tbuckley/cabot-search huggingface dataset:
Abstract 1859: Inhibition of proteasome deubiquitinase activity prevents cytoprotective aggresome formation in cancer cells
Authors: Ellin-Kristina Hillert, Slavica Brjnic, Magdalena Mazurkiewicz, Rolf Larsson, Mårten Fryknäs, Lisa Swanton, Stephen High, Stig Linder, Padraig B. D'Arcy
Journal: Cancer Research (2018)

Abstract Proteasome inhibitors kill cancer cells by inducing an acute proteotoxic stress response characterized by the cytosolic accumulation of poly-ubiquitinated proteins, ER stress and the production of reactive oxygen species (ROS). The aggresome pathway has been described as an escape mechanism from proteasome inhibitor-induced cytotoxicity that functions by sequestering the accumulated protein. We show that b-AP15, an established small molecule inhibitor of proteasome deubiquitinase activity, induces the accumulation of cytosolic poly-ubiquitin in the absence of aggresome formation. In contrast to the clinically used proteasome inhibitor bortezomib, the accumulated poly-ubiquitin complexes induced by b-AP15 remain localized in the cytoplasm and fail to form typical aggresome structures. Inhibition of aggresome formation is dependent on ubiquitin but independent of tubulin dynamics, and may result in the accumulation of a range of substrates of the intracellular transport system on microtubules. Finally, b-AP15 induces hyper-ubiquitination of the aggresome chaperone HDAC6, as well as altering HDAC6 association with the proteasome. This suggests a potential mechanism for the present findings, which will require further investigation. Our data suggests that b-AP15 inhibition of aggresome formation may circumvent a potential resistance pathway following cytotoxicity due to proteasome inhibition via the blocking of microtubule transport. Citation Format: Ellin-Kristina Hillert, Slavica Brjnic, Magdalena Mazurkiewicz, Rolf Larsson, Mårten Fryknäs, Lisa Swanton, Stephen High, Stig Linder, Padraig B. D'Arcy. Inhibition of proteasome deubiquitinase activity prevents cytoprotective aggresome formation in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1859.
Abstract 5367: Elucidating the factors determining P53 binding and transcriptomic response to DNA damage
Authors: Varsha Sundaresan, Ying Li, Benedetto DiCiaccio, Victor T. Lin, Adrian A. Acuna Higaki, Nicole F. Pelletier, Jessica T. Cheung, Lei Zhou
Journal: Cancer Research (2018)

Abstract Mutations in tp53 are thought to be one of the most common mechanisms by which cancer cells evade tumor suppression. Yet the exact mechanism of tumor suppression by P53 remains to be fully understood. The transcription factor P53 is activated in response to oncogenic stresses and exerts distinct anti-proliferative functions based on the stressor and cell type. Although numerous mammalian ChIP-Seq studies have identified thousands of P53 binding sites, the functionality of these binding sites remains to be established. To study how P53 binding following DNA damage differs between cell types, we performed comparisons between P53 ChIP-Seq data from Drosophila embryos at different developmental stages and a Drosophila cell line (Kc167). Differential expression analysis using RNA-Seq indicated that at an early stem cell-like developmental stage of Drosophila embryos there is P53-dependent induction of pro-apoptotic genes in response to irradiation but not in the later differentiated stages. We aim to establish functionally significant P53 binding sites by combining ChIP-Seq and RNA-Seq data from Drosophila embryos as well as Kc167. The functional significance of these binding sites will be identified by CRISPR-Cas9–mediated genome editing. Preliminary genome-wide motif analysis studies also exhibited that homotypic clustering of P53 consensus motifs is associated with P53 binding. We will also perform comparison studies of DNA damage-induced P53 binding in humans, mice and flies to identify analogous patterns. Preliminary studies revealed that a majority of the P53 binding sites are located at the repetitive regions of the Drosophila genome, especially the Long terminal repeats (LTRs) and Long interspersed nuclear elements (LINEs) as seen previously in mammals by other groups including Botcheva et al and Chang et al. P53 has been known to regulate the expression of retrotransposons and maintain genetic stability by keeping the number of repeats in control. We further aim to see if the functions carried out by P53 differ between repetitive vs. non-repetitive binding regions in Drosophila. This comparative genomics study will help identify the functionally significant P53 binding sites thus further our understanding of tumor suppression by P53. The knowledge obtained from this study will also be valuable in devising novel strategies to restore P53 function in cancers. Citation Format: Varsha Sundaresan, Ying Li, Benedetto DiCiaccio, Victor T. Lin, Adrian A. Acuna Higaki, Nicole F. Pelletier, Jessica T. Cheung, Lei Zhou. Elucidating the factors determining P53 binding and transcriptomic response to DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5367.
Abstract 1685: Genomics based studies of gastric tumors identify ICOS as potential target for therapeutic intervention
Authors: Heather A. Hirsch, Jason Reeves, Tong Zi, Alexander Needham, Edward Stack, David Lee, Emma Lees, Deborah A. Law, Elizabeth Trehu
Journal: Cancer Research (2018)

Abstract JTX-2011, an ICOS agonist antibody, is the first clinical program to emerge from Jounce's Translational Science Platform, which couples the choice of target mechanism to potential predictive biomarkers of response. ICOS (Inducible T cell CO-Stimulator), a co-stimulatory molecule expressed primarily on T lymphocytes, was prioritized as a target based on preclinical and clinical data suggesting that it plays an important role in the immune response to cancer. Fundamental data from our preclinical studies shows that tumor reduction occurs only in animals when a certain percentage of ICOS positive immune cells are resident within the tumor or in combination with a PD-1 inhibitor. Thus ICOS expression is a key element of our biomarker-driven approach in the ICONIC clinical trial. Based on this biomarker approach, we have identified gastric cancer as a cancer of potential interest for an ICOS-targeted immunotherapy approach. Gastric adenocarcinoma was identified as a tumor of interest based on the integrated analysis of RNA, DNA and clinical data from the Cancer Genome Atlas (TCGA). This analysis was performed within stomach adenocarcinoma (STAD) to understand the context in which ICOS is expressed. ICOS levels were correlated to gene signatures of immune infiltrate as well as other clinical attributes and molecular markers. ICOS and PD-L1 levels were assessed by IHC in human tumor samples and in biopsies from ICONIC participants.IHC and RNA analyses reveals a dynamic range of ICOS expression across gastric adenocarcinoma tumors, with high prevalence in both EBV+ and MSI-H tumors as well as a subset of EBV-/MSS tumors. While there is a correlation between ICOS, ICOS signature, PD-L1 and IFNγ signatures, RNA analysis indicates that a subpopulation of gastric tumors with lower levels of PD-L1 expression may be ICOS positive. Integrative analysis of tumors identifies gastric cancer as an attractive indication for exploration of JTX-2011 plus a PD-1 inhibitor based on the relatively high frequency of ICOS expression within this tumor type. Since ICOS expression has a dynamic range of expression, an ICOS IHC biomarker is being used to enrich for patients in a gastric cancer cohort, as well as other tumor-specific cohorts in the Phase 2 portion of the ICONIC clinical study. Citation Format: Heather A. Hirsch, Jason Reeves, Tong Zi, Alexander Needham, Edward Stack, David Lee, Emma Lees, Deborah A. Law, Elizabeth Trehu. Genomics based studies of gastric tumors identify ICOS as potential target for therapeutic intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1685.
A phase II study of combined therapy with vemurafenib (vem) and high-dose interleukin-2 (aldesleukin; HD IL-2) in patients with metastatic melanoma.
Authors: Jennifer Ann Wargo, Donald P. Lawrence, Zachary A Cooper, Dennie T. Frederick, Anita Giobbie-Hurder, Adriano Piris, Krista M. Rubin, Riley Fadden, Alexandre Reuben, Lee Starker, Keith Flaherty, Arlene Sharpe, Ryan J. Sullivan
Journal: Journal of Clinical Oncology (2015)

e20074 Background: There is growing evidence of potential synergy of BRAF-targeted therapy and immunotherapy. This phase II trial was conducted to determine the progression-free (PFS) and overall survival (OS) rates, response rates (RR), and safety of treatment with combined vem and HD IL-2. Exploratory biomarkers of response and resistance were also studied. Methods: All patients had metastatic melanoma with a BRAF V600E mutation. Patients received oral vem (960 mg twice daily) for 2 weeks, and then received HD IL-2 at 600,000 IU/kg/dose intravenously every eight hours to tolerance (maximum 14 doses). Patients remained on vem throughout the duration of treatment, and received a second course of HD IL-2 2 weeks after the first course as tolerated. This cycle consisted of 8 weeks, and was repeated as tolerated. Treatment response was assessed every 6 weeks x 6 months, then every 12 weeks. Patients had tumor samples collected pre-treatment, 1-2 weeks into vem, and 1-2 weeks after administration of HD IL-2. Results: Six patients were evaluated. The confirmed overall RR was 83.3% (95% CI: 36% to 99%) and median PFS was 35.8 weeks (95% CI: 16 to 57). No durable responses were noted. One patient had a CR in visceral sites, but progressed in the brain. Treatment was tolerable and not associated with any unexpected toxicities. CTC levels decreased during therapy in 2 evaluated patients. Two patients (1 PR, 1 PD) had longitudinal tumor biopsies demonstrating an increase in CD8+ T cells during treatment in both patients. However, CD4+ T cells and regulatory T cells were increased in the patient with PD but not in the patient with PR. Median follow-up was 88 weeks. The only Grade 4 toxicity was delirium, seen in one patient. Most common Grade 3 toxicities were fatigue (5 of 6), hypotension (3), arthralgia (3), and capillary leak (2). Conclusions: Combined vem and HD IL-2 is associated with acceptable toxicity and responses in the majority of patients treated. However, given the recent approval of two anti-PD1 antibodies and the proliferation of combined anti-PD1/PDL1 plus BRAF-targeted therapies, the place of this regimen in this changing melanoma landscape is uncertain. Clinical trial information: NCT01754376.
Abstract 138: Remote Ischemic Postconditioning Alleviates Postresuscitation Inflammatory Response and Pulmonary Edema in a Porcine Model of Cardiac Arrest
Authors: JiefengXu, SenYe, ZilongLi, MoliWang, ZhengquanWang, GuofengChen, WanchunTang
Journal: Circulation (2014)

Introduction: Systemic ischemia-reperfusion injury produced by CA and resuscitation can result in severe post-cardiac arrest syndrome; which includes systemic inflammatory response and multiple organ dysfunction syndrome such as acute pulmonary edema. We previously demonstrated that remote ischemic post-conditioning (RIpostC) improved post-resuscitation myocardial and cerebral function in a rat model of CA. In this study, we investigated the effects of RIpostC on inflammatory response and pulmonary edema after CPR in a porcine model. Hypothesis: RIpostC would alleviate post-resuscitation inflammatory response and pulmonary edema in a porcine model of CA. Methods: Fourteen male domestic pigs weighing 37 ± 2 kg were utilized. Ventricular fibrillation was electrically induced and untreated for 10 mins. The animals were then randomized to receive RIpostC or control. Coincident with the start of CPR, RIpostC was induced by four cycles of 5 mins of limb ischemia and then 5 mins of reperfusion. Defibrillation wa...
Abstract 4332: Meta-analysis of molecular features associated with aggressive prostate cancer
Authors: James C. Costello, Rani Powers, Andrew Goodspeed, Scott D. Cramer
Journal: Cancer Research (2018)

Abstract The TMPRSS2:ERG fusion is the most common genomic alteration in prostate cancer, occurring in 40-50% of primary tumors. The frequency of the ERG fusion remains between 40-50% in metastatic tumors, supporting previous findings that the fusion can drive tumor development, but is not sufficient to drive aggressive, lethal disease. Large -omic datasets collected over thousands of patient tumors, such as The Cancer Genome Atlas (TCGA), paired with outcomes present the raw data needed to associate genetic aberrations with markers of aggressive disease. Accordingly, we performed a meta-analysis of over 2,000 patient samples to identify combinations of -omic features associated with aggressive ERG fusion-positive and ERG fusion-negative prostate cancer. The data were collected from 8 independent, publicly available prostate cancer cohorts and cover range of disease phenotypes (e.g., neuroendocrine, castration resistance). Our analysis consisted of training univariate Cox regression models separately for single genomic or pairs of genomic features within each independent dataset. Based on the availability, we explored gene expression, mutation, and copy number alterations, all used to build separate models. We then combined models for a genomic feature across all datasets by weighting individual coefficients by the inverse of their squared error in a fixed effects model; final results are reported as corrected p-values. We compared and contrasted results from combined models within data type (i.e., only gene expression) to models integrating multiple data types. Interestingly, we find that the genomic features associated with aggressive disease differed based on ERG status. We report genomic loci that are altered in all patients, but associate with aggressive disease only in patients with an ERG fusion. We also report loci that co-occur or are mutually exclusive of the ERG fusion and associated with aggressiveness. For example, SPOP mutations are known to be mutually exclusive of ERG fusions. We report a finer stratification of patients with SPOP mutations based on biochemical relapse. Our results present a compressive meta-analysis of molecular features in prostate cancer and identify novel molecular subtypes associated with aggressive disease. Citation Format: James C. Costello, Rani Powers, Andrew Goodspeed, Scott D. Cramer. Meta-analysis of molecular features associated with aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4332.
Thermo- and pH-dual responsive polymeric micelles with upper critical solution temperature behavior for photoacoustic imaging-guided synergistic chemo-photothermal therapy against subcutaneous and metastatic breast tumors
Authors: Zhe Yang, Rui Cheng, Chenyang Zhao, Na Sun, Huiyan Luo, Ya Chen, Zerong Liu, Xian Li, Jie Liu, Zhongmin Tian
Journal: Theranostics (2018)

Chemo-photothermal therapy shows great potential for inhibiting tumor growth. However, achieving maximal chemo-photothermal synergistic efficacy is challenging because of the low efficiency of controllable chemo-drug release in response to external or internal triggers. Thus, a nano-delivery system that could effectively achieve photothermal therapy and dual stimuli-responsive (heat and pH) drug release to inhibit both primary breast tumor growth and metastases is required.
Abstract 4892: Del-1 promotes the proliferation and migration of tamoxifen-resistant breast cancer
Authors: Yee Soo Chae, Jong Gwang Kim, Jae-Hwan Jeong, Soo Jung Lee, Jeeyeon Lee, Jin Hyang Jung, Ho Yong Park, Moon-Chang Baek, Senten Richard J, Ji Young Park
Journal: Cancer Research (2018)

Abstract Background: We previously demonstrated a prognostic role of exosomal Del-1 with breast cancer patients. However, the mechanisms of Del-1 expression are barely understood. Development of resistance to tamoxifen is an important clinical issue in the treatment of breast cancer. Accordingly, we investigated the function of Del-1 in tamoxifen-resistant (TAMR) breast cancer cell line and tumor specimens. Materials and Methods: Del-1 expression in MCF7 and TAMR MCF7 cells was performed by quantitative RT-PCR, western blot, and ELISA. The effects of Del-1 with RNA interference on proliferation, migration and invasion of TAMR MCF7 cells were observed by MTT, wound healing and Matrigel transwell assay. Meanwhile, the tumoral expression of Del-1 was determined immunohistochemistry (IHC) from 10 tamoxifen resistant-breast cancer patients. Tumor tissue before (tamoxifen sensitive) and after tamoxifen resistance were assessed. Results: Del-1 was highly expressed in TAMR MCF7 cells compared to MCF7 cells (p&amp;lt;0.001). And the expression of secretory del-1 was also increased in the culture media of TAMR MCF7 cells. Moreover, down-regulation of Del-1 significantly inhibited the proliferation and migration of TAMR MCF7 cells. There was no difference in the invasion of TAMR MCF7 cells. Increased Del-1 expression was preferentially observed in in TAMR tumor tissues when compared to tamoxifen sensitive or normal breast tissue. Conclusion: Prominent expression of Del-1 in TAMR MCF7 cells was associated with the proliferation and migration of TAMR MCF7 cells. And the tumoral expression of Del-1 was also significantly associated with tamoxifen resistance. These results suggest that the expression of Del-1 promote tamoxifen resistance in breast cancer cells and could be a novel target for anti-breast cancer treatment. Citation Format: Yee Soo Chae, Jong Gwang Kim, Jae-Hwan Jeong, Soo Jung Lee, Jeeyeon Lee, Jin Hyang Jung, Ho Yong Park, Moon-Chang Baek, Senten Richard J, Ji Young Park. Del-1 promotes the proliferation and migration of tamoxifen-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4892.
Impact of bariatric surgery on breast cancer disease burden in the obese breast cancer survivor.
Authors: Anne Hudson Blaes, Gyorgy Simon, Mehmet Ugurbil, Gretchen Sieger, Sayeed Ikramuddin
Journal: Journal of Clinical Oncology (2018)

e13072 Background: Excess body weight has been associated with worsening breast cancer (BC) survival. While bariatric surgery (BS) has been associated with less incident BC, it is unclear the role BS plays after BC diagnosis. Methods: We conducted a retrospective cohort study of patients undergoing BS 2004-2017, median follow-up of 3 years, using de-identified data from a large U.S. commercial insurance database (OptumLabs® Data Warehouse). Using claims data, we identified women with incident early-stage BC 2001 to 2011 using previously validated algorithms. We captured claims for patients undergoing BS with > 1 year of no BC treatment before their surgery date (CPT-4 code: 43644, 43645, 43659, 43770, 43775 or ICD-9 procedure code: 44.38, 43.82, 44.89, and 44.95). For each case, controls were identified (incident BC and no history of BS). Controls were required after BC diagnosis to have a time distance equal to the difference of the case’s BC diagnosis and BS, to be eligible for BS in a 6-month window (body mass index > = 35 kg/m2, not having 20 comorbid illnesses that would exclude them from being eligible for BS), and have follow-up. Outcome of interest: BC events after BS defined as chemotherapy (pharmacy claim/procedure code), diagnosis of metastatic disease, or breast re-surgery. Multivariable Cox proportional-hazards models were used to examine these events up to 11 years after bariatric surgery compared to the matched nonsurgical patients. Results: 53575 incident BC cases and 29766 eligible controls were identified; 108 BS cases were identified as having no BC events > 1 year before their surgery date. The relative risk of BC events for patients who underwent BS was 45% lower than control group (See table 1). Conclusions: For obese enrollees with incident BC, BS is associated with reduction in BC events compared to non-surgical care. A randomized control trial of BS versus best medical management should be considered. Table 1. Cox Model Hazard Ratios. Variables Hazard Ratio P-Value 95 % Confidence Interval Diabetes 1.152 0.0023 (1.094, 1.214) Hypertension 1.190 < 0.0001 (1.134 1.248) GERD 1.231 0.0004 (1.157, 1.309) Sleep Apnea 1.457 < 0.0001 (1.365, 1.555) Bariatric Surgery 0.534 0.0001 (0.394, 0.724)
Prognostic Value of Myocardial Viability in Medically Treated Patients With Global Left Ventricular Dysfunction Early After an Acute Uncomplicated Myocardial Infarction
Authors: EugenioPicano, RosaSicari, PatriziaLandi, LauroCortigiani, RiccardoBigi, ClaudioColetta, AlfonsoGalati, JoannaHeyman, RobertoMattioli, MarioPrevitali, WilsonMathias, ClaudioDodi, GiovanniMinardi, JorgeLowenstein, GiovanniSeveso, AlessandroPingitore, AlessandroSalustri, MauroRaciti
Journal: Circulation (1998)

Background—Residual viable myocardium identified by dobutamine stress after myocardial infarction may act as an unstable substrate for further events such as subsequent angina and reinfarction. However, in patients with severe global left ventricular dysfunction, viability might be protective rather than detrimental. The aim of this study was to assess the impact on survival of echocardiographically detected viability in medically treated patients with global left ventricular dysfunction evaluated after acute uncomplicated myocardial infarction. Methods and Results—The data bank of the large-scale, prospective, multicenter, observational Echo Dobutamine International Cooperative (EDIC) study was interrogated to select 314 medically treated patients (271 men; age, 58±9 years) who underwent low-dose (≤10 μg · kg−1 · min−1) dobutamine for the detection of myocardial viability and high-dose dobutamine for the detection of myocardial ischemia (≤40 μg · kg−1 · min−1 with atropine ≤1 mg) performed 12±6 days afte...