tbuckley/cabot-search huggingface dataset:
Abstract 1437: Improving efficacy and accuracy of CAR-T cells for neuroblastoma
Authors: Babak Moghimi, Sakunthala Muthugounder, Shahab Asgharzadeh
Journal: Cancer Research (2019)

Abstract Background: Anti-disialoganglioside (GD2) specific CAR T-cell therapy has shown limited efficacy in children with recurrent/refractory neuroblastoma (NBL). A recent pre-clinical study demonstrated significant neurotoxicity in mice treated with CAR T-cells bearing a high-affinity anti-GD2 short chain variable fragments (scFv; Richman S et al. 2017). To devise a safe and more efficacious CAR T-cells, we developed a gated CAR T-cell system utilizing the Syn-Notch technology. Methods: GD2 and CD19 specific Syn-Notch gated systems were constructed by linking corresponding scFv to the Notch core followed by Gal4Vp64. Upon target recognition, Gal4VP64-dependent UAS element would initiate expression of the B7H3-BBZ CAR. Reporter activity of CD19 or GD2 Syn-Notch systems were monitored using flow cytometry after exposure to CD19+ transduced CHLA255 NBL cell line. In vitro cytotoxicity was assessed using DIMSCAN and xCELLigence impedance assays at varying Effector: Target ratios. NSG mice with established metastatic CHLA255(GD2+CD19+) NBL were treated with 1x10^7 transduced and control T cells and monitored for disease burden. Results and discussion: Jurkat and human primary T cells were successfully transduced with the Syn-Notch system. GD2-Notch-Gal4VP64 and CD19-Notch-Gal4VP64 T-cells effectively activated downstream reporter in exposure to CHLA255(GD2+CD19+) within 6 hours of exposure but not in the presence of NBL cells lacking GD2 or CD19. The GD2 system exhibited greater leakiness than the CD19 counterpart. GD2- Syn-Notch-B7H3-BBZ or CD19- Syn-Notch-B7H3-BBZ CAR T-cells demonstrated statistically significant cytotoxicity against CHLA255(GD2+CD19+) NBL cell line. Preliminary in vivo data also show the anti-tumor effect of these gated CAR systems compared to mock-transduced T-cells. Conclusions: We have successfully established a novel GD2-B7H3 gated system using the Syn-Notch technology, and demonstrate successful specificity to both antigen targets. This system increases the specificity of CAR T-cells against GD2 and B7H3 positive neuroblastoma tumors and likely minimize GD2-induced toxicity. These gated CARs show great promise for establishing immunotherapies that maximize tumor specificity while minimizing toxicity. Citation Format: Babak Moghimi, Sakunthala Muthugounder, Shahab Asgharzadeh. Improving efficacy and accuracy of CAR-T cells for neuroblastoma [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 1437.
Abstract 3007: Validation of an NGS panel assay for detection of hotspot cancer somatic mutations
Authors: Wenzhi Li, Henry She, Xiaohua Tian, Margaret Neja, Adrian Harris, Yuhua Li
Journal: Cancer Research (2019)

Abstract Background The gene tests to predict whether cancers respond to specific targeted therapies or prediction of prognosis has quickly increased over the last decade. Next-generation sequencing (NGS) has become a powerful tool for high-throughput and sensitive gene mutation testing, which is required for development of targeted therapies, clinical trials, and further research. The aim of this study was to validate the AmpliSeq for Illumina Cancer Hotspot Panel v2 on the Illumina MiSeq platform and simultaneously analyze 2800 somatic mutations across the hotspot regions of 50 genes, including SNP and small INDEL, with known associations to cancer, as identified in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. This panel enables the study of the genes associated with different cancer types, including the cancers of the lung, colon, breast, thyroid, oral, bladder, prostate, liver, kidney, ovarian and cervix, etc. Methods and findings We validated this assay using the genomic DNA extracted from human paraffin-embedded (FFPE) samples and peripheral blood with negative control DNA (NA12878), positive control DNA (HD701), blank control as well as the global proficiency testing samples. Following two lab scientists parallel NGS library preparation, sequenced on Miseq platform (2x150 PE) and analyzed using a pipeline centered on Illumina Basespace, the somatic mutations were called at an average number of reads coverage &amp;gt;2500X, variant frequency cutoff 1%. An integrated test report can be generated within five working days. Panel sequencing analysis showed that the mutations are 100% concordance with known mutations and consistent in four runs, between lab personal performances, different input DNA concentrations (1ng-100ng), etc. Briefly, 25 mutations were detected in the FFPE samples and 20 mutations detected in proficiency testing samples. The variant types, HGVS ID and frequency are 100% match with its standard results which are a prove of precision and sensitivity. Conclusions A sensitive, high-throughput, pan-cancer mutation panel for NGS analysis of cancer hot-spot mutations in 50 genes was highly repeatable and reproducible and validated for routine application in a gene testing lab. Note: This abstract was not presented at the meeting. Citation Format: Wenzhi Li, Henry She, Xiaohua Tian, Margaret Neja, Adrian Harris, Yuhua Li. Validation of an NGS panel assay for detection of hotspot cancer somatic mutations [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 3007.
Abstract 2195: Real-world experience with afatinib as first-line treatment in advanced non-small cell lung cancer in a university hospital
Authors: Taewon Jang, Jaehoon Kim
Journal: Cancer Research (2019)

Abstract Purpose: In patients with non-small cell lung cancer (NSCLC), mutations in the epidermal growth factor receptor (EGFR) have been associated with sensitivity to EFGR-Tyrosin Kinase Inhibitors (TKIs). The aim of this study was to analyze clinical efficacies of first line afatinib treatment. Experimental Design: We collected patients with EGFR mutation positive NSCLC who started first-line afatinib treatment between Jan 2015 and Sep 2017. We reviewed clinical characteristics of the patients, laboratory finding, tumor response rate, side effects, progression free survival (PFS), 2nd biopsy result, and overall survival (OS), retrospectively. Results: Forty six patients were available for analysis among all 62 patients (1st to 8th line chemotherapy). At the time of data analysis in October 2018, nine patients were still on afatinib. Median age was 67.4 years-old. 20 (44%) patient had EGFR 19 deletion, 25 (54%) EGFR L858R mutation, 1 (2%) S768I. 10 patients (21.7%) had brain metastasis at baseline study. Tumor response was 58.7% with partial response, no change 19.6%, progressive disease 2%, and non-evaluable 19.6%. Mean follow-up time was 21.6 months (13.5 to 42.5 month) from start of afatinib treatment. Twenty-eight progression or death events were observed. Median PFS was 13.5 months (95% CI: 10.5 to 16.5 months). There were no differences in smoking, gender, EGFR types. 37 patients (80.4%) had dose reduction from initial dose. 6 patients (13.1%) discontinued due to afatinib toxicity. 6 patients (13%) had G3 toxicity, but usually manageable by dose reduction or supportive care. 1 case of doxycycline induced pneumonitis occurred. The PFS of dose reduction group due to adverse events was longer than standard group (14.9 months vs 10.1 months, p=0.023). In dose reduction group, body weight was low (53.1 kg vs 68.4 kg, p=0.002), the ratio of never smoker (87.9% vs 37.5%, p=0.001) and female (87.4% vs 47.4%, p=0.048) were higher than standard group. After progression, 2nd biopsy was done in 17 patients. T790M mutation was detected in 8 patients, so detection rate was 47.1%. 6 patients received oximertinib treatment. Median OS was 38.6 months. Conclusions: Afatinib is one of appropriate first-line treatment option for patients with advanced EGFR positive NSCLC. The dose reduction due to adverse events was common in low-body weight female never smoking patients, but the PFS was increased. With use of new 3rd-gen EGFR TKIs in the first-line setting, optimal sequencing of EGFR TKIs needs to be validated in maximizes treatment outcomes. Citation Format: Taewon Jang, Jaehoon Kim. Real-world experience with afatinib as first-line treatment in advanced non-small cell lung cancer in a university hospital [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 2195.
Elevated Levels of Type 2 Respiratory Innate Lymphoid Cells in Human Infants with Severe Respiratory Syncytial Virus Bronchiolitis
Authors: Luan D. Vu, David Siefker, Tamekia L. Jones, Dahui You, Ryleigh Taylor, John DeVincenzo, Stephania A. Cormier
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Studies of the immune responses at the site of respiratory syncytial virus (RSV) infection are sparse despite nearly five decades of research into understanding RSV disease.
Characterization of three pairs of prostate cells lines derived from tumor and adjacent normal tissues
Authors: Bernadette Palazzolo, Henry Heng, Ramzi Mohammad, Panteli Theocharous, James F. Eliason
Journal: Cancer Research (2005)

1974   Paired cell lines have been derived from tumor and adjacent normal tissue from three prostate cancer specimens. These lines were immortalized with genes from human papilloma virus. The line OPCT-1 was from a tumor sample obtained from a 68 year old patient with TNM Stage T1cN0M0 and a Gleason score of 6 (3+3). The OPCN-1 line was from the adjacent normal tissue of this patient. The OPCT-2 and OPCN-2 lines were similarly derived from a 58 year old patient with T2aN0M0 and Gleason score of 5 (2+3). The OPCT-3 and OPCN-3 lines were from a 54 year old patient with T3aN0M0 and Gleason score of 4 (2+2). None of the patients received chemo- or hormonal therapy before surgery. The doubling times of the OPCT-1 (1.1d) and OPCT-2 (1.8d) lines in culture are shorter than those for their adjacent normal lines (OPCN-1 = 2.7d; OPCN-2 = 2.9d). In contrast, the doubling time for OPCT-3 (2.1d) is not significantly different from that for OPCN-3 (2.3d). In a methylcellulose-based clonogenic attachment-independent growth assay, only the three tumor-derived lines formed colonies in these cultures, indicating that they are tumor derived. The results of spectral karyotype analysis from 10 mitotic figures each demonstrated variable chromosome numbers and numerous aberrations (both clonal and non-clonal). OPCT-1 has an average number of 49 (range = 48-50) chromosomes with trisomy 8, 9 and 20 observed for almost all mitotic figures, plus a chromosome 5 fragment. Two clonal translocations were detected as t(3; 8) and t(9; 19). The range of chromosome numbers was 60-86 for OPCT-2 and there were multiple chromosomal fragments. Two clonal translocations were detected as t(1; 3) and t(4; 5). For 7 out of 10 mitotic figures, non-clonal chromosomal aberrations (translocations) were detected indicating an unstable genome. The chromosome numbers of OPCT-3 vary from 62-110. Three clonal translocations were detected as t(10; 21), t(20; 13) and dic(14; 14). The adjacent normal lines also had aberrant karyotypes with multiple non-clonal aberrations. The range of chromosomes numbers were 59-84 for OPCN-1 with two clonal translocations [t(9; 17) and t(9; 19)], 78-94 for OPCN-2 with two clonal translocations [t(4; 19) and t(19; 4; 19; 4; 19)], and 62-78 for OPCN-3 with four clonal translocations as [t(3; 14), t(1; 10; 14), t(14; 15), and t(6; 22)]. These results indicate that although the lines derived from adjacent normal tissue are functionally different from the tumor derived lines, the karyotype analysis indicates that they have a considerable degree of genomic instability. This may reflect the inherent diversity and heterogeneity of the cancerous prostate gland.
Abstract 3047: Connective tissue growth factor: Novel therapeutic target for non-small cell lung cancer
Authors: Priyanka Chaudhary, Marie-Liesse Labat, Guangfang Wang, Mark Onaitis
Journal: Cancer Research (2019)

Abstract Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC), which accounts for 85% of all lung cancer cases, includes adenocarcinoma, squamous cell lung carcinoma and large-cell lung carcinoma. Despite recent advances in targeted therapies for adenocarcinoma, they are effective in only a small percentage of patients while there are no targeted therapies available for squamous cell lung cancer. Therefore, it is critical to identify novel intervention strategies against NSCLC. In the present study, we have identified connective tissue growth factor (CTGF) as a possible therapeutic target for NSCLC. CTGF is an extracellular-matrix (ECM) associated protein, which is involved in cellular processes like cell adhesion, migration, proliferation, differentiation, survival, apoptosis and senescence. CTGF has been associated with both oncogenic as well as tumor suppressive activities in context of different cancer types. The function of CTGF in lung cancer pathogenesis remains controversial. We performed immunohistochemistry on tissue microarray containing 60 cases, which clearly suggested that CTGF expression increases in lung carcinoma. More specifically, among other subtypes, squamous cell lung cancer cases expressed more CTGF compared to their matched normal tissues. To determine the functional role of CTGF in NSCLC, we employed both genetic and pharmacologic approaches to inhibit CTGF activity. Our results clearly demonstrated that CTGF inhibition by both lentiviral knockdown as well as monoclonal antibody against CTGF (FG-3019) caused marked inhibition in cell proliferation, colony formation and xenograft growth in immunodeficient mice. We have also found that CTGF knockdown causes cell cycle arrest and apoptosis. Furthermore, we tested the efficacy of FG-3019 along with drugs like cisplatin and gemcitabine in patient-derived xenograft (PDX) model of squamous cell lung cancer. Our results demonstrated that CTGF inhibition enhances the effects of gemcitabine chemotherapy in PDX model of squamous cell lung carcinoma. These results clearly suggested that CTGF has a profound effect on lung tumorigenesis, as its inhibition not only causes attenuation in tumor growth but also potentiates the chemotherapeutic sensitivity of commonly used drugs for NSCLC. We have also elucidated that tumor hypoxia and Yap signaling are responsible for CTGF up-regulation in lung carcinoma. Overall, our study underscores the significance of CTGF inhibition in non-small cell lung carcinoma and offers the potential use of FG-3019 for its treatment. Citation Format: Priyanka Chaudhary, Marie-Liesse Labat, Guangfang Wang, Mark Onaitis. Connective tissue growth factor: Novel therapeutic target for non-small cell lung cancer [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 3047.
Pharmacological Management of Delirium—Reply
Authors: Ping-Tao Tseng, Kuan-Pin Su
Journal: JAMA Psychiatry (2019)

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Engraftment of NOD/SCID mice with human neuroblastoma xenograft with IMR-32: Experimental in vivo model for immunotherapy in human neuroblastoma
Authors: Weiwei Fortino, M. Brigid Bradley, Carmella Van de Ven, Mitchell S. Cairo
Journal: Cancer Research (2004)

5469   Neuroblastoma, a primitive neuroectodermal tumor, is characterized by metastatic disease at diagnosis and a poor prognosis despite myeloablative autologous stem cell transplantation (Matthay et al, N Engl J Med 341:1165, 1999). NOD/SCID mice provide an excellent murine xenograft model for the study of tumor immunology (Hudson et al, Leukemia 12:2029, 1998, Robin et al, J Exp Med 189:1601, 1999). In this study we sought to characterize tumor associated antigens (TAA) of the human neuroblastoma line, IMR-32, to establish a xenograft with IMR-32 and determine cell dose and time to tumor development in a NOD/SCID mouse for the study of novel immunotherapies. IMR-32, was characterized using reverse transcription PCR analysis for expression of specific TAAs including GAGE1, MAGE3 and N-MYC. The random oligo(dT) primer was used for the first strand cDNA synthesis by AMV retrotranscriptase (Roche). The primer pairs used in the amplification PCR were 5’GTGGACATACTCAGTGGC3’ and 5’CGAAACTCTGACTCGGAG3’ for N-MYC, 5’AGACGCTACGTA-GAGCC3’ and CCATCAGGACCATCTTCA for GAGE1, 5’GGAGTCCTCATAGGATTGGCTCC and GAAGCCGGCCCAGGCTCGGTGA for MAGE3, respectively. The annealing temperatures were 60°C for MAGE3 and N-MYC, 55°C for GAGE1. The PCR programs were 1min at 94°C, 35 cycles of 1 min at 94°, 1 min at annealing temperature for each gene, 1.5 min at 72°C, plus 7 min final extention at 72°C. To determine cell dose needed to achieve human neuroblastoma tumor engraftment, IMR-32 cells were injected subcutaneously into the left flank of adult NOD/SCID mice (4-6 months old). Groups of animals (n=5) received either matrigel only (control), 1x10 6  cells  ( dose 1) or 1x10 7  cells (dose 2). The mice were monitored for evidence of tumor engraftment, rate of tumor growth and survival. Tumor size was determined at its greatest circumference by measurement with calipers. IMR-32 expressed GAGE1 and N-MYC amplified genes but was negative for MAGE3. There was no growth in 0/5 animals in the control group, 4/5 animals at dose level 1 and 5/5 animals at dose level 2. A two-way analysis of variance comparing the doses of tumor cells confirmed that the dose of IMR-32 had a significant impact on size and time to tumor engraftment (p
Abstract 13116: Improving the Outcome of Patients with Perioperative Right Ventricular Failure Through a Minimal Invasive Right Ventricular Assist Device Implantation Technique
Authors: Diyar Saeed, Alexander Albert, Ralf Westenfeld, Bujar Maxhera, Udo Boeken, Artur Lichtenberg
Journal: Circulation (2012)

OBJECTIVE: Temporary right ventricular assist device (RVAD) may be required to support patients with perioperative refractory right ventricular failure (RVF). We hypothesize that a minimally invasi...
Abstract 5855: Cardiac Fibrosis and Cellular Hypertrophy Predict the Degree of Reverse Remodeling and Improvement in Cardiac Function during Left Ventricular Assist System Support
Authors: Shunsuke Saito, Goro Matsumiya, Taichi Sakaguchi, Tomoyuki Fujita, Toru Kuratani, Hajime Ichikawa, Yoshiki Sawa
Journal: Circulation (2008)

[Background] There has been increasing reports of myocardial recovery after left ventricular assist system (LVAS) support. However, there still exists limited information as to in which patient pop...
Abstract 2106: Role of organic cation transporter-1 (OCT-1) in drug resistance condition of ph+ chronic myeloid leukemia (CML)
Authors: Saumya Patel, Krupa Shah, Rakesh Rawal
Journal: Cancer Research (2019)

Abstract A solute carrier (SLC) superfamily member, a major influx protein Organic Cation Transporter-1 (OCT-1), reported to be involved in influx of the Imatinib and other drugs in target cells. Despite the excellent responses to Imatinib and other tyrosine kinase inhibitors (TKIs) in CML, around a quarter of patients demonstrate primary resistance or suboptimal response within one year of therapy. Hence, present study mainly emphases the possible translocation mechanism of Imatinib, major TKIs and other chemotherapeutic agents that is mediated by OCT-1 transporter and OCT-1 gene expression level in progressive phases of CML. Homology based comparative modeling of OCT-1 protein, and its in-depth systemic interaction binding pattern analysis with Imatinib and other TKIs were conducted using computational modeling and molecular dynamics studies, respectively. Quantitative expression analysis of OCT-1 has also been evaluated in patients receiving Imatinib alone, hydroxyurea alone or both drug in different CML phases such as chronic, accelerated and blastic crisis phases for both in bone marrow and PBMNC samples (n=120). The interaction profile of Imatinib with OCT-1 revealed major conformational between ligand and protein interaction sites. However, generated protein-ligand complexes proceeded for molecular dynamics studies (100ns) that have confirmed the selectivity of Imatinib and other drugs towards the OCT-1 and possible translocation path of ligands in the OCT-1 cavities. In quantitative gene expression analysis, downregulation of OCT-1 expression as evident by decreased fold change values in patients with blastic crisis compared to chronic phase responsible for lower uptake of Imatinib into the cells. Hence, cells can not achieve optimum Imatinib inhibitory concentration which may be responsible for disease progression and ultimately leads to drug resistance. Thus, proposed combined computational and experimental approaches suggests OCT-1 mediated activation of bcr-abl independent mechanism, which may be potential confounder of developing Imatinib resistance in CML patients. Citation Format: Saumya Patel, Krupa Shah, Rakesh Rawal. Role of organic cation transporter-1 (OCT-1) in drug resistance condition of ph+ chronic myeloid leukemia (CML) [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 2106.