tbuckley/cabot-search huggingface dataset:
Abstract 3905: Anti-tumor effect of combined irreversible electroporation and liposome-encapsulated NVP-BEZ235
Authors: Tian Li, Lucas Wang, Yang Qiao, Burapol Singhana, Marites P. Melancon
Journal: Cancer Research (2016)

Abstract Introduction Irreversible electroporation (IRE) is a technique that uses electrical pulses to cause disruption in the lipid bilayer integrity by creating nanopores. Regions that are close to the probe will have a permanent, irreversible damage to the cells, while farther away regions will subject the cell membranes to re-seal (reversible). This reversible region provides opportunity for enhanced nanoparticle uptake. In this study, we tested the efficacy of combined IRE and nanoparticle-mediated drug delivery in vitro and in vivo in a hepatocellular carcinoma model. Methods Liposome-encapsulated NVP-BEZ235 (L-BEZ) was made from hydration-sonication, followed by an optional extrusion step. Particle size was tested via dynamic light scattering. BEZ concentration was quantified by fluorescence. Cytotoxicity of IRE and its drug combinations was tested on Hep3B cells using ECM 830 (BTX Harvard Apparatus) at 1600 V/cm field strength. In vivo efficacy was studied on nude mice bearing Hep3B xenografts with single dose of IRE, or drug alone (L-BEZ or BEZ at 4 mg/kg, intratumoral injection), and its combinations. Results and Discussion Liposomes range from 100-500 nm in hydrodynamic volume. Highest loading efficiency achieved was 90% (1.8 mg/mL of BEZ). To test the release of BEZ from the liposome, solution of L-BEZ was treated with IRE and the supernatant was tested against Hep3B cells. The extract from L-BEZ had a significantly higher cytotoxicity (51%) as compared to the empty liposome (20%) with a p-value&amp;lt;0.05. This suggests that IRE can release BEZ from the liposome. The LC50 values of L-BEZ and BEZ was determined to be the same (47 ng/mL). In vitro combination treatment of L-BEZ + IRE showed higher cytotoxicity than the controls (BEZ + IRE, BEZ alone, and IRE alone). In vivo, IRE and its combinations significantly suppressed tumor growth more than non-IRE treated groups. Histology showed a median percent necrosis for L-BEZ + IRE (37%) doubled compared to IRE treatment alone (17%). Conclusion The use of minimally invasive IRE in combination with nanoparticle-mediated drug delivery treatment is a promising technique to achieve local disease control in hepatocellular carcinoma. Citation Format: Tian Li, Lucas Wang, Yang Qiao, Burapol Singhana, Marites P. Melancon. Anti-tumor effect of combined irreversible electroporation and liposome-encapsulated NVP-BEZ235. [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 3905.
Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy
Authors: Lucie Heinzerling, Patrick A. Ott, F. Stephen Hodi, Aliya N. Husain, Azadeh Tajmir-Riahi, Hussein Tawbi, Matthias Pauschinger, Thomas F. Gajewski, Evan J. Lipson, Jason J. Luke
Journal: Journal for ImmunoTherapy of Cancer (2016)

Immune-checkpoint blocking antibodies have demonstrated objective antitumor responses in multiple tumor types including melanoma, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC). In melanoma, an increase in overall survival has been demonstrated with anti-CTLA-4 and PD-1 inhibition. However, a plethora of immune-mediated adverse events has been reported with these agents. Immune-mediated cardiotoxicity induced by checkpoint inhibitors has been reported in single cases with variable presentation, including myocarditis and pericarditis. Among six clinical cancer centers with substantial experience in the administration of immune-checkpoint blocking antibodies, eight cases of immune-related cardiotoxicity after ipilimumab and/or nivolumab/pembrolizumab were identified. Diagnostic findings, treatment and follow-up are reported. A large variety of cardiotoxic events with manifestations such as heart failure, cardiomyopathy, heart block, myocardial fibrosis and myocarditis was documented. This is the largest case series to date describing cardiotoxicity of immune-checkpoint blocking antibodies. Awareness, monitoring of patients with pre-existing cardiac disorders and prompt evaluation by the treatment team is essential. Treatment including application of steroids is critical for patient safety.
RAS Pathway Mutations in Down Syndrome-Associated Acute Lymphoblastic Leukemia in Japan
Authors: Tatsuya Ito, Kiminori Terui, Isamu Hanada, Fumika Ikeda, Tsutomu Toki, Rika Kanezaki, Tomohiko Sato, Takuya Kamio, Ko Kudo, Shinya Sasaki, Yoshihiro Takahashi, Yasuhide Hayashi, Takeshi Inukai, Hiroki Hori, Etsuro Ito
Journal: Blood (2015)
Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms and fatigue in women with breast cancer starting adjuvant letrozole: The VITAL trial.
Authors: Qamar J. Khan, Bruce F. Kimler, Pavan S. Reddy, Priyanka Sharma, Jennifer R. Klemp, Carol J. Fabian
Journal: Journal of Clinical Oncology (2012)

9000 Background: Musculoskeletal (MS) pain and fatigue are common in women on adjuvant Aromatase Inhibitors (AIs) and lead to reduced compliance. Pilot studies suggest a positive impact of vit D on MS pain and disability from AIs. We conducted a bi-institutional, double blind, placebo controlled randomized trial to study the impact of 30,000 I.U of vit D3 in preventing worsening of MS pain and fatigue in women starting letrozole. Methods: Women with stage I-III breast cancer starting adjuvant AI and a 25(OH)D level of 40 ng/ml or less were eligible. Women with prior renal stones or hypercalcemia were excluded. All subjects received letrozole, plus standard dose vitD3 (600 IU) and calcium (1200 mg) daily, all provided by the study. Women were randomly assigned to 30,000 IU of oral vitD3 wkly (vitD arm) or matched placebos (PL arm) for 24 weeks. The following were assessed at baseline, 12 wks, and 24 wks (end of study): 1) 25OHD levels, 2) symptoms tools (BFI – Brief Fatigue Inventory, HAQII - Health Assessment Questionnaire II, Qualitative Joint Pain (none, mild, moderate, severe), BPI – Brief Pain Inventory) and 3) hand grip strength with a dynamometer. Results: 160 women (80/arm) were enrolled from 4/09 to 7/10. There were no differences between the two arms in demographics/tumor characteristics. Median age was 61, median BMI was 29.8 kg/m2. 43% had adjuvant chemotherapy. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12 wks and 31 at 24 wks in the PL arm and 22, 53 and 57 in vitD arm. One patient in the PL arm developed mild hypercalcemia. There were no SAEs. 147 subjects were evaluable for efficacy. 3 subjects, all in the PL arm discontinued early due to a MS adverse event. At wk 24, a higher proportion of women in PL (51%) vs vitD arm (37%) had a protocol defined MS event (worsening of joint pain, disability from joint pain or discontinuation of Letrozole due to MS symptoms) (p=0.069). A significantly higher proportion of women in PL (72%) vs vitD arm (42%) had an adverse QOL event (worsening of pain, disability or fatigue) (p=&lt;0.001). Conclusions: 30,000 IU/week of vitamin D3 is safe and results in decreased adverse QOL events from adjuvant aromatase inhibitors in women with breast cancer.
Abstract 3596: KLLN protects genomic stability by maintaining H3K9 trimethylation (H3K9me3) at the pericentric heterochromatin
Authors: Madhav Sankunny, Emily Nizialek, Farshad Niazi, Charis Eng
Journal: Cancer Research (2016)

Abstract Dysregulation in the maintenance of chromatin organization resulting in genomic instability is a major driving force for inappropriate development and carcinogenesis. Tumor suppressor genes play a critical role in this regulation through the maintenance of epigenetic marks. Our study focuses on the role of KLLN in the maintenance of pericentric H3K9 trimethylation (H3K9me3) and genomic stability. Germline hypermethylation of KLLN resulting in decreased KLLN expression has been linked to Cowden cancer-predisposition syndrome (CS) in PTEN mutation negative patients. KLLN is a tumor suppressor gene necessary for p53-mediated apoptosis. The protein mediates S-phase arrest and is known to have DNA binding ability. Here, we first used chromatin immunoprecipitation-based sequencing (ChIP-seq) to investigate regions of KLLN binding on the genome and compared it to regions of H3K9me3 enrichment. We used H3K9 specific histone methyltransferase (HMT) activity assay and immunoblotting to measure levels of H3K9me3. Immunostaining was used to study the localization of KLLN, and micronuclei frequency and aberrations in chromosome number was used to assess chromosomal instability. Analysis of ChIP-seq shows enrichment of KLLN binding in regions of H3K9me3. Overexpression of KLLN using plasmid-based transfection correlates with increased H3K9 methyltransferase activity and increased global H3K9me3, while loss of KLLN expression through siRNA-mediated knockdown had an opposite effect. We also established that KLLN localizes to pericentric regions, and loss of KLLN results in dysregulation of pericentric heterochromatin, with consequent chromosomal instability manifested by increased micronuclei frequency and numerical chromosomal aberrations. KLLN regulation of H3K9me3 could be correlated with its interaction with deleted in breast cancer (DBC1). DBC1 is a known inhibitor of SUV39H1, a H3K9 specific histone methyltransferase responsible for maintenance of pericentric heterochromatin. We hypothesize that KLLN sequesters DBC1 through their interaction, thereby abrogating DBC1 inhibition of SUV39H1, resulting in maintenance of pericentric heterochromatin and genomic stability. Our study therefore suggests a critical role for KLLN in the deterrence of tumor initiation and progression. SIGNIFICANCE: Our study demonstrates a clear role for KLLN in maintenance of chromatin organization thereby maintaining genomic stability, which begins to uncover the basis of KLLN as a tumor suppressor and as a susceptibility gene for inherited cancers. Citation Format: Madhav Sankunny, Emily Nizialek, Farshad Niazi, Charis Eng. KLLN protects genomic stability by maintaining H3K9 trimethylation (H3K9me3) at the pericentric heterochromatin. [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 3596.
Abstract 2704: Radiotherapy and immunotherapy in cancer: A mathematical model
Authors: Raphael Serre, Xavier Muracciole, Joseph Ciccolini, Sebastien Benzekry, Dominique Barbolosi
Journal: Cancer Research (2016)

Abstract The rise of immunotherapy is a major breakthrough in oncology. Recently, the combination of radiotherapy with the blockade of immune checkpoint inhibitors such as the PD1-PDL1 axis or the CTLA4 pathway has shown a synergistic potential: in addition to the direct cell kill induced by irradiation, radiotherapy unleashes neoantigens that can further induce an anti-tumoral immune response. However, this immune response can be inhibited by the immunosuppressive nature of the tumor micro-environment (TME). Hence, radiotherapy combined with immune check-point inhibitors is a promising solution and is the subject of preclinical and clinical research. However, defining the most efficient scheduling between radiotherapy and immunotherapy is a crucial issue that cannot be properly addressed solely by empirical trial-and-error practices. Consequently, developing mathematical models that can describe the synergy between immune checkpoint inhibitors and radiotherapy is critical. Hence, we have built a pharmocodynamic model of the combination of radiotherapy with inhibitors of the PD1-PDL1 axis and/or the CTLA4 pathway. We describe a mathematical representation of how a growing tumor first elicits and then inhibits an anti-tumoral immune response. This anti-tumoral immune response is described by a primary and a secondary response. The primary immune response appears first and is down-regulated by the PD1-PDL1 axis, while the secondary immune response happens next and is down-regulated by the CTLA4 pathway. We describe the effects of irradiation by a slightly modified version of the Linear-Quadratic model. In particular, we explain the biphasic relationship between the size of a tumor and its immunogenicity, as measured by the abscopal immune response. The ability of the model to forecast pharmacodynamic endpoints was retrospectively validated by reproducing results from experimental studies investigating radiotherapy and immune checkpoint inhibitors. This model clarifies the issue of synchronisation of immunotherapy with radiotherapy and it also explains why the CTLA4 blockade often occurs with a delay. The model also explains why a sustained response to immunotherapy may or may not happen after treatment discontinuation. We believe that this mathematical model could be further used as a simulation tool to help decision-makers determine the optimal scheduling between radiotherapy and immunotherapy and could be a building block for the in-silico design of optimized multimodal strategies. Citation Format: Raphael Serre, Xavier Muracciole, Joseph Ciccolini, Sebastien Benzekry, Dominique Barbolosi. Radiotherapy and immunotherapy in cancer: A mathematical model. [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 2704.
Abstract 5116: Phosphatidylserine-targeting antibodies augment anti-tumor activity of PD-1 antibodies and alter immuno-profiles in murine triple negative breast cancers
Authors: Michael J. Gray, Jian Gong, Ryan N. Parks, Michaela M.S. Hatch, Van Nguyen, Christopher C.W. Hughes, Jeff T. Hutchins, Bruce D. Freimark
Journal: Cancer Research (2016)

Abstract Current treatments for triple negative breast cancers rely primarily upon surgical intervention and chemotherapy. Unfortunately, chemotherapies have the propensity to help establish an immunosuppressive condition in part though exposure of phosphatidylserine (PS) in the tumor microenvironment. We demonstrate that treatment of the murine triple negative breast cancer E0771 using a PS-targeting antibody inhibits in vivo growth, and significantly enhances the anti-tumor activity of antibodies directed to the checkpoint inhibitor PD-1. Combinational treatment by antibodies targeting PS and PD-1 increased the number of tumor infiltrating lymphocytes (TILs) to a greater extent than observed with single-arm therapies. Furthermore, combination of PS and PD-1 targeting antibodies provides a distinct survival advantage over treatment by either agent alone, which correlates with an increase in complete tumor regression and the onset of a durable immune mediated response capable of rejecting a secondary challenge by the same tumor. Finally, immune-profiling analysis of tumor RNA using Nanostring revealed that the combination antibody therapy enhanced immune regulatory pathways including MHC class I/II expression, antigen processing and presentation, and leukocyte and macrophage functions. Combined, our data suggest that in triple negative breast cancers antibody therapy blocking PS-associated immunosuppression may further enhance immunotherapies directed at immune checkpoint inhibitors, including those targeting the PDL-1/PD-1 axis. Citation Format: Michael J. Gray, Jian Gong, Ryan N. Parks, Michaela M.S. Hatch, Van Nguyen, Christopher C.W. Hughes, Jeff T. Hutchins, Bruce D. Freimark. Phosphatidylserine-targeting antibodies augment anti-tumor activity of PD-1 antibodies and alter immuno-profiles in murine triple negative breast cancers. [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 5116.
Abstract 4502: Molecular impact of in vitro exposure to electronic cigarette vapor in human bronchial epithelium
Authors: Elizabeth Moses, Teresa Wang, George R. Jackson, Sean Corbett, Eduard Drizik, Daniel Brooks, George O’Connor, Catalina Perdomo, Steven Dubinett, Patrick Hayden, Marc E. Lenburg, Avrum Spira
Journal: Cancer Research (2016)

Abstract Electronic cigarettes (ECIGs) are an emerging alternative tobacco product thought by some to potentially be safer than traditional tobacco cigarettes (TCIGs). Despite the increasing prevalence of ECIG use, few studies have evaluated the potential physiological effects of ECIG exposure. In this study we aimed to determine the global gene expression effects of ECIG exposure on bronchial epithelium in vitro. Human bronchial epithelial cells (HBECs) grown at Air Liquid Interface (ALI) were exposed to TCIG smoke and ECIG vapor derived from tobacco or menthol flavored products with and without nicotine. We identified a number of gene expression alterations that were induced by both ECIG and TCIG exposure as well as a novel set of changes uniquely induced by ECIG exposure. ECIG exposure induced the expression of genes involved in oxidative and xenobiotic stress pathways and increased the production of reactive oxygen species, similar to, but generally lower in magnitude than, the effects of TCIGs. Furthermore, TCIG and ECIG exposure both decreased the expression of genes involved in cilia assembly and movement, suggesting that the integrity of the bronchial epithelium is concordantly impaired by both exposures. We additionally identified a number of ECIG-specific cell cycle and cell division pathway changes. Finally, we observed that ECIG-induced changes were dependent on both flavor and nicotine content. Together, these results indicate that ECIG vapor can induce cellular stress and molecular alterations within airway epithelium that share similarities with the effects of TCIG smoke. Based on these findings, further studies are warranted to determine whether ECIG use will lead to similar deleterious health outcomes as those caused by TCIGs. Citation Format: Elizabeth Moses, Teresa Wang, George R. Jackson, Sean Corbett, Eduard Drizik, Daniel Brooks, George O’Connor, Catalina Perdomo, Steven Dubinett, Patrick Hayden, Marc E. Lenburg, Avrum Spira. Molecular impact of in vitro exposure to electronic cigarette vapor in human bronchial epithelium. [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 4502.
CD9 Alters Migration and Morphology of CD9-Positive B Acute Lymphoblastic Leukemia Cells
Authors: Audrey Vallée, Elisabetta Dondi, Jacinthe Bonneau, Christine Leroy, Anne-Gaelle Rio, Marie-Bérengère Troadec, Nadine Varin-Blank, Marie-Dominique Galibert, Virginie Gandemer
Journal: Blood (2011)
A Patient-Specific Ex Vivo Screening Platform for Personalized Acute Myeloid Leukemia (AML) Therapy
Authors: Diana Azzam, Claude-Henry Volmar, Al-Ali Hassan, Aymee Perez, Justin M. Watts, Fernando Vargas, Roy Elias, Francisco Vega, Arthur Zelent, Christopher R. Cogle, Claes Wahlestedt, Ronan T. Swords
Journal: Blood (2015)
Somatic BRCA1 mutations determine different responses to platinum-based chemotherapy
Authors: E. Ignatova, M. Frolova, E. Glazkova, M. Stenina, A. Petrovsky, A. Burdennyy, V. Loginov, M. Filippova, L. Lyubchenko, S. Tjulandin
Journal: Annals of Oncology (2015)
UK’s first maternity service for rape survivors opens in London
Authors: Penny Warren
Journal: BMJ (2016)

My Body Back Maternity Clinic, the UK’s first antenatal service for women affected by sexual violence, opened at The Royal London Hospital on 29 July.

The clinic is jointly organised by Barts Health NHS Trust and the rape support charity My Body Back Project. It’s an extension of a clinic that has been running since August 2015, where specially trained staff offer cervical screening, contraceptive advice, and testing for sexually transmitted infections to women who have been assaulted or raped and who might not otherwise come forward for medical care.

Pavan Amara, a 28 year old …
Characterization of a novel, small molecular weight IGFI-R inhibitor
Authors: Konstantina Grosios, Francesco Hofmann, Josef Brueggen, Hansgeorg Capraro, Robert Cozens, Doriano Fabbro, Pascal Furet, Carlos Garcia-Echeverria, Georg Martiny-Baron, Juergen Mestan, Thomas Meyer, Mark A. Pearson
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5977 

The IGFI-R is a transmembrane receptor that is activated upon binding its cognate ligands IGF-I and IGF-II. Ligand binding leads to activation of the intrinsic cytoplasmic kinase domain and activation of multiple intracellular signalling pathways. Ligand mediated activation of the receptor has been associated with increased survival and proliferation. Expression of the receptor is required for transformation by multiple oncogenes and the ability of cells to grow in an anchorage independent manner. Although apparently not mutated, overexpression of IGFI-R, as well as its ligands, has been documented in multiple tumours. Functional ablation of the receptor, either by the use of anti-sense oligonucleotides, expression of dominant negative receptor mutants or antagonistic antibodies, is associated with inhibition of growth and increased apoptosis in vitro and blockade of primary tumour growth and metastatic spread in preclinical animal models. Consequently, inhibition of the IGFI-R is considered a valid approach by which tumours could be therapeutically targeted. Here we present the characterisation of a pyrrolo[2,3-d]pyrimidine derivative that specifically inhibits the kinase activity of the IGFI-R. Inhibitor treatment is associated with blockade of IGFI-R autophosphorylation and downstream signalling, thereby abrogating IGF-I mediated proliferation and survival. Finally, we present evidence that administration of this agent inhibits IGFI-R signalling in vivo , effectively preventing the growth of implanted tumours.