tbuckley/cabot-search huggingface dataset:
Abstract 1936: Comprehensive long non-coding RNA expression profiling from the TCGA HNSCC RNA-sequencing data
Authors: Nijiro Nohata, Martin Abba, Panomwat Amornphimoltham, J. Silvio Gutkind
Journal: Cancer Research (2016)

Abstract Objectives; Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer types in the world. Despite of considerable advances in multimodality therapy, including surgery, radiotherapy and chemotherapy, the overall 5-year survival rate for patients with HNSCC is only 40% - 50%. Although a growing body of evidence indicates that long non-coding RNAs (lncRNAs) contribute to the initiation and development of various types of cancers, the role of lncRNA expression in human HNSCC remains unknown. In this study, we aimed to establish the onco-lncRNAome profiling of HNSCC from The Cancer Genome Atlas (TCGA) project. Materials and Methods; The Atlas of Noncoding RNAs in Cancer (TANRIC) database (http://ibl.mdanderson.org/tanric/_design/basic/index.html) was employed to retrieve the lncRNA expression information from the TCGA HNSCC RNA-sequencing data. Our recently generated RNA-sequencing data from 22 representative HNSCC cell lines (OPC-22 panel) were also included in this study. Bioinformatics approaches, such as differential gene expression analysis, survival analysis, principal component analysis, and Co-LncRNA enrichment analysis were performed. Results; Using TCGA HNSCC RNA-sequencing data from 426 HNSCC and 42 adjacent normal tissues, we identified 728 lncRNA transcripts significantly and differentially expressed in HSNCC. Among the 728 lncRNAs, 55 lncRNAs were significantly associated with cancer prognosis (overall survival and/or recurrence free survival). We also identified 140 lncRNA transcripts significantly and differentially expressed between Human Papilloma Virus (HPV) positive tumors and HPV negative tumors. 30 lncRNA transcripts were distinctly expressed between TP53 mutated tumors and TP53 wild type tumors. Among them, there were 19 overlapping genes up-modulated in HPV positive and TP53 wild type tumors. Co-LncRNA enrichment analysis suggested that protein-coding genes that are co-expressed with cancer-associated lncRNAs might be involved in malignant progression. Of interest, many differentially expressed lncRNAs in HNSCC were reflected in the HNSCC cell line panel. Conclusion; LncRNAs profiling could provide novel insights into the potential mechanisms of HNSCC oncogenesis. A unique set of lncRNAs may represent potential targets for diagnosis, therapy and prevention of HNSCC. Citation Format: Nijiro Nohata, Martin Abba, Panomwat Amornphimoltham, J. Silvio Gutkind. Comprehensive long non-coding RNA expression profiling from the TCGA HNSCC RNA-sequencing data. [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 1936.
Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure
Authors: G. Cintron, G. Johnson, G. Francis, F. Cobb, J. N. Cohn
Journal: Circulation (1993)

Background. In congestive heart failure patients, a single measurement of left ventricular ejection fraction (LVEF) provides important prognostic information. The importance, if any, of improvement or worsening in serial LVEF has not been defined. The Department of Veterans Affairs Cooperative Vasodilator-Heart Failure Trials (V-HeFT) data base was analyzed to determine the prognostic importance of LVEF changes. Methods and Results. The data bases for V-HeFT I (n=642) and V-HeFT II (n=804) were analyzed. All patients had heart failure with documented exercise intolerance and abnormal LVEF or cardiac dilatation by chest x-ray or echocardiography
Gemcitabine-based combinations (gem+x) vs gemcitabine (gem) alone in the treatment of advanced pancreatic cancer: a meta- analysis of sixteen randomized trials
Authors: V. Heinemann, A. Hinke, S. Böck, R. Labianca, C. Louvet
Journal: Journal of Clinical Oncology (2007)

4515 Background: Sixteen randomised trials have compared Gem-based combination chemotherapy to Gem alone in advanced and metastatic pancreatic cancer. This analysis was performed to better define the role of combination chemotherapy in pancreatic cancer. Methods: The meta-analysis included 16 studies comparing Gem vs. Gem+X. Fifteen trials were evaluable for survival, the primary end-point of the investigation. Overall, 4465 patients (pts) were included, 2222 pts in the Gem+X arm, and 2243 pts in the Gem arm). The analysis was predominantly based on published summary data. Results: Three groups were formed: combinations with platinum analogs, fluoropyrimidines, or other cytotoxic agents. Five trials evaluated platinum-based combinations (3 cisplatin, 2 oxaliplatin). The combined analysis indicated a hazard ratio (HR) of 0.85 (95% CI: 0.76–0.96) demonstrating a significant (p=0.010) superiority of the combination. Further 6 trials investigated the combination of Gem with fluoropyrimidines (3 5-FU, 3 capecitabine). Again, a significant superiority of the combination therapy was observed with a HR of 0.90 (95% CI: 0.81–0.99; p=0.030). Among the fluoropyrimidine combinations greatest homogeneity of results was observed in trials combining gemcitabine with capecitabine. In four randomised trials no improvement of survival was observed when Gem was combined with other cytotoxic agents such as pemetrexed, exatecan or irinotecan (HR=0.99; 95% CI: 0.88–1.10; p=0.80). When all 15 evaluable trials are taken together, an overall hazard ratio of HR=0.91 (95% CI: 0.85–0.97; p=0.004) was achieved. Five trials including 1682 pts provided adequate information on baseline performance status (PS). Combination chemotherapy had a marked benefit on survival in pts with a good PS (HR=0.76; 95%CI: 0.67 - 0.87; p&lt;0.0001), while it was not more effective than Gem alone in pts with an initially poor PS (HR=1.08; 95% CI: 0.90 - 1.29). Conclusions: A meta-analysis of fifteen randomised trials indicated a significant survival benefit for Gem+X as compared to Gem alone when Gem was combined with either a platinum analog or capecitabine. This benefit was greatest in pts with a good PS, while no benefit was evident in poor PS pts. No significant financial relationships to disclose.
Molecular markers and survival after recurrence in stage III colon cancers from NCCTG N0147 and NSABP C-08 adjuvant chemotherapy trials.
Authors: Frank A. Sinicrope, Qian Shi, Carmen Joseph Allegra, Thomas C. Smyrk, Stephen N. Thibodeau, Richard M. Goldberg, Jeffrey P. Meyers, Greg Yothers, Daniel J. Sargent, Steven R. Alberts
Journal: Journal of Clinical Oncology (2016)

3600 Background: The identification of biomarkers that can predict patient survival after recurrence (SAR) of cancer is important to guide clinical decision-making. We determined the association of molecular markers in the primary tumor with SAR in patients with stage III colon carcinomas treated with adjuvant FOLFOX-based chemotherapy in two clinical trials. Methods: In randomized trials of adjuvant FOLFOX ± cetuximab (NCCTG N0147) or FOLFOX + bevacizumab (NSABP C-08), we determined the association of somatic BRAFV600E and KRAS exon 2 mutations and DNA mismatch repair (MMR) status in colon adenocarcinomas with patient SAR. Cox models were utilized and adjusted for clinicopathological features and time-to-recurrence data. The interaction effect of the anatomic site of the primary tumor on the impact of biomarkers on SAR was determined. Results: Among patients with colon cancer recurrence [N0147 (N = 871); C-08 (N = 524)], those with tumors harboring mutant BRAFV600E had significantly worse SAR compared to those with non-mutated BRAF and KRAS genes [HR 2.45 (95% CI, 1.85-3.25, Padjusted < .0001]. Mutant BRAFV600E was also associated with significantly poorer outcome for tumors with proficient (p) DNA mismatch repair (pMMR) [HR 2.64 (95% CI, 1.96-3.57), Padjusted < .0001] and with deficient (d) MMR [HR 2.70 (95% CI, 1.23-5.93), Padjusted = .014]. Significant interactions were found for MMR (P = .027) and KRAS (P = .014) status by primary tumor site for SAR, with significantly better SAR for dMMR tumors of the proximal vs distal colon [HR 0.57 (95% CI, 0.39-0.81), Padjusted = .023], and significantly worse SAR for mutant KRAS tumors of the distal colon [codon Conclusions: Patients whose tumors harbored BRAFV600E mutations and were dMMR or pMMR had significantly shorter SAR. The significant adverse impact of KRAS mutations on SAR was limited to patients with distal cancers, indicating that KRAS should be interpreted by primary tumor site. These molecular markers may, therefore, inform patient management and treatment decisions at the time of tumor recurrence. Clinical trial number: NCCTG NO147, NCT00079274; NSABP C-08, NCT00096278
O-003 Long-term outcome from the SCALOP trial: a multi-centre randomized phase II trial of gemcitabine or capecitabine-based chemoradiation (CRT) for locally advanced pancreatic cancer (LAPC)
Authors: C. Hurt, J. Bridgewater, S. Falk, S. Cummins, H. Wasan, T. Crosby, G. Radhakrishna, C. Jephcott, R. Roy, A. McDonald, R. Ray, G. Joseph, J. Staffurth, R. Abrams, G. Griffiths, T. Maughan, S. Mukherjee
Journal: Annals of Oncology (2016)
Abstract 2180: Drug-like inhibitors of SGK1: Discovery and optimization of low molecular weight fragment leads
Authors: James Zapf, Todd Meyer, Warren Wade, Laura Lingardo, Ayse Batova, Gordon Alton, Peter Pallai
Journal: Cancer Research (2016)

Abstract Triple negative (ER, PR and HER2/neu negative) breast cancers (TNBC) constitute 15-24% of breast cancers, but account for a disproportionate share of mortality. TNBC tumors are more aggressive, lack a targeted therapy, and are prone to relapse and metastasis after cytotoxic drug treatments, the only drug therapy currently available. Serum and glucocorticoid-regulated kinase 1 (SGK1) promotes the growth, invasiveness and chemo-resistance of cancer cells and is overexpressed in 48% of breast cancers, yet is not detected in normal breast tissue. In particular, SGK1 is overexpressed in TNBC cells and knockdown of SGK1 blocks the proliferation and invasiveness of TNBC cells. Thus, SGK1 is an attractive targeted therapy for TNBC. In the SGK1 inhibitors that have been reported previously, poor physicochemical properties have prevented these inhibitors from being active in vivo and advancing to the clinic. To discover drug-like inhibitors of SGK1, we used our technology platform (Leap-To-Lead™) and a fragment-based screening approach to find SGK1 inhibitor scaffolds. Low molecular weight inhibitors like ours are more readily optimized for potency while retaining drug-like properties. From this screen, we identified 11 scaffolds as novel inhibitors of SGK1. Four scaffold series had clear structure activity relationships (SAR). To illustrate the potential of these scaffolds, we carried out a limited synthetic expansion around one scaffold and improved potency more than 600-fold (SGK1 IC50 = 1 μM; LE = 0.4). Several compounds dose-dependently inhibited the proliferation of a TNBC cell line (MDA-MB-231) and inhibited the phosphorylation of the biomarker protein N-Myc downstream regulated 1 (NDRG-1). Unlike previously reported SGK1 inhibitors, our fragment lead compounds show excellent cellular penetration in Caco-2 assays. In summary, a fragment-based screening approach was used to identify four novel scaffolds with clear SAR trends. A single scaffold series was further optimized and shows anti-proliferative activity and biomarker modulation in a TNBC cell line. These SGK1 inhibitor series represent excellent starting points for further SAR studies and development of a novel preclinical candidate. Citation Format: James Zapf, Todd Meyer, Warren Wade, Laura Lingardo, Ayse Batova, Gordon Alton, Peter Pallai. Drug-like inhibitors of SGK1: Discovery and optimization of low molecular weight fragment leads. [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 2180.
G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up.
Authors: Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller
Journal: Journal of Clinical Oncology (2014)

8527 Background: The role of whole brain radiotherapy (WBRT) in first-line therapy of primary CNS lymphoma (PCNSL) has been increasingly questioned. This is the final report of the G-PCNSL-SG-1 trial evaluating WBRT in primary therapy of PCNSL after a median follow-up (MFU) of 81.2 months. Methods: G-PCNSL-SG-1 (www.clinicaltrials.gov NCT00153530) had randomised immunocompetent patients with newly diagnosed PCNSL to high-dose methotrexate (HDMTX) - based chemotherapy (CHT) followed by WBRT or CHT alone. We hypothesized that the omission of WBRT from first-line treatment would not compromise overall survival (OS; primary endpoint), using a non-inferiority design with a margin of 0.9. Results: Of 551 patients who entered the study 524 fulfilled the eligibility criteria (primary eligibility population), 410 entered the post-HDMTX phase (intention-to-treat, ITT population), and 320 were treated per protocol (PP). OS with versuswithout WBRT was different neither in the ITT (HR 0.997, 95%CI 0.79-1.26, p=0.98) nor in the PP population (HR 1.03, 95%CI 0.79-1.35, p=0.82). In the ITT population CR patients experienced neither a progression-free survival (PFS) benefit from the last HDMTX-based CHT (PFS-2) (HR 0.84, 95% CI 0.60-1.19, p=0.33) nor an OS benefit (HR 1.13, 95% CI 0.77-1.66, p=0.53) with WBRT. In CR patients of the PP population, WBRT conferred a benefit for PFS-2 (HR 0.68, 95%CI 0.46-1.01, p=0.059), but no OS benefit (HR 1.06, 95%CI 0.69-1.63, p=0.78). In non-CR patients of the ITT population, a benefit of PFS-2 (HR 0.58, 95%CI 0.44-0.77, p<0.001), but not of OS (HR 0.86, 95%CI 0.64-1.16 p=0.32) was found with WBRT; in non-CR patients of the PP population, WBRT conferred a benefit of PFS-2 over CHT alone (HR 0.41, 95%CI 0.29-0.57, p<0.001) and a trend for OS, too (HR 0.76, 95%CI 0.54-1.08, p=0.12). Conclusions: Despite improvement in PFS, particularly in patients without CR to HDMTX-based CHT, no significant difference in OS was found when WBRT was omitted from primary therapy in this long-term follow-up. The PFS afforded by WBRT has to be balanced against its long-term toxicity. Clinical trial information: NCT00153530.
Abstract 3863: Cancer immunotherapy: Could TK1 be used as a target for colon cancer
Authors: Michelle H. Townsend, Evita G. Weagel, Wei Meng, Craig Chandler, Richard A. Robison, Kim L. O’Neill.
Journal: Cancer Research (2016)

Abstract The aim of this study is to determine whether Thymidine Kinase 1 (TK1) would be a suitable target for future immunotherapeutic treatment of colon cancer. The salvage pathway enzyme TK1 has been shown to be upregulated in cancer patients due to active proliferation of cancer cells and the resulting high demand for nucleotides. Present in both the cytosol and the serum of cancer patients, TK1 levels can be used to not only predict cancer occurrence, but also to predict tumor aggressiveness and future remission. While serum levels of TK1 have been established, surface expression of the enzyme have not been fully characterized. In colon cancer cells, TK1 has been shown to strongly associate with the plasma membrane. In this project we explored the presence of TK1 on the surface of colon cancer cells (HT29 and SW620 cell lines) using flow cytometry, confocal microscopy, scanning electron microscopy, membrane separation, and cytoplasmic staining. Using fluorescent antibodies conjugated to FITC, expression levels as high as 19% are observed in HT29's and 12% in SW620's in comparison to sodium potassium ATPase surface levels of 11% and 6% respectively. Confocal microscopy images revealed direct overlap between cells stained with a rhodamine red membrane dye and with a FITC conjugated anti-TK1 antibody which indicates a direct relationship between TK1 and the cellular surface of cancer cells. To further confirm surface expression, TK1 levels were assessed using gold labeling and scanning electron microscopy. Gold levels indicate the physical location of the TK1 on the surface of the colon cancer cells and their relative abundance. TK1 surface levels in colon cancer cells corresponded with the surface expression levels of sodium potassium ATPase and share relatively the same abundance. These results strongly indicate a direct relationship between TK1 and the surface of colon cancer cells, and suggests TK1 as a potential target for future immunotherapeutic treatment. Citation Format: Michelle H. Townsend, Evita G. Weagel, Wei Meng, Craig Chandler, Richard A. Robison, Kim L. O’Neill. Cancer immunotherapy: Could TK1 be used as a target for colon 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 3863.
Abstract 4444: DNA methylation age is accelerated in breast tissue of healthy women donors
Authors: Mary E. Sehl, Patricia A. Ganz, Steve Horvath
Journal: Cancer Research (2016)

Abstract Background: Advanced age and cumulative estrogen exposure are well known risk factors for breast cancer. However, the mechanisms underlying the link between cellular senescence, chronic estrogen stimulation, increased cell cycling, and breast carcinogenesis are poorly understood. We examined epigenetic alterations that occur in the female breast with advancing age, and estrogen exposure. Methods: We utilized specimens from 49 women healthy tissue donors from the Komen Tissue Bank who donated both breast tissue and peripheral blood at two time points spaced at least 2 years apart. Ages of the donors ranged from 18-65 years and they were grouped by menopausal status (27 pre- and and 22 post-menopausal) and parity (21 nulliparous). We assessed epigenome-wide DNA methylation levels (Illumina 450K platform) from DNA extracted from breast and blood tissue, and calculated tissue “DNA methylation age (DNAm age)” based on methylation levels at 353 CpGs that have been shown to strongly correlate with chronologic age across tissues. We examined the relationship between this outcome and age and variables related to cumulative estrogen exposure, including age at menarche, gravidity, parity, and menopausal status. Results: DNAm age was highly correlated with chronological age in our sample (cor = 0.8, p&amp;lt;0.001), within both peripheral blood (cor = 0.94, p&amp;lt;0.001) and breast tissues (cor = 0.88, p&amp;lt;0.001). When we examine the residuals for each sample from our regression analysis of DNAm age versus chronological age, we find that age acceleration is significantly increased in breast relative to peripheral blood tissue (p&amp;lt;0.001). In a multivariate regression analysis, we found that earlier age at menarche (β = -0.62, p = 0.04) and higher gravidity (β = 0.95, p = 0.03) were associated with higher DNAm age. Conclusions: We find that DNAm age is accelerated in breast tissue compared with peripheral blood cells in a population of healthy donors to the Komen Tissue Bank. We further note a significant association between DNAm age and early menarche, and rising number of pregnancies, suggesting that cumulative cell cycling with menstrual cycles and the tissue plasticity occurring with pregnancy may contribute to accelerated epigenetic age in the female breast. Citation Format: Mary E. Sehl, Patricia A. Ganz, Steve Horvath. DNA methylation age is accelerated in breast tissue of healthy women donors. [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 4444.
Spatiotemporal T790M heterogeneity in individual patients with non-small cell lung cancer (NSCLC) after acquired resistance to EGFR-tyrosine kinase inhibitor (TKI).
Authors: Akito Hata, Nobuyuki Katakami, Hiroshige Yoshioka, Katsuhiro Masago, Shiro Fujita, Yukihiro Imai, Keisuke Tomii, Akihiro Nishiyama, Tadashi Ishida
Journal: Journal of Clinical Oncology (2014)

8067 Background: The secondary EGFR mutation T790M accounts for approximately half of acquired resistances to EGFR-TKI. A favorable prognosis was demonstrated in patients (pts) with NSCLC harboring T790M compared to those without T790M. Since T790M is mediated by TKI exposure, poor TKI penetration to central nervous system (CNS) and TKI withdrawal may affect T790M status and prognosis. Methods: We retrospectively reviewed T790M status and clinical course of pts who had undergone multiple rebiopsy in our institutes. Postprogression survival (PPS) after initial TKI failure was analyzed according to T790M status. Results: Between May 2008 and January 2014, 132 pts with EGFR-mutant NSCLC received rebiopsy after acquired resistance to EGFR-TKI. Of 132 pts, 22 underwent rebiopsy at multiple sites, and 14 received repeated rebiopsies of the same lesion. Of 19 pts who underwent rebiopsy from both CNS (18 cerebrospinal fluids [CSF] and 1 brain tumoral tissue) and thoracic lesions (5 lung tissues and 14 pleural effusions), 10 were thoracic-T790M-positive. Of these 10 pts, 9 were CNS-T790M-negative. Conversely, all 10 thoracic-T790M-negatives were CNS-T790M-negative. Median PPS of thoracic/CNS-T790M-negative was 20.1 months, and thoracic-T790M-positive/CNS-T790M-negative were 11.2 months (p=0.3798). PPS was 40 months in the only thoracic/CNS-T790M-positive. In 14 pts who received repeated rebiopsies at the same lesion (7 lung tissues, 4 CSFs, and 3 pleural effusions), T790M status of lung lesions varied in 3 pts after TKI-free interval. In all 3 pts whose T790M status changed from positive to negative, EGFR-TKI rechallenge was effective. The 2 of these pts, after progression of TKI rechallenge therapy, T790M status changed from negative to positive again. There was also a pt whose CSF T790M status changed from negative to positive after high-dose erlotinib therapy. Conclusions: T790M status in an individual pt can be spatiotemporally heterogeneous due to selective pressure from TKI. Our data support personalized therapeutic strategies after acquired resistance, such as local ablation for oligoprogressive CNS metastases and EGFR-TKI rechallenge.