tbuckley/cabot-search huggingface dataset:
Abstract 461: Combined analysis of circulating epithelial cell count and serum thyroglobulin for differentiating disease status of the patients with papillary thyroid carcinoma
Authors: Ching-Ping Tseng, Jen-Der Lin, Hung-Chih Lin, Ju-Chien Cheng
Journal: Cancer Research (2016)

Abstract Papillary thyroid carcinoma (PTC) is one type of thyroid cancer and accounts for about 80% of the cases. Routine surveillance by serum thyroglobulin (Tg) and medical imaging is the current practice to monitor disease progression of the patients. However, the presence of anti-Tg antibody or other influence factors may discount the value of serum Tg in disease monitoring. Whether enumeration of circulating epithelial cells (CECs) and its combined analyses with serum Tg help to define disease status of PTC patients was investigated. CECs were first enriched from the peripheral blood of the healthy control subjects (G1, n = 17) and the patients at disease-free status (G2, n = 26) or with distant metastasis (G3, n = 22). The number of CECs expressing epithelial cell adhesion molecule (EpCAM) was determined by immunofluorescence microscopy analyses. The medium number of EpCAM+-CECs was 6 (intequartile range 1-11), 12 (interquartile range 7-16) and 91 (interquartile range 31-206) cells/ml of blood for G1, G2 and G3, respectively. EpCAM+-CEC counts were significantly higher in G3 than in G1 (p&amp;lt;0.05) and G2 (p&amp;lt;0.05). Our data further revealed that combined analysis of serum Tg with EpCAM+-CEC defined the disease status (disease-free vs. distant metastasis) in 46 (95.8%) of the 48 patients with the AUC equivalent of 0.962 (p&amp;lt;0.0001) in the ROC analysis. The sensitivity and specificity of the assay was 100% and 92.3%, respectively. Moreover, all 22 patients (100%) with metastatic status were defined accordingly. These data demonstrate that combined analysis of serum Tg with EpCAM+-CECs is suitable to distinguish the patients at disease-free status from the patients with distant metastasis. CEC testing thereby can supplement the current standard methods for monitoring disease status of PTC. Citation Format: Ching-Ping Tseng, Jen-Der Lin, Hung-Chih Lin, Ju-Chien Cheng. Combined analysis of circulating epithelial cell count and serum thyroglobulin for differentiating disease status of the patients with papillary thyroid carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 461.
Variable Cyst Development in Autosomal Dominant Polycystic Kidney Disease: The Biologic Context
Authors: Wouter N. Leonhard, Hester Happe, Dorien J.M. Peters
Journal: Journal of the American Society of Nephrology (2016)

Patients with autosomal dominant polycystic kidney disease (ADPKD) typically carry a mutation in either the PKD1 or PKD2 gene, which leads to massive cyst formation in both kidneys. However, the large intrafamilial variation in the progression rate of ADPKD suggests involvement of additional factors other than the type of mutation. The identification of these factors will increase our understanding of ADPKD and could ultimately help in the development of a clinically relevant therapy. Our review addresses the mechanisms by which various biologic processes influence cyst formation and cyst growth, thereby explaining an important part of the inter- and intrafamilial variability in ADPKD. Numerous studies from many laboratories provide compelling evidence for the influence on cyst formation by spatiotemporal gene inactivation, the genetic context, the metabolic status, the presence of existing cysts, and whether the kidneys were challenged by renal injury. Collectively, a solid basis is provided for the concept that the probability of cyst formation is determined by functional PKD protein levels and the biologic context. We model these findings in a graphic representation called the cystic probability landscape, providing a robust conceptual understanding of why cells sometimes do or do not form cysts.
Abstract 2438: Genome-wide screen reveals a role for glucocorticoids in B cell development that can be exploited to improve treatment of B cell acute lymphoblastic leukemia
Authors: Miles Pufall, Karina Kruth, Sarah K. Tasian
Journal: Cancer Research (2016)

Abstract Glucocorticoids (GCs) are a component of highly effective therapy for B cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer. Although successful in 90% of patients, the prognosis for the remaining 10% is dismal. Because sensitivity to GCs alone predicts outcome well, we hypothesized that enhancing or restoring GC sensitivity can improve outcome. To first determine how GCs kill B-ALL cells, we first measured the transcriptional response of sensitive B-ALL samples to dexamethasone (dex). In addition to apoptotic genes (BIM, BCL2), and metabolic genes (TXNIP) identified in other studies that contribute to cell death, we also found broad regulation of B cell development genes, including key checkpoints (ITGA4, IL7R, and BCL6). This suggested that high levels of GCs push arrested B-ALL cells through development, resulting in cell death. To validate these results, and to identify cellular pathways that modulate GC cytotoxicity, we used a next-generation shRNA screen to knock down every protein-coding gene in the genome. The screen identified 265 genes that significantly modulate GC sensitivity. In addition to validating the importance lymphoid development genes, the screen revealed which cofactors and chromatin modifiers collaborate with GR to orchestrate cell death gene programs. Further we were able to map critical signaling pathways with high resolution, including the pro-survival B cell receptor pathway. Inhibition of PI3Kδ at the apex of this pathway potentiated the response of GC-regulated genes to dex, and synnergized with dex to induce cell death in even the most refractory B-ALL tissue. These results indicate a previously unrecognized for GCs in B cell development that can be exploited to improve both the potency and treatment of lymhoid disease. Citation Format: Miles Pufall, Karina Kruth, Sarah K. Tasian. Genome-wide screen reveals a role for glucocorticoids in B cell development that can be exploited to improve treatment of B cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2438.
Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin
Authors: M N Cruickshank, J Ford, L C Cheung, J Heng, S Singh, J Wells, T W Failes, G M Arndt, N Smithers, R K Prinjha, D Anderson, K W Carter, A M Gout, T Lassmann, J O'Reilly, C H Cole, R S Kotecha, U R Kees
Journal: Leukemia (2016)

To address the poor prognosis of mixed lineage leukemia (MLL)-rearranged infant acute lymphoblastic leukemia (iALL), we generated a panel of cell lines from primary patient samples and investigated cytotoxic responses to contemporary and novel Food and Drug Administration-approved chemotherapeutics. To characterize representation of primary disease within cell lines, molecular features were compared using RNA-sequencing and cytogenetics. High-throughput screening revealed variable efficacy of currently used drugs, however identified consistent efficacy of three novel drug classes: proteasome inhibitors, histone deacetylase inhibitors and cyclin-dependent kinase inhibitors. Gene expression of drug targets was highly reproducible comparing iALL cell lines to matched primary specimens. Histone deacetylase inhibitors, including romidepsin (ROM), enhanced the activity of a key component of iALL therapy, cytarabine (ARAC) in vitro and combined administration of ROM and ARAC to xenografted mice further reduced leukemia burden. Molecular studies showed that ROM reduces expression of cytidine deaminase, an enzyme involved in ARAC deactivation, and enhances the DNA damage–response to ARAC. In conclusion, we present a valuable resource for drug discovery, including the first systematic analysis of transcriptome reproducibility in vitro, and have identified ROM as a promising therapeutic for MLL-rearranged iALL.
Abstract 3585: KIF11 silencing or inhibition induces chromosome instability
Authors: Yasamin Asbaghi, Zelda Lichtensztejn, Laura Thompson, Kirk McManus
Journal: Cancer Research (2016)

Abstract Chromosome Instability (CIN) is defined as an increase in the rate at which whole chromosomes or large parts are gained or lost. CIN is not only associated with virtually all tumor types, but it is associated with aggressive tumors, the acquisition of multi-drug resistance and consequently poor patient prognosis. Despite these associations, the genes and molecular defects that contribute to CIN are only poorly understood. Recently, we performed a high content screen that identified KIF11, a microtubule associated motor protein, as a candidate CIN gene. Here, we couple RNAi-based gene silencing with biochemistry and cell biology to show that diminished KIF11 expression and/or function induce CIN. HCT116 cells were employed, as they are a karyotypically stable colorectal cancer cell line of epithelial origin that has been used for similar CIN studies. KIF11 was either silenced (both individual and pooled siRNA duplexes) or inhibited (Monostrol) and expression levels were determined by Western blots. To determine whether KIF11 silencing or inhibition affects DNA content, two phenotypes frequently associated with CIN, namely increases in nuclear area and micronucleus formation were evaluated. Fluorescence microscopy was employed on DAPI-counterstained samples and revealed statistically significant increases both nuclear area and micronucleus formation following KIF11 silencing and inhibition relative to controls. Next, flow cytometry was performed on propidium iodide labeled samples to assess whether increases in DNA content were associated with the changes in nuclear area. As predicted, increases in the proportion of cells with &amp;gt;G2/M DNA content occurred within the KIF11 silenced populations. Finally, mitotic chromosome spreads were generated and chromosomes were manually enumerated from 100 spreads per condition/control. Subsequent Kolmogorov-Smirnov tests identified statistically significant increases in the cumulative distribution frequencies of mitotic chromosome numbers within the spreads generated from the KIF11 silenced cells relative to controls. To extend our findings beyond the colorectal cancer cell context employed above, analogous studies were performed in hTERT cells (karyotypically stable fibroblast cell line) with very similar results. Collectively, these data indicate that KIF11 expression and function are normally required to maintain genome integrity. They further suggest that the loss of KIF11 expression and/or function may be a contributing factor in the etiology of tumorigenesis in colorectal cancer and perhaps other tumor types as well. Citation Format: Yasamin Asbaghi, Zelda Lichtensztejn, Laura Thompson, Kirk McManus. KIF11 silencing or inhibition induces chromosome instability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3585.
Urinary Angiogenin Reflects the Magnitude of Kidney Injury at the Infrahistologic Level
Authors: Quentin Tavernier, Iadh Mami, Marion Rabant, Alexandre Karras, Pierre Laurent-Puig, Eric Chevet, Eric Thervet, Dany Anglicheau, Nicolas Pallet
Journal: Journal of the American Society of Nephrology (2016)

The ribonuclease angiogenin is a component of the mammalian stress response that is secreted by renal epithelial cells on activation of the inositol–requiring enzyme 1 α (IRE1 α )–active spliced X–box binding protein 1 (sXBP1) axis and instrumental to the adaptation to AKI associated with endoplasmic reticulum stress. To determine whether the amount of angiogenin in urine of individuals with a kidney injury reflects the magnitude of the lesions and provides information on the risk of organ failure, we examined individuals referred for a kidney injury and determined the biochemical characteristics of urinary angiogenin and its diagnostic and prognostic values. Urinary angiogenin did not correlate with the urinary concentrations of high molecular weight proteins and correlated only weakly with low molecular weight proteins, suggestive of tubular production. In a cohort of 242 kidney transplant recipients with acute allograft dysfunction, higher urinary angiogenin concentrations at the time of the biopsy associated with worse renal function and higher proteinuria but did not correlate with histologic lesions as defined in the Banff classification. Kidney transplant recipients with urinary angiogenin amounts in the highest 50% had a risk of graft failure 3.59 times as high (95% confidence interval, 1.12 to 15.94) as that of patients with amounts in the lowest 50%. Finally, the amount of urinary angiogenin reflected the activity of the IRE1 α -XBP1 axis in allografts. Our approach identified urinary angiogenin as a noninvasive indicator of the extent of tissue damage, independent of the histologic lesions, and a risk predictor of kidney allograft failure.
A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of GS-5745 combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma.
Authors: Johanna C. Bendell, Alexander Starodub, Xi Huang, Julia D. Maltzman, Zev A. Wainberg, Manish A. Shah
Journal: Journal of Clinical Oncology (2017)

TPS217 Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 is expected to block paracrine signaling and metastasis and to alter the immune microenvironment within the tumor. GS-5745 (800 mg every 2 weeks) with mFOLFOX6 was examined in a Phase 1b study in 40 patients with gastric and GEJ adenocarcinoma (GS-US-296-0101), and demonstrated encouraging activity without added toxicity. Additionally, decreased serum biomarkers suggested inhibition of MMP9 enzymatic activity by these agents. These data support the hypothesis that GS-5745 treatment inhibits MMP9 activity and that the inhibition may lead to improved clinical outcomes. Methods: This phase 3, randomized, double-blind, multicenter study investigates the efficacy and safety of GS-5745 combined with mFOLFOX6 in subjects with untreated gastric and GEJ adenocarcinoma. Total of 430 eligible subjects with advanced gastric and GEJ cancer will be randomized in a 1:1 manner to mFOLFOX6 plus GS-5745 or mFOLFOX6 plus placebo. Stratification factors include ECOG status (0 v 1), geographic region (Latin America v All other countries), and primary tumor site (gastric v GEJ). CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. mFOLFOX6 will be administered on Days 1 and 15 of each 28-day treatment cycle for a total of 6 cycles followed thereafter by leucovorin (LV) and 5-fluorouracil (5-FU) dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. GS-5745/placebo 800 mg will be infused on Days 1 and Day 15 of each 28 day cycle until disease progression. Primary endpoint is OS, and secondary endpoints include PFS, ORR (RECIST 1.1), and safety. The study is designed to have an 85% power to detect clinically meaningful improvement in overall survival at the one-sided significance level of 0.025. The association of exploratory biomarkers with study drug response will also be evaluated. Enrollment opened Oct. 2015. Clinical trial information: NCT02545504.
The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia
Authors: Paul J. Coleman, Anthony L. Gotter, W. Joseph Herring, Christopher J. Winrow, John J. Renger
Journal: The Annual Review of Pharmacology and Toxicology (2016)

Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABA A ) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABA A receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage–specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies.
Clinical correlation with codon-specific mutations in metastatic colorectal cancer.
Authors: Sophia C. Kamran, Jeffrey W. Clark, Darrell R. Borger, Jackie Szymonifka, Eunice Lee Kwak, Lawrence Scott Blaszkowsky, Janet E. Murphy, Lipika Goyal, Jill N. Allen, Jennifer Yon-Li Wo, Andrew X. Zhu, A. John Iafrate, Ryan Bruce Corcoran, David P. Ryan, Theodore S. Hong
Journal: Journal of Clinical Oncology (2016)

3596 Background: Mutational status in colorectal cancer (CRC) impacts response to EGFR inhibition, prognosis, and may affect response to chemoradiation. It is unclear if obesity or other clinical characteristics, including smoking and diabetes, increases the predilection for certain genotypes. The purpose of the following study was to explore the relationship between clinical factors, codon-specific mutations and overall survival (OS). Methods: Metastatic colorectal cancer patients were retrospectively analyzed; clinical characteristics including smoking, diabetes, and body mass index (BMI) were extracted from medical records. Genotyping was performed for > 150 mutations across 15 commonly mutated cancer genes including NRAS, KRAS, PIK3CA, BRAF, and PTEN as part of their clinical management and recorded. Logistic regression was used to establish associations between clinical characteristics and genotypes. Results: 394 metastatic CRC patients were identified. Median age was 58 (range 25-89). 219 (56%) were male. 202 (51%) were non-smokers. 61 had diabetes. 272 patients had a BMI ≥ 25. 136 patients had KRAS mutations, the most common of which was G12D (37%). Diabetes was associated with a higher incidence of KRAS (odds ratio [OR] 1.9 95% CI 1.1-1.3; p = 0.02) and PIK3CA mutations (OR 2.4 95% CI 1.1-5.0; p = 0.02), but not OS. KRAS mutations were not significantly associated with BMI ≥ 25 nor OS. BRAF mutations were significantly associated with poorer OS (hazard ratio [HR] 1.9 95% CI 1.3-2.7; p < 0.001). Current smokers were more likely to have CTNNB1 mutations (OR 11.3 95% CI 1.5-83.2; p = 0.02) and G12D KRAS mutations (OR 5.6 95% CI 1.0-30.3). Current smokers were less likely to have BMI ≥ 25 (OR 0.44; p = 0.02). Patients with BMI ≤ 18.5 have an association with poor OS (HR 2.6 95% CI 1.1-6.4; p = 0.03), although this needs to be corroborated with a larger sample size. Conclusions: A statistically significant association was found between diabetes and KRAS and PIK3CA mutations. The association of BRAF mutations and decreased overall survival was significant, concordant with previous reports. Smokers were more likely to harbor G12D KRAS mutations, and low BMI (≤ 18.5) trended toward poorer overall survival.
Abstract 1165: TRPM8 is avidly targeted for degradation in prostate cancer
Authors: Swapna Asuthkar, Eleonora Zakharian
Journal: Cancer Research (2016)

Abstract Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing receptor and a hallmark Ca2+ channel of the prostate epithelium. The TRPM8 mRNA is overexpressed in early prostate tumors with high androgen levels, while anti-androgen therapy greatly reduces its expression. Thus, androgens, which are at the crossroads of several signaling pathways, appear to be associated with TRPM8-mediated Ca2+ signaling. Although, TRPM8 mRNA levels are upregulated during prostate cancer progression, this upregulation is not adequately translated to the TRPM8 protein levels. We identified that the lower TRPM8 protein abundance and activation in LNCaP cells is associated with increased ubiquitination and loss of TRPM8 from the plasma membrane (PM). The mass-spectrometry analysis of TRPM8, immunoprecipitated from LNCaP cells identified ubiquitin-like modifier-activating enzyme 1 (UBA1). PYR-41, a potent inhibitor of the initial enzyme in the ubiquitination cascade, UBA1, increased TRPM8 activity on the PM of LNCaP cells. Our data indicate that PMTRPM8 plays a protective role in prostate cancer progression accompanied by enhanced activation of p53 and Caspase-9. In addition, we found that the promoter region of trpm8 possesses putative binding sites for p53 and that the overexpression of p53 increased the TRPM8 mRNA levels. Our findings support previous studies that suggest the fine balance between AR and p53 expression that regulates androgen-dependent growth of prostate cancer. Thus, we hypothesize that TRPM8 activity significantly contributes to anti-tumor defense mechanism and may serve as a novel therapeutic target in prostate cancer. Citation Format: Swapna Asuthkar, Eleonora Zakharian. TRPM8 is avidly targeted for degradation in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1165.
Rituximab Sensitizes B-CLL Cells with Inactivated p53 to Fludarabine.
Authors: Martin Trbusek, Sona Cejkova, Jitka Chumchalova, Zdenek Pospisil, Jana Smardova, Petr Kuglik, Michael Doubek, Yvona Brychtova, Sarka Pospisilova, Jiri Mayer
Journal: Blood (2006)
Abstract SY29-01: Deciphering oncogenic translation programs
Authors: Hans-Guido Wendel
Journal: Cancer Research (2016)

Abstract New technologies provide precise measures of translation across the transcriptome. In particular, transcriptome-scale ribosome foot printing in conjunction with deep RNA sequencing developed by N. Ignolia and colleagues has shifted the focus in the field towards the output of mRNA translation. We can now measure differential mRNA translation programs and determine RNA sequence and structural features that guide translational responses to cellular and environmental cues. This has direct implications to cancer and beyond. It also extends our understanding of gene expression from transcriptional control to the regulation of protein production. We will provide examples of how these new approaches to studying mRNA translation are leading to new insight into cancer biology and therapy. Citation Format: Hans-Guido Wendel. Deciphering oncogenic translation programs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY29-01.