tbuckley/cabot-search huggingface dataset:
Abstract B61: Encyclopedic noninvasive liquid biopsies for differential diagnosis in prostate cancer
Authors: Darshana A. Patil, Dadasaheb Akolkar, Revati Patil, Pooja Fulmali, Pradip Fulmali, Akshay Ainwale, Navin Srivastava, Vineet Datta, Cynthe Sims, Ajay Srinivasan, Rajan Datar
Journal: Clinical Cancer Research (2020)

Abstract Differential diagnosis of prostatic adenocarcinomas is based on histopathologic analysis of tumor tissue obtained by transrectal ultrasound (TRUS)-guided biopsies. However, such invasive biopsies are associated with pain, procedural expenses, sequelae, and risk of complications. Though immunocytochemistry (ICC) profiling of circulating tumor cells (CTCs, defined as EpCAM+, panCK+, CD45-) has been previously attempted for diagnosis in some cancers, it has been unviable due to limited yields of CTCs. For the first time we used enrichment of CTCs that permit meaningful ICC profiling for diagnosis of prostate cancers in suspected cases as contradistinguished from cases of benign enlargement of prostate (BEP). We obtained 15 mL of venous blood draw from 650 individuals, of whom 65 had a confirmed diagnosis of either prostate adenocarcinoma and 585 were diagnosed with benign prostate hyperplasia. CTCs were enriched from PBMCs fraction using an epigenetically acting enrichment process that is lethal towards normal (nonmalignant) cells but confers survival privilege on apoptosis-resistant CTCs. Harvested CTCs were confirmed by immunostaining for EpCAM and pan-CK. ICC profiling of these CTCs was also performed with organ-specific markers PSMA and AMACR. Viable CTCs could be obtained from 58 samples (89.2%) out of 65 confirmed prostate cancer cases. Among the 40 samples that were characterized by deep ICC profiling, all samples (100%) were positive for PSMA and AMACR. Among the benign cases, CTCs were observed in 10 samples (1.7%), of which all 10 were positive for PSMA but negative for AMACR. These patients are being followed up. Possibility of other cancers is not ruled out in these patients. Our results show that ICC-based characterization of CTCs can provide necessary diagnostic information noninvasively to substitute for conventional procedures dependent on tissue extraction. Citation Format: Darshana A. Patil, Dadasaheb Akolkar, Revati Patil, Pooja Fulmali, Pradip Fulmali, Akshay Ainwale, Navin Srivastava, Vineet Datta, Cynthe Sims, Ajay Srinivasan, Rajan Datar. Encyclopedic noninvasive liquid biopsies for differential diagnosis in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B61.
Screening for candidate biomarkers of TB in stimulated blood: another step in the quest for a test?
Authors: Myrsini Kaforou
Journal: Thorax (2020)

It is estimated that each year approximately one-third of all tuberculosis (TB) cases remain either undiagnosed or unreported.1 Countries are intensifying their efforts to narrow the gaps between TB incidence and notifications through improving surveillance, diagnosis and access to healthcare. A major impediment in this effort is that diagnostic tests are not sufficiently sensitive or specific to accurately identify all TB cases. New tools are urgently needed for the diagnosis of TB to achieve global TB control.

The WHO considers non-sputum biomarker-based tests for rapidly diagnosing TB to be of utmost priority.1 Human host-based biomarkers have great potential, as they can enhance confirmatory diagnosis particularly in sputum negative and/or culture negative adult, and paediatric cases.2 In children, the paucibacillary nature of the disease and the more common extrapulmonary presentations are the main reasons why microbiological confirmation is achieved in only a small proportion of children that receive TB treatment.3

Host immune biomarkers have been widely used in tests for diagnosing TB infection, such as the interferon-gamma (IFN-γ) release assays (IGRAs), which are based on ex-vivo stimulation of host blood with Mtb-specific antigens. Stimulation of blood or host cells with Mtb antigens gives rise to amplified quantifiable antibody, cytokine or cellular immune responses (reviewed in the study of Yong et al 4).

Samples …
Mechanism of RNA modification N6-methyladenosine in human cancer
Authors: Zijian Zhou, Jiancheng Lv, Hao Yu, Jie Han, Xiao Yang, Dexiang Feng, Qikai Wu, Baorui Yuan, Qiang Lu, Haiwei Yang
Journal: Molecular Cancer (2020)

Abstract Since the breakthrough discoveries of DNA and histone modifications, the field of RNA modifications has gained increasing interest in the scientific community. The discovery of N6-methyladenosine (m6A), a predominantly internal epigenetic modification in eukaryotes mRNA, heralded the creation of the field of epi-transcriptomics. This post-transcriptional RNA modification is dynamic and reversible, and is regulated by methylases, demethylases and proteins that preferentially recognize m6A modifications. Altered m6A levels affect RNA processing, degradation and translation, thereby disrupting gene expression and key cellular processes, ultimately resulting in tumor initiation and progression. Furthermore, inhibitors and regulators of m6A-related factors have been explored as therapeutic approaches for treating cancer. In the present review, the mechanisms of m6A RNA modification, the clinicopathological relevance of m6A alterations, the type and frequency of alterations and the multiple functions it regulates in different types of cancer are discussed.
Abstract 15085: The Potential Clinical Role of Cathepsin K and Autophagy in the Prevention of Alcoholic Cardiomyopathy
Authors: Rui Guo, Hui Yang, Yunliang Zhang, Baoxin Li, Xin Liu, Li Zhong
Journal: Circulation (2019)

Introduction: Long-term heavy drinking is an independent risk factor for the development of heart disease. We have previously demonstrated that chronic alcohol induces alcoholic cardiomyopathy acco...
Altered atrial cytosolic calcium handling contributes to the development of postoperative atrial fibrillation
Authors: Funsho E Fakuade, Vanessa Steckmeister, Fitzwilliam Seibertz, Judith Gronwald, Stefanie Kestel, Julia Menzel, Julius Ryan D Pronto, Karim Taha, Fereshteh Haghighi, George Kensah, Charles M Pearman, Felix Wiedmann, Arco J Teske, Constanze Schmidt, Katharine M Dibb, Aschraf El-Essawi, Bernhard C Danner, Hassina Baraki, Blanche Schwappach, Ingo Kutschka, Fleur E Mason, Niels Voigt
Journal: Cardiovascular Research (2020)

Abstract Aims Atrial fibrillation (AF) is a commonly occurring arrhythmia after cardiac surgery (postoperative AF, poAF) and is associated with poorer outcomes. Considering that reduced atrial contractile function is a predictor of poAF and that Ca2+ plays an important role in both excitation–contraction coupling and atrial arrhythmogenesis, this study aims to test whether alterations of intracellular Ca2+ handling contribute to impaired atrial contractility and to the arrhythmogenic substrate predisposing patients to poAF. Methods and results Right atrial appendages were obtained from patients in sinus rhythm undergoing open-heart surgery. Cardiomyocytes were investigated by simultaneous measurement of [Ca2+]i and action potentials (APs, patch-clamp). Patients were followed-up for 6 days to identify those with and without poAF. Speckle-tracking analysis of preoperative echocardiography revealed reduced left atrial contraction strain in poAF patients. At the time of surgery, cellular Ca2+ transients (CaTs) and the sarcoplasmic reticulum (SR) Ca2+ content were smaller in the poAF group. CaT decay was slower in poAF, but the decay of caffeine-induced Ca2+ transients was unaltered, suggesting preserved sodium-calcium exchanger function. In agreement, western blots revealed reduced SERCA2a expression in poAF patients but unaltered phospholamban expression/phosphorylation. Computational modelling indicated that reduced SERCA activity promotes occurrence of CaT and AP alternans. Indeed, alternans of CaT and AP occurred more often and at lower stimulation frequencies in atrial myocytes from poAF patients. Resting membrane potential and AP duration were comparable between both groups at various pacing frequencies (0.25–8 Hz). Conclusions Biochemical, functional, and modelling data implicate reduced SERCA-mediated Ca2+ reuptake into the SR as a major contributor to impaired preoperative atrial contractile function and to the pre-existing arrhythmogenic substrate in patients developing poAF.
Abstract 218: Efficacy and Safety of a Novel Transnasal Cooling Device for Targeted Temperature Management (CoolStat™)
Authors: Fabrizio Assis, Emma G Bigelow, Raghuram Chava, Sunjeet Sidhu, Aravindan Kolandaivelu, Henry Halperin, Harikrishna Tandri
Journal: Circulation (2018)

Background: Targeted temperature management (TTM) is recommended as a standard of care for post cardiac arrest patients. Current TTM methods have significant limitations to be used in an ambulatory setting. We explored the efficacy and safety of a novel non-invasive transnasal evaporative cooling device (CoolStat™). Methods: Eleven pigs underwent hypothermia therapy using a transnasal cooling device (CoolStat™). CoolStat™ induces evaporative cooling by blowing de-humidified ambient air over the nose in a unidirectional fashion. CoolStat’s efficacy and safety were assessed by applying different cooling strategies (Groups A, B and C). In group A (efficacy study; n=5, TTM for 8h), time to achieve brain target temperature, and the percentage of time in which the temperature ranged within 0.5 o C after reaching the target temperature were investigated. In the safety assessment (Groups B and C), two worst-case therapy situations were reproduced: in group B (n=3), continuous maximum air flow (65L/min) was applied without temperature control and, in group C (n=3), subjects underwent 24-hour TTM (prolonged therapy). Hemodynamic and respiratory parameters, nasal mucosa integrity (endoscopic assessment) and other therapy-related adverse effects were evaluated. Results: Efficacy study. CoolStat™ cooling therapy successfully induced and sustained managed hypothermia in all subjects. Brain target temperature was achieved in 0.5±0.6h and kept within a ±0.5 o C range for the therapy duration (99.9±0.1%). All animals completed the safety studies. Maximum air flow (Group B) and 24-hour (Group C) therapies were well-tolerated and no significant damage was observed on nasal mucosa for neither of the groups. Conclusion: CoolStat™ was able to efficiently induce and maintain hypothermia using unidirectional high flow of dry air into the nostrils of porcine models. CoolStat therapy was well-tolerated and might account for early hypothermia in cardiac arrest settings.
FRI0390 IMPACT OF ULTRASONOGRAPHY‑DETECTED QUADRICEPS CALCIFIC TENDONITIS ON PAIN AND FUNCTION IN PATIENTS WITH PRIMARY KNEE OSTEOARTHRITIS
Authors: M. A. Mortada, Y. A. Amer
Journal: Annals of the Rheumatic Diseases (2020)

Background: Calcific tendonitis is most commonly seen around shoulder joint. Few cases of quadriceps calcific tendonitis (QCT) of were reported. Routine use of ultrasonography in diagnosis of knee osteoarthritis has resulted in detection of many cases of QCT. Up to the best of our knowledge, this is the first study to detect impact of QCT in knee osteoarthritis by ultrasonography. Objectives: To compare pain, function, and clinical and radiological findings among primary KOA patients with or without ultrasonography-detected QCT. Methods: A prospective, observational study study was conducted on 214 patients with knee OA in the period between february 2019 to july 2019. Ultrasonography of knee joints was done according to EULAR guidelines. Quadriceps calcific tendonitis is defined as hyperechoic mass within the quadriceps tendon with posterior shadowing. The patients were categorized into two groups according to the presence or absence of QCT. Radiological grades of Kellgren–Lawrence were recorded. Pain and functional status was assessed by visual analog scale (VAS), Health Assessment Questionnaire-II (HAQ-II), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Results: QCT were detected in 25 (11.6%) patients. Most cases of QCT were detected in vastus lateralis 18 (72%), then in vastus intermedius 5 (20%) and only 2 cases were detected in vastus medialis. QCT were detected mainly in advanced stages of knee OA; 22 cases of QCT were found in patients with grade 4 KOA. The presence of QCT was statistically significant related ( P &lt; 0.05*) with age, VAS, HAQ-II, WOMAC subscales, synovitis and effusion. Conclusion: Quadriceps calcific tendonitis is not rare. Ultrasonography can detect QCT in many cases with advanced knee OA. QCT is associated with increased pain and dysfunction in knee OA References: None Disclosure of Interests: None declared
Abstract PHB05: Mechanism-based computational models to study interplay between EGFR inhibitors and KRAS mutants
Authors: Edward C. Stites
Journal: Cancer Research (2020)

Abstract An early genotype-to-phenotype relationship in cancer personalized medicine was that KRAS mutations confer resistance to EGFR inhibitors in colorectal cancer. Confusingly, phase 3 clinical trials found that patients with the KRAS G13D mutation were an exception to this rule. That constitutively active KRAS mutants would cause resistance to EGFR inhibitors seemed intuitive, and it appeared inconsistent with known mechanisms of RAS biology for any constitutively active KRAS mutant to behave differently. We have developed a computational model that describes the biochemical mechanisms of RAS signal regulation. Simulations of this mass-action model reproduce known patterns of RAS pathway activation. The incorporation of the specific biochemical parameters for different KRAS mutants has allowed us to uncover novel, non-obvious insights into the response of KRAS G13D and KRAS G12C colorectal cancers to EGFR inhibition. For KRAS G13D, the model revealed EGFR inhibition leads to reduced wild-type HRAS and NRAS signaling in KRAS G13D cancers, but not KRAS G12D or KRAS G12V cancers. The model also revealed a critical dependence upon tumor suppressor NF1, and that the impaired binding of KRAS G13D to NF1 frees NF1 to act on wild-type RAS. Importantly, our computational predictions have been prospectively validated experimentally. Our computational model has also revealed that cotreatment of KRAS G12C colorectal cancer with EGFR and KRAS G12C inhibitors results in a depletion of the active forms of both wild-type and mutant RAS proteins, which we have also confirmed experimentally. For both KRAS G13D and KRAS G12C colorectal cancers, our work demonstrates how computational models can identify behaviors that logically follow from what is known, but which the complexity of the RAS signaling network has prevented from previously being uncovered despite extensive, empirical, experimental efforts. This abstract is also being presented as Poster B51. Citation Format: Edward C. Stites. Mechanism-based computational models to study interplay between EGFR inhibitors and KRAS mutants [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHB05.
Inhibition of Bruton tyrosine kinase in patients with severe COVID-19
Authors: Mark Roschewski, Michail S. Lionakis, Jeff P. Sharman, Joseph Roswarski, Andre Goy, M. Andrew Monticelli, Michael Roshon, Stephen H. Wrzesinski, Jigar V. Desai, Marissa A. Zarakas, Jacob Collen, Keith M. Rose, Ahmed Hamdy, Raquel Izumi, George W. Wright, Kevin K. Chung, Jose Baselga, Louis M. Staudt, Wyndham H. Wilson
Journal: Science Immunology (2020)

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.
Identification of SARS-CoV-2 Vaccine Epitopes Predicted to Induce Long-Term Population-Scale Immunity
Authors: Mark Yarmarkovich, John M. Warrington, Alvin Farrel, John M. Maris
Journal: Cell Reports Medicine (2020)

Here we propose a SARS-CoV-2 vaccine design concept based on identification of highly conserved regions of the viral genome and newly acquired adaptations, both predicted to generate epitopes presented on major histocompatibility complex (MHC) class I and II across the vast majority of the population. We further prioritize genomic regions that generate highly dissimilar peptides from the human proteome and are also predicted to produce B cell epitopes. We propose sixty-five 33-mer peptide sequences, a subset of which can be tested using DNA or mRNA delivery strategies. These include peptides that are contained within evolutionarily divergent regions of the spike protein reported to increase infectivity through increased binding to the ACE2 receptor and within a newly evolved furin cleavage site thought to increase membrane fusion. Validation and implementation of this vaccine concept could specifically target specific vulnerabilities of SARS-CoV-2 and should engage a robust adaptive immune response in the vast majority of the population.
Abstract A14: Detection of a biomarker for B-cell non-Hodgkin lymphomas or leukemias using circulating tumor DNA without the use of PCR or next-gen sequencing
Authors: Jessica A. Stewart, Ashok S. Bhagwat
Journal: Clinical Cancer Research (2020)

Abstract There is a critical need for the development of cheap, safe, and accurate tools for cancer surveillance. Patients diagnosed with cancer require an accurate assessment of tumor burden through the course of their treatment, and the need for tumor surveillance is even more acute for many indolent B-cell malignancies such as follicular lymphoma and chronic lymphocytic leukemia. Over the past several years, we have developed an assay that quantifies a tumor biomarker for many different types of B-cell non-Hodgkin lymphomas or leukemias (B-NHLs). This biomarker, uracils in DNA, originates from the activity of a B-cell maturation enzyme, activation-induced deaminase (AID), which converts cytosines in DNA to uracil. AID is normally not expressed in circulating B cells or any other human tissue and hence this marker is not present in any other types of cells in the human body. We have developed an ELISA-like assay using chemicals with a fluorescence readout that can detect this biomarker in DNA with high sensitivity without PCR or NGS. We will present applications of this technology to genomic DNA from B-NHL tumors and circulating tumor DNA in blood plasma of such patients. Our data show we can detect the presence of this marker in DNA of patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Citation Format: Jessica A. Stewart, Ashok S. Bhagwat. Detection of a biomarker for B-cell non-Hodgkin lymphomas or leukemias using circulating tumor DNA without the use of PCR or next-gen sequencing [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A14.
Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors
Authors: Maddalena Centanni, Sreenath M. Krishnan, Lena E. Friberg
Journal: Clinical Cancer Research (2020)

Various biomarkers have been proposed for sunitinib therapy in gastrointestinal stromal tumor (GIST). However, the lack of "real-life" comparative studies hampers the selection of the most appropriate one. We, therefore, set up a pharmacometric simulation framework to compare each proposed biomarker.Models describing relations between sunitinib exposure, adverse events (hand-foot syndrome, fatigue, hypertension, and neutropenia), soluble VEGFR (sVEGFR)-3, and overall survival (OS) were connected to evaluate the differences in survival and adverse events under different dosing algorithms. Various fixed dosing regimens [4/2 (weeks on/weeks off) or 2/1 (50 mg), and continuous daily dosing (37.5 mg)] and individualization approaches [concentration-adjusted dosing (CAD), toxicity-adjusted dosing (TAD), and sVEGFR-3-adjusted dosing (VAD)] were explored following earlier suggested blood sampling schedules and dose-reduction criteria. Model-based forecasts of biomarker changes were evaluated for predictive accuracy and the advantage of a model-based dosing algorithm was evaluated for clinical implementation.The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) increased median OS as compared with a fixed dose schedule (19.9 and 21.5 months, respectively) and CAD (19.7 and 21.3 months, respectively), without markedly raising the risk of intolerable toxicities. Changes in neutrophil count and sVEGFR-3 were accurately forecasted in the majority of subjects (>65%), based on biweekly blood sampling.Dose adjustments based on the pharmacodynamic biomarkers neutrophil count and sVEGFR-3 can increase OS while retaining drug safety. Future efforts could explore the possibility of incorporating a model-based dose approach in clinical practice to increase dosing accuracy for these biomarkers.
Clinical evaluation of serological IgG antibody response on the Abbott Architect for established SARS-CoV-2 infection
Authors: K.L. Chew, S.S. Tan, S. Saw, A. Pajarillaga, S. Zaine, C. Khoo, W. Wang, P. Tambyah, R. Jureen, S.K. Sethi
Journal: Clinical Microbiology and Infection (2020)
Abstract 13790: Diagnosing Implantable Cardiac Device Infection in Cases of Clinical Uncertainty Using 18F-FDG-Positron Emission Tomography; Reducing Ambiguity With Nuclear Cardiology
Authors: Oliver G Wright, Mohammad Ali, Matthew J Memmott, Fozia Ahmed
Journal: Circulation (2019)

Purpose: Implantable Cardiac Electronic Device infection can be challenging to diagnose, especially when classed as “possible” by current guidelines. 18F-FDG PET/CT has emerged as a novel imaging t...
Abstract 10350: Pediatric Cardiac Retransplantation: A 25 Year Single Center Experience
Authors: Nicole M DeMarais, Philip T Thrush, Michael C Monge, Lauren Balmert, Carl L Backer, Sarah J Wilkens, Bradley S Marino, Elfriede Pahl
Journal: Circulation (2019)

Background: In pediatric heart transplantation (HT), late mortality from cardiac allograft vasculopathy (CAV) is the leading cause of retransplantation (reTx), with inferior survival reported for r...