tbuckley/cabot-search huggingface dataset:
Abstract 999: Unravelling myeloid and T cell compartment interactions through a novel approach to tumor multimodal analysis combining whole slide multiplexed immunofluorescence and gene expression profiling
Authors: Natalie Zwing
Journal: Cancer Research (2018)

Abstract Understanding the role of myeloid cells in tumor biology requires a systems approach combining phenotypic and functional biomarkers. As a model system, colorectal cancer (CRC) tumors represent well-described clinically relevant immune subtypes. Distinct immune patterns have been reported involving the myeloid cells acting as immune suppressors for CD8 cytotoxic T cells. We hypothesized that myeloid derived suppressor cells (MDSCs) and CD8 T cells co-localize due to their direct interactions. A cohort of 85 CRC primary tumors were analyzed by multiplexed immunohistochemistry/ immunofluorescence and subsequent quantitative and qualitative whole slide image analysis. To define the functional status of the identified immune cell populations, their corresponding signatures were analyzed by gene expression profiling. Combining density and distribution of both myeloid cells and T cells as well as their distance to epithelial cancer cells, specific patterns were observed. In both microsatellite stable (MSS) and instable (MSI) tumors, MDSCs showed a comparable stromal distribution. By contrast, in MSI cases only, effector T cells tended to accumulate in the tumor epithelium suggesting they overcome the immunosuppressive environment. Additionally, the assessment of CD8 T cell morphology revealed changes potentially reflecting their cancer cell eliminating properties. This multimodal analysis represents a novel approach to characterize and understand the role of the myeloid compartment through a combination of morphological and spatial characteristics of the T cell compartment. Citation Format: Natalie Zwing. Unravelling myeloid and T cell compartment interactions through a novel approach to tumor multimodal analysis combining whole slide multiplexed immunofluorescence and gene expression profiling [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 999.
Acute Hemodynamic Improvement by Thermal Vasodilation in Congestive Heart Failure
Authors: ChuwaTei, YutakaHorikiri, Jong-ChunPark, Jin-WonJeong, Kyoung-SigChang, YoshihumiToyama, NobuyukiTanaka
Journal: Circulation (1995)

Background A warm-water bath (WWB) or sauna bath (SB) has generally been considered inappropriate for patients with severe congestive heart failure (CHF). However, a comprehensive investigation of the hemodynamic effects of thermal vasodilation in CHF has not been previously undertaken. Methods and Results To investigate the acute hemodynamic effects of thermal vasodilation in CHF, we studied 34 patients with chronic CHF (mean age, 58±14 years). Clinical stages were New York Heart Association functional class II in 2, III in 19, and IV in 13 patients. Mean ejection fraction was 25±9%. After a Swan-Ganz catheter was inserted via the right jugular vein, the patient had a WWB for 10 minutes at 41°C or an SB for 15 minutes at 60°C. Blood pressure, ECG, echo-Doppler, expiration gas, and intracardiac pressures were recorded before, during, and 30 minutes after each bath. Oxygen consumption increased mildly, pulmonary arterial blood temperature increased by 1.2°C, and heart rate increased by 20 to 25 beats per m...
Probucol Attenuates Left Ventricular Dysfunction and Remodeling in Tachycardia-Induced Heart Failure
Authors: RyoNakamura, KensukeEgashira, YoujiMachida, ShunjiHayashidani, MotohiroTakeya, HideoUtsumi, HiroyukiTsutsui, AkiraTakeshita
Journal: Circulation (2002)

Background— Oxidative stress and inflammation are potentially involved in the pathogenesis of heart failure (HF). We examined whether antioxidant and antiinflammatory treatment with probucol decreases myocardial oxidative stress and inflammation and attenuates the progression of left ventricular (LV) dysfunction and remodeling (dilatation) in tachycardia-induced HF. Methods and Results— We studied 3 groups of dogs: a sham-operated control group and 2 other groups that underwent ventricular pacing at 240 bpm with and without probucol treatment (100 mg/kg IP per week) for 4 weeks. Dogs that underwent ventricular pacing for 4 weeks developed signs of HF, such as a reduction in the LV ejection fraction and increases in the LV end-diastolic dimension and LV end-diastolic pressure. Myocardial oxidative stress, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6,-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO), was significantly increased. There was an increase in myocardial monocyte infiltr...
Gene editing for inflammatory disorders
Authors: David T Ewart, Erik J Peterson, Clifford J Steer
Journal: Annals of the Rheumatic Diseases (2018)

Technology for precise and efficient genetic editing is constantly evolving and is now capable of human clinical applications. Autoimmune and inflammatory diseases are chronic, disabling, sometimes life-threatening, conditions that feature heritable components. Both primary genetic lesions and the inflammatory pathobiology underlying these diseases represent fertile soil for new therapies based on the capabilities of gene editing. The ability to orchestrate precise targeted modifications to the genome will likely enable cell-based therapies for inflammatory diseases such as monogenic autoinflammatory disease, acquired autoimmune disease and for regenerative medicine in the setting of an inflammatory environment. Here, we discuss recent advances in genome editing and their evolving applications in immunoinflammatory diseases. Strengths and limitations of older genetic modification tools are compared with CRISPR/Cas9, base editing, RNA editing, targeted activators and repressors of transcription and targeted epigenetic modifiers. Commonly employed delivery vehicles to target cells or tissues of interest with genetic modification machinery, including viral, non-viral and cellular vectors, are described. Finally, applications in animal and human models of inflammatory diseases are discussed. Use of chimeric autoantigen receptor T cells, correction of monogenic diseases with genetically edited haematopoietic stem and progenitor cells, engineering of induced pluripotent stem cells and ex vivo expansion and modification of regulatory T cells for a range of chronic inflammatory diseases are reviewed.
Diagnostic Value of Plasma Levels of Brain Natriuretic Peptide in Arrhythmogenic Right Ventricular Dysplasia
Authors: KiyotakaMatsuo, ToshioNishikimi, ChikaoYutani, TakashiKurita, WataruShimizu, AtsushiTaguchi, KazuhiroSuyama, NaohikoAihara, ShiroKamakura, KenjiKangawa, MakotoTakamiya, KatsuroShimomura
Journal: Circulation (1998)

Background—Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by local or diffuse wall motion abnormalities in the right ventricle (RV), associated with recurrent ventricular tachycardia (VT) of RV origin. Brain natriuretic peptide (BNP) was first isolated from a porcine brain extract. In humans, BNP is expressed predominantly in the ventricles of failing hearts, and its expression has been observed primarily in myocytes in the interstitial fibrous area in dilated cardiomyopathy. We hypothesized that BNP is increasingly secreted from the residual myocytes within the atrophic tissue in patients with ARVD. Methods and Results—Plasma BNP levels were measured in 17 patients with ARVD, 12 patients with idiopathic RV outflow tract tachycardia (RVOT), and 120 control subjects. We performed cardiac catheterization, RV endomyocardial biopsy, electron- beam CT, and biventricular endomyocardial mapping in the ARVD patients. There was a significant increase in plasma BNP levels in the ARVD patients co...
Effectiveness of a Mailed Colorectal Cancer Screening Outreach Program in Community Health Clinics
Authors: Gloria D. Coronado, Amanda F. Petrik, William M. Vollmer, Stephen H. Taplin, Erin M. Keast, Scott Fields, Beverly B. Green
Journal: JAMA Internal Medicine (2018)

<h3>Importance</h3> Approximately 24 million US individuals receive care at federally qualified health centers, which historically have low rates of colorectal cancer screening. The US Preventive Services Task Force recommends routine colorectal cancer screening for individuals aged 50 to 75 years. <h3>Objective</h3> To determine the effectiveness of an electronic health record (EHR)-embedded mailed fecal immunochemical test (FIT) outreach program implemented in health centers as part of standard care. <h3>Design, Setting, and Participants</h3> This cluster randomized pragmatic clinical trial was conducted in 26 federally qualified health center clinics, representing 8 health centers in Oregon and California, randomized to intervention (n = 13) or usual care (n = 13). All participants were overdue for colorectal cancer screening during the accrual interval (February 4, 2014 to February 3, 2015). <h3>Interventions</h3> Electronic health record-embedded tools to identify eligible adults and to facilitate implementation of a stepwise mailed intervention involving (1) an introductory letter, (2) a mailed FIT, and (3) a reminder letter; training, collaborative learning, and facilitation through a practice improvement process. <h3>Main Outcomes and Measures</h3> Effectiveness was measured as clinic-level proportions of adults who completed a FIT, and secondarily, any colorectal cancer screening within 12 months of accrual or by August 3, 2015. Implementation was measured as clinic-level proportions of adults who were mailed an introductory letter and ordered a FIT. <h3>Results</h3> Twenty-six clinics with 41 193 adults (mean [SD] age, 58.5 [6.3] years; 22 994 women) were randomized to receive the direct mail colorectal screening intervention (13 clinics; 21 134 patients) or usual care (13 clinics; 20 059 patients). Compared with usual care clinics, intervention clinics had significantly higher adjusted clinic-level proportion of participants who completed a FIT (13.9% vs 10.4%; difference, 3.4 percentage points; 95% CI, 0.1%-6.8%) and any colorectal cancer screening (18.3% vs 14.5%; difference, 3.8 percentage points; 95% CI, 0.6%-7.0%). We observed large variation across health centers in effectiveness (FIT completion differences range, −7.4 percentage points to 17.6 percentage points) and implementation (proportion who were mailed a FIT range, 6.5% to 68.2%). The number needed to mail to achieve a completed FIT was 4.8 overall, and 4.0 in clinics that mailed a FIT reminder. <h3>Conclusions and Relevance</h3> An EHR-embedded mailed FIT outreach intervention significantly improved rates of FIT completion and rates of any colorectal cancer screening. Higher rates of colorectal cancer screening occurred in clinics that successfully implemented the mailed outreach program. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT01742065
Abstract 3090: Phenol modifying influence on genotoxic effect in organism during peroral combined administration with benzo[a]pyrene
Authors: Olga Ostash, Igor Chernichenko, Nina Balenko, Elena Vinarska, Lyudmila Grigorenko, Svetlana Lukyanchuk, Oksana Shvager
Journal: Cancer Research (2018)

Abstract In the modern world in different spheres of life, people experience a load of the complex of numerous chemical compounds of different types, which have a wide range of biological effects - from toxic ones to mutagenic and carcinogenic. For instance, people suffer from the growth of cancer, which is one of the direct consequences of the impact of environmental pollution by chemical compounds. It has now been proved that the development of cancer is determined not only by the initiating effect of chemical carcinogens, but also by the modifying effect of the concomitant toxic compounds. The aim of this work was experimental study of the role of toxic substances (phenol) in the modification of the evidence of genotoxic and immunological changes in organism in the early stages of carcinogenic activity (benzo[a]pyrene).The studies were conducted with random-bred white male mice. Peroral administration was applied to animals taken benzo[a]pyrene (day-dose 0.1mg), benzo[a]pyrene - phenol (day-dose 0.1; 0.002 mg). Genotoxic changes in forestomach were assessed with the help of micronuclear test. The carcinogenic effect (forestomach papillomas) and common regularities of genotoxical and immunological changes in relation to carcinogenesis and their dose and treatment duration dependence under benzo[a]pyrene (day-dose 0,1mg), benzo[a]pyrene and phenol (day-dose 0,1; 0,002 mg) complexes oral administration in random-bred white mice were established. The noted regularities conducted in interrelation and identical directivity of mutagenic (increasing of micronucleus incidence) and immunological (reducing the relative number of T-lymphocytes) indexes changes in relation to carcinogenesis, presence of reliable cross-correlation connections between them in the end of the first months. Besides, the modifying effect of phenol on the carcinogenesis that appeared by increasing of micronucleus incidence, immunosuppression and index of forestomach papillomas multiplicity was determined. The findings detect the presence of cancer risk from the action of carcinogenic and toxic substances, the formation of which begins in the early period (at the end of the first month) and manifests itself as a genotoxic effect in combination with immunosuppression, which must be taken into account in the hygienic assessment of the state of the environment. Citation Format: Olga Ostash, Igor Chernichenko, Nina Balenko, Elena Vinarska, Lyudmila Grigorenko, Svetlana Lukyanchuk, Oksana Shvager. Phenol modifying influence on genotoxic effect in organism during peroral combined administration with benzo[a]pyrene [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 3090.
Whole exome sequencing identifies an AMBN missense mutation causing severe autosomal-dominant amelogenesis imperfecta and dentin disorders
Authors: Ting Lu, Meiyi Li, Xiangmin Xu, Jun Xiong, Cheng Huang, Xuelian Zhang, Aiqin Hu, Ling Peng, Decheng Cai, Leitao Zhang, Buling Wu, Fu Xiong
Journal: International Journal of Oral Science (2018)

Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular, and cellular interactions. Ameloblastin (AMBN, also named "amelin" or "sheathlin") is the second most abundant enamel matrix protein known to have a key role in amelogenesis. Amelogenesis imperfecta (AI [MIM: 104500]) refers to a genetically and phenotypically heterogeneous group of conditions characterized by inherited developmental enamel defects. The hereditary dentin disorders comprise a variety of autosomal-dominant genetic symptoms characterized by abnormal dentin structure affecting either the primary or both the primary and secondary teeth. The vital role of Ambn in amelogenesis has been confirmed experimentally using mouse models. Only two cases have been reported of mutations of AMBN associated with non-syndromic human AI. However, no AMBN missense mutations have been reported to be associated with both human AI and dentin disorders. We recruited one kindred with autosomal-dominant amelogenesis imperfecta (ADAI) and dentinogenesis imperfecta/dysplasia characterized by generalized severe enamel and dentin defects. Whole exome sequencing of the proband identified a novel heterozygous C-T point mutation at nucleotide position 1069 of the AMBN gene, causing a Pro to Ser mutation at the conserved amino acid position 357 of the protein. Exfoliated third molar teeth from the affected family members were found to have enamel and dentin of lower mineral density than control teeth, with thinner and easily fractured enamel, short and thick roots, and pulp obliteration. This study demonstrates, for the first time, that an AMBN missense mutation causes non-syndromic human AI and dentin disorders.
Abstract LB-140: CAR T cells that target full-length MUC1 enrich for MUC1* and induce metastasis
Authors: Cynthia C. Bamdad, Andrew K. Stewart, Luke T. Deary, Benoit J. Smagghe, Pengyu Huang, Nelson D. Glennie, Tyler E. Swanson
Journal: Cancer Research (2018)

Abstract Purpose: Investigate the rationale for CAR Ts that target full-length MUC1 (MUC1-FL) rather than the cleaved, growth factor receptor form, MUC1*. Over 75% of solid tumors aberrantly express MUC1. However, attempts to create an effective therapeutic by targeting MUC1-FL have all failed. No therapeutic that targets the cleavage product, MUC1*, has ever been tested in humans. On cancer cells, most of the MUC1-FL is enzymatically cleaved, releasing the bulk of the extra cellular domain and leaving a truncated transmembrane protein - MUC1*. There are currently two CAR T therapeutics (based on antibody 5E5 or SM3) being developed that target aberrant O-linked glycans. Importantly, MUC1* has no sites for O-linked glycans and is not recognized by 5E5 or SM3. Experimental Procedures: Human ovarian cancer cells that express both MUC1-FL and MUC1* were implanted into the intraperitoneal (i.p.) space of female NSG mice. IVIS measurement verified engraftment. A cleavage enzyme that is overexpressed in most solid tumors and known to cleave MUC1-FL to MUC1* was injected into i.p. space to simulate the effect of a therapeutic that would eliminate cells expressing MUC1-FL. Human cancerous tissue specimens were probed with antibody VU4H5 that recognizes tandem repeats of MUC1-FL, 5E5 that recognizes aberrant O-linked glycans on tandem repeats of MUC1-FL, and anti-MUC1* antibody huMNC2. Summary New Data: Elimination of cells expressing MUC1-FL, by cleaving MUC1-FL to MUC1*, caused tumors to grow dramatically (average 221-times in only 9 days) and metastasize. IHC studies showed that 30% of breast cancers do not express MUC1-FL but only express MUC1*. No tumor specimens were positive for MUC1-FL but negative for MUC1*. Our studies show that as tumor stage progresses, expression of MUC1* increases as MUC1-FL decreases. Over 95% of breast, 83% ovarian, 78% pancreatic and 71% lung cancers reacted with our anti-MUC1* antibody huMNC2-scFv (n&amp;gt;3,000). huMNC2-CAR44 T cells inhibited growth of MUC1* positive and MUC1-FL/MUC1* positive tumors, even after metastasis. Conclusions: CAR T cells that target full-length MUC1 will enrich the tumor for MUC1*, increasing tumor growth and inducing metastasis. Citation Format: Cynthia C. Bamdad, Andrew K. Stewart, Luke T. Deary, Benoit J. Smagghe, Pengyu Huang, Nelson D. Glennie, Tyler E. Swanson. CAR T cells that target full-length MUC1 enrich for MUC1* and induce metastasis [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 LB-140.
Coronary Vasospasm-Related Sudden Cardiac Arrest in the Community
Authors: Victor Waldmann, Wulfran Bougouin, Nicole Karam, Kumar Narayanan, Ardalan Sharifzadehgan, Christian Spaulding, Olivier Varenne, Alain Cariou, Xavier Jouven, Eloi Marijon
Journal: Journal of the American College of Cardiology (2018)
Predictors of Disease Course in Patients With Acute Myocarditis
Authors: KoichiFuse, MakotoKodama, YujiOkura, MasahiroIto, SatoruHirono, KiminoriKato, HaruoHanawa, YoshifusaAizawa
Journal: Circulation (2000)

Background—Clinical manifestations of acute myocarditis, with distinct onset, vary from asymptomatic to fatal. The predictors of the course of the disease in patients with acute myocarditis at initial presentation have not yet been established. In this study, we examined the predictive values of various parameters in the disease course of patients with myocarditis. Methods and Results—Twenty-one consecutive patients who had been diagnosed as having acute myocarditis by histological examinations were analyzed. The patients with myocarditis were divided into the survival group (n=13) and the fatal group (n=8). We examined the parameters of the clinical state, hemodynamic variables, required therapies, biochemical laboratory data, and cytokines. The control groups were composed of 23 patients with old myocardial infarction and 20 healthy volunteers. The fatal group had lower blood pressure and higher pulmonary capillary wedge pressure compared with those values in the survival group. Mechanical ventilation s...
In Vivo Monitoring of Inflammation After Cardiac and Cerebral Ischemia by Fluorine Magnetic Resonance Imaging
Authors: UlrichFlögel, ZhaopingDing, HendrikHardung, SebastianJander, GabyReichmann, ChristophJacoby, RolfSchubert, JürgenSchrader
Journal: Circulation (2008)

Background— In this study, we developed and validated a new approach for in vivo visualization of inflammatory processes by magnetic resonance imaging using biochemically inert nanoemulsions of perfluorocarbons (PFCs). Methods and Results— Local inflammation was provoked in 2 separate murine models of acute cardiac and cerebral ischemia, followed by intravenous injection of PFCs. Simultaneous acquisition of morphologically matching proton (1H) and fluorine (19F) images enabled an exact anatomic localization of PFCs after application. Repetitive 1H/19F magnetic resonance imaging at 9.4 T revealed a time-dependent infiltration of injected PFCs into the border zone of infarcted areas in both injury models, and histology demonstrated a colocalization of PFCs with cells of the monocyte/macrophage system. We regularly found the accumulation of PFCs in lymph nodes. Using rhodamine-labeled PFCs, we identified circulating monocytes/macrophages as the main cell fraction taking up injected nanoparticles. Conclusions...