tbuckley/cabot-search huggingface dataset:
Abstract 1149: Humanized knock-in mouse models for evaluating in vivo efficacy of immune-oncology drugs targeting inhibitory immune checkpoint molecules
Authors: Baozhu Zhang, Chaoshe Guo, Yuelei Shen, Yanan Guo
Journal: Cancer Research (2018)

Abstract Recently, increasingly attention has been paid to the development of immuno-oncology (IO) drugs, due to the promising clinical results acquired by CTLA-4, PD-1 and PD-L1 antibodies. However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step. Mouse surrogate antibodies were often used in immune-competent mice with murine syngeneic tumor models to evaluate in vivo efficacy of the IO drugs. However, the efficacy of a surrogate antibody cannot fully represent the human drug in the clinical scenario. In most cases, a human monoclonal antibody does not have mouse cross-reactivity. Therefore, we generated humanized knock-in mouse to evaluate the in vivo efficacy of human IO antibodies. For example, human PD-1 knock-in (B-hPD-1) mice were generated with a chimeric PD-1 receptor, which is recognizable by human PD-1 antibodies, and can be used to test human PD-1 antibody in vivo efficacy. Mouse cancer cell lines including colon cancer MC38, melanoma B16F10 and lung cancer LLC1 were genetically modified with over-expression of hPD-L1 and knock-out of mPD-L1, and used to evaluate the in vivo efficacy of human PD-L1 antibodies. Additionally, more knock-in mice targeting inhibitory immune checkpoint molecules were developed, such as B-hPD-L1, B-hCTLA-4, B-hLAG3, B-hTIM3, B-hTIGIT, B-hBTLA, B-hSIRPa et al,. Humanized knock-in mice, pairing with genetically modified mouse cancer cells, represent a promising in vivo efficacy model for the development of IO drugs, and contribute to the clinical translation of animal studies. Citation Format: Baozhu Zhang, Chaoshe Guo, Yuelei Shen, Yanan Guo. Humanized knock-in mouse models for evaluating in vivo efficacy of immune-oncology drugs targeting inhibitory immune checkpoint molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1149.
Absence of Association Between Infectious Agents and Endothelial Function in Healthy Young Men
Authors: PaulKhairy, StéphaneRinfret, Jean-ClaudeTardif, RichardMarchand, StanShapiro, JamesBrophy, JocelynDupuis
Journal: Circulation (2003)

Background— Although several studies have reported correlations between infections and coronary artery disease, associations with endothelial dysfunction, its precursor, have not been established. This study assessed whether infection with Chlamydia pneumoniae (CP), cytomegalovirus (CMV), Epstein-Barr virus (EBV), or Helicobacter pylori (HP) is associated with decreased endothelial function. Methods and Results— Sixty-five male subjects, aged 20 to 45 years, with no risk factors or known coronary artery disease were enrolled in a seroepidemiological cross-sectional study. Endothelial function was determined by flow-mediated brachial vasodilation. Serum antibodies consisting of anti-CP IgG and IgM, anti-CMV IgG, anti-EBV nuclear antigen, and anti-HP IgG and markers of inflammation including high-sensitivity C-reactive protein were measured. Average age was 29.3±5.5 years. Seroprevalence values were 65.1%, 34.9%, 88.9%, and 14.3% for CP, CMV, EBV, and HP, respectively. Average values for endothelium-depende...
Reporting of stepped wedge cluster randomised trials: extension of the CONSORT 2010 statement with explanation and elaboration
Authors: Karla Hemming, Monica Taljaard, Joanne E McKenzie, Richard Hooper, Andrew Copas, Jennifer A Thompson, Mary Dixon-Woods, Adrian Aldcroft, Adelaide Doussau, Michael Grayling, Caroline Kristunas, Cory E Goldstein, Marion K Campbell, Alan Girling, Sandra Eldridge, Mike J Campbell, Richard J Lilford, Charles Weijer, Andrew B Forbes, Jeremy M Grimshaw
Journal: BMJ (2018)

This report presents the Consolidated Standards of Reporting Trials (CONSORT) extension for the stepped wedge cluster randomised trial (SW-CRT). The SW-CRT involves randomisation of clusters to different sequences that dictate the order (or timing) at which each cluster will switch to the intervention condition. The statement was developed to allow for the unique characteristics of this increasingly used study design. The guideline was developed using a Delphi survey and consensus meeting; and is informed by the CONSORT statements for individual and cluster randomised trials. Reporting items along with explanations and examples are provided. We include a glossary of terms, and explore the key properties of the SW-CRT which require special consideration in their reporting.
Transforming Psychiatry into Data-Driven Medicine with Digital Measurement Tools
Authors: Honor Hsin, Menachem Fromer, Bret Peterson, Collin Walter, Mathias Fleck, Andrew Campbell, Paul Varghese, Robert Califf
Journal: npj Digital Medicine (2018)

Psychiatry has been limited by historically rooted practices centered primarily on subjective observation. Fields such as oncology have progressed toward data-driven clinical decision-making that combines subjective clinical assessment of symptoms and preferences with biological measures such as genetics, biomarkers, imaging, and integrative physiology to derive quantitative risk scores and decision support. In contrast, psychiatry has just begun to scratch the surface of measurement-based care with validated clinical questionnaires. An opportunity exists to improve modern psychiatric care with novel data streams from digital sensors combined with clinical observation and subjective self-report. The prospect of integrating this complex information with modern computational and analytical methods could advance the field, both in research and clinical practice. Here we discuss this possibility and propose some key priorities to enable these innovations toward improving clinical outcomes in the future.
The Effect of Tetraethylpyrophosphate (TEPP) on the Transmembrane Potentials of Pacemaker and Non-pacemaker Fibers of Isolated Rabbit Atrium
Authors: Morriskleinfeld, Johnmagin, Edwardstein
Journal: Circulation Research (1960)

When 7 x 10-7M tetraethylpyrophosphate (TEPP) was administered as constant perfusion, the results were: (1) A progressive slowing of atrial rate and subsequent block in conduction; (2) A decrease in slope of the prepotential of pacemaker fibers; (3) No significant change in membrane resting potential of sinoatrial and atrial fibers, even during block in conduction; (4) An accelerated repolarization of both types of fibers. Simultaneously with the changes in electrical activity TEPP consistently produced a progressive decrease in inotropism. Pyridine 2-aldoxime methiodide (PAM) in concentrations of 1.26-2.52 x 10-4M consistently reversed the effects of TEPP. The inotropism often exceeded the control. The data suggests that 1) the changes in transmembrane potential produced by TEPP are principally due to an acetylcholine action, 2) the decrease in contractility is more intimately related to a disturbance in metabolic energy, and 3) the reversibility of the TEPP effects by PAM is due to a reactivation of ace...
Prospective evaluation of front-line chemo-immunotherapy (C-IT) with oregovomab (2 alternative dosing schedules) carboplatin-paclitaxel (C-P) in advanced ovarian cancer (OC)
Authors: P. Braly, C. Chu, Y. Collins, R. Edwards, A. Gordon, W. McGuire, L. M. Smith, C. Nicodemus, M. Method
Journal: Journal of Clinical Oncology (2007)

3024 Background: Chemotherapy (C) induced bone marrow suppression has been assumed to inhibit the generation of augmented immune responses. This has limited investigation of front-line C-IT in OC. Temporal relationship of IT administration relative to C has not been established. Oregovomab is a CA125 specific MAb in development as an OC adjuvant treatment to induce tumor specific immunity. Methods: Patients (pts) awaiting staging laparotomy for presumptive OC were consented to the study and contributed primary tumor samples. Qualifying pts were subsequently randomized to concurrent C-IT with antibody administered at cycles 1, 3, and 5 (Arm A) or 8 ± 2 days following cycles 1, 3, and 5 (Arm B) of standard C-P. Both arms received additional infusions of oregovomab every 12 weeks until progression; response to C-IT was assessed at 36 weeks. Results: Forty stage III/IV pts (18 Arm A; 22 Arm B) were randomized and dosed. More pts in Arm A (39%) were stage IV vs Arm B (14%) however 27% of Arm B pts had &gt;2cm residual disease vs. 11% in Arm A. Complete clinical response (CR) to surgery and C-IT was achieved in 15 pts (83%) in Arm A and 17 pts (77%) in Arm B. For pts with = 2 cm residual disease, 88% in Arm A had = 65 U/mL CA125 prior to/at cycle 3, normalized CA125 and a CR post C-IT compared to 75% of pts in Arm B. Robust Ab2 antibody response (&gt;100 ng/mL) was achieved in 94% of Arm A and 68% of Arm B pts. The immune response developed earlier in Arm A. After one injection of oregovomab, 31% of pts in Arm A vs. 0% in Arm B generated HAMA &gt; 3000 ng/mL and Ab2 &gt; 100 ng/mL (P=0.016 Fisher’s Exact Test). Such an early and vigorous response pattern has not been seen in previous oregovomab studies which have not included concomitant front-line C. There were no IT related serious adverse events. Conclusions: Contrary to expectations, concurrent C-P resulted in enhanced immune stimulation with oregovomab. Interestingly, concurrent infusion of oregovomab was more immunogenic than delayed infusion. Clinical activity was favorable and safety profiles were similar to that expected for C alone. Further randomized evaluation of front-line CP-oregovomab vs CP is warranted. [Table: see text]
Rates of Overtreatment and Treatment-Related Adverse Effects Among Patients With Subsegmental Pulmonary Embolism
Authors: Ismail A. Raslan, Jaron Chong, Benoît Gallix, Todd C. Lee, Emily G. McDonald
Journal: JAMA Internal Medicine (2018)

potential implications of overlooking key findings.A focus of high-value care has been eliminating unnecessary testing.Another approach would be to identify lower-cost alternatives.
Abstract 427: High-quality whole-genome sequencing of FFPE samples
Authors: Shannon T. Bailey, Jim Lund, Hao Wang, Weiren Cui, Chen Hao, Hongye Sun, Jeffrey R. Gulcher
Journal: Cancer Research (2018)

Abstract Next-generation sequencing analysis of formalin-fixed, paraffin-embedded (FFPE) samples has the potential to lead to major advances in cancer treatment and prevention. However, whole-genome sequencing of these samples has remained challenging due to the difficult process of isolating high-quality DNA and distinguishing true variant calls from artifacts. Previous studies have attempted to overcome these challenges by using whole-exome sequencing or smaller exon panels at high coverage depths to analyze FFPE samples. While these approaches have produced useful results, they have had varying degrees of success, tend have coverage biases due to probe capture issues, and are limited to only a fraction of the genome. Thus, there has not been widespread adoption of using FFPE samples for next-generation sequencing. In an attempt to improve on the process of next-generation sequencing of FFPE samples, we first developed an efficient DNA extraction method that produces high quantities of high-quality DNA. Whole-genome sequencing of DNA generated by this method demonstrated uniform high coverage that was comparable to DNA prepared from fresh frozen samples at the same sequencing depth. This result is in contrast with data generated from DNA isolated by a traditional FFPE extraction method, which had lesser sequencing coverage even with twice the sequencing depth. Further analysis of the data generated using our method demonstrated similar numbers of mutations called and mutational signatures without artifact contamination. We extended this analysis to a large cancer cohort consisting of over 1,000 FFPE samples in tumor normal pairs that were up to 6 years old. Whole-genome sequencing of these samples demonstrate that there was an average of 98% of the genome covered at 20X or greater using our method with no drop off for the older samples. Mutational analyses of these samples demonstrate similar findings as that previously published using TCGA datasets. In summary, our study of greater than 1,000 samples is the largest report of whole-genome sequencing of FFPE samples to date. Our results demonstrate the feasibility of using our method to assay tissues stored in archival tissue biobanks, analyze patient samples for clinical trial recruitment, or examining sections as part of normal clinical workflows, all of which hold the potential for greatly benefiting human health. Citation Format: Shannon T. Bailey, Jim Lund, Hao Wang, Weiren Cui, Chen Hao, Hongye Sun, Jeffrey R. Gulcher. High-quality whole-genome sequencing of FFPE samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 427.
Abstract P070: Comparison of Heritability Estimation Using the Principal Components Calculated by Maximizing Variance and Heritability for OSA Traits
Authors: JingjingLiang, TaoFeng, BrianCade, XihongLin, RichaSaxena, KevinGleason, XiaofengZhu, SusanRedline
Journal: Circulation (2015)

RATIONALE: Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive pauses in breathing during sleep associated with significant cardiovascular morbidity. Accumulating study results suggest that there are strong genetic contributions for this disease as defined by the apnea hypopnea index (AHI), the number of breathing pauses per hour of sleep. Using this metric, it has been shown that OSA significantly aggregates within families (1-2); heritability for the AHI is estimated to vary from about 20 to 40% (2-3). However, the AHI is only one index from several that describe OSA severity, and may not be the most relevant phenotype for genetic studies. It has not, however, been clear how to systematically assess heritability of multiple correlated and uncorrelated OSA traits. METHODS: To identify OSA related phenotypes that are most heritable to inform discovery of genetic risk variants for the disease, heritability analysis of multiple OSA related phenotypes were conducted using family da...
Abstract 155: KDM4 inhibition targets breast cancer stem-like cells
Authors: Jochen Maurer
Journal: Cancer Research (2018)

Abstract Traditional treatments for breast cancer fail to address therapy-resistant cancer stem-like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem-like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSC regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Citation Format: Jochen Maurer. KDM4 inhibition targets breast cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 155.
Abstract 528: Identification of MYC as a novel repressor of miR-29 in pancreatic ductal adenocarcinoma
Authors: Jason Kwon, Kayla Quirin, Tricia Factora, Janaiah Kota
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease with a dismal 5-year survival rate of 8%. The lack of effective therapies reinforces the need to better understand molecular mechanisms in PDAC. In our previous work, we found that downregulation of miR-29 is a common phenomenon of PDAC, and its restored expression had a potent tumor-suppressive effect in pancreatic cancer cells. However, the mechanism associated with the loss of miR-29 in PDAC has yet to be elucidated. In our initial work, using PDAC cell lines, we found that miR-29 is downregulated independent of KRAS. In an effort to understand the transcriptional factors mediating miR-29 repression, we selected several transcription factors that have a role in PDAC pathogenesis and binding sites in the miR-29 promoter region. siRNA mediated knockdown (KD) of three candidate transcription factors, SMAD4, MYC, and Gli3 revealed that the KD of MYC resulted in the highest gain of miR-29 expression (2-fold increase). Furthermore, MYC nuclear localization negatively correlates with miR-29 expression in various pancreatic cancer cell lines, and treatment of pancreatic cancer cells with small-molecule MYC inhibitor resulted in a dosage-dependent increase of miR-29 expression. miR-29a/b1 locus located on human chromosome 7 has two canonical MYC binding motifs upstream of the miR-29 transcription start site, which were functionally validated via luciferase assay. Finally, autophagy has been shown to be upregulated by MYC and is known to mitigate stressors of the integrated stress response (ISR) pathway in cancer. In our previous work, we showed that miR-29 blocks autophagy in pancreatic cancer cells. Consistently, we found miR-29 overexpression led to decreased cancer cell viability in combination with gemcitabine and induced the ISR as indicated by increased phospho-eIF2α. Taken together, our results demonstrate that MYC plays a key role in the regulation of miR-29 expression in pancreatic cancer. Furthermore, our data indicate the potential use of miR-29 as a novel therapeutic agent for PDAC, and these results could help form the basis for future studies to develop a more targeted approach of miR-29 therapeutic administration. Citation Format: Jason Kwon, Kayla Quirin, Tricia Factora, Janaiah Kota. Identification of MYC as a novel repressor of miR-29 in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 528.
Immune cell subset differentiation and tissue inflammation
Authors: Pu Fang, Xinyuan Li, Jin Dai, Lauren Cole, Javier Andres Camacho, Yuling Zhang, Yong Ji, Jingfeng Wang, Xiao-Feng Yang, Hong Wang
Journal: Journal of Hematology & Oncology (2018)

Immune cells were traditionally considered as major pro-inflammatory contributors. Recent advances in molecular immunology prove that immune cell lineages are composed of different subsets capable of a vast array of specialized functions. These immune cell subsets share distinct duties in regulating innate and adaptive immune functions and contribute to both immune activation and immune suppression responses in peripheral tissue. Here, we summarized current understanding of the different subsets of major immune cells, including T cells, B cells, dendritic cells, monocytes, and macrophages. We highlighted molecular characterization, frequency, and tissue distribution of these immune cell subsets in human and mice. In addition, we described specific cytokine production, molecular signaling, biological functions, and tissue population changes of these immune cell subsets in both cardiovascular diseases and cancers. Finally, we presented a working model of the differentiation of inflammatory mononuclear cells, their interaction with endothelial cells, and their contribution to tissue inflammation. In summary, this review offers an updated and comprehensive guideline for immune cell development and subset differentiation, including subset characterization, signaling, modulation, and disease associations. We propose that immune cell subset differentiation and its complex interaction within the internal biological milieu compose a "pathophysiological network," an interactive cross-talking complex, which plays a critical role in the development of inflammatory diseases and cancers.
Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose
Authors: Jean-PhilippeCollet, JohanneSilvain, AntoineLandivier, Marie-LaureTanguy, GuillaumeCayla, AnneBellemain, NicolasVignolles, SophieGallier, FarzinBeygui, AnaPena, GillesMontalescot
Journal: Circulation (2008)

Background— Clopidogrel loading has mostly been studied in clopidogrel-naive patients. Whether clopidogrel-treated patients readmitted for an acute coronary syndrome or percutaneous coronary intervention can benefit from a new load of clopidogrel and at what dose remain unknown. Our aim was to evaluate the impact of 3 different strategies of administration of a loading dose of 900 mg clopidogrel in patients already treated with a maintenance dose of 75 mg clopidogrel for at least 7 days on residual platelet aggregation. Methods and Results— Patients treated long term by clopidogrel 75 mg/d were assigned to receive a first loading dose of 300, 600, or 900 mg clopidogrel and 4 hours later a second loading dose of 600, 300, or 0 mg, respectively, to achieve a total loading dose of 900 mg in all patients. Platelet aggregation was evaluated at baseline, at 4 hours after the initial load (and before second load), and at 24 hours using light transmission aggregometry with 20 μmol ADP and the point-of-care assay...
Risk factors for situs defects and congenital heart disease in primary ciliary dyskinesia
Authors: Sunayna Best, Amelia Shoemark, Bruna Rubbo, Mitali P Patel, Mahmoud R Fassad, Mellisa Dixon, Andrew V Rogers, Robert A Hirst, Andrew Rutman, Sarah Ollosson, Claire L Jackson, Patricia Goggin, Simon Thomas, Reuben Pengelly, Thomas Cullup, Eleni Pissaridou, Jane Hayward, Alexandros Onoufriadis, Christopher O’Callaghan, Michael R Loebinger, Robert Wilson, Eddie Mk Chung, Priti Kenia, Victoria L Doughty, Julene S Carvalho, Jane S Lucas, Hannah M Mitchison, Claire Hogg
Journal: Thorax (2018)

Primary ciliary dyskinesia (PCD) is associated with abnormal organ positioning (situs) and congenital heart disease (CHD). This study investigated genotype–phenotype associations in PCD to facilitate risk predictions for cardiac and laterality defects. This retrospective cohort study of 389 UK patients with PCD found 51% had abnormal situs and 25% had CHD and/or laterality defects other than situs inversus totalis. Patients with biallelic mutations in a subset of nine PCD genes had normal situs. Patients with consanguineous parents had higher odds of situs abnormalities than patients with non-consanguineous parents. Patients with abnormal situs had higher odds of CHD and/or laterality defects.