tbuckley/cabot-search huggingface dataset:
Abstract 4115: Comparison of IL-4 receptor targeting elastin-like polypeptide based on size and structure
Authors: Boyeon Seo, Vijaya Sarangthem, Aena Yi, Rang-Woon Park
Journal: Cancer Research (2018)

Abstract For novel drug delivery systems, in order to improve clinical outcomes clear optimization of size, shape, multifuntionality, and site-specificity are highly considered. As molecular size significantly influenced the biodistribution, precise control of molecular sizes must be considered for optimum targeting effect in cancer therapy. Elastin like polypeptide (ELP), has been utilized as an attractive vehicle for cancer therapy as it provide unparalleled control over sequence and structure in genetic level thereby allowing generation of various polymers with defined architectures and functional properties. In this study, we designed various multivalent elastin-like polypeptide based tumor targeting polymer in which multiple copies of IL-4 receptor (IL-4R) targeting ligands, AP1 peptide were subjected into ELP polymer backbone periodically to enhance affinity and avidity towards IL-4R- highly expressed tumor cells. Several ELP with different molecular sizes and structure from unimer to micelle forming polymer have been designed to investigate the pattern of accumulation in tumor, as well as their bio-distribution in vivo. Different percentage of cell binding and uptake depend on size, number of targeting peptides, or based on unimer compared with micelle were determined. The high molecular weight AP1-ELP showed superior binding activity with faster entry and efficiently processed in the IL-4R dependent endocytic pathway compared to low molecular weight polypeptides. In addition the high molecular weight, micelle forming AP1-ELP displayed better tumor penetration and extensive retention in tumor tissue with decrease non-specific accumulation in vital organs compared to low molecular weight AP1-ELP in xenograft model. It was suggested that superior binding activities shown by A86 and A100 may depends on multiple presentation of ligands upon transition to micelle like structure rather than increased number of targeting ligands and molecular weight. Thus this study have significance in demonstrating different pattern underlying unimer and micelle forming ELP mediated tumor targeting as well as biodistribution in vivo. Citation Format: Boyeon Seo, Vijaya Sarangthem, Aena Yi, Rang-Woon Park. Comparison of IL-4 receptor targeting elastin-like polypeptide based on size and structure [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 4115.
Efficacy and Safety of Febuxostat Extended and Immediate Release in Patients With Gout and Renal Impairment: A Phase <scp>III</scp> Placebo‐Controlled Study
Authors: Kenneth G. Saag, Michael A. Becker, Andrew Whelton, Barbara Hunt, Majin Castillo, Krisztina Kisfalvi, Lhanoo Gunawardhana
Journal: Arthritis & Rheumatology (2018)

To assess the efficacy and safety of febuxostat extended release (XR) and immediate release (IR) in patients with gout and normal or impaired renal function.This was a 3-month, phase III, multicenter, double-blind, placebo-controlled study. Patients (n = 1,790) with a history of gout and normal or impaired (mild-to-severe) renal function were randomized to receive placebo, febuxostat IR 40 or 80 mg, or febuxostat XR 40 or 80 mg once daily (1:1:1:1:1 ratio). End points included proportions of patients with a serum urate (UA) level of <5.0 mg/dl at month 3 (primary end point), a serum UA level of <6.0 mg/dl at month 3, and ≥1 gout flare requiring treatment over 3 months (secondary end points).Both febuxostat formulations led to significantly greater proportions of patients achieving a serum UA level of <5.0 mg/dl or <6.0 mg/dl at month 3 (P < 0.001 for all comparisons versus placebo). Equivalent doses of febuxostat XR and IR had similar treatment effects on serum UA level end points; however, a significantly greater proportion of patients achieved a serum UA level of <5.0 mg/dl with XR 40 mg versus IR 40 mg. Similar proportions of patients experienced ≥1 gout flare across treatment groups. Rates of treatment-emergent adverse events were low and evenly distributed between treatment arms. A preplanned subgroup analysis demonstrated that febuxostat formulations were well tolerated and generally effective on serum UA level end points (versus placebo) across all renal function subgroups.Both formulations of febuxostat (XR and IR) were well tolerated and effective in patients with gout and normal or impaired renal function, including patients with severe renal impairment.
Abstract 12191: The Posterior Circulation and Right Hemisphere are Particularly Vulnerable to Neurological Insult During Transcatheter Aortic Valve Replacement (TAVR)
Authors: Jonathon P Fanning, Allan J Wesley, Darren L Walters, David G Platts, John F Fraser
Journal: Circulation (2015)

Introduction: Stroke is among the most feared complication for patients undergoing TAVR. Despite maturation of the procedure, cerebrovascular events (CVEs) remain poorly defined, with clinically apparent CVEs representing only the ‘tip-of-the-iceberg’. MRI detection of cerebral infarction provides a useful surrogate marker for characterizing the full extent of cerebrovascular injury in this setting. Hypothesis: Anatomical distribution of MRI-defined brain infarction is heterogeneous involving multiple vascular territories in a classical embolic pattern. Methods: Thirty-six patients undergoing TAVR with the Edwards SAPIEN-XT TM at The Prince Charles Hospital, Australia, were prospectively enrolled. Participants underwent brain MRI, including diffusion weighted imaging (DWI) sequences, pre-procedure and 3 days post-procedure. Clinical assessment for CVEs included serial National Institute of Health stroke scale assessments at baseline, daily for 3 days post-procedure and again at 6 weeks. Results: The mean (±SEM) participant age was 82.17 (±1.1) years. Patients were of a moderate-to-high risk with Society of Thoracic score 6.29 (±0.09) and EuroSCORE II 6.75 (±1.1). There were no clinically apparent CVEs. MRI assessments identified 81 new DWI lesions in 16 of 27 participants (59.26%), mean 2.54 (±0.77) lesions/patient and 0.14 (±0.08) cm 3 /lesion. Anatomical characterization of these lesions can be found in the Table. Conclusions: Subclinical neurological injury is common with TAVI. Injury is predominantly right-sided, cortical and involving the posterior cerebral circulation. These results reveal unique considerations for neuroprotective strategies in TAVI.
Abnormal Uterine Doppler Is Related to Vasculopathy in Pregestational Diabetes Mellitus
Authors: MarekPietryga, JacekBrązert, EwaWender-Oėgowska, RomualdBiczysko, MariuszDubiel, SaemundurGudmundsson
Journal: Circulation (2005)

Background— The aim of the study was to evaluate the relation between maternal placental Doppler velocimetry, levels of the maternal glucose, and clinical signs of vasculopathy in pregnancy complicated by pregestational diabetes mellitus. Methods and Results— A retrospective study of 155 pregestational diabetic women between the 22nd and 40th weeks of pregnancy, categorized in White classification as B, 49; C, 40; D, 22; R, 20; F, 5; and RIF, 19. Cases in classes R, F, and R/F were defined as having vasculopathy. Doppler velocimetry of umbilical and uterine arteries was evaluated for vascular impedance, both in terms of pulsatility index (PI) for both arteries and a notch in early diastole in the uterine arteries. The last examination before delivery was used for analysis. Increased umbilical artery PI was seen in 19 and a uterine artery abnormality in 45 cases. There was a correlation between levels of HbAlc and increased vascular impedance in the uterine and umbilical arteries. Signs of increased uterin...
Abstract 329: Highly potent and selective ATM kinase inhibitor M3541: A clinical candidate drug with strong antitumor activity in combination with radiotherapy
Authors: Thomas Fuchss, Werner W. Mederski, Frank T. Zenke, Heike Dahmen, Astrid Zimmermann, Andree Blaukat
Journal: Cancer Research (2018)

Abstract M3541 is an ATP-competitive inhibitor of the Ataxia telangiectasia mutated (ATM) kinase (IC50 &amp;lt; 1 nM), which targets tumor cell survival and growth by inhibiting double-strand break (DSB) repair as well as checkpoint control. DSB repair is crucial for survival of malignant tumor cells, especially under treatment with DNA damaging chemo- and radiotherapy. As such, the rationale of pharmacological inhibition of ATM is to increase and maintain the extent of unrepaired DNA damage generated by radio-, chemotherapy, and targeted therapies to drive tumor cells into cell death. We have developed an orally administered, sub-nanomolar potent &amp; selective kinase inhibitor of ATM, M3541, for cancer therapy in combination with DNA damaging modalities. Here, we present the optimization of initial hit matter &amp; its structure-activity relationships leading to our clinical candidate M3541, its chemical structure (first-time disclosure) &amp; preclinical characterization using biochemical, cellular &amp; human tumor xenograft models. M3541 sensitizes tumor cell lines to radiation therapy in vitro and strongly enhances the anti-tumor activity of ionizing radiation in vivo. These effects are due to the inhibition of ATM kinase activity as demonstrated by the levels of the phosphorylation of its primary downstream target CHK2 in human tumor cell lines. M3541 is currently being investigated in a multicenter Ph I clinical trial. Citation Format: Thomas Fuchss, Werner W. Mederski, Frank T. Zenke, Heike Dahmen, Astrid Zimmermann, Andree Blaukat. Highly potent and selective ATM kinase inhibitor M3541: A clinical candidate drug with strong antitumor activity in combination with radiotherapy [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 329.
Abstract 15371: APOE Genotype Influences the Relation Between Adiposity and Plasma Lipid Levels in Patients With Vascular Disease: The SMART Study
Authors: Charlotte Koopal, Yolanda van der Graaf, Folkert W Asselbergs, Jan Westerink, Frank L Visseren
Journal: Circulation (2013)

Introduction: APOE genotype is suggested to play a role in the heterogeneity of plasma lipid levels. Whether and how APOE genotype influences the effect of adiposity on lipids is unclear. We evaluated the relation between adiposity measures and lipids according to APOE genotype in patients with manifest vascular disease. Methods: This cross-sectional study was performed in 5512 patients with clinically manifest arterial disease from the Secondary Manifestations of ARTerial disease (SMART) study (59 e2 homozygotes (e2e2), 670 e2 heterozygotes (e2h), 3214 e3 homozygotes (e3e3) and 1569 e4 carriers (e4c)). Lipids of interest were non-HDL cholesterol (non-HDL-c), LDL cholesterol (LDL-c) and triglycerides (TG). Patient characteristics were age, sex, body mass index (BMI), waist circumference (waist), abdominal fat measured by ultrasound (abdominal fat), metabolic syndrome and diabetes mellitus (DM). Results from regression analyses are given as β-coefficient with 95% confidence interval after adjustment for ag...
Abstract 13645: Prognostic Value of Pulmonary Artery Pressure Assessment during Ankle Flexing Exercise in Patients with Heart Failure Showing Functional Mitral Regurgitation
Authors: AtsushiTanaka, YoshikazuOmae, MasatoTakenaka
Journal: Circulation (2014)

Introduction: Presence of functional mitral regurgitation (MR) is a useful marker of increased mortality in patients with heart failure. Because functional MR can change dynamically in response to loading conditions, several manuscripts have reported advantages of stress echocardiography for assessment of dynamic component of functional MR. Recently, we have developed a new stress echocardiography using ankle-flexing exercise, namely ankle flexing stress echocardiography (AFSE). AFSE has a unique feature that venous return rapidly increases without remarkable blood pressure augmentation. Hypothesis: We hypothesized that rapid increase of venous return could directly alter pulmonary arterial pressure and elevated pulmonary artery pressure might be associated with poor prognosis. The aim of this study was to evaluate whether the increase of pulmonary artery pressure during AFSE was associated with future cardiac events in patients with heart failure. Methods: Between August 2012 and May 2014, 52 consecutive...
Prostaglandin E2 Inhibits Elastogenesis in the Ductus Arteriosus via EP4 Signaling
Authors: UtakoYokoyama, SusumuMinamisawa, AkiShioda, RyoIshiwata, Mei-HuaJin, MunetakaMasuda, ToshihideAsou, YukihikoSugimoto, HirokiAoki, TomoyukiNakamura, YoshihiroIshikawa
Journal: Circulation (2014)

Background—Elastic fiber formation begins in mid-gestation and increases dramatically during the last trimester in the great arteries, providing elasticity and thus preventing vascular wall structure collapse. However, the ductus arteriosus (DA), a fetal bypass artery between the aorta and pulmonary artery, exhibits lower levels of elastic fiber formation, which promotes vascular collapse and subsequent closure of the DA after birth. The molecular mechanisms for this inhibited elastogenesis in the DA, which is necessary for the establishment of adult circulation, remain largely unknown. Methods and Results—Stimulation of the prostaglandin E2 (PGE2) receptor EP4 significantly inhibited elastogenesis and decreased lysyl oxidase (LOX) protein, which catalyzes elastin cross-links in DA smooth muscle cells (SMCs), but not in aortic SMCs. Aortic SMCs expressed much less EP4 than DASMCs. Adenovirus-mediated overexpression of LOX restored the EP4-mediated inhibition of elastogenesis in DASMCs. In EP4-knockout mic...
Influence of Gallogen and Diethanolamine Upon Induced Hypercholesterolemia in the Rat
Authors: Seymourdayton
Journal: Circulation Research (1958)

The diethanolamine salt of the mono (α,p-dimethylbenzyl) ester of d-camphoric acid (Gallogen) augmented diet-induced hypercholesterolemia and hyperlipemia in the rat, while depressing liver cholesterol and total lipid concentrations. Diethanolamine had virtually identical effects. Gallogen, given orally to rats with biliary fistulas had a slight hydrocholeretic effect, but did not influence biliary excretion of cholesterol, cholic acid, or chenodeoxycholic acid.
Abstract 1818: Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib in NPM-ALK positive lymphoma
Authors: Yanrong Li, Kai Wang, Jingdong Zhang
Journal: Cancer Research (2018)

Abstract ALK-positive Anaplastic Large Cell Lymphoma (ALCL), harboring NPM-ALK fusion gene, is sensitive to dual ALK/MET inhibitor crizotinib. However, cancer cells eventually develop resistance to crizotinib after remarkable initial responses, the mechanisms of crizotinib resistance in NPM-ALK positive ALCL remained unclear. To investigate the mechanisms of ALCL cells resistant to crizotinib, we established a model of acquired resistance to crizotinib by gradually exposing sensitive NPM-ALK-positive ALCL cell line to higher concentration of crizotinib. We found that NPM-ALK G1269A mutation were selected in 400nM resistant clones and activation of IGF-1R pathway. Then we generated a G1269A-mutated sub-lines by limiting dilution, which were sensitive to second-generation ALK inhibitor NVP-TAE684. IGF-1R inhibitor picropodophyllotoxin had no effect on these sub-clones and didn't change sensitivity to first and second generation ALK TKIs. But IGF-1R inhibitor increased sensitivity to crizotinib and NVP-TAE684 in 400nM crizotinib-resistant cells. Thus, we have shown that IGF-1R pathway and NPM-ALK G1269A mutation contribute to resistance to ALK TKIs and combined ALK/IGF1R inhibition improves therapeutic efficacy. Citation Format: Yanrong Li, Kai Wang, Jingdong Zhang. Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib in NPM-ALK positive lymphoma [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 1818.
Lysophosphatidylcholine Activates p38 and p42/44 Mitogen-Activated Protein Kinases in Monocytic THP-1 Cells, but Only p38 Activation Is Involved in Its Stimulated Chemotaxis
Authors: QingJing, Sun-MeiXin, Wen-BoZhang, PingWang, Yong-WenQin, GangPei
Journal: Circulation Research (2000)

Abstract—Oxidized LDLs (OxLDLs) have been shown to be involved in recruitment of blood monocytes into the arterial subendothelial space, which is the earliest step in atherogenesis, but the underlying molecular mechanisms are poorly understood. The present study demonstrated that lysophosphatidylcholine (LPC), a major phospholipid component of OxLDL, strongly evoked phosphorylation and activation of p38 and p42/44 mitogen-activated protein kinases in monocytic cells. The stimulation of p38 and p42/44 occurred in a dose- and time-dependent manner, reaching the maximal activation at 25 μg/mL LPC within 5 minutes. Interestingly, inhibition of p38 activation by OxLDL or LPC, using its selective inhibitors (SB203580 and SKF86002), completely blocked OxLDL- or LPC-stimulated chemotaxis of THP-1 cells, which was measured in a transwell chemotaxis assay. In contrast, inhibition of p42/44 activation by its potent inhibitor (PD98059) did not block OxLDL- or LPC-stimulated chemotaxis. Moreover, expression of a p38 d...
Abstract 1530: A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor responses by CAR T cells
Authors: Sherly Mardiana, Liza B. John, Michael H. Kershaw, Paul A. Beavis, Phillip K. Darcy
Journal: Cancer Research (2018)

Abstract Adoptive immunotherapy utilising chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematological cancers, with up to 90% complete remission being reported in patients with acute lymphoblastic leukemia (ALL). However, this success is not currently transferrable to solid malignancies due in part to the immunosuppressive tumor microenvironment limiting CAR T cell responses. Given that activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong co-stimulatory signals for augmenting and diversifying T cell responses, we hypothesized that the combination of α-4-1BB and CAR T cell therapy would result in improved anti-tumor responses. Using a human-Her2 self-antigen mouse model, we found that α-4-1BB significantly enhanced CAR T cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Investigation into the mechanism revealed increased expression of IFNγ and the proliferation marker Ki67 by tumor-infiltrating CAR T cells when combined with α-4-1BB. The importance of IFNγ was demonstrated in vivo where synergistic effects of the combination therapy were abrogated when IFNγ was depleted. Strikingly, we also found that α-4-1BB significantly reduced host immunosuppressive cells at the tumor site including regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs), correlating with an increased therapeutic response. Investigation in immunocompromised RAG -/- mice showed reduced synergistic effects following the combination therapy, suggesting some contribution by host T cells. Furthermore, we found increased frequency of endogenous T cells and dendritic cells in the tumor-draining lymph nodes, supporting potential engagement of host immune cells. We therefore conclude α-4-1BB has a multifunctional role for enhancing CAR T cell responses including engagement of endogenous immune cells, and this combination approach has high translational potential given that CAR T cell therapy has recently been FDA approved for pediatric ALL, and that α-4-1BB is currently being tested in clinical trials against various types of cancer. Citation Format: Sherly Mardiana, Liza B. John, Michael H. Kershaw, Paul A. Beavis, Phillip K. Darcy. A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor responses by CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1530.
Serum Soluble Heat Shock Protein 60 Is Elevated in Subjects With Atherosclerosis in a General Population
Authors: QingboXu, GeorgSchett, HannesPerschinka, ManuelMayr, GeorgEgger, FriedrichOberhollenzer, JohannWilleit, StefanKiechl, GeorgWick
Journal: Circulation (2000)

Background—Work from our laboratory has proven that increased titers of anti-heat shock protein 60 (HSP60) antibodies are associated with atherosclerosis and that HSP60-reactive T-cells are present in atherosclerotic lesions. Recent studies from others demonstrated that HSP60 directly activates endothelial cells and macrophages. Methods and Results—To explore the possibility that HSP60 exists in the circulation, where it could exert its functions, we performed a population-based study with 826 subjects aged 40 to 79 years. The following items were measured in all participants: serum soluble HSP60 (sHSP60); anti-Escherichia coli lipopolysaccharide; anti-HSP65, anti-Chlamydia, and anti-Helicobacter pylori antibodies; and a variety of acute phase reactants (C-reactive protein, α1-antitrypsin, and ceruloplasmin) and markers of systemic inflammation. Carotid atherosclerosis was assessed twice (1990 and 1995), and 15 other risk factors were evaluated. Our data show that levels of sHSP60 were significantly eleva...
Impact of direct-acting antiviral therapy on the need for liver transplantation related to hepatitis C in Germany
Authors: Kerstin Herzer, Guido Gerken, Daniela Kroy, Frank Tacke, Julius Plewe, Dennis Eurich, Ulrich Spengler, Christian P. Strassburg, Martin-Walter Welker, Sven Pischke, Martina Sterneck, Arianeb Mehrabi, Karl Heinz Weiss, Adam Herber, Thomas Berg, Tim Zimmermann, Peter R. Galle, Hauke Heinzow, Hartmut Schmidt, Antoaneta Markova, Yvonne Serfert, Michael P. Manns, Stefan Zeuzem, Heiner Wedemeyer
Journal: Journal of Hepatology (2018)