tbuckley/cabot-search huggingface dataset:
Abstract 4086: Critical roles of FRS2beta, a feedback inhibitor of ErbB-ERK signaling, for communication between cancer stem cells and their niche during mammary tumorigenesis
Authors: Yukino Machida, Natsuko Kimura, Arinobu Tojo, Ko-ichi Akashi, Hideyuki Saya, Issay Kitabayashi, Noriko Gotoh
Journal: Cancer Research (2016)

Abstract Inflammatory microenvironment contributes to tumorigenesis. Although it is thought that breast cancer stem cells (CSCs) appear and grow in the inflammatory microenvironment that is called CSC niche, it remains largely unclear how it occurs. Here, we uncovered FRS2beta, a feed-back inhibitor of ERK activity in progenitor cells, plays critical roles for various cytokine production to increase progenitor cell- and CSC- state, and create the CSC niche. Expression levels of FRS2beta were increased in mammary tumors of MMTV-ErbB2 mice than in normal mammary tissues. Deficiency of FRS2beta greatly delayed mammary tumorigenesis, decreased mammosphere-forming ability and tumor stroma, a component of the CSC niche. Expression levels of various cytokines, including IGF1 and CXCL12, stemness- and stroma-inducing cytokines, respectively, were reduced in FRS2beta-mutant mammospheres, pre-cancerous mammary and tumor tissues. Furthermore, expression levels of FRS2beta were higher in CD44highCD24low CSCs-enriched population in patient-derived breast cancer tissues. Thus the mechanisms to maintain progenitor cell-state by prevention of excess ERK activity may permit production of various cytokines to create CSC niche, and allow appearance and growth of CSCs. These results suggest that treatment with MEK inhibitors may allow survival of CSCs, raising the risk of recurrence. We provide a rationale of combination therapy targeting both FRS2beta and MEK inhibitors to eradicate tumors. Citation Format: Yukino Machida, Natsuko Kimura, Arinobu Tojo, Ko-ichi Akashi, Hideyuki Saya, Issay Kitabayashi, Noriko Gotoh. Critical roles of FRS2beta, a feedback inhibitor of ErbB-ERK signaling, for communication between cancer stem cells and their niche during mammary tumorigenesis. [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 4086.
Abstract P2-12-11: Does postmastectomy radiotherapy improve survival in patients with 1-3 positive axillary lymph nodes? A systematic review and meta-analysis of the current literature
Authors: A Kasem, H Headon, K Mokbel
Journal: Cancer Research (2016)

Abstract In breast cancer with more than four positive axillary lymph nodes, it is common practice to deliver radiotherapy to the affected site following a mastectomy. However, less is known about the benefit s this might offer in women with 1-3 positive lymph nodes. In order to assess whether postmastectomy radiotherapy has any benefit in these women, a meta-analysis was performed to assess whether postmastectomy radiotherapy improved overall survival or reduced locoregional recurrence in this group of women. It was found that postmastectomy radiotherapy significantly reduced the risk of locoregional recurrence, with a relative risk ratio of 0.3 (95% confidence interval 0.23-0.38), and resulted in a small benefit in overall survival, with a relative risk ratio of 1.03 (95% confidence interval 1.00-1.07). Therefore, in women with 1-3 positive lymph nodes, postmastectomy radiotherapy reduces the risk of locoregional recurrence and is associated with a small benefit in overall survival, so should be recommended within this group after careful multidisciplinary discussion. Citation Format: Kasem A, Headon H, Mokbel K. Does postmastectomy radiotherapy improve survival in patients with 1-3 positive axillary lymph nodes? A systematic review and meta-analysis of the current literature. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-12-11.
Stopping Tumor Necrosis Factor Inhibitor Treatment in Patients With Established Rheumatoid Arthritis in Remission or With Stable Low Disease Activity: A Pragmatic Multicenter, Open‐Label Randomized Controlled Trial
Authors: Marjan Ghiti Moghadam, Harald E. Vonkeman, Peter M. ten Klooster, Janneke Tekstra, Dirkjan van Schaardenburg, Mirian Starmans‐Kool, Elisabeth Brouwer, Reinhard Bos, Willem F. Lems, Edgar M. Colin, Cornelia F. Allaart, Inger L. Meek, Robert Landewé, Hein J. Bernelot Moens, Piet L. C. M. van Riel, Mart A. F. J. van de Laar, Tim L. Jansen
Journal: Arthritis & Rheumatology (2016)

Objective Tumor necrosis factor inhibitor (TNFi) biologic agents are an effective treatment for rheumatoid arthritis (RA). It is unclear whether patients whose disease is in remission or who have stable low disease activity need to continue use of TNFi or can stop this treatment. This study was undertaken to assess whether patients with established RA who are in remission or have stable low disease activity can effectively and safely stop their TNFi therapy. Methods The study was designed as a pragmatic multicenter, open‐label randomized controlled trial. Inclusion criteria were a diagnosis of RA according to the American College of Rheumatology 1987 classification criteria, as well as use of a TNFi for at least 1 year along with a stable dose of disease‐modifying antirheumatic drugs and a Disease Activity Score in 28 joints (DAS28) of &lt;3.2 over the 6 months preceding trial inclusion. Patients were randomized in a 2:1 ratio to either stop or continue treatment with their current TNFi. Flare was defined as a DAS28 of ≥3.2 during the 12‐month follow‐up period and an increase in score of ≥0.6 compared to the baseline DAS28. Results In total, 531 patients were allocated to the stop group and 286 to the TNFi continuation group. At 12 months, more patients had experienced a flare in the stop group (272 [51.2%] of 531) than in the continuation group (52 [18.2%] of 286; P &lt; 0.001). The hazard ratio for occurrence of a flare after stopping TNFi was 3.50 (95% confidence interval [95% CI] 2.60–4.72). The mean DAS28 in the stop group was significantly higher during the follow‐up period compared to that in the continuation group ( P &lt; 0.001). Of the 195 patients who restarted TNFi treatment after experiencing a flare and within 26 weeks after stopping, 165 (84.6%) had regained a DAS28 of &lt;3.2 by 6 months later, and the median time to a regained DAS28 of &lt;3.2 was 12 weeks (95% Cl 10.7–13.3). There were more hospitalizations in the stop group than in the continuation group (6.4% versus 2.4%). Conclusion Stopping TNFi treatment results in substantially more flares than does continuation of TNFi in patients with established RA in remission or with stable low disease activity.
Angiogenic Factors eNOS and VEGF Have Increased Expression in Granulocytes of JAK2V617F Homozygous Forms of Polycythemia Vera,
Authors: Vladan P Cokic, Dragana Markovic, Olivera Mitrovic, Sanja Vignjevic, Dragoslava Djikic, Bojana B Beleslin-Cokic, Maja Perunicic, Bojana Ilic, Gordana Jovcic, Mirjana Gotic, Constance Tom Noguchi, Alan N Schechter
Journal: Blood (2011)
Abstract LB-310: NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) reduces oxidative stress to promote hepatocellular carcinoma
Authors: Robin Kit-Ho Lai, Irix Ming-Jing Xu, David Kung-Chun Chiu, Aki Pui-Wah Tse, Larry Lai Wei, Cheuk-Ting Law, Derek Lee, Chun-Ming Wong, Maria Pik Wong, Irene Oi-Lin Ng, Carmen Chak Lui Wong.
Journal: Cancer Research (2016)

Abstract Background &amp; Aims: Liver is a major metabolic organ, yet the detailed metabolic alterations driving hepatocellular carcinoma (HCC) remain elusive. The rapid growing nature of HCC results in oxygen deprivation or hypoxia in regions of tumors with insufficient blood supply. Hypoxia unbalances the electron flow through the electron transport chain (ETC) resulting in reactive oxygen species (ROS) accumulation. Here we aim at delineating the mechanisms by which HCC evades oxidative stress. Methods: We performed transcriptome sequencing to study the gene expression profile in both HCC patients and HCC cell line. The mRNA expression of 100 paired HCC and corresponding non-tumorous tissues were analyzed. Stable RNAi knockdown by shRNA and genetic knockout by TALEN were established in HCC cells for functional characterization. Results: We demonstrated that HCC cells specifically utilized the mitochondrial protein NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 gene (NDUFA4L2), in the complex I of the ETC, to survive hypoxia. NDUFA4L2 was drastically over-expressed in human HCC and closely associated with poor clinical outcomes in HCC patients. We confirmed that NDUFA4L2 was regulated by HIF-1α in HCC cells. Inactivation of HIF-1α/NDUFA4L2 in different HCC cell lines increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and ROS-mediated apoptosis in HCC cells. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vitro and in vivo. In addition, HIF inhibitors, digoxin and sorafenib, significantly suppressed growth of tumors that expressed high level of NDUFA4L2 in orthotopic HCC model. Conclusions: Our results have unprecedentedly uncovered the clinical relevance and oncogenic roles of NDUFA4L2 in HCC. Citation Format: Robin Kit-Ho Lai, Irix Ming-Jing Xu, David Kung-Chun Chiu, Aki Pui-Wah Tse, Larry Lai Wei, Cheuk-Ting Law, Derek Lee, Chun-Ming Wong, Maria Pik Wong, Irene Oi-Lin Ng, Carmen Chak Lui Wong. NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) reduces oxidative stress to promote hepatocellular 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 LB-310.
P245 Standardisation of Bronchoscopy Training Across Yorkshire and Humber Deanery: Abstract P245 Table 1
Authors: F Chowdhury, A Gondker, N Acharya, R Naseer, J Hill, J Hogg, J Kastelik, S Renshaw, S Bianchi
Journal: Thorax (2012)

<h3>Background</h3> Reduced exposure to bronchoscopyis a key issue for respiratory trainees with effect on their confidence in undertaking the procedure and thus patient safety. Studies have shown that simulation improves confidence in bronchoscopy skills but do not explore the most optimal teaching methods. <h3>Aim</h3> To assess two different methods of delivering bronchoscopy simulation training <h3>Methods</h3> Two half day simulation bronchoscopy courses were designed independently within the Yorkshire and Humber Deanery. Course 1 concentrated on providing a knowledge based training consisting of a didactic lecture followed by equal time spent on a Symbionixsimulator and on the BTS e-learning hub website. Course 2 provided pre-course material in the form of BTS guidelines and bronchoscopy procedure pocketbook. The course focused on hands-on simulation training using a bronchoscopy manikin and the Symbionix simulator. All candidates completed pre and post course Likert scale questionnaires in six areas relating to participant knowledge and confidence in using a bronchoscope. <h3>Results</h3> Overall 30 trainees; 15 in each course were evaluated. Candidates had performed between 0 to &gt;300 previous bronchoscopies and were from across the SpR years. Both courses delivered significant improvement in confidence scores in all of the six areas assessed. The greatest improvement was found in confidence levels in technical ability (see table 1). Course 1 candidates showed a greater confidence improvement in factual skills (such as knowledge of contra-indications of the procedure and anatomy). Course 2 demonstrated that 93% of candidates agreed that the simulator helped to improve technical ability in contrast to 100% with manikin exposure. 100% of candidates found the pocketbook was a useful adjuvant to the course with 93% agreeing that they would find this useful to complement their training. <h3>Conclusions</h3> A combined and standardised bronchoscopy simulation course incorporating lectures and pre-course materials but focusing on hands on experience on both a manikin and a simulator is therefore considered to provide greatest educational benefit. This course is now active in Yorkshire and the Humber and is to be mandated for all new trainees to the programme. Each SpR will also be re-assessed after a 3-month period incorporating a competency-based assessment approach. Authors 1 and 2 are first authors
The Novel 2nd Generation Small Molecule MEK Inhibitor, AZD-6244, Induces Cell Death in Lymphoma Cells Lines, Primary Cells, and in a Human Lymphoma Xenograft Model.
Authors: Savita Bhalla, Ron Gartenhaus, Bojie Dai, Sheila Prachand, Arindam Mukherjee, Rebecca L Elstrom, Leo I. Gordon, Andrew M. Evens
Journal: Blood (2009)
Variability in LDL cholesterol is linked to poorer cognitive performance in older people
Authors: Susan Mayor
Journal: BMJ (2016)

Greater variability in low density lipoprotein (LDL) cholesterol is associated with poorer cognitive performance in older people, a large international study has shown.1

Researchers assessed the association between variability in LDL cholesterol and tests of cognitive function in 4428 people (aged 70 to 82) with pre-existing vascular disease or at increased risk of vascular disease who were taking part in a prospective randomised trial of pravastatin. They also looked at the impact of LDL cholesterol variability on levels of white matter in the brain …
Abstract LB-239: Induction of therapeutic soluble decoy EGFR variants by antisense manipulation of RNA processing
Authors: Jeong Eun Park, Lee Spraggon, Luca Cartegni
Journal: Cancer Research (2016)

Abstract Activation of the receptor tyrosine kinase (RTK) signaling pathways represents a key aspect of tumorigenesis in a broad range of human cancers. Thus, targeting of pathogenic RTKs, mainly with small molecule inhibitors and antibodies, has become an attractive therapeutic approach for cancer therapy. However, resistance by multiple mechanisms, including mutational re-activation of RTK signaling, activation of alternative RTK pathways, EMT transition and others, inevitably occurs over time. We recently identified a number of novel secreted soluble decoy RTKs isoforms (sdRTKs) generated by an U1-snRNP-dependent alternative intronic polyadenylation mechanism. We therefore developed a novel antisense-based method to effectively activate the expression of these sdRTKs, both in vitro and in vivo. This leads to the generation of endogenous dominant negative variants of RTKs, which can specifically affect the signaling of pathogenic RTKs and therefore provides a novel cancer therapy approach. Employing specific antisense compounds designed to activate intronic polyA sites, we are able to induce natural truncated EGFR variants that encode its extracellular ligand-binding domain but lack the intracellular signaling domain. These compounds thus can inhibit EGFR signaling by a three fold-mechanism: 1) removal of FL receptor, 2) sequestration of ligands and 3) non-productive dimerization with residual receptors. They are therefore designed to affect signaling both of targeted cells and of bystanders. Here we will show that, using this approach, we can target EGFR signaling both in vitro and in tumors. Importantly, with this method we can bypass the emergence of resistance typically seen with targeted drug treatments. Further development of this methodology will therefore provide the basis for an exciting novel approach to targeting and inhibiting oncogenic EGFR signaling and other pathways in a variety of cancers. Citation Format: Jeong Eun Park, Lee Spraggon, Luca Cartegni. Induction of therapeutic soluble decoy EGFR variants by antisense manipulation of RNA processing. [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-239.
Bortezomib(Velcade®)-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation
Authors: Laurent Garderet, Simona Iacobelli, Philippe Moreau, Mamoun Dib, Denis Caillot, Dietger W Niederwieser, Tamas Masszi, Jean Fontan, Mauricette Michallet, Alois Gratwohl, Giuseppe Milone, Chantal Doyen, Brigitte Pegourie, Roman Hajek, Philippe Casassus, Brigitte Kolb, Carine Chaleteix, Bernd Hertenstein, Francesco Onida, Heinz Ludwig, marie Christiane Vekemans, Nicolas Ketterer, Anne Daguenel, Norbert C. Gorin, jean Luc Harousseau, Theo de Witte, Curly Morris, Gosta Gahrton
Journal: Blood (2010)
Efficacy and safety of nivolumab monotherapy in metastatic urothelial cancer (mUC): Results from the phase I/II CheckMate 032 study.
Authors: Padmanee Sharma, Petri Bono, Joseph W. Kim, Pavlina Spiliopoulou, Emiliano Calvo, Rathi Narayana Pillai, Patrick Alexander Ott, Filippo G. De Braud, Michael A. Morse, Dung T Le, Dirk Jaeger, Emily Chan, Christopher T. Harbison, Chen-Sheng Lin, Marina Tschaika, Alex Azrilevich, Jonathan Rosenberg
Journal: Journal of Clinical Oncology (2016)

4501 Background: Minimal antitumor activity of existing therapies and the observation of immune dysfunction in bladder cancer have prompted evaluation of immunotherapy in this malignancy. Nivolumab (fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody) monotherapy has shown survival benefit in patients (pts) with melanoma, lung cancer, and renal cell carcinoma. Here, we report efficacy and safety of nivolumab monotherapy in pts with mUC after ≥1 prior line of platinum-based therapy in an open-label, multicenter phase I/II study (NCT01928394). Methods: Pts (unselected by PD-L1 expression status) with mUC received nivolumab 3 mg/kg intravenously every 2 weeks until progression or discontinuation. Primary endpoint was objective response rate (ORR; RECIST 1.1). Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of 78 treated pts (median age 65.5 years; range, 31–85), 65.4% had received ≥2 prior therapies. At a median follow-up of 213 days (range, 22–499), 33.3% of pts remain on therapy; primary reason for treatment discontinuation was disease progression. Median number of doses was 8.5 (range, 1–34); 70.5% received >4 doses. Efficacy findings are shown in the table. Outcomes by PD-L1 expression will be included in the presentation. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 20.5% of pts; most frequent were increased lipase and increased amylase (3.8% each) and fatigue, decreased neutrophils, and dyspnea (2.6% each). Grade 5 TRAEs occurred in 2.6% of pts (pneumonitis [n=1] and thrombocytopenia [TTP; n=1]). No grade 3 or 4 pneumonitis or TTP was reported. Conclusions: Nivolumab monotherapy demonstrated promising efficacy and acceptable safety in previously treated, unselected pts with mUC. OS data are encouraging. Clinical trial information: NCT01928394.Parameter Nivolumab All treated pts (N=78) ORR (confirmed), % (95% CI) 24.4 (15.3−35.4) Median PFS, months (95% CI) 2.8 (1.5−5.5) Median OS, months (95% CI) Not estimable (NE) (7.0−NE) 12-month OS rate, % (95% CI) 51.6 (37.0−64.5) Median time to response, months (SD) 1.5 (2.1) Median DOR, months (95% CI) NE (5.5−NE)
Multiplatform comprehensive kinase analysis of muscle-invasive bladder cancer (MIBC) to identify potentially actionable therapeutic targets.
Authors: Vipin Lohiya, Christopher Willey, Eddy Shih-Hsin Yang, Michael Crowley, Joshua Anderson, Deborah L Della Manna, Gurudatta Naik, David Crossman, Sooranarayana Varambally, Darshan S Chandrashekar, Guru Sonpavde
Journal: Journal of Clinical Oncology (2016)

e16014 Background: Kinases appear to be major molecular drivers of MIBC. Given that kinases are therapeutically actionable, we performed comprehensive multiplatform analysis of kinases in matched MIBC tumor and normal tissue to prioritize their relevance. Methods: We collected fresh frozen tumor and adjacent normal tissue from 24 MIBC patients. After macrodissection to demarcate tumor from normal tissue, the samples underwent analysis of kinases using platforms to assess DNA, RNA and kinase activity. Next Generation Sequencing (NGS) of 515 kinase genes was performed using the Agilent Kinome capture and run on the Illumina HiSeq2500 at PE100bp. The Nanostring nCounter platform analyzed the expression (RNA) of 519 kinase genes. Global kinase activity of tissue lysates was measured using Pamstation-12, high-content phospho-peptide substrate microarray system (PamGene International). Upstream kinase prediction was performed (adapted from www.phosphonet.ca) and network mapping was done with GeneGo MetaCore. Ingenuity pathway analysis data was performed to integrate tumor over-expression at the activity and gene expression level with coexisting missense mutations at DNA level. Results: PTK6 (Protein-tyrosine kinase 6) exhibited increased activity by PamGene kinomics and gene overexpression by nanostring in a large subset of tumors (n = 11). NGS revealed a missense mutation on the tyrosine kinase domain of PTK6 in one tumor. TTN, OBSCN, PIK3CA, EPHA5, FASTK and MAST1 harbored missense mutations in multiple tumors. Copy number analysis showed that RIPK3 and PAK4 (p21 protein-activated kinase 4) were amplified in ≥ 2 tumors and also had gene expression up-regulation. Kinases involved in cell cycle and p53 signaling pathways were upregulated in the majority of tumors when examining gene expression. Conclusions: Comprehensive analysis of kinases at the DNA, RNA and protein activity levels discovered alterations of PTK6, RIPK3 and PAK4 kinases in > 1 platform. Further validation of these kinases as therapeutic targets is warranted. Alterations of multiple other kinases, and cell-cycle controlling and p53 pathways appeared similar to previous reports.