tbuckley/cabot-search huggingface dataset:
Abstract 451: The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints
Authors: Nicolas Jose Llosa, Michael Cruise, Ada Tam, Elizabeth Wick, Elizabeth Hechenbleikner, Janis Taube, Lee Blosser, Hongni Fan, Hao Wang, Ming Zhang, Brandon Luber, Nickolas Papadopoulos, Kenneth Kinzler, Bert Vogelstein, Cynthia Sears, Robert Anders, Drew Pardoll, Franck Housseau
Journal: Cancer Research (2015)

Abstract We examined the immune microenvironment of primary colorectal cancer (CRC) using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry and functional analysis of tumor infiltrating lymphocytes. A subset of CRC displayed high infiltration with activated CD8+ CTL as well as activated Th1 cells characterized by IFN-γ production and the Th1 transcription factor Tbet. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly up-regulated expression of multiple immune checkpoints, including five - PD-1, PD-L1, CTLA-4, LAG-3 and IDO - currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of CRC. Significance. The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair defective subset of CRC selectively up-regulates at least 5 checkpoint molecules that are targets of inhibitors currently being clinically tested. Citation Format: Nicolas Jose Llosa, Michael Cruise, Ada Tam, Elizabeth Wick, Elizabeth Hechenbleikner, Janis Taube, Lee Blosser, Hongni Fan, Hao Wang, Ming Zhang, Brandon Luber, Nickolas Papadopoulos, Kenneth Kinzler, Bert Vogelstein, Cynthia Sears, Robert Anders, Drew Pardoll, Franck Housseau. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 451. doi:10.1158/1538-7445.AM2015-451
Clinical-Scale Expansion of Human Bone Marrow-Derived Mesenchymal Stromal Cells to Treat Patients After Ischemic Stroke.
Authors: Patrick J Hanley, Zhuyong Mei, Bing Yang, Osman Mir, Kaushik Parsha, April Durett, R. Brent Rice, Maria G Cabreira-Hansen, Sean I Savitz, Adrian P. Gee
Journal: Blood (2012)
Trying to find a cure for cystic fibrosis: CFTR biomarkers as outcomes
Authors: Patrick Lebecque
Journal: European Respiratory Journal (2013)

Trying to find a cure for cystic fibrosis: CFTR biomarkers as outcomesTo the Editor:In a recent issue of the European Respiratory Journal, DE BOECK et al. [1] provided a systematic review of the clinimetric properties of cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, giving supporting evidence for promoting these biomarkers as surrogate end-points.The authors are to be congratulated not only for having collected exhaustive data about CFTR biomarkers and attempted to clarify their role but also for having led tremendous efforts towards standardisation of these techniques over recent years.They concluded that available data demonstrate reliability, validity and responsiveness of nasal potential difference (NPD), as well as validity and responsiveness of sweat chloride levels.However, one may wonder whether these conclusions are in agreement with the results of the last randomised clinical trials involving the three most promising small molecules in the context of searching for a CFTR mutationspecific treatment.A phase 3 randomised clinical trial evaluating the effects of ataluren has been recently completed [2].The study involved 238 patients carrying at least one class I CFTR mutation who were randomised to receive ataluren or placebo for 48 weeks.From a pragmatic point of view, statistically significant benefit in terms of forced expiratory volume in 1 s (FEV1) was restricted to patients who were not using inhaled tobramycin, and the magnitude of the benefit was comparable to that reported with inhaled tobramycin [3].The pulmonary exacerbation rate was 23% lower in favour of ataluren.In keeping with a previous study, sweat chloride levels were unchanged.In contrast to the three much smaller previous studies, epithelial chloride secretion as assessed by NPD did not improve.This raises several possibilities.If ataluren is an effective drug, the validity of NPD and sweat chloride as CFTR biomarkers may be questioned; if ineffective, the reliability of NPD may be doubted.Furthermore, in patients homozygous for the F508del mutation, lumacaftor alone [4,5] or in combination with ivacaftor [5] induced similar, modest (,10 mmol?L -1 ) but significant decreases in sweat chloride.However, improvement of FEV1 was only observed when combining the drugs.Again, this challenges the above conclusions, casting doubt on the validity of the biomarkers and raising the possibility that FEV1 improvement in these studies might be unrelated to ion transport correction.CFTR biomarkers as surrogate end-points: recent trials cast doubt on validity of NPD and sweat chloride measurements http://ow.ly/nuTOD
611. Alpha-Dystrobrevin-3 Prevents Myopathy and Restores Diaphragm Function in the Alpha-Dystrobrevin Null Mouse
Authors: Guy L. Odom, Glen B. Banks, Marvin E. Adams, Kenneth L. Bible, Stanley C. Froehner, Jeffrey S. Chamberlain
Journal: Molecular Therapy (2015)

The dystrophin-glycoprotein complex (DGC) primarily functions as a structural element enabling a linkage between the cytoskeleton and the extracellular matrix. Alpha-dystrobrevin (α-Db), a dystrophin subfamily member, is a component of the DGC within striated muscles. Decreasing amounts of α-Db from the sarcolemma contributes to severity of disease in several muscular dystrophies including Duchenne muscular dystrophy (DMD). The functional roles of α-Db1 and α-Db2 in muscle have been well studied. However, the role of a-Db3 has largely been ignored because it lacks many of the known functional domains present in α-Db1 and α-Db2. Importantly, we demonstrate by whole-body adeno-associated viral vector gene transfer into α-dystrobrevin-null mice, that α-DB3 becomes integrated within the DGC, localizes to costameres, prevents muscle degeneration, synapse fragmentation, myotendinous junction defects and corrects diaphragm functional capacity. Further, we demonstrate α-Db3 can bind the sarcoglycan complex in vitro. Thus, the association of α-Db3 within the DGC appears essential for its function, providing a direct link similar to dystrophin, with transmembrane and cytoplasmic DGC components whose absence likely contributes to sarcolemma fragility and/or disruption of signaling pathways in multiple muscular dystrophies.
Abstract 2917: Caspase-8 expression is predictive of tumor response to death receptor 5 agonist antibody conatumumab in Ewing's sarcoma
Authors: Zhigang Kang, D Seth Goldstein, Yunkai Yu, Paul S. Meltzer, David M. Loeb, Liang Cao
Journal: Cancer Research (2015)

Abstract Despite good initial response to cytotoxic chemotherapy, approximately 30% of Ewing's sarcoma (EWS) patients who present with localized tumors develop recurrent disease, which is associated with poor prognosis. Addressing this clinical challenge requires the development of targeted therapies. This study shows that many EWS cell lines are selectively sensitive to a death receptor DR5 antibody and are more resistant to a DR4 antibody. Preclinical evaluation of these cell lines indicates their sensitivity to human DR5 agonist antibody conatumumab in vitro, which induces rapid activation of caspase-8 and apoptosis. Further analysis reveals the correlation of sensitivity to conatumumab with the expression of caspase-8, with its catalytic activity both necessary and sufficient to confer such sensitivity. In vivo, conatumumab has active against both EWS cell lines and a patient-derived xenograft with higher caspase-8 expression, but is not effective against another patient-derived xenograft with lower caspase-8 expression. These studies suggest the potential of conatumumab as a therapeutic agent against EWS and caspase-8 as a biomarker for correlative studies. Citation Format: Zhigang Kang, D Seth Goldstein, Yunkai Yu, Paul S. Meltzer, David M. Loeb, Liang Cao. Caspase-8 expression is predictive of tumor response to death receptor 5 agonist antibody conatumumab in Ewing's sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2917. doi:10.1158/1538-7445.AM2015-2917
Skeletal Muscle Density Is Independently Prognostic of Outcomes in Newly Diagnosed Mantle Cell Lymphoma Patients: Post Hoc Analysis of LYM 3002
Authors: Michael P. Chu, Andrew Belch, Lixia Pei, Xue (Loya) Yang, Tadeusz Robak, Brendan Rooney, Andrew Cakana, Helgi van de Velde, Michael B Sawyer
Journal: Blood (2015)
Abstract 4034: Macrophage-dependent activation of a non-canonical NOTCH-RhoA signaling pathway regulates tumor cell intravasation
Authors: Jose Javier Bravo Cordero, Minna Roh-Johnson, Jeanine Pignatelli, Maja Oktay, Louis Hodgson, John Condeelis
Journal: Cancer Research (2015)

Abstract Intravital imaging of rodent mammary tumors has shown that direct contacts between a Mena expressing tumor cell, a perivascular macrophage and an endothelial cell forms a microanatomical structure named TMEM (Tumor Microenvironment of Metastasis). Clinical studies have shown that the number of TMEM is correlated with an increased risk of developing distant metastasis in breast cancer patients. While TMEM is an excellent prognostic marker for predicting metastasis the mechanisms of TMEM assembly and function are not understood. Recently, we showed that heterotypic cell contact between tumor cells and macrophages induces the formation of invadopodia in tumor cells, invasive structures necessary for matrix degradation and required for tumor cell intravasation. Using high resolution FRET imaging, we further found that macrophage-induced invadopodium formation is dependent on RhoA activation in the tumor cell. However, what remained to be determined was the signaling pathway that regulated this heterotypic cell contact-mediated phenomenon. We explored the role of NOTCH, a known receptor involved in heterotypic cell contact signaling, in stimulating macrophage-dependent tumor cell invadopodium formation and transendothelial migration. We found that, in the absence of Notch signaling, macrophage-induced invadopodium formation and tumor cell intravasation are abolished. Moreover, RhoA is no longer activated in tumor cells upon macrophage contact when Notch signaling is perturbed. These results show that Notch signaling regulates heterotypic cell contact mediated invadopodium formation through RhoA activation, and reveals a novel non-canonical NOTCH/RhoA pathway as a molecular target to prevent TMEM function and therefore metastasis. Citation Format: Jose Javier Bravo Cordero, Minna Roh-Johnson, Jeanine Pignatelli, Maja Oktay, Louis Hodgson, John Condeelis. Macrophage-dependent activation of a non-canonical NOTCH-RhoA signaling pathway regulates tumor cell intravasation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4034. doi:10.1158/1538-7445.AM2015-4034
Merging of Children's Oncology Group and Pediatric Health Information Systems Data to Determine Resource Utilization and Treatment Costs on AAML0531: A Report From the Children's Oncology Group
Authors: Richard Aplenc, Brian T. Fisher, Lillian Sung, Ron Keren, Todd A. Alonzo, Mathew Hall, Yuan-Shung V. Huang, Yimei Li, Xianqun Luan, Robert B. Gerbing, David Bertoch, Alix E. Seif, Peter C. Adamson, Alan S. Gamis
Journal: Blood (2011)
646. Isolation and Evaluation of Novel Anti-AAV2 and AAV3B Antibody Clones from a Human Donor
Authors: April R. Giles, Roberto Calcedo, Surina Boyd, Qiuyue Qin, Mark Schneider, Anna Tretiakova, James M. Wilson
Journal: Molecular Therapy (2015)

Neutralizing antibodies against AAV, whether generated via natural exposure or viral vector, have been shown to significantly reduce the efficiency of gene transfer, particularly following intravenous administration. One proposed approach to overcoming this obstacle is the engineering of an AAV capsid that is able to evade neutralization by these antibodies. The epitopes of a handful of antibodies have been mapped to their respective AAV capsids via cryo-EM or X-ray crystallography, but these antibodies are most often mouse monoclonals and their relevance to human vector immunology is unknown. In addition, these antibodies likely represent only a small fraction of the humoral response to AAV, as no comprehensive panel against a single serotype has been studied; rather, one or two quality capsid:Fab structures have been obtained for a given serotype. Given recent advancements in B cell cloning technologies, it is now possible to develop a panel of human monoclonals against AAV for the evaluation of neutralizing capacity and epitope mapping to identify the immunodominant regions of the AAV capsid. To obtain these monoclonals, we screened 30 human donors for NAbs against AAV2 and AAV3B and selected the donors with a titer of 1:320 against AAV3 and a titer of 1:40 against AAV3B. We obtained bulk switched memory B cells via magnetic bead sorting and seeded single sorted cells on irradiated 3T3-msCD40L cells in the presence of IL-2 and IL-21 and cultured cells for 2 weeks to promote expansion and antibody secretion. Culture supernatants were screened for AAV2 and AAV3B reactivity via ELISA; of positive clones obtained, 39% were specific for AAV2, 41% were specific for AAV3B, and the remaining 20% were reactive towards both AAV2 and AAV3B. In order to obtain heavy and light chain sequences for expression and characterization of these antibodies, we have performed nested PCR based on conserved regions in the immunoglobulin gene for some anti-AAV monoclonals and are currently completing PCR on the remaining clones. Of the sequences obtained thus far, the majority display a substantial amount of somatic hypermutation relevant to corresponding germline sequences; the percentage of base pair substitutions resulting in a missense mutation within the complementarity-determining regions was approximately 80%, with the frequency of mutation averaging 0.26 per residue. Mutations preferentially occurred in CDRs over framework regions, again suggesting that these antibodies have undergone maturation in response to exposure to AAV antigen. Subsequent analysis of the neutralizing capacity of these antibodies as well as the mapping of their epitopes will provide critical information for evaluating the feasibility of designing AAV variants capable of evading neutralization by anti-AAV antibodies.
Genetic Susceptibility to Anthracycline-Related Congestive Heart Failure (CHF) in Survivors of Hematopoietic Cell Transplantation (HCT)
Authors: Saro H. Armenian, Yan Ding, George Mills, Can-Lan Sun, Kalyanasundaram Venkatraman, F. Lennie Wong, David Senitzer, Shirong Wang, Stephen J. Forman, Smita Bhatia
Journal: Blood (2012)
ERdj5 sensitizes neuroblastoma cells to ER stress-induced apoptosis via regulation of eLF2a signaling
Authors: Christophoros Thomas, Giannis Spyrou
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5266 

The accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) (ER stress) induces a coordinated adaptive program called the unfolded protein response (UPR). The UPR alleviates stress by upregulating protein folding and degradation pathways and inhibiting protein synthesis. Translational repression is mediated by increased phosphorylation of eukaryotic translation initiation factor 2a (eIF2a). Although the activation of the UPR normally succeeds in restoring ER homeostasis, persistent or intense ER stress can trigger apoptosis. Here we demonstrate that the Thioredoxin domains-containing novel ER-resident chaperone molecule ERdj5 affects cell survival and controls eIF2a phosphorylation and signaling in response to ER stress. We show that overexpression of ERdj5 induces both G1/S cell cycle arrest and apoptosis in neuroblastoma cells in response to ER stress. ERdj5 overexpression delays the eIF2a dephosphorylation and the translational recovery normally observed late in the stress response by decreasing the expression of GADD34, a subunit of the PP1-holophosphatase complex that dephosphorylates eIF2a when the stress is overcome. Furthermore, defective recovery of protein synthesis impairs translation of stress-induced proteins in the ERdj5-overexpressing cells. These observations indicate that ERdj5-mediated delay of translational recovery decreases cancer cell resistance to apoptosis induced by ER stress.
Risk Factors That Increase Risk of Estrogen Receptor–Positive and –Negative Breast Cancer
Authors: Karla Kerlikowske, Charlotte C. Gard, Jeffrey A. Tice, Elad Ziv, Steven R. Cummings, Diana L. Miglioretti
Journal: JNCI Journal of the National Cancer Institute (2016)

Background: Risk factors may differentially influence development of estrogen receptor (ER)–positive vs –negative breast cancer. We examined associations with strong, prevalent risk factors by ER subtype.
Development of Novel Stem Cell Transplantation and Gene-Immunotherapy Using WT1-Specific T-Cell Receptor Gene.
Authors: Toshiki Ochi, Hiroshi Fujiwara, Kozo Nagai, Toshiaki Shirakata, Kiyotaka Kuzushima, Sachiko Okamoto, Junichi Mineno, Hiroshi Shiku, Hidetoshi Ozawa, Fumihiko Ishikawa, Masaki Yasukawa
Journal: Blood (2009)
Distinct Expression Patterns in Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) Characterized by Uniparental Disomy.
Authors: Lars Bullinger, Jan Kronke, Ursula Botzenhardt, Sabrina Heinrich, Katja Urlbauer, Simone Miller, Christian Schon, Richard F. Schlenk, Karlheinz Holzmann, Konstanze Dohner, Hartmut Dohner
Journal: Blood (2008)
Universal Genetic Testing for Younger Patients With Colorectal Cancer
Authors: Eduardo Vilar, Elena M. Stoffel
Journal: JAMA Oncology (2016)

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The value of bone scanning, liver ultrasonography and chest radiography in breast cancer staging
Authors: F. Puglisi, A. Follador, A. M. Minisini, G. G. Cardellino, S. Russo, S. Di Terlizzi, C. Andreetta, G. Aprile, A. Piga
Journal: Journal of Clinical Oncology (2004)

6065 Background: Bone scanning (BS), liver ultrasonography (LU) and chest X-ray (CXR) are commonly used in patients (pts) with newly diagnosed breast cancer as part of baseline staging. However, in absence of symptomatic disease, the usefulness of this routine metastatic workup is not evidence based. Methods: We selected the study sample from 557 patients with newly diagnosed breast cancer who were consecutively referred to our institution between February 1999 and August 2003. For each diagnostic test we analyzed the detection rate defined as the number of pts with abnormal test results indicative of metastases divided by the total number of pts tested. In addition, sensitivity and specificity were calculated (cases categorized as suspicion by the tests were computed as positive). Initial suspicion was confirmed by other independent tests (bone X-ray, CT scan, MRI) in order to identify “true” positive diagnoses. Results: At baseline, BS was performed in 412 pts, LU in 412 pts and CXR in 428 pts. After the initial staging investigations, 33 pts (7.7% of our evaluable cohort) were diagnosed as having metastatic disease. BS detected skeletal metastases in 6.31% of pts, LU detected liver metastases in 0.62% of pts and CXR detected lung metastases in 0.93% of pts. Sensitivity and specificity were 100% and 93.5%, 100% and 93.6%, 100% and 96.9%, respectively for BS, LU and CXR. All pts with either LU or CXR indication of metastases were previously classified as having stage III disease. On the contrary, only 27% of bone metastases were detected in pts with stage III. Accordingly, the detection rate in stage III pts was 14%, 5.6% and 7.2%, respectively for BS, LU and CXR. Conclusions: These findings suggest that the diagnostic workup to detect metastases is unnecessary in the majority of pts with newly diagnosed breast cancer. The study also shows that radiological staging tests may be indicated for specific pts categories such as those with stage III disease. No significant financial relationships to disclose.
Methyl Dehydro-Jasmonate Has Anti-Inflammatory Effect Cells and Its Molecular Targets Mir-155 and NF-Kb Pathway against LPS Stimulation On RAW264.7.
Authors: Hye-Ja Lee, Hung-The Dang, Gyeoung-Jin Kang, Jee H Jung, Hee-Kyoung Kang, Hyejin Shin, Josef T. Prchal, Eun-Sook Yoo, Donghoon Yoon
Journal: Blood (2009)
Targeting the p27Kip1 E3 Ubiquitin Ligase for the Treatment of Multiple Myeloma and Other Hematological Malignancies.
Authors: Qing Chen, Weilin Xie, Deborah J. Kuhn, Peter M. Voorhees, Derek Mendy, Antonia Lopez-Girona, Veronique Plantevin, Weiming Xu, Laura De Parseval, Laura G. Corral, Emilia Glezer, Kyle Chan, Frank Mercurio, Robert Z. Orlowski
Journal: Blood (2006)