tbuckley/cabot-search huggingface dataset:
Potent anticancer activity of the pan-deacetylase inhibitor panobinostat (LBH589) as a single agent in in vitro and in vivo tumor models
Authors: Wenlin Shao, Joseph Growney, Yun Feng, Ping Wang, Yan Yan-Neale, Gregory O'Connor, Paul Kwon, Yung-mae Yao, Stephen Fawell, Peter Atadja
Journal: Cancer Research (2008)

735  Panobinostat (LBH589) is a pan-deacetylase (pan-DAC) inhibitor, which exhibited potent anticancer activities in both in vitro and in vivo tumor models. Panobinostat inhibited in vitro enzyme activities of all 11 class I, II, and IV histone deacetylase (HDAC) isoforms. In cellular assays, panobinostat treatment potently induced transcriptional activation of the p21 promoter in reporter gene assays, and inhibited cell viability of a broad spectrum of cancer cell lines at nanomolar concentrations. In comparison with other deacetylase inhibitors, panobinostat displayed the most extensive and the most potent anticancer activity. Panobinostat selectively induced apoptosis in cancer cells, but not in normal human epithelial cells, fibroblasts, or peripheral blood mononuclear cells. Treatment of cancer cells with panobinostat resulted in increased acetylation levels of histones, tubulin, and HSP90, supporting its pan-inhibitory effect on all HDAC isoforms. In addition to cancer cell lines, panobinostat demonstrated single-agent anti-tumor activity in several in vivo xenograft tumor models. Intravenous administration of panobinostat (5× per week for 3 weeks) led to dose-dependent tumor growth inhibition at 5 mg/kg and 10 mg/kg, and tumor regression at a dose of 20 mg/kg in the HCT116 colon tumor xenograft model, accompanied by robust and durable acetylation of histones H3 and H4. Furthermore, good correlation was observed between panobinostat exposure and response of histone acetylation in HCT116 tumors, suggesting that panobinostat specifically inhibited deacetylases in vivo. Taken together, our data demonstrate that panobinostat is a highly potent pan-DAC inhibitor that exhibits consistent and cancer-specific cytotoxic activity in a variety of tumor models examined, and thus promises to be a highly active anticancer therapeutic agent.
Pharmacogenetic Analysis of Polymorphisms in Pharmacological Pathway of Vincristine, Doxorubicine and Dexamethasone (VAD Regimen) To Predict Response in Patients with Multiple Myeloma.
Authors: Krzysztof Jamroziak, Ewa Balcerczak, Mariusz Panczyk, Sylwester Piaskowski, Agnieszka Janus, Barbara Cebula, Marek Mirowski, Piotr Smolewski, Halina Urbanska-Rys, Piotr Cichocki, Tadeusz Robak
Journal: Blood (2005)
Comparison of the Low Toxicity Tecam Conditioning Regimen to BEAM in Patients with Lymphoma Requiring Autologous Stem Cell Transplantation
Authors: Dana Rosenberg, Erel Joffe, Uri Rozovski, Chava Perry, Ilya Kirgner, Svetlana Trestman, Odelia Gur, Freddy Aviv, Nadav Sarid, Albert Kolomansky, Lily Gepstein, Yair Herishanu, Elizabeth Naparstek
Journal: Blood (2015)
Mismatch Repair Deficiency, Microsatellite Instability, and Survival
Authors: Elizabeth C. Smyth, Andrew Wotherspoon, Clare Peckitt, David Gonzalez, Sanna Hulkki-Wilson, Zakaria Eltahir, Matteo Fassan, Massimo Rugge, Nicola Valeri, Alicia Okines, Madeleine Hewish, William Allum, Sally Stenning, Matthew Nankivell, Ruth Langley, David Cunningham
Journal: JAMA Oncology (2017)

Mismatch repair (MMR) deficiency (MMRD) and microsatellite instability (MSI) are prognostic for survival in many cancers and for resistance to fluoropyrimidines in early colon cancer. However, the effect of MMRD and MSI in curatively resected gastric cancer treated with perioperative chemotherapy is unknown.
Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML
Authors: Sanduni U. Liyanage, Rose Hurren, Veronique Voisin, Gaëlle Bridon, Xiaoming Wang, ChangJiang Xu, Neil MacLean, Thirushi P. Siriwardena, Marcela Gronda, Dana Yehudai, Shrivani Sriskanthadevan, Daina Avizonis, Aisha Shamas-Din, Mark D. Minden, Gary D. Bader, Rebecca Laposa, Aaron D. Schimmer
Journal: Blood (2017)
Pregnancy-Related Immune Adaptation Promotes the Emergence of Highly Virulent H1N1 Influenza Virus Strains in Allogenically Pregnant Mice
Authors: Géraldine Engels, Alexandra Maximiliane Hierweger, Julia Hoffmann, René Thieme, Swantje Thiele, Stephanie Bertram, Carola Dreier, Patricia Resa-Infante, Henning Jacobsen, Kristin Thiele, Malik Alawi, Daniela Indenbirken, Adam Grundhoff, Svenja Siebels, Nicole Fischer, Violeta Stojanovska, Damián Muzzio, Federico Jensen, Khalil Karimi, Hans-Willi Mittrücker, Petra Clara Arck, Gülsah Gabriel
Journal: Cell Host & Microbe (2017)
Abstract P1-10-09: Delineation of internal mammary nodal target volumes in breast cancer radiotherapy
Authors: KR Jethwa, MM Kahila, KN Hunt, LC Brown, KS Corbin, SS Park, ES Yan, JC Boughey, RW Mutter
Journal: Cancer Research (2017)

Abstract Purpose/Objectives: The optimal clinical target volume (CTV) for internal mammary node irradiation (IMNI) is uncertain in an era of increasingly conformal volume-based treatment planning for breast cancer. We mapped the location of gross internal mammary lymph node (IMN) metastases in order to identify areas at highest risk for harboring occult disease. Methods and Materials: Patients with axial imaging of IMN disease, including fluorodeoxyglucose F-18 (FDG18) positron emission tomography (PET-CT) and magnetic resonance imaging (MRI), were identified from a breast cancer registry. The IMN location was transferred by a radiation oncologist and breast radiologist onto the corresponding anatomic position on representative axial CT images of a patient in the treatment position. Distribution of lymph nodes, and their location was compared with consensus group guidelines of IMN target delineation. Results: Sixty-seven patients with 130 IMN metastases were mapped. The location was in the first three intercostal spaces in 102 of 130 (78%) nodal metastases. Eighteen of 130 (14%) IMN were located caudal to the third intercostal space, while 10 of 130 (8%) IMN were located cranial to the first intercostal space, including 3 patients with isolated IMN metastases at that location in the absence of distant disease. Of the 102 nodal metastases within the first three intercostal spaces, 54 (53%) were located within the RTOG consensus volume. Relative to the internal mammary (IM) vessels, 19 (19%) nodal metastases were located medially with a mean distance of 2.2 mm (SD 2.9 mm), while 29 (28%) were located laterally with a mean distance of 3.6 mm (SD 2.5 mm). Ninety and ninety-five percent of lymph nodes within the first three intercostal spaces would have been encompassed within a 4 mm and 6 mm medial and lateral expansion on the IM vessels, respectively. Conclusions: For women with indications for elective IMNI, a 4 mm medial and lateral expansion on the IM vessels within the first 3 intercostal spaces may be appropriate. In women with known IMN involvement, cranial extension to the confluence of the IM vein with the brachiocephalic vein +/- caudal extension to the 4th or 5th interspace with a 6 mm medial and lateral expansion may be considered, provided that normal tissue constraints are met. Citation Format: Jethwa KR, Kahila MM, Hunt KN, Brown LC, Corbin KS, Park SS, Yan ES, Boughey JC, Mutter RW. Delineation of internal mammary nodal target volumes in breast cancer radiotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-09.
Efficient Removal of Immunoglobulin Free Light Chains by Hemodialysis in Multiple Myeloma: In-Vitro and In-Vivo Studies.
Authors: Colin A. Hutchison, Paul Cockwell, Steven Reid, Katie Chandler, Graham P. Mead, John Harrison, John Hattersley, Neil D. Evans, Michael J. Chappell, Mark Cook, Hermann Goehl, Markus Storr, Arthur R. Bradwell
Journal: Blood (2006)
Intravascular hemolysis and the pathophysiology of sickle cell disease
Authors: Gregory J. Kato, Martin H. Steinberg, Mark T. Gladwin
Journal: Journal of Clinical Investigation (2017)

Hemolysis is a fundamental feature of sickle cell anemia that contributes to its pathophysiology and phenotypic variability. Decompartmentalized hemoglobin, arginase 1, asymmetric dimethylarginine, and adenine nucleotides are all products of hemolysis that promote vasomotor dysfunction, proliferative vasculopathy, and a multitude of clinical complications of pulmonary and systemic vasculopathy, including pulmonary hypertension, leg ulcers, priapism, chronic kidney disease, and large-artery ischemic stroke. Nitric oxide (NO) is inactivated by cell-free hemoglobin in a dioxygenation reaction that also oxidizes hemoglobin to methemoglobin, a non–oxygen-binding form of hemoglobin that readily loses heme. Circulating hemoglobin and heme represent erythrocytic danger-associated molecular pattern (eDAMP) molecules, which activate the innate immune system and endothelium to an inflammatory, proadhesive state that promotes sickle vaso-occlusion and acute lung injury in murine models of sickle cell disease. Intravascular hemolysis can impair NO bioavailability and cause oxidative stress, altering redox balance and amplifying physiological processes that govern blood flow, hemostasis, inflammation, and angiogenesis. These pathological responses promote regional vasoconstriction and subsequent blood vessel remodeling. Thus, intravascular hemolysis represents an intrinsic mechanism for human vascular disease that manifests clinical complications in sickle cell disease and other chronic hereditary or acquired hemolytic anemias.
Abstract PR09: Polymeric mechanical amplifiers of tumor apoptosis
Authors: Michael John Mitchell, Robert Langer
Journal: Cancer Research (2017)

Abstract Regulation of receptor-mediated phenomenon at the nanoscale in a controlled manner remains a challenge for a broad range of fields, including cell biology, medicine, and bioengineering. Fluid forces play a crucial role in receptor-mediated signaling necessary for physiological function, while materials such as nanoparticles have demonstrated potential for spatiotemporal control of cellular signaling. Here, we have developed polymeric mechanical amplifiers that tether to the cell surface and increase receptor-mediated apoptosis in the presence of physiological fluid flow. The mechanical amplifiers consist of both non-degradable and biodegradable polymer nanoparticles that are tethered to the surface of tumor cells via polyethylene glycol (PEG) linkers. Tethered nanoparticles, in the presence of fluid shear forces observed in vivo, increased the therapeutic effect of a TNF superfamily death ligand (TRAIL) on colon and prostate tumor cells by as much as 50% compared to soluble TRAIL treatment alone, while exerting negligible toxic effects on normal cells. Increasing the number of nanoparticles conjugated to the tumor cell surface enhanced TRAIL-mediated apoptosis under fluid shear exposure, while the therapeutic effect under static conditions was not altered. Our results suggest that the enhanced therapeutic response using polymeric nanoparticles is both receptor-mediated apoptosis-specific and does not affect doxorubicin efficacy. Inhibition studies indicate the response is caspase signaling-dependent, and increased tumor cell death receptor expression in the presence of shear forces is also observed. We show that targeted polymeric nanoparticles delivered to tumor cells in vivo mechanically amplified a subsequent treatment of soluble TRAIL, and reduced both circulating tumor cells in blood and overall tumor cell burden in vivo by over 90%. We conclude that surface-bound polymeric nanoparticles enhance receptor-mediated apoptosis in the presence of physiological shear forces, and represents a potentially new application for a broad range of nanotechnologies to maximize the capacity of receptor-mediated signaling and function in the presence of a ligand. This abstract is also being presented as Poster B35. Citation Format: Michael John Mitchell, Robert Langer. Polymeric mechanical amplifiers of tumor apoptosis. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR09.
PP11. RNA-SEQ ANALYSIS OF PRIMARY AND RECURRENT GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTIC STRATEGIES
Authors: Dr Combiz Khozoie, Mr Richard Perryman, Dr Fernando Abaitua, Dr Babar Vaqau, Dr Kevin O’Neill, Dr Nelofer Syed
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour. High patient mortality arising from a high propensity for tumour recurrence has driven a need to characterize the genetic changes associated with recurrent GBM. Here, we present a comprehensive landscape of transcriptome profiles of 10 primary and recurrent GBM cancers using RNA-seq, revealing extensive recurrent-specific gene expression changes and somatic mutations. Perturbation of the extracellular matrix, and enhanced ECM degradation, emerge as important changes accompanying GBM recurrence; this perturbation is multimodal and implicates diverse functions including enhanced matrix metalloproteinase (MMP) mediated ECM degradation, silencing of collagen encoding genes (e.g. COL1A1, COL1A2, COL3A1, COL6A3) or their mutation (e.g. COL7A1), and enhanced ECM degradation via dysregulation of SAPK/JNK signaling. Mutational signature analysis revealed striking enrichment of C to T transitions, accounting for 40 to 50% of all base-substitution mutations, implicating CT transition enhancing mutagenic processes in the etiology of GBM. Aberrant epigenetic regulation consistent with dysfunctional polycomb-mediated gene repression manifests in inappropriate activation of putative tumour promoter genes in recurrent tumours. Of 188 genes identified as differentially expressed in our GBM cohort, 38 genes were shared in a separate validation cohort of tumours from the TCGA GBM database. This includes seven genes (ADM, HPCAL4, SNCB, SV2B, TMEM130, H19, VSNL1) with correlations between gene expression and patient survival according to Kaplan-Meier plots generated from TCGA data. This study has highlighted new insights into GBM tumour recurrence and revealed potential novel candidates as prognostic biomarkers and rational therapeutic targets.
A positron emission tomography (PET) study to assess the degree of neurokinin-1 (NK<sub>1</sub>) receptor occupancy in the human brain after single doses of netupitant to healthy male subjects.
Authors: Giorgia Rossi, Silvia Olivari Tilola, Cecilia Rudengren
Journal: Journal of Clinical Oncology (2012)

9054 Background: Netupitant (NETU) is a highly selective neurokinin 1 (NK 1 ) receptor antagonist for the prevention of nausea and vomiting associated with emetogenic chemotherapy. In this study, PET imaging with the NK 1 receptor-binding–selective tracer 11 C-GR205171 was used to determine the levels and the duration of central NK 1 receptor occupancy (RO) achieved by therapeutic doses of NETU. Methods: This was a single dose, randomized, open-label, PET study investigating the degree of NK 1 RO in human brain after single oral doses of NETU (100, 300 or 450 mg) in 6 healthy male subjects. PET scans and blood samples for NETU determination were obtained up to 96 hrs post dose. The Patlak model was used to define the net uptake rate of 11 C-GR205171 in the brain regions of interest while the percent of NK 1 RO was calculated as the relative difference between the uptake rate at baseline and post-treatment administration. Results: NETU plasma concentrations over the 100 mg to 450 mg dose range were comparable with those obtained in previous single dose studies. A NK 1 RO of 90% or higher was achieved with all tested single oral doses in the majority of the outlined brain regions 6 hrs after dosing (corresponding to netupitant Cmax). All doses had a long duration of blockade of NK 1 receptors with the 300 mg dose showing moderate (62%) to high (94%) NK 1 RO for all investigated brain regions at 96 hrs post dose. The relationship between NETU concentration and NK 1 RO, assessed using a sigmoid Emax model, indicated that in the striatum, the reference brain area with the highest NK 1 receptor expression, a concentration of 225 μg/L of NETU corresponded to an NK 1 RO of 90%. This data suggests that a single oral dose between 100 and 300 mg NETU would be needed to reach 90% NK 1 RO levels in human brain. Conclusions: PET results demonstrate that NETU is a potent agent targeting NK 1 receptors with a high degree of occupancy for a long duration. NETU, given as single doses of 100 to 450 mg was well tolerated.
Abstract P2-01-35: A one-day protocol with activities lower than 20 MBq for the detection of sentinel lymph nodes - Experience after 150 cases
Authors: H-C Kolberg, S Afsah, U Winzer, L Akpolat-Basci, M Stephanou, C Liedtke
Journal: Cancer Research (2017)

Abstract Introduction: Common protocols for the detection of sentinel lymph nodes (SLN) in early breast cancer often include injection of the tracer one day before surgery. In order to detect enough activity on the day of surgery, the applied activity in many protocols is as high as several hundred MBq. Even in common one-day protocols the activity applied is often up to 50 MBq. We developed a one-day protocol with a mean activity lower than 20 MBq in order to reduce radiation exposure for patients and staff. Here we are presenting our experience after 150 cases. Material and methods: 150 patients with clinically and sonographically negative axilla (cN0) and no multicentricity underwent a SLN biopsy using a low-dose protocol performed on the day of surgery. After ultrasound-guided injection of the tracer (Technetium99) lymphoscintigraphy was performed in all cases. 7 minutes before the first cut 5 ml blue dye was injected in the region of the areola. Fresh-frozen sections of the SLN(s) were not performed. Results: In 149 of 150 patients (99.3%) at least one SLN could be identified by lymphoscintigraphy. The detection rate during surgery with combined tracers Technetium99 and blue dye was 100%. The mean applied activity was 17.8 MBq (9-20). A mean number of 1.3 (0-5) SLNs were identified by lymphoscintigraphy, a mean number of 1.7 (1-5) SLNs were removed during sentinel lymph node biopsy. 36 patients received a secondary axillary dissection according to the historical standard because of involved SLNs. In 11 cases (30.6%) additional involved lymph nodes were found. Conclusion: One-day protocols with an activity lower than 20 MBq are a safe alternative to two-day protocols with significantly higher radiation doses. Using Technetium99 and blue dye in a dual tracer approach, detection rates of 100% are possible in clinical routine with minimal radiation exposure for patients and staff. The number of removed lymph nodes, the rate of secondary axillary dissections and the number of cases with additional involved lymph nodes is not higher than in published trials. Citation Format: Kolberg H-C, Afsah S, Winzer U, Akpolat-Basci L, Stephanou M, Liedtke C. A one-day protocol with activities lower than 20 MBq for the detection of sentinel lymph nodes - Experience after 150 cases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-35.
OP15. ENHANCEMENT OF MYELOID DENDRITIC CELLS THROUGH MAPK P38 INHIBITION PROMOTES T CELL PROLIFERATION AND RESTORES ADAPTIVE IMMUNITY IN GBM PATIENTS
Authors: Dr Jason Adhikaree, Dr Andrew Jackson, Prof Poulam Patel
Journal: Neuro-Oncology (2017)

INTRODUCTION: Immunotherapy is an emerging backbone to oncology treatment in a number of cancers, mainly due to the advent of checkpoint blockade therapy. In Glioblastoma (GBM) immunotherapies such as peptide vaccines and laboratory generated monocyte-derived dendritic cells (moDC) are demonstrating promise in advanced stages of clinical trials. Recently however, a number of studies have highlighted the immune advantages circulating DC possess. We previously showed that the potential novel adoptive transfer of isolated circulating myeloid DC (MDC1) may be hampered in GBM patients due to reduced numbers of MDC1 and suppressed production of the key Th1-polarising cytokine IL-12. Importantly, IL-12 production by MDC1 was rescued and enhanced upon exposure to a MAPK p38 inhibitor (p38i). The increase in IL-12 with p38i was unique to MDC1s and in contrast to its effects on moDC. Here we tested the hypothesis that p38i enhances the capacity of MDC1 to promote T-cell proliferation. METHOD: Paramagnetic bead isolation kits were used to isolate circulating MDC1, CD4+ cells or peripheral blood lymphocytes (PBL) from mononuclear cells. A model of GBM:DC interaction was devised in which DC were co-cultured with tumour lysate (TL) from U87 (TL:DC ratio 50:1), or dexamethasone (Dex) 10-6M. The p38i, BIRB0796 1μM, was added to inhibit the MAPK pathway in MDC1s. The impact of GBM/Dex on DC function was determined in a mixed lymphocyte reaction (MLR) with PBL as responders. Further experiments, determined the impact of checkpoint inhibitors (Ipilimumab and Pembrolizumab) on the MLR. The MLR supernatants were analysed for IFN-γ and IL-10. RESULTS: Exposure to TL or Dex markedly inhibited the capacity of MDC1 to stimulate an MLR (p=0.001 and p<0.001 respectively). However, pre-treatment with p38i reversed this increasing proliferation above that of control cells (TL, p=0.001; DEX, p=0.021). Analysis of the supernatants of p38i-treated MDC1 stimulated PBL, showed a prominent increase in the Th1-cytokine IFN-γ. The addition of checkpoint inhibitors to TL or Dex treated MDC1 also restored T-cell proliferation. However, the greatest proliferation was observed with the combination of p38i MDC1s and checkpoint inhibitors. This combination was associated with further increases in IFN-γ secretion. CONCLUSION: MAPK p38 inhibited MDC1s stimulate an adaptive immune response greater than that of healthy MDC1s. Furthermore, this can reverse immunosuppression from Dex and TL on DCs, experienced by GBM patients. Interestingly, the combination of p38i MDC1 with checkpoint blockade inhibitors was most favourable at stimulating a lymphocyte response, postulating an advantageous immunotherapeutic strategy in patients.