tbuckley/cabot-search huggingface dataset:
Abstract 1048: Modulation of lipid metabolism through inhibition of acetyl-CoA carboxylase with ND-646 leads to potent inhibition of breast cancer cell growth <i>in vitro</i> and <i>in vivo</i>
Authors: Jennifer L. Rocnik, Wenyan Miao, Geraldine Harriman, Jeremy Greenwood, Sathesh Bhat, H. James Harwood, Rosana Kapeller, William F. Westlin
Journal: Cancer Research (2016)

Abstract Metabolic attenuation is a promising approach to cancer therapy and rate-limiting steps in key biosynthetic pathways are particularly attractive targets. Many cancer types are dependent on fatty acid synthesis as a primary source of energy and for providing lipids for expansion of cell and nuclear membranes in rapidly proliferating cells. The rate-limiting enzyme in fatty acid synthesis, acetyl-CoA carboxylase (ACC), has been shown to be highly expressed in human breast cancer. ACC is thought to be critical for the growth and survival of cancer cells, especially within a tumor microenvironment where exogenous fatty acids might be limited. Effective therapeutic options for triple negative breast cancer are limited and identification of robust targeted agents without overt toxicity for this indication are especially needed. Dual inhibition of the ACC isozymes, ACC1 and ACC2, results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. We have identified ND-646, a potent, selective, allosteric inhibitor of ACC with broad tissue distribution that binds to the ACC biotin carboxylase domain and potently inhibits the dimerization and enzymatic activity of both ACC1 (IC50 = 3.5nM) and ACC2 (IC50 = 4.1nM). Profiling the potency of ND-646 in vitro in a panel of breast cancer cell lines including triple negative and BRCA1 mutant cell lines demonstrated potent inhibition of cell proliferation with IC50s&amp;lt;100nM. The anti-proliferative effects were more pronounced when cells were cultured in media containing delipidated serum. Daily oral dosing of ND-646 at 25 mg/kg BID, 50 mg/kg QD, and 50 mg/kg BID in mice bearing orthotopic triple negative MDA-MB-468 breast cancer xenografts led to tumor growth inhibition of 60-70% that correlated with compound exposure and target engagement in the tumor. Analysis of ND-646 treated tumors demonstrated disruption of tumor tissue architecture and induction of apoptosis and necrosis suggesting a direct effect on cell survival. These results provide further evidence that de novo lipogenesis is an important mediator of breast cancer cell growth and survival, and that selective inhibition of ACC is a viable therapeutic strategy for treatment of breast cancer. Citation Format: Jennifer L. Rocnik, Wenyan Miao, Geraldine Harriman, Jeremy Greenwood, Sathesh Bhat, H. James Harwood, Rosana Kapeller, William F. Westlin. Modulation of lipid metabolism through inhibition of acetyl-CoA carboxylase with ND-646 leads to potent inhibition of breast cancer cell growth in vitro and in vivo. [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 1048.
Cine CT demonstration of nonfixed upper airway obstruction
Authors: S. R. Ell, H. Jolles, J. R. Galvin
Journal: Journal of Clinical Investigation (1986)

AJR 146:669-677, April 1986 0361 -803x/86/1 464-0669 © American Roentgen Ray Society Cine CT, with its very rapid imaging capabilities, was used to evaluate eight adult patients suspected of nonfixed upper airway obstruction. A method was developed for such imaging, which provides 10 images at each of 12 contiguous levels, extending from the soft palate through the extrathoracic trachea. These give a dynamic view of the airway during at least one full respiratory cycle and take about 6 sec to obtain. Results were compared with similar studies in 10 normal volunteers. Seven of the patients showed intermittent obstruction on cine CT, while the eighth wasjudged normal. All results agreed with subsequentfurther investigations or confirmed clinical diagnoses. The pathology demonstrated included chondromalacia, laryngeal spasm, and polychondritis. Four patients were evaluated for sleep apnea. All showed dynamic abnormalities of the airway, although they were studied awake and asymptomatic, during normal quiet respiration. All were subsequently shown to have severe sleep apnea. We conclude that cine CT has the potential to provide information quickly and noninvasively on upper airway dynamics and has certain definite advantages over conventional studies.
Abstract 3627: Automated, purification-free, Ion AmpliSeq™ library preparation from FFPE samples using the Ion Torrent™ Ion Chef™ System
Authors: Tanya Biorac, Michael Allen, Francis B. Peters, Cristina Van Loy, Kate Rhodes, Mark Andersen
Journal: Cancer Research (2016)

Abstract The ability to produce high quality libraries from FFPE samples is ever more important for next-generation sequencing. Quick turnaround time from sample to answer and simple protocols are critical components for this process. The Ion Chef and Ion AmpliSeq Kit for Chef DL8 is an automated system that has proven to reliably generate quality libraries from purified high molecular weight genomic DNA, in addition to formalin-fixed paraffin embedded (FFPE) DNA samples. We have further developed a simple and robust protocol for preparing DNA libraries from FFPE samples with no nucleic acid purification required. Our protocol is compatible with all Ion AmpliSeq panels and generates eight balanced libraries on the Ion Chef Instrument in under 8 hours, with less than 1 hour hands-on time. We observed equivalent or better sequencing performance using this method compared to a 16-hour manual FFPE DNA extraction protocol. This method has shown to work with low, medium, and high input FFPE samples from different tissue types on a single run. We evaluated a variety of FFPE samples using 1 or 2 pool Ion AmpliSeq DNA research panels containing assays designed to known oncogenes. We were able to generate and successfully sequence DNA libraries from a single FFPE slice as small as 2 mm X 2 mm. Minimal sample handling is an advantage for the NGS platform with this robust protocol. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Tanya Biorac, Michael Allen, Francis B. Peters, Cristina Van Loy, Kate Rhodes, Mark Andersen. Automated, purification-free, Ion AmpliSeq™ library preparation from FFPE samples using the Ion Torrent™ Ion Chef™ System. [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 3627.
Abstract 2860: Loss of expression of the metastasis suppressor CREB3L1 is associated with high-grade metastatic breast cancer and poorer prognosis
Authors: Paul Mellor, Alison Ward, Deborah Anderson
Journal: Cancer Research (2016)

Abstract The unfolded protein response (UPR) is required for proper protein folding in the endoplasmic reticulum under conditions of stress such as those encountered in the tumor microenvironment. Recently, a number of studies have suggested a role for the unfolded protein response in the development of cancer, more specifically in regulating the balance between cell death, dormancy and the growth of cancer cells in the tumor microenvironment. This study examined the role of CREB3L1 (cAMP-responsive element-binding protein 3-like protein 1), a member of the UPR, in breast cancer development and metastasis. Initial experiments identified the loss of CREB3L1 expression in metastatic breast cancer cell lines compared to low- or non-metastatic cell lines. When metastatic cells were transfected with CREB3L1 they demonstrated reduced invasion and migration in vitro, as well as a significantly decreased ability to survive under non-adherent or hypoxic conditions. Interestingly, in an in vivo rat mammary tumor model, CREB3L1 expressing cells not only failed to form metastases compared to CREB3L1 null cells but regression of the primary tumors was seen in 70% of the animals as a result of impaired angiogenesis. Microarray and ChIP on Chip analyses identified changes in the expression of many genes involved in cancer development and metastasis, including a decrease in those involved in angiogenesis. To determine if these findings translated to human breast cancer, real-time PCR analysis of CREB3L1 expression in human breast cancer tissues of differing grade (n = 213) was performed. Expression of CREB3L1 was elevated in low and medium grade tissue but substantially reduced in high grade tissue, compared to normal. Analysis of the on-line TCGA database of breast cancer samples identified a strong inverse relationship between CREB3L1 gene methylation and the loss of CREB3L1 mRNA expression. Low expression of CREB3L1 was associated with a poorer prognosis with a shorter relapse-free survival for luminal A and triple negative breast cancer patients. These data suggest that CREB3L1 plays an important role in suppressing tumorgenesis and loss of expression is required for the development of a metastatic phenotype. In addition CREB3L1 expression may be a useful marker for determining patient prognosis. Citation Format: Paul Mellor, Alison Ward, Deborah Anderson. Loss of expression of the metastasis suppressor CREB3L1 is associated with high-grade metastatic breast cancer and poorer prognosis. [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 2860.
High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis C associated cirrhosis
Authors: Helder Cardoso, Ana Maria Vale, Susana Rodrigues, Regina Gonçalves, Andreia Albuquerque, Pedro Pereira, Susana Lopes, Marco Silva, Patrícia Andrade, Rui Morais, Rosa Coelho, Guilherme Macedo
Journal: Journal of Hepatology (2016)
Outcome of Younger Adults with Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse: A Graall Study
Authors: Alexandre Desjonqueres, Patrice Chevallier, Xavier Thomas, Françoise Huguet, Thibault Leguay, Marc Bernard, Jacques-Olivier Bay, Emmanuelle Tavernier, Aude Charbonnier, Françoise Isnard, Mathilde Hunault, Pascal Turlure, Marc Renaud, Jean-Noel M. Bastie, Chantal Himberlin, Stephane Lepretre, Bruno Lioure, Véronique Lhéritier, Vahid Asnafi, Kheira Beldjord, Marina Lafage, Norbert Ifrah, Herve Dombret
Journal: Blood (2014)
Imaging synaptic density in the living human brain
Authors: Sjoerd J. Finnema, Nabeel B. Nabulsi, Tore Eid, Kamil Detyniecki, Shu-fei Lin, Ming-Kai Chen, Roni Dhaher, David Matuskey, Evan Baum, Daniel Holden, Dennis D. Spencer, Joël Mercier, Jonas Hannestad, Yiyun Huang, Richard E. Carson
Journal: Science Translational Medicine (2016)

Synaptic density in the living human brain was measured with positron emission tomography and a synaptic vesicle glycoprotein 2A tracer.
Abstract 608: Comprehensive drug testing of patient-derived conditionally reprogrammed cells from castration-resistant prostate cancer
Authors: Khalid Saeed, Vesa Rahkama, Samuli Eldfors, Dmitrii Bychkov, John Patrick Mpindi, Bhagwan Yadav, Tero Aittokallio, Peter Horvath, Donna Peehl, Lassi Paavolainen, Caroline Heckman, Krister Wennerberg, Tuomas Mirtti, Antti Rannikko, Olli Kallioniemia, Päivi Östling, Taija af Hällström
Journal: Cancer Research (2016)

Abstract Culture of human prostate cancer (PCa) progenitor cells would facilitate the discovery and testing of new, potentially curative therapies for PCa. Here, we established and characterized patient-derived conditionally reprogrammed cells (CRCs) from seven patients to determine their biological properties (genomic, transcriptomic, protein expression) and to apply these cells to test efficacies of 306 emerging and clinically approved drugs. The patient samples came from both primary prostate cancer as well as from advanced Castration-Resistant Prostate Cancer (CRPC). Patients with primary prostate cancer generated six benign CRC cultures which all had an androgen receptor (AR)-negative, basal/transit-amplifying phenotype with few CNAs. In 3D cell culture, these cells could re-express AR. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Bcl-2 family inhibitor navitoclax emerged as the most potent cancer-specific drug for the CRCs from CRPC patient. Other drug efficacies observed included taxanes, mepacrine and retinoids, thus covering both existing (and clinically validated) as well as new drug efficacies. In conclusion, comprehensive cancer-pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently tested in clinical trials of CRPC. Citation Format: Khalid Saeed, Vesa Rahkama, Samuli Eldfors, Dmitrii Bychkov, John Patrick Mpindi, Bhagwan Yadav, Tero Aittokallio, Peter Horvath, Donna Peehl, Lassi Paavolainen, Caroline Heckman, Krister Wennerberg, Tuomas Mirtti, Antti Rannikko, Olli Kallioniemia, Päivi Östling, Taija af Hällström. Comprehensive drug testing of patient-derived conditionally reprogrammed cells from castration-resistant 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 608.
Abstract 3564: MUC13 protects colorectal cancer cells from death by activating the NF-κb pathway and is a potential therapeutic target
Authors: Yong H. Sheng, Yaowu He, sumaira Z. hasnain, Ran Wang, Hui Tong, Daniel T. Clarke, Rohan Lourie, Iulia Oancea, kuanyau wong, John W. Lumley, Timothy H. Florin, Philip Sutton, John. D. Hooper, Nigel A. Mcmillan, Michael A. Mcguckin
Journal: Cancer Research (2016)

Abstract MUC13 is a transmembrane mucin glycoprotein that is overexpressed by many cancers, although its functions are not fully understood. NF-κB is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently up-regulating BCL-XL. MUC13 promoted TNF-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NEMO. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signalling in response to both TNF and DNA damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to death in response to cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers. Citation Format: Yong H. Sheng, Yaowu He, sumaira Z. hasnain, Ran Wang, Hui Tong, Daniel T. Clarke, Rohan Lourie, Iulia Oancea, kuanyau wong, John W. Lumley, Timothy H. Florin, Philip Sutton, John. D. Hooper, Nigel A. Mcmillan, Michael A. Mcguckin. MUC13 protects colorectal cancer cells from death by activating the NF-κb pathway and is a potential therapeutic target. [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 3564.
P135 Physical activity profile of patients with COPD during an exercise class: what are patients actually doing early in the rehabilitation course?: Abstract P135 Table 1
Authors: T Maheswaran, L Houchen-Wolloff, SJ Singh
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Pulmonary rehabilitation (PR) is recommended by the British Thoracic Society for patients that suffer from COPD; it is typically delivered in supervised sessions. Daily physical activity (PA) is often recorded as an outcome following PR, with variable results. National guidelines recommend that older adults should accumulate 150 min of moderate intensity activity in bouts of 10 min or more. We wanted to objectively measure the amount and intensity of PA, which patients actually accumulate during 1 PR session. This is the first study to profile PA during a PR exercise class in this way and could be useful for home training and general PA advice. <h3>Methods</h3> We conducted a prospective study on patients diagnosed with COPD that were enrolled for PR at Glenfield Hospital, Leicester. 12 PR sessions include walking [85% speed derived from the incremental shuttle walk test (ISWT)], leg/arm bike, and resistance training. We placed Sense-Wear™ monitors (SWM) on the patients’ arm during session 2 only. Analysis took place on Innerview™ computer software. <h3>Results</h3> The patient cohort consisted of 20 patients: 60% female, mean age of 70.1 years (SD – 8.3 years), BMI 28.6 (SD 7.9), FEV<sub>1</sub>/FVC ratio 60.8 (SD 17.3). 90% of the patients were either smokers or ex-smokers. The baseline ISWT of the group was 199.5 (SD 145.0) metres. Table 1 shows that in our cohort, patients were exercising in the 0–1.5 METs range for 52% of the time (sedentary activity), 1.5–3 METs – 31% of the time (light activity) and for 17% of the time, they were exercising above 3 METs (moderate activity). <h3>Conclusion</h3> The results highlight that, early in the PR programme COPD patients were not achieving 10 min of moderate intensity activity during 1 PR session, as recommended in national guidance. However, documented inaccuracies of the SWM, for instance at slow speeds of walking and when the arm is fixed may account for these results. Future work should aim to discover if the time spent above 3 METS increases later in the programme. In addition, we could use the PA profile of each patient to tailor home and class training progression.
Abstract 3732: Combined targeting of NOXA and GSTpi effectively kills mantle cell lymphoma cells
Authors: Markus Kleih, Simon Heine, Michael Dengler, Lea Schaaf, Elisabeth Hoering, Heike Horn, German Ott, Walter E. Aulitzky, Heiko van der Kuip
Journal: Cancer Research (2016)

Abstract Mantle cell lymphoma (MCL) is clinically characterized by an aggressive course and only transient response to chemotherapy. Therefore, new treatment strategies for this malignancy are warranted. The genetic hallmark of MCL is the t(11;14)(q13;q32) translocation leading to deregulated expression of cyclin D1. It has been reported recently that cyclin D1 overexpression in MCL is associated with constitutively high levels of GSTP1 and PMAIP1 transcripts, coding for the glutathion S-transferase pi (GSTpi) and for the proapoptotic protein NOXA, respectively. Whereas GSTpi protein is stably expressed, NOXA half-life turned out to be extremely short in this B cell lymphoma leading to constitutively low levels of this BH3-only protein in these cells. We asked if this MCL typical phenotype can be utilized for a selective treatment by stabilizing NOXA protein and concurrent inhibition of GSTpi activity. By screening different compounds known to stabilize NOXA protein and GSTpi inhibitors we found that combination of the fatty acid synthase (FASN) inhibitor Cerulenin together with Ezatiostat or Ethacrynic Acid is not only effective but also selective for MCL cells. Cell death induced by lethal doses of Cerulenin was dependent on Cyclin D1 since siRNA-mediated knockdown of Cyclin D1 partially rescued cells from apoptosis. Combinatory treatment of cells with sub-lethal doses of Cerulenin together with Ezatiostat/Ethacrynic Acid had no effect on viability of fibroblasts from normal donors but effectively killed both MCL cell lines as well as primary cells from MCL patients. Importantly, Cerulenin-mediated NOXA accumulation was significantly further elevated upon combination with GSTpi inhibitors and associated with a concomitant induction of reactive oxygen species (ROS) levels. Cell death was dependent on both NOXA and ROS since either inhibition of ROS by GSH or Catalase or siRNA-mediated knockdown of NOXA was sufficient to almost completely rescue cells from Cerulenin/GSTpi inhibitor induced apoptosis. In conclusion we demonstrate that combined pharmacological inhibition of GSTpi activity and stabilization of NOXA protein via inhibition of fatty acid synthase might be an effective strategy to selectively kill MCL cells and offer novel treatment options. Citation Format: Markus Kleih, Simon Heine, Michael Dengler, Lea Schaaf, Elisabeth Hoering, Heike Horn, German Ott, Walter E. Aulitzky, Heiko van der Kuip. Combined targeting of NOXA and GSTpi effectively kills mantle cell lymphoma 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 3732.
<i>FUT2</i>genotype influences lung function, exacerbation frequency and airway microbiota in non-CF bronchiectasis
Authors: Steven L Taylor, Richard J Woodman, Alice CH Chen, Lucy D Burr, David L Gordon, Michael A McGuckin, Steve Wesselingh, Geraint B Rogers
Journal: Thorax (2016)

<h3>Objective</h3> To assess whether <i>FUT2</i> (<i>secretor</i>) genotype affects disease severity and airway infection in patients with non-cystic fibrosis bronchiectasis. <h3>Participants</h3> Induced sputum samples were obtained from 112 adult patients with high-resolution CT scan-proven bronchiectasis and at least two exacerbations in the previous year, as part of an unrelated randomised control trial. <h3>Outcome measures</h3> Presence of null <i>FUT2</i> polymorphisms were determined by gene sequencing and verified by endobronchial biopsy histochemical staining. Outcome measures were FEV<sub>1</sub>% predicted, exacerbation frequency, and bacterial, fungal and viral components of the microbiota (measured by culture independent approaches). <h3>Results</h3> Patients were grouped by <i>FUT2</i> loss-of-function genotype; categorised as non-secretors (n=27, <i>sese</i>), heterozygous secretors (n=54, <i>Sese</i>) or homozygous secretors (n=31, <i>SeSe</i>). FEV<sub>1</sub>% was significantly lower in <i>SeSe</i> patients compared with <i>sese</i> patients (mean 61.6 (SD 20.0) vs 74.5 (18.0); p=0.023). Exacerbation frequency was significantly higher in <i>SeSe</i> (mean count 5.77) compared with <i>sese</i> (4.07; p=0.004) and <i>Sese</i> (4.63; p=0.026) genotypes. The time until first exacerbation was significantly shorter in <i>SeSe</i> compared with <i>Sese</i> (HR=0.571 (95% CI 0.343 to 0.950); p=0.031), with a similar trend for <i>sese</i> patients (HR=0.577 (0.311 to 1.07); p=0.081). <i>sese</i> had a significantly reduced frequency of <i>Pseudomonas aeruginosa</i>-dominated airway infection (8.7%) compared with <i>Sese</i> (31%; p=0.042) and <i>SeSe</i> (36%; p=0.035). In contrast, fungal, viral and non-dominant bacterial components of the microbiome were not significantly different between <i>FUT2</i> genotypes. <h3>Conclusions</h3> <i>FUT2</i> genotype in patients with non-cystic fibrosis bronchiectasis was significantly associated with disease outcomes, with homozygous secretors exhibiting lower lung function, higher exacerbation number and a higher frequency of <i>P. aeruginosa</i>-dominated infection. <h3>Trial registration number</h3> ACTRN12609000578202 (anzctr.org.au); Pre-results.