tbuckley/cabot-search huggingface dataset:
Abstract 257: Evaluation of organic cation transporter 1 (OCT1, SLC22A1) as transporter for sorafenib
Authors: Claudia Neul, Sharyn D. Baker, Alex Sparreboom, Elke Schaeffeler, Stefan Laufer, Matthias Schwab, Anne T. Nies
Journal: Cancer Research (2016)

Abstract The multikinase inhibitor sorafenib is approved for the treatment of advanced clear-cell renal and hepatocellular carcinomas, yet, patients’ survival is prolonged for only several months (Wilhelm et al., Mol Cancer Ther 2008). The understanding of this poor efficacy remains incomplete. One reason for treatment failure may be the high interindividual variability in pharmacokinetics of the orally-given sorafenib. Membrane transporters may contribute to pharmacokinetics of sorafenib and its metabolites as recently reported for the hepatic solute carrier (SLC) organic anion transporter family member 1B1 (OATP1B1) and OATP1B3 (Zimmerman et al, Clin Cancer Res 2013). In contrast, the role of organic cation transporter 1 (OCT1), which is also a major hepatic uptake transporter (Nies et al, Handb Exp Pharmacol 2011), for cellular uptake of sorafenib is controversial (Hu et al, Clin Cancer Res 2009; Swift et al, Drug Metab Dispos 2013; Herraez et al, Hepatology 2013). We therefore sought to comprehensively elucidate the impact of OCT1 on cellular sorafenib uptake by using a combination of different in vitro cell culture models and in vivo approaches involving experiments with Oct1 knockout (-/-) mice. Firstly, we analyzed cellular accumulation of radiolabeled sorafenib by the mammalian cell line HEK293 stably expressing OCT1. Despite overexpression of a functional OCT1 transporter, cellular uptake of neither sorafenib nor its active metabolite sorafenib N-oxide was increased. Next, we studied sorafenib and sorafenib N-oxide pharmacokinetics in mice with a homozygous genetic deletion of the Oct1 transporter. The deficiency of Oct1 had no influence on plasma and hepatic sorafenib and sorafenib N-oxide concentrations. Finally, we investigated sorafenib transport into the human hepatocellular carcinoma cell lines HepG2 and HuH7. Although neither OCT1 mRNA nor protein was detected, a considerable cellular accumulation of sorafenib was observed in both cell lines. Expression profiling of a panel of 55 relevant SLC drug uptake transporters identified several potential novel candidates mediating sorafenib accumulation. We conclude from these findings that cellular uptake of sorafenib and sorafenib N-oxide is independent of OCT1 and that other, as yet unidentified, transport mechanisms are responsible for cellular sorafenib uptake. Supported by the Robert Bosch Foundation, Stuttgart, Germany and the ICEPHA Grant Tübingen-Stuttgart, Germany. Citation Format: Claudia Neul, Sharyn D. Baker, Alex Sparreboom, Elke Schaeffeler, Stefan Laufer, Matthias Schwab, Anne T. Nies. Evaluation of organic cation transporter 1 (OCT1, SLC22A1) as transporter for sorafenib. [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 257.
Hunt is accused of “underhand” cover up over health department finances
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The chair of the House of Commons Public Accounts Committee has accused England’s health secretary, Jeremy Hunt, of “an underhand attempt” to cover up the poor state of the Department of Health’s finances, by timing their publication at the end of the current parliamentary session.

The health department’s annual accounts were published on Thursday 21 July, the day …
PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction?
Authors: Claud Grigg, Naiyer A. Rizvi
Journal: Journal for ImmunoTherapy of Cancer (2016)

Research in cancer immunology is currently accelerating following a series of cancer immunotherapy breakthroughs during the last 5 years. Various monoclonal antibodies which block the interaction between checkpoint molecules PD-1 on immune cells and PD-L1 on cancer cells have been used to successfully treat non-small cell lung cancer (NSCLC), including some durable responses lasting years. Two drugs, nivolumab and pembrolizumab, are now FDA approved for use in certain patients who have failed or progressed on platinum-based or targeted therapies while agents targeting PD-L1, atezolizumab and durvalumab, are approaching the final stages of clinical testing. Despite impressive treatment outcomes in a subset of patients who receive these immune therapies, many patients with NSCLC fail to respond to anti-PD-1/PD-L1 and the identification of a biomarker to select these patients remains highly sought after. In this review, we discuss the recent clinical trial results of pembrolizumab, nivolumab, and atezolizumab for NSCLC, and the significance of companion diagnostic testing for tumor PD-L1 expression.
Response to: ‘Infliximab and CT-P13 immunogenicity assessment in PLANETAS and PLANETRA main and extension studies: utility of laboratory methods description’ by Francesca Meacci<i>et al</i>
Authors: Jürgen Braun
Journal: Annals of the Rheumatic Diseases (2016)

We sincerely appreciate the interest shown by Dr Francesca Meacci and colleagues in the comparative immunogenicity evaluations of reference infliximab and CT-P13 (biosimilar infliximab) that were performed in the PLANETAS and PLANETRA clinical trials and their trial extension studies.1–7 In addition, we acknowledge their specific comments regarding the potential value of the Gyrolab platform and its many practical advantages as a laboratory method.7

In order to provide robust antidrug antibody (ADA) data, both electrochemiluminescence and Gyrolab (Gyros AB, Uppsala, Sweden) were used for PLANETRA and PLANETAS studies. To ensure a thorough evaluation of an ADA response (or absence of such a response), it is usually necessary to perform the following three procedures: (1) screening, (2) confirmation and (3) characterisation. The screening assay determines overall ADA status, categorising samples as ADA positive or ADA negative according to the presence or absence …
Abstract 1256: Multi-focal control of mitochondrial gene expression by oncogenic MYC provides effective therapeutic targets in cancer
Authors: Amanda Taylor, Clare Adams, Xiao-yong Zhang, Victoria Gennaro, Justin Cotney, Gerald Shadel, Craig Cameron, Christine Eischen, Steven McMahon
Journal: Cancer Research (2016)

Abstract The MYC transcription factor is the most dramatically overexpressed gene product in human cancer. However, defining the MYC-driven transcriptome critical to malignant transformation has remained a challenge, in part because MYC controls several thousand genes. Consequently, little progress has been made in the identification of sensitive nodes downstream of MYC that might be targeted therapeutically in order to interrupt its oncogenic signaling. To overcome this impediment, we performed a screen for downstream MYC effector pathways that are selectively linked to MYC's functional properties. Via this strategy, we identified the mitochondrial RNA polymerase (POLRMT) as a direct downstream target of MYC. POLRMT induction by MYC regulates transcription of the mitochondrial genome, as well as mitochondrial DNA replication. Recent studies have shown that POLRMT also interacts with a mitochondrial ribosomal RNA methyltransferase TFB1M to regulate mitochondrial ribosome assembly. Notably, blocking induction of POLRMT (or TFB1M) by MYC converts the cellular response to MYC activation from enhanced cell cycle progression to apoptotic cell death. Of immediate clinical relevance, compounds blocking mitochondrial gene expression at any of several steps cause acute synthetic lethality with oncogenic levels of MYC. Among these compounds, the mitochondrial targeting antibiotic Tigecycline is FDA-approved and well-tolerated in patients. Tigecycline eliminates tumor formation and dramatically improves survival in our animal model of MYC-driven lymphoma. Evidence presented here demonstrates that uncoupling of MYC's nuclear and mitochondrial transcriptomes exposes a point of exquisite vulnerability in tumor cells. Although targeting MYC as a therapeutic strategy has proven to be challenging in the past, our identification of a new node of sensitivity in MYC-driven cancers offers a potential for broad therapeutic implications. Citation Format: Amanda Taylor, Clare Adams, Xiao-yong Zhang, Victoria Gennaro, Justin Cotney, Gerald Shadel, Craig Cameron, Christine Eischen, Steven McMahon. Multi-focal control of mitochondrial gene expression by oncogenic MYC provides effective therapeutic targets in 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 1256.
Abstract 1311: High order drug combinations are required to effectively kill colorectal cancer cells
Authors: Thomas Horn, Stephane Ferretti, Nicolas Ebel, Angela Tam, Samuel Ho, Fred Harbinski, Ali Farsidjani, Matt Zubrowski, William R. Sellers, Robert Schlegel, Dale Porter, Erick Morris, Jens Wuerthner, Sebastien Jeay, Joel Greshock, Ensar Halilovic, Levi A. Garraway, Giordano Caponigro, Joseph Lehar
Journal: Cancer Research (2016)

Abstract Tumors are complex biological systems that often retain proliferative capacity even when challenged with drug treatment. Given this resiliency, drug combinations may provide greater therapeutic benefit, however, which molecules to combine and how many to include in combinations for effective responses is not clear yet. Using image-based proliferation and apoptosis assays in colorectal cancer cell lines we systematically investigated combinations that ranged in number from two to six drugs and targeted critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds, but often yielded only cytostatic responses. Enhanced cytotoxicity was observed when additional processes including apoptosis and cell cycle were targeted as part of the combination. In many cases, where cell lines were resistant to two- and three-way drug combinations, increased expression of anti-apoptotic proteins was observed and induction of cytotoxic responses required up to fourth-order combinations. Our results demonstrate that high-order drug combinations might be needed to kill cancers and show how systematic drug combination screening together with a molecular understanding of drug responses can guide their identification. Citation Format: Thomas Horn, Stephane Ferretti, Nicolas Ebel, Angela Tam, Samuel Ho, Fred Harbinski, Ali Farsidjani, Matt Zubrowski, William R. Sellers, Robert Schlegel, Dale Porter, Erick Morris, Jens Wuerthner, Sebastien Jeay, Joel Greshock, Ensar Halilovic, Levi A. Garraway, Giordano Caponigro, Joseph Lehar. High order drug combinations are required to effectively kill 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 1311.
Platelets Having a W127X Mutation in GPIX Express Sufficient Residual Amounts of the GPIbα Chain to Support Ristocetin-Mediated Agglutination and Adhesion to VWF and Collagen Under Conditions of Flow.
Authors: Taisuke Kanaji, Yuka Takata, Masaaki Moroi, Ritsuko Seki, Eijiro Oku, Masayuki Sano, Sachie Nakazato, Kenji Izuhara, Eizaburo Sueoka, Yutaka Imamura, Takashi Okamura
Journal: Blood (2008)
Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues
Authors: P. Lundquist, P. Artursson
Journal: Advanced Drug Delivery Reviews (2016)

In this contribution, we review the molecular and physiological barriers to oral delivery of peptides and nanoparticles. We discuss the opportunities and predictivity of various in vitro systems with special emphasis on human intestine in Ussing chambers. First, the molecular constraints to peptide absorption are discussed. Then the physiological barriers to peptide delivery are examined. These include the gastric and intestinal environment, the mucus barrier, tight junctions between epithelial cells, the enterocytes of the intestinal epithelium, and the subepithelial tissue. Recent data from human proteome studies are used to provide information about the protein expression profiles of the different physiological barriers to peptide and nanoparticle absorption. Strategies that have been employed to increase peptide absorption across each of the barriers are discussed. Special consideration is given to attempts at utilizing endogenous transcytotic pathways. To reliably translate in vitro data on peptide or nanoparticle permeability to the in vivo situation in a human subject, the in vitro experimental system needs to realistically capture the central aspects of the mentioned barriers. Therefore, characteristics of common in vitro cell culture systems are discussed and compared to those of human intestinal tissues. Attempts to use the cell and tissue models for in vitro–in vivo extrapolation are reviewed.
Abstract 143: Mutational landscape of colorectal adenomas reveals potential signatures for progression
Authors: Shu-Hong Lin, Gottumukkala S. Raju, Chad Huff, Jian Gu, Jiun-Shen Chen, Scott Kopetz, David G. Menter, Ernest Hawk, Lopa Mishra, Yuanquing Ye, Xifeng Wu
Journal: Cancer Research (2016)

Abstract Introduction: Colorectal cancer (CRC) continues to rank as one of the most common cancers in the U.S. and around the world. Colorectal adenoma is the well-established precursor of CRC, yet only a very small proportion of adenomas progress to CRC. Therefore, identification of biomarker associated with adenoma progression is vital for risk stratification and development of intervention strategies. We hypothesize that genomic analysis of adenoma will lead to better understanding of tumorigenesis and identification of novel biomarkers. Methods: We carried out whole exome sequencing (WES) on tissues and paired blood in 14 sessile serrated adenoma (SSA) and 36 tubulovillous adenoma (TVA) patients. Frequently mutated genes from TVA along with significantly mutated genes of TCGA colorectal adenocarcinoma were further investigated in an additional 100 pairs of TVA by targeted sequencing. Results: 1) WES revealed similar somatic mutation frequency but distinctive mutated genes in TVA and SSA. 2) All adenomas included in WES were non-hypermutators with mutation frequency ranged from 0.55 to 3.71 (average: 1.49) non-silent somatic mutations per million base, which is significantly lower than that of TCGA non-hypermutators that ranged from 0.48 to 10.11 (average 4.47, p &amp;lt; 2.2×10⁁-16). 3) MutSigCV v1.4 discovered shared and unique significantly-mutated genes (SMG) in TVA and SSA reflecting difference in biology. 4) Targeted sequencing confirmed the findings in WES with a better estimate of population frequency for genes of interest. 5) Unsupervised clustering achieved high discrimination between adenoma and adenocarcinoma. 6) A subset of mutations that best discriminate adenoma and adenocarcinoma were identified by random Forest. Conclusions: We discovered a set of genes with distinctive mutation pattern between adenoma and adenocarcinoma. We are conducting functional analysis to explore the potential of these genes as progression driver and risk predictors. We predict that the findings of this project will help lay the foundation to inform development of surveillance program and preventive intervention in CRC. Citation Format: Shu-Hong Lin, Gottumukkala S. Raju, Chad Huff, Jian Gu, Jiun-Shen Chen, Scott Kopetz, David G. Menter, Ernest Hawk, Lopa Mishra, Yuanquing Ye, Xifeng Wu. Mutational landscape of colorectal adenomas reveals potential signatures for progression. [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 143.
Meta-Analysis Of Overall Risk Of Lymphoma In Patients With Inflammatory Bowel Disease On Thiopurine Therapy With Inclusion Of New Nationwide Population Based Studies: Differences Between Referral Center Studies and Population Based Studies
Authors: David S Kotlyar, James D Lewis, Laurent Beaugerie, Ann Tierney, Colleen Brensinger, Edward Loftus, Javier Gisbert, Wojciech C Blonski, Manuel Van Domselaar, Maria Chaparro, Sandipani Sandilya, Gary R Lichtenstein
Journal: Blood (2013)
Autologous Peripheral Blood Stem Cell Transplant for Relapsed or Refractory T-Cell Non-Hodgkin’s Lymphoma Results in Inferior Long Term Survival when Compared to Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphomas.
Authors: Jack W. Hsu, Priya Singh, Stuart L. Goldberg, Andrew L. Pecora, David S. Siegel, Scott D. Rowley
Journal: Blood (2004)
Identification of a novel plasmid-mediated colistin-resistance gene, mcr-2, in Escherichia coli, Belgium, June 2016
Authors: Basil Britto Xavier, Christine Lammens, Rohit Ruhal, Samir Kumar-Singh, Patrick Butaye, Herman Goossens, Surbhi Malhotra-Kumar
Journal: Eurosurveillance (2016)

We identified a novel plasmid-mediated colistin-resistance gene in porcine and bovine colistin-resistant Escherichia coli that did not contain mcr-1. The gene, termed mcr-2, a 1,617 bp phosphoethanolamine transferase harboured on an IncX4 plasmid, has 76.7% nucleotide identity to mcr-1. Prevalence of mcr-2 in porcine colistin-resistant E. coli (11/53) in Belgium was higher than that of mcr-1 (7/53). These data call for an immediate introduction of mcr-2 screening in ongoing molecular epidemiological surveillance of colistin-resistant Gram-negative pathogens.
Abstract 4788: Discovery of potent and selective inhibitors of ERK1/2 with a unique mechanism of action
Authors: Yongqi Deng, Ahmed Samatar, Gerald Shipps, Alan Cooper, Brian Long, Donnar Carr, Li Xiao, Alan Hruza, Tong Wang, Liang Zhu, Yang Nan, Mehul Patel, Kiran Muppalla, Hugh Zhu, Babu Sobhana Boga, Xiaolei Gao
Journal: Cancer Research (2016)

Abstract Activation of the RAS/MAPK pathway occurs via a cascade of protein phosphorylation events which culminate in the phosphorylation &amp; activation of ERK 1/2. Aberrant activation of this pathway has been demonstrated in several human tumor types. Inhibitors of this pathway in clinical development target upstream kinases, BRAF or MEK. Only a few ERK 1/2 has been reported. The goal of the ERK program was to develop a targeted therapy that is guided by a clear patient selection / responder identification plan based on BRAF and K/NRAS mutations. Utilizing an affinity based high-throughput screening strategy (ALIS), we discover a novel class of small molecule ERK 1/2 inhibitors. Optimization of this chemical series led to the discovery of SCH 772984, which is highly selective ERK1/2 inhibitor, inhibiting cell proliferation selectively in tumor cell lines with an activated MAPK pathway and causes significant tumor regression in vivo in BRAF &amp; RAS mutant xenograft models. Based on insights gained through crystallographic analysis, SCH 772984 and related compounds have a unique ERK binding mode which results in a novel dual mechanism of inhibition, blocking ERK phosphorylation by MEK as well as inhibiting ERK kinase activity. This novel mechanism enables the use of ERK phosphorylation as a target engagement biomarker. Biological differences between pathway inhibition at the level or ERK vs. inhibition of upstream kinases are being examined. The SAR and crystal structures of this series ERK inhibitors will be reported. Citation Format: Yongqi Deng, Ahmed Samatar, Gerald Shipps, Alan Cooper, Brian Long, Donnar Carr, Li Xiao, Alan Hruza, Tong Wang, Liang Zhu, Yang Nan, Mehul Patel, Kiran Muppalla, Hugh Zhu, Babu Sobhana Boga, Xiaolei Gao. Discovery of potent and selective inhibitors of ERK1/2 with a unique mechanism of action. [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 4788.
Treatment of non-muscle invasive bladder cancer.
Authors: Kim N. Danforth, Janet S. Lee, Tiffany Q. Luong, Corrine E. Munoz-Plaza, Erin Elizabeth Hahn, Brian S. Mittman, Ronald K. Loo, Stephen G. Williams
Journal: Journal of Clinical Oncology (2015)

e15505 Background: Most bladder cancer patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC). Tumor recurrence among NMIBC patients is common. Post-operative intravesical chemotherapy following a transurethral resection of bladder tumor (TURBT) has been shown to reduce tumor recurrence, and in the U.S., most commonly consists of mitomycin C (MMC). However, despite being widely recommended, post-operative MMC is reportedly used infrequently. Methods: We conducted a mixed-methods study to determine treatment practices for NMIBC, identify opportunities for care improvement, and assess facilitators and barriers to guideline consistent care. Electronic health record data from 2008-2013 were used to assess treatment of NMIBC patients following their first TURBT within Kaiser Permanente Southern California, a large integrated delivery system. A survey was sent to all urologists regarding treatment practices, facilitators, and barriers, and 1:1 interviews were conducted with 9 urologists. Results: Among 1,780 newly diagnosed NMIBC patients, 28% received post-operative MMC following their first TURBT: 15% were treated with post-operative MMC only, and 13% received both post-operative MMC and induction Bacillus Calmette-Guérin immunotherapy. Additionally, 26% of NMIBC patients were treated with induction BCG alone following their first TURBT. Urologists reported that patient refusal of post-operative MMC was rare. They also reported that the most common reason for not administering post-operative MMC was a tumor resection that was too deep. Findings from the urologist survey and interviews identified several factors that, if improved, might contribute to increased use of post-operative MMC. These include simplifying the pharmacy ordering process, developing institutional ‘best practice’ guidelines (including detailed information on indications/contraindications for post-operative MMC use), and providing feedback to urologists on their own treatment practices (e.g., a ‘dashboard’ summary). Conclusions: Consistent with national data, our research suggests that there are opportunities to improve guideline-consistent care of NMIBC patients. Study findings are now being used to improve care quality within our organization.