tbuckley/cabot-search huggingface dataset:
Limited versus extended pelvic lymphadenectomy in patients with bladder cancer undergoing radical cystectomy: Survival results from a prospective, randomized trial (LEA AUO AB 25/02).
Authors: Juergen E. Gschwend, Matthias M. Heck, Jan Lehmann, Herbert Ruebben, Peter Albers, Axel Heidenreich, Patrick de Geeter, Johannes M. Wolff, Detlef Frohneberg, Thomas Schnoeller, Tilman Kälble, Michael Stoeckle, Arnulf Stenzl, Markus Mueller, Uwe-Bernd Liehr, Michael Truss, Stephan Roth, Joachim Leissner, Margitta Retz
Journal: Journal of Clinical Oncology (2016)

4503 Background: The extent of pelvic lymph node dissection (PLND) in bladder cancer patients (pts.) undergoing radical cystectomy may affect survival according to retrospective studies. The German Urologic Oncology Group (AUO) reports mature data of the first prospective, randomized clinical trial to evaluate the impact of a limited versus an extended PLND. Methods: Pts. with high-grade T1 or invasive urothelial bladder cancer (cT2-T4a) from 16 German centers were randomized 1:1 to receive a limited versus an extended PLND at the time of radical cystectomy. Limited PLND included 6 fields (bilateral obturator, internal and external iliac nodes) and extended PLND defined 14 fields (in addition bilateral deep obturator fossa, presacral, paracaval, interaortocaval and paraaortal nodes up to the inferior mesenteric artery). Pts. with neoadjuvant chemo- or radiotherapy were excluded, adjuvant chemotherapy was allowed. The primary endpoint was recurrence-free survival (RFS). Cancer-specific survival (CSS) was a secondary endpoint. The planned total sample size was 400 to detect an improvement in 5-year RFS from 50% to 65% (90% power, 2-sided test, p < 0.05) in the extended arm. Results: In total, 375 of 437 pts. were randomized from 02/2006 to 08/2010 and eligible for intention-to-treat analysis (191 limited and 184 extended PLND). The tumor was locally confined (≤ pT2 pN0) in 49.6% of patients and 24.0% were node positive (pN+). The median number of dissected nodes was 19 in the limited and 32 in the extended arm. The 5-year RFS rate was 62.0% in the limited compared to 69.3% in the extended arm which was statistically not significant (Hazard ratio (HR) = 0.80, 95% Confidence Interval (CI) (0.54-1.19); log-rank p = 0.28). The 5-year CSS rate was improved from 66.2% in the limited to 77.5% in the extended arm which was statistically not significant (HR = 0.70, 95%CI 0.45-1.10; log-rank p = 0.13). Conclusions: We observed a trend but no significant difference toward improved RFS and CSS with an extended PLND. The rate of recurrence was lower than expected in the limited arm, which might be due to the high number of resected nodes in this arm. Clinical trial information: NCT01215071.
Abstract LB-131: Birinapant and carboplatin co-therapy can effectively target platinum resistant ovarian cancer initiating cells
Authors: Vincent La, Rachel Fujikawa, Deanna Janzen, Liat Bainvoll, Sanaz Memarzadeh
Journal: Cancer Research (2016)

Abstract High-grade serous ovarian cancers (HGSOCs) contain CA125-negative cancer-initiating cells resistant to standard platinum therapy. High expression of cellular inhibitors of apoptosis proteins (cIAPs) in these platinum resistant HGSOC initiating cells causes resistance to apoptosis despite platinum-induced DNA damage. cIAPs can be degraded with the addition of birinapant, a SMAC-mimetic, sensitizing cancer initiating cells to carboplatin and resulting in their elimination. Using in vitro drug assays, we demonstrate that more than half of human HGSOCs (13/23 independent samples) can be targeted with birinapant and carboplatin co-therapy. Importantly, treatment with this co-therapy eliminated tumor cells irrespective of their clinically-defined platinum sensitivity suggesting that this therapeutic approach could be efficacious with patient who have platinum sensitive and/or resistant disease. Pre-clinical trials in mice bearing intra-peritoneal low-passage human-derived HGSOC cell lines demonstrate that birinapant and carboplatin co-therapy significantly improves overall survival. A vast majority of co-therapy treated mice are still alive, 5 months after all animals treated with vehicle or carboplatin monotherapy have succumbed to tumor. Given that co-therapy was efficacious in approximately 50% of HGOSCs, evaluation of biomarkers that can predict this response are clinically relevant. The expression of cIAP levels were quantified using western blot and then immunohistochemistry in the CA125 negative fraction of our 23 clinical samples. We found that expression of ≥24ng of cIAP in the CA125-negative HGSOC cell lysate could accurately predict response to co-therapy with 100 percent accuracy. Detection and quantification of cIAP in CA125 negative cells by immunohistochemistry (IHC) could also predict a response to co-therapy with 95 percent accuracy. We report on careful analysis of two sets of biomarkers specifically measuring druggable targets in ovarian cancer initiating cells that could predict a response to co-therapy with birinapant and carboplatin. This therapeutic approach, that can overcome platinum resistance in ovarian cancer initiating stem cells, will be tested in an upcoming clinical trial alongside our proposed companion diagnostic biomarkers of response. Citation Format: Vincent La, Rachel Fujikawa, Deanna Janzen, Liat Bainvoll, Sanaz Memarzadeh. Birinapant and carboplatin co-therapy can effectively target platinum resistant ovarian cancer initiating 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 LB-131.
Abstract 465: CD44 as a potential therapeutic target and prognosis marker for glioblastoma
Authors: Fengfei Wang, Xin Shen, Jessica Pruszynski, Jason Huang, Batool Kirmani, Erxi Wu, Ekokobe Fonkem
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM) is a common and very aggressive primary brain tumor with no cure. The current diagnosis relying on magnetic resonance imagining, computed tomography, and biopsy is a very expensive and aggressive process. More effective therapeutic strategies such as target therapies and simplified early diagnosis tools are urgently needed for GBM management and prognosis. As recent reports suggest that GBM expresses CD44, a type-I transmembrane glycoprotein, is a marker of cancer stem cell and therapy resistance, with a goal of identifying a therapeutic target and a prognosis maker for GBM, we analyzed several data sets previously detected by microarrays using an online R2 Genomics analysis and visualization platform (http://r2.amc.nl). Through examining of the expression levels of CD44 in the tissues of normal cerebellum (without brain tumor) and in GBM tissues, we find that the expression level of CD44 in GBM is higher than that in non-brain tumor tissues. Comparing the expression levels of CD44 in Primary and recurrent GBMs, GBM cell lines, neuron stem cell lines, and normal cortex tissues, we observe that the expression levels of CD44 in recurrent GBMs are higher than primary GBMs; the CD44 levels in GBM cell lines are similar to neuron stem cell lines which are significantly higher than that in the normal cortex tissues. We further evaluated the correlation of CD44 levels with patients’ overall survival in 4 available complete data sets in the R2 database, including 2 from The Cancer Genome Atlas (TCGA) database. We show that an elevated level of CD44 in GBM is associated with a short overall survival time although variations exist from cohort to cohort. In addition, we studied the effect of p53 status on CD44 expression, we reveal that CD44 level is higher in the GBMs carrying p53 mutation compared to those with wild-type p53. Taken together, these results indicate that CD44 could be a potential therapeutic target of GBM and the expression level of CD44 in the GBM may be an indicator of poor outcome for patients with GBM. Citation Format: Fengfei Wang, Xin Shen, Jessica Pruszynski, Jason Huang, Batool Kirmani, Erxi Wu, Ekokobe Fonkem. CD44 as a potential therapeutic target and prognosis marker for glioblastoma. [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 465.
Junior doctors will have whistleblowing protection added to contracts
Authors: Abi Rimmer
Journal: BMJ (2016)

Health Education England (HEE) has introduced whistleblowing protection for junior doctors. The organisation said that this provided a new legal route to allow trainees to make legal claims against HEE if they believe that it has caused detriment to their career.1

The BMA, which campaigned for the change, said that this would close a loophole in which HEE, the body responsible for training junior doctors, was exempt from any legal responsibility for whistleblowers because it is not technically an employer. HEE said that this was not something the organisation itself could change.

The UK government promised to look at the loophole in whistleblower protection for junior doctors, after a judgment of the …
Discontinuation of HMA Therapy after Achieving Complete or Partial Response: Retrospective Analysis of Survival after Long-Term Follow up
Authors: Monica Cabrero, Elias Jabbour, Naval Daver, Gautam Borthakur, Courtney D. DiNardo, Jorge E. Cortes, Zach Bohannan, Victoria Sukholutsky, Farhad Ravandi, Sherry Pierce, Tapan Kadia, Naveen Pemmaraju, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2014)
Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry
Authors: Anne Trinh, Kari Trumpi, Felipe De Sousa E Melo, Xin Wang, Joan H. de Jong, Evelyn Fessler, Peter J.K. Kuppen, Marlies S. Reimers, Marloes Swets, Miriam Koopman, Iris D. Nagtegaal, Marnix Jansen, Gerrit K.J. Hooijer, George J.A. Offerhaus, Onno Kranenburg, Cornelis J. Punt, Jan Paul Medema, Florian Markowetz, Louis Vermeulen
Journal: Clinical Cancer Research (2016)

Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high-quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles toward widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular colorectal cancer subtyping in a multicenter study.
Abstract 5280: A web-based platform for exploring ‘omics and clinical data from healthy breast tissues
Authors: Xingyan Kuang, Catalin Marian, Cenny Taslim, Min-Ae Song, Daniel Weng, Jo L. Freudenheim, Theodore Brasky, Kun Huang, Kevin Coombes, Peter G. Shields
Journal: Cancer Research (2016)

Abstract Integrating ‘omics, epidemiology and clinical data from healthy patients and their biologic samples is important for identifying the determinants of early carcinogenesis. In a cross-sectional study of 249 women with no history of cancer and who underwent reduction mammoplasty, whole transcriptome (i.e., gene expression) and epigenome (i.e., methylation and microRNA) data were collected from dissected breast tissues. An extensive epidemiologic questionnaire ascertained data on breast cancer risk factors. Subjects with benign lesions considered at risk for future cancer were excluded. In order to manage, analyze, and share these data efficiently, we organized the data into a relational database to support a series of web-based tools for analyzing and visualizing the multidimensional data in an intuitive graphical user interface (GUI). The current platform improves upon existing web resources that integrate ‘omics and clinical data by including novel features that allow for greater flexibility of bioinformatics analyses. It also focuses on the ‘omics as an outcome, rather, e.g., what epidemiology risk factor or particular gene is associated with downstream effects across the ‘omics. Such features include: 1) a plot function that can visualize up to 4 dimension data chosen by a user from the 3 types of genetic profiles and more than 100 clinical and biomedical variables; 2) a differentiation visualization tool based on the ‘omics data of 2 groups of samples; and 3) miRNA target gene network generated by the correlations between gene expression and miRNA expression of our patient samples and validated miRNA target gene database. The GUI facilitates the discovery of research scientists by reducing complex biological and clinical data into easily understandable views. Even without the expertise of computational biology, researchers can integrate and analyze the high dimensional data that they are interested conveniently on our user-friendly designed platform. Citation Format: Xingyan Kuang, Catalin Marian, Cenny Taslim, Min-Ae Song, Daniel Weng, Jo L. Freudenheim, Theodore Brasky, Kun Huang, Kevin Coombes, Peter G. Shields. A web-based platform for exploring ‘omics and clinical data from healthy breast tissues. [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 5280.
P0843 : On-treatment viral kinetics do not predict SVR in patients with advanced liver disease receiving sofosbuvir in combination with daclatasvir or simeprevir for 12 weeks
Authors: C. Hezode, S. Chevaliez, G. Scoazec, M. Bouvier-Alias, I. Ruiz, M. Francois, A. Mallat, C. Feray, J.-M. Pawlotsky
Journal: Journal of Hepatology (2015)
Abstract 1067: A paradoxical observation for its upregulation and the prognostic significance about miR-7 in esophageal squamous cell carcinoma
Authors: Kano Masayuki, Yasunori Matsumoto, Isamu Hoshino, Kentaro Murakami, Yasunori Akutsu, Hisahiro Matsubara
Journal: Cancer Research (2016)

Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers of the gastrointestinal tract. However, molecular indicators of the origin of cellular deregulation in ESCC have not been identified. MicroRNAs (miRNAs), noncoding RNAs 21-25 nucleotides in length, regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. A search for miRNAs with a tumor-suppressive function in ESCC was performed using the miRNA expression signatures. miRNA signatures from ESCC identified miRNAs that are downregulated in common, and these miRNAs are candidate tumor suppressors. Gain-of-function analysis revealed that 3 transfectants (miR-145, miR-133a and miR-133b) inhibit cell proliferation and cell invasion. These miRNAs, which have conserved sequences in the 3’UTR of FSCN1, inhibited FSCN1 expression. The signal from a luciferase reporter assay was significantly decreased at 2 miR-145 target sites and 1 miR-133a/b site, suggesting both miRNAs directly regulate FSCN1. An FSCN1 loss-of-function assay found significant cell growth and invasion inhibition, implying an FSCN1 is associated with ESCC carcinogenesis. The identification of tumor-suppressive miRNAs, miR-145, miR-133a and miR-133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis. On the other hands, miRNAs upregulated in cancer is the candidates of tumor marker. The miRNA expression signatures we perform for ESCC revealed seven upregulated miRNAs in ESCC. In the upregulated miRNAs of miRNA expression signatures, miR-7 downregulation is the independent poor prognostic factor for ESCC patients paradoxically.miR-7 expression is reported upregulated or downregulated variously in the same carcinoma (eg. Gastric adenocarcinoma). The correlation between patients’ prognosis and miR-7 expression has not yet reported in Pubmed research in Dec. 2015. And the target genes of miR-7 is not clarified. Citation Format: Kano Masayuki, Yasunori Matsumoto, Isamu Hoshino, Kentaro Murakami, Yasunori Akutsu, Hisahiro Matsubara. A paradoxical observation for its upregulation and the prognostic significance about miR-7 in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1067.
Abstract 2797: Role of the ST6Gal-I glycosyltransferase in protecting tumor cells against hypoxia
Authors: Robert B. Jones
Journal: Cancer Research (2016)

Abstract A change in surface glycosylation was one of the first identified hallmarks of a cancer cell, however an understanding of how altered glycosylation affects cancer cell biology remains unclear. Our group has shown that ST6Gal-I, a glycosyltransferase that adds negatively charged sialic acids to surface receptors in a α2-6-linked manner, is upregulated in many cancer types. Through modulating the activity of various receptors, ST6Gal-I can act as a pro-survival factor in a variety of settings, including resistance to some chemotherapeutics. Tumor microenvironment plays a crucial role in cancer progression. One key component of the tumor microenvironment is the availability of oxygen, and in solid tumors there can be areas of hypoxia. Hypoxia leads to the induction of hypoxia inducible factors (HIFs), which are transcriptional regulators of the cellular response to low oxygen tension. HIFs such as HIF-1a, regulate the transcription of many proteins necessary for cells to survive when challenged by hypoxia. In this study we demonstrated that forced overexpression of ST6Gal-I in both ovarian and pancreatic cancer cell lines increased the stabilization of HIF-1a after treatment with the hypoxia mimetics desferrioxamine and DMOG, and when grown in a hypoxic environment. Correspondingly, knockdown of ST6Gal-I inhibited the stabilization of HIF-1a in these same conditions. Additionally, ST6Gal-I activity stimulates pro-survival signaling through phosphorylated NFκB and AMPK in these same models. These signaling pathways have been shown to be important for cellular survival in hypoxic environments. Markers of HIF-1a-induced transcription were investigated through qRT-PCR, and it was revealed that the ST6Gal-I-mediated stabilization of HIF-1a increased the levels of PDHK1and GLUT1 mRNA. Both GLUT1 and PDHK1 promote the shift in glucose metabolism when cells are in a low oxygen environment. Taken together, these data indicate that ST6Gal-I acts as a pro-survival factor by eliciting a more robust response by HIF-1a. The finding that a glycosyltransferase regulates the cellular response to hypoxia represents a novel paradigm in hypoxia signaling. Citation Format: Robert B. Jones. Role of the ST6Gal-I glycosyltransferase in protecting tumor cells against hypoxia. [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 2797.
Abstract 4261: Novel tumor microenvironment (TME) restored 3D cell culture model and humanized patient-derived xenograft model for cancer research and drug evaluation
Authors: Jing Zhang, Dabing Yang, Huilin Wang, Qiong Song, Hui Li, JP Shaw, Tianjing Deng
Journal: Cancer Research (2016)

Abstract New anticancer drug development is an expensive and time consuming process, which typically can take more than 10 years and cost over a billion dollars. Although a majority of late discovery drug candidates demonstrate potency in preclinical models, most will ultimately fail to achieve efficacy in clinical trials. While recent strides have been made to improve preclinical models, the continued widespread use of traditional models creates translational challenges during clinical development. An intrinsic challenge for drug developers is to close the gap between preclinical modeling and translational efficiency for patients. Accurately modeling core attributes of the human tumor microenvironment (TME) in preclinical models is key for identifying novel targets, lowering toxicity and improving translational success. Even for advanced patient-derived xenograft (PDX) in vivo models, the cytokines generated by murine stromal cells fail to replicate many important paracrine networks, which can mislead preclinical pharmacology outcome data. To address this gap, we have begun to establish and characterize nearly 1,000 novel patient tumor samples, spanning over a dozen cancer indications, into robust human TME-restored 3D cell culture models and humanized patient derived xenograft models. Our goal is to improve overall patient-derived tumor model initiation success rates and subsequent translational pharmacology. Citation Format: Jing Zhang, Dabing Yang, Huilin Wang, Qiong Song, Hui Li, JP Shaw, Tianjing Deng. Novel tumor microenvironment (TME) restored 3D cell culture model and humanized patient-derived xenograft model for cancer research and drug evaluation. [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 4261.
Abstract 3521: The effect of MazF, Escherichia coli ribonuclease, on gastric adenocarcinoma (AGS cells)
Authors: Maryam Saffarian, Jeremy Tzeng
Journal: Cancer Research (2016)

Abstract Apoptosis is a gene-directed program that could be inhibited by several factors such as the disruption of the balance between pro-apoptotic and anti-apoptotic proteins, the impaired death receptor signalling or the reduced caspase functions. Several studies have shown that ribonucleases or antibiotics can induce apoptosis in mammalian cells through the shutoff of the protein synthesises. MazF produced by E. coli is a ribonuclease protein that cleaves mRNAs at ACA sequence sites and inhibits their translation. Thus, we hypothesized that the overexpression of MazF proteins in cancer cells could lead to the induction of apoptosis. In the present study, the ACA-less mazF gene was inserted into pSF-T7-EMCV T7 IRES expression plasmid. The mRNAs of mazF gene were synthesized in in vitro conditions, and one μg/ml of the mRNA was transferred into AGS (Gastric adenocarcinoma) cell line. The incidence of apoptosis was detected by conducting caspase 3/7 and Annexin-V assays. The results showed that 99.83% of cells were detached after 18 hours, 0.0086% of cells remained attached without apparent apoptosis, but 0.101% of attached cells were under apoptotic conditions. The results suggest that MazF protein has an ability to induce apoptosis in AGS cells. Since this protein can cleave mRNAs at ACA sites, it could inhibit protein synthesis, reduce the growth rate, and induce apoptosis in cancer cells. This finding is the first report of the application of MazF as an anti-cancer agent for the induction of apoptosis in AGS cell line. Citation Format: Maryam Saffarian, Jeremy Tzeng. The effect of MazF, Escherichia coli ribonuclease, on gastric adenocarcinoma (AGS 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 3521.