tbuckley/cabot-search huggingface dataset:
Clinical, signaling pathway, and cellular effects of epidermal growth factor receptor (EGFR) inhibition with gefitinib in combination with paclitaxel and radiation in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: C. T. Allen, E. A. Donovan, Z. Chen, D. Gius, J. C. Morris, C. Vanwaes
Journal: Journal of Clinical Oncology (2006)

15540 Background: EGFR, overexpressed in &gt;90% of SCCHN, activates pathways that modulate proliferation, apoptosis, and therapeutic resistance. We examined the clinical, signaling, and cellular effects of EGFR inhibition in serial tumor biopsies in patients (Pts.) with locally advanced SCCHN receiving the EGFR-inhibitor gefitinib (GEF) in combination with paclitaxel (PTX) and radiation (XRT). Methods: Phase I dose-escalation study of concurrent GEF 250 mg with weekly PTX 45mg/m 2 x 6 doses and XRT to 72Gy. Eligiblity: SCCHN, Stage III-IVB, age ≥18 yr., no prior XRT or chemotherapy, ECOG ≤2, adequate organ function and informed consent. Endpoints include determination of maximum tolerated dose (MTD) and immunostaining of tumor pre- and post-treatment for expression of phospho-EGFR, Akt, Erk1/2, STAT3, NF-κB p65, Ki67, and TUNEL, and measurement of serum IL-6, IL-8, VEGF, HGF and GROα to assess the functional effects of EGFR-inhibition. Results: Four Pts., median age 63 yr. (range 41–83), 3 men, 1 woman were treated. Aspiration pneumonia and interstitial pneumonitis were each observed in 1 Pt and prolonged Grade 3/4 mucositis in all 4 Pts. Three Pts achieved a CR, with one Pt requiring neck dissection to remove a residual node. One Pt had a local CR but rapidly developed pulmonary metastasis. One Pt. exhibited decreased staining of all signaling phosphoproteins and Ki67 with increased TUNEL staining. Decrease or increase in IL-8, VEGF and HGF at one month corresponded with response or progression in two patients. Conclusions: Pulmonary complications and prolonged mucositis were dose-limiting. EGFR inhibition affects downstream signaling, cell survival and serum factors in a subset of patients. No significant financial relationships to disclose.
267PD Survival, clinical activity and safety of intraperitoneal carboplatin combined with intravenous dose-dense paclitaxel in patients with ovarian carcinoma: a retrospective study of 69 cases
Authors: Y. Imai, K. Hasegawa, S. Sato, Y. Yano, A. Ogasawara, A. Miyasaka, A. Yabuno, A. Kurosaki, H. Yoshida, K. Fujiwara
Journal: Annals of Oncology (2015)
Fevipiprant, a prostaglandin D 2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial
Authors: Sherif Gonem, Rachid Berair, Amisha Singapuri, Ruth Hartley, Marie F M Laurencin, Gerald Bacher, Björn Holzhauer, Michelle Bourne, Vijay Mistry, Ian D Pavord, Adel H Mansur, Andrew J Wardlaw, Salman H Siddiqui, Richard A Kay, Christopher E Brightling
Journal: The Lancet Respiratory Medicine (2016)
Characterization of CEBPA Mutations and Promoter Hypermethylation in Pediatric Acute Myeloid Leukemia.
Authors: Iris H.I.M. Hollink, Marry M. van den Heuvel-Eibrink, Susan T.C.J.M. Arentsen-Peters, Martin Zimmermann, Justine K. Peeters, Peter J. Valk, Brian V. Balgobind, Gertjan J.L. Kaspers, Evelina S.J.M. de Bont, Siebold S.N. de Graaf, Jan Trka, Jan Stary, Jean-Michel Cayuela, Andre Baruchel, Ursula Creutzig, Dirk Reinhardt, Rob Pieters, C. Michel Zwaan
Journal: Blood (2009)
ST03: A randomized trial of perioperative epirubicin, cisplatin plus capecitabine (ECX) with or without bevacizumab (B) in patients (pts) with operable gastric, oesophagogastric junction (OGJ) or lower oesophageal adenocarcinoma.
Authors: Elizabeth C Smyth, Ruth E Langley, Sally P Stenning, Laura Stevenson, William H. Allum, Heike Grabsch, Derek Alderson, Angela M Riddell, Thomas Crosby, Robert Mason, Michael Griffin, Wasat Mansoor, Linda Evans, Gary William Middleton, Matthew T. Seymour, Stephen Falk, David Smith, Katherine Anne Sumpter, Jane M Blazeby, David Cunningham
Journal: Journal of Clinical Oncology (2012)

TPS4143 Background: Perioperative ECX chemotherapy is a standard of care for localised gastric/OGJ/lower oesophageal adenocarcinoma (Cunningham NEJM 2006). B is a monoclonal antibody targeting VEGF-A, and in combination with chemotherapy results in improved response rates (RR) and progression free survival in advanced gastric cancer (Ohtsu JCO 2011). The aim of ST03 is to assess the safety and feasibility (stage I, first 200 pts) and efficacy (stage II) of the addition of B to perioperative ECX chemotherapy. Methods: ST03 is a multicentre, open-label, phase II/III randomised trial ongoing at 92 UK centres; sites in Germany will open in 2012. Eligibility criteria are histologically proven, untreated, resectable, lower oesophageal, OGJ or gastric adenocarcinoma; age ≥18 years; WHO PS 0-1; and adequate cardiac ejection fraction (EF). Exclusion criteria are TIA/CVA or MI ≤1 year; uncontrolled hypertension; ≥Grade II NYHA heart failure; recent gastrointestinal inflammatory conditions or major surgery/trauma/open biopsy &lt;28d of study entry. Pts receive 3 pre- and 3 postoperative ECX (epirubicin 50 mg/m 2 iv D1, cisplatin 60 mg/m 2 iv D1 and capecitabine 1250mg/m 2 /D1-21) +/- B 7.5mg/kg D1 q3wk during chemotherapy, then 6 Bev q3wk (investigational arm). Surgery is pre-specified and laparoscopic procedures allowed only after quality assurance review. All specimens undergo central pathology review; blood and tissue collection for translational correlates is ongoing. The primary outcome measures for Stage I (safety results including cardiac EF) have been reported (Okines ASCO 2011). The stage II primary outcome measure is overall survival. Secondary outcome measures are RR, resection rate, disease free survival, toxicity, and QoL. An MRI substudy is open, a PET substudy is planned. 558 of ~950 pts required have been recruited, accrual expected to complete in 2013. An embedded pilot study within ST03 randomising HER2 positive patients to ECX ± lapatanib will open in 2012. Trial sponsored and co-ordinated by the MRC Clinical Trials Unit and funded by Cancer Research UK (CRUK06/025, NCT00450203).
Thiocarbmoylation Chemistry Based Pegylation Of αα Fumaryl-Hb Is Unique As It Does Not Induce An Increase In Oxygen Affinity: High Oxygen Affinity Pegylated Crosslinked Hbs Are Better As Oxygen Therapeutics
Authors: Fantao Meng, Amy Tsai, Marcos Intaglietta, Seetharama A. Acharya
Journal: Blood (2013)
ZFN-Driven Gene Editing Prevents HLA-A Expression On Hematopoietic Stem Cells -Improving The Chance Of Finding An HLA-Matched Donor
Authors: Hiroki Torikai, Tiejuan Mi, Sonny O Ang, Loren Gragert, Martin Maiers, Sourindra Maiti, Kirsten Switzer, Helen Huls, Andreas Reik, Michael C. Holmes, Philip D Gregory, Richard E Champlin, Elizabeth J Shpall, Laurence J N Cooper
Journal: Blood (2013)
Incidence of Acute Respiratory Distress Syndrome—Reply
Authors: Giacomo Bellani, Tai Pham, John Laffey
Journal: JAMA (2016)

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PMO-254 Comparison of IBDQIP scores for two services within one trust: Abstract PMO-254 Figure 1
Authors: E Fernandez, D Hall
Journal: Gut (2012)

<h3>Introduction</h3> The Heart of England NHS Foundation Trust is one of the largest in England, with over 1200 beds and serves over a million people throughout north and east Birmingham and surrounding areas. It has three sites: Birmingham Heartlands, Good Hope Hospital and Solihull Hospital. <h3>Methods</h3> Good Hope Hospital and Heartland &amp; Solihull Hospitals entered data separately into IBD Quality Improvement Project. Services were asked to meet as a team to enter data about their service. The majority teams were able to complete data entry within 2–3 h. Each team comprised of two Consultant gastroenterologists a Consultant Colorectal surgeon and an IBD CNS. Results were not discussed between services at the time of data entry. After completion the sites requested comparative results and arranged a joint meeting to discuss the outputs. <h3>Results</h3> As a response to this the teams reviewed their data together and agreed the following action points: (1) Good Hope Hospital will join Heartlands and Solihull9s Transition Clinic at Birmingham Children9s Hospital. This takes place twice a year and a joint team from both sites will attend. (2) A shared care agreement for patient9s on immunosuppressive, between primary and secondary care is being devised for use across the Trust. (3) Nutritional support, which was initially available at Heartlands but has been extended to Good Hope. (4) Heartlands hospital have recently trialled a changed on-call system, to provide daily Gastroenterology ward rounds, to improve appropriate patient flow to specialist gastroenterology beds. <h3>Conclusion</h3> (1) There are significant differences in service provision between the two services within the same Trust (2) The Trust covers a large geographical area and differing population sizes. Despite now existing within the same directorate services have maintained their historical ways of working. (3) This assessment has provided a catalyst for joint working and improved care for patients. <h3>Competing interests</h3> None declared. <h3>Reference</h3> 1. Quality Service standards for the healthcare of people who have Inflammatory Bowel Disease http://www.ibdstandards.org.uk/
Abstract 2924: Metastasis-associated protein 1 induces tamoxifen resistance in MCF7 breast cancer cells
Authors: Min-Ho Lee, Dahae Koh, Mi-Ock Lee
Journal: Cancer Research (2016)

Abstract Tamoxifen is most commonly used to treat estrogen receptor-alpha positive breast cancer, but its therapeutic benefit is limited by the development of drug resistance. Metastasis associated protein 1 (MTA1) is a cancer progression-related gene and has been reported to be overexpressed in a variety of human cancers including breast cancer. Here, we showed that transient overexpression of MTA1 in MCF7 breast cancer cells results in tamoxifen resistance, whereas si-RNA mediated knockdown of MTA1 was more susceptible to tamoxifen-induced growth inhibition. Moreover, stable overexpression of MTA1 in MCF7 cells promoted cell proliferation and reduced tamoxifen sensitivity. To explore the mechanisms of MTA1-mediate tamoxifen resistance, we used microarray analysis to profile the gene expression patterns of MTA1 overexpress MCF7 stable cells after tamoxifen treatment. From microarray data analysis, 538 genes were selected as associated with MTA1-mediated tamoxifen resistance (P &amp;lt; 0.05, LPE test; cutoff ≥ 1.5-fold). The Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis revealed that the predominant biological processes associated with these genes are M phase, negative regulation of cell proliferation, mitosis and M phase of mitotic cell cycle. Further, we found that cell-cycle regulator Cyclin D1 and cyclin B1 protein levels were increased in MTA1 overexpression MCF7 stable cells. Analyses of publicly available patient data sets indicated that MTA1 levels are higher in patients after endocrine therapy failure (recurrence), compared to those of responders (non-recurrence). These results suggest that MTA1 may contributed tamoxifen resistance through the regulation of cell cycle components. Citation Format: Min-Ho Lee, Dahae Koh, Mi-Ock Lee. Metastasis-associated protein 1 induces tamoxifen resistance in MCF7 breast 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 2924.
Identification of PDGFR-β activation as a potential bypass resistance pathway in a rhabdomyosarcoma (RMS) model of acquired resistance to IGF-1 receptor blockade.
Authors: Christine Heske, Choh Yeung, Liang Cao, Xiaolin Wan, Lee J. Helman
Journal: Journal of Clinical Oncology (2014)

10046 Background: IGF-1R and its ligands have been shown to be potentially important therapeutic targets for sarcomas. Phase II sarcoma trials using IGF-1R blockade yielded clinically meaningful responses in unselected patients with pediatric type sarcomas. However, most responses were short-lived with rapid onset of resistance. Similarly, data from mouse xenograft RMS models showed initial response with subsequent resistance. Evaluation of tumor samples from treated mice showed persistently down-regulated IGF-1R, but rebound AKT phosphorylation, suggesting that resistance was not from loss of antibody activity against IGF-1R, but rather the result of a bypass pathway. We therefore sought to model acquired resistance in human RMS cells. Methods: Human RMS cell lines resistant to IGF-1R blockade were generated in xenografts from a highly sensitive parent cell line. Additional cell lines were selected for in vitro resistance. Parental and resistant lines were screened with a receptor phosphotyrosine array. Differences in expression were confirmed with Western Blot analysis and electrochemiluminescence detection. Cell growth under dual pathway inhibition was tested in vitro using IGF-1R antibody and several kinase inhibitors. Results: Screening of parental and resistant lines revealed increased phosphorylation of PDGFR-β in resistant cells. PDGFR-β and IGF-1R share several signaling pathways (PI3K, MAPK/ERK), suggesting that PDGFR-β activation may act as a bypass mechanism to activate AKT. Target inhibition of PDGFR-β in resistant cells was achieved with pazopanib. Proliferation assays have shown that dual inhibition of IGF-1R and PDGFR-β in resistant clones enhances cell growth inhibition in vitro. Similar studies are ongoing using xenografted tumors. Conclusions: Activation of PDGFR-β may be responsible for resistance to IGF-1R blockade in some RMS. This mechanism may also explain the rapid onset of resistance seen in clinical trials using IGF-1R blockade. Therapy targeting both IGF-1R and PDGFR-β may be a rational combination to treat RMS and prevent onset of resistance in some patients.
Toll‐like Receptor 9 Signaling Is Augmented in Systemic Sclerosis and Elicits Transforming Growth Factor β–Dependent Fibroblast Activation
Authors: Feng Fang, Roberta Goncalves Marangoni, Xingchun Zhou, Yang Yang, Boping Ye, Anna Shangguang, Wenjie Qin, Wenxia Wang, Swati Bhattacharyya, Jun Wei, Warren G. Tourtellotte, John Varga
Journal: Arthritis & Rheumatology (2016)

Although transforming growth factor β (TGFβ) is recognized as being a key trigger of fibroblast activation in systemic sclerosis (SSc), prominent innate immunity suggests that additional pathways contribute to disease persistence. Toll-like receptor 9 (TLR9) is implicated in autoimmunity and fibrosis; however, the expression, mechanism of action, and pathogenic role of TLR9 signaling in SSc remain uncharacterized. The aim of this study was to explore the expression, activity, and potential pathogenic role of TLR9 in the context of skin fibrosis in SSc and in mouse models of experimental fibrosis.Expression and localization of TLR9 were evaluated in SSc skin biopsy specimens and explanted skin fibroblasts. Fibrotic responses elicited by type A CpG oligonucleotide and mitochondrial DNA (mtDNA) were examined in human skin fibroblasts by a combination of real-time quantitative polymerase chain reaction, Western blot analysis, transient transfection, immunofluorescence microscopy, and functional assays. Expression of TLR9 was examined in 2 distinct mouse models of experimental fibrosis.Skin biopsy specimens obtained from 2 independent cohorts of SSc patients showed up-regulation of TLR9, and myofibroblasts were the major cellular source. Moreover, SSc skin biopsy specimens showed evidence of TLR9 pathway activation. CpG induced robust TLR9-dependent fibrotic responses in explanted normal fibroblasts that could be blocked by bortezomib and were mediated through the action of endogenous TGFβ. Mice with experimental fibrosis showed a time-dependent increase in TLR9 localized primarily to myofibroblasts in the dermis.In isolated fibroblasts, TLR9 elicits fibrotic responses mediated via endogenous TGFβ. In patients with SSc, mtDNA and other damage-associated TLR9 ligands in the skin might trigger localized activation of TLR9 signaling, TGFβ production, and consequent fibroblast activation. Disrupting this fibrotic process with inhibitors targeting TLR9 or its downstream signaling pathways might therefore represent a novel approach to SSc therapy.
Azacitidine Prolongs Survival and Time to AML Transformation in High-Risk Myelodysplastic Syndrome (MDS) Patients ≥ 65 Years of Age.
Authors: Lewis R. Silverman, David R. McKenzie, Bercedis L. Peterson, Erin P. Demakos, Neil T. Malone, James F. Holland, Richard A. Larson
Journal: Blood (2005)
Is a second transurethral resection of high-grade T1 bladder tumors always necessary?
Authors: James Ryan Mark, Nicholas Brent Drury, Caroline Arden Merwarth, Kris E Gaston, Ornob Proteek Roy, Stephen Boyd Riggs
Journal: Journal of Clinical Oncology (2016)

e16009 Background: Routine use of a second transurethral resection (TUR) for all high-grade T1 (HGT1) bladder tumors is supported by AUA, EAU, and NCCN guidelines. We have observed significant pelvic discomfort and urinary side-effects following second TUR leading us to question if it is an absolute necessity. Therefore, we examined the rate of upstaging or residual disease on second TUR for patients diagnosed with HGT1 bladder cancer on initial resection. Methods: We retrospectively evaluated patients from September 2012 to May 2015 with clinically staged HGT1 disease after an initial TUR who then underwent a second TUR within 90 days. A complete initial resection was defined as having all visible tumor resected and muscle present in the specimen. A total of 25 surgeons performed the initial diagnoses and second TURs. Results: Of 134 patients who were clinically diagnosed with HGT1 disease on initial TUR, 55 underwent a second resection within 90 days. Thirty-four cases were considered to have a complete initial TUR, and 21 were incomplete. Of the 21 cases with an incomplete initial TUR, 6 (28.6%) were upstaged ( ≥ T2) on repeat resection. Of the 34 cases with a complete initial TUR, none (0%) were upstaged on second resection. Of these cases with a complete initial TUR, 15 (44.1%) had no residual tumor on second TUR, and 19 (55.9%) had residual noninvasive tumor, of which 12 (63.2%) had multifocal tumors on initial resection. In all, 15 (44.1%) had no disease (T0), 10 (29.4%) had persistent T1 tumor, 8 (23.5%) had Ta tumor, and 1 (2.94%) had Tis on second TUR after a complete initial resection. Conclusions: Upstaging to ≥ T2 disease was not seen in our series after complete initial TUR (defined above) and occurred in 28.6% after incomplete initial TUR. In light of cost and potential morbidity, further stratification and reevaluation of the need for ubiquitous second resection should be considered.
Abstract 2707: Quantitative analysis of the role of androgen receptor in radiation treatment for prostate cancer
Authors: Mengdi Qian, Alexandru Almasan, Evren Gurkan-Cavusoglu
Journal: Cancer Research (2016)

Abstract The purpose of this study is to quantitatively investigate the mechanism of androgen receptor (AR) and non-homologous end joining (NHEJ) interaction after and ionizing radiation (IR) and androgen deprivation therapy (ADT) treatment. In most clinical treatment approaches, a combination of ADT and IR is used in order to improve prostate patients’ overall survival probability. It is found that AR interacts with NHEJ pathway, a major double strand break (DSB) repair pathway. We have developed a mathematical model of the NHEJ pathway that is composed of a series of ordinary differential equations. The kinetic rate constants constitute the unknown parameters of the model and we have estimated these parameters using least square estimation. The data sets used in the parameter estimation were obtained from the literature and they were from both in vitro experiments as well as clinical data from prostate cancer patients. Both sets of data demonstrated the effects of AR on DSB repair by NHEJ. The in vitro data suggest that AR enhances DSB repair by inducing expression/activity of DNA-PKcs, which is a key protein in NHEJ. The clinical data show that the effect is through the first NHEJ protein complex that is recruited to DSB, Ku70/80. We have developed the models for IR treatment alone or in combination with ADT to determine which of these mechanisms can explain the behavior in both data sets simultaneously. We have carried out sensitivity analysis and identifiability tests on all the parameters from both models in order to determine the parameters that are reliably estimated. We have shown that when the rate constant for the initiation protein Ku70/80 is decreased to half in the IR+ADT case compared to the IR only case, the model outputs captured the observations in both experimental and clinical data. The rate constant for Ku70/80 is proved to be both sensitive and identifiable, indicating that the two-fold difference in the rate constants of IR only and IR+ADT cases is biologically relevant. Therefore, we conclude that when ADT is applied, AR significantly slows down the kinetic activity of Ku70/80, thus the DSB repair by NHEJ. The suppression of AR activity through ADT has the potential to enhance the IR treatment outcomes for the prostate cancer patients that are resistant to IR-only treatment. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gurkan-Cavusoglu. Quantitative analysis of the role of androgen receptor in radiation treatment for prostate 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 2707.