tbuckley/cabot-search huggingface dataset:
Abstract LB-164: DNA ligase IV modulates the cellular response to DNA replication stress
Authors: Grace Hooks, Yasmin Anchondo, Neelam Sharma, Jac Nickoloff, Amanda Ashley
Journal: Cancer Research (2016)

Abstract Correctly repairing DNA damage is crucial to the survival and genomic integrity of cells. Double strand breaks (DSBs) are particularly problematic DNA damage; failure to properly repair DSBs can precede genomic instability leading to cancer. Because of the high proliferative index of cancer cells, replication toxins are successfully used to treat cancer. The two major DNA DSB repair pathways are homologous recombination and nonhomologous end-joining (NHEJ). DNA ligase IV is a central component of NHEJ, performing the final ligation step to reseal the broken DNA ends, in concert with XRCC4. We determined cells lacking the early acting NHEJ protein, and DNA damage response signaling kinase, DNA-PK, restarted DNA replication forks quicker than wild-type following replication stress. The role of other NHEJ proteins in replication fork restart is unclear. Our goal was to investigate whether ligase IV, a protein that appears to function exclusively in NHEJ, is involved in the replication stress response. We tested the hypothesis that ligase IV delays replication restart following exposure to replication toxins. Ligase IV knockdown was confirmed by qPCR and western blotting. siRNA knockdown of ligase IV alone reduced cell viability and it reduced EdU incorporation after replication stress. The opposite effects of DNA-PK and ligase IV on the speed of replication fork restart suggests that NHEJ, per se, does not directly affect replication fork restart. We previously demonstrated that DNA-PK regulates replication fork restart, at least in part, by phosphorylating RPA32, which in turn regulates ATR activation and downstream checkpoint functions. Ligase IV deficiency may influence replication fork restart indirectly, for example, by causing spontaneous DSBs to persist longer, limiting availability of repair factors needed for fork restart (saturation effect). A not mutually exclusive possibility is that fork restart is hindered by persistent DSBs due to checkpoint activation. Understanding how NHEJ proteins impact the replication stress response may provide opportunities for developing more effective cancer treatments. Citation Format: Grace Hooks, Yasmin Anchondo, Neelam Sharma, Jac Nickoloff, Amanda Ashley. DNA ligase IV modulates the cellular response to DNA replication stress. [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 LB-164.
Abstract 1292: Camalexin, an indole phytoalexin from Arabidopsis thaliana, displays activity against ovarian cancer stem cells
Authors: Roman Mezencev, John F. McDonald
Journal: Cancer Research (2016)

Abstract Ovarian cancer is the most lethal of all gynecological cancers. Current treatment of advanced ovarian cancers, which includes debulking surgery and chemotherapy, is initially effective in majority of patients; however, 70-90% of them eventually develop disease recurrence with limited treatment options. This recurrence can be attributed to therapy-resistant cancer stem cells (CSC), which represent a subset of all malignant cells that form the bulk of ovarian cancers. CSC may remain as a minimal residual disease after the bulk of ovarian tumor mass has been removed by surgery and/or chemotherapy; therefore, there is considerable current interest in the development of new therapies that can effectively target this insidious subpopulation of tumor cells. Here we report on the anticancer activity of camalexin, a major indole phytoalexin of Arabidopsis thaliana, against ovarian cancer stem cells. We demonstrate that camalexin inhibits proliferation and induces cell death in ovarian cancer stem cells that exhibit various molecular mechanisms of anticancer drug resistance. Furthermore, we present the mode of action of this prospective anticancer agent identified by combined approach that included in silico predictions, comprehensive analysis of whole-genome gene expression data and target-specific assays. Lastly, we demonstrate the relevance of the identified mode of action in context of ovarian cancer cell signaling. Citation Format: Roman Mezencev, John F. McDonald. Camalexin, an indole phytoalexin from Arabidopsis thaliana, displays activity against ovarian cancer stem cells. [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 1292.
Prospective assessment of a gene signature potentially predictive of clinical benefit in metastatic melanoma patients following MAGE-A3 immunotherapeutic (PREDICT)
Authors: P. Saiag, R. Gutzmer, P.A. Ascierto, M. Maio, J.-J. Grob, P. Murawa, B. Dreno, M. Ross, J. Weber, A. Hauschild, P. Rutkowski, A. Testori, E. Levchenko, A. Enk, L. Misery, C. Vanden Abeele, I. Vojtek, O. Peeters, V.G. Brichard, P. Therasse
Journal: Annals of Oncology (2016)

Genomic profiling of tumor tissue may identify gene signatures (GS) predictive of tumor response to treatment. We prospectively evaluated a GS linked to clinical benefit following MAGE-A3 immunotherapeutic in patients with advanced melanoma. One-year overall survival was similar in patients with and without the GS: the GS was not predictive of outcome after MAGE-A3 immunotherapeutic treatment.BackgroundGenomic profiling of tumor tissue may aid in identifying predictive or prognostic gene signatures (GS) in some cancers. Retrospective gene expression profiling of melanoma and non-small-cell lung cancer led to the characterization of a GS associated with clinical benefit, including improved overall survival (OS), following immunization with the MAGE-A3 immunotherapeutic. The goal of the present study was to prospectively evaluate the predictive value of the previously characterized GS.Patients and methodsAn open-label prospective phase II trial ('PREDICT') in patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma.ResultsOf 123 subjects who received the MAGE-A3 immunotherapeutic, 71 (58.7%) displayed the predictive GS (GS+). The 1-year OS rate was 83.1%/83.3% in the GS+/GS- populations. The rate of progression-free survival at 12 months was 5.8%/4.1% in GS+/GS- patients. The median time-to-treatment failure was 2.7/2.4 months (GS+/GS-). There was one complete response (GS-) and two partial responses (GS+). The MAGE-A3 immunotherapeutic was similarly immunogenic in both populations and had a clinically acceptable safety profile.ConclusionTreatment of patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma with the MAGE-A3 immunotherapeutic demonstrated an overall 1-year OS rate of 83.5%. GS- and GS+ patients had similar 1-year OS rates, indicating that in this study, GS was not predictive of outcome. Unexpectedly, the objective response rate was lower in this study than in other studies carried out in the same setting with the MAGE-A3 immunotherapeutic. Investigation of a GS to predict clinical benefit to adjuvant MAGE-A3 immunotherapeutic treatment is ongoing in another melanoma study.This study is registered at www.clinicatrials.gov NCT00942162.
Abstract 2233: PI3K/Akt/mTOR signaling and plasma membrane proteins are implicated in responsiveness to adjuvant dendritic cell vaccination for metastatic colorectal cancer
Authors: David Qian, Jinyoung Byun, Xiangjun Xiao, Stephanie Her, Arief Suriawinata, Christopher Amos, Richard Barth
Journal: Cancer Research (2016)

Abstract Purpose: We have previously demonstrated that metastatic colorectal cancer patients who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared to patients in whom immune responses do not occur. We sought to characterize the patterns of T lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine. Methods: Cytotoxic, memory, and regulatory T cells in resected metastases and in surrounding normal liver tissue from 22 patients (11 responders and 11 non-responders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the Combined Multivariate and Collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on genes that encode plasma membrane proteins. Results: There was no relationship between vaccine response and intra-tumor, peri-tumor, or hepatic densities of T cell subpopulations. Associated genes were found to be statistically enriched in PI3K, Akt, and mTOR signaling pathways (P &amp;lt; 0.001). With respect to prediction, applying a consistent score cutoff over the 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%). Conclusions: Adjuvant dendritic cell vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as neoantigens on tumor cell surfaces. Citation Format: David Qian, Jinyoung Byun, Xiangjun Xiao, Stephanie Her, Arief Suriawinata, Christopher Amos, Richard Barth. PI3K/Akt/mTOR signaling and plasma membrane proteins are implicated in responsiveness to adjuvant dendritic cell vaccination for metastatic colorectal cancer. [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 2233.
Abstract 720: Novel prognostic stromal subtypes in triple-negative breast cancer
Authors: Crista Thompson, Sadiq M. Saleh, Nicholas Bertos, Mathieu Gigoux, Tina Gruosso, Margarita Souleimanova, Hong Zhao, Michael T. Hallett, Morag Park
Journal: Cancer Research (2016)

Abstract Breast cancer is a heterogeneous disease in terms of presentation, morphology, molecular profile and response to therapy. Gene expression profiling has identified intrinsic molecular subtypes that are associated with clinical markers (ER, PR, HER2) as well as prognosis and survival. However, it is well established that the intrinsic molecular profiles of breast tumors are not sufficient to perfectly predict disease outcome. Increasing evidence indicates that characteristics of the breast stroma influence tumor progression and response to therapy. Previous work in our lab has demonstrated that gene expression signatures in human stroma can predict outcome of breast cancer patients independently of clinical parameters and molecular subtypes. In this study, we expand our findings by focusing on a previously underrepresented subset of breast tumors that have no detectable ER, PR or HER2 (termed Triple-Negative, TN). TN tumors, which represent approximately 15% of all breast cancers, are typically associated with poor outcome. However, the contribution of the stroma to the underlying heterogeneity of TN breast cancer and its corresponding influence on therapeutic response is not well understood. To address this, we isolated TN tumor epithelial and stromal tissues by laser capture microdissection and subjected them to gene expression profiling. Class discovery revealed distinct gene-clusters (stromal properties) which are associated with prognosis in TNBC whole tumor samples. Analysis of the genes comprising each stromal property suggests that the properties primarily represent the prevalence of distinct cell types, namely T cells, B cells, activated fibroblasts, and myoepithelial cells. Importantly, these properties are not mutually exclusive, i.e. some tumors are associated with multiple stromal properties. While confirming the heterogeneity of TN-associated stroma, this also indicates that a multi-parameter classification better reflects the true nature of the tumor microenvironment. This project provides the first integrated in-depth analysis of the contribution of tumor stromal processes to TN disease heterogeneity, and positions the tumor microenvironment for therapeutic intervention. Citation Format: Crista Thompson, Sadiq M. Saleh, Nicholas Bertos, Mathieu Gigoux, Tina Gruosso, Margarita Souleimanova, Hong Zhao, Michael T. Hallett, Morag Park. Novel prognostic stromal subtypes in triple-negative breast cancer. [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 720.
Abstract 2307: Improved CAR safety by a non-lethal switch to control CAR activity at the T-cell surface membrane
Authors: Alexandre Juillerat, Alan Marechal, Jean-Marie Filhol, Philippe Duchateau, Laurent Poirot
Journal: Cancer Research (2016)

Abstract Adoptive immunotherapy using engineered T-cells has emerged as a powerful approach to treat cancer. The potential of this approach relies on the ability to redirect the specificity of T cells through genetic engineering. Novel specificities in T cells have been typically implemented through the genetic transfer of the so-called chimeric antigen receptors (CARs). CARs are synthetic receptors that associated an extracellular targeting moiety with one or more intracytoplasmic signaling domain derived from lymphocyte activation receptors. Present CAR architectures are designed to combine all relevant domains within a single polypeptide, thereby; they combines advantages of MHC unrestricted target recognition to the potent native effector mechanisms of the T cell. Although adoptive transfer of CAR T cells is proven to be an effective strategy to cancer therapy, potential adverse effects such as Cytokines Release Syndrome (CRS) and/or the risk of on-target off-tumor targeting are still a major concern. To date only suicide mechanisms that can eradicate the engineered T-Cell “at will” or mRNA CAR transfection approaches have been proposed to addresses this safety issue. Here, we describe the development of a small molecule based switch-on technology to control the surface presentation of a chimeric antigen receptor in T-cells. By grafting protein domains that can interact upon addition of a small molecule drug in the hinge domain of the CAR architecture, we are able to turn a T-cell endowed with an engineered CAR from an off-state to an on-state, in term surface presentation as well as for its specific cytolytic properties. This system offers the advantage of a “transient CAR T-cell” for safety while letting open the possibility of multiple cytotoxicity cycles using a small molecule drug. This non-lethal control system of CAR engineered T-cells represents an important advance for the safety of this technology. Citation Format: Alexandre Juillerat, Alan Marechal, Jean-Marie Filhol, Philippe Duchateau, Laurent Poirot. Improved CAR safety by a non-lethal switch to control CAR activity at the T-cell surface membrane. [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 2307.
Selection and characterization of the novel anti-human PD-1 FV78 antibody from a targeted epitope mammalian cell-displayed antibody library
Authors: Longlong Luo, Shi Wang, Xiaoling Lang, Tingting Zhou, Jing Geng, Xinying Li, Chunxia Qiao, Jiannan Feng, Beifen Shen, Ming Lv, Yan Li
Journal: Cellular and Molecular Immunology (2016)
Abstract 912: Mist1+ secretory progenitor cells can give rise to cancer in the intestine and colon
Authors: Yoku Hayakawa, Kosuke Sakitani, Woosook Kim, Yagnesh Tailor, Karan Nagar, Kazuhiko Koike, Samuel Asfaha, Timothy C. Wang
Journal: Cancer Research (2016)

Abstract Intestinal crypts are maintained by long-lived intestinal stem cells (ISCs) which reside near the base of glands. Above the ISC pool, there are short-lived progenitors that can supply lineage-specific differentiated cell types into the villus. Notch and Wnt pathways play a key role for determining the stem/progenitor cell function and their cell fate, and regulating cancer development in the gastrointestine. Although it has been well established that ISCs are a major origin of intestinal cancer, it remains unknown whether intestinal progenitor population can give rise to cancer. We use Mist1-CreERT mice and induce Notch and Wnt activation by mating with LSL-Notch1-IC mice and/or Apc flox mice. We found that a bHLH transcriptional factor Mist1 is expressed in Paneth cells (Lysozyme+CD24high) as well as short-lived secretory progenitors (Lysozyme-CD24low) in the intestine. Mist1+ secretory progenitors are radio- and chemo-resistant, but do not show stem cell interconversion even after intestinal injury or Lgr5 ablation. However, aberrant Notch activation changes Mist1+ cells to Lgr5+ long-lived enterocyte progenitors, with loss of secretory lineage differentiation. Mist1+CD24low progenitor population can form intestinal organoids with Notch activation in vitro. Mist1+ secretory progenitors can give rise to intestinal cancer by simultaneous Notch and Wnt activation by loss of Apc gene, while loss of Apc in Mist1 lineage alone does not develop cancer. In the colon, Mist1 marks colonic secterory progenitors that become to lineage trace and can be a cancer-initiating cell after Notch activation or DSS-induced colonic injury. These results provide the clear evidence of cellular plasticity dependent on Notch signaling in the gut, and suggest short-lived progenitors as another cellular origin of cancer besides ISC pool. Citation Format: Yoku Hayakawa, Kosuke Sakitani, Woosook Kim, Yagnesh Tailor, Karan Nagar, Kazuhiko Koike, Samuel Asfaha, Timothy C. Wang. Mist1+ secretory progenitor cells can give rise to cancer in the intestine and colon. [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 912.
Donor Lymphocyte Infusions (DLI) After Peripheral Blood Stem Cell Transplantation. A Retrospective Analysis of 357 Patients by the Chronic Leukemias Working Party EBMT.
Authors: Grzegorz Wladyslaw Basak, Anja van Biezen, Ronald Brand, Christoph Schmid, Cesare Guglielmi, Anton Schattenberg, Richard Szydlo, Peter A. Von Dem Borne, Leo Verdonck, Donald W. Bunjes, Wieslaw Wiktor-Jedrzejczak, Eduardo Olavarria, Theo de Witte
Journal: Blood (2009)
Transcription Factor Trps1 Promotes Tubular Cell Proliferation after Ischemia-Reperfusion Injury through cAMP–Specific 3′,5′-Cyclic Phosphodiesterase 4D and AKT
Authors: Yang Ju-Rong, Chen Ke-Hong, Huang Kun, Fu Bi-Qiong, Lin Li-Rong, Zhang Jian-Guo, Li Kai-Long, He Ya-Ni
Journal: Journal of the American Society of Nephrology (2016)

Trichorhinophalangeal 1 (Trps1) is a transcription factor essential for epithelial cell morphogenesis during kidney development, but the role of Trps1 in AKI induced by ischemia-reperfusion (I/R) remains unclear. Our study investigated Trps1 expression during kidney repair after acute I/R in rats and explored the molecular mechanisms by which Trps1 promotes renal tubular epithelial cell proliferation. Trps1 expression positively associated with the extent of renal repair after I/R injury. Compared with wild-type rats, rats with knockdown of Trps1 exhibited significantly delayed renal repair in the moderate I/R model, with lower GFR levels and more severe morphologic injury, whereas rats overexpressing Trps1 exhibited significantly accelerated renal repair after severe I/R injury. Additionally, knockdown of Trps1 inhibited and overexpression of Trps1 enhanced the proliferation of renal tubular epithelial cells in rats. Chromatin immunoprecipitation sequencing assays and RT-PCR revealed that Trps1 regulated cAMP-specific 3',5'-cyclic phosphodiesterase 4D (Pde4d) expression. Knockdown of Trps1 decreased the renal protein expression of Pde4d and phosphorylated Akt in rats, and dual luciferase analysis showed that Trps1 directly activated Pde4d transcription. Furthermore, knockdown of Pde4d or treatment with the phosphatidylinositol 3 kinase inhibitor wortmannin significantly inhibited Trps1-induced tubular cell proliferation in vitro Trps1 may promote tubular cell proliferation through the Pde4d/phosphatidylinositol 3 kinase/AKT signaling pathway, suggesting Trps1 as a potential therapeutic target for kidney repair after I/R injury.
Defining the mechanisms of response and resistance to anti-PD-1 therapy: An exploratory phase II study of pembrolizumab in advanced melanoma (ADAPTeM).
Authors: Kroopa Joshi, Andrew J.S. Furness, Theres Oakes, James Heather, Lavinia Anne Spain, Yien Ning Sophia Wong, Assma Ben Aissa, Mark Stares, Myles JF Smith, Dirk C Strauss, Andrew J Hayes, Teresa Marafioti, Samra Turajlic, Martin Eric Gore, Karl Peggs, Benjamin Chain, Sergio Quezada, James M. G. Larkin
Journal: Journal of Clinical Oncology (2016)

TPS9599 Background: Several large-scale clinical trials of pembrolizumab have demonstrated substantial efficacy and survival benefit in metastatic melanoma (MM). However, responses are limited to a fraction of patients (pts), highlighting the need to decipher the mechanisms that drive resistance and identify biomarkers predictive of response, thus guide the rational development of new combinations of immunomodulatory drugs. ADAPTeM will compare paired intratumoral and peripheral immune responses in responders and non-responders following PD-1 blockade, focusing on i) baseline and therapy-induced expression of co-inhibitory and co-stimulatory receptors on T cell subsets and ii) characterisation of the intratumoral T cell receptor (TCR) repertoire with peripheral tracking of these clones in the blood and correlation with clinical response. Methods: Suitable patients will undergo longitudinal blood sampling and core biopsies of subcutaneous (SC) or lymph node (LN) metastases prior to treatment, after 6 weeks of therapy and at disease progression. Pembrolizumab 200mg administered 3-weekly will be continued for 2 years providing pts are deriving clinical benefit. The accrual target is 40 pts. Key inclusion criteria: stage III unresectable or stage IV melanoma (cutaneous or mucosal), presence of SC or LN metastases, any number of previous lines of therapy/treatment naïve patients. Serial biopsies will be evaluated by multi-parametric flow cytometry with i) phenotypic characterisation of the frequency and function of tumour infiltrating T lymphocytes (TILs) ii) expression of co-inhibitory and co-stimulatory molecules including PD-1/CTLA-4/LAG-3/OX40/4-1BB/GITR/ICOS/TIM-3/TIGIT and correlation with clinical response. Multiplex immunohistochemistry will be used for geographical mapping of the tumour immune landscape assessing distribution and spatial relationships between tumour, TILs and myeloid cells. Quantitative high-throughput sequencing will be utilised to characterise the intratumoral TCR repertoire assessing both alpha and beta TCR chains, with peripheral tracking of tumoral clones and correlation with clinical response. Clinical trial information: NCT02663258.