tbuckley/cabot-search huggingface dataset:
Abstract LB-226: Utilizing 486 gene assay on a NGS platform to validate guideline-adherent tumor mutational burden (TMB) module to calculate TMB
Authors: PANKAJ K. AHLUWALIA, ASHIS MONDAL, SUDHA ANANTH, SALEH HENEIDI, VAMSI KOTA, RAVINDRA KOLHE
Journal: Cancer Research (2019)

Abstract Introduction: The quantification of TMB has emerged as a highly promising biomarker in predicting immunotherapeutic responses. The application of whole exome sequencing to measure TMB has shown to predict response to immunotherapy. Multiple studies have shown that TMB quantification using large panels are comparable to whole exome sequencing and are more practical for implementation in clinical care. The QIAseq TMB panel is a new NGS assay designed to detect genetic alterations in 486 genes, along with MSI and TMB score. Methods: The validation was guided by the joint consensus recommendation for validation of NGS assays by the AMP &amp; CAP and NYSDOH. The validation included evaluations of precision, analytic sensitivity, analytic specificity, accuracy, reportable range, and reference range for TMB. DNA from of 60 samples which were characterized on Foundation CGP assay were used during the validation. Libraries were prepared using the QIAseq TMB panel kit and sequenced on NextSeq 550. The TMB module used for calculation of TMB in this validation was designed and developed by QIAGEN. TMB was calculated as the number of somatic mutations (SNVs and Indels only) per megabase (Mb) of the target region (1.2 Mb for QIAseq TMB panel). Results: In silico analysis using the TCGA data by QIAGEN QCI pipeline showed that the QIAseq TMB panel estimates TMB at a high level of concordance with whole exome sequencing (WES). The data show a high correlation (r2 = 0.98) between the TMB values determined using WES data and TMB using the QIAseq TMB panel data. Our validation data shows significant correlation (r2 = 0.94) among TMB values on the QIAseq panel and Foundation one CGP. Conclusions: In this validation we demonstrate that the QIAseq TMB assay can be used to reliably predict TMB across a wide range of cancer types using the QIAGEN QCI TMB module. Our lab’s experience provides an example for others that may wish to implement TMB testing by NGS on a comprehensive panel. Citation Format: PANKAJ K. AHLUWALIA, ASHIS MONDAL, SUDHA ANANTH, SALEH HENEIDI, VAMSI KOTA, RAVINDRA KOLHE. Utilizing 486 gene assay on a NGS platform to validate guideline-adherent tumor mutational burden (TMB) module to calculate TMB [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 LB-226.
Abstract 53: Characterization of a Feline HFpEF Model Induced by Slow Progressive Pressure Overload
Authors: Markus Wallner, Remus M Berretta, Shu-Yu Sun, Kersten M Small, Jeffrey B Madwed, Constantine D Troupes, Thomas E Sharp, Giulia Borghetti, Mark A Oyama, Philip R Fox, Steven R Houser
Journal: Circulation Research (2016)

Rationale: The prevalence of Heart Failure with preserved Ejection Fraction (HFpEF) is almost equal to that of Heart Failure with reduced Ejection Fraction (HFrEF) and represents a major public health problem. There are no proven effective treatments for HFpEF, partially attributable to the lack of well-established animal models for HFpEF. Hypothesis: Cats develop a HFpEF phenotype similar to patients after induction of slow progressive pressure overload. Methods and Results: Female and male short hair cats, aged 2 months, underwent either aortic constriction, with a customized pre-shaped band, or sham procedure. In contrast to immediate pressure overload, this approach results in a slow progressive pressure overload during growth. Transthoracic echocardiography was performed at baseline and 1, 2, 3, and 4 months after banding. Concentric LV hypertrophy was observed and heart weight to body weight ratio significantly increased in banded male and female cats compared to sham (male: 8.5±1.6 vs. 4.5±0.4; female: 7.4±0.2 vs. 4.9±0.8; p&lt;0.05). Wet/dry lung weight ratio, indicating pulmonary congestion, did not differ between groups. End-diastolic wall thickness was significantly increased in banded cats at 2, 3 and 4 months, while the end-diastolic diameter and systolic function did not differ between banded and sham cats at any time point. A significant left atrial (LA) enlargement was observed in banded cats at 3 and 4 months, as measured by an increased LA/aorta ratio and increased LA area. LA ejection fraction was significantly decreased after aortic constriction (male sham vs. banded: 75.4±0.2 vs. 47.3±0.2; p&lt;0.01; female sham vs. band: 75.4±2.1 vs. 53.9±4.4; p&lt;0.05). Diastolic function, assessed by tissue Doppler imaging, was impaired in banded cats. Summary and Conclusion: Slow progressive pressure overload in cats induces severe LV concentric hypertrophy, LA enlargement and dysfunction without causing LV dilation or systolic dysfunction, mimicking many clinical phenotypes in HFpEF patients. Further characterization will include incorporating invasive measurements, exercise capacity and serum biomarkers and testing of novel therapies.
Abstract 5141: T-cell receptor repertoire analysis by next-generation sequencing peripheral blood mononuclear cells from multiple myeloma or smoldering multiple myeloma patients
Authors: Yong Zhang, Svetlana Petrovskaya, Emma C. Scott, Luis Santana-Quintero, Tigran Ghazanchyan, Amy Rosenburg, V. Ashutosh Rao, Gideon M. Blumenthal, Marc Theoret, Richard Pazdur, Julia A. Beaver, Dickran Kazandjian
Journal: Cancer Research (2019)

Abstract Multiple myeloma (MM) is a hematological malignancy mostly assessed by bone marrow involvement, so it is attractive to develop a method using peripheral blood. We hypothesized that peripheral blood mononuclear cells (PBMCs) may replace tedious and invasive bone marrow biopsies as a biomarker. In this study, we aimed to investigate if T-cell receptor (TCR) repertoire has clinical significance in MM or Smoldering MM (SMM) diagnosis or prognosis. Using baseline genomic DNA (PBMC) from 24 patients with SMM and 31 patients with MM, we performed next-generation sequencing on the Illumina NextSeq 500 platform by immunoSEQ TCRB Kits from Adaptive Biotechnology to quantitatively assay the complementarity determining region 3 (CDR3) of human T-cell receptor β (TCRβ) gene. To evaluate T-cell diversity and clonality, we performed pipeline analysis by ImmunoAnalyzer from Adaptive Technology, and downloaded sequencing data with manual analysis by JMP13 software. Compared to TCRB data from 280 normal control (Age &amp;gt; 40) PBMCs (Nat Genet. 2017, 49(5):659-665), we found less TCR templates from both MM and SMM baseline based on size of TCRB repertoire, and less TCR rearrangements or unique clonotypes based on structure of TCRB repertoires. Only MM baseline showed higher maximum clonotype frequency. No difference of T-cell clonality was found from MM and SMM. Furthermore, we performed the same sequencing on 18 SMM patients at different treatment time points including chemotherapy after cycle 8, 20, and 32. Our results showed patient samples after cycle 8 had less TCR templates and TCR rearrangements compared to those from the other three time points although no significant difference were found in maximum clonotype frequency or T-cell clonality. TCR overlap analysis will be further performed to track potential clonotype changes. Thus, we identified TCR repertoire analysis may have potential clinical significance as biomarker assay for MM and SMM patients. Citation Format: Yong Zhang, Svetlana Petrovskaya, Emma C. Scott, Luis Santana-Quintero, Tigran Ghazanchyan, Amy Rosenburg, V. Ashutosh Rao, Gideon M. Blumenthal, Marc Theoret, Richard Pazdur, Julia A. Beaver, Dickran Kazandjian. T-cell receptor repertoire analysis by next-generation sequencing peripheral blood mononuclear cells from multiple myeloma or smoldering multiple myeloma patients [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 5141.
Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: systematic review and meta-analysis of randomised controlled trials
Authors: Tracey J Brown, Julii Brainard, Fujian Song, Xia Wang, Asmaa Abdelhamid, Lee Hooper
Journal: BMJ (2019)

Abstract Objective To assess effects of increasing omega-3, omega-6, and total polyunsaturated fatty acids (PUFA) on diabetes diagnosis and glucose metabolism. Design Systematic review and meta-analyses. Data sources Medline, Embase, Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, Clinicaltrials.gov, and trials in relevant systematic reviews. Eligibility criteria Randomised controlled trials of at least 24 weeks’ duration assessing effects of increasing α-linolenic acid, long chain omega-3, omega-6, or total PUFA, which collected data on diabetes diagnoses, fasting glucose or insulin, glycated haemoglobin (HbA 1c ), and/or homoeostatic model assessment for insulin resistance (HOMA-IR). Data synthesis Statistical analysis included random effects meta-analyses using relative risk and mean difference, and sensitivity analyses. Funnel plots were examined and subgrouping assessed effects of intervention type, replacement, baseline risk of diabetes and use of antidiabetes drugs, trial duration, and dose. Risk of bias was assessed with the Cochrane tool and quality of evidence with GRADE. Results 83 randomised controlled trials (mainly assessing effects of supplementary long chain omega-3) were included; 10 were at low summary risk of bias. Long chain omega-3 had little or no effect on likelihood of diagnosis of diabetes (relative risk 1.00, 95% confidence interval 0.85 to 1.17; 58 643 participants, 3.7% developed diabetes) or measures of glucose metabolism (HbA 1c mean difference −0.02%, 95% confidence interval −0.07% to 0.04%; plasma glucose 0.04, 0.02 to 0.07, mmol/L; fasting insulin 1.02, −4.34 to 6.37, pmol/L; HOMA-IR 0.06, −0.21 to 0.33). A suggestion of negative outcomes was observed when dose of supplemental long chain omega-3 was above 4.4 g/d. Effects of α-linolenic acid, omega-6, and total PUFA on diagnosis of diabetes were unclear (as the evidence was of very low quality), but little or no effect on measures of glucose metabolism was seen, except that increasing α-linolenic acid may increase fasting insulin (by about 7%). No evidence was found that the omega-3/omega-6 ratio is important for diabetes or glucose metabolism. Conclusions This is the most extensive systematic review of trials to date to assess effects of polyunsaturated fats on newly diagnosed diabetes and glucose metabolism, including previously unpublished data following contact with authors. Evidence suggests that increasing omega-3, omega-6, or total PUFA has little or no effect on prevention and treatment of type 2 diabetes mellitus. Systematic review registration PROSPERO CRD42017064110.
Abstract 1107: LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target
Authors: Su Jin Lee, Sun-ju Byeon, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Kyoung-Mee Kim, Seung Tae Kim
Journal: Cancer Research (2019)

Abstract We performed prospective immunohistochemical analysis of LAG3 for 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Most patients (428/430, 99.5%) were evaluable for LAG3 expression by immunohistochemistry. In total, 18.5% (79/428) of the evaluated cancers expressed LAG3, including pancreatic (33.3%, 2 of 6), gastric (24.7%, 21 of 85), colorectal (23.6%, 48 of 203), melanoma (12.5%, 1 of 8), genitourinary (9.5%, 4 of 46), biliary tract (6.3%, 1 of 16), and sarcoma (5.4%, 2 of 37), but not miscellaneous (0.0%, 0 of 14) or hepatocellular (0.0%, 0 of 15) cancer. Among 149 metastatic CRC patients, there was no statistically significant difference in gender, age, primary tumor site, pathologic differentiation, KRAS and NRAS status, BRAF status, and microsatellite instability according to LAG3 status (expressed vs. non-expressed). Among 53 metastatic GC patients, LAG3 was only significantly associated with EBV status (P = .042). Our results add to the emerging literature on LAG3 expression in various cancer types and support the need for extended clinical exploration of this target for immunotherapy. Citation Format: Su Jin Lee, Sun-ju Byeon, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Kyoung-Mee Kim, Seung Tae Kim. LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target [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 1107.
Analysis of Pathologic Complete Response 10 Weeks After Radiotherapy—A Radiobiological Sin
Authors: Eric C. Ko, Claire Vanpouille-Box, Silvia C. Formenti
Journal: JAMA Oncology (2019)

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No IL-18BP? Avoid HAV
Authors: Michael S. Diamond
Journal: The Journal of Experimental Medicine (2019)

Fulminant viral hepatitis occurs in a very small number of infected individuals. Until now, the basis for this phenotype has remained unknown. In this issue of JEM, Belkaya et al. (https://doi.org/10.1084/jem.20190669) identify a deletion in the IL18BP gene in a severely affected child that results in excessive natural killer cell activation and uncontrolled killing of hepatocytes.
Efficacy of FOLFIRI as a second-line in extrapulmonary poorly-differentiated neuroendocrine carcinoma
Authors: C. Fabregat Franco, M. Nieva Muñoz, F. Pérez Martín, J. Ruffinelli, C. Santos Vivas, C. Sánchez, R. Salazar, A. Teule
Journal: Annals of Oncology (2019)
Abstract 16260: p122RhoGAP/DLC-1 Overexpression Enhances Intracellular Calcium Concentration in Response to Acetylcholine in Isolated Vascular Smooth Muscle Cells
Authors: Yoshihiro Kimura, Kenji Hanada, Maiko Senoo, Noritomo Narita, Masato Narita, Manabu Yonekura, Hiroaki Ichikawa, Makoto Tanaka, Ken Okumura, Hirofumi Tomita
Journal: Circulation (2017)

Backgrounds: We previously reported that phospholipase C (PLC)-δ1 activity was enhanced in patients with coronary spastic angina (CSA) and there was a significant positive correlation between PLC a...
Abstract 696: High-throughput screening of therapeutic combinations against ovarian cancer
Authors: Peng Zhou, Alan S. Wong
Journal: Cancer Research (2019)

Abstract Applying synergistic drug combinations can increase efficacy of cancer treatment. However, conventional methods for identifying those combinations involve testing of every possible combination including different dosages for each agent, are difficult to scale due to the huge amount of efforts and costs needed. To tackle this problem, we have developed CombiGEM-CRISPR (combinatorial genetics en masse-CRISPR) to enable high-throughput assembly and screening of pair-wise gene combinations. By applying CombiGEM-CRISPR,phenotypes of combinatorial gene knockouts could be used to predict the effects of drug inhibitor combinations targeting the matching gene products. We designed a pair-wise sgRNA library comprising 25,281 combinations for interrogating 52 genes that are overexpressed in ovarian cancers. By pooled evaluation of their effects on cell proliferation, our screening identified new combinations that inhibit ovarian cancer cell growth. Therefore, our work accelerates the discovery of new therapeutic options against ovarian cancer through applying CombiGEM-CRISPR. Citation Format: Peng Zhou, Alan S. Wong. High-throughput screening of therapeutic combinations against ovarian 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 696.
Abstract 3211: MTL-CEBPA combined with radiofrequency ablation and immunotherapy enhances immunological anti-tumour response in an HCC mouse model
Authors: Mikael H. Sodergren, Kai-Wen Huang, Vikash Reebye, Cheng-Ean Chee, Dimitris Zacharoulis, Robert Habib, David Blakey, John Rossi, Nagy Habib
Journal: Cancer Research (2019)

Abstract The transcription factor CEBPA (CCAAT/enhancer-binding protein alpha) is recognised for its antiproliferative effects. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA and amongst other effects causes and immunomodulatory effect on peripheral granulocytes. Radiofrequency ablation (RFA) is standard treatment for some tumour types such as liver cancer and induces modulation of both innate and adaptive immune systems. To investigate any synergistic effect of MTL-CEBPA with RFA and immune checkpoint inhibition we initiated a reverse translation experiment, where syngeneic BNL hepatocellular carcinoma tumour cells were injected in the two opposite flanks of immunocompetent BALB/c mice (n=8 in each group). Treatments for hepatoma bearing mice included: 1) RFA on one flank (day 0), 2) Anti-PD-1 inhibition immunotherapy (RMP1-14 antibody, BioXCell, West Lebanon, NH, USA at 200 μg IV/mouse/dose on days 0, 2 &amp; 5) and 3) MTL-CEBPA (3mg/kg IV/mouse/dose on days 0, 2 &amp; 5) as well as combinations of all 3 interventions. We found that tumour control on the opposite flank was augmented by addition of RFA and most significant in the triple combination group (RFA + anti-PD1 + MTL-CEBPA) in which 2/8 animals showed a complete response and 5/8 a partial response. This was also the only group that showed a statistically significant increase in CD8+ (Cytotoxic) as well as CD49b+/CD45+ (Natural Killer) tumour infiltrating lymphocytes. These data suggest a clinical role for combination treatment with checkpoint blockade, RFA and MTL-CEBPA through synergistic priming of the immune tumour response, enabling RFA to have a pronounced anti-tumour abscopal effect. Citation Format: Mikael H. Sodergren, Kai-Wen Huang, Vikash Reebye, Cheng-Ean Chee, Dimitris Zacharoulis, Robert Habib, David Blakey, John Rossi, Nagy Habib. MTL-CEBPA combined with radiofrequency ablation and immunotherapy enhances immunological anti-tumour response in an HCC mouse model [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 3211.
Abstract 1534: MEDI5083, a novel CD40L-Fc fusion protein, activates the CD40 pathway on antigen presenting cells and promotes a robust anti-tumor immune response in a B16F10 murine tumor model
Authors: Sean Turman, Kelly McGlinchey, YaYa Wang, Deepali Malhotra, Ronald Herbst, Yue Wang
Journal: Cancer Research (2019)

Abstract Targeting CD40 with its natural ligand (CD40L) enhances the immune-stimulatory functions of dendritic cells, B cells, monocytes and macrophages, resulting in T cell priming, expansion and differentiation. Thus, activation of the CD40 pathway is an attractive strategy to boost anti-tumor immune responses. MEDI5083 is a novel fusion protein consisting of a hexameric recombinant human CD40L structure covalently linked to human IgG4p Fc. In this study, we present the functional characterization of MEDI5083. MEDI5083 specifically bound to human CD40 and triggered surface CD40 internalization. As a result, MEDI5083 exerted robust CD40 agonist activities as measured by NF-κb activation in Ramos and THP1 cell lines. In assays using primary human B cells and myeloid cells, MEDI5083 potently upregulated co-stimulation molecules including MHCII, CD80 and CD86, and induced secretion of pro-inflammatory cytokines, such as TNFα and IL6. To examine the anti-tumor activity in mice, we constructed a murine surrogate of MEDI5083 (mCD40L-Fc) which has similar physical and target binding properties to those of MEDI5083. In the B16F10 syngeneic mouse model, repeated dosing of mCD40L-Fc significantly decreased tumor volume and/or delayed tumor growth, compared with isotype control dosed animals. Combination treatment of mCD40L-Fc with anti-PD-L1 and/or anti-CTLA-4 further enhanced the anti-tumor immune response. Moreover, treatment with mCD40L-Fc alone or in combination with anti-PD-L1 or anti-CTLA-4 induced elevated levels of TH1 cytokines IFNγ and IL12 in serum, and increased numbers of intratumoral CD8+ T cells, compared with isotype control treated animals. Thus, mCD40L-Fc elicits robust immune activation and significant anti-tumor activity against B16F10 tumors, which have low responsiveness to checkpoint inhibitors. The insights obtained from the preclinical studies support the development of MEDI5083, which is currently in clinical development for a broad spectrum of malignancies. Citation Format: Sean Turman, Kelly McGlinchey, YaYa Wang, Deepali Malhotra, Ronald Herbst, Yue Wang. MEDI5083, a novel CD40L-Fc fusion protein, activates the CD40 pathway on antigen presenting cells and promotes a robust anti-tumor immune response in a B16F10 murine tumor model [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 1534.
Abstract 16816: Are the Triggers From the Left Atrial Appendage Critical in Determining the Long-Term Outcome of Catheter Ablation in Patients With Long-Standing Persistent Atrial Fibrillation? Results From 5-Year Follow-Up
Authors: Domenico G Della Rocca, Sanghamitra Mohanty, Chintan Trivedi, Carola Gianni, John D Burkhardt, Javier E Sanchez, Rodney Horton, G J Gallinghouse, Richard Hongo, Salwa Beheiry, Luigi Di Biase, Amin Al-Ahmad, Andrea Natale
Journal: Circulation (2017)

Background: In recent years catheter ablation techniques and strategies have evolved substantially. Despite all the efforts, post-ablation recurrence still has been a key issue and targeting non-PV...