tbuckley/cabot-search huggingface dataset:
M7 Designing around placebo inhaler device concerns and improving asthma healthcare professional patient training
Authors: MJ Sanders, R Bruin
Journal: Thorax (2016)

<h3>Introduction</h3> Effective asthma control with drug therapy delivered via pressurised metered dose inhalers (pMDIs) is critically dependent on good inhaler technique. Healthcare professionals (HCPs) dedicate significant time and resources to patient education and review sessions, which tend to focus on the co-ordination of pMDI actuation with the slow inspiratory breath. Tools exist to facilitate this experience: dummy pMDIs, add-on devices which whistle at the ideal inspiratory flow rate and the highly valued but difficult-to-obtain placebo pMDIs. The latter currently offer the closest real-life training experience but are hampered by the multiple-use concerns of cross-infection (or confident decontamination), HCP-only demonstration, and unnecessary exposure to fluorocarbon propellants. The alternative of training with the active pMDI raises the issues of overdosing and drug wastage. <h3>Methods</h3> Our self-imposed project brief was to design an improved low-cost solution to the placebo/drug pMDI training conundrum which included patient participation as an absolute, the ability of the HCP to visually assess technique, avoidance of contamination, and compatibility with different actuator formats; and specifically excluded, for example, validation and implementation of new decontamination techniques. <h3>Results</h3> The solution is an add-on device, confirmed to fit all UK active and placebo pMDIs. The device (Figure 1, Flo-Checkä) is inserted into the pMDI actuator mouthpiece orifice and completely occludes the aerosol path. The lip-guard feature prevents mouth-contact contamination of the actuator and, when the patient inhales, inspiratory air is drawn in via side vents engineered to mimic the general resistance of a pMDI. <h3>Conclusions</h3> A survey of manufacturer-supplied respiratory support devices in relation to all UK inhaled products (London Medicines Evaluation Network, 2013) revealed an almost universal lack of product specific devices with the exception of the Accuhalerâ (Glaxo Group Limited) and Symbicortâ (AstraZeneca AB) training whistles; neither of which addresses the issues raised above. Several specific placebo pMDIs are available but the pharmaceutical industry is cognizant of fluorocarbon use justification, the danger of misinterpretation as an active product, and manufacturing a low volume high unit-cost product. It is hoped that developments such as the Flo-Check address some of the issues: for manufacturer, patient and HCP.
Prevalence of the Activating JAK2 Tyrosine Kinase Mutation V617F in the Budd-Chiari Syndrome.
Authors: Raj K. Patel, Nicholas Lea, Michael A. Heneghan, Nigel Westwood, Dragana Milojkovic, Kumar Thanigaikumar, Deborah Yallop, Roopen Arya, Antonio Pagliuca, Joop Gaken, Nigel A. Heaton, Ghulam J. Mufti
Journal: Blood (2005)
Sensitizing Leukemic Cells to NF-κB Inhibitor Treatment by Repressing TNFα-Mediated, NF-κB-Independent Survival Signaling
Authors: Andrew Volk, Yechen Xiao, Junping Xin, Dewen You, Rachel Schmidt, Shubin Zhang, Wei Wei, Peter Breslin, Sucha Nand, Jiwang Zhang
Journal: Blood (2012)
Telomere Length and Telomerase Complex Mutations in Pediatric Acute Myeloid Leukemia
Authors: Anna M. Aalbers, Rodrigo T. Calado, Neal S. Young, Christian M. Zwaan, Colin O. Wu, Sachiko Kajigaya, Eva A. Coenen, André Baruchel, Karin Geleijns, Valerie de Haas, Gertjan J.L. Kaspers, Taco W. Kuijpers, Dirk Reinhardt, Jan Trka, Martin Zimmermann, Rob Pieters, Vincent H.J. van der Velden, Marry M. van den Heuvel-Eibrink
Journal: Blood (2012)
Abstract 467: Oxidized lipids contribute to the suppression function of myeloid derived suppressor cells in cancer
Authors: Filippo Veglia, Vladimir Tyurin, Valerian Kagan, Dmitry Gabrilovich
Journal: Cancer Research (2015)

Abstract Immune evasion is an emerging hallmark of cancer progression. It is established that the defects in the function of antigen presenting cells and the accumulation of myeloid derived suppressive cells (MDSCs) are critical drivers of tumor mediated immune evasion. MDSCs represent a heterogeneous population of immature and pathologically activated myeloid cells that are expanded in many cancers and suppress immune responses by several defined mechanisms. Our recent findings indicate that the massive accumulation of oxidized lipids in dendritic cells (DCs) resulted in profound defects in their ability to mount antitumor responses. In this study we observed that MDSCs from tumor bearing mice and from cancer patients have higher amount of lipids than their counterpart in tumor free mice and healthy donors, respectively. The content of lipids in MDSC was even much higher in MDSCs infiltrating the tumor, and the accumulation of lipids in MDSC seems be caused by the uptake of extracellular lipids. MDSCs with a highest content of lipids showed a stronger ability to suppress antigen specific CD8 T cell responses than MDSCs with a normal content of lipids. By using mass-spectrometry we identified different oxidized species in lipids accumulated in MDSC from both tumor bearing mice and patients with cancer. Myeloperoxidase (MPO) and reactive oxygen species (ROS) were responsible for the oxidation of lipids in MDSCs. Lack of MPO or ROS in MDSC almost completely abrogated the oxidation of lipids in these cells. Furthermore the reduced amount of oxidized lipids in MDSC from MPO KO mice or following the pharmacological inhibition of their oxidative machinery resulted in a profound defect in MDSC suppressive activity. In line with these findings, unsaturated fatty acids, highly susceptible to oxidation, favored the expansion of highly suppressive MDSC from hematopoietic progenitors in vitro, as oppose to non-oxidizable saturated fatty acids. Together, our data suggest that MDSCs have increased ability to pick up lipids from the microenvironment and to oxidize them via their potent oxidative machinery. In turn oxygenated lipids contribute to the suppressive activity of MDSC. The regulation of the oxidation of lipids in MDSC could be an attractive therapeutic strategy in cancer. Citation Format: Filippo Veglia, Vladimir Tyurin, Valerian Kagan, Dmitry Gabrilovich. Oxidized lipids contribute to the suppression function of myeloid derived suppressor cells in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 467. doi:10.1158/1538-7445.AM2015-467
BILATERAL INTERNAL MAMMARY ARTERY IMPLANTATION
Authors: Okio Teramoto, Iwao Fukuta, Shigeharu Takenaka, Yoshihiro Asai, Hidetoshi Kurahashi, Tetsuya Tajika, Mitsuya Murase, Minoru Tanaka, Koji Tamoto, Tomoyoshi Ishihara, Hiromichi Tsuchioka, Toshio Abe, Yotaro Iyomasa, Itsuro Fukukei
Journal: Circulation (1972)

556The feasiblity of operation on a patient with widespread coronary artery disease was described. The patient in this report was failing in spite of competent medical therapy and was considered from following of ECG findings as a progressive cornary artery disease. His obstructive disease was rather severe and the arteriographic findings clearly indicated the widespread diffused occlusive disease of the left coronary artery. Bilateral internal mammary artery implantation was performed with a median strenotomy. During the period of between the postoperative third and tenth months, the patient had markedly symptomatic improvement and his anginal attacks were gradually disappeared. ECG findings in the sixth month after operation revealed significant improvement of coronary insufficiency. Cineangiographic evaluation per-formed 10 months postoperatively revealed both implanted internal mammary arteries to be patent, and demonstrated new anastomotic channels between the implants and diseased coronary arteries. The case reported clearly demonstrates that bilateral internal mammary artery implantation can contribute large quantities of arterial blood to the coronary arterial system of a patient with widespread diffused coronary artery disease.
Abstract 4980: Rational design of combination therapies and block of acquired targeted drug resistance
Authors: Hadas Reuveni, Lana Kuperschmidt, Shani Carmi, Neta Moskovitz, Salomon Stemmer, Izhak Haviv
Journal: Cancer Research (2015)

Abstract Recent successes of targeted drugs on end stage cancer patients highlight the value of mutation-based biomarkers with high positive predictive value for drug response predictions. However, the impact of these drugs is often temporary, and the patients progress to acquired resistance. A common mechanism of drug evasion involves feedback mechanisms that increase expression or phosphorylation-driven activation of an alternative oncogenic pathway. The objective of this work was to set up a streamlined methodology for pre-clinical assessment of the novel drug for refractory cancer targeting, with specific focus of personalized medicine, mediated by sequencing, and seek combination therapies that would block the spontaneous drug evasion. We explored the efficacy of the combination approach on a panel of cancer patient derived xenografts in mice, using tumor size, or metabolic imaging as an end point. Each cancer case was subject to target somatic mutation screening, which resulted in a targeted drug recommendation, and then, mouse groups were treated either with sequeincing-based therapy, or with combination of these therapies with blockers of the suspected evasion mechanisms. As a blocker of the evasion mechanism and epithelial to mesenchymal transition, we characterized the utility of a molecule that leads to the destruction of IRS1/2 of the IGF1R pathway. IRS1/2 are altered during EMT and drug resistance, thus blocking them could block drug resistance, and found multiple scenarios, where the combination of this blockage with currently used targeted drugs, such as Erlotinib, Zelboraf, and Gleevec, all increase the attenuation of the cancer growth and progression. Addition of the IRS1/2 destruction to Erlotinib and Zelboraf resistant H&amp;N and melanoma cancers, respectively, lead to regression of the recurrent tumor mass. This combination therapy was further characterized by shRNA-negative screens, and kinome activity profiling, to assess further drug treatments that could be added, and in search for biomarkers that would identify patients likely to respond to the therapeutic combinations, We believe blocking the IGF1R in combination with drugs that inhibit the MAPK and tyrosine kinase receptor pathways may increase the progression free survival and expand the responding population within an array of cancer types, many of which are currently refractory to chemotherapy. Citation Format: Hadas Reuveni, Lana Kuperschmidt, Shani Carmi, Neta Moskovitz, Salomon Stemmer, Izhak Haviv. Rational design of combination therapies and block of acquired targeted drug resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4980. doi:10.1158/1538-7445.AM2015-4980
Phase I trial of gene-mediated cytotoxic immunotherapy in combination with chemoradiation for locally advanced pancreatic cancer.
Authors: M. Bloomston, C. Marsh, J. Walker, W. Coyle, H. Marx, S. Tahiri, C. Moran Cruz, L. K. Aguilar, E. Aguilar-Cordova, V. M. Chung
Journal: Journal of Clinical Oncology (2011)

195 Background: More than 80% of patients with pancreatic cancer present with locally advanced or metastatic disease and have a median survival of only 6 months. Immunotherapy approaches may improve outcomes. Gene Mediated Cytotoxic Immunotherapy (GMCI) is an approach that generates a systemic anti-tumor vaccine effect through intra-tumoral delivery of an adenoviral vector expressing the HSV-thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug and synergy with chemoradiation. The mechanisms of action involve tumor cytotoxicity, activation of antigen presenting cells and stimulation of systemic anti-tumor T-cell immunity. Safety with potential efficacy has been demonstrated in multiple clinical studies. This is the first application of GMCI in pancreatic cancer. Methods: This study evaluated 4 dose levels of AdV-tk (3x10 10 to 1x10 12 vector particles) injected into locally advanced tumors via EUS or CT-guidance before and during week 3 of standard 5-FU-chemoradiation. Valacyclovir (Valtrex, GSK) prodrug was given for 14 days after each of 2 AdV-tk injections. Results: The study completed accrual with 13 patients enrolled and 12 completing therapy with 3 at each of the 4 dose levels. One patient refused further participation during course 1 after recovering from azotemia. Median age was 64 years (range 55-81) and median baseline CA19-9 was 1634 U/ml. No dose limiting toxicities and no injection related complications occurred. Possibly related grade 3-4 toxicities, all of which were transient, included dehydration, azotemia and worsening elevation of bilirubin and AST. Kaplan-Meier estimated median survival is 12.2 months with 6 patients still alive at 8-20 months. Two patients achieved a partial response by RECIST criteria. One occurred in week 6 despite discontinuing 5-FU/radiation during week 1. The other had gradual decrease of a 7 cm tumor over 11 months. Serum CA19-9 levels decreased in 8/8 evaluable patients by 32-91% at 3 months after treatment initiation. Conclusions: AdV-tk can be safely injected into pancreatic tumors and combined with standard chemoradiation. Early results are highly encouraging and justify further evaluation in a phase II study. [Table: see text]
533. Genomic Excision of PiggyBac Transposon Cassettes by Lentiviral Protein Transduction of GagPol-Fused, Excision-Only PiggyBac Transposase
Authors: Kristian A. Skipper, Sofie Andersen, Rasmus O. Bak, Yujia Cai, Jacob G. Mikkelsen
Journal: Molecular Therapy (2016)

The PiggyBac (PB) transposon system is a potent nonviral gene delivery tool with relevance in both gene therapy and cell reprogramming for production of induced pluripotent stem cells (iPSCs). Moreover, by taking advantage of the ability of the PB transposase to excise transposon-embedded gene cassettes from the genome without leaving footprints, the PB system is unique in facilitating seamless genome editing. The need for intracellular production of the transposase, however, raises concerns related to delivery and to cytotoxicity caused by sustained transposase expression and insertional mutagenesis. Furthermore, transposon re-integration may decrease the overall efficiency of the PB-mediated excision as well as increasing the risk of adverse secondary insertions. Based on our previous work, we present a new approach for lentivirus-based delivery of PB transposase. By fusing the hyperactive PB transposase, hyPBase, to the C-terminus of the GagPol polyprotein, we show robust incorporation and subsequent release of the transposase in matured lentiviral particles. Furthermore, in an effort to limit transposon re-integration, we engineered a hyPBase variant carrying three missense mutations. This novel hyPBase variant, hyPBaseExc+/Int−, demonstrates integration levels very close to background levels, thus limiting the risk of reintegration. Notably, the ability of hyPBaseExc+/Int− to excise transposons from plasmid-borne as well as from genomically integrated PB transposon cassettes is increased up to 6.3-fold relative to the original hyPBase transposase. By fusing the hyPBaseExc+/Int− to the C-terminus of GagPol, transposase protein can be efficiently delivered to cells by lentiviral protein transduction and, in our model system, performs seamless genomic excision of PB transposon cassettes in a copy number and dose-dependent manner, resulting in excision in up to 23.6% of virus-treated cells. Using a transposon containing the puro-deltaTK transgene cassette, we furthermore show that cells with successful excision can be enriched 17-fold by negative selection with FIAU. We believe that protein transduction of hyPBaseExc+/Int− may increase the applicability and safety of transposase-directed genomic excision in iPSCs and in hard-to-transfect cell types including hematopoietic cells.
Abstract 5024: Implications of MAPK pathway inhibition on monocytes and tumor-associated macrophages in melanoma
Authors: Gabriela Gremel, Maria Romina Girotti, Amaya Viros, Garry Ashton, Helen Bradley, Elena Galvani, Rebecca Lee, Alberto Fusi, Paul Lorigan, Richard Marais
Journal: Cancer Research (2015)

Abstract Plasticity in T-cell populations during response and onset of resistance to targeted therapy has been well documented. More recently, macrophage-derived tumor necrosis factor has been described to drive resistance to MAPK pathway inhibition, yet little is known on the adaptation of tumor-associated macrophage populations to treatment and disease progression in human melanoma. To test for alterations in macrophage abundance following resistance to MAPK pathway inhibition, we applied a fluorescence-based co-staining strategy on melanoma specimens, representing tissue collected from patients before treatment and at relapse. In addition, we established in vitro co-culture systems to study the paracrine effects of melanoma cells on various aspects of monocyte differentiation and macrophage activation in the background of MAPK inhibition and resistance. Resistance to targeted therapy was found to be associated with an increase in the number of tumor-resident macrophages. In vitro co-culture of melanoma cell lines with monocytes isolated from the peripheral blood of healthy donors or with CSF1-differentiated macrophages in the presence or absence of MAPK inhibition led to profound changes in monocyte/macrophage marker expression, indicating a direct interplay between the two cell populations upon MAPK pathway inhibition. Our data show that macrophages play an integral role in the changing immune-microenvironment during the course of MAPK pathway inhibition. Elucidation of mechanisms driving these processes will result in strategies to optimize treatment combinations and consecutive treatment outcomes for melanoma patients. Note: This abstract was not presented at the meeting. Citation Format: Gabriela Gremel, Maria Romina Girotti, Amaya Viros, Garry Ashton, Helen Bradley, Elena Galvani, Rebecca Lee, Alberto Fusi, Paul Lorigan, Richard Marais. Implications of MAPK pathway inhibition on monocytes and tumor-associated macrophages in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5024. doi:10.1158/1538-7445.AM2015-5024
P37 Preliminary normal values for structured light plethysmography tidal breathing parameters and age and gender differences
Authors: S Fakhr, L O’Reilly, R Wilson, B Cooper, R Iles
Journal: Thorax (2016)

<h3>Introduction</h3> This is the first report from an ongoing study to define normal values for Structured Light Plethysmography (SLP) tidal breathing parameters in adults. Structured Light Plethysmography (SLP) is a non-contact, non-invasive respiratory measurement technology that utilises the movement of thoraco-abdominal (TA) wall to measure a range of tidal breathing parameters. Various studies have been using SLP but lack of normative values can make any clinical judgement difficult. <h3>Methods</h3> :As a part of an on-going collaboration between PneumaCare Ltd. and Queen Elizabeth (QE) Hospital (Birmingham, UK), 107 healthy adult subjects between ages of 18 to 69 were measured with SLP during 4 to 5 minutes of seated tidal breathing. Parameter means and standard deviations for males and females aged 18–39 and 40–69 were calculated and gender and age related comparisons were made (t-test). <h3>Results</h3> Tables 1 summarises the normative values for males and females older and younger than 40 years. Three parameters showed age related differences and one parameter showed a gender related difference. <h3>Conclusion</h3> Preliminary normal values for SLP derived tidal breathing parameters are reported. Some gender and age related differences are apparent. It is interesting that tPTEF/tE was significantly lower in the older participants, possibly a sign of natural airway obstruction associated with age.
The 2nd Generation Proteasome Inhibitor, MLN2238: Potent Induction of Cell Death in T-Cell Lymphoma (TCL) and Hodgkin Lymphoma (HL) Cell Lines and in Two Human Lymphoma Xenograft Models.
Authors: Ravi Dashnamoorthy, Irawati Kandela, Savita Bhalla, Jasmine Galloway, Irina Zaretsky, Andrew Mazar, Andrew M. Evens
Journal: Blood (2012)
Re: Karim A. Touijer, James A. Eastham. The Sentinel Lymph Node Concept and Novel Approaches in Detecting Lymph Node Metastasis in Prostate Cancer. Eur Urol 2016;70:738–9
Authors: Rodolfo Montironi, Silvia Gasparrini, Roberta Mazzucchelli, Francesco Massari, Liang Cheng, Antonio Lopez-Beltran, Francesco Montorsi, Marina Scarpelli
Journal: European Urology (2016)
Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer: cross-over analysis from the SHIVA trial
Authors: L. Belin, M. Kamal, C. Mauborgne, C. Plancher, F. Mulot, J.-P. Delord, A. Gonçalves, C. Gavoille, C. Dubot, N. Isambert, M. Campone, O. Trédan, F. Ricci, M. Alt, D. Loirat, M.-P. Sablin, X. Paoletti, V. Servois, C. Le Tourneau
Journal: Annals of Oncology (2016)
Successful Post-Remission Therapy Using LMP1/LMP2a-Specific Cytotoxic T Lymphocytes (CTLs) in Extranodal NK/T Cell Lymphoma
Authors: Sung-Eun Lee, Hyun-Jung Sohn, Suk Kyeong Lee, Hyung Seok Moon, Jung A Hong, Seung-Eun Jung, Kyung-Sin Park, Sung-Hoon Kim, Byung-Ock Choi, Young Seon Hong, Tai-Gyu Kim, Seok-Goo Cho
Journal: Blood (2011)