tbuckley/cabot-search huggingface dataset:
Abstract 3515: Functional antigen presentation is required to interpret the tumor mutation burden (TMB) test
Authors: Gustavo C. Cerqueira, Laurel A. Keefer, Donna Nichol, Julie R. Meyer, Nicholas C. Dracopoli
Journal: Cancer Research (2019)

Abstract Therapeutic response to checkpoint inhibitors requires a prior, suppressed immune response that is released by a monoclonal antibody blocking the interaction of the checkpoint receptors with their cognate ligands. The presence of this suppressed immune response can be detected by a variety of tests including tumor mutation burden (TMB), tumor infiltrating leukocytes, T-cell receptor clonality, circulating interferons and cytokines, and upregulation of the expression of the checkpoint ligands. Today, TMB has proven to be the most predictive biomarker of response to immunotherapy. TMB is a surrogate marker of immune response. The test works by sampling a small region of the cancer genome to estimate the number of mutations/Mb of the cancer exome. A high TMB score is associated with better response to immunotherapy because it carries more somatic mutations and a higher chance of presenting an immunogenic neoepitope that will lead to CD-8+ T-cell mediated destruction. Restriction or loss of antigen presentation caused by mutations and loss of heterozygosity (LOH) of the beta-2-microglobulin (B2M) and HLA Class I genes has been shown to be a common means of evading CD-8+ T-Cell destruction. Consequently, the outcome for high TMB tumors will be dependent on their ability to present antigens, so that the mutation count will not matter in cells that are unable to present antigens in their HLA Class I/B2M complex. We propose that TMB should be considered together with the ability of the tumor to present these putative neoantigens. To test this hypothesis, we used the PGDx elio™ Tissue Complete test (507 genes in 1.3 Mb) to measure TMB and antigen presentation in the same assay. We tested 212 cancer patients and showed that in FFPET samples with &amp;gt;20% tumor content, we could detect LOH of the MHC Class I and B2M genes with &amp;gt;90% accuracy compared to whole exome data from the same sample. These data confirmed our hypothesis that it was possible to measure TMB and evaluate the genes involved in antigen presentation in the same in silico analysis of a 507 gene next-generation sequencing (NGS) panel. We are currently using this combined analysis to measure TMB and somatic alterations of the antigen presentation complex in several different cancers and to test the hypothesis that adding neoantigen presentation capability to TMB scores will significantly improve prediction of response to a variety of immunotherapies. Citation Format: Gustavo C. Cerqueira, Laurel A. Keefer, Donna Nichol, Julie R. Meyer, Nicholas C. Dracopoli. Functional antigen presentation is required to interpret the tumor mutation burden (TMB) test [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 3515.
Vaccine hesitancy: misinformation on social media
Authors: Jack J Broadbent
Journal: BMJ (2019)

Not that long ago, infectious disease was a pervasive fear in the minds of parents. Vaccines were embraced and brought along a new age of medicine. The fear that once gripped parents is no more. Infectious diseases are out of sight and out of mind, replaced by reports on side effects and additives, which leave many wondering if all these …
Abstract 4035: Protein tyrosine kinase 7 (PTK7) biomarker analysis in patients (pts) treated with PF-06647020, a PTK7 antibody-drug conjugate (ADC), in a phase I dose expansion study
Authors: Amy Jackson-Fisher, Navi Mehra, Roberto Gianani, Pamela Whalen, Pamela Vizcarra, Shibing Deng, Stephen McComish, Xiaohua Xin, Eric L. Powell
Journal: Cancer Research (2019)

Abstract Background: PF-06647020, an ADC comprising a humanized monoclonal antibody against PTK7, a cleavable valine-citrulline linker, and an auristatin payload, is being investigated in an ongoing Phase I clinical trial in pts with advanced solid tumors. We hypothesized that response to a PTK7-directed ADC would correlate with PTK7 expression in the pts tumor. We report preliminary baseline PTK7 expression in pts tumors and clinical response using a novel CLIA validated laboratory developed test (LDT). Methods: We developed and validated an LDT comprising an anti-PTK7 immunohistochemistry assay with digital tissue analysis using Flagship Biosciences Inc’s cTA® platform to detect membrane-associated PTK7 in formalin-fixed paraffin embedded (FFPE) epithelial malignancies of ovary, breast and lung. Tumor samples were immunolabeled with the LDT and image analysis was applied to derive a digital H-score. Specifically the digital image annotation included desired regions of analysis (ROA) and excluded regions not of interest. The cTA® platform identified each cell in a given ROA and quantified an overall H-score for malignant epithelial cell membranes immunolabeled for PTK7. Non-small cell lung cancer (NSCLC) pts with H-scores ≥ 56.8 were eligible for enrollment whereas ovarian cancer (OVCA) pts were enrolled unselected. Triple negative breast cancer (TNBC) pts were initially enrolled unselected, but after review a requirement for H-scores ≥ 92.8 was implemented for enrollment. Results: PTK7 IHC was performed on baseline FFPE samples from 69 pts and digital H-scores were generated (Table 1). An additional 7 pt samples were not amenable to analysis with the cTA® platform. Conclusions: A novel CLIA validated LDT was developed and implemented to assess PTK7 baseline levels in FFPE tumors from pts treated with PF-06647020. Clinical responses tended to correlate with H-scores that were higher than the mean for each tumor type. Table 1.PTK7 digital H-scores in Phase I dose expansionNumber of SamplesMinimum H-scoreMaximum H-scoreMean H-scoreMean H-score of Non-respondersMean H-score of RespondersOVCA31120089.280.2111.2NSCLC1993287167.8159.2200.3TNBC1953258159.2147.0224.3 Citation Format: Amy Jackson-Fisher, Navi Mehra, Roberto Gianani, Pamela Whalen, Pamela Vizcarra, Shibing Deng, Stephen McComish, Xiaohua Xin, Eric L. Powell. Protein tyrosine kinase 7 (PTK7) biomarker analysis in patients (pts) treated with PF-06647020, a PTK7 antibody-drug conjugate (ADC), in a phase I dose expansion study [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 4035.
Association Between the Implementation of a Population-Based Primary Care Payment System and Achievement on Quality Measures in Hawaii
Authors: Amol S. Navathe, Ezekiel J. Emanuel, Amelia Bond, Kristin Linn, Kristen Caldarella, Andrea Troxel, Jingsan Zhu, Lin Yang, Shireen E. Matloubieh, Elizabeth Drye, Susannah Bernheim, Emily Oshima Lee, Mark Mugiishi, Kimberly Takata Endo, Justin Yoshimoto, Isaac Yuen, Sheryl Okamura, Michael Stollar, Jeffrey Tom, Michael Gold, Kevin G. Volpp
Journal: JAMA (2019)

Hawaii Medical Service Association (HMSA), the Blue Cross Blue Shield of Hawaii, introduced Population-based Payments for Primary Care (3PC), a new capitation-based primary care payment system, in 2016. The effect of this system on quality measures has not been evaluated.To evaluate whether the 3PC system was associated with changes in quality, utilization, or spending in its first year.Observational study using HMSA claims and clinical registry data from January 1, 2012, to December 31, 2016, and a propensity-weighted difference-in-differences method to compare 77 225 HMSA members in Hawaii attributed to 107 primary care physicians (PCPs) and 4 physician organizations participating in the first wave of the 3PC and 222 233 members attributed to 312 PCPs and 14 physician organizations that continued in a fee-for-service model in 2016 but had 3PC start dates thereafter.Participation in the 3PC system.The primary outcome was the change in a composite measure score reflecting the probability that a member achieved an eligible measure out of 13 pooled Healthcare Effectiveness Data and Information Set quality measures. Primary care visits and total cost of care were among 15 secondary outcomes.In total, the study included 299 458 HMSA members (mean age, 42.1 years; 51.5% women) and 419 primary care physicians (mean age, 54.9 years; 34.8% women). The risk-standardized composite measure scores for 2012 to 2016 changed from 75.1% to 86.6% (+11.5 percentage points) in the 3PC group and 74.3% to 83.5% (+9.2 percentage points) in the non-3PC group (differential change, 2.3 percentage points [95% CI, 2.1 to 2.6 percentage points]; P < .001). Of 15 prespecified secondary end points for utilization and spending, 11 showed no significant difference. Compared with the non-3PC group, the 3PC system was associated with a significant reduction in the mean number of primary care visits (3.3 to 3.0 visits vs 3.3 to 3.1 visits; adjusted differential change, -3.9 percentage points [95% CI, -4.6 to -3.2 percentage points]; P < .001), but there was no significant difference in mean total cost of care ($3344 to $4087 vs $2977 to $3564; adjusted differential change, 1.0% [95% CI, -1.3% to 3.4%]; P = .39).In its first year, the 3PC population-based primary care payment system in Hawaii was associated with small improvements in quality and a reduction in PCP visits but no significant difference in the total cost of care. Additional research is needed to assess longer-term outcomes as the program is more fully implemented and to determine whether results are generalizable to other health care markets.
Final Results from the Phase 3 Traial Areta Comparing a Novel, Extended-Release Anagrelide Formulation to Placebo in Essential Thrombocythemia Patients with Defined Risk Status
Authors: Heinz Gisslinger, Christoph Klade, Kudrat Abdulkadyrov, Slawomira Kyrcz-Krzemien, Elena Karyagina, Anait L. Melikyan, Krzysztof Warzocha, Barbara Grohmann-Izay, Juri Hodisch, Rudolf S. Widmann, Robert Kralovics, Petro E. Petrides, Jiri Schwarz, Jean-Jacques Kiladjian
Journal: Blood (2016)
Response to: ‘Impact of Janus kinase inhibitors on the risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials’ by Lee and Song
Authors: Wenhui Xie, Shiyu Xiao, Zhuoli Zhang
Journal: Annals of the Rheumatic Diseases (2019)

We would like to thank Drs Lee and Song for their methodological comment1 on our recent publication.2 First, Cochran Q has been widely used for assessing heterogeneity in which p values are obtained by comparing the statistic with a χ2 distribution. Due to poor power in detecting true heterogeneity, especially in a circumstance of small sample size, the establishment of a cut-off p value is complicated and the cut-off has not been definitively set yet. At present, using a cut-off of 0.1 or 0.053 4 for significance could be considered, although the former is applied more commonly. A cut-off of …
Abstract 20886: Lack of Efficacy With Ranolazine in Patients Treated With Concomitant Amiodarone: Results From the RAID Trial
Authors: Jonathan P Piccini, James P Daubert, Ignatius G Zarraga, Peter M Jessel, Karen MacMurdy, Merritt Raitt, Mark C Haigney, Arthur Moss, Wojciech Zareba
Journal: Circulation (2017)

Introduction: Patients with implantable cardioverter defibrillators (ICD) are often treated with amiodarone. We sought to determine if the efficacy of ranolazine, a late-Na current blocker therapy,...
Abstract 5310: Novel, single-tube, multiplex rhPCR technology for detection of low-frequency variants in <i>BRCA1</i> and <i>BRCA2</i>
Authors: Nicole Sponer, Yu Wang, Junzhou Wang, Shengyao Chen, Kevin Lai, Scott Rose, Patrick Lau
Journal: Cancer Research (2019)

Abstract Targeted next-generation sequencing (NGS) technologies serve as critical tools for cancer diagnostics. For example, individuals with pathological BRCA1 and BRCA2 (BRCA1/2) mutations have a dramatically increased risk for certain cancers, including breast and ovarian cancer. Those mutations are either germline or somatically acquired, and play an important role in cancer risk assessment, prevention of malignancy, and management of disease. A variety of methodologies are currently available to screen for BRCA1/2 mutations. Amplicon-based sequencing technologies are prevalent due to their easy workflow but have specific challenges due to inherent limitations of PCR, such as difficulties with amplification of overlapping amplicons for contiguous coverage in a single-tube or with detection of somatic low-frequency variants due to high polymerase error rates. We developed a robust, highly multiplex rhPCR workflow to screen for BRCA1/2 mutations across their entire coding regions in a single-tube. This method allows for detection of low-frequency variants through use of unique molecular identifiers (UMIs), which correct for PCR and sequencing errors and dramatically increase specificity. This method supports a wide DNA input range (1 to 50 ng) from cell-free, formalin-fixed paraffin-embedded (FFPE), or small biopsy samples. Our rhAmpSeq™ chemistry uses a two-enzyme system coupled with uniquely designed RNA-DNA hybrid primers, which enable the amplification of overlapping, multiplexed amplicons. Thus, we eliminate the need to split precious DNA samples into multiple tubes and prevent UMI hopping. Here, we demonstrate the performance of our novel, highly specific amplicon-based technology for detection of low-frequency variants of BRCA1/2 and compare our technology to current industry standards. Citation Format: Nicole Sponer, Yu Wang, Junzhou Wang, Shengyao Chen, Kevin Lai, Scott Rose, Patrick Lau. Novel, single-tube, multiplex rhPCR technology for detection of low-frequency variants in BRCA1 and BRCA2 [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 5310.
Abstract 1261: Targeting Wee1 in laryngeal squamous cell carcinoma
Authors: Meng-Ling Yuan, Qi-Wei Jiang, Yang Yang, Jia-Rong Huang, Zhi Shi
Journal: Cancer Research (2019)

Abstract WEE1 is a tyrosine kinase that regulates G2/M cell cycle checkpoint and frequently overexpressed in various tumors. However, the expression and clinical significance of WEE1 in human laryngeal squamous cell carcinoma (LSCC) are still unknown. In this study, we found that WEE1 was highly expressed in LSCC tissues compared with adjacent normal tissues. Importantly, overexpression of WEE1 was correlated with T stages, lymph node metastasis, clinical stages and poor prognosis of LSCC patients. Furthermore, inhibition of WEE1 by MK-1775 induced cell growth inhibition, G2/M cell cycle arrest and apoptosis with the increased intracellular reactive oxygen species (ROS) levels in LSCC cells. Pretreatment with ROS scavenger N-acetyl-L-cysteine could reverse MK-1775-induced ROS accumulation and cell apoptosis in LSCC cells. MK-1775 also inhibited the growth of LSCC xenografts in nude mice. Altogether, these findings suggest that WEE1 is a potential therapeutic target in LSCC, and inhibition of WEE1 is the prospective strategy for LSCC therapy. Note: This abstract was not presented at the meeting. Citation Format: Meng-Ling Yuan, Qi-Wei Jiang, Yang Yang, Jia-Rong Huang, Zhi Shi. Targeting Wee1 in laryngeal squamous cell carcinoma [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 1261.
Abstract 1159: Association of ALDH7A1 overexpression with chemotherapy resistance and cancer stem cell in lung cancer
Authors: Yuto Yasuda, Yuichi Sakamori, Hiroaki Ozasa, Hitomi Ajimizu, Tetsuya Oguri, Ken Maeno, Takahiro Tsuji, Takashi Nomizo, Tomoko Yamamoto, Hironori Yoshida, Toyohiro Hirai, Young Hak Kim
Journal: Cancer Research (2019)

Abstract Aldehyde dehydrogenases (ALDHs) play a major role in the oxidation of aldehydes. Certain isoforms of ALDH is related to cancer stem cells (CSCs) responsible for tumor initiating, drug resistance and metastasis. ALDH1A1 and ALDH3A1 have been known for CSC markers of lung cancer. Since these two isoforms and ALDH7A1 are involved in cellular structural and osmoregulatory function, we focused on function of ALDH7A1 in lung cancer. We established SN-38 resistant DMS53 (DMS53-SR) and SN-38 or gemcitabine resistant NCI-H23 (H23-SR or H23-GR, respectively) by intermittent and dose-escalating exposure of the agent. The expression of ALDH7A1 was upregulated in DMS53-SR and H23-SR/H23-GR compared with DMS53 and NCI-H23, respectively. ALDH7A1 expression was altered using a plasmid to overexpress ALDH7A1 in DMS53. ALDH7A1 overexpression led to a slight increase of IC50 of SN-38, upregulation of SOX2, and tumor sphere formation. Overexpression of ALDH7A1 in DMS53 have enhanced tumorigenic capacity in vivo. These data suggested that ALDH7A1 might be a marker of CSC and a therapeutic target of lung cancer. Citation Format: Yuto Yasuda, Yuichi Sakamori, Hiroaki Ozasa, Hitomi Ajimizu, Tetsuya Oguri, Ken Maeno, Takahiro Tsuji, Takashi Nomizo, Tomoko Yamamoto, Hironori Yoshida, Toyohiro Hirai, Young Hak Kim. Association of ALDH7A1 overexpression with chemotherapy resistance and cancer stem cell in 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 1159.
Abstract 695: Using PSA dynamics to predict patient-specific responses to intermittent androgen deprivation
Authors: Renee Brady, Heiko Enderling
Journal: Cancer Research (2019)

Abstract Intermittent androgen deprivation therapy (IADT) is an attractive treatment approach for biochemically recurrent prostate cancer, whereby cycling treatment on and off has been shown to limit toxicities and reduce cumulative dose. While IADT has been shown to delay the development of treatment resistance, underlying mechanisms and actionable biomarkers are required to accurately predict when resistance will emerge and how to maximally delay time to progression. We developed a quantitative framework to simulate the enrichment of prostate cancer stem cell dynamics during treatment as a plausible mechanism of resistance evolution. Using simulated dynamics of cancer stem cells and non-stem cancer cells we derive longitudinal blood serum prostate-specific antigen (PSA) concentrations that were calibrated to and validated with data of 86 patients undergoing multiple cycles of IADT. Model analysis suggests that cancer stem cell proliferation patterns correlate with PSA dynamics and patient outcomes. Learning these dynamics adaptively from the earlier treatment cycles in individual patients can predict the evolution of resistance in subsequent IADT cycles with a predictive power of 80%, which warrants prospective evaluation in a clinical setting. Citation Format: Renee Brady, Heiko Enderling. Using PSA dynamics to predict patient-specific responses to intermittent androgen deprivation [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 695.
Doctors declare climate emergency and call for tighter targets
Authors: Richard Hurley
Journal: BMJ (2019)

The BMA should declare a “climate emergency” and campaign for carbon neutrality by 2030, doctors at the BMA’s annual representative meeting agreed on 26 June.

The association should act on the report of the United Nations Intergovernmental Panel on Climate Change, they said. This report outlined huge benefits to keeping temperature rises this century to 1.5°C, compared with a world that warms …
Abstract 5482: Reduction of Established Atherosclerosis in Hypercholesterolemic Mouse Models by ATI-5261: a Novel α-helix Peptide that Stimulates ABCA1 Cholesterol Efflux with High Efficiency
Authors: John K Bielicki, Haiyan Zhang, Rakia Azhar, Jan Johansson, Salman Azhar
Journal: Circulation (2008)

Apolipoprotein(apo)s of HDL stimulate cholesterol efflux via the ATP-binding cassette transporter A1 (ABCA1), generating HDL and reversing the macrophage foam-cell phenotype. Despite these anti-atherogenic roles, the impact of specifically promoting ABCA1 cholesterol efflux on atherosclerosis development is largely unknown. Progress in this area has been hindered by a lack of synthetic agonists and/or apo mimetics optimized to mediate ABCA1 cholesterol efflux. The latter can be attributed, in part, to the fact that long segments of α-helical structure constituting the C-terminal (CT) domains of apoA-I and E are required to mediate ABCA1 cholesterol efflux efficiently. To begin to address these issues, we compressed the activity determinants of these CT helices into a single α-helix, creating a peptide (ATI-5261) that stimulates ABCA1 efflux with apo molar efficiency. Treatment of LDLr−/− mice made atherosclerotic by a high-fat western-diet (13 weeks) with ATI-5261 (30 mg/kg) ip on alternate days for 6 weeks reduced atherosclerosis by ~30%, as judged by lesion-area (Sudan IV) covering the aorta (7.9±2 vs.11.3±2.5% control, p=0.011), and the lipid-content (oil-red O) of aortic-sinus plaque (25±5.8 vs. 33±4.9% control, p=0.034). In similarly designed studies, ATI-5261 reduced atherosclerosis in apoE−/− mice by ~45% (lesion-area = 14±8 vs. 25±9% control, p=0.011; plaque lipid-content = 22±6 vs. 41±7% control, p=0.001). The minimum effective dose of ATI-5261 was 3 mg/kg in apoE−/− mice, consistent with the potent cholesterol efflux activity of the peptide. In both mouse models, ATI-5261 reduced atherosclerosis to the same extent as ATI-5261:POPC complexes (~7 nm). Single ip injection of ATI-5261 increased reverse cholesterol transport from macrophage foam-cells to feces for up to 48 h. To our knowledge, ATI-5261 is the first synthetic α-helix able to reduce atherosclerosis in mice having substantial plaque-lipid accumulation. This did not require peptide formulation with phospholipids and was achieved in the presence of vastly different lipoprotein profiles and plasma cholesterol concentrations. The data suggest that accelerating ABCA1 lipid-efflux may represent a viable approach to reduce atherosclerosis and stabilize vulnerable plaque.
Serum level of miRNA-143 as a potential prognostic marker in patients with colorectal cancer and synchronous metastatic disease
Authors: Z. Mihaylova, D. Ivanova, G. Mihaylova, O. Tasinov, N. Nazifova-Tasinova, D. Petkova, A. Garev, R. Manev, N. Conev, I. Donev, M. Radanova
Journal: Annals of Oncology (2019)
Abstract 19666: Calpain Inhibition Improves Myocardial Perfusion in a Swine Model of Chronic Myocardial Ischemia
Authors: Ashraf A Sabe, Nassrene Y Elmadhun, Jun Feng, Yuhong Liu, Frank W Sellke
Journal: Circulation (2014)

Hypothesis: Calpain overexpression is implicated in aberrant angiogenesis in chronic myocardial ischemia. We hypothesized that calpain inhibition (CI) would improve collateral dependent perfusion i...
RBC membrane camouflaged prussian blue nanoparticles for gamabutolin loading and combined chemo/photothermal therapy of breast cancer
Authors: Bin Liu, Wenmiao Wang, Jialong Fan, Ying Long, Feng Xiao, Muhammad Daniyal, Chunyi Tong, Qian Xie, Yuqing Jian, Bin Li, Xiaochi Ma, Wei Wang
Journal: Biomaterials (2019)