tbuckley/cabot-search huggingface dataset:
Abstract 1453: Development of a novel PD-1 vaccine and in combination with two Chimeric HER-2 peptide vaccine provides synergistic inhibition of tumor growth in a syngeneic Balb/c model challenged with CT26/HER-2 carcinoma cell line
Authors: Tanios Bekaii-Saab, Jay Overholser, Yuhong Yang, Manuel Penichet, Pravin Kaumaya
Journal: Cancer Research (2019)

Abstract Background: Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer and demonstrated impressive activity across a broad set of cancer subtypes, even at advanced and metastatic stages of disease. Contrary to treatment with monoclonal antibodies, chimeric B-cell cancer vaccines have the advantage of producing a specific immune response that can potentially induce memory B &amp; T cell responses, while reducing immune evasion and suppression. Methods: We have translated two HER-2 combination peptide vaccines (B-Vaxx) to the clinic in a Phase 1/2b trial to safely deliver curative and transformative cancer immunotherapies to advanced cancer patients. We have created and established the development of a novel B-cell peptide vaccine (Key-Vaxx) with high immunogenicity that binds to human PD-1 and produces tumor inhibition in vivo in an animal model of colon cancer. Here, we describe the transferable CT-26-HER2 neu tumor model in Balb/c was used to test for synergistic effects of anti-PD1 immunization therapy in combination with anti-HER2 immunization therapy to determine whether this combination could increase immunogenicity, enhance anti-tumor responses and provide synergistic benefit in inhibiting tumor growth. Results: We show robust HER-2 and PD-1 antibody responses in all vaccinated mice indicating that the combined vaccination is effective in reducing tumor growth in a Balb/c syngeneic model of colon carcinoma versus either the PD-1 vaccine or more importantly the positive control gold standard that is anti-mouse PD-1 monoclonal antibody. The vaccine combination was found to be safe and did not appear to exhibit toxicity or autoimmunity. Conclusion: Development of a novel PD-1 vaccine in combination with two Chimeric HER-2 peptide vaccine provides synergistic inhibition of tumor growth with no evidence of toxicity or autoimmunity. A clinical trial with the combination is under planning. Citation Format: Tanios Bekaii-Saab, Jay Overholser, Yuhong Yang, Manuel Penichet, Pravin Kaumaya. Development of a novel PD-1 vaccine and in combination with two Chimeric HER-2 peptide vaccine provides synergistic inhibition of tumor growth in a syngeneic Balb/c model challenged with CT26/HER-2 carcinoma cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1453.
Abstract 2487: Application of RegTools to TCGA samples for the identification of tumor-specific splice variants
Authors: Kelsy C. Cotto, Yang-Yang Feng, Zachary L. Skidmore, Obi L. Griffith, Malachi Griffith
Journal: Cancer Research (2019)

Abstract The interpretation of variants in cancer is frequently focused on direct protein coding alterations. However, this analysis strategy excludes somatic mutations in non-coding regions of the genome and even exonic mutations may have unidentified non-coding consequences. To address this issue, we created RegTools (Feng et al. 2018), a free, open-source software package that integrates analysis of somatic variant calls from genomic data with splice junctions extracted from transcriptomic data in order to efficiently identify variants that may cause aberrant splicing in tumors. Initially, this software was developed using 188 cancer samples from 4 cancer types and enabled us to identify important non-coding variants which would otherwise be undervalued or perhaps even completely ignored by traditional methods and annotators. Here, we present the application of RegTools to over 10,000 TCGA samples in an effort to identify somatic variants that are associated with alternative splicing patterns within these tumors. In order to perform this analysis, we obtained all tumor samples that had somatic variant VCF files and RNA-seq bam files from the Genomic Data Commons (GDC). Included within these samples are more than 700 solid tissue normal samples, which will be used as a panel of normals in order to filter out variants and splicing events that are not tumor specific. We plan to present on the significance of our findings when analyzing these samples within their respective tumor type and across all tumor types. We also plan to present on whether these aberrant splicing events that result from somatic mutations might interfere with predicted neoantigens pVAC-Seq (Hundal et al. 2016). RegTools is freely available and open source (www.regtools.org). Citation Format: Kelsy C. Cotto, Yang-Yang Feng, Zachary L. Skidmore, Obi L. Griffith, Malachi Griffith. Application of RegTools to TCGA samples for the identification of tumor-specific splice variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2487.
Association of quality of paediatric epilepsy care with mortality and unplanned hospital admissions among children and young people with epilepsy in England: a national longitudinal data linkage study
Authors: Dougal S Hargreaves, Sandeepa Arora, Carolina Viveiro, Daniel R Hale, Joseph L Ward, Christopher Sherlaw-Johnson, Russell M Viner, Colin Dunkley, J Helen Cross
Journal: The Lancet Child & Adolescent Health (2019)
Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study
Authors: L. Boschung-Pasquier, A. Atkinson, L.K. Kastner, S. Banholzer, M. Haschke, N. Buetti, D.I. Furrer, C. Hauser, P. Jent, Y.A. Que, H. Furrer, B. Babouee Flury
Journal: Clinical Microbiology and Infection (2019)

Toxic serum cefepime trough concentrations are not well defined in the current literature. We aimed to define a more precise plasma trough concentration threshold for this antibiotic's neurological toxicity and to identify individuals at risk for developing neurotoxic side effects.Retrospective study including all individuals who underwent cefepime therapeutic drug monitoring (TDM) between 2013 and 2017. Individuals with cefepime concentrations other than trough were excluded. The primary outcome was to assess the incidence of neurotoxicity and its relationship with cefepime plasma trough concentrations. Secondary outcomes were the relationship of renal function, cefepime daily dose, age, and cerebral and general co-morbidities with the occurrence of neurotoxicity. We also compared the mortality rate during hospitalization in individuals with and without neurotoxicity, and the possible impact of neuroprotective co-medications on outcomes.Cefepime concentrations were determined in 584 individuals. Among 319 individuals with available trough concentrations included, the overall incidence of neurotoxicity was 23.2% (74 of 319 individuals). Higher cefepime plasma trough concentrations were significantly associated with risk of neurotoxicity (no neurotoxicity 6.3 mg/L (interquartile range (IQR) 4.1-8.6) versus with neurotoxicity 21.6 mg/L (IQR 17.0-28.6), p <0.001). Individuals with presumed cefepime neurotoxicity had a significantly lower renal function (estimated glomerular filtration rate 82.0 mL/min/1.73 m2 (IQR 45.0-105.0) versus 35.0 mL/min/1.73 m2 (IQR 23.3-53.3], p <0.001), and significantly higher in-hospital mortality (19 (7.8%) versus 26 (35.1%) individuals, p <0.001). No neurotoxic side effects were seen below a trough concentration of 7.7 mg/L. Levels ≥38.1 mg/L always led to neurological side effects.In individuals with risk factors for cefepime neurotoxicity, such as renal insufficiency, TDM should be systematically performed, aiming at trough concentrations <7.5 mg/L.
Abstract 1: A small molecule inhibits Nrf2 expression and activity in cancer cells
Authors: Di Zhang, Corbin Livingston, Thomas Dexheimer, Edmund Ellsworth, Aaron Odom, Karen Liby
Journal: Cancer Research (2019)

Abstract Activation of the Nrf2-Keap1-ARE pathway is a master defense mechanism protecting against oxidative and electrophilic stress. Nrf2 was traditionally considered cancer-preventing, as Nrf2 deficiency enhances susceptibility to carcinogens in a variety of mouse models. However, increasing evidence suggests a tumor-promoting role for Nrf2 in established tumors: gain of function mutations in NFE2L2, which activates the Nrf2 pathway, or loss of function mutations in its negative regulator, Keap1, have been found most frequently in lung cancer. Constitutive activation of the Nrf2 pathway is associated with chemoresistance and poor survival. Nrf2 inhibitors, therefore, become potential novel drugs for cancer treatment and needed tool compounds to study the Nrf2 pathway in cancer. To identify Nrf2 inhibitors, we conducted a high throughput screen with a diverse set of small molecules (~6500 compounds). 890 compounds were identified as hits, and a funnel strategy was applied to filter through the hits and select lead compounds. Although other known Nrf2 inhibitors were identified, a potentially novel compound, MSU225, was chosen as a lead for further evaluation. MSU225 downregulated tBHQ (tert-butyl hydroquinone)-induced Nrf2 transcriptional activity in a luciferase assay without inducing cell death. When A549 human lung cancer cells, in which Keap1 is mutated inducing constitutive activation of Nrf2, were treated with 5 µM MSU225, the mRNA expression of HMOX1, NQO1, GST1A1, GCLC, GCLM, and UGT1A6, all downstream targets of Nrf2, were decreased. Moreover, MSU225 significantly (p&amp;lt;0.05) decreased the protein level of Nrf2 in A549 cells. The effect of MSU225 on Nrf2 protein levels was blocked by the proteasome inhibitor MG132, suggesting MSU225 enhances Nrf2 degradation through the proteasome system. In addition, MSU225 inhibited the growth of human lung cancer cells (A549, H460, A427) in soft agar. Cells addicted to Nrf2 were more susceptible to MSU225 for suppression of cell proliferation than cells not addicted to Nrf2. MSU225 also sensitized A549 cells to carboplatin treatment. Our results suggest that MSU225 is a novel Nrf2 inhibitor, and additional in vivo studies will be done to determine if it can be used to treat experimental lung cancer. Citation Format: Di Zhang, Corbin Livingston, Thomas Dexheimer, Edmund Ellsworth, Aaron Odom, Karen Liby. A small molecule inhibits Nrf2 expression and activity in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1.
Abstract 355: A novel anti-HER2 antibody that displays superior synergetic effects in Trastuzumab mediated HER2-overexpressing tumor arrest
Authors: Haomin Huang, xuesai zhang, jianhe Chen, Le Zhao, qingrou Li, zhenping zhu
Journal: Cancer Research (2019)

Abstract The majority of patients with metastatic breast cancer on Trastuzumab, an anti-HER2 monoclonal antibody, generally develop resistance to the drug within a year after initiation of the treatment. Therefore, there is an unmet need for a novel agent to treat HER2 overexpressing breast cancers. Here we described a novel anti-HER2 humanized monoclonal antibody, 19H6-hu, which binds to HER2 ECD with high affinity and could inhibit the proliferation of multiple HER2-overexpressing cancer cell lines as a single agent, though, to a lesser degree when compared to Trastuzumab alone. Interestingly, when in combination with Trastuzumab, 19H6-hu exhibited much stronger potency in inhibition of BT474, N87 and SKBR3 cell growth relative to that of Perjeta in combination with Trastuzumab as well as in suppression of tumor growth in vivo when compared to Trastuzumab alone. Alanine scanning demonstrated that the antibody binds to an alpha-helix located within the domain III and in proximity to the domain IV of HER2 ECD, which is different from the known binding sites of Trastuzumab and Perjeta. Western blotting further confirmed that 19H6-hu in combination with Trastuzumab is more efficacious in blocking phosphorylation of ERK and phosphorylation of HER2 at Y1248 when compared to Trastuzumab in combination with Perjeta or applied alone. Thereby, our results highlight the functional variability of HER2 domains and provide a new insight into the design of HER2-targeting agents. Citation Format: Haomin Huang, xuesai zhang, jianhe Chen, Le Zhao, qingrou Li, zhenping zhu. A novel anti-HER2 antibody that displays superior synergetic effects in Trastuzumab mediated HER2-overexpressing tumor arrest [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 355.
Abstract 693: Deep learning analysis of circulating tumor DNA identified a pan-tumor molecular subtype with enhanced response to durvalumab (anti-PDL1)
Authors: Song Wu, Sriram Sridhar, Han Si, Michael Kuziora, Judson Englert, Shaad E. Abdullah, Philip Dennis, Feng Xiao, Guozhi Gao, Koustubh Ranade, Brandon W. Higgs
Journal: Cancer Research (2019)

Abstract Tumor mutation burden (TMB) has emerged as a promising predictive biomarker for anti-PD1/L1; however, whether somatic mutations in specific genes can sensitize to immunotherapy is poorly understood. We used deep learning to identify molecular subtypes from mutations detectable in circulating tumor DNA (ctDNA) and associated these with outcomes with anti-PDL1 (durvalumab) and durvalumab + anti-CTLA4 (tremelimumab) therapy. Patient blood samples from 4 nonrandomized phase 2 trials evaluating durvalumab (NCT01693562, 1L+ solid tumors; NCT02087423, 3L+ NSCLC) or durvalumab+ tremelimumab (NCT02000947, 2L+ NSCLC; NCT02261220, 2L+ solid tumors) were sequenced with the Guardant 360 assay of 73 genes. CtDNA mutations were examined pre-treatment in a discovery cohort of 818 patients composed of &amp;gt;15 tumor types and validated in a cohort of 94 patients composed of &amp;gt;5 tumor types. Deep learning neuron network was computed using Tensorflow to identify 4 unique molecular subgroups. Kaplan-Meier analysis was calculated and objective response rates (ORR) were assessed with RECISIST v1.1. The subgroups consisted of: DS1 (N = 215/818, 26%) enriched in RB1 mutations (17%) and low TMB, DS2 (N = 237/818, 29%) enriched in ARID1A (33%), NFE2L2 (8%), and cKIT (13%) mutations, DS3 (N = 251/818, 31%) enriched in EGFR, ERBB2, BRAF and STK11 mutations, and DS4 (N = 115/818, 14%) enriched in TERT, FGFR3, and PIK3CA mutations. In the discovery cohort, the DS2 subgroup had most improved outcomes (mOS=24.6 months, mPFS=3.7 months, ORR=27%) compared to the other 3 subgroups. DS1 subgroup had the worst outcomes (mOS=6.3 months, mPFS=1.6 months, ORR=10%), while the biomarker evaluable population (BEP, n=818) had ORR=17%. In the validation cohort, DS2 also had the most improved outcomes (mOS=not reached, mPFS=13.2 months, and ORR=64%), with the BEP (n=94) having an ORR=37%. PD-L1 was not correlated with any specific molecular subgroup, while an IFNg mRNA signature trended with correlation with subgroup DS2. Deep learning analysis of ctDNA identified a molecular subgroup with enhanced response to anti-PDL1 treatment in multiple tumor types. Citation Format: Song Wu, Sriram Sridhar, Han Si, Michael Kuziora, Judson Englert, Shaad E. Abdullah, Philip Dennis, Feng Xiao, Guozhi Gao, Koustubh Ranade, Brandon W. Higgs. Deep learning analysis of circulating tumor DNA identified a pan-tumor molecular subtype with enhanced response to durvalumab (anti-PDL1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 693.
Abstract 2666: ARD1-mediated Hsp70 acetylation protects cancer cells against the cellular stress
Authors: Ji Hae Seo, So-Jin Shin, Jin Young Kim, Seungmee Lee, Hyewon Chung, Chi-Heum Cho
Journal: Cancer Research (2019)

Abstract The 70 kDa heat shock proteins (Hsp70s) are a family of ubiquitously expressed intracellular proteins that are required for the maintenance of protein homeostasis. Hsp70 is highly induced in response to cellular stressors, including oxidative stress, hyperthermia, hypoxia and changes in pH, contributing to cellular resistance to stress-induced cell death. Most tumor cells, which live under continuous stress conditions, express elevated levels of Hsp70 to combat these harsh conditions and suppress apoptosis. During cellular stress, Hsp70 maintains protein homeostasis through two opposing mechanisms: protein refolding and degradation. However, the mechanisms by which Hsp70 balances these opposing functions under stress conditions remain unknown. Here, we demonstrate that Hsp70 preferentially facilitates protein refolding after stress, gradually switching to protein degradation via a mechanism dependent on ARD1-mediated Hsp70 acetylation. During the early stress response, Hsp70 is immediately acetylated by ARD1 at K77, and the acetylated Hsp70 binds to the co-chaperone Hop to allow protein refolding. Thereafter, Hsp70 is deacetylated and binds to the ubiquitin ligase protein CHIP to complete protein degradation during later stages. In addition, this switch is essential for the maintenance of protein homeostasis and ultimately rescues cancer cells from stress-induced cell death. Therefore, ARD1-mediated Hsp70 acetylation is a key regulatory mechanism that enables Hsp70-expressing cancer cells to be more resistant to proteotoxic stress, and regulation of Hsp70 K77 acetylation might be helpful to cancer treatment. Note: This abstract was not presented at the meeting. Citation Format: Ji Hae Seo, So-Jin Shin, Jin Young Kim, Seungmee Lee, Hyewon Chung, Chi-Heum Cho. ARD1-mediated Hsp70 acetylation protects cancer cells against the cellular stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2666.
Abstract 5220: Transcription regulatory networks associated with luminal master regulator expression and breast cancer survival
Authors: Jung S. Byun, Sandeep Singhal, Samson Park, Dae IK Yi, Ambar Caban, Nasreen Vohra, Eliseo J. Perez-Stable, Anna Napoles, Kevin L. Gardner
Journal: Cancer Research (2019)

Abstract The disparity in breast cancer burden of African Americans compared with European Americans is one of the most revealing instances in oncology associated with ethnicity. Recent studies demonstrated that there were highly intratumoral genetic heterogeneity and increased the frequency of basal subtypes among African Americans than European Americans. Because significant race-based disparities in breast cancer patients with hormone-receptor positive still persistent even after reflecting socio-economic status, there may be substantial roles playing by intrinsic biological factors contributing to the disparities. Transcriptional regulation governed by estrogen receptor plays critical roles in major changes in chromatin landscape that facilitate the assembly of other transcriptional complexes affecting mammary tumor initiation and proliferation. We investigated the estrogen receptor and its essential pioneer transcription factors how their expressions are associated with racial disparity with their prognostic significance. Co-expression analysis of estrogen receptor and its pioneer transcription factors suggest that ER-positive patients of women of European ancestry show much more favorable survival than women of African ancestry. Differential comparison of protein expression integrated with network-level gene expression analysis reveals significant differences in the predictive ability of the luminal master regulators based on race and survival. Moreover, we identified genes in the downstream of these master regulators that are highly correlated with race and survival. The comparative analysis of the predictive value of race-based cutoffs suggests that these master regulators of luminal differentiation have reduced transcriptional activity in the downstream regulatory network pathways in African ancestry. Functional characterization of the luminal master regulators and their downstream pathways may provide a better understanding of the intrinsic mechanisms that drive racial disparities in breast cancer survival. Citation Format: Jung S. Byun, Sandeep Singhal, Samson Park, Dae IK Yi, Ambar Caban, Nasreen Vohra, Eliseo J. Perez-Stable, Anna Napoles, Kevin L. Gardner. Transcription regulatory networks associated with luminal master regulator expression and breast cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5220.
Allele-specific gene editing prevents deafness in a model of dominant progressive hearing loss
Authors: Bence György, Carl Nist-Lund, Bifeng Pan, Yukako Asai, K. Domenica Karavitaki, Benjamin P. Kleinstiver, Sara P. Garcia, Mikołaj P. Zaborowski, Paola Solanes, Sofia Spataro, Bernard L. Schneider, J. Keith Joung, Gwenaëlle S. G. Géléoc, Jeffrey R. Holt, David P. Corey
Journal: Nature Medicine (2019)
Claudins are abnormally expressed in prostate cancer
Authors: Claudia Coutinho-Camillo, Silvia Lourenco, Francisco Fonseca, Fernando Soares, Renata Coudry
Journal: Cancer Research (2008)

4478  Claudins, a large family of essential tight junction (TJ) proteins are abnormally regulated in human carcinomas, suggesting that they might represent potential targets for cancer detection, diagnosis and therapy. In this study, using a Tissue Microarray (TMA) comprising elements of prostate adenocarcinoma (210 cases), benign prostatic hyperplasia (57 cases) and atrophy (9 cases), we have analyzed the expression of claudins-1, 2, 3, 4, 5, 7, 11 by immunohistochemistry. All claudins tested were present in the prostate samples studied with exception of claudin-11, which was not detected in any sample but was positive in the controls. We found evidence of reduction of claudin 4 expression (p=0.023) and increased expression of claudins 2, 3 and 5 (p=0.062, p