tbuckley/cabot-search huggingface dataset:
Abstract 5275: An integrated pipeline for TCGA data analysis
Authors: Kaixian Yu, Yun Xu, Ke Tang, Albert Steppi, Jun Zhou, Zheng Ouyang, Jinfeng Zhang
Journal: Cancer Research (2016)

Abstract The accumulation of publicly available high-throughput experimental data has made analyzing the data a bottleneck in scientific discovery. In this study, we explore a computational, high-throughtput approach for identifying cancer related biological factors using the data available at the Cancer Genome Atlas (TCGA). We developed an integrative genomic analysis (IGA) tool, which performs multiple analysis tasks, including gene/protein level differential expression analysis, gene set level enrichment analysis and network/pathway level comparison. Several data types can be analyzed, including RNA-seq, DNA methylation, miRNA-seq, and proteomics. By varying cancer types, race groups, and data types, we are able to generate a large set of novel findings, which may serve as experimental targets for biologists and biochemists. Interactive reports are generated to facilitate further exploration of the biological significance of findings. With the high-throughput approach and intgrative tools, the bottlenect for us now shifts to publishing these results. We invite researchers in cancer research community to collaborate with us to publish the findings. Citation Format: Kaixian Yu, Yun Xu, Ke Tang, Albert Steppi, Jun Zhou, Zheng Ouyang, Jinfeng Zhang. An integrated pipeline for TCGA data analysis. [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 5275.
The relationship between primary tumor sidedness and prognosis in colorectal cancer.
Authors: Deborah Schrag, Shicheng Weng, Gabriel Brooks, Jeffrey A. Meyerhardt, Alan P. Venook
Journal: Journal of Clinical Oncology (2016)

3505 Background: Clinical trials including CALGB/SWOG 80405 reveal differences in overall survival for patients with colorectal cancer based on the location of the 1° tumor yet this information is not routinely included in study design, reporting or patient counseling. Objective: To evaluate the impact of 1° tumor location on prognosis among stage-specific cohorts of patients with colorectal cancer. Methods: The Surveillance Epidemiology and End Results Program (SEER) tracks sidedness of primary colorectal cancers. We characterized the 1° site using SEER data as R-sided 1° = cecum to transverse colon; L-sided 1° = splenic flexure to sigmoid descending colon; 1° rectum = rectosigmoid and rectal. We identified patients with diagnoses of primary colorectal cancer in a SEER region between 2007 and 2011 and followed through 2013 by stage at diagnosis. We measured median and3-year survival and used Kaplan-Meier plots and Cox regression used to compare OS across groups. Age, gender, race, ethnicity, and year of diagnosis were included in adjusted Cox models to estimate the hazard ratio (HR) for death of rectal and right-sided relative to left-sided tumors. Results: Right sided 1° CRC had inferior prognosis to both left-sided and rectal cancers and this difference persisted after adjusting for differences in other clinical and demographic characteristics. The association was less consistent for stage I and II cancers. Conclusions: In a population-based series of patients with stage III and IV CRC, patients with R-sided tumors had inferior survival. This heterogeneity argues for consistent reporting of 1° site and further research including molecular sub-typing to better understand the mechanisms underpinning this phenotypic difference in prognosis. Stage/location of primary tumor N Median survival 3-year survival probability % Unadjusted HR (95% CI) Adjusted HR (95% CI) Stage IV Left 4784 17.0 27 1.0 1.0 Right 7579 8.7 16 1.40 (1.35-1.46) 1.20 (1.15-1.25) Rectal 4392 17.4 26 0.99 (0.94-1.04) 1.02 (0.97-1.07) Stage III Left 6394 n/a 71 1.0 1.0 Right 13748 59 62 1.39 (1.32-1.46) 1.17 (1.11-1.23) Rectal 5745 n/a 70 1.02 (0.96-1.08) 1.10 (1.04-1.17)
An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria
Authors: Abigail Liebow, Xingsheng Li, Timothy Racie, Julia Hettinger, Brian R. Bettencourt, Nader Najafian, Patrick Haslett, Kevin Fitzgerald, Ross P. Holmes, David Erbe, William Querbes, John Knight
Journal: Journal of the American Society of Nephrology (2016)

Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylate metabolism, arises from mutations in the enzyme alanine-glyoxylate aminotransferase. The resulting deficiency in this enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other tissues, with systemic oxalosis and ESRD being a common outcome. Although a small subset of patients manages the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant, which requires life-long immune suppression and carries significant mortality risk. In this report, we discuss the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis. Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and nonhuman primates. ALN-GO1 also increased urinary glycolate concentrations in normal nonhuman primates and in a genetic mouse model of PH1. Notably, ALN-GO1 reduced urinary oxalate concentration up to 50% after a single dose in the genetic mouse model of PH1, and up to 98% after multiple doses in a rat model of hyperoxaluria. These data demonstrate the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and provide a clear rationale for clinical trials with this compound.
Multidrug-Resistant Tuberculosis Treatment in North Korea: Is Scale-Up Possible?
Authors: Kwonjune J. Seung, Molly Franke, Stephen W. Linton
Journal: PLoS Medicine (2016)

Points• Multidrug-resistant tuberculosis (MDR TB) is one of the most serious public health problems facing North Korea, which has been included as one of the 30 countries on the World Health Organization's (WHO) high-burden MDR TB country list.• Current international funding for TB control in North Korea is dominated by the Global Fund for AIDS, Tuberculosis and Malaria (GFATM), which focuses almost exclusively on drug-susceptible TB.• The Eugene Bell Foundation (EBF) began treating MDR TB patients in collaboration with the North Korea Ministry of Public Health (MOPH) in 2008.Since then, close to 4,000 patients have been enrolled in treatment, over 1,000 patients in 2015 alone.• The North Korean MDR TB treatment program has demonstrated better results than many other countries.MDR TB treatment should be scaled up immediately to the many North Koreans who need it.
SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes<i>FADD</i>and<i>BIRC2</i>
Authors: Danielle F. Eytan, Grace E. Snow, Sophie Carlson, Adeeb Derakhshan, Anthony Saleh, Stephen Schiltz, Hui Cheng, Suresh Mohan, Shaleeka Cornelius, Jamie Coupar, Anastasia L. Sowers, Lidia Hernandez, James B. Mitchell, Christina M. Annunziata, Zhong Chen, Carter Van Waes
Journal: Cancer Research (2016)

Comparison of tumors from The Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus inhibitor of apoptosis repeat containing BIRC2 (cIAP1), affecting about 30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR, and Western blotting. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation. Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNFα or TRAIL and inhibited cIAP1>XIAP>IAP2. Combination of birinapant and TNFα induced sub-G0 DNA fragmentation in sensitive lines and birinapant alone also induced significant G2-M cell-cycle arrest and cell death in UM-SCC-46 cells. Gene transfer and expression of FADD sensitized resistant UM-SCC-38 cells lacking FADD amplification to birinapant and TNFα, supporting a role for FADD in sensitization to IAP inhibitor and death ligands. HNSCC varied in mechanisms of cell death, as indicated by reversal by inhibitors or protein markers of caspase-dependent apoptosis and/or RIPK1/MLKL-mediated necroptosis. In vivo, birinapant inhibited tumor growth and enhanced radiation-induced TNFα, tumor responses, and host survival in UM-SCC-46 and -11B xenograft models displaying amplification and overexpression of FADD+/- BIRC2 These findings suggest that combination of SMAC mimetics such as birinapant plus radiation may be particularly active in HNSCC, which harbor frequent FADD/BIRC2 genomic alterations. Cancer Res; 76(18); 5442-54. ©2016 AACR.
PTU-186 Baseline characteristics as a predictor of response to linaclotide (constella®) in patients with irritable bowel syndrome with constipation: a pooled analysis of 2 phase 3 trials: Abstract PTU-186 Table 1
Authors: C Díaz, M Falques, D Vilardell, J Fortea, JM Johnston
Journal: Gut (2015)

<h3>Introduction</h3> In 2 Phase 3 trials in irritable bowel syndrome with constipation (IBS-C) (Trial 31, Trial 302), linaclotide 290 μg once-daily (Constella<sup>®</sup>; LIN) treatment was superior to placebo (PBO) based on European Medicines Agency co-primary endpoints (rate of abdominal pain/discomfort responders [Trial 31: 54.8% vs 41.8%; Trial 302: 54.1% vs 38.5%; <i>P &lt; </i>0.001]; IBS degree-of-relief responders [Trial 31: 37.0% vs 18.5%; Trial 302: 39.4% vs 16.6%; <i>P &lt; </i>0.0001]). A potential association between baseline patient characteristics and likelihood of therapeutic response to LIN is unclear. <h3>Method</h3> This pooled analysis evaluated potential predictive value of baseline characteristics in 2 pivotal Phase 3 trials in IBS-C by comparing demographics and baseline symptoms (Table) for LIN 12-week non-responders vs responders, defined as: 1) abdominal pain/discomfort responders (≥30% reduction in abdominal pain and/or discomfort score [11-point scales], with neither worsening from baseline, for ≥6/12 weeks) and 2) IBS degree-of-relief responders (symptoms ‘considerably’ or ‘completely’ relieved for ≥6/12 weeks). <h3>Results</h3> The pooled analysis included 1602 patients (LIN, n = 805; PBO, n = 797). Baseline characteristics were similar for responders and non-responders in the LIN and PBO groups for both endpoints (Table 1). Abdominal discomfort scores and body mass index were also similar for responders and non-responders (not shown). <h3>Conclusion</h3> The baseline demographics and disease characteristics analysed did not predict treatment response to LIN or PBO in patients with IBS-C in the Phase 3 pivotal trials. <h3>Disclosure of interest</h3> C. Díaz Employee of: Almirall S. A., M. Falques Employee of: Almirall S. A., D. Vilardell Employee of: Almirall S. A., J. Fortea Employee of: Almirall S. A., J. Johnston Employee of: Ironwood Pharmaceuticals.
Abstract 462: The role of Her2 overexpression in Middle Eastern papillary thyroid cancer
Authors: Abdul K. Siraj, Shaham Beg, Rong Bu, Saif AlSobhi, Fouad Al-Dayel, Khawla Al-Kuraya
Journal: Cancer Research (2016)

Abstract Thyroid cancer is the second most common malignancy among females in Saudi Arabia accounting for 7.4% of all cancers and 10.6% of all female malignant cancer. Among different subtypes, papillary thyroid cancer (PTC) is the most common subtype of thyroid cancer. Although the overall cancer related ten year survival rate for PTC has reached 90%, local, regional and distant metastasis does occur in 10% of cases. Therefore, in search for new therapeutic targets for PTC, we investigated the role of Her2 oncogene in PTC as this gene is known to be involved in other cancers such as breast cancer. The aim of this study was to determine the prevalence and prognostic role of Her2 overexpression in Middle Eastern papillary thyroid carcinoma by immunohistochemistry (IHC), Fluorescent In-Situ Hybridization (FISH) and clinical data. A tissue microarray (TMA) containing &amp;gt;1000 PTC cases with follow-up data was used. TMA sections were analysed at protein and DNA level using IHC and FISH. FISH analyses were performed to look for the gain or amplifications in Her2 gene. IHC analysis showed Her2 overexpression in 19.7% of our cases of PTC. Elevated expression was almost exclusively 2+ (194 tumors) and only rarely 3+ (1 tumor). Interestingly, no amplification of Her2 gene was visualized by FISH. Only 3% of our cases showed mildly elevated HER2 gene copy numbers not reaching the threshold for amplification. HER2 overexpression and copy number gains were unrelated to tumor stage, metastasis, patient survival and other clinical and pathological parameters. Our results demonstrated that Her2 overexpression occurs at relevant frequency in papillary thyroid cancer and in the absence of gene amplification. Additionally, expression of Her2 seems to hold no clinical value as prognostic factor in PTC Citation Format: Abdul K. Siraj, Shaham Beg, Rong Bu, Saif AlSobhi, Fouad Al-Dayel, Khawla Al-Kuraya. The role of Her2 overexpression in Middle Eastern papillary thyroid 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 462.
Abstract 459: The use of circulating SAA and CXCL4 to predict outcome of osteosarcoma at diagnosis
Authors: Ricardo J. Flores
Journal: Cancer Research (2016)

Abstract Background: Osteosarcoma is the most common malignant bone tumor in children. The survival rate of osteosarcoma is 60-70%, which has remained stagnant for the past four decades. Identifying biomarkers that can better prognosticate osteosarcoma patients and guide therapies would improve survival of this disease. Material and Methods: In this study, we used ELISA to evaluate the expression of two previously identified circulating biomarkers, namely Serum Amyloid A (SAA) and CXC Chemokine Ligand 4 (CXCL4), in a large cohort of serum samples (n = 233) obtained at from the Children's Oncology Group at initial diagnosis. The biomarkers’ expression was correlated with survival and evaluated for prognostic significance in the OS patients. Results: Analysis showed that patients with high SAA and low CXCL4 levels had significantly poorer outcome (p = 0.014, HR = 1.68), which was independent of initial metastasis status. The 5-year overall survival rates for the “high-risk” and “low-risk” groups were 47% (95% CI; 36% - 62%) and 64% (95% CI; 57% - 72%), respectively. In addition, low tumor expression of CXCL4 correlated with poor survival (p = 0.017) in an osteosarcoma tissue microarray. In conclusion, this study reports a novel prognostic model consisting of high SAA and low CXCL4 levels in sera that prognosticates osteosarcoma patients at initial diagnosis. This model could serve as the basis for future biomarker-guided clinical trials by incorporating targeted therapy for the poor prognostic population. Citation Format: Ricardo J. Flores. The use of circulating SAA and CXCL4 to predict outcome of osteosarcoma at diagnosis. [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 459.
Systemic therapy in clear cell sarcoma.
Authors: A. Constantinidou, R. L. Jones, O. Al-Muderis, K. Thway, S. Ashley, M. R. Scurr, D. R. D'Adamo, M. Keohan, R. G. Maki, I. R. Judson
Journal: Journal of Clinical Oncology (2010)

10098 Background: Clear cell sarcoma is a rare soft tissue sarcoma subtype associated with the characteristic translocation t(12;22)(q13;q12). There have been few studies documenting the response rate and progression-free survival in clear cell sarcoma patients treated with palliative chemotherapy. Methods: The prospectively maintained databases of two referral centres were searched to identify clear cell sarcoma patients treated with chemotherapy. Results: Twenty-four patients were treated with palliative first-line chemotherapy with a median age of 30 years at diagnosis. All patients underwent surgical resection of the primary tumour as initial management. At the time of analysis 22 patients had died and 2 were lost to follow-up. There were 18 males and 6 females. Two of these patients were treated with neoadjuvant chemotherapy at the time of initial diagnosis and received palliative systemic therapy on progression. One of these achieved a partial response and the response of the other to neoadjuvant therapy was not known. For the patients receiving chemotherapy for recurrent/metastatic disease (n=24), one (4%) achieved a partial response and 9 (37%) had stable disease. Fourteen patients (58%) progressed on therapy. The median progression-free survival was 11 weeks (95%CI, 3-20 weeks). The median overall survival from commencing first-line chemotherapy was 39 weeks (95%CI, 34-45 weeks). Second-line chemotherapy was administered to 12 patients, 11 (92%) of these progressed and one (8%) had stable disease. Of the 5 patients treated with third-line chemotherapy, 4 (80%) progressed and one (20%) had stable disease. One patient that received fourth-line chemotherapy maintained stable disease for 4 months. Conclusions: Conventional chemotherapy has minimal activity in clear cell sarcoma as documented by the response rate of 4% and median progression-free survival of 11 weeks in this retrospective series. These data provide a reference for response and outcome in the assessment of novel agents in this histological subtype. No significant financial relationships to disclose.
Abstract 5053: Tumor cell clustering - Identification of new regulators
Authors: Valérie LOBJOIS, Bernard Ducommun
Journal: Cancer Research (2016)

Abstract Cancer cell aggregation is a key process involved at different stages of tumor evolution, during primary tumor growth, metastatic cells dissemination and secondary tumor evolution. Thus, understanding principles that govern and modulate the ability of cancer cells to aggregate might pave the way for new therapeutic opportunities. We investigated cancer cell aggregation independently of cell migration or matrix adhesion and demonstrated that the cell-cell adhesion protein E-cadherin and the desmosome proteins DSG2 and DSC2 are both involved this process (Saias, 2015). Strikingly, elevated expression of these proteins in primary tumors has also been reported to be associated with blood detection of clusters of highly metastatic circulating tumor cells and poor prognosis (Aceto, 2014). We also reported that Myosin IIa applies a counter force that slows down aggregation indicating that acto-myosin cytoskeleton tension favors aggregation. To further decipher the regulation of this process, we developed arrays of hydrogel microwells and robust microscopy-based quantification assay to monitor the kinetics of aggregation of tumor cells in the absence of cell - substrate adhesion. We performed a candidate approach and found that several other members of the cadherin superfamily are involved in the aggregation process. We also conducted a small molecule screen to identify other pathways involved in regulating aggregation of tumor cells. We will report unpublished results on the characterization of the molecular bases of aggregation properties in various tumor cell types and on the identification of new regulatory mechanisms that modulate this process. - Saias L, Gomes A, Cazales M, Ducommun B, Lobjois V. Cell-cell adhesion and cytoskeleton tension oppose each other in regulating tumor cell aggregation. Cancer Res. (2015) 75(12); 1-8 - Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 2014;158:1110-22. Citation Format: Valérie LOBJOIS, Bernard Ducommun. Tumor cell clustering - Identification of new regulators. [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 5053.
Clinical risk stratification optimizes value of biomarkers to predict new onset heart failure in a community-based cohort
Authors: F. P. J. Brouwers, R. A. De Boer, K. Damman, M. P. Van den Berg, R. T. Gansevoort, Stephan Bakker, J. L. Hillege, D. J. Van Veldhuisen, P. Van der Harst, W. H. Van Gilst
Journal: European Journal of Heart Failure (2014)
Effect on survival of postoperative therapy in patients with primary small cell carcinoma of esophagus (SCCE): An analysis of multicenter clinical outcomes.
Authors: Zou Bing Wen, Li Tao, Ma Dai Yuan, Zhou Qiang, Yong Xu, Lu Li, Meijuan Huang, Jiang Zhu, Lin Zhou, Jin Wang, Yu Zhang, You Lu
Journal: Journal of Clinical Oncology (2012)

e14648 Background: To retrospectively evaluate the therapy pattern and survival in patients with dissection of primary SCCE. Methods: This study included 89 patients from four centers in southwest China who underwent radical section of SCCE without any preoperative therapy. 36 were treated with postoperative chemoradiotherapy (POCRT), and 53 with postoperative chemotherapy (POCT) alone. The radiation dose to clinical target volume (CTV) was 50 Gy (varying between 44 and 52 Gy), while the cycles of platinum-based chemotherapy ranged from two to six with a median of four. Results: The 5-year overall survival rate (OS) and 5-year disease-free survival rate (DFS) were 16.4% and 14.3% for all patients,respectively. The 5-year overall survival rate was 21.5% in the POCRT group, and 12.9% in the POCT group (p=0.013). The 5-year DFS was 21.3% in POCRT group and 9.3% in POCT group (p=0.028). There was significant difference in 5-year local recurrence-free survival (LRFS) between POCRT and POCT (LRFS: 74.6% vs. 45.3%, p=0.022), while no difference for 5-year distant recurrence-free survival (DRFS: 37.3% vs. 17.4%, p=0.101). Subgroup analysis revieled that there were obvious difference in 5-year OS and DFS between patients received radiotherapy less than 75 days after surgery and ≥ 75 days (OS: 35.6% vs. 8.6%, p=0.046; DFS: 24.9% vs. 7.3%, p=0.020), while received radiotherapy less than 75 days after surgery have worse DRFS (p=0.041). In a multivariate analysis, age ≥59 years was associated with significantly worse OS while with lymph node involved infulence DFS. Tumor size more than 3cm, absence of radiotherapy and less than 4 cycles chemotherapy were poor prognostic factors for both overall survival and disease-free survival. Conclusions: Our analysis shows that postoperative chemotherapy improved OS and DFS in patients with dissection of SCCE, while radiotherapy was given less than 75 days after surgery may improve DRFS and OS. In those patients received postoperative chemotherapy less than 4 cycles is the most important characteristic associated with decreased survival.
A Novel Role For Histone Deacetylase 11 (HDAC11) In Plasma Cell Differentation and Survival
Authors: Eva Sahakian, Jason B. Brayer, John Powers, Mark Meads, Allison Distler, Susan Deng, Melissa Alsina, Taiga Nishihori, Rachid Baz, Javier Pinilla-Ibarz, Eduardo M. Sotomayor, Kenneth Shain
Journal: Blood (2013)
EP42675, a New Dual Action Anticoagulant: Pharmacodynamic and Pharmacokinetic Profile, and Interactions with Acetylsalicylic Acid, Clopidogrel, and Unfractionated Heparin.
Authors: Pierre Gueret, Chantal Krezel, Paul van Giersbergen, Eliane Fuseau, Thierry Lamy, Eric Neuhart
Journal: Blood (2009)