tbuckley/cabot-search huggingface dataset:
Abstract 2839: Specific mutant tumor DNA can be detected in ovarian cystic fluid of an unknown ovarian tumor cyst
Authors: Karin Sundfeldt, Björg Kristjansdottir, Bert Vogelstein
Journal: Cancer Research (2015)

Abstract Can we detect rare mutations in ovarian cystic fluid of unknown severity in order to develop a molecular genetic test for epithelial ovarian cancer? Background: Benign and malignant ovarian cysts are difficult to distinguish. Early diagnose is life saving, however 75% of ovarian adenocarcinomas is found in late stage. Approx. one operated ovarian cyst in 7-10 are found to be cancer and potentially life-threatening, subjecting the woman to unnecessary oophorectomy and morbidity. A genetic test of fine needle aspirated cystic fluid has to be very accurate to be able to substitute the histopathologic examination following surgery. Methods: DNA was purified from 78 ovarian cystic fluids (collected at the time of operation) from serous adenomas/adenocarcinomas and corresponding tumor tissues and subjected to state-of-the-art genetic analysis. We evaluated ∼10,000 bp for subtle mutations (single base substitutions, small insertions, small deletions). Under the conditions used, mutations present in &amp;gt;0.1% of template molecules could be detected. The analyses were carried out in a completely blind fashion. We then evaluated the DNA of the primary tumor. Results: We detected zero, one, or two mutations per cyst. The same mutations were identified in the corresponding tumor tissue, and no others. This dramatically confirms the specificity of the approach. 91% of the malignant cysts (n = 32) had at least one mutation and 62% of these were in TP53; 17% in low (n = 12) and 90% in high (n = 20) grade serous adenocarcinoma regardless of stage. In low-grade tumors mutations in KRAS dominated over PIK3C and PTEN. 65% of the borderline type (LMP n = 20) tumors had a BRAF V600E mutation. The mutant allelic fraction was much higher in malignant than benign tumors; the DNA concentration was relatively low in 20 benign cysts and no mutations were identified in this group consisting of 10 serous adenoma and 10 simple cysts (healthy controls). Results will be correlated to survival. Conclusion: Data proofs that we can detect mutant tumor DNA corresponding to the primary ovarian tumor in the ovarian cystic fluid. Data suggest that gene-testing of ovarian cystic fluid could aid in diagnostics and further guide its management. Citation Format: Karin Sundfeldt, Björg Kristjansdottir, Bert Vogelstein. Specific mutant tumor DNA can be detected in ovarian cystic fluid of an unknown ovarian tumor cyst. [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 2839. doi:10.1158/1538-7445.AM2015-2839
Abstract 1949: Oncogenic signaling in amphiregulin- and EGFR-expressing PTEN-null human breast cancer
Authors: Christiana S. Kappler, Stephen T. Guest, Ericka L. Smith, Jonathan C. Irish, Elizabeth Garrett-Mayer, Zachary Kratche, Stephen Ethier
Journal: Cancer Research (2015)

Abstract A subset of triple negative breast cancer (TNBC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) and loss of PTEN, and patients with these factors have a poor prognosis. In addition, approximately half of all basal breast cancers show autocrine activation of EGFR by amphiregulin (AREG), resulting in altered receptor trafficking and downstream signaling. However, despite the strong rationale for targeting EGFR in the treatment of TNBC, EGFR inhibitors have performed poorly in clinical trials. To further analyze the signaling processes active in this subset of TNBC, we performed reverse-phase protein array (RPPA) analysis on SUM149 cells, a highly tumorigenic and metastatic PTEN-null cell line that expresses high levels of AREG and EGFR, and MCF10A cells, a non-transformed mammary epithelial cell line cultured in the presence of either EGF or AREG. This analysis identified a number of signaling components mediated specifically by amphiregulin, including marked changes in integrin expression and increased levels of fibronectin, which is known to be a mediator of invasive capacity via interaction with integrin β1. RPPA analysis also revealed elevated AKT activity in SUM-149 cells, which was not surprising given the lack of PTEN expression. Interestingly, this AKT activity is not abrogated by treatment with the EGFR inhibitor gefitinib, nor by treatment with PI3K inhibitors. These findings and the results of preliminary experiments in SUM149 cells re-expressing PTEN suggest that AKT activity in these cells is, at least partly, independent of EGFR and PI3K activity. In addition, expression profiling demonstrated that AREG-activated EGFR regulates gene expression differently than EGF-activated EGFR, and functional analysis via genome-scale shRNA screening identified a set of genes, including PLK1 and BIRC5, that are regulated by EGFR in MCF10A cells but uncoupled from EGFR signaling in SUM149 cells, although they are essential for the survival of SUM-149 cells. Thus, our results demonstrate that in cells with constitutive EGFR activation and PTEN loss, critical survival genes are uncoupled from regulation by EGFR, a mechanism that is likely to mediate resistance to EGFR inhibitors. Citation Format: Christiana S. Kappler, Stephen T. Guest, Ericka L. Smith, Jonathan C. Irish, Elizabeth Garrett-Mayer, Zachary Kratche, Stephen Ethier. Oncogenic signaling in amphiregulin- and EGFR-expressing PTEN-null human breast cancer. [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 1949. doi:10.1158/1538-7445.AM2015-1949
Abstract 4299: MicroRNA 200c regulates cytochrome P450 1B1-mediated docetaxel resistance in renal cell cancers
Authors: Inik Chang, Yozo Mitsui, Shinichiro Fukuhara, Ankurpreet Gill, Darryn K. Wong, Soichiro Yamamura, Varahram Shahryari, Z. Laura Tabatabai, Rajvir Dahiya, Dong Min Shin, Yuichiro Tanaka
Journal: Cancer Research (2015)

Abstract Cytochrome P450 1B1 (CYP1B1) is up-regulated in many types of cancer. It has been suggested that CYP1B1 may be a general tumor biomarker and have an important function in cancers. Despite its high protein expression and enzymatic activity in renal cell cancer (RCC), functional significance of CYP1B1 has not been elucidated. Here we explored the functional role and regulatory mechanism of CYP1B1 in RCC. Reduction of CYP1B1 levels fail to prevent in vitro tumorigenicity such as proliferation, apoptosis, and cell cycle progression of RCC cells. Moreover, the expression levels are not associated with tumor type, stage, Fuhrman grade and 5-year survival probability after surgery. Instead, alteration of CYP1B1 expression regulates the chemosensitivity of RCC cells to docetaxel suggesting its critical contribution to the RCC chemoresistance. Additionally, miR-200c, which is significantly down-regulated in RCC tissues and cell lines regulates CYP1B1 mRNA, protein and enzyme activity. An inverse association was also observed between the expression levels of miR-200c and CYP1B1 protein in RCC tissues. Thus, high expression of CYP1B1 could be a result of decreased miR-200c expression in RCC. Finally, alteration of miR-200c levels affects the chemosensitivity of RCC cells. Restoration of docetaxel resistance by exogenous expression of CYP1B1 in miR-200c-over-expressing cells indicates that CYP1B1 is a functional target of miR-200c. These results suggest that CYP1B1 up-regulation mediated by low miR-200c is one of the mechanisms underlying resistance of RCC cells to docetaxel. Therefore, expression of CYP1B1 and miR-200c in RCC may be useful as a prediction for docetaxel response. Citation Format: Inik Chang, Yozo Mitsui, Shinichiro Fukuhara, Ankurpreet Gill, Darryn K. Wong, Soichiro Yamamura, Varahram Shahryari, Z. Laura Tabatabai, Rajvir Dahiya, Dong Min Shin, Yuichiro Tanaka. MicroRNA 200c regulates cytochrome P450 1B1-mediated docetaxel resistance in renal cell cancers. [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 4299. doi:10.1158/1538-7445.AM2015-4299
Quantitative Assessment of T Cell Repertoire Recovery after Double Unit Cord Blood Transplantation Demonstrates Early T Cell Diversity and Correlation Between CMV Reactivation and CD8 Clonal Domimance
Authors: Miguel Perales, Ying Taur, Ingrid Leiner, Marissa N Lubin, Boze Susac, Eric G. Pamer, Juliet N. Barker
Journal: Blood (2014)
Abstract 2353: Noncanonical NF-κB activation mediates STAT3-stimulated IDO up-regulation in myeloid-derived suppressor cells in breast cancer
Authors: Jinpu Yu, Yue Wang, Hui Li, Xiubao Ren
Journal: Cancer Research (2015)

Abstract Immunotherapy for cancer treatment is achieved through the activation of competent immune effector cells and the inhibition of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). While MDSCs have been shown to contribute to breast cancer development, the mechanism underlying MDSCs-mediated immunosuppression is unclear. We have identified a poorly differentiated MDSC subset in breast cancer suppressing T-cell function through signal transducer and activator of transcription (STAT) 3-dependent indoleamine 2,3 dioxygenase (IDO) up-regulation. Here we investigated the mechanisms underlying aberrant expression of IDO in MDSCs. MDSCs were induced by co-culturing human CD33+ myeloid progenitors with MDA-MB-231 breast cancer cells. Increased STAT3 activation in MDSCs was correlated with activation of the noncanonical nuclear factor-κB (NF-κB) pathway, including increased NF-κB-inducing kinase (NIK) protein level, phosphorylation of cytoplasmic inhibitor of NF-κB kinase (IKK) α and p100, and RelB-p52 nuclear translocation. Blocking STAT3 activation with the small molecule inhibitor JSI-124 significantly inhibited the accumulation of NIK and IDO expression in MDSCs. Knock-down of NIK in MDSCs suppressed IDO expression, but not STAT3 activation. RelB-p52 dimers were found to directly bind to the IDO promoter, leading to IDO expression in MDSCs. IL-6 was found to stimulate STAT3-dependent, NF-κB-mediated IDO up-regulation in MDSCs. Furthermore, significant positive correlation between the numbers of pSTAT3+ MDSCs, IDO+ MDSCs, and NIK+ MDSCs was observed in human breast cancers. These results demonstrate a STAT3-NF-κB-IDO pathway in breast cancer-derived MDSCs, which provides insight into understanding immunosuppressive mechanisms of MDSCs in breast cancer. Citation Format: Jinpu Yu, Yue Wang, Hui Li, Xiubao Ren. Noncanonical NF-κB activation mediates STAT3-stimulated IDO up-regulation in myeloid-derived suppressor cells in breast cancer. [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 2353. doi:10.1158/1538-7445.AM2015-2353
459. CAR-Transduced T Cells Demonstrate Increased CTL Function
Authors: Stephen E. Braun, Edith Walker, Gauham Sahu, Gail Skowron, Preston A. Marx, Andrew G. MacLean, Dorothee von Laer, Richard P. Junghans
Journal: Molecular Therapy (2015)

Infection with HIV-1 results in CD4+ T cell depletion and the subsequent loss of immune function results in AIDS. Although HAART lowers plasma viremia, it requires life-long drug therapy. However, elite controllers are able to exert control over viral replication in the absence of cART therapy by maintaining polyfunctional HIV-specific T cells with high avidity TCR binding that target CTL epitopes where escape mutants have reduced fitness. To mimic increase immunosurveillance of elite controllers and prevent viral replication in a non-controlled setting, we will transduce T cells with CD4-CAR vectors to bolster and redirect the "designer T cells" (dTc) towards an HIV-specific target. Chimeric antigen receptors (CARs) are fusion proteins of an extracellular antigenbinding domain linked to intracellular T cell signaling domains. In CD4-CARs, the CD4 extracellular domain binds directly to diverse HIV envelopes and redirects the CTL activity. Env/CD4 binding is independent of both the MHC restriction and Nef down regulation. As in elite controllers, CD4-CARs targets an essential viral function where mutations would lower viral fitness and make viral escape difficult to achieve. The first-generation CD4-CAR vector, with only the T-cell receptor zeta (TCRζ) intracellular domain, killed Env+ cells in vitro but failed to control viremia in clinical trials. Recent studies with anti-tumor CARs show that additional co-stimulatory signals (CD28 and 4-1BB) improved CTL function in vitro, in murine models, and showed objective tumor regression in clinical trials. We hypothesize that genetically modified T cells designed to increase CTL killing of HIV+ cells, to persist in vivo, and to prevent viral infection will provide durable viral suppression in vivo and eliminate the need for life-long drug therapy as modeled by elite controllers. To determine what signaling domains would be necessary to mimic this immune protection, we developed a series of CD4-CAR vectors with various intracellular signaling domains. To protect dTc from infection, we co-transduced cells with the membrane-associated C46 (maC46), a fusion inhibitor tethered to dTc, that binds HIV and blocks viral replication thereby providing a strong selective advantage to transduced cells. Therefore, we stimulated PBMCs with αCD3αCD28 and co-transduced T cells with the series of CD4-CAR and maC46 vectors. To evaluate the functional activity of the dTc, we measured 1) HIV Env-specific cytotoxicity, 2) cytokine production using IFN-γ ELIspot, and 3) CAR-specific proliferation of dTc. CD4-CAR T cells demonstrated Env+ specific killing, increased frequency of IFN-γ spot-forming cells, and CAR-specific proliferation. Our long-term goal, to adoptively transfer dTc with increased CTL function (cytokine production, proliferative capacity, viral suppression). The control of viremia in the absence of HAART would revolutionize HIV treatments for patients with AIDS.
Authors’ reply to Pérol and colleagues
Authors: Lars G Hemkens, Despina G Contopoulos-Ioannidis, John P A Ioannidis
Journal: BMJ (2016)

We thank Perol and colleagues for their reflections on our work on how routinely collected data might complement randomised controlled trials.1 2 We agree that routinely collected data may be used to analyse any number of associations for combinations of medical interventions, patient characteristics, settings, and concurrent treatments. They may indeed …
Heme Oxygenase-1: A Potential Modulator of Inflammation and Vaso-Occlusion in Sickle Cell Disease.
Authors: John D. Belcher, Thomas E. Welch, Hemachandra Mahaseth, Khalid M. Sonbol, Paul R. Bowlin, John C. Bischof, Robert P. Hebbel, Gregory M. Vercellotti
Journal: Blood (2004)
338. Evaluation of TALENs and the CRISPR/Cas9 Nuclease System To Correct the Sickle Cell Disease Mutation
Authors: Megan D. Hoban, Dianne Lumaquin, Caroline Kuo, Zulema Romero, Courtney Young, Michelle Ho, Joseph Long, Nathan Coss, Carmen Bjurstrom, Michelle Mojadidi, Roger P. Hollis, Donald B. Kohn
Journal: Molecular Therapy (2015)

Targeted genome editing technology can correct the sickle cell disease mutation of the beta-globin gene in hematopoietic stem and progenitor cells (HSCs). The correction induces production of red blood cells that synthesize normal hemoglobin proteins. Transcription Activator-Like Effector Nucleases (TALENs) and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 nuclease systems have been developed to target the sickle mutation in the beta-globin gene for site-specific cleavage to facilitate precise correction of the sickle mutation by a co-delivered homologous donor template. K562 cells were electroporated with TALEN and CRISPR/Cas9 expression plasmids and, using the Surveyor Nuclease Assay (Cel-1), cleavage rates were quantified and compared between TALEN- and CRISPR/Cas9-treated cells. Of the six CRISPR/Cas9 guides tested, each of them led to target disruption of the beta-globin locus with the highest cleavage rates upwards of 35% of alleles. Of 4 distinct TALEN pairs generated, only 2 demonstrated targeted cleavage at rates nearing 10% of alleles. In addition to on-target cleavage at beta-globin, nuclease off-target cleavage at other beta-globin family genes was evaluated for each technology by Cel-1 of nucleofected K562 cells. Here the two TALEN pairs demonstrate cleavage in the highly-homologous delta-globin gene with the optimal TALEN pair cleaving 11% of alleles. In this assay, of the 6 CRISPR guides tested, none showed off-target disruption of delta-globin or any of the other beta-globin cluster genes. Of note, in each of the tested guides, at least one base differed from the target site in beta-globin to the respective sequence in delta-globin in the 10bp PAM proximal region. Further experiments are being conducted to determine the genome-wide off-target effects of each of these nucleases. Upon co-delivery of a plasmid donor template containing the corrective base at the sickle site as well as a restriction fragment length polymorphism (RFLP) for rapid assessment of targeted gene modification, both nuclease technologies led to gene modification. Gene modification rates were assayed by qPCR with primers specific to the modified base. TALENs drove gene modification rates of 18%, while the optimal CRISPR guides resulted in 37% modification in K562 cells without sorting for transfected cells. These results provide the basis for pursuing the use of the CRISPR/Cas9 nuclease system for targeted correction of the sickle mutation in human HSCs.
The Novel Bispecific Antibody [(CD20)2xCD16] Efficiently Triggers Lysis of Neoplastic B Cells
Authors: Pia Glorius, Anne Baerenwaldt, Christian Kellner, Matthias Staudinger, Paul W.H.I. Parren, Jan G. J. van De Winkel, Andreas Humpe, Thomas Valerius, Roland Repp, Falk Nimmerjahn, Martin Gramatzki, Matthias Peipp
Journal: Blood (2010)
Autologous Bone Marrow-Derived Stem Cell Therapy: A Promising and Prospective Approach in the Treatment of Patients with Severe Buerger’s Disease.
Authors: Zoltan Boda, Miklos Udvardy, Katalin Razso, Mariann Szarvas, Zsolt Olah, Peter Ilonczai, Judit Toth, Laszlo Jambor, Janos Hunyadi, Tamas Sipos, Gabriella Kovacs, Janos Kappelmayer, Katalin Farkas, Zoltan Vereb, Eva Rajnavolgyi
Journal: Blood (2008)
The Immune-Inhibitory Receptor Osteoactivin Is up-Regulated In Monocyte-Derived Dendritic Cells Upon Exposure to Tyrosine Kinase Inhibitors
Authors: Michael Gutknecht, Mark-Alexander Schwarzbich, Julia Salih, Lothar Kanz, Helmut R. Salih, Susanne M. Schmidt, Frank Grünebach
Journal: Blood (2010)
Arsenic Trioxide (ATO) as Induction Therapy Achieves Early Complete Cytogenetic Remission In Acute Promyelocytic Leukemia (APL)
Authors: Hari Menon, Amol Akhade, Manju Sengar, Pratibha Amare, P. Subramanian, Reena Nair, Anuradha Chougule
Journal: Blood (2010)
REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy.
Authors: Maurice Perol, Tudor-Eliade Ciuleanu, Oscar Arrieta, Kumar Prabhash, Konstantinos N. Syrigos, Tuncay Göksel, Keunchil Park, Ruben Dario Kowalyszyn, Joanna Pikiel, Grzegorz Czyzewicz, Sergey Orlov, Conrad R. Lewanski, Ekaterine Alexandris, Annamaria Zimmerman, Nadia Chouaki, William J. John, Sergey Yurasov, Edward B. Garon
Journal: Journal of Clinical Oncology (2014)

LBA8006^ Background: RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The REVEL study evaluated the efficacy and safety of RAM+DOC vs. PL+DOC (DOC) in patients (pts) with stage IV nonsquamous (NSQ) and squamous (SQ) NSCLC after platinum-based therapy. Methods: Pts with NSQ and SQ stage IV NSCLC were randomized 1:1 (stratified by sex, region, ECOG PS, and prior maintenance therapy) to receive DOC 75 mg/m 2 in combination with either RAM 10 mg/kg or PL on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS), and objective response rate (ORR). Results: Between Dec 2010 and Feb 2013, 1,253 pts (26.2% SQ) were randomized (RAM+DOC: 628; DOC: 625). Pt characteristics were balanced between arms. ORR was 22.9% for RAM+DOC and 13.6% for DOC (P&lt;0.001). The hazard ratio (HR) for PFS was 0.762 (P&lt;0.0001); median PFS was 4.5 months (m) for RAM+DOC vs. 3.0m for DOC. REVEL met its primary endpoint; the OS HR was 0.857 (95% CI 0.751, 0.98; P=0.0235); median OS was 10.5m for RAM+DOC vs. 9.1m for DOC. OS was longer for RAM+DOC in most pt subgroups, including SQ and NSQ histology. Grade ≥3 adverse events (AEs) occurring in &gt;5% of pts on RAM+DOC were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all pts: 2.1% vs. 1.6%; SQ pts: 3.8% vs. 2.4%). Conclusions: REVEL demonstrated a statistically significant improvement in ORR, PFS, and OS for RAM+DOC vs DOC in NSCLC pts with stage IV NSCLC as second-line treatment after platinum-based therapy. Benefits were similar in NSQ and SQ pts, and no unexpected AEs were identified. Clinical trial information: NCT01168973.
Individualized treatment schedule and investigator ‘s defined time to resistance (TTRi) may prolong survival in patients with metastatic renal cell carcinoma (mRCC)
Authors: Manuela Schmidinger, Ursula Vogl, Markus Margreiter, Shahrokh F. Shariat, Christoph Zielinski
Journal: Journal of Clinical Oncology (2015)

e15585 Background: Sequential treatment with sunitinib and axitinib was shown to improve survival in mRCC up to 33.7 months. Modifying the schedule of sunitinib (to 2 weeks on-1 week off in stead of 4 weeks on-2 weeks off) appears to improve tolerability without impairing progression-free survival (PFS). The aim of this analysis was to investigate the outcome of an upfront sunitinib 2/1-schedule in real world patients. As RECIST-defined PFS may not always reflect the duration of clinical benefit in daily practice, investigator’s perceived occurrence of resistance, defined as time from start of sunitinib to resistance from investigator’s perspective (TTRi) was used as an endpoint leading to switch of treatment Methods: a single centre retrospective analysis was conducted to evaluate outcomes of patients who received upfront first-line sunitinib on a 2 weeks on-1 week off schedule. Sunitinib was given at a dose of 50 mg until investigator’s defined occurrence of resistance (TTRi). Dose escalations were permitted at occurrence of RECIST-defined progression and treatment was continued until TTRi Results: 37 consecutive clear cell mRCC-patients were included in this analysis. Most patients (94%) had an ECOG of 0 and were intermediate risk (51%). Ninety-seven percent of patients had undergone cytoreductive surgery. The most common site of metastases was the lung (73%), followed by lymph nodes (38%), bone (24%) and liver (19%). Thirty-two and 30% of patients had two and 3+ metastatic sites. TTRi was 34.3 months (95%CI: 0.12-71.3). Dose escalations were performed in 32% of patients. At occurrence of TTRi, patients were offered a median number of 2 subsequent treatment lines (range 0-5). Strategies beyond first-line mostly included axitinib (60%), everolimus (53%) and sunitinib-rechallenge (53%). The median overall survival was 75.1 months (95%CI: n.r). Conclusions: Individualized sunitinib scheduling and investigator- rather than RECIST-driven sunitinib-treatment duration may dramatically improve survival when compared to historical data in mRCC.