tbuckley/cabot-search huggingface dataset:
Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials
Authors: Jack Cuzick, Adam R. Brentnall, Corrinne Segal, Helen Byers, Caroline Reuter, Simone Detre, Elena Lopez-Knowles, Ivana Sestak, Anthony Howell, Trevor J. Powles, William G. Newman, Mitchell Dowsett
Journal: Journal of Clinical Oncology (2017)

Purpose At least 94 common single nucleotide polymorphisms (SNPs) are associated with breast cancer. The extent to which an SNP panel can refine risk in women who receive preventive therapy has not been directly assessed previously. Materials and Methods A risk score on the basis of 88 SNPs (SNP88) was investigated in a nested case-control study of women enrolled in the International Breast Intervention Study (IBIS-I) or the Royal Marsden study. A total of 359 women who developed cancer were matched to 636 controls by age, trial, follow-up time, and treatment arm. Genotyping was done using the OncoArray. Conditional logistic regression and matched concordance indices (mC) were used to measure the performance of SNP88 alone and with other breast cancer risk factors assessed using the Tyrer-Cuzick (TC) model. Results SNP88 was predictive of breast cancer risk overall (interquartile range odds ratio [IQ-OR], 1.37; 95% CI, 1.14 to 1.66; mC, 0.55), but mainly for estrogen receptor–positive disease (IQ-OR, 1.44; 95% CI, 1.16 to 1.79; P for heterogeneity = .10) versus estrogen receptor–negative disease. However, the observed risk of SNP88 was only 46% (95% CI, 19% to 74%) of expected. No significant interaction was observed with treatment arm (placebo IQ-OR, 1.46; 95% CI, 1.13 to 1.87; tamoxifen IQ-OR, 1.25; 95% CI, 0.96 to 1.64; P for heterogeneity = .5). The predictive power was similar to the TC model (IQ-OR, 1.45; 95% CI, 1.21 to 1.73; mC, 0.55), but SNP88 was independent of TC (Spearman rank-order correlation, 0.012; P = .7), and when combined multiplicatively, a substantial improvement was seen (IQ-OR, 1.64; 95% CI, 1.36 to 1.97; mC, 0.60). Conclusion A polygenic risk score may be used to refine risk from the TC or similar models in women who are at an elevated risk of breast cancer and considering preventive therapy. Recalibration may be necessary for accurate risk assessment.
Abstract 5498: Multiple mechanisms of action may contribute to the lymphoma cell-killing activity of SH7139
Authors: Monique Cosman Balhorn, Saphon Hok, Rod Balhorn
Journal: Cancer Research (2015)

Abstract The tridentate selective high affinity ligand (SHAL) SH7139 is selectively cytotoxic at sub-nanomolar concentrations to lymphoma cells over-expressing HLA-DR10. Recent studies suggest SH7139 is unusual in that multiple mechanisms may contribute to its killing of targeted tumor cells. Electron microscopy data suggest one mechanism involves the triggering of a cell-signaling event that leads to the induction of apoptosis when SH7139 binds to a unique site on HLA-DR10 (the same region/epitope recognized by the Lym-1 antibody). A second mechanism appears to involve the internalization of SH7139 by tumor cells and the subsequent release of it's three individual recognition elements/ligands by metabolic cleavage of the amide bonds that link them to a scaffold (a unique feature of SHALs). Analogous to the process of toxin delivery by antibody-drug conjugates, once these ligands are released inside the cell, they can each inhibit a different key pathway required for tumor cell survival. Additional metabolic conversions of these ligands by the tumor cells to toxic metabolites may also contribute to cell killing through the inhibition of a number of other critical cellular functions. The third proposed mechanism is based on the fact that the target receptor HLA-DR10 participates in the activation of T-cells. The binding of SH7139 to the antigen binding pocket of HLA-DR10 may trigger an immune response that targets the cancer cells with bound drug. All three proposed mechanisms are currently under study. If multiple diverse mechanisms of action contribute to SH7139's cytotoxicity, it will be extremely difficult for lymphoma cells to develop a resistance to the drug. This research was supported by the National Cancer Institute Phase II SBIR Award R44CA159843-02 to SHAL Technologies Inc. Part of this work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. Citation Format: Monique Cosman Balhorn, Saphon Hok, Rod Balhorn. Multiple mechanisms of action may contribute to the lymphoma cell-killing activity of SH7139. [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 5498. doi:10.1158/1538-7445.AM2015-5498
Abstract A88: The synthetic triterpenoid CDDO-Imidazolide reduces immune cell infiltration and cytokine secretion in the KC mouse model of pancreatic cancer
Authors: Ana Sofia Leal, Michael B. Sporn, Patricia A. Pioli, Karen T. Liby
Journal: Cancer Research (2016)

Abstract Survival rates for pancreatic cancer remain at 7-8%, and as the incidence and deaths are expected to increase, new drugs are needed for the prevention and treatment of this devastating disease. LSL-KrasG12D/+;Pdx-1-Cre (KC) mice replicate the genetics, symptoms and histopathology found in human pancreatic cancer. Immune cells infiltrate into the pancreas of these mice and produce inflammatory cytokines that promote tumor growth. This process can be accelerated with the administration of lipopolysaccharide (LPS) or caerulein so KC mice at 9 weeks of age were injected once a week for 4 weeks with LPS (4mg/kg). One or four weeks after the LPS injections, plasma, pancreas and spleens were collected. KC mice were particularly sensitive to the effects of LPS, as only 48% of the KC mice survived an LPS challenge while 100% of wildtype (WT) mice survived. Survival was increased when KC mice were pre-treated with the triterpenoid CDDO-Imidazolide (CDDO-Im) (71% survival). LPS increased the percentage of CD45+ immune cells in the pancreas and immunosuppressive Gr1+ myeloid derived suppressor cells (MDSC) in the spleen of KC mice. In contrast, CDDO-Im decreased the infiltration of CD45+ cells into the pancreas and the percentage of Gr1+ MDSC in the spleen of KC mice challenged with LPS. Levels of inflammatory cytokine levels also were markedly higher in KC mice vs. WT mice challenged with LPS. Pre-treatment with CDDO-Im decreased the production of IL-6, CCL-2, VEGF, and G-CSF in the KC mice. These cytokines are prognostic markers in pancreatic cancer or play important roles in the progression of this disease. Disrupting inflammation during tumorigenesis with drugs such as CDDO-Im might be useful for preventing pancreatic cancer, especially in high risk populations. Citation Format: Ana Sofia Leal, Michael B. Sporn, Patricia A. Pioli, Karen T. Liby.{Authors}. The synthetic triterpenoid CDDO-Imidazolide reduces immune cell infiltration and cytokine secretion in the KC mouse model of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A88.
Abstract 3109: A functional microRNA screening approach that identifies microRNAs affecting melanoma cell invasion
Authors: Claudia E.M. Weber, Chonglin Luo, Agnes Hotz-Wagenblatt, Wolfram Osen, Tim Holland-Letz, Stefan B. Eichmüller
Journal: Cancer Research (2015)

Abstract Melanoma is a fast progressing tumor which tends to metastasize at small size and at early time point. miRNA profiling has been performed for a variety of cancer types, however, the results obtained differ substantially among published studies. Therefore, it is of major interest to unravel miRNA networks involved in melanoma progression as, for example, in tumor cell invasion. In order to follow this aim, we established a functional screening approach based on a high-throughput invasion assay using a human miRNA mimics library consisting of 988 miRNAs (miRBase Version 13.0). Applying this strategy, we could identify miRNAs that enhanced the invasive capacity of A375 melanoma cells (oncogenic miRNAs), as well as miRNAs with a lowering effect on invasiveness, latters found predominantly down-regulated in melanoma and thus considered as tumor-suppressors. miR-339-3p was one of the promising candidates which inhibited invasion when transfected into different melanoma cell lines. In addition, miR-339-3p expression was significantly decreased in melanoma cell lines compared to normal human melanocytes. Furthermore, the myeloid leukemia cell differentiation protein (MCL-1) was identified as a novel target of miR-339-3p and found to be down-regulated by miR-339-3p both on protein and on mRNA level. MCL1 down-regulation by siRNA could mimic inhibited invasion as observed after miR-339-3p transfection. Our findings indicate that miR-339-3p can act as a tumor suppressor in melanoma and its expression might contribute to the varying degrees of aggressiveness among different melanomas. We believe that our approach can unravel possible therapeutics checkpoints which might be used therapeutically, to counteract tumor spread. Citation Format: Claudia E.M. Weber, Chonglin Luo, Agnes Hotz-Wagenblatt, Wolfram Osen, Tim Holland-Letz, Stefan B. Eichmüller. A functional microRNA screening approach that identifies microRNAs affecting melanoma cell invasion. [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 3109. doi:10.1158/1538-7445.AM2015-3109
Abstract 1012: Discovery and synthesis of novel autophagy inhibitors with anti-proliferative activity in lung and pancreatic cancer cells
Authors: Juan Sironi, Lars Ulrik Nordstroem, Evelyn Aranda, Marina Shcherba, Roman Perez-Soler, Peng Wu, Edward L. Schwartz
Journal: Cancer Research (2015)

Abstract Autophagy is an emerging therapeutic target in cancer chemotherapy. It is a regulated catabolic process that degrades damaged cellular proteins and organelles, and helps to maintain cellular homeostasis and biosynthesis during nutrient starvation, metabolic stress, oncogenic transformation, and in response to chemotherapeutic drugs. Recent studies using mouse genetic models of lung and pancreatic cancer reported dramatic tumor regressions when autophagy was ablated, either genetically or pharmacologically, in either the tumors or systemically in the mouse. These studies provide pre-clinical proof of principle that strategies to inhibit autophagy can be therapeutically efficacious in solid tumors. The autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) have single agent antiproliferative activity against human cancer cell lines, however low potency may limit their antitumor efficacy clinically. As part of our ongoing chemistry program to discover novel autophagy inhibitors, we synthesized a series of chloroquine analogs which retained the 4-aminoquinoline subunit and incorporated different substituted triazoles into the target structure. These compounds were tested for growth inhibition against H460, HCC827, H520 and H1703 human lung cancer cell lines, and BxPC3 pancreatic cancer cells. The most potent compound, EAD1, had IC50s ranging from 5.8 μM to 11 μM in the cells, and was 8-fold more potent than CQ and HCQ. EAD1 inhibited autophagy, as judged by the cellular accumulation of the autophagy-related autophagosome proteins LC3-II and p62, and induced apoptosis. The increases in LC3-II levels by the analogs were inversely correlated with their growth inhibitory IC50s, suggesting that autophagy blockade is closely linked to inhibition of cell proliferation. In contrast to HCQ, the cytotoxic actions of EAD1 were not reversible after a 24 hour treatment. Furthermore, the mechanism of action of EAD1 appears to partially differ from that of HCQ, including possible interactions with mTOR/TORC1-mediated pathways. EAD1 is a viable lead compound for evaluation of the anti-tumor activity of autophagy inhibitors in vivo. Citation Format: Juan Sironi, Lars Ulrik Nordstroem, Evelyn Aranda, Marina Shcherba, Roman Perez-Soler, Peng Wu, Edward L. Schwartz. Discovery and synthesis of novel autophagy inhibitors with anti-proliferative activity in lung and pancreatic cancer cells. [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 1012. doi:10.1158/1538-7445.AM2015-1012
Robust Assessment of Genomic Imbalance in Diffuse Large B-Cell Lymphoma Confirms Inferior Outcome Is Associated with Genomic Complexity and Identifies Potential Therapeutic Pathway Targets
Authors: Lizalynn Dias, Venkata Thodima, Asha Guttapalli, Geetu Mendiratta, Sergei I Syrbu, Jane Houldsworth
Journal: Blood (2014)
Thalidomide / Dexamethasone (TD) Vs. Bortezomib (Velcade)â/Thalidomide / Dexamethasone (VTD) Vs. VBMCP/VBAD/Velcadeâ as Induction Regimens Prior Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM): Results of a Phase III PETHEMA/GEM Trial.
Authors: Laura Rosiñol, Ma Teresa Cibeira, Joaquin Martinez, Maria Victoria Mateos, Albert Oriol, Ma José Terol, Jose García-Laraña, Dolores Hernández, Javier de la Rubia, Anna Sureda, Juan Besalduch, Luis Palomera, Yolanda Gonzalez, Ma Asuncion Echebeste, Joaquin Díaz-Mediavilla, Felipe de Arriba, Adrian Alegre, Miguel T Hernández, Juan José Lahuerta, J.F F San Miguel, Joan Blade
Journal: Blood (2009)
Rare epidermal growth factor receptor (EGFR) mutations in a 425 patients population with non-small cell lung cancer (NSCLC): clinical, molecular and survival data. The IRCCS Candiolo experience
Authors: R. Laface, T. Venesio, C. Cagnazzo, K. Pollato, T. Cicako, M. Aglietta, L. Garetto
Journal: Annals of Oncology (2015)
SRSF2 Mutations Impair Nuclear Aggregation and Represent a Novel Mechanism Of Spliceosomal Dysregulation In CMML
Authors: Eric Padron, Sateesh Kunigal, Xiaoyi Ren, Jeffrey S. Painter, Rainer Metcalf, Joseph Johnson, Ling Zhang, Jeffrey E Lancet, Rami S Komrokji, Kenyon Daniels, Alan List, Pearlie K Epling-Burnette
Journal: Blood (2013)
371. AAV9-Mediated Over-Expression of Hippocampal Neuritin Prevents Extremely Low-Frequency Electromagnetic Field Exposure-Induced Impairment of Recognition Memory
Authors: Yanai Mei, Qianru Zhao, JunMei Lu, Jinjing Yao, Zhengyu Zhang, Chen Ling
Journal: Molecular Therapy (2016)

Extremely low-frequency (50Hz) electromagnetic fields (ELF MFs) are ubiquitously present in various environments during daily life. The major sources of ELF MFs pertaining to the general public are in-house installations, household appliances and power lines. Animal studies have shown that ELF MFs exposure may interfere with the activity of brain cells, thereby generating behavioral and cognitive disturbances. However, the underlying mechanisms and possible preventions are still unknown. In our preliminary studies, we found that ICR mice that were exposed to ELF MFs had deficits in hippocampus-dependent recognition memory but no concurrent changes in their locomotor activity. Further experiments revealed that ELF MFs exposure reduced dendritic spine densities of hippocampal CA1 pyramidal cells. Meanwhile, there was no significant effect on dendritic spine diameter or length. Since previous work has shown that neuritin, an important neurotrophin, has the ability to increase the spine density of hippocampal pyramidal neurons, we decided to explore whether neuritin is capable of reversing ELF MFs exposure-induced decreases in dendritic spine density. To this end, adeno-associated virus serotype 9 (AAV9) vectors carrying human neuritin cDNA were produced and stereotaxically injected into the CA1 region of the mouse hippocampus (0.2µl per mouse) 7 days before exposure to ELF MFs. Two control groups were injected in hippocampus with the same volume of AAV-GFP or saline. Western blot analysis indicated that the expression of neuritin was increased by 60.2 ± 5.8% in the hippocampus. We then quantified the effects of AAV9-mediated neuritin over-expression on hippocampal dendritic spine number and subsequent recognition memory in mice of both non-ELF MFs and ELF MFs exposure groups. After a 2.5-week infection period, a significant increase in spine density was observed in the AAV-neuritin group. On the other hand, there was no significant difference in dendritic diameter or length among all three groups of mice. Additionally, after ELF MFs exposure (1mT) for 12 h/day for 10 days, the spine density of pyramidal neurons obtained from neuritin-overexpression mice was no longer reduced. Consequently, the recognition memory test of AAV-neuritin mice showed a significant increase in recognition index when compared to AAV-control mice. Collectively, our study provided evidence for the association between ELF MFs exposure, impairment of recognition memory, and resulting changes in hippocampal dendritic spine density. Furthermore, overexpression of neuritin has the ability to prevent the ELF MFs-exposure-induced effect by increasing the hippocampal spine density.
Two-stage implant-based breast reconstruction compared with immediate one-stage implant-based breast reconstruction augmented with an acellular dermal matrix: an open-label, phase 4, multicentre, randomised, controlled trial
Authors: Rieky E G Dikmans, Vera L Negenborn, Mark-Bram Bouman, Hay A H Winters, Jos W R Twisk, P Quinten Ruhé, Marc A M Mureau, Jan Maerten Smit, Stefania Tuinder, Yassir Eltahir, Nicole A Posch, Josephina M van Steveninck-Barends, Marleen A Meesters-Caberg, René R W J van der Hulst, Marco J P F Ritt, Margriet G Mullender
Journal: The Lancet Oncology (2016)
Pralatrexate (PDX) IS Active in Cutaneous T-Cell Lymphoma: Preliminary Results of a Multi-Center Dose-Finding Trial.
Authors: Steven M. Horwitz, Madeleine Duvic, Youn Kim, Jasmine M. Zain, Mary Jo Lechowicz, Patricia Myskowski, Hanna Weissbrot, Danielle Wright, Lacey Chance, Tony Koutsoukos, Pablo Cagnoni, Michael Saunders, Owen A. O’Connor
Journal: Blood (2008)
OS3.1 Differential impact of Ang-2, VEGF-A and dual Ang-2/VEGF-A blocking on the efficacy of radio- and chemotherapy in a glioblastoma model
Authors: G. Solecki, M. Osswald, M. Glock, D. Weber, M. Gömmel, H. Müller, O. Krieter, W. Wick, F. Winkler
Journal: Neuro-Oncology (2016)

In addition to identifying the murine HLA-DR1-restricted TCR, we have analysed IDH1R132H-specific TCRs from a patient with a progressive IDH1R132H-mutated astrocytoma, who has been treated with an IDH1(R132H) vaccine on a compassionate use basis.Single T-cells from this patient, who had a high baseline mutation-specific T-cell response, specifically responding to IDH1(R132H), were expanded in vitro and subjected to single-cell-sorting and subsequent TCR sequencing.11 different TCR sequences have been identified.The long-term goal is to develop an adoptive T-cell therapy using autologous IDH1R132H-specific T cells. OS2.
Abstract 4219: Small G protein Rac GTPases regulate the maintenance of glioblastoma stem-like cells
Authors: Yun-Ju Lai, Jui-Cheng Tsai, Ying-Ting Tseng, Etty N. Benveniste
Journal: Cancer Research (2015)

Abstract Glioblastoma is the most common and aggressive malignant primary brain tumor in adults. Its invasiveness and resistance to traditional therapies make it a highly recurrent malignant disease with poor prognosis. The existence of glioblastoma stem cells (GSC) may account for its invasiveness and high recurrence, so GSCs become a suitable target for developing new treatments. Rac proteins belong to the Rho small GTPase subfamily, which major functions include regulation of cell movement, proliferation, and survival. However, most of the studies focused on Rac1 but not other Rac family proteins. To investigate whether other Rac proteins, Rac2 and Rac3, can serve as new therapeutic targets for glioblastoma, especially for glioblastoma stem cells, we examined the effects of Rac1-3 on glioblastoma cells-derived tumorspheroids (glioblastoma stem-like cells). We found that Rac1-3 are important for cell proliferation and colony formation of glioblastoma stem-like cells. We also established the zebrafish xenotransplantation model to further study the effects of Rac proteins in glioblastoma, and observed that the cells expressing control scramble short-hairpin RNA sequence induced angiogenesis in the egg yolk of the fish, while the cells expressing siRacs shrank inside the fish and did not induce angiogenesis. The overall survival rates of fishes were also higher in the fishes injected with siRac cells instead of fishes with control scramble RNA cells. Furthermore, Rac proteins also involve in STAT3 and ERK activation, and regulate the GSC marker expression such as CD133, Sox2 and HIF-2α in glioblastoma stem-like cells. In conclusion, Rac proteins can serve as the potential therapeutic targets against glioblastoma and its stem cells. Citation Format: Yun-Ju Lai, Jui-Cheng Tsai, Ying-Ting Tseng, Etty N. Benveniste. Small G protein Rac GTPases regulate the maintenance of glioblastoma stem-like cells. [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 4219. doi:10.1158/1538-7445.AM2015-4219
208. Single-Cell Gene Expression Profiles of Genetically Modified T Cells for Adoptive Immunotherapy
Authors: Sonny O. Ang, Laurence J.N. Cooper
Journal: Molecular Therapy (2015)

System-level characterization of cell states requires detailed portrayal of cellular components such as gene transcripts or proteins. Here, we exploit a robust single-cell platform technology to characterize T cells expanded ex vivo intended for human application. Coupled with advanced custom analytics, we identify "drivers" (relatively few, but vital) genes which orchestrate T-cell activation and clonal expansion programming, versus "passengers" (relatively many, less critical) or resultant/downstream transcripts. Detailed analyses reveal that there is considerable variability between individual activated T cells, implying that cell state may undergo multiple stepwise transitions in a stochastic manner. Compared to interrogation of bulk T-cell populations (e.g., analyzed using RNA-Seq, microarrays, and Northern blotting), where heterogeneity in expression signals is attenuated by temporal and cell-cycle averaging, the genetic heterogeneity between cells in isogenic populations may be a reflection of fundamental phenomena such as transcriptional bursting. Our model describes cell state oscillation in tandem with transcriptional repressive (closed chromatin) and permissive conformations (open chromatin), versus simpler probabilistic models of transcription. T-cell variability can significantly impact upon individual cell behavior within seemly isogenic populations, and may be essential in molding survival and cytotoxicity within certain contexts, such as the rapidly changing and stressful tumor microenvironments. We find that lactate dehydrogenase A (LDHA) is a leading indicator for the metabolic adaptation during T-cell activation and together with other energetics related genes such pyruvate kinase isoform 2 (PKM2), can be harnessed to adjust our culture conditions during ex vivo expansion. These cellular fingerprints suggest useful ways for tuning the balance between oxidative and non-oxidative glucose metabolism to enhance the killing and thus therapeutic potential of our T cells. Our framework to harness catalogs of gene expression data into clinically-applicable insights can be adapted for meaningful characterization of other therapeutically-relevant source populations such as hematopoietic stem cells and reprogrammed NK cells. This is being reduced to practice by understanding the heterogeneity within and between genetically modified T-cell products generated for clinical use.