tbuckley/cabot-search huggingface dataset:
A retrospective study of SPAG5 expression and its clinical implications in &gt;8,000 patients of ER positive (ER+) breast cancer (BC): Genomic, transcriptomic and protein analysis.
Authors: Tarek M. A. Abdel-Fatah, Devika Agarwal, Dong-Xu Liu, Roslin Russell, Oscar M Rueda, Lorinc Pongor, Balazs Gyorffy, Paul M Moseley, Andrew Green, A Graham Pockley, Robert Rees, Carlos Caldas, Ian O. Ellis, Graham Ball, Stephen Chan
Journal: Journal of Clinical Oncology (2016)

575 Background: We recently have identified SPAG5 as a novel oncogene that was common in PAM50 Luminal B. Herein, we test the prognostic and predictive significance of SPAG5 gene, transcript and protein expression in ER+ BC. Methods: The correlation between SPAG5 gene copy number aberrations and its transcript with BC specific survival (BCSS) were determined in the ER+ subgroup of the METABRIC (Molecular Taxonomy of BC International Consortium; n = 1498), the Cancer Genome Atlas BC project (TCGA BRCA; n = 709) and in publically available ER+ BC genomic datasets (n = 3044). The relationship between SPAG5 mRNA and protein expression with relapse free survival (RFS) was studied in untreated lymph node negative ER+ BC (n = 606 and 588; respectively) and in ER+ patients treated with 5 years of adjuvant tamoxifen (n = 876 and 429; respectively). The relationship between the pathological complete response (pCR) after anthracycline neoadjuvant chemotherapy (AC Neo ACT) with SPAG5mRNA [(MD Anderson cohort (n = 297) and NCT00455533 phase II trial (n = 101)] and protein expression [Nottingham cohort; (n = 200)] was also tested. The median values of SPAG5 mRNA and protein expression were used as cut-offs. Results: SPAG5 gain/amplification was found in 165/1498 (11%; METABRIC) and 137/709 (19.3%; TCGA-BRCA) of ER+ BCs, and was more common in ER+HER2+ compared to ER+HER2- (31.3% vs., 13.6%) and was associated with shorter BCSS (HR (CI 95%): 1.55 (1.18-2.04), p = 0.00021). In untreated ER+LN- and tamoxifen treated ER+Luminal A BC, mRNA SPAG5+ was associated with shorter RFS [(HR (CI 95%): 1.25 (1.11-1.42), p = 0.0003) and [(HR (CI 95%): 1.66 (1.16-2.39), p = 0.0053); respectively]. In tamoxifen treated ER+Luminal B BC SPAG5 mRNA (+) and (-) had similar RFS (HR (CI 95%): 1.15 (0.76-1.74), p = 0.50). Multivariable logistic regression model showed SPAG5mRNA+ to predict pCR in ER+ BC treated with AC Neo ACT [MD Anderson cohort (OR (95%CI): 2·18 (1·08-4·38); p = 0·029 and Phase II trial (OR (CI 95%): 3·83 (1·01-14·55); p = 0·049)]. Conclusions: SPAG5 is a prognostic biomarker that predicts response to AC-Neo-ACT in ER+BC which can help to optimize systemic treatment in luminal B-BC.
Low tumor cell detection rate in bone marrow of patients with primary breast cancer after elimination of stroma cells: Comparison of immunocytology and molecular analysis of CK19 and mammaglobin 1
Authors: S. Kaul, M. Aggarwal, A. Eichler, C. Sohn, N. Fersis
Journal: Journal of Clinical Oncology (2007)

1075 Background: Rapidly self-renewing stroma cells of the bone marrow (RS cells) are MUC-1 and cytokeratin positive at a rate of 56% (475/850). Elimination of RS cells by size exclusion results in a positivity rate of 2.6% (36/1407) in primary breast cancer patients. We have used preanalytical immunomagnetic tumor cell enrichment followed by molecular detection of CK19 and Mammaglobin1 (MA) transcripts for an independent verification of the bright-field immunocytology results. Material and Methods: Mononuclear cells (2x10 6 ) from bone marrow of 1,407 patients with primary breast cancer were analysed by standardized cytospin immunocytology techniques. Disseminated tumor cells (DTC) were stained with CK8/18/19 antibodies 5D3 and A45-B/B3 using either the APAAP technique (Dako Techmate 500) or the enhanced SA-FastRed method (Ventana). Parallel DTC consisted of immunomagnetic tumor cell selection of 1x10 7 BM cells using the cell membrane glycoproteins EpCAM and MUC-1 as targets. CK 19 and MA transcripts were determined by conventional and quantitative real time RT-PCR. Results: Using acetic acid and periodate blocking steps before immunocytology 36 from 1407 (2.6%) breast cancer patients operated between 1999 and 2005 at the University Hspital Heidelberg were scored DCT positive using computer assisted automated (Chromavision ACIS II) picture analysis. From this group 186 bone marrow samples were used for molecular tumor cell detection. By RT-PCR analysis of 1x10 7 immunomagnetically purified BM cells only 6 from 186 (3.2%) samples were CK19 and MG positive. Discussion: Detection rates of tumor cells in bone marrow from non-metastatic breast cancer patients has been reported to be in the range of 0% to 100%. We show here that proliferating bone marrow stroma cells of the RS type are positive for various antigens including CK polypeptides 7, 8, 18 and 19. Elimination of these cells by size exclusion results in a tumor cell detection rate of 2,6% in 1,407 BM probes. This low detection rate could be verified in 186 BM probes by CK19 and mammaglobin1 RT-PCR. We conclude that standard immunocytology in bone marrow is severely impaired by cytokeratin expression of RS-type stroma cells. No significant financial relationships to disclose.
Abstract 1511: Mutational signatures from RNA-seq data distinguish HPV(+) and HPV(-) HNSCC
Authors: Pelle Hall, Shama Virani, Charles Warden, Yanxiao Zhang, Lada Koneva, Katie M. Rentschler, Alisha Virani, Laura S. Rozek, Maureen A. Sartor
Journal: Cancer Research (2016)

Abstract IntroductionHead and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide, and an increasing percentage of HNSCC cases are associated with human papillomavirus (HPV) which have improved prognosis compared to HPV(-) HNSCC. Identifying distinctions between HPV(+) and HPV(-) HNSCC may lead to improved prognosis or new treatments, such as determining mutagen(s) that are driving accumulation of genetic variants in each tumor. A recent approach uses the fact that different mutagens cause different types of mutations, referred to as a mutagen's signature. By comparing the mutations in a tumor sample with the mutagen signatures, the mutagens responsible for most of the mutations in the tumor can be identified. We hypothesized that mutational signatures could distinguish HPV(+) from HPV(-) HNSCC tumors. Materials and Methods We performed RNA-sequencing on 18 HPV(+) and 18 HPV(-) tumor samples collected from HNSCC patients by the University of Michigan Head and Neck SPORE. Variant calling was performed on each sample using a GATK best practices for RNA-seq pipeline. These variants were then filtered to include only variants that were both rare (&amp;lt;5%) and predicted to have a functional effect. The bases 5’ and 3’ of each variant were extracted to identify its sequence context. The observed mutations in each sample were then approximated by a non-negative linear combination of previously reported mutagen signatures. Certain signatures are associated with dysregulation of particular pathways; this dysregulation was validated with expression and mutation analysis of the RNA data. Results In the studied HNSCC tumors, signatures related to aging and impaired DNA repair were responsible for the largest proportion of the mutations found. The signatures that were significantly different between HPV(+) and HPV(-) tumors were associated with APOBEC editing and defective DNA mismatch repair. Expression and mutational analysis validated that APOBEC is more active in HPV(+) than HPV(-) tumors. Interestingly, signatures associated with smoking were not among the most relevant. Conclusion The evaluation of mutational signatures in HNSCC tumors identified the main sources of mutations for HNSCC. The differences in mutational signatures between HPV(+) and HPV(-) identify distinct methods of carcinogenesis for these two subtypes of HNSCC. Citation Format: Pelle Hall, Shama Virani, Charles Warden, Yanxiao Zhang, Lada Koneva, Katie M. Rentschler, Alisha Virani, Laura S. Rozek, Maureen A. Sartor, The UM Head and Neck SPORE Investigators. Mutational signatures from RNA-seq data distinguish HPV(+) and HPV(-) HNSCC. [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 1511.
Abstract 313: Type II interleukin 1 receptor-modulated SETBP-1/SET/PP2A/p-ERK signaling reduces the therapeutic activity of regorafenib against human colorectal cancer cells
Authors: Ai-Chung Mar, Chun-Ho Chu, Shung-Haur Yang, Jeng-Kai Jiang, Chung-Wai Shiau, Te-Chang Lee
Journal: Cancer Research (2016)

Abstract Regorafenib, a newly approved multi-kinase inhibitor by US FDA, has recently demonstrated overall survival benefits in late-stage colorectal cancer (CRC) patients. We have preliminarily observed that the expression type II interleukin 1 receptor (IL1R2), an IL-1 decoy receptor, was closely associated with regorafenib resistance in human CRC cells. We also found that IL1R2 expression was associated with poor prognosis and 5-year survival of CRC patients. In this study, we conducted experiments to elucidate the mechanisms underlying which IL1R2 is involved in regorafenib resistance. We first demonstrated that silencing of IL1R2 in HT29 cells overcame its resistance to regorafenib, whereas ectopic expression of IL1R2 in HCT116 cells reduced its sensitivity to regorafenib in either in vitro or in vivo assay systems. In addition, we established regorafenib-resistant DLD-1 cells (DLD-1-R) by long-term culturing DLD-1 cells in the presence of regorafenib, and we observed that protein expression of IL1R2 was increased in DLD-1-R cells compared to the parental DLD-1 cells. Furthermore, our results showed that IL1R2 expression was positively associated with p-ERK levels, which are crucial for survival of cancer cells. Pretreatment of HT29, IL1R2-overexpressing HCT116, and DLD-1-R cells with MEK/ERK inhibitor U0126 significantly reversed their regorafenib resistance in in vitro and in vivo systems. Mechanistically, we revealed that increased p-ERK levels in IL1R2-overexpressing cells were due to the decrease of PP2A activity instead of its expression levels. Since PP2A is a phosphatase of ERK, we further demonstrated that IL1R2 mediated through transcriptionally enhancing the expression of SETBP-1. The formation of SETBP-1/SET/PP2A complex decreased the activity of PP2A. Taken together, our present study identified IL1R2 was a potential prognostic and staging biomarker of CRC patients. Significantly, we also demonstrated a new molecular mechanism involved in regorafenib resistance and the combination of regorafenib and MEK/ERK inhibitor is a rationale regime to overcome regorafenib resistance in CRC patients. Citation Format: Ai-Chung Mar, Chun-Ho Chu, Shung-Haur Yang, Jeng-Kai Jiang, Chung-Wai Shiau, Te-Chang Lee. Type II interleukin 1 receptor-modulated SETBP-1/SET/PP2A/p-ERK signaling reduces the therapeutic activity of regorafenib against human colorectal cancer cells. [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 313.
Weight Gain Not an Issue With Mediterranean Diet
Authors: Anita Slomski
Journal: JAMA (2016)

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Efficacy of Rabbit Anti-Thymocyte Globulin (ATG) Compared to Horse ATG In Severe Aplastic Anemia
Authors: Manuel Afable Manuel Afable, Mohammed Shaik, Yuka Sugimoto, Michael Clemente, Ramon V. Tiu, Sanjay R. Mohan, Nelli Bejanyan, Paul Elson, Matt Kalaycio, Anjali Advani, Ronald Sobecks, Alan E. Lichtin, Mikkael A. Sekeres, Jaroslaw Maciejewski
Journal: Blood (2010)
PWE-102 Is there a difference in polyp detection rates by time of day?: Abstract PWE-012 Figure 1
Authors: T Maheswaran, R Warburton, R Tighe
Journal: Gut (2012)

<h3>Introduction</h3> The endoscopy literature<sup>1 2</sup> has raised concerns regarding variations in polyp detection rates during the day. One mechanism for this is thought to be operator fatigue which increases as the day progresses. However, published data so far has been conflicting.<sup>3 4</sup> This is worrying as one purpose of colonoscopy is to detect and remove polyps in order to prevent cancer via the adenoma-carcinoma sequence. Therefore polyp detection rates in the East Anglian Bowel Cancer Screening Programme (BCSP) between 2006 and 2011 were reviewed and analysed. Bowel cancer screening colonoscopies in England are conducted for individuals between the ages of 60 and 74 with a positive faecal occult blood test. The procedures are performed by accredited bowel cancer screening colonoscopists under gold standard conditions. <h3>Methods</h3> The National Health Service BCSP database was retrospectively interrogated and polyp detection rates were calculated. <h3>Results</h3> In total 19 152 bowel cancer screen procedures were performed between the hours of 07:00 and 17:00. Although there is a variation in the number of procedures performed per hour 325–3445 (see Abstract PWE-102 figure 1), less at the beginning and end of a list, there is no significant difference in the polyp detection rate. Differences in polyp detection rates were calculated from the data for 08:00 (the baseline). <h3>Conclusion</h3> No significant difference in polyp detection rates by time of day was detected in patients undergoing colonoscopy through a national bowel cancer screening programme. This should reassure endoscopists and patients alike. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Lee A,</b> Iskander JM, Gupta N, <i>et al. Am J Gastroenterol</i> 2011;<b>106</b>:1475–65. 2. <b>Long MD,</b> Martin C, Sandler RS, <i>et al. J Clin Gastroenterol</i> 2011;<b>45</b>:253–8. 3. <b>Munson GW,</b> Harewood GC, Francis DL. <i>Gastrointestinal Endoscopy</i> 2011;<b>73</b>:467–75. 4. <b>Gurudu SR,</b> Ratuapli SK, Leighton JA, <i>et al. Am J Gastroenterol</i> 2011;<b>106</b>:1466–71.
Abstract 2576: Radiation therapy delay and risk of ipsilateral breast tumors in women with ductal carcinoma <i>in situ</i>
Authors: Ying Liu, Shumei Yun, Min Lian, Graham Colditz
Journal: Cancer Research (2016)

Abstract Objectives: To examine the relationship between radiation therapy delay and risk of subsequent breast events in the ipsilateral breast and to identify factors that are associated with delay in women with ductal carcinoma in situ (DCIS). Methods: From the Missouri Cancer Registry, we identified the women who were diagnosed with first primary DCIS between 1996 and 2011 and treated with breast conserving surgery (BCS). Radiation therapy delay was defined as the first radiation therapy that was delivered greater than eight weeks after BCS. Propensity scores were calculated for radiation therapy delay and no radiation therapy during the first course of treatment. A propensity score-adjusted Cox proportional hazards regression analysis was conducted to estimate the hazard ratio (HR) of ipsilateral breast tumors. Logistic regression analysis was conducted to identify factors associated with delay. Results: Among 5,916 patients, 1,053 (17.8%) received radiation therapy greater than eight weeks after BCS and 1,702 (28.8%) did not receive radiation therapy during the first course of treatment. During the 72- month follow-up, 182 (3.1%) developed ipsilateral breast tumors. After adjustment for propensity scores, the HR of ipsilateral breast tumors was 1.26 (95% CI, 1.00-1.59; p = 0.049) for radiation therapy delay and 1.35 (95% CI, 1.03-1.76; p = 0.03) for no radiation therapy compared with timely radiation therapy. Radiation therapy delay was associated with black race, being non-married and on Medicaid, later years of diagnosis, larger tumor size micropapillary architecture, and positive surgical margin. Conclusions: Receipt of radiation therapy greater than eight weeks after BCS was associated with a significantly increased risk of ipsilateral breast tumors in women with DCIS. Timeliness of radiation therapy should be improved, particularly for black and Medicaid patients. Citation Format: Ying Liu, Shumei Yun, Min Lian, Graham Colditz. Radiation therapy delay and risk of ipsilateral breast tumors in women with ductal carcinoma in situ. [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 2576.
Brenda Mary Slavin
Authors: Catherine Andrews, Brendan Slavin, John Slavin
Journal: BMJ (2016)

Brenda Slavin (nee Stewart) was educated at Whalley Range High School, Manchester. Her family emigrated to South Africa in1948, cutting short her school certificate. Times were hard, and she was sent out to train and work as a secretary, but, in addition to shorthand and typing, she surreptitiously added Latin to her night school studies and, with this under her belt, was admitted to preclinical studies at Witwatersrand University. She was a good student and was stimulated by two teachers in particular, who shaped her future interests throughout life—Raymond Dart, of Australopithecus fame, and Sidney Brenner, a future Nobel laureate in biochemistry. She obtained an intercalated BSc in biochemistry in 1953. Her aim was that, with a bachelors degree, she could demonstrate and earn a little, to offset the costs of being a clinical student. A senior lecturer, an alumnus of her old school, recognised her talents, intervened, and advised her to go to Edinburgh for her clinical studies, lending her the initial money to make this change.

In Edinburgh she met Gerry, a student in the same year, who was to become her husband of 57 years. They graduated in 1957, and, after house jobs in Edinburgh’s teaching hospitals, she accompanied him to the Bechuanaland protectorate for his national service. There, as a medical officer, she initially studied malnutrition among infants and schoolchildren in the Bamangwato reserve. She then undertook general duties in bush clinics and hospitals. …
Abstract LB-311: Elevated kynureninase protein expression is associated with KEAP1 mutant non-small cell lung cancer and is predictive of poor overall survival
Authors: Johannes F. Fahrmann, Jennifer Dennison, Eunice Murage, Hong Wang, Edwin J. Ostrin, Ayumu Taguchi, Samir Hanash
Journal: Cancer Research (2016)

Abstract Purpose: To identify signatures related to tryptophan metabolism independent of indoleamine 2,3-dioxygenase (IDO) that are predictive of tumor behavior. Introduction: Recent evidence has pointed to the importance of tryptophan catabolites on immune suppression and promotion of tumor growth. IDO1 is a rate-limiting enzyme in tryptophan catabolism currently targeted in clinical trials. Tryptophan catabolism can occur in IDO-negative tumors and resulting metabolites may have immunosuppressive and potential autocrine functions. Our late breaking finding is that we have uncovered signatures related to tryptophan metabolism independent of IDO that impact clinical outcome in NSCLC. Experimental Procedures: We initially carried out integrated genomic and proteomic profiling of 114 cancer cell lines. Small interfering RNA transfection experiments were used to evaluate the effect of KYNU knockdown on cell viability. TCGA data was analyzed to determine clinical relevance. Results: We identified kynureninase (KYNU), an enzyme involved in tryptophan metabolism that mediates formation of anthranilate and 3-hydroxyanthranilate, as uniquely overexpressed at the RNA and protein levels in NSCLC compared to other cancer types. These findings were not conserved for IDO or tryptophan 2,3-dioxygenase (TDO2), rate-limiting enzymes in tryptophan metabolism. Knockdown of KYNU reduced cell viability of NSCLC cell lines tested. Upregulation of KYNU was highly associated with KEAP1 mutational status and positively correlated with numerous Nrf-2 regulated-genes at both the protein and mRNA level. These findings were confirmed using TCGA data. KYNU mRNA levels predicted worse outcomes in stage II and III NSCLC adenocarcinoma and squamous cell carcinoma in TCGA cohorts independently of other covariates (P = : 0.008). Conclusion: We have uncovered a unique signature in NSCLC reflective of aberrant tryptophan metabolism mediated by elevated KYNU but not IDO/TDO2. KYNU expression is highly associated with KEAP1 mutational status. High KYNU mRNA levels was predictive of worse clinical outcomes in NSCLC. Citation Format: Johannes F. Fahrmann, Jennifer Dennison, Eunice Murage, Hong Wang, Edwin J. Ostrin, Ayumu Taguchi, Samir Hanash. Elevated kynureninase protein expression is associated with KEAP1 mutant non-small cell lung cancer and is predictive of poor overall survival. [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-311.