and p=0.041 respectively). Spearman's correlation coefficient showed a strong positive correlation between Nocth1-4 members and their receptors and Hif1-α and β genes. Highlight the correlation found between: Notch1 and Hif1-α (Spearman's rho = 0.740, significance level 0.01) and Hif1-β and Jagged1 (Spearman's rho = 0.752, significance level 0.01). Conclusions: Our findings indicated that the co-expression of Notch receptors, their ligands and Hif-1 α and Hif1- β subunits may play a role in human RCC. Notch cascade may represent a novel and therapeutically accessible pathway in chromophobe and clear RCC. More detailed studies of these crossing pathways should be continued in the future.
Clonosight: A Standardized Clinical Assay for Measurement of Minimal Residual Disease in Leukemias and Lymphomas
Authors: Thomas D. Willis, Tom Asbury, Victoria Carlton, Lei Fang, Mark Klinger, Martin Moorhead, Kaliprasad Pothuraju, Li Weng, Jianbiao Zheng, Malek Faham
Journal: Blood (2012)
Abstract 4479: ONC201 is non-toxic at efficacious doses in vitro and in vivo
Authors: Joshua E. Allen, Wafik S. El-Deiry
Journal: Cancer Research (2015)

Abstract ONC201 is a small molecule that is entering clinical trials based on its favorable preclinical profile that includes robust anti-tumor activity in several preclinical models of advanced cancers. Despite inducing a strong cytotoxic response in tumor cells, ONC201 does not induce cell death in normal cells under the same conditions. In addition to a lack of cytoxicity towards normal cells, ONC201 also does not appear to be genotoxic based on gamma-H2AX assessment. Recent mechanistic studies have implicated the early stage induction of the ER stress response by ONC201, which includes induction of DR5 as part of its pro-apoptotic response. Biochemical studies reveal that ONC201 does not induce DR5 in normal cells at doses that cause strong DR5 induction in tumor cells. In accordance with in vitro profile, efficacious ONC201 dose schedules in murine models are also well tolerated without apparent alterations of normal tissue histology or significant loss of body weight. Similar observations were revealed in GLP toxicology studies in beagle dogs and Sprague-Dawley rats. Dogs received a single dose of 0, 4.2, 42, or 120 mg/kg by oral gavage, which represents a human equivalent of 0, 125 mg, 1.25 g, and 3.57 g, respectively. Rats received 0, 12.5, 125, or 225 mg/kg ONC201 by oral gavage, which represents a human equivalent of 0, 125 mg, 1.25 g, and 2.25 g, respectively. There were no deaths or dose-limiting toxicities. The only findings that were observed in both rats and dogs occurred at the highest doses tested and were mild and reversible: decreased activity (no indications of anemia), decreased food consumption (weight loss only seen in rats), and salivation. The NOAEL was at least 42 mg/kg in dogs and at least 125 mg/kg in rats. In summary, these in vitro and in vivo studies support that ONC201 has a large and favorable therapeutic index that is compelling given its powerful single agent anti-tumor efficacy. The coupling of the strong efficacy and safety profile of ONC201 is unique among cancer therapies and opens a broad range of clinical applications for its future development, including potential for combinatorial therapeutics. Citation Format: Joshua E. Allen, Wafik S. El-Deiry. ONC201 is non-toxic at efficacious doses in vitro and in vivo. [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 4479. doi:10.1158/1538-7445.AM2015-4479
Influenza-binding antibodies immobilise influenza viruses in fresh human airway mucus
Authors: Ying-Ying Wang, Dimple Harit, Durai B. Subramani, Harendra Arora, Priya A. Kumar, Samuel K. Lai
Journal: European Respiratory Journal (2016)

Airway mucus is thought to serve as a dynamic filter that can trap respiratory viruses in the dense mucin network [1], and quickly eliminate them along with airway mucus from the respiratory tract. Nevertheless, viruses must penetrate airway mucus to infect the airway epithelium, and we and others have found that various viruses can readily penetrate physiological mucus gels [2–4]. We were particularly interested in whether airway mucus can serve as a barrier against influenza viruses, due to the prevalence and health burden of seasonal outbreaks. It has been suggested that airway mucus protects against influenza by presenting sialylated "decoys" on mucins that bind to influenza haemagglutinin and trap the virions in mucus. Alternatively, we have shown that antibodies in cervicovaginal mucus can trap viruses via multiple low-affinity Fc–mucin bonds between antibodies on the virus surface and mucins, akin to a Velcro patch [4]. To gain insight into how airway mucus might serve as a barrier against influenza, we characterised the mobility of influenza virions and virus-like particles (VLPs) in human airway mucus using real-time high-resolution multiple particle tracking. Common influenza viruses are immobilised in fresh human airway mucus, probably by influenza-binding antibodies <http://ow.ly/yxu0305bqh6> We thank Christina Parker (University of North Carolina, Chapel Hill, NC, USA) for technical assistance. Reagents were kindly provided by Suryaram Gummuluru (Boston University, Boston, MA, USA), Julie Nelson (University of North Carolina, Chapel Hill) and Peter Palese (Mount Sinai School of Medicine, New York, NY, USA).
Comfort Care Request for Preterm Infant: Prescriptive Analysis
Authors: Harvey Berman, Peter M. Koch, Jack P. Freer, Geert Craenen
Journal: The American Journal of Bioethics (2016)

This is the case of a mother, 24 weeks pregnant, delivering a baby prematurely. She worries that the neonate will be impaired and, adding to her distress, that as a migrant worker with an 8-year-ol...
The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene
Authors: Léon C. L. van Kempen, Margaret Redpath, Mounib Elchebly, Kathleen Oros Klein, Andreas I. Papadakis, James S. Wilmott, Richard A. Scolyer, Per-Henrik Edqvist, Fredrik Pontén, Dirk Schadendorf, Anke F. van Rijk, Stefan Michiels, Anne Dumay, Anne Helbling-Leclerc, Philippe Dessen, Jasper Wouters, Marguerite Stass, Celia M. T. Greenwood, Ghanem E. Ghanem, Joost van den Oord, Jean Feunteun, Alan Spatz
Journal: Science Translational Medicine (2016)

A protein phosphatase regulator modulates tumorigenicity in a dose- and X chromosome–dependent manner.
Evidence That T Cells Specific for Non-Hematopoietic Cells Trigger the Development of Acquired Aplastic Anemia
Authors: Tatsuya Imi, Hiroyuki Maruyama, Takamasa Katagiri, Yoshitaka Zaimoku, Kana Maruyama, Noriharu Nakagawa, Kohei Hosokawa, Ken Ishiyama, Hirohito Yamazaki, Koichi Kashiwase, Shinji Nakao
Journal: Blood (2015)
Integration of Rituximab and Liposomal Doxorubicin (DOXIL®) Into CODOX-M/IVAC for HIV-Negative and HIV+ Adults with Untreated Burkitt's Lymphoma (BL): Results of a Prospective Multicenter Phase II Study
Authors: Andrew M. Evens, Kenneth R. Carson, Chadi Nabhan, Borko Jovanovic, Paul Barr, Lilia Gallot, Irene Helenowski, Paolo F. Caimi, Stephanie A. Gregory, Leo I. Gordon
Journal: Blood (2011)
Abstract 646: Structurally guided development of meditope-based antibody-drug conjugates
Authors: Michael M. Matho, Elisabeth M. Gardiner, Calin D. Dumitru
Journal: Cancer Research (2015)

Abstract Meditopes are cyclic peptides that bind the Fab fragment noncovalently, in a novel and unique site, outside the paratope. This property can be utilized to harness cytotoxic payloads to an antibody in a site-specific and consistent manner. One of the originally described peptides, named cQFD, presents a moderate affinity for the humanized antibody cetuximab (KD = 0.43 uM). The binding site involves residues from the heavy as well as the light chain of the antibody, and from both sides of the variable-to-constant hinge of the Fab domain, with a predominance for residues of the variable region. A similar affinity of cQFD to trastuzumab was achieved by mutating thirteen specific residues of the antibody, all located in the variable (Fv) region of the Fab domain; Nine of which are located in the light chain (LC: V9, I10, R39, T40, N41, G42, S43, R45, I83, D85, A100), two in the heavy chain (HC: S40 and I89). We refer to those mutations as to the “meditope enabling”. Via a combined approach, we (i) looked into peptide modifications to increase meditope's affinity for the antibody, and (ii) evaluated the transferability of this approach onto a panel of human antibodies of therapeutic relevance. Based on X-ray crystallography analysis, antibody modeling—in the case of antibodies for which no structure is available—and guided docking, we suggested a number of modifications (point mutations and/or peptide extension) that were subsequently tested via surface plasmon resonance. The top meditope leads were conjugated to MMAE and DM1 and their binding was reassessed to a number of humanized/IgG1 antibodies-confirming that payload conjugation does not interfere with meditope binding and also that meditope enabling and binding does not interfere with antigen binding. Finally, the complexes between antibodies and meditope-drug conjugates were tested in vitro in a panel of tumor cell lines, to measure and rank the efficacy of those leads in our ADC pipeline for further development as novel oncology therapeutics. Citation Format: Michael M. Matho, Elisabeth M. Gardiner, Calin D. Dumitru. Structurally guided development of meditope-based antibody-drug conjugates. [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 646. doi:10.1158/1538-7445.AM2015-646
Clinical Utility of PRV-1 mRNA Expression Levels in Polycythemia Vera and Essential Thrombocythemia.
Authors: Hung Chang, Yu-Shin Hung, Chia-Hui Chang, Yu-Hui Huang, Tung-Liang Lin, Tung-Huei Lin, Po Dunn, Jin-Hou Wu, Po-Nan Wang, Ming-Chung Kuo, Tzung-Chih Tang, Lee-Yung Shih
Journal: Blood (2012)
Abstract 4488: Folate receptor targeted therapy using small molecule drug conjugates constructed with high affinity antifolate ligands
Authors: Christopher P. Leamon, Joseph A. Reddy, Iontcho R. Vlahov, Fei You, Hanna F. Klein, Paul J. Kleindl, Melissa Nelson, Marilynn Vetzel, Patrick J. Klein, Larry H. Matherly, Aleem Gangjee
Journal: Cancer Research (2015)

Abstract Folate receptor (FR)-targeted small molecule drug conjugates (SMDC) have shown promising clinical results. To date, all related SMDCs have been constructed with folic acid. Whereas folic acid displays very high affinity for the FR (kd ∼ 0.1 nM), antifolates with similar high binding affinity and specificity have also been reported. This knowledge prompted our investigation towards substituting the folic acid targeting moiety in our SMDCs with high affinity antifolates, such as CB3717 (a thymidylate synthase inhibitor), and the glycinamide ribonucleotide formyltransferase (GARFTase) inhibitors, AG94 and AG147, thereby testing the hypothesis that greater antitumor activity should result from the combination of inhibitors. Using mice bearing FR-positive human tumor xenografts, we observed curative activity with a CB3717-based vinca alkaloid SMDC under conditions where no cures resulted with vintafolide (EC145) treatment. Similarly, tubulysin SMDCs constructed with AG94 and AG147 were found to produce curative activity using a dosing regimen where a folic acid-tubulysin conjugate did not. Of note, treatment of mice with simple co-mixtures of the antifolates and untargeted drugs was found to be ineffective, thereby confirming the need for linking the two moieties together to produce maximal activity. Taken together, these studies demonstrate that high affinity antifolates can be used in an SMDC format serving as both a high affinity targeting ligand and as a second drug having different, and perhaps a complementary mechanism of action to yield greater antitumor activity. Citation Format: Christopher P. Leamon, Joseph A. Reddy, Iontcho R. Vlahov, Fei You, Hanna F. Klein, Paul J. Kleindl, Melissa Nelson, Marilynn Vetzel, Patrick J. Klein, Larry H. Matherly, Aleem Gangjee. Folate receptor targeted therapy using small molecule drug conjugates constructed with high affinity antifolate ligands. [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 4488. doi:10.1158/1538-7445.AM2015-4488
Quality of Life after High Dose Chemotherapy with Autologous Hematopoietic Progenitor Cell Support Long Term Follow-Up.
Authors: Marylou Nesbitt, Kenneth A. Ault, Fred Aronson, Marjorie A. Boyd, Delvyn Caedren Case, Matthew Dugan, Kurt Ebraham, Jacqueline Hedlund, Helen Ryan, Kristiina Hyrkas
Journal: Blood (2007)
Impact of <i>MGMT</i> methylation status on 1p/19q intact anaplastic gliomas
Authors: E. Franceschi, A. Tosoni, M. Ermani, F. Spagnolli, L. La Torre, R. J. Galzio, E. Pozzati, A. Talacchi, F. Benevento, A. A. Brandes
Journal: Journal of Clinical Oncology (2009)

e13003 Background: Chromosomes 1p/19q codeletion has been recognized as a prognostic and predictive factor in patients (pts) with grade 3 gliomas. Non-codeleted (intact) anaplastic oligodendroglioma showed a survival comparable to that usually observed in pts with anaplastic astrocytomas; MGMT methylation status, moreover, has been found to be a prognostic factor in glioblastoma and anaplastic gliomas (AG). Methods: A retrospective analysis was made using a database of 253 AG pts followed prospectively between January 1998 and August 2008. We evaluated only pts who met the following inclusion criteria: age ≥ 18 years; PS 0–2; histological diagnosis of AG with 1p/19q intact, as determined by FISH analysis; treatment with postoperative radiotherapy (RT) and chemotherapy (CT); MGMT status determined using methylation specific PCR. The study aim was to evaluate the role of MGMT methylation status in 1p/19q codeleted AG pts. The log-rank test was used to evaluate the significance of the prognostic variables. Results: 67 pts (m/f: 35/32, median age: 41.3 years, range: 18–70 years) were enrolled. Histology was anaplastic oligodendroglioma in 17 pts, anaplastic oligoastrocytoma in 20 pts, and anaplastic astrocytoma in 30 pts; all these pts were 1p19q intact and received surgery, RT, and CT. MGMT status, assessable in 58 pts (86.6%), was methylated in 33 pts (56.9%), and unmethylated in 25 pts (43.1%). Median progression-free survival (PFS) was 32.3 months (95%CI: 9.9–54.7). No enhancement at time of diagnosis (p = 0.003), gross total resection (p = 0.03), age (p = 0.001), and MGMT methylation (p = 0.05) were significantly correlated with better PFS. Median survival was 65.2 months (95% CI: 45–85.3). Only age (p = 0.001) and KPS (p = 0.02) correlated with a better survival. Conclusions: MGMT methylation status may provide adjunctive prognostic information in pts with 1p/19q intact AG, indicating a prolonged PFS in pts harboring MGMT promoter methylation. No significant financial relationships to disclose.
Abstract 2868: SETDB1 accelerates non-small cell lung cancer (NSCLC) tumorigenesis through WNT signalling pathway
Authors: Qiaoyang Sun, Lingwen Ding, Jinfen Xiao, Lee Goodglick, David Chia, Vei Mah, Mohammad Alavi, Ngan Doan, Jonathan W. Said, Henry Yang, H.Phillip Koeffler
Journal: Cancer Research (2015)

Abstract Histone methylation deregulation leads to disruption of chromatin structure and gene expression pattern in many human cancers. Histone H3 lysine K9 methyltransferase, SETDB1 (SET domain, bifurcated 1) is initially reported to control heterochromatin structure, repress gene expression and be essential in early embryogenesis. Studies have recently shown its involvement in boosting tumorigenesis in different kinds of human cancers, including lung cancer. However, the mechanism underlying its ability to promote tumorigenesis remains largely unknown. In our study, we sought to investigate the oncogenic role of SETDB1 in NSCLC. Our immunohistochemistry found that 72% out of 387-lung cancer cases stained positively for SETDB1, compared to 46% samples of normal bronchial epithelium (p&amp;lt;0.0001). Moreover, the percent positive cells and their intensity of positivity correlated with cancer grades. Ectopic expression of SETDB1 in NSCLC cell lines enhanced clonogenic growth in vitro and significantly enlarges tumor size in vivo; while depleting endogenous SETDB1 expression with shRNAs suppressed NSCLC cells proliferation and tumor formation. Analyzing the expression pattern of cells with forced expression of SETDB1 combined with TOP/FOP luciferase assay and western blotting showed that WNT/β-catenin signaling was activated upon overexpression of SETDB1, as well as upregulation of its downstream targets, c-Myc and Cyclin D1. ChIP assay showed that SETDB1 binds to WNT relevant genes, such as APOE, IGFBP4, FZD1 and LRP8 and upregulates their transcription, which is very distinct from its canonical suppressing function of H3K9 trimethylation. Interestingly, we also noted that SETDB1 was able to repress P53 expression, while diminishing P53 expression reciprocally enhanced SETDB1 expression. In summary, our study demonstrates that SETDB1 enhances NSCLC tumorigenesis through activating WNT/β-catenin signaling and repressing tumor suppressor P53. Our novel findings provide new insight into a non-canonical function of SETDB1 in activating gene expression, and suggest therapeutic benefit of targeting SETDB1 in NSCLC having high expression level of this protein. Citation Format: Qiaoyang Sun, Lingwen Ding, Jinfen Xiao, Lee Goodglick, David Chia, Vei Mah, Mohammad Alavi, Ngan Doan, Jonathan W. Said, Henry Yang, H.Phillip Koeffler. SETDB1 accelerates non-small cell lung cancer (NSCLC) tumorigenesis through WNT signalling pathway. [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 2868. doi:10.1158/1538-7445.AM2015-2868