tbuckley/cabot-search huggingface dataset:
Abstract 560: Retrospective evaluation, of the randomized Phase 3 MARQUEE trial of tivantinib (T) + erlotinib (E) versus placebo (P) + erlotinib (E) using VeriStrat in patients with previously treated nonsquamous NSCLC
Authors: Giorgio Scagliotti, Wallace Akerley, Joachim von Pawel, Joanna Roder, Dale Shuster, Brian Schwartz, Dominic Spinella
Journal: Cancer Research (2015)

Abstract Background: MET, the high-affinity receptor for hepatocyte growth factor, is frequently deregulated in human cancer and is thought to be involved in resistance to EGFR TKIs. Tivantinib is an orally administered MET inhibitor currently under development as a cancer therapy. The Phase 3 MARQUEE trial enrolled 1048 subjects with locally-advanced or metastatic non-squamous NSCLC who had received one or two lines of prior systemic therapy. Patients were randomized 1:1 to T+E (N = 526) or P+E (N = 522) until disease progression. In the ITT population, addition of tivantinib to erlotinib significantly improved PFS and ORR but did not improve OS, the primary endpoint. VeriStrat® (VS) is a multivariate serum protein test that utilizes MALDI-TOF mass spectrometry to assign a “GOOD” (VS-G) or “POOR” (VS-P) classification and has demonstrated broad prognostic and predictive utility for EGFR TKI treatment regimens. Methods: Pre-treatment serum samples from the MARQUEE study were blinded to clinical outcome and analyzed by VeriStrat. Clinical benefit of T+E vs. P+E was analyzed as a function of VS status, in the ITT population as well as in pre-defined subgroups. Results: A total of 996 subjects were classified: 718 as VS-G and 278 as VS-P. Subjects testing VS-G had superior outcomes to those testing VS-P in both the T+E arm (OS HR = 0.32, CI: 0.26-0.41, p&amp;lt;0.0001; PFS HR = 0.55, CI: 0.44-0.69, p&amp;lt;0.0001) and P+E arm (OS HR = 0.43, CI: 0.34-0.55, p&amp;lt;0.0001; PFS HR = 0.70, CI: 0.55-0.88, p&amp;lt;0.028). VeriStrat status was a significant, independent predictor of OS, in these erlotinib treated patients, after adjustment for EGFR mutation, KRAS mutation, or MET IHC status. However, VeriStrat did not predict OS or PFS benefit for T+E vs. P+E (treatment * VS interaction p-value for OS of p = 0.09 and PFS of p = 0.19). VS was neither predictive nor prognostic for tivantinib effect in any molecular subgroup. Conclusion: These data support the previously demonstrated ability of VS to be both prognostic and predictive for survival in erlotinib treated patients, but not for tivantinib treated patients. Citation Format: Giorgio Scagliotti, Wallace Akerley, Joachim von Pawel, Joanna Roder, Dale Shuster, Brian Schwartz, Dominic Spinella. Retrospective evaluation, of the randomized Phase 3 MARQUEE trial of tivantinib (T) + erlotinib (E) versus placebo (P) + erlotinib (E) using VeriStrat in patients with previously treated nonsquamous NSCLC. [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 560. doi:10.1158/1538-7445.AM2015-560
Abstract 4888: Clinical sequencing in the National Institute of Health's Clinical Sequencing Exploratory Research (CSER) Program
Authors: Catherine Crawford, Charlisse Caga-Anan, Dave Kaufman, Alexander Lee, Jean Mcewen, Sheri Schully, Carolyn Hutter, Lucia Hindorff
Journal: Cancer Research (2015)

Abstract To evaluate best uses of and support the integration of genomic sequencing into the clinical workflow, the National Human Genome Research Institute and National Cancer Institute co-fund the Clinical Sequencing Exploratory Research (CSER) project. This initiative aims to 1) leverage NHGRI's experience in genomic sequencing and analysis to facilitate adoption of these methods into patient care, 2) develop and disseminate best practices for the integration of genomic sequencing into clinical care, and 3) research the ethical, legal, and psychosocial (ELSI) implications of bringing broad genomic data into the clinic. The CSER Consortium includes nine multi-disciplinary projects, nine ELSI-specific projects, a Coordinating Center and NHGRI's Intramural ClinSeq program. Four of the multi-disciplinary projects and one ELSI project have a specific focus on cancer settings and outcomes: CanSeq (Dana-Farber Cancer Inst.), BASIC3 (Baylor College of Med.), ONCOSEQ (Univ. of Michigan), and NEXT Medicine (Univ. of Washington) are developing robust frameworks for the integration of whole exome sequencing (WXS) in tumor and germline samples. By measuring the effectiveness of novel platforms for returning results, analyzing the costs and benefits of using sequencing technology to identify rare variants, and evaluating patient experiences, these projects will help define best practices for incorporating WXS into cancer management. As of August 2014, these projects had collected WXS data from 415 patients (269 adults and 146 children). The CSER consortium also has nine working groups that strive to advance best practices and communicate lessons learned to the community regarding the use of genomic sequence data in the clinical workflow. The Tumor Working Group explores the unique technical, interpretive, and ethical challenges involved in clinical sequencing of both somatic and germline cancer genomes. This presentation will highlight progress to date, anticipated products and results, and the relationship between these cancer sequencing projects and broader CSER consortium efforts. Citation Format: Catherine Crawford, Charlisse Caga-Anan, Dave Kaufman, Alexander Lee, Jean Mcewen, Sheri Schully, Carolyn Hutter, Lucia Hindorff. Clinical sequencing in the National Institute of Health's Clinical Sequencing Exploratory Research (CSER) Program. [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 4888. doi:10.1158/1538-7445.AM2015-4888
Abstract 5450: Naturally occurring mutations in the MPS1 gene predispose cells to kinase inhibitor drug-resistance
Authors: Mark D. Gurden, Isaac Westwood, Amir Faisal, Sébastien Naud, Jack Cheung, Craig McAndrew, Amy Wood, Jessica Schmitt, Kathy Boxall, Grace Mak, Paul Workman, Rosemary Burke, Swen Hoelder, Julian Blagg, Rob Van Montfort, Spiros Linardopoulos
Journal: Cancer Research (2015)

Abstract Acquired resistance is the greatest challenge to the effectiveness of targeted anti-cancer therapies in the clinic. With several MPS1 inhibitors under pre-clinical development, we aimed to investigate how cancer cells will develop resistance against these inhibitors; therefore we modeled acquired resistance using a range of MPS1 inhibitors. We identified and characterized five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed that several MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. One mutation in particular, p.C604W, which is close to the gatekeeper residue, rendered MPS1 resistant to all the inhibitors we tested. However, we were able to design new compounds to specifically overcome this mutation, which in fact targeted the mutant with more potency than the wild-type MPS1 protein. Importantly, we show that these mutations are present in untreated cancer cell lines and primary tumour samples, and also pre-exist in normal lymphoblast and breast tissues. Furthermore, to confirm this is not specific to MPS1, we show that the EGFR p.T790M mutation is also pre-existing in cancer cell lines and normal tissue. Our data therefore suggest that mutations conferring resistance to targeted therapy are naturally occurring mutations in normal and cancer cells that are not introduced due to cancer cells being more mutagenic. Citation Format: Mark D. Gurden, Isaac Westwood, Amir Faisal, Sébastien Naud, Jack Cheung, Craig McAndrew, Amy Wood, Jessica Schmitt, Kathy Boxall, Grace Mak, Paul Workman, Rosemary Burke, Swen Hoelder, Julian Blagg, Rob Van Montfort, Spiros Linardopoulos. Naturally occurring mutations in the MPS1 gene predispose cells to kinase inhibitor drug-resistance. [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 5450. doi:10.1158/1538-7445.AM2015-5450
Biomarkers for Diagnosis and Prognosis of Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation
Authors: Christen L Mumaw, Ayman Akil, Nieves Velez de Mendizabal, Qing Zhang, Nisha Raiker, Jeffrey Yu, Maribel Diaz-Ricart, Enric Carreras, Laura S. Haneline, Kent A. Robertson, Lindsey Elmore, Rose Case, Jamie Renbarger, Samir Hanash, Robert R. Bies, Sophie Paczesny
Journal: Blood (2014)
Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation
Authors: Zhigang Lu, Jingjing Xie, Guojin Wu, Jinhui Shen, Robert Collins, Weina Chen, Xunlei Kang, Min Luo, Yizhou Zou, Lily Jun-Shen Huang, James F Amatruda, Tamra Slone, Naomi Winick, Philipp E Scherer, Cheng Cheng Zhang
Journal: Nature Medicine (2016)
348. Characterization of Cas9-Mediated Genome Editing in Human T Cells
Authors: G. Grant Welstead, Jennifer Gori, Justin Fang, McKensie Collins, Will Selleck, Ari Friedland, Hari Jayaram, David Bumcrot
Journal: Molecular Therapy (2015)

Genome editing via CRISPR/Cas9 promises to provide a novel class of therapies for a variety of human diseases. To unlock the potential of the CRISPR/Cas9 technology, a deeper understanding of its efficacy in different primary cell types is required. A cell type of particular interest for gene editing is the human T cell due to its central role in the evolving cancer immunotherapy field. To better understand the utility of Cas9-mediated gene editing for engineering human T cells, we surveyed a variety of delivery modalities including electroporation of RNA and administration of ribonucleic acid-protein complexes. Additionally, we assessed the functionality of different Cas9 variants in human T cells. Here we report our findings including genome editing in human T cells using CRISPR/Cas technology.
203. Prevention of Alzheimer's-Like Symptoms Using Lentiviral-Mediated Secreted Amyloid Precursor Protein-Alpha Overexpression in a Transgenic Mouse Model
Authors: Valerie Tze Yeen Tan, Mohammad Fairuz Yahaya, Lucia Schoderböck, Hollie Wicky, Wickliffe Abraham, Stephanie Hughes, Bruce Mockett
Journal: Molecular Therapy (2015)

Alzheimer's disease (AD) is a neurodegenerative disease that is associated with memory loss and poor cognition. Pathologically, the disease is characterised by amyloid plaques and neurofibrillary tangles. The abnormally high level of amyloid-β is thought to be due in part to an imbalance in amyloid precursor protein cleavage whereby there is an increase in amyloid-β production concomitant with a decrease in the production of secreted amyloid precursor protein-alpha (sAPPα). sAPPα is neuroprotective, supports neurogenesis and regulates learning and memory. In the current study, a lentiviral vector containing sAPPα and green fluorescent protein (GFP) cDNA, under the control of a synapsin promoter was injected bilaterally into the hippocampus of 4-month old male APPSwe/PS1ΔE9 transgenic mice at four sites per hemisphere. The two control groups consisted of B6/C3 wild-type and transgenic littermates injected with an control vector containing only GFP. At 12 months of age, animals underwent behavioural testing to examine hippocampus-dependent memory performance. There were no significant differences between groups in the open field and elevated plus maze tests of activity and anxiety. During acquisition of spatial memory in a water maze, transgenic controls showed poor learning, as the total distance to the platform (3.0 m±0.7) was significantly higher than that for wild-type controls (1.79 m±0.43). However, this impaired learning effect was prevented in the transgenic sAPPα group (1.38 m±0.18. Transgenic mice injected with control vector performed poorly at water maze probe trials testing spatial memory retention, and had to swim a lot further to reach the target (35.45 m±2.85); however, in transgenic mice treated with sAPPα (26.07 m±1.83) performance was significantly improved (p < 0.05). Moreover, transgenic-sAPPα animals performed similarly to wildtype animals (25.43 m±2.03). There were no significant differences between groups in a dry-land spatial memory task – the Barnes maze, or a contextual fear-conditioning test. These results indicate that the overexpression of sAPPα is persistent for at least up to 8 months, and could prevent Alzheimer's-like behavioural deficits in an animal model. Supported by a grant from the Health Research Council of New Zealand.
Abstract 2792: Polymorphisms in vitamin D-related genes and risk of breast cancer
Authors: Joy Shi, Anne Grundy, Harriet Richardson, Angela Brooks-Wilson, John Spinelli, Kristan J. Aronson
Journal: Cancer Research (2015)

Abstract Vitamin D is hypothesized to decrease breast cancer risk by controlling cell proliferation, differentiation and apoptosis, and estrogen synthesis and signalling in breast tissue. Transport of circulating vitamin D to sites of action is facilitated by vitamin D binding protein, encoded by the GC gene, whereupon it binds to the vitamin D receptor, encoded by the VDR gene. Given that polymorphisms in the GC and VDR gene have not been consistently associated with breast cancer risk, our objective was to assess the associations of vitamin D-related genes with breast cancer risk, accounting for ethnicity and menopausal status, and to determine these associations according to tumour receptor status defined by expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). A case-control study of 1,037 breast cancer cases and 1,050 controls age-frequency matched in Vancouver, British Columbia and Kingston, Ontario was used. The distribution and associations of 21 single nucleotide polymorphisms (SNPs) of the GC and VDR gene with breast cancer risk and breast tumour subtypes were investigated among premenopausal and postmenopausal European and Asian women in stratified analyses. Following false discovery rate adjustment, no SNP was associated with breast cancer risk among any subgroup. However, among European women, two SNPs in the VDR gene, rs1544410 (OR = 0.38, 95% CI: 0.21 - 0.70) and rs7967152 (OR = 2.80, 95% CI: 1.62 - 4.85) were associated with risk of ER-/PR-/HER2+ breast tumour subtype, but not with other breast tumour subtypes. Breast tumour subtypes are proposed to be etiologically distinct disease states, with different risk factors and prognostic outcomes. Interactions between variations in vitamin D-related genes and breast tumour subtypes are biologically plausible given our current understanding of anticarcinogenic properties of vitamin D elicited through the regulation of cell growth and reproductive hormone synthesis. These findings provide additional insight into the etiologic differences among breast tumour subtypes. Citation Format: Joy Shi, Anne Grundy, Harriet Richardson, Angela Brooks-Wilson, John Spinelli, Kristan J. Aronson. Polymorphisms in vitamin D-related genes and risk of breast cancer. [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 2792. doi:10.1158/1538-7445.AM2015-2792
Relief for Painful Intercourse
Authors: Rebecca Voelker
Journal: JAMA (2017)

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Abstract POSTER-BIOL-1337: Omentum promotes suppression against peritoneal tumors
Authors: Selene Meza-Perez, Maria de la Luz Garcia-Hernandez, Aaron Silva-Sanchez, Javier Rangel-Moreno, Uma Mudunuru, Edith M Lord, Troy D. Randall
Journal: Clinical Cancer Research (2015)

Abstract Purpose: The metastasis of ovarian cancer to the omentum is associated with poor clinical outcomes. Although the omentum has immune function due to the activities of milky spots, the role of the omentum in anti-tumor immunity has not been rigorously addressed. We hypothesize that the omentum directly modulates anti-tumor immunity to metastasized tumor cells. Experimental procedure: We examined metastases and immunological function in mice that expresses SV40 T antigen oncogene under the Mullerian Inhibitory Substance type II Receptor promoter (MISIIR-Tag). In separate experiments we also implanted 3 x 106 EG7.1.15 cells (murine thymoma that express chicken ovalbumin (OVA)) intraperitoneally (i.p.) to induce peritoneal tumors. We used flow cytometry to analyze cells from the omentum and peritoneal exudate from mice with or without tumors. Results: Omental tumor growth induced by EG7.1.15 cells is associated with an increase in CD4+CD25+FoxP3+ T regulatory cells (Tregs) and CD103+ DCs, while tumor-specific CD8+ T cells are reduced. Although tumor-specific CD8+ T cells generated in the periphery prior to tumor onset prevent omental and peritoneal tumor growth, tumor-specific CD8+ T cells generated after tumors are established in the omentum are unable to mediate tumor clearance. The induction of tolerance requires the omentum, is dependent on FoxP3+ Tregs, is tumor antigen-specific and takes place in as few as 6 days. The metastasis of ovarian tumor cells into the omentum also correlates with an increase in Tregs. Deleting Tregs in both models reduces tumor burden. Conclusions: Metastasis of tumor cells to the omentum leads to immunological tolerance rather than immunity – even when tumor cells express foreign antigens. Thus, the omentum has an immunological activity that prevents, rather than promotes, immunity to peritoneal tumors. Citation Format: Selene Meza-Perez, Maria de la Luz Garcia-Hernandez, Aaron Silva-Sanchez, Javier Rangel-Moreno, Uma Mudunuru, Edith M Lord PhD, Troy D. Randall. Omentum promotes suppression against peritoneal tumors [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1337.
The Impact of a Pre-Existing Psychiatric Diagnoses on a Newly Diagnosed Acute Leukemia Patient's Emotional Functioning During Induction Chemotherapy as Measured by the Brief Symptom Inventory-18 (BSI-18).
Authors: Dawn Speckhart, Scott R. Solomon, Asad Bashey, Lawrence Morris JR, Tina Berry, H. Kent Holland
Journal: Blood (2010)
Abstract 5458: Elevated level of Fibrillarin induces chemoresistance by interfering p53 pathway in cancers
Authors: Teng Xu, Suthakar Ganapathy, Meijun Long, Chul Ha, Zhi-Min Yuan, Hang Su
Journal: Cancer Research (2015)

Abstract Fibrillarin (FBL), an rRNA 2′-O-methyltransferase, has long been recognized as the enzymatic unit of the C/D box small nucleolar ribonucleoprotein (snoRNP) involved in the first step of pre-rRNA processing. It is not until recently that the link between FBL and cancers has been unveiled. As a direct regulatory target of Myc and p53, FBL is frequently upregulated in breast cancers and prostate cancers. High expression of FBL has also been shown to be associated with poor survival in patients with breast cancer. Our recent study found that FBL overexpression contributes to tumorigenesis and confers cellular resistance to chemodrugs. However, the underlying mechanism of chemoresistance elicited by FBL upregulation is still elusive. Here, we studied the molecular roles of FBL on p53 response. The p53 pathway in response to etoposide and actinomycin D were examined in a variety cell lines including U-2OS, MCF7, H1299, ZR75-1, A549 and an FBL inducible cell line. Western blotting and immunofluorescent staining were employed to examine protein level and their cellular localization. We found that ectopic expression of FBL enhanced the protein level of MDM2, resulting in decreased p53 accumulation and activity in response to chemodrugs. Interestingly, MDM2 was partially recruited to the nucleoli under stimuli. FBL depletion abrogated the nucleolar recruitment of MDM2 and subsequently dampened p53 activation. In conclusion, physiological level of FBL sequesters and stabilizes MDM2 in the nucleoli, therefore inhibits p53 degradation. When upregulated in cancers, FBL stabilizes nucleus MDM2 and promotes the degradation of p53 Citation Format: Teng Xu, Suthakar Ganapathy, Meijun Long, Chul Ha, Zhi-Min Yuan, Hang Su. Elevated level of Fibrillarin induces chemoresistance by interfering p53 pathway in cancers. [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 5458. doi:10.1158/1538-7445.AM2015-5458
The Peripheral Blood Lymphocyte to Monocyte Ratio At Diagnosis Is a Potent Outcome Predictor in Diffuse Large B-Cell Lymphoma Treated with R-CHOP: A Long-Term Analysis On 973 Patients Receiving Chemotherapy with or without Rituximab
Authors: Alessandro Rambaldi, Cristina Boschini, Federica Delaini, Elena Oldani, Andrea Rossi, Anna Maria Barbui, Giuseppe Gritti, Daniele Caracciolo, Marco Ladetto, Angela Gueli, Alberto De Crescenzo, Roberto Passera, Liliana Devizzi, Alessandro M. Gianni, Corrado Tarella
Journal: Blood (2012)
Prophylaxis of Invasive Pulmonary Aspergillosis with Nebulized Lipid Complex Amphotericin B Is Feasible, Well Tolerated and Safe in Children with Acute Leukemia. Results of a Phase II Open Trial
Authors: Maria Trabazo, Albert Catala, Ruben Berrueco, Gabriela Corbalan, Anna Ruiz, Maria Poveda, Mireia Camos, Montserrat Torrebadell, Teresa Toll, Anna Alonso, Montserrat Mesegue, Joan Vinent, Maria Luisa Martin-Saenz, Cristina Llanos, Alicia Castaneda, Amadeu Gene, Teresa Juncosa, Jesus Estella, Susana Rives
Journal: Blood (2014)