tbuckley/cabot-search huggingface dataset:
Abstract LB-175: ATM regulates radiation-induced translational control of gene expression
Authors: Stacey L. Lehman, Amy Wahba, Kevin Camphausen, Philip J. Tofilon
Journal: Cancer Research (2016)

Abstract The cellular radioresponse is composed of processes regulated by constitutively expressed proteins and processes regulated by new gene expression. While processes regulated by constitutively expressed proteins, such as those participating in DNA repair and cell cycle arrest, have been extensively studied, the radiation-induced changes in gene expression are not well defined. Previously, we have demonstrated that translation plays an important role in regulating gene expression in response to radiation. In glioblastoma cells, treatment with radiation affects more genes at the translational level than at the transcriptional level. Specific transcripts were found to be recruited to or away from polysomes without global changes in the polysome profile of the cells. Here, we utilized microarray analysis of polysome-associated transcripts in the glioblastoma stem-like cell line NSC11 to demonstrate that the DNA damage response kinase ATM controls the translation of a subset of genes as part of the radioresponse. Cells were incubated with the ATM inhibitor KU-60019 at a dose of 500nM for one hour, exposed to 2 Gy, and harvested for polysome extraction one hour after irradiation. ATM inhibition blocked translational changes of approximately one third of genes that were affected by radiation. Gene enrichment analysis revealed that genes translationally regulated by ATM were significantly involved in a number of cellular processes, indicating that ATM-mediated translational control may have functional consequences on the cellular radioresponse. By GSEA, cells treated with radiation alone were highly enriched for terms involving mitochondrial structure and function, cellular respiration, and oxidative stress as compared to irradiated cells treated with the ATM inhibitor. Other significantly enriched categories of functional interest included the spliceosome, RNA catabolic processes, the small nuclear ribonucleoprotein complex, and phospholipid and phosphoinositide metabolism. Analysis of UTR regulatory elements revealed that a significant percentage of the genes translationally upregulated by ATM in irradiated cells were enriched for HuR binding sites, which suggests a potential mechanism for polysome recruitment of these transcripts. Overall, these findings uncover a novel network of post-transcriptional gene regulation orchestrated by ATM and provide a framework to identify potential new molecules and pathways that govern tumor cell radiosensitivity. Citation Format: Stacey L. Lehman, Amy Wahba, Kevin Camphausen, Philip J. Tofilon. ATM regulates radiation-induced translational control of gene expression. [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 LB-175.
Abstract 3979: Metabolic pathways associated with urinary metabolite biomarkers differentiate bladder cancer patients from healthy controls
Authors: Won Tae Kim, Seok Joong Yun, Chunri Yan, Pildu Jeong, Ye Hwan Kim, Il-Seok Lee, Sunghyouk Park, Sung-Kwon Moon, Yung-Hyun Choi, Young Deuk Choi, Jayoung Kim, Wun-Jae Kim
Journal: Cancer Research (2016)

Abstract Our high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry study identified bladder cancer (BCA)-specific urine metabolites, including carnitine, acylcarnitines, and melatonin. The objective of the current study was to determine which metabolic pathways are perturbed in BCA based on our previously identified urinary metabolome. Significant alterations in the carnitine-acylcarnitine and tryptophan metabolic pathways were detected in urine specimens from BCA patients compared to those of healthy controls. The expression of eight genes involved in the carnitine-acylcarnitine metabolic pathway (CPT1A, CPT1B, CPT1C, CPT2, SLC25A20, and CRAT) or tryptophan metabolism (TPH1 and IDO1) was assessed by RT-PCR in our BCA cohort (n = 135). CPT1B, CPT1C, SLC25A20, CRAT, TPH1, and IOD1 were significantly downregulated in tumor tissues compared to adjacent normal bladder tissues (p &amp;lt; 0.05 all) of patients with non-muscle invasive bladder cancer, whereas CPT1B, CPT1C, CRAT, and TPH1 were downregulated in those with muscle invasive bladder cancer (p &amp;lt; 0.05), with no changes in IDO1 expression. In this study, alterations in the expression of genes associated with the carnitine-acylcarnitine and tryptophan metabolic pathways, the most perturbed pathways in BCA, were determined. Our findings provide insight into the mechanisms underlying BCA-associated metabolic flux perturbation. Citation Format: Won Tae Kim, Seok Joong Yun, Chunri Yan, Pildu Jeong, Ye Hwan Kim, Il-Seok Lee, Sunghyouk Park, Sung-Kwon Moon, Yung-Hyun Choi, Young Deuk Choi, Jayoung Kim, Wun-Jae Kim. Metabolic pathways associated with urinary metabolite biomarkers differentiate bladder cancer patients from healthy controls. [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 3979.
Abstract 300: Inhibition of oncogenic MAPK signaling in melanoma triggers SOX2-dependent adaptive drug resistance
Authors: Stefanie Flueckiger, Andrea Aloia, Lukas Frischknecht, Amanda Tuozzo, Davide Croci, Olga Shakhova, Christian Britschgi, Reinhard Dummer, Mitchell Paul Levesque, Wilhelm Krek
Journal: Cancer Research (2016)

Abstract Treatment of metastatic melanoma with BRAFV600E-specific small molecule inhibitors (BRAFi) provides dramatic clinical relief response but fails to suppress long-term tumor growth in the long-term. Extensive studies have uncovered identified a number of resistance-causing genetic alterations that, which are acquired upon continued drug exposure. However, little is known about the changes in gene expression programs changes during the critical time before drug resistance is manifested on at the genomic level. These changes may lead to adaptive drug resistance and hence, represent vital mechanisms by which tumor cells survive the acute drug insult prior to acquisition of resistance-causing mutations. Using a combination of RNAseq and molecular analyses, we find that acute inhibition of oncogenic MAPK signaling by BRAFi or MEKi in established and primary patient-derived melanoma cell cultures, leads to a rapid induction of the stem cell maintenance and pluripotency factor SOX2. Immunohistochemical analysis of Sox2 expression in melanoma sections derived from BrafV600E/Pten−/−-mice treated for 36 hours with BRAFi/MEKi confirmed the emergence of a Sox2-positive melanoma subpopulation in vivo. SOX2 Ectopic ectopic expression of SOX2 protected melanoma cells from the anti-proliferative effects of BRAFi indicative ofindicating a role for SOX2 in mediating drug resistance. Furthermore, siRNA-mediated depletion or overexpression experiments of SOX2 unveiled revealed that it is necessary and sufficient for the expansion of a drug-tolerant SOX2+CD24+ cell population. This subpopulation is characterized by increased migratory and invasive behavior as well as an increased proliferative potential in the presence of BRAFi when compared to SOX2+CD24− cells. These results imply that BRAFi treatment induces a SOX2-dependent cellular program with features of adaptive drug resistance. Suppression of drug-dependent induction of SOX2 or its downstream effector pathways could potentially extend the clinical efficacy of BRAFi. Citation Format: Stefanie Flueckiger, Andrea Aloia, Lukas Frischknecht, Amanda Tuozzo, Davide Croci, Olga Shakhova, Christian Britschgi, Reinhard Dummer, Mitchell Paul Levesque, Wilhelm Krek. Inhibition of oncogenic MAPK signaling in melanoma triggers SOX2-dependent adaptive drug resistance. [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 300.
Abstract 1858: Analyzing the impact of MDM2 overexpression on cell cycle pathway-related genes using polymerase chain reaction array
Authors: Priya Dondapati, Thiagarajan Venkatesan, Appu Rathinavelu
Journal: Cancer Research (2016)

Abstract The human homologue of the mouse double minute 2 (MDM2) oncogene has been well characterized as a negative regulator of the tumor suppressor p53. It has been established that p53 regulates genes that are involved in cell cycle arrest, apoptosis, DNA repair and senescence. MDM2 interacts primarily with p53 in an autoregulatory negative feedback loop and targets it for ubiquitylation and proteasomal degradation there by attenuating p53 cell cycle arrest and apoptosis functions. Studies have shown that MDM2 also exerts its effects via p53 independent pathways. These p53-independent functions of MDM2 may have a role in cancer etiology and progression, yet the exact function and significance of these interactions are not fully understood. MDM2 is overexpressed in more than 40 different types of malignancies, including wide varieties of carcinomas and sarcomas, which is believed to be associated with worse clinical prognosis and increased likelihood of distant metastases. Hence, MDM2 is proving to be a key player in human cancer and thus an important target for therapeutic intervention. In this study, we aimed to investigate the effects of MDM2 overexpression on cell cycle pathways by using LNCaP prostate cancer cells and MDM2 transfected LNCaP-MST. The LNCaP-MST cells expressed at least 10-folds higher levels of MDM2 mRNA due to transfection. We used the Human Cell Cycle PCR array to compare the gene expression profiles of LNCaP and LNCaP-MST cells. Our experimental results clearly indicated that MDM2 modulates the expression of cell cycle related genes. The following genes were found to be significantly down-regulated in LNCaP-MST cells compared to LNCaP: CCND2, GADD45A, RB1, RBBP8, CDKN1A and TP53. Genes such as BIRC5, CDK1 were found to be significantly up-regulated. Heat map and scatter plot analysis further confirmed the alterations in the expression levels of these genes following the MDM2 overexpression. In addition, cluster analysis further denoted that the gene expression patterns positively correlated with cell proliferation and tumor growth. Our experimental results offer conclusive evidence that MDM2 can impact the cancer growth and metastatic potential by altering the gene expressions in the cell cycle pathway. (The financial support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale is gratefully acknowledged). Citation Format: Priya Dondapati, Thiagarajan Venkatesan, Appu Rathinavelu. Analyzing the impact of MDM2 overexpression on cell cycle pathway-related genes using polymerase chain reaction array. [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 1858.
Lymphatic mapping and sentinel node biopsy (SNB) in patients with melanoma: A systematic review.
Authors: N. de Rosa, D. Silbermins, M. E. Valsecchi, S. L. Wong, G. H. Lyman
Journal: Journal of Clinical Oncology (2010)

e19022 Background: SNB is a widely used technology for staging patients with melanoma. A systematic review of SNB in melanoma was commissioned by ASCO in support of clinical practice guidelines in this setting. Methods: A literature search of electronic databases from 1980 to the present was undertaken. Dual blind data extraction of selected articles was conducted. Primary outcomes included proportion successfully mapped and test performance based on completion lymph node dissection (CLND) or nodal recurrence. Results: Eligibility criteria were met for 176 studies of SNB in melanoma patients including 65 prospective and 111 retrospective studies (51,532 patients). The number of patients in each trial varied from 11 to 3,000 (mean 293; median 167) of which 46% were female and 54% male. Mean age of patients across studies was 52.1 years. Tumor site was extremity, trunk, and head and neck in 46%, 36% and 13% of patients, respectively. Mean Breslow thickness was 2.28 mm with ulceration in 24.6% of patients. Proportion of patients successfully mapped ranged from 12% to 100%, averaging 92% with 14.8% of patients with more than 1 drainage basin. Among patients successfully mapped, 18.3% had one or more positive sentinel nodes. While 20% of patients underwent CLND, only 1.8% were conducted regardless of SNB results. Among patients with a positive SNB, 21.7% had additional positive nodes in the CLND. The duration of followup ranged from 4-81 months, averaging 37 months across all studies. Among patients with a negative SNB, recurrent disease was reported in 10.9% including 3.4% in the nodal basin. Among patients with a positive SNB, recurrent disease was reported in 39.5% including 7.7% in the nodal basin. The SNB false-negative rate for nodal recurrence was reported in 135 studies ranging from 0% to 42% and averaging 12.8% across studies. Disease-free survival at 5 years was reported in 41 studies by SNB status with medians of reported rates of 50% and 84% in SNB positive and negative patients, respectively. Conclusions: While often utilized, SNB test performance in melanoma varies and its value in clinical management needs further clarification. Clinical practice guidelines for SNB in melanoma are under development by ASCO. No significant financial relationships to disclose.
Abstract 2890: ERCC5 variant rs2296147 T-allele creates a predicted TP53 binding site and up-regulates transcript abundance in normal bronchial epithelial cells, while rs17655 C-allele is linked to miRNA binding site variant and down regulates
Authors: Xiaolu Zhang, Erin L. Crawford, Thomas M. Blomquist, Sadik A. Khuder, Jiyoun Yeo, Albert M. Levin, James C. Willey
Journal: Cancer Research (2016)

Abstract Background: Excision repair cross-complementation group 5 (ERCC5) gene plays an important role in nucleotide excision repair (NER) and dysregulation of ERCC5 is associated with increased lung cancer risk. This study was conducted to characterize cis-acting genetic variants responsible for inter-individual variation in ERCC5 transcript regulation in normal bronchial epithelial cells (NBEC). Methods: We determined genotypes at putative ERCC5 cis-regulatory single nucleotide polymorphic sites (SNP) rs751402 and rs2296147, and marker SNPs rs1047768 and rs17655. Using a recently developed targeted sequencing method, ERCC5 allele-specific transcript abundance was assessed in NBEC RNA from 55 individuals heterozygous for rs1047768 and 21 subjects heterozygous for rs17655. Syntenic relationships among alleles at rs751402, rs2296147 and rs1047768 were assessed by allele-specific PCR followed by Sanger sequencing. We assessed association of NBEC ERCC5 allele-specific expression at rs1047768 with haplotype and diplotype structure at putative ERCC5 promoter cis-regulatory SNPs rs751402 and rs2296147. Results: Genotype analysis revealed higher inter-individual variation in allelic ratios in cDNA samples relative to matched gDNA samples at both rs1047768 and rs17655 (p&amp;lt;0.0001 and p = 0.0005 respectively). By haplotype analysis, mean expression was higher at the rs1047768 alleles syntenic with rs2296147 T allele compared to rs2296147 C allele (p = 0.0030). Sequence analysis predicts that T allele at SNP rs2296147 creates a TP53 binding site. Mean expression was higher at rs17655 G allele (p&amp;lt;0.0001) which is syntenic with G allele at a linked SNP rs873601 (r2 = 0.74). C allele at SNP rs873601 is predicted to create a miRNA binding site. Conclusions: These data support the conclusion that T allele at SNP rs2296147 creates a TP53 binding site and up-regulates ERCC5 while C allele at SNP rs873601 creates a miRNA binding site and down-regulates ERCC5. Variation in ERCC5 transcript abundance associated with allelic variation at these SNPs is likely associated with variation in NER function in NBEC and lung cancer risk. Citation Format: Xiaolu Zhang, Erin L. Crawford, Thomas M. Blomquist, Sadik A. Khuder, Jiyoun Yeo, Albert M. Levin, James C. Willey. ERCC5 variant rs2296147 T-allele creates a predicted TP53 binding site and up-regulates transcript abundance in normal bronchial epithelial cells, while rs17655 C-allele is linked to miRNA binding site variant and down regulates. [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 2890.
Impairment of Immunoproteasome Function by Cigarette Smoke and in COPD.
Authors: Kammerl Ie, Dann A, Mossina A, Brech D, Lukas C, Vosyka O, Nathan P, Conlon Tm, Wagner De, Overkleeft Hs, Prasse A, Rosas Io, Straub T, Krauss-Etschmann S, Königshoff M, Preissler G, Winter H, Lindner M, Hatz R, Behr J, Heinzelmann K, Yildirim Aö, Noessner E, Eickelberg O, Meiners S
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Abstract Chronic obstructive pulmonary disease patients and in particular smokers are more susceptible to respiratory infections contributing to acute exacerbations of disease. The immunoproteasome is a specialized type of proteasome destined to improve major histocompatibility complex (MHC) class I-mediated antigen presentation for the resolution of intracellular infections. To characterize immunoproteasome function in COPD and its regulation by cigarette smoke. Immunoproteasome expression and activity were determined in bronchoalveolar lavage (BAL) and lungs of human donors, COPD, and IPF patients, as well as in cigarette smoke-exposed mice. Smoke-mediated alteration of immunoproteasome activity and MHC I surface expression were analysed in human blood-derived macrophages. Immunoproteasome-specific MHC I antigen presentation was evaluated in spleen and lung immune cells that had been smoke-exposed in vitro or in vivo. Immunoproteasome and MHC I mRNA expression was reduced in BAL cells of COPD patients and in isolated alveolar macrophages of COPD and IPF patients. Exposure of immune cells to cigarette smoke extract in vitro reduced immunoproteasome activity and impaired immunoproteasome-specific MHC I antigen presentation. In vivo, acute cigarette smoke exposure dynamically regulated immunoproteasome function and MHC I antigen presentation in mouse BAL cells. End-stage COPD lungs showed markedly impaired immunoproteasome activities. We here show for the first time that the activity of the immunoproteasome is impaired by cigarette smoke resulting in reduced MHC I antigen presentation. Regulation of immunoproteasome function by cigarette smoke may thus alter adaptive immune responses and add to prolonged infections and exacerbations in COPD and IPF.
Abstract 116: Study of TERT promoter and FGFR3 mutations in upper-tumor urothelial carcinomas
Authors: Roger Mouawad, Souheyla Bensalma, Xiaoping Su, Frederick Allanic, Eva Comperat, Morgan Rouprêt, JeanPhillipe Spano, Gabriel Malouf, David Khayat
Journal: Cancer Research (2016)

Abstract Background: Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes represent the most recurrent somatic alterations in urothelial carcinomas of the bladder. However, data regarding frequency and prognostic values of these alterations in upper-tumor urothelial carcinoma (UTUC) remain limited. Methods: DNA was extracted from 31 UTUC including 12 cases arising in the ureter and 19 in renal pelvis. Somatic mutations of TERT promoter and FGFR3 gene were assessed by Sanger sequencing. The generated sequences were analyzed by seqscape and mutational status of each of those genes were correlated with clinico-pathological tumor features. Disease-free survival and overall survival were estimated using the Kaplan-Meier method. Results: Median patient's age was 72 years (range: 41-83) with a male predominance (90.3%). Mutation status of TERT and FGFR3 were obtained in all tumors. Out of 31 UTUC, 81% were classified as high-grade including 56% which were muscle-invasive (≥pT2). TERT and FGFR3 mutations were detected in 19 (61%) and 14 (46%) tumors, respectively. Of note, 8 (26%) out of them harbored both mutations. In the TERT-mutated subgroup, we observed higher incidence of men as compared to TERT non-mutated subgroup (p = 0.04); in addition, we did not identify any other significant differences regarding other clinico-pathological features. This was also the case for FGFR3 mutations, although we observed a higher frequency in tumors arising in the ureter (66.6%) as compared to those located in renal pelvis (28.5%) (p = 0.11). Neither mutations of FGFR3 nor TERT were associated with progression-free survival and patient's overall survival. Conclusion: Our study identified a high rate of somatic mutations in FGFR3 and TERT which were similar between muscle-invasive and non-muscle invasive tumors as well as between tumors arising in the ureter or renal pelvis. As targeted inhibitors are being investigated in this setting, these results might have implications for patient's management. Citation Format: Roger Mouawad, Souheyla Bensalma, Xiaoping Su, Frederick Allanic, Eva Comperat, Morgan Rouprêt, JeanPhillipe Spano, Gabriel Malouf, David Khayat. Study of TERT promoter and FGFR3 mutations in upper-tumor urothelial carcinomas. [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 116.
YKL-40 Associates with Renal Recovery in Deceased Donor Kidney Transplantation
Authors: Jeremy Puthumana, Isaac E. Hall, Peter P. Reese, Bernd Schröppel, Francis L. Weng, Heather Thiessen-Philbrook, Mona D. Doshi, Veena Rao, Chun Geun Lee, Jack A. Elias, Lloyd G. Cantley, Chirag R. Parikh
Journal: Journal of the American Society of Nephrology (2016)

Deceased donor kidneys with AKI are often discarded for fear of poor transplant outcomes. Donor biomarkers that predict post-transplant renal recovery could improve organ selection and reduce discard. We tested whether higher levels of donor urinary YKL-40, a repair phase protein, associate with improved recipient outcomes in a prospective cohort study involving deceased kidney donors from five organ procurement organizations. We measured urinary YKL-40 concentration in 1301 donors (111 had AKI, defined as doubling of serum creatinine) and ascertained outcomes in the corresponding 2435 recipients, 756 of whom experienced delayed graft function (DGF). Donors with AKI had higher urinary YKL-40 concentration ( P &lt;0.001) and acute tubular necrosis on procurement biopsies ( P =0.05). In fully adjusted analyses, elevated donor urinary YKL-40 concentration associated with reduced risk of DGF in both recipients of AKI donor kidneys (adjusted relative risk, 0.51 [95% confidence interval (95% CI), 0.32 to 0.80] for highest versus lowest YKL-40 tertile) and recipients of non-AKI donor kidneys (adjusted relative risk, 0.79 [95% CI, 0.65 to 0.97]). Furthermore, in the event of DGF, elevated donor urinary YKL-40 concentration associated with higher 6-month eGFR (6.75 [95% CI, 1.49 to 12.02] ml/min per 1.73 m 2 ) and lower risk of graft failure (adjusted hazard ratio, 0.50 [95% CI, 0.27 to 0.94]). These findings suggest that YKL-40 is produced in response to tubular injury and is independently associated with recovery from AKI and DGF. If ultimately validated as a prognostic biomarker, urinary YKL-40 should be considered in determining the suitability of donor kidneys for transplant.
Suicide risk and absconding in psychiatric hospitals with and without open door policies: a 15 year, observational study
Authors: Christian G Huber, Andres R Schneeberger, Eva Kowalinski, Daniela Fröhlich, Stefanie von Felten, Marc Walter, Martin Zinkler, Karl Beine, Andreas Heinz, Stefan Borgwardt, Undine E Lang
Journal: The Lancet Psychiatry (2016)