tbuckley/cabot-search huggingface dataset:
Abstract 5031: Distribution of single nucleotide polymorphisms related to paclitaxel and carboplatin toxicity in ovarian cancer patients
Authors: Miguel Cordova, Maria L. Bravo, Isidora Arriagada, Elisa Cumsille, Luis Quiñones, Erasmo Bravo, Raimundo Correa, Juan E. Leiva, Cesar Paredes, Mauricio Cuello, Carolina Ibañez, Marcelo Garrido, Gareth I. Owen
Journal: Cancer Research (2017)

Abstract Introduction: Standard first-line treatment for ovarian cancer consists in the combined use of taxanes and platinum, with neuropathies and neutropenia the most frequent and complex adverse drug reactions (ADRs) requiring clinical management. These adverse effects may be related to differing levels of drug transport and metabolism brought about by intrinsic genetic characteristics of the patients. Single nucleotide polymorphisms (SNPs) are now recognized as key factors in the variability of drug response. In a cohort of Chilean ovarian cancer patients we analyzed the frequencies of several SNPs previously reported to be associated with paclitaxel and carboplatin ADRs. Methods: Blood samples were obtained with informed consent from adult ovarian cancer patients (n = 120). DNA was extracted and SNPs within the ABC transporter and CYP P450 gene families were genotyped. High specificity Taqman probes were used. Results: Four SNPs associated with risk of ADR within the ABC transporter family showed genotypic frequencies ranging between 0 - 23%. Frequencies for the ADR-associated variants in the CYP P450 family were 4 - 90%. Finally, for the CYP2C8 enzyme, whose function is essential in paclitaxel metabolism, the frequencies of risk-associated SNPs ranged from 2.10% to 13.6%. Conclusions: SNPs associated with paclitaxel and carboplatin ADRs are highly prevalent in the Chilean population of ovarian cancer patients studied. The identification of these variants may help avoid severe ADRs associated with chemotherapy regimes. Funding: CORFO 13CTI21526-P6 &amp; 13IDL2-18608 Citation Format: Miguel Cordova, Maria L. Bravo, Isidora Arriagada, Elisa Cumsille, Luis Quiñones, Erasmo Bravo, Raimundo Correa, Juan E. Leiva, Cesar Paredes, Mauricio Cuello, Carolina Ibañez, Marcelo Garrido, Gareth I. Owen. Distribution of single nucleotide polymorphisms related to paclitaxel and carboplatin toxicity in ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5031. doi:10.1158/1538-7445.AM2017-5031
Abstract 171: Targeting the tumor microenvironment: inhibition of carbonic anhydrase 9 impedes brain tumor initiating cell chemoresistance and delays glioblastoma growth in vivo
Authors: Nathaniel H. Boyd, Kiera Walker, Paul C. McDonald, Mark O. Bevensee, Yancey G. Gillespie, Burt Nabors, Shoukat Dedhar, Anita B. Hjelmeland
Journal: Cancer Research (2017)

Abstract Brain tumor initiating cells (BTICs) are resistant to chemo- and radiotherapy, providing a reservoir for tumor recurrence and a desirable target for glioma treatments. Standard of care for glioblastoma (GBM; grade IV astrocytoma) includes the chemotherapeutic agent temozolomide, which prolongs life expectancy by months and is not curative. Prior studies suggested the efficacy of chemotherapies including temozolomide was increased by reducing expression of carbonic anhydrase 9 (CA9). CA9 is a hypoxia responsive gene elevated in tumors that is important for regulating intracellular pH and contributing to the acidic extracellular microenvironment. After confirming basal and hypoxia-induced expression of CA9 in GBM BTICs, we targeted CA9 activity with the small molecule inhibitor SLC-0111 alone or in combination with temozolomide. In multiple GBM BTIC lines, SLC-0111 reduced cell growth in vitro and showed additional benefit when used concurrently with temozolomide. Importantly, SLC-0111 inhibited the enrichment of BTICs after temozolomide treatment as determined via BTIC marker expression and neurosphere formation capacity. These data suggested the potential of SLC-0111 as a chemosensitizer, which we next evaluated in preclinical studies using a subcutaneous recurrent GBM model. GBMs treated with SLC-0111 in combination with temozolomide significantly regressed and the resulting in vivo growth delay was greater than that of temozolomide or SLC-0111 alone. Together, our data suggest that SLC-0111 can sensitize GBM BTICs to the chemotherapy temozolomide and significantly delay disease progression. Citation Format: Nathaniel H. Boyd, Kiera Walker, Paul C. McDonald, Mark O. Bevensee, Yancey G. Gillespie, Burt Nabors, Shoukat Dedhar, Anita B. Hjelmeland. Targeting the tumor microenvironment: inhibition of carbonic anhydrase 9 impedes brain tumor initiating cell chemoresistance and delays glioblastoma growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 171. doi:10.1158/1538-7445.AM2017-171
Abstract 4806: Strategies to overcome the heterogeneity of tumor cells in breast cancer therapy
Authors: Gloria M. Calaf, Marcela Gallardo, Debasish Roy, Richard Ponce-Cusi
Journal: Cancer Research (2017)

Abstract Breast carcinogenesis is a multistage process that involves mutations and alterations attributed to exposure to exogenous environmental substances and endogenous agents as female hormones. To overcome the heterogeneity of tumor cells in breast cancer therapy several strategies must be considered from the bench to clinical settings. It is proposed four strategies: Analysis to determine 1) Apoptosis, 2) Epithelial-mesenchymal transition (EMT), 3) CD44/CD24 gene and protein expression in cells derived from mammospheres and 4) MicroRNAs as miR34a and others by the effects of chemotherapeutic drugs (as pamidronate (Pam), 5-Fluorouracil (5-FU) and antioxidants as Curcumin (Cur) (diferuloylmethane) derived from Curcuma longa. Pam, a bisphosphonate is used in the treatment of breast cancer. 5-FU is a chemotherapeutic agent for the treatment of a variety of solid cancers that arrest cell cycle and induce apoptosis in cancer cells. We evaluated genes and proteins targeted by these drugs and antioxidants in a triple positive cell line, as MCF7 and a negative, MDA-MB-231 for hormonal receptors, respectively and in an in vitro breast cancer model induced by radiation and estrogen that was developed with a normal immortalized breast epithelial cell line, MCF-10F exposed to low doses of high LET (linear energy transfer) alpha particles (150 keV/μm) of radiation, and cultured in presence of 17β-estradiol. We used: i) MCF-10F, ii) Alpha3, a malignant non-tumorigenic, iii) Alpha5, a tumorigenic one and iv) Tumor2 cell line derived from Alpha5 injected into the nude mice. Previous results showed increased cell proliferation, anchorage independency, invasive capabilities and tumor formation in nude mice, microsatellite instability and loss of heterozygosity in chromosomes 6, 8, 11 and 17 and mutations of c-Ha-ras and Rho-A in Alpha5 and Tumor2 compared to the control MCF-10F and their counterparts. Pam, 5-FU and Cur inhibited migration and invasion in both cell lines, and also decreased c-Ha-ras, Rho-A, p53, and Cav-1 gene expression by RT-qPCR. These compounds also induced 1) apoptotic effect on Bcl-xL and Bax gene and protein expression and by flow cytometry; 2) changes in EMT markers such as Snail, Slug, Axl, 3) CD44/CD24 alterations and 4) target MicroRNAs as miR34a on different process. It can be concluded that strategies to overcome the heterogeneity of tumor cells can be used to interfere with genes involved in critical steps in breast carcinogenesis. Grant: Tarapacá University, Arica, Chile (GMC). Short tittle: Strategies in breast cancer therapy Citation Format: Gloria M. Calaf, Marcela Gallardo, Debasish Roy, Richard Ponce-Cusi. Strategies to overcome the heterogeneity of tumor cells in breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4806. doi:10.1158/1538-7445.AM2017-4806
Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy
Authors: Jicheng Lv, Hong Zhang, Muh Geot Wong, Meg J. Jardine, Michelle Hladunewich, Vivek Jha, Helen Monaghan, Minghui Zhao, Sean Barbour, Heather Reich, Daniel Cattran, Richard Glassock, Adeera Levin, David Wheeler, Mark Woodward, Laurent Billot, Tak Mao Chan, Zhi-Hong Liu, David W. Johnson, Alan Cass, John Feehally, Jürgen Floege, Giuseppe Remuzzi, Yangfeng Wu, Rajiv Agarwal, Hai-Yan Wang, Vlado Perkovic
Journal: JAMA (2017)

<h3>Importance</h3> Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. <h3>Objective</h3> To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. <h3>Design, Setting, and Participants</h3> The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m<sup>2</sup>after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. <h3>Interventions</h3> Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. <h3>Main Outcomes and Measures</h3> The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. <h3>Results</h3> After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m<sup>2</sup>; urine protein excretion, 2.40 g/d) and 2.1 years' median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (<i>P</i> = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%];<i>P</i> &lt; .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%];<i>P</i> = .02). <h3>Conclusions and Relevance</h3> Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01560052
Mutational Landscapes of Smoking-Related Cancers in Caucasians and African Americans: Precision Oncology Perspectives at Wake Forest Baptist Comprehensive Cancer Center
Authors: Ville Kytola, Umit Topaloglu, Lance D. Miller, Rhonda L. Bitting, Michael M. Goodman, Ralph B. D`Agostino, Rodwige J. Desnoyers, Carol Albright, George Yacoub, Shadi A. Qasem, Barry DeYoung, Vesteinn Thorsson, Ilya Shmulevich, Meng Yang, Anastasia Shcherban, Matthew Pagni, Liang Liu, Matti Nykter, Kexin Chen, Gregory A. Hawkins, Stefan C. Grant, W. Jeffrey Petty, Angela Tatiana Alistar, Edward A. Levine, Edgar D. Staren, Carl D. Langefeld, Vincent Miller, Gaurav Singal, Robin M. Petro, Mac Robinson, William Blackstock, Bayard L. Powell, Lynne I. Wagner, Kristie L. Foley, Edward Abraham, Boris Pasche, Wei Zhang
Journal: Theranostics (2017)

Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics.This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods:The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016.The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%).Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry.Results: Tobacco-related cancers exhibit a high mutational load.These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3).These tobacco-related cancers also exhibit augmented tumor heterogeneities.Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status.The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied.Both cohorts also revealed 5 genes (e.g.CDK8) significantly amplified in the African-American population.Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer.TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.
Abstract 1705: Slide-based multi-parametric immunophenotyping of human blood samples by cyclic immunofluorescence using the Accucyte-CyteFinder system
Authors: Jia-Ren Lin, Lance U'Ren, Gregory J. Baker, Joshua J. Nordberg, Zoltan Maliga, Jackie L. Stilwell, Eric P. Kaldjian, Peter K. Sorger
Journal: Cancer Research (2017)

Abstract Immunophenotyping is an approach to measuring the abundance and functional state of immune cells as a means to understand mechanisms of homeostasis, identify biomarkers of disease, and measure therapeutic and adverse responses to drugs such as immune checkpoint inhibitors. Such studies are conventionally performed using flow cytometry together with combinations of immunomarkers that allow for identification of cell type, maturation state, and activation status. Here we describe a method for profiling circulating human leukocytes with highly-multiplexed immunofluorescence microscopy. The method has distinct advantages over flow cytometry in that it has greater sensitivity for detecting rare cell populations, allows for repeat analysis and long-term storage of precious biological samples, and obviates the requirement for spectral deconvolution. Using an open-source multiplexed immunofluorescence protocol referred to as cyclic immunofluorescence (CycIF), and commercially available reagents and instruments (AccuCyte and CyteFinder; RareCyte Inc.), we show that imaging can provide 16-plex, single-cell intensity data in addition to information on cellular morphology. Analytic technologies borrowed from the field of mass cytometry, such as ViSNE and Phenograph, allow for downstream phenotypic analysis and high-dimensional biomarker discovery. Current efforts now aim to expand the number of validated immune targets and combine imaging with single-cell picking and sequencing technologies. Citation Format: Jia-Ren Lin, Lance U'Ren, Gregory J. Baker, Joshua J. Nordberg, Zoltan Maliga, Jackie L. Stilwell, Eric P. Kaldjian, Peter K. Sorger. Slide-based multi-parametric immunophenotyping of human blood samples by cyclic immunofluorescence using the Accucyte-CyteFinder system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1705. doi:10.1158/1538-7445.AM2017-1705
Abstract 3567: Sequencing the human TCRβ repertoire on the Ion S5™ System
Authors: Denise S. Topacio-Hall, Tim Looney, Yongming Sun, Lauren Miller, Elizabeth Linch, Geoffrey Lowman, Lifeng Lin, Mark Andersen, Fiona Hyland, Ann Mongan
Journal: Cancer Research (2017)

Abstract Next-generation Sequencing (NGS) is proving an important tool in increasing understanding of the human immune system, and thereby cancer immunology. αβ-T cells are the primary constituents of human cell-mediated adaptive immunity. The antigen specificity of each αβ-T cell is encoded in the 500-600 bp transcript encompassing the variable portion of the rearranged TCRα and TCRβ subunits, which can be read via NGS in a process termed repertoire sequencing. Until now, the main challenge the field faces is the lack of a technology that can provide a contiguous read of 600 bp to minimize the complexity of designing bias-prone primers and informatics challenges of stitching short reads. Here we leverage the long read capability of Ion 530™ chip to comprehensively sequence all three CDR domains of the TCRβ chain. The Ion 530™ chip offers greater than 15 M productive reads, allowing a multiplex of 2-4 samples with sufficient coverage for most repertoire profiling studies. Initial testing with Leukocyte total RNA demonstrates that this multiplex PCR assay produced repertoires that were much more similar to data derived from 5’RACE protocol than the commonly used BIOMED2 primer set. This result suggested that the use of long reads minimizes bias by allowing targeting of less variable regions. To further assess the performance of the assay, we designed a model system of 30 plasmid controls containing common human T-cell CDR3 sequences. Each plasmid was amplified individually and sequenced to confirm the detection of a single clonal population. Analytical sensitivity of the assay and accuracy of the accompanied analysis solution were further evaluated by spiking in plasmid concentrations from 10 pg to 0.0001 pg (5 million to 50 copies) in a background of 100 ng cDNA reverse transcribed from leukocyte total RNA. Results showed the assay offers linearity over 5 orders of magnitude of decreasing input concentration. In summary, we have demonstrated a NGS workflow for TCRβ sequencing that offers multiplex flexibility on Ion S5 with sample to answer in less than 48 hours. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Denise S. Topacio-Hall, Tim Looney, Yongming Sun, Lauren Miller, Elizabeth Linch, Geoffrey Lowman, Lifeng Lin, Mark Andersen, Fiona Hyland, Ann Mongan. Sequencing the human TCRβ repertoire on the Ion S5™ System [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3567. doi:10.1158/1538-7445.AM2017-3567
Design of Cancer Assays for Pharmaceutical Agents: Reply
Authors: Joseph L. Ciminera
Journal: JNCI Journal of the National Cancer Institute (1985)

Journal Article Design of Cancer Assays for Pharmaceutical Agents: Reply Get access Joseph L. Ciminera Joseph L. Ciminera Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 74, Issue 5, May 1985, Page 1152, https://doi.org/10.1093/jnci/74.5.1152 Published: 01 May 1985
Abstract 914: Age-associated neoplastic transformation of mammary stem cells
Authors: Xiang Gu, Hakim Bouamar, Kyle Pressley, LuZhe Sun
Journal: Cancer Research (2017)

Abstract Incidence rate of breast cancer increases significantly with age. However, the mechanism of age-associated mammary tumorigenesis is unknown. Although mammary stem/progenitor cells have been proposed as the cells of origin for breast cancer, the mechanism remains largely elusive. Previously we discovered that in the old (28 to 30 month-old) mouse mammary gland, the luminal cells in the hyperplastic lesions elevated expression of CD49f, which is a basal cell marker. This led to an increased percentage of mammary stem cells (MaSCs) marked by CD49fhi in the old in comparison to the young (3 to 6 month-old). Similarly, old (&amp;gt;60 yr) human mammary ducts in the adjacent normal tissues from patients with breast cancer showed more hyperplastic lesions and CD49fhi luminal cells than young (&amp;lt;40 yr) tissues. Regenerated mammary glands by the old CD49fhi MaSCs through in vivo transplantation in cleared mammary fat pads showed more hyperplastic and dysplastic lesions than those regenerated by the young CD49fhi MaSCs, suggesting the old CD49fhi MaSCs contain transformed MaSCs. Moreover, gene set enrichment analysis of whole genome transcriptome data showed that they also have elevated expression of luminal cell specific genes and reduced expression of basal cell specific genes. Through large scale screening with flow cytometry guided by bioinformatics analysis, we found that Lin- CD24med CD49fhi CD13+ CD73- mammary epithelial cells had increased number of MaSCs. By comparing young (3 to 6 months old) and old Balb/C mice, we found that the frequency of this specific MaSCs was significantly increased by four folds in old mammary epithelial cells (young: 4%, old: 16%). In contrast, relative percentage of Lin- CD24med CD49fhi CD13- CD73+ cells significantly decreased (young: 46%, old: 16%) during aging while the CD13 and CD73 double positive or double negative subpopulations remained unchanged. CD13+ CD73- cells generated significantly many more mammospheres (around 40 spheres per 1,000 cells) in suspension culture than other three types of cells (around 2 spheres per 1,000 cells). However, there was no significant difference between the young and old in terms of sphere formation efficiency for any of the four subpopulations marked by CD13 and CD73. We are studying whether anyone of these four subpopulation from CD49fhi old cells will generate more hyperplastic and dysplastic lesions in regenerated glands than the other subpopulations as well as than the corresponding young subpopulation. Our study show that CD13 and CD73 may be the markers for the identification of tumor-initiating MaSCs. Citation Format: Xiang Gu, Hakim Bouamar, Kyle Pressley, LuZhe Sun. Age-associated neoplastic transformation of mammary stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 914. doi:10.1158/1538-7445.AM2017-914
Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1
Authors: T-C Teh, N-Y Nguyen, D M Moujalled, D Segal, G Pomilio, S Rijal, A Jabbour, K Cummins, K Lackovic, P Blombery, E Thompson, P G Ekert, G Lessene, S P Glaser, D C S Huang, A W Roberts, M A Guthridge, A H Wei
Journal: Leukemia (2017)
Human resources estimates and funding for antibiotic stewardship teams are urgently needed
Authors: C. Pulcini, C.M. Morel, E. Tacconelli, B. Beovic, K. de With, H. Goossens, S. Harbarth, A. Holmes, P. Howard, A.M. Morris, D. Nathwani, M. Sharland, J. Schouten, K. Thursky, R. Laxminarayan, M. Mendelson
Journal: Clinical Microbiology and Infection (2017)