tbuckley/cabot-search huggingface dataset:
Abstract IA23: Variation in the immune cell infiltrate and expression of PD-L1 in sarcoma subtypes
Authors: Irene L. Andrulis
Journal: Clinical Cancer Research (2018)

Abstract The presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment has been associated with clinical characteristics and prognosis in various cancers, although the role of TILs in sarcoma is unclear. Adult soft tissue sarcomas are a heterogeneous group of tumors that would benefit from the identification of new prognostic markers and novel therapeutic strategies. The purpose of this study was to determine whether there are specific subgroups of soft tissue sarcomas that contain TILs and/or express immune checkpoint proteins, and if so, the clinical importance. We performed immunohistochemistry (IHC) on sections from 99 tumors and found that certain soft tissue sarcomas such as leiomyosarcoma and liposarcoma exhibit little or no immune infiltrate and immune checkpoint proteins. In contrast, a subset of undifferentiated pleomorphic sarcomas (UPS) and myxofibrosarcomas contain TILs and express PD-L1 and PD-1. Evaluation of expression of PD-L1 by IHC has been controversial; however, we observed a significant positive correlation comparing the levels of PD-L1 determined by IHC on tumor sections and RT-qPCR of mRNA from quick frozen primary tumors. We detected PD-L1 expression in a well-characterized group of osteosarcomas in addition to UPS and myxofibrosarcoma. We are now integrating data from RNA-sequencing and next-generation sequencing to investigate the molecular differences in tumors with and without PD-L1 expression. These studies suggest that there may be individuals with specific sarcomas who may be good candidates to benefit from immunotherapies targeting PD-L1/PD-1 based on their tumor characteristics. Citation Format: Irene L. Andrulis. Variation in the immune cell infiltrate and expression of PD-L1 in sarcoma subtypes [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA23.
Induction of Monocyte Chemoattractant Protein-1 Synthesis in Human Monocytes During Transendothelial Migration In Vitro
Authors: MasafumiTakahashi, Jun-IchiMasuyama, UichiIkeda, TadashiKasahara, Sei-IchiKitagawa, Yu-IchiTakahashi, KazuyukiShimada, ShogoKano
Journal: Circulation Research (1995)

Abstract Monocyte chemoattractant protein-1 (MCP-1, or monocyte chemotactic and activating factor) plays important roles in the recruitment of monocytes and thus in the development of atherosclerosis. In this study, we determined whether MCP-1 synthesis was induced by the cellular interaction between monocytes and endothelial cells during the process of transendothelial migration. We found that when human peripheral blood monocytes (2.5×106 cells) and umbilical vein endothelial cells (HUVECs; 5.0×105 cells) were cocultured for 5 hours, 7.9 ng/mL MCP-1 was secreted into the medium, whereas when the two were cultured separately, MCP-1 levels were 1.0 and 0.9 ng/mL, respectively. Furthermore, the use of interleukin-1β (IL-1β)–pretreated HUVECs in cocultures induced twice the levels of MCP-1 as in unstimulated HUVEC culture. Conditioned medium had transendothelial chemotactic activity for monocytes, and this activity was completely abolished by addition of anti–MCP-1 antibody. Although MCP-1 mRNA levels were ...
Regional Alteration of the Transient Outward Current in Human Left Ventricular Septum During Compensated Hypertrophy
Authors: PatrickBailly, Jean-PierreBénitah, MaudMouchonière, GuyVassort, PacoLorente
Journal: Circulation (1997)

Background A large calcium-insensitive transient outward current (Ito) has been recorded in atria, left ventricular (LV) free wall, and right ventricular septal subendocardium of the human heart. Recent studies suggested a major contribution of this current to the electrical heterogeneity of the heart. However, no data have been reported on the distribution of Ito density within the LV septal wall from compensated human LV hypertrophy. Methods and Results Microelectrode and patch-clamp techniques were used to record action potentials and Ito in myocytes isolated from superficial (<3 mm deep) and deep (3 to 6 mm deep) layers of LV septum from patients with aortic stenosis and compensated LV hypertrophy. Subendocardial specimens were also obtained from undiseased donor hearts. In none of the superficial subendocardial cells from diseased hearts was a macroscopic Ito recorded (n=42), whereas in cells from the same location from donor hearts, a typical Ito was clearly present, with a peak density of 5.88±0.78...
Anti-platelet drugs and their necessary interaction with endothelial mediators and platelet cyclic nucleotides for therapeutic efficacy
Authors: Rebecca B. Knowles, Timothy D. Warner
Journal: Pharmacology & Therapeutics (2018)

For many millions of patients at secondary risk of coronary thrombosis pharmaceutical protection is supplied by dual anti-platelet therapy. Despite substantial therapeutic developments over the last decade recurrent thrombotic events occur, highlighting the need for further optimisation of therapies. Importantly, but often ignored, anti-platelet drugs interact with cyclic nucleotide systems in platelets and these are the same systems that mediate key endogenous pathways of platelet regulation, notably those dependent upon the vascular endothelium. The aim of this review is to highlight interactions between the anti-platelet drugs, aspirin and P2Y12 receptor antagonists and endogenous pathways of platelet regulation at the level of cyclic nucleotides. These considerations are key to concepts such as anti-platelet drug resistance and individualized anti-platelet therapy which cannot be understood by study of platelets in isolation from the circulatory environment. We also explore novel and emerging therapies that focus on preserving haemostasis and how the concepts outlined in this review could be exploited therapeutically to improve anti-thrombotic efficacy whilst reducing bleeding risk.
Lower Mortality From Coronary Heart Disease and Stroke at Higher Altitudes in Switzerland
Authors: DavidFaeh, FelixGutzwiller, MatthiasBopp
Journal: Circulation (2009)

Background— Studies assessing the effect of altitude on cardiovascular disease have provided conflicting results. Most studies were limited because of the heterogeneity of the population, their ecological design, or both. In addition, effects of place of birth were rarely considered. Here, we examine mortality from coronary heart disease and stroke in relation to the altitude of the place of residence in 1990 and at birth. Methods and Results— Mortality data from 1990 to 2000, sociodemographic information, and places of birth and residence in 1990 (men and women between 40 and 84 years of age living at altitudes of 259 to 1960 m) were obtained from the Swiss National Cohort, a longitudinal, census-based record linkage study. The 1.64 million German Swiss residents born in Switzerland provided 14.5 million person-years. Relative risks were calculated with multivariable Poisson regression. Mortality from coronary heart disease (−22% per 1000 m) and stroke (−12% per 1000 m) significantly decreased with incre...
Abstract 1573: A clinical biomarker assay to quantitate MIP-1a in human serum
Authors: Li Chin Wong, Oitak Wong, Omar F. Laterza, Xuemei Zhao
Journal: Cancer Research (2018)

Abstract Macrophage inflammatory protein 1-alpha (MIP-1alpha, MIP-1α, CCL3) is a cytokine that is involved in the acute inflammatory state in recruitment and activation of polymorphonuclear leukocytes through binding to the receptors CCR1, CCR4 and CCR5. MIP-1α is expressed by macrophages, dendritic cells and lymphocytes. Crucial in immune response against infection and inflammation, MIP-1α induces the synthesis and release of IL-6, IL-10 and TNFα. As a proinflammatory chemokine, MIP-1α is primarily associated with cell adhesion and migration of monocytes to inflammatory tissues. In addition, MIP-1 α inhibits the proliferation of hematopoietic stem cells in vitro and in vivo. Expression levels of MIP-1 α have provided important information in the progression of diseases such as multiple myeloma, lung cancer, multiple sclerosis, HIV infection, allergic asthma and sepsis. Citation Format: Li Chin Wong, Oitak Wong, Omar F. Laterza, Xuemei Zhao. A clinical biomarker assay to quantitate MIP-1a in human serum [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 1573.
Thrombin Activity and Early Outcome in Unstable Angina Pectoris
Authors: DiegoArdissino, Piera AngelicaMerlini, GabriellaGamba, PaoloBarberis, GloriaDemicheli, SophieTesta, ElisabettaColombi, ArnaldoPoli, RaffaelaFetiveau, CarloMontemartini
Journal: Circulation (1996)

Background The blood coagulation system is frequently activated in the acute phase of unstable angina, but it is unknown whether the augmented function of the hemostatic mechanism may serve as a marker of increased risk for an early unfavorable outcome. Methods and Results Plasma concentrations and 24-hour urinary excretion of fibrinopeptide A were prospectively determined in 150 patients with unstable angina. All patients underwent 24-hour Holter monitoring, during which time urine was collected; at the end of this period, a blood sample was taken and coronary arteriography was performed. The patients were followed up for the occurrence of cardiac events (death and myocardial infarction) until they underwent coronary revascularization or until they were discharged from the hospital. Fibrinopeptide A plasma levels and 24-hour urinary excretion were found to be abnormally elevated in 50% and 45% of the study population, respectively. During hospitalization, 11 patients developed myocardial infarction and 2...
Abstract 147: Targeting USP22 suppresses tumorigenicity and enhances sensitivity to cisplatin in cancer-initiating cells from lung adenocarcinoma through downregulating ALDH1A3
Authors: Keqiang Zhang, Xinwei Yun, Jinhui Wang, Melisa Bonner, Lu Yang, Jun Wu, Dan J. Raz
Journal: Cancer Research (2018)

Abstract We previously found that loss of monoubiquitination of histone H2B (H2Bub1) was associated with poor differentiation and enhanced malignancy of lung adenocarcinoma. Herein, we investigated the expression and roles of USP22, an H2Bub1 deubiquitinase, in cancer-initiating cells (CICs) with stem cell-like characteristics from primary lung adenocarcinoma. CICs from patient-derived cancer tissues were isolated and characterized, and the association of USP22 with CICs was investigated using flow cytometry, aldehyde dehydrogenase (ALDH) activity, Western blot, and fluorescence microscope assays. The impact of USP22 on stem cell-like characteristics and cisplatin resistance in CICs was examined by in vitro tumorsphere formation, in vivo transplantation, and apoptosis assays. We identified that USP22 is predominantly expressed in CICs, a subpopulation of cells with high expression of CD133 stem cell biomarker. The expression of USP22 in CICs is dramatically reduced upon serum-induced differentiation. Moreover, knockdown of USP22 significantly suppressed in vitro tumorsphere formation and in vivo xenograft growth in NOD-SCID mice. Notably, USP22 is dramatically elevated in tumorsphere cells that survived cisplatin treatment, while knockdown of USP22 significantly sensitizes tumorsphere cells to cisplatin. Interestingly, ALDH1A3, a dominant isoform of ALDH implicated in enhancing cisplatin resistance in lung adenocarcinoma, is significantly downregulated upon knockdown of USP22 in tumorsphere cells. Furthermore, knockdown of ALDH1A3 significantly sensitizes tumorsphere cells to cisplatin. Therefore, our data indicate that USP22 plays critical roles in tumorigenicity and cisplatin resistance in lung adenocarcinoma, and targeting USP22 may represent a potential therapeutic approach to eliminate CICs in lung adenocarcinoma through downregulation of ALDH1A3 expression. Citation Format: Keqiang Zhang, Xinwei Yun, Jinhui Wang, Melisa Bonner, Lu Yang, Jun Wu, Dan J. Raz. Targeting USP22 suppresses tumorigenicity and enhances sensitivity to cisplatin in cancer-initiating cells from lung adenocarcinoma through downregulating ALDH1A3 [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 147.
Abstract 19395: Variation Between Intended and Actual Delivery of Ventilatory Parameters During CPR
Authors: Magda L Wernovsky, Abhishek Bhardwaj, Audrey L Blewer, Anne Grossestreuer, Benjamin S Abella, Marion Leary
Journal: Circulation (2016)

Background: It has been shown that healthcare providers (HCP) often perform ventilations outside of recommended guidelines during resuscitation. Data suggest that cardiac arrest survival is sensitive to ventilation quality. Objective: To assess the variation between actual HCP ventilation parameters provided to patients during resuscitation compared with both guidelines and HCP perceptions of delivered care. Design/Methods: We performed an observational study which captured time synchronized respiratory data from adult resuscitation events at 2 sites between 02/2015-04/2016 using a respiratory profile monitor (Philips Respironics NM3). Respiratory Rate (RR) and Tidal Volume (TV) were analyzed. HCP were asked to estimate the RR and TV delivered. RR and TV were averaged per min over the course of the event and then compared to the reported perceived care and Guideline recommendations. Results: Ten cardiac arrest events (59%) had surveys completed by HCP; 596 average respiratory data points by minute were an...
Abstract 916: A screen to target EGFR (C797S) in osimertinib-resistant lung cancer identifies brigatinib-based combinations that synergistically inhibit cell growth
Authors: Matthew J. Martin, Nicolas Floc'h, Chrysiis Michaloglou, M Raymond Finlay, Richard A. Ward, Paul D. Smith, Darren A. Cross
Journal: Cancer Research (2018)

Abstract Up to 20% of non small-cell lung cancers are driven by activating mutations in EGFR (EGFRm). While EGFR tyrosine kinase inhibitors (TKIs) have proven highly effective in the clinic (e.g. gefitinib in first line EGFRm and osimertinib in T790M post-TKI resistance), acquired resistance mechanisms present an obstacle to curing EGFR-driven disease. To-date, approximately 20% of osimertinib-resistant cases in the 2nd line setting are EGFRm/T790M/C797S, and there is currently no approved therapy for these “triple-mutant” (TM) patients. We have obsrerved that the ALK inhibitor brigatinib shows moderate, equipotent activity against both EGFR-TM and the single activating mutant. We used this information to screen a panel of compounds to identify brigatinib-based combinations that could effectively target EGFR-TM-expressing cells. Among the most potent combination partners were selumetinib and other inhibitors of the MAP kinase pathway. These agents were able to synergistically impair growth of TM cells when combined with brigatinib in vitro, and accordingly show prolonged suppression of downstream pathway biomarkers in combination- vs. brigatinib monotherapy-treated cells. Further, we have shown effective combinations can dramatically enhance apoptotic cell death compared to brigatinib treatment alone. Critically, neither monotherapy treatment with effective combination partners, nor combinations based on osimertinib showed growth inhibition in the EGFR triple-mutant setting. Taken together, these data suggest novel therapeutic strategies for patients in this critical area of unmet need that warrant further preclinical testing. Citation Format: Matthew J. Martin, Nicolas Floc'h, Chrysiis Michaloglou, M Raymond Finlay, Richard A. Ward, Paul D. Smith, Darren A. Cross. A screen to target EGFR (C797S) in osimertinib-resistant lung cancer identifies brigatinib-based combinations that synergistically inhibit cell growth [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 916.
Abstract LB-327: Identification of novel sodium iodide symporter (NIS) interactors which modulate iodide uptake
Authors: Alice Fletcher, Rebecca Thompson, Martin Read, Andrew Turnell, Vicki Smith, Chris J. McCabe
Journal: Cancer Research (2018)

Abstract Ablative radioiodide therapy is an effective treatment for thyroid cancer, but around a quarter of patients do not accumulate therapeutically-sufficient doses of radioiodide due to decreased expression and/or plasma membrane (PM) localization of the sodium iodide symporter (NIS). Putative use of radioiodide therapy in breast cancer is hampered by low levels of NIS membrane localisation. Currently, the regulation of NIS trafficking is ill-defined. Mass spectrometry was performed on proteins co-immunoprecipitating with lentivirally expressed NIS in whole cell and plasma membrane extracts. NIS activity was significantly altered by ADP-ribosylation factor 4 (ARF4) and valosin containing protein (VCP) in TPC1 thyroid and MDA-MB-231 breast cancer cells lentivirally-expressing NIS. ARF4 downregulation markedly decreased radioiodide uptake, and VCP downregulation increased radioiodide uptake in thyroid and breast cells. Transient overexpression of these genes significantly reversed siRNA effects on NIS function. Co-immunoprecipitation assays confirmed NIS interacts with ARF4 and VCP in vitro, and proximity ligation assays revealed the subcellular sites of interaction. Critically, human primary thyroid culture experiments confirmed that ARF4 and VCP regulate endogenous NIS function in vivo. In addressing the mechanisms of NIS trafficking we identified a C-terminal VXPX motif of NIS which is required for Arf4 regulation, whilst TIRF microscopy revealed coincident Arf4 and NIS localization to shared PM vesicles. Pharmacological inhibitor studies identified that the VCP inhibitors Eeyarastatin-1 and NMS-873 overcome VCP inhibition of NIS function. VCP, which is central to ER-associated Degradation (ERAD), selectively targeted a dimeric form of NIS, which we now identify through co-immunoprecipitation, 3D modelling and Förster resonance energy transfer (FRET) assays. TCGA data analysis of 58 matched papillary thyroid cancers revealed that Arf4 was significantly repressed and VCP highly upregulated in thyroid cancer, providing a putative explanation for repressed NIS function. Our data suggest a possible model for NIS trafficking: NIS dimerises in the ER, a process monitored by VCP and the ERAD pathway, with correctly processed and folded NIS being trafficked to the PM via C-terminal interaction with Arf4. We thus now identify two new potential therapeutic targets for enhancing radioiodide uptake in patients with radioiodide-refractory thyroid cancer. Citation Format: Alice Fletcher, Rebecca Thompson, Martin Read, Andrew Turnell, Vicki Smith, Chris J. McCabe. Identification of novel sodium iodide symporter (NIS) interactors which modulate iodide uptake [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-327.
Long-term effectiveness of one and two doses of a killed, bivalent, whole-cell oral cholera vaccine in Haiti: an extended case-control study
Authors: Molly F Franke, Ralph Ternier, J Gregory Jerome, Wilfredo R Matias, Jason B Harris, Louise C Ivers
Journal: The Lancet Global Health (2018)

No study of long-term protection following killed oral cholera vaccination has been done outside of the historically cholera-endemic areas of south Asia, or has examined protection after a single-dose vaccination regimen. To address this, we examined the duration of protection of the standard two-dose regimen and an incomplete regimen of one dose up to 4 years after vaccination in Haiti.In the setting of two-dose vaccination campaigns with a killed, bivalent, whole-cell oral cholera vaccination, we did a case-control study from October, 2012 through November, 2016. Eligible participants were required to be resident in the vaccine catchment area (Artibonite Department or Central Department) where they were recruited at the start of the study; and be eligible for the vaccination campaign (ie, aged ≥12 months, not pregnant, and living in the region at the time of the vaccine campaign). Patients with cholera had a positive stool culture and were recruited from cholera treatment centres. Community controls were matched to people with cholera by age group, time, and neighbourhood. We did adjusted matched regression analyses to calculate vaccine effectiveness and examine heterogeneity in effectiveness over time. The primary outcome was the effectiveness of one and two oral cholera doses as compared with zero doses from 2 months to 48 months after vaccination, measured by self reporting.Among 178 people assigned to the case group and 706 people assigned to the control group, we found no evidence that two-dose effectiveness decreased during follow-up. In adjusted analyses, the average cumulative 4 year effectiveness for two doses was 76% (95% CI 59-86). In contrast, single-dose effectiveness decreased over time in a log-linear fashion, with a predicted vaccine effectiveness of 79% at the end of 12 months (95% CI 43-93), which declined to zero before the end of the second year.In a setting of epidemic and newly endemic cholera in Haiti, single-dose vaccination with killed, bivalent, whole-cell oral cholera vaccination provided short-term protection; however, vaccination with two doses was required for long-term protection, which lasted up to 4 years after vaccination. These results add to the evidence in support of the use of killed, bivalent, whole-cell oral cholera vaccination as part of comprehensive cholera control plans.US National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the Bill & Melinda Gates Foundation.