tbuckley/cabot-search huggingface dataset:
Abstract 4260: Dynamic modeling of macrophage plasticity in bone metastatic prostate cancer
Authors: Etienne A. Baratchart, Chen Hao Lo, Conor Lynch, David Basanta
Journal: Cancer Research (2018)

Abstract Tumor-associated macrophages, particularly those with an anti-inflammatory phenotype, have long been implicated in the progression of primary solid malignancies, including prostate cancer. Metastatic prostate cancer typically manifests in the bone where it induces painful osteogenic lesions that are incurable. Bone is naturally rich in myeloid-derived macrophages whose temporal polarization into pro- (M1) and anti-inflammatory (M2) phenotypes is critical for regulating the bone repair program mediated by bone-resorbing osteoclasts and bone-building osteoblasts. However, the dynamics of macrophage polarization in the context of bone metastatic prostate cancer are underexplored and difficult to address with traditional biologic approaches. To address the role of macrophage polarization in the context of bone metastatic prostate cancer, we first investigated the macrophage polarization temporal dynamics in normal bones and analyzed macrophage plasticity in vivo subsequent to intratibial injury. Bone marrows were isolated at several time points and profiled by flow cytometry for pro- and anti-inflammatory monocyte macrophage content. Contralateral tibias were analyzed for bone volume, osteoblast and osteoclast numbers. We then designed a mathematical model describing the different cell population dynamics in the bones. Generation of the model required testing a number of assumptions regarding macrophage polarization behavior. For example, it is unknown whether M1 resolves at the initial stages of bone injury repair through death or by repolarizing into M2. For each aspect, competing mechanistic assumptions were proposed and simulated by sets of ODEs. The best-fitting assumptions for each aspect were integrated into a single comprehensive ODE model to fully describe the dynamics of the bone resident cell populations during bone remodeling. This experimentally validated model is now being used to address how bone resident cells respond to metastatic prostate cancer cells. In conclusion, we have generated an ODE model that describes macrophage polarization over time during bone repair and how pro- and anti-inflammatory macrophages interact with bone stromal cells. The mathematical model predictions are in agreement with our biologic experiments in vivo and will allow us to interrogate how macrophage polarization impacts the behavior of metastatic prostate cancer cells in the bone microenvironment. Citation Format: Etienne A. Baratchart, Chen Hao Lo, Conor Lynch, David Basanta. Dynamic modeling of macrophage plasticity in bone metastatic prostate cancer [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 4260.
Abstract 11598: Is Therapeutic Drug Monitoring of Direct Anticoagulants Really Unnecessary?
Authors: Bernadette Baldin, Marion Warembourg, Guillaume Bardy, Loïc Startari, Fanny Rocher, Anne Spreux, Thibaud Lavrut, Milou-Daniel Drici
Journal: Circulation (2015)

Introduction: no routine monitoring is deemed necessary with direct oral anticoagulants dabigatran (D) and rivaroxaban(R). Yet, their misuse may lead to inefficacy or increased risk of bleeding. Hypothesis: due to the prevalence of elderly patients in our medical center, the pharmacology department was asked to measure R and D plasma concentrations. Therefore we aimed not only to check their prescription adequacy but also to evaluate whether bleeding or thrombosis adverse events were associated with drug concentrations clearly outside of their expected “normal” range. Methods: Patients receiving R or D for either AFib, deep venous thrombosis or its prevention were included and had blood samples drawn for drug measurements, by HPLC-tandem mass spectrometry. Adequacy of the patient prescription was checked by pharmacists according D &amp; R respective SmPCs. A robust and conservative method was applied to evaluate anticoagulant concentrations : D &amp; R concentrations were blindly deemed “normal” when within the [IC] 95 limits (peak and trough, relative to the dose) observed in the respective RE-LY and Rocket-AF pivotal studies, as compared to “out of range” when outside of these limits. Results: 287 consecutive patients from our center had their concentration of R (n=219 : 76%) or D (n = 68 : 24%) measured. The inadequacy of the prescriptions was 31.4% alltogether. Seventy patients presented with bleeding (n = 48, 17%) or thrombosis (n = 22, 8%), that either led to their admission in emergency, or occurred in the hospital wards. Bleedings and thrombosis were significantly associated with out-of-range concentrations (p&lt;0.01). Patients with hemorrhages had higher concentrations (R: 194 VS 83 μg.l -1 and D: 128 VS 80 μg.l -1 ) whereas thrombosis were associated with lower ones (R: 75 VS 106 μg.l -1 D: 29 VS 93 μg.l -1 ). HAS-BLED Score was 2.0 ± 0.9 for bleeding cases as compared to 1.5 ± 0.9 (p&lt;0.01). Conclusions: therapeutic drug monitoring of direct oral anticoagulants might not be superfluous, at least for R &amp; D, especially in patients with a higher score HAS-BLED.
Aortic Function in Arterial Hypertension Determined by Pressure-Diameter Relation
Authors: ChristodoulosStefanadis, JohnDernellis, CharalambosVlachopoulos, CostasTsioufis, EleftheriosTsiamis, KonstantinosToutouzas, ChristosPitsavos, PavlosToutouzas
Journal: Circulation (1997)

Background Aortic elastic properties, important determinants of left ventricular function and coronary blood flow, are compromised in hypertension. The aim of this study was to determine aortic function in hypertensive patients and in normal subjects before and after administration of diltiazem, a calcium antagonist widely used in the treatment of essential hypertension. Methods and Results The aortic pressure-diameter relation was obtained before and after diltiazem administration in 15 hypertensives and 15 control normotensives. Instantaneous diameter of the thoracic aorta was acquired with a high-fidelity intravascular catheter developed in our institution and previously validated. Instantaneous aortic pressure was measured simultaneously and at the same aortic level with a catheter-tip micromanometer. Energy loss due to the viscosity of aortic wall was measured from the area of the loop. Aortic distensibility was calculated using the formula 2×(pulsatile change in aortic diameter)/([diastolic aortic d...
Abstract 3969: Lipocalin-2-targeted small interference RNA for inflammatory breast cancer treatment
Authors: Ginette S. Santiago-Sanchez, Fatma Valiyeva, Bisrat Debeb, Pablo E. Mejia
Journal: Cancer Research (2018)

Abstract Inflammatory Breast Cancer (IBC) is an aggressive form of invasive breast cancer with low survival rate. Available therapies to treat this type of cancer are almost limited to surgery and radiation therapy. Potential therapeutic targets for IBC treatment include the oncogene Her2 and the Epidermal Growth Factor Receptor (EGFR). However, these therapies have not been successful since not all IBC tumors are Her2-amplified and development of resistance to treatment has also been observed. Hence, there is a critical need for novel therapeutic targets for IBC treatment. One of such possibilities is Lipocalin-2 (LNC2). LCN-2 is a secreted glycoprotein and an adipokine superfamily member that posses roles in transport of small lipophilic molecules in circulation, innate immunity, and iron homeostasis. High levels of LCN2 have been observed in invasive breast cancer human tissue. Additionally, LCN2 has been linked with breast cancer tumorigenesis and metastasis. Therefore, the purpose of our study is to assess if LCN2 is a plausible therapeutic target to treat IBC. Western blot analysis was used to assess the LCN2 protein level in a panel of IBC (MDA-IBC-3, SUM-149) and non-IBC cell lines (MCF-7, MDA-MB-231, MDA-MB-438). IBC cell lines showed a significantly higher expression of the LCN2 protein in comparison to the non-IBC cell lines. We decreased the expression of the LCN2 protein with small interference RNA (siRNA) molecules. Silencing of IBC cells with LCN2-targeted siRNA molecules decreased the LCN2 protein expression levels in almost fifty percent. Colony formation assay demonstrated that siRNA-mediated LCN2 silencing in MDA-IBC-3 and SUM-149 cell lines resulted in a significant decrease in cell proliferation. Taken together these results suggest that LCN2 may become a right target for IBC treatment. Ongoing experiments include cell invasion assays to determine if LCN2-targeted siRNAs reduce the metastatic potential, increase apoptosis and block cell cycle progression. Acknowledgements: This work is supported by the University of Puerto Rico Comprehensive Cancer Center and the U54 partnership with MD Anderson Cancer Research Center. Citation Format: Ginette S. Santiago-Sanchez, Fatma Valiyeva, Bisrat Debeb, Pablo E. Mejia. Lipocalin-2-targeted small interference RNA for inflammatory breast cancer treatment [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 3969.
Effect of Hyperhomocysteinemia on Plasma or Tissue Adenosine Levels and Renal Function
Authors: Ya-FeiChen, Pin-LanLi, Ai-PingZou
Journal: Circulation (2002)

Background— Hyperhomocysteinemia (hHcys) is considered an independent risk factor of cardiovascular diseases. Recent studies in our laboratory have shown that hHcys produced glomerular dysfunction and sclerosis independently of hypertension. However, the mechanism mediating these pathogenic effects of homocysteine (Hcys) is poorly understood. Because Hcys and adenosine (Ado) are simultaneously produced via hydrolysis of S-adenosylhomocysteine (SAH), we hypothesized that hHcys may produce its pathogenic effects by decrease in plasma or tissue Ado concentrations. Methods and Results— l-Hcys (1.5 μmol/min per kilogram) was infused intravenously for 60 minutes to produce acute hHcys in Sprague-Dawley rats. Plasma Hcys levels increased from 6.7±0.4 to 14.7±0.5 μmol/L, but Ado decreased from 141.7±15.1 to 52.4±6.8 nmol/L in these rats with acute hHcys. This hHcys-induced reduction of Ado was also observed in the kidney dialysate. In rats with chronic hHcys, plasma Ado levels were also significantly decreased. B...
On the Genesis of the Absolute Ventricular Arrhythmia Associated with Atrial Fibrillation
Authors: Kazuoyamado, Mitsuharuokajima, Kazuhikohori, Tetsurofujino, Hiroshigemuraki, Hitoshihishida, Tosijikobayashi
Journal: Circulation Research (1968)

Genetic factors in the formation of the long R-R interval in ventricular arrhythmia associated with atrial fibrillation were investigated in the isolated rabbit heart which was perfused using Langendorff's technique. The trans-membrane action potentials recorded from a single cell within the A-V node or within its vicinity were analyzed, and contiguous bipolar-lead electrograms simultaneously recorded from the right atrium and ventricle. Atrial fibrillation was induced by the combined application of acetylcholine solution and electrical stimulation. Atrial excitation was mainly blocked in the right atrium and in the anterior half of the A-V node. To clarify further the time-correlation between the right atrial electrogram and the A-V nodal responses, the pattern of atrio-ventricular conduction was studied by applying only the electrical stimulation at high frequency without acetylcholine. The conduction was mainly blocked in the same sites as in the above experiment and the pattern of the conduction block...
Optimal Treatment of Obesity-Related Hypertension
Authors: JürgenScholze, ElmarGrimm, DanaHerrmann, ThomasUnger, UlrichKintscher
Journal: Circulation (2007)

Background— Current guidelines for the treatment of hypertension do not provide specific recommendations for obese hypertensive patients. To identify an optimal treatment regimen for obese hypertensive patients, we studied the interactions between a drug-based weight loss approach by sibutramine and different antihypertensive drug regimens. Methods and Results— This was a prospective, 16-week double-blind placebo-controlled randomized multicenter study in 171 obese hypertensive patients. After a 2-week run-in period, patients receiving 1 of the 3 antihypertensive combination therapies (felodipine 5 mg/ramipril 5 mg [n=57], verapamil 180 mg/trandolapril 2 mg [n=55], or metoprolol succinate 95 mg/hydrochlorothiazide 12.5 mg [metoprolol/hydrochlorothiazide; n=59]) were assigned randomly to sibutramine (15 mg) or placebo. Sibutramine treatment resulted in a significantly greater decrease in body weight, body mass index, and waist circumference and a significant increase in diastolic blood pressure during 24-h...
The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
Authors: Sean D. Reiff, Rose Mantel, Lisa L. Smith, J.T. Greene, Elizabeth M. Muhowski, Catherine A. Fabian, Virginia M. Goettl, Minh Tran, Bonnie K. Harrington, Kerry A. Rogers, Farrukh T. Awan, Kami Maddocks, Leslie Andritsos, Amy M. Lehman, Deepa Sampath, Rosa Lapalombella, Sudharshan Eathiraj, Giovanni Abbadessa, Brian Schwartz, Amy J. Johnson, John C. Byrd, Jennifer A. Woyach
Journal: Cancer Discovery (2018)

Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. In vitro treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib.Significance: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. Cancer Discov; 8(10); 1300-15. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1195.
Ultra-rapid, sensitive and specific digital diagnosis of HIV with a dual-channel SAW biosensor in a pilot clinical study
Authors: Eleanor R. Gray, Valérian Turbé, Victoria E. Lawson, Robin H. Page, Zara C. Cook, R. Bridget Ferns, Eleni Nastouli, Deenan Pillay, Hiromi Yatsuda, Dale Athey, Rachel A. McKendry
Journal: npj Digital Medicine (2018)

Despite widened access to HIV testing, around half of those infected worldwide are unaware of their HIV-positive status and linkage to care remains a major challenge. Current rapid HIV tests are typically analogue risking incorrect interpretation, no facile electronic data capture, poor linkage to care and data loss for public health. Smartphone-connected diagnostic devices have potential to dramatically improve access to testing and patient retention with electronic data capture and wireless connectivity. We report a pilot clinical study of surface acoustic wave biosensors based on low-cost components found in smartphones to diagnose HIV in 133 patient samples. We engineered a small, portable, laboratory prototype and dual-channel biochips, with in-situ reference control coating and miniaturised configuration, requiring only 6 µL plasma. The dual-channel biochips were functionalized by ink-jet printing with capture coatings to detect either anti-p24 or anti-gp41 antibodies, and a reference control. Biochips were tested with 31 plasma samples from patients with HIV, and 102 healthy volunteers. SH-SAW biosensors showed excellent sensitivity, specificity, low sample volumes and rapid time to result, and were benchmarked to commercial rapid HIV tests. Testing for individual biomarkers found sensitivities of 100% (anti-gp41) and 64.5% (anti-p24) (combined sensitivity of 100%) and 100% specificity, within 5 min. All positive results were recorded within 60 s of sample addition with an electronic readout. Next steps will focus on a smartphone-connected device prototype and user-friendly app interface for larger scale evaluation and field studies, towards our ultimate goal of a new generation of affordable, connected point-of-care HIV tests.
Ibalizumab in Multidrug-Resistant HIV — Accepting Uncertainty
Authors: Virginia Sheikh, Jeffrey S. Murray, Adam Sherwat
Journal: New England Journal of Medicine (2018)

The FDA has recommended a streamlined trial design for assessing drugs' safety and efficacy in patients with multidrug-resistant HIV infection, and ibalizumab has recently undergone such a trial. But clinicians and patients should recognize this design's limitations.
Abstract MP59: Mediating the Medical, Economic and Social Impact of HF: There is an APP for That
Authors: LindaHouston-Feenstra, MercyKagoda, WayneDysinger, SamirChatterjee, NaglaAlnosayan, AlaAlluhaidan, SharonFabbri, DenisePeterson
Journal: Circulation (2015)

The continued rise in cost of Heart failure (HF) management, begs the question, why can advances in science and medicine not stem this rising cost? Why do patients fail to adhere to prescribed medications and lifestyle recommendations? Lack of effective training for patient/families challenge successful transition to home due to conflicts generated by pressure within the patient’s home environment reinforced by societal attitudes about food. This pilot was designed as a multidisciplinary project, including information systems professionals, clinicians, and patients working together to develop/evaluate a customized mobile phone application (app). Using, home based monitoring of daily weights, blood pressure, heart rate, blood glucose, and a dash board of cumulative data accessed daily by clinicians. A built in algorithm identifies patients’ risk for re-admission based on changes in their vital signs or self-reported symptoms defined by clinical staff as representing best practices pathways decision points....
Current Perspective on the Role of Apoptosis in Atherothrombotic Disease
Authors: ZiadMallat, AlainTedgui
Journal: Circulation Research (2001)

Abstract—Thrombus formation on a disrupted atherosclerotic plaque is a threatening event that leads to vessel occlusion and acute ischemia. In this current perspective, we present evidence for apoptosis as a major determinant of the thrombogenicity of the plaque lipid core and a potential contributor to plaque erosion and associated thrombosis. Moreover, apoptosis may directly affect blood thrombogenicity through the release of apoptotic cells and microparticles into the bloodstream.
Abstract 12446: Comparison of Midterm Outcomes After Surgical Correction in Patients With Biventricular Obstruction Hypertrophic Cardiomyopathy
Authors: Shanshan Zhai, Chaomei Fan, Jun Yan, Shuiyun Wang, Yunhu Song, Yinjian Yang, Xiying Guo, Shuoyan An, Zhimin Wang, Fujian Duan, Shihua Zhao, Yishi Li
Journal: Circulation (2016)

Introduction: Data on the incidence, natural history and treatments of biventricular obstruction hypertrophic cardiomyopathy are limited. Objective: We aimed to the compare midterm outcomes of surgery and medication in biventricular outflow tract obstruction(BVOTO) HCM with left ventricular outflow tract obstruction (LVOTO) HCM and non-obstructive hypertrophic cardiomyopathy (NOHCM). Methods: Among 4945 HCM patients, we identified 43 with BVOTO and recruited age and sex matched 54 with LVOTO and 52 with NOHCM. The primary endpoint was all cause death and second endpoints were cardiovascular events. Results: Age and male were paired among BVOTO, LVOTO and NOHCM (26±17 ys, 30±18 ys, 31±16 ys P=0.3; 57%, 66%, 69%, p=0.5). More patients with BVOTO (69%) had NYHA III/IV than with LVOTO (51%)and NOHCM (15%) (p=0.000). And patients with BVOTO (5.6%±4 %) had higher risk of SCD than with LVOTO (3.9%±1.8%) and NOHCM (2.9%±2.1%)(p=0.000). In BVOTO, 20 patients had left-and-right sided correction (LRVC-B) (1 died and 5 had III AVB), 12 patients accepted left-sided correction (LVC-B) (1 died and 1 occurred III AVB) while 11 patients received medication. At the last follow-up, patients in LRVC-B and LVC-B had a reduction in left and right ventricular intracavity pressure gradient and NYHA class (vs before myectomy, p &lt; 0.001). And no death occurred in the remained 147 patients. The second endpoint-free survival rates of BVOTO were less than LVOTO and NOHCM while the rates were similar among LRVC-B, LVC-B, LVC-L and NOHCM groups. (Fig1ab) Independent predictors of the second endpoint were age (HR 1.05,95%CI 1.0-1.1), RVOTO (HR 1.06,95%CI 1.03-1.10), myectomy (HR 0.16,95%CI 0.03-0.61) and pre-NYHA (HR 4.1,95%CI 2.1-8.33). Conclusions: Patients with BVOTO had more severe symptoms. Both LRVC-B and LVC-B could improve symptom but LRVC-B had a higher risk of III AVB. Mid-term outcomes after surgical correction in BVOTO were similar to that in NOHCM.
Molecular Targeted Therapies Elicit Concurrent Apoptotic and GSDME-Dependent Pyroptotic Tumor Cell Death
Authors: Haijiao Lu, Shengzhe Zhang, Jie Wu, Minjiang Chen, Mei-Chun Cai, Yujie Fu, Wenfeng Li, Jing Wang, Xiaojing Zhao, Zhuang Yu, Pengfei Ma, Guanglei Zhuang
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The induced death signals following oncogene inhibition underlie clinical efficacy of molecular targeted therapies against human cancer, and defects of intact cell apoptosis machinery often lead to therapeutic failure. Despite potential importance, other forms of regulated cell death triggered by pharmacologic intervention have not been systematically characterized. Experimental Design: Pyroptotic cell death was assessed by immunoblot analysis, phase-contrast imaging, scanning electron microscopy, and flow cytometry. Tumor tissues of patients with lung cancer were analyzed using IHC. Functional impact of pyroptosis on drug response was investigated in cell lines and xenograft models. Results: We showed that diverse small-molecule inhibitors specifically targeting KRAS-, EGFR-, or ALK-driven lung cancer uniformly elicited robust pyroptotic cell death, in addition to simultaneously invoking cellular apoptosis. Upon drug treatment, the mitochondrial intrinsic apoptotic pathway was engaged and the mobilized caspase-3 protease cleaved and activated gasdermin E (GSDME, encoded by DFNA5), which permeabilized cytoplasmic membrane and executed cell-lytic pyroptosis. GSDME displayed ubiquitous expression in various lung cancer cell lines and clinical specimens, including KRAS-mutant, EGFR-altered, and ALK-rearranged adenocarcinomas. As a result, cooccurrence and interplay of apoptosis and pyroptosis were widespread in lung cancer cells, succumbing to genotype-matched regimens. We further demonstrated that pyroptotic cell death partially contributed to the drug response in a subset of cancer models. Conclusions: These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anticancer therapeutics.